Organic synthesis with the most abundant transition metal–iron: from rust to multitasking catalysts

Abstract

In industries and academic laboratories, several late transition metal-catalyzed prerequisite reactions are widely performed during single and multistep synthesis. However, besides the desired products, these reactions lead to the generation of numerous chemical waste materials, by-products, hazardous gases, and other poisonous materials, which are discarded in the environment. This is partly responsible for the creation of global warming, resulting in climate adversities. Thus, the development of environmentally benign, cheap, easily accessible, and earth-abundant metal catalysts is desirable to minimize these issues. Certainly, iron is one of the most important metals belonging to this family. The field of iron catalysis has been explored in the last two-three decades out of its rich chemistry depending on its oxidation states and ligand cooperation. Moreover, this field has been enriched by the promising development of iron-catalyzed reactions namely, C–H bond activation, including organometallic C–H activation and C–H functionalization via outer-sphere pathway, cross-dehydrogenative couplings, insertion reactions, cross-coupling reactions, hydrogenations including hydrogen borrowing reactions, hydrosilylation and hydroboration, addition reactions and substitution reactions. Thus, herein an inclusive overview of these reaction have been well documented.

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Sujoy Rana

Sujoy Rana obtained his BSc in Chemistry from Ramakrishna Mission Vidyamandira College, Belur, Howrah in 2009 and MSc in Chemistry from the Indian Institute of Technology, Kanpur in 2011. Successively, he joined in the PhD programme at the Indian Institute of Technology, Bombay. He worked with Prof. Debabrata Maiti and received his PhD Degree in 2017. Also, he was a National Post-doctoral Fellow at IISER Kolkata with Prof. Sayam Sen Gupta. In 2018, he joined in the Department of Chemistry, NBU as an Assistant Professor and started his independent career. His research interests focus on “Electro- and Photo-catalysis with Base Metals”.

Jyoti Prasad Biswas

Jyoti Prasad Biswas was born and raised in the state of Assam, India. He completed his BSc form Jagiroad College under Gauhati University. He obtained his Master's Degree from Tezpur University, Assam. In 2016, he joined the Indian Institute of Technology Bombay. Currently, he is perusing his PhD on metal-catalysed C–H functionalization under the supervision of Prof. Debabrata Maiti.

Sabarni Paul

Sabarni Paul was born and brought up in Cooch Behar, West Bengal. She completed her BSc from Acharya Brojendra Nath Seal College and obtained her Master's Degree from the University of North Bengal in 2019. She received a DST-INSPIRE Scholarship from 2014 to 2019. Currently, she is working on base-metal catalysis for developing novel synthetic transformations with Dr Sujoy Rana at the University of North Bengal, Darjeeling, West Bengal.

Aniruddha Paik

Aniruddha Paik was born in 1996 in Haldia, West Bengal. He obtained his BSc in Chemistry from Mahishadal Raj College, Mahishadal and obtained his MSc from Vidyasagar University, Midnapore. Recently, he qualified for the CSIR NET (LS) and joined Dr Sujoy Rana's group as a Project Assistant in University of North Bengal, Darjeeling, to pursue his PhD. He is working on the area of Electro and Photocatalyzed reactions and synthetic methodology.

Debabrata Maiti

Debabrata Maiti received his PhD from John Hopkins University (USA) in 2008 under the supervision of Prof. Kenneth D. Karlin. After postdoctoral studies at the Massachusetts Institute of Technology (MIT) with Prof. Stephen L. Buchwald (2008–2010), he joined the Department of Chemistry at IIT Bombay in 2011, where he is currently an Associate Professor. His research interests are focused on the development of new and sustainable synthetic and catalytic methods.

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1. Introduction

Catalysis is an important synthetic tool, which is widely used to accomplish the transformations required for the synthesis of drugs, natural products, and various fine chemicals. It enhances the atom economy of the reaction and reduces the energy consumption and cost of the production.¹ A high percentage of catalysts used in organic synthesis comprises of transition metals (TMs) due to their variable oxidation states and co-ordination numbers.^1a,2,3 Among the various TMs, the late transition metals (e.g. Ru,⁴ Pd,⁵ Rh,⁶ and Ir⁷) catalysts have been immensely used for the development of different synthetic methods since the 1960s. Especially, palladium catalysis has been extensively used in cross-coupling reactions for the formation of carbon–carbon and carbon–heteroatom bonds.⁸ Further, many C–H activation reactions, including both directed and non-directed reactions, are being pursued with the late TM catalysts of Ru, Pd, Rh, Ir, Ru, etc.⁹ However, the fundamental problem associated with late TM catalysts is their high price and toxicity to the environment.^1b,10 The metal waste products from late TM catalysis contribute to the pollution in the Earth's crust and oceans. Therefore, chemists are concerned over the use of late transition metal catalysts in synthetic chemistry. Presently, many research groups focus on the development of alternative catalytic methods involving the Earth-abundant and less-toxic 3d metals for organic synthesis considering sustainable chemistry.^1a–d,11,12 Contextually, the use of cheap, easily accessible, iron catalysts in organic synthesis can bring a renaissance in the field of catalysis. Notably, iron is the most abundant metal on the Earth's surface among the 3d, 4d and 5d metals (Fig. 1).^1b,10c,13 Since the time of evolution, iron has become an indispensable part of different biological systems and metabolic processes. Similarly, it is found in numerous metalloenzymes and metalloproteins prevailing in nature and the human body.¹⁴ Thus, it is one of the most important congeners among the 3d metals. Moreover, if the cost of metallic iron is compared with the other late transition metals, it is found that iron is less expensive by several magnitudes (Fig. 2).¹⁰ Thus, the utilization of iron catalysts is certainly a sustainable approach.

Fig. 1 Relative abundance of different transition metals in the Earth's surface.

Fig. 2 Price comparison among iron and other transition metals used in catalysis (Source: Sigma Aldrich).

The use of iron salts as a precatalyst in synthetic chemistry was initiated a long time ago. In the 1940s, and 1970s, Kharash and Fields¹⁵ employed iron salts for the homocoupling of Grignard reagents, which was long before the discovery of the nickel¹⁶ and palladium¹⁷ catalyzed cross-coupling reactions in the late 1960s and early 1970s, respectively. Subsequently, in the 1970s, Kochi and Tamura utilized iron catalysts for carbon–carbon bond formation reactions.¹⁸ Unlike the late TMs, iron can have different oxidation states ranging from 2− to 6+. Hence, iron catalysis can be utilized to perform different types of reactions occurring via different elementary pathways by altering its oxidation states in the presence of suitable ligands.^3k Evidently, it can participate in different reaction pathways such as single electron transfer (SET), oxidative addition (OA), transmetalation, reductive elimination, sigma bond metathesis, atom transfer reactions (ATR), hydrogen atom abstraction (HAA), and oxygen atom rebound (OAR). For example, high-valent iron intermediates with formal oxidation states of 4+ and 5+ can perform site selective C–H oxidation reactions involving the HAA and OAR pathways very well. On the other hand, iron intermediates with the 2−, 0, 1+, 2+ and 3+ oxidation states are responsible for C–C and C–X (X = N, O, S, etc.) bond formation reactions involving oxidative addition, transmetallation, reductive elimination, ATR, etc. Furthermore, iron-catalyzed C–H activation reactions occur with iron having the 2+ or 3+ oxidation state, involving the σ-bond metathesis pathway, transmetallation, and reductive elimination. Thus, many reactions are well performed using iron catalysts in the presence of different nitrogen and phosphorous ligands. Notably, the multitasking ability of iron in participating in these reactions arises from the metal–ligand cooperativity.

It is remarkable that in the last two-three decades iron catalysis has been extensively developed and is utilized in organic synthesis, which is evident from the publication of research articles, books and review articles.^1–3,10 The recent discovery of iron-catalyzed distal C–H functionalization reactions has started a new dimension in iron catalysis. Furthermore, many current discoveries of iron-catalyzed C–H activation methods, cross-coupling reactions, cross-dehydrogenative coupling, C–H hydroxylation reactions, asymmetric transfer hydrogenations, etc. have initiated a new horizon in organic synthesis. Therefore, based on its rich chemistry, iron catalysis can possibly be utilized in every type of reaction executed by late and heavy transition metals. Notably, the iron-catalyzed reactions including C–H bond activations, C–H oxidations, C–H halogenations, insertion reactions, cross-dehydrogenative coupling (CDC), cross-coupling, reduction, addition, elimination, isomerization, and substitutions reactions are outlined chronologically together with detailed mechanistic discussions. Mainly, herein, we illustrate the iron-catalyzed reactions from the early stages to more recent developments.

2. Iron-catalyzed C–H bond activation

Transition metal-catalyzed C–H bond activation/functionalization reactions have emerged as a vital strategy in organic synthesis since the discovery of the first metal-mediated C–H bond activation with ruthenium in 1993.¹⁹ Thereafter, Pd, Rh and Ir-catalyzed C–H activation reactions have been explored to construct carbon–carbon and carbon–heteroatom bonds.^4–9,20 Importantly, C–H bond activation is one of the sustainable approaches being utilized to diminish the number of steps required in multistep synthesis. Moreover, considering sustainable chemistry, the utilization of the earth abundant metal, iron-catalyzed C–H activation methods in synthetic chemistry is desirable. Contextually, herein, we depict the iron-catalyzed C–H bond activation methodologies in a chronological way together with a detailed mechanistic discussion.

C–H bond activation can occur via two different elementary pathways, including organometallic C–H activations and outer sphere pathway-based C–H bond activation.²¹ These two approaches are discussed as follows: (i) organometallic C–H activation: the organometallic C–H activation proceeds via co-ordination of a C–H bond to the vacant site of a metal. Subsequently, it gets cleaved by different elementary pathways to create an organometallic intermediate. The elementary steps of organometallic C–H bond activation can be categorized into three types: (a) oxidative addition: the C–H bond adds to a low-valent iron complex for the formation a C–Fe–H species, and the oxidation state of the metal centre changes by two units (Scheme 1a). (b) σ-Bond metathesis: this particular elementary step occurs concertedly via a four-member transition state. The ligand/group (R′) of the iron-complex acts as a base to remove the hydrogen atom of the C–H bond, and concomitantly ligand exchange occurs, resulting in the formation of a C–H bond-activated organo-iron-complex. Here, the oxidation state of the metal centre does not change. This process is also called deprotonative metalation (Scheme 1b). The third elementary step is well known, (c) electrophilic substitution (Scheme 1c). The iron-catalyzed C–H activations through electrophilic substitutions are mainly discussed in the later part of this review (Section 10.3). (ii) Outer sphere pathway for C–H bond activation: outer sphere C–H bond activation generally proceeds through two different types of elementary pathways. The first is direct insertion of a C–H bond into the ligand sphere of a transition metal complex, where the ligand (group) of the catalyst recognises functionality in the substrate (Scheme 2) (mainly C–H bonds in the present discussion). On the other hand, the second pathway proceeds via hydrogen atom abstraction (HAA) from C–H bonds by high-valent metal species. We demonstrate these C–H functionalization reactions consecutively (Sections 2 and 3).

Scheme 1 Elementary mechanistic pathways for C–H activation.

Scheme 2 C–H bond activation via the outer sphere mechanism.

2.1 Organometallic C–H activation

The fundamental investigation of iron-mediated C–H activation was started in 1968 by Hata et al.²² Subsequently, different research groups including Corriu et al.,²³ Jesson et al.,²⁴ Field et al.²⁵ and Knochel et al.²⁶ set up mechanistic foundations for iron-mediated C–H activation based on stoichiometric studies. In 1968, Hata et al. first reported C–H bond activation upon the irradiation of a 1,2-bis(diphenylphosphino)ethane-ligated complex, where the ortho-metalated iron(II)hydride complex was generated via the oxidative addition of an ortho C–H bond directly to the iron(0) complex.²² Later, in 2009, Camadalni and co-workers developed a method for C–H bond activation with an iron(II) complex via the σ-bond metathesis pathway.²⁷ Notably, the iron-catalyzed C–H activation reactions have been explored with directing group and non-directing group-based approaches. In both strategies, C–H bonds act as hidden functional groups. In this subsection, we describe the C–H activation of different C–H bonds involving organoiron intermediates and classify them based on the elementary pathways such as the oxidative addition and σ-bond metathesis pathways.

2.1.1 Iron-catalyzed C(sp²)–H functionalisation with carbon nucleophiles.
2.1.1.1 Iron-catalyzed arylation or heteroarylation of C(sp²)–H bonds using carbon nucleophiles. Organoiron complexes can activate various types of C–H bonds stoichiometrically. However, early attempts to develop iron-catalyzed C–H bond activation by Jones et al.²⁸ have not been exploited for synthetic utility due to the low efficiency of the reactions. However, the serendipitous discovery by Nakamura and co-workers marked the beginning of C–H bond activation in 2008. In this reaction, they found an unexpected ternary coupling product in 8% yield during the optimization of the cross-coupling reaction between 2-bromopyridine and phenyl zinc reagent under an oxygen atmosphere (Scheme 3).²⁹ The side product led to the discovery of a new research direction from the cross-coupling reaction to C–H activation. They tried to justify the reason for the formation of the side product and found that air leaked in the reaction flask. Thereafter, they discovered that dichloroisobutane (DCIB) should be used as oxidant for the formation of the desired C–H activation product and to reduce the formation of the diphenylated product (Scheme 4).^29b In addition, the organozinc reagent (Ph₂Zn) obtained from phenyl lithium or Mg-free organozinc reagent did not provide the desired product. Moreover, the steric effect of the substituents present in the aryl moiety of the organozinc reagent has an adverse effect on the formation of the reaction (2-tolylzinc reagent cannot deliver any product). Importantly, the reaction takes place at 0 °C, which is different from the other C–H bond activation reactions, requiring a temperature above 80 °C.³⁰

Scheme 3 Serendipitous discovery of iron-catalyzed C–H activation.

Scheme 4 Iron-catalyzed directed C–H bond arylation of α-benzoquinoline with arylzinc reagent.

Notably, benzoquinoline, 2-phenylpyridine, 2-phenylpyrimidine, and 4-phenylpyrimidine were well tolerated under the optimized condition of the reaction. Although, there was no solid evidence regarding the mechanistic pathway, they hypothesized that the 1,10-phenanthroline ligand and TMEDA coordinate with iron(III) and zinc, respectively, and it involves the redox cycle of iron in the presence of the oxidant DCIB. Thus, C–C bond formation via C–H bond activation by a new class of homogeneous iron catalysts has been well established.

Subsequently, in 2009, the same group developed a reaction methodology for ortho-C–H bond activation of aromatic imines using the aforementioned catalytic system, resulting in the formation of ortho-arylated ketones and aldehydes upon hydrolysis (Scheme 5).³¹ Interestingly, this iron(III)-containing catalytic system can perform ortho C–H bond activation with respect to the electrofugal leaving group, whereas with the same substrate, the para C–H bond is activated via the Pd-catalyzed Negishi coupling reaction. Notably, this reaction also occurs at a temperature of 0 °C and can tolerate a large number of reactive functional groups such as aryl bromides, chlorides, triflates, and sulphonates. Importantly, the mild oxidant DCIB is essential for the iron-catalyzed C–H arylation over C–X (X = Br and OTf) bond activation. Various aromatic ketimines and aromatic aldimines are also compatible in the reaction. Although the aromatic ketimines provided only mono-arylation products in presence of two accessible ortho C–H bonds, the aromatic aldimine resulted in the formation of a mixture of mono- and di-arylated products due to the higher conformational flexibility of the aldimines.

Scheme 5 Iron-catalyzed ortho-C–H bond activation of aryl amines with diphenyl zinc.

In 2010, they reported the iron(III)-catalyzed chelation-controlled arylation of olefins without the use of any external ligands.³² Importantly, this reaction methodology provides the substituted olefins with good regio- and stereoselectivity in high yield. Notably, this was the first application of oxidative Heck coupling in the presence of an iron catalyst using an organozinc reagent and Grignard reagent as the nucleophilic partner. In the same year, the same group achieved the arylation of imines and 2-phenyl pyridines under iron catalysis in the presence of molecular oxygen (Scheme 6) as the oxidant in place of DCIB.³³ They introduced it in the reaction mixture through the process of slow diffusion. However, although molecular oxygen acts as a green and cost-effective oxidant, the presence of DCIB as an oxidant provides superior results.

Scheme 6 Iron-catalyzed direct arylation of aromatic imines in the presence of molecular oxygen.

Further in 2011, they reported that cyclic and acyclic olefins having a directing group such as pyridine or imine provide only stereospecific arylation of the olefinic C–H bond to afford the syn-product with respect to the directing group.³⁴ Moreover, they discovered that upon changing the aromatic co-solvent from tetrahydrofuran (THF) to chlorobenzene in Et₂O, the ratio of the isomerization product of the starting material (Scheme 7) varied from 95 : 5 (Z/E) to 97 : 3 (Z/E). In addition, vinyl pyridine bearing the tert-butyl group at the 1 position undergoes the reaction to provide the exclusive formation of the Z-isomer (99% isolated yield) together with >99 : 1 ratio of Z : E isomer. On the other hand, without the use of the oxidant, i.e. 1,2-dichloro-2-methyl propane, the olefin isomerisation product (E isomer) is obtained as the major product. Based on the two aforementioned facts, they hypothesized that the reduced iron species is involved in isomerization, which indeed established the role of the Grignard reagent as the reducing agent. Moreover, the aromatic cosolvent serves as a ligand for the low-valent iron species,³⁵ which is formed during the course of the reaction and prevents the interaction with the olefin product to deliver the syn-product. Again, this low valent iron species is not the iron hydride because it did not give any hydrogenation product in the reaction (Scheme 7). Thus, they concluded that this reaction methodology (Scheme 7) is different from the previous one,³² which followed the oxidative Heck coupling reaction. In the oxidative Heck coupling, the generated five-membered metallacycle upon the addition of aryliron species to the olefinic bond undergoes β-hydride elimination and forms the desired anti-selective product (Scheme 8b) together with the formation of the reduced product of the starting material, which is indeed the major side reaction of the oxidative Heck coupling.³² On the other hand, for the reaction methodology (Scheme 7), the authors proposed the involvement of the five-member metallacycle, which undergoes reductive elimination upon interaction with the oxidant to provide the syn-selective product (Scheme 8a). Importantly, here, no reduced product of the starting material was obtained. It should be noted that the slow addition of the Grignard reagent is required to prevent the immediate iron-catalyzed homocoupling of PhMgBr and to increase the performance of the iron catalyst.^36,37 The reaction was completed within 5 min of slow addition at a lower temperature (0 °C).

Scheme 7 Iron-catalyzed stereospecific arylation of 1-substituted vinyl pyridine with Grignard reagents.

Scheme 8 Iron-catalyzed C–H activation (a) during stereospecific syn-arylation and (b) oxidative Heck coupling reaction.

The reports regarding directed C–H bond activation published up to 2011 used a large amount of zinc salt in the presence of an aryl Grignard reagent to form the aryl zinc reagent. However, the attempts to use only the Grignard reagent (G.R.) failed due to the homocoupling of the aryl moiety of the G.R. Thus, in 2011, the Nakamura group modified the catalytic conditions of the reaction, i.e. slow addition of the G.R. to suppress the oxidative homocoupling and use of chlorobenzene as the cosolvent to stabilize the low-valent iron intermediate. These modifications created an approach to use the G.R. alone to provide the stereospecific arylation of the olefinic C–H bond with a high reaction rate (the reaction was completed within 5 min during the addition of the G.R. at 0 °C). Notably, both the N-heteroaromatic and the aromatic ketimines are well tolerated (Scheme 9).³⁸

Scheme 9 Iron-catalyzed stereospecific ortho-C–H arylation of olefins with Grignard reagent alone.

To gain to insight into the reaction intermediate and the mechanistic pathway, the Nakamura group performed several stoichiometric studies. The reaction between Fe(acac)₃ and the dtbpy (4,4′-di-tert-butyl bipyridine) ligand together with the slow addition of PhMgBr resulted in the formation of an organometallic intermediate, which was quenched by D₂O to deliver the deuterium-incorporated ortho product. This result indeed suggests the formation of the ortho-metalated ferracycle intermediate, which undergoes reductive elimination upon interaction with the mild oxidant DCIB (Scheme 10).

Scheme 10 Quenching of ortho-metalated ferracycle intermediate with D₂O.

Moreover, the similarity in the large magnitude in both the intramolecular (KIE = 3.1) and intermolecular (KIE = 3.4) kinetic isotope effect value suggests the reversible coordination of the pyridyl nitrogen atom to the iron catalyst followed by C–H bond cleavage (the first irreversible step of the catalytic cycle) (Scheme 11). Based on the experiments and literature studies, they proposed a catalytic cycle consisting of four steps (Scheme 12). Initially, the reversible coordination between the pyridyl nitrogen atom and the iron centre generates species II followed by irreversible metalation of the ortho C–H bond associated with the elimination of the arene, resulting in the formation of active organoiron intermediate III. Thereafter, the formation of a carbon–carbon bond upon the interaction with DCIB via the reductive elimination from ortho-ferrated intermediate III produces the desired coupling product together with the formation of isobutene and dichloroiron species. Finally, the transmetalation of the dichloroiron species with the aryl Grignard reagent regenerates the active species I to complete the catalytic cycle. However, although the proposed mechanistic pathway is in accordance with the mechanistic information gained thus far, further studies were required to understand the nature of the reactive intermediate and the bond breaking and formation.

Scheme 11 Kinetic isotope effect study for iron-catalyzed directed C–H bond arylation.

Scheme 12 Proposed mechanistic pathway of iron-catalyzed-directed C–H bond arylation based on the experimental results.

Accordingly, Chen and co-workers performed extensive theoretical studies to get better insight into the mechanism of the iron-mediated C–H functionalization reactions.³⁹ They proposed that the two-state reactivity (TSR) of Fe(II) and Fe(III) causes the C–H activation. In this two-state reactivity condition, the high-spin ground state of Fe(II) or Fe(III) is crossed over by both the low-spin singlet and doublet state. However, this C–H activation is energetically less favourable for iron in the Fe(0) or Fe(I) oxidation state. Holland also demonstrated a similar spin acceleration phenomenon for various organometallic reactions.⁴⁰ The Fe(II) formed due to the C–H cleavage via activation and transmetalation of the aryl moiety undergoes oxidation to Fe(III) via a one-electron transfer mechanism by the oxidant DCIB. Additionally, studies also revealed that the Fe(I) species formed after the C–C bond formation is also oxidised by DCIB to regenerate the active catalyst, Fe(II). Furthermore, calculations also confirmed the vital role of the ligand sphere in the stabilization of the low-spin state and assistance for the TSR mechanism during C–H activation. This observation was supported by the experimental findings by Nakamura and co-workers for C–H functionalization with arylboron compounds.⁴¹ Based on these observations, Chen's group proposed the involvement of one of the following two possible mechanistic cycles: the Fe(III)/Fe(I) cycle (Scheme 14) or Fe(II)/Fe(III)/Fe(I) cycle (Scheme 13).^39,41

Scheme 13 Proposed mechanistic pathway of Fe(II)/Fe(III)/Fe(I) based on density functional theory.

Scheme 14 Proposed mechanistic pathway of Fe(III)/Fe(I) based on density functional theory.

Recently, in 2019, Neidig and co-workers investigated the triazole-assisted iron-catalyzed C–H arylation reaction originally performed by Ackermann and co-workers⁴² using freeze-trapped ⁵⁷Fe Mössbauer, MCD (magnetic circular dichroism) and EPR (electron paramagnetic resonance) spectroscopy together with synthetic and reaction studies, providing detailed structural insight into the reactive intermediates. They isolated and identified the in situ-formed iron intermediates, which represent a transformation pathway for the C–H activation reaction (Scheme 15).⁴³ Based on spectroscopic studies, they suggested that the initial formation of the substrate-bound but non-activated Fe(II) intermediate I occurred through the reduction of Fe(III) to Fe(II) by Ar₂Zn. Thereafter, upon the addition of dppbz and excess Ar₂Zn, C–H activation occurs, producing low-spin cyclometalated iron(II) aryl complex II. Then it undergoes the rate-determining slow transmetalation step upon the addition of more Ar₂Zn, forming complex III. This complex III is suggested to be the reactive species since it reacts with DCIB to form the product.

Scheme 15 Reactivity transformations of the observed iron intermediates in triazole-assisted iron-catalyzed C–H activation.

Notably, the formation of this iron species through transmetalation has been found to have a high activation barrier, and thus a high temperature is required for C–C bond formation. To elucidate the role of oxidants in the catalysis, they suggested that the oxidant DCIB oxidizes the off-cycle reduced iron species and the transient on-cycle Fe(I) species. In addition, DCIB promotes the reductive elimination of transmetalated complex III. Furthermore, based on the stoichiometric reaction, they suggested an Fe(II)/Fe(III)/Fe(I) cycle, which is consistent with the proposed mechanism using DFT studies.

In 2012, Nakamura's group reported the iron-catalyzed monoselective ortho arylation of secondary benzamides with organozinc reagents in the presence of an aryl Grignard reagent and TMEDA (Scheme 16).⁴⁴ Notably, primary benzamides and bulkier N-isopropylcarboxamides and N-phenylcarboxamides did not deliver the desired monoarylated C–H activation product, which indeed suggests the importance of the steric and electronic factor during the coordination of the substrate. Importantly, only the mono-arylated product was obtained with high selectivity. Mainly, ortho substitution of the mono-arylated product forces the amide anionic directing group out of the arene plane, preventing the formation of the second metallacycle. Thus, the reason for the formation of the mono-arylated product is rationalized based on the above steric factor.

Scheme 16 Iron-catalyzed ortho monoarylation of N-methylbenzamide.

This synthetic transformation has some disadvantages also. One of the disadvantages is the requirement of a preformed Grignard reagent or zinc reagent. Thus, it limits the substrate scope and the functional group tolerance. Hence, the nitrogen-directed C–H functionalization of arenes and alkenes with aryl bromide is promoted in the presence of metallic magnesium, which is a new approach to handle organometallic reagents.⁴⁵

In 2014, Nakamura and co-workers reported the iron-catalyzed 8-quinolylamide-directed C–H arylation reaction of a variety of aromatic, heteroaromatic and olefinic substrates with aryl and alkenyl boron compounds together with the formation of <5% of side product (Scheme 17).^41,46–49 The phenylboronic acid pinacol ester was activated in the presence of butyllithium followed by in situ boron to iron transmetalation catalyzed by zinc halide. The catalytic system consisted of iron(III) salt, zinc(II) salt, and a diphosphine ligand (dppen) having a conjugated backbone. Notably, borate acts as both a base to deprotonate the amide N–H and C–H bonds and a coupling partner. The synthetic transformation protocol shows much broader substrate scope compare to the Grignard or zinc reagent due to the lower nucleophilicity and better functional group tolerance of borate. Aryl fluoride, chloride, bromide, ether, amine, sulphide, trifluoromethyl, cyano and ester groups are well tolerated. Heteroaromatics such as thiophene and indoles can also be used as a substrate. In addition, mono-arylation takes place in the case of arylcarboxamide, possessing a meta-substituent, while the reaction with a simple benzamide and para-substituted benzamide provides a mixture of mono and diarylated product. Arenecarboxamide together with alkenecarboxamide was well explored under the reaction conditions. The amount of biphenyl formed is suppressed to a synthetically viable level by carrying out the reaction at lower temperature (30 °C) due to the lower stability of the corresponding ferracycle. Additionally, using tiglamide as the substrate, the arylation product is obtained with high Z selectivity, while the Z/E isomerization product is obtained in high yield using acrylamide as the substrate. During the investigation of the mechanism, they found some key factors regarding the mechanism. The stoichiometric reaction provides 95% yield of the C–H arylated product together with the formation of a small amount of biphenyl without the presence of the mild oxidant DCIB (Scheme 18). This result is an indication of the effective participation the phenyliron(III) intermediate in C–H cleavage and C–C bond formation through metallacycle I rather than being consumed by the oxidation of the phenyl ligand. Thus, the stoichiometric experiment supports the Fe(III)/Fe(I) mechanistic pathway, where the Fe(I) intermediate reacts with the mild oxidant DCIB to regenerate the Fe(III) species. The other two important factors of the reaction are the presence of the zinc co-catalyst and a bis(phosphine) ligand having a conjugated backbone (dppen). Here, the aryl group undergoes transmetalation from borate to zinc in the absence of the iron catalyst. This is supported by the ¹¹B-NMR spectroscopic analysis (Scheme 19).

Scheme 17 Iron(III)-catalyzed aryl–aryl coupling with arylboron compounds assisted by bidentate auxiliary.

Scheme 18 Experimental evidence of C–H bond cleavage by iron(III) species in the absence of DCIB oxidant.

Scheme 19 Evidence of boron-Zn transmetalation.

Moreover, the electron-donating ligand such as dppf or dppe prevented the reaction, while the electron-accepting ligand such as 1,10-phenanthroline or dppen promoted the reaction via the metal-to-ligand charge transfer (MLCT) in the case of ferracycle intermediate I. This suggests the involvement of the iron(I) intermediate, which is formed during C–C bond formation via reductive elimination of the initial iron(III) intermediate.

In 2014, Ackermann and co-workers reported the easily accessible novel 1,2,3-triazole-enabled iron-catalyzed C–H bond arylation of arenes and alkenes with excellent chemo and diastereoselectivities (Scheme 20).⁴² The directing group TAM showed a better result due to the stabilization of the low-valent iron intermediate in the presence of the dppe ligand in comparison to the 8-quinolylamine directing group (reported by Nakamura's group). Interestingly, the syn-selective arylation product of acrylamide was obtained in 57% yield without Z/E isomerization under the reaction conditions (Scheme 21).

Scheme 20 Iron-catalyzed arylation of benzamides assisted by triazole (TAM).

Scheme 21 Iron-catalyzed stereospecific C–H arylation of acrylamide assisted by triazole (TAM).

In the same year, Deboef and co-workers reported the imine-directed iron catalyzed ortho arylation via C–H bond activation of aromatic heterocycles such as pyridines, furans and thiophenes (Scheme 22).⁵⁰ The conversion of the starting material was complete within 15 min at 0 °C. Moreover, the GCMS analysis only demonstrated the existence of the unreacted starting material, the desired ortho arylated heterocycles as the desired product and aryl homocoupling product from the aryl Grignard reagent. Here, the additive KF was used to reduce the formation of the homocoupling product from the Grignard reagent.

Scheme 22 Iron-catalyzed arylation of heteroaromatics via directed C–H bond activation with Grignard reagent.

All the aforementioned ortho C–H bond arylation methods require a bi or tridentate amide as the directing group and a specific iron–ligand system. However, in 2019, for the first time, Duan and co-workers⁵¹ developed a method of ortho arylation of benzamides using a mixed titanate complex in the presence of a weakly co-ordinating amide group (CONHMe) and an iron catalyst (FeCl₃/TMEDA) (Scheme 23). Here, the Ti-1 complex with ArMgBr and TMPMgCl·LiCl effectively deprotonate the amide and execute the ortho C–H bond arylation via ferration with amide. The synthetic reaction protocol shows high tolerance towards steric hindrance and sensitive functional groups under the catalytic condition of FeCl₃/TMEDA in the absence of phosphine or NHC ligand. This synthetic transformation method using a Knochel-type Grignard reagent for ortho arylation accomplished the facile synthesis of series of valuable compounds such as urolithin B and crinasiadine. Moreover, highly hindered diarylation is also possible to afford the fully substituted thiophene.

Scheme 23 Iron-catalyzed C–H bond arylation of benzamides.

In 2010, Daugluis and co-workers reported the deprotonative alkylation of heteroarenes and electron-withdrawing group-containing arenes in the presence of a catalytic amount of iron(III) chloride together with the TMPMgCl·LiCl base, trans-N,N′-dimethylcyclohexane-1,2-diammine as the ligand and THF solvent (Scheme 24).⁵² Different heteroarenes such as furan, thiophene, pyridine and arenes with ester and cyano groups were efficiently alkylated using primary and secondary halides as the electrophiles. Further, the presence of radical intermediates was suggested from the observation of ring-opening product formation using cyclopropylmethyl bromide as the substrate.

Scheme 24 Iron-catalyzed deprotonative alkylation of pyridine derivative.

In 2017, Ackermann and co-workers designed a new trisubstituted 1,2,3-triazole (TST) as the directing group for the C–H bond functionalization of electron-rich benzyl and aryl amines by an iron catalyst.⁵³ Notably, this TST group is easily removable by using aqueous HCl in 1,4-dioxane. Here, FeCl₃/dppen in the presence of the mild oxidizing agent 2,3-dichlorobutane (DCB) was used to achieve the C–H methylation, ethylation and arylation product with chemoselectivity. The synthetic utility of this transformation is the racemization-free modification of an enantiomerically enriched benzyl amine (Scheme 25).

Scheme 25 Racemization-free C–H methylation of benzyl amine.

2.1.1.2 Iron-catalyzed alkylation of C(sp²)–H bonds using carbon nucleophiles. The alkylation of the C(sp²)–H bond with an alkyl metal compound is more challenging due to the possibility of fast β-hydride elimination compared to C–H bond arylation.⁵⁴ However, although the ortho-alkylation of N-methylbenzamide and N-heterocyclic substrates has been achieved using cobalt catalysts,^55–58 these results were not achieved using iron catalysts due to the decomposition of the alkyliron species. However, this reaction was successful by preventing the early reduction of the organoiron intermediate through saturation of the intermediate towards new coordination. Basically, the alkene cannot coordinate to the organoiron intermediate due to the absence of a vacant site, and thus the decomposition of intermediate can be delayed.

In 2015, Nakamura and co-workers reported the iron-catalyzed directed alkylation of alkenes and arenes possessing a bidentate directing group (e.g. 8-quinolylamide auxiliary) in combination with a bis(phosphine) ligand (dppen) together with a primary and secondary alkylzinc halide (Scheme 26).⁵⁹ Monoalkylzinc halide was found to be a better alkyl donor than dialkylzinc or alkylmagnesium halide due to the weaker reducing ability of monoalkylzinc to stabilize the organoiron(III) active species. The desired alkylated product was obtained in high yield with high Z stereoselectivity. Homocoupling of the organozinc reagent and β-hydrogen elimination were significantly suppressed under the reaction conditions. Notably, primary alkyl and benzyl groups were introduced smoothly, while a mixture of linear and branched alkyl products (e.g. for i-PrMgBr, branched : linear = 21 : 79) was obtained with acyclic secondary alkyl groups due to partial isomerization.

Scheme 26 Iron-catalyzed directed alkylation of alkenes with monoalkylzinc reagent.

Earlier attempts for iron-catalyzed methylation proceeded with the formation of the desired product in low yield.³² In 2015, Nakamura and co-workers reported the conversion of the C(sp²)–H and C(sp³)–H bonds to the corresponding C–Me bond by using commercially available AlMe₃ or its air-stable derivative, the bis(trimethylaluminium)-1,4-diazabicyclo-[2.2.2]octane adduct [DABCO·2AlMe₃], as an effective methyl donor.⁶⁰ The reaction progresses in the presence of a catalytic amount of an inorganic iron(III) salt and diphosphine ligand together with 2,3-dichlorobutane (DCIB) as the stoichiometric oxidant (Scheme 27). This reaction tolerates a variety of amide substrates bearing a piconyl or 8-aminoquinolyl-directing group, enabling the methylation of a variety of (hetero)aryl, alkenyl and alkyl amides. The authors also proposed that the mild reactive aluminium reagent prevented early reduction of organoiron(III) reactive species. Thus, the weaker reducing ability of AlMe₃ than magnesium and zinc reagents is responsible for the very high turnover number of the catalyst, i.e. 6500. Notably, the C–H alkylation reaction using alkyl aluminium is sensitive to the size of the aluminium reagent. Consequently, triethyl aluminium undergoes the reaction smoothly, while large alkyl aluminium reagents such as triisobutyl aluminium and trioctyl aluminium cannot perform the reaction.

Scheme 27 Iron-catalyzed methylation using trimethylaluminum.

Furthermore in 2016, they discovered a combination of a mildly reactive methyl aluminium reagent and new tridentate phosphine ligand, 4-((bis-(2-diphenylphosphanyl)phenyl)phosphanyl)-N,N-dimethyl aniline (Me₂N-TP), for ortho C–H bond functionalization of the C–Me bonds in aromatics and heteroaromatics bearing simple carbonyl groups under mild oxidative conditions without the need for any additional directing groups.⁶¹ Other ligands such as monodentate phosphine, bidentate phosphine and nitrogen ligands are ineffective (Scheme 28). Moreover, the reaction is chemoselective and was successfully used for the gram-scale synthesis of the mono-ortho-methylation product from arenecarboxylic acids without affecting the boronate moiety. Notably, the catalyst was not poisoned in the presence of coordinative heteroatoms such as nitrogen and sulfide. Aryl carboxylic acids having substituents at the meta-position undergo selective mono-methylation at the less hindered C–H site, while for 4-substituted benzoic acid and benzoic acid, a mono and dimethylated product is obtained. The reaction conditions also tolerate a variety of functional groups such as boronic ester, halide, sulphide, heterocycles and enolizable ketones. The catalytic system is powerful enough to methylate all four ortho C–H bonds of benzophenone. The exclusive monomethylated product was obtained in the case of tert-butyl phenyl ketone. Xanthone, dibenzosuberenone, and thioxanthone afford the corresponding products, while fluorenone does not provide any product due to the small ionic size of iron not permitting the formation of the ferracycle.

Scheme 28 Effect of different ligands in iron-catalyzed direct ortho methylation of m-toluic acid.

In 2015, Ackermann and co-workers reported the C–H bond methylation of (hetero)arenes and alkenes using TAM as the directing group.⁶² Here, FeCl₃ showed the best catalytic efficiency with the dppe ligand in the presence of dimethylzinc as the methylating agent. They also reported the ethylation of arenes using diethylzinc. Notably, anilides also afforded the ortho-methylated product (Scheme 29).

Scheme 29 Triazole-assisted iron-catalyzed methylation of C(sp²)–H bond.

2.1.2 Iron-catalyzed C(sp²)–H bond activation with carbon electrophiles. Iron-catalyzed C–H functionalization reactions with carbon nucleophiles transfer the organic groups from an organometallic compound to the substrate in the presence of a mild oxidant.⁶³ In 2013, Nakamura and co-workers reported for the first time that an electrophile can also be used as a coupling partner in iron-catalyzed C–H functionalization.⁶⁴ This type of reaction does not require an oxidant, rather a non-nucleophilic base is essential to deprotonate the C–H bond. Various types of bond formation have been achieved via this reaction protocol using different types of electrophiles such as alkyl electrophiles,⁶⁵ allylic electrophiles^64,66 and amine electrophiles.⁶⁷
2.1.2.1 Iron-catalyzed alkylation of C(sp²)–H bond with carbon electrophiles. In 2014, Nakamura and co-workers reported the iron-catalyzed alkylation of alkenes, arenes and heteroarenes possessing an 8-quinolylamide group as the directing group with primary and secondary alkyl tosylates, mesylates and halides.⁶⁵ Fe(acac)₃/diphosphine catalyst/ligand and ArMgBr (as a base) were utilized to carry out the reaction (Scheme 30).

Scheme 30 C(sp²)–H alkylation of tiglamide with phenethyl tosylate using Fe(acac)₃.

A notable feature of this reaction is the use of mesylates, tosylate derivatives, as a source of alkyl electrophiles, which were largely ignored before as alkyl donors for C–H functionalization. Here, specifically the 8-aminoquinoline directing group was essential for the formation of the product and dry NaI was added to suppress the amount of arylation side product. Moreover, the ligand plays an important role for the suppression of the undesired cross-coupling product together with the C–H arylation product. Diphosphine ligands having a π-bridge or conjugated backbone such as dppen or dppbz are effective for the formation of the product. Here, dppen showed the best efficacy. Notably, diphosphine ligands devoid of a π-bridge such as dppe or monodentate phosphine and bipyridine ligands are ineffective to produce the desired product. The reaction proceeds stereospecifically for alkene substrates and it provides only the syn-alkylated product. However, it takes place without the loss of the regiochemical integrity of the starting material, which indicates that β-elimination of an iron hydride does not interfere with the reaction. Moreover, the reaction proceeds with the loss of the stereochemistry of the chiral centre with a secondary tosylate. The loss of the stereochemistry of the chiral centre connected to a tosyl group indicates the radical-like character of the C–Fe bond in the intermediate, which is formed prior to C–C bond formation. Moreover, the radical nature of the alkyl iron intermediate was confirmed by the radical clock experiment using 5-hexenyl tosylate, affording mainly the cyclized product without the olefin isomerization, while the ring-opening product was obtained under the same reaction conditions with cyclopropylmethyl bromide (Scheme 31).⁶⁸ In addition, the radical scavenger TEMPO completely inhibits the reaction. This indeed supports the radical character of the organoiron intermediate. A variety of functional groups such as alkyl chloride, aryl halide and ester are well tolerated under the reaction conditions. Interestingly, alcohols also act as an alkyl donor in this reaction protocol after in situ conversion of the alcohol into the corresponding mesylate. However, tertiary alkyl halides do not react under the reaction conditions.

Scheme 31 Radical-clock experiment for direct ortho alkylation of carboxamides with (pseudo) alkyl halides under iron catalysis.

Cook and co-workers in 2014 reported an iron-catalyzed methodology for the ortho-alkylation of carboxamides using the aforementioned 8-aminoquinoline as the directing group (Scheme 32).⁶⁹ Here, a catalytic amount of Fe(acac)₃ was used in the presence of the dppe ligand instead of the dppen ligand used by Nakamura for a similar-type reaction. The base PhMgBr is added slowly in the reaction mixture.⁶⁵ The reaction proceeds without over alkylation and provides high levels of regioselectivity. Moreover, the benzylation reaction is performed in air using reagent grade THF. Interestingly, secondary benzyl chlorides, e.g. 1-chloroethyl benzene, provided the benzylated product without isomerization in 11% yield together with a dimerized product in 33% yield.

Scheme 32 Iron-catalyzed ortho benzylation of arenecarboxamide with benzyl halides.

This is the first example of directed C–H functionalization with a secondary benzylic electrophile. The reaction with secondary alkyl bromides provides over alkylation product. However, the overalkylation product can be suppressed in the presence of one equivalent of the radical scavenger 2,6-di-tert-butyl-4-methylphenol (BHT) by trapping the transient secondary alkyl radical. Interestingly, some secondary allyl bromides and iodides produce a mixture of linear and branched product. Moreover, the time (5–8 min) required for the reaction is much less, which indicates the fast generation of highly reactive organoiron species formed by the slow addition of Grignard reagent.

In continuation of the above report, they further reported the robust iron-catalyzed ortho arylation of alkyl amides with primary electrophiles (Scheme 33).⁷⁰ The reaction condition is very similar to the aforementioned strategy. However, the addition time and amount of reagents were slightly modified. The reaction also provides the desired product in high yields with regioselectivity. Further, the reaction is completed within 10 min, and was performed in bio-derived 2-methyl tetrahydrofuran solvent during a gram-scale synthesis. Notably, aryl amides having electron-donating substituents decrease the energy of substrate co-ordination. Thus, they lead to a higher conversion to the product. On the other hand, aryl amides bearing electron-withdrawing substituents increase the energy of the substrate coordination and inhibit the rate of the conversion relative to the electron-rich substrate. A radical clock experiment showed a similar result in comparison to the report by Nakamura. Moreover, the authors performed intramolecular and intermolecular kinetic experimental studies. A small intermolecular KIE (K_H/K_D = 1.5, up to 6% yield) and a significant intramolecular KIE (K_H/K_D = 2.9) were observed. Based on these experiments, they proposed a plausible mechanistic explanation involving the turnover-limiting binding of the substrate to iron, followed by rapid and irreversible C–H cleavage.

Scheme 33 Iron-catalyzed alkylation of arenecarboxamide with primary alkyl halides using Fe(acac)₃ together with the dppe ligand.

In 2016, Ackermann and co-workers reported the robust iron-catalyzed C–H alkylation of arenes and heteroarenes by a triazole-directing group in the presence of Fe(acac)₃/dppe as the catalytic system and phenylmagnesium bromide as the base additive (Scheme 34).⁷¹ The reaction protocol proceeds well in the presence of secondary and primary alkyl bromides. Notably, methyl iodide also undergoes the reaction. The robustness of the iron catalyst is reflected by the tolerance of the ether and ester functional groups. Notably, the yield of the product is suppressed in the presence of the radical scavenger TEMPO. This suggests that the reaction may proceed via a single electron-type reaction mechanism.

Scheme 34 Triazole-assisted direct C(sp²)–H alkylation of arene carboxamides in the presence of an iron catalyst.

2.1.2.2 Iron-catalyzed allylation of C(sp²)–H bonds using carbon electrophiles. Nakamura and co-workers in 2013 reported the first example of the iron-catalyzed ortho allylation of aromatic carboxamide with allyl ethers.⁶⁴ Arenes possessing N-(quionolin-8-yl)-amide as the directing group undergo ortho-allylation in the presence of iron(III)salt/dppen as the catalyst/ligand system and ZnCl₂·TMEDA as an additive. Notably, 3.4 equiv. of tert-BuCH₂MgBr is necessary to afford the desired allylated product. One equivalent of it is consumed to deprotonate the amide proton and other 2.4 equivalents form 1.2 equivalents of (t-BuCH₂)₂Zn. Notably, the potential side reaction of organozinc with allylphenyl ether and oxidative C–H functionalization with organometallic reagent were not observed in this case. Allylic substrates having a better leaving group such as allyl chloride, acetate and carbonate are less effective. Moreover, a variety of electron-rich and electron-deficient arenes are well tolerated to provide the allylated product with monoselectivity. Notably, iron-catalyzed isomerisation of the double bond to the styrene product was not observed (Scheme 35). The allyl phenyl ether having α-substitution afforded only the γ-product in high yield with a stereoisomeric mixture (E/Z = 59 : 41). Notably, the E/Z ratio remained constant throughout the reaction, indicating that the stereomixture is not due to the isomerization of the product. Instead, it is due to the allylation step. Allyl phenyl ethers having β and γ substituents do not participate in the reaction. Additionally, an intermolecular KIE (K_H/K_D = 1.1) indicated that the reaction proceeds via fast iron-catalyzed C–H activation, followed by the reaction of the resulting intermediate with the allyl phenyl ethers.

Scheme 35 Monoselective ortho C–H allylation of arenecarboxamide using phenyl allyl ether in the presence of an iron catalyst.

Later, ortho allylation of 1-arylpyrazoles with allyl phenyl ether via iron-catalyzed C–H activation was reported in 2014 (Scheme 36).⁶⁶ The desired allylation is selectively obtained in the presence of iron(III)salt/dtbpy as the catalyst/ligand and phenylzinc reagent as a base additive. The catalytic system consisted of a bipyridine-type ligand and the diphenylzinc base acts as the key for favouring the formation of intermediate I. The undesired C–H phenylation is suppressed to less than 3%. Notably, the choice of the allylating reagent is the most important. Allylic electrophiles bearing a poor leaving group such as thiolate, amide, and siloxy are mostly recovered, while those having a better leaving group such as acetate, benzoate, carbonate and chloride are not effective for the formation of the desired product. However, the phenoxide anion generated during the reaction process causes catalytic deactivation. Thus, complete conversion of the reaction does not occur, and the starting material is recovered. Moreover, substrates having an electron-donating group at the para-position of the aryl group proceed well, while substrates containing an electron-withdrawing group at the para position of the aryl group are less reactive. The allylation of the meta-substituted substrates takes place selectively at the less hindered position in good yield. The reaction of N-arylpyrazole provides the desired allylated product with exclusive monoselectivity in a γ-selective fashion. Other N-heterocycles such as 2-phenylpyridine or benzoquinoline are unreactive or react poorly under the reaction conditions.

Scheme 36 Iron-mediated allylation of N-arylpyrazole using allyl electrophiles.

In 2016, Ackermann and co-workers reported the ortho C–H allylation of hetero(arenes) and alkenes bearing a triazole amide auxiliary (Scheme 37).⁷¹ They used Fe(acac)₃/dppe as the catalytic/ligand system and phenylmagnesium bromide as the base additive. Allylic chlorides and secondary allylic chlorides were used as electrophile sources. This optimized catalyst was used for the first iron-catalyzed C–H allylation in alkenes. Acyclic alkenes are allylated with syn-selectivity without E/Z isomerization. Allyl chlorides having substitution at the α- and γ-position afford a mixture of linear and branched products relative to the high γ-regioselectivity, as reported by Nakamura and co-workers. Notably, here the branched product is the major product.

Scheme 37 Triazole-directing group-assisted ortho allylation of (hetero)arene and alkenecarboxamide.

2.1.2.3 Iron-catalyzed arylation of C(sp²)–H bond using carbon electrophiles. Iron-catalyzed C–H bond arylation is quite challenging because of the higher bond energy of the Ar–X bond than the alkyl–X bond. Previously, one formal iron-catalyzed C–H coupling was reported with aryl bromides in the presence of metallic magnesium and diamine ligand and an organic dihalide.⁷² The use of a 1 : 1 mixture of tetrahydrofuran and 1,4-dioxane is essential for the C–H bond arylation. The reaction probably proceeds via in situ formation of the Grignard reagent, followed by participation of the Grignard reagent in the iron-catalyzed oxidative C–H bond arylation (Scheme 38).

Scheme 38 Arylation of N-directed C(sp²)–H with aryl halides in the presence of an iron catalyst.

In 2017, Butenschön and Schmeil introduced the iron-catalyzed ortho-arylation and -alkylation of ferrocene substituted by an ortho-directing group (ODG) bearing a bidentate ODG, producing excellent yields of the ortho-substituted ferrocenes (Scheme 39a).⁷³ The ortho-arylation reaction was found to give excellent yields of product, while the ortho-alkylation resulted in low to moderate yields. The moderate yields of the product for the methylation and ethylation reaction are found due to the formation of side products via the undesirable dehydrogenative dimerization of ferrocene derivatives. In addition, they presented the enantioselective iron-catalyzed C–H activation using (R,R)-ChiraPhos as the chiral ligand with iron(III) acetylacetonate forming ortho-phenylated ferrocenes in excellent yields and enantiomeric excess of up to 46% (Scheme 39b).

Scheme 39 ortho-Phenylation and alkylation of ferrocene in the presence of an iron catalyst.

In 2019, Nakamura and co-workers reported the homocoupling-free iron-catalyzed reaction of (hetero)arene and (hetero)arene or olefin containing an N-(quinolin-8-yl)amide group, resulting in high yields of cross-coupled products (Scheme 40).⁷⁴ The reaction is performed by using Fe(acac)₃ combined with bisphosphine ligand, dppen as the catalyst in the presence of the organozinc reagent Zn(CH₂SiMe₃)₂ as the base and dichloropropane (DCP) as a mild oxidizing agent.

Scheme 40 Iron-promoted two-fold C–H activation/cross-coupling reaction.

This reaction was found to be very efficient for coupling (hetero)arenes and alkene carboxamides with thiophene derivatives, giving excellent yields. Thiophenes with both electron-rich and electron-deficient substituents give good yields of monoarylated product. On the other hand, although arene carboxamides with electron-donating substituents react well, arene carboxamides bearing electron-withdrawing groups remain inactive. In addition, cyclic and acyclic alkenamides react stereospecifically, giving only the Z-products. The reaction conditions tolerate various functional groups such as ether, ketone, tertiary amine and aryl silane. Furthermore, benzene and halobenzenes provide low to moderate yields on reaction with arene carboxamides. This reaction has been suggested to proceed through two consecutive C–H activation steps (Scheme 41). The activation step involves amide group-assisted arene C–H deprotonation to form ferracycle I, followed by C–H deprotonation of the heteroarene by the ferracycle to form short-lived species II. In this species II, the two reactants remain connected via coordination of the amide anion with iron. Deuterium leveling experiments demonstrated the presence of fast equilibrium between species I and II. Then, iron species II undergoes slow irreversible deprotonation, generating diorganoiron(III) intermediate III. Thereafter, cross-coupled intermediate IV is formed by the reductive elimination of intermediate III, followed by the formation of the final product and subsequent oxidation to the active Fe(III) species.

Scheme 41 Proposed mechanism of iron-catalyzed two fold C–H activation/cross-coupling.

2.1.3 Iron-catalyzed C(sp³)–H functionalisation with carbon nucleophiles.
2.1.3.1 Iron-catalyzed arylation, heteroarylation and alkenylation of C(sp³)–H bonds with carbon nucleophiles. The C(sp³)–H bond functionalization can also be performed in the presence of an iron catalyst. In this process, metal coordination becomes much more difficult than that with the C(sp²)–H bond due to the absence of a π-system. Nakamura and co-workers in 2010 reported an iron-catalyzed C–H activation method for C–C bond formation at the α-position of aliphatic amines through intramolecular 1,5-hydrogen transfer.⁷⁵ They discovered this method during the cross-coupling reaction between 4-iodotoluene with phenylzinc reagent in THF solvent (Scheme 42).

Scheme 42 C–H phenylation of tetrahydrofuran with phenylzinc in the presence of an iron catalyst.

The same reaction also occurs during the preparation of phenylmagnesium bromide from bromobenzene in the presence of a catalytic amount of Fe₂O₃. This type of reaction proceeds via the reductive generation of an aryl radical from iodoarenes, followed by hydrogen abstraction by the aryl radical to form a radical at the 2-position of THF. Then, the recombination of the 2-tetrahydrofuranyl radical with iron and subsequent reductive elimination lead to the formation of the C–C bond.⁷⁶ Subsequently, Nakamura and co-workers used the idea of THF arylation to examine a variety of pyrrolidine derivatives. They envisioned that the N-IBn group can serve as an internal trigger for the cleavage of the C–H bond next to the amine group to generate aryl radical I upon interaction with the organoiron species through single-electron transfer from iron. Aryl radical I intramolecularly abstracts the α-hydrogen via 1,5-hydrogen transfer to form α-aminoalkyl radical II, followed by C(sp³)–C(sp²) bond formation through reactive organoiron intermediate III to generate the desired product (Scheme 43).

Scheme 43 α-Functionalization of aliphatic amine via 1,5-hydrogen transfer under iron catalysis.

The reaction proceeds within 15–30 min and the rate of the reaction is insensitive to the substituents of the aryl Grignard reagent. When an alkenyl Grignard reagent is used, the alkenylation product is obtained in good yield (Scheme 44). The reaction conditions were applied to a variety of aliphatic amines, including both cyclic and acyclic amines. However, the rate of the reaction is sluggish with anilides, affording the arylation product in low yield. Notably, a deuterium labelling experiment confirmed the intramolecular 1,5-hydrogen transfer and an intermolecular KIE experiment indicated that the 1,5 hydrogen-transfer step is not involved in the turnover-limiting step.

Scheme 44 Iron-mediated α-alkenylation of amines through a 1,5-hydrogen-transfer mechanism.

Further in 2013, they utilized this reactivity for the iron-catalyzed allylic arylation of olefins via C(sp³)–H activation.⁷⁷ Mesityl iodide was used as the oxidant for the transformation. Mechanistically, PhMgBr in the presence of an iron(III) salt first generates Ph[Fe] species, which undergoes a reaction with mesityl iodide to generate reactive coordinatively unsaturated phenylmesityl iron intermediate I. Then, intermediate I coordinates with the olefin to form intermediate II, followed by the abstraction of the allylic hydrogen atom to generate two π-allylic iron species III and IV. The abstraction of the hydrogen atom is independent of the steric effect of the mesityl group. It should be noted that the reductive elimination occurs selectively from intermediate III to form the arylated product. The reductive elimination does not occur from IV due to the steric effect of the mesityl group (Scheme 45). The regio and stereoselectivity of the reaction together with the deuterium labelling experiment suggested that C–H bond activation is the slowest step of the catalytic cycle. Notably, the catalytic turnover number reaches up to 240. Under similar conditions, PhMgBr can arylate cyclohexane in 10% yield. This result indeed suggests the very high reactivity of the organoiron catalytic species and potential C–H bond activation strategy of simple hydrocarbons. The difference in reactivity between trans and cis-β-methyl styrene and the observed regioselectivity are in agreement with the formation of an allyl iron intermediate rather than a free radical pathway.

Scheme 45 Iron-catalyzed allylic arylation of alkenes with arylmagnesium reagents.

In the same year, they reported the β-arylation of carboxamides via iron-catalyzed C(sp³)–H bond activation.⁷⁸ A 2,2-disubstituted propionamide possessing an 8-aminoquinolinyl group as the directing group was arylated at the β-methyl position with an organozinc reagent in the presence of the organic oxidant DCIB and a catalytic amount of iron(III) salt together with the bisphosphine ligand at 50 °C (Scheme 46).

Scheme 46 Iron-catalyzed arylation of C(sp³)–H via a reactive ferracycle intermediate.

This reaction is very sensitive towards the structure of the directing group, substrate and choice of ligand. The reaction shows a preference for C–H bond activation on the methyl group over the benzyl group present in the substrate. This suggests that the reaction has less radical character, which is consistent with the more organometallic character involving the formation of ferracycle A. The NH–Q-directing group and dppbz ligand are found to be the most effective for the reaction conditions. Further, investigation of the cyclic substrates revealed some interesting information. Evidently, cyclohexane and cyclopentanecarboxamide react well to provide the arylated product in moderate yields, while the corresponding cyclobutane and cyclopropanecarboxamide do not afford the desired product. The authors explained these observations based on the bond angle and the distance of CH₃–C–C(=O) during the formation of the reactive ferracycle intermediate. The bond angle (θ) and distance between the β-hydrogen and amide nitrogen (l) are larger in the case of the unreactive substrate (Scheme 47), making the formation of the ferracycle intermediate less feasible. Here, the kinetic isotope effect (KIE) experiment indicated that the cleavage of the C(sp³)–H bond is involved in the rate-determining step.

Scheme 47 Effect of angle and distance on iron-catalyzed β-arylation of aliphatic carboxamide.

Ackermann and co-workers in 2014 extended this concept to the activation of the C(sp³)–H bond of aliphatic amides possessing the 1,2,3-triazole-based auxiliary TAM.⁴² Interestingly, the reaction conditions and selectivity using TAM as a directing group were the same as the reactions bearing 8-quinolyl amide as the directing group (Scheme 48). However, this reaction has some drawbacks since it provides the arylation product together with the formation of the biaryl homo-coupling product. Here, they suggested that two organic groups are transferred to the iron in the presence of an organozinc reagent, facilitating the reductive elimination pathway to a low-valent iron centre (Scheme 48).

Scheme 48 Triazole-directing group-assisted β-arylation of aliphatic carboxamide in the presence of an iron catalyst.

In this context, in 2016, Nakamura and co-workers reported a method for the arylation, heteroarylation and alkenylation of C(sp³)–H bonds of propionamides possessing 8-quinolylamide as the directing group with an organoborane reagent (Scheme 50).⁷⁹ Here, a zinc(II) salt (20 mol%) was used as the co-catalytic system in presence of iron(III) catalyst (10 mol%). This Zn(II) co-catalyst was found to assist the deprotonation of the amide and iron/boron transmetalation. Moreover, (Z)-1,2-bis-(diphenylphosphino)ethane (dppen) and its electron-rich congener (Z)-1,2-[bis(4-methoxyphenyl)phosphine]ethane (p-OMe-dppen) bearing a conjugated backbone were used due to the stabilization of low-valent organoiron species through spin delocalisation over the ligand. Several amide substrates that react very sluggishly with organozinc reagents (e.g. 2-phenyl-substituted propionamide) provided the product in good yield with borate. In the case of alkenylation, (E)-alkenyl borate reacted with 100% stereoretention, while the (Z)-alkenyl borate reacted with 83% stereoretention. Based on the previous results together with a related study on the stoichiometry and a density functional study (DFT), the authors proposed the reaction mechanistic pathway. Notably, in the presence of organoborane reagent, only one organic group is transferred to a high-valent iron-center in each step of the catalytic cycle, suppressing the formation of the by-product and catalytically inactive reduced species. The zinc-assisted deprotonation of the amide in the substrate generates zinc amide III (Scheme 49). Notably, the amide deprotonation by lithium borate is very slow in the absence of the zinc salt. Further, iron/boron transmetalation affords intermediate IV. However, C–H bond activation via the oxidative pathway is unlikely due to the unfavourable oxidation of Fe(III) to Fe(V). Thus, C–H activation occurs via the σ-bond metathesis pathway. Particularly, monophenyliron complex IV undergoes C–H activation through transition state VIIIvia σ-bond metathesis and generates intermediate metalacycle IX. Finally, ferracycle IX undergoes reductive elimination in the presence of phenyl anion to form the C–C bond, and apparently, unstable organoiron(I)-intermediate X (Scheme 49), which is stabilized in the presence of a ligand.

Scheme 49 Possible reaction pathway with suggested co-ordination geometry.

Scheme 50 β-Arylation of aliphatic carboxamide with arylborate reagents in the presence of Fe/Zn co-catalytic system.

2.1.3.2 Iron-catalyzed alkylation of C(sp³)–H bonds using carbon-nucleophiles. Construction of the C(sp³)–C(sp³) bond via iron-catalyzed C(sp³)–H activation is challenging due to the weak interaction between the iron catalyst and saturated C(sp³)–H bonds, and the poor stability of both the C(sp³)–H ferracycle and the alkyl iron species together with the high propensity of the alkyliron intermediate to undergo β-hydride elimination.

Nakamura and co-workers in 2010 first reported an example of the iron-catalyzed alkylation of C(sp³)–H bonds during their study on the α-functionalization of amines through 1,5-hydrogen transfer under iron catalysis.⁷⁵ A similar mechanism involving hydrogen atom abstraction was discussed (see Scheme 43). Here, an alkylmagnesium halide is used for the alkylation at the α-position of the amine in moderate yield together with the formation of a large amount of homo-coupling product due to the dimerisation of hexylmagnesium bromide (Scheme 51).

Scheme 51 Iron-promoted α-alkylation of aliphatic amine with alkylmagnesium halides via a 1,5-hydrogen transfer pathway.

In 2018, Nakamura and co-workers developed a selective γ-C–H arylation method at the alkyl side chain of 2-iodoalkylarenes with diphenylzinc using a catalytic amount of Fe(acac)₃ and N-heterocyclic carbene ligand in fluorobenzene solvent (Scheme 52).⁸⁰ The aromatic halide is reported to direct the arylation of the γ-C–H bond of the alkylarene with high regioselectivity. It was proposed that initially the in situ-generated organoiron transfers one electron to the aryl iodide to form iron intermediate 1, followed by the transfer of γ-H through 1,5-hydrogen shift-generating species 2 (Scheme 52). Then, the recombination and reductive elimination of complex 2 result in the formation of the C–C bond. Notably, the involvement of the radical pathway in the formation of intermediate 1 was proven by the ring-closing product in the reaction with 1-(but-3-ene-1-yl)-2-iodobenzene. Further, the deuterium labelling experiment showed no incorporation of deuterium in the phenylated product, whereas nearly 97% deuterium was incorporated in the dehalogenated by-product. Various 2-haloalkylarenes reacted with diarylzinc reagents in this reaction protocol to afford moderate yields of the single regioisomer as the product formed via 1,5-hydrogen shift together with the dehalogenated by-product.

Scheme 52 Remote arylation of 2-iodobutylbenzene catalyzed by iron and the proposed reaction intermediates.

In 2015, Nakamura and co-workers reported the methylation of 2,2-disubstituted propionamide in the presence of Fe(acac)₃/Ph-dppen as the catalyst/ligand system.⁶⁰ Here, trimethylaluminium is used as the methylating agent and 2,3-dichlorobutane is used as the oxidant (Scheme 53).

Scheme 53 β-Methylation of carboxamide using trimethylaluminium under iron catalysis.

Ackermann and co-workers in the same year reported the methylation of the β C–H bond of an aliphatic carboxamide bearing a triazole auxiliary (TAM) in the presence of dimethylzinc (Scheme 54).⁶² Notably, it follows the organometallic C–H activation pathway instead of cleavage of the C–H bond. Moreover, the activation of the primary C–H bond is preferred over the benzylic C–H bond and the methylation product is not obtained with the secondary C–H bond.

Scheme 54 Triazole-assisted iron-promoted β-methylation of carboxamide.

2.1.4 Iron-catalyzed addition of C(sp²)–H bonds to alkenes, alkynes and allenes. In 2011, Nakamura and co-workers utilized iron-catalyzed [4+2] benzannulation for the synthesis of phenanthrene derivatives via the reaction between an alkyne and biaryl or 2-alkenylphenyl Grignard reagent (Scheme 55).⁸¹ Here, the Fe(acac)₃/4,4′-di-tert-butyl-2,2′-bipyridyl (dtbpy) ligand is used as the catalytic system in the presence of 1,2-dichloro-2-methylpropane as the oxidant. The reaction protocol provides 9-substituted or 9,10 disubstituted phenanthrene and its derivative in moderate to excellent yield. The reaction occurs via the formation of 5-membered ferracycle intermediate I, followed by alkyne insertion and reductive elimination to afford the desired product. The other probable mechanistic pathway involving carbometalation of alkyne to generate alkyl iron species II followed by intermolecular C–H activation/reductive elimination can be ruled out based on the deuterium labelling experiment. This reaction is chemoselective since some sensitive functional groups such as bromide, trifluoromethyl, trimethylsilyl and olefin are well tolerated. The application of 1,3-diyne with 2-biphenylmagnesium bromides affords the annulation product on both acetylenic moieties to give a twisted, congested bis-phenanthrene derivative having some importance in materials science (Scheme 56).⁸² Notably, a variety of alkynes including alkenyl aryl alkyne, alkyl aryl alkyne, dialkyl alkyne and even a terminal alkyl such as phenylacetylene have been well explored under the reaction conditions. Also, highly electron-deficient and sterically hindered alkynes are compatible under the reaction conditions.

Scheme 55 [4+2] Benzannulation of alkynes with biaryl or 2-alkenylphenyl Grignard reagents under iron catalysis.

Scheme 56 [4+2] Benzannulation of 1,2-diyne with biaryl Grignard reagents in the presence of an iron catalyst.

In 2012, they reported the synthesis of polysubstituted naphthalenes via the iron-catalyzed [2+2+2] oxidative annulation of arylmagnesium with two molecules of internal alkynes via C–H bond activation in the presence of 1,10-phenanthroline ligand.⁸³ The reaction proceeds through the iron-catalyzed carbometalation of the alkynes with an aryl Grignard reagent to form alkenyl iron species I, followed by intramolecular C–H bond activation to form five-membered ferracycle II. Then the insertion of a second molecule of alkyne leads to the formation of III, followed by reductive elimination and oxidation by DCIB, which delivers the cyclization product and the iron catalyst is regenerated simultaneously. Both the diaryl alkynes and dialkyl alkynes are well tolerated. However, the yield of the product with dialkyl alkynes is poor. The main limitation of the present reaction is the lack of regioselectivity. Consequently, alkynes and Grignard reagents possessing different aryl groups provide a mixture of regioisomers because of the isomerization of intermediate I, leading to the generation of two different ferracycles II (Scheme 57).

Scheme 57 Iron-promoted [2+2+2] annulations between alkynes and Grignard reagents.

Adak and Yoshikai in 2012 reported the iron–bisphosphine complex-catalyzed annulation reaction of arylindium reagents and alkynes to produce substituted naphthalenes in good yield (Scheme 58).⁸⁴ Here, no additional oxidant is required for the catalytic turnover, although the overall transformation appears to be an oxidative coupling of the arylindium reagents and alkynes. They proposed the generation of an indium hydride species to regenerate the iron catalyst. Arylindium reagents possessing electron-donating substituents react faster than electron-deficient substituents. Further, substituted dialkyl alkynes, diaryl alkynes and aryl alkyl alkynes are tolerated, but result in the formation of a lower amount of product. The reaction progresses with high regioselectivity to produce 1,4-dialkyl-2,3-diphenylnapthalenes using 1-phenylpropyne or 1-phenyl-1-butyne as the substrate. The selectivity indeed suggests a mechanism involving the insertion of alkyne into ferracycle I formed after carbometallation, followed by C–H activation to form bis(alkenyl)iron species II. Then reductive elimination generates naphthalene instead of forming aryl alkenyl-ligated iron intermediate III (Scheme 59). Notably, unsymmetrical dialkyl alkenes produce an equimolar mixture of four regioisomers.

Scheme 58 Annulations of arylindium with alkynes under iron-catalysis.

Scheme 59 Probable mechanistic pathway for the iron-assisted [2+2+2] annulation reaction between arylindium and alkyne.

In 2014, Yoshikai and co-workers reported the iron-catalyzed imine-directed C-2 alkylation and alkenylation of indoles with vinylarenes and alkynes (Scheme 60).⁸⁵ The reaction is initiated by the formation of an iron–N-heterocyclic carbene catalyst from an iron(III) salt and an imidazolinium salt together with Grignard reagent. Notably, this is the first example of an iron-catalyzed hydroarylation involving directed C–H activation. The cis-isomer of β-methylstyrene bearing aryl and silyl substituents reacts well, while trans-β-methylstyrene does not react significantly. This indeed suggests the importance of olefin coordination to the organoiron intermediate. Various alkynes including diaryl alkynes, dialkyl alkynes, and silyl alkynes are well tolerated under the reaction conditions. Further, the reaction results in good regio and stereoselective product formations. Using an unsymmetrical diaryl acetate bearing a mesityl and a phenyl group as the substrate, 70% yield of alkenylation product was obtained with exclusive regioselectivity. Similarly, high regioselectivity was observed with silyl alkynes and styrene, where the C–C bond is formed at the distal position to the silyl group. To gain mechanistic insight for this reaction protocol, a deuterium labelling experiment was performed. It revealed that the D atom of the C-2 position of indole is incorporated completely into the vinylic position (97% incorporation). Thus, based on the deuterium-labelling experiment, a plausible catalytic cycle was suggested. It involves chelation-assisted oxidative addition of the C–H bond to iron, followed by migratory insertion of the alkene or alkyne into the Fe–H bond. Subsequently, reductive elimination from the resulting diorganoiron species leads to the formation of the desired product together with regeneration of the iron catalyst (Scheme 61). Notably, the observation regarding the H/D scrambling experiment suggests that the oxidative addition and migratory insertion are reversible. Moreover, the rate of the reaction and the regioselectivity are controlled in the reductive elimination step.

Scheme 60 Iron-catalyzed imine-directed C-2 alkenylation of indoles with alkynes.

Scheme 61 Proposed mechanistic pathway of iron-catalyzed imine-directed C2 alkenylation of indole with alkynes.

In the case of a stoichiometric reaction, the iron(0) carbonyl complex is inserted into the arene C–H bond in the presence of an imine-directing group.^86–88 Thus, based on this stoichiometric reaction, Wang and co-workers described an iron-catalyzed redox-neutral [4+2] cyclization reaction between internal alkynes and aromatic imines to afford cis-3,4-dihydroisoquinolines (Scheme 62).⁸⁹ In 2016, Nakamura and co-workers reported an oxidative C–H activation strategy to synthesize pyridine and isoquinoline derivatives through the coupling of amides and alkynes.⁹¹ Here, an iron(III) salt and cis-1,2-bis(diphenylphosphino)ethylene (dppen) as the ligand are used together with the mild organic oxidant 1,2-dichloropropane (DCP) to promote both C–H bond cleavage and C–N bond formation. The dppen ligand helps to stabilize the unstable iron(I) intermediate via single-electron transfer (SET), which is generated after the formation of the C–C bond through the reductive elimination of the Fe(III) species.⁹⁰

Scheme 62 Annulations of N–H imines with internal alkynes through C–H activation under the catalytic activity of Fe₃(CO)₁₂.

A broad range of internal alkynes including diaryl alkynes, dialkyl alkynes, silyl alkynes, 1,3 diyne and enynes are well tolerated under the reaction conditions. However, terminal alkynes do not afford the desired annulation product. Moreover, an unsymmetrical alkyne provides the pyridone derivative with high regioselectivity controlled by the β-substituents present on the alkeneamide substrate. The observed regioselectivity arises because of the steric effects present in the substrate (Scheme 63).

Scheme 63 Iron-promoted annulations of alkeneamides with alkyne.

Notably, the nature of the organometallic base is very important to get achieve selectivity for the formation of the product between alkenylation and cyclization. Notably, using mono-organic zinc halide as the base, the alkenylation product was observed as the major product, regardless of the presence or absence of the oxidant. On the other hand, the cyclization product is obtained as the major product using diorganozinc as the base in the presence of DCP oxidant. This suggests the formation of the common ferrate intermediate IV for both pathways, and the strong nucleophilic diorganozinc reagent helps in the formation of a ferrate species, which immediately undergoes oxidation to promote C–N bond formation (Scheme 64). In 2018, they developed the iron-catalyzed annulation of a bidentate directing group bearing carboxamide with internal alkyne using Fe(acac)₃ and cis-1,2-bis(diphenylphosphino)ethane (dppen) as the catalyst–ligand system in the presence of in situ-generated phenylzinc chloride from PhMgBr and ZnCl₂ as the base (Scheme 65).⁹¹ Various electron-rich and electron-deficient benzamides and diphenylacetylenes were reacted under the reaction conditions, and high yields of the corresponding indenone derivatives were obtained. The reaction is initiated with ortho C–H activation of the carboxamide in the presence of an iron catalyst and organozinc chloride to produce complex I (Scheme 65). This is followed by insertion of alkyne to generate intermediate II. Thereafter, cyclization occurs in the presence of a Lewis acid, ZnCl₂, forming indenone as the desired product.

Scheme 64 Organometallic base-regulated selective formation of oxidative annulations or alkenylation products.

Scheme 65 Carboxamide annulations using internal alkynes in the presence of an iron catalyst.

Further, they developed a directed alkylation method for carboxamides by olefins through a carbometalation pathway in the presence of an iron catalyst, giving high yields of the desired monoalkylated product (Scheme 66).⁹² This reaction is an alternative to the Murai-type reactions, which provide the alkylated product through C–H activation followed by the reaction between the metal intermediate and alkene via hydrometalation.^93,94 Initially, ortho C–H activation of the carboxamides with a quinoline directing group is performed in the presence of iron(III) acetylacetonate together with a bipyridine ligand, forming iron intermediate I followed by its regioselective carbometalation to olefin using the in situ-generated phenylzinc base from ZnCl₂ and PhMgBr to generate stable alkylzinc intermediate II (Scheme 66). Finally, this intermediate is either deuterated by DCl or trapped by allyl bromide, affording the corresponding linear alkylated product. Notably, a wide range of carboxamides and mono-substituted alkenes result in the formation of the corresponding linear alkylated products selectively in high yields without the presence of any branched alkyl products. The reaction conditions also tolerate different functional groups such as bromide, ester, silane and boron, demonstrating its synthetic utilities.

Scheme 66 Iron-catalyzed ortho alkylation of carboxamides.

In 2018, Ackermann and co-workers reported the first iron-catalyzed allene annulations via a unique C–H/N–H/C–O/C–H functionalization, giving different substituted isoquinolones in high yields (Scheme 67).⁹⁵ The allenyl acetates react with a variety of TAH-directed substituted benzamides in the presence of dppe (1,2-bis(diphenylphosphino)ethane)-ligated iron(III) acetylacetonate and in situ-generated diarylzinc as the base, resulting in high yields of site- and chemo-selective isoquinolones. Based on the higher reactivity of electron-deficient arenes in the intermolecular competition experiments, they suggested the involvement of the ligand-to-ligand hydrogen transfer (LLHT) mechanism for C–H activation. Also, based on the observation of the hydroarylation product for the reaction using the acetate-free allene, the presence of oxidation-induced reductive elimination was suggested. Mechanistically, the annulation is initiated with easy C–H metalation and subsequent allene migratory insertion, followed by oxidation-induced reductive elimination, generating iron allyl complex I (Scheme 68). Thereafter, allyl iron complex I was proposed to undergo unique intermolecular C–H activation by 1,4-iron migration, generating allyl-benzylic iron intermediate II. Then, intermediate II undergoes proto-demetalation with the amide motif of the TAM/H benzamide substrates, resulting in exo-methylene-3,4-dihydroisoquinoline III. Finally, the desired isoquinolone is produced by the isomerization of III.

Scheme 67 Iron-promoted allene annulations.

Scheme 68 Proposed catalytic cycle for C–H/N–H/C–O/C–H activation.

In 2019, Mo et al. reported iron-catalyzed C–H/N–H alkyne annulations using triazole amide as the directing group (Scheme 69).⁹⁶ A wide variety of TAH-benzamides (TAH = 1,2,3-triazole directing group) undergo the reaction, producing moderate to excellent yields of the corresponding isoquinolones. Notably, the mild reaction conditions tolerate different substituents on the aryl group of the TAH amides and on propargylic acetates.

Scheme 69 Iron-catalyzed C–H alkyne annulation.

Based on the obtained higher yields for the electron-deficient arenes in the intermolecular competition experiments, they proposed a ligand-to-ligand hydrogen transfer (LLHT) mechanism. Further, Mössbauer studies revealed the presence of high-spin iron(II) intermediates. Mechanistically, the C–H/N–H annulation catalytic cycle is initiated with C–H activation via LLHT, generating species I, followed by co-ordination of propargylic substrates to I, producing intermediate II (Scheme 70). Then, intermediate II undergoes rapid migratory insertion to form complex III. Thereafter, complex IV is formed by the cleavage of the C–O bond of the acetate leaving group of complex III. Then, the ligated allene moiety is inserted into the N–Fe bond of complex IV to form annulated iron complex V. Finally, proto-demetalation of V produces the desired isoquinolone with concomitant regeneration of the active catalyst.

Scheme 70 Proposed mechanistic cycle for the iron(II)-catalyzed C–H activation/annulations of propargyl acetates.

2.1.5 Iron-catalyzed C–X (X = N, O, B, etc.) bond-formation via C–H activation reactions.
2.1.5.1 Iron-catalyzed amination of C–H bonds. The first example of intramolecular amination was introduced by Berslow and Gellman in 1983. The intramolecular nitrogen functionalization of the saturated carbon atom of 2,5-diisopropylbenzenesulfonamide (I) was executed in the presence of the iron–porphyrin complex Fe(III)(TPP)(Cl) (TPP = tetraphenylporphyrin) in acetonitrile (Scheme 71).⁹⁷ Initially, the starting material reacts with phenyliodone diacetate (PIDA) and KOH/MeOH to give the (imidoiodo)benzene derivative (II). This is followed by its decomposition in the presence of Fe(III)(TPP)Cl in CH₃CN to generate the insertion product (III) together with a small amount of the unsaturated sufonamide (IV).

Scheme 71 Intramolecular nitrogen functionalization at the saturated carbon of 2,5-diisopropylbenzenesulfonamide.

In 2014, Nakamura and co-workers reported a stoichiometric method with chloroamine to form an in situ-generated ferracycle intermediate, which affords the amination product (Scheme 72).⁹⁸ Following this report, they developed the synthesis of anthranilic acid derivatives via the ortho amination of aromatic carboxamides with N-chloroamines. Aromatic carboxamides bearing 8-quinolinylamide as a directing group undergo ortho amination with N-chloroamines and N-benzylamines in the presence of iron(III) salt/dppbz ligand and an organometallic base (PhMgBr). Importantly, they employed the double slow addition strategy to develop a catalytic reaction. This strategy inhibits the direct reaction between N-chloroamine and PhMgBr, which prevents the catalytic turnover. Notably, the directing group and the bis(phosphine) ligand (dppbz) are crucial for the formation of the desired product with high yield and good selectivity.

Scheme 72 Iron-catalyzed ortho C–H functionalization of carboxamides with N-chloromorpholine via a ferracycle intermediate.

They also showed that the electronic effect of the bis(phosphine) ligand plays an important role in dictating the product selectivity. A more electron-rich ligand favours the formation of the phenylation product, whereas a less electron-rich ligand favours the formation of the aminated product. Notably, a further increase in the number of fluorine atoms in the ligand decreases the yield of the product (Scheme 73). A variety of chloramines including cyclic and acyclic chloramines are well tolerated under the reaction conditions. Moreover, the reaction is very sensitive to the steric effect, and in all cases, only the monoaminated product is obtained selectively without diamination.

Scheme 73 Iron-promoted C–H amination through double slow additions and reactivity of different ligands.

In 2015, Nakamura and co-workers developed the iron-catalyzed intramolecular ring-closing C–H amination of o-phenylenediamines to synthesize 2,7-disubstituted 5,10-diaryl-5,10-dihydrophenazines (Scheme 74).⁹⁹ The author suggested two possible mechanistic pathways. In the first pathway, C–H bond activation occurs, followed by reductive elimination to form the C–N bond. In the other mechanistic pathway, the reaction occurs via the electrophilic amination pathway. The substituted dihydrophenazine derivatives are used in hole-injection materials in organic electroluminescence (OEL) devices.

Scheme 74 Intramolecular C–H amination under iron catalysis and its plausible mechanism.

Very recently in 2020, Flack and co-workers developed the operationally simple and sustainable iron-catalyzed selective amination of the benzylic meta-C–H bond in the presence of picolinates as the directing group (Scheme 75).¹⁰⁰ The reaction is performed using FeCl₃ together with hydroxylamine-O-sulfonic acid (HOSA) in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) solvent and triethyl amine as the base. Based on the spectroscopic data, only the meta-aminated product was reported to be formed among the three possible regioisomeric amination products. Notably, the substrates with substituents at one or both ortho positions afford the desired products with high yields. Based on this observation, they suggested the direct addition reaction to the aromatic π system. Moreover, the kinetic isotope effect study revealed that C–H cleavage is not the rate-determining step, and thus the possibility of the C–H activation pathway was excluded. Thus, electrophilic aromatic substitution (S_EAr) was suggested as the most probable pathway for the functionalization. This is consistent with the rapid reaction of the para-methoxy-substituted substrate, demonstrating the influence of electron-donating substituents on the S_EAr functionalization.

Scheme 75 Selective benzylic meta C–H bond amination in the presence of an iron catalyst.

2.1.5.2 Iron-catalyzed borylation and silylation of C–H bonds. In 2013, Mankad and co-workers developed a heterobimetallic Cu–Fe and Zn–Fe complex catalyzing C–H borylation. The C–H borylation of arenes was carried out previously using noble metal catalysts. The optimal catalyst, i.e. (IPr)Cu–FeCp(CO)₂, requires only 5% loading under photochemical conditions to show efficient activity (Scheme 76).¹⁰¹ This bimetallic catalytic system is highly robust under the reaction conditions. Notably, it can be reused by adding some additional substrates to the reaction mixture.

Scheme 76 Fe–Cu cooperativity-induced C–H borylation under iron catalysis and its proposed mechanism.

Notably, the reaction protocol is very sensitive to the steric bulk of arene systems. In the case of substituted toluene at the ortho position, no borylation product is obtained. The authors proposed a plausible mechanistic pathway consisting of three steps. Initially, B–H bimetallic oxidative addition undergoes via metal–metal bond cleavage, followed by photochemical C–H borylation by the resulting boryl iron intermediate. Finally, H–H bimetallic reductive elimination occurs to liberate hydrogen with the concomitant formation of a metal–metal bond.

The dehydrogenative C–H borylation with a bimetallic complex was well explored by Mankad and co-workers.¹⁰¹ Further, in 2015, the particular dehydrogenative C–H borylation by a mononuclear iron catalyst without any additive was developed by Darcel and co-workers.¹⁰² They reported the dehydrogenative borylation of a simple hetero(arene) with pinacolborane in the presence of iron/bis(diphosphine) (dmpe) ligand (Scheme 77). Both FeH₂(dmpe)₂ and FeMe₂(dmpe)₂ were proven to be good catalysts for the reaction protocol. The corresponding borylated compound is obtained in moderate to good yield with 5% catalyst loading under the photochemical condition (350 nm). Based on the stoichiometric reactivity study and isolation of the original trans-hydride(boryl) iron complex, [Fe(H)(Bpin)(dmpe)₂], the authors proposed the mechanistic pathway. Initially, dmpe-ligated iron(0) complex 1 reacts with arenes the reversible oxidative addition of the C–H bond to iron to generate iron hydride intermediate 2. Then, the iron hydride complex undergoes a reaction with HBpin to give the borylated arene and to form iron dihydride precatalyst 3. Thereafter, precatalyst 3 reductively eliminates hydrogen via the regeneration of dmpe-ligated iron (0) complex 1. Notably, the reaction can also proceed via other pathways involving an iron boryl hydride complex.

Scheme 77 Iron-catalyzed C–H borylation of arenes under UV irradiation together with the proposed mechanism.

Direct silylation of inert C–H bonds provide an easy approach for the synthesis of organosilane compounds having wide applications in organic synthesis,¹⁰³ bioactive compounds,¹⁰⁴ organic materials,¹⁰⁵etc.¹⁰⁶ There are a few methods for the synthesis of organosilicon compounds such as the traditional cross-coupling method¹⁰⁷ for the introduction of a silyl group in organic molecules, involving the reaction between an organometallic compound and silicon electrophile,¹⁰⁸ and other transition metal-catalyzed C–H silylation reactions.¹⁰⁹ Iron-catalyzed methods for the silylation of the C–H bond involving organoiron species are very rare. In 2014, Nagashima and co-workers developed a disilaferracycledicarbonyl complex containing weakly coordinated η²-(H-Si) ligands for carrying out the C–H silylation reaction.¹¹⁰ The C-3 selective silylation of indole derivatives and stoichiometric C–H bond functionalization of arenes were achieved using the above-mentioned well-defined iron complex (Scheme 78). Similarly, Ito et al. reported the silylation of C–H bonds through an NCN-pincer-type iron–carbonyl–silyl complex.¹¹¹

Scheme 78 C-3 selective C–H silylation of N-methylindole.

In 2017, Yoshigoe et al. presented an iron-catalyzed ortho-selective C–H borylation procedure for a 2-phenylpyridine derivative with the 9-bicycloboranonane (9-BBN) dimer in the presence of iron(III) bromide, resulting in ortho-borylated products in moderately high yields (Scheme 79).¹¹² Both electron-withdrawing and donating groups on the phenyl and pyridyl ring of 2-phenylpyridine are well tolerated, giving good yields of borylated products. In addition, various substrates are efficiently borylated using this reaction protocol.

Scheme 79 Iron-catalyzed C–H borylation of 2-arylpyridines.

Mechanistically, the formation of complex I occurs initially from the reaction of 2-phenylpyridine and 9-BBN via a Lewis acid base interaction (Scheme 80). This is followed by the elimination of one molecule of HBr in the presence of FeBr₃, forming complex II. Thereafter, successive elimination of HBr (first cycle) or H₂ (after the first cycle) through iron-catalyzed C–H bond activation occurs, forming ferracycle III. Then, this ferracycle undergoes reductive elimination, producing the desired product together with the concomitant generation of iron(I) species.

Scheme 80 Proposed mechanism for ortho-selective C–H borylation.

In 2018, Yoshikai and co-workers reported the N–H imine-directed C–H silylation of pivalophenone N–H amine with hydrosilane in the presence of [Fe₃(CO)₁₂] as a catalyst and norbornene as a hydrogen acceptor in chlorobenzene solvent (Scheme 81).¹¹³ Various pivalophenone imines containing para-substituents such as Me, Ph, OMe, OCF₃, NMe₂, SMe and Cl undergo the reaction, giving moderate yields of the desired silylated products. Notably, this reaction provides a way for the formation of ortho-silylated benzonitrile under peroxide photolysis of the products, converting the imine group to a cyano group. Based on deuterium labelling experiments, it was suggested that the C–H activation undergoes through a reversible pathway.

Scheme 81 Iron-catalyzed C–H silylation of pivalophenone.

2.1.5.3 Iron-catalyzed tritiation of C–H bonds. In 2016, Chirik and co-workers reported that an iron complex, [bis(arylimdazol-2-ylidene)pyridine iron bis(nitrogen)], can be used as a catalyst for the exchange of deuterium and tritium with the arene C–H bond using deuterium and tritium gas based on the concept of reversible oxidative addition of C–H bonds of arenes with dihydrogen via a low-valent iron complex.¹¹⁴ The authors proposed that the site selectivity of the iron catalyst is orthogonal to the currently used iridium catalysts (Scheme 82). Thus, the present method of tritiation of C–H bonds in orthogonal positions compared to Ir-catalyzed methods can be important means for drug discovery. Interestingly, this synthetic protocol has been used for the tritiation of commercial drug molecules such as Cinacalet.

Scheme 82 Iron-catalyzed tritiation of arenes.

2.1.5.4 Iron-catalyzed ethoxylation of C–H bonds. In 2018, Ding and co-workers developed the first iron-catalyzed ethoxylation of an aryl C–H bond-bearing DMEDA (DMEDA = 1,2-dimethylethylenediamine) directing group using iron(III) acetylacetonate in the presence of cobalt as a co-catalyst together with methenamine ligand, Ag₂O additive and AgOPiv as the oxidant (Scheme 83).¹¹⁵ Various types of benzamide substrates containing electron-donating and electron-withdrawing groups on the phenyl ring undergo the reaction, giving good yields of the ethoxylated product. Notably, para- and meta-substituted benzamides give better results than the ortho-substituted derivatives. Also, meta-substituted benzamides give the ethoxylation products through the regioselective reaction at the less hindered C–H bond.

Scheme 83 Iron-catalyzed C–H ethoxylation reaction.

The plausible mechanism of the reaction starts with the formation of complex I through the reaction of benzamide, Co(OAc)₂ and methenamine with the iron catalyst (Scheme 84). This is followed by basic pivalate anion-assisted C–H activation to produce intermediate II. Thereafter, reductive elimination from intermediate II generates another intermediate, III. Finally, this intermediate undergoes deprotonation to give the desired product together with the concomitant regeneration of iron by the oxidation of Ag⁺. Also, the Co(OAc)₂ formed in the final step is recycled in this process.

Scheme 84 Plausible mechanism for iron-catalyzed C–H ethoxylation.

2.1.5.5 Iron-catalyzed direct insertion to C–H bonds. Ge and co-workers in 2016 reported the iron-catalyzed E-selective dehydrogenative borylation of vinyl arenes with pinacolborane¹¹⁶ (Scheme 85). Here, they used an iron(0) Fe(PMe₃)₄ complex. Monosubstituted and disubstituted vinyl arenes undergo the synthetic transformation. Furthermore, this reaction protocol can be used for the further transformation of the resulting vinyl boronate esters to develop one-pot synthetic procedure for the functionalization of vinylic C–H bond of vinylarenes. Mechanistically, this iron-catalyzed reaction proceeds via the syn insertion of vinylarenes into the Fe-boryl species. Then the β-hydride elimination from the syn coplanar conformation of the borylalkyl iron intermediate leads to the formation of the desired product.

Scheme 85 Iron-promoted E-selective dehydrogenative borylation of vinylarenes.

In 2016, Pérez and co-workers reported the first instance of the iron-catalyzed selective direct functionalization of aryl sp² C–H bonds with ethyl diazoacetate using an iron complex containing the tetradentate PyTACN ligand (PyTACN = 1-(2-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclonoane) together with 8 equiv. of NaBAr₄^F (BAr₄^F = tetrakis(bis-3′5-trifluoromethylphenyl)borate) as the Cl or OTf scavenger (Scheme 86).¹¹⁷ The reaction methodology affords the insertion products exclusively without the formation of the usually observed cycloheptatriene derivatives obtained by the Buchner addition reaction.¹¹⁸

Scheme 86 Direct functionalization of aryl C(sp²)–H with ethyl diazoacetate under iron catalysis.

Also, for alkylbenzenes, the C(sp²)–H bonds are selectively functionalized over the C(sp³)–H bonds. However, several monoalkyl-substituted benzenes undergo selective functionalization at the C(sp²)–H bonds to give the desired products in moderate to excellent yields. Substrates bearing electron-withdrawing groups such as Cl and CF₃ were found to be inactive.

Based on the observations from kinetic studies and Hammett studies, they proposed the mechanistic pathway for the reaction (Scheme 87). It was suggested that the initial halide loss of the iron precatalyst in the presence of a halide scavenger forms dicationic species I, followed by its binding with the diazo compound in a dihapto manner to generate species II. Then, species II is converted to metallocarbene species III through the loss of an N₂ molecule. Thereafter, the arene reacts with the carbene ligand of complex IIIvia an outer sphere mechanism, generating Wheland-type¹¹⁹ intermediate IV. Finally, a 1,5-hydrogen shift in intermediate IV results in the formation of the product together with the concomitant regeneration of I. Later, computational studies on the reaction supported the formation of the Wheland-type intermediate. They also revealed the formation of this intermediate via hydrogen atom transfer from the arene to the carbonyl group of the carbene, resulting in the formation of high chemoselectivity towards the insertion product.

Scheme 87 Reaction pathway for arene functionalization by carbene insertion via an electrophilic aromatic substitution mechanism.

2.2 C–H functionalisation via outer sphere pathway

2.2.1 C–H bond oxidation via small molecule iron-catalyst. C–H bond oxidation is a very common phenomenon in nature and non-heme iron-based oxygenase enzymes, including cytochrome P-450(CYP) and α-ketoglutarate-dependent oxygenases, which constantly perform selective C–H bond oxidation of different naturally occurring drug molecules.¹²⁰ For example, the heme and non-heme iron oxygenases, Ecd-H and Ecd-G, respectively, present in echinocandin B execute the selective aliphatic C–H bond oxidation of free L-homotyrosine and assembled macrocyclic peptide (at ornithine) existing in the building blocks of echinocandin.¹²¹ However, although oxygenase enzymes accomplish selective C–H oxidation in nature, synthetic protocols or catalysts cannot achieve the enzyme-like selectivity. Notably, in the synthetic scenario, C–H bond oxidation is less selective due to the similar bond strengths of different types of aliphatic C–H bonds¹²² (pK_a ∼ 50 and BDE ∼ 96–101 kcal mol⁻¹). Therefore, targeting a specific C–H bond is quite challenging. Accordingly, developing C–H bond oxidation reactions to achieve enzymatic selectivity will be highly impactful in synthetic chemistry. There are two approaches for C–H bond oxidation. The first is using stoichiometric organic reagents (hydroxyl/alkoxyl radical or oxidant) and the other is using transition metal catalysts.¹²³ Here, we discuss non-heme iron-catalysed selective C–H bond oxidation methods.

In 1894, Fenton discovered a method using hydrogen peroxide and iron(II)–sulphate (FeSO₄) in acidic condition to oxidise the C–H bonds present in a compound.¹²⁴ After four decades of its discovery, Haber–Weiss proposed the mechanism of the Fenton reaction.¹²⁵ Mechanistically, iron(II) (Fe²⁺) is oxidized by H₂O₂ to give iron(III) (Fe³⁺) and the hydroxyl radical (˙OH) and hydroxide ion (⁻OH) (Fig. 3). Then, the in situ-formed reactive hydroxyl radical carries out C–H bond oxidation. Notably, the hydroxyl radical is the second most reactive radical after the fluorine radical (based on the oxidation potential comparison). Notably, oxidation by the Fenton reagent is rapid and exothermic due to the formation of a strong bond (H–OH, BDE ∼ 119 kcal mol⁻¹).¹²⁶ Further, this reagent is a non-selective oxidant and provides a mixture of secondary and tertiary oxidized product (in a 1 : 1 ratio). However, the selectivity in C–H bond oxidation is very important in organic synthesis. In 1980, iron salts together with a monodentate pyridine ligand (used in solvent quantity) in acetic acid (AcOH) were used for C–H bond oxidation, which is known as GIF chemistry (Fig. 4). This method basically converts a saturated hydrocarbon into ketone at room temperature under mild conditions. This reaction has been proposed to proceed via the formation of a high-valent iron(V)–oxo intermediate. Notably, the hydroxyl radical does not form in this reaction similar to the Fenton chemistry. This method results in the formation of the secondary oxidized product in a greater amount than the tertiary oxidized product.¹²⁷

Fig. 3 Reaction mechanistic pathway for Fenton chemistry.

Fig. 4 Mechanistic pathway of GIF chemistry.

In synthetic chemistry, stoichiometric electrophilic organic heterocyclic (e.g. dioxiranes and oxaziridines) oxidants are primarily used for tertiary C–H bond oxidation. In the early 20th century, most of the oxidation reactions were performed using 3-methyl (trifluoromethyl)dioxirane (TFDO) as the oxidizing agent. However, it is not a good oxidizing reagent due to its operational difficulties.¹²³ Moreover, it cannot tolerate the structural diversity of different substrates. Biologically, non-heme iron enzymes such as methane monooxygenase¹²⁸ (MMO) and rieske-dioxygenase¹²⁹ can successfully catalyse C–H bond oxidation via intermediate diiron(IV)–oxo and iron(V)oxo species, respectively. Thus, these biological systems inspired chemists to develop synthetic models for selective C–H bond oxidation catalysts.

2.2.1.1 Bio-mimetic synthetic model for C–H bond oxidation. In 1997, Prof. Que Jr. and co-workers reported the first example of non-heme iron-catalyzed stereospecific alkane hydroxylation in the presence of an oxidant (H₂O₂).¹³⁰ They employed tripodal a nitrogen ligand [(TPA) = (tris(2-methylpyridyl)amine)] in an iron catalyst system, providing excellent reactivity. Further modification in electronic and steric properties of this tripodal ligand system significantly improved its reactivity.¹³¹ Moreover, in this work, they showed evidence of iron(V)–oxo species as the key species executing C–H oxidation. Subsequently, they synthesised an Fe^II complex [Fe^II(^Me₂PyTACN)(CF₃SO₃)₂] and characterised it via X-ray crystallography (Scheme 88).¹³² The X-ray diffraction structure showed the presence of a distorted octahedral low-spin iron(II) centre containing a tetradentate ligand (^Me₂PyTACN) together with two triflate anions in a cis fashion. This iron complex shows high catalytic activity in the presence of H₂O₂ as an oxidant for the oxidation of cyclohexane and other tertiary C–H bonds present in substrates such as dimethylcyclohexene, adamantane and 2,3-dimethyl butane. They proposed the formation of the active intermediate, an HO–Fe^V=O complex, towards alkane oxidation with an iron complex. The reaction pathway using this non-heme Fe(II) catalyst is different from the former Fe^III(TPA) complex.

Scheme 88 Iron complexes with TACN ligand.

The reaction using TACN ligands was proposed to proceed via an unusual rebound-like mechanism (Scheme 89).¹³³ Notably, the cis configuration of the two hydroxyl groups in the catalytic system is different from stereo-requirement of the trans-configuration in the heme complex. This is a unique feature in the non-heme catalytic system.

Scheme 89 Mechanistic pathway of C–H bond oxidation.

The aforementioned C–H bond oxidation protocol by Que and co-workers is the fundamental work on the development of selective iron-catalyzed oxidation reactions. This fundamental study actually helped chemists develop several other C–H bond oxidation catalysts. Selective iron-catalyzed C–H bond oxidation methods were pioneered by White and co-workers in 2007.¹³⁴ Subsequently, selective catalysts towards C–H bond oxidation reactions were developed by several other groups. Here, we discuss these iron-catalyzed C–H bond oxidation methods in a chronological manner.

2.2.1.2 Catalytic methods for C–H bond oxidation and epoxidation. To accomplish the selective oxidation of aliphatic C(sp³)–H bonds, White and co-workers developed an iron-catalyzed aliphatic C–H bond oxidation protocol using an Fe^II(PDP) complex [PDP = 2-({(S)-1-(pyridine-2-yl-methyl)pyrrolidin-2-yl][pyrrolidin-1yl}methyl)pyridine] (Scheme 90).¹³⁴ The higher rigidity present in the PDP ligand leads to an increase in selectivity in C–H bond oxidation. Here, site selectivity is dictated by different factors, i.e. electronic, steric, and stereo-electronic factors, of the substrate. Electron-rich tertiary C–H bonds show higher reactivity than primary and secondary C–H bonds. Thus, electronic factors rather than the steric effect of C–H bonds play the key role in this transformation.

Scheme 90 Iron-catalysed oxidation of unactivated sp³ C–H bond.

Notably, the presence of an electron-withdrawing group at the α or β carbon of the unactivated C–H bond decreases its reactivity. Particularly, the presence of acetate, ester, carbonyl and halogen functional groups decreases the reactivity of adjacent C–H bonds. Consequently, the remote tertiary C–H bonds show better reactivity than the adjacent C–H bond (Scheme 91). The chemoselectivity and the stereoselectivity of the reaction can be due to concerted C–H bond oxidation by the electrophilic oxidant.¹³⁵

Scheme 91 Reactivity of different C–H bonds.

The synthetic application of the reaction protocol has been extended to complex substrates where the selectivity rule determines the fate of C–H bond oxidation. For example, the most electron-rich and least sterically hindered 3° C–H bond at the C-10 position undergoes oxidation in the case of the natural product (+)-artemisinin (Scheme 92a). Interestingly, the iron-catalyzed process using the Fe^II(PDP) catalyst affords a higher yield of the desired product and requires a shorter time than the enzymatic reaction. Further, carboxylate-directed hydroxylation followed by in situ lactonization of tetrahydrogibberellic acid affords the lactone product in 52% yield with a requirement of recycling the starting material once (Scheme 92). Notably, the slow addition strategy results in a higher conversion without decreasing the site selectivity or chemoselectivity.¹³⁶ More interestingly, the hydroxylation product of (+)-artemisinin and tetrahydrogibberellic acid is obtained in high yield without recycling the recovered starting material (Scheme 92b). Furthermore, this synthetic protocol has been applied for the diversification of natural products having potential application in drug discovery with high chemo and regioselectivity.

Scheme 92 Synthetic application of aliphatic C–H bond oxidation by the Fe^II(PDP) complex.

Encouraged by these initial results, they further worked on the selective oxidation of more abundant secondary C–H bonds.¹³⁷ Notably, secondary C–H bonds have higher steric hindrance, but lower electron density compared to tertiary bonds. Therefore, the selective oxidation of secondary C–H bonds can be a useful method for methylene C–H functionalization. Here, the highly chemoselective and diastereoselective oxidation products are obtained in the case of complex molecules. The observed selectivity is governed by electronic, steric, and stereo-electronic factors. To clarify, a diterpenoid-derived dione having 14 secondary C–H bonds and two tertiary C–H bonds undergoes oxidation selectively at the C-2 position. In this system, two tertiary C–H bonds are electronically and sterically deactivated according to the selectivity rule. The side chain and the B ring are electronically deactivated due to the presence of the electron-withdrawing carbonyl functionality. Thus, the least bulky site (C-2 position) of the A ring is the active site for the oxidation. The C-2 and C-3 oxidized product were obtained in 52% and 28% (isolated yield), respectively. The starting material (12%) was recovered after completion of the reaction (Scheme 93). Similarly, another complex molecule, pleuromutilone, affords highly chemo, regioselective and stereoselective C-7 equatorial oxidized products (Scheme 94) under the optimized reaction conditions.

Scheme 93 Combined effects towards predictable and highly selective secondary C–H bond oxidation.

Scheme 94 Combined effects towards diastereoselective methylene oxidation.

Inspired by these bioinspired iron catalysts for C–H oxidation, Ribas and Costas in 2009 jointly developed a catalyst that is structurally related to [Fe^II(MEP)(CH₃CN)₂]²⁺ and [Fe^II(BPBP)(CH₃CN)₂]²⁺ (reported by White and Chen) (Scheme 95).¹³⁸

Scheme 95 Nitrogen ligands used in C–H oxidation catalysts.

They introduced another non-heme iron catalyst, [Fe^II((S,S,R)-(MCPP))(CF₃SO₃)₂], supported by a nitrogen-based chiral ligand (MCPP) containing the bulky pinene group at the remote position of the pyridine ring. Notably, this bulky and rigid ligand backbone protected the iron centre of the catalyst from external perturbation by oxygen and prevents the decomposition of the catalyst via bimolecular processes. Moreover, the chiral 1,2-cyclohexane diamine backbone imparts rigidity to the ligand, which allows the predetermination of topological chirality and determines the relative orientations of the robust pinene CH₃ groups with respect to the metal sites.

The ellipsoid model of the solid-state molecular structure of [Fe^II(MCPP)(CF₃SO₃)₂] shows that the distorted octahedral iron(II) centre contains a ligand with cis-α topology. The nitrogen atoms of the two pyridine rings are in a trans fashion and two aliphatic nitrogens are situated cis to each other. The catalyst exhibits high stereospecificity and regioselectivity during hydroxylation, suggesting the involvement of a highly selective high valent iron–oxo complex instead of any free radical-type intermediates (Scheme 96). Notably, the aforementioned catalyst shows good selectivity towards tertiary C–H bonds, although there is a presence of statistically more important secondary C–H bonds in the substrates. This preference for the tertiary position indicates that the strength of the C–H bond is a major factor in dictating the site selectivity. This catalyst shows better selectivity and efficiency compared with the results using the [Fe^II(MEP)(CF₃SO₃)₂], [Fe^II(BPBP)(CF₃SO₃)₂], and [Fe^II(PyTACN)(CF₃SO₃)₂] catalysts. Both the electronic and steric factors play a major role to differentiate C–H bonds. For example, the regiospecific oxidation of the tertiary C–H bond of (−)-acetoxy-p-menthane was observed using [(S,S,R)-Fe^II(MCPP)(CF₃SO₃)₂]/H₂O₂ as the catalyst/oxidant system in 62% yield with only 1% catalyst loading. Here, the hydroxylation occurs more readily at the more accessible (C-1)–H bond to give the corresponding product (Scheme 96). Further, it is believed that non-heme iron-complex I is oxidized by H₂O₂ to generate intermediate iron–oxo complex II, which reacts with C–H bonds via hydrogen atom transfer and the oxygen rebound pathway to provide the hydroxylation product (Scheme 97).

Scheme 96 Regiospecific hydroxylation of (−)-acetoxy-p-menthane.

Scheme 97 Proposed mechanism of iron-catalyzed C–H oxidation.

Substrate-controlled site-selective C–H bond oxidation protocols were developed using small molecule non-heme iron catalysts up to 2012. Later in 2013, White and co-workers developed another small molecule non-heme iron catalyst, [Fe^II(CF₃PDP)]²⁺. This non-heme iron catalyst demonstrates the trajectory restriction governed strategy to provide predictable, catalyst-controlled site selectivity in simple and complex molecules.¹³⁹ Basically, the presence of pendent aryl rings at the 5-position of the pyridine rings of PDP ligand having an ortho-CF₃ group deactivates the ligand towards oxidation due to its electron withdrawing property. Further, steric bulk present in the ligand system enforces a perpendicular arrangement of the biaryl rings, where the CF₃ groups extend towards the active sites of the catalyst and narrow the cone of approach trajectories to 76° (Scheme 98). Thus, site selectivity is primarily governed by the nonbonding interaction between the catalyst and substrate. It is observed that the Fe^II(PDP) catalyst can differentiate between 3° and 2° aliphatic C–H bonds based on electronic, steric and stereo-electronic factors. Consequently, the Fe^II(PDP) catalyst provides substrate control selectivity. Interestingly, using the Fe^II(CF₃PDP) catalyst on the same substrate affords the secondary C–H bond oxidized product in a major amount. Thus, the Fe^II(CF₃PDP) catalyst can alter the intrinsic site selectivity of the oxidation product obtained by the Fe^II(PDP) catalyst. Subsequently, a qualitative mathematical model was developed, which helps to relate the site selectivity of the aforementioned catalyst to the properties of the substrate. They also applied this model to (+)-artemisinin. This natural product has nine potential sites for oxidation, and among them, only C-10 and C-9 are the likely sites for oxidation based on the unfavourable electronic and steric factors at the other sites. They calculated the site selectivity ratio to be 1 : 1.3 (C-9 : C-10) using the [(S),(S)-Fe^II(PDP)] catalyst and their model. Thus, C-10 is the most appropriate site for oxidation according to their model. Experimentally, 54% yield of the (+)-10-β-hydroxy-artemisinin was obtained together with 23% yield of (+)-9-oxo-artemisinin in a 2 : 1 (C-10 : C-9) ratio. On the other hand, the same reaction with the [(S),(S)-Fe^II(CF₃PDP)] catalyst showed the calculated site selectivity ratio of 17 : 1 (C-9 : C-10). Thus, it favours oxidation at the C-10 position based on the large steric difference parameter, affording 52% yield of (+)-9-oxo-artemisinin as the major product (Scheme 99).

Scheme 98 Trajectory restriction strategy for catalyst control of C–H oxidation.

Scheme 99 Overriding of the inherent site selectivity of C–H bond oxidation.

Imide-containing heterocycles diminish the basicity of nitrogen due to the presence of two carbonyl moieties at both adjacent positions of nitrogen (Scheme 100).¹⁴⁰ Consequently, they tolerate the oxidative condition and promote remote C(sp³)–H functionalization without the addition of any additives. The same reaction protocol with a strong Brønsted acid having a strong coordinating counterion (e.g. triofluoroacetic acid or sulphuric acid) is not an effective additive to provide the desired product. Both substituted piperidine and pyridine are well tolerated under the oxidative condition of the reaction. Selective oxidation of the remote 3° C(sp³)–H bond is observed with the Fe^II(PDP) catalyst in the presence of additives and H₂O₂/ACOH as the oxidant, without the detection of either the benzylic or methylenic oxidation product. On the other hand, the 2° C(sp³)–H oxidized product is obtained with high selectivity in the presence of the Fe^II(CF₃PDP) catalyst and H₂O₂/ACOH as the oxidant system together with the aforementioned additives.

Scheme 100 Strategy for the remote aliphatic C–H bond oxidation in nitrogen-containing molecules.

Although the yield of the isolated product decreases using HBF₄ as an additive, it has advantages in the presence of sterically hindered substituents attached to nitrogen, causing retardation in effective BF₃ co-ordination. The remote oxidation product was obtained in good yield with electron-rich pyridine, whereas a lower yield of product was obtained in the presence of electron-deficient substrates. Oxidation in the late-stage diversification of medicinally important complex molecules has been performed using the aforementioned nitrogen tolerance strategies in the presence of either [Fe^II(PDP)]²⁺ or [Fe^II(CF₃PDP)]²⁺ catalyst. For instance, in general, streptovitacin is obtained via an eight-step de novo synthesis with 7% overall yield. However, it can be prepared via the direct one-step oxidation of cycloheximide in the presence of [Fe^II(S,S)-PDP]²⁺ catalyst in excellent yield (50%) using the above mentioned reaction protocol (Scheme 101).

Scheme 101 Late-stage functionalization of nitrogen-containing molecules.

Further in 2016, the oxidative diversification of amino acids and peptides by the aforementioned two small molecule catalysts, [Fe^II(PDP)]²⁺ and [Fe^II(CF₃-PDP)]²⁺, was reported. These catalysts are capable of facilitating targeted C–H bond oxidative modification with the retention of the α-centre chirality (Scheme 102).¹⁴¹ Oxidation of proline to 5-hydroxyproline is furnished via the formation of versatile intermediates. These intermediates are transformed to rigid arylated derivatives or flexible linear carboxylic acids, olefins, alcohols and amines in both monomer and peptide forms. This C–H bond oxidation strategy has the capacity for generating diverse amino acids and peptide molecules. Subsequently, four ‘chiral pool’ amino acids were converted into twenty-one chiral unnatural amino acids. The newly formed unnatural amino-acids represent seven distinct functional group arrays. Moreover, late-stage C–H functionalization of single proline-containing tripeptide resulted in the formation of eight tripeptides. Each of the tripeptides belongs to different unnatural amino acids. Additionally, a macrocyclic pentapeptide containing a proline moiety was transformed to a product containing linear unnatural amino acids via late-stage C–H bond oxidation.

Scheme 102 Iron-catalysed pre-assembly oxidative modification of proline.

In 2016, Costas and Gebbink developed another set of chiral non-heme iron catalysts, [Fe^II(^tipsMCP)(OTf)₂] 1 and [Fe^II(^tipsPDP)(OTf)₂] 2, containing sterically bulky chiral ligands for executing the regioselective oxidation of alkyl C–H bonds in the presence of H₂O₂ as an oxidant.¹⁴² These bulky chiral ligands were synthesized by introducing the bulky tris(isopropyl)silyl (TIPS) moiety at the meta-position of two pyridine rings of chiral tetradentate aminopyridine ligands, PDP and MCP. The corresponding iron catalysts 1 and 2 and their enantiomeric analogues are employed for C–H oxidation reactions (Scheme 103). Notably, both iron catalysts have backbones with different natures and exhibit a well-defined and constrained envelope around the cis-labile position of the iron centre, where the reactive Fe=O unit is formed upon reaction with H₂O₂. Interestingly, while executing the C–H oxidation of different substrates, the bulkier TIPS-substituted catalysts, Λ-^tips1 and Λ-^tips2, provided better yields of the corresponding C–H oxidized product compared to the unsubstituted iron catalysts, Δ-1′ and Δ-2′. Further, they performed control experiments with two iron catalysts, 1 and 2, to examine the ability of the catalysts to differentiate between secondary and tertiary C–H bonds (2°/3°). Additionally, they envisaged the role of the ligand backbone of the catalysts in discriminating two different methylenic sites differing in steric hindrance (K₃ and K₂, Scheme 103). To elucidate the above cases, the C–H oxidation reaction between catalysts and trans-1,2-dimethylcyclohexane is discussed.

Scheme 103 Schematic diagram of iron catalysts 1 and 2 and their catalytic reactivity.

Interestingly, catalyst Λ-^tips1 preferentially oxidises secondary C–H bonds over tertiary C–H bonds (with a ratio of C–H oxidation products of 2°/3° = 13) during the reaction with trans-1,2-dimethylcyclohexane, whereas catalyst Λ-1′ shows slow selectivity between secondary and tertiary C–H bonds (ratio of C–H oxidized products of 2°/3° = 3). Notably, the similar reactions with catalysts Λ-^tips2 and Λ-2′ provide the secondary and tertiary C–H oxidized products with the ratio of 2°/3° = 4 and 2°/3° = 1, respectively (Scheme 103). Further, a better ratio of different methylenic sites, K₂ and K₃ oxidized products, is obtained with the bulkier catalyst, Λ-^tips1 (K₃/K₂ = 3), compared to the unsubstituted catalyst, Λ-1′ (K₃/K₂ = 1.9). Thus, the discrimination between different methylenic sites is improved by the introduction of steric bulk in the catalyst, Λ-^tips1. Here, the nature of the backbone and rigidity present in the system play a significant role in determining the selectivity. Moreover, they accomplished the site-selective oxidation between the methylenic sites of terpenoid and steroidal substrates using all the catalysts. Notably, they observed unprecedented site selectivity during C–H oxidation of trans-androsterone acetate (Scheme 104). In this substrate, the C6 and C12 methylenic sites are oxidized by employing the four chiral catalysts, Λ-^tips1, Δ-^tips1, Λ-^tips2 and Δ-^tips2. Interestingly, the Λ-^tips1 and Λ-^tips2 catalysts preferentially oxidise the C6 site, whereas Δ-^tips1 and Δ-^tips2 oxidize the C12 site. Thus, the present study revealed the role of the chirality of the ligand backbone present in the catalyst in determining the site selectivity during product formation.

Scheme 104 C–H oxidation of trans-androsterone acetate and site selectivity.

Furthermore in 2016, Basallote, Company and Costas reported the reaction of [Fe^II(PyNMe₃)(CF₃SO₃)₂] with an excess amount of peracetic acid, resulting in the formation of a meta-stable compound existing as a pair of electromeric species, [Fe^II(PyNMe₃)(OOAc)]²⁺ and [Fe^V(PyNMe₃)(O)(OAc)]²⁺, in fast equilibrium (Scheme 105).¹⁴³ Species 2 (2a and 2b) is kinetically competent for oxidising strong olefinic C–H bonds (with bond dissociation energies of up to 100 kcal mol⁻¹) through the initial hydrogen atom transfer (HAT) mechanism. Notably, oxygen atom transfer (OAT) from the pair of electronic species occurs extremely fast in the olefinic substrate to generate epoxide. This was confirmed by stopped-flow UV-vis analysis. The rate of epoxidation of olefin depends on the electron density of the olefin substrate. More substituted double bonds show a faster rate due to the inductive effect (+I) of the substituents, causing the accumulation of more electron density at the double bond.

Scheme 105 Non-heme iron-catalysed oxygen atom transfer to olefin.

The above-mentioned statement also supports the electrophilic character of the Fe^V=O species generated during oxygen atom transfer (OAT) in the course of epoxidation.

In 2017, Sengupta and co-workers reported a synthetic method describing a peroxidase-mimicking iron complex, [Fe^III(b-TAML)(OH₂)], which catalyzed the photocatalytic hydroxylation and epoxidation of alkanes and alkenes.¹⁴⁴ Here, [Ru^II(bpy)₃]Cl₂ and [Co^III(NH₃)Cl]Cl₂ were used as the photosensitizer and one-electron acceptor in acetonitrile–phosphate buffer solution, respectively. Notably, water was used as the oxygen atom source (Scheme 106). This was confirmed by an H₂O¹⁸ labelling experiment. More than 90% of the ¹⁸O-labelled oxygen atoms were incorporated in the hydroxylated and epoxide product. The high electron-donating tetra-anionic N-donors stabilised the high-valent iron–oxo species such as [Fe^V(b-TAML)(O)]⁻ and [(b-TAML)Fe^IV(O)]²⁻, which selectively catalysed the oxidation of the unactivated alkanes and alkenes. The hydroxylation of unactivated alkanes having several substrates including natural products was mostly observed at the tertiary C–H bond with 3° : 2° selectively up to ∼100 : 1. Mechanistically, an active [{(b-TAML)Fe^IV}₂-μ-oxo]²⁻ (2) dimer is generated from the starting complex (1) via one-electron and one-proton transfer (proton-coupled electron transfer, PCET) process. The subsequent disproportionation of 2 occurs upon the addition of the substrate, assisting the generation of Fe^V=O species via the regeneration of 1 (Scheme 107).

Scheme 106 Photocyclic oxygenation of hydrocarbons.

Scheme 107 Proposed mechanism of photocatalytic C–H oxidation.

In the same year, they developed an iron-catalyzed synthetic protocol describing peroxidase-mimicking chemistry using an iron catalyst-containing biuret-modified TAML macrocyclic ligand framework (NO₂-b-TAML) (Scheme 108). The modified iron catalyst, NO₂[Fe^III-(b-TAML)(Cl)]²⁻, can carry out the selective oxidation of unactivated 3° C–H bonds and activated 2° C–H bonds with a low catalyst loading (1 mol%). This synthetic protocol provides high product yield with excellent mass balance and configuration retention using m-CPBA as an oxidant under near-neutral conditions.¹⁴⁵ Notably, selective 3° C–H bond oxidation occurs at a faster rate in the case of the cis-isomer than the trans-isomer. This can be attributed to the reactivity of both isomers, including the strain present in the system, which is released in the transition state of the cis-isomer.

Scheme 108 Iron-catalyzed selective C–H bond oxidation.

Moreover, the selectivity between aliphatic C–H bond oxidation of the 3° and 2° sites of any complex molecule is predicted based on the electronic, steric, and stereo-electronic effect. The high selectivity using this reaction protocol is due to the involvement of high-valent iron(IV)–oxo intermediates instead of organic radicals. For example, the complex molecule (+)-artemisinin having five 3° C–H bonds together with the fragile endoperoxide moiety affords (+)-10-β-hydroxyartemisinin in 38% yield. Further, the oxidation of the α-ethereal C–H bond (activated 2° C–H bond) occurs exclusively in the case of ambroxide, having nine possible sites of oxidation (Scheme 109). Notably, this is in contrast to the oxidation by PDP complexes reported by White and co-workers.¹³⁷

Scheme 109 Oxidation of C–H bonds in complex natural molecule by an iron catalyst.

Overall, a total of 18 substrates including arenes, N-heterocycles and polar functional groups are well tolerated under the optimized reaction conditions. However, although White and co-workers¹⁴⁰ reported remote C–H bond oxidation having basic heteroaromatic nitrogen groups in the presence of Brønsted and Lewis acids as additives, the aforementioned method using the NO₂[Fe^III-(b-TAML)(Cl)]²⁻ catalyst provides remote C–H bond oxidation (Scheme 110) without the use of Brønsted and Lewis acids as additives.

Scheme 110 Oxidation of 3° C–H bonds in the presence of N-heterocycles with NO₂[Fe-(b-TAML)] complex.

Thus far, the discussed non-heme iron catalysts have been utilized for the selective C–H oxidation of natural products. Fascinatingly, besides this, some artificial enzymes have been developed for the selective oxidation of a highly conjugated norditerpene alkaloid isolated from the Nigella glandulifera plant. In 2017, Arnold and Stoltz reported the first enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A through biocatalytic late-stage C–H bond oxidation using an iron co-factor containing artificial metalloenzymes, i.e. engineered cytochrome P-450 (8C7) enzyme, in 12 steps with an overall yield of 5%.¹⁴⁶ This method leads to chemo as well as regioselective allylic 2° C–H bond oxidation even in the presence of four other oxidisable positions. Noticeably, this enzymatic technique provides a turnover of up to 1700 to the C-7 mono-oxygenation product (Scheme 111). Importantly, the other reported traditional chemical oxidation methods^147,148 failed to give the desired C–H bond oxidation product.

Scheme 111 Synthesis of nigelladine A via engineered cyt P-450.

In 2019, Han and co-workers reported an iron-catalyzed efficient methodology for the oxidation of methylarenes and alkylarenes to deliver arylaldehydes, arylketones and aryl esters efficiently.¹⁴⁹ They employed a combination of iron(II) phthalocyanine (1 mol%) and ferrocene (10 mol%) as a catalyst in the presence of K₂S₂O₈ (1 equiv.) as an oxidant, together with polymethylhydroxy silane (PMHS) as an activator. Moreover, the reaction was carried out in a CH₃CN/H₂O (1 : 1) solvent mixture under ambient air (1 atm of O₂) at 80 °C (Scheme 112). Interestingly, toluenes bearing electron-donating groups such as methyl, polymethyl, 4-tert-butyl, and diethylphenyl phosphate produced the desired selective oxidized product in high yield (86–92% yield). Also, electron-withdrawing substituents (bromo, iodo, sulfonyl, etc.) containing toluene derivatives provided the desired arylaldehyde at a slow reaction rate with high yield (60–94% yield) in the presence of an increased amount of oxidant (3 equiv. of K₂S₂O₈). Remarkably, the one-step oxidation of methylthiophenes to the corresponding thenaldehydes (90% yields) was achieved using this reaction protocol. Importantly, thenaldehydes are widely used for the synthesis of the chemotherapeutic medicine teniposide, a common hepatoprotectant tenylidone, and the insectifuge pyrantel.

Scheme 112 Iron-catalyzed oxidation of methyl aromatics.

Most intriguingly, the present methodology has been found to be compatible in the presence of unprotected boronic acids, which are very sensitive towards reagents such as bases, organic acids and oxidants due to unstable tricoordination nature of the boron centre.¹⁵⁰ Thus, the present protocol chemoselectively oxidizes the aromatic methyl moiety in the presence of boronic acid to generate carbonyl compounds in good to excellent yields. Notably, for this particular type of reaction, they utilized FeCl₂ (10 mol%) as the catalyst instead of the combination of ferrocene, iron(II) phthalocyanine and tetra-butyl ammonium bromide (TBAB), in the presence of the same oxidant/PMHS/solvent system. Notably, aldehydoarylboronic acids have high synthetic versatility due to the presence of both nucleophilic (C–B bond) and electrophilic (C=O bond) moieties. The robustness of this reaction protocol leads to the late-stage oxidation of complex molecules such as dehydroabetic acid, gemfibrozil, and tocopherol nicotinate.

Mechanistically, the reaction is initiated via oxidation of the Fe(II) center by persulfate to form Fe(III) species and sulfate radical anion I (Scheme 113). Notably, this Fe(III) species is further reduced for the regeneration of Fe(II) species in the presence of PMHS. Then, radical I reacts with alkylarenes via the single-electron transfer mechanism (SET) to generate alkylaromatic cation II. This cation is very acidic and readily eliminates benzylic hydrogen for the further formation of intermediate radical III. Notably, the formation of radical intermediate III was confirmed by trapping it with the radical scavenger 2,2,6,6-tetramerthylpiperodinooxy (TEMPO). Subsequently, radical intermediate III reacts with molecular oxygen (O₂) to form benzyl peroxide radical IV followed by abstraction of hydrogen from PMHS. Thereafter, hydroperoxide V undergoes the elimination of water molecule for the formation of the desired aryl aldehydes.¹⁵¹ However, the possibility of self-reaction of two benzyl peroxide radicals IV cannot not be excluded during the formation of the aldehyde.¹⁵²

Scheme 113 Mechanistic pathway of iron-catalyzed oxidation of methyl aromatics.

Very recently in 2020, Costas and co-workers introduced another synthetic method describing an iron complex, (R, R)-Fe^tipsPDP(OTf)₂ (Λ-^tips2), catalysed site and product chemoselective aliphatic C–H bond oxidation of polyfunctional substrates in the presence of hydrogen peroxide as a terminal oxidant and fluorinated alcohol as the solvent (Scheme 114).¹⁵³ The reaction is performed in the presence of a fluorinated solvent such as 1,1,3,3,3,3-hexafluoro-2-propanol (HFIP), exhibiting a strong polarity reversal in the hydroxyl moiety of 1,2-diols due to hydrogen bonding. This hydrogen bonding strongly deactivates the proximal C–H bonds, and thus inhibits proximal C–H bond oxidation. Further, this methodology provides access to the predominant hydroxylation of remote and non-activated C–H bonds, providing orthogonal chemo-selectivity to existing alcohol oxidation methods (Scheme 114). Furthermore, this reaction protocol was successfully applied for executing C–H oxidation of sugars, steroids and other densely functionalized substrates without protecting the hydroxyl functionalities. For example, the anticancer drug capecitabine composed of a highly polar functional group-enriched core together with an oxidation-sensitive five-member cyclic ether possessing a tertiary C–H bond at the γ position and syn 1,2-diol at the α and β positions are well tolerated under the standard reaction conditions. Noteworthily, the cyclic ether moiety is connected to a fluorinated N-heterocyclic moiety connected to an alkyl carbamate moiety. Also, several 4, 5, 6-member metal chelating units are present, having the ability to deactivate the metal catalyst (Scheme 115). However, despite these complexities, capecitabine undergoes hydroxylation (50% yields) at the remote methylenic sites of the alkyl chain (68% conversion) together with the formation of 12% of the corresponding carbonyl compound, keeping the densely functional core intact.

Scheme 114 C–H oxidation of polyhydroxylated molecules and its possible mechanism.

Scheme 115 Iron-catalyzed oxidation of capecitabine.

2.2.1.3 Catalytic methods for the formation of C(sp³)–C bond via iron–carbene intermediate. Although, enzymatic and small molecule iron catalysts are capable of C(sp³)–H oxidation involving high valent iron–oxo complexes, the catalytic transformation of the C(sp³)–H bond to a C(sp³)–C bond via an iron–carbene intermediate has been a long-term challenge for chemists. However, in 2017, White and co-workers reported the iron phthalocyanine-catalyzed allylic and benzylic C(sp³)–H alkylation via an isoelectronic iron–carbene intermediate.¹⁵⁴ The electrophilicity of a disubstituted diazo compound having a benzylic or allylic moiety enhances the reactivity by producing a strongly electrophilic metallocarbene. Subsequently, the metalocarbene is involved in the C–H bond insertion pathways. Notably, sulfonate ester diazo-precursors are found to be the best diazo compound, producing strongly electrophilic metallocarbene and increasing the C–H alkylation reactivity according to the results obtained via¹³C-NMR spectroscopy (Scheme 116).

Scheme 116 Catalytic C(sp³)–H alkylation via an iron–carbene intermediate.

Moreover, the catalyst [PcFe^III]Cl having π-accepting character in the presence of non-coordinating counterions make it more electrophilic, leading to a significant increase in the yield of the C–H insertion product with excellent selectivity. After precise investigation of the non-coordinating counterion to enhance the electrophilic character of the iron catalyst, NaBAr^F₄ exhibits the best result as a coordinating counter ion to increase the yield of the insertion product. Mechanistically, an electrophilic iron–carbene intermediate initiates the homolytic C–H bond cleavage. Then the organo-iron intermediate undergoes the radical rebound mechanistic pathway to form the C–C bond. A stabilized allylic radical is preferred over the secondary aliphatic radical formed during the stepwise olefin oxidation process (Scheme 117). Interestingly, the reaction proceeds via a stepwise mechanistic pathway, which was concluded from the results of the kinetic isotope effect study. The stepwise mechanistic pathway actually improves the chemoselectivity for C–H insertion over cyclopropanation compared to the rhodium catalyst pathway. The intermolecular KIE study indicated C–H bond cleavage is involved in the rate-determining step of the reaction. Notably, scrambling of the olefin geometry is observed using [PcFe^III]Cl as the catalyst, which is consistent with the more stable allylic radical intermediate. The extent of olefin isomerisation is dependent on the electronic substitution of the ligand.

Scheme 117 Mechanistic hypothesis of catalytic C(sp³)–H alkylation via an iron–carbene intermediate.

2.2.1.4 Wacker-type oxidation. The palladium (Pd)-catalyzed oxidation of olefins to carbonyl compounds is known as Wacker–Tsuji oxidation. It involves substrates that are readily available, inexpensive and thermally-air and water stable. This oxidation protocol is one of the most straightforward strategies for the preparation of carbonyl compounds. It has wide application in the synthesis of natural products, pharmaceuticals, and commodity chemicals. However, this type of oxidation also has some limitations. The oxidation of electron-deficient internal alkenes cannot be achieved by this process due to the increase in congestion and decrease in electron density of the double bonds, leading to the strong reluctance to generate the η²-Pd olefin complex. Although, Pd-catalyzed Wacker oxidation for the formation of carbonyl compounds from olefin compounds is well known, the late transition metal Pd is very toxic, inexpensive and has low abundance in the Earth's crust. Therefore, the development of alternative catalysts based on the cheap, non-toxic, earth abundant transition metals is of immense importance. Although iron-catalyzed Wacker oxidations are very rare, Che and co-workers¹⁵⁵ in 2011 reported the iron-catalyzed anti-Markovnikov oxidation of terminal alkenes to aldehydes using iodosylbenzene as an oxidant via a tandem epoxidation–isomerization (E–I pathway) pathway. The iron(III) porphyrin complex [(2,6-Cl₂TPP) Fe(OTf)] was employed as the catalyst, delivering the desired product regioselectively in good yield (Scheme 118).

Scheme 118 Iron-catalyzed Wacker-type oxidation of styrene using iodosylbenzene.

In 2012, Lahiri and co-workers reported an efficient method of iron-catalyzed regioselective oxidation of styrene with the anti-Markovnikov formation of acetal.¹⁵⁶ This method utilizes an iron catalyst, Fe(BF₄)₂·6H₂O, in the presence of pyridine-2,6-dicarboxylic acid as the supporting ligand and iodobenzenediacetate (PhI(OAc)₂) as an oxidant in methanol under aerial circumstances (Scheme 119). Further, the use of a dehydrating agent, molecular sieves (3 Å), in the reaction is crucial to achieve better yield of the desired product by minimizing the rearranged product. A wide range of different aromatic and aliphatic cyclic olefins are well tolerated chemoselectively to provide the terminal acetals. In contrast to the anti-Markovnikov selectivity observed in the present method, the palladium-catalyzed acetilization reaction provides Markovnikov selectivity.¹⁵⁷

Scheme 119 Iron-catalyzed oxidation of olefin to aldehyde with anti-Markovnikov selectivity.

Based on the literature, a plausible mechanism for this reaction was suggested. It is believed that the reaction proceeds via the generation of iron–oxo intermediate I, which reacts with the olefin in a side-way approach to generate intermediate II, followed by a 1,2-hydride shift and two successive solvent nucleophilic attacks at the β position from intermediate III, leading to the formation of the desired product (Scheme 120).

Scheme 120 Iron-catalyzed oxidation of olefin to aldehyde with anti-Markovnikov selectivity.

In the same year, they developed another method of regioselective oxidation of terminal alkenes to aldehyde using the same iron catalyst and supporting ligand in the presence of iodosyl benzene as the oxidant in chloroform.¹⁵⁸ Different aromatic, aliphatic and terminal olefins together with alkenyl olefins were found to be compatible under the standard reaction conditions (Scheme 121). Based on the experimental results and literature reports, the tentative mechanism of the reaction was proposed, involving two possible pathways, namely tandem epoxidation–isomerization (pathway a) and pinacol-like rearrangement (pathway b) (Scheme 122).^159,160

Scheme 121 Iron-catalyzed oxidation of olefin to aldehyde with anti-Markovnikov selectivity.

Scheme 122 Iron-catalyzed oxidation of olefin to aldehyde with anti-Markovnikov selectivity.

Earlier in 2011, Che and co-workers studied the iron–porphyrin catalyzed anti-Markovnikov oxidation of both terminal aryl and aliphatic olefins to aldehyde using PhIO as an oxidant.¹⁶¹ However, due to the shortcoming of using PhIO as an oxidant, in 2014, they synthesized an iron-catalyst, [Fe^III(TF₄DMAP)OTf], in the presence of H₂O₂ as the terminal oxidant for the anti-Markovnikov oxidation of terminal aryl alkenes to aldehydes (Scheme 123).¹⁶² It has been presumed that initially [Fe(Por)]⁺ is converted to the [Fe(O)(Por)] complex in the presence of H₂O₂, which takes part in the reaction with terminal aryl alkenes to afford the corresponding epoxide, followed by the regeneration of the [Fe(Por)]⁺ complex, inducing isomerization of the epoxide to the desired product.

Scheme 123 Iron-catalyzed anti-Markovnikov addition of terminal alkenes.

Significantly, similar to C–H oxidation, iron co-factor-containing artificial metalloenzymes can also be used in the anti-Markovnikov oxidation of olefins. In 2017, Arnold and co-workers reported the high-valent metal–oxo-mediated anti-Markovnikov oxidation of alkenes using an engineered cytochrome P-450 (aMOx) enzyme in combination with alcohol dehydrogenase (ADH) and oxygen as a terminal oxidant.¹⁶³ Generally, the high-valent metal–oxo-mediated reaction proceeds via the concerted epoxidation pathway having a low energy barrier, resulting in the formation of the epoxidation product. However, this reaction also provides the direct anti-Markovnikov oxidation product when it proceeds via the formation of the high energy carbocationic intermediate (Scheme 124). This unstable intermediate is stabilised via 1,2-hydride migration, which was also confirmed by an isotopic labelling study. Noteworthily, the asymmetric induction in the case of this methodology arises due to the 1,2-hydride migration. Moreover, the enantioselectivity originates from the locked arrangement of the substrates in a specific conformation, which aligns one of the C–H bonds coplanar to the empty p orbital of the carbocation intermediate. Notably, a wide variety of styrenes are oxidized to the anti-Markovnikov carbonyl product with a TTN of 3800 and 81% selectivity. The para-substituted styrenes are converted into the desired products with high selectivity, while that with meta and ortho substitutions exhibit a lower level of selectivity (Scheme 125). Accordingly, this suggests that the direct anti-Markovnikov oxidation is a catalyst-controlled process, which depends on the exact orientation of the substrate to prevail over epoxidation.

Scheme 124 Mechanistic pathway of epoxidation and anti-Markovnikov oxidation.

Scheme 125 anti-Markovnikov hydration of alkenes via aMOx.

Subsequently, influenced by the chemistry of cytochrome P-450^163,164 and the recent reports published by Barton and co-workers,¹⁶⁵ Han et al. first developed an iron-catalyzed highly efficient and selective oxidation protocol. Here, polymethylhydroxysilane (PMHS) is used as the reductant in alcohol for the aerobic oxidation of styrene, internal olefins and electron-deficient aryl olefins to ketones (Scheme 126).¹⁶⁶

Scheme 126 Iron-catalyzed Wacker-type oxidation in ambient air.

Subsequently, the substrate scope was tested under the optimized reaction conditions. A series of styrenes that are normally challenging substrates for the Wacker oxidation were found to afford the desired product in good to excellent yield with excellent selectivity. Substrates having electron-donating substituents and electron-withdrawing substituents in the aryl rings give a comparative yield. Moreover, a wide range of functional groups such as halo groups (Cl, Br, and I), esters, benzyl chloride, nitro group and carboxylic acids are well tolerated. Particularly, the presence of several readily oxidizable groups such as aldehyde, phenol, silane, and arylboronic acids and strong coordinating pyridyl groups are well tolerated. Notably, under slightly modified conditions, i.e. using Fe(acac)₂ as the catalyst and t-BuOH as the solvent, aliphatic terminal olefins undergo smooth conversion into the expected ketone with complete Markovnikov selectivity. In contrast to Pd-catalyzed Wacker-type oxidation, electron-deficient internal alkenes such as trans-benzylideneacetone and heterocyclic trans-4-(2-thienyl)-but-3-en-2-one undergo the reaction to produce the desired product. Additionally, an aliphatic internal alkene, (3Z)-hept-3-en-1-ol, which is completely unreactive, was reported by Sigman¹⁶⁷ and co-workers to be an efficient substrate exhibiting sufficient reactivity. Moreover, this synthetic protocol is applied for the oxidation of natural products and synthetic compounds with high complexity. For instance, a derivative of the antibacterial drug pleuromutlin underwent the reaction protocol to deliver the desired oxidized product in 70% yield. The mechanistic pathway of the iron-catalyzed Wacker-type oxidation of olefins to ketones using molecular oxygen as the sole oxidant in the presence of reductive silane is shown in Scheme 127.

Scheme 127 Proposed mechanistic pathway of iron-catalyzed aerobic Wacker-type oxidations of olefins.

Initially, the olefin reacts with iron(III) hydride to generate the alkyl iron-intermediate. The iron–hydride is formed from the reaction between the iron(II) salt and hydrosilane. Notably, the best catalytic efficiency is shown by FeCl₂ towards this transformation. The reaction intermediate with oxygen generates the carbon-centered radical, followed by the generation of an iron–peroxide complex. At this stage, the iron–peroxide complex undergoes a concerted pathway with simultaneous O–O and C–H bond breaking to afford the ketone product via the formation of the Fe(III)–OH species. The Fe(III)–OH species is reduced by hydrosilane to regenerate the Fe(II) catalyst. The intermediate carbon-centred radical was intercepted with the radical scavenger galvinoxyl. Thus, this suggests that the reaction proceeds via the radical pathway. Furthermore, no deuterium was incorporated in the product using EtOD as the solvent, while 96% deuterium was incorporated at the α-position of the ketone using (EtO)₃SiD as the silane. This indicates the addition of hydrogen across the olefin from the hydrosilane.

The Wacker-type oxidation of 1-decene to 2-decanone by di-oxygen catalyzed by Pd(OAc)₂, hydroquinone and iron(II) phthalocyanin (FePc) in acidic aqueous dimethylformamide was reported by Ford and co-workers in 1990.¹⁶⁸ The transformation provides high yield at room temperature within 40 min. The factors controlling the activity of the multi-component catalyst are the structure and morphology of the FePc catalyst. The iron catalyst exists in the β-FePc form and dimeric-μ-oxo diiron FePc species. The dimeric μ-oxo form of the FePc catalyst is highly active due to its high surface area and less crystalline character than the other possible form. However, the scope for oxidation using this synthetic method is limited by the solubility of 1-decene in aqueous DMF.

Subsequently, in 2018, Knölker and co-workers developed a mild and operationally simple procedure with excellent chemoselectivity and functional group tolerance.¹⁶⁹ In this reaction protocol, they used a hexadecafluorinated iron–phthalocyanine complex (PcFeF₁₆) (Fig. 5) as the catalyst with a stoichiometric amount of triethylsilane as an additive in the presence of molecular oxygen for the oxidation of olefin into ketones with good to high yields (Scheme 128).

Fig. 5 Structure of iron–phthalocyanine and hexadecafluorinated iron–phthalocyanine catalyst.

Scheme 128 Iron-catalyzed Wacker-type oxidation using oxygen as the sole oxidant.

This catalytic system shows better reactivity than FePc due to its better solubility in ethanol and the electron-withdrawing effect of its fluorine substituents. Notably, the ketone product is obtained in up to 95% yield with 100% regioselectivity, while the corresponding alcohol is obtained as the side-product. Mechanistically, a μ-oxo-bridged diiron complex is initially formed from the parent iron–phthalocyanine complex (Scheme 129). The corresponding diiron complex was also detected by ESI mass-spectroscopy. This diiron complex undergoes formal dissociation to generate two iron complex fragments. Then, the nucleophilic attack of the anionic species at the silicon atom of the triethylsilane leads to the formation of a pentavalent silicon anion intermediate, providing an iron(III) hydride species via the hydride transfer to the cationic species. The Fe(III)–hydride complex transfers the hydrogen atom to the alkene. Thereafter, it follows the same mechanistic pathway mentioned in Scheme 127.

Scheme 129 Proposed mechanistic pathway for the Fe(Pc)F₁₆-catalyzed oxidation of olefins to ketones.

2.2.1.5 Baeyer–Villiger-type oxidation. Adolf Baeyer and Victor Villiger discovered the oxidation of menthone to the corresponding lactone using a mixture of sodium persulfate and concentrated sulphuric acid. Thereafter, this persulfuric acid was replaced by other organic per-acids such as m-CPBA, trifluoroperacetic acid and perbenzoic acid. Thus, the conversion of ketone into the ester in the presence of per-acid as an oxidant has become one of the most well-known and widely applied organic reactions, which is known as Baeyer–Villiger (B–V) oxidation. However, the organic peracids used in the oxidation reactions are hazardous and expensive. Thus, using clean and inexpensive oxidants is extremely significant and attractive from an environmental and economic viewpoint. The aerobic Baeyer–Villiger (B–V) oxidation of ketones in the presence of aldehyde was reported using Fe₂O₃ and Fe–MCM-41 under heterogeneous conditions.¹⁷⁰ However, the drawback of the MCM-41 system is its unidirectional pore system. Thus, to overcome this drawback, Koodali and co-workers in 2008 discovered a highly active mesoporous catalyst, Fe-MCM-48, for the Baeyer–Villiger oxidation of cyclohexanones and the bulky molecule 2-adamantanone system.¹⁷¹ The catalyst can be reused for at least three catalytic cycles without any loss in activity. Notably, cubic MCM-48 with its interwoven and continuous 3D regular pore system provides favourable mass-transfer kinetics and is a better candidate for catalytic applications. Powder XRD (X-ray diffraction) and DR (diffuse reflectance) studies indicated the incorporation of Fe³⁺ into the silica pore wall in a tetrahedral position. Moreover, this material has a large surface area (1979 m² g⁻¹) and large pore volume (1.2 cm³ g⁻¹).

In biology, oxygenase enzymes such as cytochrome P-450 carry out the oxygenation of different bio-molecules.¹⁷² Inspired by these enzymes, Ji et al. in 2008 reported the highly efficient selective Baeyer–Villiger (B–V) oxidation for the first time using iron(III)–meso-tetraphenylporphyrin [(TPP)Fe^IIICl] with molecular oxygen in the presence of benzaldehyde for the conversion of ketones into lactones (Scheme 130).¹⁷³ Notably, the oxidation of cyclohexanone catalyzed by the iron metalloporphyrin involves radical species. Thus, toluene was used as the solvent for the transformation due to its reluctance to undergo radical addition. However, although different metals (Ru, Mn, Fe, and Co) were tried with the TPP ligand, iron showed the best efficacy for the oxidation reaction. The reason for this is that the catalytic activity and selectivity of different metalloporphyrins depend on the stability of the different valences of their metal atoms and their electric potentials. Notably, cyclic ketones are more efficiently oxidized than acyclic ketones. Moreover, six-membered cyclic ketones are the most efficient among the cyclic ketones to generate the corresponding oxidized products. The turnover number (TON) of the (TPP)FeCl catalyst can be maximized to 71 000 for the large-scale oxidation of cyclohexanone.

Scheme 130 Aerobic oxidation of ketones catalyzed by iron(III) meso-tetraphenylporphyrin chloride.

Here, ε-caprolactone was obtained in 96% yield in the presence of benzaldehyde, while the use of isobutyraldehyde afforded the product in only 11% yield. To investigate this difference, they further studied the mechanistic pathway. Based on the results of in situ FTIR, UV-vis spectroscopy and starch/KI experiments, they proposed the mechanistic pathway (Scheme 131).¹⁷⁴ In the initial step of the mechanistic pathway, the iron–porphyrin reacts with the aldehyde to generate the acyl radical, which reacts with the molecular oxygen to give the acyl peroxy radical. The resultant acyl peroxy radical as a carrier in the chain mechanism reacts with another molecule of aldehyde to generate peroxybenzoic acid. The peroxybenzoic acid is involved in two pathways, A and B, in the presence of benzaldehyde and isobutyraldehyde, respectively. In the presence of benzaldehyde (pathway A), it reacts with another iron–porphyrin molecule to generate a high-valent iron(V)–porphyrin intermediate via the elimination of benzoic acid. Then, the intermediate combines with cyclohexanone to take part in the oxygen transfer step, affording ε-caprolactone. However, in the presence of isobutyraldehyde (pathway B), peroxybenzoic acid attacks the activated ketone to generate a Criegee adduct, followed by protolysis to afford a lactone (Scheme 131).

Scheme 131 Probable mechanistic pathway of cyclohexanone to ε-caprolactone.

2.2.2 Iron-mediated C–H halogenations. Organic molecules containing carbon halogen bonds have immense importance both in biology and industry. More than 5000 natural products are known to contain carbon halogen bonds.¹⁷⁵ Among the many important and useful biologically active molecules containing carbon halogen bonds, some representative examples are vancomycin and chloramphenicol, which show antibiotic activity, whereas salinosporamide A acts as an anticancer agent.¹⁷⁵ Notably, if the halogen atom is removed from the structural motif of these molecules, they do not exhibit any activity. Further, halogenated compounds are extensively used as precursors for the synthesis of natural products, drugs and agricultural products due to the versatile reactivity of the C–X (X = Cl, Br, and F) bond.¹⁷⁶ Therefore, the catalytic transformation of C–H bond to the C–X bond via any synthetically viable method is very essential in organic synthesis.
2.2.2.1 Halogenations in Nature. Nature has the ability to synthesize all the useful bioactive molecules and valuable natural products containing carbon halogen bonds. There are several enzymes that perform halogenation in nature, such as (a) heme–iron peroxidaseses, (b) vanadium-dependent haloperoxidase, and (c) non-heme–iron halogenases.¹⁷⁵ Interestingly, these enzymes contain first row transition metals as a metal co-factor in their active sites. Among these enzymes, the heme and vanadium-dependent haloperoxidase enzymes perform non-specific halogenations in the presence of hydrogen peroxide at multiple sites of bio-molecules due to the release of hypohalous acid.¹⁷⁶ However, in the case of non heme–iron halogenase enzymes, molecular oxygen oxidizes the metal co-factor iron(II) centre and forms the high valent cis-iron(IV)–oxo–halide intermediate (S = 2), which performs regio- and stereospecific C–H halogenations of bio-molecules. For example, the α-keto glutarate (α-KG)-dependent non-heme halogenase enzyme performs C(sp³)–H halogenations by overriding hydroxylation reactions. This enzyme has been identified from SyrB2 during the biosynthesis of Syringomycin E.¹⁷⁵ The active site of this enzyme contains iron(II), which is coordinated with two histidine moieties, one aspartate moiety, one chloride and one water molecule (Scheme 132). Mechanistically, the iron–oxo–halide intermediate abstracts the hydrogen atom (HAA) from the C–H bond to generate a nascent radical and iron(III) halide species. This nascent radical and iron(III) halide complex are placed in the enzyme in such a way that the radical selectively undergoes rebound with the halide and provides the selective halogenated product.¹⁷⁷ The observed selectivity with halogenase enzymes via chloro rebound of the alkyl radical can be rationalised based on the following factors: (i) the relative differences in redox potential of the rebound site, i.e. between OH and X radical, (ii) the pattern of hydrogen bonding at the active site, (iii) the selectivity of enzyme due to the relative position of the substrate, (iv) dynamics in the rebound intermediate, and (v) deactivation of the hydroxyl group by protonation or CO₂ interference. Among them, the relative positioning of the substrate in the protein cavity is widely accepted for favouring selective halogen transfer.¹⁷⁸ However, the perfect positioning of the substrate between the halide and hydroxide in the absence of a protein chain is quite challenging, which is an unavoidable issue in the case of biomimetic synthetic analogues of non-heme iron(IV)–oxo halide complexes, resulting in the formation of a mixture of halogenation and hydroxylation products.

Scheme 132 Mechanism for halogenation by α-KG-dependent non-heme halogenase enzyme.

2.2.2.2 Bio-mimetic halogenations by synthetic non-heme iron complexes. Since the 1990s to the present, there have been extensive efforts to understand and mimic the active site structure and reactivity of halogenase enzymes. Thereafter, with the biomimetic synthesis mimic analogues of these enzymes, their functional reactivity have been tested. In this section, the attempts to mimic the structural and functional behaviour of iron-based non-heme halogenase enzymes are discussed.

In 1993, Que and co-workers first reported the synthesis and structure of biomimetic non-heme iron complexes, [Fe^III(TPA)X₂](ClO₄) [X = Cl, Br, and N₃] [TPA = tris(2-pyridylmethyl)amine]. Treatment of this complex in presence of stoichiometric amount of tert-butyl hydroperoxide, and subsequently cyclohexane affords cyclohexylbromide.¹⁷⁹ The kinetic isotope effect (KIE) between cyclohexane and d₁₂-cyclohexane (K_H/K_D = 7–10) suggests that a hydrogen atom abstraction (HAA) step is involved in the rate-determining step of this reaction. The observed values of KIE significantly vary with nature of the tripodal ligand system and halide groups. Thus, they proposed the involvement of iron(III)–alkyl peroxide I (Scheme 133) and high-valent iron(V)–oxo–halide intermediate II, where the iron centres coordinate with one halide atom. Initially they assumed that intermediates I and II can participate in the HAA step in the presence of the substrate (cyclohexane and adamantine) (Scheme 133). However, the experiments with different peracids having different R (R = tertiary-butyl, i.e. t-Bu, and cumyl group, i.e. [PhCMe₂]) groups do not affect the fate of the reaction.

Scheme 133 C–H halogenations by model high-valent non-heme iron–oxo model complex, [Fe^V(TPA)(O)(X₂)].

Thus, it was concluded that intermediate II does HAA from the C–H bonds of cycloalkanes. Further, they observed that the high efficiency of the ligand (X) is transferred to the substrates with respect to ROOH. Additionally, the lack of formation of the alkyl radical homocoupling product together with the failure of 4-methyl-2,6-di-tert-butyl phenol to affect the reaction supports that iron(IV)–oxo–hydroxo–halide species III and the radical remain in the cage. Then, the nascent radical reacts via the halide rebound pathway, resulting in the major halogenated products together with minor hydroxylation product. The observed selectivity was rationalized based on the difference in redox potential between chloride and hydroxide during radical transfer from the intermediate C (E_Cl˙/Cl⁻ = 1.36 V vs. NHE, E_HO˙/HO⁻ = 2.02 V vs. NHE).

In 2006, Que and co-workers synthesized and characterized Fe(IV)–oxo–halide complex 2, [Fe^IV(TPA)(O)X]⁺.¹⁸⁰ The presence of N,N,N-tris(2-pyridylmethyl)amine (TPA) as a ligand provides a tripodal topology around the iron centre having a labile sixth coordination site adjacent to the oxo group. Treatment of peracid and 3 equivalents of NR₄X (X = CF₃CO₂, Cl, and Br) with iron(II)-complex 1, [Fe^II(TPA)(NCMe)](OTf)₂, in acetonitrile at −40 °C affords a series of metastable [Fe^IV(TPA)(O)X]⁺ complexes 2 (Scheme 134). Spectroscopic studies and DFT calculation confirmed the cis geometry of the MeCN group with respect to the oxo ligand, which can be substituted by a chloride or bromide ion in the presence of NR₄X [X = Cl, and Br]. Later, they introduced the TMG₂dien [2′,2′-(2-2′-(methylazanediyl)-bis(ethane-1,2-diyl))bis(1,1,3,3-tetramethylguanidine)] ligand with Fe(II) for the synthesis of cis-[Fe^IV(TMG₂dien)(O)(X)]⁺5 (Fig. 6).¹⁸¹ In 2007, Noack and Seigbahn demonstrated that high valent [Fe^IV(TPA)(O)(Cl)]⁺2 (Scheme 134) is capable of stereospecific alkane chlorination involving a chloride anion rather than a chlorine radical¹⁸²via computational studies. Moreover, they also reported that the HAA step is the rate-determining step of the oxidative chlorination reaction and this reaction proceeds via the concerted mechanistic pathway. However, Visser¹⁸³ and co-workers reported that the stereochemistry significantly affects the selectivity based on a DFT study. The cis geometry of the oxo ligand with an amine-N ligand favours halogenation, while the trans geometry favours the hydroxylation reaction. Further, in 2010, Comba and co-workers developed the halogenation reaction of alkanes using a low molecular weight non-heme iron(II)-complex containing the bispidine ligand system (L = 3,7-dimethyl-9-oxo-2,4-bis(2-pyridyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate methyl ester).¹⁸³ They observed that the KIE value and yield ratio between the halogenated and hydroxylated products are sensitive towards the nature of the oxidant. This is due to the involvement of different high-valent iron intermediates, e.g. Fe^IV and Fe^V, and unwanted alkoxide radical (OR/OH radical in the case of oxidant-like TBHP and H₂O₂). Here, [Fe^IV(bispidine)(O)(Cl)]²⁺3 (Fig. 6) was proposed as the key intermediate to carry out the reaction via HAA and the halide rebound pathway.¹⁸³ The kinetic isotope effect value was determined to be (KIE = 14) between normal C–H- and C–D-containing substrates. Also, they found the preferential tertiary (by 3) over the secondary C–H bond abstraction via the rate-limiting HAA step.

Scheme 134 Synthesis of high-valent non-heme iron–oxo model complex, [Fe^IV(TPA)(O)(X)]⁺.

Fig. 6 Non-heme iron–oxo–halide complexes used as structural and functional mimic of halogenases.

Later, Costas and co-workers utilized the 1-(20-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane (PyTACN) ligand to synthesize [Fe^IV(PyTACN)(O)(Cl)]⁺ complex 4 (Fig. 6), and subsequently employed it for C–H halogenations with different substrates.¹⁸⁴ However, complex 4 did not provide any halogenation product during reaction with cycloalkanes. This is due to the strong coordination of the halide group to the metal centre, which provides higher stability to complex 4 (Fig. 6).

In 2014, Maiti and co-workers reported a method for the oxidative chlorination/bromination of electron-rich arenes and olefins in the presence of a biomimetic non-hemeiron(II)-complex as the catalyst, iodosyl benzene (as the oxidant) and halide sources (KCl and KBr) in methanol solvent (Scheme 135).¹⁸⁵ Different electron-rich arenes and olefins were halogenated using a stoichiometric amount of non-heme iron(II)–halide complexes, [Fe^II(TPA)X₂] (X = Cl and Br) in the presence of PhIO in acetonitrile solvent. Moreover, the catalytic halogenation reactions of arenes and olefins were performed using [Fe^II(TPA)(CH₃CN)₂](ClO₄)₂ as the catalyst in the presence of external halide sources in methanol solvent. Interestingly, under these reaction conditions, halo-methoxylation products were obtained with olefins.

Scheme 135 Non-heme iron-catalyzed halogenations of arenes and olefins.

Further studies were carried out to understand the mechanism of the reaction. Notably, no aliphatic halogenations were observed under the reaction conditions. Moreover, the low-temperature ESI-mass spectroscopy study at −40 °C from the reaction between [Fe^II(TPA)Br] 2 (Scheme 136) and iodosyl benzene enabled the detection of [Fe^IV(TPA)(O)(Br)]⁺ species I (Scheme 136). Additionally, the authors detected the iron(III)methoxy halide species [Fe^III(OMe)(X)]⁺III from the reaction mixture by ESI-MS study. The EPR study of the same reaction mixture suggested that [Fe^III(OMe)(X)]⁺ is possibly a high-spin species. Thus, based on the preliminary experiments and intermediates detected, a plausible mechanism involving the X⁺ equivalent was proposed. It was presumed that intermediate III undergoes oxidative transformation to generate reactive iron-bound hypohalite species IV, which possibly accomplishes the electrophilic halogenations (Scheme 136).

Scheme 136 Proposed mechanism of electrophilic halogenations by non-heme halide complexes.

In 2016, Paine and co-workers developed a non-heme iron complex, [Fe^II(Tp^Ph₂)(benzilate)] (Tp^Ph₂ = hydrotris(3,5-diphenyl-pyrazol-1-yl)borate), and generated non-heme iron(IV)oxo–aquo complex I in the presence of a proton source and dioxygen molecule.¹⁸⁶ Treatment of complex I with pyridinium perchlorate and tetrabutylammonium halide produced reactive iron(IV)–oxo–halide intermediate 6via the substitution of a water molecule with halide (Scheme 137). Subsequently, complex 6 (Fig. 6) reacted with different substrates and resulted in major halogenations together with minor hydroxylation products. Notably, this is the first example of a non-heme model complex involving oxygen (O₂) as the oxidant to obtain a halogenated product. In the same year, Que and co-workers carried out C–H bond halogenation reactions using [Fe^IV(TQA)(O)(Cl)]⁺ (7) [TQA = tris-((quinolyl-2-methyl)amine)] and [Fe^IV(TQA)(O)(Br)]⁺ (7), which are generated via ligand exchange from [Fe^IV(TQA)(O)(MeCN)]²⁺ with halide sources at a low temperature (Fig. 6).¹⁸⁷ Notably, this is the only synthetic complex to reproduce the Mössbauer parameters of the spin (S = 2) of the iron(IV)–oxo–halide intermediate of the α-KG-dependent halogenase enzymes. Thus, a higher selectivity (compare to other synthetic analogues) for the formation of the halogenated product was achieved together with the hydroxylation product. However, halogenations by this synthetic cis-iron(IV)–oxo–halide complex do not match the selectivity of the halogenase enzyme.

Scheme 137 Mechanistic proposal for the formation of electrophilic iron–oxygen oxidant and its role in C–H bond halogenations.

Recently, in 2018, Maiti and co-workers developed a selective C–H halogenation reaction using non-heme iron(IV)–oxo and iron(II)–halide complexes, where the former acted as a radical generator via HAA from the substrates and the latter as a halide atom donor (Scheme 134).¹⁸³ Precisely, the authors utilized pentadentate ligand, 2PyN2Q [1,1-di(pyridin-2-yl)-N,N-bis(quinolin-2-ylmethyl)methanamine], supported non-heme iron(IV)–oxo 8 and iron(II)–halide complexes 9 and 10 (Scheme 138). After the generation of complex 8, i.e. [Fe^IV(2PyN2Q)(O)]²⁺ from [Fe^II(2PyN2Q)(OTf)₂] in the presence of m-CPBA (meta-chloroperbenzoic acid) in acetonitrile at room temperature, different halide sources such as tetra-butyl ammonium chloride and bromide (Bu₄N⁺Cl⁻ or Bu₄N⁺Br) were added to the reaction mixture together with cyclohexane.¹⁸⁸ However, no halogenated products were obtained from this reaction. This observation can be explained due to the lack of formation of the [Fe^IV(2PyN2Q)(O)X]⁺ intermediate by the halide exchange reaction between the pentadentate ligand containing the iron(IV)–oxo complex and halide sources. Subsequently, the room temperature stable iron(IV)–oxo, [Fe^IV(2PyN2Q)(O)]²⁺8, was used for hydrogen atom abstraction (HAA) from the aliphatic substrates in conjunction with iron(II)–halide complexes [Fe^II(2PyN2Q)(X)]⁺ (X = Cl, Br) 9 and 10 to provide the halogen atom to the cage-escaped carbon centred radical.

Scheme 138 Selective halogenations by a non-heme iron(IV)–oxo, [Fe^IV(2PyN2Q)(O)]²⁺, in the presence of [Fe^II(2PyN2Q)X]²⁺ as the halide source.

Interestingly, cyclohexane delivers the cyclohexylbromide derivative selectively in 90% yield (with respect to the limiting reagent [Fe^II(2PyN2Q)(Br)]Br) under the standard reaction conditions (Scheme 139). Moreover, various cycloalkanes and toluene derivatives are well tolerated under the reaction conditions to provide the selective halogenated product together with a minor amount of oxidized product in some cases (Scheme 136). A kinetic isotope effect was observed using toluene and d₈-toluene under the halogenation reaction conditions (KIE = 13.5). Thus, this indicates that the initial HAA step is involved in the rate-determining step. Further, the radical trapping experiments during the reaction between 8 and cyclohexane in the presence of CCl₃Br provided exclusively cyclohexylbromide. This suggests that the radical generated via the HAA pathway undergoes dissociation from the cage with iron(III)–hydroxide, which is trapped by the Br˙ radical coming from the cleavage of the C–Br bond of CCl₃Br. Subsequently, the cage-escaped radical reacts selectively with the iron(III)–halide via the halide rebound pathway. Moreover, the feasibility of this particular halide rebound step was tested using pre-oxidized iron(III)–halide complexes (prepared from iron(II)–halide and m-CPBA) instead of iron(II)–halide complexes under the standard reaction conditions.

Scheme 139 Proposed mechanism of non-heme iron(IV)–oxo [Fe^IV(2PyN2Q)(O)]²⁺-mediated C–H halogenation.

Noticeably, the selective halogenation product was obtained from the above reaction. Furthermore, DFT calculation revealed that the sterically bulkier pentadentate ligand 2PyN2Q (compared to N4Py) exerted a large difference in the electronic structure of [Fe(2PyN2Q)(O)]²⁺. This difference in electronic structure exerts a high energy barrier in the oxygen rebound process (pathway I) and favours the low energetic cage-escaped pathway for the radical (pathway II). Further, the computational study revealed the reason for the selectivity in halogenation over hydroxylation. Firstly, it suggested that the cage-escaped radical preferentially penetrates the coordination sphere of the iron(III)–halide complex (due to its high electron affinity) since it is an energetically favourable pathway compared to oxygen rebound with iron(III)–hydroxide in the cage. Secondly, it also suggested that hydroxide substitution (pathway III) by the halide counter anions present in non-heme iron(II)–halide complexes 9 and 10 is a spontaneous process. Finally, the transition-state calculations demonstrated that the halide rebound (pathway IV) of the radical with the iron(III)–halide is an energetically downhill process due to the longer Fe–Cl bond compared to oxygen rebound with iron(III)–hydroxide, which has been found to be an uphill process due to the short Fe–O bond distance. Thus, based on the experimental and computational studies, a plausible mechanism was proposed involving the aforementioned pathways (Scheme 139).

The present bio-inspired stoichiometric halogenation reactions involving high-valent iron(IV)-complexes depict the different mechanistic aspects of C–H halogenation reactions. However, the present situation demands iron-catalyzed methods for the selective halogenation of aliphatic C–H bonds considering the importance carbon–halogen compounds. Contextually, Groves and co-workers developed manganese porphyrin catalyzed halogenation reactions including chlorination and fluorination, where selective halogenated products are obtained together with a minor amount of hydroxylation product.¹⁸⁹ However, in the case of iron catalysis, there is no report on methods for catalytic aliphatic C–H halogenation. Thus, iron catalysis remains elusive and challenging for the development of catalytic aliphatic C–H halogenation reactions.

3. Cross dehydrogenative coupling (CDC) reaction

Transition metal or organic reagent-mediated carbon–carbon (C–C) and carbon–heteroatom (C–X) (X = N, O, P, S, Se, etc.) bond formation involving two different C–H bonds or one C–H and one X–H bond is formally known as the cross dehydrogenative coupling (CDC) reaction.¹⁹⁰ In this reaction, the direct coupling of either two C–H bonds (to form a C–C bond) or one C–H bond and another nucleophilic coupling partner, X–H (to form C–X bond), requires a suitable oxidant.¹⁹¹ Moreover, in this process, two hydrogen atoms are eliminated. There are several benefits of the CDC reaction. Firstly, it does not require the prefunctionalization or preparation of any starting material. Secondly, the starting materials are easily available. Interestingly, this strategy improves the atom economy and the step economy of oxidative coupling.^192,193 However, the CDC reaction has been found to be challenging due to the poor reactivity of C–H bonds, and thus the chemists have developed new methods to activate different types of C–H bonds for the formation of C–C and C–X bonds. Contextually, here, we elucidate the prospects of the most abundant transition metal, iron, catalyzed CDC reactions. We classify the iron-catalyzed CDC reactions into different topics based on the type of bond formed via CDC, e.g. C–C or C–X. Then each topic is further divided into sub-topics based on the hybridization and types of bonds participating in the reactions. Li et al. in 2007 reported the first example of an iron-catalyzed CDC reaction, describing the formation of the C–C bond.¹⁹⁴

3.1 CDC between C (sp³)–H and X (sp³)–H (X = C, N, O, S, etc.) bonds

Iron-catalyzed CDC of C(sp³)–H is quite challenging due to its low reactivity originating from the high bond energy and absence of suitable co-ordination sites for the iron catalyst compared to the oxidative coupling of C(sp²)–H or C(sp)–H bonds. In the iron-catalyzed CDC reaction, the oxidant abstracts a hydrogen atom from the C–H bond to generate carbon-centred radical I, followed by the generation of carbocationic intermediate IIvia the single-electron transfer (SET) process. Finally, the nucleophile attacks carbocation intermediate II, resulting in the formation of the desired product (Fig. 7).¹⁹⁵

Fig. 7 Mechanistic pathway of iron-catalyzed CDC reaction.

Alternatively, the C–H bond adjacent to the heteroatom is abstracted via the SET mechanistic pathway and generates radical cation III, which is readily α-deprotonated by the oxidant to generate carbenium ion IV. Finally, it is attacked by an incoming nucleophile to give the final coupled product (Fig. 8).¹⁹⁵ Notably, here the deprotonation of Nu–H occurs either before or after the attack to the carbocationic intermediate depending on the acidity of the Nu–H bond.

Fig. 8 Mechanistic pathway of CDC involving C–H bonds adjacent to the hetero-atom.

3.1.1 Carbon–carbon (C–C) bond formation. In the following section, the direct oxidative coupling of the C(sp³)–H bond with the benzylic C–H bond to construct the C–C bond is discussed.
3.1.1.1 C–C bond formation with benzylic C(sp³)–H bonds. Based on Li's earlier investigation, diphenyl methane has been chosen as one of the standard substrates due to the presence of two activated C–H bonds at the benzylic position.¹⁹⁴ The other active coupling partner is the 1,2-dicarbonyl compound. The best efficacy is shown by FeCl₂ as a catalyst compared to Cu or Co salts. The use of the di-tert-butyl peroxide (DTBP) instead of tert-butyl hydro peroxide (TBHP) as an oxidant increases the yield of the product. Notably, this is the first example of an iron-catalyzed CDC reaction. The synthetic method is applicable to both cyclic and acyclic benzylic compounds. The electronic effect of the substituents shows very little effect on the yield of the product (Scheme 140).

Scheme 140 Iron-catalyzed benzylic alkylation with active dicarbonyl methylene compounds.

Mechanistically, the initial formation of the tert-butoxyl radical occurs in the presence of ferrous chloride via homolytic cleavage of tert-butyl hydroperoxide (TBHP). Then the tert-butoxyl radical abstracts a hydrogen atom from the benzylic C(sp³)–H bond, which results in the formation of a benzylic radical (Scheme 141). On the other hand, the Fe(III) catalyst reacts with the 1,3-dicarbonyl compound to form a chelate Fe-enolate complex. Finally, the electrophilic radical is attacked by the benzylic radical in the chelate complex, affording the product via the regeneration iron(II). The isolated yield of the product is increased up to 80% upon increasing the reaction time. Notably, the reaction is also found to proceed efficiently at room temperature.

Scheme 141 Probable mechanistic pathway for iron-promoted benzylic alkylation.

Later in 2007, Li and Zhang employed inactive cycloalkanes for the oxidative coupling reaction with active 1,3-diketone in the presence of di-tertiary butyl peroxide (DTBP) as an oxidant and iron salt as a catalyst.¹⁹⁶ However, the active catalyst is the chelated Fe–enolate complex, which is formed from the reaction between iron(II) chloride and the dicarbonyl compound (Scheme 142). Notably, the same reaction protocol was also conducted on different types of cycloalkanes such as cyclohexane, cyclopentane, cycloheptane, norbornane, adamantane and n-hexane systems. Notably, the reaction with the norbornane system provides the alkylation product as a mixture of two diastereomers in a 1 : 1 ratio. Here, the desired product was not obtained from the reaction of the bridgehead C–H bonds. Moreover, when the adamantane system was reacted with ethyl benzoylacetate, a mixture of the alkylation product and the coupling product on the more substituted carbon was obtained with a 4 : 1 ratio. Interestingly, n-hexane also yields two regioisomeric alkylation products with β-ketoester (in 1 : 2 ratio). The slightly higher ratio of the corresponding alkylation product is due to the formation of the more stable radical at the C₃-methylene position rather than the alkylation at the C₂-methylene position.

Scheme 142 Iron-catalyzed alkylation of activated 1,3-diketones with simple cycloalkanes.

Li et al. in 2012 described the oxidative coupling reaction of a 1,3-dicarbonyl compound with a toluene derivative in place of cycloalkanes¹⁹⁶ in the presence of iron(II)-acetate/di-tert-butylperoxide (DTBP) as the catalyst/oxidant system (Scheme 143).¹⁹⁷ Various substituted toluenes undergo the oxidative coupling efficiently with the 1,3-dicarbonyl compound under the optimized conditions. The mechanistic pathway suggests that the benzylic radical undergoes addition to the benzoyl methano-iron species in this reaction.

Scheme 143 Iron-catalyzed alkylation of toluene derivatives with 1,3-dicarbonyl compounds.

In 2015, Song et al. reported an iron-catalyzed tandem cross-dehydrogenative coupling reaction of toluene derivatives with 1,3-dicarbonyl compounds using 2,3-dicholoro-5,6-dicyano-1,4-benzoquinone as the oxidant.¹⁹⁸ Notably, 1,3-dicarbonyl compounds bearing electron-donating groups such as alkyl (e.g. methyl and ethyl), aryl and alkoxide were found to react efficiently under the reaction conditions. Moreover, electron-withdrawing substituents (e.g. F) on the aromatic ring of aryl-β-ketone esters are also well tolerated. This reaction proceeds through initial sp³–sp² coupling followed by sp³–sp³ oxidative coupling to afford the desired product. The reaction is proposed to be initiated by the homocoupling of two molecules of aryl methane to form a diarylmethylene intermediate. Then the intermediate participates in the CDC reaction with the 1,3-dicarbonyl compound to give the final desired product (Scheme 144).

Scheme 144 Iron-catalyzed tandem CDC between toluene derivatives and 1,3-dicarbonyls.

In 2012, Xu et al. reported the iron-catalyzed benzylic C(sp³)–H vinylation of 2-methyl aza-arenes with N,N-dimethyl amides.¹⁹⁹ Mainly, one of the carbon atoms present in the N,N-dimethyl moiety of N,N-dimethyl amides is transferred to the 2-methyl aza-arenes to give the desired product in good yield (Scheme 145). Thus, the N-methyl amide acts as the carbon source for vinylation. Notably, among the different amides, N,N-dimethyl formamide and N,N-dimethyl acetamide provide the desired product. Also, different electron-donating and electron-withdrawing aromatic rings provide the desired product in good to excellent yields. Further, they performed control experiments gain mechanistic insight. Notably, the reaction failed to give the vinylation product when it was carried out in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as a radical scavenger. Thus, this suggests that the reaction may occur via a radical pathway. Moreover, the observed primary kinetic isotope effect (KIE, K_H/K_D = 2) reveals that the cleavage of the C–H bond of the N,N-dimethyl amide is involved in the rate-determining step. Thus, based on these results, it was proposed that enamine intermediate I is generated from the model substrate 2-methyl-3-phenylquinoxaline 1 in the presence of iron(III) (Scheme 146). Subsequently, intermediate I attacks iminium ion intermediate III to generate the desired vinylated product Vvia elimination.

Scheme 145 Iron(III)-catalyzed vinylation of benzylic C–H bonds.

Scheme 146 Probable mechanism of benzylic vinylation.

In 2013, a similar type of iron-catalyzed vinylation of 2-methyl quinolines with N,N-dimethyl formamide in the presence of TBHP was reported by Wang et al.²⁰⁰ Notably, based on the successful radical experiment and primary kinetic isotope effect study, the authors proposed a similar type of mechanism involving enamine and iminium intermediates as mentioned in Scheme 146. In 2015, Li et al. utilized N,N-dimethyl acetamide for the α-methylation of ketones in the presence of FeCl₃ as a catalyst to form α,β unsaturated carbonyl compounds in moderate to excellent yield (Scheme 147).²⁰¹ Various types of ketones such as aryl and alkyl ketones, enones and dicarbonyl compounds are well tolerated in the standard reaction protocol.

Scheme 147 Iron(III)-catalyzed α-methylenation of ketones.

In 2016, Su and co-workers described the iron(III) catalyzed CDC of 3-benzylic indoles with active methylene or indoles groups via a mechanically induced high speed ball-milling process (HSBM) at room temperature in the absence of solvent.²⁰² Notably, HSBM is a green mechanical technique for the formation of nanomaterials, which promotes chemical reactions with high efficacy, energy economy and even new reactivity. The reaction affords the desired 3-aryl methyl indole derivatives in moderate to high yield within 21 min of grinding. Here, silica gel is used as a grinding auxiliary for better substrate mixing (Scheme 148).

Scheme 148 Iron-catalyzed CDC of 3-benzylic indoles.

Although, iron(II) and iron(III) show catalytic activity in this method, iron(III) salts show better efficacy. Further, among the different iron salts, Fe(NO₃)₂·9H₂O was chosen due to its ease of handling. The best result was obtained using DDQ as the oxidant. However, it is added in several portions to avoid radical polymerization. Both the electron-withdrawing substituents and electron-donating aryl substituents including the oxidation-sensitive OH group in the 3-aryl methyl of indoles are well tolerated to afford moderate to excellent yields of the corresponding product. Notably, electron-rich substituents give a better product yield. However, indoles are also taken as nucleophiles in place of the active methylene group. Here, both N-substituted and N-free indoles are tolerated under the standard optimized conditions to give the bis-indole derivative. The nucleophiles, indoles (R³ = indole), possessing an electron-donating groups provide a lower yield of product compared to that with electron-withdrawing groups.

In 2018, Oshima and Yazaki reported ligand-supported chemoselective cross-dehydrogenative coupling using hydrocarbon feedstock with non-tautomerizable 2-acylimidazole under mild conditions.²⁰³ The synthetic transformation is based on the simultaneous catalyst-controlled activation strategy, i.e. in situ catalytic activation of 2-acyl imidazole and catalyst control radical generation from the hydrocarbon to form the desired product. The tert-butoxy radical from DTBP is generated in the presence of FeCl₂ as the catalyst and L₁ as the ligand after screening of the conditions. This method using the catalyst/ligand system allows catalyst-control radical generation from hydrocarbons (Scheme 149). Notably, an undesired homo-coupling product of toluene (i.e. dibenzyl) was obtained under the optimized conditions. Several control experiments revealed that no product is obtained in the absence of either FeCl₂ or ligand.

Scheme 149 CDC of 2-acylimidazole with benzylic C–H bonds.

The reaction does not occur at 80 °C in the absence of ligand. However, a moderate yield of the desired product is obtained when the reaction is carried out at 120 °C. Evidently, the generation of tert-butoxy radical is facilitated by thermal heating at a higher temperature. Rationally, the utilization of a ligand in the presence of the FeCl₂ catalyst can accelerate the homolytic cleavage of DTBP to generate the radical even at a lower temperature.

Based on a series of mechanistic studies, a plausible catalytic cycle was proposed (Scheme 150). Initially, iron(III)-based intermediate I is formed in the presence of FeCl₂ and DTBP through the Fenton-type reaction with the help of the L₁ ligand. Then 2-acyl imidazole coordinates with the iron intermediate to afford iron(III) and iron(III)-based intermediate II. Subsequently, enolization occurs in intermediate II, where two iron species act as a Lewis acid/Brønsted base co-operative catalyst system, facilitating the generation of enolate III and radical intermediate IV. On the other hand, the cleavage of the benzyl C–H bond (Ph-CH₂-H: BDE= 89.6 ± 0.6 kcal mol⁻¹) is accomplished by the tert-butoxy radical (t-BuO-H: BDE = 105.7 ± 0.7 kcal mol⁻¹) to generate benzyl radical V. Notably, the cleavage of the benzyl C–H bond occurs with the help of the Fe^II/L₁ system and not by thermal degradation. Then benzyl radical V undergoes coupling with enolate III rather than radical intermediate IV to afford intermediate VI. Finally, the iron(II) centre in VI is oxidized and delivers the desired product in good yield with the regeneration of active iron species I.

Scheme 150 Plausible mechanistic pathway for iron-catalyzed CDC of 2-acylimidazole.

Recently in 2019, Cai et al. reported the regioselective ligand-supported α C–H alkylation of N-methyl anilines (without any directing group) by cross dehydrogenative coupling between two C(sp³)–H sources.²⁰⁴ Different types of C(sp³)–H bonds including cyclic alkanes, cyclic ethers and toluene derivatives are used as coupling partners. Notably, the desired product is not obtained when anisole is used as the substrate instead of amine. A variety of N-methylanilines having electron donating groups such as OMe and Me at the C(4) position of the phenyl ring and electron-withdrawing groups such as cyano, halogen, trifluoromethyl and phenyl groups provide moderate to excellent yield of the desired products. This indicates that the position of the substituents in the phenyl ring does not have any significant role in the reaction yield. Notably, the best catalytic efficacy was shown by FeCl₂ in the presence of 3,4,7,8-tetramethyl-1,10-phenanthroline as the ligand (Scheme 151). Notably, the anion bound to the iron plays a crucial role in the catalysis. The yield of the desired product increased by using Na₂CO₃ as an additive. Interestingly, the formation of the desired product was not observed using radical scavengers such as TEMPO or BHT. Thus, this suggests that the reaction may occur via the radical pathway. Further, a trace amount of product is obtained in the absence of the iron catalyst, indicating the importance of the iron catalyst in electron transfer. Also, the product is not obtained in the absence of TBHP. Clearly, this suggests that TBHP plays the role of an oxidant and radical initiator. Moreover, the ligand acts as an activating agent for the catalyst to facilitate the reaction. The additive Na₂CO₃ acts as a base for deprotonation.

Scheme 151 Regioselective α-C–H alkylation of N-methyl anilines.

Interestingly, the reaction also occurs under an argon atmosphere, indicating no requirement of additional O₂ for the reaction. Thus, based on these experiments, a plausible mechanism of the reaction was suggested, as shown in Scheme 152, where in situ generated radical II is formed from substrate 1via the SET process. Then, it undergoes reduction in the presence of a base additive. Finally, radical–radical coupling between radical II and the cyclohexyl radical provides the desired product III.

Scheme 152 Mechanism of regioselective α-C–H alkylation of N-methyl anilines.

3.1.1.2 CDC with C(sp³)–H bond adjacent to heteroatom. C(sp³)–H bonds adjacent to a heteroatom are highly desirable for the direct functionalization and derivation of heteroatom-containing organic compounds. Inspired by iron-catalyzed CDC with biphenyl methane derivatives, Li et al. reported iron-catalyzed C–C bond formation via the direct oxidation of α-C–H bonds of ether with 1,3-dicarbonyl compounds.²⁰⁵ Among the different iron catalysts, FeCl₂, FeBr₂, Fe(OAc)₂, and Fe₂(CO)₉ were found to be equally efficient for the CDC reaction between THF (tetrahydrofuran) and benzoylacetate. Both the cyclic and the linear ether derivatives with 1,3-dicarbonyl compounds are well tolerated to give the desired product in good yield. Notably, substrates containing sulfur and nitrogen as heteroatoms are also compatible under this C–H bond oxidative transformation (Scheme 153).

Scheme 153 Iron-catalyzed oxidative coupling between C–H bonds adjacent to heteroatoms and 1,3-dicarbonyls.

Further, Li and co-workers extended their reaction protocol with N,N-dimethyl aniline and two equivalents of 1,3-dicarbonyl compound to obtain a methylene-bridged bis-1,3-dicarbonyl compound (Scheme 154).²⁰⁶ Notably, they used N,N-dimethylaniline as the methylenic source for the first time in this type of reaction. The best catalytic efficiency was exhibited by Fe₂(CO)₉. Based on several experiments, a plausible reaction pathway was proposed. Initially, one molecule of N,N-dimethylaniline and another molecule of 1,3-dicarbonyl compound undergoes iron-catalyzed cross-dehydrogenative coupling to form intermediate I. Then, intermediate I undergoes substitution with another molecule of 1,3-dicarbonyl compound via the SN² pathway to give the final product via the removal of N-methyl aniline as the leaving group. The other feasible mechanistic pathway is initiated by the Cope elimination of I to form intermediate II, which undergoes Michael addition with the second molecule of 1,3-dicarbonyl to afford the desired product (Scheme 155).

Scheme 154 Neutral diiron-nonacarbonyl-catalyzed dialkylation of the methylene group with 1,3-dicarbonyls.

Scheme 155 Probable mechanistic pathways for the dialkylation of the methylenes.

Based on the same concept, Li et al. in 2011 used N-alkyl tertiary amines in place of N,N-dimethylamine as alkylating agents. The CDC reaction between two molecules of N-alkyl tertiary amines and 1,3-dicarbonyl compound in the presence of the Fe₂(CO)₉/TBHP system was reported.²⁰⁷ The reaction protocol affords various β-1,3-dicarbonyl aldehydes in moderate to good yields. Notably, the synthetic transformation is completed within 10 min at room temperature. Initially, the reaction starts via condensation between two molecules of N-alkyl tertiary amines to generate α-β-unsaturated aldehyde. Then, the unsaturated aldehyde undergoes Michael addition with the 1,3-dicarbonyl compound to afford the desired product (Scheme 156).

Scheme 156 Oxidation of N-alkyl tertiary amines through CDC.

In 2011, Hayashi and Shirakawa reported the cross dehydrogenative coupling between tetrahydroisoquinolines with nitroalkanes in the presence of the FeCl₃/DTBP catalyst/oxidant system (Scheme 157).²⁰⁸ This synthetic method results in the formation of various 1-nitroaldol-substituted tetrahydroisoquinolines in excellent yields.

Scheme 157 CDC of tetrahydroisoquinolines with nitroalkanes and activated methylenes.

Additionally, activated methylene compounds have also been successfully used as nucleophilic sources. Furthermore, Li et al. described a similar type of synthetic transformation using magnetic Fe₃O₄ or CuFe₂O₄ nanoparticles as a catalyst. Noteworthily, this catalyst can easily be recovered and used for at least nine runs without any loss in activity.^209,210 Moreover, the CDC between isochromans with 1,3-dicarbonyl compounds was reported by Mancheño and Richter using the Fe(II)triflate/oxammonium salt of TEMPO as the catalyst/oxidant system.²¹¹ The reaction is very solvent dependent. No products are obtained by employing solvents such as dichloroethane (DCE), tetrahydrofuran (THF), acetonitrile (MeCN) and toluene. Surprisingly, further substitution at the benzylic position of isochroman inhibits the reaction. This can be rationalized based on the enhanced steric hindrance in the ether.

The iron(II)-chloride-catalyzed oxidative coupling of propargylic ethers with 1,3-dicarbonyl compounds was reported by Zhang and co-workers. This synthetic method affords various propargylated β-dicarbonyl compounds in moderate yield (Scheme 158).²¹² In 2015, the novel iron-catalyzed dual oxidative tandem annulation of a glycine derivative with tetrahydrofuran were reported by Huo's group.²¹³ This synthetic methodology is performed under mild reaction conditions to afford various quinoline-fused lactones in moderate yield. Notably, various glycine esters having electron-withdrawing groups and electron-donating groups at the meta, para and ortho positions of the phenyl ring provide the desired product smoothly. However, when 2-methyl tetrahydrofuran or 2-5-dimethyl tetrahydrofuran is used as the substrate, lower yields of the desired quinoline-fused lactones are obtained. Based on several experiments, the authors suggested a possible reaction mechanistic pathway (Scheme 159). Initially, the glycine ester and THF are transformed into an aryl amine derivative and dihydrofuran (DHF), respectively, in the presence of FeCl₂/TBHP. Then, the oxidative imino Diels–Alder reaction between them generates a tetrahydroquinazoline intermediate, followed by isomerization in the presence of 12 M hydrochloric acid (HCl), resulting in the formation of the final product.

Scheme 158 Iron-catalyzed oxidative coupling of propargylic ethers with 1,3-dicarbonyls.

Scheme 159 Dual-oxidative dehydrogenative tandem annulation of glycine derivatives with THF.

3.1.2 Iron-catalyzed C–N bond formation. Transition metal-catalyzed C–N bond formation reactions have emerged as powerful tools for the synthesis of N-containing organic compounds. Tremendous efforts for the construction of C–N bonds such as Buchwald–Hartwig coupling,²¹⁴ Ullman coupling,²¹⁵ and N-arylation of amides²¹⁶ have been attempted employing late transition metal catalysts. However, pre-functionalized starting materials are required for the aforementioned methods. However, direct C–H bond amidation will be very useful for making C–N bonds. Here, we demonstrate the iron-catalyzed C–N bond formation reactions, which are divided into different subsections based on the types of C–H bonds.
3.1.2.1 Benzylic C(sp³)–H amidation reaction. In 2008, Fu and co-workers reported the first example of the iron-catalyzed amidation of the benzylic C(sp³)–H bond via the CDC reaction.²¹⁷ The synthetic transformation is carried out in the presence of efficient, inexpensive and air stable FeCl₂/NBS as the catalyst/oxidant system together with carboxamides and sulfonamides as a nitrogen source. The corresponding desired products are obtained in moderate to excellent yield under the optimized conditions. This iron-catalyzed benzylic C(sp³)–H bond amidation is initiated by the generation of bromosulfonamide or bromocarboximide intermediate Ivia the bromination of sulfonamide or carboximide with N-bromo succinamide (NBS) (Scheme 160). Then intermediate I reacts with FeCl₂ to generate intermediate II. Thereafter, intermediate II undergoes conversion into iron-nitrene complex III, which reacts with benzylic C(sp³)–H via insertion into C–H (transition state IV) bonds, providing the desired product.

Scheme 160 Iron-catalyzed benzylic C(sp³)–H bond amidation.

3.1.2.2 Amidation of C(sp³)–H bond adjacent to heteroatoms. The iron-nitrene complex can be used as a key intermediate during the synthesis of nitrogen-containing organic compounds. However, a new approach for the C–N bond formation process was established by Li et al. in 2010.²¹⁸ The authors reported the iron-catalyzed oxidative C–N bond formation of azoles and ethers in good to excellent yield. Notably, imidazole and its derivatives undergo C–N bond formation with THF in the presence of FeCl₃·6H₂O/TBHP as the catalyst/oxidant system in good yield. Moreover, benzimidazole and various ethers are also amidated in good yields using the standard reaction protocol (Scheme 161). Mechanistically, the hydroxide ion is generated from the reaction between Fe²⁺ and t-BuOOH. Then, it abstracts the N–H proton from the imidazole system to give anion intermediate I.

Scheme 161 Oxidative C–H amination between azole derivative and various ethers.

On the other hand, the α-C–H bond of the ether is activated by the iron salt and tert-butoxyl radical to form radical intermediate II, which is oxidized by Fe³⁺ and generates oxonium intermediate III. Thereafter, the nucleophilic attack of anionic intermediate I to oxonium intermediate III provides the desired coupling product (Scheme 162).

Scheme 162 Probable mechanistic pathway of oxidative C–N bond formation of azole derivatives and ethers.

In 2012, Zhu et al. described the FeCl₂/TBHP reagent-catalyzed direct amination of aryl amides with N-substituted pyrolidin-2-one to afford the desired product in moderate to excellent yield in a regioselective manner (Scheme 163).²¹⁹ Here, the methylenic C(sp³)–H bond adjacent to nitrogen is aminated. In 2014, Bao et al. reported a similar reaction with the FeCl₃ catalyst and TBHP oxidant system in the absence of a ligand.²²⁰ Yang et al. in 2013 reported the iron-catalyzed direct C-1 amination of isochroman derivatives with aniline derivatives (Scheme 164).²²¹ The C-1 position adjacent to the heteroatom oxygen is oxidized to form the oxonium ion intermediate. Subsequently, this intermediate is attacked by N-nucleophiles to yield a variety of hemiacetals selectively in good to excellent yield.

Scheme 163 Iron-catalyzed amination of N-substituted pyrrolidin-2-ones.

Scheme 164 Iron-catalyzed amination of isochroman derivatives.

In 2014, Gu et al. developed an efficient method of iron-catalyzed one-pot oxidative tandem cyclization for the formation of benzoxazole from 2-(aryloxy)-anilines.²²² Based on the experimental observations and previous results, a plausible mechanistic pathway was suggested. It is believed that the tert-butoxyl radical (t-BuO˙) (formed from the reaction between Fe²⁺ and DTBP) abstracts the hydrogen atom adjacent to the oxygen of 2-(aryloxy)anilines to form a carbon-centered radical, followed by oxidation to form the oxonium ion intermediate via the SET process. Subsequently, intramolecular attack of the nitrogen atom of aniline to the oxonium ion intermediate affords the desired product (Scheme 165).

Scheme 165 Iron-promoted tandem oxidative cyclization for the synthesis of substituted benzoxazoles.

In 2018, Chikhalia and co-workers developed an iron-catalyzed cross dehydrogenative C–N coupling of thiohydantions with amines. The reaction is performed with 1,3-dibenzyl-2-thiohydantoin 1a and 2-aminopyridine 2a using FeCl₃/TBHP as the catalyst/oxidant (in 1,4-di-oxane as the solvent) system at 80 °C under aerobic conditions (Scheme 166).²²³ The desired product is obtained in 86% yield under the optimized reaction conditions. Notably, both heteroaryl amines and anilines are well tolerated under the reaction conditions.

Scheme 166 Iron-catalyzed CDC of thiohydantoins with amine.

They proposed a possible mechanistic pathway for the C(sp³)–H amination of 1,3-dibenzyl-2-thiohydantoin (Scheme 167). Initially, tertiary-butyl hydroperoxide (TBHP) splits into a hydroxyl anion and tert-butoxy radical (t-BuO˙), followed by HAA from 1 and SET oxidation generates cation II (Scheme 167). On the other hand, anion III is formed via the deprotonation of 2-aminopyridine 2, which reacts with cation II to produce the desired product.

Scheme 167 Possible mechanistic pathway of iron-catalyzed CDC of thiohydantoins.

3.1.3 Iron-catalyzed carbon–oxygen (C–O) bond formation through CDC. The direct esterification and etherification of the C–H bond have attracted much attention from chemists over the last few years. This process involves the oxidative coupling of commercially available starting materials to provide high step efficiency and atom economy. We divide this particular C–O bond formation reaction based on the different types of C–H bonds involved.
3.1.3.1 C–O bond formation with benzylic C(sp³)–H bond through CDC. In 2012, Urabe et al. reported a method for the Fe(acac)₃-catalyzed synthesis of tert-butyl peroxyacetals via C–H bond oxygenations.²²⁴ Various olefinic and acetylenic tert-butyl peroxyacetals and unsaturated peroxy ortho-esters result in the formation of the desired product in good to excellent yields (Scheme 168).

Scheme 168 Iron-catalyzed synthesis of tert-butyl peroxyacetals.

A reaction mechanistic pathway was proposed for the formation of tert-butyl peroxyacetals (Scheme 169). Initially, the tert-butoxy radical abstracts a hydrogen atom from the ether to form the radical intermediate, which results in the formation of a carbocation intermediate via the SET mechanistic pathway in the presence of an iron salt. Thereafter, the nucleophilic attack by t-BuOOH provides the final product.

Scheme 169 Probable mechanistic pathway for the synthesis of tert-butyl peroxyacetals.

In 2015, Zhang and co-workers developed a straightforward strategy for the formation of various α-keto benzyl esters using benzyl derivatives with benzoylformic acids in the presence of FeF₃/DTBP as the catalyst/oxidant system in an inert atmosphere (Scheme 170).²²⁵ Various benzyl derivatives having electron donating groups are well tolerated under the reaction conditions. However, benzyl derivatives with electron-withdrawing groups afford a poorer yield of the desired product. On the other hand, benzoylformic acids having both electron-withdrawing groups (e.g. F, Cl, Br, and CF₃) and electron-donating groups (e.g. Me and OMe) are well tolerated under the reaction conditions. The plausible mechanistic pathway suggests that nucleophilic attack by benzoylformic acids on the benzyl carbocation, which is forms via the oxidation of the benzyl C–H bond, results in the synthesis of the product.

Scheme 170 Iron-catalyzed esterification of a benzylic C–H bond.

3.1.3.2 C–O bond formation with propargylic C(sp³)–H bond through CDC. In 2012, Jiao et al. reported an oxidative C(sp³)–O bond formation protocol between aryl propargyl azides and carboxylic acids in the presence of FeCl₂/DDQ as the catalyst/oxidant system (Scheme 171).²²⁶ Noteworthily, a diverse range of aryl propyne substrates containing electron-withdrawing groups such as chloro and bromo and electron-donating groups (e.g. OMe and Me) are well tolerated. Moreover, a variety of carboxylic acids such as aliphatic acids, acids having aryl and double bonds, and even sterically hindered carboxylic acids are well tolerated under the reaction conditions. The reaction proceeds smoothly in dichloroethane (DCE) solvent to yield the product in 45–83% yield. The azides are derived in situ from the reaction between NaN₃ and the corresponding chlorides. However, although propargyl chlorides are structurally similar to the azide group, they do not undergo the synthetic transformation. This suggests that the azide group can act as an assisting group to facilitate the synthetic transformation. The products formed in the reaction are further transformed into other useful products such as 4,5-disubstituted-1,2,3-triazoles, 3-alkoxyenols and benzotriazole.

Scheme 171 Iron-catalyzed coupling between aryl propargyl azides and carboxylic acids.

Considering the mechanistic perspective, it was proposed that the reaction proceeds through the single-electron oxidation mechanism between propargyl azides and the FeCl₂/DDQ system to form radical intermediate I, which is further oxidized to cationic intermediate II (Scheme 172). Successively, the nucleophilic attack of the carboxylic acid to carbocationic intermediate II produces the desired product with the regeneration of the active catalyst. Notably, cation II is stabilized due to the presence of the azido group.

Scheme 172 Probable mechanistic pathway for oxidative dehydrogenative C–O bond formation.

3.1.3.3 C–O bond formation with a C(sp³)–H bond adjacent to a heteroatom through CDC. In 2005, Pearson and Kwak reported a reaction protocol demonstrating the iron-catalyzed oxidation of chiral 2-pyrrolidino-1-ethanol derivatives to oxazolopyrrolidines in a stereoselective manner (Scheme 173).²²⁷

Scheme 173 Iron-catalyzed chemoselective oxidation of chiral 2-pyrrolidino-1-ethanols.

This reaction protocol involves a tricarbonyl(cyclohexadiene)iron complex as the catalyst and trimethyl N-oxide (Me₃NO) as the oxidant. According to the proposed mechanism, it was presumed that the trimethyl-N-oxide possibly removes one CO ligand from the metal carbonyl and also eases the demetallation of the diene–Fe(CO)₃ complex.²²⁸ However, although the detailed mechanistic pathway of this reaction protocol is not clear, it is assumed that the coordination of the actual oxidant to the –OH group, followed by simultaneous intramolecular oxidation of amine gives the product. Notably, here the iminium intermediate reacts with the –OH group to generate an oxazolidine ring.

In 2011, Hayashi et al. depicted the FeCl₃-catalyzed C–H bond oxidation of alkyl amides to α-(tert-butoxy)alkylamides in the presence of FeCl₃/DTBP as the catalyst/oxidant system.²²⁹ Here, nucleophilic attack by the tert-butyl alcohol to the in situ generated acyliminium salt produces the desired α-(tert-butoxy)alkylamide (Scheme 174).

Scheme 174 Iron-catalyzed oxidation of alkylamides to tert-butoxy-alkylamides.

In the same year, Liang et al. reported a similar type of C–O bond formation methodology by the oxygenation of C(sp³)–H bonds adjacent to the nitrogen atom of unprotected aryl ureas in the presence of FeSO₄/TBHP as the catalyst/oxidant combination in water (Scheme 175).²³⁰ Various N-arylpyrrolidine-1-carboxamides having electron-withdrawing groups such as p-methoxyphenyl and p-methylphenyl and electron-withdrawing groups are well tolerated under the reaction conditions. Noteworthily, 2-methyl-N-phenylpiperidine-1-carboxamide does not give any product due to the steric effect of the methyl group on the piperidine ring. The reaction protocol provides an efficient simultaneous dioxygenation of both α-positions with respect to the nitrogen atom, generating various tert-butoxylated and hydroxylated aryl ureas in good yield.

Scheme 175 Iron-catalyzed oxygenation of aryl ureas.

Mechanistically, initially, TBHP splits to form a tert-butoxyradical (t-BuO˙) in the presence of FeSO₄. Then, t-BuO˙ reacts with another molecule of TBHP to generate the tert-butyl peroxy radical (t-BuOO˙). The peroxyl radical reacts with aminyl radical I (which is generated through the oxidation of aryl urea 1) to generate the unstable N-(tert-butylperoxyl)-urea II. Thereafter, elimination of the tert-butyl peroxy radical generates a new rearranged carbon radical IIIvia 1,4-hydrogen radical transfer. Notably, radical III is trapped by tert-butanol to give α-tert-butoxylated urea IV and regenerates TBHP. TBHP abstracts the other hydrogen atom adjacent to nitrogen. Thus, the hydroxyl group is introduced to the second α-position of IV (Scheme 176).

Scheme 176 Plausible mechanistic pathway of C(sp³)–H oxygenation of aryl urea.

Tang et al. in 2015 developed an efficient methodology for the functionalization of pyrrolones with alcohol in the presence of an iron catalyst.²³¹ This reaction protocol is carried out in the presence of Fe(OTf)₃ as the catalyst. Notably, pyrrolones containing variety of electron-donating groups such as p-methoxyphenyl or p-methylphenyl and electron-donating groups such as p-chlorophenyl groups are well tolerated under the reaction conditions. Moreover, primary or allylic alcohols were found to be a good nucleophile for this reaction methodology. However, isopropanol and trifluoroethanol afford a lower yield of the desired product. Here, pyrrolones in the presence of the iron catalyst and molecular oxygen then form an acyliminium ion intermediate. Then, nucleophilic attack of alcohols to the intermediate affords the corresponding product (Scheme 177).

Scheme 177 Iron-catalyzed oxidative coupling of pyrrolones with alcohols.

Chang and Wang in 2014 described the iron-catalyzed oxidative coupling between salicylaldehyde and cyclic ethers through direct α-C–H functionalization of ethers in the presence of labile –CHO group.²³² The corresponding acetals are obtained in moderate to excellent yield in this transformation (Scheme 178). Notably, simple salicylaldehyde and its derivatives with electron-withdrawing groups such as 5-OCF₃ and 5-Br together with electron-donating 5-CMe₃ and 5-Me groups provide the desired product in good to excellent yield. However, 5-NO₂-substituted salicylaldehyde does not result in the formation of the desired product.

Scheme 178 Iron-catalyzed oxidative coupling between salicylaldehydes and cyclic ethers.

In 2014, Han et al. reported a reaction method for the oxidative CDC-based esterification of the C–H bonds of ethers with carboxylic acid in the presence of Fe₂(CO)₉ and TBHP as the catalyst and oxidant system (Scheme 179).²³³ Mainly, aromatic acids and phenyl acetic acids together with symmetric and asymmetric ethers are well tolerated under the standard reaction protocol to give the desired product. Notably, only the methylenic C–H bond adjacent to one of the oxygen atoms is selectively esterified using non-equivalent ethers such as 1,3-dioxolane since the hydrogen atom abstraction from the C–H bond in between the oxygen atom generates the highly unstable bridge-head radical intermediate. Hence, the oxidative esterification reaction occurs regioselectively. Further, the decarboxylative alkenylation of cyclic ether was executed using cinnamic acid as the substrate under the same reaction conditions. The possible mechanistic pathway was described as follows. Initially, μ-oxo, μ-carboxylic diiron(III) intermediate I is formed upon the reaction between the iron catalyst and carboxylic acid in the presence of an oxidant. Then, intermediate I is oxidized to Fe(IV) intermediate II, followed by its reaction with the cyclic ether, generating intermediate III. Finally, the cross-coupling from intermediate III affords the desired product with concomitant regeneration of the Fe(III) species.

Scheme 179 Iron-catalyzed direct C–O bond formation.

Additionally, the intermolecular competitive kinetic isotope effect (KIE = 3) suggests that cleavage of the C(sp³)–H bond adjacent to the oxygen atom may be involved in the rate-determining step (Scheme 180). Based on the same concept, in 2017, Liu and Ying reported an alternative method using Fe^IIITECPCl/DTBP as the catalyst/oxidant (Scheme 181) for the synthesis of ester derivatives.²³⁴ This reaction was suggested to follow a similar mechanistic pathway as mentioned above to give the regioselective product.

Scheme 180 Probable mechanistic pathway for direct C–O bond formation.

Scheme 181 Iron porphyrin-catalyzed coupling of cycloether and aromatic acid.

3.2 CDC between C (sp³)–H and X(sp²)–H bonds

3.2.1 Carbon–carbon (C–C) bond formation.
3.2.1.1 Benzylic C(sp³)–H bond. Shi et al. in 2009 reported a method regarding the cross-dehydrogenative arylation (CDA) of benzylic C–H bonds of electron-rich arenes in the presence of FeCl₂ and DDQ as the oxidant (Scheme 182).²³⁵ Various diarylmethanes and electron-rich arenes are well tolerated and the desired products are obtained in good yield regioselectively. Notably, an increase in the yield of the product was observed upon increasing the nucleophilicity of the electron-rich system. Thus, this suggests that the reaction proceeds via the Friedel–Crafts electrophilic substitution-type mechanistic pathway. Further, a double CDA product is obtained in high yield in the presence of more electron-rich arenes (i.e. 1,2,3-trimethoxy benzene).

Scheme 182 Iron-catalyzed CDA between aryl C–H and benzylic C–H bonds.

Mechanistically, the diarylmethane undergoes the SET process to form the benzyl radical in the presence of an iron catalyst. This benzyl radical further undergoes another SET process to form the benzyl cation. Subsequently, Friedel–Crafts-type alkylation by the electron-rich arenes followed by abstraction of a proton by the reduced hydroquinone affords the desired product via the regeneration of the catalyst (Scheme 183). The large intramolecular kinetic isotope effect (K_H/K_D = 6.0) indicates that the cleavage of the benzylic C–H bond is involved in the rate-determining step of the reaction.

Scheme 183 Probable reaction mechanistic pathway of iron-catalyzed cross-dehydrogenative arylation (CDA).

In their subsequent studies, they considered that the electron-rich alkene as the nucleophile, which can react with the in situ generated carbocationic intermediate. However, in their initial studies, they found that styrene can be applied to construct the C–C bond with diphenylmethane by CDC via a Heck-type reaction. Unfortunately, styrene with electron-rich or electron-deficient substituents in its phenyl ring fails to afford the desired product. Subsequently, instead of styrene, they used 1-aryl vinyl acetate, which smoothly afforded the cross-coupling product in good to excellent yield in the presence of FeCl₂/DTBP as the catalyst/oxidant system. Notably, the observed electronic feature of the substrate diarylmethane does not support the hypothesis of pathway B (Scheme 185).

The synthetic transformation produces the keto product with vinyl acetate via a pseudo C(sp³)–C(sp³) coupling (Scheme 184), different from the product obtained from styrene.²³⁶ Various vinyl acetates and diarylmethanes were tested under the optimized conditions. Both the electron-withdrawing groups and electron-donating groups on the phenyl ring of the diarylmethanes were well tolerated. Notably, the synthetic transformation also tolerates simple toluene and provides a moderate product yield.

Scheme 184 Iron-catalyzed benzylic C–H activation for C–C bond formation.

According to their proposed hypothesis, the reaction is started with the abstraction the benzylic C(sp³)–H in presence of iron salt and DTBP and generates the radical intermediate I (Scheme 185). Then the radical intermediate is oxidized to generate the benzyl carbocation intermediate IIvia the single electron transfer (SET) process. The reaction may proceed through two possible pathways (A and B) involving the reactive intermediates I and II. In the pathway A, the radical intermediate I, iron catalyst and tert-butoxy radical (generated from di-tertiarybutyl peroxide, DTBP) undergoes electrophilic addition with aryl-vinyl acetate to form Fe coordinated radical intermediate III which subsequently results information of the desired product via the β-session with the regeneration of Fe(II) catalyst as well as AcOt-Bu as by-product. On the other hand, in pathway B, the benzyl cation intermediate II is intercepted by the vinyl acetate to produce the desired product. An intermolecular competitive kinetic isotopic effect (K_H/K_D = 2.4) have indicated involvement of proton abstraction in the rate-determining step.

Scheme 185 Mechanistic pathway of iron-catalyzed C–H activation for C–C bond formation.

Later, Li et al. reported another method describing FeBr₃-catalyzed cross-dehydrogenative arylation (CDA) of 3-substituted oxindoles with electron-rich arenes and heteroaromatic compounds under aerobic conditions (Scheme 186).²³⁷ This reaction provides 3,3-disubstituted oxindoles in moderate to good yield.

Scheme 186 Iron-catalyzed CDA between 3-substituted oxindoles and arenes.

Recently in 2019, Nishikata and co-workers reported a reaction protocol for the tertiary C–H alkylation of heteroarenes via the iron-enhanced reactivity of radicals for the generation of functionalized quaternary carbons (Scheme 187).²³⁸ Notably, bromides possessing alkyl, aryl, arylester, and arylamide groups are well tolerated under the reaction conditions. Moreover, substituted benzofurans, thiophenes and furan derivatives having alkyl, ketone and aldehyde groups were found to be well compatible. Here, the alkyl radical is generated through the abstraction of Br from the α-bromocarbonyl compound via the SET pathway with an iron(II) salt to generate the oxidised iron(III) species. Subsequently, iron(III) co-ordinates to the carbonyl group of the resulting alkyl radical having enhanced reactivity.

Scheme 187 Iron-catalyzed tertiary C–H alkylation of heteroarenes and plausible mechanism.

Actually, the co-ordination of Fe^III species with the carbonyl group of the alkyl radical was confirmed by DFT studies. Interestingly, only tertiary C–H alkylation is possible using this reaction protocol. Neither the primary nor the secondary alkyl radical reacts with heteroarenes because of the lower stability of these radicals. Moreover, the desired product was not obtained in the presence of the radical scavenger BHT or TEMPO. Thus, this suggests that the reaction proceeds via the radical pathway. Initially, tertiary alkyl radical I is generated by the reaction between Fe(II) and the α-bromocarbonyl compound. Then, radical I undergoes addition to the C-2 position (highest nucleophilicity calculated by Fukui indices) of benzofuran to form II. Subsequently, intermediate II reacts with the iron bromide species to generate III together with the regeneration of Fe(II). Finally, intermediate III undergoes elimination in the presence of base to afford the desired product (Scheme 187).

3.2.1.2 CDC with C(sp³)–H bond adjacent to heteroatom. Tetrahydroisoquinolines (THIQs) and indoles are very common substructures found in medicinal products and natural products. In 2009, Li et al. developed a one-pot reaction protocol for the oxidation of C–H bonds adjacent to the oxygen atom with an indole derivative in the presence of FeCl₂ as the catalyst and di-tertiary butyl peroxide (DTBP) as the oxidant.²³⁹ The reaction proceeds via C–O bond cleavage (Scheme 188). Mechanistically, the in situ-generated indole–ether adduct reacts effectively with another molecule of electron-rich indole to give the 1,1-biaryl product (Scheme 189). The synthetic transformation follows the Friedel–Crafts alkylation-type reaction. Only the mono indolation product of isochroman is selectively obtained with the electron-poor 4-nitro indole. Thus, this indicates that the first indolation step is easy and does not depend on the properties of indole, while the second indolation step is the rate-determining step and proceeds efficiently only with electron-rich indoles.

Scheme 188 Iron-catalyzed tandem C–H bond oxidative coupling.

Scheme 189 Possible mechanistic pathway for the iron-catalyzed synthesis of 1,1-bis-indolylmethanes.

Later, in 2010, Schnürch and co-workers reported an efficient solvent- and ligand-free iron-catalyzed method for the indolation and arylation of N-Boc-protected tetrahydroisoquinolines (THIQs) and isochromans, respectively.²⁴⁰ Among the different iron salts such as FePO₄, Fe₂(SO₄)₃, and Fe(NO₃)₂·9H₂O, the iron-nitrate salt exhibits the best catalytic activity (Scheme 190). Moreover, no desired product is obtained without the use of the oxidant TBHP. Notably, this reaction fails when molecular oxygen is used as the oxidant with or without the presence of the radical inhibitor azobisisobutyronitrile (AIBN). Various electron-withdrawing groups such as nitro and chloro and electron-donating groups (e.g. 5-OCH₃) at the C-5 position of the indoles are well tolerated under the reaction conditions. However, the free amine and the ester functionality on the indole provide very poor yields of the desired product. Importantly, azaindoles and electron-rich arenes can also be used as suitable substrate materials besides indoles. Interestingly, isochromans can also be employed as the starting substrate in place of THIQs. Although the cross-dehydrogenative coupling between isochromans and indoles yielded the bis-indolation product,²⁴¹ the coupling between the electron-rich 1,4-dimethoxy benzene and isochroman afforded the desired arylation product in 55% yield. In previous reports,²⁴² the deprotection of the protecting groups (PG) after the indolation step failed. However, this report mentioned the effective cleavage of the Boc-protecting group under high-temperature microwave conditions within a few seconds to give the product in good yield.

Scheme 190 Iron-catalyzed oxidative indolation and arylation.

Notably, this practical oxidative reaction is completely suppressed when 1.5 equivalents of the radical scavenger TEMPO is added. Thus, the reaction mechanism proceeds via the radical pathway. The most probable mechanistic pathway is depicted in Scheme 191. Initially, the iron catalyst coordinates to the NH of the indole and the carbonyl of the Boc-protecting group, forming complex A. Thereafter, the addition of THBP leads to iron-mediated cleavage of peroxide, which results in the formation of a water molecule via hydrogen abstraction from THIQ. Subsequently, coordination of the tert-butyl group to the iron centre occurs. Then radical addition leads to intermediate C, which undergoes oxidation to afford the desired product.

Scheme 191 Proposed mechanistic pathway of iron-catalyzed indolation and arylation.

Afterwards, Ge and Zhou reported the CDC reaction of coumarins with ethers in the presence of an iron catalyst via the C(sp³)–H bond oxidation of ethers in 2015.²⁴³ Notably, this reaction is performed between different ethers and various coumarins having electron-withdrawing groups and electron-donating groups, which provides a moderate to good yield of ether-substituted coumarin derivatives. However, the reaction between electron-withdrawing nitro-substituted coumarins with 1,4-dioxane cannot afford the desired product. Mechanistically, the in situ-generated radical attacks the α-position of coumarin esters to form more a stable radical intermediate. Thus, α-ether-substituted coumarin derivatives are obtained in a regiospecific manner (Scheme 192). Here, DABCO is used as the ligand. A trace amount of desired product is obtained in the absence of the ligand.

Scheme 192 Iron-catalyzed CDC between coumarins with ether.

In the same year, Correa et al. reported the direct α-arylation of ethers with azoles in the presence of FeF₂/TBHP as the catalyst/oxidant combination.²⁴⁴ Here, FeF₂ plays a major role in both heterolytic cleavage of the oxidant and oxidation of the carbon radical to the oxonium ion intermediate. Interestingly, several functional groups such as esters, amides, halides and ethers associated with benzothiazoles are well tolerated under the reaction conditions. However, substituted benzothiazoles with electron-deficient substituents provide a lower product yield. On the other hand, besides tetrahydrofuran, other cyclic and acyclic ethers such as 1,3-dioxalane and 1,4-dioxane are also used in the reaction. Moreover, this methodology is used for the synthesis of a variety of C2-alkylated products of (benzo)azoles constituting a straightforward strategy for the generation of medicinally important heterocyclic compounds (Scheme 193).

Scheme 193 Iron-catalyzed arylation of ethers with azoles.

Itami and Wunsh in 2009 reported the iron-catalyzed oxidative coupling of N-methyl amines with different heteroarenes.²⁴⁵ The reaction mainly proceeds via the formation of the iminium ion intermediate by the abstraction of a hydrogen atom predominately from the methyl C–H bond of N-methyl. The transformation takes place selectively in the N-methyl C–H bond in the presence of other reactive C–H bonds such as acidic benzylic C–H bond and the C–H bond α to the carbonyl group in the substrate. This oxidative coupling transformation was applied to the intermolecular oxidative coupling between thiophene, furans and indoles with methylamines (Scheme 194). Further, this methodology was applied for intramolecular oxidative coupling for the formation of benzazepine-like bicyclic nitrogen heterocycles. However, a low GC yield (27%) of the product was recorded. The reason for the low yield of the product was attributed to the difficulty in the cyclization step to form seven-member rings. However, the product shows good binding affinity and selectivity towards σ₁,²⁴⁶ σ₂, and NMDA²⁴⁷ receptors (Scheme 195).

Scheme 194 Iron-catalyzed oxidative coupling between heteroarenes and N-methyl amines.

Scheme 195 Intramolecular oxidative coupling for the synthesis of benzazepine-like bicyclic nitrogen heterocycle.

In 2012, Deng et al. developed a novel method for the tandem cross-dehydrogenative coupling (CDC) of terminal allylic C(sp³)–H with C(sp²)–H of styrene via benzoannulation in order to synthesize polysubstituted naphthalene (Scheme 196).²⁴⁸ They mainly utilized styrene (1.5 equivalents) and FeCl₃ (2 equivalents) in nitromethane at room temperature to afford biologically and synthetically important polysubstituted naphthalenes. Initially, substrate 1 reacts with an allylic methyl group syn to the 1-phenyl group via CDC reaction in the presence of 20 mol% FeCl₃ to afford the desired product. Further, the authors speculated about the possibility of C–C bond coupling between styrene and its derivative together with the in situ-generated carbocation species from substrate 1.

Scheme 196 Iron-catalyzed synthesis of naphthalenes via a tandem CDC process.

The substrate scope for the above-mentioned transformation has been tested. Substrates with strong electron-donating substituents on either Ar₁ or Ar₂ do not provide the desired product. Other weakly electron-donating and electron-withdrawing substituents on either Ar₁ or Ar₂ give moderate to good yield of the substituted naphthalene. Interestingly, in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), no desired product is obtained. This implies that the reaction occurs via a radical intermediate (Scheme 197).

Scheme 197 Possible mechanistic pathway for iron-catalyzed tandem CDC.

In 2013, You and co-workers described the oxidative coupling of N-(pyridine-2-ylcarbonyl)-substituted α-amino acid derivatives with indoles in the presence of FeCl₃·6H₂O/DTBP (Scheme 198).²⁴⁹ The 2-pyridine carbonyl group is an ideal substituent as the N-protecting group due to its high coordinating and better elimination ability. Other activating substituents at the amino group, i.e. imidazol-2-ylcarbonyl, 2-quinolin-2-ylcarbonyl, isoquinoline-1-ylcarbonyl and pyrimidin-2-ylcarbonyl groups, are found to be less effective. Also, non-nitrogen-containing substituents are not effective under this synthetic transformation. This method has been well explored with various functional groups on both α-amino acids and nucleophiles. It affords a series of α-quaternary α-amino acid derivatives in good yield. Mechanistically, it is presumed that the 2-picolinamido-α-tertiary amino acid coordinates with Fe^III to form intermediate I. Then, the tert-butoxy radical (generated from DTBP) abstracts α-H from the intermediate to generate radical intermediate II. Radical intermediate II undergoes an SET process to form α-ketimine intermediate III. Thereafter, the addition of nucleophile to radical intermediate III is facilitated due to the coordination of Fe²⁺ with the picolin-amido group. Notably, this coordination mainly activates the α-ketimine to afford α-quaternary α-amino acid esters as the product. Interestingly, this reaction was also carried out under an N₂ atmosphere, and the desired product was obtained in 39% yield. This suggests that the re-oxidation of the released Fe²⁺ occurs in the presence of air and di-tertiarybutyl peroxide (DTBP) to complete the catalytic cycle (Scheme 199).

Scheme 198 Iron-catalyzed oxidative coupling between the α-C(sp³)–H bonds of α-quaternary α-amino acid esters and arenes.

Scheme 199 Plausible mechanism of the C(sp³)–H bond oxidation of α-substituted α-amino acid ester.

Doyle and co-workers in the same year reported the FeCl₃-catalyzed aerobic C–H bond functionalization of tertiary anilines including tetrahydroisoquinolines.²⁵⁰ The reaction protocol affords facile functionalization with siloxyfuran, nitroalkanes and other nucleophiles using the cheap FeCl₃ as a the catalyst and the green oxidant O₂. The oxidation of tertiary anilines under the Fe(III)/O₂ system forms a reactive iminium ion intermediate. This intermediate undergoes an oxidative Mannich reaction to give the corresponding product with various nucleophiles. The addition of one equivalent of weak acid such as 1,1,1,3,3,3-hexafluro-2-propanol (HFIP) is required to promote the oxidative aza-Henry reaction in the presence of coupling partner nitroalkanes to inhibit the coordination of Fe(III) with the amine reactant or to activate the nitroalkanes (Scheme 200).

Scheme 200 Iron-catalyzed aerobic C–H functionalization of tertiary anilines.

After exploring the substrate scope of the reaction, it was proposed that the electron transfer between FeCl₃ and amine produced the radical cation and iron(II) chloride. This process may be feasible by considering the redox potential comparison between the Fe(III)/Fe(II) (+0.77 V vs. NHE) and amine/radical cation redox pairs (+0.79 V/+1.08 V vs. NHE). The abstraction of one hydrogen atom from the radical cation generates the iminium-ion intermediate through iron(II)-bound dioxygen. The resultant peroxo-species enters the Haber–Weiss or Fenton-like reaction to complete the process (Scheme 201).

Scheme 201 Possible reaction mechanism for the iron-catalyzed aerobic C–H functionalization of tertiary anilines.

Later in 2018, Wan and Guo reported a synthetic method for the iron-catalyzed C-2 cyanomethylation of indoles and pyrroles via direct oxidative CDC with acetonitrile derivatives.²⁵¹ The best yield of the product is obtained by performing the reaction under an argon atmosphere (Scheme 202). Notably, this synthetic method tolerates different C-3-substituted indoles and furnishes the desired product in good yield. This method is facilitated in the presence of pyrimidinyl as the directing group. Interestingly, changing the directing group from pyrimidinyl to pyridyl, Me or Ac group leads to a decrease in the yield. Notably, N-pivoloylindol as the N-protecting group delivers the C3-cyano methylation product instead of the desired C2-cyano methylation product. This method is also well compatible with aurin, tryptophan and melatonin analogues, leading to the formation of the corresponding products. The corresponding product of the tryptophan analogue is used for rapid diversification for the synthesis of non-natural amino acids. On the other hand, the product obtained from melatonin is utilized as a dietary supplement and neuro-hormone drug discovery.

Scheme 202 Iron-catalyzed C-2 cyanomethylation of indoles.

Based on the experimental findings and literature studies, a plausible mechanistic pathway was proposed. Initially, the Fe(OAc)₂ catalyst is oxidized by DTBP to give the active Fe(III) species I and tert-butoxy radical. Subsequently, the tert-butoxy radical abstracts the hydrogen atom from acetonitrile to form radical II. On the other hand, the coordination-based directed C–H insertion of N-(2-pyrimidyl)-indole 1 with Fe(III) species generates metallacycle intermediate III together with the formation of tert-butyl alcohol. Radical II reacts with intermediate III and generates another organoiron intermediate IV. Finally, the desired product 2 is obtained via reductive elimination together with the regeneration of the Fe(II) system, completing the catalytic cycle (Scheme 203).

Scheme 203 Probable mechanistic pathway of iron-catalyzed C-2 cyanomethylation of indoles.

3.2.2 Carbon–nitrogen (C–N) bond formation through CDC.
3.2.2.1 C–N bond formation with benzylic C(sp³)–H bond. In 2011, Chen and Qiu reported an iron-catalyzed C–N bond formation method between the imidazole moiety and benzylic hydrocarbons (Scheme 204).²⁵² This reaction was investigated with the starting material having no pre-functionalization. Thus, it is a technique for the direct amidation of benzylic C(sp³)–H bonds to form valuable nitrogen-containing compounds. Mechanistically, a benzyl cation intermediate undergoes nucleophilic attack by the imidazole moiety. In 2012, Chen et al. reported a similar synthetic method.²⁵³ In 2014, Bolm et al. developed an efficient method for C–N bond formation by hetero-CDC between sulfoximines and diarylmethanes.²⁵⁴ This reaction results in the formation of N-alkylated sulfoximines with α-branched substituents (Scheme 205).

Scheme 204 Iron-catalyzed C–N coupling of imidazoles and benzylic compounds.

Scheme 205 Iron-catalyzed CDC between sulfoximines and diarylmethanes.

3.2.2.2 C(sp³)–H bond adjacent to heteroatom. In 2010, Li et al. reported the N-alkylation of azoles via the oxidation of C(sp³)–H bonds adjacent to the oxygen atom of ether (Scheme 206).²¹⁸ This reaction was performed with a variety of azoles and ethers after establishing the optimized conditions, affording the desired product in good to excellent yield. In 2015, Wang and He reported a similar type of method using aryl tetrazole as the coupling partner.²⁵⁵

Scheme 206 Iron-catalyzed N-alkylation of azoles.

The probable reaction mechanism is described in Scheme 207. Mechanistically, the nucleophilic attack of intermediate I (which is formed via the abstraction of a proton from azoles) to oxonium ion intermediate III affords the desired product. The electronic property of the azoles in this reaction was investigated by a competition experiment. The result of the competition experiment indicates that the reactivity of the azole is related to the nucleophilicity of its conjugate bases rather than its acidity. This is in good accordance with the nucleophilic reaction. Further, the observed primary kinetic isotope effect (K_H/K_D = 4.0) suggests that the cleavage of the α-C–H bond to the oxygen atom of ether is involved in the rate-determining step (Scheme 207).

Scheme 207 Plausible mechanistic pathway for the N-alkylation of azoles.

In 2012, Chen et al. described another method for the N-alkylation of azole derivatives with amides and sulfonamides (Scheme 208).²⁵⁶ This reaction proceeds via the oxidative cleavage of the C(sp³)–H bond adjacent to the nitrogen atom of amides and sulfonamides to give a variety of azole derivatives. These azole derivatives are structural motifs in N-heterocyclic carbene (NHC) and ionic liquids. A similar reaction protocol was reported by Reddy et al. in 2015.²⁵⁷ In 2013, Bao et al. developed a reaction protocol demonstrating the intramolecular oxidative amination of aryl hydrazones for the generation of indazoles using FeBr₃/O₂ as the catalyst/oxidant system (Scheme 209).²⁵⁸ They also synthesized 1,3,5-trisubstituted pyrazoles of phenylhydrazones via intramolecular oxidative coupling.

Scheme 208 Iron-catalyzed N-alkylation of azoles.

Scheme 209 Iron-catalyzed synthesis of indazoles and pyrazoles.

In 2014, Hazra and co-workers reported an iron-catalyzed oxidative deamination procedure for the regioselective synthesis of functionalized imidazopyridine derivatives (Scheme 210).²⁵⁹ The coupling reaction is carried out between 2-aminopyridine and nitroalkane to afford the imidazopyridine derivative. Notably, 2-aminopyridine with methyl substitution irrespective of the position on the pyridine ring affords the desired the product in good yield. Moreover, nitroalkane and the other coupling partners of the reaction having different functionalities such as –Me, –SMe, –Cl, and –F, and having acid-sensitive groups (such as –CO₂Me and oxymethylene) are well tolerated under the reaction conditions. Notably, aliphatic nitroalkanes such as 3-methyl-1-nitro-1-but-ene and (2-nitrovinyl)cyclohexane do not give any product. Further, the reaction protocol was applied to styrenes to react with 2-aminopyridine. The reaction with styrene requires an extra requirement of an oxidant (TEMPO) and provides good yields of the imidazopyridines. Based on preliminary observations, the authors presumed that the reaction starts with (Scheme 211) the Michael addition of 2-amino pyridine with nitroalkane, generating adduct compound I. Then, the oxidation of adduct compound I occurs by the iron catalyst through the SET process followed by cyclization and deprotonation, resulting the desired product.

Scheme 210 Iron-catalyzed synthesis of imidazopyridine.

Scheme 211 Probable mechanistic pathway for the iron-catalyzed synthesis of imidazopyridine.

3.2.3 Carbon–oxygen (C–O) bond formation through CDC. In 2009, Li et al. reported a methodology involving FeCl₃·6H₂O-catalyzed tandem oxidative coupling and annulations between phenols and β-keto esters for the generation of polysubstituted benzofurans (Scheme 212).²⁶⁰ Among the various types of iron salts, FeCl₃·6H₂O was found to be the best. Notably, para-substituted phenols having substitutions such as methyl, tert-butyl, –CH₂Ph, and chloro, and ortho-substituted phenols having allyl and –CH₂Ph substitutions are well tolerated under the reaction conditions. Contradictorily, phenols with strong electron-withdrawing groups such as nitro and acetate do not give any product. The water of crystallization present in the ferric chloride salt plays a vital role in the transformation. The reaction is completely inhibited in the presence of 4 Å molecular sieves. Thus, it has been proposed that water may help in the proton transfer process involved in the reaction. The transformation is promoted in the presence of other proton sources such as methanol, ethanol, acetic acid, benzoic acid and tert-butanol. The primary kinetic isotope effect study (K_H/K_D = 1.0 ± 0.1) indicated the non-involvement of aromatic C–H bond cleavage in the rate-determining step.

Scheme 212 Iron-catalyzed tandem oxidative coupling and annulations between phenols and β-keto esters.

Mechanistically, the reaction initiates with the formation of Feⁿ⁺-chelated species I followed by reductive elimination to produce adduct II. Then, adduct II undergoes tautomerisation to form phenol III, which subsequently undergoes intramolecular condensation to afford the desired product. The iron catalyst in this method plays a dichotomous catalytic role. It acts as a transition metal catalyst in the oxidative coupling step and a Lewis acid in the condensation step (Scheme 213). This methodology was applied to the total synthesis of coumestrol.²⁶¹ Particularly, it was utilized for the first stage of the two-step synthesis (Scheme 214). It mainly involves a modified aerobic oxidative cross-coupling reaction between 3-methoxy phenol and 2-(2,4-dimethoxy benzoyl)acetate in the presence of FeCl₃/2,2 bipyridine/DTBP as the catalyst/ligand/oxidant system. The coupled product undergoes sequential deprotonation followed by lactonization, affording coumestrol in 59% overall yield.

Scheme 213 Probable mechanistic pathway for the iron-catalyzed oxidative reaction of phenols and β-keto esters.

Scheme 214 Total synthesis of coumestrol via iron-catalyzed CDC.

Recently in 2018, Xuan and co-workers carried out the formal synthesis of lithospermic acid via the CDC reaction between ortho-bromo phenol and β-keto ester (Scheme 215).²⁶²

Scheme 215 Formal synthesis of lithospermic acid via CDC.

3.3 CDC between C(sp³)–H and C(sp)–H bonds

In 2009, Vogel et al. developed a chemoselective method for the FeCl₂-catalyzed oxidative coupling of silyl group-protected terminal alkynes with two different tertiary amines.²⁶³ Notably, the methyl amino group reacts much more rapidly than the other alkyl amino groups present in the substrate. Interestingly, the reaction protocol was successfully applied to a large variety of aromatic and aliphatic amines in the presence of FeCl₂/DTBP as the catalyst/oxidant system. The chemoselectivity of the reaction originates from the steric hindrance of the substituents of the substrates. Mechanistically, the FeCl₂ catalyst generates the iminium ion intermediate via the SET oxidation process (Scheme 216). Then, the intermediate is attacked by the nucleophile, the alkynyl carbanion, to form coupled product I. Thereafter, treatment with tetra-n-butylammonium fluoride (TBAF) removes the triethyl silyl group and generates aniline derivative II. Further, compound II reacts with another alkynyl moiety in the presence of an iron catalyst and DTBP, which results in the formation of asymmetric diamine via a double CDC process.

Scheme 216 Chemoselective iron-catalyzed oxidative coupling with two different tertiary amines.

Subsequently, Hu et al. reported an efficient route for the synthesis of quinolines via the FeCl₃-catalyzed oxidative coupling of N-aryl glycine derivatives with alkynes.²⁶⁴ This methodology results in the synthesis of a series of substituted quinolines in good yield. Notably, C(sp³)–H/C(sp)–H coupling followed by intramolecular Friedel–Crafts reaction is responsible for the formation of the desired product (Scheme 217).

Scheme 217 Synthesis of quinolines by iron-catalyzed oxidative coupling of N-arylglycine derivatives.

3.4 CDC between C(sp²)–H and X(sp³)–H bonds

Subsequently, in the same year, Sun et al. reported an environmentally benign methodology for the amination of benzoxazoles with the green oxidant H₂O₂.²⁶⁵ This one-pot synthesis involves two steps. Initially, the ring opening of benzoxazole generates the amidine intermediate, followed by iron-catalyzed oxidative intramolecular cyclization to afford the desired product (Scheme 218).

Scheme 218 Iron-catalyzed amination of benzoxazoles with hydrogen peroxide.

In 2014, Lei and co-workers developed an efficient method for the oxidative coupling of amides with aldehyde using FeBr₂ as the catalyst and TBHP as the oxidant.²⁶⁶ A variety of amides and aldehydes were explored as substrates under the optimized conditions for the direct formation of imine product. Mechanistically, the aryl bromide intermediate is formed in situ from aldehyde and reacts with amides to provide the desired product (Scheme 219).

Scheme 219 Iron-catalyzed oxidative coupling between amides and aldehydes.

3.5 CDC between C(sp²)–H and X(sp²)–H bonds

3.5.1 C(sp²)–H bonds of arenes. Biaryl coupling is one of the most important tools in organic synthesis. In 2008, Wang et al. reported a facile and efficient protocol involving an intramolecular oxidative coupling reaction using iron(III) chloride as the catalyst for the synthesis of phenanthrene-9-carboxylic acid from a mixture of E and Z-2,3 biphenyl acrylic acid. The reaction is performed at room temperature and excellent yields of products are obtained (Scheme 220).²⁶⁷ Moreover, this methodology has been utilized for the synthesis of naturally occurring alkaloids such as tylophorine, deoxytylophorinine and antofine.

Scheme 220 Iron-catalyzed intramolecular biaryl coupling.

Later, in 2010, Zhang et al. reported a method for the synthesis of 3,3′-biindolyl derivatives, implicating the intermolecular oxidative homocoupling of indoles using iron(III) chloride as the catalyst under aerobic conditions (Scheme 221).²⁶⁸ Additionally, Zheng et al. reported the synthesis of fused porphyrin dimers by intermolecular homo-coupling using Fe(OTf)₃ as the catalyst.²⁶⁹ In 2011, Chandrasekharam and co-workers reported the iron-catalyzed cross-dehydrogenative coupling (CDC) of two aromatic compounds using TBHP as the oxidant (Scheme 222).²⁷⁰ This direct oxidative coupling is very selective for the formation of the C–C bond at the ortho position to the functional group of the substrate. Notably, various substitutions on anilines such as alkyl, halide, alkoxy and cyano groups are well tolerated under the reaction conditions. However, electron-donating alkoxy substituted anilines exhibited a reduction in yield. This C–C bond-forming methodology affords a variety of functionalized 2,2′-disubstituted biaryl compounds. Notably, this method does not give any homo-coupled product under the mild optimized conditions due to the sufficient difference in the oxidation potential between the two coupling partners (difference of 440 mV). Moreover, this methodology is not sensitive to air or moisture. In 2013, they synthesized various anilido-dibenzo furanols by applying the above methodology. Notably, these products have moderate to good antimicrobial activity.²⁷¹

Scheme 221 Iron-catalyzed intermolecular oxidative homo-coupling of indoles.

Scheme 222 Iron-catalyzed direct biaryl coupling.

Later on, Pappo et al. described an efficient method for selective oxidative unsymmetrical biphenol coupling using FeCl₃/DTBP as the catalyst/oxidant system in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) solvent (Scheme 223).²⁷² The kinetic studies of the reaction protocol support the formation of the chelated radical-anion coupling mechanism, where both phenolic partners are attached to the catalyst during the C–C bond-forming step. The mechanistic pathway is shown in Scheme 224. Initially, two phenolic partners A and B undergo reversible binding with peroxide and iron salt to form complex I. The peroxide bond is cleaved from the metal, followed by an SET process to generate phenoxyl A˙ radical-bound complex II. This particular step is involved in the rate-limiting step. The latter electrophile reacts with chelated phenol(ate)complex B to form III or with a second chelated phenol(ate) A in a homo-coupling process. The desired products including biphenol and tert-butyl alcohol are obtained by the ligand exchange process.

Scheme 223 Iron-catalyzed oxidative unsymmetrical biphenol coupling.

Scheme 224 Probable mechanistic pathway of chelated radical-anion oxidative coupling.

The chemoselectivity of the reaction is determined by the phenol oxidation step and coupling step. Additionally, based on the mechanistic study, the authors proposed a general model (Scheme 225) regarding the feasibility of the cross-coupling reaction for the given pair of phenols. This is well supported by the electrochemical method and density functional theory calculations. They specifically proposed some key factors as follows: (i) phenol A undergoes selective oxidation to phenoxyl radical A in the presence of the other phenol partner B (E_oxA < E_oxB), (ii) the coupling reaction takes place via the radical-anion coupling pathway, and (iii) phenol B is a stronger nucleophile than phenol A (N_A > N_B) (where N is the theoretical global nucleophilicity).

Scheme 225 General concepts for the cross-coupling of phenols.

3.5.2 C(sp²)–H bond of alkenes. In 2010, Liang et al. reported a synthetic procedure for the preparation of indoles via iron-catalyzed direct oxidative coupling. The iron catalyst in combination with quantitative oxidant Cu(OAc)₂–CuCl₂ facilitates the C(sp²)–C(sp²) coupling.²⁷³ The conversion towards the desired product is very low in the absence of an iron catalyst. Thus, the involvement of an iron catalyst is essential for this reaction.

Mechanistically, an iron–copper bimetallic chelate complex is believed to be formed via the coordination of nitrogen and the double bond (Scheme 226). This helps to enhance the reactivity of the enolates. Further, electrocyclic ring closing within the chelated complex results in the formation of key intermediate I. Finally, a proton is eliminated from I to give aromatically stable indole derivatives. The substrate scope for this method was well studied. It was found that the electron-donating group at the para position and electron-withdrawing group at the ortho position produce the desired product in high yield.

Scheme 226 Iron-catalyzed direct oxidative coupling for the synthesis of indoles.

In 2015, Lei and co-workers described a novel chemoselective method related to the oxidative C(sp²)–H/C(sp²)–H cross-coupling reaction between electron-rich arenes and alkenes using FeCl₃/DDQ as the catalyst/oxidant system (Scheme 227).²⁷⁴ In this method, the direct arylation product is obtained using diarylethylenes as the substrate, whereas the double arylation product is obtained using styrene derivatives as the substrate. Notably, various diarylethylenes such as 2-2′-(ethane-1,1-diyl)dinaphthalene and 1,1-dinapthalenes possessing electron-withdrawing and electron-donating groups are well tolerated under the reaction conditions. Further, the radical trapping experiment and EPR (electron paramagnetic resonance) study support that the reaction proceeds via the radical pathway. Notably, DDQ plays a key role in the formation of the aryl radical. Further, the XAFS (X-ray absorption fine structure) study revealed that the oxidation state of the iron catalyst does not change during the reaction. Thus, it can be proposed that FeCl₃ acts as a Lewis acid catalyst. Mechanistically, electron-rich arenes are oxidized by DDQ to form the aryl radical. Then the aryl radical is intercepted by the C=C bond (from olefins) to yield the radical intermediate, which then undergoes oxidation to form the cation, followed by the elimination of one proton to afford the desired triarylethylene product (Scheme 228).

Scheme 227 Iron-catalyzed oxidative coupling between electron-rich arenes and diarylethylenes.

Scheme 228 Probable mechanistic pathway for CDC between electron-rich arenes and diaryl-ethylenes.

3.5.3 C(sp²)–H bond of carbonyl. In 2013, Studer and co-workers developed a facile method describing iron-catalyzed CDC via base-promoted homolytic aromatic substitution (BHAS) for the synthesis of fluorenones and xanthones (Scheme 229).²⁷⁵ The synthetic method is executed with readily accessible ortho-formyl biphenyls and ortho-formyl biphenyls ethers using TBHP as the oxidizing agent to synthesize fluorenones and xanthones, respectively. Notably, various formylated biaryls having electron-donating groups (e.g. methyl, tert-butyl, and OMe) and electron-withdrawing groups (e.g. F, Br, and SiMe₃) at the para position of the radical-accepting arenes are well tolerated under the reaction conditions. However, the meta-substituted congener reacted with low regioselectivity. In contrast to the common BHAS reaction, this reaction does not require a halide as a radical leaving group and an external strong base. Consequently, it helps to enhance the step efficiency and atom economy of the overall process. From a mechanistic viewpoint, it was presumed that initially, the tert-butoxy radical is formed in the presence of TBHP and Fe(II) salt (Scheme 230). Thereafter, the radical abstracts the hydrogen atom from aldehyde to form acyl radical I, which attacks the arenes to form cyclohexadienyl radical II, followed by deprotonation via an in situ-generated hydroxide anion (OH⁻), producing biaryl radical anion III. Finally, radical anion III reacts with tert-butyl hydroperoxide (TBHP) to afford the desired product. Notably, there is no need for an external base due to the in situ generation of the basic hydroxide anion (OH⁻).

Scheme 229 Iron-catalyzed CDC via base-promoted homolytic aromatic substitution (BHAS).

Scheme 230 Plausible mechanistic pathway for BHAS reaction.

In 2015, Li et al. reported a reaction protocol regarding the oxidative coupling of alkenes with the C(sp³)–H bonds of formamide. They employed two sets of reaction conditions, depicted as pathways A and B (Scheme 231A and B, respectively). Firstly, the tert-butoxy peroxide radical is formed in the presence of tert-BuOK and TBHP. Then, this radical abstracts a hydrogen atom from the C(sp³)–H bond of formamide. However, the ability of alkenes to react with the C(sp³)–H bond of formamide decreases due to presence of FeCl₃ and the tert-butoxy radical in pathway B.²⁷⁶ Noteworthily, the tert-butoxy radical is consumed by Feⁿ⁺¹ to form the Feⁿ⁺(t-BuO) species. Thus, it suppresses the formation of the t-BuOO˙ radical. The reaction initiates upon the generation of carbonyl radical I by hydrogen atom abstraction from formamide by the tert-butoxy radical. Then, radical I reacts with alkenes to generate alkyl radical II. Subsequently, radical II is converted to Fe³⁺(Ot-Bu) and an alkyl cation(III) via the SET process in the presence of Fe³⁺. Finally, β-hydrogen elimination from alkyl cation III by the tert-butoxy anion and base, DABCO, gives the desired product and tert-butanol (Scheme 232).

Scheme 231 Oxidative coupling of alkenes with formamide.

Scheme 232 Probable mechanistic pathway for the direct oxidative coupling between alkenes and formamide.

Later, in 2016, Hazra and co-workers reported a direct method for the 1,2-dicarbonylation of imidazoheterocycles using oxoaldehydes through cross-dehydrogenative coupling in ambient air using FeCl₃ as the catalyst in toluene (Scheme 233).²⁷⁷ The present reaction protocol is also applicable to indolizines. Moreover, imidazopyridine produces bisimidazopyridine with arylaldehyde under the optimized reaction conditions.

Scheme 233 Iron-catalyzed CDC between imidazoheterocycles and oxoaldehydes.

Based on experimental evidence, they proposed the possible mechanism of the reaction. It was presumed that the reaction occurs via a non-radical pathway. Initially, FeCl₃ catalyses the addition of phenylglyoxal to benzo[d]imidazo[2,1-b]thiazole at the C-3 position to generate Fe(III)-chelated benzo[d]imidazo[2,1-b]thiazole intermediate I. Then, the Fe(III)-based intermediate is oxidized to Fe(IV)oxo complex II through aerial oxidation. Subsequently, the desired product is obtained via reductive elimination. Simultaneously, Fe(II) is oxidized to Fe(III) in the presence of air to complete the catalytic cycle (Scheme 234).

Scheme 234 Probable mechanism for iron-catalyzed CDC between imidazoheterocycles and oxoaldehydes.

3.6 CDC between C(sp³)–H with C(sp)–H

In 2009, Volla and Vogel et al. described the C(sp)–C(sp³) coupling reaction between terminal alkynes and tertiary amines (Scheme 235).²⁷⁸ Notably, FeCl₂ shows the best catalytic activity under the optimized reaction conditions. The desired product is obtained under the solvent-free conditions using FeCl₂/DTBP as the catalyst/oxidant system.

Scheme 235 Iron-catalyzed oxidative coupling between alkynes with dimethylanilines.

In 2011, Bobade et al. reported the iron-catalyzed oxidative alkylation of azoles with terminal alkynes under ligand- and solvent-free conditions.²⁷⁹ The reaction of phenylacetylene bearing an electron-donating group affords a higher yield, while an electron-withdrawing group results in a lower yield of the product due to the dimerization of the alkynes. Notably, the reaction mechanism is insensitive to the steric hindrance of the substituent on the terminal alkyne group. A series of 2-alkynylated benzoxazoles and benzothiazoles was obtained in high yield with the help of this method (Scheme 236). Mechanistically, deprotonation of azole at the C(2)–H bond takes place in the presence of DTBP to form an azole radical, which reacts with an in situ-generated iron-acetylide complex to give the 2-alkynylzole product via the regeneration of the Fe(II) species.

Scheme 236 Iron-catalyzed oxidative alkynylation of azoles with terminal alkynes.

Later, in 2012, Jiao et al. developed the oxidative coupling between terminal alkynes and benzylic ethers and alkanes.²⁸⁰ Notably, the Fe(OTf)₂ and DDQ combination shows the best catalytic efficiency (Scheme 237).

Scheme 237 Fe-Catalyzed oxidative coupling between terminal alkynes with benzylic ethers and alkanes.

3.7 Tandem carbon–carbon and C–Heteroatom oxidative coupling reaction

In 2012, Panda and Jena reported a synthetic method elucidating the tandem C–C and C–N oxidative coupling and subsequent annulation reaction for the synthesis of substituted pyrazoles.²⁸¹ The present method provides a route for the regioselective synthesis of 1,3-di- and 1,3,5-tri-substituted pyrazoles between hydrazones and vicinal diols using FeCl₃/TBHP as the catalyst/oxidant (Scheme 238). This reaction affords the desired product in good yields under aerobic conditions. Notably, the presence of an electron-donating group on the N-aryl group enhances the reactivity of hydrazone by increasing the nucleophilicity of the nitrogen. However, the presence of an electron-withdrawing group such as nitro on the N-phenyl ring retards the rate of the reaction. Furthermore, in this methodology, various electron-donating groups and electron-withdrawing groups at the C(3) position of the aryl ring are well tolerated under the reaction conditions.

Scheme 238 Iron-catalyzed synthesis of pyrazoles.

Further, the tandem C–C and C–N oxidative coupling and cyclization was reported in the same year by Hu and co-workers for the synthesis of quinolines between N-alkylaryl amines and alkenes (Scheme 239).²⁸² The thorough optimization of the reaction showed that the combination of FeCl₃ as the catalyst and di-tertiarybutylhydroperoxide (DTBP) as the oxidant provides the best yield. In 2015, Gopalaiah and Chandrudu reported the synthesis of various 1,3-benzazoles via the oxidative carbon–carbon, carbon–heteroatom coupling reaction (Scheme 240).²⁸³ The coupling reaction between benzylamines with 2-amino/hydroxyl/mercapto-anilines produces the desired substituted benzoxazoles, benzimidazoles, and benzothiazoles in moderate to good yields under aerobic conditions.

Scheme 239 Iron-catalyzed synthesis of quinolines.

Scheme 240 Iron-catalyzed synthesis of 1,3-benzazoles.

3.8 Different C–H functionalization reactions via CDC

Heteroaryl sulphides are important structural motifs in many pharmaceutically active compounds and advanced materials. Thus, the formation of heteroaryl thioethers via the direct thiolation of heteroarene C–H bonds with thiols is a very desirable method. In 2012, Gao and Yu reported a facile method for the copper(II)-mediated thiolation of the heteroarene C–H bond in the presence of a Lewis acid catalyst (i.e. FeF₂) (Scheme 241).²⁸⁴ The Lewis acid FeF₂ activates the heteroarenes, which are coupled with thiols in the presence of copper(II).

Scheme 241 Iron-catalyzed thiolation of heteroarenes.

Organophosphorus compounds are found in a wide range of nucleotides, pharmaceuticals and phosphine-containing ligands. They also play an important role in cell metabolism, growth, cell division and genetic processes. In 2009, Ofial et al. developed an efficient method for the iron-catalyzed oxidative α-phosphonation of tertiary amines with dialkyl H-phosphonates (Scheme 242).²⁸⁵ The reaction protocol affords the synthesis of new C–P bonds containing non-functionalized starting materials.

Scheme 242 Iron-catalyzed phosphonation of tertiary amines.

In 2010, Tatsumi and Ohki described a regioselective method involving dehydrogenative borylation of furans and thiophenes with pinacolborane using a coordinatively unsaturated NHC iron complex as the catalyst (Scheme 243).²⁸⁶ The reaction is carried out in the presence of tert-butylethylene to trap evolved hydrogen from the coupling partners during borylation. Further, it facilitates the reaction to proceed in the forward direction. Notably, the reaction protocol is regioselective due to the formation of the borylated product at the 2(5)-position of heterocycles in good yield.

Scheme 243 Iron-catalyzed dehydrogenative borylation of heteroarenes.

In 2018, Darcel and co-workers reported a borylation method for the iron-catalyzed dehydrogenative borylation of terminal alkynes (Scheme 244).²⁸⁷ They used a catalytic system consisting of Fe(OTf)₂ (2.5 mol%) and DABCO (1 mol%). This catalytic system selectively promotes the dehydrogenative borylation of aromatic as well as aliphatic terminal alkynes to provide the alkynylboronate derivatives in the presence of 1 equivalent of pinacolborane at 100 °C in toluene. Notably, the presence of para-electron-withdrawing substitution on the arylacetylene derivatives requires a shorter reaction time compared to arylacetylene derivatives having para-electron-donating substituents. This methodology is applicable to a variety of terminal alkynes. However, the reaction protocol is not compatible with terminal alkynes possessing primary amine, alcohol or carboxylic acid derivatives. Mechanistically, the Lewis acid Fe(OTf)₂ activates the B–H bond of pinacolborane to enhance the electrophilicity of the boron centre to react with the acetylenic derivative. This process is accelerated due to the presence of DABCO, which helps to increase the nucleophilicity of the terminal alkylenic carbon.

Scheme 244 Iron-catalyzed dehydrogenative borylation of terminal alkynes.

Carbon–heteroatom especially carbon–sulphur (S) and selenium (Se) bonds are very common in natural products and pharmaceuticals. Recently, in 2019, Xu et al. established an iron-catalyzed CDC reaction protocol for the direct synthesis of C(sp³)–S/Se bonds from oxindoles, phenylacetamides, pyrazolones, phenylacetonitrile and ethyl cyanoacetate with thiols and selenols using FeCl₃/K₂CO₃ as the catalyst/base system in DMSO solvent (Scheme 245).¹⁹³ Here, molecular oxygen is employed as an ideal green oxidant. Notably, this reaction is broadly used in the chemical industry and in the modification of drugs.

Scheme 245 Iron-catalyzed CDC of oxindoles.

After exploring the substrate scope, they performed a radical trapping experiment to gain mechanistic insight. Interestingly, in the presence of TEMPO, no desired product was obtained. Thus, this suggests that the reaction proceeds via the involvement of radical intermediates. Based on the preliminary observations, a plausible mechanistic pathway was hypothesized (Scheme 246). Initially, indolin-2-one is readily oxidized to the corresponding radical Ivia the single-electron transfer (SET) pathway in the presence of a base. Meanwhile, disulfide II is generated by the oxidative coupling of thiols in the presence of molecular oxygen. Finally, radical intermediate I attacks disulfides II to afford the desired product IV together with sulfide radical III. This sulfide radical is converted to disulfides in the presence of oxygen.

Scheme 246 Plausible mechanistic pathway of CDC of oxindoles.

4. Decarboxylative coupling

Metal-mediated decarboxylative coupling is a powerful strategy to form carbon–carbon and carbon–heteroatom bonds, involving less expensive and commercially available carboxylic acids and their derivatives.²⁸⁸ Generally, in this strategy, the C–C bond next to carboxylate groups is cleaved, whereas a new C–C bond or C–heteroatom bond is formed. This decarboxylative coupling is an alternative strategy to traditional cross-coupling reactions involving organometallic reagents. In this section, we discuss iron-catalysed decarboxylative coupling reactions.

The iron-catalyzed decarboxylation of a variety of allylic phenols to form allylic ethers was described by Trivedi and Tunge²⁸⁹ in 2009. The decarboxylative allylation of the allylic phenol is catalyzed by Bu₄N[Fe(CO)₃NO] catalyst in the presence of PPh₃ using methyl tert-butyl ether (MTBE) as the solvent. Notably, this reaction takes place via the formation of a π-allylic iron intermediate instead of σ-allyl intermediate (Scheme 247). Moreover, the position of the oxygen nucleophile in the product is not dependent on the position of the leaving group in the reactant. Thus, this suggests that the reaction is regiospecific.

Scheme 247 Formation of the π-allylic iron intermediate.

Notably, the observed regioselectivity is a kinetic phenomenon and is not due to the equilibrium shifting to a more stable product. A variety of phenols having electron-withdrawing and electron-donating groups are well tolerated under the reaction conditions, obtaining good to excellent yields of the decarboxylating coupling products. The reaction protocol is also effective for the sterically demanding ortho-substituted phenolates (Scheme 248).

Scheme 248 Regioselective iron-catalyzed decarboxylative allylic esterification.

In 2011, Li and co-workers reported the iron-catalyzed decarboxylative cross-coupling reaction between proline derivatives and substituted β-naphthols to form C(sp²)–C(sp³) bonds.²⁹⁰ For example, N-benzyl proline and β-naphthol in the presence of FeSO₄/DTBP as the catalyst/oxidant system afford the desired product in moderate to excellent yield (Scheme 249). According to the proposed mechanism, initially, amino acid derivative 1 undergoes oxidative decarboxylation in the presence of iron(II) and oxidant to generate imine-type intermediate I (Scheme 250). Subsequently, the intermediate coordinates with iron, resulting in the formation of intermediate II. Finally, intermediate II undergoes coupling with the incoming nucleophile to afford the desired product via transient intermediate III. Concomitantly, the iron catalyst is regenerated.

Scheme 249 Iron-catalyzed decarboxylative C(sp³)–C(sp²) coupling of proline derivatives and β-naphthols.

Scheme 250 Proposed mechanism for iron-catalyzed decarboxylative coupling between proline and β-naphthol.

Later, in 2013, Pan and co-workers reported the decarboxylative coupling of aryl vinyl carboxylic acid with cycloalkanes using Fe(acac)₃/DTBP as the catalyst/oxidant system (Scheme 251).²⁹¹ The electron-donating group and electron-withdrawing group at any position of the aryl ring provide the desired product in excellent yields (84–91%). However, there is a slight decrease in the yield of the product with the ortho-substituted substrate. Further, a lower yield of product was obtained due to steric hindrance when 2,6-disubstituted aryl vinyl carboxylic acid was employed as the substrate. The reaction exclusively provides the trans-product in a stereospecific manner. The radical intermediate was trapped in the presence of several radical scavengers such as TEMPO or AIBN.

Scheme 251 Fe(acac)₃-catalyzed alkenylation of cycloalkane.

Thus, it was presumed that the reaction may proceed through the radical pathway (Scheme 252). Initially, Fe(III) catalyses the cleavage of DTBP to generate the tert-butoxy radical in the presence of aryl vinyl carboxylic acid. Then, the tert-butoxy radical (t-BuO˙) abstracts the hydrogen from cyclohexane to generate a cyclohexane radical. Thereafter, the radical attacks the α-position of the double bond to generate a more stable radical intermediate. Finally, the radical intermediate undergoes oxidative decarboxylation in the presence of Fe(III) to deliver the product. The Fe(III) catalyst is regenerated in the presence of DTBP and cinnamic acid via oxidation.

Scheme 252 Plausible mechanistic pathway of iron-catalyzed alkenylation.

Later, in the same year, they reported sp³(C)–sp²(C) coupling under similar reaction conditions by changing one of the coupling partners, i.e. cyclic ether instead of cycloalkane is used (Scheme 253).²⁹² Moreover, the reaction follows the same mechanistic pathway as stated above. Further, the substrate scope was explored under the optimal conditions. It was observed that the electronic effect of cinnamic acid hardly affects the reactivity. The substrate scope of cyclic ether was also tested. Notably, the reactions are also carried with tetrahydrofuran and tetrahydropyran. A lower yield is obtained with tetrahydropyran. Then, different types of heterocyclic acrylic acids such as thiophene and furan were also tested, which all afforded the desired product in good yield. Besides, they also explored the reaction protocol with 1-naphthyl acrylic acid, which provided the desired product in 73% yield.

Scheme 253 Fe(acac)₃-catalyzed alkenylation of cyclic ether.

Following the same concept, Mao and co-workers developed the direct alkylation of the sp³(C)–H bond of toluene via the decarboxylation of cinnamic acid under ligand-free conditions in a regioselective manner.²⁹³ Notably, they utilized the less expensive ferrocene as the catalyst and DTBP as the oxidant at 110 °C (under an argon environment) (Scheme 254). Interestingly, a good result was also obtained by using Fe₃O₄ in the form of nanoparticles (70–80 nm) as a reusable catalyst for seven cycles in the absence of ligand. The substrate scope for both coupling partners was investigated. It was found that electron-rich and electron-deficient cinnamic acid together with heteroaryl acrylic acid afford the desired product in good yields. Moreover, both mesitylene and xylene are well tolerated under the reaction conditions and only the mono-coupled product is obtained. Further, the observed primary kinetic isotope effect (KIE = 5) suggests the involvement of sp³(C)–H bond cleavage in the rate-limiting step.

Scheme 254 Iron-catalyzed alkenylation of toluene.

Notably, all the previous reactions were performed under inert conditions for 24 h to afford the product. Interestingly, when the reaction was carried out under aerobic conditions, it required a very short time (6 h) for completion. Recently, in 2018, following the aforementioned reaction protocol, Esteves and Buarque developed a cross-coupling reaction between cinnamic acid and 1,4-dioxane with excellent yield (86% yield) (Scheme 255).²⁹⁴ Here, FeCl₃·6H₂O is held in the pores of a layered crystalline imine-based mesoporous covalent organic framework (TPB-DMTP-COF) with the surface area of 1200 m² g⁻¹. The pores of 34 Å afford the material FeCl₃@TPB-DMTP-COF, which works as an iron-based heterogeneous catalyst. Basically, the nanopores within the COF are entropically favoured. Further, they increase the vibrational breathing modes and the local pressure, which are beneficial for the rate of reaction. The reaction method provides the trans-product stereoselectively. This can be explained based on the presence of a common radical intermediate, which gets enough time to equilibrate into the suitable conformation via the elimination of molecular CO₂ to afford the trans product.

Scheme 255 Iron-catalyzed alkenylation of cyclic ether under aerobic conditions.

In 2015, Guo and co-workers described the decarboxylative cross-coupling reaction between α-oxo carboxylic acid and acrylic acid under a nitrogen atmosphere using FeCl₂ as the catalyst and K₂S₂O₈ as the oxidant to give the α-β-unsaturated compound in high yield (84% yield) (Scheme 256).²⁹⁵ A broad range of substrates underwent this synthetic transformation with good functional group tolerance. Further, the yield of the reaction was improved by adding two equivalents of HCOO₂Na·2H₂O as a base. The best yield was obtained using a mixture of H₂O and DMSO (H₂O : DMSO = 17 : 3) as the solvent. Moreover, a trace amount of product was obtained in the presence of radical scavengers such as TEMPO or hydroquinone. Thus, it was suggested that the reaction may proceed via the radical pathway.

Scheme 256 Iron-catalyzed oxidative radical decarboxylative cross-coupling of α-oxocarboxylic acids.

Based on the literature and experimental observations, a plausible mechanistic pathway was proposed, involving radical intermediates (Scheme 257). Initially, acyl radical II is generated from α-oxocarboxylate 1 in the presence of FeCl₂ and K₂S₂O₈via oxidative radical decarboxylation. Notably, 21% yield of the desired product was obtained without the addition of FeCl₂. This result suggests that α-oxocarboxylate 1 is activated only by K₂S₂O₈ to produce intermediate II. Then, the addition of benzoyl radical II to the double bond of acrylic acid III results in a more stable radical intermediate IV. Then radical intermediate IV undergoes β-elimination to afford the desired product 2 together with the release of a second molecule of carbon dioxide (CO₂). Further, a gram-scale synthesis was performed for the above-mentioned reaction protocol. The reaction of 1.5 g (10 mmol) of benzoylformic acid with 2.0 equivalents of cinnamic acid generated the desired product in 62% yield under the standard conditions.

Scheme 257 Mechanistic pathway of iron-catalyzed oxidative radical decarboxylative cross-coupling reaction.

The quinazolinones are an important class of nitrogen heterocycles found in a large number of natural products having a broad range of biological activity. Generally, the condensation reaction between o-aminobenzimide and aldehyde/alcohol/carboxylic acid together with their derivatives are required for the synthesis of the quinazoline moiety. However, Kumar and co-workers reported the iron(III) chloride-catalyzed decarboxylative deaminative functionalization of phenylglycine.²⁹⁶ A one-pot synthetic route starting with less expensive nitroarenes for the formation of quinazolinones and the benzimidazole moiety was developed in this reaction protocol. Various 2-nitrobenzonitriles and phenyl glycine in the presence of 10 mol% of FeCl₃ in toluene with 2 equivalents of K₂CO₃ as the base (at 120 °C) yielded the desired product in high yield (Scheme 258). Electron-withdrawing groups such as chloro, bromo, nitro, and trifluoromethyls are well tolerated.

Scheme 258 Iron-catalyzed decarboxylative–deaminative functionalization of phenyl glycine derivatives.

Notably, benzimidazoles are obtained by the reaction between 2-nitro-N,N-diphenylamine and phenyl glycine under the same reaction conditions (Scheme 258). The reaction mechanism was proposed based on several experiments and a literature survey (Scheme 259). Firstly, phenyl glycine 2 undergoes decarboxylation and deamination constructively to convert into benzaldehyde in the presence of a metal catalyst. The ammonia generated during the deamination process reduces the nitro group of 2-nitrobenzonitrile 1 in the presence of FeCl₃ to form 2-aminobenzonitrile F. Then, intermediate F and benzaldehyde condense to form imine G, which undergoes controlled base-induced hydration to form X. Then, intermediate X cyclises to provide 2,3-dihydroquinazoline-4(1H)one H. Intermediate H may also be beneficial for the conversion of 1 to Fvia the well-known transfer hydrogenation²⁸⁸ and is converted to the desired product 3.

Scheme 259 Plausible mechanistic pathway for the synthesis of 4(3H)-quinazolinone synthesis.

Recently, in 2019, Jin and Sun reported the iron-catalyzed regioselective decarboxylative alkylation of coumarins and chromones with alkyl diacyl peroxides.²⁹⁷ The alkyl diacyl peroxide is easily synthesized from the corresponding carboxylic acid. This alkyl diacyl peroxide is easily decomposed to form an alkyl radical in the presence of an iron catalyst. The present reaction method is regioselective since the in situ-generated alkyl radical attacks the α-position of coumarin 1 having a higher electron density than the β-position. On the other hand, a similar electron-rich alkyl radical attacks the β-position of chromone 2 instead of the α-position since it possesses a higher electron density (Scheme 260).

Scheme 260 Iron-catalyzed decarboxylative alkylation of coumarin and chromone.

Notably, coumarin having electron-withdrawing groups or electron-donating groups at the 6-position of the aromatic ring are well tolerated. Even strong electron-withdrawing groups such as nitrile (CN) and nitro (NO₂) are also well tolerated in this decarboxylative coupling, affording the α-substituted product in good yield. Moreover, coumarins having an electron-donating group or electron-withdrawing group at the 7/8 position of the aromatic ring were found to be compatible with the above reaction method. This method was also explored for a variety of alkyl diacyl peroxides.

Based on controlled experiments and literature reports, a probable mechanism was proposed (Scheme 261). Initially, iron(III) in the presence of alkyl the radical is reduced to iron(II). Then, iron(II) is oxidized by alkyl diacyl peroxide to provide alkyl radical I by the extrusion of molecular CO₂via an SET process. Alkyl radical I attacks the coumarin and chromone in the preferable position to form radicals II and III, respectively. Finally, radical intermediates II and III are converted to the desired products 3 and 4 through the elimination of alkyl-COOH by the SET process, respectively.

Scheme 261 Proposed mechanism of iron-catalyzed decarboxylative alkylation.

5. Iron-catalyzed insertion reaction

5.1 Carbene and nitrene insertion

Iron–porphyrin and related complexes are known to carry out numerous reactions in biological and synthetic systems and insertion reactions are not the exception. Gross and co-workers showed that both corrole and porphyrin-based iron complexes are effective towards carbene insertion in N–H, O–H and olefinic double bond (Scheme 262).²⁹⁸ Ethyl diazoacetate (EDA) was used as the carbene precursor for N–H insertion of various aniline derivatives and morpholine. Interestingly, in the presence of both aniline and olefin, insertion takes place completely in the N–H bond only with the iron–corrole complex, thus providing high selectivity. Subsequently, Woo's group reported iron(III)tetraphenylporphyrin chloride, Fe(TPP)Cl, as an effective catalyst for N–H carbene insertion.²⁹⁹ In addition to EDA, dimethyl diazomalonate and methyl phenyldiazoacetate were tested successfully as carbene sources. The Hammett study suggested that the transition state is partially cationic in nature, and is stabilized by the resonance effect to some extent. The nucleophilic attack by the amine nitrogen on the electron-deficient carbene carbon was also implied from the negative value of reaction constant (ρ). This is consistent with the reluctance of a second N–H insertion due to the decrease in the nucleophilicity of the nitrogen centre. Interestingly, the intermediate formed after nucleophilic attack from amine is trapped with β,γ-unsaturated α-keto esters to form three-component products (Scheme 263).³⁰⁰ This reaction uses mild conditions and only 1 mol% of the porphyrin catalyst to synthesise complex molecules.

Scheme 262 Iron–porphyrin-catalyzed carbene insertion.

Scheme 263 Carbene insertion into C–H and O–H bonds.

In the presence of a catalytic chiral bisoxazoline ligand, FeCl₂·4H₂O can catalyse the insertion of carbene into O–H bonds (Scheme 264).³⁰¹ Not only various alcohols are compatible with this method, but α-diazoarylacetate-derived carbenes can be enantioselectively inserted to water O–H bonds with more than 90% yield and 90% ee in most cases. Structural rigidity of the ligand is presumed to be crucial in order to control the enantioselectivity. Moreover, a variety of structurally complex chiral molecules can be synthesized from the appropriate products including the drug clopidogrel. Similar chiral spirobisoxazoline ligands have also been used for carbene insertion into N-substituted indoles at the electronically favoured C-3 position, although with moderate ee.³⁰² The KIE was determined to be 5.06, which is indicative of proton transfer in the rate determining step.

Scheme 264 Iron–terpyridine complex-mediated nitrene insertion.

Che's group utilized the ligand 4,4′,4′′-trichloro-2,2′:6′,2′′-terpyridine for complexation with iron as a catalyst for nitrene transfer reaction to olefins. N-Tosyl-iodinanes (PhINTs) and N-nosyl-iodinanes (PhINNs) were used as the nitrene precursor to afford aziridines in excellent yields.³⁰³ The heterogenized version of the catalyst is derived by attaching the catalyst to poly(ethyl glycol), and similar result was obtained for aziridination. Also, 2-azidoarylimine obtained from 2-azidoaniline and aldehyde can undergo intramolecular nitrene insertion into the imine C(sp²)–H bond in the presence of catalytic FeBr₂.³⁰⁴ The dearomatised intermediate formed (Scheme 265) undergoes tautomerization to form benzoimidazole derivatives. Various aryl aldehydes and 2-azidoaniline react successfully; however, aliphatic aldehydes do not produce any products.

Scheme 265 Nitrene insertion into imine C–H bond.

The [Fe^III(F₂₀-tpp)Cl] (F₂₀-tpp = meso-tetrakis(pentafluorophenyl)porphyrinatodianion) complex is also found to be effective towards nitrene insertion in the olefinic double bond and C–H bond (Scheme 266).^305,306 In the presence of N₃-R, mono olefinic substituted styrenes produce aziridines, whereas α-substituted styrenes yield allylic amines. In the case of alkylarenes, C–H insertion has been observed at the benzylic position. A plethora of substrates were reported by Che's group to undergo nitrene insertion by this method. They were also successful in synthesizing N-heterocycles via intramolecular insertion. Indole, indoline, tetrahydroquinoline and highly decorated quinazolinone and dihyroquinazoline can be synthesized by utilizing a single method. The indole synthesis of azidoacrylate was later simplified by Bolm's group using only Fe(OTf)₂ as the catalyst and β-azido cinnamic esters as the substrate.³⁰⁷ The theoretical study on [Fe^III(F₂₀-tpp)Cl] revealed that an iron-nitrene intermediate indeed plays a crucial role and the N₂ liberation step is the probable rate-determining step.³⁰⁸ When the indoline formation reaction was carried out with a substrate such that the product formed has a leaving group present at the C-2 position (e.g. –OR) (Scheme 267), an unexpected alkyl migration was observed, forming an 2,3-dialkyl-substituted indole derivative.³⁰⁹ This behaviour was presumed to occur via the formation of an iminium ion upon removal of the leaving group, and subsequent proton abstraction. The groups of both Chan and Che also independently documented nitrene insertion into the aldehyde C–H bond using FeCl₂ in conjunction with a pyridine-based ligand (Scheme 268).^310,311

Scheme 266 Iron–porphyrin-catalyzed intramolecular nitrene insertion.

Scheme 267 Formation of 2,3-disubstituted indoles.

Scheme 268 Nitrene insertion into aldehyde C–H bond.

Betley and co-workers described that iron dipyrromethene complexes are capable of amination at the benzylic position of toluene in the presence of alkylazide (Scheme 269).³¹² The very high k_H/k_D value of 12.8 indicates C–H activation as the rate-determining step. Moreover, the observation of 1,2-diphenylethane in the reaction mixture is indicative of radical formation. Also, the formation of an Fe-imide intermediate was confirmed by X-ray crystallography. Thus, the authors proposed the most plausible mechanistic cycle for the formation of the Fe-imide intermediate from the iron dipyrromethene complex and alkylazide, which abstracts a hydrogen from toluene. Then the benzyl radical rebounds with the amide ligand co-ordinated with iron to form the final amine product (Scheme 270). Further, the kinetic isotope effect study gave a high value of primary KIE = 12.8, excluding the possibility of an insertion pathway.

Scheme 269 Iron dipyrromethene-catalyzed C–H nitrene insertion.

Scheme 270 Proposed mechanism of iron-dipyrromethane-catalyzed C–H amination.

Che's group explored the scope of iron-imide mediated amination using the [Fe(qpy)(MeCN)₂](ClO₄)₂ (qpy = 2,2′:6′,2′′:6′′,2′′′:6′′′,2′′′′-quinquepyridine) complex and PhINR.³¹³ They were also able to synthesize various heterocycles through intramolecular amination. In another report, Betley's group used aliphatic alkylazides to form various pyrrolidine derivatives catalyzed by a similar system (Scheme 269).³¹⁴ The famous pentadentate non-heme iron complex [Fe(N4Py)(CH₃CN)](ClO₄)₂ (N4Py = N,N-bis(2-pyridyl-methyl)bis(2-pyridyl)methylamine) was used by Liu's group to achieve amination of the benzylic C(sp³)–H bond using TsNBrNa as the amine source (Scheme 272).³¹⁵

The Lewis acidic Fe(OTf)₂-catalyzed carbene insertion in the Si–H bond was reported by Ollevier's group (Scheme 271).³¹⁶ Under the optimized conditions, α-aryl-α-diazoacetates were reacted with R₃SiH in the presence of 5 mol% of iron catalyst in CH₂Cl₂ at 40 °C. The enantioselective version of the reaction was also developed using a chiral hexamethyl-1,1′-spirobiindane-based bisoxazoline ligand (HMSI-BOX) with excellent ee.³¹⁷ In another report, diazoacetonitrile was used as the carbene source for insertion into N–H and S–H bonds, thus providing α-amino nitriles and α-mercapto nitriles as products.

Scheme 271 Carbene insertion into Si–H and N–H bonds.

Scheme 272 Fe–N4Py complex-catalyzed nitrene insertion.

In 2014, Betley and co-workers developed a chemoselective method depicting iron-catalyzed intermolecular C–H amination of olefinic substrates in the presence of dipyrrinato iron catalysts 1 and 2 and organic azides (Scheme 273).³¹⁸ During the course of the reaction, the iron catalyst reacts with the organic azide and forms high-spin iron-imido radical intermediate 3, which actively executes the C–H amination reaction.

Scheme 273 Iron-mediated N-group transfer reaction with olefinic substrates.

Notably, it was suggested that the unique electronic structure of iron-imido intermediate 3 governs the chemoselectivity of the reaction. The present synthetic method tolerates different benzylic substrates and styrenyl substrates to give C–H amination and aziridination products, respectively. More interestingly, the α-linear olefinic substrates (during reaction with catalyst 2) containing allylic C–H bonds exclusively provide the amination product at the terminal position with no formation of aziridine products.

Thus, the observed regioselectivity was rationalized based on the steric bulk between the ligand backbone and the adamantyl imido fragment. Further, the reaction between iron catalysts with cis-β-methyl styrene exclusively provides the linear allylic amination product, suggesting the involvement of H-atom abstraction followed by radical recombination to give the amination product.

Later in 2017, following their work in 2013, they reported another method for the iron-dipyrrinato complex-catalyzed diastereoselective synthesis of 2,5-disubstituted pyrrolidines from aliphatic azides (Scheme 274).³¹⁹ Interestingly, in this method, the dipyrrinato–iron phenoxide complex shows the best diastereoselectivity among other variant of catalysts. Different aliphatic azides containing both electron-donating and electron-withdrawing substituents are well amenable to provide the desired products. Notably, among the iron alkoxide and aryloxide catalysts, iron phenoxide 4 was found to be the best to exhibit high diastereoselectivity. Moreover, from the mechanistic investigation with experimental and theoretical studies, it was suggested that the reaction may occur via a direct C–H amination pathway (as shown in Scheme 270).

Scheme 274 Iron-catalyzed diastereoselective C–H amination of disubstituted pyrrolidines.

Recently, Arnold's group reported a number of pioneering works on iron co-factor-containing artificial metalloenzyme-catalyzed C–H functionalization. In the very first example of carbene insertion into the C–H bond catalyzed by metalloenzymes, they utilized mutated P411s derived from P450_BM3 of Bacillus megaterium (Scheme 275). After screening a variety of catalysts, P411-CHF was found to be best for the selective benzylic C–H alkylation via carbene insertion.³²⁰ An enantiomeric ratio of up to 98.6 : 1.4 and turnover number of up to 2150 were obtained with this methodology at ambient temperature. Various substituents at the benzene ring such as methoxy, bromo, and silyl are well tolerated under the reaction conditions. It was presumed that the reaction proceeds via the formation of a high-valent iron(enzyme)–carbene intermediate. Fascinatingly, this particular catalyst selectively delivers benzylic alkylation over cyclopropanation in the presence of an olefinic double bond. Moreover, they applied the method during the formal synthesis of lyngbic acid. This protocol was further extended to carbene insertion into allylic, propargylic and α-amino C–H bonds.

Scheme 275 P411-CHF-catalyzed asymmetric carbene insertion.

In a subsequent report, Arnold's group found that the P411-PFA variant effectively catalyzes the α-amino C–H fluoroalkylation of aryl dialkyl amines (Scheme 276).³²¹ Both diazotrifluoroethane and diazopentafluoropropane are compatible alkylating agents for various N-alkyl anilines to provide a turnover number of up to 2100. Notably, the use of aryl pyrolidines as the substrate yields R-enantiomer of the alkylated product with excellent ee with the present catalyst. Moreover, they also found that a quadruple mutant enzyme, P411-PFA-(S), was equally effective in producing the S-enantiomer. This strategy was also extended to (α)diazo-(γ)lactones as a carbene source with a linage of P411–C10 variants (Scheme 277).³²²

Scheme 276 Heme–iron metalloenzyme-catalyzed asymmetric fluoroalkylation.

Scheme 277 Site-selective amidation of indoles with P411-IA enzyme variants.

Meanwhile, they also explored nitrene insertion reactions into C–H bonds using mutated iron-heme enzymes. Upon testing various mutants, it was observed that P411-IA and a few of its variants were effective for the C2 amidation of indoles with sulfonyl azides (Scheme 278).³²³ Although the scope of the reaction was not studied in detail, promising numbers with respect to yields and turnovers were obtained.

Scheme 278 Intramolecular asymmetric amination.

The systematic mutation of the P411 enzyme provides extremely effective P411_Diane variants for intramolecular nitrene insertion into C–H bonds (Scheme 279).³²⁴ Sulfamyl azide was used to produce the nitrene intermediate, which is inserted enantioselectively in the enzymatic environment into an activated C–H bond to form a chiral 5-6-membered diamine thiadiazolidine dioxide. Both secondary and tertiary C(sp³)–H bonds adjacent to arene or olefin can be subjected to insertion. Not only various substituents on the arene ring such as methyl, halide, and methoxy are compatible with the reaction protocol, but thiophene instead of arene also provided the desired product in 99% ee. Another variant of P411_Diane (P411_Diane1I327P) was then established to be effective for the same reaction with primary.

Scheme 279 Asymmetric amination of benzylic and allylic C–H bond.

C–H bonds with excellent ee. Moreover, similar to carbene insertion, slight modification of the protein chain affords the reverse enantioselectivity. The computational study supports that the heme-ferrous cofactor first forms iron-nitrenoid species with the azide, which then abstracts hydrogen from the C–H bond to form a carbon-centered radical. The protein chain controls enantioselective rebound between the carbon radical and nitrogen provides the chiral insertion product.

Recently, Arnold's group established similar enzyme-catalyzed amination at the benzylic and allylic positions.³²⁵ They presumed that pivolylammonium triflate would provide an unprotected iron-nitrenoid intermediate with heme iron and deliver selective insertion with the help of a systematically mutated protein chain. Indeed, the P411–B2 variant was found to be excellent for this purpose. High yield and enantioselectivity were obtained under the reaction protocol for various cyclic and acyclic benzylic and allylic substrates.

6. Iron-catalyzed cross-coupling reaction

Metal-catalyzed cross-coupling is a standard tool for carbon–carbon bond formation. Its importance is due to its extensive application in the synthesis of many natural products, pharmaceutically active compounds, polymers and various fine chemicals. The cross-coupling between organic electrophiles and organometallic nucleophiles in various hybridization is catalyzed by transition metals. This field is dominated by the late transition metals such as palladium, iridium and rhodium.^5–7 However, presently the world needs green and cheaper alternatives to late transition metals. Notably, iron has been found to be one of the best alternatives since it is abundant, cheap, non-toxic and environmentally benign. Overall, it presents a greener approach for carbon–carbon cross-coupling reactions. Here, we well document the iron-catalyzed cross-coupling reactions with detailed mechanistic discussions.

The early reports of iron catalysis were found from the work of Kharash in 1941¹⁵ and Kochi in 1971.¹⁸ However, despite these early reports, iron catalysis remained unexplored for a long time until Caheiz significantly highlighted its high synthetic potential in 1998.³²⁶ Since then, a renaissance commenced in this field with an immense increase in the number of reports and reviews.^{3h,3l,327–354}

Here, we focus on presenting an overview of the thorough development of iron catalysis in carbon–carbon cross-coupling reactions from Kharash's and Kochi's early work to recent investigations. Generally, iron-catalyzed cross-coupling involves two different types of coupling partners, one is electrophilic and the other is nucleophilic. In this section, we divide this topic into subsections based on the type of electrophiles and nucleophiles used in the reaction.

6.1 Cross-coupling of alkenyl and alkynyl electrophiles with various nucleophilic partners

6.1.1 Halides as electrophilic partners.
6.1.1.1 Cross-coupling with alkylmagnesium nucleophiles. The first iron-catalyzed cross-coupling between alkenyl halide and alkyl Grignard reagent was reported by Kochi and Tamura in 1971 (a, Scheme 280).¹⁸ This reaction proceeds stereospecifically, giving the E or Z cross-coupled product from the corresponding E or Z vinyl bromides.^18b In this context, the use of an iron catalyst containing a diketone ligand such as Fe(dbm)₃ (dbm = dibenzoylmethane) shows the highest conversion rate using less vinyl bromides.^18d

Scheme 280 Cross-coupling of alkenyl halides and alkyl Grignard reagents.

While investigating Kochis's work, in 1998 Caheiz et al. found that using NMP (N-methylpyrrolidione) co-solvent increases the yield to a greater extent (b, Scheme 280).^355,356 High stereoselectivity has also been reported for the reaction conditions. In addition, the dialkylation of 1,1-dichoro-1-alkenes in the presence of Fe(acac)₃ catalyst was reported.³⁵⁷ Surprisingly, the presence of NMP in this dialkylation reaction decreases the yield. However, tetrahydrofuran (THF) as the solvent at −30 °C provides a good product yield.

In 2012, Caheiz et al. showed the use of iron(II) arylthiolates as a potent catalyst for the coupling of alkenyl halides with alkyl Grignard reagents (c, Scheme 280).³⁵⁸ Notably, the use of NMP as a co-solvent, which is classified as reprotoxic, is avoided in the reaction. The products are observed in high yields with complete retention of the configuration at the double bond.

Thomas and co-workers developed a cross-coupling reaction between alkenyl halides and Grignard reagents, affording alkanes in moderate to high yields (Scheme 281).³⁵⁹ This cross-coupling is performed using a dipyridyldiiminoiron(II) complex as the catalyst. The post-synthesis reduction of alkene to alkane is performed using N,N-dimethylaminoborohydride as the reducing agent.

Scheme 281 Iron-catalyzed hydride-mediated reductive cross-coupling.

Recently in 2019, Noël and co-workers presented a selective and practical method for the cross-coupling of alkynyl chlorides with alkylmagnesium halides in the presence of iron catalysts and NHC ligand (Scheme 282a).³⁶⁰ The catalytic system with iron(III) acetylacetonate and SIPr·HCl affords the best result. They also coupled styrenyl chlorides with Grignard reagents in the presence of the same iron catalyst without any ligand (Scheme 282b). Notably, various electro-neutral, electron-donating and electron-withdrawing substituents are well tolerated with both styrenyl and alkynyl chlorides, giving excellent yields of the desired coupled product. The stereochemistry of the β-chloro styrene substrates is retained in the coupled products. Further, they combined the formation of a Grignard reagent and iron-catalyzed cross-coupling reaction in a single continuous flow process. This uninterrupted flow process results in both the C(sp)–C(sp³)- and C(sp²)–C(sp³)-coupled product with the same stereoselectivity and yields in absence of a ligand. Additionally, around the same time, Caheiz et al. introduced a very potent method for the cross-coupling between alkenyl halides and alkyl Grignard reagents, giving high yields of coupled products on the gram scale (Scheme 283).³⁶¹ The reaction is successfully performed using a catalytic amount of iron(III) chloride in the presence EtOMgCl in THF. The latter is prepared by the metalation of EtOH with isopropylmagnesium chloride in THF. A wide variety of Grignard reagents undergo the stereoselective cross-coupling reaction, producing high to excellent yields of desired olefins with complete retention of stereochemistry. Notably, the use of alkoxide magnesium salts provides a cheap and eco-friendly alternative to the toxic NMP additive or expensive ligand.

Scheme 282 Cross-coupling of alkenyl and alkynyl halides with alkylmagnesium halides.

Scheme 283 Iron-catalyzed cross-coupling of alkenyl halides and alkyl Grignard reagents.

6.1.1.2 Cross-coupling with aryl magnesium nucleophiles. Kochi in his works demonstrated the first iron-catalyzed cross-coupling of phenylmagnesium bromide with an alkenyl halide, but the yield was poor (a, Scheme 284).^18c Later, Molander et al. investigated on the same reaction and modified it.³⁶² They reported that the use of DME and decreasing the temperature can significantly increase the yield (32% to 62%) (b, Scheme 284). Later, Cahiez et al. mentioned the use of sulfolane in placing of NMP as a cosolvent to increase the yield of the Fe(acac)₃-catalyzed cross-coupling of alkenyl bromide and phenylmagnesium chloride (c, Scheme 284).³⁵⁵

Scheme 284 Iron-catalyzed arylation of alkenyl halides.

In 2011, von Wangelin and co-workers reported a domino process involving the iron-catalyzed preformation of aryl Grignard reagent and subsequent cross-coupling with alkenyl bromides.³⁶³ The catalytic system consists of iron(III) chloride with TMEDA (N,N,N′,N′-tetramethylethelenediammine) in a 1 : 4 ratio. This catalytic solvent serves for both the aryl Grignard formation and the cross-coupling (d, Scheme 284). Notably electron-rich aryl bromides and heteroaryl bromides are incompatible in this method due to the incomplete formation of the Grignard reagent and side reaction. They require an iron-free preformation using Mg and LiCl (e, Scheme 284). Both procedures result in the formation of high yields of corresponding styrene derivatives. The iron-catalyzed stereoselective Kumada–Corriu cross-coupling was used as a key step in the synthesis of the anticancer agent combrestatin-A-4.³⁶⁴ Additionally, the large-scale synthesis of the calcium sensing receptor antagonist cinacalcet hydrochloride was reported using alkenyl chloride and aryl Grignard in the presence of Fe(acac)₃.³⁶⁵

Further in 2012, synthetically important and biological motif 1,1-diarylethylenes were prepared via a cross-coupling reaction catalyzed by an iron–copper co-catalyst system. Polyoxygenated 1-halostyrenes are coupled with aryl Grignard reagents in the presence FeCl₃ and copper(I) thiophene-2-carboxylate (CuTC) of the catalyst combination, affording good to excellent yields of the corresponding products (f, Scheme 284).³⁶⁶ However, the individual use of Cu and Fe catalysts gives unsatisfactory results. A large substrate scope was reported, ranging from electron-withdrawing group-substituted to electron-donating-substituted aryl Grignard reagents.

6.1.1.3 Cross-coupling with alkynyl magnesium nucleophiles. In 2008, Nakamura and co-workers demonstrated the iron(III) chloride-catalyzed reaction between alkynyl Grignard nucleophiles and alkenyl bromides (Scheme 285).³⁶⁷ The reaction provides a very efficient pathway for the synthesis of conjugated enynes. The enynes are significantly used in many bioactive molecules and drug intermediates. Moreover, lithium salts such as LiBr and LiCl accelerate the reaction significantly. An Fe(0)/Fe(II) catalytic cycle was proposed in this methodology.

Scheme 285 Coupling of alkynyl Grignard nucleophile and alkenyl bromide.

6.1.1.4 Cross-coupling with organomanganese nucleophiles. In 1996, Caheiz and co-workers performed a reaction between alkenyl halides and alkylmanganese chlorides in the presence of iron catalysts. They obtained very efficient conversion using Fe(acac)₃ in THF solvent together with NMP as the co-solvent. The substituted olefins were obtained with excellent stereoselectivity (Scheme 286).³⁶⁸

Scheme 286 Cross-coupling of alkenyl halides and organomanganese reagents.

Recently in 2019, Knochel and co-workers reported a method for the iron-catalyzed cross-coupling of alkenyl iodides and bromides with benzylmanganese halides in the presence of iron(II) chloride in THF (Scheme 287).³⁶⁹ The benzylmanganese reagents are readily prepared from the corresponding benzyl halides by treatment with manganese turnings and MnCl₂·2LiCl in THF. Various functionalized benzylmanganese reagents are added to the alkenyl electrophiles as and iodoacrylates derivatives with retention of the configuration at the double bond. Notably, high yields of polyfunctionalized alkenes are produced using this method. Through mechanistic studies, they suggested the formation of an iron(II) ate complex as the active species, which reacts with the alkenyl electrophile.

Scheme 287 Cross-coupling of alkenyl iodides with benzylmanganese nucleophiles in the presence of an iron catalyst.

6.1.1.5 Cross-coupling with organolithium nucleophiles. Recently in 2019, Wong et al. developed an efficient synthetic method involving an iron-mediated coupling reaction between organolithium compounds and alkenyl iodides (Scheme 288).^370,371 A large variety of substrates undergo stereospecific coupling, providing moderate to good yields of the coupled products. The best results were obtained using iron(III) acetylacetonate precatalyst and DavePhos as the ligand. The reaction protocol is also efficient for gram-scale synthesis, providing the respective desired product in satisfactory yields.

Scheme 288 Cross-coupling of alkenyl halides with organolithium reagents.

6.1.2 Sulphonate as the electrophilic partner.
6.1.2.1 Cross-coupling with organomagnesium nucleophiles. In cross-coupling reactions, enol triflates are preferred as the electrophilic partner due to their easy preparation from the corresponding ketones. Füstner et al. reported the cross-coupling of a large variety of alkenyl tosylates with alkyl and aryl Grignard reagent in moderate to high yields (a, Scheme 289).³⁷² The reaction was found to be highly regioselective. Thus, a large number of functional groups such as esters, ethers, carbamates, acetals and lactones are tolerated on the electrophilic partners.

Scheme 289 Cross-coupling reaction of alkenyl tosylates and organomagnesium reagent.

They proposed a low-valent Fe(II−) metal cluster having the formal composition of [Fe(MgX₂)]_n as the active site. This species is believed to be formed by the reduction of the iron precatalyst via β-hydride elimination. However, an effective reaction is also given by methylmagnesium bromide despite the absence of β-hydrogen. In this context, the presence of an iron–ate complex was predicted. Accordingly, successful coupling occurs by employing the ‘ate’ complex [Me₄Fe][Li₂(OEt)₂], resulting in high product yields.³⁷³ Notably, the reaction protocol was applied to the synthesis of many natural products such as latrunculin A^374,375 and latrunculin B.³⁷⁵ Also, the formal synthesis of latrunculins C, M and S was successfully performed using the same methodology. Fürstner et al. also demonstrated the formation and catalytic potential of a homoleptic organoferrate complex [(Me₄Fe)(MeLi)][Li(OEt)₂] in the iron-catalyzed cross-coupling of alkenyl triflate with methylmagnesium bromide.³⁷³

In 2008, Tam and co-workers developed an iron-catalyzed coupling reaction between a bicyclic alkenyl triflate and Grignard reagents. A wide range of aliphatic and aromatic Grignard reagents are coupled using Fe(acac)₃ as the precatalyst. The best yields are obtained using DMPU (DMPU = N,N′-dimethylpropyleneurea) or THF/NMP as the solvent at −25 °C (b, Scheme 289).^376,377 The disubstituted bicyclo cross-coupled product is also obtained in good yield (c, Scheme 289).

Furthermore, a successful method for the preparation of stereodefined β,β-disubstituted α,β-unsaturated esters was developed using an iron-catalyzed cross-coupling reaction (Scheme 290).³⁷⁸ Also, methoxy carbonyl group-substituted E- and Z-vinyl tosylates are efficiently coupled to Grignard reagents with complete stereoretention. The highest yields with E-enol tosylates are obtained using iron(III) chloride, whereas Z-enol tosylates prefer Fe(DMB)₃ (DMB = dibenzoylmethane) as the precatalyst. Notably, tetrahydrofuran (THF) was found to be the most suitable solvent for this transformation.

Scheme 290 Stereocomplementary iron-catalyzed cross-coupling of (E)- and (Z)-enol tosylates.

6.1.2.2 Cross-coupling with organocopper nucleophiles. In 2005, Knochel and co-workers introduced an iron-mediated coupling of alkenyl sulfonates using functionalized arylcopper reagents as the nucleophilic partners (Scheme 291).³⁷⁹ The desired olefins are obtained in good yields using Fe(acac)₃ as the catalyst in DME (DME = dimethoxyethane) solvent. Notably, arylcopper reagents are prepared from the corresponding arylmagnesium derivatives by treatment with a copper(I) cyanide–di(lithium chloride) complex.

Scheme 291 Cross-coupling of alkenyl sulfonates and organocopper reagents.

6.1.3 Phosphate as the electrophilic partner. Enol phosphates are also used as the leaving group in the electrophilic partner of cross-coupling together with tosylates and halides since they are easily accessible from the corresponding ketones. In 1998, Caheiz et al. were the first to introduce vinyl phosphate electrophiles in iron-catalyzed cross-coupling with butylmagnesium bromide.³²⁶ They prepared trisubstituted olefins from a Z/E mixture of enol phosphates in a stereoselective way (a, Scheme 292).³⁸⁰ The reaction proceeds with a kinetic differentiation between E and Z isomers. In a mixture of E and Z olefins, the E isomers react preferentially and stereoselectively (b, Scheme 292). The coupling was observed to be chemoselective in the presence of an alkyl chloride, ester, ketone or nitrile.

Scheme 292 Cross-coupling of alkenyl phosphates and Grignard reagents.

In addition, a one-pot procedure was also reported for the preparation of enol phosphates from the corresponding ketone and subsequent cross-coupling to form the product. This method provides the desired coupled product in good yields (Scheme 293).³⁸⁰ Caheiz et al. in their following reports demonstrated a new route for the stereoselective preparation of terminal-conjugated dienes with significant yields. Purposefully, they performed the coupling between Grignard reagents and dienol phosphates in the presence of Fe(acac)₃ as a precatalyst.³⁸¹ This procedure was applied to the synthesis of the pheromone of Diparopsis castanea. Also, the synthesis of 4-substituted tetrahydropyridines was successfully carried out using vinyl phosphates produced from 4-piperidones via iron-catalyzed cross-coupling.³⁸² Evans et al. synthesized a potent and selective k-opioid receptor agonist, salvinorin A.^383,384 In the key step of this synthetic pathway, the iron-catalyzed cross-coupling reaction with alkenyl enol phosphates is used.

Scheme 293 Preparation and coupling of enol phosphates in a one-pot procedure.

6.1.4 Carboxylates as electrophilic partners. The carboxylates are good electrophilic partners due to their easy availability and low cost compared to the corresponding halides and sulfonates. In 2009, Shi and co-workers studied the cross-coupling between vinyl pivalates and alkyl Grignard reagent (Scheme 294a).^385,386 It was reported that the counter anion of the Grignard reagent has a significant effect on product formation. The primary alkylmagnesium chlorides react well, while the bromides give very poor results. However, the addition of excess of LiCl together with Grignard bromides resolves this problem. The yield of the coupling of n-hexyl magnesium chlorides increased to a good extent with the addition of NHC ligands together with iron(III) chloride (75% to 93%) (Scheme 294b).^385,386 Both cyclic and acyclic alkenyl pivalates give good yield. However, no significant conversion is observed using methyl Grignard reagents, and secondary Grignard reagents.

Scheme 294 Cross-coupling of alkenyl pivalates with Grignard reagents.

A unique example of iron-catalyzed ring opening and subsequent alkenyl-X/methylMgBr cross-coupling was developed by Fürstner and co-workers (Scheme 295).³⁸⁷ The ring opening of the 2-pyrone substrates occurs upon nucleophilic attack of the methyl Grignard reagent in the presence of iron(III) acetylacetonate. Mainly, dienyl carboxylates are obtained with the retention of configuration at the double bond. The authors proposed a conjugate addition mechanism rather than an oxidative addition/reductive elimination. This new methodology has been applied for the synthesis of several natural products such as the cytotoxic tryptamine derivative granulatamide B and marine macrolide pateamine A.³⁸⁴

Scheme 295 Iron-catalyzed formal ring opening/cross-coupling of 2-pyrone.

Notably, the easily accessible alkenyl acetates were coupled with alkyl and arylmagnesium halides by von Wangelin and co-workers using simple iron salts under mild conditions (Scheme 296).³⁸⁸ Importantly, the thermodynamically favoured acylation and deprotonation reaction are suppressed under the reaction conditions. A wide substrate scope was presented with respect to both coupling partners.

Scheme 296 Cross-coupling of alkenyl acetates with alkyl magnesium halides in the presence of a simple iron catalyst.

In 2016, Rivera et al. introduced a cross-coupling reaction of stereodefined N,N-dimethyl enol carbamates and organomagnesium reagents in the presence of simple iron(III) chloride in a THF/NMP solvent mixture, affording tri- and tetrasubstituted acrylates in high yields (Scheme 297).³⁸⁹ Although, a large number of alkyl Grignard reagents were found to give high yields of products, the phenyl and isopropyl Grignard reagents resulted in poor product yields. They also demonstrated the tolerance of highly reactive functional groups such as esters in this reaction.

Scheme 297 Cross-coupling of enol carbamates and organomagnesium reagents.

6.1.5 Chalcogen as the electrophilic partner. Alkenyl aryl sulfides are also used as electrophiles in the iron-catalyzed cross-coupling reaction with Grignard reagents (Scheme 298).³⁹⁰ The coupling occurs chemoselectively at the alkenyl site in the presence of Fe(acac)₃ in THF at room temperature. However, moderate yields are observed for the reaction.

Scheme 298 Regioselective cross-coupling of alkenyl-aryl sulfides with Grignard reagents.

In 2008, Vogel et al. reported the iron-catalyzed desulfinylative cross-coupling of alkenesulfonyl chlorides with alkyl or arylmagnesium halides (Scheme 299).³⁹¹ The reaction was accomplished using Fe(acac)₃ as the catalyst with perfect retention of the geometry of the double bond. Alkenyl selenides and tellurides were also found to be good electrophilic partners in the iron-catalyzed cross-coupling reaction (Scheme 300).³⁹² The reaction proceeds with complete retention of the configuration at the double bond, giving good product yields. Particularly, the use of triethyl amine as the ligand is beneficial for the complete conversion of the reaction.

Scheme 299 Desulfinylative cross-coupling of sulfonyl chlorides and Grignard reagents.

Scheme 300 Iron-catalyzed cross-coupling of alkenyl tellurides and Grignard reagents.

6.2 Cross coupling of aryl electrophiles with various nucleophilic partners

6.2.1 Coupling with organomagnesium nucleophiles.
6.2.1.1 Using alkyl Grignard reagents. Pridgen et al. first reported the iron(III) acetylacetonate-catalyzed cross-coupling reaction of aryl halides with Grignard reagents.³⁹³ They efficiently coupled o-chloroarylimine with an alkyl Grignard reagent in the presence of an iron catalyst. The Fe(acac)₃-catalyzed cross-coupling of alkyl Grignard with aryl and heteroaryl electrophiles was well investigated by Fürstner et al. (a and b, Scheme 301).^394,395 A wide variety of functionalized aryl and heteroaryl chlorides, triflates and tosylates produce the cross-coupled products in high yields. Interestingly, aryl bromides and iodides afford lower yields compared to chloride, triflates and tosylates. Moreover, this method presents a complementary approach to the corresponding palladium catalysis.

Scheme 301 Cross-coupling of aryl halides and alkylmagnesium bromides.

The gram-scale synthesis of the liquid crystalline material 4-nonyl benzoic acid was reported by Fürstner et al. in 2005.³⁹⁶ The same method was utilized for the selective monoalkylation of dichloroarenes and heteroarenes, affording the corresponding product in good yields (c, Scheme 301).³⁷² Notably, this methodology is superior to the corresponding palladium-catalyzed reaction. This procedure was successfully applied in the synthesis of the immunosuppressive agent FTY720. Both aryl chloride and triflate are efficient as a starting material for the synthesis of the same target.^397,398

Furthermore, the iron-catalyzed monoalkylation procedure was utilized for the synthesis of the macrocyclic spermidine alkaloid (−)-isooncinotine.³⁹⁹ An iron–salen catalyst is used for the consecutive alkylation of two different alkyl groups with 2-chloro-6-trifloxypyridine. This alkylation is the key step in the synthesis of the odoriferous alkaloid (R)-(+)-muscopyridine (Scheme 302).⁴⁰⁰

Scheme 302 Synthesis of (R)-(+)-muscopyridine via iron-catalyzed cross-coupling reaction.

In 2004, Hocek and co-workers reported a dichotomy in the regioselective cross-coupling reactions of 6,8-dichloropurines with palladium-catalyzed phenyl boronic acid and iron-catalyzed methyl magnesium chloride (Scheme 303).⁴⁰¹ The palladium catalysis with one equivalent of phenyl boronic acid gives 8-chloro-6-phenylpurine (Scheme 303a),⁴⁰² whereas iron catalysis affords the 6-chloro-8-methylpurine derivative (Scheme 303b)⁴⁰³ as the major product.

Scheme 303 Dichotomy in cross-coupling catalyzed by palladium and iron.

Similar types of iron-catalyzed selective monomethylation of dichloro- and trichloro-heterocyclic arenes were also reported.^404–406 4-Substituted pyrrolo[3,2-c]quinolines were synthesized via the cross-coupling of alkyl and arylmagnesium halides with 4-chloro pyrrolo[3,2-c]quinoline in the presence of an iron catalyst.⁴⁰⁶ The reactions are completed in a short time of 30 min, resulting in moderate to excellent yields in the presence of a THF/NMP solvent mixture.

In addition to chlorides, heteroaryl sulfonates and phosphates were proven to be efficient electrophilic partners in iron-catalyzed cross-coupling. The best yields are obtained using iron(III) chloride in a THF/NMP solvent mixture at a low temperature (Scheme 304a).⁴⁰⁷ Furthermore, the cross-coupling of heteroaryl sulfamate with phenylmagnesium bromide was performed using Fe(acac)₃ and TMEDA (Scheme 304b).

Scheme 304 Cross-coupling of heteroaryl tosylates and sulfamates with Grignard reagents.

In 2011, Wolf et al. studied the catalytic properties of a low-oxidation state iron complex in the cross-coupling reaction.⁴⁰⁸ The catalytic efficacy of the complexes was investigated by using these complexes in the cross-coupling of aryl, alkenyl and alkyl electrophiles with alkyl and arylmagnesium bromides. They concluded that the oxidation state of the precatalyst has little significance in its catalytic performance. However, a labile coordination environment is necessary. Consequently, an anionic bis-anthracene iron complex affords good results.

The synthesis of 2-substituted furans was successfully accomplished in moderate yields using the iron-catalyzed cross-coupling reaction of 2-bromofuran with Grignard reagents. The reaction is catalyzed by Fe(acac)₃ in DMPU (N,N′-dimethylpropyleneurea) solvent (Scheme 305).⁴⁰⁹ It is important to note that the corresponding palladium-catalyzed reaction did not afford the desired product.

Scheme 305 Synthesis of 2-substituted furans.

N-Heterocyclic carbenes are significantly used as ligands in the iron-catalyzed cross-coupling of non-activated electron-rich aryl chlorides with alkyl Grignard reagents (Scheme 306).⁴¹⁰ The best results are obtained using the tetrahydrate of iron(III) chloride as the catalyst. In this reaction protocol, primary Grignard reagents are coupled with excellent yields, whereas secondary alkyl nucleophiles give moderate yields. The above synthetic method of the iron-catalyzed cross-coupling of aryl chlorides with alkyl Grignard reagents was used for the construction of pentapodal ω-functional derivatives of corannulene.⁴¹¹

Scheme 306 Cross-coupling of aryl halides and alkyl Grignard reagent in the presence of iron salt and NHC ligand.

Later in 2013, a selective and simple iron-promoted cross-coupling reaction of aryl chlorides especially o-chlorostyrenes with alkyl Grignard reagents was developed by von Wangelin and co-workers (Scheme 307).⁴¹² Both electron-rich and electron-poor aryl chlorides give good yields in the presence of Fe(acac)₃ in a THF/NMP (10 : 1) solvent mixture.

Scheme 307 Coupling of o-chlorostyrenes and Grignard reagents.

In the same year, Fox et al. reported the use of TMEDA (tetramethylethylenediamine) as a cheap and easily removable ligand for the iron-catalyzed coupling of aryl chlorides with alkyl Grignard reagents.⁴¹³ This method allows a very low catalyst loading (0.1–1 mol%) and high conversions for different substrates containing ester, amide and trifluoromethyl functional groups. In addition to alkenyl pivalates, Shi et al. accomplished the cross-coupling with 2-naphthyl pivalates in the presence of iron catalysts. Interestingly, the yield was found to increase dramatically from moderate to high by changing the substrate from 2-naphthyl pivalates to 2-naphthyl-N,N-dimethyl carbamate. Notably, both reactions are catalyzed by iron(III) chloride in the presence of NHC ligand (Scheme 308).³⁸⁵

Scheme 308 Cross-coupling of aryl pivalates and alkylmagnesium halides.

Iron(II) arylthiolates are used as a precatalyst for the cross-coupling of aryl halides with alkyl Grignard reagents, giving good yields of the coupled product.³⁵⁵ Aryl sulfamates and carbamates are also coupled with arylmagnesium chlorides (Scheme 309).^344,414 This reaction is performed using iron(II) chloride and NHC ligand in dichloromethane solvent. A wide scope of electrophiles ranging from electron-deficient arenes and heteroarenes to electron-rich arenes is observed. This method has been used for the synthesis of polyfunctionalized arenes due to its directing group ability and low reactivity compared to conventional cross-coupling.

Scheme 309 Cross-coupling of aryl sulfamates and carbamates with alkyl Grignard reagent.

Cook and Agarwal presented a similar reaction for the iron-catalyzed coupling of arylsulfamates and tosylates with primary and secondary alkyl Grignard reagents.⁴¹⁵ In the case of isopropyl nucleophile, FeF₃·3H₂O is essential to slow down the isomerization and enhance the branched to linear selectivity.

Wang and Guo developed the cross-coupling reaction between trimethyl ammonium triflates and alkyl magnesium reagents in the presence of iron(III) acetylacetonate in a THF/NMP mixture (Scheme 310).⁴¹⁶ A series of functional groups on both coupling partners are well tolerated. Secondary and primary Grignard reagents possessing β-hydrogens are found to be compatible with the reaction conditions, providing good yields. The adenosine A_2A receptor antagonist ST1535 was synthesized via the cross-coupling of 2-chloropurine and n-butylmagnesium chloride in the presence of Fe(acac)₃.⁴¹⁷

Scheme 310 Cross-coupling of trimethyl ammonium triflates and Grignard reagents.

Further in 2015, Wang and co-workers described the iron-promoted coupling reaction of N-heteroaromatic tosylates with alkyl and aryl Grignard reagents, producing high yields of the coupled products (Scheme 311).⁴¹⁸ A large variety of tetrasubstituted pyrimidines are synthesized from the corresponding pyrimidin-2-yl tosylates using FeCl₃ in a mixture of THF/NMP for alkyl Grignard reagents and Fe(acac)₃ in TMEDA for aryl nucleophiles.

Scheme 311 Reaction of pyrimidin-2-yl tosylates with Grignard reagents.

In 2017, Piontek and Szostak reported the iron-catalyzed C(sp²)–C(sp³) cross-coupling reaction between polyaromatic tosylates and alkyl Grignard reagents in the presence of Fe(acac)₃ and NMP as an O-coordinating ligand (Scheme 312).⁴¹⁹ This procedure affords high yields of alkylated polycyclic arenes having considerable applications as common motifs in a wide range of electronic materials, pharmaceuticals and high-performance fluids. Moreover, a large variety of polyaromatic substrates and β-hydrogen containing Grignard reagents are found to give high yields of products. The mild conditions of the reaction allow the coupling of polyaromatic substrates bearing sensitive carboxylic-derived functional groups.

Scheme 312 Iron-catalyzed cross-coupling of polyatomic tosylates and alkyl Grignard reagents.

Further in 2018, Bisz and Szostak reported the iron-catalyzed cross-coupling between chlorosulfonamides and alkyl Grignard reagents in the presence of mild iron(III) acetylacetonate as a precatalyst and NMP as a ligand in THF, producing good to excellent yields of alkylated benzosulfonamides (Scheme 313).⁴²⁰ The alkyl benzosulfonamides are synthetically very important due to their immense application for the production of a large number of pharmaceuticals, agrochemicals and plasticizers. Notably, a wide variety of functionalized benzosulfonamides are efficiently coupled with a large number of Grignard reagents including challenging β-hydrogen-containing Grignard reagents to produce excellent yields of desired products. Interestingly, there is no attack of the Grignard reagent on the electrophilic sulfonamide bond in any of the reported examples. The sulfonamides have been demonstrated as one of the most reactive activating groups for iron-promoted cross-coupling reactions.

Scheme 313 Cross-coupling of chlorosulphonamide and alkyl Grignard reagents.

They also reported the use of the green and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as a solvent for the iron-catalyzed cross-coupling reaction.⁴²¹ They successfully coupled aryl chlorides and tosylates with β-hydrogen-possessing Grignard reagents in the presence of iron(III) acetylacetonate in 2-MeTHF, resulting in the formation of good to excellent yields of products. Notably, a wide range of aryl and heteroaryl chlorides and tosylates react with various Grignard reagents with high yields, demonstrating the high efficiency of the reaction. Further in 2019, they introduced N-methylcaprolactum as a non-toxic alternative to the carcinogenic N-methylpyrrolidine (NMP) used as a co-solvent for different iron-catalyzed cross-coupling reactions. The efficiency of the reaction was demonstrated through the iron-catalyzed alkylation of aryl chlorides and tosylates, providing excellent yields of products.⁴²²

Furthermore, they presented the first reactivity study on the effects of amides as O-coordinating ligands for the iron-mediated cross-coupling reaction of aryl and heteroaryl chlorides with β-hydrogen-containing Grignard reagents, finding some efficient alternatives to the reprotoxic NMP (Scheme 314).⁴²³ Several highly efficient ligands such as TMU (TMU = tetramethyl urea), N-cyclic and coordinating benzamides have been discovered through these studies. These investigations led the way towards eco-friendly and sustainable chemistry by replacing the carcinogenic NMP.

Scheme 314 Iron-catalyzed cross-coupling of heteroaryl halides with alkyl Grignard reagents using newly introduced ligands.

In 2019, the same group demonstrated an efficient protocol for the synthesis of alkyl substituted amides via the cross-coupling of chlorobenzamide derivatives and alkyl Grignard reagents in the presence of iron(III) acetylacetonate and O-coordinating ligands such as TMEDA and NMP (Scheme 315).⁴²⁴ The methodology affords high yields of the desired products, providing good tolerance to a large number of sensitive amide substituents. They also showed the method to be compatible with the challenging alkyl Grignard reagents possessing a β-hydrogen. Overall, a wide substrate scope was reported. Notably, the products have broad application in the fields of pharmaceuticals, agrochemicals and different biologically active molecules. This protocol was utilized for the synthesis of the 5-HT receptor antagonist.

Scheme 315 Iron-promoted cross-coupling of chlorobenzamide derivatives and alkyl Grignard reagents.

Around the same time, Szostak and co-workers developed an efficient iron-catalyzed cross-coupling reaction for aryl and heteroaryl chlorides with alkyl Grignard reagents possessing β-hydrogen atoms using a low catalyst loading (Scheme 316).⁴²⁵ The reaction is performed in the presence of the environment-friendly cyclic urea ligand 1,3-dimethyl-2-imidazolidinone (DMI). A broad range of substrates with various functional groups are compatible with this reaction protocol, producing high yields of the corresponding coupling products.

Scheme 316 Iron-catalyzed cross-coupling with low catalyst loading.

6.2.1.2 Using aryl Grignard reagents. Unsymmetrical biaryl compounds are often found in natural products such as alkaloids and numerous biologically active components of pharmaceuticals and agrochemicals. Thus, aryl–aryl bond formation is one of the most important tools of modern synthetic chemistry.

Although the earliest efforts of iron-assisted aryl–aryl bond formation was made by Fürstner et al., they were unsuccessful in accomplishing an efficient coupling. The phenylmagnesium bromide mainly undergoes homocoupling to form biphenyl. Indeed, this phenomenon was reported by Kharash.^15,426 Notably, they reported that in the presence of a catalytic amount of iron salt, homocoupling of the aryl Grignard reagent occurs when aryl halides are present as oxidizing agents.^427,428 In 2002, Figadère et al. were the first to couple aryl moieties using the iron-catalyzed cross-coupling reaction.⁴²⁹ They coupled phenyl Grignard reagents with 2-halo and 3-halo quinolines together with substituted halopyridines in the presence of Fe(acac)₃ in THF, obtaining the desired product in moderate to good yields (a, Scheme 317). Based on the same conditions, Ple and co-workers coupled substituted heteroaryl chlorides with phenylmagnesium chlorides and 3-pyridylmagnesium chlorides.⁴³⁰ However, the yields of the products obtained were moderate (b, Scheme 317).

Scheme 317 Iron-catalyzed cross-coupling between aryl halides and aryl Grignard reagents.

The most efficient method for selective biaryl coupling was introduced by Hatekeyma and Nakamura in 2007, giving excellent yields of product. The substituted aryl halides are coupled with arylmagnesium halides in the presence of iron trifluoride trihydrate, ethylmagnesium bromide and NHC ligand (Scheme 318).^431,432 The ethylmagnesium bromide added to the precursor catalyst helps in the generation of the active iron species via the reduction of the precursor. Most importantly, the iron fluorides in combination with the NHC ligand significantly suppress the homocoupling reaction. In comparison to the reactivity of aryl halides under Fürstner's conditions,^394–396 the chlorides are more reactive than bromides and iodides. On the other hand, aryl fluorides were found to be inert to the conditions. The method also affords high yields of coupled products using sterically hindered mesityl magnesium bromide as the nucleophilic partner.

Scheme 318 Biaryl cross-coupling catalyzed by the combination of iron fluorides and NHC ligands.

In 2012, von Wangalin et al. came up with a synthetic method for biaryl synthesis from o-chlorostyrenes and aryl Grignard reagents using iron(III) acetylacetonate as the catalyst (Scheme 319).⁴³³ The o-chlorostyrenes were found to be exceptionally efficient compared to m- or p-chlorostyrenes. Most interestingly, the substrate with methyl or phenyl substituents at the vinyl group of the m- and p-chlorostyrenes gave good yields of the coupled products. The less basic fluoro-substituted arylmagnesium bromides as the nucleophilic partner gave the best yields. Actually, the vinyl substituents undergo coordination to the iron catalyst, followed by haptotropic migration to the location of the C–Cl bond.

Scheme 319 Cross-coupling of chlorostyrenes and Grignard reagent.

Further, Knochel et al. used iron(III) bromide to efficiently couple N-heterocyclic halides with aryl Grignard reagents (Scheme 320).⁴³⁴ The solvent combination of methyl tert-butyl ether (MTBE) and THF at room temperature gave the best results with improved yield. Moreover, a large variety of heteroaryl electrophiles extending from halopyridine, haloquinoline, and pyrimidine to diazines provide satisfactory results in good yields. Both the electron-withdrawing and electron donating-substituents on the aryl Grignard species are significantly tolerated. Later, the application of isoquinoline as a ligand was found to improve the yield and the rate for the reaction (Scheme 321).⁴³⁵ They coupled halogenated pyrimidine, triazine, and pyridines together with other heteroaryl halides with the functionalized aryl Grignard reagent, obtaining good yields of product. This method enhances the rate to a greater extent. Notably, they synthesized the challenging heteroaryl-heteroaryl coupling product by utilizing this methodology. However, the cross-coupling of 1,4-chlorobromobenzene or 1,4-dibromobenzene with phenylmagnesium bromide in the presence of iron(III) chloride yields mixtures of p-terphenyl and homo-coupled biphenyl as the products.⁴³⁶

Scheme 320 Cross-coupling of N-heteroaryl chlorides with phenylmagnesium bromide.

Scheme 321 Iron-catalyzed cross-coupling using isoquinoline as the ligand.

Aryl chlorides were coupled with arylmagnesium reagents by Duong et al. in 2014 using iron(III) tert-butoxide in the presence of N-heterocyclic ligand and sodium tert-butoxide base.⁴³⁷ This method is very efficient for the formation of aryl–aryl cross-coupled products in excellent yields. Most importantly, the utilization of tert-butoxide in the reaction suppresses the homocoupling reaction by hindering the reduction of the iron precursors by the aryl Grignard reagents. Further in 2015, they reported the catalytic efficiency of iron(II) triflates together with N-heterocyclic carbene ligand for the cross-coupling of aryl chlorides and tosylates with aryl Grignard reagents, producing high yields of coupled products (Scheme 322).⁴³⁸ Both the electron-donating and electron-withdrawing substituents including the highly deactivating trifluoromethyl group on the coupling partners are well tolerated under the reaction conditions, producing significant yields. Also, a number of functional groups such as ether, alkene, tertiary amines and silyl protected phenols are found to be compatible in this reaction.

Scheme 322 Iron-catalyzed biaryl formation using NHC ligand.

In 2017, Huynh and Duong studied the influence of the structural factors of the NHC ligands for the Fe(OTf)₂/NHC-catalyzed cross-coupling of chlorobenzene and p-tolylmagnesium bromide.⁴³⁹ The yields of the products are dependent on a number of structural parameters. These factors include the bulk of the N-substituents, the counterions present in the carbene precursors and the degree of unsaturation of the NHC backbone. Notably, the stereo-electronic properties of the NHC ligands were evaluated using HEP (Huynh's electronic parameter) and %V_bur calculations. Through these extensive studies, SIPrNap was found to be the most efficient NHC ligand for the above-mentioned reaction protocol with both aryl chlorides and tosylates as the electrophilic partner. Recently, in 2018 they demonstrated the first structure–activity relationship (SAR) studies on expanded-ring N-heterocyclic carbenes as ligands in the iron-promoted cross-coupling of aryl halides and aryl Grignard reagents.⁴⁴⁰ NHC ligands with different ring sizes and different bulky N-aryl substituents were prepared and evaluated for their catalytic activity. The N-mesityl substituted seven-membered NHC, 7Mes·HCl, showed the best catalytic activity for aryl–aryl cross-coupling using Fe(OTf)₂ and sodium tert-butoxide (Scheme 323). The catalyst system provides very good yields of product with a large number of substrates.

Scheme 323 Iron-catalyzed aryl–aryl cross-coupling using expanded ring size NHC ligand.

Around the same time, Duan and co-workers introduced an iron-based catalyzed cross-coupling reaction between aryl halides and aryl Grignard reagents (Scheme 324).⁴⁴¹ The catalytic system consists of FeCl₃/TMEDA together with Ti(OEt)₄ as the co-catalyst in a THF/toluene solvent mixture in the presence of phenolate additive. The phenolate group induces a bimetallic cooperation between the two metals, and thus increases the catalytic activity of the iron system. Various aryl and heteroaryl halides bearing different substituents were coupled with the common Grignard reagents and with Knochel-type Grignard reagents.⁴⁴² Moreover, high yields of the cross-coupled products are obtained together with the suppression of side products (homo-coupled and dehalogenated products). Notably, for the Knochel-type Grignard reagents, the yield of the products increases with the removal of the in situ formed isopropyl halides before the cross-coupling reaction. However, the aryl chlorides give poor yields of products under this condition.

Scheme 324 Fe/Ti-co-catalyzed biaryl coupling of aryl halide and aryl Grignard reagent.

Further in 2019, they reported that a similar Fe–Ti co-catalyst system with NHC ligand can be used for the efficient cross-coupling of various (hetero)aryl electrophiles and aryl Grignard reagents (Scheme 325).⁴⁴³ The weakly electrophilic aryl chlorides are efficiently coupled, affording good yields of product. In addition, oxygen-based aryl electrophiles such as ArOTs, ArOSO₂NMe₂, and ArOCONMe₂ undergo chemoselective biaryl coupling in the presence of sensitive functional groups. The reaction shows good tolerance for a large number of functional groups on both coupling partners. Further, this reaction protocol was successfully exploited for the synthesis of the terphenyl intermediate anidulafungin.

Scheme 325 Fe/Ti-co-catalyzed biaryl coupling of various aryl electrophiles with aryl Grignard reagents.

6.2.2 Coupling with organocopper nucleophiles. The formation of homocoupling products has been a major issue for the aryl–aryl cross-coupling reaction. Accordingly, Knochel and co-workers developed a method of cross-coupling with suppressed biaryl formation using aryl and heteroaryl copper nucleophiles (a, Scheme 326).⁴⁴⁴ The organocopper reagents are prepared from the corresponding arylmagnesium by reaction with CuCN·2LiCl. The functionalized arylcopper reagents react with aryl halides in the presence of a catalytic amount of Fe(acac)₃ in a DME/THF (3 : 2) solvent mixture, leading to coupled products in good yields. Interestingly, a contrast in the reactivity of aryl halides was observed for arylcopper reagents in comparison to arylmagnesium species. The aryl triflates showed poor reactivity, whereas the tosylates were completely unreactive. The presence of both electron-donating substituents is well tolerated with slight variations in yield.

Scheme 326 Cross-coupling of aryl halides and arylcopper nucleophiles.

On further investigation on arylcopper reagents, they revealed that the presence of the amide functionality on the aryl iodide made the reaction faster, resulting in high yields of the coupled products. Excellent yields were obtained by using iodoquinolines as substrates (b and c, Scheme 326).⁴⁴⁵ A range of functional groups on the benzamides and quinolines are well tolerated, leading to functionalized biphenyls and 8-phenylquinolin-29(1H)-ones, respectively.

6.2.3 Coupling with organoboron nucleophile. The Suzuki–Miyaura cross-coupling between aryl halides and arylboric acids was performed by employing an iron(III) chloride precatalyst together with 2-diphenylphosphinopyridine (dppy) ligand at an elevated pressure (15 000 bar).⁴⁴⁶ It was suggested that pressure accelerates the reduction of the metal precatalyst to the catalytically active oxidation state. Also, the catalytic decomposition is suppressed in the presence of pressure. Further in 2009, the Suzuki coupling reaction of heteroaryl halides with sodium tetraphenylborates using an iron-zinc catalyst was developed by Bedford et al.⁴⁴⁷ Hetero bi-phenyls were produced in good to high yields.

6.2.4 Coupling with organolithium nucleophiles. In 2016, Wong and co-workers investigated the iron-catalyzed cross-coupling of aryl halides with alkyllithium reagents as the nucleophilic partners (Scheme 327).^444,448 They reported the use of [(FeCl₃)₂(TMEDA)₃] in THF at 0 °C to provide the best yields of coupled products. This protocol affords high yields of products with a wide range of substrates. Notably, electron-donating groups and bulky functional groups are well tolerated, giving good product yields. The practicability of this method was demonstrated by the satisfactory yields of coupled products in a gram-scale reaction.

Scheme 327 Iron-catalyzed cross-coupling of aryl halides and alkyllithium reagents.

6.2.5 Coupling with organomanganese nucleophiles. Benzylic manganese chlorides were efficiently coupled with aryl and heteroaryl halides by Knochel and co-workers using iron(II) chlorides in THF (Scheme 328).⁴⁴⁹ The products were obtained in good yields together with good tolerance of different functional groups such as esters, nitriles and ketones.

Scheme 328 Cross-coupling of heteroaryl halides with benzylmanganese chlorides.

6.2.6 Coupling with alkynyl nucleophiles. The use of alkynyl compounds as nucleophiles in the iron-catalyzed cross-coupling reaction was reported by Tsai et al. The alkynyl nucleophile 4-aryl-2-methylbut-3-yn-2-ol remaining in the protected form was coupled with aryl iodides in the presence of an iron catalyst in water. This is an example of a one-pot Sonogashira–Hagihara coupling reaction. The catalyst system consists of iron(III) chloride hexahydrate with cationic 2,2′-bipyridyl ligand in water together with zinc powder as the reductant and KOH as the base. The reaction protocol results in good yields of symmetrical and asymmetrical diarylalkynes (Scheme 329).⁴⁵⁰

Scheme 329 One-pot Sonogashira coupling of aryl iodides and 4-aryl-2-methylbut-3-yn-2-ols.

6.3 Cross-coupling of acyl electrophiles with various nucleophilic partners

The earliest instance of iron catalysis in ketone synthesis by reaction between acyl halides and Grignard reagent was found in the reports by Cook and co-workers in 1953.⁴⁵¹ The reaction with ferric chloride as the catalyst gives the highest yields compared to that of other metallic halides as the catalyst. They were successful in synthesizing straight-chain aliphatic ketones in good yields.

Thereafter, thorough investigations on this iron-catalyzed ketone formation reaction were performed by Marchese et al.^452–455 They demonstrated that a catalytic amount of iron(III) acetylacetonate helps in efficiently coupling acyl chlorides with Grignard reagents (Scheme 330a). Notably, the concomitant alcohol formation is stopped in the presence of an iron catalyst. Later, Fürstner and co-workers reinvestigated this reaction using the same catalytic system and showed that a wide variety of substrates were coupled efficiently, giving good to excellent yields of the desired products.³⁷²

Scheme 330 Cross-coupling of acyl electrophiles and Grignard reagents.

Later, in 2004, Knochel and co-workers developed the reaction between arylacyl cyanides and organomagnesium reagents in the presence of Fe(acac)₃ in THF (Scheme 330b).⁴⁵⁶ The polyfunctional benzophenone derivatives were formed in high yields. The acyl cyanides were evidenced to be better acylating agents in comparison to acyl chlorides since the cyano group increases the reactivity of the adjacent carbonyl group. In contrast, the chlorine of acyl chloride decreases the reactivity by acting as a donor atom. The iron-catalyzed reaction of Grignard reagents and acyl chloride is very useful from a synthetic point of view.³⁸⁴ Additionally, due to its extensive use in ketone synthesis, it was successfully employed during the synthesis of latrunculin A^374,375 and B.³⁷⁵ It was also used in a key step for the synthesis of the musk odorant (3R)-(Z)-5-muscenone (Scheme 331).⁴⁵⁷

Scheme 331 Synthesis of (3R)-(Z)-5-muscenone.

6.4 Cross-coupling of alkyl electrophiles with various nucleophilic partners

6.4.1 Coupling with aryl nucleophiles.
6.4.1.1 Coupling using organomagnesium reagents. The cross-coupling reaction with alkyl electrophiles is a challenging task for researchers due to the accompanying side reaction. The major side reaction together with the cross-coupling is β-hydride elimination, producing olefins. Another side reaction found is the dehalogenation reaction producing alkanes. However, two methods for efficient alkyl–aryl cross-coupling were developed by Nakamura⁴⁵⁸ and Hayashi.⁴⁵⁹ In 2004, Nakamura et al. described the reaction of alkyl halides with aryl Grignard reagents in the presence of iron(III) chloride and TMEDA in THF at low temperature. The synthetic procedure resulted in the formation of high yields of coupled product with much less homo-coupled product. Importantly, the use of TMEDA suppresses the side reactions such as olefin formation (a, Scheme 332).⁴⁵⁸ On the other hand, Hayashi et al. were able to couple aryl Grignard reagents with β-hydrogen-containing alkyl halides under the influence of Fe(acac)₃ in diethyl ether (b, Scheme 332). Secondary and primary alkyl bromides were found to be good coupling partners, giving moderate to good yields.⁴⁵⁹

Scheme 332 Iron-catalyzed cross-coupling of alkyl halides and Grignard reagents.

Fürstner et al. used the well-defined low-valent iron complex [Li(TMEDA)]₂[Fe(C₂H₄)₄] to achieve the coupling between alkyl halides and aryl Grignard reagent in excellent yields (c, Scheme 332).^373,460 Among the halides, the bromides and iodides are more reactive compared to chlorides. A large variety of alkyl iodides and bromides are coupled efficiently, resulting in high product yields.

Later, mild reaction conditions using an iron–salen complex as the active catalyst were used by them to accomplish the cross-coupling of β-hydrogen-containing alkyl halides with aryl Grignard reagents (Scheme 333).⁴⁶¹ The alkyl arenes were produced in good yields. Notably, a low level of the β-eliminated product and the dehalogenated product is maintained under the reaction conditions.

Scheme 333 Aryl–alkyl coupling catalyzed by iron–salen complex.

In 2005, Bedford et al. reported that an FeCl₃ precatalyst and amine ligands efficiently catalyzed the coupling of alkyl halides bearing β-hydrogen with aryl Grignard reagents (a, Scheme 334).⁴⁶² The highest conversion was obtained using triethylamine and DABCO together with a minor amount of elimination and hydrodehalogenated products. Additionally, the use of iron(III) chloride with phosphine, phosphite or arsine ligands is found to overcome the limitation of the slow addition procedure, as reported by Nakamura et al. (b, Scheme 334).⁴⁶³ The desired alkyl arenes are obtained in high yields. A radical mechanism was inferred from the radical clock experiment using methyl cyclopropane, resulting in the ring-opening product. They also reported that the use of N-heterocyclic ligands gives high product yields (c, Scheme 334).

Scheme 334 Aryl–alkyl cross-coupling in the presence of amine, phosphine, and NHC ligand.

An excellent yield of alkyl–aryl cross-coupled products was also obtained with the use of iron nanoparticles as the active catalyst.⁴⁶⁴ The iron nanoparticles are either prepared separately and then stabilized by polyethylene glycol (PEG) or formed in situ and stabilized by 1,6-bis(diphenylphosphino)hexane.

In 2011, the ortho-phenylene-tethered bisphosphine ligand-containing iron(II) chloride complex FeCl₂(3,5-t-Bu₂-SciOPP) was prepared by Nakamura et al. It is used in the Kumada–Corriu coupling between alkyl halides and aryl Grignard reagents (Scheme 335).⁴⁶⁵ High catalytic activity is shown by the complex since tertiary alkyl halides are also coupled together with primary and secondary halides, resulting in good yields. Notably, the ring-opening product for the reaction with (iodomethyl)cyclopropane in the catalytic condition confirms the presence of radical intermediates. Around the same time, Yamaguchi and Asami reported the synthesis of a tridentate β-aminoketonato iron complex and its application as an effective catalyst in the cross-coupling reaction of alkyl halides with aryl Grignard reagents.⁴⁶⁶

Scheme 335 Alkyl–aryl cross-coupling catalyzed by iron bis-phosphine catalyst.

The chemoselective coupling of an α-bromocarboxylic acid derivative was performed by Nakamura and co-workers using the simple Fe(acac)₃ precatalyst in THF at −78 °C (Scheme 336).⁴⁶⁷ The reaction proceeds efficiently, resulting in good to high yields of the corresponding phenylacetic acid derivatives as the coupled product. The bulky tert-butyl esters are used to reduce the nucleophilic attack of the Grignard reagents at the carbonyl centre.

Scheme 336 Chemoselective iron-catalyzed cross-coupling of α-bromocarboxylic acid.

Later, in 2015, they reported the first iron-catalyzed enantioselective coupling of α-chloro- and α-bromoalkanoates with aryl Grignard reagents in the presence of catalytic amounts of Fe(acac)₃ and the P-chiral bisphosphine ligand BenzP* (Scheme 337).⁴⁶⁸ The optically active α-arylalkanoates are synthesized in high yields through this efficient protocol. Various electron-rich, electron-deficient and electron-neutral aryl Grignard reagents provide good yields of products, while the ortho-substituted aryl Grignard reagents undergo slow reaction, giving poor yields. The deprotected products are used as important molecules in pharmaceuticals as nonsteroidal anti-inflammatory analgesics and cyclooxygenase inhibitors.³⁸⁴

Scheme 337 Enantioselective reaction of α-haloalkanoates with Grignard reagent in the presence of chiral ligand.

In 2006, Gartner and co-workers demonstrated the use of the air-stable ionic liquid butylmethylimidazoliumtetrachoroferrate (bmim-FeCl₄) as a catalyst to carry out the biphasic cross-coupling of alkyl halides with aryl Grignard reagents.⁴⁶⁹ Most importantly, the ionic liquid catalyst was recollected and reused after simple decantation of the ethereal layer containing the products. The catalyst can be recycled effectively for up to four times.

In 2007, two new catalytic systems for the cross-coupling of alkyl halides and aryl Grignard reagents were developed by Caheiz and co-workers.⁴⁷⁰ One of the systems consists of Fe(acac)₃ together with an HMTA/TMEDA (1 : 2) (HMTA = hexamethylenetetramine) ligand mixture (Scheme 338a) and the other consists of the new complex [(FeCl₃)₂(TMEDA)₃] (Scheme 338b). Both catalytic systems worked efficiently for the coupling reaction with secondary and primary alkyl halides, giving good product yields. Notably, this is the first use of HMTA in a cross-coupling reaction catalyzed by transition metals. This method is employed for the large-scale production of sec-butyl benzene. The catalyst system of iron salt and TMEDA is also used for the cross-coupling of the alkyl bromides and biphenyl magnesium bromides, resulting in high yields of the desired coupled products.⁴⁷¹

Scheme 338 Alkyl–aryl cross-coupling using different iron catalyst system.

In 2008, Kozak and co-workers synthesized an iron(III) amine-bis(phenolate) complex and used it as a catalyst in the coupling of β-hydrogen-containing primary and secondary alkyl halides with aryl Grignard reagents (Scheme 339).⁴⁷² The yield varied from low to high depending on the substrate. Furthermore, the double cross-coupling reaction of dichloromethane with aryl Grignard reagents is performed using a similar but dimeric iron(III) bisphenolate complex, resulting in diaryl methane together with 1,2-diarylethane as the side product.⁴⁷³o-Tolylmagnesium bromide alone results in high yields of products. Also, FeCl₃ is an effective catalyst for the coupling, giving moderate yields of product. A significant amount 1,2-diarylethane was also found as the side product.

Scheme 339 Aryl–alkyl cross-coupling in the presence of iron amine-bis(phosphine) complex.

In 2011, Knochel et al. demonstrated that the diastereoselective cross-coupling of cyclic iodohydrin derivatives with aryl Grignard reagents can be performed using a substoichiometric amount of FeCl₂·LiCl. TBS-protected (TBS = tert-butyldimethylsilyl) iodohydrins undergo cross-coupling with aryl and heteroarylmagnesium halides, producing high yields of thermodynamically more stable trans products in excellent selectivity (Scheme 340).⁴⁷⁴

Scheme 340 Diastereoselective cross-coupling of cyclic iodohydrin.

Alkanesulfonyl chlorides were found to undergo desulfinylative cross-coupling with Grignard reagents in the presence of simple Fe(acac)₃ in a THF/NMP solvent mixture at an elevated temperature (Scheme 341).³⁹¹ A wide variety of alkanesulfonyl chlorides and aryl Grignard reagents undergo this reaction with good yields.

Scheme 341 Desulfinylative cross-coupling forming alkyl–aryl compounds.

Gao and co-workers reported the use of the NHC-ligand containing anionic iron(II) complex [Fe(IPr)Br₃](HIPr)·PhMe as a highly efficient catalyst in the cross-coupling of p-tolylmagnesium bromide with cyclohexyl bromide.⁴⁷⁵ Successful conversion was obtained with a very low catalyst loading of 0.5–1 mol%, giving the product in very high yields. Together with cyclohexyl bromides, other alkyl halides such as cyclopentyl bromide, 2-bromohexane and 1-bromooctane afford high product yields. Thereafter, well characterized di- and tetra-N heterocyclic carbene-bearing Fe(II) complexes were found to be catalytically active in the cross-coupling reaction.⁴⁷⁶ Their catalytic activity was evaluated using the same standard cross-coupling reaction between cyclohexyl bromides and p-tolylmagnesium bromides. Both complexes were found to be efficient, affording good yields, but were less active compared to the abovementioned anionic iron(II) complex having two NHC ligands.

In 2012, Nakamura and co-workers developed a simple catalytic system consisting of an N-heterocyclic carbene ligand and iron(III) chloride, which gave high yields of the coupling product (Scheme 342).⁴⁷⁷ The cross-coupling of a wide range of primary, secondary and tertiary alkyl chlorides with aryl Grignard reagents occurs under this catalytic system. Most importantly, this method was efficiently applied to the arylation of the challenging polychloroalkanes, yielding high conversions.

Scheme 342 Alkyl–aryl cross coupling using NHC ligand bearing an iron catalyst.

Around the same time, Deng and co-workers came up with a method for the arylation of primary alkyl fluorides with aryl Grignard reagents under the catalytic activity of a dinuclear iron(II) complex having an NHC ligand (Scheme 343).⁴⁷⁸ A large variety of Grignard reagents and primary alkyl fluorides was cross-coupled with good to excellent yields. In the reaction with cyclopropylmethyl fluoride as the substrate, a ring-opened terminal alkene was formed together with the desired cross-coupled product and the aryl–aryl homocoupling product. This result indicates the presence of a radical intermediate in the reaction.

Scheme 343 Arylation in the presence of a dinuclear iron catalyst.

A series of iron(III)-containing imidazolium salts were synthesized and investigated for their catalytic efficiency in the benchmark cross-coupling reaction of cyclohexyl bromide with p-tolylmagnesium bromide.⁴⁷⁹ All six salts investigated were highly efficient precatalysts, resulting in good to excellent yields of the coupled products. Interestingly, the catalytic efficiency can be varied by varying the N-substituents in the imidazole ring.

In 2013, Denmark and Cresswell demonstrated the first systematic study of alkyl aryl thioethers as electrophiles in the iron-catalyzed cross-coupling reaction. After extensive optimization, they found that aryl–alkyl cross-coupling by the cleavage of the C(sp³)–S bond occurs in the presence of iron(III) acetylacetonate in cyclopentylmethyl ether (CPME) solvent at room temperature (Scheme 344).⁴⁸⁰ Also, the reaction of secondary alkyl sulfones is catalyzed under the same conditions together with 8 equiv. of TMEDA as the additive.

Scheme 344 Cross-coupling of thioether and sulfones with Grignard reagents.

Bis(phenol)-functionalized benzimidazolium-based iron(III) complexes have been efficiently used for the coupling of primary and secondary alkyl halides containing β-hydrogens with aryl Grignard reagents.⁴⁸¹ Compared to FeCl₃ and FeBr₃, which are highly hygroscopic, these complexes exist as non-hygroscopic and air-stable solids, making them easier to handle. One of the complexes used for coupling was found to be highly efficient, resulting in excellent yields with much less β-hydride elimination products. Also, the same complex was recycled and worked efficiently even after eight runs.

Thereafter in 2014, Fürstner et al. developed a new method for the arylation of alkyl halides with the bulky ortho-substituted aryl Grignard reagents using iron(II) chloride with bis(diethylphosphino)-ethane (depe) as a ligand (Scheme 345).⁴⁸² High yields were obtained with the alkyl bromides and chlorides together with a large variety of iodides. Moreover, the procedure also allows the arylation of neopentylic electrophiles with mesitylmagnesium bromides. Notably, the in situ generated and isolated [(depe)Fe(Mes)₂] was suggested as the active catalyst species for the coupling using mesitylmagnesium bromide. This complex is generated in situ from [(depe)₂FeCl₂] upon treatment with MesMgBr.

Scheme 345 Iron-catalyzed cross-coupling with mesityl magnesium halides by bisphosphine iron complex.

Recently in 2018, Zhang and co-workers introduced the first example of iron-promoted cross-coupling of arylmagnesium halides with difluoroalkyl bromides, producing biologically beneficial coupled products (Scheme 346).⁴⁸³ Iron(III) chloride is utilized together with modified TMEDA ligand having bulky butylene substitution at one of the carbon atoms of its ethylene backbone. Notably, this was the first report where substituted TMEDA was used deliberately in iron-catalyzed cross-coupling. The procedure affords the coupling of a wide range of difluoroalkyl bromides with a large number of substituted Grignard reagents, producing high yields of desired products. The reaction conditions also tolerate many important functional groups such as silyl ether, sulfuryl, ester, thiazole and ferrocenyl groups. Furthermore, the first coupling reaction of bromodifluoromethane with a Grignard reagent was successfully executed using this methodology.

Scheme 346 Cross-coupling of difluoroalkyl bromides and arylmagnesium halides using butylene-substituted TMEDA.

6.4.1.2 Coupling using organozinc reagents. The iron-catalyzed coupling of primary and secondary alkyl halides with arylzinc reagents was demonstrated by Nakamura and co-workers in 2005. The reaction is performed in the presence of iron(III) chloride as the precatalyst and TMEDA as the ligand (Scheme 347).⁴⁸⁴ Most interestingly, the presence of magnesium is necessary for the reaction to occur. Further, an improvement in the functional group tolerance is observed compared to Grignard reagents due to the mild reactivity of arylzinc reagents. Diarylzinc and mixed diorganozinc containing trimethylsilyl methyl ligand are used to produce high yields of alkyl–aryl and alkyl–heteroaryl-coupled products. Also, they cross-coupled labile and low reactive polyfluorinated aryl metals with alkyl halides using 1,2-bis(diphenylphosphino)benzene (DPPBz) ligand instead of TMEDA with iron salt to produce the coupled products (Scheme 348).⁴⁸⁵ A variety of mono-, di- and triflorophenylzinc reagents are satisfactorily coupled with the secondary alkyl chlorides, primary bromides and chlorides. The formed polyfluorinated products are key structural units for a number of drugs, agrochemicals and dyes.

Scheme 347 Iron(III) chloride-catalyzed cross-coupling between alkyl halides and arylzinc reagents.

Scheme 348 Cross-coupling of polyfluorinated-arylzinc and alkyl halides.

Later in 2009, the same group reported an efficient procedure for the iron-catalyzed cross-coupling of alkyl tosylates with arylzinc reagents in the presence of excess of tetramethylethylenediamine (TMEDA) and magnesium salts. The arylzinc reagents are prepared in situ from aryl Grignard reagents or aryl lithium compounds with zinc halide-TMEDA in the presence of magnesium dihalides (Scheme 349a).⁴⁸⁶ Notably, the use of ZnI₂ as the zinc halide gives the best results since the cross-coupling reaction proceeds from the in situ-generated alkyl iodides rather than the sulfonates. Another method utilizes a mixed diorganozinc reagent bearing a non-transferable trimethylsilylmethyl ligand in the presence of TMEDA for the installation of functionalized arenes in alkyl tosylates (Scheme 349b).

Scheme 349 Cross-coupling of alkyl tosylates and aryl Grignard reagents.

In 2012, Quin and co-workers reported the first example of coupling of α-halo-β,β-difluoroethylene substrates with in situ-generated arylzinc reagents (Scheme 350).⁴⁸⁷ The catalyst system is comprised of iron(II) chloride and 1,3-bis(diphenylphosphino)propane (dppp) co-ligand together with the TMEDA ligand. They suggested the presence of radical intermediates in the reaction.

Scheme 350 Iron-catalyzed cross-coupling of α-halo-β-β-difluroethylene substrate and arylzinc reagents.

6.4.1.3 Coupling using organoboron nucleophile. In 2010, Nakamura and co-workers developed an efficient protocol for the iron-catalyzed Suzuki–Miyaura coupling of alkyl halides and aryl boronates using iron(II) chloride, diphosphine ligand and magnesium bromide (Scheme 351).⁴⁸⁸ They designed two novel iron diphosphine complexes bearing a sterically hindered o-phenylene-tethered diphosphine ligand and found that they were efficient in the abovementioned coupling reaction, resulting in good to excellent yields of products. The presence of magnesium bromide as a co-catalyst is also necessary. A variety of lithium arylboronates prepared in situ from the corresponding arylboronic acid pinacol ester and alkyllithium were found to participate in the reaction. It is noteworthy that the ring-opening product formed during the reaction of (bromomethyl)cyclopropane indicates the presence of alkyl radicals. In contrast to this method, Bedford et al. accomplished the same reaction using the simple iron(III) acetylacetonate or iron complexes containing inexpensive diphosphine ligands such as 1,2-bis(diphenylphosphino)ethane (dppe) and 1,3-bis(diphenylphosphino)propane (dppp) (Scheme 352).⁴⁸⁹ However, the procedure for the formation arylboronate and the necessity of magnesium bromide were same. A wide range of substrates gave satisfactorily high yields of products.

Scheme 351 Iron-catalyzed cross-coupling of aryl boronates and alkyl halides.

Scheme 352 Alkyl–aryl cross-coupling of alkyl halides and aryl boronates in the presence of iron bis(phosphine) complex.

6.4.1.4 Coupling using organoaluminum nucleophiles. Organoaluminum reagents have also been used as nucleophilic partners for the cross-coupling reaction in the presence of an iron catalyst. Nakamura and co-workers reported the first iron-catalyzed Negishi coupling of arylaluminum reagents and alkyl halides in the presence of the well-defined iron complex FeCl₂(DPPBz) (DPPBz = 1,2-Bis(diphenylphosphino)benzene).⁴⁹⁰ The in situ generated aluminate complexes are the active species. Notably, the aluminate complex remains in dynamic equilibrium with the unreactive neutral aluminium species and the equilibrium is maintained by the in situ-generated MgX₂ salts.

Later, they performed the cross-coupling reaction of non-protected chlorocyclohexanols with aryl aluminum, producing aryl alkanols in the presence of their previously synthesized bisphosphine complex FeCl₂(SciOPP) (Scheme 353).⁴⁹¹ The in situ-generated aluminum alkoxide offers high catalytic activity and enhanced diastereoselectivity with the formation of excellent yields of trans product.

Scheme 353 Diastereoselective cross-coupling of chlorocyclohexanols and aryl aluminium reagents using FeCl₂(TMS-SciOPP) complex.

Recently in 2019, Nakamura and co-workers developed a C(sp³)–C(sp³) Negishi cross-coupling reaction between alkyl halides and alkylaluminium reagents using a catalytic system consisting of Fe(OAc)₂, bisphosphine ligand, and Bn-Nixantphos (Scheme 354).⁴⁹² Notably, the addition of potassium fluoride is necessary for the conversion. This methodology efficiently produces moderate to good yields of products with complete suppression of the undesirable β-hydrogen elimination. The ring-opening products for the reaction of (bromomethyl)cyclopropane suggest the presence of radical intermediates.

Scheme 354 Cross-coupling reaction alkyl halides and alkylaluminium reagents using iron salts with Bn-Nixantphos.

6.4.1.5 Coupling using organomanganese nucleophiles. In 2017, Knochel and co-workers developed the cross-coupling reaction between di(hetero)arylmanganese reagents and primary and secondary alkyl halides using iron(II) chloride in THF as the catalytic system (Scheme 355).⁴⁹³ A wide variety of functionalized di(hetero)aryl manganese substrates react with functionalized primary and secondary alkyl halides, producing moderate to high yields of the desired products. Notably, no rearrangement of the secondary alkyl halides is found in this reaction.

Scheme 355 Iron-catalyzed cross-coupling of diarylmanganese reagents and alkyl halides.

6.4.2 Coupling with alkenyl nucleophiles. In 2007, Caheiz et al. demonstrated the iron-catalyzed coupling of primary and secondary alkyl halides with an alkenyl Grignard reagent in the presence of iron(III) acetylacetonate, together with TMEDA (TMEDA = tetramethylethylenediamine) and HMTA (HMTA = hexamethylenetetramine) in a 1 : 2 : 1 ratio, respectively (Scheme 356).⁴⁹⁴ A large variety of primary and secondary alkyl bromides and iodides are coupled successfully and provide the desired products in excellent yields. Also, the chlorides are inefficient for coupling under the reaction conditions. The reaction is highly stereoselective with good retention of the E/Z ratio of the starting materials in the coupled product.

Scheme 356 Iron-catalyzed cross-coupling of alkyl halides and alkenyl Grignard reagents.

Later in the same year, a very similar reaction was also reported by Cossy et al. using FeCl₃ and TMEDA in THF.⁴⁹⁵ A wide substrate scope was presented with good tolerance of various functional groups. This method was applied for the introduction of an E-trisubstituted terminal double bond in the spiroketal core of spirangien A.⁴⁹⁶ It was also utilized for the formal synthesis of spirangien A, as reported by Rizzacasa et al.⁴⁹⁷ Moreover, the same reaction was used in the course of the synthesis of (+) allokainic acid (Scheme 357),⁴⁹⁸ the rennin inhibitor aliskiren,⁴⁹⁹ and ent-amphidinol.⁵⁰⁰

Scheme 357 Synthesis of (+)-allokainic acid.

In 2009, Nakamura et al. utilized iron(III) chloride in the presence excess TMEDA ligand in THF for the selective cross-coupling of alkyl halides with alkenylzinc reagents (Scheme 358).⁵⁰¹ Different functionalized alkyl bromides with cyano, acetoxy and carbamate functional groups are well tolerated, providing good yields of the products. The stereochemistry of the starting alkenylzinc is retained throughout the coupling reaction.

Scheme 358 Cross-coupling of alkyl halides and alkenyl zinc reagents in the presence of an iron catalyst.

Further, they reported the Suzuki–Miyaura cross-coupling of E- and Z-alkenylboronic acid pinacol esters with alkyl halides in the presence of sterically congested (bisphosphine)iron complexes as the active catalysts (Scheme 359).⁵⁰² The reaction proceeds in a stereoselective manner, producing high yields of coupled products. Alkyl bromides and iodides possessing acetoxy, benzoyl, carbamate, ethoxycarbonyl and cyano groups are well tolerated. Notably, the presence of magnesium salts is essential for the transformation to proceed.

Scheme 359 Alkenyl-alkyl cross-coupling using FeCl₂(TMS-SciOPP) complex.

Togni's reagent was employed for the trifluoromethylation of terminal olefins using potassium vinyltrifluoroborates in the presence of a catalytic amount of FeCl₂ (Scheme 360).⁵⁰³ Good yields of products are obtained using 2-arylvinyltrifluoroborates and 2-heteroarylvinyltrifluoroborates as the substrates. The yields can be increased by decreasing the catalyst loading in acetonitrile solvent. The E-configuration of substrates is retained with high selectivity, while pure Z-isomers result in stereoconvergence, providing the E product exclusively. Through these observations, the authors inferred the absence of the transmetalation/reductive elimination mechanism. Instead they suggested a mechanism involving radicals or carbocations.

Scheme 360 Iron(II)-catalyzed trifluoromethylation of potassium vinyltrifluoroborates using Togni's reagent.

6.4.3 Coupling with alkynyl nucleophiles. In 2011, Nakamura and co-workers performed an iron-catalyzed Sonogashira-type reaction between alkyl halides and alkynyl Grignard reagents in the presence of the sterically hindered bisphosphine iron complex [FeCl₂(3,5-tBu₂-SciOPP)] (Scheme 361).⁵⁰⁴ The peripheral steric bulk of the complex results in the chemoselective reaction at the alkyl halide site in the presence of alkenyl triflates. The procedure affords high yields of the C(sp³)–C(sp²)-coupled product.

Scheme 361 Cross-coupling of alkyl halides with alkynyl Grignard reagent.

In contrast to Nakamura's method, Hu et al. introduced a procedure for coupling alkynyl Grignard reagents to alkyl halides in the absence of any phosphine ligand. They used simple iron(II) bromides in a THF/NMP solvent mixture at room temperature to accomplish the reaction, affording good yields of substituted alkynes (Scheme 362).⁵⁰⁵ The mild conditions of this reaction facilitate the alkynylation of a wide variety of functionalized cyclic and acyclic secondary alkyl halides and primary alkyl halides.

Scheme 362 Alkyl–alkynyl cross-coupling using iron(II) bromides.

6.4.4 Coupling with alkyl nucleophiles. C(sp³)–C(sp³) bond formation is one of the most challenging reactions since this bond lacks suitable coordination or π-backbone to coordinate with metal centres. This reaction is very important from a synthetic point of view in organic chemistry. The first successful iron-catalyzed C(sp³)–C(sp³) coupling of alkyl halides with alkyl Grignard reagents was performed by Chai and co-workers in 2007.⁵⁰⁶ They used iron(II) acetate together with XantPhos in diethyl ether to obtain the products in moderate yields.

The coupling between polychlorinated alkyl solvents and alkylmagnesium halides was developed using an iron catalytic system comprised of a pincer ligand bearing an iron(III) complex in THF.⁵⁰⁷ This process efficiently removes the toxic solvents dichloromethane, chloroform and carbon tetrachloride, with the subsequent formation of value-added products.

In 2012, Nakamura and co-workers developed the iron catalyzed alkyl–alkyl Suzuki–Miyaura cross-coupling of non-activated alkyl halides with alkylboron compounds (Scheme 363).⁵⁰⁸ The coupled products are formed in high yields due to the catalytic presence of iron(III) acetylacetonate and XantPhos ligand. It is noteworthy that alkyl borates are prepared by hydroboration of the corresponding alkenes followed by activation using isopropyl Grignard reagent. The reaction conditions show tolerance to different functional groups on both coupling partners, resulting in significant yields of the desired products. This reaction has been successfully utilized for the synthesis of long chain fatty acid derivates.

Scheme 363 Alkyl–alkyl cross-coupling using XantPhos-containing iron complex.

In 2013, Cárdenas et al. employed iron(II) acetate and an NHC ligand (IMes·HCl) to accomplish the alkyl–alkyl Kumada-type cross-coupling of alkyl iodides with alkyl Grignard reagents (Scheme 364).⁵⁰⁹ The β-elimination reaction is suppressed significantly with the formation of the desired coupled product in good yields. Based on mechanistic investigations, they suggested a radical pathway involving Fe(I) as the active species.

Scheme 364 Iron-catalyzed cross-coupling of alkyl halides and alkyl Grignard reagent.

The iron-mediated cross-coupling reaction of homobenzylic methyl esters with alkyl Grignard reagents via C–O bond cleavage was reported by Shi and co-workers. Iron(II) fluorides with the tricyclohexylphosphine ligand provide the best results in o-xylene solvent (Scheme 365).⁵¹⁰ They hypothesized that the reaction proceeds through dehydroalkoxylation, producing alcohol and the styrene derivative as intermediates, followed by carbometalation of the styrene intermediates with the Grignard reagent. A wide variety of methyl ethers containing different aryl groups at the β-position give good yields of C(sp³)–C(sp³)-coupled product. The importance of the counter anion of Grignard reagents is demonstrated by the different reactivities of the chlorides and bromides. Although n-hexylMgCl gives a good result, n-hexylMgBr remains unreacted.

Scheme 365 Iron-catalyzed cross-coupling of homobenzylic methyl esters with Grignard reagents.

In 2016, Fürstner introduced the first iron-promoted cross-coupling reaction of tert-alkyl electrophiles, 1-alkynylcyclopropyl tosylates, with alkyl Grignard reagents in the presence of a catalytic amount of Fe(acac)₃, resulting in high yields of the tosylate-substituted alkylated product (Scheme 366).⁵¹¹ Most importantly, the usually observed allene side products are not obtained except for the reaction using branched alkyl- or arylmagnesium reagents. Notably, the produced (1-methylcyclopropyl)ethynyl group acts as an important structural motif for many bioactive compounds.

Scheme 366 Reaction of 1-alkynylcyclopropyl tosylates and alkyl Grignard reagents catalyzed by iron.

Around the same time, Wong and co-workers utilized the iron complex [(FeCl₃)₂(TMEDA)₃] for the cross-coupling of alkyl halides and alkyllithium reagents, obtaining good yields of products.^363,440

6.5 Cross-coupling of benzyl, allyl and propargyl electrophiles with various nucleophilic partners

The early instances of iron-catalyzed reaction between Grignard reagent and propargyl halides were found in the reports by Pasto et al. in 1976.^512,513 The use of a catalytic amount of iron(III) chloride yielded allenes as the major product. Later, Yamamoto and co-workers performed iron-catalyzed selective coupling between allylic phosphates and Grignard reagents. This synthetic protocol affords the S_N2 products preferentially over the S_N2′ products.^514,515 High yields of product were reported using iron(III) acetylacetonate as the precatalyst. The tricyclo alkyl Grignard reagents are also coupled with propargylic halides and allylic halides in the presence of the same iron salt.⁵¹⁶

The structurally well-defined ferrate complex [Li(TMEDA)]₂[Fe(C₂H₄)₄] catalyzes the coupling reaction of propargylic, benzylic and allylic halides with phenyl Grignard reagents, providing excellent yields of the desired products (Scheme 367).^373,460 In addition, the benzyl bromides are coupled in moderate yields with arylmagnesium halides in the presence of an amine bisphenolate iron complex prepared by Kozak et al.⁴⁶⁴

Scheme 367 Cross-coupling of allylic halides and arylmagnesium reagents using ferrate complexes.

(E)-Styrenesulfonyl chlorides undergo desulfinylative cross-coupling with n-hexyl- and n-octylmagnesium bromides in the presence of Fe(acac)₃, giving moderate yields of products.³⁹¹ Also, allylsulfonyl chlorides are coupled similarly with aryl and alkyl Grignard reagents, providing high yields under the same reaction conditions (Scheme 368).⁵¹⁷ Moreover, a wide range of substituted aromatic Grignard reagents together with one heteroaromatic Grignard reagent are well tolerated. Both but-2-ene-1-sulfonyl chloride and but-3-ene-2-sulfonyl chloride form the same ratio of regioisomers. The linear product is preferred over the branched product. Through this observation, it was suggested that a same type of intermediate is formed from both species followed by coupling with the Grignard reagent with the same regioselectivity.

Scheme 368 Desulfinylative cross-coupling of allysulfonyl chlorides and aryl Grignard reagents.

A mixed iron–zinc catalytic system catalyzes the Suzuki coupling of different benzyl halides with sodium or potassium tetraarylborates, producing good to excellent yields of coupled product (Scheme 369a).⁴⁴⁷

Scheme 369 Cross-coupling of benzyl halides with arylborates and arylzinc reagents.

The Negishi coupling between aryl zinc reagents and benzyl halides is performed using the same iron complex bearing the 1,2-bis(diphenylphosphino)benzene ligand (Scheme 369b).⁵¹⁸ The complex shows good catalytic activity, giving excellent yield of selective-coupled products. Notably, the coupling occurs selectively at the benzylic halide in the presence of aryl halides.

A simple procedure for the iron-catalyzed cross-coupling of allyl electrophiles with arylmagnesium bromides was developed by von Wangelin and co-workers in 2010 (Scheme 370).⁵¹⁹ This method employs a one-pot procedure for the formation of Grignard reagents and subsequent coupling of allyl electrophiles. The reaction is successfully accomplished in the presence of ligand-free iron(III) acetylacetonate. A wide range of allylic electrophiles act as suitable substrates together with allyl acetates. This simple method efficiently tolerates electron-withdrawing and electron-donating substituents on the aryl reagents, giving the best results with ortho-oxygen substituents. Prenyl acetate, crotyl acetate and cinnamyl acetate as electrophiles afford the linear and branched regioisomers via the S_N and S_N′ pathways, respectively. The linear allylarene is formed as the major product from prenyl acetate with 9 : 1 selectivity. Although crotylation gives lower regioselectivity, cinnamyl acetate provides the linear product exclusively.

Scheme 370 Iron-catalyzed aryl–allyl cross-coupling.

In 2013, Bedford et al. revealed the versatile activity of the simple bis(diphenylphosphino)ethane ligand containing an iron complex in the coupling of benzyl halides with organozinc, organoboron, organoaluminum and organoindium reagents.⁵²⁰ The complexes presented excellent activity, producing high yields of products in the reaction with all the above-mentioned nucleophilic partners. In the same year, benzyl chlorides were selectively coupled with aryl Grignard nucleophiles in the presence of iron(II) chloride and ortho-phenylenebisphosphine ligands by Nakamura and co-workers. Most importantly, the products are formed according to the electronic properties of the bisphosphine ligands (Scheme 371).⁵²¹ It was found that electron-rich substituents on the ligand provide good yield of the coupled product. In contrast, electron-deficient substituents result in reductive homocoupling of the benzyl chlorides. The investigation of substrate scope using an iron(II) catalyst bearing electron-rich bisphosphine ligands revealed the feasibility of a wide range of aryl Grignard reagents for the reaction.

Scheme 371 Iron-catalyzed cross-coupling of mesitylmagnesium halides and benzyl halide.

In the same year, an air-stable and non-hygroscopic iron(III) amine-bis(phenolate) complex was employed by Kozak et al. for the cross-coupling of benzyl chlorides and bromides with arylmagnesium halides, providing low to high yields of products (Scheme 372).⁵²² In some instances, the homo-coupled products were formed in major amounts.

Scheme 372 Cross-coupling of benzyl halides and aryl Grignard reagents using iron(III) amine-bis(phenolate) complex.

In 2014, 4-ethynyloxetan-2-ones were coupled with aryl and alkyl Grignard reagents by Zang et al. in the presence of iron(III) chloride hexahydrate (FeCl₃·8H₂O), resulting in the ring-opened 4-alkynoic acids in good yields (Scheme 373).⁵²³ The reaction occurs regioselectively to produce the alkynoic acid in a major amount together with a minor amount of allenes as by-products. The prevalence of S_N2 substitution reaction at the β-carbon atom of the 4-ethyloxetan-2-one was inferred from the complete inversion of configuration at that site.

Scheme 373 Iron-catalyzed reaction of 4-(trimethylsilylethynyl)oxetan-2-one with Grignard reagents affording 4-alkynoic acids.

An iron-catalyzed allyl–alkyl cross-coupling reaction was employed by von Wangelin et al. for the selective deallylation of allylphenyl ethers (Scheme 374).⁵²⁴ The best results were obtained using ethylmagnesium nucleophiles in the presence of iron(II) chloride in an m-xylene/THF solvent mixture. A wide variety of functionalized ethers efficiently produced the corresponding phenols or alcohols in high yields. Furthermore, allylic and benzylic halides were also used in the iron-mediated Suzuki–Miyaura coupling with arylboron compounds.⁴⁸¹

Scheme 374 Deallylation of aryl ethers using an iron catalyst.

In 2016, Bäckvall and co-workers introduced a reaction protocol for the synthesis of substituted α-allenols using the iron-catalyzed cross-coupling of propargyl carboxylates and Grignard reagents (Scheme 375).⁵²⁵ They investigated the process using two classes of propargyl substrates, A and B. Both classes of substrates provide high yields of the desired substituted α-allenols. The catalytic system consists of simple iron(III) acetylacetonate in diethyl ether solvent. A wide range of functional groups such as silyl ethers, carbamates and acetals, together with a large number of Grignard reagents are well tolerated under the mild conditions of the reaction. Interestingly, sterically congested Grignard reagents give the highest yields. Notably, the starting propargylic substrates are readily prepared via a one-pot synthesis.

Scheme 375 Iron-catalyzed coupling reaction of propargylic substrates and Grignard reagents.

6.6 Miscellaneous examples of cross-coupling with various coupling partners

The Sonogashira cross-coupling reaction between terminal phenylacetylenes with iodo-aryl derivates was reported in 2016 using the iron(II) complex FeCl₂(bdmd) and co-catalyst [Cu(CH₃CN)₄]BF₄ in 1,4-dioxane (bdmd = bis((diphenylphosphanyl)methyl)diphenylsilane) (Scheme 376).⁵²⁶ Different functional groups at the para position such as fluoro, methoxy, acetyl and phenyl are well tolerated, giving moderate to good yields of the desired coupling products. The ortho-amine or hydroxyl substituents are found to produce significantly higher yields. This result is either due to co-ordination of the functional groups to the iron centre or the ortho-directing effect. Various control experiments revealed that the presence of both iron and copper complexes is necessary for the transformation to occur.

Scheme 376 Iron-catalyzed Sonogashira cross-coupling of terminal phenyl acetylenes and iodoaryl derivatives.

In the same year, Iwasaki et al. presented the iron-promoted cross-coupling reaction of aryl vinyl ethers with aryl Grignard reagents through the selective cleavage of the vinylic C–O bond in the presence of simple iron(II) chlorides, providing the styrene derivatives in good to excellent yields (Scheme 377).⁵²⁷ Both electron-withdrawing and donating substituents and other functional groups on the aryl nucleophiles are well tolerated.

Scheme 377 Cross-coupling of aryl vinyl ethers with aryl Grignard reagents using an iron catalyst.

In 2017, Nakamura and co-workers developed the first iron-catalyzed stereoselective cross-coupling of less reactive glycosyl halides with aryl metal reagents, producing high yields of a variety of aryl and vinyl C-glycosides (Scheme 378).⁵²⁸ This transformation occurs efficiently in the presence of a catalytic system consisting of iron(II) chloride and the bulky bisphosphine ligand TMS-SciOPP in THF. The reaction was suggested to proceed through a radical reaction, as confirmed by the radical clock reaction. This reaction was employed for the synthesis of a sodium-glucose co-transported 2 (SGLT2) inhibitor, Canagliflozin.

Scheme 378 Iron-catalyzed cross-coupling of glycosyl bromide and diarylzinc reagents.

Recently in 2018, Cao and co-workers demonstrated the synthesis of pinacol esters of arylboronic acid via the iron-catalyzed cross-coupling between bis(pinacolato)diboron (B₂pin₂) and aryl fluorides (Scheme 379).⁵²⁹ The reaction is carried out in the presence of iron(II) chloride and LiHMDS (lithium hexamethyldisilazide) base in the solvent mixture of toluene and HMPA. Notably, the experiments are carried under an argon atmosphere. Only biaryl fluorides afford the desired borylation product in moderate to good yields, whereas other aryl fluorides provide unsatisfactory results.

Scheme 379 Iron-promoted cross-coupling of aryl fluorides and bis(pinacolato)diboron.

6.7 Mechanistic elucidations of cross-coupling reactions

The mechanism of iron catalysis in cross-coupling was not well established compared to that of palladium- and nickel-catalyzed reactions until the recent studies by Neidig and co-workers. Since iron can exhibit various oxidation and spin states, the possible reaction pathway and reactive intermediates are highly dependent on the reaction conditions and the coupling partner. Thus, detailed mechanistic insight into iron-catalyzed cross-coupling reactions remained elusive for a long time until Fürstner et al. showed some reactive intermediates based on experimental evidence.^373,460 Although Kochi proposed the initial mechanism based on experimental evidence, it lacked more reasonable evidence at that time.

Since then, different mechanistic hypotheses have been reported starting from the early investigations by Kochi to the recent reports of iron-catalyzed cross-coupling reactions using different advanced spectroscopic techniques. In this section, the proposed mechanisms are summarized and classified into two broad categories based on the number of electrons transferred.

6.7.1 Two-electron transfer mechanisms. The first investigation on mechanism was performed by Kochi and co-workers for the cross-coupling of alkenyl halides and Grignard reagents. They proposed a mechanism analogous to that of palladium- and nickel-catalyzed cross-coupling considering the experimental evidence (Scheme 380).^18d,530,531 The mechanism initiates with oxidative addition of the alkenyl electrophile to the iron centre (I), followed by transmetalation with alkylmagnesium halides, and finally reductive elimination of III to from the coupled product. Fe(I) in this Fe(I)/Fe(III) catalytic cycle is formed from the reduction of the Fe(III) or Fe(II) precatalyst by the alkylmagnesium halides. Further, through ESR studies, they identified the formation of an S = 1/2 iron(I) species from the reaction between methylmagnesium bromide and iron salts. It was hypothesized that the side products were formed from the disproportionation of the alkyl-Fe(III) species.

Scheme 380 Mechanism of iron-catalyzed cross-coupling of alkenyl halides and Grignard reagents as proposed by Kochi.

The proposal of the S = 1/2 iron(I) intermediate by Kochi remained a mystery for a long time until Neidig and co-workers identified it using advanced EPR (electron paramagnetic resonance) and MCD (magnetic circular dichroism) studies. In 2014, they synthesized and characterized a homoleptic tetramethyliron(III) ferrate complex [MgCl(THF)₅][FeMe₄] from the reaction of FeCl₃ with methyl magnesium bromide in THF.⁵³² It was reported that on warming this square planar complex, spin S = 3/2 is converted to S = 1/2 iron(I) species initially proposed by Kochi as the active intermediate. Also, the evolution of ethane during this process confirmed the intermediate of the complex during the reduction of FeCl₃ to form the reduced species in the catalytic process. Later in 2016, they isolated a novel iron methyl cluster, [MgCl(THF)₅][Fe₈Me₁₂], and characterized it as the species consistent with Kochi's S = 1/2 iron(I) species.⁵³³ Notably, the direct reaction of the iron(I) species with electrophile gave a negligible result. However, the combination of MeMgBr with the electrophile led to the fast and selective formation of the coupled product. Notably, the formation of Me₁₂Fe₈⁻ cluster ions by the treatment of Fe(acac)₃ with MeMgX (X = Cl, Br) was confirmed through the electrospray ionization (ESI) mass spectroscopy investigation by Koszinowski and Parchomyl in 2017.⁵³⁴ In addition, they reported the disappearance of the ferrate cluster in the presence of the chelating ligand TMEDA. However, Neidig and co-workers reported the formation of a trimethyliron(II) ferrate species, [Mg(NMP)₆][FeMe₃]₂, instead of the [Fe₈Me₁₂]⁻ cluster in the presence of NMP as a co-solvent in the reaction.⁵³⁵ Through the combination of GC analysis and Mössbauer spectroscopic studies they found that the complex was highly reactive for the selective formation of the cross-coupled products. They also demonstrated the interaction of the six NMP molecules with the magnesium through their carbonyl oxygens, which preferentially stabilized the complex over the [Fe₈Me₁₂]⁻ cluster formation. Further, they investigated the effect of β-hydrogen atom-bearing Grignard reagents such as EtMgBr on the fate of iron salts under similar reaction conditions. They observed the presence of the iron species [Fe₈Et₁₂]⁻ and [FeEt₃]⁻, which are analogous to the species formed in the presence of NMP. These species also have similar catalytic competencies.⁵³⁶

The presence of low-valent iron active species was proposed by Fürstner et al. They proposed a catalytic cycle based on Fe(II−) and Fe(0) species for the coupling between aryl halides and Grignard reagents.^373,394,395 In this process, the Fe(III) or Fe(II) salts are reduced by excess Grignard reagent to form a highly nucleophilic iron ensemble, [Fe^II−(MgX₂)]_n. This process is well established in the reports regarding the formation of “inorganic Grignard reagents” by Bogdanović et al. (Scheme 381).^537,538 [Fe(MgX)₂]_n remains as a cluster containing iron and magnesium centres connected via covalent intermetallic bonds. This nucleophilic cluster undergoes a catalytic cycle similar to the well-established pathway for cross-coupling reactions catalyzed by nickel and palladium (Scheme 382).^394,395

Scheme 381 Reduction of alkyl Grignard reagents to form the “inorganic Grignard reagent”.

Scheme 382 Proposed catalytic cycle with low-valent iron as the active species.

The Fe(II−) species I oxidatively inserts into the aryl halides owing to its high nucleophilic character with the release of magnesium halide. It was proposed that the resulting Fe(0) complex II is alkylated by a Grignard reagent to form complex III. Finally, reductive elimination of III occurs to form the desired coupled product with the regeneration of the catalytically active Fe–Mg species (Scheme 382). Notably, the reduction of the iron precatalyst by the alkyl Grignard reagent occurs with the concomitant β-hydride elimination of the alkyl substituent of the Grignard reagent. Therefore, the presence of β-hydrogen is a necessary condition for the occurrence of the above mechanism. This fact was evidenced from the inactivity of methylmagnesium halides, which did not provide any product compared to higher alkyl Grignard towards aryl halides in the presence of suitable precatalysts.^378,379 Accordingly, Fürstner et al. demonstrated the formation of the homoleptic organoferrate complexes [(Me₄Fe)(MeLi)][Li(OEt₂)]₂ and [Ph₄Fe][Li(Et₂O)₂][Li(1,4-dioxane)] from the reaction of methyllithium and phenyllithium with FeCl₃, respectively.

It was observed that these complexes are moderately nucleophilic and react efficiently with activated electrophiles such as acyl chlorides and alkenyl triflates.^373,539 They also synthesized several lithium ferrate complexes having low formal oxidation states, which showed successful reactivity with aryl chlorides and allyl halides. Alkyl, allyl, benzyl and propargyl halides were also coupled with organomagnesium reagents in the presence of the above-mentioned ferrate complexes. However, in accordance with the experimental observations, they suggested the presence of interconnected catalytic cycles with the formal oxidation states of Fe(I)/Fe(III), Fe(0)/Fe(II), and the previously mentioned Fe(II−)/Fe(0).

In addition, in 2016, Parchomyk et al. utilized electrospray-ionization (ESI) mass spectroscopy for the identification and characterization of in situ-formed ionic species as intermediates during the reactions of iron-catalyzed cross-coupling reactions.⁵⁴⁰ They studied the Fe(acac)₃-catalyzed cross-coupling reaction of PhMgCl with i-PrCl in THF and investigated the effects of various ligands and additives on the reaction. They reported the formation of different anionic iron ‘ate’ complexes having various nuclearity and oxidation states such as mononuclear phenylferrates [Ph₃Fe^II]⁻ and [Ph₄Fe^III]⁻ formed by the addition of excess of PhMgCl to Fe(acac)₃. Moreover, the gas-phase fragmentation experiment showed that the addition of i-PrCl to this reaction results in the formation of the heteroleptic complex [Ph₃Fei-Pr]⁻. This heteroleptic complex undergoes reductive elimination to form the cross-coupled product. Further, in 2018 have reported studies with a wide range of simple iron precursors and Grignard reagents in tetrahydrofuran.⁵⁴¹ All the iron precursors resulted in the formation of organoferrates R_nFe_m⁻, with large variations in aggregation (1 ≤ m ≤ 8) and oxidation state (I to IV) depending on the nature of the organic counterpart. Several organoferrates react with organyl halides and pseudo halides, forming heteroleptic complexes. These heteroleptic complexes upon gas-phase fragmentation result in reductive elimination to produce the cross-coupled products. Notably, the aggregation and the oxidation states are influence by the presence of additive and ligands such as TMEDA and dppbz.

In 2008, Nakamura et al. proposed a mechanism involving Fe(0) and Fe(II) as the on-cycle species for the cross-coupling of alkenyl halides with alkynyl Grignard reagents to form enynes (Scheme 383).³⁶⁷ The iron(III) chlorides are initially reduced to low-valent Fe(0) alkynyl species I together with the formation of diyne as the side product from the Grignard reagent.

Scheme 383 Mechanism for the iron-catalyzed cross-coupling of alkenyl halides and alkynyl Grignard reagents.

Importantly, the presence of lithium salt accelerates the initial reduction process. The alkenyl halide is oxidatively added to the Fe(0) active species. This is followed by reductive elimination of high-valent ferrate complex II to produce the corresponding enyne together with the formation of complex III. A molecule to alkynyl Grignard reagent is added to complex III to regenerate active iron species I.

A unique metalate mechanism with the Fe(II)/Fe(IV) catalytic cycle was proposed by Nakamura et al. for the coupling reaction between aryl chlorides and aryl Grignard reagents in the presence of iron fluorides and NHC ligands (Scheme 384).⁴³² The mechanism proceeds with the initial formation of heteroleptic metalate complex I from the aryl magnesium reagent and iron(II) fluorides followed by oxidative addition to an aryl halide, producing higher valent Fe(IV) species II. Thereafter, this species undergoes reductive elimination to give the asymmetrical biaryl product with subsequent formation of Fe(II) complex III. In the final step of the cycle, transmetalation of species III with the Grignard reagent results in the regeneration of reactive intermediate I. Through density functional theory (DFT) calculation and controlled experiments they suggested that the initial transmetalation and homocoupling are suppressed in the presence of the strong coordination of the fluoride ions.

Scheme 384 Fe(0)/Fe(II) mechanism for iron-catalyzed cross-coupling between aryl halides and aryl Grignard reagent.

Consequently, the metalate mechanism is favoured in comparison to the well-established Fe(0)/Fe(II) mechanism (Scheme 385) of palladium- and nickel-catalyzed cross-coupling reactions.

Scheme 385 Proposed metalate mechanism for iron-catalyzed cross-coupling between aryl halides and aryl Grignard reagent.

Further, Norrby et al. investigated the cross-coupling of aryl electrophiles and alkyl Grignard nucleophiles using Hammett and computational studies.^542,543 They proposed the presence of Fe(I) complex I as the active species. This species can undergo transmetalation before or after oxidative addition, forming Fe(III) complex II (Scheme 386). Fe(III) complex II in turn undergoes reductive elimination, resulting in the coupled product and a new Fe(I) complex. The oxidative addition is the rate-limiting step and transmetalation is the fast step. The cycles containing oxidation states lower than Fe(I), that is Fe(II−)/Fe(0), Fe(I−)/Fe(0) and Fe(0)/Fe(II), are disfavoured from a thermodynamic point of view. Mainly, the low-valent iron species can act as an active precatalyst but cannot be regenerated in the catalytic cycle due to the high energy barrier for the required reductive elimination process. The low temperature kinetic investigation of the reaction also supported the Fe(I)–Fe(III) catalytic cycle.⁵⁴⁴ Quantification of the product showed that Grignard reagents alone can reduce the iron precatalyst to Fe(I) as the lowest oxidation state.⁵⁴⁵ Further, the computational study revealed the presence of the S = 3/2 spin state for the active catalyst even though Fe(III) salts having the S = 5/2 spin state were used as the precatalyst.

Scheme 386 Two mechanisms proposed by Norrby and co-workers.

In contrast, Ren et al. performed theoretical analysis of the mechanism of the in situ-generated low-valent iron species, [Fe(MgX)₂], as postulated by Fürstner. They performed density functional theory (DFT) calculations for the iron-catalyzed coupling of 4-chlorobenzoic acid methyl ester and n-hexylmagnesium chloride.⁵⁴⁶ They generalized the Fe(II−)/Fe(0) catalytic cycle into three steps, consisting of the oxidation of [Fe(MgBr)₂] to form the arylated species followed by the addition of the Grignard reagent, forming the aryl-alkyl Fe–Mg cluster, and finally reductive elimination, resulting in the coupled product with the regeneration of [Fe(MgX)₂]. Notably, according to Fürstner's mechanism, the oxidative addition is associated with the removal of magnesium dihalide followed by the addition of the Grignard reagent. In relation to this, it was concluded that the addition of Grignard reagent undergoes a low energy barrier when it occurs before the removal of MgX₂. The final reductive elimination was found to be the rate-limiting step.

Recently in 2018, Neidig and co-workers reported the formation of iron-phenyl species [FePh₂(μ-Ph)]₂²⁻ from the reaction of 4 equivalents PhMgBr and Fe(acac)₃ in THF at −80 °C, which is stabilized in the presence of NMP.⁵⁴⁷ On performing the reaction at −30 °C, they isolated a tetranuclear iron-phenyl cluster Fe₄(μ-Ph)₆(THF)₄. This tetranuclear species was found to be reactive to bromocyclohexane, giving the coupled product rapidly, whereas the species [FePh₂(μ-Ph)]₂²⁻ remained unreactive to electrophiles. Further synthetic studies revealed the formation of analogous tetranuclear iron species using both 4-F-PhMgBr and p-tolylMgBr.

In 2012, Bedford and co-workers demonstrated the influence of Fe(I) complexes in the Negishi cross-coupling between benzyl halides and diarylzinc reagents in the presence of diphenylphosphinobenzene (dpbz)-containing iron(III) complexes.⁵⁴⁸ The early formation of the homocoupling product in the reaction indicated the reduction of the Fe(III) precatalyst to an Fe(I) intermediate species. In this context, they synthesized and characterized three Fe(I)(dpbz)₂ complexes (I, II, and III) to gain better insight into the catalytic efficacy of Fe(I) intermediates in the cross-coupling reaction (Scheme 386). The complexes were found to be very efficient as catalytic species on application to the cross-coupling of diarylzinc with benzyl electrophiles and 2-pyridyl halides, giving high yields of products (Scheme 387). Through this comparable efficiency of the Fe(I) complexes to that of the Fe(III) precatalyst, Fe(I) was suggested as the lowest kinetically relevant species. Through further investigation on the same reaction using XAFS spectroscopy, they recently reported that during the turnover, the diphosphine ligand co-ordinates predominantly to the Zn(II) ions instead of iron.⁵⁴⁹ Their studies also revealed the presence of homoleptic arylferrates formed by the reaction of the iron precursors with excess diarylzinc reagents. Furthermore, they proposed the formation of a mixed Fe–Zn(dpbz) species, having crucial role in the catalytic activity. The presence of Fe(I) as the active species was also confirmed by Bauer and co-workers through X-ray absorption studies.⁵⁵⁰

Scheme 387 Structure of I, II, and III and their application in cross-coupling reactions.

The role of the TMEDA ligand in the iron-promoted cross-coupling reaction of alkyl halides and bulky aryl Grignard reagents was thoroughly investigated by Bedford and co-workers in 2013.⁵⁵¹ In these reactions, the homoleptic organo-iron is formed as the catalytically active species. The neutral complexes containing TMEDA react more slowly than that of the homoleptic ligand. However, TMEDA plays a role in the suppression of the competing reaction by trapping the corresponding off-cycle intermediates. Notably, Fe(II) appears to be the lowest oxidation state for the system containing bulky aryl Grignard reagents due to the resistance in reductive elimination. However, lower oxidation states below Fe(II) are feasible in the presence of smaller and less bulky aryl Grignard reagents. The formation of the Fe(I) complex for smaller aryl Grignard such as benzyl and tolylmagnesium halides was confirmed by the presence of the S = 1/2 spin state in EPR measurements.

In 2014, Lefèvre and Jutand carefully studied the coupling reactions of aryl and heteroaryl halides and aryl Grignard reagents catalyzed by iron(III) acetylacetonate using ¹HNMR, cyclic voltammetry, EPR and DFT.⁵⁵² They reported the formation of two reduced complexes produced via the reduction of Fe(acac)₃ in the presence of excess of PhMgBr.⁴⁶⁰ One of them was identified as [PhFe^II(acac)(thf)_n] and the other as [PhFe^I(acac)(thf)]⁻. The Fe(II) species remains inert to aryl or heteroaryl halides. In contrast, the Fe(I) complex reacts in two different pathways depending on the substrates. The aryl halides are reduced by the Fe(I) species in a monoelectronic inner-sphere reduction pathway, resulting in the corresponding arenes and homocoupling products. On the other hand, the heteroaryl chlorides react with [PhFe^I(acac)(thf)]⁻via the oxidative addition/reductive elimination pathway to afford the coupled products.

Although several possible mechanistic pathways have been proposed, recent studies using advanced spectroscopic methods are more consistent with the Fe(I)/Fe(II) catalytic cycle.

6.7.2 One-electron transfer mechanisms. In addition to the two-electron transfer mechanisms, the ideology of radical mechanisms was introduced when Nakamura and co-workers in 2004 observed high stereoconvergence for the cross-coupling of trans- and cis-1-bromo-4-t-butylcyclohexane, producing the trans product selectively.³⁴³ Since, oxidative addition is associated with complete retention of the configuration of the substrates, this stereoconvergence gives evidence of radical intermediacy. In the same year, Fürstner et al. observed a complete loss of optical purity during the arylation of (R)-2-bromooctane by PhMgBr. Together with this, the ring closure prior to the cross-coupling for a substituted cyclic iodo acetal containing a terminal double bond was observed. Through these observations, they suggested the involvement of a radical pathway. Later in 2005, Beford and co-workers presented a simplified radical-based mechanistic pathway (Scheme 388).⁵⁵³ In the initial step, the iron(III) precatalyst is reduced by the Grignard reagent, producing low-valent active iron species I. This active iron species undergoes single-electron transfer to generate alkyl radical II.

Scheme 388 Single-electron transfer mechanism proposed by Bedford.

This alkyl radical remains associated with the iron centre during the transmetalation step. Iron-aryl complex III formed through transmetalation with the Grignard reagent is attacked by an alkyl radical, followed by elimination of the coupled product with concomitant regeneration active species I.

A similar mechanism was proposed by Caheiz et al. for the alkylation of aryl Grignard reagents having 0, I+ and II+ as the on-cycle oxidation states (Scheme 389).⁴⁷⁰ Initially, the Fe(III) precatalyst is reduced by arylmagnesium halides, producing Fe–Mg cluster-type active species I having iron in the zero oxidation state. The transmetalation step was suggested to precede the electron transfer process. Thereafter, the oxidative addition of the alkyl halide occurs in two consecutive steps, consisting of the generation of alkyl radical III and its subsequent addition to the iron centre with the concomitant release of MgX₂. Species IV thus formed undergoes reductive elimination, forming the coupled product together with the regeneration of the active Fe(0) complex.

Scheme 389 Single-electron transfer mechanism proposed by Caheiz et al.

In 2009, Nagashima and co-workers presented a mechanistic overview of the cross-coupling of alkyl halides and aryl Grignard reagents, elucidating the role of the TMEDA ligand in the reaction (Scheme 390).⁵⁵⁴ The mechanism initiates with the formation of an Fe(II) complex (TMEDA)Fe(Ar)₂ (I) from FeCl₃ and the aryl Grignard reagent, followed by the addition of an alkyl halide to it. In this addition process, diaryliron(II) complex I undergoes one-electron oxidation to form diaryl(halogeno)iron(III) complex II together with the formation of an alkyl radical. The alkyl radical remains in close association to the iron(III) complex. Next, this alkyl radical abstracts one aryl radical from the diaryliron(III) complex, resulting in the alkylated arene and aryl(halogeno)iron(II) complex III. Thereafter, this Fe(II) species undergoes transmetalation to regenerate the initial Fe(II) species, I. Notably the active diaryliron(II)–TMEDA complex was isolated and its structure was determined by X-ray crystallography. Also, the lifetime of the radical intermediate was estimated using radical clock experiments by applying the reaction conditions separately to 1-bromo-5-hexene (a) and bromomethyl cyclopropane (b) (Scheme 391). Although the latter gave fast ring-opening products, no cyclopentyl product was observed for 1-bromo-5-hexene.

Scheme 390 Single-electron transfer mechanism of iron–TMEDA complex.

Scheme 391 Radical clock experiment using 1-bromo-5-hexene (a) and bromomethyl cyclopropane (b).

In 2010, Nakamura and co-workers demonstrated a similar Fe(II)/Fe(III) catalytic cycle for the iron-catalyzed Suzuki–Miyaura coupling between lithium borates and alkyl halides using iron(II) diphosphine complexes (Scheme 392).⁴⁸⁸ The effect of the bisphosphine ligand-containing iron complexes, FeCl₂(SciOPP), in this reaction and in the Kumada reaction was investigated by Neidig and co-workers using Mössbauer spectroscopy, magnetic dichroism (MCD), and DFT studies.^555,556 They have identified in situ FeMes₂(SciOPP) as the active catalyst for the cross-coupling reaction of mesitylmagnesium bromide (MesMgBr) with primary alkyl halides in the presence of the bisphosphine iron complex FeCl₂(SciOPP). The advanced spectroscopic techniques also revealed the formation of the FeXMes(SciOPP) (X = halides) complex together with the mesityldecane product for the reaction of primary alkyl halides with FeMes₂(SciOPP). This observation was in accordance with the previous proposals of Fe(II)/Fe(III) catalytic mechanisms.

Scheme 392 SET mechanism for iron bisphosphine complex-catalyzed cross-coupling reaction.

Further spectroscopic studies were performed by the Neidig group on the Suzuki–Miyaura and Kumada coupling of phenyl nucleophiles with secondary alkyl halides in the presence of the same iron–SciOPP complexes.⁵⁵⁷ They reported the formation of an Fe(0)(η⁶-biphenyl)(SciOPP) complex by the reaction of FeCl₂(SciOPP) and phenyl nucleophiles. Although the reactivity of low-valent species in the cross-coupling reaction is known, the iron(0) complex was found to be catalytically incompetent species towards electrophiles. In contrast, the mono- and bis-phenylated Fe(II) species produced prior to the reductive elimination were identified and found to be much more reactive toward electrophiles, giving the cross-coupled product in catalytically relevant rates. Furthermore, the monophenylated iron(II) species has higher selectivity towards coupled product formation for both the Suzuki–Miyaura and Kumada coupling reactions. Additionally, the presence of a significant amount of under transmetalated iron for both reactions indicated that the mono-phenylated iron complex Fe(Ph)X(SciOPP) (X = Br and Cl) is the prevalent active species.

The same FeCl₂(SciOPP) complex was utilized for the alkynylation of non-activated alkyl halides by Nakamura and co-workers.⁵⁰⁴ A single-electron transfer mechanism was proposed analogous to the other mechanisms for the reaction using the same iron–SciOPP complex. Hu and co-workers also suggested a similar mechanism in their alkyl–alkynyl cross-coupling using a phosphine-free iron catalyst.⁵⁰⁵ Accordingly, in 2017, Neidig and co-workers provided detailed insight into the iron–SciOPP catalyzed alkynylation reaction of alkyl halides and alkynyl Grignard reagents using different inorganic spectroscopic methods and thorough reaction studies.⁵⁵⁸ They studied the reaction using (triisopropylsilyl)ethynylmagnesium bromide as the nucleophile with cycloheptyl bromide electrophile using FeBr₂(SciOPP) as the catalyst. They demonstrated the in situ formation of mono-, bis- and tris-alkynylated iron(II) SciOPP complexes upon the initial addition of the iron–SciOPP catalyst to the Grignard reagent. The rapid redistribution of the alkynyl ligand attached to these species made them inaccessible in THF solvent. However, these species were found to be stable in non-polar solvents such as toluene and were assessed for their reactivity towards electrophiles. The tris-alkynylated iron(II)–SciOPP species was catalytically inefficient, remaining unreactive to the cycloheptyl bromide electrophile. On the other hand, the neutral mono- and bis-alkynylated iron(II)–SciOPP species readily reacted with the electrophile to generate the coupled products at catalytically relevant rates. Also, the rate of addition of the Grignard reagent was found to have a significant effect on the yields and selectivity of product formation. Furthermore, the role of the steric bulk of the Grignard reagent was well demonstrated in this study.

Nakamura and co-workers proposed a combined mechanistic cycle for their first iron-catalyzed enantioselective and chemoselective cross-coupling between alkyl halides and Grignard reagents using a chiral–bisphosphine–iron complex.⁵⁵⁹ They suggested the occurrence of either the Fe(II)/Fe(III)/Fe(I) (in-cage) or Fe(II)/Fe(III) mechanistic (out-of-cage) pathway, having a common organoiron(II) intermediate I as the active species (Scheme 393). Notably, the coupling reaction initially undergoes iron-promoted C–Cl activation to generate complex III together with alkyl radical formation. This is followed by C–C bond formation via the in-cage or out-of-cage pathway. They re-evaluated the mechanistic pathways in 2017 using DFT and MC-AFIR methods.⁵⁶⁰ The mechanistic cycle proposed after computational studies consists of initial C–Cl bond activation of active species I, generating complex II. Thereafter, metal-radical coordination occurs via transmetalation, forming intermediate III. Then, coordination between iron centre III and the radical occurs to generate species IV. Finally, C–C coupling occurs via reductive elimination in species IV to give the desired product together with the regeneration of the active species (Scheme 394). It was suggested that both the iron(I) and iron(II) species are generated in the reaction before the addition of the electrophile. Notably, the iron(I) species initiates the C–Cl activation process. Furthermore, the C–C bond formation by the reaction of the iron(II) species and radical species via the inner-sphere mechanism is the selectivity-determining step of the cycle. On the other hand, Gutierrez and co-workers on employing quantum mechanical calculations demonstrated that the formation of the product occurs via the low-energy quartet spin state of iron instead of the high-energy sextet spin state.⁵⁶¹ The stereoselectivity is observed due to the presence of key non-covalent interactions such as π-donor/acceptor and C–H–π interactions.

Scheme 393 Originally proposed combined mechanistic cycle for iron-catalyzed enantioselective cross-coupling.

Scheme 394 Modified mechanistic pathway for Fe-catalyzed enantioselective cross-coupling reaction.

Nakamura and co-workers also proposed a similar radical mechanism for their iron–SciOPP-catalyzed stereoselective anomeric arylation of glucosyl halides and aryl metal reagents.⁵⁶² Radical clock experiments confirmed the presence of glycosyl radical intermediates. Further, DFT studies revealed that the relative stability of the glycosyl radical conformers results in the high diastereoselective nature of the reaction.

A plausible mechanism involving a radical intermediate was presented by them for the cross-coupling of non-activated chloroalkanes with aryl Grignard reagents in the presence of iron N-heterocyclic carbene catalysts (Scheme 395).⁴⁶⁷ Initially, iron(III) chloride is reduced to NHC-bearing iron(II) intermediate I on reaction with the Grignard reagent and imidazolium salt in the induction step. Thereafter, ferrate(II) intermediate complex II is formed, which has been suggested as the active species of the catalytic cycle. Then, an SET mechanism operates via the homolytic cleavage of the C–Cl bond of the alkyl chloride, generating the alkyl radical and iron(III) complex III. The radical remains bound to the iron centre in the solvent cage and it recombines with the aryl ligand of the iron centre to form the desired coupled product. Deng and co-workers also investigated the mechanistic aspects of the iron-catalyzed cross-coupling reaction with NHC ligands.⁵⁶³ They reported the synthesis and characterization of the NHC-bearing ferrous phenyl complex [(IPr₂Me₂)₂FePh₂] and studied its reactivity towards C–C bond formation. The complex prepared from the reaction of ferrous chloride with PhMgBr and IPr₂Me₂(IPr₂Me₂ = 1,3-diisopropyl-4,5-dimethylimidazole-2-ylidene) was found to react with alkyl halides, affording the cross-coupling products together with the formation of the monophenyliron(II) complex (IPr₂Me₂)₂FePhX. They suggested the involvement of the single-electron transfer (SET) mechanism for the C–X bond cleavage in alkyl halides through the observation of the ring-opening product for the reaction with cyclopropylmethyl bromide. Also, the formation of alkenes and alkanes as side products confirmed the presence of radical intermediates in the reaction.

Scheme 395 Radical mechanism with N-heterocyclic carbene ligand.

Further in 2015, Tonzetich and co-workers studied the mechanism of cross-coupling reactions catalyzed by H-heterocyclic carbene ligand-containing iron complexes.⁵⁶⁴ They employed the iron precatalyst [FeCl₂(μ-Cl)₂(IPr)₂] to perform detailed mechanistic studies by means of radical clock, radical trapping and single turnover experiments. Through these studies, they proposed a radical-based catalytic cycle involving an Fe(II)/Fe(III) redox couple (Scheme 396). The proposed cycle begins with the transmetalation of the iron(II) precursor, forming arylated iron(II) active species I. This is followed by halogen atom abstraction of the alkyl halide to form alkyl radical and iron(III) intermediate II. This alkyl radical after dissociation from the metal solvent cage reacts with the aryl group present on II, forming the coupled product together with the concomitant regeneration of Fe(II) complex III. Finally, transmetalation of the formed Fe(II) complex results in the regeneration of active species I.

Scheme 396 Mechanism for cross-coupling using [FeCl₂(μ-Cl)₂(IPr)₂].

Notably, Càrdenas and co-workers proposed an Fe(I)/Fe(II)/Fe(III) catalytic cycle with Fe(I) as the active species for the cross-coupling between alkyl iodides and acetyl group-containing alkyl Grignard reagents using Fe(OAc)₂ together with the NHC ligand IMes·HCl.⁵⁰⁹ The existence of Fe(I) species in the reaction medium was confirmed by EPR spectroscopy, showing the presence of the S = 1/2 species. In addition, the radical clock experiments suggested the participation of radical intermediates. Thus, the two-step oxidative addition of the alkyl halide was suggested, consisting of homolytic cleavage of the alkyl halide forming an alkyl radical and Fe(II) species (II/III′), followed by collapse of the alkyl radical with the Fe(II) complex, resulting in the Fe(III) complex (IV) (Scheme 397). This Fe(III) complex undergoes reductive elimination to form the coupled product. The Fe(I) active species (I) can be evolved either through oxidative addition of the alkyl halide (cycle A) or through transmetalation of the Grignard reagent (cycle B) (Scheme 397). However, both cycles afford the coupled product via reductive elimination of iron(III) species II.

Scheme 397 Catalytic cycle for iron catalysis using NHC ligand proposed by Càrdenas and co-workers.

Accordingly, in 2018, Neidig and co-workers reinvestigated this reaction to gain better insight into the reactive species using a series of inorganic spectroscopic techniques together with inorganic synthesis of model complexes or reactive intermediates and reaction studies.⁵⁶⁵ Employing the iron–NHC-catalyzed reaction of (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide with 1-iodo-3-phenylpropane, they identified and demonstrated the in situ formed [(IMes)Fe((1,3-dioxan-2-yl)ethyl)₂] (X) as the reactive species (Scheme 398). In contrast to previous proposals, the S = 1/2 iron species were found to be minor off-cycle species. The high reactivity of the bis-alkylated species [(IMes)Fe((1,3-dioxan-2-yl)ethyl)₂] towards electrophiles was demonstrated by its two turnovers with respect to iron, producing the cross-coupled product with selectivity similar to a catalytic reaction. The reason behind the much lower β-hydride elimination from the alkyl nucleophile in the Càrdenas reaction conditions was disclosed through this investigation. The resistance to β-hydride elimination is due to the presence of a five-membered chelate ring in iron(II) of the bis-alkylated species, which is formed by the chelation of the ligated alkyl group through its carbon and one oxygen of the acetyl moiety.

Scheme 398 Iron-catalyzed cross-coupling of (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide with 1-iodo-3-phenylpropane in the presence of isolated active catalyst X.

Moreover, other bulkier NHC ligands were found to be less effective in the catalysis due to the inhibition of this chelate formation as result of their bulkiness.

Nakamura and co-workers also proposed a two-step oxidative addition analogous to the proposals of Càrdenas for their iron catalyzed alkyl–alkyl Suzuki–Miyaura cross-coupling (Scheme 399).⁵⁰⁸ The catalytic cycle proceeds with initial homolytic cleavage of the alkyl halide, producing the alkyl radical with concomitant first-step oxidation of the Fe(n) species (I) to Fe(n + 1) species (II). This is followed by the addition of the alkyl radical to the iron centre, causing the next one-electron oxidation, forming the intermediate Fe(n + 2) species (III). Finally, reductive elimination of this intermediate Fe(n + 2) species produces the coupled product together with regeneration to the initial reactive species (I) via transmetalation to intermediate IV.

Scheme 399 Mechanistic cycle for iron-catalyzed alkyl–alkyl Suzuki–Miyaura cross-coupling.

In addition, in 2015, Hu and co-workers reported a unique bimetallic and radical oxidative addition in their proposed catalytic cycle for the alkyl–aryl Kumada coupling using a pincer ligand-bearing iron complex.⁵⁶⁶ They also established the presence of an Fe(II) aryl ‘ate’ complex as the active species.

Nakamaura and co-workers proposed a radical mechanism for their iron-catalyzed coupling of halohydrins with aryl aluminium reagents, which was very similar to the mechanism for their cross-coupling using iron–NHC complexes.⁴⁹¹ Further, Bedford et al. depicted a radical pathway for describing the iron-mediated Negishi coupling of benzyl halides and phosphates.⁵¹⁸ Furthermore, the DFT calculation and competitive kinetic experiments by Norrby and co-workers in 2015 justified the radical nature of iron-catalyzed cross-coupling reactions. In their studies with cross-coupling of Grignard reagents and alkyl halides, they suggested that the reaction of the alkyl halides goes through an atom-transfer-initiated radical pathway.^567,568

7. Iron-catalyzed reduction reactions

7.1 Hydrogenation

7.1.1 Alkene and alkyne hydrogenation. In 1964, Frankel et al. first described the hydrogenation of methyl linoleate using iron–carbonyl complexes.⁵⁶⁹ The diene in the presence of Fe(CO)₅, high H₂ pressure and elevated temperature were believed to undergo isomerization initially to form a conjugate diene then a π-complex intermediate (Scheme 400).

Scheme 400 Isomerization and reduction of dialkenes with [Fe(CO)₅].

This intermediate further undergoes stepwise reduction to monoene and then methyl stearate. Various dienes are expected to be formed in the first reduction step when triene is subjected to the reaction conditions, which indeed was observed.⁵⁷⁰ However, further hydrogenation was detected only for the conjugated dienes, while the non-conjugatable dienes remained unreacted. Although these reports showed great potential in iron-catalyzed hydrogenation, little exploration has been found until the start of 21st century. In 2004, Chirik's group synthesized Fe(0) bis(imino)pyridine complexes (ⁱPrPDI)Fe(N₂)₂ [ⁱPrPDI = ((2,6-CHMe₂)₂C₆H₃N=CMe)₂C₅H₃N] with two N₂ co-ordination, which showed promising reactivity towards the hydrogenation of alkenes (Scheme 401).⁵⁷¹

Scheme 401 Alkene reduction with nitrogen-based pincer iron complexes.

A TOF of 1814 mol h⁻¹ was observed for the hydrogenation of 1-hexene with 0.3 mol% of catalyst under 1 atm hydrogen pressure. However, the reactivity was found to be highly substrate dependent. A year later, the same group developed various iron(0)α-diimine complexes and tested them for hydrogenation (Scheme 401).⁵⁷² Interestingly, when cyclooctadiene (COD) co-ordinated [ArN=C(Me)C(Me)=NAr]Fe(η²:η²-1,5-C₈H₁₂) was treated with H₂ in C₆D₁₂, it reduced one double bond of COD; however, the use of C₆D₆ gave a thermodynamically more stable [ArN=C(Me)C(Me)=NAr]Fe(η⁶-C₆D₆) complex instead of hydrogenation. Both the COD and cyclooctene complexes were also found to be competent in hydrogenating 1-hexene to hexane, but with a relatively lower TOF.

Further experimental as and computational studies revealed that indeed co-ordination of the arene group deactivates both the bis(imino)pyridine and α-diimine complexes (Scheme 401).⁵⁷³

Thus, as expected, the reactivity of the bis(imino)pyridine improved upon changing the substitution on the imine nitrogen to an isopropyl group.⁵⁷⁴ Upon optimization of the various parameters, a range of functional group tolerance was also found.^575–577 The reaction is believed to proceed via the oxidative addition of H₂ to the metal center upon ligand dissociation of labile N₂. Then migratory insertion into the olefin gives an alkyl iron intermediate, followed by reductive elimination to give the final product. Wangelin's group synthesized a series of diamine-based BIAN-Fe complexes and found that (dipp₂BIAN)FeCl₂ [dipp₂BIAN = 2,6-diisopropylphenyl bis(imino)acenaphthene] was a very good candidate for alkene hydrogenation; however, it requires a strong reducing agent such as n-BuLi.⁵⁷⁸

In 2009, de Vries co-workers carried out hydrogenation using iron nanoparticles synthesized by reducing FeCl₃ with a Grignard reagent.^579,580 The Fe-NPs with a size of 2.67 ± 0.60 nm were presumed to be coated with MgCl and THF. The NPs were excellent candidates for the hydrogenation of alkenes and alkynes, and the controlled experiment showed that none of the starting materials such FeCl₃ or Grignard reagents were responsible for this reactivity. The kinetic experiments revealed that alkynes react better with these NPs than alkenes. Moreover, both the alkane and cis-alkene formed during the hydrogenation of alkynes and the ratio could be controlled to obtain one major form by optimizing the parameters. Later, in 2011, Breit's group synthesized Fe-NPs deposited on chemically-derived graphene from Fe(CO)₅.⁵⁸¹ Initially, 0.9 mol% of catalyst converted 43% of 1-hexene to hexane under 20 bar H₂ pressure and 100 °C. However, the use of 5 mol% EtMgCl resulted in near full conversion, which is possibly due to surface activation by the Grignard reagent. Wangelin's group improvised a strategy and used FeCl₃ and EtMgCl to generate an in situ-reduced catalyst which can carry out hydrogenation of aromatic alkenes (Scheme 402).⁵⁸² Thomas's group further improved this strategy by using FeCl₂ as a precatalyst, ⁱPrMgCl as a reducing agent and additional tetradentate iminopyridine as a ligand (Scheme 402).⁵⁸³ Chaudret's group synthesized ultra-small Fe nanoparticles with a size of 1.5 ± 0.2 via the decomposition of {Fe(N[Si(CH₃)₃]₂)₂}₂, which also proved to be an excellent catalyst towards the hydrogenation of alkenes and alkynes to alkane in >99% yield in most cases.⁵⁸⁴

Scheme 402 Alkene reduction with in situ-generated Fe-NPs.

Beller and co-workers utilized Fe(BF₄)₂·6H₂O in conjunction with the [P(CH₂CH₂PPh₂)₃] [PP₃] ligand to achieve the partial reduction of arylacetylenes to the corresponding styrene derivatives (Scheme 403).⁵⁸⁵ Interestingly, formic acid was used as the reducing agent at 40 °C to deliver of the styrene product with >99% yield in most cases. It was believed that the triphosphine co-ordinated iron forms a dihydride complex upon reaction with HCOOH, eliminating CO₂. Subsequent hydrogen transfer to the co-ordinated alkene followed by reductive elimination affords the final product. Similarly, a ferraboratrane ligated with triphosphine-borane (TPB) underwent heterolytic H₂ addition to form (TPB)(μ-H)Fe(L)(H), which in turn could hydrogenate styrene across the double bond (Scheme 404).⁵⁸⁶ Milstein and co-workers synthesized a pincer-based [(^HACRPNP)Fe(CH₃CN)(η²-CH₃CHCNBH₃)] [^HACRPNP = 4,5-bis((diphenylphosphino)-9H-acridine-10-ide)] complex to carry out the hydrogenation of aromatic alkynes (Scheme 404).⁵⁸⁷ They were able to optimize the reaction in favour of selective E-alkene formation, although the selectivity is attributed to the isomerization of the Z-isomer into more stable form under the reaction conditions.

Scheme 403 Arylacetylene reduction by PP₃·Fe(BF₄)₂ system.

Scheme 404 Pincer complexes for alkene and alkyne reduction.

Complementary to this, FeCl₃/EtMgCl-derived Fe-NPs stabilized by an ionic liquid selectively provided the Z-isomer upon the hydrogenation of alkynes with molecular hydrogen. In 2016, Jones and co-workers utilized a PNP pincer-based (PNP^iPr)Fe(H)(CO) [PNP^iPr = N(CH₂CH₂PiPr₂)₂] complex to hydrogenate styrenes and activated olefins (Scheme 404). Under 1 atm H₂ pressure, they obtained 100% NMR yields for many styrene derivatives including 2-vinylpyridine. The reaction is believed to proceed in a stepwise manner, where hydride transfer from the metal is followed by proton transfer. Recently, a carbazolide-based PNP ligand co-ordinated ferroushydrido complex was reported by Gade's group, which also showed similar alkene hydrogenation reactivity.⁵⁸⁸

In 2014, Nakazawa and co-workers synthesized[2,5-bis(triphenylsilyl)-3,4-butylene-(η⁵-C₄COEEt₂H)]Fe(CO)₂H (E = Si, Ge) complexes bearing Si–H and Ge–H bonds.⁵⁸⁹ These complexes could perform transfer hydrogenation of p-tolylacetylene in the presence of IPA, although with poor yield and selectivity (Scheme 405). The mechanism described by the authors involves CO substitution by the alkyne and subsequent insertion into the Fe–H bond. The Si–H bond distantly bound with the Cp ring adds oxidatively to form another Fe–H bond. Finally, reductive elimination gives the product and the catalyst is regenerated by taking two hydrogens from IPA, leaving acetone as the by-product.

Scheme 405 Fe–H/Si–H co-operative transfer hydrogenation.

With the aim of achieving chiral hydrogenation, Chirik and co-workers synthesized a number of bis(phosphine)iron(II)dialkyl complexes with bidentate chiral phosphine ligands.⁵⁹⁰ Although high yields for the hydrogenation of pro chiral alkenes were obtained, the enantioselectivity was non-detectable. It was concluded that under the reaction conditions, iron dissociates from the ligand and forms an Fe(0) amorphous species, which is responsible for the observed reactivity; however, the ligand cannot participate to induce stereoselectivity.

The groups of Wolf and Wangelin documented hydrogenation with bis(η⁴-anthracene)ferrate complexes (Scheme 406). Interestingly, the metal is in the 1− oxidation state and termed as “quasi naked” metal species.^591,592 The reactivity of these 18-electron complex species probably starts by losing an arene ligand to undergo H₂ oxidative addition. The ferrate complex showed decent reactivity; however, the cobalt analogue was found to be better catalyst.

Scheme 406 “Quasi-naked” iron complex in hydrogenation.

In 2017, Wangelin and co-workers reported that treating Fe[N(SiMe₃)₂]₂ with diBAL-H formed different sizes of Fe_4–7 nanostructures (Scheme 407).⁵⁹³ The metal ions with the oxidation states of 0, 1+, and 2+ arrange themselves in a planner geometry, while the ligand is situated in the periphery. Except for the Fe₄ clusters, bridging hydrogens were found in the crystal structures. These nano-clusters are responsible for the excellent reactivity of Fe[N(SiMe₃)₂]₂/DIBAL-H in the hydrogenation of alkenes, particularly tetrasubstituted alkenes. Recently, disilaferracyclic isocyanide complexes were also shown to be very effective for the hydrogenation of tri- and tetra-substituted alkenes with H₂.⁵⁹⁴ The reaction initiates with the removal of one ligand and co-ordination of two H₂. Successive Si–Fe/H–H metathesis forms two Si–H bonds, which further undergo two-fold metathesis with Fe–C(alkene) to provide the final product (Scheme 408).

Scheme 407 Fe[N(SiMe₃)₂]₂/diBAL-H-derived iron nano-clusters.

Scheme 408 Disilaferracyclic complex-mediated hydrogenation of alkenes.

In 2018, a Knölker iron complex modified at the Cp ring and one CO substituted by the PPh₃ ligand showed selective hydrogenation of α,β-unsaturated ketones. Firstly, cesium isopropoxide is formed in situ from IPA and cesium carbonate and reacts with the metal complex to give the hydride complex. In the key step, both the substrate oxygen and Cp-ligand oxygen interact with Cs⁺ simultaneously; thus, only olefin can interact with the metal centre. Hence, highly selective olefin hydrogenation is observed even in the presence of carbonyl.

7.1.2 Hydrogenation of carbonyls and their derivatives. In 1981, Marko's group initially studied the hydrogenation of aldehydes and ketones to alcohols in an Fe(CO)₅-catalyzed reaction.⁵⁹⁵ Initially, CO and H₂O are used in presence of Et₃N as the hydrogen source. It is believed that the base abstracts a proton and CO reacts with OH⁻ to form formate. The adduct of tetracarbonylhydroferrate, [HFe(CO)₄]⁻ with Et₃NH was presumed to be the actual catalyst.

Two different hydrogens sources, i.e. one proton from [Et₃NH]⁺ and the other from iron carbon-hydride, are essential for the reaction to proceed (Scheme 409). Later, they found that the direct use of molecular hydrogen as a hydrogenating agent enhances the reactivity and provides evidence in favour of nucleophilic attack on the carbonyl by [HFe(CO)₄]⁻.⁵⁹⁶

Scheme 409 Carbonyl reduction with [Fe(CO)₅].

Beller's group reported the transfer hydrogenation of ketones to secondary alcohols using the [Fe₃(CO)₁₂]/terpy/PPh₃ catalytic system and isopropanol as the hydrogenating agent (Scheme 410).⁵⁹⁷ Deuterium labelling studies revealed the involvement of the monohydride transfer mechanism, that is the metal hydride species is involved only in the transfer of hydrogen from the donor carbon centre to the ketone carbon; however, the dihydride mechanism cannot be ruled out completely. The same reaction could also be carried out with an in situ-generated iron–porphyrin complex simply by replacing the terpy and PPh₃ ligands with porphyrin.⁵⁹⁸ Later, this iron–porphyrin transfer hydrogenation chemistry was further extended to the reduction of α-hydroxyprotected ketones.⁵⁹⁹

Scheme 410 [Fe₃(CO)₁₂]-catalyzed transfer hydrogenation.

Casey and co-workers utilized a cyclopentadienone tricarbonyl iron complex (Knölker's iron complex) to achieve the hydrogenation of ketones (Scheme 411).^600,601 In the presence of sufficient H₂ pressure, the catalyst shuttles between the hydrogenated and dehydrogenated forms, where the former hydrogenates the ketone to form dehydrogenated species, which in turn goes back to the hydrogenated form upon the addition of H₂.⁶⁰² The reaction presumably starts with H-bond formation between the catalyst –OH and ketone group, followed by insertion into the Fe–H bond. Then, one molecule of H₂ oxidatively adds to the metal, while one of these two hydrogen atoms transfers to the cyclopentadienone to regenerate the catalyst. However, the computation study suggested that the hydrogenation proceeds via an outer-sphere concerted mechanism, that is simultaneous transfer of both hydrogens to the substrate.^603–607

Scheme 411 Knölker's iron complex in transfer hydrogenation.

The asymmetric version of this reaction was carried out by Gao's group in 2004 using [Et₃NH]⁺[HFe₃(CO)₁₁]⁻ in conjunction with the chiral diaminodiphosphine ligand; however, the yield and enantiomeric excess were inconsistent with the variation in substrate.⁶⁰⁸ In 2008, Morris’ group utilized the [Fe(NCMe)(CO){(R,R)-cyP₂N₂}](BF₄)₂ complex equipped with the chiral tetradentate PNNP ligand system (R,R)-cyP₂N₂ [(R,R)-{PPh₂(o-C₆H₄)CH=NC₆H₁₀N=CH(o-C₆H₄)PPh₂}] for this purpose (Scheme 412).^609,610 In contrast to Gao's diaminodiphosphine, they used a diiminodiphosphine system together with potassium tertiarybutoxide as the base; however, the imine was presumed to undergo hydrogenation into amine under the reaction conditions. Nonetheless, no improvement in enantiomeric excess was observed. Therefore, a series of diiminodiphosphine ligands was synthesized with 1,2-diphenyldiiminoethane in their backbone instead of cyclohexanediimine to give better reactivity towards the asymmetric transfer hydrogenation of ketones and imines.^611–613 Interestingly, ligands with Cy or ⁱPr substitution at the phosphorus center and acetonitrile co-ordination at the two-axial position of the iron were inactive.

Scheme 412 PNNP-based iron catalyst-mediated asymmetric transfer hydrogenation of carbonyl compounds.

Further improvement revealed that bis(eneamido)-based PNNP ligands are also potentially good candidates.^614–617

After optimization of various substituents on the imine backbone and phosphorus center and axial ligands, the 5,5,5-fused membered PNNP-based bis(eneamido)diphosphine and PNNHP-based amine(imine)diphosphine were found to be the best, having phenyl substitution at the phosphorus and CO and halide as the axial ligands. For instance, (S,S)-[Fe(CO)(Br)(PAr₂CH₂CH=NCHPhCHPhN=CHCH₂PAr₂)]BPh₄ can provide enantiomeric excess and TON of up to 99% and 6000, respectively.^618–627

Experiments and computations suggest that the hydrogen from the –OH of IPA transfers to the imine-nitrogen and the hydrogen from –CHMe₂ to iron, probably in a concerted pathway (Scheme 412). The hydride complex then interacts with the –CO bond of the substrate in similar but reverse step for hydrogen transfer from N to O and Fe to C, forming the alcohol product. However, careful observation revealed that the first generation 6,5,6-PNNP-based complexes follows a different mechanism. The formation of Fe-NPs with a size of 4.5 nm was detected in those cases, where the chiral ligands were found to be surface bound, and hence enantioselectivity was observed.^628,629 Moreover, a mechanism for catalyst deactivation occurs via isomerisation of the ligand double bonds, which is dependent on the ligand architecture.⁶³⁰ Thus, it has a major contribution towards varying reactivity with respect to different substituents.

Milstein and co-workers synthesized a tridentate PNP pincer ligand-based iron hydride catalyst to achieve the hydrogenation of ketones.⁶³¹ The complex [(ⁱPrPNP)FeH(CO)Br] [(i-PrPNP = 2,6-bis(diisopropylphosphinomethyl)pyridine)] synthesized from the dibromo complex by treatment with NaHBEt₃ could catalyze various ketones in the presence of H₂ with a TON of up to 1880. Interestingly, the mechanism is believed to involve a dearomatized intermediate stabilized by ethanol (Scheme 413). The parent complex upon treatment with NaBH₄ gives an iron-borohydride complex, which is also an equally active hydrogenating catalyst.⁶³² The combination of experimental and computational studies suggested that ethanol co-ordination rearomatizes the ligand. Subsequently, dual hydrogen atom transfer occurs to the ketone, one from the ligand arm to the carbonyl carbon, and the other from co-ordinated EtOH to the carbonyl oxygen. The addition of H₂ to the resultant complex gives back the native catalyst.⁶³³ However, in a more recent report, Kirchner indicates that the insertion of the carbonyl –C=O group into the Fe–H bond is more probable, and thus the reaction proceeds via the inner-sphere mechanism.⁶³⁴ In 2015, PONOP ligand-based complexes were reported by Hu's group.⁶³⁵ The complexes are structurally similar to that of PNP with no Fe–O co-ordination, and thus similar reactivity was observed towards hydrogenation.

Scheme 413 Dearomatization mechanism involved in pyridine-based PNP pincer ligands.

Morris's group synthesized a chiral version of a PNP′ pincer ligand-based complex (S,S)-[Fe(Ph₂PCH(Ph)CH(Me)N=CHCH₂PCy₂)(NCCH₃)₃]²⁺ (Scheme 414).⁶³⁶ It could effectively catalyze ketone to aldehyde in the presence of LiAlH₄, t-AmylOH and KO(t-Bu) in excellent yields and decent enantiomeric excess (ee). Moreover, using (diphenylphosphinoyl)-propiophenoneimine as the substrate, they obtained the corresponding amine in 90% ee. Kirchner synthesized another asymmetric version of the complex using the chiral BINEPINE group at one phosphorus end; however, the two diastereomeric forms were not isolated, and therefore it cannot be used for asymmetric reactions.⁶³⁷ A plethora of other chiral PNP′ and PNHP′ pincer ligands with various backbone substituents were synthesized and tested for the reduction of ketones and imines to obtain enantiomeric excess as good as 96%.^638–646 Although the mechanism varies from one catalyst to another, these non-aromatic ligand-based complexes are believed to show dual hydrogen transfer from iron to the carbonyl carbon and nitrogen to the carbonyl oxygen. Recently, the ionic liquid 1-butyl-2,3-dimethyl-imidazolium-bis(trifluoromethylsulfonyl) ([bm₂im][NTf₂]) supported on silica was used as a biphasic medium for catalysis with a PNP-based complex.⁶⁴⁷ In the presence of DBU at 50 bar H₂ pressure, the system provided >98% yield of various aldehydes.

Scheme 414 PNP-based pincer complexes in asymmetric transfer hydrogenation.

A PNN-based complex [Fe(H)(CO)(MeCN)L_PNN](BF₄) [L_PNN = 2-{(di-tert-butylphosphino)methyl}-6-{1-((mesitylimino)ethyl}pyridine)] with one imine arm and one phosphine arm in the ligand was reported by Milstein's group.⁶⁴⁸ A similar dearomatization mechanism was proposed for hydrogenation, although it was found to be less reactive than pyridine-based PNP systems.

In 2010, Royo's group synthesized Fe(II) complexes with cyclopentadiene-substituted NHC ligands (Scheme 415).⁶⁴⁹ The four-legged piano-stool geometric complexes showed excellent reactivity towards the transfer hydrogenation of ketones with IPA. An iron(II)–bis(isonitrile) complex was studied for asymmetric transfer hydrogenation, but achieved only moderate enantiomeric excess.⁶⁵⁰ The authors proposed that one of the isocyanide groups is involved in transferring hydrogen to the carbonyl carbon in a Meerwein–Ponndorf–Verley (MPV) mechanism. In 2012, Funk and co-workers modified Knölker's iron catalyst by one CO substitution with alkylnitriles, and the acetonitrile co-ordinated complex was found to be an excellent catalyst towards the transfer hydrogenation of aldehydes and ketones.⁶⁵¹ Simultaneously, Berkessel's group synthesized a chiral version of the complex by replacing one of the CO ligands with a chiral phosphoramidite ligand (Scheme 416).⁶⁵² The complex converted 90% of acetophenone to 1-phenylethanol under UV radiation; however, only 31% ee of the (S) isomer was observed. In the subsequent year, the groups of Beller and Renaud also modified the Knölker's-type complex with various substitutions at the Cp ring to catalyze the reaction in water.^653,654 The tetrahedral bis-(N-heterocyclic carbene)–iron complex reported by Glorius's group was found to be equally effective.⁶⁵⁵ Mono NHC substitution by Bala's group⁶⁵⁶ and alkyl/aryl substitution at the cyclodipentanone by Funk's group were also explored.⁶⁵⁷ In 2016 Wills et al. carried out further experiments on an approach similar to that of Berkessel, although no improvement was obtained.⁶⁵⁸ On the contrary, Gennari synthesized chiral BINOL-based (cyclopentadienone)iron complexes (Scheme 416).⁶⁵⁹ They proposed that preferential Re-face attack on the metal hydride would form the S isomer as the major form; however, the maximum enantiomeric excess obtained was 54%.

Scheme 415 Various complexes utilized in the transfer hydrogenation of carbonyls.

Scheme 416 Asymmetric transfer hydrogenation with bi(diisocyanide) and modified Knölker's iron complexes.

In 2017, Piarulli's group introduced another modification in the form of [bis(hexamethylene)cyclopentadienone]irontricarbonyl, which was found to be very effective for carbonyl reduction in the presence of Me₃NO activator.⁶⁶⁰ Wu and co-workers used Knölker's iron catalyst in a water gas-shift reaction to achieve the hydrogenation of aromatic aldehydes.⁶⁶¹ A combination of paraformaldehyde and water/DMSO was used to generate formic acid in situ, which further degraded to liberate H₂. The H₂ reacts with carbonyls in the presence of the iron catalyst to form the corresponding alcohols.

Due to the lower enantioselectivity obtained in their first attempt, Gao's group shifted their attention from PNNP ligands to P₂N₄-type macrocyclic ligands (Scheme 417).^662,663 The 22-membered cyclic ligand showed exceptional reactivity for asymmetric hydrogenation with 0.5 mol% Fe₃(CO)₁₂ under 50 bar H₂ pressure. The scope of the substrate included hydrogenation of aryl ketones, heterocyclic ketones and β-ketoesters, all with excellent yields and ee. The experimental results suggest the formation of NPs embedded in a ligand environment; thus, the heterogeneous nature of the catalysis was proposed.

Scheme 417 Asymmetric carbonyl reduction by chiral macrocyclic N₄P₂, N₂P₂ and (NH)₂P₂ complexes.

A series of N₂P₂ macrocyclic ligands was introduced by Mezzetti's group (Scheme 417).⁶⁶⁴ The well-defined cyclic diimine–diphosphine iron complexes were active in the asymmetric transfer hydrogenation of ketones with IPA; however, could only induce moderate enantioselectivity. The axial ligands have a significant effect on the reactivity and tert-butyl nitrile was found to be the best. Later, they shifted to the saturated version (NH)₂P₂, which gives excellent enantioselectivity for both carbonyls and imines.^665–669 An increase in the P–Fe–P bite angles has a positive impact on stereoselectivity, although it led to harsh conditions for sterically bulky substrates. These complexes are also effective towards the conversion of benzil to chiral benzoin.

Beller and co-workers developed [FeF(L)][BF₄] [L = tris{2-(diphenylphosphino)phenyl}phosphine or PP₃] using the TetraPhos ligand for the selective carbonyl reduction of α,β-unsaturated aldehydes (Scheme 418).^670,671 They optimized the reaction to favour the formation of vinyl alcohol with >99% selectivity. Since the active catalyst is hexa-co-ordinated, one of the phosphines must dissociate for aldehyde to co-ordinate. Thus, the steric factor plays a crucial role in the observed selectivity. In addition, the catalyst also performs the reduction of various other aldehydes effectively. In another report by the same group, they showed that the catalytic NADH model and H₂ combination is an effective hydrogenating agent in the presence of an Fe₃(CO)₁₂ and Fe(OTf)₃ mixture for the selective ketone reduction of β-ketoesters (Scheme 418).⁶⁷² Both iron catalysts are proposed to play a well-defined role. However, the Fe₃(CO)₁₂-catalyzed hydrogenation NAD model was ineffective in promoting transfer hydrogenation. On the contrary, due to its higher Lewis acidity, the Fe(III) salt could reduce the LUMO of the substrate, easing hydrogenation by the NADH model.

Scheme 418 Reduction of conjugated carbonyls and their derivatives.

Recently, Sun and co-workers synthesized a series of PSiP-based Fe(II)–hydride complexes by adding the ligand Si–H bond oxidatively to the metal (Scheme 419).⁶⁷³ These complexes were found to be effective in the transfer hydrogenation of various aldehydes with IPA. It is believed that the co-ordinated aldehyde is first inserted into the Fe–H bond and takes a proton from the IPA to give the product. The hydrogen of the alcohol carbon is abstracted by the metal to regenerate the active catalyst.

Scheme 419 PSiP-based Fe(II)–hydride complex-mediated transfer hydrogenation.

In 2019, Li's group utilized three selenophenolatohydridoiron(II) complexes, cis-[(H)(SeAr)Fe(PMe₃)₄], for the transfer hydrogenation of aldehydes (Scheme 420).⁶⁷⁴ For Ar = Ph, the best results were obtained and various benzaldehydes, alkenyl and alkynyl aldehydes could be transformed to the corresponding alcohols using this methodology.

Scheme 420 Iron-selenophenoleto complex-catalyzed transfer hydrogenation.

Knölker's iron complex has been reported to be the active catalyst in the hydrogenation of imines. Beller's group used chiral 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (TRIP) in conjunction with Knölker's complex to achieve amines from the corresponding imines with excellent enantioselectivity (Scheme 421).⁶⁷⁵ The authors proposed from NMR experiments that the chiral ligand interacts simultaneously with both the oxygen atom of the complex ligand and iron-bound N–H bond to control the stereoselectivity. This protocol was further extended to the synthesis of chiral 1-arylethyl amines from arylacetylenes and anilines.⁶⁷⁶ The in situ-generated imine from the hydroamination of alkenes was treated with the above combination of catalyst and ligand to obtain chiral secondary amines with decent enantiomeric excess (Scheme 421). On the other hand, the catalyst was utilized by Benaglia's group for the diastereoselective hydrogenation of chiral imines.⁶⁷⁷ The [bis(hexamethylene)cyclopentadienone]irontricarbonyl complex synthesized by Piarulli's group was also an equally effective catalyst for the hydrogenation of imines.⁶⁷⁸

Scheme 421 Synthesis of chiral amines via reduction of imines.

The iron-catalyzed reduction of CO₂ was demonstrated with [FeH(PP₃)]BF₄ in the presence of molecular hydrogen (Scheme 422).⁶⁷⁹ Later, the TON of the transformation was improved by approximately three-fold by changing the complex to [FeF(PP₃)]BF₄.⁶⁸⁰ The reaction proceeds via H₂ coordination to form [FeH(H₂)(PP₃)](BF₄), which is converted to the dihydride complex in the presence of a base. Subsequently, CO₂ inserts into the Fe–H bond, giving the co-ordinated iron-formate species. The base present in the medium abstracts the formate and the cycle continues. The PNP ligand-based complex developed by Milstein's group also catalyzed the reduction of CO₂ with a lower TON (Scheme 423).⁶⁸¹ However, the important fact is that the latter reaction can be carried out in water medium. The pyrazine-based PNP ligand also developed by Milstein's group showed similar reactivity.⁶⁸² In contrast, Bernskoetter and co-workers presented a non-aromatic pincer ligand HN{CH₂CH₂(PR₂)}-based complex to improve the CO₂ hydrogenation tremendously and obtained a high turnover number (58 990), although reactivity is dependent on the ancillary ligand (Scheme 423).^683,684

Scheme 422 [(PP)₃Fe-F]-catalyzed CO₂ reduction.

Scheme 423 CO₂ reduction with PNP pincer complexes.

Further, 2,6-diaminopyridyl-bis(diisopropylphosphine)iron(II) carbonylbromide is another complex reported for promoting the reaction.

The water-soluble version of the PP₃ ligand was synthesized using sulphate substituents on the phenyl rings of –PPh₂·Fe(BF₄)₂ in the presence of a hydrophilic ligand, which was found to be suitable for the reduction of CO₂ with H₂ in aqueous medium.⁶⁸⁵ The rac-isomer of a linear tetraphosphine iron(II) complex was reported by Gonsalvi in favour of bicarbonate hydrogenation.⁶⁸⁶ The iron–hydride complex was believed to be the key intermediate, as was in Beller's work. The computation study predicted that the most favourable reaction pathway involves the disproportionation of two bicarbonates into carbonate, water and CO₂, which in turn react with the Fe–H complex.⁶⁸⁷ An iron(II) chloride complex of hydrotris(1-pyrazolyl)methane was employed by Martins’ group, which could deliver methanol from carbon-dioxide (Scheme 424).⁶⁸⁸ It was presumed that the iron–hydride bond is formed with the help of the ligand and CO₂ inserts there, producing formaldehyde and water. A second hydrogenation of formaldehyde at the metal center releases methanol.

Scheme 424 Hydrogenation of CO₂ to methanol.

The (SiP^R₃)Fe(L)(H) [SiP^R₃ = [Si(o-C₆H₄PR₂)₃]⁻] complex was reported by Peters and co-workers for the reduction of CO₂ (Scheme 425).⁶⁸⁹ The use of triethylammonium chloride was necessary in the reaction, which underwent metathesis with Fe-formate to form triethylammonium formate. Similarly, Knölker's catalyst was investigated by Zhou's group to obtain a TON of only up to 307.⁶⁹⁰

Scheme 425 Other catalysts for the reduction of CO₂.

The PNP pincer ligands have been found to be effective towards hydrogenation of esters (Scheme 426). Milstein's catalyst showed promising results to catalyze the hydrogenation of alkyl trifluoroacetate to form two alcohol products.⁶⁹¹ The groups of Beller and Guan individually used non-aromatic PNP ligands and could diversify the protocol to various other esters.^692,693 In the first step, hemiacetal is formed upon reduction of the carbonyl group, which degrades into alcohol and aldehyde. The aldehyde undergoes hydrogenation for a second time to yield the final product. Guan extended this methodology to coconut oil-derived samples containing mostly methyl laurate and other ester derivatives.⁶⁹⁴ This methodology is not only scalable, but can be used in the direct reduction of coconut oil. Pignataro presented that the (cyclopentadienone)iron complexes were equally effective.

Scheme 426 Hydrogenation of esters.

Similar to alkyl trifluoroacetate, the corresponding amides, i.e. N-substituted trifluoroacetamides, also underwent hydrogenation with [(ⁱPr-PNP)Fe(H)(Br(CO))].⁶⁹⁵ The initial hydrogenation of the carbonyl group formed a hemiaminal, which forms an equilibrium with aldehyde and amine. Under the reaction conditions, the aldehyde further hydrogenates to alcohol, and thus the equilibrium shifts towards the right. The non-aromatic PNP-based iron–carbonyl complexes were used by Sanford and Bernskoetter with small variations at the phosphorus center, whereas Langer's group used the corresponding iron-borohydride complex.^696,697 All these complexes show excellent reactivity for amide hydrogenation to amines and alcohols.

Beller's group also optimized the reduction of nitriles to amines with the PNP-based iron-borohydride catalyst in IPA (Scheme 427).^698,699 The two-fold transfer hydrogenation starts with the elimination of BH₃ and concerted dual hydrogenation to form imine. The imine undergoes hydrogenation for a second time to finally produce amine. On the other hand, Milstein's group employed bis(2-diisopropylphosphinobenzyl)amine as the PNP ligand to obtain up to 99% yield with various aromatic and aliphatic nitriles.⁷⁰⁰ They also extended the protocol to hydrogenative cross-coupling of nitriles with amines.⁷⁰¹ The partially hydrogenated nitriles to imine are trapped by an amine to form a gem-diamine, which eliminates an NH₃ moiety to produce the secondary imine.

Scheme 427 Hydrogenation of nitriles.

γ-Valerolactone (GVL) is of high industrial importance due to its manifold application, particularly because it can be used as biofuel. The easiest way to synthesize GVL is via the hydrogenation of the bioproduct levulinic acid or its ester (Scheme 428). To replace the precious metal catalyst for this transformation, Fu's group optimized the reaction with iron(II) catalysts in conjunction with multidentate phosphine ligands.⁷⁰² It was found that Fe(OTf)₂ in the presence of the tris[(2-diphenylphosphino)ethyl]phosphine ligand can provide GVL from levuliniate ethyl ester in 99% yield. Formic acid was used as the hydrogen source at 140 °C. A cheaper catalyst, [Fe₃(CO)₁₂], in the presence of imidazole as a base was used by Burtoloso's group to obtain 92% yield at the cost of an elevated temperature of 180 °C.⁷⁰³ Upon further optimization, Fu's group found that Casey's catalyst is more effective and can provide GVL in 95% yield in a transfer hydrogenation reaction with IPA at 100 °C.⁷⁰⁴

Scheme 428 Transformation of levulinic ester to γ-valerolactone.

7.1.3 Heterocycle hydrogenation. Chiral heterocyclic compounds are highly desirable in organic synthesis. The efficient and step-economic synthesis of chiral tetrahydroquinoxaline was reported by Beller's group through an iron-catalyzed hydrogenation.⁷⁰⁵ Initially, quinoxalines are subjected to hydrogenation with Knölker's iron complex and chiral phosphate auxiliary ligands under 5 bar H₂ pressure. High yields and enantioselectivity were obtained for various quinoxalines and benzoxazines (Scheme 429). Interestingly, when 1,2-phenylenediamine and phenylglyoxal were treated under the reaction conditions, an enantiomeric ratio of 95 : 5 of the resultant 1-phenyl-1,2,3,4-tetrahydroquinoxaline was obtained. The reaction proceeds via the formation of diamine first, which undergoes twofold hydrogenation by the iron catalyst, and the phosphate ligand is believed to control the stereochemistry via hydrogen bonding.

Scheme 429 Asymmetric hydrogenation of quinoxalines and benzoxazine.

A year later, Jones and co-workers reported the hydrogenation of quinolines, substituted indole and pyridine with a PNP-based iron borohydride catalyst and potassium tertiary-butoxide base (Scheme 430).⁷⁰⁶ The authors presented that the same catalyst is capable of performing the reverse reaction in the absence of the base.

Scheme 430 PNP pincer-based iron complex-catalyzed hydrogenation of N-heteroarenes.

7.2 Reduction with other reagents

7.2.1 Alkene reduction. In 1977, Ashby and co-workers found during the optimization of alkene reduction with LiAlH₄ that FeCl₂ and FeCl₃ can catalyze the reaction; however no extensive study was performed.^707,708 In 1991, Kano's group studied iron(II)-porphyrin catalysis in styrene reduction with BH⁴⁻.^709,710 They proposed that an alkyliron(III) complex is formed first in the presence of BH⁴⁻, which undergoes homolytic dissociation to form a benzyl radical, and subsequently to ethylbenzene (Scheme 431).

Scheme 431 Iron–porphyrin-catalyzed reduction of alkenes with sodium borohydride.

In 2012, Prabhu and co-workers developed the FeCl₃-catalyzed reduction of alkenes with hydrazine (Scheme 432).⁷¹¹ In the optimized conditions, they utilized 5 mol% of the catalyst and 1.5 equivalent of hydrazine in EtOH under aerobic conditions to obtain reduced alkene with up to 99% yield. Both the internal and terminal olefins together with the terminal alkynes could be reduced under the reaction conditions. Most promisingly, various other functional groups such as acid, ester, and nitro are well tolerated under the reaction conditions. Experimental evidence suggest that FeCl₂(H₂NNH₂) is probably the active catalyst for the transformation.

Scheme 432 Alkene reduction using hydrazine.

Thomas’ group reported alkene reduction with the Fe(OTf)₂ and NaHBEt₃ (or NaBH₄) combination (Scheme 433).⁷¹² A variety of substrates including alkynes and a mixture of alkene and alkane are well tolerated. The mechanism of the reaction was reported to unclear; however, a radical pathway was suggested due to the stoppage of the reaction with a radical scavenger. In 2015, Wangelin and coworkers optimized the FeCl₃-catalyzed hydrogenation with LiAlH₄ and excellent yields were obtained for various styrene derivatives.⁷¹³ It was suggested that initially the reaction proceeds in a homogeneous manner; however, the formation of a nanocluster over time is possible, and hence a decrease in reactivity occurs.

Scheme 433 Alkene reduction using NaHBEt₃ as the reducing agent.

7.2.2 Carbonyl reduction. In 2006, Radivoy and co-workers developed the reduction of carbonyls and imines with a stoichiometric amount of FeCl₂ and lithium powder (Scheme 434).⁷¹⁴ A catalytic amount of 4,4′-di-tert-butylbiphenyl as the electron carrier is necessary for the transformation. More surprisingly, high stereoselectivity was observed for cyclic ketones. The authors proposed that the dissolving-metal reduction mechanism occurs for this transformation.

Scheme 434 Carbonyl reduction using super stoichiometric ferrous chloride.

7.2.3 Reductive amination. The first iron-catalyzed reductive amination of carbonyls was reported by Bhanage's group in 2008.⁷¹⁵ The reaction was carried out in the presence of the FeSO₄·7H₂O/EDTANa₂ system in a biphasic medium, viz. organic substrate phase and aqueous catalyst solution (Scheme 435). Both primary and secondary amines were utilized for the amination of aldehydes and ketones under 400 psi H₂ pressure. Although a moderate yield of amines was obtained, the formation of a small amount of alcohol was consistent. The homogeneous version of the reaction was reported by Beller's group using Fe₃(CO)₁₂ in toluene (Scheme 435).⁷¹⁶ Moreover comparatively improved yields were obtained at 65 °C instead of 150 °C in the previous case.

Scheme 435 Reductive amination via hydrogenation of imine.

Renaud's group used Knölker's iron complex for this transformation, which was found to be quite effective (Scheme 436).⁷¹⁷ After detailed experimental and computational studies, the authors recommended a plausible mechanism.⁷¹⁸ In the first step, one CO is eliminated as CO₂ and H₂ is added to form Fe–H and –OH on the Cp ring. Then the imine or iminium formed from the carbonyl and amine undergoes outer-sphere two-fold hydrogen transfer to yield the product.

Scheme 436 Reductive amination with Knölker's-type iron catalyst.

Sodium borohydride was used as the reducing agent in a Fe(OTf)₃-catalyzed reaction.⁷¹⁹ However, iron plays a different role in this process by activating carbonyl through its Lewis acidity (Scheme 437). Then the imine formed is reduced by NaBH₄ to amine. Chusov et al. developed the hydrogen-free reductive amination of carbonyls with super stoichiometric iron pentacarbonyl (Scheme 438).⁷²⁰ Under solvent-free conditions, various cyclic amines were used at a temperature of 130 °C. Another approach was described by Taddei's group, where a mixture of IPA/water was utilized as the hydrogen source (Scheme 439).⁷²¹ The NaOH and DMAP-promoted reaction was best catalyzed by Fe₂(CO)₉. It was proposed that NaOH reacts with the iron complex to form Na[HFe(CO)₄], eliminating carbon-dioxide. The hydride complex transfers hydride to the imine carbon, while the nitrogen takes a proton from water. The DMAP-Fe species formed in this process is transformed to a hydride complex by NaOH and 4-dimethylaminopyridineoxide is formed, which in turn is converted to DMAP in the presence of IPA, releasing acetone and water.

Scheme 437 Lewis acidic iron-catalyzed amination of carbonyls.

Scheme 438 Reductive amination with super stoichiometric iron-pentacarbonyl.

Scheme 439 IPA/water as hydrogen source for reductive amination.

Recently, Darcel and co-workers reported two different iron–carbene complexes and achieved two different amination products from levulinic acid and its esters (Scheme 440).⁷²² The use of [CpFe(CO)₂(IMes)][I] [IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene] as the catalyst gave pyrrolidones, whereas [Fe(CO)₄(IMes)] selectively produced pyrrolidine in the presence of PhSiH₃. Fascinatingly, 2-formylbenzoic acid also underwent cyclic amination to produce isoindolines. Mechanistically, the imine is hydrosilylated by the metal catalyst, followed by cyclization to pyrrolidone. Depending on the conditions, the pyrrolidone undergoes further reduction to cyclic amine. This protocol was further extended to the synthesis of 5, 6 and 7-membered cyclic amines from 4-aminobutanoic acid, 5-aminopentanoic acid and 6-aminohexanoic acid, respectively, using the latter complex, which followed a similar reaction pathway.⁷²³

Scheme 440 Cyclic amine formation via reduction of in situ-generated imine.

7.2.4 Reductive etherification. In 2005, Oriyama et al. reported the reductive etherification of various aldehydes and ketones in an Fe(III)Cl₃-catalyzed reaction. Benzyl silyl ether (BnOTMS) was used for etherification in the presence of triethyl silyl hydride as the reducing agent (Scheme 441).⁷²⁴ Advantageously, the transformation was carried out at room temperature or lower to obtain excellent yields within minutes. In a later report, they optimized the reaction in favour of using alcohols directly with the same catalyst.⁷²⁵ Then, the scope of the reaction was extended not only to various alcohols, but also towards the synthesis of chiral ether from chiral alcohol.

Scheme 441 Reductive etherification with ferric chloride.

The Cp*Fe(CO)₂(4-C₆H₄CH₃) complex was utilized by Argouarch et al. for the reductive etherification of aldehydes with dialkoxymethylsilane (Scheme 442).⁷²⁶ UV irradiation is required for the reaction in order to activate the catalyst through CO ligand dissociation. The 16-electron complex is believed to act as a Lewis acid and activates the carbonyl compound. The reaction proceeds via the formation of hemiacetal.

Scheme 442 [Cp*Fe(CO)₂Ar]-catalyzed reductive etherification.

In 2015, Leino's group introduced Fe(III) oxo acetate in conjunction with Et₃SiH and Me₃SiCl to form self-condensed ether from various aldehydes (Scheme 443).⁷²⁷ They also extended the etherification with alkoxy trimethylsilyl. The reaction possibly proceeds via initial hydrosilylation of one carbonyl molecule followed by the addition of another aldehyde in an S_N2 fashion. The acetal is further reduced to generate the ether molecule.

Scheme 443 Fe(III)–oxo–acetate catalysis in reductive etherification.

7.2.5 Reduction of heteroatomic groups.
7.2.5.1 Nitro reduction. In 1972, while studying the complexation of Fe₃(CO)₁₂ with p-nitrophenylbutadiene, Landesberg and co-workers obtained a complex with the corresponding amine instead (Scheme 444).⁷²⁸ Further, they found that the reduction is also possible for nitrobenzene with an equivalent amount of Fe₃(CO)₁₂. The source of hydrogen was explained to be from methanol solvent, whereas the oxygen atoms of the nitro group combined with the carbon-monoxide to liberate carbon-dioxide.

Scheme 444 Nitroarene reduction with Fe(CO)₅.

In 1975, during the optimization nitroarene reduction with H₂, Knifton showed the potential of Fe(CO)₃(PPh₃)₂ to catalyze the reaction;⁷²⁹ however, three decades later, Chaudhari's group reported ferrous sulphate heptahydrate as an efficient catalyst for the hydrogenation of nitroarenes (Scheme 445).⁷³⁰ The substrate–aqueous biphasic system in the presence of EDTANa₂ was developed to provide the corresponding anilines at a TOF of up to 529 h⁻¹ under 27.2 atm H₂ pressure. Purposefully, Beller's group synthesized Fe₂O₃ nanoparticles deposited on nitrogen-doped graphene (Scheme 446).⁷³¹ The size of the of the oxide particles was found to be 20–80 nm, which consist of smaller particles with a size of 2–5 nm. The heterogeneous catalyst was instrumental in carrying out the conversion of nitroarene to aniline under 50 bar H₂ pressure in an H₂O–THF solvent system.

Scheme 445 FeSO₄-Catalyzed hydrogenation of nitro groups.

Scheme 446 Iron nanostructures deposited on graphene for nitro reduction.

Various carbonyl, ester, amide and heterocyclic substituents on the substrates remained untouched during the hydrogenation. The same group later employed the P(PhPPh₂)₃ ligand system to synthesize the corresponding iron(II)tetrafluoroborate complex (Scheme 447), which is an excellent catalyst for the hydrogenation of the –NO₂ group.⁷³² Mechanistically, it was proposed that first hydrogenation of the nitro group eliminates a water molecule to form nitrosoarene. Further hydrogenation of nitrosoarene gives hydroxylamine and then aniline. An alternate pathway is the formation azobenzene, which undergoes two-fold hydrogenation to give aniline.

Scheme 447 Reduction of nitroarenes with TetraPhos–iron complex.

The iron-catalyzed reduction of nitroarenes via hydrosilylation was reported in 2010 by Beller's group.⁷³³ FeBr₂ in combination with PPh₃ was found to be the best catalyst for this transformation in the presence of PhSiH₃. Later, it was found that 1,1,3,3-tetramethyldisiloxane (TMDS) also serves the purpose of reduction using Fe(acac)₃ as the catalyst. Various functional group tolerance was observed including cyano, ester and acid.^734,735

Most interestingly, when dinitrobenzene was subjected to the reaction, only one of the nitro groups was reduced.

Hydrazine has also been used in many instances as a reductant for this transformation. Lu's group used resin-supported hydrazine hydrate in the presence iron oxide hydroxide as a catalyst.⁷³⁶ The reactions were also performed on the gram scale under reflux conditions in isopropanol to obtain more than 95% yield within minutes. It was proposed that Fe(III) is first reduced by hydrazine to Fe(II), which in turn is oxidised by the nitro group followed by hydrogen transfer. In contrast, Singh's group utilized iron(II) phthalocyanine (FePc) as the catalyst in combination with free hydrazine.⁷³⁷ Magnetically separable Fe₃O₄ nanoparticles were employed for the hydrogenation of nitroarenes with hydrazine (Scheme 448).⁷³⁸ However, nitroalkanes gave a very poor yield, which is attributed to the weaker co-ordination of the aliphatic nitro group to the NPs. Interestingly, the production of nitrogen and water as the only biproduct allowed the catalyst to be reused by simply washing with ethanol. Later, the in situ generation of Fe₃O₄ nanocrystals was realized by reducing Fe(acac)₃ with hydrazine, which in turn catalyzed the nitro reduction.⁷³⁹ Iron-phenanthroline deposited over carbon powder synthesized via the pyrolysis of an Fe(OAc)₂/1,10-phenanthroline mixture with Vulcan XC72R is an excellent effective catalyst also. In the presence of 4 equivalents hydrazine amine, a large number of aromatic and heterocyclic nitro compounds were reduced in more than 90% yield. γ-Fe₂O₃–polymer porous composites were also reported by Su's group to be effective towards the reduction with hydrazine.⁷⁴⁰

Scheme 448 Fe₃O₄-Catalyzed nitro reduction with hydrazine.

The first transfer hydrogenation of nitroarenes with IPA was obtained in the presence of γ-Fe₂O₃ (Scheme 449).⁷⁴¹ In the presence of the strong base KOH, moderate yields were obtained under reflux conditions. The reaction is believed to proceed in a pathway similar to the Meerwin–Ponderof–Verley reaction. The catalyst-adsorbed alkoxide transfers the hydride to the nitro group in the MPV mechanism, while the proton is transferred from the catalyst surface. On the contrary, formic acid is the most suitable hydrogen transfer agent with Beller's Fe(BF₄)₂·6H₂O/PP₃ catalyst.⁷⁴² However this reaction follows a similar mechanism proposed for the reduction with molecular hydrogen. In 2014, Thomas’ group realised this transformation using NaBH₄ as the reducing agent in an Fe(OTf)₃-catalyzed reaction (Scheme 450).⁷⁴³ The authors achieved a wide substrate scope, having an important advantage of room temperature reaction.

Scheme 449 Transfer hydrogenation of nitroarenes with γ-Fe₂O₃/IPA system.

Scheme 450 Iron-catalyzed nitro reduction with sodium borohydride.

7.2.5.2 Azide reduction. The bis(imino)pyridineiron complex (^iPrPDI)Fe(N₂)₂ [(ⁱPrPDI = (2,6-ⁱPr₂C₆H₃N=CMe)₂C₅H₃N)] synthesized by Chirik's group was shown to be effective for the reduction of aryl azide to aniline.⁷⁴⁴ The authors proposed that the reaction proceeds via H₂ addition across the Fe–N bond, then reductive elimination of –H and –NHAr finally provides the reduced product (Scheme 451).

Scheme 451 Bis(imino)pyridine iron-catalyzed reduction of azides.

Dash's group utilized Fe₃O₄ nanoparticles in the presence of hydrazine as a reducing agent (Scheme 452).⁷⁴⁵ Various aryl azides and sulfonyl azides were transformed into amines using the catalyst in water medium. The reaction possibly starts with the oxidation of hydrazine to diimide, which transfers two hydrogens to the adjacent internal nitrogens in a concerted pathway. Subsequent hydrogen transfer from the second nitrogen eliminates N₂ and gives the aniline.

Scheme 452 Reduction of azides with hydrazine catalyzed by Fe₃O₄ nanoparticles.

7.2.5.3 Sulfoxide reduction. In 2011, Enthaler reported the iron-catalyzed reduction of sulfoxides to sulfides.⁷⁴⁶ Fe₂(CO)₉ was used as the catalyst in combination with polymethylhydrosiloxane or PhSiH₃ as the reducing agent (Scheme 453). Various aryl sulfoxides including cyano and nitro-substituted sulfoxides and a few aliphatic sulfoxides undergo reduction to the corresponding sulfides. It is believed that the –SO group first co-ordinates to the metal center and gets activated. Subsequent interaction with the reductant provides the final product.

Scheme 453 Iron(0)-catalyzed reduction of sulfoxides.

Royo's group synthesized an NHC substituted cyclopentadienyl-based iron(II) complex and utilized it for the reduction of sulfoxides (Scheme 454).⁷⁴⁷ Both aliphatic and aromatic sulfides were prepared in the presence of PhSiH₃. The control experiments showed that the yield of the reaction is highly affected by radical trapping reagents, and thus a radical pathway was proposed.

Scheme 454 NHC-substituted cyclopentadienyl-based iron(II) complex-mediated sulfoxide reduction.

7.2.6 Hydrogen borrowing reaction. The iron-catalyzed hydrogen borrowing reaction was performed by Deng's group in 2010.⁷⁴⁸ In the FeCl₂-catalyzed reaction, sulphonamides are coupled with benzylic alcohols to obtain N-alkylated products (Scheme 455). The transformation initiates with the oxidation of alcohol by the Fe(II) catalyst in the presence of a base to aldehyde, followed by the nucleophilic attack of nitrogen. The imine formed in this process is reduced by the Fe(0) species presumably via the transfer hydrogenation mechanism. Both reactants were varied to obtain a plethora of N-alkylsulphonamides with more than 90% yield using this methodology. A similar reaction between heterocyclic amines such as benzimidazole, pyridine, and pyrimidine and alcohol was executed to obtain N-alkylation using iron(II)phthalocyanine as the catalyst (Scheme 456).⁷⁴⁹

Scheme 455 N-Alkylation of sulphonamides via hydrogen borrowing reaction.

Scheme 456 Iron(II)phthalocyanine-catalyzed N-alkylation of amines.

In 2014, Barta and co-workers utilized Knölker's iron catalyst for the hydrogen borrowing coupling of aromatic and aliphatic amines with various alcohols (Scheme 457).⁷⁵⁰ The catalyst is believed to behave identically as in transfer hydrogenation.

Scheme 457 Knölker's iron complex-catalyzed borrowing hydrogen reaction of alcohol with amine.

The two hydrogens from the alcohol is first taken by the catalyst, one by the metal the other by cyclopentadienone, which are later transferred to the imine. Remarkably, the use of diols provides N-heterocycles of various sizes via consecutive intramolecular coupling. In a subsequent report, they also presented one-pot hetero dialkylation with two different alcohols based on their reactivity towards primary and secondary amines.⁷⁵¹ They also showed that unprotected amino acids undergo N-alkylation with alcohols, although the yields are poor compared to the ruthenium catalyst counterpart.⁷⁵²

Knölker's catalyst was further employed by Sundararaju's group to obtain allylamines from allyl alcohols and various other unsaturated amines by Wills’ group.^753,754

However, in all these reports, only primary alcohols were utilized, whereas secondary alcohols remained hardly explored probably due to their lower reactivity. Zhao and co-workers visualized that one explanation for this low reactivity is the slow imine formation with a ketone (Scheme 458).⁷⁵⁵ Thus, they employed a Lewis acid, specifically AgF, and consequently drastic enhancement of the reactivity of secondary alcohols was observed. The authors attributed this enhancement to the faster Lewis acid co-ordination-assisted imine formation pathway.

Scheme 458 Lewis acid-enhanced hydrogen borrowing reaction of secondary alcohol.

Darcel's group pioneered α-alkylation of ketones by benzyl alcohol derivatives using Knölker's-type complex (Scheme 459).⁷⁵⁶ Initially, the formation of the desired coupling product is accompanied with transfer hydrogenation from alcohol to ketone. Thorough optimization revealed that the use of the PPh₃ ligand and Cs₂CO₃ base together with catalyst selectively produced α-alkylated ketones. This reaction follows a similar mechanism, where the alcohol transfers two hydrogens to the complex and undergoes aldol condensation with ketone and subsequent olefin reduction. The computational study revealed that enone reduction proceeds via the formation of enol followed by tautomerization.⁷⁵⁷ Fascinatingly, 2-amino benzylalcohol undergoes two-fold coupling with ketones and produces quinoline without getting reduced.

Scheme 459 α-Alkylation of ketones.

In 2017, utilizing the concept of borrowing hydrogen, Piersanti and co-workers performed C-3 benzylation of indoles with benzyl alcohol (Scheme 460).⁷⁵⁸ Iron–phthalocyanine was found to be the best catalyst in the presence of cesium carbonate base. The control experiments showed that the dehydrogenated alcohol condenses with indole, forming benzylideneindolenine, which in turn undergoes reduction to the desired product. In addition to benzaldehyde derivatives, different heterocyclic aldehydes are also compatible under the reaction conditions.

Scheme 460 C-3 benzylation of indoles via hydrogen borrowing reaction.

7.2.7 Hydrodehalogenation. In 1988, Brunet's group reported the first example of aryl iodide reduction with iron pentacarbonyl.⁷⁵⁹ In the presence of a catalytic amount of complex and potassium carbonate, Ar–I was converted to Ar–H in methanol (Scheme 461). The [HFe(CO)₄]⁻ species is believed to be the active catalyst and the hydrogen is abstracted from the solvent. Most interestingly, chloro and bromo aryl iodides undergo selective reduction at the C–I bond with no traces of other products.

Scheme 461 Reduction of aryl iodides with iron pentacarbonyl.

In 2004, Takahashi and co-workers developed the FeCl₃-catalyzed dechlorination of arylchlorides with Grignard reagents.⁷⁶⁰ The authors proposed that in situ-generated [Fe(MgCl)₂] reacts with Ar–Cl to produce [ArFeMgCl], which in turn forms [(Ar)(Bu)Fe(MgCl)₂] with BuMgCl (Scheme 462). This intermediate is more prone towards reductive elimination and can only be diverted to β-hydride elimination by increasing the electron density on the metal center, which they achieved by electron-donating group substitution on the arene ring. Wangelin's group reoptimized the reaction and found that catalytic Fe(acac)₃ in combination with ^tBuMgCl reduced this discrepancy to some extent.⁷⁶¹ Both electron-withdrawing and donating and ortho-substituted aryl halides undergo dehalogenation. Although, C–I > C–Br > C–Cl selectivity was observed for the same substrate, individually all three types of bonds can be reduced when present in different substrates. Interestingly, a few alkyl bromides also produced debromination under the reaction conditions. Later, this strategy was extended to the mono dehalogenation of 2,2-dibromocyclopropylarenes and 2,2-dichlorocyclopropylarenes (Scheme 463).⁷⁶² The diastereoselectivities of the reactions were moderate; however, no ring-opening product was obtained.

Scheme 462 Hydrodehalogenation of aryl chlorides.

Scheme 463 Mono dehalogenation of 2,2-dihalocyclopropylarenes.

Recently, Rasappan's group demonstrated the dehalogenation of aromatic and aliphatic halides with PhSiH₃ in the presence of FeCl₃ catalyst (Scheme 464).⁷⁶³ Mechanistically, PhSiH₃ promotes the formation of metal hydride species to which R–X oxidatively adds to form a metal-alkyl-hydride intermediate. Then, reductive elimination of –R and –H provides the desired product.

Scheme 464 PhSiH₃-Mediated dehalogenation.

7.3 Iron-catalyzed hydrosilylation reactions

7.3.1 Hydrosilylation of alkenes and alkynes. Hydrosilylation is an important strategy to synthesize organosilane compounds, which are key precursors for developing complex molecular entities and other valuable materials.⁷⁶⁴ Most of these reactions require stable, non-toxic and easily accessible silanes as reducing agents in the presence of suitable transition metal catalysts. Similar hydrosilylation methods using metal catalyst and silanes can reduce different organic molecules, and thus afford atom economical and sustainable hydrogenation methods compared to the stoichiometric reductions using NaBH₄ and LiAlH₄.⁷⁶⁵

The first instance of iron-catalyzed hydrosilylation of alkenes was introduced by Nesmeyanov et al. in 1962.⁷⁶⁶ The reaction was performed using [Fe(CO)₅] or colloidal iron as the catalyst. A mixture of alkylsilanes (hydrosilylation reaction product) and vinylsilanes (dehydrogenative silylation product) was obtained depending on the amount of trialkylsilanes used. Notably, the reaction of ethylene with 0.2 equiv. of triethylsilane specifically produced the triethylvinylsilane in 92% yield, whereas, 3 equiv. of triethylsilane resulted in the formation of tetraethylsilane with 79% yield (Scheme 465).

Scheme 465 Fe(CO)₅-Catalyzed hydrosilation of ethylene.

Further, the formation of alkanes, alkylsilanes and alkenylsilanes upon the photoirradiation of Fe(CO)₅ in the presence of alkene and trialkylsilanes was reported by Schroeder et al.⁷⁶⁷

In 1993, Murai and co-workers achieved the selective dehydrogenative hydrosilylation of styrenes with triethylsilane by using Fe₃(CO)₁₂ as the catalyst.⁷⁶⁸ The corresponding (E)-β-(triethylsilyl)styrene derivatives were obtained in high yields with complete selectivity. The complexes bearing multivinylsilicon ligands efficiently catalyzed the hydrosilylation and dehydrogenative silylation of styrene with trisubstituted silanes and hydrosiloxanes (Scheme 466).^766,769

Scheme 466 Hydrosilylation and dehydrogenative silylation of styrene using multivinylsilicon ligand-bearing iron complex.

In 2004, Chirik and co-workers synthesized and characterized diiminopyridineiron(0) dinitrogen complexes, which catalyze the hydrosilylation of alkenes and alkynes. Both bis(nitrogen), (i-PrPDI)Fe(N₂)₂ (i-PrPDI = ((2,6-CHMe₂)₂C₆H₃N = CMe)₂C₅H₃N), and its mono(dinitrogen) analogue, (i-PrPDI)Fe(N₂), were found to catalyze the hydrosilylation of terminal and cyclic alkenes, giving the anti-Markovnikov product exclusively with high TOFs (TOF = turn over frequency) (Scheme 467).^770–772 Also, the reactions were efficiently performed with a low catalyst loading (≤0.3 mol%) in a non-polar solvent at ambient temperature. The terminal alkenes react most rapidly followed by the gem-disubstituted olefins and other internal olefins. Moreover, in this reaction, phenyl silane is added to diphenylacetylene in the presence of the complexes, resulting in the selective formation of the corresponding ‘E’-vinyl silane. Notably, the isolated intermediate iron(0) bis(silane) complex, (i-PrPDI)Fe(η²-SiH₃Ph)₂, was identified as a competent catalyst for the hydrosilylation of 1-hexene. Further, in comparison to the methyl-substituted precursor, (i-PrPDI)Fe(N₂)₂, the phenyl-substituted complex (i-PrPhPDI)Fe(N₂)₂ showed superior catalytic activity towards the hydrosilylation of 1-hexene. On the other hand, the reverse is true for hindered substrates such as cyclohexene and (+)-(R)-limonene.⁷⁷²

Scheme 467 Hydrosilylation of 1-hexene in the presence of PDI iron(0) complexes.

Recently in 2017, Lam et al. elucidated the mechanism of the bis(imino)pyridine iron complex ((PDI)Fe)-catalyzed hydrosilylation of olefins using DFT calculations (Scheme 468).⁷⁷³ A mechanism similar to the Chalk–Harrod mechanism⁷⁷⁴ was proposed. The DFT calculation also supported the formation of the regioselective anti-Markovnikov product based on the requirement of a lower activation energy for anti-Markovnikov migration compared to Markovnikov migration. The mechanism initiates with the co-ordination of the olefin to active catalytic species A to form complex B. This is followed by co-ordination of hydrosilane to complex B to generate C. Most importantly, in contrast to the actual Chalk–Harrod mechanism, direct anti-Markovnikov hydride migration occurs from the co-ordinated silane into the Fe-bound olefin without early oxidation addition of Si–H at the metal centre. Thereafter, Si–C reductive elimination of (PDI)Fe(alkyl)(SiR₃) (D) produces the desired alkylsilane with the concomitant regeneration of the active catalytic species. It is worth mentioning that the iron center can adopt a variety of spin states due to the presence of the redox non-innocent bis(imino)pyridine (PDI) ligand. Consequently, a variation occurs in the electronic configuration in the complexes involved in the mechanism.

Scheme 468 Plausible mechanism of hydrosilylation of alkenes using bis(imino)pyridine iron catalyst.

In 2013, Thomas and co-workers reported an efficient iron-catalyzed procedure for the hydrosilylation of alkenes and alkynes using an FeCl₂ precatalyst and bis(imino)pyridine ligand L₁ in the presence of ethylmagnesium bromide (Scheme 469).⁷⁷⁵ The in situ-generated active iron catalyst affords the hydrosilylation products in excellent yields with high chemo, regio and stereoselectivity. A wide variety of styrene derivatives containing electron-withdrawing and electron-donating groups undergo this reaction. Various functional groups such as aniline, ester, ketone, nitrile and aldimine are well tolerated under the reaction conditions. Notably, hydrosilylation of internal alkynes gives (E)-vinylsilanes in high yield via the syn-addition of Si–H. However, the trans-addition of the Si–H bond leads to the formation of (Z)-vinylsilanes from the terminal alkynes.

Scheme 469 Iron-catalyzed hydrosilylation of alkene with bis(imino)pyridine ligand-containing complex.

Sterically hindered tertiary silanes were added to terminal alkenes using bis(imino)pyridine(dinitrogen) iron complexes, [(^EtPDI)Fe(N₂)]₂(μ₂-N₂) and [(^MePDI)Fe(N₂)]₂(μ₂-N₂) (Scheme 470).⁷⁷⁶ Hydrosilylation occurred very efficiently under mild reaction conditions using very low catalyst loadings (∼0.004–0.05 mol%). The anti-Markovnikov hydrosilylation products were obtained regioselectively with high yields.

Scheme 470 Iron-catalyzed hydrosilylation in the presence of bis(imino)pyridine dinitrogen complex.

In 2016, Thomas and co-workers introduced a very efficient procedure for the hydrosilylation of alkenes and alkynes using an air-and moisture-stable iron(II) pre-catalyst, [^EtBIPFe(OTf)₂] (^EtBip = 2,6-bis[1-(2,6-diethylphenyliminoethyl]pyridine)), in the presence of ⁱPr₂NEt as the activator for the catalyst.⁷⁷⁷ A wide range of aliphatic and aromatic terminal alkenes undergo efficient anti-Markovnikov hydrosilylation to give the desired linear silanes in excellent yields with complete regioselectivity (Scheme 471a). Hydrosilylation occurs chemoselectively at the terminal alkenes in the presence of various functional groups such as ketone, ester and imine. Also, terminal alkynes afford the (Z)-vinylsilanes with excellent selectivity under the reaction conditions (Scheme 471b). Notably, the practicability of the reaction was proven by the completion of the gram-scale hydrosilylation of 1-octene in 10 min using a very low catalyst loading of 0.25 mol% under an air atmosphere. Importantly, the catalytic system is equally effective in an air and inert atmosphere.

Scheme 471 Iron-catalyzed hydrosilylation of alkenes and alkynes in the presence of air- and moisture-stable iron complex.

The monohydrosilylation of the C₄ alkene of 1,2,4-trivinylcyclohexane (TVCH) with tertiary alkoxysilanes was achieved under the catalytic activity of various aryl-substituted bis(imino)pyridine iron dinitrogen complexes.⁷⁷⁸ Notably, the hydrosilylation reaction is utilized for the manufacture of tires having a low rolling resistance. Among the iron complexes, (^iPrPDI)Fe(N₂)₂ and (4-Me₂N-^iPrPDI)Fe(N₂)₂ (4-Me₂N-^iPrPDI = 2,6-(2,6-ⁱPr₂–C₆H₃N=CMe)₂-4-Me₂N–C₅H₂N) showed the highest selectivity (>98%) towards monohydrosilylation using MD′M (MD′M = (Me₃SiO)₂MeSiH) at the desired 4-vinyl position of the substrates (Scheme 472). Notably, the bis(imino)pyridine iron dinitrogen complexes exhibited better catalytic efficiency compared to the commercially utilized platinum catalysts.⁷⁷⁹

Scheme 472 Selective hydrosilylation of 1,2,4-trivinylcyclohexane (TVCH) in the presence of bis(imino)pyridine iron complexes.

Nakazawa and co-workers reported the synthesis of a number of iron complexes containing substituted terpyridine ligands. Some of these complexes exhibited catalytic activity in the hydrosilylation of alkenes in the presence of NaHBEt₃ as the activator of the catalyst. The unsymmetrically disubstituted terpyridine complexes showed high efficiency with turnover numbers of up to 1533 for the hydrosilylation of 1-octene and 1-hexene using diphenylsilane, phenylsilane and methylphenylsilane. Selective single- and double-hydrosilylation of the alkenes occurs depending on the amount of catalyst used (Scheme 473).⁷⁸⁰

Scheme 473 Hydrosilylation of 1-octene in the presence of iron complexes containing substituted terpyridine ligands.

Around the same time, the Chirik group established the catalytic efficiency of a 2,2′:6′,2′′-terpyridine iron dialkyl complex, (terpy)Fe(CH₂SiMe₃)₂, for the hydrosilylation of 1-octene with tertiary hydrosilanes (Scheme 474).⁷⁸¹ In addition, complete hydrosilylation (>95%) of vinylcyclohexene oxide (VCHO) was achieved using (terpy)Fe(CH₂SiMe₃)₂ as the catalyst to give the synthetically important anti-Markovnikov product with the oxirane moiety remaining intact. However, the conversion was unsuccessful using bis(imino)pyridine iron complexes and a platinum catalyst.⁷⁷¹

Scheme 474 Hydrosilylation of vinylcyclohexene oxide (VCHO) in the presence of (terpy)Fe(CH₂SiMe₃)₂ as the catalyst.

Electron-donating phosphinite-iminopyridine (PNN) ligand-bearing pincer iron complexes were prepared and characterized by Huang and co-workers in 2013.⁷⁸² These iron complexes on treatment with NaHBEt₃, catalyze the hydrosilylation of a wide range of alkenes using alkylsilanes such as PhSiH₃ and Ph₂SiH₂. Complex C₁ performs most efficiently for the hydrosilylation of various alkenes with good functional group tolerance (Scheme 475). High yields of anti-Markovnikov products were obtained by the reaction conditions under the catalysis of this complex. Significantly, the hydrosilylation methodology was applied for the synthesis of the insecticide silafluofen.

Scheme 475 Hydrosilylation of alkenes under the catalytic activity of PNN–iron complexes.

In 2016, Nakazawa and co-workers reported the synthesis of iminobipyridine iron(II) complexes A–D and demonstrated their catalytic efficiency towards the hydrosilylation of alkenes by silanes such as PhSiH₃, Ph₂SiH₂, PhMeSiH₂ and Ph₂MeSiH in the presence of NaBHEt₃ as the activating agent.⁷⁸³ Hydrosilylation of 1-octene with Ph₂SiH₂ occurred very efficiently in the presence of a catalytic amount (0.008 mol%) of complex B to give Ph₂(octyl)SiH in 96% yield with a TON as high as 12 038 (Scheme 476). Notably, the iminobipyridine complexes with NaBHEt₃ resulted in the formation of dialkylated and trialkylated silanes together with monoalkylated silanes as the hydrosilylation product. Further, ketimine-type iminobipyridine (BPI) iron complexes were also synthesized, which exhibited high catalytic activity in the hydrosilylation reaction of alkenes using primary, secondary and tertiary silanes to afford the corresponding monoalkylated and dialkylated silanes.⁷⁸⁴ Among the complexes, (^HBPI^Mes,Me)FeBr₂ (E) showed the highest TON of 42 000 for the iron-catalyzed hydrosilylation of 1-octene with Ph₂SiH₂ using only 0.001 mol% catalyst loading (A–D, E in Scheme 476). However, analogous to the aldimine-type iminobipyridine, these complexes also need NaBHEt₃ for activation.

Scheme 476 Alkene hydrosilylation catalyzed by iminobipyridine iron complexes.

In 2015, Lu and co-workers reported the first enantioselective iron-catalyzed asymmetric hydrosilylation reaction of 1,1-disubstituted aryl alkenes to give the anti-Markovnikov product using iron complexes bearing iminopyridineoxazoline ligands.⁷⁸⁵ High yields of hydrosilylation products were obtained with high enantioselectivity in the presence of NaBHEt₃ as the catalyst activator. Chiral oxazoline-substituted iminopyridine iron complex C2 gave the best result on activation with NaBHEt₃ (Scheme 477). The electron-rich and electron-deficient α-alkylstyrenes undergo the reaction with moderate chemoselectivity to give good to excellent yields of products. Although, fluoro, methoxy, trifluoromethyl, chloro and ketimine groups are tolerated, functional groups such as ketone, aldehyde, ester and alcohols react with silanes.

Scheme 477 Iron-catalyzed asymmetric hydrosilylation of 1,1-disubstituted aryl alkenes.

Recently in 2018, they introduced an iron-catalyzed enantioselective hydrosilylation procedure for terminal aliphatic alkenes, resulting in the formation of Markovnikov addition products selectively. This reaction was conducted in the presence of a catalytic amount of chiral oxazolineiminopyridine (OIP) iron complex C3 together with sodium tert-butoxide as the activator (Scheme 478).⁷⁸⁶ A wide range of aliphatic alkenes gave high yields of the branched product with high regioselectivity (branched/linear: >97/3) and high enantioselectivity (>99% ee). The reaction condition tolerates various functional groups such as ether, halide, silyl, protected alcohol, ester, amide, acetal and amine. Further, heterocycles such as 2-naphthalene, pyridine, indole and furan are also tolerated.

Scheme 478 Markovnikov hydrosilylation of olefins in the presence of chiral oxazolineiminopyridine (OIP) iron complex.

Iron complexes bearing 2,9-diaryl-1,10-phenanthroline ligands have been found to exhibit efficient catalytic activity for the hydrosilylation of internal and terminal alkenes with high selectivities. Zhu and co-workers synthesized these complexes and demonstrated their reactivity in the hydrosilylation of alkenes.⁷⁸⁷ Iron complex C4 catalyzes the reaction of internal alkenes in the presence of EtMgBr as a reducing agent to afford the benzylic hydrosilylation product selectivity in moderate to high yields (Scheme 479). Various β-methyl styrenes form high yield of the corresponding branched silanes. The reaction conditions tolerate various functional groups on β-methyl styrenes. In addition, these catalysts show high Markovnikov selectivity for the hydrosilylation of terminal alkenes such as terminal styrenes and also for 1,3-dienes. The mechanistic studies were performed through deuteration experiment studies, kinetic isotopic effect experiments and density functional theory (DFT) calculations. Based on the mechanism, they rationalized the high benzylic selectivity for the hydrosilylation of alkenes by the π–π interaction between the phenanthroline of the ligand and the phenyl group of the alkene.

Scheme 479 Hydrosilylation of terminal and internal alkenes in the presence of 1,10-phenanthroline ligand-bearing iron complexes.

In 2016, Nagashima and co-workers used the combination of Fe(OPv)₂ (Pv = pivolyl) and 1-adamantyl isocyanide (CNAd) in a 1 : 2 ratio for the hydrosilylation of styrenes with PMDS (PMDS = 1,1,3,3,3-pentamethyldisiloxane). This reaction afforded the corresponding anti-Markovnikov products in high yields.⁷⁸⁸

In 2010, Ritter and coworkers synthesized well-defined bis(aryl) iron(II) precatalyst C6 and used it in the 1,4-hydrosilylation of 1,3-dienes by triethoxysilane to give the corresponding linear allylsilanes predominantly (Scheme 480).⁷⁸⁹ The active catalyst formed in situ by using iminopyridine ligand L controls the high regioselectivity towards the predominant formation of the linear products (linear/branched: >94/6). Additionally, the allylsilanes were obtained with high stereoselectivity (E/Z ratio >99 : 1).

Scheme 480 Iron-catalyzed 1,4-hydrosilylation of 1,3-dienes.

The hydrosilylation of alkynes to vinylsilanes in the presence of Fe₂(CO)₉ and tributylphosphine was reported by Enthlaler and co-workers in 2011.⁷⁹⁰ A number of substituted diphenylacetylenes were hydrosilylated by (EtO)₃SiH to afford high yields of (Z)-stilbenes with excellent selectivity at the alkynes in the presence of various functional groups such as aldehydes, esters, amides, epoxide and alkenes.⁷⁹¹

Plietker and co-workers reported the synthesis and use of the iron hydride complex Fe(H)(CO)(NO)(Ph₃P)₂ in the stereodivergent hydrosilylation of internal alkynes.⁷⁹² Most importantly, the iron catalyst together with triethylamine additives afforded either the E- or Z-selective hydrosilylation product depending on the nature of the silane. The stereoselectivity is directed by the steric demand. The sterically hindered silane PhMe(CH₂=CH)SiH resulted in the selective formation of ‘E’-vinylsilanes. Contradictorily, the less hindered silane PhSiH₃ generated the ‘Z’-vinylsilanes selectively in high yields. However, the selectivity is also dependent on the substituents on the alkynes (Scheme 481). Although the diaryl and aryl/alkyl acetylenes give either the ‘Z’- or ‘E’-vinylsilanes according to the used silanes, the dialkyl acetylenes affords the ‘E’-configured vinylsilanes independent of the used silanes.

Scheme 481 Iron-catalyzed stereodivergent hydrosilylation of alkynes with two different silanes.

7.3.2 Hydrosilylation of aldehydes and ketones. The reduction of carbonyl compounds has been successfully performed by using hydrosilylation besides the more powerful reduction procedures such as hydrogenation and transfer hydrogenation. Further, hydrosilylation in the presence of iron catalysts provides an efficient, affordable and environmentally clean alternative to other metal catalysts such as rhodium, ruthenium, and iridium.

The early instance of iron-catalyzed hydrosilylation was shown by Brunner and Fisch in 1990.⁷⁹² The corresponding silylated ether was obtained from the reaction of acetophenone and diphenylsilane in the presence of a catalytic amount of the iron complex [Fe(Cp)(CO)(X)(L)] (X = COMe, Me; L = (S)-(+)-Ph₂P[N(Me)CH(Me)Ph]) (Scheme 482). Notably, silylated enol ethers are not formed in this reaction.

Scheme 482 Iron-catalyzed hydrosilylation reported by Brunner et al.

Later in 2007, Beller and co-workers employed Fe(OAc)₂ in combination with the tricyclohexylphosphine (PCy₃) ligand for the hydrosilylation of aldehydes with polymethylhydrosliloxane (PMHS) (Scheme 483).⁷⁹³ Basically, the aldehydes are converted to the corresponding silylether intermediates followed by basic workup to form the corresponding alcohols. Various substituted benzaldehydes are reduced chemoselectively in the presence of functional groups such as ester, cyano, chloro, bromo, nitro, fluoro, and o-benzyl to give the corresponding benzyl alcohols in high yields. Heteroaryl aldehydes and aliphatic α and β-unsaturated aldehydes are also hydrosilylated in moderate to high yields. Again, this procedure is also used for the hydrosilylation of ketones using PMHS.⁷⁹⁴

Scheme 483 Hydrosilylation of aldehydes in the presence of Fe(OAc)₃ and PCy₃ ligand.

The substituted arylalkyl ketones give good to excellent yields (81–96%) of benzyl alcohols, whereas dialkyl ketones give moderate yields (50–87%) of corresponding alcohols. Further, the enantioselective reduction of ketones is achieved in the presence of Fe(OAc)₂ and the chiral diphosphine ligand, (S,S)-Me-DuPhos (Scheme 484). The aryl ketones are reduced efficiently to give the corresponding alcohols with high enantioselectivity (up to 99%).⁷⁹⁵

Scheme 484 Iron-catalyzed hydrosilylation of ketones using Fe(OAc)₂ and (S,S)-Me-DuPhos.

On the other hand, Nishiyama and co-workers reported the hydrosilylation of ketones with (EtO)₂MeSiH using Fe(OAc)₂ in combination with nitrogen-based ligands such as N,N,N′,N′-tetramethylethylene diamine (TMEDA), bis(oxazolinyl)pyridine (pybox-dm) and bis-tert-butyl-bipyridiene (bipy-tb) (Scheme 485). This methodology provides moderate to excellent yields (50–90%) of the corresponding alcohols.⁷⁹⁶ Also, completely selective reduction of aromatic and aliphatic ketones with (EtO)₂MeSiH is achieved by employing Fe(OAc)₂ together with sodium thiophene-2-carboxylate (STC) (Scheme 485).⁷⁹⁷

Scheme 485 Iron-catalyzed hydrosilylation of ketones in the presence Fe(OAc)₂ with TMEDA ligand or STC as an additive.

The iron catalyst obtained from the Fe(OAc)₂ precatalyst and chiral bis(oxazolinylphenyl)amine (Bopa) ligands was very efficient in the asymmetric hydrosilylation of phenyl ketones with high enantioselectivity.^796,798 The corresponding ‘R’-configured alcohols were obtained with enantioselectivity of up to 88% ee using the iron Bopa-dpm (L) catalyst. In contrast, the ‘S’-configured alcohols were provided with high enantioselectivity (up to 95% ee) by the (S,S)-Bopa/FeCl₂ (C6) complexes in the presence of zinc powder as the additive (Scheme 486).⁷⁹⁹

Scheme 486 Iron-catalyzed asymmetric hydrosilylation of phenyl ketones.

In 2011, Theil and co-workers reported the iron-catalyzed hydrosilylation of aldehydes and ketones with PMHS using the catalyst precursors prepared from the combination of N1-alkylated 2-(3(5)-pyrazolylpyridine) ligands and iron octanoate [Fe(O₂C₈H₅)₂] (Scheme 487).⁸⁰⁰ The practicability of this catalytic system was demonstrated by the efficient reduction of aromatic aldehydes and ketones, and aliphatic ketones with excellent yields of up to 99%.

Scheme 487 Iron-catalyzed hydrosilylation of aldehydes and ketones using iron octanoate together with N1-alkylated 2-(3(5)-pyrazolylpyridine) ligands.

Around the same time, Plietker and co-workers used Bu₄N[Fe(CO)₃(NO)] (TBAFe) together with the PCy₃ ligand for the hydrosilylation of aldehydes and ketones to give moderate to high yields of the corresponding alcohols.^801,802 Notably, the reactions occur with low catalyst loadings (1.0–2.5 mol%) (Scheme 488).

Scheme 488 Hydrosilylation of ketones in the presence of TBA iron complex.

In 2010, Tilley and co-workers utilized the low-valent, cost-effective, highly active catalyst [Fe{N(SiMe₃)₂}₂] for the hydrosilylation of ketones and aldehydes at 23 °C (Scheme 489).⁸⁰³ Various functional groups such as ether, cyclopropyl, olefin bromoaryl, dimethylamino and nitrile groups are well tolerated under the reaction conditions.

Scheme 489 Iron-catalyzed reduction of ketones via hydrosilylation.

Further, in 2013, Turenlet and co-workers reported the synthesis and utilization of N-phosphinoamidinate ligand-containing iron(II) bis(trimethylsilyl)amide complex C7 as a precatalyst in the room temperature hydrosilylation of carbonyl compounds with phenylsilane (Scheme 490).⁸⁰⁴ This catalytic system is very efficient in reducing a wide range of carbonyl compounds including substituted ketones, enones, and esters. The reaction occurs in the presence of a very low catalyst concentration (0.01–1.0 mol% Fe) with only one equiv. of phenylsilane relative to the carbonyl compound. Togni and co-workers performed the hydrosilylative reduction of acetophenone with phenylsilane using a pentacoordinated cyclopentadienyl-containing stereogenic diamine ligand (L) together with the iron precursor Fe(OAc)₂. Although high conversion is provided by the catalytic system, the enantioselectivity is low (37%).⁸⁰⁵

Scheme 490 Iron-catalyzed hydrosilylation using N-phosphinoamidinate ligand-bearing complex.

In 2008, Chirik and co-workers developed catalytically efficient bis(imino)pyridine (PDI) iron complexes for the hydrosilylation of aldehydes and ketones with PhSiH₃ and Ph₂SiH₂ (Scheme 491).⁸⁰⁶ The complex (^iPrPDI)Fe(N₂)₂ (C8) was found to catalyze the hydrosilylation of p-tolualdehyde and acetophenone to give the corresponding silyl ethers in less than one hour. Further, complexes C9 and C10 are highly efficient in the hydrosilylative reduction of a broad range of aromatic ketones and aliphatic ketones. Notably, the α,β-unsaturated ketones are chemoselectively reduced to the corresponding unsaturated alcohols.

Scheme 491 Hydrosilylation of ketones in the presence of bis(imino)pyridine complexes.

In 2011, Guan and co-workers synthesized the phosphonite-based pincer ligand (POCOP)-bearing iron–hydride complex [2,6-(iPr₂PO)₂C₆H₃]Fe(H)(PMe₃)₂ (C11) and applied it in the hydrosilylation of aldehydes and ketones (Scheme 492).⁸⁰⁷ A wide range of carbonyls are efficiently reduced by (EtO)₃SiH in the presence of a catalytic amount of the iron–hydride complex. The corresponding alcohols are obtained in high yields without affecting the substituted functional groups such as –F, Me₂N–, MeO–, –NH₂ and pyridyl groups. From a mechanistic point of view, they suggested that the active catalytic species is generated by the dissociation of PMe₃ of CO in the initial step. Further, the cationic iron POCOP-pincer complexes C12 and C13 show superior catalytic efficacy compared to their hydride counterparts.^808,809

Scheme 492 Iron-catalyzed hydrosilylation of aldehydes and ketones in the presence of iron POCOP-pincer complex.

In 2014, Sun and co-workers reported the synthesis of tridentate bis(phosphine)silyl [PSiP] ligand-containing hydrido iron(II) complex C14 and used it for the hydrosilylation of aldehydes and ketones.⁸¹⁰ Excellent catalytic efficiency was shown by the complex, giving 100% yield of benzyl alcohol in the reduction of benzaldehydes with (EtO)₃SiH in the presence of 1 mol% of catalyst (Scheme 493). Further, diphosphinito PCP ligand-based iron complexes C15 and C16 demonstrated catalytic efficiency towards the hydrosilylation of ketones and aldehydes.^811,812 Complex C15 showed slightly higher activity compared to C14. High yields of corresponding alcohols were obtained by reducing ketones with (EtO)₃SiH using only 0.3% catalyst loading. In 2016, iron complexes with a similar structure such as (2,6-bis(di-tert-butyl-phosphinomethyl)pyridine) [(t-BuPNP)FeCl₂] (C17) and (2,6-bis(di-tert-butyl-phosphinito)pyridine) [(t-BuPONOP)FeCl₂] (C18) were synthesized by Findlater and co-workers. These complexes exhibited higher activities for the room temperature hydrosilylation of ketones and aldehydes with (EtO)₃SiH.⁸¹³

Scheme 493 Hydrosilylation of ketones and aldehydes in the presence of various iron-pincer complexes.

In 2014, Driess and co-workers synthesized a new bis(silyl)pyridine pincer-type [SiNSi] ligand-containing iron(0) complex, [SiNSi]Fe(PMe)₂ (C19) (Scheme 494), and demonstrated it as an efficient catalyst for the hydrosilylation of ketones.⁸¹⁴ Further, through combined experimental and theoretical studies, they revealed that the activation of carbonyl species and silane occurs at the ligand sphere (silyl ligand) instead of the direct involvement of the iron(II) site.⁸¹⁵ Significantly, all the processes throughout the reduction, that is activation of the reactant, bond forming, and bond breaking, occur at the periphery of the iron centre.

Scheme 494 Iron-catalyzed hydrosilylation of aldehydes and ketones by bis(silyl)pyridine pincer-type iron complex and NNN-pincer ligand-bearing iron complex.

Lee and co-workers utilized an NNN-pincer ligand-bearing low co-ordinate iron(II) complex (C20) (Scheme 494) for the hydrosilylation of carbonyl compounds with PhSiH₃ at room temperature.⁸¹⁶ In 2008, Gade and co-workers reported the synthesis of the chiral bis(pyridylimino)isoindole (bpi) pincer ligand-containing iron complex [Fe(tertapheny-carbpi)(OAc)] (C21) and achieved the asymmetric hydrosilylation of ketones under its catalytic activity.⁸¹⁷ The ketones are hydrosilylated using PMHS or (EtO)₂SiH followed by basic workup to give the corresponding alcohols with stereoselectivities of up to 93% ee (Scheme 495).

Scheme 495 Iron-catalyzed asymmetric hydrosilylation of ketones to alcohol using chiral bpi-pincer iron complex.

Further, the asymmetric hydrosilylation of ketones with PhSiH₃ was performed by Chirik and co-workers using the enantiopure pyridine bis(oxazoline)iron complex (^iPrPybox)Fe(CH₂SiMe₃)₂ (C22) together with B(C₆H₅)₃ as an activator in diethyl ether.⁸¹⁸ This catalytic system provides the corresponding alcohols with moderate enantioselectivity up to 54% ee. Notably the bis-oxazoline iron complex (^iPrBox)Fe(CH₂SiMe₃)₂ also shows similar reactivity (Scheme 496). In 2010, Nishiyama and co-workers utilized a similar bis(oxazolinyl)-phenyl ligated iron complex, (S,S)-(Phebox-ip)FeBr(CO)₂ (C23), together with sodium acetate for the asymmetric hydrosilylation of 4-phenylacetophenone with (EtO)₂MeSiH as the hydride source. A high yield (99%) of R alcohol was obtained with enantioselectivity of 66% ee under the reaction conditions (Scheme 496).⁸¹⁹ On the other hand, the complex (Phebox-ip)Fe(CO)₂(SiMe₃) (C24) alone gave the ‘R’-alcohol with 32% ee under similar reaction conditions with toluene as the solvent.⁸²⁰

Scheme 496 Asymmetric hydrosilylation of aldehydes and ketones in the presence of chiral iron complexes.

In 2015, Huang and co-workers synthesized unsymmetrical iminopyridine-oxazoline (IPO) iron complex C25 having a structure similar to the pybox ligand with one arm modified.⁸²¹ They utilized this chiral complex together with NaBHEt₃ for the asymmetric hydrosilylation of ketones. Various aryl-alkyl ketones and alkyl ketones were hydrosilylated stereoselectively, giving the desired alcohols in high yields (up to 99%) with up to 93% ee.

Around the same time, Gade and co-workers applied chiral boxmi (boxmi = bis(oxazolinylmethylidene)isoindoline) NNN-pincer ligated iron alkoxide complex C26 for the asymmetric hydrosilylation of ketones with (EtO)₂MeSiH (Scheme 497).⁸²² This complex was highly efficient as a catalyst to give high yield of the corresponding alcohols with enantioselectivity as high as 99% ee. Notably, a TOF (turnover frequency) of 240 h⁻¹ at −40 °C was shown by the catalyst.

Scheme 497 Iron-catalyzed asymmetric hydrosilylation of ketones in the presence of chiral boxmi pincer iron alkoxide complex.

Mechanistically, active alkoxide complex I undergoes σ-bond metathesis with the silane in the initial step to form iron hydrido complex II together with the generation of silyl ether (Scheme 498).⁸²³ Next, species II undergoes co-ordination to ketone. This is followed by the subsequent insertion of the ketone to the Fe–H bond to regenerate active complex I. Notably, this step is the stereoselectivity-determining step of the reaction.

Scheme 498 Proposed mechanism for the asymmetric hydrosilylation of ketones by C26.

After the initial use of piano stool iron complexes in the hydrosilylation of ketone by Brunner in 1990,⁷⁹² Nikonov and Vyboishchikov performed the hydrosilylation of benzaldehyde with PhMeSiH₂ in the presence of dihydride silyl complex C28 (Scheme 499).⁸²⁴ This complex was prepared from cationic phosphine complex C27. Notably, complex C27 also catalyzes the hydrosilylation of benzaldehyde using PhSiH₃ as the hydride donor.

Scheme 499 Hydrosilylation of benzaldehyde with piano stool-type iron silyl complex.

A series of phosphine-containing cyclopentadienyl iron carbonyl complexes (C29–C33) was utilized by Darcel and co-workers for the hydrosilylation of aldehydes and ketones.⁸²⁵ The cationic complexes with PF₆ as the counter anion (C29–C31) under irradiation of visible light gave better results towards the hydrosilylation of aldehydes using PMHS of phenylsilane as the hydride source (Scheme 500). On the other hand, the hydrosilylation of ketones was successfully performed using neutral complex C33. Moderate to high yields of corresponding alcohols were obtained from both processes.

Scheme 500 Hydrosilylation of aldehydes in the presence of piano stool iron complexes prepared by Darcel and co-workers.

Further, N-heterocyclic carbene (NHC)-bearing cyclopentadienyl stool complexes were applied as suitable catalysts for the hydrosilylation of ketones and aldehydes.⁸²⁶ In 2010, Royo and co-workers reported the hydrosilylation of aldehydes with (EtO)₂MeSiH under the catalytic activity of iron complex C34, bearing a chelating NHC-cyclopentadienyl ligand (Scheme 501).⁸²⁷ Thereafter, in 2011, Darcel and co-workers used the NHC-containing piano stool iron complex [CpFe(CO)₂(IMes)]⁺I⁻ (C35) for the catalytic hydrosilylation of aldehydes of aldehydes and ketones.⁸²⁸ Complex C36 was prepared by photoirradiation of C35 by visible light (Scheme 501). Aldehydes and ketones were reduced efficiently with PhSiH₃ in the presence of complex C35 under visible light irradiation. On the other hand, no such activation was necessary for the catalytic hydrosilylation with complex C36. The corresponding alcohols were obtained in moderate to high yields. Furthermore, the conversion rate and yield of the reaction were found to increase on performing the reaction in solvent-free conditions.⁸²⁹ Also, a lower temperature (50 °C) is required compared to the temperature in toluene (70 °C).

Scheme 501 NHC–iron complex-catalyzed hydrosilylation of aldehydes and ketones.

Cationic cyclopentadienyl piano-stool complex C37 bearing 1,3-disubstituted imidazolidin-2-ylidene as the NHC ligand was exploited as a suitable catalyst for the hydrosilylation of aldehydes and ketones with phenylsilane under neat conditions (Scheme 502).⁸³⁰ The aldehydes were reduced very efficiently at 100 °C giving the full conversion in much less time (5 min to 1 h). However, the full conversion of ketones to their corresponding alcohols took slightly more time (4 h). Around the same time, zwitterionic piano-stool NHC–iron complexes were employed for the hydrosilylation of aldehydes and ketones.⁸³¹ The complex having an NHC ligand with a malonate backbone, C38, was the most efficient complex among the complexes to catalyze the reduction of aromatic aldehydes in the presence of visible light irradiation by diphenylsilane with high chemoselectivity (Scheme 502). Similar visible light-activated catalytic activities were also shown by piano-stool-structured iron complexes bearing benzamidazole (e.g.C39) and imidazole (e.g.C40)-derived NHC ligands (Scheme 502).⁸³² The activity of the benzamidazole-derived NHC iron complexes was more efficient compared to the imidazole-based analogues towards the hydrosilylation of benzaldehyde and acetophenone with phenylsilane. Substituents such as bromo, nitro, nitrile, dimethylamino, methoxy and methane on the aldehyde substrates were well tolerated under this reaction condition. Furthermore, piano-stool complexes bearing monodentate triazolylidene ligands such as C41 were developed and used by Albrecht and co-workers as active catalysts in the hydrosilylation of aldehydes and ketones (Scheme 502).⁸³³ Very high efficiency was exhibited by complex C41 in the hydrosilylation of aldehydes with phenylsilane, giving a high TOF of up to 14 400 h⁻¹ using a very low amount of catalyst (0.1 mol%) in 1,2-dichloromethane solvent. However, the hydrosilylation reaction rate for ketones is lower than that for aldehydes. It is noteworthy that an induction period of 20–30 min was observed before a sharp increase in activity during the course of hydrosilylation of aldehydes.

Scheme 502 Iron-catalyzed hydrosilylation of ketones and aldehydes in the presence of piano-stool NHC iron complexes.

In addition to the NHC-ligated iron-stool complexes, various other iron complexes containing NHC ligands were developed, which are efficient in hydrosilylation of aldehydes and ketones. In 2012, Glorius and coworkers reported the use of the square planar NHC iron(II) complex, (IMes)₂FeMe₂ (C42), as an effective catalyst for the hydrosilylation of 2′-acetonapthone with hydride donors such as (EtO)₃SiH and Ph₂SiH₂ (Scheme 503).⁸³⁴ They also synthesized diamine-bridged bis-NHC iron dichloride complex C43 and applied it for the catalytic hydrosilylation of acetophenone with Ph₂SiH₂.⁸³⁵ This complex in combination with methyllithium in THF catalyzes the hydrosilylation reaction to give the corresponding alcohol with a high yield of 95%. Further, the iron(0) NHC complex Fe(IMes)(CO)₄ (C44) prepared by Royo and co-workers was effective as a catalyst in the hydrosilylation of benzaldehyde derivatives and acetophenone (Scheme 503).⁸³⁶ High yields of corresponding benzyl alcohols were obtained using phenylsilane as the reducing agent in the presence of a catalytic amount of C44 in THF solvent at room temperature. Recently, in 2018, Song and co-workers reported the synthesis of N-picolyl N-heterocyclic ligand bearing iron complex C45.⁸³⁷ This complex was used for the catalytic hydrosilylation of ketones with excess PMHS to give alcohols in high yields. Notably, the high catalytic efficiency of this complex was proved by complete conversion in the presence of a low catalyst loading of 0.02 mol%.

Scheme 503 Hydrosilylation of aldehydes and ketones in the presence of NHC–iron complexes C42–C45.

In 2011, Adolfsson and co-workers performed the hydrosilylation of ketones with PMHS using an in situ catalyst formed from Fe(OAc)₂ and NHC precursor IMes·HCl together with nBuLi as a base in THF at 65 °C (Scheme 504).⁸³⁸ Various ketones including arylalky-, dialkyl- and heteroarylketones were reduced to the desired alcohols in high yields (>99%) without affecting the other functional groups. A similar in situ-formed catalyst using 1-(2-hydroxyethyl)-3-methylimidazolium triflate, [HEMIM][OTf], as the NHC precursor catalyzed the hydrosilylation of ketones and aldehydes with a greater efficiency than IMes·HCl (Scheme 504).⁸³⁹ The catalytic system using [HEMIM][OTf] showed a high TOF of 200 h⁻¹ with ketones compared to the TOF of 10 h⁻¹ using IMes·HCl.

Scheme 504 Hydrosilylation of ketones using in situ-formed iron–NHC complexes.

The combination of PHMS and FeCl₃ in DCE (DCE = 1,2-dichloroethane) was used by Campagne for the reduction of aldehydes and ketones to the corresponding alkanes in the presence of microwave irradiation (Scheme 505).⁸⁴⁰ This simple and inexpensive procedure provides good to excellent yields of the methylene derivatives.

Scheme 505 Reduction of aldehydes and ketones to methylene compounds in the presence of an iron catalyst.

A large number of iron hydride complexes from Fe(PMe)₄ were synthesized and used for the catalytic hydrosilylation of aldehydes and ketones by Sun, Li and co-workers. Starting from complex C46 in 2014,⁸⁴¹ followed by complexes C47 in 2015,⁸⁴²C48 in 2016,⁸⁴³C49 in 2017⁸⁴⁴ and C50 in 2018,⁸⁴⁵ they were demonstrated to be very efficient catalysts for the hydrosilylation of aromatic and aliphatic aldehydes and ketones with (EtO)₃SiH (Scheme 506). Notably, the selective reduction of α,β-unsaturated aldehydes and ketones to the corresponding α,β-unsaturated alcohols was performed in the presence of C48, C49, and C50. Additionally, the selenophenolato analog of C49 was reported as an effective catalyst for hydrosilylation reactions.⁸⁴⁶

Scheme 506 Hydrosilylation of ketones and aldehydes in the presence of iron hydride complexes.

The iron-bearing diphenylphosphinoethane (DPPE) ligand, [(DPPE)₂Fe(H)₂] (C51), was reported by Darcel and coworkers as a suitable pre-catalyst for the reduction of aldehydes and ketones with PMHS together with the presence of NaB(OEt)₄ as a co-catalyst (Scheme 507).⁸⁴⁷ This system provides the corresponding alcohols in high yields of up to 99% upon activation with visible light. The aromatic and heteroaromatic aldehydes and ketones with bromo-, methoxy-, cyano- and amino-functional groups give high yields of the desired products.

Scheme 507 Reduction of aldehydes and ketones to alcohols in the presence of iron–dppe complex.

In 2015, Findlater and co-workers used the iron complex with a bis(arylimino)acenapthene framework, BIAN-Fe(C₇H₈), for the hydrosilylation of aldehydes and ketones with Ph₂SiH₂ under neat conditions (Scheme 508).⁸⁴⁸ Various substituted aldehydes and ketones undergo efficient chemoselective hydrosilylation to form the desired alcohols in high yields with good functional group tolerance.

Scheme 508 Iron-catalyzed hydrosilylation of aldehydes and ketones using BIAN-Fe(C₇H₈).

Around the same time, Thomas and co-workers reported the hydrosilylation of ketones and aldehydes with (EtO)₃SiH using air-moisture-stable amine bis(phinolate)iron complex C52 in CD₃CN solvent (Scheme 509).⁸⁴⁹ This catalytic system can efficiently reduce a large number of aldehydes and ketones, including α,β-unsaturated aldehydes and ketones, to their corresponding alcohols. The mild reaction conditions tolerate various functional groups such as CN, OMe, CF₃, Cl, F and OCF₃. In 2015, Peters and co-workers employed the DPB ligated iron complex [(DPB)Fe]₂(N₂) (C53) (DPB = bis(o-diisopropylphosphinophenyl)phenylborane) (Scheme 509) for the reduction of aldehydes and ketones via hydrosilylation with Ph₂SiH₂.⁸⁵⁰ Most aldehydes and ketone were hydrosilylated in excellent yields, except for the carbonyl compounds with high steric hindrance at the carbonyl site (e.g. tert-butyl methyl ketone and cyclopentanone). Further in 2016, Fernanadez and coworkers reported the synthesis and use of anthraquinonic ligand-bearing iron complex C54 as an active catalyst for the hydrosilylation of ketones at low catalyst loadings (0.25 mol%).⁸⁵¹ Another similar complex, C55, also catalyzes the reduction of a wide range of aldehydes and ketones to the corresponding alcohols using (EtO)₃SiH as the reductant (Scheme 510).⁸⁵² Full conversions of the reactions were obtained with only 0.25–0.5 mol% catalyst loadings.

Scheme 509 Hydrosilylation of ketones and aldehydes using iron catalysts.

Scheme 510 Reduction of ketones to alcohols in the presence of anthraquinoic iron complexes.

7.3.3 Hydrosilylation of imines. There are much less reports on the iron-catalyzed hydrosilylation of imines. The first instance of iron-catalyzed hydrosilylation of aldimines and ketimines was reported by Darcel and Sortais in 2012. This reaction was performed using PhSiH₃ in the presence of a catalytic amount of the well-defined complex [Fe(Cp)(IMes)(CO)₂]I (C56) in neat conditions under visible light irradiation (Scheme 511).⁸⁵³ Various aldimines and ketimines were efficiently converted to the corresponding amines through hydrosilylation followed by basic workup. Although the aldimines give the desired products at 30 °C, ketimines require a temperature as high as 100 °C.

Scheme 511 Iron-catalyzed hydrosilylation of imines in the presence of NHC–iron complex 56C₁.

Then, in 2016, Mandal and co-workers designed a unique NHC iron(0) complex, C57, and applied it in the hydrosilylation of imines with phenylsilane (Scheme 512a).⁸⁵⁴ This complex promotes the reduction of aldemines and ketimines to high yields of corresponding amines at room temperature with a very low catalyst loading as low as 0.005 mol% in DMSO, giving a high TOF of 17000. The mild reaction conditions provide hydrosilylation with high chemoselectivity, tolerating a large number of functional groups such as nitro, ketone, ester, nitrile, unsaturated double bond and acid group. Additionally, imines containing sugar derivatives were efficiently reduced to the biologically important N-alkylated sugar derivatives using this catalytic system (Scheme 512b).

Scheme 512 Hydrosilylation of imines by unique NHC iron(0) complex C57 and its application.

They investigated the mechanism of the reaction and proposed a Chalk–Harrod mechanistic pathway based on DFT calculations. Initially, iron precatalyst C57 undergoes dissociation of a CO molecule to form active species I, having 16 electrons (Scheme 513). Subsequently, the phenylsilane undergoes oxidative addition to this electron-deficient active species, generating intermediate II. Then this intermediate undergoes another dissociation of the CO ligand together with concomitant co-ordination of the imine derivative to form III. Thereafter, species IV is formed by hydride migration from the iron centre of III to the coordinated imine together with the attachment of a CO ligand to the iron centre. Finally, reductive elimination occurs to form the silylated amine together with the regeneration of active species I.

Scheme 513 Proposed mechanism for the iron-catalyzed hydrosilylation of imines in the presence of iron complex C57.

The direct reductive amination (DRA) of aldehydes and ketones was performed via the hydrosilylation reaction in the presence of iron catalysts. In 2010, Enthler first demonstrated a procedure for the formation of secondary amines by the DRA of aldehydes with anilines in the presence of FeCl₃ together with excess PHMS (Scheme 514).⁸⁵⁵ A wide range of aldehydes and substituted anilines underwent the reaction, forming the desired secondary amines in high yields. Then in 2012, Darcel and co-workers reported the DRA of substituted benzaldehydes with secondary amines under hydrosilylation conditions using cyclopentadienyl piano-stool iron complex C58 bearing a phosphanyl-pyridine chelating ligand (Scheme 514).⁸⁵⁶ The reaction is performed by employing PMHS in dimethylcarbonate solvent at 40 °C.

Scheme 514 Iron-catalyzed DRA of benzaldehyde derivative via hydrosilyalation.

Further, in 2014, N-alkylated anilines were synthesized from homoallylic or allylic alcohols and anilines (both primary and secondary) through DRA catalyzed by Fe(cod)(CO)₃ (cod = cycloocta-1,5-diene) in ethanol under visible light irradiation (Scheme 515).⁸⁵⁷ A large number of allylic and homoallylic alcohols underwent efficient reaction with various primary and secondary amines to give moderate to high yields of desired N-alkylated anilines. Notably, the hydrosilylation is performed with hydrosilane, PMHS. Most importantly, the reaction occurs via a three-step one sequence consisting of isomerization of allylic alcohol, condensation and hydrosilylation.

Scheme 515 Iron-catalyzed DRA for the preparation of N-alkylated anilines from allylic alcohols and secondary amines.

7.3.4 Hydrosilylation of nitro compounds. Nitroarene derivatives can be reduced to the corresponding anilines via hydrosilylation reactions. Initially, in 2009, Nagashima and co-workers observed the selective hydrosilylation of the nitro group in N,N-dimethyl-p-nitrobenzamide using TMDS (TMDS = 1,1,3,3-tetramethyldisiloxane) as the reducing agent to form N,N-dimethyl-p-aminobenzamide.⁸⁵⁸ Subsequently, in 2010, Beller and co-workers reported the reduction of nitroarenes with phenylsilane to the corresponding anilines in the presence of a catalyst formed in situ from the FeBr₂ precatalyst and triphenylphosphine (Ph₃P) (Scheme 516).⁸⁵⁹ A large number of substituted nitro arenes and heteroarenes were chemoselectively reduced to the respective anilines in high yields with various functional groups remaining intact.

Scheme 516 Iron-catalyzed hydrosilylation of nitroarenes.

Around the same time, Lemaire and co-workers performed the reduction of aromatic nitro derivatives to amine derivatives utilizing a mixture of Fe(acac)₃ and tetramethyldisiloxane (TMDS) at 60 °C.^860,861 This reaction procedure tolerates functional groups such as cyano, bromo, ester, acid and aldehydes. Further, in 2016, Thomas and co-workers applied amine-bis(phenolate) ligand-bearing complex C59 for the similar reduction of nitroarenes to the corresponding amines (Scheme 517).⁸⁶² A wide range of substituted nitroarenes were chemoselectively reduced by (EtO)₃SiH in acetonitrile solvent at 80 °C in the presence of a catalytic amount of the iron(III) complex. The efficiency of the procedure was demonstrated by the yields of the corresponding amines and tolerance to carbonyl, imine, ester, cyano and sulfonyl functional groups.

Scheme 517 Reduction of nitroarenes to amines in the presence of amine bis(phenolate) ligand-bearing iron complex.

In 2015, Baran and co-workers demonstrated a unique procedure for the synthesis of hindered amines from nitroarenes and alkenes via a reductive hydroamination reaction. The olefin hydroamination reaction was performed under the catalytic activity of Fe(acac)₃ in the presence of PhSiH₃ as the reductant in ethanol.⁸⁶³ Notably, the desired amines were obtained from the N,O-alkylated adduct via its reductive cleavage using Zn powder (Scheme 518). A huge number of substituted amines were produced in moderate yields (24–80%) together with tolerance to a large number of functional groups. From a mechanistic point of view, it was proposed that nitroarenes are initially reduced to the corresponding nitrosoarenes followed by adduct formation with alkyl radicals from alkenes. Thereafter, the adduct undergoes cleavage at the N–O bond to give the corresponding hindered amines.

Scheme 518 Synthesis of hindered amine from nitroarene and alkenes in the presence of an iron catalyst.

Recently in 2017, indoles were prepared via the reductive cyclization of ortho-nitrostyrenes in the presence of Fe(OAc)₂ in combination with 4,7-(MeO)₂phen as the ligand and phenylsilane as the reducing agent (Scheme 519).⁸⁶⁴ The reaction occurs via the formation of nitrosostyrenes as the intermediate, followed by electrocyclization to generate N-hydroxyindone and its subsequent reduction by phenylsilane to produce the desired indoles. Notably, active iron–hydride species is formed by the reduction of the iron precatalyst by phenylsilane. This procedure affords high yields of indoles from their corresponding nitrostyrenes.

Scheme 519 Preparation of indoles from ortho-nitrostyrene via iron-catalyzed reductive cyclization.

7.3.5 Hydrosilylation of carboximides. The reduction of carboxylic amides is very difficult due to their thermodynamic stability. The reduction can occur at the C–N bond to form the alcohol or amines can be formed by the cleavage of the C–O bond (Scheme 520).⁸⁶⁵ The developed iron catalysts have been found to reduce the carboxamide chemoselectively via C–O bond cleavage to form amines. Further, tertiary carboxamides are more prone to reduction than secondary amides. However, the primary amides are the least reactive and are very difficult to reduce to primary amines. Notably, primary amides usually undergo dehydration to nitriles under hydrosilylation conditions.^866–868

Scheme 520 Two reduction pathways for carboxylic amide.

In 2009, Beller and co-workers reported the first instance of iron-mediated hydrosilylation of amides with PMHS using a catalytic amount of [Fe₃(CO)₁₂] to form the corresponding amines (Scheme 521).⁸⁶⁹ A wide range of aliphatic, aromatic, heterocyclic and heteroaromatic tertiary amines undergo efficient reduction with high functional group tolerance. The secondary amides are also reduced in high yields under this reaction condition but only in the presence of PhSiH₃ as the reducing agent.

Scheme 521 Iron-catalyzed hydrosilylation of carboxamides in the presence of [Fe₃(CO)₁₂].

Around the same time, Nagashima and co-workers also reported the use of [Fe₃(CO)₁₂] together with [Fe(CO)₅] as efficient catalysts for the reduction of carboxamides to amines with TMDS as the hydrosilane (Scheme 522a).⁸⁵⁸ The reduction was also successfully performed under photoirradiation of the reaction system by a high pressure mercury lamp for 9 h at room temperature (Scheme 522b). Both the thermal- and photo-assisted procedures afforded good yields of the corresponding amines from the amides. Further, in 2011, they introduced a new procedure for carboxamide hydrosilylation using the heptanuclear iron carbonyl cluster [Fe₃(CO)₁₁(μ-H)]₂Fe(DMF)₄ and BDSB (BDSB = 1,2-bis-(dimethylsilyl)benzene) as a reductant to give the products in less time and at a lower catalyst loading (0.5 mol%).⁸⁷⁰

Scheme 522 Reduction of tertiary carboxamide to amines in the presence of iron catalysts.

In 2011, Darcel and Sortais utilized the well-defined NHC-bearing piano-stool iron complex [Fe(Cp)(CO)₂(IMes)]I (C60) as a very effective catalyst in hydrosilylation of amides with phenylsilane under visible light activation (Scheme 523).⁸⁷¹ Tertiary and secondary amides were efficiently reduced to the corresponding amides with moderate yield in neat conditions at 100 °C.

Scheme 523 Iron-catalyzed hydrosilylation of carboxamides by NHC–iron complex.

In situ-formed NHC–iron complexes have also been applied for the hydrosilylation of carboxamides. In 2013, Adolfsson and co-workers performed the hydrosilylation of tertiary amides with PMHS as the hydrosilane using the NHC–iron catalyst developed in situ from Fe(OAc)₂ and [PhHEMIM][OTf] in the presence of LiCl and nBuLi (Scheme 524).⁸⁷² Notably, the chemoselectivity of the reaction increased in the presence of the LiCl additive. Additionally, it also increased the rate of the reaction by increasing the activity of the catalytic system.

Scheme 524 Hydrosilylation of carboximides in the presence of in situ-generated NHC–iron complex.

Also, the chelated bis-NHC ligand-containing iron(0) complex [Fe{(^DippC:)₂CH₂}(η⁶-C₆H₆)] (C61) (^DippC: = bis-(N-Dipp-imidazole-ylidene)methylene) was shown to be an efficient catalyst for amide reduction with the reductant Ph₂SiH₂ at 70 °C (Scheme 524).⁸⁷³ This catalytic system afforded the desired amines in good to excellent yields.

Recently, in 2019, Turculet and co-workers synthesized two low-coordinate iron(II) complexes C62 and C63 bearing N-(phosphinoaryl)anilide as a P,N ligand and demonstrated their catalytic activity in the reduction of tertiary amides via hydrosilylation with PhSiMe₃ to form the corresponding amines.⁸⁷⁴ Although three-coordinate complex C62 and four-coordinate complex C63 showed similar activity at 80 °C, C62 was equally efficient at room temperature (Scheme 525). Various tertiary amines including sterically hindered N,N-dibenzylbenzamide were efficiently reduced to their corresponding amines with high yields. Notably, in contrast to the previously reported iron catalysts, this catalytic system does not require any photochemical activation. In addition, the N-phosphinoamidinate-ligated iron complex (P,N)Fe(N(SiMe)₂) (C64) was found to catalyze the hydrosilylative reduction of N,N-dibenzylbenzamide to dibenzylamine using PhSiH₃ (Scheme 525).⁸⁷⁵

Scheme 525 Iron-catalyzed hydrosilylation reaction of carboxamides in the presence of N-(phosphinoaryl)anilido iron complexes.

The troublesome reduction of primary amides to primary amines was successfully performed by Beller and co-workers by the consecutive use of two different iron complexes.⁸⁷⁶ The reaction was performed in two steps starting from dehydration of primary amide to the corresponding nitrile using the complex [NHEt₃][Fe₃H(CO)₁₁] together with (EtO)₂MeSiH in toluene. This was followed by reduction of the nitrile to primary amine by (EtO)₂SiH in the presence of Fe(OAc)₂ with terpyridine ligand L (Scheme 526). This methodology produced the primary amines in moderate yields.

Scheme 526 Iron-catalyzed reduction of primary amides to primary amines.

7.3.6 Hydrosilylation of nitriles. There are only two reports of the iron-catalyzed hydrosilylation of nitriles due to the relative stability of nitriles, and thus difficulty in their reduction. In 2016, the double hydrosilylation of aryl and alkyl nitriles was performed by Nakazawa and co-workers using Me₂PhSiH in the presence of the catalytic [Fe₃(CO)₁₂] in combination with indium trichloride (Scheme 527).⁸⁷⁷ The double-hydrosilylation products were selectively formed without any formation of the single hydrosilylation product. Additionally, the reaction is also feasible in presence of the iron-indium complex [Fe(MeCN)₆][Fe(CO)₄(InCl₃)₂] (C65) to give moderate yields of the desired disilylamine adducts as the products.

Scheme 527 Iron-catalyzed hydrosilylation of nitriles.

Recently in 2019, Mandal and co-workers employed phenalenyl ligand-bearing iron(III) complex C66 for the reduction of nitrile to primary amine with PMHS in the presence of KO(t-Bu) in THF at 70 °C (Scheme 528).⁸⁷⁸ Various aromatic, heteroaromatic and aliphatic nitriles were reduced to the corresponding primary amines via hydrosilylation under this reaction condition. The reaction procedure chemoselectively reduces the substituted nitriles in the presence of functional groups such as –OCH₃, –F, –Cl, –Br, C=C, and –CF₃. Notably, all the primary amines were isolated as their hydrochlorinated salts by treating them with methanolic HCl solution in Et₂O.

Scheme 528 Iron-catalyzed hydrosilylation of nitriles in the presence of phenalenyl-based iron catalyst.

7.3.7 Hydrosilylation of carboxylic esters. Carboxylic esters are reduced to aldehydes or alcohols or ethers via the chemoselective cleavage of different bonds depending on the conditions (Scheme 529). All the chemoselective reductions have been achieved under iron catalysis.

Scheme 529 Selective cleavage of esters to form ether, alcohol or aldehydes.

In 2012, Darcel and Sortais reported the first ester hydrosilylation reaction catalyzed by a well-defined iron complex, [Fe(Cp)(CO)₂(PCy)₃][PF₆] (C67), in neat conditions and under visible light activation at 100 °C (Scheme 530).⁸⁷⁹ The complex catalyzes a large variety of esters including aliphatic esters, aromatic esters, alkanoates and acetates to give the corresponding primary alcohols in good yields. In 2013, a similar hydroslilyation of carboxylic esters to alcohols by PMHS was performed using Fe(stearate)₂ together with the ligand NH₂CH₂CH₂NH₂ at 100 °C (Scheme 531a).⁸⁸⁰ Around the same time, N-phosphinoamidinate ligand-bearing three coordinate iron complex C68 was applied by Turculet and co-workers for a similar conversion at room temperature (Scheme 531b).⁸⁰⁴ Notably, the alcohols were obtained via the hydrosilylation of esters with phenylsilane at low catalyst loadings.

Scheme 530 Iron-catalyzed hydrosilylation of carboxylic esters by cyclopentadienyl iron complex C67.

Scheme 531 Hydrosilylation of esters to alcohols in the presence of different iron catalyst systems.

On the other hand, the selective reduction of esters to ethers was achieved by Beller and co-workers in 2012. The reaction was performed at 100 °C using 10 mol% of [Fe₃(CO)₁₂] in combination with 3 equiv. of TMDS in toluene (Scheme 532).⁸⁸¹ A broad range of aromatic and aliphatic esters were reduced via hydrosilylation to their corresponding ethers in high yields.

Scheme 532 Iron-catalyzed selective reduction of esters to ethers.

Again, esters were specifically reduced to aldehydes using the fully characterized⁸⁸² NHC–iron complex [(IMes)Fe(CO)₄] (C69) and hydrosilanes under UV irradiation at room temperature (Scheme 533).⁸⁸³ The reaction methodology chemoselectively reduces various esters, ranging from methyl, benzyl ester, substituted methyl acetates, aliphatic esters and lactones to the corresponding aldehydes and lactols in high yields. The diethylsilane and diphenylsilane give the best results depending on the substrate ester.

Scheme 533 Iron-catalyzed reduction of esters to aldehydes and lactones to lactols.

From a mechanistic point of view, the reaction is initiated with the release of a CO ligand through UV activation to form 16-electron complex I (Scheme 534).⁸⁸³ This is followed by the formation of intermediate complex IIvia the oxidative addition of hydrosilane to I. Then, the C=O bond of the ester is either inserted in the Fe–H or Fe–Si bond, forming the corresponding complex III or IV. Finally, the silylated acetal is produced via reductive elimination from complex III or IV together with the regeneration of active iron(0) species I.

Scheme 534 Proposed mechanistic pathway for the reduction of esters to aldehydes.

In addition to esters, acid chlorides were also reduced to aldehydes by employing the catalytic system consisting of iron oxide (FeO) and tris(2,4,6-trimethylphenyl)phosphine together with PhSiH₃,⁸⁸⁴ and moderate yields of the desired aldehydes were obtained.

7.3.8 Hydrosilylation of carboxylic acids. The chemoselective reduction of carboxylic acids to give either alcohol or aldehyde is a very difficult task (Scheme 535). There few examples of this reduction using iron catalysts.

Scheme 535 Reduction of carboxylic acid to aldehydes or alcohols.

The selective reduction of carboxylic acids to aldehydes or alcohols was reported by Darcel and co-workers. The alcohols were selectively obtained from carboxylic acids via a one-pot procedure using the (COD)Fe(CO)₃ (C70) catalyst together with phenylsilane under UV radiation at room temperature. The carboxylic acids were specifically converted to the corresponding alcohols in good yields (Scheme 536).⁸⁸⁵ In contrast, the aldehydes were selectively produced by performing the reaction in the presence of (t-PBO)Fe(CO)₃ (C71) and TMDS at 50 °C.

Scheme 536 Iron-catalyzed chemoselective reduction of carboxylic acids to alcohols and aldehydes.

7.3.9 Hydrosilylation of urea and carbon dioxide. The formation of formamidines via the selective reduction of the C=O bond of urea is very difficult. Basically, formamidines undergo over-reduction to form aminals, amines and methanol. However, Cantat and co-workers overcame this problem by employing a mixture of Fe(acac)₂ and tetraphos (L) in THF as the catalytic system (Scheme 537).⁸⁸⁶ The urea derivatives were reduced via hydrosilylation with PhSiH₃ to give moderate to high yields of formamidines (A) together with the formation of a lower amount of carboimides (B). Further, the same catalytic system at room temperature was able to reduce CO₂ selectively to form formamide and methylamine derivatives.⁸⁸⁷

Scheme 537 Iron-catalyzed reduction of urea to fromamidines (A) and carboimides (B).

7.3.10 Hydrosilylation of sulfoxides. The first iron-catalyzed hydrosilylative reduction of sulfoxides to sulfides was reported by Enthaler and co-workers in 2011.⁸⁸⁸ The sulfoxides were efficiently reduced to their corresponding sulfides with PhSiH₃ or PMHS using [Fe₂(CO)₉] in toluene at 100 °C (Scheme 538). Different sulfoxides undergo chemoselective reduction at the S=O bond in the presence of various reducible functional groups such as esters, cyano, sulfonyl, epoxides, alkenyl and aldehyde groups to give excellent yields of the sulfides.

Scheme 538 Fe₂(CO)₉-Catalyzed hydrosilylative reduction of sulfoxides.

Thereafter in 2012, Royo and co-workers applied well-defined iron complex-bearing NHC-functionalized cyclopentadienyl-chelated complex C72 in together with AgBF₄ for the similar hydrosilylation of sulfoxides with PhSiH₃ in toluene (Scheme 539).⁸⁸⁹ This reaction condition also afforded the desired sulfides in high yields.

Scheme 539 Iron-catalyzed hydrosilylative reduction of sulfoxides to sulfides in the presence of C72.

7.4 Hydroboration

Metal-mediated hydroboration reaction is a very straightforward and efficient method for the synthesis of organic boronates.⁸⁹⁰ These boronates are widely used as intermediates in organic synthesis, particularly as nucleophilic partners in Suzuki-Miyaura⁸⁹¹ cross-coupling and C–H activation reactions to construct carbon–carbon bonds or carbon–heteroatom bonds.⁸⁹² Moreover, hydroboration reactions are very selective and atom-economical reactions.⁸⁹² In these reactions, pinacolborane or catecholboranes are employed as the boron source due to their stability towards atmospheric oxidation. Previously, different heavy transition metal complexes (Rh and Ir) have been used efficiently in homogeneous hydroboration reaction.⁸⁹³ Throughout the last two-three decades, significant progress has been achieved in iron-catalyzed hydroboration reactions, which are discussed chronologically in the following section.

7.4.1 Hydroboration of alkenes and alkynes. The stoichiometric functionalization of alkenes and arenes using the [FeCp(Bcat)(CO)₂] complex for the activation of the unreactive C–H bond to form aryl or arene catecholborane was developed by Hartwig and co-workers in 1993.^894,895 Later, in 2009, Ritter and co-workers reported the first iron-catalyzed 1,4-hydroboration of pinacolborane (HBpin) to 2-substituted 1,3-diene using a combination of imino-pyridine ligand, ferrous chloride and a reducing agent (magnesium) at room temperature (Scheme 540).⁸⁹⁶ This reaction was completed within 4 min to 4 h depending on the starting substrate. Notably, this hydroboration methodology is chemoselective and regioselective. Both the isolated C=C bond and ester group are well tolerated under the reaction conditions to afford only the 1,4-hydroboration product. Moreover, the reaction only delivers the E-alkenes exclusively even with unsymmetrical dienes.

Scheme 540 Iron-catalyzed 1,4-hydroboration of 1,3-dienes.

Similarly, in 2014, Huang and co-workers reported the 1,4-hydroboration of 1-aryl substituted 1,3-diene for the regio and stereoselective synthesis of secondary benzylic Z-allylboronates using a series of new imino-bypyridine iron complexes having bulky diphenylphosphinomethylketimine substituents (Scheme 541).⁸⁹⁷ The iron complex was used as a precatalyst which, formed an active catalyst⁸⁹⁸in situ upon the addition of NaBEt₃H (two equivalents relative to Fe). Interestingly, both the electron-withdrawing group and the electron-donating group present at the meta- and para-position of the aryl group afforded the desired branched products in high yield. Moreover, the 1,4-disubstituted internal dienes also delivered the benzylic allylic boronate with good selectivity.

Scheme 541 Iron-catalyzed 1,4-hydroboration of 1-aryl substituted 1,3-dienes.

Throughout the last few years, the hydroboration of olefins has been performed using bidentate ligand-containing iron complexes. Later, Huang et al. first introduced the idea of using a tridentate ligand, which was found to be essential for iron-catalyzed hydroboration.⁸⁹⁹ The use of the tridentate ligand generates a less electrophilic iron centre, which helps in the easy formation of the olefin-ligated Fe^II-boryl intermediate during the catalytic cycle of alkene hydroboration. Purposefully, they employed an electron-rich iron complex bearing a bipyridyl-based phosphine ligand (PNN)⁹⁰⁰ (catalyst 3) in the presence of NaBEt₃H and pinacolborane (Scheme 543). The reaction regioselectively provides the anti-Markovnikov hydroboration product together with the chemoselective hydroboration of the terminal alkenes in the presence of multiple C=C bonds in a polyene system. This methodology works well for simple acyclic α-olefins, 1,1-disubstituted α-olefins and alkenes bearing functional groups such as silyl, ether, acetal, and amine. Notably, the reaction protocol does not result in the formation of the desired products during the hydroboration with internal alkenes. Furthermore, when the reaction is conducted with styrene in the presence of HBpin in THF, it does not only produce the linear hydroboration product, but also generates the dehydrogenative hydroboration product and ethylbenzene as side products. However, the selectivity during the formation of the product is solvent dependent. Changing the solvent from tetrahydrofuran to acetonitrile increased the yield of the linear hydroboration product. Interestingly, in presence of 40 mol% of acetonitrile, side product formation was inhibited.

Based on the preliminary data, the authors proposed the mechanistic cycle. Initially, in presence of NaHBEt₃, the alkene coordinates to the iron centre to produce complex A, followed by the oxidative addition of HBpin to complex A, generating formal 18-electron Fe(II)-boryl hydride species B. Thereafter, the terminal alkene (except vinylarenes) undergoes selective 1,2-insertion into the Fe–H bond (pathway I) to generate linear alkyl complex C, followed by reductive elimination to deliver the desired anti-Markovnikov product. On the other hand, vinyl arenes having no α-substituents generate the dehydrogenative borylation (pathway II) product via the insertion of vinyl arenes into the Fe–B bond rather than the Fe–H bond of complex B. The dehydrogenative borylation proceeds via the formation of η³-benzyl Fe(II) species D, a formal 18-electron complex, which undergoes η³-η¹ rearrangements followed by β-hydride elimination to form the vinylboronate ester (Scheme 542).

Scheme 542 Proposed mechanistic pathway for the iron-catalyzed hydroboration and dehydrogenative borylation.

Later, Chirik and co-workers used a bis(imino)pyridine iron dinitrogen complex (Scheme 543, catalyst 4) for the anti-Markovnikov synthesis of alkyl boronates.⁹⁰¹ Noteworthily, the reaction was performed in the absence of organic solvent, which extended the substrate scope of this methodology. Consequently, the reaction promotes the hydroboration of terminal, internal, cyclic and geminal alkenes with high activity and selectivity using a catalytic mixture of 1 mol% of [^i-Pr(PDI)Fe(N₂)₂] (catalyst 4) and HBpin. Particularly, for internal alkenes, e.g. cis-4-octene, a mixture of 1- and 4-octylboronate products was obtained in a 5 : 1 ratio within 24 h of reaction, indicating an isomerization process. Notably, the reaction methodology is also performed with styrene to obtain the selective anti-Markovnikov hydroboration product in the presence of 1 mol% of catalyst 4. Furthermore, 1-phenyl propylboronate ester and 2-phenyl propylboronate ester are obtained from the catalytic hydroboration of α- and cis-β-methyl styrene after 24 h of reaction.

Scheme 543 Iron-catalyzed hydroboration of alkenes.

Successively, Thomas and co-workers reported the regio, chemo and stereoselective iron-catalyzed hydroboration of alkenes and alkynes using a catalytic combination of dichloro iron(II)complex (Scheme 543, catalyst 5) or in situ formation of 1 mol% of precatalyst from FeCl₂ and free bis(imino)pyridine ligand in the presence of EtMgBr with pinacolborane in THF at room temperature.⁹⁰² Terminal alkenes substituted with aryl chloride, fluoride and bromide and substrates having more than one unsaturated group such as esters, alcohols, amide, imines, and amines are well tolerated under the standard reaction conditions. In addition, this synthetic methodology was also applied for the hydroboration of internal alkenes, e.g. cyclooctene, and the hydrogermylation of styrene, obtaining the selective linear hydrogermylated product in 86% yield. Interestingly, this is the first reported example of an iron-catalyzed hydrogermylation reaction.

Later, Darcel and Sortais used a molecular-defined iron NHC complex [(MesI)Fe(CO)₄] (Scheme 543, catalyst 6) for the hydroboration of functionalized terminal alkenes at room temperature.⁹⁰³ The reaction was performed under UV irradiation (350 nm) in the presence of HBpin and absence of organic solvent. Various functional groups such as ester, acetal, ether, silylether, epoxide, and nitrile are well tolerated under the reaction conditions.

In 2014, Szymczak and co-workers synthesized aminobispyridine (N,N,N) Fe(II) complexes, [Fe^II(bMepi)(THF)]OTf (Scheme 543, catalyst 7) and [Fe(bMepi^Me)(OTf)₂] (Scheme 543, catalyst 8) to catalyze the hydroboration reaction of terminal linear and cyclic olefins together with HBpin and NaBEt₃H at room temperature under neat conditions.⁹⁰⁴ Their idea of introducing an alkyl group at the remote site of the ligand backbone modifies the electronic environment of the secondary coordination sphere of the ligand by tuning the electrophilicity of the iron complex. Consequently, this characteristic of the ligand helps to catalyze the hydroboration reaction at an increased rate, affording the corresponding vinyl boronate esters as the desired product with distinct regioselectivity from internal and terminal alkynes under the same reaction conditions.

Additionally, when the hydroboration reaction of styrene was performed in presence of the [Fe(bMepi)(THF)]OTf (Scheme 543, catalyst 7) catalyst, the anti-Markovnikov hydroboration product was obtained as the major product (75% yield) together with the formation of the dehydrogenative borylation and hydrogenation product (11% yield of side products). On the other hand, under the same reaction conditions, using [Fe(bMepi^Me)(OTf)₂] as the catalyst (catalyst 8) afforded only 81% yield of the anti-Markovnikov hydroboration product. However, when cis-4-octene was subjected to [Fe(bMepi^Me)(OTf)₂], a mixture of alkyl boronates was delivered as the product, whereas only linear boronates were obtained using [Fe(bMepi)(THF)]OTf as the catalyst, indicating the isomerization of the C=C bond followed by hydroborylation.

In 2015, Rauchfuss and co-workers developed a series of new phosphine-diimine ligands via the condensation reaction between 2-(diphenylphosphino)aniline (PNH₂) and a variety of formyl and ketopyridine derivatives.⁹⁰⁵ Noteworthily, the authors synthesized a low-spin [Fe PN^HPy^R]²⁺ (R = Me, H) complex (Scheme 543, complex 9) using a combination of ferrous halide and the ligand generated from the condensation reaction between PNH₂ and pyridine carboxylate and its 6-methyl derivatives. This low-spin complex was used for the hydroboration of 1-octene in together with HBpin and NaBEt₃H at room temperature.

In 2016, Webstar and co-workers reported two iron(II) β-diketiminate complexes (Scheme 543, complex 10) for the regio and chemoselective hydroboration of alkenes and alkynes in the presence of HBpin or HBcat in a 1 : 1 reagent ratio without any requirement of external reducing agents or activator.⁹⁰⁶ With the first catalyst 10A, terminal linear olefins delivered the anti-Markovnikov product (45–99% yield) using HBpin in C₆D₆ solvent for 16 h at room temperature. Moreover, functional groups such as epoxide, ketone, and phosphine are well tolerated under the reaction conditions. Interestingly, only terminal double bonds are hydroborylated, keeping the other multiple double bonds present in the molecule intact. Using the same catalyst at 60 °C, styrene also undergoes the reaction to give the exclusive formation of the anti-Markovnikov hydroborylated product. Importantly, the specific formation of 2-phenylpropyl boronate esters and 1-phenylpropyl boronate esters was obtained during the hydroboration reaction of α- and cis-β-methylstyrene, respectively. Furthermore, second catalyst 10B having different steric and electronic characteristics in its ligand structure can change the reactivity of styrene, i.e. only the Markovnikov hydroborylated product is obtained without any formation of the dehydrogenative hydroborylation and hydrogenation product. Notably, double hydroborylation of diphenylacetylene occurs to afford the geminal dipinacolborane product.

In the same year, Turculet and co-workers reported an N-phosphinoamidinate-coordinated iron catalyst for the isomerization–hydroboration of terminal, germinal and internal alkenes using 1,3-dimethyl-1,3-diaza-2-boracyclopentane at 65 °C (Scheme 544, complex 11).⁹⁰⁷ Evidently, more challenging substrates such as trans-4-octene provide the terminal hydroboration product selectively under the reaction conditions. Notably, 1,3-dimethyl-1,3-diaza-2-boracyclopentane is a better hydroboron reagent source than HBpin or benzo-1,3,2-diazaborolane for the above-mentioned methodology. Further, Zhou and co-workers reported the hydroboration of styrenes and heteroaryl alkenes in the presence of a simple catalytic system having bis(pinacolato)diboron, FeCl₂ (0.1–10 mol%), K-O(t-Bu) (1.2 equivalent) and t-BuOH (1 equivalent) in THF at 65 °C for 12 h.⁹⁰⁸ This transformation provides the selective anti-Markovnikov product with 64–99% yield.

Scheme 544 Iron-catalyzed isomerization–hydroborylation of internal olefins.

The catalytic systems discussed thus far performing the hydroboration of styrene generated the selective anti-Markovnikov product. However, the regioselective formation of the Markovnikov hydroborylation product using an iron-based catalytic system was not discovered until 2016. However, in 2017, Lu and co-workers reported the highly-Markovnikov-selective hydroboration of styrenes using a catalytic system containing an iron catalyst containing an oxazolinyl phenyl picolinamide (OPPA) (12) ligand, HBpin, and NaBEt₃H in toluene at 30 °C for 18 h to deliver the branched hydroboration product with up to >50 > 1 (branched > linear product) (Scheme 545).⁹⁰⁹ The electronic nature of the substitution present in styrene does not affect in the selective formation of the desired product in good yield. Furthermore, the late-stage synthesis of bioactive molecules possessing styrene such as (+) menthol and vitamin E have also been exclusively converted to the corresponding selective branched products in moderate yield.

Scheme 545 Iron-catalyzed Markovnikov selective hydroboration of styrenes.

Furthermore, Thomas and co-workers reported two series of structurally related alkoxytethered NHC iron(II) complexes, which performed the activator-free regioselective hydroboration of terminal alkene systems (Scheme 546).⁹¹⁰ Notably, using iron complex 14 and HBpin under neat conditions at room temperature with styrene, the selective branched hydroboration product was obtained with the improved selectivity of branched: linear ratio from 5 : 1 to 37 : 1. On the other hand, the use of styrene derivatives with HBCat and iron complex 13 led to the formation of the anti-Markovnikov (linear) hydroboration product. However, because of the difficulties in the purification of catechol boronic ester, these products were oxidised in the presence of H₂O₂/NaOH to the linear alcoholic product or transesterified with pinacol to provide the primary alkyl boronic ester. Although enantioselective hydroboration of alkenes is very rare, Lu and co-workers in 2014 first reported asymmetric hydroboration using imino-pyridine oxazoline (IPO) iron catalyst 15 for the formation of the anti-Markovnikov hydroboration product of 1,1-disubstituted aryl arenes with pinacolborane (Scheme 547).⁹¹¹ Notably, the imino-pyridine group stabilized the iron catalyst and the chiral oxazoline group controlled the enantioselectivity. The reaction was also well proceeded in the presence of a variety of substituted styrenes including electron-rich and electron-deficient substituents. Notably, silylether, tertiaryamines and methylsulphides are also well tolerated under the reaction conditions. In addition, the isolated and bench-stable chiral alkyl boronic esters were also transformed into a variety of chiral compounds such as alcohols, amines and fluorinated boronic derivatives.

Scheme 546 Iron-catalyzed systems for the selective anti-Markovnikov and Markovnikov hydroborylation of styrenes.

Scheme 547 Iminopyridineoxazoline iron-catalyzed asymmetric hydroboration of 1,1-disubstituted aryl alkenes.

Simultaneously, the hydroboration of alkynes was reported by Enthaler using [Fe₂(CO)₉] as a catalyst in the presence of pinacolborane to afford vinyl boronate esters (Scheme 548, condition A).⁹¹² Although E-vinyl boronate derivatives were obtained selectively from the terminal alkynes, a more complex mixture of regioisomers was obtained from the internal non-symmetric alkynes. Furthermore, iron-nanoparticles (np-Fe₃O₄) or anhydrous FeCl₃ were also used as a catalyst for the monoborylation of alkynes using bis(pinacolato)diboron (Scheme 548, condition B).⁹¹³ The E-vinyl boronates were obtained as the product with high regio and stereoselectivity in good to excellent yield. Notably, the catalyst was used for six consecutive cycles without loss in its activity.

Scheme 548 Iron-catalyzed hydroboration of alkynes.

In 2017, Nishibayashi and co-workers synthesized an iron catalyst possessing a pyrrolidine-based PNP pincer ligand to catalyze the hydroboration of alkynes with pinacolborane at room temperature to provide E-alkenyl boranes under ambient conditions (Scheme 548, catalyst 16).⁹¹⁴ Although meta and para-tolylacetylenes provide the alkenyl borane in good yield, the ortho analogue does not afford any desired product in reasonable yield, indicating the role of steric hindrance in inhibiting the reaction. Both aromatic and aliphatic alkynes were converted to the desired product under the reaction conditions. However, internal alkynes such as diphenylacetylene did not afford any desired product. Importantly, the reaction methodology only provides the complete selective hydroboration reaction of alkynes, even in the presence of the alkene moiety. Interestingly, the turnover number (TON) of the catalyst was found to be 710 for the hydroboration reaction between alkynes and hydroborane at high temperature (60 °C). Notably, this is the highest TON reported to date for the iron-catalyzed hydroboration reaction.

In the same year, Kirchner and co-workers synthesized a non-classical iron(II) polyhydride compound bearing a tridentate PNP pincer-type ligand with the general formula [Fe(PNP)(H)₂(η²-H₂)] (Scheme 549).⁹¹⁵ As soon as this compound is added to excess BH₃·THF, it results in the formation of a complex for the chemo, regio and stereoselective hydroboration reaction of terminal alkynes to generate the respective vinyl boronate with high Z-selectivity.⁹¹⁶ However, internal alkynes do not provide any type of desired product. Further, when the reaction was performed in C₆D₆, vinylboronates were obtained having the E : Z ratio of 29 : 71 to 1 : 99 within 3 to 16 h.

Scheme 549 Iron-catalyzed hydroboration of alkynes.

In 2019, Findlater and co-workers reported two iron complexes, (BIAN)Fe(I)-η⁶-toluene (Scheme 550, catalyst 18) and FeCl₂(BIAN) (Scheme 550, catalyst 19) [BIAN = bis(2,6-diisopropylaniline)acenaphthrene], which catalyzed the regioselective hydroboration of alkenes and alkynes.⁹¹⁷ Linear vinyl and alkyl boronic esters were obtained respectively in the presence of pinacolborane and an activator (Nat-BuO) at 70 °C under neat conditions. Notably, the first catalyst, [(BIAN)Fe(I)η⁶-toluene] (Scheme 550, catalyst 18), was used for the hydroboration of terminal alkynes. Various terminal phenylacetylenes having electron-withdrawing and electron-donating substituents were hydroborated in good yields. On the other hand, the second catalyst, FeCl₂(BIAN) (Scheme 550, catalyst 19) was used for the hydroboration of internal alkynes. This is due to the increased steric characteristics of the internal alkynes, which destabilise the close approach of the substrates to the iron centre rather than the co-ordination of the η⁶-toluene group. To rationalize the reaction, bis(trimethylsilyl)acetylene provided a mixture of isomers containing both the hydrogenated (GC yield = 33%) and non-hydrogenated products. Moreover, styrene bearing both electron-donating and electron-withdrawing substituents delivered the selective anti-Markovnikov hydroboration product in good yield with a ratio of linear: branched of >98 : 2.

Scheme 550 Iron-catalyzed hydroboration of alkynes.

Recently, Plietker and co-workers have reported a structurally-defined iron–hydride complex, [FeH(CO)(NO)(PPh₃)₂], which catalyzes the stereoselective hydroboration of internal alkynes (Scheme 551).⁹¹⁸ Both aliphatic and aromatic alkynes undergo the reaction to provide the corresponding vinylboronates with very high Z/E selectivity in moderate to good yields in the presence of either HBpin or B₂pin₂ as a boron source. Importantly, in the case of asymmetric internal alkynes, the regioselectivity of the product solely depends on the boron source. Using HBpin as the boron source, the Markovnikov product is obtained with good regioselectivity, while the complementary anti-Markovnikov product is obtained in comparable regioselectivity using B₂pin₂/MeOH as the boron source. This type of regioselectivity indicates the involvement of different catalytic species during the catalytic cycle depending on the boron source.

Scheme 551 Hydroboration of alkynes via iron catalysis.

Vinylcyclopropane (VCP) is a very useful synthon, which has been used particularly for the making of all carbon rings. In 2017, Lu and co-workers reported the Markovnikov-type hydroboration of VCP using the iron complex IPO·FeCl₂ (Scheme 552, catalyst 20) in the presence of HBpin and NaBEt₃H in toluene at room temperature for 0.5 h.⁹¹⁹ Iron catalyst 20 provides regioselective C–C bond cleavage of VCP, affording homoallylic organoboronic esters with E-selectivity. Notably, a variety of functional groups such as amino, sulphide, silylether, halides, remote C=C bond and thienyl are well tolerated under the reaction conditions. To implement the asymmetric transformation, the reaction between various racemic vinylcyclopropanes and HBpin using complex 21 was carried out to afford various chiral homoallylic boronic esters in 39–97% yield with 72–99% ee. These chiral homoallylic boronate esters were also converted to the chiral poly-substituted tetrahydrofuran and tetrahydropyran.

Scheme 552 Iron-promoted hydroboration of vinylcyclopropane.

Based on the preliminary studies, the authors proposed a reaction mechanistic pathway. Initially, iron–hydride complex A is generated from IPO·FeCl₂ and NaBEt₃H. Then, complex A undergoes coordination with the alkene part of vinylcyclopropane to form complex B. Thereafter, complex B undergoes alkene insertion into the iron–hydride bond followed by selective β-carbon elimination to generate complex D. Finally, complex D undergoes ligand exchange with HBpin to generate the homoallylic boronate ester with simultaneous regeneration of iron–hydride complex A (Scheme 553).

Scheme 553 Proposed mechanistic pathway of iron-catalyzed hydroboration of vinylcyclopropane.

Later, Wang and co-workers reported the catalytic hydroboration of N-heteroarenes using the N₂-bridged diiron complex [Cp*-(Ph₂PC₆H₄S)Fe]₂[(μ-N₂)] (22) in the presence of pinacolborane in C₆D₆ at 50 °C.⁹²⁰N-Borylated-1,2-reduced derivatives (61–99% yield) were obtained using this reaction strategy in high regioselectivity (Scheme 554, catalyst 22).

Scheme 554 Iron-promoted hydroboration of the double bond of heterocycles.

7.4.2 Hydroboration reaction of carbonyl compounds. The iron-catalyzed hydroboration reaction of alkenes and alkynes using catecholborane and pinacolborane has been well reported by renown research groups. Similarly, hydrofunctionalisation of carbonyl compounds is also an important area in organic synthesis. The product obtained from the hydroboration reaction of carbonyl compounds can be converted to the corresponding alcohol (primary and secondary) via the hydrolysis of boronate esters. Although this type of the reaction has already been reported using the first-row transition metals (Cu,⁹²¹ Mn,⁹²² Ti,⁹²³ and Zn⁹²⁴), main group elements (Ca,⁹²⁵ Mg,⁹²⁶ Al,⁹²⁷ Sn,⁹²⁸ Ge,⁹²⁸ Pb,⁹²⁹ Ga,⁹³⁰ and Ge⁹³¹) and lanthanides,⁹³² the iron-catalyzed hydroboration reaction of carbonyl compounds was first reported in 2017 by Findlater and co-workers. They reported the room temperature hydroboration of aldehydes and ketones using Fe(acac)₃ as the precatalyst in the presence of NaBEt₃H and HBpin in THF for 24 h (Scheme 555, condition A).⁹³³ Further, the hydroboration reaction of trans-cinnamaldehyde led to the generation of two products, i.e. α,β-unsaturated-3-phenyl-2-propane-1-ol and 2-phenylethanol as the major and minor product, respectively. Interestingly, this reaction methodology was found to be chemoselective with respect to the hydroboration of aldehydes over ketones.

Scheme 555 Iron catalyzed hydroboration of carbonyl compounds.

In the same year, Bai and co-workers reported a low-coordinated homoleptic tri-tert-butylphosphoranimido iron(II) dimer for the hydroboration of carbonyl compounds at room temperature (Scheme 555, catalyst 23).⁹³⁴ Various aldehydes and ketones were converted to the respective alcohol in 54–90% yield in the presence of the iron(II) catalyst (used in low catalytic amount) with HBpin in a solution of benzene for 13 h after simple acidic quenching. Simultaneously, Tong and Wang also reported the room temperature hydroboration of carbonyl compounds using an iron(II) hydride complex bearing a tetradentate PSNP ligand in combination with pinacolborane in a solution of C₆D₆ for 20–40 min (Scheme 555, catalyst 24, condition E).⁹³⁵

In 2018, Hein and Baker synthesized a five-coordinated, paramagnetic imine-coupled Fe(II) complex, [Fe (N₂S₂)₂] (used in low catalytic amount (0.1 mol%)), which catalyzed the selective hydroboration reaction of carbonyl compounds in the presence of pinacolborane at room temperature to deliver the borate ester in 26–99% yield (Scheme 555, catalyst 25, condition F).⁹³⁶ Noteworthily, this iron(II) complex is prepared from the readily available benzothiazolidine ligand [S^MeN^HS] having a potentially labile thioether donor. The advantage of this reaction methodology is the chemoselectivity of the aldehyde group in the presence of ketones. Various mono and disubstituted aldehydes are well tolerated under the reaction conditions, even in the presence of various functional groups such as nitriles, alkenes, amines and halides.

Subsequently, Geetharani and co-workers developed easily synthesized iron(II) amide complexes that catalyze the selective hydroboration of carbonyl compounds in the presence of pinacolborane without any additive (Scheme 555, condition B).⁹³⁷ Various aldehydes having substituents such as methoxy, cyano, nitro, hydroxyl, and halides are well tolerated under the reaction conditions. Interestingly, the wide functional group tolerance of this reaction methodology is much better than the methodologies of Bai and co-workers⁹³⁴ using Fe₂(NP^tBu₃)₄ (do not contain any examples having cyano and hydroxyl groups) and Findlater and co-workers⁹³³ using Fe(acac)₃ (do not contain any examples having cyano, nitro and hydroxy groups). Interestingly, this methodology is also chemoselective. Clearly, α-unsaturated aldehyde reacts with only the carbonyl functionality, keeping the alkene moiety intact.

Concurrently, Zhang and co-workers reported the catalytic hydroboration of ketones with pinacolborane using the 2D iron(II) coordination polymer (CP) of a divergent 4,2′,6′,4′′-terpyridine(tpy) derivative (Scheme 555, condition C).⁹³⁸ Various ketones having different functional groups such as nitro, nitrile, alkene, alkynes and amides are well tolerated under the reaction conditions to provide the boronate ester in good to excellent yield. These boronate esters on hydrolysis via silica gel column chromatography are converted to the corresponding alcohols. Notably, this solid iron catalytic system is more active towards the hydroboration reaction of ketones compared to aldehydes, exhibiting the opposite trend from the other iron-catalyzed methods for hydroboration.^932,936

In 2018, Gade and co-workers reported an ultrafast iron-catalyzed reduction of functionalized ketones using a molecularly defined chiral boxmi iron alkyl complex (used in a low catalytic amount of 0.5 mol%) (Scheme 556, complex 26).⁹³⁹ This reaction strategy led to the enantioselective generation (ee up to >99%) of halohydrins, oxaheterocycles (oxiranes, oxetanes, tetrahydrofuran and dioxiranes) and amino alcohols via the boronate ester intermediate. Interestingly, the gram-scale synthesis of 3-chloro-1-phenylpropan-1-ol was successfully executed using this reaction methodology. Moreover, this chemical is the basis for the formation of the anti-depression drug (R)-fluroxetine following the original synthesis by Corey and co-workers.⁹⁴⁰

Scheme 556 Iron-catalyzed hydroboration of ketones.

7.4.3 Dehydrogenative borylation. Vinyl boronate esters can be efficiently produced via the catalytic dehydrogenative borylation of styrene derivatives. Many research groups such as Ge,⁹⁴¹ Sortais and Darcel⁹⁴² in 2016 reported the molecular-defined iron complex-catalyzed selective dehydrogenative borylation of vinylarenes in the presence of pinacolborane. The E-vinyl boronate esters are obtained in high yield (60–94%) from mono and disubstituted vinylarenes using the Fe(PMe₃)₄ complex and norbornene system in a solution of hexane at 50 °C for 18 h (Scheme 557, condition A).⁹⁴¹ Various functional groups such as acetals, imines, furyl, amino, boronates and PPh₂ are well tolerated under the reaction conditions. Notably, the presence of a hydrogen accepter, i.e. norbornene was found to be essential for the reaction, and consequently in the absence of this hydrogen quencher, the desired product was detected in a trace amount.

Scheme 557 Iron-catalyzed dehydrogenative borylation of alkene.

Around the same time, Darcel and co-workers synthesized a series of dicarbonyl PCP iron hydride complexes for the selective dehydrogenative borylation of styrene derivatives in combination with HBpin (Scheme 557, 27a or 28, condition B).⁹⁴² Vinyl boronate esters were produced in high yield (up to 80% isolated yield) from styrene derivatives using a combination of either catalyst 27 or 28 with pinacolborane under neat conditions and UV irradiation (350 nm) for 24 h at room temperature.

8. Addition reaction

8.1 Carbometalation

The iron-catalyzed carbometalation across strained olefin was first introduced by Nakamura and co-workers (Scheme 558).⁹⁴³ Utilizing FeCl₃ as the catalyst, the carbometalation of cyclopopenone acetal was achieved with both organomagnesium and organozinc reagents. They trapped the organometallic intermediate. Notably, in the absence of the iron catalyst, the reaction do not give the product. More interestingly, the asymmetric version was developed with the aid of phosphine- and amine-based chiral ligands. This opened up a new direction for iron-catalyzed asymmetric synthesis. Various aryl, alkyl and alkenyl organometallic reagents are compatible under the reaction conditions. In 2007, Kotora's group found that a specifically designed iron catalyst accomplished the selective alkylative cyclisation of 2-chloro-1,7-dienes in the presence of organoaluminium compounds (Scheme 559).⁹⁴⁴ Although no evidence was provided in support of carboalumination, a high probability of the addition of AlR₃ across the double bond can be considered.

Scheme 558 Carbometalation of strained olefins.

Scheme 559 Cyclization of 2-chloro-1,7-dienes via carbometallation.

Subsequently, Lam and co-workers used trialkylaluminium reagent to carbometalate electron-poor cyclopropenes, which undergo ring opening (Scheme 560).⁹⁴⁵ Expectedly, the regioselectivity is dictated by substitution on the alkene, where the more substituted carbon is preferentially attacked by the alkyl nucleophile. A plethora of different electron-poor cyclopropenes are tolerated under the reaction conditions. In a few instances, even lower than an equivalent amount of trialkylaluminium produced a good product yield, indicating the possibility of multiple alkyl group transfer.

Scheme 560 Ring opening of electron-poor cyclopropenes.

The plausible mechanism suggests that the presence of ester groups in the ring is essential to stabilize the intermediate during the reaction. Later, it was shown that tuning of the ligand can suppress ring cleavage through electrophilic trapping.⁹⁴⁶ Heterobicyclic alkenes undergo carbometalation in the presence of FeCl₃ and ZnR₂ but do not show ring opening in the presence of electron-deficient phosphine-based ligands (Scheme 561). A suitable electrophile then replaces the metal from the organometallic intermediate to provide doubly substituted bicyclic heterocycles. A number of possible electrophilic substitutions such as deuteration, iodination, alkylation, and acylation make it a versatile methodology. More promisingly, the asymmetric version was also achieved by using chiral phosphine ligand systems.

Scheme 561 Aryl diphosphine ligand-promoted carbometalation.

The iron-promoted carbometalation of alkynes was demonstrated by Hayashi using arylmagnesium bromide (Scheme 562).⁹⁴⁷ Simple 4-octyne upon reaction with a Grignard reagent in the presence of Fe(acac)₃ provides a carbometalated intermediate, which can be trapped by various electrophiles such as H₂O, D₂O, and PhCHO to generate the corresponding substituted alkenes. Although CuBr is required to increase the yield, it does not take part in addition across the triple bond, rather it promotes the transmetalation step. Later, this reaction was improved with the aid of a catalytic carbene ligand.⁹⁴⁸ Fe(acac)₃/carbene not only enhanced the reactivity, but also diversified the substrate scope of the reaction, including electrophilic substitution such as iodination and allylation. The authors attributed this enhancement to the ease of the transmetalation step with the Fe(carbene) complex, which is believed to be the bottleneck with Fe/Cu catalysis. This protocol can also be extended to propargyl and homopropargyl alcohol to obtain substituted allyl and homoallyl alcohols.⁹⁴⁹ However, only a phosphine ligand is sufficient in conjunction with an iron catalyst to promote alkylmagnesiation. High regioselectivity is observed due to coordinating nature of the –OH group. Two intermediates (Scheme 563), viz. (vinyl)Fe-coordinated with alcohol and magnesium-included cyclic intermediate, are presumed to be possible and can lead to the formation of the final product via transmetalation. Later, the Fe–Cu cooperative reaction was further extended to perform sequential reactions merging with alkyl exchange under the same conditions to provide diversely substituted olefins.⁹⁵⁰ Conjugative dialkynes can also be carbometalated across one of the triple bonds to provide vinylalkynes.⁹⁵¹ Interestingly, when phenyl-silyl substituted unsymmetrical diyne is used, selective addition at the phenyl terminal is observed.

Scheme 562 Fe–Cu co-operative mechanism for alkyne carbometalation.

Scheme 563 NHC-promoted aryl magnesiation.

Alkyllithium reagents also behave in a similar fashion. Hosomi and co-workers found that butyllithium can be added across a triple bond using Fe(acac)₃ catalyst in toluene at −20 °C (Scheme 563).⁹⁵² Several electrophiles can also be trapped during the reaction; however, only heteroatom-containing substrates undergo carbolithiation. This preference is due to the chelation effect that can be administered by the heteroatom to the catalyst. This discrepancy was resolved later using a different condition using FeCl₃ in diethyl ether (Scheme 564).^953,954 It has been found that the iron catalyst was first reduced by alkyllithium, which acted as the real catalyst. Thus, the efficiency of the reaction was enhanced by pre-treatment with zinc to reduce iron. Inspired by the catalytic system for carbomagnesiation, carbolithiation was further extended to aryl and vinyl lithiation as well. In the case of aryllithium addition, the reaction proceeds with the substituent at different positions even with silyl substitution.

Scheme 564 Iron-catalyzed carbolithiatzon of alkynes.

Urabe and co-workers found that if enynes are used as substrates, intramolecular cyclization occurs to provide five- and six-membered products depending on the distance between the double and triple bond, with an exogenous double bond as a residue of alkyne (Scheme 565).⁹⁵⁵ The reagent combination of FeCl₂/t-BuMgCl is the best combination for this transformation. The substrates invariably require electron-withdrawing groups such as ester, amide, and nitrile at the terminal position of both the alkene and alkyne. However, when it is applied to dienes, unexpectedly fused cyclic ketones are observed as the final product due to rapid Dickmann condensation to provide a thermodynamically more stable product. An analogous protocol was reported specifically for the synthesis of pyrrole and THF derivatives containing one exocyclic double bond from amines and ethers.⁹⁵⁶ However, diethyl zinc was mentioned to be essential, which probably assists the elimination step in order to obtain final product.

Scheme 565 Addition of Grignard reagent to dialkynes and allenes.

Allenes when subjected to Grignard reagents in the presence of Fe(acac)₃ afforded α,β-unsaturated alkenoates with predominant Z-selectivity (Scheme 566).^957–959 The dienolate intermediate can be trapped with acyl chloride to form the Z-isomer of the α-acylated product. However, the same reaction selectively provides the E-isomer when allyl carboxylic acid ester is used. Moreover, using allylic acetate in conjunction with Pd catalyst affords α-allylated alk-3(Z)-enoate and allyl halide with CuI selectively gives the E-version of the product. The same strategy can be utilized to synthesize allyl silanes by employing silyl substituted allenes.

Scheme 566 Cyclization of enynes.

8.1.1 Hydroalkylation, hydroalkenylation and hydroalkynylation. Iron-catalyzed hydoalkylation was first demonstrated by Beller and co-workers.⁹⁶⁰ Acetyl acetone was added to various styrene derivatives using a cheap FeCl₃·6H₂O catalyst (Scheme 567). A similar observation was reported by Prim and co-workers together with hydroamination.⁹⁶¹ In addition to styrene derivatives, cyclic diene and heterocyclic olefins are also compatible towards hydroalkylation with acetyl acetones. Although acetyl acetone is used in excess, its availability makes the reaction beneficial. Later, the addition of a styrene derivative to butadiene derivatives was achieved by an in situ reduced FeCl₂ catalyst (Scheme 568).⁹⁶² The deuterium labelling experiment favored 1,4-hydoalkenylation. The co-ordinated styrene and dienes can undergo oxidative coupling, which is followed by α-σ rearrangement. The seven-membered η¹-allyl ferracycle then undergoes β-hydride elimination, and subsequent reductive elimination with co-ordinated hydride yields the product (Scheme 569). Both intramolecular hydroalkylation and hydroalkenylation were demonstrated with the aid of a pre-synthesized iron pincer catalyst (Scheme 570).⁹⁶³ Notably, 2-butynyl allyl tosylamine provides 3,4-disubstituted pyrrolidine with an exocyclic cis-double bond. In the presence of 4 atm H₂, the reaction produces a mixture of unsaturated and fully saturated version of the product, and deuterium labelling confirmed hydroalkylation. Similarly, diyne substrates produce doubly exocyclic olefin-substituted products.

Scheme 567 Hydroalkylation of styrenes.

Scheme 568 1,4-Hydoalkenylation to butadiene.

Scheme 569 Mechanism of 1,4-hydoalkenylation.

Scheme 570 Cyclization of enyne with iron-pincer complex.

In 2009, Tu and co-workers developed FeCl₃-catalyzed addition of the α-C–H bond of primary alcohols across olefinic double bonds (Scheme 571).⁹⁶⁴ It was observed that the alkyl group selectively coupled at the less hindered side of the alkene. This behaviour and other experiments support the mechanism in which the metal abstracts a hydrogen from the α-position of the alcohol to form Fe^IV–H species and an alkyl radical. Since the addition of the radical to the less hindered side of the olefin will produce the more stable intermediate, the above-mentioned selectivity was observed. Various aliphatic alcohols including phenethyl alcohols could be coupled with a number of styrene derivatives.

Scheme 571 Addition alcoholic C–H bond across double bond.

Iron-catalyzed E-selective head-to-tail styrene dimerization was demonstrated by Corma et al. in a regioselective manner.⁹⁶⁵ In this respect, it was observed that a comparatively higher acidic iron catalyst Fe(NTf)₃ works best in 1,4-dioxane. Although various aryl substituted styrenes yield products, their internal analogues do not produce any product. Through controlled reactions, it was suggested that a benzylic cationic Fe(III) species is formed, which is attacked by another co-ordinated styrene molecule, producing the coupled product, and the catalyst is regenerated simultaneously. Moreover, α-EWG ketene dithioacetals can also be added to styrene molecules effectively in an iron-catalyzed reaction.⁹⁶⁶

Although the possibility of forming three different products including styrene dimerization exists, Yu and co-workers optimized the reaction in favor of the formation of R₂C=SR′₂ with Fe(OTf)₃ (Scheme 572). A related mechanism was been suggested, where the stabilization by two –SR groups towards the cationic intermediate could be attributed as the driving force for heteromolecular coupling over styrene dimerization.

Scheme 572 Styrene dimerization and addition of ketene dithioacetals to styrene.

It was found that treating olefins with iodobenzene in the presence of FeCl₂ and NaBH₄ can yield the same result as hydroalkylation. The intramolecular version of the reaction produces the cyclized product with diastereoselectivity upon treatment with FeCl₂/NaBH₄ in acetonitrile (Scheme 573).⁹⁶⁷ The use of deuterated NaBD₄ confirmed that the hydrogen of the other end of the alkene is transferred from the reducing agent. However, a different mechanism was proposed, where the iron catalyst is majorly involved in the electron transfer process to generate a radical from iodoalkane. The cyclized radical then abstracts a hydrogen radical from BH⁴⁻.

Scheme 573 Intramolecular hydroalkylation.

The hydroalkynylation of norbornene with simple phenyl acetylene was first reported by Sakakura and co-workers with limited diversity (Scheme 574).⁹⁶⁸ The yield of the reaction is highly dependent on hardness of the metal ion, and in turn the acidity.

Scheme 574 Iron-catalyzed hydroalkynylation.

Thus, Fe³⁺ was found to be the best catalyst among many others, which is also consistent with the ease of the formation of the cationic intermediate. The co-ordinated acetylene then reacts with the cationic species quite similar to the other two versions to provide the hydroalkynylated product. FeCl₃ also catalyzes the dimerization of terminal alkynes to provide enynes in the presence of potassium alkoxide.⁹⁶⁹ Although the yields are moderate, the E/Z selectivity is poor and aliphatic alkynes do not produce any results. Improved selectivity was realised later upon changing the ligand DMEDA to dppe. Not only different substituents such as halide, methoxy and amine on the arene ring were tolerated under this protocol, but a thiophene-substituted terminal alkyne also gave a promising yield.⁹⁷⁰ It was observed that the yield decreases drastically in the presence of a radical quencher. Thus, a radical pathway was suggested with Fe in the 4+ oxidation state as one of the key intermediates.

8.1.2 Two-fold C–C bond formation. It was accidentally found that 2-benzhydryl-1,3-diphenylpropane-1,3-dione and ethyl 2-benzhydryl-3-oxo-3-phenylpropanoate undergo an exchange reaction in the presence of catalytic FeCl₃via the formation of the diphenylmethylium ion. This cation is then trapped by various alkenes and alkynes to form dihydroindenes and indenes, respectively (Scheme 575).⁹⁷¹ Chen and co-workers optimized the indene formation reaction from simple diphenylmethane to enhance its effectivity using NBS as the oxidizing agent.⁹⁷² The similar reactivity observed with bromodiphenylmethane led to the assumption of pre-bromination by NBS before the formation of the cation stimulated by the iron catalyst.

Scheme 575 Dihydroindene formation through diphenylmethylium intermediate.

Li and co-workers reported the iron-catalyzed 1,2-alkylarylation of activated alkene.⁹⁷³ Different substituted oxindoles were synthesized from N-alkyl–N-aryl acrylamide by alkylation with heteroatom-containing alkanes followed by intramolecular arylation (Scheme 576). The reaction was best realized with catalytic FeCl₃ in conjunction with DBU as the ligand and TBHP as the oxidant. The kinetic isotope effect (k_H/k_D = 1) and radical trapping experiment suggested a radical mechanism may occur. The hydroperoxide in the presence of a, iron catalyst abstracts a hydrogen atom from the alkane adjacent to the heteroatom. Thus, the alkane radical attacks acrylamide and subsequent ring formation occurs. Later, it was observed that the alkyl radical can also be generated from the peroxides to carry out 1,2-methylarylation in a mechanistically similar fashion.^974,975 The alkoxy radical rearranges itself to form a methyl radical, leaving carbonyl, which can enter the reaction cycle. Further, alcohols and PhSO₂CF₂I instead of ethers were also established to be compatible with slight modification of the reaction conditions.^976,977 The latter case uses hydrogen peroxide to generate a radical from PhSO₂CF₂I, and thus provides fluorinated heterocycles.

Scheme 576 N-Alkyl–N-aryl acrylamide cyclization triggered by alkyl radical.

The iron-catalyzed reaction of 2-biarylmagnesium bromide with alkyne and 1,2-diyne to synthesize phenanthrene and bis-phenanthrene derivatives via [4+2] benzannulation was described earlier in Section 2 (Schemes 55 and 56).^81,82 Also, the reaction of aryl Grignard reagents and arylindiums with alkynes to form naphthalene derivatives via [2+2+2] benzannulation was depicted in the same section (Schemes 55 and 56, respectively).^81,82

The N-alkyl aniline can form an iminium ion in the presence of a base, and thus can also undergo annulation with alkyne in the presence of FeCl₃ (Scheme 577). Indeed, a variety of substituted quinoline derivatives were reported by Liu's group.⁹⁷⁸

Scheme 577 Fused aromatic product formation via two-fold C–C bond formation.

8.1.3 Carbon–carbon/carbon–heteroatom bond formation. In 2009, Liu's group established that alkyl halides can be added across a triple bond in an iron-catalyzed reaction.⁹⁷⁹ Various benzyl bromide and benzyl chloride derivatives are activated by the Lewis acid FeCl₃, forming the benzylic cation (Scheme 578).

Scheme 578 Iron-catalyzed aryl bromination.

Electrophilic addition of this cation to alkyne results in the formation of a vinyl cation. The halide is then transferred from XFeCl₃⁻ to yield the alkenyl halide (Scheme 579). The styrene double bond can also be decorated with C–Cl and C–C bond formation in an FeCl₃-catalyzed reaction.⁹⁸⁰ Mechanistically, 1,3-dithiane in the presence of NCS is halogenated at the 2-position (Scheme 580), which forms two radicals in the presence of Fe(III). Sequential coupling of these radicals with styrene forms the product. The formation of the favoured benzylic radical possibly drives is towards observed regioselectivity.

Scheme 579 Addition of aryl halide across alkyne.

Scheme 580 In situ-generated alkyl halide addition to styrene.

Similarly, the addition of perfluoroiodides across terminal alkynes can be achieved (Scheme 581).⁹⁸¹ FeBr₂ has been used as a catalyst in this particular transformation in dioxane solvent at 60 °C. A comparable radical mechanism was speculated for this transformation. A series of cross-coupling reactions was performed by the authors to show the applicability of the transformation. FeBr₂ catalyzes the addition of acid chloride to alkynes and the formation of β-chloro vinyl ketones.⁹⁸² However a concerted mechanism has been proposed instead of radical. The chloroacylation reaction was further extended by Cheng's group with a broad substrate scope.⁹⁸³ The authors indeed support the concerted mechanism (Scheme 582) and predict that the favoured intermediate dictates the regioselectivity being halide substitution at the benzylic position.

Scheme 581 FeBr₂-Catalyzed perfluoroalkyl iodination.

Scheme 582 Chloroacylation of alkynes.

The FeCl₂-catalyzed carbonylation–peroxidation of alkenes by alkylperoxide and aldehydes was reported by Li and co-workers (Scheme 583).⁹⁸⁴ An alkoxy radical is catalyzed by Fe(II), consequently forming a carbonyl radical, which is trapped by TEMPO. Thus, radical attack on the alkene and subsequent interaction with another peroxide molecule drive the reaction forward. In addition to the diverse substrate scope, authors showed the transformation of a selected substrate to epoxide by treatment with DBU.

Scheme 583 Carbonylation–peroxidation of alkenes.

A porphyrin-based diiron complex was employed by Sorokin's group to achieve the hydroacylation of olefins in the presence of peroxide (Scheme 584).⁹⁸⁵ The electronic interplay between the two iron atoms the causes facile formation of an alkoxy radical, and subsequent radical additions result in hydroacylation.

Scheme 584 Diiron porphyrin-catalyzed C–C bond formation.

Similarly, Plietker's group showed that C–O and C–C bond formation can be realized in the alkoxy allylation of highly activated olefins (Scheme 585).⁹⁸⁶ An allylalkyl carbonate was used for this purpose in presence of Bu₄N[Fe(CO)₃(NO)] catalyst. The interaction of the allylalkyl carbonate with the catalyst eliminates CO₂ and forms an [Fe]-allyl complex together with an alkoxide ion. Nucleophilic attack of the alkoxide onto the activated olefin generates another carbanion, which reacts with [Fe]-allyl to form the product. However, this protocol fails with substituted allyls. A three-component reaction was then developed, where Boc-protected allyl alcohols were used as the allylic source and simple alcohols as the alkoxide source to obtain identical products. This methodology was also extended to phosphono-allylation using (MeO)(O)PH instead of alcohol.⁹⁸⁷

Scheme 585 Alkoxy allylation-activated olefins.

The synthesis of dihydrobenzofuran derivatives was reported by the groups of Pappo and Lei separately from phenol and olefins (Scheme 586).^988,989 In the latter case, the reaction shuts down in the presence of TEMPO and in the absence of DDQ, and thus the formation of a phenoxy radical was proposed. The phenoxy radical adds to the olefin aided by the iron catalyst to form the cyclized product, giving different substituted dihydrobenzofurans.

Scheme 586 Formation of dihydrobenzofuran via C–C and C–O bond formation.

N-Aryl-N-(2-alkynyl)toluenesulfonamides undergo cyclization in the presence of FeCl₃ under reflux conditions in DCE (Scheme 587).⁹⁹⁰ The alkyne activated by the iron catalyst undergoes 6-endo-dig cyclization to form an ionic species, from which the tosyl group leaves to yield the quinoline moiety. A variety of quinolines have been shown to be prepared using this method. Interestingly, when a structurally similar alkynyl amide was treated under similar conditions, spirocyclic pyrimidine was observed instead of the formation of a six-membered cycle (Scheme 587).⁹⁹¹ The iron-catalyzed synthesis of oxindoles has been achieved via the formation of C–S and C–C bonds in the reaction between N-alkyl–N-arylacrylamide and arenesulphinic acids.⁹⁹² The reaction proceeds through the formation of an ˙SO₂Ar radical under aerobic conditions. Subsequent attack on the acrylamide and cyclization construct differently substituted oxindoles. 1,4-Diphenyl-2-trifluoromethylbut-1-en-3-yne upon reaction with (RX)₂ (X = S, Se) provides poly-substituted naphthalenes (Scheme 588).⁹⁹³ Since (RX)₂ is known to be a good candidate as a radical generatorit was assumed that it can cyclize similar to the formation of quinoline. However, a radical route is expected instead of an ionic pathway, which was indeed observed as the reaction is quenched upon the addition of TEMPO.

Scheme 587 Cyclization of N-aryl-N-(2-alkynyl)toluenesulfonamides.

Scheme 588 Iron-catalyzed C–C and C–S/Se bond formation.

Deng and co-workers reported the synthesis of vinyl sulfides by reacting alkynes with sodium salts of arylsulphinates (Scheme 589).⁹⁹⁴ Fascinatingly, in the formation of tetra-substituted vinyl thioethers, both aryl and thioaryl groups are provided solely from sodium sulphinates; however, with uncontrolled stereoselectivity.

Scheme 589 Synthesis of vinyl sulphides.

8.1.4 Carboxylation and carbonylation. In an excellent report, Beller's group described the synthesis of succinimides from alkyne with CO and NH₃ (Scheme 590).⁹⁹⁵ The reaction proceeds through the formation of a metallacycle by the insertion of two equivalents of carbon monoxide followed by nucleophilic attack of ammonia to one of the –C=O bonds and then to the other carbonyl (Scheme 591). An optimum CO pressure is essential since high concentration deactivates the catalyst. A number of alkynes and primary amines are presented to be suitable for this transformation. The scope of this reaction was further extended to the synthesis of highly complex succinimides by combining it with Sonogashira coupling.⁹⁹⁶ Moreover, oxidative dehydrogenation of succinimides with DDQ give the corresponding maleimides also. In this regard, the synthesis of Himanimide A was performed with improved efficiency, and the first synthesis of Himanimide B was also reported.⁹⁹⁷

Scheme 590 Synthesis of succinimides via CO insertion.

Scheme 591 Mechanism for the synthesis of succinimides via CO insertion.

The same group carried out extensive optimization to achieve mono-carbonylation.⁹⁹⁸ Indeed, it was found that selective mono-carbonylation is controlled by a specific ligand (Scheme 592) and reduced CO pressure to 10 atm. The scope of cinnamides are diversified with respect to both N-substitution and olefin substitution.

Scheme 592 Mono CO insertion to Fe–C bond.

The iron-catalyzed synthesis of β-hydroxyesters was reported by Taniguchi and co-workers from alkenes and carbazates (Scheme 593).⁹⁹⁹ The hydrazine undergoes N₂ elimination to form an alkoxycarbonyl radical, the addition of which to alkene generates a tertiary radical. Trapping of this radical by atmospheric oxygen results in the desired β-hydroxyesters. Various aryl, alkynyl, bicyclic and heterocyclic substituted olefins undergo product formation. The iron-mediated carboxylation of styrenes can be achieved from CO₂ insertion (Scheme 594).¹⁰⁰⁰ The addition of a bis(arylimine)pyridine ligand gives the best result together with Grignard reagent. The Grignard reagent (EtMgX) helps to activate the styrene molecule and forms an α-Grignard reagent with the substrate via transmetalation. Subsequent CO₂ insertion gives the desired α-acid product. Surprisingly, reversal of selectivity is observed for ortho-methyl-substituted styrenes, presumably because of steric factors.

Scheme 593 Iron-catalyzed carboxylation of alkenes.

Scheme 594 Carboxylation of styrenes with CO₂.

Both Yu's and Du's groups independently reported the synthesis of alkylester-substituted oxindole from N-alkyl N-aryl acrylamides and carbazates via arylalkoxycarbonylation (Scheme 595).^1001,1002 This reaction uses FeCl₂·4H₂O together with TBHP in MeCN. A similar radical pathway is followed as that described for β-hydroxyester formation by carbazates; however, the termination step involves ring closing with the ortho-carbon center of the N-aryl group. Carbazates when react with 2-isocyanobiphenyl in the presence of Fe(acac)₂ and TBHP to produce phenanthridine-6-carboxylates.¹⁰⁰³ The use of a radical trapping agent stopped the reaction, and k_H/k_D was shown to be unity. Therefore, a similar radical mechanism can be proposed for this transformation also.

Scheme 595 Iron-catalyzed arylalkoxycarbonylation.

8.1.5 Ring-opening reaction. The catalytic activity of iron towards the ring opening of epoxides was first documented by Yamashita in 1988.¹⁰⁰⁴ However, it was found that other 3d metals such as Mn, Zn and Cu are superior to Fe. Later, it was found that FeCl₃ can be effective for the alcoholysis of epoxides.¹⁰⁰⁵ This reaction was presumed to proceed via a radical cation mechanism, where electron transfer from the epoxide to Fe(II) is followed by nucleophilic attack. The presence of a radical intermediate is also supported by a radical trapping experiment. The stereochemistry consistently remains trans; however, the regioselectivity is dependent on the substituents present on the epoxide. Moreover, a silica-supported FeCl₃ catalyst also showed similar activity with a number of nucleophiles such as halides, hydroxides and nitrates in addition to alkoxides.¹⁰⁰⁶ It was further observed that compared to other metal catalysts, the heterogeneous catalyst showed high enantioselectivity with chiral epoxides.

Asymmetric ring opening of meso-epoxides with anilines was reported by Ollevier's group for the enantioselective synthesis of 2-aminols.^1007,1008 An iron(II)-per chlorate [Fe(ClO₄)₂] catalyst together with Bolm's ligand is effective for this transformation to obtain up to 90–96% ee (Scheme 596). Characterization of the active catalyst shows that the bipyridine-bound iron probably co-ordinates with the epoxide-oxygen and dictates the addition of amine through steric interference.

Scheme 596 Asymmetric ring opening of epoxides.

Meso-aziridines react with amines in the presence of FeCl₂(mep) and AgSbF₆ to give diamines. Various N-substituted aziridines and anilines are compatible with this reaction, providing excellent yields (Scheme 597).¹⁰⁰⁹

Scheme 597 Ring-opening reaction of meso-aziridines.

A very interesting iron-catalyzed synthesis of quinoline from aniline and styrene oxide via C–O and C–C bond cleavage in tandem was presented by Wang and co-workers (Scheme 600).¹⁰¹⁰ It was proposed that the amine attacks the epoxide, which results in C–O bond breakage to form an enamine. Addition of another epoxide followed by ortho C–H bond activation of aniline and C–C bond cleavage forms a metallacycle. Reductive elimination and subsequent dehydrogenation give the final product. Despite the complicated mechanism of this reaction, is believed to be operational, and a good number of quinoline derivatives can be synthesized.

Propargyl epoxides react with Grignard reagent in the presence of 5 mol% Fe(acac)₃ to provide allenols (Scheme 598).¹⁰¹¹ Both terminal and internal alkynes show similar reactivity. It is evident that this reaction is consistent towards forming syn allenoles, which is opposite to that observed for Cu catalysis in the literature.

Scheme 598 Iron-catalyzed ring opening of propargyl epoxides.

This is probably because of the metal co-ordination with oxygen during the transfer of the nucleophile. This reaction was also effectively utilized in the total synthesis of amphidinolide X.^1012,1013

The activated vinyl cyclopropane ring can be opened in the presence of a suitable Grignard reagent (Scheme 599).¹⁰¹⁴ A secondary alkylmagnesium bromide works best for the transformation. The carbanion generated in the process can also be trapped by allyl bromide or propargyl bromide. Although reasonable yields are obtained, the E : Z ratio is not consistent. Amusingly, alkynyl cyclopropane also provides allene under the conditions. Plietker et al. also observed similar reactivity of the allylic C–C bond of vinylic cyclopropanes; however, they utilized the combination of TBAFe and NHC ligands (Scheme 601).¹⁰¹⁵ The iron-catalyzed ring opening of 7-oxabicyclo[2.2.1]hept-2-enes was performed by Irie's group to obtain 5,6-cis-disubstituted cyclohexa-1,3-dienes (Scheme 602).¹⁰¹⁶ The monoene product obtained after ring opening in the iron(III) hydroxide oxide-catalyzed reaction was further transformed to the diene by treatment with Zn. The FeCl₃-catalyzed ring opening of tetrahydrofuran derivatives was documented by Sajiki's group (Scheme 603).¹⁰¹⁷ They have trapped the ring opening intermediate with different nucleophiles to obtain the corresponding substituted alcohols.

Scheme 599 Ring opening of activated vinyl cyclopropanes.

Scheme 600 Synthesis of quinoline from aniline and styrene oxide via C–O and C–C bond cleavage.

Scheme 601 TBA-Fe-catalyzed ring opening of vinyl cyclopropanes.

Scheme 602 Iron-catalyzed ring opening of 7-oxabicyclo[2.2.1]hept-2-enes.

Scheme 603 Ring opening of tetrahydrofurans.

8.1.6 Ring expansion. In 2005, Hilt and co-workers showed that FeCl₂ can catalyze the ring expansion of arylepoxides to form tetrahydrofuran derivatives in the presence of Zn as the reducing agent and obtained moderate chemo and regio-selectivity (Scheme 604).¹⁰¹⁸ It was observed that in the absence of either iron or zinc, the reaction does not proceed. Thus, a reduced form of the iron catalyst is the active catalyst, presumably in the 1+ oxidation state. The epoxide accepts an electron from Fe(I) via single-electron transfer (SET) and reacts with the olefin. Subsequent back-electron transfer to Fe(II) results in the formation of the carbocationic intermediate, which tends to undergo cyclization. The authors also showed the one-step synthesis of the natural product calyxolane using this methodology. Moreover, intramolecular ring expansion provides interesting bicyclic compounds. Later, the same group showed that the use of salen ligands considerably improved the yield of the reaction and the diastereoselectivity of the bicyclic products.^1019,1020N-Tosylated aziridins also showed similar reactivity with acetylenes to form 2-pyrroline derivatives (Scheme 605).¹⁰²¹ However, no reducing agent is required for this transformation, and thus Fe(III) is supposedly the active catalyst. Interaction of the aziridine with FeCl₃ forms a zwitterionic intermediate, to which aryl acetylene is added to extend the length of the zwitterion. Spontaneous cyclization of this intermediate yields the ring-expanded product. A number of 2,4-diaryl-substituted 2-pyrrolines have been synthesized using this protocol. Ring expansion of activated cyclopropanes with isothiocyanates was reported by Li and co-workers.¹⁰²² Both vinyl and aryl cyclopropanes were found to be compatible with the [3+3] cycloaddition of R–N=C=S to the zwitterionic intermediate of the cyclopropane (Scheme 606).

Scheme 604 Ring expansion of arylepoxide.

Scheme 605 FeCl₃-Catalyzed ring expansion of aziridines.

Scheme 606 [3+3] cycloaddition of R–N=C=S to the zwitterionic intermediate of cyclopropane.

Yoon and co-workers presented that iron-catalyzed ring expansion is also feasible with oxaziridines (Scheme 607).¹⁰²³ Styrenes react with N-sulfonyl oxaziridines in the presence of Fe(acac)₃ in acetonitrile to form oxazolidines in excellent yields. It was found that the use of Fe(NTf₂)₂ in conjunction with a chiral 4,5-dinaphthyl-substituted bis(oxazoline) ligand provides enantioselective transformation with high enantiomeric excess.¹⁰²⁴ Moreover, chiral 1,2-hydroxyamine can be obtained by the straightforward ring opening of these oxazolidines.

Scheme 607 Ring expansion reaction of oxaziridine.

Iron-catalyzed ring expansion of aziridines with isoselenocyanates provides iminoazoselenolidine in water medium (Scheme 608).¹⁰²⁵ This reaction is also believed to proceed via the [3+2] cycloaddition mechanism. A plethora of differently substituted iminoazoselenolidines have been synthesized. Fascinatingly, substitution of Se with N, O or S does not alter the reactivity and different classes of heterocycles can be obtained. In another report, Waser and co-workers established the [3+2] annulation of aldehydes to donor–acceptor cyclopropanes (Scheme 608).¹⁰²⁶ The use of phthalimide and gem-diester as the donor–acceptor combination was observed to be the best for the formation of tetrahydrofurans.

Scheme 608 Ring expansion of aziridine and cyclopropane.

Various iron complexes have been reported for the synthesis of cyclic carbonates from epoxides with carbondioxide.^1027–1033 Among them, triphenylamine-based iron complexes have been extensively studied and successful towards the catalytic ring expansion of epoxides with CO₂. Kleij and co-workers synthesized an iminophenol-based complex, which in conjunction with NBu₄X catalyzes the formation of dioxolanones. Döring and co-workers showed that the well characterized tetradentate ligated complex can also carry out this transformation with a high turnover number in solvent-free conditions (Scheme 609).

Scheme 609 Synthesis of cyclic carbonates from epoxides.

8.2 Cycloaddition

The iron-catalyzed cyclopropanation reaction was first investigated with iron(II)porphyrin systems.¹⁰³⁴ Styrenes were found to be highly susceptible towards [2+1] cycloaddition with diazo compounds such as EDA (Scheme 610). It is believed that the reaction proceeds via the formation of Fe-carbene species that interacts with olefin to form a radical intermediate, which was also supported by secondary KIE. The free rotation of the radical allows the opportunity to minimize steric hindrance, and hence the trans-product is obtained in a major amount, although a few anomalies are also observed. For obvious reasons, the ratio depends on the steric factors of substituents on the porphyrin ring and diazo compound.¹⁰³⁵ Lowering the temperature also significantly enhances the trans-selectivity. For instance, in the cyclopropanation of styrene with EDA with (TTP)Fe, the trans/cis ratio significantly changes from 8.8 : 1 to 29 ± 2 upon changing the temperature from room temperature to −78 °C. In a comparative study, Woo and co-workers found that (tmtaa)Fe and (saldach)Fe show poorer reactivity compared to (TTP)Fe; however, the result for (tmtaa)Fe slightly improved with p-tolyldiazomethane.¹⁰³⁶

Scheme 610 [2+1] cycloaddition of styrene with diazoalkane.

Nguyen and co-workers developed μ-oxo-bis[(salen)iron(III)] complexes to catalyze the cyclopropanation reaction from diazo compounds (Scheme 611).^1037,1038 These air-stable catalysts do not require an inert atmosphere like the previous catalysts. A fraction of the diazo reagent first reduces the iron(III)–salen dimer to iron(II)–salen species, which again reacts with diazoalkane to form an Fe–carbene intermediate. The formation of ethyl glyoxylate in the process of catalyst reduction with EDA can be spectroscopically detected. It was observed that substitution on the ligand does not have an adverse effect of the reactivity, but the use of an internal styrene causes the yields to decrease drastically compared to terminal styrenes.

Scheme 611 μ-Oxo-bis[(salen)iron(III)]-catalyzed cyclopropanation.

Lai and co-workers used the Halterman iron porphyrin [P*Fe(Cl)] to achieve asymmetric cyclopropanation (Scheme 612).¹⁰³⁹ The catalyst provides moderate trans-selectivity and reasonable enantiomeric excess of the trans-product. The presence of the carbene intermediate can be detected spectroscopically. The Hammett study suggested that the carbene intermediate may be slightly electropositive at the carbene center and the benzylic position may be partially cationic in the transition state. Interestingly, donor solvents such as THF increases the trans-selectivity probably through co-ordinating to the iron center at the sixth position. A similar asymmetric reaction was reported by Simonneaux's group with 2,2,2-trifluorodiazoethane to obtain trans-1-trifluoromethyl-2-arylcyclopropane.¹⁰⁴⁰ The catalyst was also transformed into a water-soluble catalyst by sulphonate substitution on the ligand and a comparable result was obtained.¹⁰⁴¹

Scheme 612 Halterman iron porphyrin-catalyzed asymmetric cyclopropanation.

Chiral C1 and C2-2,2′:6′,2′′-terpyridine iron complexes can catalyze asymmetric cyclopropanation reactions effectively.¹⁰⁴² The native chloro-co-ordinated complex is reluctant towards catalysis, and thus requires treatment with AgOTf prior to the reaction. The bulkiness of the substitution on the ligand has a positive effect only up to a certain extent. However, unlike previous cases, a U-shaped Hammett plot was observed. A DFT study on cyclopropanation with Cp(CO)(L)Fe=CHR revealed that there are two possible pathways that the metal-carbene can add to the olefin: (1) co-ordination of ethene to iron, gradual interaction with the iron–carbene bond to form a 4-membered metallacycle and subsequent reductive elimination, and (2) direct attack of the ethene double bond on the carbene carbon (Scheme 613).^1043,1044

Scheme 613 Two possible pathways for iron-catalyzed cyclopropanation.

Carreira's group in 2010 developed the cyclopropanation of styrenes by in situ-generated F₃CCH carbene from F₃CCH₂NH₂·HCl in aqueous medium (Scheme 614).¹⁰⁴⁵ The reaction is best catalyzed by 3 mol% of [Fe(TPP)Cl] in water to obtain trans-1-trifluoromethyl-2-arylcyclopropanes in excellent yields and exclusively trans-product. Later, this protocol was extended to synthesize trifluoromethyl-substituted alkynyl and vinylcyclopropanes.¹⁰⁴⁶ Remarkably, only the terminal double bond undergoes cyclopropanation and a single trans-isomer is obtained. A similar approach has been also utilized to synthesize arylcyclopropyl esters via in situ carbene formation from EtO₂CCH₂NH₃Cl.¹⁰⁴⁷ However, only the maximum of 10 : 1 trans-selectivity has been obtained in this instance.

Scheme 614 Iron–porphyrin-catalyzed cyclopropanation.

N-Methyl-N-nitroso-p-toluenesulfonamide in 6 M KOH can form diazomethane, which was used as an advantage by Carreira's group to add methylene across the double bond to synthesize simple cyclopropanes.¹⁰⁴⁸ Although the use of 6 M KOH left limited choices for catalyst, the previous best catalyst [Fe(TPP)Cl] is also efficient for this transformation. A similar strategy was also reported by Werz and co-workers using N-methyl-N-nitroso-m-carboxyphenylsulfonamide as the diazomethane precursor (Scheme 614).¹⁰⁴⁹

To improve the stereoselectivity, Gallo and co-workers synthesized an exotic iron–porphyrin complex with C2 symmetry.¹⁰⁵⁰ A TOF of 120 000 h⁻¹ was obtained with mere 0.005 mol% catalyst loading for the cyclopropanation of α-methyl styrene with EDA. Moreover, >99 : 1 trans-selectivity was observed with an enantiomeric excess of up to 87%.

An analogous iron-catalyzed aziridination reaction via [2+1] cycloaddition of nitrene and alkene by [Fe(TPP)Cl] was documented by Mansuy and co-workers in 1984.¹⁰⁵¹ However they showed the superiority of the corresponding Mn complex over the iron complex in most instances. [Fe(TPP)Cl]-catalyzed aziridination was thoroughly catalyzed by Zhang's group using bromamine-T as the nitrene source (Scheme 615).¹⁰⁵² The reaction is not restricted to only styrenes, but different cyclic and acyclic olefins have also been shown to undergo the nitrene transfer reaction. It is believed that bromamine-T first reacts with [Fe(TPP)Cl] to form Fe = nitrene, which interacts with olefin to provide the final product. Interestingly, structurally similar iron–phthalocyanines have also been found to be equally effective in carrying out the aziridination of styrene derivatives and cyclohexene.

Scheme 615 Iron–porphyrin-catalyzed aziridination.

Hossain and co-workers introduced a chiral iron-pybox complex in order to achieve chiral aziridination.¹⁰⁵³ Interestingly, they used N-benzylideneaniline as a substrate and EDA as a carbine source for the formation of aziridine (Scheme 616). Although they could induce chirality, the yields and enantiomeric excess were poor. The experimental and DFT studies carried out by Halfen's group on nitrene transfer aziridination by various non-heme iron complexes revealed that there is more than one pathway involved, and the most prominent one may be the formation of a four-membered metallacycle similar to carbene chemistry.¹⁰⁵⁴

Scheme 616 Asymmetric aziridination with iron–pybox complex.

Recently, Latour, Maldivi and Maiti reported a rigorous mechanistic investigation on the non-heme iron complex-mediated aziridination of styrenes by means of both experiment and computation.¹⁰⁵⁵ It was found that the reactivity of these iron-nitrene complexes is dependent on the electron affinity of the active species, where the higher the electron affinity, the higher tendency for attack on the double bond. Thus, [(2PyN2Q)Fe^IV(NTs)]²⁺ was found to be a better catalyst than [(N₄Py)Fe^IV(NTs)]²⁺ for this purpose. The reason being presence of quinoline in the former results in weaker ligation by the nitrogen, and hence increases the electron affinity of iron.

Bolm and co-workers were able to optimize the aziridination of olefins using iron triflate as a catalyst (Scheme 617).¹⁰⁵⁶ In the presence of 5 mol% of Fe(OTf)₂, various styrenes and cyclooctene provide up to 90% yield in MeCN. Later, it was found that the use of ethylmethylimidazolium bis[(trifluoromethyl)sulfonyl]amide improved the reaction drastically, for instance styrene yielded >95% of the product compared to 82%.¹⁰⁵⁷ In this case, the chiral pybox ligands also show potential chiral inductivity; however, with very low ee.

Scheme 617 Iron triflate-catalyzed aziridination of olefins.

The iron-catalyzed [2+2] cycloaddition of imines with ketenes was demonstrated by Fu's group in 2005 (Scheme 618).¹⁰⁵⁸ A chiral iron complex was used to obtain enantioselective β-lactams. However, the most intriguing part is that the cis and trans selectivity were highly dependent of the substitution at the imine nitrogen, and while the N-tosyl imine gave the cis product majorly, N-triflyl showed higher cis selectivity. Thus, two different mechanisms are thought to occur, originating from the different stabilities of the tautomerized forms of the imines. Since N-tosyl imine prefers the neutral form, the ketene attacks the imine, and because the more stable conformation of the N-triflyl imine is the ionic form, the reverse attack may be operative.

Scheme 618 [2+2] cycloaddition of imine with ketene.

Chirick and co-workers developed the iron complex (iPrPDI)Fe(N₂)₂ {iPrPDI = 2,6-(2,6-iPr₂C₆H₃NCMe)₂C₅H₃N}, which catalyzed the [2+2] cycloaddition of α,ω-dienes to obtain the corresponding bicyclic compounds (Scheme 619).¹⁰⁵⁹ A similar type of complex was later employed for the formation of vinyl cyclobutane from the cycloaddition of butadiene and ethylene.¹⁰⁶⁰ It was proposed that to the co-ordinated butadiene, ethylene adds oxidatively to form crystallographically characterized intermediate X. Subsequent reductive elimination yields the final product. In another report, Waser and co-workers documented the FeCl₃·Al₂O₃-catalyzed cycloaddition of enimides and alkylidene malonates to obtain β-amino acid cyclobutane derivatives.¹⁰⁶¹

Scheme 619 [2+2] cycloaddition of α,ω-dienes.

The synthesis of cyclopentenones from alkenes and/or alkynes via [2+2+1] cycloaddition catalyzed by Fe(CO)₅ was first reported in 1953. Since then, numerous reports have been published on studies centred on this reaction and its application towards organic synthesis.^1062–1068 The reaction proceeds via ligand substitution by two alkynes (Scheme 620). Oxidative coupling of the co-ordinated alkynes then forms a five-membered metallacycle. Insertion of one CO group expands the ring size to six, and subsequent reductive elimination provides the desired product. [2+2+1] cycloaddition can also be applied to the cyclization between ketamine, alkene and carbon monoxide.

Scheme 620 [2+2+1] cycloaddition catalyzed by Fe(CO)₅.

Itoh's group reported the [3+2] cycloaddition of 1,4-quinones and styrenes to obtain 2,3-dihydrobenzofuran derivatives (Scheme 621).¹⁰⁶⁹ The most suitable catalyst was alumina-supported Fe(ClO₄)₃ in acetonitrile. Later, it was observed that ionic liquids have an adverse effect on the reaction, and accordingly improved the efficiency significantly. The authors proposed a mechanism for the transformation, where the Fe³⁺ ion oxidizes the styrene moiety to form a radical cation and Fe²⁺. This Fe²⁺ in turn reduces quinone to deliver a radical anion, which reacts with the previous intermediate to form a new 5-membered ring. The ionic behaviour of the intermediate is also supported by the anion dependency of the ionic liquid. An asymmetric [3+2] cycloaddition between diphenylnitrone and methacrolein was reported with a chiral iron-cyclopentadienyl base catalyst.¹⁰⁷⁰ Although isoxazolidines are formed in decent yields, the regioselectivity is poor in most cases. In another excellent method, Bolm and co-workers reported the synthesis of tetrazoles from Ar-CN and TMS-N₃.¹⁰⁷¹ Fe(OAc)₂ catalyzed the reaction in DMF/H₂O at 80 °C to provide excellent yields of tetrazole derivatives.

Scheme 621 Iron-catalyzed [3+2] cycloaddition.

Wang and co-workers documented the cycloaddition of azomethine ylides and dialkyl maleates in the presence of FeCl₂ and a chiral bidentate ligand.¹⁰⁷² The imino ester is believed to co-ordinate with the metal center to form an azomethine ylide dipole followed by attack from maleates. The chiral ligand controls the orientation of the second edition to provide chiral pyrrolidines. Interestingly, maleimides can also be reacted under the protocol to form bicyclic chiral heterocycles. A similar asymmetric [3+2] cyclization of isocyanoesters with azodicarboxylates was also observed in the presence of an Fe(acac)₃ catalyst.¹⁰⁷³

Okamoto's group extensively optimized the cyclotrimerization of triynes (Scheme 622).^1074–1076 Both FeCl₃ and FeCl₂ showed similar reactivity towards the [2+2+2] cycloaddition in the presence of a suitable NHC ligand. The reaction initiates with the oxidative cyclization of two alkynes followed by insertion to the last alkyne. Finally, reductive elimination provides the aromatic end product. This procedure can be extended towards the synthesis of biaryls from hexaynes.

Scheme 622 [2+2+2] cycloaddition of triynes.

9. Elimination and Isomerization

9.1 Elimination

The first iron-catalyzed elimination reaction was reported by Beller's group.¹⁰⁷⁷ [Et₃NH][HFe₃(CO)₁₁] in the presence of silanes catalyzes the formation of nitriles from amides (Scheme 623). Silane swaps amide hydrogens to form bis(silyl)amide, which is in equilibrium with N,O-bis(silyl)imidate, dominated towards the latter. Cyanide then forms upon elimination of disiloxane. Different substituted aryl amides, benzothiophenes, furans and even vinyl amides are transformed to their corresponding nitrile products efficiently. Later, Enthaler drastically simplified the reaction conditions and showed that the reaction proceeds excellently in the presence of FeCl₂·4H₂O and N-methyl-N-(trimethylsilyl)trifluoroacetamide at a lower temperature.¹⁰⁷⁸

Scheme 623 Iron-catalyzed transformation of amide to cyanide.

The dehydration of fructose and sucrose has also been shown to be catalyzed by FeCl₃–Et₄NBr to give 5-hydroxymethylfurfural (Scheme 624).¹⁰⁷⁹ However the same method results in very poor yield for glucose. This indicates ketose is more susceptible to undergo dehydration than aldose under the reaction conditions. For the production of furfural from xylose, a biphasic system was used. FeCl₃·6H₂O, NaCl and xylose were employed in aqueous medium combined with 2-methyltetrahydrofuran as the second phase to obtain a yield of up to 70%.¹⁰⁸⁰ Most interestingly, crude lignocellulose provided furfural in the organic phase at a rate of 3.5 g L⁻¹ h⁻¹. Later, the synthesis of 5-hydroxymethyl-2-furfural from fructose was scaled up using an imidazolium-attached polystyrene resin-supported NHC ligand and iron salt.¹⁰⁸¹ The bilayer extraction technique was utilized to obtain up to 73% yield and the catalyst was found to be reusable also.

Scheme 624 Dehydration of sugar molecules.

Ryu's group in 2012 developed the iron-catalyzed decarbonylation of aliphatic carboxylic acid to form olefins (Scheme 625).¹⁰⁸² It was observed that FeCl₃ in the presence of KI, Ac₂O, 1,5-bis(diphenylphosphino)pentane (DPPPent) and CO catalyzes the reaction. However, although FeI₂ produces a similar result, it fails in the absence of KI. Moreover, 20 atm pressure of CO is also required for the reaction to proceed. Thus, Fe(CO)_mI_n has been proposed to be the active species, which interacts with anhydride formed from Ac₂O and the substrate. Subsequent CO removal and β-hydride elimination result in α-olefins. The dehydration of propargyl alcohols can be achieved in an FeCl₃-catalyzed reaction in the presence of a 1,2,3-triazole ligand to form enynes (Scheme 626).¹⁰⁸³ The chemoselectivity is controlled by the specific ligand by tuning the electronics of the iron center. Remarkably, they also synthesized very fancy 1,4-enediynes using this methodology.

Scheme 625 Decarbonylation of acids.

Scheme 626 Dehydration of propargyl alcohols.

9.2 Isomerization

In 1962, while working with π-ally iron carbonyl complexes, Pettit and co-workers found that iron carbonyl complexes can convert allylic alcohol to carbonyl compounds via the formation of an allyl-Fe intermediate.¹⁰⁸⁴ Logan and co-workers in 1967 showed several examples of allyl alcohol isomerization using Fe(CO)₅ as the catalyst under the combination of heating and radiation (Scheme 627).¹⁰⁸⁵ Various groups studied the mechanism in-depth and showed different substrate compatibility using iron–carbonyl complexes under UV-irradiation.^1086,1087 Among them, Grée's group pioneered not only Fe(CO)₅-catalyzed enol–carbonyl isomerization, but various synthetic utilizations of this reaction.^1088–1090 As described by Grée et al., the pentacarbonyliron complex undergoes two-CO ligand dissociation in the presence of light to form an olefin co-ordinated complex. Then a shift in the double bond takes place via the formation of a metal–hydride–allyl complex. The resultant α-enol undergoes rapid tautomerization into the corresponding saturated carbonyl compound. Both primary and secondary cinnamyl alcohols, and conjugated allyl alcohols can be converted to carbonyls.

Scheme 627 Isomerization of allyl alcohol to carbonyl.

The formation of the enol intermediate triggered investigation of aldol-condensation.^1091,1092 Indeed it was found that in the presence of an external aldehyde, the enol intermediate can be trapped to produce the aldol product in the presence of Fe(CO)₅ catalyst, although the regioselectivity has been found to be substrate specific. A computational study showed that the reaction between the free enol with the carbonyl is the least energy demanding. Both 1,2- and 1,1-di-substituted disubstituted alcohols are compatible under the reaction conditions; however, sterically hindered carbonyls gave lower yields. Thus, the catalyst was modified to (bda)Fe(CO)₃ and (COT)Fe(CO)₃, which are superior to the pentacarbonyliorn complex. Moreover, carbonyls containing attached protected amine groups and isolated double bonds could also be treated for condensation with the above-mentioned catalysts.

In addition, Fe(CO)₅ can catalyze intramolecular condensation following isomerization. For example, vinylic furanose derivatives can be converted into cyclopentenones.¹⁰⁹³ It is unclear whether isomerization or ring opening takes place first (Scheme 628), but both paths lead to the formation of an acyclic enol-aldehyde intermediate, which undergoes intramolecular aldol reaction, followed by crotonization, leading to the product. Similarly, 3-vinyl-1,3-dihydroisobenzofuran-1-ol can undergo ring opening, isomerization and condensation to form indenone.¹⁰⁹⁴ Moreover, this strategy has also been utilized to synthesize gabosines and 4-methyl-3-piperidones.^1095,1096 Renaud and co-workers also showed that a tetra(isonitrile)-based iron complex can catalyze trifluoromethylated allyl alcohols into the corresponding carbonyl compounds.¹⁰⁹⁷

Scheme 628 Isomerization of vinylic furanose derivatives.

In 1966, Davison and co-workers showed that in polyunsaturated fatty acids with isolated double bonds, when treated with Fe(CO)₅ under high temperature of around 180 °C, isomerization takes place to form conjugated di and triene co-ordinated to Fe(CO)₃.¹⁰⁹⁸ The conjugated polyenes can be isolated upon decomplexation. Similarly, A-prostaglandins with separate double bonds can be converted into C-prostaglandins via triiron dodecacarbonyl-catalyzed isomerization (Scheme 629).¹⁰⁹⁹ Moreover, the reactivity of the diene carbonyl-iron can be utilized to realize various other derivatives. Waegell and co-workers found that 4-vinylcyclohexenes can be converted to cyclohexadienes in an Fe(CO)₅-catalyzed reaction.¹¹⁰⁰ Periasamy et al. reported that the combination of Na₂Fe(CO)₄/CuCl or Na₂Fe(CO)₄/BrCH₂CH₂Br can isomerize terminal olefins into the corresponding internal olefins at room temperature.¹¹⁰¹ The deuterium scrambling pattern of α-deuterated 3-ethyl-1-pentene with Fe₃(CO)₁₂ revealed that both metal hydride addition-elimination and π-allyl metal hydride are involved in the isomerization; however, the extent of each mechanism depends on the catalyst system.¹¹⁰²

Scheme 629 Iron carbonyl-catalyzed isomerization of dialkenes.

Wangelin and co-workers developed another method to isomerize alkenes to the corresponding styrene derivatives using 5 mol% Fe(acac)₃ in the presence of PhMgBr as the reducing agent (Scheme 630).¹¹⁰³ 3-Allyl pyridine and terminal aliphatic alkenes are also transformed into internal isomers. Treatment of cis-stilbene under the same reaction conditions gives trans-stilbene in 97% yield. More interestingly, allylated products formed from arylbromides can be in situ isomerized. Another reaction condition was developed for similar reactivity, where Fe₃(CO)₁₂ was used as a catalyst in the presence of KOH/H₂O.¹¹⁰⁴

Scheme 630 Isomerization of alkenes to corresponding styrene derivatives.

Hayashi and co-workers reported that Fe–Cu cooperative catalysis can isomerize secondary Grignard reagents into primary Grignard reagents (Scheme 631).¹¹⁰⁵ When 2-hexyl magnesium bromide was treated with FeCl₃/CuBr/PBu₃, followed by chloro(phenyl)silane treatment, silylation at the 1-position occurs in 83% with >99% selectivity. The reaction almost stops in the absence of both catalysts. It was proposed that oxidative addition followed by β-hydride elimination and subsequent olefin insertion form alkyliron species, which undergoes trans metalation with CuRMgBr. Finally, reductive elimination from the Cu center gives the isomerized product.

Scheme 631 Isomerization of Grignard reagents.

The FeBr₂-catalyzed [1,2]-shift of α-arylaldehydes was reported by Martin's group (Scheme 632).¹¹⁰⁶ It was found that for tertiary α-arylaldehydes upon treatment with FeBr₂ in toluene under heating condition, a [1,2]-shift is observed. However, the nature of the shifting group is highly dependent on the nature of the aryl group. If the aryl group can sufficiently stabilize a carbocation, an aliphatic group migrates, otherwise migration of the aryl group itself is observed.

Scheme 632 FeBr₂-Catalyzed [1,2]-shift of α-arylaldehydes.

9.3 Cycloisomerization

Takacs’ group and a few others extensively studied the iron-catalyzed intramolecular carbocyclization of triene ethers.^1107–1114 It was observed that both the nature of cyclization and stereochemistry are highly substrate dependent. For instance, the triene substrate (Scheme 633) in the presence of 10 mol% bpy·Fe(0) in benzene gives the five-membered product in a major amount; however, the substrate triene diether under the same conditions gives the 6-membered product. Similarly, depending on the substituent R² being hydrogen or alkyl, cis or trans selectivity is observed. Several natural products such as mitsugashiwalactone, isoirkdomyrmecin, and protoemetinoi have also been synthesized using this protocol as one of the key steps.^{1110,1112,1114} Mechanistically it was proposed that all three alkenes co-ordinate to the iron center followed by oxidative cyclization. Finally, β-hydride elimination and subsequent reductive elimination provide the end product (Scheme 634). Interestingly, the amine substrate also undergoes similar cyclization to form a bicyclic compound in the presence of catalytic Fe(acac)₃ and bioxazoline ligand (Scheme 635).¹¹⁰³

Scheme 633 Carbocyclization of trienes.

Scheme 634 Mechanism of carbocyclization of trienes.

Scheme 635 Cyclization of aminotriene.

Fürstner and co-workers developed the Fe(0)-catalyzed cycloisomerization of enynes in 2005.¹¹¹⁵ [CpFe(C₂H₄)₂][Li(tmeda)] was found to be best for the transformation, giving excellent yields. A series of 5, n (n = 5, 6, 7, 8, 10, 12) bicyclic molecules were synthesized together with a few exocyclic cyclopentane derivatives. Another method for the synthesis of exocyclic double bond-substituted cyclopentanes was described by Lee and co-workers via the Conia-ene type cyclization of 2-alkynic 1,3-dicarbonyls catalyzed by FeCl₃ (Scheme 636).¹¹¹⁶ The mechanism was presumed to proceed via the formation of an enol-alkyne iron complex and subsequent stereospecific 5-exo-dig cyclization.

Scheme 636 Iron-catalyzed 5-exo-dig cyclization.

The asymmetric version was later reported by White's group using a well-designed iron–salen complex.¹¹¹⁷ Various α-alkynyl-β-keto esters were converted into Conia-ene cyclized product with excellent ee. Thiophenes substituted at the 3-position give fused heterocycles with α,β-unsaturated ketone via Nazarov cyclization in the presence the FeCl₃ catalyst (Scheme 637).¹¹¹⁸ Similar nitrogen-containing heterocycles were also reported by Itoh's group; however, 2-substituted pyrroles were used as the substrate.¹¹¹⁹ Later, it was found that 2-substituted indoles, benzofurans and benzothiophenes showed similar reactivity.¹¹²⁰ The asymmetric version of the iron-catalyzed Nazarov catalyst was developed by the same group using a chiral 2,6-dioxazoline-substituted pyridine ligand.¹¹²¹ The cyclization reaction was effectively utilized in the total synthesis of xanthocidin.¹¹²²

Scheme 637 Synthesis of fused heterocycles.

9.4 Intramolecular ring expansion

In the transformation of epoxide to tetrahydrofuran via the addition of an external olefin,¹¹²³ epoxyalkenes are supposed to provide bicyclic compounds upon intramolecular ring expansion. It was found that Fe(salen) catalyzes the cyclization of simple epoxyalkenes separated by three –CH₂– groups to form hexahydrocyclopenta[c]furans, whereas incorporation of an oxygen atom in between provides tetrahydrofuro[3,4-c]furans (Scheme 638).^1124,1125 Electron-rich arene substitution at the epoxide end shows higher reactivity, while enhanced diastereoselectivity is observed for ketone and ester substitution.

Scheme 638 Tetrahydrofuro[3,4-c]furans via intramolecular ring expansion.

In 2009, Jiao and co-workers developed the iron-catalyzed ring expansion of alkynylcyclopropyl alkanols to cyclobutanols (Scheme 639).¹¹²⁶ The catalyst loading of 10 mol% of FeCl₂ in O₂ atmosphere works best for this transformation. It is presumed that is Fe(II) oxidized to Fe(III) in the presence of molecular oxygen, which co-ordinates with alkyne and abstracts hydroxide to form a cyclopropylmethyl cation. Subsequent 1,2-alkyl migration and recombination of the hydroxide provides the final product. Although to a lesser extent, the trans geometry is dominant, this is probably due to attack of hydroxide from the less hindered side.

Scheme 639 Ring expansion of alkynylcyclopropyl alkanols to cyclobutanols.

Zheng's group found that the synthesis of indole derivatives from vinyl nitrenes via direct amination to an aromatic C–H bond can be effected with the FeCl₂ catalyst compared to previously reported Pd and Rh catalysis (Scheme 640).¹¹²⁷ The Fe(II) species first co-ordinates with vinyl nitrene to form an iron-azirine complex. Subsequently, C–N bond cleavage results in an Fe-nitrene complex, which attacks the aromatic C–H bond and indole formation is realized via five-centered 6-π electrocyclization. Ketone-substituted vinyl nitrenes also undergo cyclization in the presence of FeCl₃ under an inert atmosphere to form isoxazoles.¹¹²⁸ A similar mechanism can explain this reaction, where the Fe–nitrene interacts with the carbonyl group instead of the carbocation.

Scheme 640 Synthesis of indole derivatives from vinyl nitrenes.

10. Iron-catalyzed substitution reactions

10.1 Nucleophilic substitution reaction

Nucleophilic substitution is one of the fundamental reactions in organic chemistry. It is an essential tool to make carbon–carbon and carbon–heteroatom bonds in a regio/stereo/chemo and diastereoselective manner.¹¹²⁹ In the classical organic chemistry, stoichiometric organic/inorganic reagents were used for S_N reactions. However, the use of transition metal catalysts has revolutionized this field. It has enabled to achieve the chemo, regio and stereoselective synthesis in a predictable manner. The earliest example of iron-mediated S_N reaction was the iron-catalyzed Friedel–Crafts alkylation.¹¹³⁰ The initial developments of iron-promoted S_N reactions were well documented by Bolm in 2004.^3h Thereafter, a comprehensive outline of the iron-catalyzed S_N reactions was documented by Knölker in 2015.^3l Thus, herein we have summarized the iron-catalyzed benzylic and allylic substitutions up to the Knölker reports in a tabular way and then demonstrate the recent reports elaborately. The S_N reactions require one electrophile-bearing leaving group and a nucleophile. The incoming nucleophile in general attacks the nucleophilic carbon of the electrophile and forms a bond with the concomitant elimination of the leaving group. Depending on the steric and electronic properties of the electrophile and the conditions, the reaction proceeds via three different pathways, namely S_N1, S_N2 and S_N2′.^1129a In the S_N1 pathway, the substrates undergo ionization in the presence of strongly acidic condition and generate a stable carbocation intermediate, which is attacked by the nucleophile to form C–C/C–heteroatom bonds. Notably, this reaction results in the formation of a mixture of enantiomers when it is executed with a pure enantiomeric substrate (Scheme 641).

Scheme 641 General substitution reaction pathways of S_N1 and S_N2.

On the other hand, the reaction occurring via the S_N2 pathway proceeds through a concerted pathway and results in the formation of the desired products in a stereospecific way. Similarly, in the S_N2′ pathway, the reaction goes through conjugate addition with the electrophile in a concerted pathway (Scheme 642). Notably, Lewis acidic iron-catalyzed reactions can occur through the above-mentioned three pathways. The iron center of these catalysts coordinates with the leaving group and polarizes the electron density and enhance the partial positive charge on the carbon to facilitate the substitution reaction. The iron-catalyzed S_N reactions are mostly limited to electrophiles in which their leaving groups have π-conjugation with benzyl, allyl and propargyl groups. Among them, benzylic substitution reactions are mostly catalyzed by Lewis acidic iron catalysts and have been found to proceed majorly through the S_N1/S_N2 pathways. Additionally, these catalysts, can promote the allylic and propargylic substitutions reactions.

Scheme 642 General reaction pathways for allylic substitution by Lewis acidic and anionic iron catalysts.

The iron-catalyzed S_N reactions at sp³ allylic carbon are widely used for C/N/O/S-alkylation reactions. Importantly, the regio/stereo-chemical outcome of the allylic substitution reactions depends on the reaction pathways involved, depending on the nature of the catalysts, ligands and electrophiles. The possible pathways for Lewis acid-catalyzed reactions were previously shown (Scheme 642a and b).^1129a The reaction may proceed through concerted S_N2 or S_N2′ pathways to result in the formation of stereo and regioselective products. Also, it can occur via an allylic cationic intermediate, producing a mixture of stereo/regioisomeric products (Scheme 642a). Besides these, some neutral, anionic (ferrates) and Lewis acidic iron catalysts have been employed for the allylic substitution reactions. These reactions generally occur through either σ-allyl (double S_N2′ pathway) or π-allyl pathways (through the formation of η³-allyl-iron intermediate). Notably, these two possible pathways govern the selectivity in product formation. Mainly, when the reaction occurs through the σ-allyl pathway, it results in the formation of regio/stereoselective products with the retention of the configuration at stereogenic center. On the other hand, the reaction occurring through the π-allyl pathway produces regioisomeric products and the observed regioselectivity in this case depends on the substituents present in the substrates. In the following sections, the benzylic, allylic and propargylic substitution reactions are summarized consecutively. We classify these reactions based on the types of electrophiles and type of bond formed.

10.1.1 Nucleophilic substitution at sp³ benzylic C–X bonds.
10.1.1.1 Carbon–carbon/carbon–heteroatom bond formation. The benzylic S_N reactions are generally employed as a standard tool to construct carbon–carbon and carbon–heteroatom bonds by different synthetic chemistry groups across the globe. Lewis acidic iron catalysts have been extensively used for these reactions with benzylic electrophiles. Numerous benzylic electrophiles including benzylic alcohols, benzyl methyl ethers, carboxamides containing vinylogous benzylic alcohols, N-benzyl sulfonamides, secondary and tertiary silyl ethers and vinylogous benzylic ethers are utilized for S_N reactions to form carbon–carbon (Tables 1 and 2) and carbon–heteroatom bonds (Tables 3 and 4). Particularly, the iron-catalyzed S_N reactions proceeding through the S_N1 pathway in the presence of Lewis acidic iron catalysts such as iron(III)–chloride (FeCl₃) and iron(III)-triflate (Fe(Otf)₃) have been utilized to form carbon–carbon bonds with different carbon-centered nucleophiles.^1131–1140 However, the possibility of the S_N2 pathway for these reactions cannot be completely excluded. Moreover, a carbon-supported iron-ionic liquid was also used for the benzylation of 1,3-dicarbonyls.¹¹³⁴ Also, the Lewis acidic iron(III) chloride has been applied for the decarboxylative alkylation of β-keto acids with benzyl alcohols.¹¹³⁵ Similarly, carbon–carbon bond formation reactions occurring through benzylic substitutions have been described (Table 2).^1141–1148 Among these reactions, the β-alkylation of secondary benzylic alcohols by primary alcohols (Table 2, entry 3) proceeds through the three successive steps, including oxidation, aldol condensation and reduction in the presence of ferrocene carboxaldehyde as the catalyst.¹¹⁴³ According to the proposed mechanism, initially both alcohols are oxidized to carbonyl compounds via hydride transfer to the ferrocene catalyst, generating the iron–hydride species. Then, the base-mediated aldol condensation between these two carbonyl compounds results in the formation of an α,β-unsaturated ketone. Finally, this ketone is reduced by iron–hydride species to generate the alkylation product. It is interesting to note that the initial oxidation of alcohols via hydrogen transfer and the final reduction of unsaturated ketones by iron–hydride species follow the well-known hydrogen auto transfer or hydrogen borrowing reactions.^{748–758,1144} However, despite the abundance of normal organic compounds as C-centered nucleophiles, allyl trimethyl silanes have been used as C-based nucleophiles with benzylic electrophiles (Table 1, entries 8 and 11, and Table 2, entries 7 and 8).^{1139,1140,1148} Furthermore, an organo-silane derivative has been used as an electrophile linked to benzylic-propargylic alcohol (Table 2, entry 4).¹¹⁴⁵ More intriguingly, ferrocenylmethanol is used as electrophile for C-alkylations (Table 2, entry 5).¹¹⁴⁵ Furthermore, in addition to C-centered nucleophiles, different N/S-centered nucleophiles have been employed to construct carbon–heteroatom bonds (Tables 3 and 4).^1149–1159 Importantly, an iron-catalyzed Ritter-type reaction has been performed to make C–N bond-containing compounds (Table 3, entry 2).¹¹⁵⁰ Also, together with the concept of S_N reactions, the hydrogen-borrowing reactions have been applied to make C–N bonds in the presence of magnetite (Fe₃O₄) and the mix-metal oxide NiCuFeO_x as catalysts, respectively (Table 3, entries 3–6).^1151,1152 Additionally, sulfur-centered nucleophiles are also used to synthesize C–S bond-containing compounds (Table 3, entries 7–9).¹¹⁵³ Also, the homoallylic alcohols participate as electrophiles to make C–heteroatom bonds, where the nucleophile attacks the terminal double bond, followed by the formation of π-an allyl-iron intermediate, resulting in the generation of double-bond-isomerized products (Table 3, entry 9).¹¹⁵³ Notably, in Table 4, besides the Lewis acidic iron catalysts such as [FeCl₃ and Fe(Otf)₃], the iron-cyclopentadienyl carbonyl complex[Fp][Otf] catalyst has been used for the benzylic substitutions (Table 4, entries 3 and 4).^1156–1159 Thus far, the described N-alkylation reactions in Table 3 proceed through the hydrogen auto transfer pathway. However, recently in 2016, the simple S_N reaction has been applied for N-alkylations by Maurya and coworkers. They developed a method for the ligand-free iron(II)-catalyzed N-alkylations of hindered secondary and primary alcohols with different amines.¹¹⁶⁰ The Lewis acid iron(II)-bromide was found to be the best catalyst in the presence of potassium hydrogen sulfate in toluene solvent (Scheme 643). Notably, different amines including primary, secondary and heterocyclic amines together with various benzyl alcohols and heteroaryl methanol are well tolerated for N-alkylation under the optimized conditions to produce the desired products in good to excellent yields. Further, this methodology has been utilized for the amination of different naturally occurring alcohols such as nerol, geraniol and phytol in good yields. Based on control experiments, a simple carbocation pathway has been suggested for this reaction (Scheme 644). It is believed that initially the benzylic alcohol coordinates with iron(II)-bromide to generate intermediate a, which reacts with another molecule of FeBr₂to form intermediate ether b. Then, the stable intermediate b reacts with FeBr₂ to generate carbocationic species d, which is trapped by the different aryl amines to provide N-alkylated products.

Table 1 Carbon–carbon bond formation nucleophilic substitution at benzylic carbon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1		MeOH		–OH	Fe(NO3)3·9H2O (2 mol%) MeOH, 80 °C	SN1 pathway
2				–OH	FeCl3·9H2O (5 mol%) MeNO2, 80 °C	SN1 pathway
3				–OH	FeCl3 (10 mol%) CH2Cl2, reflux	SN1 pathway
4				–OH	FeCl3 (10 mol%) CH2Cl2, reflux	SN1 pathway
5				–OH	FeCl3 (5 mol%) MeOH, reflux	SN1 pathway
6				–OH	FeCl3 (15 mol%) 0.45 equiv. AgSbF6 DCE, 80 °C	SN1 pathway
7				–OH	Fe(OTf3)3 (5 mol%) TfOH (10 mol%) DCE, reflux	SN1 pathway
8				–OH	FeCl3·5H2O (10 mol%) CH2Cl2, rt	SN1 pathway
9				–NHCOPh	FeCl3 (10 mol%) MeNO2, rt	SN1 pathway
10					FeCl3 (10 mol%) MeNO2, rt	SN1 pathway
11				–NHCOPh	FeCl3 (10 mol%) CH2Ac2 (10 mol%) MeNO2, 50 °C	SN1 pathway

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Table 2 Carbon–carbon bond formation through nucleophilic substitution at benzylic carnon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1				–NHTs	FeCl3 (10 mol%) DCE, 60 °C	SN1 pathway
2				–OAc	FeCl3 (5 mol%) 15 mol% AgOTf DCE, rt	SN1 pathway
3				–OH		Three steps:
						(i) Oxidation of alcohol
						(ii) Aldol condensation
						(iii) Reduction
4				–OH	FeCl3 (10 mol%) CH2Cl2, rt	SN1 pathway
5				–OH	[Fp][OTf] (10 mol%) CH2Cl2, rt Fp = Cp(CO)2Fe	SN2/SN1 pathway
6				–OH	Fe(OTf)3 (10 mol%) PhCl, 130 °C	SN1 pathway
7				–OMe	FeCl3 (10 mol%) CH2Cl2, rt	SN1 pathway
8		Me3Si–CN		–OMe	FeCl3 (10 mol%) CH2Cl2, rt	SN1 pathway

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Table 3 Carbon–carbon bond formation through nucleophiclic substitution at benzylic carbon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1				–OH	FeCl3 (5 mol%) MeNO2, reflux	SN1 pathway
2				–OH	FeCl3·9H2O (10 mol%) 2 equiv. H2O sealed tube, 150 °C	SN1 pathway (Ritter type reaction)
3		Ph–NH2		–OH	Fe3O4 (20 mol%) 2 equiv. KOt-Bu dioxane, 150 °C	Hydrogen auto transfer pathway (hydrogen borrowing mechanism)
4		Ph–NH2		–OH	Cat. NiCuFeOx xylene, reflux	Hydrogen auto transfer pathway (hydrogen borrowing mechanism)
5				–OH	Cat. NiCuFeOx xylene, reflux	Hydrogen auto transfer pathway (hydrogen borrowing mechanism)
6		(NH4)2CO3		–CO2	Cat. NiCuFeOx xylene, reflux	Hydrogen auto transfer pathway (hydrogen borrowing mechanism)
7				–OH	FeCl3 (15 mol%) 1.2 equiv. TMSCI CH2Cl2, reflux	SN^1 pathway
8				–OH	FeCl3 (15 mol%) 1.2 equiv. TMSCI CH2Cl2, reflux	SN^1 pathway
9				–OH	FeCl3 (15 mol%) 1.2 equiv. TMSCI CH2Cl2, reflux	Attack at terminal double bond and isomerization via π-allyl intermediate
10				–OH	FeCl3 (30 mol%) DCE, reflux	SN1 pathway
11		TMSN3		–OSiMe3	FeCl3 (5 mol%) 1.1 equiv. TMSN3 DCE, rt	SN1 pathway

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Table 4 Carbon–heteroatom bond formation through nucleophiclic substitution at benzylic carbon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1		TMSN3		–OMe	FeCl3 (5 mol%) 1.1 equiv. TMSN3 DCE, rt	SN1 pathway
2		TMSN3		–OBn	FeCl3 (5 mol%) 1.1 equiv. TMSN3 DCE, rt	SN1 pathway
3				–OH	[Fp][OTf] (10 mol%) CH2Cl2, rt	SN1/SN2 pathway
4				–OH	[Fp][OTf] (10 mol%) CH2Cl2, rt	SN1/SN2 pathway
5		Ar–NH2		–(PhCO)2CH2	FeCl3·6H2O (10 mol%) DCE, 100 °C	SN1 pathway
		Ar = p-NO2-Ph
6		Ar–SO2NH2		–NHTs	FeCl3 (20 mol%) 1.3 equiv. TsNH2 CH2Cl2, rt	SN1 pathway
		Ar = p-Me-Ph
7		TMsN3		–OMe	FeCl3 (20 mol%) 1.3 equiv. TMsN3 CH2Cl2, rt	SN1 pathway
8		TsNH2		–OMe	FeCl3 (5 mol%) 1.1 equiv. TMSN3 DCE, rt	SN1 pathway
9		TsNH2		–OMe	FeCl3 (20 mol%) 1.3 equiv. TsNH2 CH2Cl2, rt	SN1 pathway

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Scheme 643 Iron-catalyzed N-alkylation of benzyl/heteroaryl alcohols with amines.

Scheme 644 Proposed mechanism of iron-catalyzed N-alkylation with benzyl alcohols and heteroaryl alcohols.

10.1.2 Nucleophilic substitution at sp³ allylic C–X bonds.
10.1.2.1 Carbon–carbon/carbon–heteroatom bond formation. Similar to benzylic sp³ substitutions, allylic substitutions have been developed for the formation of carbon–carbon and carbon–heteroatom bonds (Tables 5 and 7 and Tables 8 and 9 respectively). Interestingly, this field of allylic substitutions has been chronologically established with different iron carbonyl complex-mediated reactions. Initially, it was started with the neutral diiron nonacarbonyl [Fe₂(CO)₉] as a catalyst by Nicholas et al.¹¹⁶¹ Thereafter, different anionic iron carbonyl complexes such as tricarbonyl nitrosyl ferrates, [Fe(CO)₃NO]Na, [Fe(CO)₃NO](Nbu₄) (TBAFe), were utilized by the groups of Nicholas, Roustan, Xu and Plietker for the development of regio/stereoselective allylic S_N reactions.^1162–1168 Notably, the selectivity depends on the nature of the electrophiles, nucleophiles and catalysts. Mainly, the Heiber-type (TBAFe) and other anionic complex-catalyzed regio/stereoselective C-alkylation reactions are described (Table 5).^{1163–1165,1168} These reactions have been found to proceed via the σ-allyl pathway (Table 5, entries 1–4), and consequently result in the formation of regio/stereoselective products.^{1163–1165,1168} The role of ligands is vital for the successful implementation of allylic substitutions. Generally, phosphorus, nitrogen and carbene-based ligands are employed in the presence of TBAFe and other anionic complexes (Table 5, entries 3 and 4). These ligands generally enhance the stability and reactivity of iron complexes. Thus, the role of ligands in allylic substitutions was illustrated (Tables 5–7).

Table 5 Carbon–carbon bond formation through nucleophiclic substitution at allylic carbon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1		NaCH(CO2Et)2		–OAc	[Fe(CO3)NO](Na) (10 mol%) THF, reflux, 14 h	σ-Allyl pathway (double SN2′ pathway)
2		NaCH(CO2Et)2		–OCO2Me	[Fe(CO3)NO](Na) (25 mol%) CO (1 atm) THF, reflux, 12 h	σ-Allyl pathway (double SN2′ pathway)
3				–OCOO(i-Bu)	TBAFe (2.5 mol%) PPh3 (3 mol%) DMF, 80 °C	σ-Allyl pathway (double SN2′ pathway)
4				–OCOO(i-Bu)		π-allyl pathway
5		PhH		–OH	Cat. Fe^3+-K-10 clay benzene, reflux	Friedel–Crafts alkylation of arenes with allylic alcohols
6		PhH		–OMe	Cat. Fe^3+-K-10 clay benzene, reflux	Friedel–Crafts alkylation of arenes with allylic alcohols

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Table 6 Carbon–carbon bond formation through nucleophilic substitution at alllylic carbon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1				–Boc	[Bu4N][Fe(CO)3NO] (5 mol%) TMEDA (5.5 mol%) toluene, 80 °C	σ-Allyl pathway (double SN2′ pathway)
2				–OAc		SN2′ pathway
3				–OH		SN1 pathway

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Table 7 Carbon–heteroatom bond formation through nucleophiclic substitution at allylic carbon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1		Ar–NH2 Ar = p-Me-Ph		–OCO(Oi-Bu)	TBAFe (2.5 mol%) PPh3 (5.5 mol%) Pip·HCl DMF, 80 °C	σ-Allyl pathway (double SN2′ pathway)
2		PhSO2Na			PhSO2Na (1.2 equiv.) TBAFe (5 mol%) L (6 mol%) DMF/MeOC2H4OH, 80 °C L = PR3 R = 4-OMe-Ph	σ-Allyl pathway (double SN2′ pathway)
3				–OAc		SN2′ pathway
4				–OH		SN2′ pathway
5		Ph–SH				σ-Allyl pathway (double SN2′ pathway)

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Particularly, Plietker and coworkers employed NHC ligands to improve the substrate scope and selectivity in allylic substitutions.¹¹⁶⁷ Interestingly, the different substituents such as tert-butyl and mesityl groups on the NHC ligand alter the reaction pathway. Moreover, a structurally well-characterized π-allyliron complex has been employed for this substitution reaction in the presence of an N-heterocyclic carbene ligand (Table 5, entry 6).¹¹⁶⁸ Later, the allylic substitution of allylic alcohols with arenes was developed in the presence of Lewis acid FeCl₃-contaminated K-10 montmorillonite clay, providing the stereoselective formation of E- or Z-olefins (Table 5, entries 5 and 6).¹¹⁶⁹ Notably, in these reactions, the starting alcohols are prepared by Baylis–Hillman reaction. The reaction has been presumed to proceed through the Friedel–Crafts alkylation pathway via conjugate addition of arenes to allylic alcohols. Besides phosphines and NHC ligands, nitrogen ligands (TMEDA) are also used for the allylic substitutions (Table 6, entry 1) in the presence of [Bu₄N][Fe(CO)₃NO] as the catalyst, affording regioselective products.¹¹⁷⁰ The neutral diiron-nonacarbonyl complex has also been used for diastereoselective C-alkylation reactions (Table 6, entry 2).¹¹⁷¹ Moreover, besides the neutral and anionic iron catalysts, the Lewis acid iron catalyst FeCl₃ was used for intra-molecular allylic substitution to synthesize indene rings (Table 6, entry 3), which is proposed to proceed through cationic cyclisation.¹¹⁷² This synthetic protocol has been utilized for the synthesis of (±)-junginol and epi-junginol. Later, ferrate-catalyzed C-alkylation was developed, where N, O and S-centered nucleophiles react with the allylic electrophile to form carbon–heteroatom bonds (Table 7, entries 1, 2, and 5 and Table 8, entries 1–7). The allylation of primary amines has been reported with allylic carbonates in a regio/stereoselective manner with retained configurations at the stereogenic center in case of enantiopure allyl carbonates (Table 7, entry 1).^1173,1174 Similarly, sulfonylation of allylic carbonates have also been developed employing different aryl sulfinates as nucleophiles (Table 7, entry 2).¹¹⁷⁵ Also, the Lewis acidic iron-catalyzed intramolecular diastereoselective synthesis has been utilized to synthesize substituted piperidines and tetrahydropyrans (Table 7, entries 3 and 4).^1176,1177 This methodology is applied for the diastereoselective synthesis of cis-isooxazolidines.¹¹⁷⁸ Further, the binuclear ferrate complex is employed as a catalyst for regioselective allylic sulfenylation reactions (Table 7, entry 5).¹¹⁷⁹

Table 8 Carbon–heteroatom bond formation through nucleophiclic substitution at allylic carbon

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1				–OCO2(i-Bu)		σ-Allyl pathway (double SN2′)
2				–CO2		Decarboxylative arylation via η^3-allyl iron intermediate
3				–H2O	FeCl3·6H2O (2 mol%) CH2Cl2, rt	SN2′ pathway
					FeCl3·6H2O (2 mol%) CH2Cl2, rt the NaOH/EtOH reflux
4				–OCO2(i-Bu)		SN2 pathway
5		TsNH2		–OH	FeCl3·6H2O (5 mol%) dioxane, 50 °C	SN1 pathway
6		TsNH2		–OH	FeCl3·6H2O (5 mol%) dioxane, 50 °C	SN1 pathway
7				–OH	FeCl3·6H2O (5 mol%) dioxane, 50 °C	SN1 pathway

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Afterwards, O-alkylation reactions were reported (Table 8, entries 1 and 2). The α-sulfonyl succinimides are used as nucleophile sources with allylic carbonates as electrophiles, resulting in the formation of the ipso-substitution (α-substitution) product in good selectivity (Table 8, entry 1).¹¹⁸⁰ Furthermore, allyl phenyl ethers were synthesized regioselectively starting with phenyl–allyl-carbonates in the presence of the ferrate complex PPh₃ in MTBE solvent (Table 8, entry 2).¹¹⁸¹ This reaction has been proposed to proceed through decarboxylative arylation via the formation of an η³-allyliron intermediate (π-allyl pathway) and produces the regioselective linear product. Lewis acid iron catalysts are also used for intramolecular S_N2′ allylic aminations (Table 8, entry 3).¹¹⁸² Further, the O-allylation of phenol was carried out using allyl carbonates as substrates in the presence TBAFe (catalyst) and a triazololium-based abnormal NHC ligand in THF solvent (Table 8, entry 4).¹¹⁸³ The reaction provides completely ipso-substitution and the regioselective O-allylation product and substantiates previous reports (Table 8, entry 2). Moreover, this method shows reverse selectivity in comparison to the general C-alkylation reactions, which is significantly enhanced at the allylic position in the presence of increased steric bulk. Besides, FeCl₃·6H₂O-catalyzed allylic substitutions have been developed with N/C-nucleophiles with free allylic alcohols (Table 8, entries 5–7).¹¹⁸⁴

Recently, in 2016, Pastor and co-workers developed an efficient protocol for the synthesis of quinolines, 2 and 4-allylanilines by allylic substitution (Scheme 645a–c).¹¹⁸⁵ Interestingly, they employed a Lewis acid iron(III)-based ionic liquid (A) as the catalyst for the reaction. The present method provides the desired products through the selective C-allylation pathways, which are unlike other iron-catalyzed allylation reactions, where N-alkylation occurs preferentially (as shown in Tables 1 and 2). Based on preliminary mechanistic investigations, a cationic pathway has been assumed for the formation of the desired products. In the same year, the iron-catalyzed allylic amination directly involving allylic alcohols and amines was demonstrated by Sundararaju and coworkers based on the hypothesis of hydrogen borrowing reactions (Scheme 646).⁷⁵³ They used a molecular iron catalyst, i.e. Knölker's complex A, in the presence of trimethyl N-oxide (Me₃NO) as an additive in toluene solvent.

Scheme 645 Synthesis of quinolines, 2- and 4-allyl anilines by allylic substitutions.

Scheme 646 Iron-catalyzed allylic aminations.

Notably, a variety of amines including cyclic secondary amines, aliphatic amines, benzylic amines as well as aromatic amines are well reacted with different terminally substituted allylic alcohols to produce allylic amination products in good to moderate yields under the optimized reaction conditions. Further, this method has been successfully employed for the one-pot synthesis of common drugs such as cinnarizine and naftifine, involving cinnamyl alcohol the as substrate. Based on the mechanistic investigations and literature reports on the hydrogen borrowing redox process, a possible mechanism was suggested (Scheme 647). It is presumed that catalyst A initially reacts with Me₃NO to generate intermediate B (a 16e⁻ species) via the removal of CO. Then, intermediate B coordinates with allylic alcohol 1 and generates intermediate C, in which alcohol is activated through hydrogen bonding. Thereafter one hydrogen atom is transferred from the alcohol to cyclopentadienone moiety with a concomitant change in the oxidation state of iron to generate intermediate D, which undergoes β-hydride elimination and forms iron–hydride intermediate Evia the elimination of aldehyde. Then, the aldehyde undergoes condensation with amine 2, resulting in the formation of imine, which is reduced by E (through outer-sphere hydrogenation) to produce the desired product 3.

Scheme 647 Proposed mechanism for allylic C–H amination.

In 2018, Nakata and coworkers developed the chiral auxiliary-controlled diastereo-convergent allylation reactions of allyl trimethyl silane with diastereomeric mixtures of diarylmethanols in the presence of FeCl₃ as a Lewis acid catalyst (Scheme 648).¹¹⁸⁶ Further, the present methodology was successfully applied to a variety of substrates, irrespective of the electronic and steric factors of the substituents present in the aromatic ring. The synthetic method successfully delivered the desired product in the key step during the synthesis of (R)-tolterodine. Based on the experimental evidence, a plausible reaction pathway and transition state were proposed for the reaction. It is presumed that iron initially coordinates with the hydroxyl oxygen of diarylmethanol A and generates intermediate I, which subsequently forms carbocationic intermediate II. Finally, the allyltrimethylsilane reacts with II from the sterically less hindered path b (shown in the TS) to produce the desired allylated product in a diastereoconvergent manner (Scheme 649).

Scheme 648 Iron-catalyzed diastereoconvergent allylation reactions of diarylmethanols.

Scheme 649 Proposed mechanism of iron-catalyzed diastereo-convergent allylation reactions of diarylmethanols.

10.1.2.2 Allylic substitutions with Grignard reagents. The above-described reactions deal with normal organic compounds/inorganic salts as nucleophiles. However, iron catalysts can also promote allylic substitution with Grignard reagents. The S_N2-selective iron-catalyzed allylic substitution was developed by reacting allylic phosphates with Grignard reagents, producing C-alkylated products in a stereoselective and regioselective manner (Table 9, entry 1).^514,515 Further, similar reactions have been applied for the diastereoselective synthesis of methyl cyclopropanes (Table 9, entry 2).¹¹⁸⁷ Further this concept is applied for the ring-opening reactions of allylic epoxides.

Table 9 Carbon–carbon bond formation reaction allylic substitution by Grignard reagents

Entry	Electrophile	Nucleophile	Product	Leaving group	Reaction condition	Plausible reaction pathway
1				–OTBDMS		SN2/SN2′ pathway (SN2 selective)
2				–OMe	Fe(acac)3 (10 mol%) hexane/Et2O rt	σ-Allyl pathway (double SN2′ pathway)

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In 2016, Li and coworkers described the Lewis acid iron-catalyzed α-allylic substitution of allyl ether with Grignard reagents (Scheme 650).¹¹⁸⁸ They utilized Fe(acac)₃ as the catalyst in a DCE/NMP solvent mixture at −15 °C. Interestingly, the present protocol utilized different aryloxy allyl ethers as the substrate, where phenoxy groups act as leaving groups. Moreover, different aryl and aliphatic Grignard reagents containing electronically biased substituents are well tolerated under the optimized reaction conditions, providing good to excellent yield of the allylic substitution products. Further, they carried out a deuterium labeling study to gain mechanistic insight into reaction. The labeling study with a D-labeled allyl ether provided mixtures of regioisomeric products (α and γ substituted product).

Scheme 650 Iron-catalyzed allylic substitution of aryloxy allyl ether with Grignard reagents.

Thus, this suggests the involvement of σ–π–σ equilibrium between the iron catalysts and substrates. Based on this preliminary mechanistic investigation, a tentative mechanism was proposed (Scheme 651). Initially, iron(III) is reduced to iron(I) in the presence of Grignard reagents (similar to the cross-coupling reactions). Thereafter, iron(I) takes part in the oxidative addition with the substrate to generate intermediate A, which remains in σ–π–σ equilibrium with B and C. Then, the transmetalation and final reductive elimination result in the formation of the desired products.

Scheme 651 Proposed mechanism of iron-catalyzed allylic substitution with aryloxy ethers.

Moreover, the formation of the selective α-substituted products has been rationalized based on the steric effects of the substituents in the substrates. Besides the aforesaid mechanism, the authors suggested that the reaction may also proceed through the S_N2 and S_N2′ pathways. Later, in 2018, they developed the directed iron-catalyzed allylic substitution with Grignard reagents through selective cleavage of the C–O bond using ethyl salicylate ester as a directing leaving group in the presence of a catalytic amount of iron(III)-acetyl acetonate and Grignard reagents in DCE at −20 °C (Scheme 652).¹¹⁸⁹ The reaction is started with the chelation of the phenolic group of the salicylate ester through the generation of a π-allyl iron intermediate. Notably, the present method well tolerated a variety of differently substituted phenolic crotyl ethers and salicylate O-allyl ethers in the presence of different aryls and aliphatic Grignard reagents and provided good to excellent yields of the regioselective allylic substitution products. Based on the experimental evidence, a plausible mechanism was suggested, involving sequential steps such as initial reduction of iron(III) to iron(I) in the presence of Grignard reagents, coordination with the substrate, homolytic cleavage to generate the allylic radical and the final reductive elimination from a π-allylic iron intermediate to produce the desired products (Scheme 653).

Scheme 652 Iron-catalyzed directed allylic substitutions with Grignard reagents.

Scheme 653 Proposed mechanism of directed C–O cleavage for allylic substitution with Grignard reagents.

10.1.3 Nucleophilic substitution of propargylic alcohols and acetates.
10.1.3.1 Carbon–carbon bond formation. In 2006, Zhan and co-workers reported the iron-catalyzed substitution of propargylic acetates with phenols in the presence of FeCl₃ in acetonitrile at room temperature to synthesize C–C coupling products via the Friedel–Crafts arylation reaction (Scheme 654).¹¹⁹⁰ The propargylic acetates react with various phenols, naphthols, and electron-rich aromatics, affording the corresponding substituted products in high yields. In addition, the propargylic alcohols also undergo iron-catalyzed nucleophilic ipso-substitution with allyl trimethylsilane under the same reaction conditions to give 1,5-enynes in high yields (Scheme 655a).¹¹⁹¹ Further, heteroaromatic compounds and electron-rich arenes undergo nucleophilic substitution to the propargylated arenes under the catalytic activity of FeCl₃ in acetonitrile at room temperature (Scheme 655b).¹¹⁹¹ Notably, in all the cases, high regioselectivity is maintained to give the desired propargylated products in the presence of various reactive functional groups. Also, the reaction conditions are not sensitive to air and moisture.

Scheme 654 Iron(III) chloride-catalyzed substitution of propargylic acetates.

Scheme 655 Iron-catalyzed substitution of propargylic alcohols by different carbon nucleophiles.

In 2010, Jana and co-workers employed nucleophilic substitution of propargylic alcohols for the preparation of propargyl-substituted β-dicarbonyl compounds using FeCl₃ in dichloromethane as an efficient catalytic system (Scheme 656).¹¹⁹² A variety of 1,3-dicarbonyl compounds undergo the substitution reaction with different propargylic alcohols at room temperature to give the desired substituted products in high yields.

Scheme 656 Propargylation of β-carbonyl compounds in the presence of an iron catalyst.

Around the same time, Zhan and co-workers reported the use of iron-catalyzed nucleophilic substitution of propargylic alcohols with alkynylsilanes for the synthesis of 1,4-diynes (Scheme 657).¹¹⁹³ High yields of various substituted 1,4-diynes are obtained under the catalytic activity of iron(III) chloride in nitromethane solvent at room temperature. In 2013, Bi and co-workers demonstrated a methodology for the synthesis of gem-bis(alkylthio)vinylallenes from tertiary propargylic alcohols and α-oxo ketene dithioacetals in the presence of FeBr₃ at room temperature (Scheme 658).¹¹⁹⁴ The reaction proceeds through dehydration and C(sp²)–C(sp²) coupling between the substrates under iron catalysis, affording the corresponding vinylallenes in excellent yields.

Scheme 657 Iron-catalyzed nucleophilic substitution of propargylic alcohols with alkynylsilanes.

Scheme 658 Synthesis of gem-bis(alkylthio)vinylallenes in the presence of iron catalyst.

10.1.3.2 Carbon–heteroatom bond formation. Zhan and co-workers also reported the iron-promoted nucleophilic substitution of propargylic acetates with heteroatomic nucleophiles, and alcohols together with carbon nucleophiles (Scheme 659).¹¹⁹⁰ The reaction was achieved in the presence of FeCl₃ in acetonitrile at room temperate to afford the corresponding propargylic ethers in high yields with high regioselectivity. Various propargylic acetates undergo substitution with a wide range of primary, secondary and tertiary alcohols to give the desired ethers. Additionally, the same catalyst system also catalyzes the nucleophilic substitution of propargylic alcohols with different heteroaromatic nucleophiles such as alcohols, thiols and amides, forming the corresponding C–O, C–S and C–N-bonded propargylic products, respectively (Scheme 660).¹¹⁹¹ Notably, the FeCl₃ catalyst provides a cheap, environmentally benign and overall advantageous alternative to the other transition metal catalysts such as ruthenium, rhenium, cobalt and gold complexes.

Scheme 659 Iron-catalyzed nucleophilic substitution reaction with alcohol nucleophiles.

Scheme 660 Nucleophilic substitution reaction of propargylic alcohols with different heteroatomic nucleophiles under iron catalysis.

In 2009, Campagne and co-workers utilized the iron-catalyzed nucleophilic substitution of propargylic alcohols with Cbz-protected hydroxylamine together with gold-catalyzed cyclization for the one-pot synthesis of 2,3-dihydroisoxazoles (isoxazolines) (Scheme 661a).¹¹⁹⁵ Initially, the N-protected hydroxylamine is propargylated in the presence of FeCl₃. This is followed by subsequent cyclization upon the addition of NaAuCl₄·2H₂O and DMAP as a base in the same reaction mixture to give poor to good yields of the corresponding isoxazolines. Further, the sulfonyl-protected hydroxyl amines also gives high yields of isoxazolines under similar iron(III)- and gold(III)-catalyzed one-pot reaction procedure, but with the presence of pyridine as a co-catalyst (Scheme 661b).¹¹⁹⁶ Additionally, a wide range of isoxazolines have been prepared from sulfonyl-protected hydroxylamines and propargylic alcohols via a one-pot procedure under the catalytic activity of FeCl₃ in dichloromethane and triethylamine as a base (Scheme 662). Notably, the isolable N-sulfonyl-protected propargylated hydroxylamine I is initially formed in this process. Thereafter, the hydroxylamine intermediate is converted to oxime intermediate IIvia the β-elimination of the sulfonyl species. Then, this oxime intermediate undergoes cyclization to give the isoxazoles. Furthermore, 4-iodoisoxazoles and 4-iodoisoxazolines have been obtained from I in a one-pot procedure via iodocyclization using iodine monochloride.

Scheme 661 One-pot synthesis of different isoxazolines.

Scheme 662 Iron-catalyzed one-pot synthesis of isoxazoles together with proposed reaction pathway.

In 2011, they devised an uninterrupted one-pot procedure consisting of substitution/annulations/cross-coupling/hydrogenolysis/oxidation in sequence for the preparation of trisubstituted isoxazoles from propargylic alcohols using a palladium(0) catalyst together with an iron(III) catalyst (Scheme 663).¹¹⁹⁷ After the initial propargylic substitution of Cbz-protected hydroxylamine under iron catalysis, the palladium(0) catalyst extends the sequence by promoting the annulation/cross-coupling reactions. This is followed by hydrogenolysis of Cbz and final aerobic oxidation in the same sequence to give the corresponding isoxazoles. High yields of isoxazoles are obtained through this novel one-pot procedure. Propargylic alcohols also undergo nucleophilic substitution with triazoles in the presence of FeCl₃ to afford excellent yields of propargylated triazoles.¹¹⁹⁸ The N-1 or N-2 substitution products are formed regioselectively depending on the nature of the triazole nucleophile employed in the reaction. The benzotriazole reacts through the N-1 position (Scheme 664a), whereas the 4-phenyl-substituted and 4-benzoyl-5-phenyl-disubstituted triazoles give the N-2 substitution products predominantly (Scheme 664b).

Scheme 663 Preparation of trisubstituted isoxazole via an iron–palladium-catalyzed one-pot reaction.

Scheme 664 Iron-catalyzed nucleophilic substitution of propargylic alcohols with triazoles to form propargylated triazoles.

In 2012, Shi and co-workers exploited the iron-catalyzed nucleophilic substitution of tertiary propargylic alcohols with 1,2,3-triazoles for the synthesis of allene triazoles in high yields.¹¹⁹⁹ The substitution occurs via an S_N2′ pathway, giving the corresponding allene triazoles. The N-1 allenyl-substituted products are obtained by the use of benzotriazole as the nucleophile (Scheme 665a). On the other hand, the 4-substituted 1,2,3-triazoles afford a mixture of N-1 and N-2-allene triazoles with a major amount of N-1-allenyl-substituted product (Scheme 665b).

Scheme 665 Nucleophilic substitution of tertiary propargylic alcohols by 1,2,3-triazoles in the presence of FeCl₃.

Zanotti and co-workers reported the dehydrogenative etherification of ferrocenylmethanol with various propargylic alcohols using [Fp][Otf] (Fp = [Fe(CO)₂(Cp)]⁺) as the catalyst in toluene at room temperature (Scheme 666a).¹²⁰⁰ The reaction provides good yields of the desired propargylated ferrocenylmethyl ethers. Additionally, propargylic alcohols also undergo dehydrative etherification with different alcohols such as benzyl alcohols, isopropyl alcohol, ethanol and phenol under the same reaction conditions to give moderate yields of the corresponding ethers (Scheme 666b).

Scheme 666 Iron-catalyzed dehydrogenative etherification of propargylic alcohol in the presence of [Fp][Otf].

In 2012, Zhan and co-workers introduced a new strategy for the synthesis of acrylonitrile from 3-(trimethylsilyl)propargylic alcohols and para-tolylsulfonohydrazide via iron-catalyzed propargylic substitution/aza-Meyer–Schuster rearrangement and elimination reaction in a domino process (Scheme 667).¹²⁰¹ The reaction occurs in the presence of FeCl₃ in nitromethane at 60 °C to afford a variety of acrylonitriles in moderate to high yields. A wide range of symmetric and asymmetric propargylic alcohols undergo this reaction with good functional group tolerance. Notably, this is the first example of aza-Meyer–Schuster rearrangement with the migration of the nitrogen atom. The practicability of this procedure was demonstrated by the gram-scale synthesis of acrylonitriles.

Scheme 667 Iron-catalyzed synthesis of acrylonitrile via a domino propargylic substitution/aza-Meyer–Schuster rearrangement.

Further, the same reaction conditions were utilized for the preparation of 3,4,5-substituted and 1,3,5-substituted pyrazoles from propargylic alcohols with aryl or alkyl substitution at the 3-position via a one-pot cascade reaction.¹²⁰² The one-pot procedure consists of four reactions in sequence, i.e. iron-catalyzed propargylic substitution/aza-Meyer–Schuster rearrangement/base-induced electrocyclization/thermal [1,5] sigmatropic shift. Notably, the propargylic alcohols with an aryl substituent in the C₁ position form the 3,4,5-pyrazoles via migration of the aryl group to the adjacent carbon atom (Scheme 668a). On the other hand, the alkyl group of 1-alkyl substituted propargylic alcohols undergoes migration to the adjacent nitrogen atom to give the corresponding 1,3,5-substituted pyrazoles (Scheme 668b).

Scheme 668 Synthesis of 1,3,5-pyrazoles and 3,4,5-pyrazoles using iron-catalyzed one-pot reaction.

In 2015, Bauer and co-workers reported the use of ferrocenium hexafluorophosphate ([Fc]PF₆) for the nucleophilic substitution of terminal tertiary propargylic alcohols with different alcohols (Scheme 669a).¹²⁰³ Moderate to high yields of the propargylic ethers are obtained in the presence of only 5 mol% of [Fc]PF₆ with an equimolar amount of propargylic alcohols and alcohol nucleophiles. Notably, the mixed alkyl–aryl propargylic alcohols give superior results compared to purely aromatic propargylic alcohols. Recently, in 2019, they reported the [Fc]PF₆-catalyzed etherification of cyclopropyl-substituted tertiary propargylic alcohols with primary and secondary alcohols as nuclophiles.¹²⁰⁴ The tertiary propargylic alcohols with a cyclopropyl group in the α-position provide the rearranged product, i.e. the E-configured ene-ynes containing ethers in moderate isolated yields (Scheme 669b). This rearrangement occurs through the cyclopropyl ring opening. However, the cyclobutyl-substituted propargylic alcohols (Scheme 669c) and thiophene-possessing cyclopropyl-substituted propargylic alcohols (Scheme 669d) give the corresponding propargylic ethers without any rearrangement.

Scheme 669 Iron-catalyzed etherification of terminal tertiary alcohols.

In 2016, Wang and co-workers employed propargylic alcohols with aryl amines for the synthesis of indole and 1,2-dihydroquinoline via an iron-catalyzed cascade reaction consisting of Friedel–Crafts reaction/intramolecular hydroamination reaction in sequence (Scheme 670).¹²⁰⁵ The reaction was performed in the presence of iron(III) chloride hexahydrate as the catalyst. Various substituted arylamines undergo reaction with α-diarylated propargylic alcohols to give moderate to high yields of the 1,2-dihydroquinolines. However, the propargylic alcohols with an alkyl substituent at the α-position afford indoles together with the 1,2-dihydroquinolines.

Scheme 670 Synthesis of 1,2-dihydroquinolines and indoles via iron-catalyzed cascade reaction.

10.1.4 Nucleophilic substitution of non-activated C(sp³)–X electrophiles. In 1976, Miller and Nun reported the earliest example of an iron-catalyzed S_N type substitution reaction by producing tertiary alkyl iodides from tertiary alkyl chlorides using sodium iodide under the catalytic activity of FeCl₃ in carbon disulfide at room temperature (Scheme 671).¹²⁰⁶ The iron(III) chloride acts as a Lewis acid in the reaction to facilitate the release of chloride. Different hindered alkyl chlorides were converted to their corresponding iodides in high yields of up to 100%.

Scheme 671 Nucleophilic substitution of alkyl chlorides with iodides in the presence of FeCl₃ as the catalyst.

In 2009, Cossey and co-workers developed a procedure for the Ritter reaction^1150b using FeCl₃·6H₂O at 150 °C.¹¹⁵⁰ The tert-butyl acetate undergoes reaction with nitriles and water to give good yields of the tert-butyl amides (Scheme 672a). Later, in 2014, Cook and coworkers introduced a superior iron-catalyzed Ritter reaction procedure for the synthesis of carboxamides by employing a catalytic system consisting of FeCl₃ and AgSbF₆ in dichloroethane (DCE) solvent at 100 °C.¹¹³⁷ Cyclic secondary alcohols react with acetonitrile under the reaction conditions, affording the corresponding amides in moderate yields (Scheme 672b).

Scheme 672 Preparation of carboximides via Ritter reaction in the presence of an iron catalyst.

In 2011, Martín and co-workers demonstrated the iron-catalyzed halogenations of alkyl sulphonates by employing trimethysilyl halides in the presence of iron(III) salts such as Fe(acac)₃ and FeCl₃ (Scheme 673).¹²⁰⁷ The stereochemistry of the substituted products depends on the reaction conditions and nature of the substrates. However, some of the alkyl mesylates undergo substitution with complete retention of the stereochemistry in the produced halides. Significantly, the quisylates (8-quinolinesulfonate) and pysylates (2-pyridienesulfonates) were found to be superior leaving groups compared to the mesylates under the same reaction conditions. Notably, the quisylates are halogenated with the formation of completely inverted products. Additionally, the secondary mesylates are chemoselectively halogenated in the presence of primary mesylates in the substrate under stoichiometric conditions using FeCl₃ or FeBr₃.

Scheme 673 Iron-catalyzed halogenation of alkyl sulphonates.

In 2012, He and co-workers reported a three-coupling reaction procedure for the synthesis of propargylamines from alkynes, dichloromethane and amines under the catalytic activity of iron(III) chloride in CH₃CN together with 1,1,3,3-tetramethylguanidine (TMG) as a base (Scheme 674).¹²⁰⁸ Various substituted alkynes undergo reaction with piperidine and other secondary aliphatic amines together with dichloromethane to give moderate to excellent yields of the corresponding propargylic amines. However, aromatic amines and primary amines do not give any results under the reaction conditions.

Scheme 674 Iron-catalyzed synthesis of propargylic amines via a three-component reaction.

In 2013, Shi and co-workers developed an air- and moisture-stable catalyst, NiCuFeO_x, and used it for the N-alkylation of ammonia and amines with alcohols and primary amines.¹¹⁵² A large number of primary and secondary alkylamines, and various substituted anilines are N-alkylated with a wide range of alcohols and other amines in the presence of the catalyst in xylene, giving high yields of the corresponding amines. Primary amines are also prepared in high yields from ammonia and alcohols. In addition, N-heterocyclic amines can be prepared from diols via intramolecular double alkylation (Scheme 675). In 2012, Enthaler et al. introduced an efficient procedure for the depolymerization of polyether with benzoyl chloride nucleophile under the catalytic activity of FeCl₄·4H₂O at 100 °C in neat conditions (Scheme 676a).¹²⁰⁹ A wide range of polymeric ethers are depolymerized under the reaction conditions to give high yields of corresponding chloroethers. Significantly, the process was also efficient in scale-up experiments for the depolymerization reaction of 45.0 mmol polyethylene glycol by benzoyl chloride, affording the desired 2-chloroethyl benzoate in 87% isolated yield. Chloroethers are generally converted to monomers for the formation of new polymers. Also, good yields of chloroethers were produced by employing fatty acids as nucleophiles under the same reaction protocol.¹²¹⁰

Scheme 675 N-Alkylation of ammonia and amines with alcohols in the presence of NiCuFeO_x as a catalyst.

Scheme 676 Iron-catalyzed depolymerization reactions.

Further in 2013, they reported a ring-closing depolymerization of polyTHF under iron catalysis to form good yields of highly pure tetrahydrofuran (THF) (Scheme 676b).¹²¹¹ This conversion is performed using FeCl₃ as the catalyst at in the temperature range of 100 °C to 180 °C.

Around the same time, Taniguchi and co-workers developed an alternative methodology for the Mitsunobu reaction¹²¹² using ethyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate in place of DEAD (DEAD = diethyl azodicarboxylate) together with iron phthalocyanine (Fe(Pc)) as the catalyst (Scheme 677).¹²¹³ Moderate to good yields of inverted esters with high enantiomeric excess were obtained from the reaction of various chiral alcohols with different substituted carboxylic acids. Additionally, the reaction conditions allow the substitution of alcohols with nitrogen nucleophiles in moderate yields. Most importantly, the hydrazinecarboxylate undergoes aerobic oxidation to azocarboxylate within the reaction system in the presence of the iron catalyst.

Scheme 677 Mitsunobu reaction in the presence of an iron catalyst.

10.1.5 Nucleophilic substitution of sugar derivatives. In 2000, Bessodes and co-workers reported the conversion of tri-O-acetyl-glucals to 2,3-unsaturated glycosides via the Ferrier rearrangement using alkyl alcohols in the presence of FeCl₃ in acetonitrile solvent (Scheme 678a).¹²¹⁴ The α-anomers are predominantly obtained under the reaction conditions. Later, in 2002, Krohn and co-workers also reported a similar iron-catalyzed substitution reaction.¹²¹⁵ In 2003, Tilve and co-workers demonstrated the Ferrier rearrangement of 3,4,5-tri-O-acetyl-D-glucal to 2,3-unsaturated glycosides by employing the iron-based ionic liquid [bmim]Cl-1.5FeCl₃ as the catalyst and the solvent.¹²¹⁶ Then, in 2008, Zhang and co-workers performed the iron-catalyzed glycosylation of perbenzyl and peracetyl glycals via Ferrier rearrangement to form the corresponding 2,3-unsaturated-O-glycosides with high α-selectivity (Scheme 678b).¹²¹⁷ The reactions between the glycals and various alcohols occurs under the catalytic activity of Fe₂(SO₄)₃·xH₂O and with or without the presence of microwave irradiation, giving excellent yields of products. Furthermore, a range of 2,3-unsaturated-O-glycosides with high α-anomeric selectivity have also been obtained from the reaction of 3,4,6-peracetyl glucals with a wide range of alcohols in the presence iron(III) triflate as the catalyst (Scheme 679).¹²¹⁸

Scheme 678 Glycosylation of peracetyl glycals and perbenzyl glycals in the presence of iron catalysts.

Scheme 679 Iron-catalyzed formation of 2,3-unsaturated glycoside from 3,4,6-peracetyl glucals.

10.2 Electrophilic substitution

10.2.1 C–X bond forming reactions. In 2004, Samant and co-workers reported the FeCl₃-catalyzed sulfonylation of arene rings in the presence of the ionic liquid 1-butyl-3-methylimidazolium chloride [(bmim)Cl] (Scheme 680).¹²¹⁹ Spectroscopic evidence showed that depending on the molar ratio, the mixture of ferric chloride and ionic liquid exists as [bmim]⁺[FeCl₄]⁻ and [bmim]⁺[Fe₂Cl₇]⁻. In this Friedel–Crafts sulfonylation, a similar function of FeCl₃ compared to AlCl₃ was indicated by Raman scattering experiments. Both phenyl and tolyl sulfonyl chlorides undergo electrophilic sulfonylation with various substituted benzenes.

Scheme 680 Iron-catalyzed sulfonylation of arenes.

Chen's group studied the thiolation of 1,3,5-trimethoxybenzene with disulfides in an FeBr₃-catalyzed reaction (Scheme 681).¹²²⁰ Different aryl, alkyl, allyl and heterocyclic sulfides could be substituted on the substrate in the presence of 20 mol% of catalyst in DMF at 145 °C, although the yields were poor in many cases. This protocol was extended by Zhong's group towards the thiolation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyanopyrazole at the 4-position.¹²²¹ However, a catalytic amount of iodine is required for the transformation to occur under milder conditions. The authors proposed that disulfide first reacts with iodine to form iodo-alkyl sulfide (RSI), and subsequently electrophilic substitution occurs at the C-4 position of the substrate (Scheme 681).

Scheme 681 Electrophilic thiolation with disulfides.

In 2010, the iron-catalyzed bromination of aryl azides was reported by Kuang's group.¹²²² Ferric chloride was found to be the best catalyst for the transformation in conjunction with NBS as the brominating agent. In most of the cases, bromo-substitution occurred at the ortho-position to the azide. However, it also depends on the other substituents (Scheme 682). On the other hand, iodination of electron-rich arenes was achieved using Fe(NO₃)₃, I₂ and in situ-generated alkyl carbonic acid.¹²²³ It has been proposed that carbon dioxide and ethylene glycol generate a proton in the reaction medium, which reacts with nitrate and iodine to produce an iodinium ion; however, the specific role of iron is not clear.

Scheme 682 Electrophilic halogenation of arenes.

The synthesis of aryl azides with azidocarboxylates was reported by Fang's group (Scheme 683).¹²²⁴ The electron-rich arene ring was found to undergo proton substitution with azidocarboxylates in the presence of 5 mol% FeCl₃. Notably, ferric chloride catalyzes the thioarylation of phenols (Scheme 684).¹²²⁵ In the absence of influence by other groups, 1-(arylthio)pyrrolidine-2,5-dione delivers substitution at the para-position to the hydroxyl group.

Scheme 683 Synthesis of aryl azides with azidocarboxylates.

Scheme 684 FeCl₃-Catalyzed thioarylation of phenols.

It is believed that co-ordination of the Lewis acid with succinimide triggers the generation of the arylthionium ion, which undergoes substitution at the electron-rich positions. Various thioaryls and phenol derivatives can be coupled under the reaction protocol with decent yields.

10.2.2 C–C bond forming reactions. The iron-catalyzed synthesis of bis(indolyl)methanes via the electrophilic addition of aldehydes to the 3-position of indoles was studied under various conditions (Scheme 685). In 2004, Loh's group utilized a hydrated FeCl₃ catalyst in 1-methyl-3-octylimidazolium hexafluorophosphate ([omim]PF₆) ionic liquid to attain the condensation.¹²²⁶ The optimized conditions allow various aldehydes to couple with indole with excellent yields. Palaniappan's group utilized solid a polymer-based polyindole salt prepared from indole oxidation with FeCl₃ for the condensation.¹²²⁷ Notably, the ease of separation post-transformation and reusability of the catalyst are its best features. An [Fe(III)(salen)]Cl complex also showed similar reactivity, whereas in situ-generated iron(III) dodecyl sulfate was used to achieve the transformation in water medium.^1228,1229 It is proposed that the iron co-ordinated aldehyde undergoes electrophilic attack at the 3-position of indole and eliminates water to form an exocyclic double bond. The addition of a second indole molecule to the olefin and subsequent rearrangement produce the final product. Interestingly, the iron(II)chloride–1,1′-binaphthyl-2,2′-diamine (FeCl₂–BINAM) complex can be used for the synthesis of bisindolylmethane with indole and primary alcohol (Scheme 686).¹²³⁰ The alcohol is transformed to aldehyde in situ by dicumyl peroxide (DCP), which takes part in the condensation.

Scheme 685 Electrophilic addition of aldehydes to indoles.

Scheme 686 Iron-catalyzed synthesis of bis(indolyl)methanes via alkylation with alcohols.

The iron-catalyzed Friedel–Crafts acylation in a pyridine-based ionic liquid was achieved by Malhotra's group in 2005.¹²³¹ They found that FeCl₃-[EtPy]⁺[CF₃COO]⁻ is the best combination for the acylation with acetic anhydride. Li's group reported the synthesis of xanthenes in the FeCl₃-catalyzed benzylation of phenols followed by a cyclization reaction (Scheme 687).¹²³² Although o-bromo benzyl acetates are used mostly, the corresponding o-bromo benzyl bromides and carbonates can also be used. In the first step, benzylation takes place at the ortho-position to the phenol and subsequently undergoes intra-molecular C–O coupling.

Scheme 687 Benzylation of phenols followed by cyclization.

A propargylation reaction of arenes and heteroarenes was achieved with the corresponding propargyl acetate using the same Lewis acid catalyst (Scheme 688).¹²³³ High yields for the transformation was obtained with electronically driven complete regioselectivity. In 2013, Han's group developed the electrophilic ortho-substitution of various phenols with propargyl alcohol.¹²³⁴ The resultant product undergoes rapid cyclization aided by a base present in the reaction to produce benzofurans. Noteworthily, an aryl group is invariably required at the α-position of the alcohol probably to stabilize the electropositive intermediate.

Scheme 688 Iron-catalyzed propargylation of arenes.

Wu's group synthesized triaryl methane from benzaldehydes and two arene molecules in a similar alkylation manner (Scheme 689).¹²³⁵ The benzaldehyde first attacks one of the arene rings and forms acetate in the presence of acetic anhydride, which in turn substitutes a proton from another arene. A similar triaryl methane synthesis was also reported by Shao-Hong in 2012. However, indolizines are used as arene coupling partners and no additives such as acetic anhydride was utilized.¹²³⁶ The FeCl₃-catalyzed Friedel–Crafts C-3 alkylation of indoles with alcohols was reported by Jana's group in 2007 (Scheme 690).¹²³⁷ Remarkably, in addition to allyl, aryl and heteroaryl secondary alcohols, their tertiary counterparts also undergo smooth reaction with different indole derivatives. The FeCl₃/AgSbF₆ combination was found to be effective for the alkylation of simple arenes with unactivated secondary alcohols.¹²³⁸ The same condition was also applicable for intramolecular alkylation to yield cyclic products such as tetrahydronaphthalene and other higher benzoannulene analogues.

Scheme 689 Formation of triarylmethane via electrophilic substitution.

Scheme 690 C-3 alkylation of indoles with alcohols.

Womak and co-workers reported that 2-alkylcinnamaldehydes could undergo intramolecular Friedel–Crafts reaction in the presence of FeCl₃ and (MeO)₃CH to deliver 1-alkoxy-2-alkyl-1H-indenes (Scheme 691).¹²³⁹ These indenes are further transformed into 2-alkylindanones through stepwise treatment with trimethylamine and aqueous HCl respectively. Later they found that acetic anhydride instead of (MeO)₃CH simplified the synthesis of indanones, which follows a similar reaction pathway.¹²⁴⁰

Scheme 691 Intramolecular alkylation of cinnamaldehyde.

An unusual way of iron-catalyzed benzylation of aromatics was reported from benzyl ethers.¹²⁴¹ Shi's group optimized the benzyl C–O bond breakage and subsequent Friedel–Crafts addition to arenes to obtain di- and tri-aryl methanes. Benzylation can also be achieved with N-protected imines, forming diaryl methylamine; however, highly electron-rich arenes are required (Scheme 692).¹²⁴² On the other hand, the use of aryl aziridines instead of imines under the same reaction conditions react faster to produce 2,2-diaryl-ethylamine. Similar benzylation can also be achieved with benzyl thiocyanate via unsymmetrical C–S bond cleavage in the presence of ferric bromide.¹²⁴³

Scheme 692 Electrophilic benzylation with imine and aziridine.

Intramolecular Friedel–Crafts alkylation with epoxides was reported by Pericas’ group.¹²⁴⁴ Co-ordination of the epoxide oxygen of aryl glycidyl ethers to a Lewis acid (FeBr₃) allows the formation of a carbocation, which undergoes cyclization to yield 3-chromanols or tetrahydrobenzo[c]oxepin-4-ols, depending on the chain length. Another example of intramolecular electrophilic alkylation was reported Zhou's group by synthesizing indenes from 1,1,3-triarylallyl alcohols (Scheme 693).¹²⁴⁵ Noteworthily, FeCl₃ catalyzes the formation of the tertiary carbocation; however, it is reluctant to undergo cyclization due to the steric interaction between the three aryl groups. Thus, rearrangement leads to a less substituted carbocation, which undergoes intramolecular aromatic substitution, resulting in the production of indenes. During the evaluation of the reaction scope, it was observed that two aryl groups, one at the 1-position and the other at the 3-position could be substituted with aliphatic groups or hydrogen. Moreover, the reaction condition is tolerated by various functional groups such chloro, nitro, and methoxy. Present on arene rings. Similarly, FeCl₃ is reported to catalyze the intramolecular alkylation of 2-aryl benzylalcohol¹²⁴⁶ and o-aryloxybenzaldehydes¹²⁴⁷ to produce fluorine and xanthone derivatives, respectively.

Scheme 693 Synthesis of indene via intramolecular electrophilic substitution.

4-(Arylamino)propargyl alcohols in the presence of a Lewis acidic iron catalyst form propargyl cation and isomerizes to an allenyl cation.¹²⁴⁸ The addition of this cation to the ortho-position of the arene ring produces allene-substituted tetrahydroisoquinolines. Under suitable conditions, it undergoes further isomerization to olefin-substituted dihydroisoquinoline. However, Zhou's group found that the formation of the major product is highly substrate dependent. When nitrogen was replaced with a –C(CH₂OR) group, the corresponding tetrahydronaphthalene and dihydronaphthalene were obtained at 15 °C and 60 °C, respectively (Scheme 694).¹²⁴⁹ Bandini and co-workers showed that the use of allyl alcohol instead of propargyl alcohol also produces the cyclic product in a similar pathway.¹²⁵⁰

Scheme 694 Intramolecular substitution with propargyl alcohol.

Li and co-workers developed the synthesis of xanthenes from 2-aryloxybenzaldehydes and electron-rich arenes and heteroarenes (Scheme 695).¹²⁵¹ Interestingly, they proposed that the initially formed triaryl methane undergoes C–C bond cleavage to eliminate one of the external arenes and reacts intramolecularly with the arene ring of aryloxybenzaldehyde.

Scheme 695 Synthesis of xanthenes from 2-aryloxybenzaldehydes.

Specially designed α,α-dialkyl acetoacetanilides upon treatment with 10 mol% FeCl₃ at 60 °C in acetonitrile undergo intramolecular alkenylation to deliver 4-alkylene quinolin-2-ones (Scheme 696).¹²⁵² The quaternary carbon center plays a vital role by exerting enough strain to undergo cyclization. The authors proposed that co-ordination of the Lewis acid forms a carbocation at the terminal carbonyl center, and subsequently electrophilic substitution occurs at the arene ring.

Scheme 696 Cyclization of α,α-dialkyl acetoacetanilides.

During the synthesis of the prostaglandin EP4 receptor antagonist, Gauvreau and co-workers optimized the C-3 benzylation of 2,4-dimethylthiophene with a benzyl alcohol derivative and found FeCl₃ to be the best catalyst.¹²⁵³ In contrast, Lei's group demonstrated the condensation of aldehydes with 2-naphthols (Scheme 697).¹²⁵⁴ The metal co-ordinates with aldehyde first, then undergoes two-fold electrophilic substitution at the 1-position of both naphthols to form triarylmethane. Then the two hydroxyl groups of naphthols eliminate a water molecule to produce 14-aryl(alkyl)-14-H-dibenzo-[a,j]xanthenes. Later, Zhang's group developed a solvent-free version of this reaction using an Fe(Otf)₃ catalyst.¹²⁵⁵

Scheme 697 Iron-catalyzed condensation of 2-naphthols with aldehyde.

2-Benzhydryl-1,3-diphenylpropane-1,3-dione is known to form a diphenylmethyl cation in the presence of an iron catalyst.¹²⁵⁶ Li's group utilized this concept, and found that indole derivatives undergo electrophilic substitution at the C-3 position with the cations (Scheme 698). The use of various olefins, alkynes, cycloalkyl arenes and aryl groups instead of phenyl also works well under the reaction conditions.

Scheme 698 C-3 substitution of indoles with diarylmethyl cation.

In 2010, Hayashi and co-workers reported the iron-catalyzed substitution of alkyl amides into an aryl C–H bond (Scheme 699).¹²⁵⁷ The tert-butoxide radical selectively abstracts a hydrogen from the α-C–H of the alkylamide and forms α-(tert-butoxy)alkylamides, which in turn interact with the metal catalyst to form a carbocation stabilised by the amide group. The following substitution of the cation in arene results in the desired product. Under the reaction conditions, both arenes and heteroarenes substituted with halide, ester, and methoxy groups can be coupled with cyclic and acyclic amides. In a subsequent report, they showed that this strategy is also applicable towards the alkylamination of heteroarenes and electron-rich arenes.¹²⁵⁸

Scheme 699 Iron-catalyzed amidation of arenes.

The synthesis of 5,6-dihydro-indolo[1,2-a]quinoxaline derivatives was reported by Xu's group via Pictet–Spengler cyclization (Scheme 700).¹²⁵⁹ The imine formed between 2-(indol-1-yl)arylamine and benzaldehyde undergoes substitution at the 2-position of indole in the iron-catalyzed reaction to deliver the product. Interestingly, furfuraldehyde also showed high reactivity and produced the corresponding product.

Scheme 700 Condensation of 2-(indol-1-yl)arylamine with benzaldehyde.

Yu and co-workers developed the C-3 alkenylation of indoles in 2012 (Scheme 701).¹²⁶⁰ In the first step, iron promotes the formation of phenylacetaldehyde diethylacetal with ethanol, which disintegrates to an oxocarbenium cation. Due to electronic preferences, this cation undergoes electrophilic substitution at the 3-position. The authors also proposed an alternate pathway, where direct attack of the aldehyde is followed by dehydration to produce the alkene. A variety of substituted indoles including N-allyl indole underwent alkenylation at the C-3 position under the reaction conditions.

Scheme 701 C-3 alkenylation of indoles.

The iron-catalyzed asymmetric alkylation of indoles was achieved with the combination of Fe(ClO₄)₂ and a chiral bipyridyl-diol-based ligand.¹²⁶¹ A diaryl meso-epoxide was employed as the alkylating agent to obtain chiral 1,2-diaryl-2-(3-indolyl) alcohols in excellent yield and >95% ee in all instances (Scheme 702). Interestingly, structure elucidation of the pre-catalyst showed a rare pentagonal bipyramidal geometry around the metal center co-ordinated with the ligand, two THF and one water molecule.

Scheme 702 Asymmetric alkylation of indole.

Cinnamyl alcohol undergoes dehydrative alkylation to produce 1,3-diaryl propene.¹²⁶² A cationic Fe(III)-porphyrin complex was employed by Matsubara to generate an allylic, cation which in turn underwent electrophilic substitution (Scheme 703). Regioselective C-5 allylation of protected 8-aminoquinolines with cinnamyl alcohol in an FeCl₃-catalyzed reaction was reported by Zeng's group in 2013 (Scheme 703).¹²⁶³ Both amine and pyridine nitrogens are capable of dictating the selectivity in their favour, and therefore the authors postulated that metal chelation withdraws the lone-pair electron density from N-pyridine, thus the C-5 product was observed.

Scheme 703 Iron-catalyzed dehydrative allylation.

In 2014, Leino and coworkers developed an iron-catalyzed reductive alkylation of ketones and aldehydes with arenes in the presence of catalytic FeCl₃/Fe(acac)₃ (4 mol%) and stoichiometric chlorotrimethylsilane/triethylsilane together with triethylsilylhydride.¹²⁶⁴ Similarly, in 2017, Maji and co-workers showed that cinnamyl esters and related α,β-unsaturated carbonyl compounds can also be employed for the electrophilic alkylation of arenes with the Fe(Otf)₃ catalyst.¹²⁶⁵

Although Saidi's group found an iron catalyst to be very effective towards alkylation at the C-3 position of indole only as an optimization entry,¹²⁶⁶ Itoh's group performed extensive study on the reaction. It was observed that Fe(BF₄)₃ serves as the best catalyst (Scheme 704).^1267,1268 Noteworthily, a slight change in the reaction conditions also allowed the formation of 2,3-dialkyl indoles. This strategy could also be extended for the mono and di-alkylation of pyrrole derivatives.¹²⁶⁹ Similar C-3 substitution of indole derivatives was also observed with enamides and nitroalkenes.^1270,1271 FeCl₃ helped in the formation of the iminium ion in case of enamide, whereas co-ordination to the nitro group activated nitroalkenes. Interestingly, indolynitroalkenes also underwent substitution at the para-position of ortho-haloanilines.¹²⁷² Huang's group utilized β-aryl α′-hydroxy enones to achieve the asymmetric alkylation of indoles (Scheme 705).¹²⁷³ The metal co-ordinates with the alkylating agent in a bidentate fashion and a chiral phosphoric acid ligand simultaneously. In the transition state, the ligand is likely to be hydrogen bonded with the indole nitrogen as well, and thus chirality is induced.

Scheme 704 Alkylation of indoles with various conjugated alkenes.

Scheme 705 Chiral phosphoric acid-induced asymmetric alkylation of indole.

In 2006, Beller's group introduced the FeCl₃-catalyzed substitution of (het)arenes with styrene (Scheme 706).¹²⁷⁴ A plethora of styrenes and arenes and heteroarenes form 1-aryl-1-(het)arylalkanes via the electrophilic alkylation reaction. In the subsequent year, Lu's group established the reaction with arylacetylenes, i.e. alkenylation of arenes (Scheme 706).¹²⁷⁵ The authors proposed that FeCl₃ reacts with the alkyne and produces a carbocation adjacent to the aryl group, followed by electrophilic attack on the arene ring. The observed kinetic isotope effect value of 1 supports this mechanism instead of C–H activation. Evaluation of the substrate scope revealed that the formation of the Z-isomer was predominant with internal alkynes. Remarkably, propiolic acids were also found to produce cinnamic acids in a similar fashion (Scheme 707).^1276,1277 Indoles can be employed with propiolic acid also; however, di-heteroarylation is observed, leading to bis(indol-3-yl)alkanoic acids.¹²⁷⁸ Interestingly, the reaction between propiolic acid and phenol results in the formation of coumarin.¹²⁷⁹ The authors proposed two different pathways for this observation: (i) hydroarylation followed by cyclization or (ii) esterification followed by intramolecular electrophilic substitution. On the other hand, benzyl alcohols react with aromatic alkynes, yielding indenes.¹²⁸⁰ Later, Chen and co-workers simplified the strategy by in situ generating benzyl bromides through the bromination of the benzylic C–H bond with NBS.¹²⁸¹ In both reactions, the benzyl cation probably attacks the alkyne and the resultant alkenyl cation undergoes electrophilic substitution on the arene ring.

Scheme 706 Hydroarylation of alkenes and alkynes.

Scheme 707 Electrophilic substitution with propiolic acid.

The intramolecular version of the hydroarylation of alkynes was reported by Campagne for 4-arylalkynes and by Takaki for N-propergylanilines to obtain dihydronaphthalenes and dihydroquinolines, respectively (Scheme 708).^1282,1283 Similarly, arylalkynyl phenyl sulfides and sulphonamides produce cyclic vinyl sulphides and vinylamines, respectively.¹²⁸⁴

Scheme 708 Intramolecular hydroarylation of alkynes.

The concept of electrophilic alkenylation was also utilized by Tian's group in a 3-component reaction.¹²⁸⁵ Initially, FeCl₃ catalyzes the generation of the carbonium ion from benzyl alcohol, which attacks a terminal alkyne to form an alkenyl cation. Subsequently, substitution occurs at the arene ring to produce various trisubstituted alkenes.

10.3 Radical substitution

In 2013, Pucheault's group reported the iron-catalyzed borylation of aryldiazonium salts via a radical pathway.¹²⁸⁶ In the presence of ferrocene, the diazonium salt eliminates nitrogen to produce an aryl radical, which reacts with aminoborane, yielding aryl(amino)borane (Scheme 709). This intermediate upon sequential treatment with methanol and pinacol produces aryl pinacolatoborane. Various substituted aryldiazonium salts were converted to the corresponding borylated product in a decent yield using this protocol. In 2017, Nakamura achieved the direct borylation of aryl and heteroaryl chlorides with bispinacolatoborane.¹²⁸⁷ Catalytic ferric acetylacetonate was used as the catalyst in the presence of potassium tertiary-butoxide to oxidatively add aryl chloride to the metal. This intermediate is believed to be in equilibrium with the aryl radical, which coupled with the iron-co-ordinated Bpin. Recently, Feng's group discovered that 2-aryloxypyridines underwent homolytic C–O cleavage with catalytic Fe(Oac)₂, and recoupled with Bpin to produce the corresponding borylated product.¹²⁸⁸

Scheme 709 Iron-catalyzed borylation via radical substitution.

Intramolecular dehydrogenative aromatic radical substitution with aldehydes was documented by Studer and co-workers (see Scheme 229).²⁶⁹ Under the reaction protocol, 2-arylbenzaldehydes form fluorenones, while 2-aryloxybenzaldehydes yield xanthones. The reaction initiates via the ferrocene-promoted generation of the tert-butoxy radical from t-BuOOH and subsequent HAA of the aldehyde hydrogen (see Scheme 230). The carbon radical undergoes typical base-assisted radical substitution on the arene to complete cyclization. They have also established that the radical generated from a benzaldehyde in a similar fashion reacts with 2-isocyanobiphenyls (Scheme 710).¹²⁸⁹ The resultant imidoyl radical undergoes cyclization via substitution, forming phenanthridines.

Scheme 710 Intramolecular radical substitution.

Chen and co-workers developed a halogen exchange methodology via radical substitution (Scheme 711).¹²⁹⁰ Aryl bromides upon treatment with sodium chloride and a catalytic amount of FeCl₃ were converted to aryl chloride under UV radiation. The chlorine radical is believed to be generated by the homolytic dissociation of the Fe–Cl bond. The Fe(II) species formed in the process is oxidised back to Fe(III) by molecular oxygen and takes up a Cl⁻, completing the catalytic cycle. Not only aryl bromides, various heteroaryl bromides also undergo the halogen exchange effectively.

Scheme 711 Halogen exchange reaction.

11. Miscellaneous

11.1 Radical-mediated functionalizations

In 2013, Maiti and co-workers reported the regio and stereoselective nitration of olefins in the presence of ferric nitrate and a catalytic amount of 2,2,6,6-tetramethylpiperidine (TEMPO) following their earlier works on radical-based nitrations.¹²⁹¹ The reaction provides nitro-olefins in good yields with excellent E-selectivity (Scheme 712). Notably, the nature of the solvent has a significant effect on the nitration. Non-polar solvents were found to be better solvents compared with polar solvents. A wide variety of olefins including aromatic, aliphatic and heteroaromatic olefins are well tolerated under the reaction conditions. Both the electron-withdrawing group and electron-donating group present in the substrate provide the desired nitration product in good to excellent yield. Notably, this reaction protocol can tolerate the presence of the chloromethyl group together with olefin.

Scheme 712 Iron-catalyzed selective nitration with TEMPO.

Further, a proposed mechanistic pathway has been suggested based on the experimental evidence. Initially, Fe(NO₃)₃, ferric nitrate under thermal conditions produces the nitro radical. This nitro radical then undergoes the reaction at the less hindered side of the olefin in order to generate the secondary or benzylic radical. Subsequently, this nitroalkane radical can be converted to the desired product via two possible pathways. In the first pathway (pathway a), TEMPO abstracts the hydrogen atom, whereas in the second pathway (pathway b), TEMPO is trapped and oxidises the benzylic radical to form the desired product stereoselectively (Scheme 713).

Scheme 713 Mechanistic pathway of iron-catalyzed selective nitration with TEMPO.

In the next year, they reported the generation of arylated quiniones by the iron-catalyzed oxidative addition of phenols (Scheme 714).¹²⁹² Mechanistically, the phenoxy radical is generated by the homolytic cleavage of persulphate. Subsequently, the phenoxy radical undergoes oxidation in the presence of oxygen to form quinone. The aryl radical generated from ArB(OH)₂ attacks the more electrophilic quinone due to the coordination with Fe(III)/Fe(IV) under the oxygen atmosphere to afford the quinoline-arylation product. Notably, the homo-coupled product is also generated together with the quinoline-arylation product. The generation of the homo-coupled product confirms the radical nature of the reaction. Further, the observed kinetic isotope effect study (KIE = 2.96) confirms the conversion of ArOH to quinone in the rate-determining step (Scheme 715).

Scheme 714 Iron-catalyzed oxidative arylation of phenols.

Scheme 715 Proposed mechanistic pathway of iron-catalyzed oxidative arylation of phenols.

This synthetic transformation technique was used for the total synthesis of natural products such as phellodonin, sarcodonin ε, leucomelone and betulinan A. In 2014, they developed an iron-catalyzed regioselective method for the direct arylation at the C-3 position of N-alkyl-2-pyridone (Scheme 716).¹²⁹³ Using this reaction protocol, 3-(2-methoxyphenyl)-one-2(1H)-one was synthesized, which can be further utilized as a precursor for the synthesis of the pharmaceutically relevant benzofuro[2,3-b]quinoline moiety via the successive cyclization reaction.

Scheme 716 Iron-catalyzed regioselective direct arylation at the C-3 position of N-alkyl-2-pyridone.

Based on the literature survey and experimental observations, a possible mechanistic pathway has been suggested (Scheme 717). Initially, the sulphate radical is generated thermally or in the presence of iron(II). Then, the sulphate radical reacts with arylboronic acid to form the aryl radical. Subsequently, this aryl radical reacts selectively at the C-3 position of the 2-pyridone moiety. The selective attack of the aryl radical at the C-3 position of pyridone can be rationalised due to the large coefficient of HOMO and LUMO of the C-3 atom. This results in the formation of resonance-stabilized radical adduct I. The iron(III) or sulphate radical abstracts one electron from I to generate cation II, followed by aromatisation, leading to the formation of the desired product. Under aerobic conditions, iron(II) is oxidised to iron(III).

Scheme 717 Proposed mechanistic pathway for the C-3 arylation of 2-pyridone.

In 2018, Zhong and co-workers reported the iron-catalyzed regiospecific intermolecular radical cyclization of anilines.¹²⁹⁴ The protocol does not require a ligand and directing group. The synthetic protocol allows the formation of the electrophilic anilido radical, which undergoes intermolecular [3+2] cyclization with nucleophilic α-substituted alkenes to form gem-disubstituted indulines (Scheme 718).

Scheme 718 Iron-catalyzed regiospecific intermolecular radical cyclization of anilines.

Mechanistically, N-centered neutral radical I is generated via N–H hydrogen bond abstraction by the oxidant DDQ (Scheme 719). This was confirmed by an EPR study. On the other hand, the comparison of the redox potential (E_P/2vs. SCE in MeCN) between FeCl₃ and α-substituted alkene 1 (1.85 V) rules out the pathway involving the radical cation of 1via single-electron oxidation. The electrophilicity of anilide radical I is not sufficient to attack α-substituted alkene 1. However, the coordination by the iron catalyst activates carbon-centered radical II. Here, FeCl₃ acts as a Lewis acid. Then, the cyclization takes place via the stepwise addition involving tertiary carbon radical IV. This was confirmed by a radical clock experimental study. Further, carbon-centered radical V is generated, and subsequent cleavage of the ortho C–H bond affords the desired product by aromatization of the phenyl ring with the simultaneous release of FeCl₃. The observed kinetic isotope effect (KIE, K_H/K_D = 5.7) suggests that the cleavage of the ortho C–H bond may be involved in the rate-determining step.

Scheme 719 Proposed mechanistic pathway of iron-catalyzed regiospecific intermolecular radical cyclization of anilines.

In the same year, Hazra¹²⁹⁵ and co-workers reported an iron-catalyzed and potassium persulfate-mediated thiocyanation of a wide range of 2H-indazoles at room temperature to obtain 2-aryl-3-thiocyanato-2H-indazoles as the desired product (Scheme 720). However, 2H-indazole with an electron-withdrawing group (–NO₂) in its phenyl ring and having aliphatic substituents at the N-2 position does not afford the desired product. Mechanistically, the reaction proceeds via the radical mechanistic pathway. This was confirmed by adding a radical scavenger to the reaction mixture.

Scheme 720 Iron-catalyzed potassium persulfate-mediated thiocyanation of 2H-indazol.

Based on the literature studies and controlled experiments, they proposed a mechanistic pathway (Scheme 721). Initially, ferric thiocyanate I complex is formed via ligand exchange (SCN⁻), and then it is oxidised to form the SCN radical in the presence of K₂S₂O₈. Then, the co-ordination of Fe(III) with 2-phenyl-2H-indazole results in the formation of intermediate II. Subsequently, the SCN radical reacts with intermediate II selectively at the C-3 position to form radical intermediate III. The coordination of Fe(III) with the substrate is very important to stabilize the radical in resonating structure III′. The co-ordination of the N atom of the III′ radical with Fe(III) reduces the charge density of the nitrogen atom through σ-bonding and pπ–dπ overlapping. Then, radical intermediate III is further oxidised to give carbocation IV followed by elimination of H⁺ to afford the desired product.

Scheme 721 Possible mechanistic pathway of iron-catalyzed potassium persulphate-mediated thiocyanation of 2H-indazole.

In 2019, Punniyamurthy and co-workers reported the iron-catalyzed regioselective remote C(sp³)–H carboxylation of naphthyl and quinoline amides using CBr₄ and alcohol via the co-ordination activation strategy and SET process (Scheme 722).¹²⁹⁶ The reaction in the presence of a radical scavenger such as TEMPO or BHT provides a trace amount of the desired product. Thus, the present observation suggests that reaction may involve a radical pathway. It was believed that Fe(acac)₃ reacts with PivOH to generate the active Fe(III) species, which undergoes the reaction with substrate I (Scheme 723). Simultaneously, the radical ˙CBr₃ is generated in the reaction via the SET mechanistic pathway from CBr₄ in the presence of iron(II) (iron(II) is regenerated in situ through the reduction of Fe(III) with alcohol). The ˙CBr₃ radical reacts at the electrophilic carbon atom to produce radical intermediate II, which is converted to IIIvia another SET mechanistic pathway. Subsequently, the deprotonation of III generates species IV and Fe(II) species, which is reoxidized to Fe(III) by the excess CBr₄ present under the reaction conditions. Then the deprotonation of IV by a bromide ion generates the V intermediate, which undergoes protodemetalation through the regeneration of the active Fe(III) catalyst to form intermediate VI. Finally, alcoholysis of VII provides the desired product. Notably, the scope of this synthetic protocol can be extended for the remote C-5 carboxylation of analogous 8-aminoquinolimides.

Scheme 722 Iron-catalyzed regioselective remote C(sp²)–H carboxylation of naphthyl and quinolone amides.

Scheme 723 Possible mechanistic pathway for the iron-catalyzed regioselective remote C(sp²)–H carboxylation of naphthyl and quinolone amides.

In 2017, the electron-deficient (hetero)arenes were ortho-preferentially alkylated by Bao and co-workers using the Fe(Ots)₃ iron catalyst under an N₂ atmosphere at 100 °C via an alkyl radical nucleophilic aromatic substitution reaction (Scheme 724).¹²⁹⁷ Alkyl diacyl peroxides were used as the alkyl radical source. Several electron-deficient aryl rings were ortho-alkylated under the reaction conditions to give moderate to high yields of products. Further, various alkyl diacyl peroxides give good yields of the ortho-products by reacting with ortho- and para-dichlorobenzenes. Also, heteroarenes give good to excellent yields of products via this radical alkylation. The DFT studies and HOMO–LUMO analysis also supported the observed regioselectivity of the reaction.

Scheme 724 ortho-Preferred alkylation of electron-deficient arenes in the presence of iron catalysts.

They proposed a hypothetical mechanism for the alkyl radical nucleophilic aromatic substitution (Scheme 725). Initially, the alkyl diacyl peroxide undergoes homolytic cleavage in the presence of iron(II) catalyst I at high temperature to give alkyl free radical III together with the release of CO₂. Simultaneously, Fe(II) species I undergoes single-electron transfer (SET) to form iron(III) species II. Then, delocalized radical species IV is formed via the nucleophilic attack of alkyl radical III on the electron-deficient arene. This is followed by the oxidation of IV by iron(III) species II to give delocalized carbocation species V with the concomitant regeneration of active Fe(II) species I. The carboxylate anion released in this process abstracts a proton from V to give the desired ortho-alkylated product.

Scheme 725 Proposed mechanism for the alkyl radical nucleophilic aromatic substitution.

In 2019, Guo and co-workers demonstrated that α,β-unsaturated carboxylic acids can undergo decarboxylative ketoalkylation in the presence of an iron catalyst via alkoxy radical-promoted unstrained C–C bond cleavage to produce alkenyl ketones (Scheme 726).¹²⁹⁸ This reaction has been performed successfully in the presence of ferrocene as the iron catalyst together with Bphen as the ligand in EtOH at room temperature. A broad range of substituted cinnamic acids with electron-withdrawing and electron-donating substituents react with various cycloalkylsilyl peroxides to give good yields of alkenylated product with excellent stereoselectivity towards E-alkene. The reaction conditions tolerate a large number of functional groups such as halogens, hydroxy, methoxy, trifluoromethyl and cyano groups. Moreover, seven-, eight- and twelve-membered peroxides also provided the desired products with good to excellent yields. They suggested the presence of a radical intermediate based on the observation of the products for the reactions using TEMPO.

Scheme 726 Decarboxylative keto alkylation of α,β-unsaturated carboxylic acids in the presence of an iron catalyst.

Their proposed mechanism initiates with the one-electron reduction of cyclopentyl silyl peroxide by the in situ-generated Feⁿ complex from ferrocene and Bphen to give alkoxy radical I (Scheme 727). Alkoxy radical I undergoes subsequent β-fragmentation to form radical II, followed by its attack on the C=C of cinnamic acid to give radical III. Thereafter, trimethyl silanoate deprotonates III to generate IV. This is followed the oxidation of IV by Feⁿ⁺¹, leading to the formation of diradical intermediate V. Finally, this intermediate undergoes decarboxylation, forming the desired product.

Scheme 727 Mechanism for the decarboxylative ketoalkylation of α,β-unsaturated carboxylic acids.

Recently, in 2020, Feng and co-workers reported an iron-catalyzed methodology for the silylation of (hetero)aryl chlorides (Scheme 728).¹²⁹⁹ The reaction can be fruitfully performed in the presence of the silylborane reagent Et₃Si-Bpin under the catalytic activity of FeI₂ together with 3,4,7,8-tetra-Me-phen as the ligand. A large number of aryl and heteroaryl chlorides undergo the reaction to give good to moderate yields of the silylated product. Further, the reaction condition provides good tolerance to a large number of functional groups such as hydroxyl, amine, Boc, Bpin, BnO, morpholinyl, CF₃, and alkenyl groups. This reaction has been employed in pharmaceutical chemistry for the late functionalization of molecules in the synthetic process. Pharmaceuticals such as the antitussive and antihistamine, cloperastine, and the antiemetic, buclizine and clomipramine have been successfully silylated to the corresponding products in good yields. Notably, they suggested a radical mechanism based on the results of radical clock experiments and reaction with the radical scavenger TEMPO and radical inhibitor BHT.

Scheme 728 Silylation of aryl chlorides in the presence of iron catalysts.

12. Conclusion and perspective

Over the past few decades, considerable developments have been accomplished in the field of iron catalysis to find green, non-toxic, cheap and overall sustainable alternatives to precious metal catalysts. A large number of promising and efficient iron-catalyzed reactions have been thoroughly discussed in this review. Different organic reactions such as C–H bond oxidation, cross-coupling reaction, C–H activation reaction, cross dehydrogenative coupling reactions, halogenations, hydrogenations, additions, insertion and substitution reactions are successfully performed using iron catalysts. Among them, significant progress has been made in the iron-catalyzed cross-coupling reactions. Despite the predominance of palladium catalysts in this field, iron catalysts have been proven to be competent by their ability to couple aryl, alkenyl and alkyl electrophiles with various organometallic nucleophiles with high efficiency. Also, the application of these methodologies for the total synthesis of various natural products shows the versatility of iron catalysis in cross-coupling. Furthermore, the recent elucidation of the mechanism by the in situ-generated intermediates of the iron-catalyzed cross-coupling reactions using advanced physical inorganic spectroscopic techniques has enabled researchers to gain better insight into the reaction, which will help them to develop novel reaction methods in the future. In addition to cross-coupling, C–H bond activation using iron catalysts has been investigated and developed in the last decade. Highly efficient iron-mediated procedures for the ortho C–H activation and very recently for the meta C–H activation of substrates with suitable directing groups have been well established. Although para C–H activation has been performed using noble metal catalysts such as palladium, it is yet to be achieved by iron catalysts. Moreover, several future developments with iron catalysis are yet to come including C–H activation without the use of a directing group and activation of methylene C(sp³)–H bonds. Bio-inspired non-heme iron catalysts have been synthesized and utilized in site-selective C–H oxidations, which can be predicted by the substrates and catalysts. Further, the recent discoveries have revealed the role of ligand chirality of the catalysts in tuning the site selectivity. Similarly, bio-inspired non-heme iron catalysts have been developed for selective halogenations for aliphatic C–H bonds in a stoichiometric manner. Thus, this has opened up a new scope to develop catalytic halogenation methods. On the other hand, cross-dehydrogenative coupling has emerged as an efficient tool for C–C bond formation due to the formation of the bond without the need for any pre-functionalization of the substrates. In this context, the iron-catalyzed cross dehydrogenative coupling shows a sustainable variant to the dominating late transition metals such as rhodium, iridium, ruthenium, and copper catalysis. Most intriguingly, the increase in the number of iron catalysts for the asymmetric transfer hydrogenation of prochiral ketones for the synthesis of valuable alcohols and imines has brought this to a new level.

Finally, the iron-catalyzed reactions depicted herein are very useful in organic synthesis, and some of them are found to be superior to the precious late transition metals catalysts. Indeed, the modification of different synthesized iron catalysts helps us to reduce the steps of various organic transformations. Optimistically, green and cheap iron catalysts will possibly give every possible reaction usually implemented by the toxic and precious noble metals catalysts.

List of abbreviations

PMP	Polymethylpentene
DCIB	Dichloroisobutane
TMEDA	Tetramethyethylenediamine
THF	Tetrahydrofuran
dtbpy	4,4′-Di-tert-butyl bipyridine
acac	Acetylacetonato
dppf	1,1′-Bis(diphenylphosphino)ferrocene
dppen	(Z)-1,2-Bis-(diphenylphosphino) ethane
dppe	1,2-Bis(diphenylphosphino)ethane
DCB	2,3-Dichlorobutane
DABCO	1,4-Diazabicyclo[2.2.2]octane
DME	Dimethoxyethane
dppbz	1,2-Bis(diphenylphosphino)benzene
TEMPO	(2,2,6,6-Tetramethylpiperidin-1-yl)oxidanyl
anis	Anisole
BHT	2,6-Di-tert-butyl-4-methylphenol
DCP	1,2-Dichloropropane
HOSA	Hydroxylamine-O-sulfonic acid
HFIP	1,1,1,3,3,3-Hexafluroisopropanol
dmpe	1,2-Bis(dimethylphosphino)ethane
9-BBN	9-Bicycloboranonane
DMEDA	1,2-Dimethylethylenediamine
PyTACN	1-(2-Pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclonoane
Bar4^F	Tetrakis(bis-3′5-trifluoromethylphenyl)borate
CYP	Cytochrome P-450
TFDO	(Trifluoromethyl)dioxirane
MMO	Methane monooxygenase
TPA	Tris(2-methylpyridyl)amine
PDP	2-({(S)-1-[(Pyridine-2-yl-methyl)pyrrolidin-2-yl]pyrrolidin-1yl}methyl)pyridine
PMHS	Polymethyl hydroxy silane
TBAB	Tetra-butyl ammonium bromide
TMG	1,1,3,3-Tetramethylguanidine
Tp^Ph2	Hydrotris(3,5-diphenyl-pyrazol-1-yl)borate
TQA	Tris-((quinolyl-2-methyl)amine)
DTBP	Di-tert-butyl peroxide
TBHP	tert-Butyl hydro peroxide
DDQ	2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DCE	1,2-Dichloroethane
DHF	Dihydrofuran
NBS	N-Bromo succinamide
THIQs	Tetrahydroisoquinolines
AIBN	Azobisisobutyronitrile
NMDA	N-Methyl-D-aspartate
TBAF	tetra-n-Butylammonium fluoride
DMSO	Dimethyl sulfoxide
MTBE	Methyl tert-butyl ether
EDA	Ethyl diazoacetate
F20-tpp	meso-Tetrakis(pentafluorophenyl)porphyrinatodianion
qpy	2,2′:6′,2′′:6′′,2′′′:6′′′,2′′′′-Quinquepyridine
N4Py	N,N-Bis(2-pyridyl-methyl)bis(2-pyridyl)methylamine
HMSI-BOX	Hexamethyl-1,1′-spirobiindane-based bisoxazoline ligand (HMSI-BOX)
dbm	Dibenzoylmethane
NMP	N-Nethylpyrrolidione
DMPU	N,N′-Dimethylpropyleneurea
DMB	Dibenzoylmethane
LDA	Lithium diisopropylamide
TMU	Tetramethyl urea
DMI	1,3-Dimethyl-2-imidazolidinone
dppy	2-Diphenylphosphinopyridine
HMTA	Hexamethylenetetramine
TBS	tert-Butyldimethylsilyl
CPME	Cyclopentylmethyl ether
depe	Bis(diethylphosphino)-ethane
dppp	1,3-Bis(diphenylphosphino)propane
bdmd	Bis((diphenylphosphanyl)methyl)diphenylsilane
LiHMDS	Lithium hexamethyldisilazide
COD	Cyclooctadiene
dipp2BIAN	2,6-Diisopropylphenyl bis(imino)acenaphthene
TPB	Triphosphine-borane
DBU	1,8-Diazabicyclo[5.4.0]undec-7-ene
IPA	Isopropyl alcohol
TRIP	3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate
GVL	γ-Valerolactone
TPP	Triphenylphosphine
Imes	1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
TVCH	1,2,4-Trivinylcyclohexane
VCHO	Vinylcyclohexene oxide
PNN	Phosphinite-iminopyridine
OIP	Oxazolineiminopyridine
PMDS	1,1,3,3,3-Pentamethyldisiloxane
pybox-dm	Bis(oxazolinyl)pyridine
bioy-tb	Bis-tert-butyl-bipyridiene
STC	Sodium thiophene-2-carboxylate
Bopa	Bis(oxazolinylphenyl)amine
PsiP	Bis(phosphine)silyl
bpi	Bis(pyridylimino)isoindole
IPO	Iminopyridine-oxazoline
boxmi	Bis(oxazolinylmethylidene)isoindoline
HEMIM	1-(2-Hydroxyethyl)-3-methylimidazolium
DPB	Bis(o-diisopropylphosphinophenyl)phenylborane
TMDS	1,1,3,3-Tetramethyldisiloxane
BDSB	1,2-Bis-(dimethylsilyl)benzene
^DippC:	Bis-(N-Dipp-imidazole-ylidene)methylene
Hbpin	Pinacolborane
BIAN	Bis(2,6-diisopropylaniline)acenaphthrene
VCP	Vinylcyclopropane
NCS	N-Chlorosuccinimide
TBA	Tertiary butyl alcohol
TFA	Trifluoroacetic acid
tmtaa	Dibenzotetramethyltetraaza[14]annulene
DPPPent	1,5-Bis(diphenylphosphino)pentane (DPPPent)
OTBDMS	tert-Butyldimethylsilyl ethers
DEAD	Diethyl azodicarboxylate
Bmim	1-Butyl-3-methylimidazolium
Omim	1-Methyl-3-octylimidazolium
BINAM	1,1′-Binaphthyl-2,2′-diamine (FeCl2–BINAM)

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge BRNS-India (RD/0118-BRNS000-002) (DM) and SERB-India (SRG/2019/000310) (SR) for financial support. CSIR-India is acknowledged for fellowship (JP). AP thanks SERB-India for fellowship (Project assistant fellowship from SRG/2019/000310).

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