Photoinduced deaminative strategies: Katritzky salts as alkyl radical precursors

José Tiago M. Correia , Vitor A. Fernandes , Bianca T. Matsuo , José A. C. Delgado , Wanderson C. de Souza and Márcio Weber Paixão *
Centre of Excellence for Research in Sustainable Chemistry (CERSusChem), Department of Chemistry, Federal University of São Carlos – UFSCar, São Carlos, São Paulo, 13565-905, Brazil. E-mail: mwpaixao@ufscar.br

Received 24th October 2019 , Accepted 3rd December 2019

First published on 5th December 2019


Abstract

Primary amines are one of the most predominant functional groups found in organic molecules. These entities help form the chemical architecture of natural products, bioactive molecules, synthetic building blocks and catalysts. Due to their ubiquitous presence, the development of strategies for the construction of C–C or C–X bonds through deaminative processes is of high importance. Deaminative methods offer new possibilities on the retrosynthetic rationale, and enable late-stage-functionalization of complex structures. As a result of the recent development of photoinduced processes, a variety of photo-mediated deaminative protocols employing 2,4,6-triphenyl-pyridinium salts – Katritzky Salts – as activating agents have been recently realized. This review covers the most recent developments of deaminative strategies by using Katritzky Salts as alkyl radical reservoirs, with particular concern on photoinduced processes applied to organic synthesis.


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José Tiago M. Correia

José Tiago M. Correia was born in Salvador, BA, Brazil, in 1986. He received his BSc in Chemistry in 2010 from the Federal University of Bahia (Brazil) and his MSc degree from the University of Campinas (2012). In 2017, he completed his PhD at the same university under the supervision of Prof. Fernando Coelho and had spent one-year as a visiting PhD student at Max-Planck Institut für Kohlenforschung, Mülheim an der Ruhr – Germany (2015–2016) under the supervision of Prof. Benjamin List. In 2017, he joined the group of Prof. Márcio W. Paixão as a posdoctoral research fellow and currently is conducting part of his research at Institut Català d'Investigació Química, Tarragona – Spain, where he is working under the guidance of Prof. Ruben Martin. His research interests focus on the development of new photocatalytic methodologies for the synthesis and functionalization of heterocycles.

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Vitor A. Fernandes

Vitor Alcantara Fernandes was born in Santos, SP, Brazil, in 1992. He received his BSc in Chemistry in 2015 from the Federal University of São Carlos, UFSCar, Brazil. In 2014, he spent a period at the Freie Universität Berlin in Germany, working in the Research Group of Professor Christoph Tzschucke. In 2018, he completed his MSc under the supervision of Prof. Márcio W. Paixão at the Federal University of São Carlos, UFSCar (Brazil). He is currently a PhD student at the same university. His research interests focus on asymmetric reactions, development of new catalytic methodologies and mechanistic studies.

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Bianca T. Matsuo

Bianca Taeko Matsuo was born in Ribeirão Preto, SP, Brazil, in 1992. She completed her undergraduate studies (2015) at the Federal University of São Carlos, UFSCar (Brazil) and her MSc in Chemistry at the same university (2017), with a research period at Vrije Universiteit Amsterdam in Holland. In 2017, she started her PhD studies under the guidance of Prof. Márcio W. Paixão at UFSCar. Currently, she is conducting part of her research at Emory University in collaboration with Prof. Huw M. L. Davies. Her research interests focus on the development of catalytic methodologies based on asymmetric organocatalysis, photocatalysis and intermolecular C–H functionalization.

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José A. C. Delgado

José A. C. Delgado was born in Santa Clara, Villa Clara, Cuba, in 1990. He received his BSc in Chemistry from the University of Havana (Cuba) in 2015. In 2018, he received his MSc degree working under the guidance of Prof. Márcio W. Paixão at the Federal University of São Carlos, UFSCar (Brazil). He is currently a PhD student at the same university. His research interest is focused on the development of new photocatalytic protocols for amino acid, peptide and protein modifications.

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Wanderson C. de Souza

Wanderson Costa de Souza was born in Anápolis, GO, Brazil, in 1988. He received his BSc in Chemistry in 2008 from the State University of Goiás, UEG, Brazil. In 2015, he completed his MSc under the supervision of Prof. Gilberto Lúcio Benedito de Aquino at the same institution. He is currently a PhD student under the supervision of Prof. Márcio W. Paixão at the Federal University of São Carlos, UFSCar (Brazil). His research interests focus on photocatalytic transformations.

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Márcio Weber Paixão

Márcio Weber Paixão received his BSc in Chemistry in 2003 from the Federal University of Santa Maria, UFSM, Brazil. In 2007, he completed his PhD under the supervision of Prof. A. L. Braga (UFSMBrazil) and co-supervision of Prof. Dr. Ludger Wessjohann (Leibniz Institute of Plant Biochemistry – IPB Halle – Germany), working with catalytic enantioselective methodologies. He immediately started postdoctoral studies at the University of São Paulo (Brazil) and then at the Center for Catalysis, University of Aarhus, DK, where he worked under the guidance of Prof. Karl A. Jørgensen. In 2010 he started his independent career at the Federal University of São Carlos, Brazil. In 2012 he worked as a visiting professor in the Group of Prof. Carlos F. Barbas III at The Scripps Research Institute (TSRI). In 2016–2017 he had a sabbatical research stay at the University of California, Berkeley with Prof. F. Dean Toste. His research interests focus on the development of new catalytic methodologies.


Introduction

Amines are among the most prevalent functional groups in organic molecules. They are abundant in the chemical architecture of many natural products, pharmaceuticals and agrochemicals. Moreover, the amine moiety is a key functionality in amino acids, which constitute essential building blocks for peptide synthesis (Scheme 1).
image file: c9cc08348k-s1.tif
Scheme 1 Structurally relevant scaffolds containing an amine functional group.

Considering the importance of the amine functionality, numerous mild, site-selective and straightforward synthetic methods have been developed to forge C–N bonds over the years.1 Complementary strategies for both C–C and C–X bond constructions via deaminative processes are also of great importance. In this way, site- and stereoselective alkyl chain homologation or functionalization from such a privileged functionality may open a new avenue for retrosynthetic rationalization, especially, enabling late-stage-functionalization of complex molecular architectures.

From a historical standpoint, the deaminative C–C or C–X functionalization from diazonium-salts (e.g. Sandmeyer and Balz–Schiemann reactions,2,3 Meerwein arylation,4 and Heck–Matsuda cross-coupling5) are among the most classical transformations in organic chemistry. Recently, the photocatalytic generation of aryl-radicals by single electron reduction of arenodiazonium salts has also been reported in the context of Meerwein arylation, carbonylation and cross-coupling processes.6

Moreover, due to thermal instability, the applications of aliphatic diazonium salts are very much limited to intramolecular processes, such as Demjanov and Tiffenau–Demjanov rearrangement.7,8 More recently, quaternary ammonium salts have also been used in C–C couplings. However, these methods are mostly limited to allyl-, aryl- or benzyl(trialkyl)ammonium salts, since they are highly prone to undergo elimination (Scheme 2).9


image file: c9cc08348k-s2.tif
Scheme 2 Examples of strategies for C–N bond formation and underexplored deaminative reactions.

Likewise, pyridinium salts have shown a wide range of applications in organic chemistry. Some low melting pyridinium salts have seen applications as ionic-liquids, being used as solvents, electrolytes, electrode binders or surfactants. Other salts have displayed attractive biological activity as antimicrobial, antifungal, antimalarial and anti-tumor agents.10 Last and the most important to the aim of this review, pyridinium salts are versatile building blocks for the preparation of saturated and unsaturated pyridinic derivatives (di- and tetrahydropyridines, piperidines and indolizines). Pyridinic ring opening is well explored and under appropriate reaction conditions, gives access to conjugated dienes, dienals and dienamines with many applications in synthetic organic chemistry.11 The reactivity of pyridinium salts under UV light induced photochemical conditions has also been extensively explored since the early '70s. The photoisomerization and photo-solvation products, normally obtained from these processes (bicyclic aziridines, 1,3-dihydro-2-aminocyclopentene and indolizidine derivatives respectively), could further be employed as building blocks in the total synthesis of natural products.10,11 Moreover in the '70s, Katritzky demonstrated that bulky pyridinium salts prepared from pyrylium salts and amines could act as efficient electrophiles in substitution reactions. These studies revealed that pyridinium salts derived from 2,4,6-triphenyl-pyrylium showed the best performance among the evaluated salts.12 The redox profile of Katritzky salts was studied in the '80s,13 however, their application as redox-active species for the construction of C–C bonds has not been reported until recently. Of particular relevance, the Watson group disclosed the first nickel-catalyzed deaminative Suzuki cross-coupling, employing Katritzky salts as a C-centered-radical source.14 This work was followed by the Glorius group, in which they revealed the application of the Katritzky salts in photocatalytic deaminative Minisci reactions.15 These two contributions can be recognized as important landmarks in the respective fields, serving as motivation to the growing number of methodologies that have already been developed over the last two years.

The synthetic community has witnessed fast and impressive development of photoinduced electron-transfer processes.16,17 An outstanding aspect of photocatalysis is the mild and unconventional activation of traditionally inert functional groups through the exploration of their redox potentials, excited state energies and all the intrinsic aspects of radical chemistry reactivity. Although some reviews and accounts covering the photocatalytic C–C and C–Heteroatom couplings via decarboxylation, deborylation and C–H abstraction have recently been reported,18 this fast growing field still lacks a concise review exclusively highlighting the recent advances in photocatalytic deaminative processes involving 2,4,6-triphenyl-pyridinium salts (aka. Katritzky salts).19 Recognizing this gap, herein, we deliver a more conceptual overview about the reactivity of the Katritzky salts in a photoinduced process for C–C and C–Heteroatom couplings, based on the outstanding recent reports.

General aspects of the reactivity of Katritzky salts in photocatalytic processes

Due to low reduction potentials, the alkyl pyridinium salts (E1/2 ∼ −0.90 V vs. SCE in DMF)20 serve as excellent electron acceptors and consequently, could easily be reduced to radical-zwitterionic pairs via single electron transfer (SET). The SET event arises from an excited photoredox catalyst or its reduced congener or even from an electron donor through Electron–Donor–Acceptor (EDA)-complexation (Scheme 3).13
image file: c9cc08348k-s3.tif
Scheme 3 The photochemical performance of Katritzky salts in comparison with other redox active species for the generation of alkyl radicals. a Potentials in volts versus saturated calomel electrode (SCE).21

The two different outcomes of the photocatalytic cycles can be distinguished by comparing the redox potentials of the photocatalysts (Scheme 4).


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Scheme 4 Possible mechanistic pathways for the Katritzky salt reduction: oxidative and reductive quenching.

In the first reaction pathway, the photoexcited catalyst directly reduces the alkyl-pyridinium salt (oxidative quenching pathway), forming an oxidized photocatalyst, which is then reduced by the substrate or a sacrificial electron donor to close the catalytic cycle. Similarly, in the alternative pathway, the photoexcited catalyst is first reduced by a reductant additive (reductive quenching – normally a tertiary amine) being converted to a reduced catalytic intermediate. This intermediate is capable of reducing the Katritzky salt, to get catalytic turn over. In both cases, the singly reduced pyridinium salt is rapidly decomposed to the 2,4,6-triphenylpyridine and the respective alkyl radical.

Another reactivity recently disclosed for Katritzky salts is their ability to participate in photosensitive Electron–Donor–Acceptor (EDA) complexation. In the excited state, these complexes undergo a single electron transfer (SET) from the donor molecule to the Katritzky salt, triggering a pathway similar to that described in the photoredox catalytic processes. According to studies already reported, the electron-transfer proceeds through a π-stacking interaction between the donor molecule and the electron-deficient π-system of the pyridinium ion (Scheme 5).


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Scheme 5 Reactivity of Katritzky salts as a component in electron–donor–acceptor complexes.

Carbon–carbon bond formation

C(sp2)–C(sp3) bond formation by photoredox catalysis

In 2017, Watson and co-workers reported a nickel-catalyzed Suzuki–Miyaura reaction using Katritzky salts derived from primary and secondary amines.14 This method was the first example of a cross-coupling reaction through a C–N bond activation of amines bearing unactivated alkyl groups and presented a broad reaction scope and functional group tolerance. Preliminary mechanistic investigations suggested a NiI/NiIII cycle in which the Katritzky salt is reduced by an ArNiI intermediate to the respective alkyl radical prior to being trapped by the NiII intermediate formed afterward. Inspired by this work, Glorius and co-workers envisioned that similar alkyl radicals could be easily formed via a single-electron-reduction of Katritzky salts via photocatalysis (Scheme 6).22
image file: c9cc08348k-s6.tif
Scheme 6 First reports on reduction of Katritzky salts with unactivated alkyl groups.

In the absence of a reactive nickel species, the alkyl radical could be trapped by a closed-shell organic molecule. The feasibility of this deaminative strategy was demonstrated by the introduction of a wide range of alkyl moieties in different N-heteroarenes (Scheme 7).


image file: c9cc08348k-s7.tif
Scheme 7 Deaminative strategy for the introduction of alkyl moieties in different N-heteroarenes.

This mild and efficient method exhibits a broad scope of primary amine precursors – from simple cyclic and acyclic alkyl-amines to challenging and abundant amino acids – for the regioselective alkylation of heteroarenes with distinct electronic properties. While nucleophilic alkyl radicals were employed in the Minisci-type reaction with quinolines and its derivatives, α-carboxyl radicals were the radical partners for the reaction with indoles, demonstrating that the nature of the radicals involved in this reaction is an important issue to be considered for a successful output. Moreover, it is noteworthy to mention that amino acids have been previously employed as radical precursors via photoredox decarboxylative processes,23 therefore this deaminative protocol offers a new and complementary tool for generation of alkyl radicals from the same abundant and natural feedstock.

Soon after, Xiao and co-workers24 reported the use of Katritzky salts for the development of a photocatalytic deaminative Heck-type alkylation approach (Scheme 8a). This strategy emerges as a mild alternative and complementary method for the traditional and well established palladium-catalyzed Heck arylation. After all, regardless of the huge advances that have been made in this field, the Heck alkylations still represent a great challenge due to the instability of the alkyl-palladium intermediates.25 The mechanism of this transformation occurs via an oxidative quenching pathway, where the redox cycle is closed by converting the alkyl-radical to the respective carbocation, which then suffers deprotonation to the olefinic product.


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Scheme 8 Mild Heck-type alkylation via a deaminative process.

Although only electron-poor olefins were employed, a variety of alkenes could be obtained under the reaction conditions. Moreover, the protocol shows good functional group tolerance, allowing the use of α-aryl enol ethers and enamides as starting materials, furnishing ketones and β-alkylated enamides in good to high yields. Furthermore, the authors developed a carbonylative Heck version of this strategy, affording the α,β-unsaturated ketones in good yields (60–74%).

Recently and in a similar way, Uchiyama and collaborators developed a stereodivergent approach for the synthesis of 1,2-dissubstituted alkenes by employing terminal alkenes and Katritzky salts under visible-light irradiation.26 Interestingly, the authors designed the syntheses in order to obtain the desirable diastereoisomer. For the trans isomer, they employed [Ru(bpy)3](PF6)2, whereas the cis isomer is obtained by using fac-Ir(ppy)3, due to EZ isomerization promoted by the Ir-based photocatalyst (Scheme 8b).

Notably, this protocol displayed excellent chemoselectivity, high yields and broad functional group tolerance, enabling the functionalization of challenging substrates (e.g. free amine and hydroxyl groups). In addition, this protocol proved to be efficient for styrene derivatives containing both electron-donating and withdrawing groups as well as 1,2 and 1,1-disubstituted alkenes, furnishing the products in good yields. Although the reaction presented good yields for bulky styrenes, such as mesityl derivatives, only the E isomer was obtained under both reaction conditions, suggesting that the isomerization can be blocked when highly bulky substrates are employed. To further explore the application of this approach, the authors envisioned the current protocol could be extended by including an electron-deficient olefin, leading to the three-component product. Some examples were synthesized via this strategy, although only moderate yields were obtained.

Katritzky salts can also be used as building blocks for the photocatalytic synthesis of N-heterocyclic compounds. Recently, Liu and co-workers reported a general protocol for the preparation of 6-alkylated phenanthridines using Katritzky salts derived from amino acids as alkylating agents at room temperature without any external strong oxidant (Scheme 9).27


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Scheme 9 Preparation of 6-alkylated phenanthridines promoted by an oxidative quenching of the photocatalyst.

This approach could be employed to a broad scope of substrates, in terms of both isocyanides and amino acids precursors. Among the catalyst evaluated, Ru(bpy)3(PF6)2 showed slightly better performance, being quenched by the amino acid-derived Katritzky salts without the addition of any quencher additive.

Turning back to the context of Csp2–Csp3 cross-couplings, the first photocatalytic nickel-catalyzed cross-coupling between Katritzky salts and aryl-halides was reported by Molander and co-workers (Scheme 10).28,29


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Scheme 10 The first photocatalytic nickel-catalyzed cross-coupling reaction between Katritzky salts and aryl-halides.

Given the mild basic reaction conditions employed, diverse sensitive moieties could be incorporated in the chemical architecture of the aryl-bromides (e.g. lactone, sulfonamide and pinacol boronic ester), which could be further used as a synthetic precursor for Chan-Lam or Suzuki couplings. Likewise, heteroaryl bromides – for which the corresponding boronic acids are unstable – have been successfully applied. Particularly, nitrogen-containing heteroaryl bromides (e.g. quinolone, isoquinoline) could be selectively alkylated, showing complementary reactivity to the Minisci-type photoinduced strategies previously reported. Turning attention to the scope of the alkyl pyridinium salts, it is important to highlight that Katritzky salts containing free hydroxyl groups resulted in product formation, qualifying this strategy as an orthogonal method to the MacMillan C–O bond formation.30

Concerning the photocatalytic cycle proposed for this approach, a reductive quenching cycle is operative, in which the photoexcited catalyst is reduced by triethylamine to form an intermediate capable of reducing not only the Katritzky salt but also the nickel species – both NiII source and NiI intermediates – present in the reaction medium. The Ni0 catalyst formed in the initial stage of the process is trapped by the alkyl-radical intermediate generated from the Katritzky salt to form an alkyl–NiI intermediate. Thereafter, the alkyl–NiI intermediate undergoes oxidative addition on the aryl bromide to afford a NiIII intermediate, which readily passes through reductive elimination, affording the cross-coupling product and a NiI–Br complex that must be reduced in order to regenerate the initial Ni0 catalyst.

C(sp2)–C(sp3) bond formation by photoexcitation of the electron–donor–acceptor complexes

In a very recent contribution, Glorius and co-workers reported an alkylation enabled by the photoexcitation of electron donor acceptor (EDA) complexes by visible light of a wide range of heteroarenes and enamines with Katrizitky pyridinium salts derived from amino acids and peptide feedstocks.31

In 2013, Melchiorre and co-workers reported a highly chemo- and regioselective alkylation of indoles through visible-light-mediated photoexcited EDA complexes (Scheme 11a).32 Besides, other groups have also demonstrated the utility of EDA complexes in a range of photochemical transformations.33 However, most of these strategies present substrate scope restriction – due to the need to use strong electron-deficient arenes as an acceptor.


image file: c9cc08348k-s11.tif
Scheme 11 Catalyst-free alkylation of amino acids and peptide moieties through photosensitive electron–donor–acceptor complexes.

To overcome this limitation, Glorius and co-workers have employed amino acid derived Katritzky salts as the traceless acceptors in EDA complexes. Through this method, the functionalization of a wide range of heteroarenes in moderate to good yields was accomplished (Scheme 11b). It should be highlighted that the strategy is not strongly influenced by changes in the amino acid moiety of the Katritzky salt, furnishing methionine, lysine, tyrosine, and alkyl (e.g. alanine and glycine) coupled products in comparable chemical yields. Another breakthrough of the current study is the extension of the methodology to an enamine organocatalytic variant by employing carbonyl compounds in the presence of pyrrolidine – which potentially opens a perspective to the asymmetric version.

Furthermore, there are some interesting features regarding the mechanism of this transformation (Scheme 12). To perform these mechanistic studies, the authors selected a model reaction between the pyridinium salt and indole using morpholine as a base. First, an EDA complex A is formed between the pyridinium salt and the indole, and subsequently a portion of this complex dissociates and then initiates an exergonic radical chain process. The pyridinyl radical – formed by this dissociation – can irreversibly fragment to form the electrophilic alkyl radical, which based on DFT calculations is the turnover-determining intermediate of this process. Afterward, this radical combines with the indole, affording the benzylic radical intermediate. In the next step, it is interesting to mention that considering the reduction potential of the species (−0.48 and −0.98 V, respectively), this step is thermodynamically unfavorable; thus a base-promoted electron-transfer via a concerted proton-coupled-electron-transfer (PCET) process was proposed.


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Scheme 12 Proposed mechanism for the photoinduced functionalization of heteroarenes.

C(sp)–C(sp3) bond formation by photoredox catalysis

As previously discussed, many studies have focused on the development of synthetic methods for the formation of C(sp2)–C(sp3) bonds. Conversely, there is still a lack of general approaches for the construction of C(sp)–C(sp3) bonds. To fulfill this gap, Gryko and co-workers have reported a metal-free photoredox approach that allows the formation of C(sp)–C(sp3) bonds (Scheme 13).34,35 In this work, the authors envisage that alkyl radicals – generated from Katritzky salts – could be trapped by the electrophilic alkyne derivative leading to the formation of internal alkynes.
image file: c9cc08348k-s13.tif
Scheme 13 A metal-free photoredox approach for the synthesis of internal alkynes.

The developed method was extended for a variety of substrates bearing several different functionalities – carbamates, hydroxyl groups, sulfide, halogens, ester, pyridines and alkenes – and all of them provided the desired product in moderate to excellent yields.

Furthermore, to show the applicability of the methodology, the authors have selected some complex targets – commercially available pharmaceuticals bearing the amino moiety, a steroid and an anti-inflammatory drug – to be selectively functionalized. In all cases, the desired products were obtained in moderate to good yields, demonstrating, therefore, the feasibility of this method in late-stage functionalization.

On the other hand, primary alkyl and electron-rich benzylic Katritzky salts did not undergo this transformation. A possible explanation presented by the authors is the low stability of primary radicals and the notably slow reaction rates, affording only trace amount of the product, even at prolonged reaction time.

C(sp3)–C(sp3) bond formation via photoredox catalysis

In the following section there will be presented a compilation of methods for forging C(sp3)–C(sp3) bonds from in situ generated C(sp3) radicals. Radical addition to an electron-deficient π-system is frequently employed for carbon–carbon bond formation.36a,b Moreover, it should be considered as a milder alternative to the well-established Michael addition.36c Additionally, this concept proves to be one of the most versatile tools in organic synthesis being widely applied in the construction of a broad range of natural products.36d

In this regard, one interesting approach involves the addition of carbon-centered radicals to allylic systems, which then undergo fragmentation rebuilding the double bond. In the overall process, an alkyl group can be inserted with the allylic substitution partner resembled (Scheme 14).37


image file: c9cc08348k-s14.tif
Scheme 14 Addition of alkyl radicals to allylic systems.

Based on this concept, Liu and co-workers developed a photocatalyzed allylation reaction via a deaminative strategy having Katritzky pyridinium salts as radical precursors (Scheme 15).38


image file: c9cc08348k-s15.tif
Scheme 15 A metal-free photoredox approach for accessing the synthesis of terminal alkenes.

In this work, a variety of cyclic and acyclic radicals could be allylated in good to excellent yields. Remarkably, this methodology showed a good functional group tolerance due to its mild reaction conditions, encompassing amino acid-derived Katritzky salts (e.g. alanine, tyrosine, methionine and glutamic acid). Concerning the allylic partner, allyl sulfones bearing methyl, ester, cyano and aryl moieties were also suitable when subjected to the optimized reaction conditions. Interestingly, substrates containing halogen atoms were likewise appropriate – this finding enables further cross-coupling reactions, demonstrating a sort of orthogonality.

The catalytic bis-functionalization of olefins is amongst the most powerful and important approaches in contemporary organic synthesis, becoming a subject of recently published reviews.39 Through this strategy, simple alkenes can be transformed into highly functionalized structures in a single step. Recently, Glorius, Lautens and co-workers have reported a three-component di-carbofunctionalization protocol between styrenes, arenes and alkyl radicals generated via deamination of Katritzky salts (Scheme 16).40 The first step of the reaction encompasses the alkyl radical addition across the olefin double bond, generating a stable benzylic radical that is promptly oxidized by the photocatalyst. The benzylic carbocation was subsequently trapped by the electron-rich arene via an electrophilic aromatic substitution to deliver the desired dicarbofunctionalization product.


image file: c9cc08348k-s16.tif
Scheme 16 Photocatalytic three-component dicarbofunctionalization of olefins.

The methodology showed a valuable reaction scope, especially by means of the Katritzky salts, where benzylic and amino acid derivatives afforded highly functionalized products in moderate to good yields. Notably, challenging compounds for the classic transition-metal-catalyzed strategies – e.g. those containing thioether and pyridine moieties – could be accessed by the designed protocol.

C(sp3)–C(sp3) bond formation by photoexcitation of electron donor–acceptor complexes

In a conceptually distinguishing approach, Aggarwal and co-workers have developed a catalyst-free deaminative protocol for the Giese reaction which proceeds via an Electron Donor–Acceptor complex between Katritzky pyridinium salts with either triethylamine or Hantzsch ester (Scheme 17).41 Particularly, the protocol could successfully be applied to a wide number of Michael acceptors – therefore a variety of Giese products were obtained, bearing different functional groups; for example, ester, nitrile, ketone, amide, sulfone or even more reactive moieties are tolerated (e.g. aldehydes, silanes and boronic ester).
image file: c9cc08348k-s17.tif
Scheme 17 Deaminative protocol for a Giese reaction via photosensitive electron–donor–acceptor complexes.

With respect to the Katritzky pyridinium salts counterpart, a diversity of primary, secondary, benzylic and also other complex structures (e.g. pharmaceutical and natural products) showed great performance under the optimized reaction conditions delivering the desired products in moderate to good yields.

The mild and catalyst-free deaminative conditions were also expanded to a wide range of transformations (e.g. Giese, allylation, vinylation, alkynylation), displaying high functional group tolerance (Scheme 18).


image file: c9cc08348k-s18.tif
Scheme 18 Selected examples for the versatile developed protocol under mild and catalyst-free conditions.

Moreover, a chalcogenide moiety or reduced products could also be installed under similar conditions.

Finally, this protocol disclosed similar efficacy when compared to previous methodology for the generation of the Giese adducts.

Carbon–boron bond formation

As an extension of their investigations on the development of photocatalytic borylations,42 Aggarwal and co-workers reported a photoinduced deaminative borylation of alkylamines.43 During the development of this protocol, the authors also observed that both π-stacking and coordination interactions of the reagents and solvent play a pivotal role in the C-based radical generation. These data along with control experiments led the authors to suggest a reaction pathway involving a tertiary-EDA complex (Scheme 19).
image file: c9cc08348k-s19.tif
Scheme 19 Photoinduced deaminative borylation of alkylamines via a tertiary–EDA complex.

The approach displayed good functional group tolerance, enabling the borylation of substrates bearing silyl ethers, carboxylic acids, esters, secondary amides, alkynes and olefin groups. Notably, this protocol enables the borylation of unreactive primary Katritzky salts providing the products in good yields, and also a wide range of secondary derivatives could be efficiently used in this transformation.

Concurrently, Glorius and co-workers described a similar protocol for the same transformation.44 Moreover, aside from the broad scope demonstrating the synthetic utility of the protocol, the authors also depicted a comprehensive mechanistic study. The proposed mechanism was based mostly on time-dependent density functional theory (TDDFT) calculations and quantum yield determination. Computational data suggest that the electron transfer step is thermodynamically favored and enabled by the redox potentials of the species.

The authors also performed the reaction starting directly from the amine in a one-pot process, whereby the Katritzky pyridinium salt was generated in situ. Pleasingly, the one-pot approach was even more efficient than the original protocol, affording the desired product in a better yield over the 2 steps (76% vs. 64%). Despite all the great contributions that both of these studies have fetched to the synthetic community, the most remarkable feature is the selective functionalization of densely and complex structures, such as natural products and biologically relevant molecules, as depicted in Scheme 20.


image file: c9cc08348k-s20.tif
Scheme 20 Selected examples of functionalization of biologically important structures.

Due to the mild reaction conditions, broad scope and functional group tolerance, these protocols have emerged as powerful tools for late-stage functionalization of complex molecules.45

Conclusions

Recent developments in visible light photocatalysis via radical processes have enabled distinct activation modes, revolutionizing the chemist's outlook on synthetic approaches and problems. In this regard, the use of Katritzky salts as redox-active species broadens the application of simple primary alkyl amines in an unprecedented way. These molecules, previously recognized as special building blocks for the synthesis of N-containing molecules, can promptly be counted as C–C and C–X building blocks or a new synthon in retrosynthetic analysis. Beyond applications in total synthesis, another important contribution to this field is in late-stage functionalization approaches. The possibility of functional group interchange of a specific primary amine moiety opens a new perspective for the modification of biological active molecules and peptides, impacting drug discovery and bioconjugation processes. The aim of the review was not only to highlight outstanding contributions, but also to encourage the synthetic community to discover new photocatalytic transformations.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to CNPq (306687/2017-8 and INCT Catálise), FAPESP (2019/01973-9, 14/50249-8, 15/17141-1 and 17/10015-6) for financial support. GSK is also acknowledged for the financial support. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. The authors also acknowledge Craig Day (ICIQ) and Sam Mckinnon (Emory University) for the helpful revision on the manuscript.

Notes and references

  1. For selected reviews, see: (a) J. Bariwal and E. Van der Eycken, Chem. Soc. Rev., 2013, 42, 9283 RSC; (b) M. D. Karkas, Chem. Soc. Rev., 2018, 47, 5786 RSC; (c) J. Luo and W.-T. Wei, Adv. Synth. Catal., 2018, 360, 2076–2086 CrossRef CAS.
  2. (a) T. Sandmeyer, Berichte der Dtsch. Chem. Ges., 1884, 17, 2650–2653 CrossRef; (b) H. H. Hodgson, Chem. Rev., 1947, 40, 251–277 CrossRef CAS PubMed.
  3. G. Balz and G. Schiemann, Ber, 1927, 60B, 1186–1190 CrossRef CAS; A. Roe, Org. React., 1949, 5, 193–228 Search PubMed.
  4. (a) H. Meerwein, E. Büchner and K. van Emster, J. Prakt. Chem., 1939, 152, 237–266 CrossRef CAS; (b) C. S. Rondestvedt Jr, Org. React., 1960, 11, 189–260 Search PubMed; (c) C. S. Rondestvedt Jr, Org. React., 1976, 24, 225–259 Search PubMed; (d) C. Galli, Chem. Rev., 1988, 88, 765–792 CrossRef CAS; (e) S. Kindt and M. R. Heinrich, Synthesis, 2016, 1597–1606 CAS.
  5. (a) K. Kikukawa and T. Matsuda, Chem. Lett., 1977, 159–162 CrossRef CAS; (b) J. G. Taylor, A. V. Moro and C. R. D. Correia, Eur. J. Org. Chem., 2011, 1403–1428 CrossRef CAS.
  6. D. P. Hari and B. König, Angew. Chem., Int. Ed., 2013, 52, 4734–4743 CrossRef CAS PubMed.
  7. (a) N. J. Demjanov and M. Luschnikov, J. Russ. Phys. Chem. Soc., 1901, 33, 279–283 Search PubMed; (b) N. J. Demjanov and M. Luschnikov, J. Russ. Phys. Chem. Soc., 1903, 35, 26–42 Search PubMed.
  8. (a) M. Tiffeneau and B. Tchoubar, C. R. Chim., 1937, 205, 1411–1413 CAS; (b) P. A. S. Smith and D. R. Baer, Org. React., 1960, 11, 157–188 CAS; (c) G. R. Krow, Tetrahedron, 1987, 43, 3–38 CrossRef CAS.
  9. K. Ouyang, W. Hao, W. X. Zhang and Z. Xi, Chem. Rev., 2015, 115, 12045–12090 CrossRef CAS PubMed.
  10. S. Sowmiah, J. M. S. S. Esperança, L. P. N. Rebelo and C. A. M. Afonso, Org. Chem. Front., 2018, 5, 453–493 RSC.
  11. T. Damiano, D. Morton and A. Nelson, Org. Biomol. Chem., 2007, 5, 2735–2752 RSC.
  12. (a) N. F. Eweiss, A. R. Katritzky, P. L. Nie and C. A. Ramsden, Synthesis, 1977, 634 CrossRef CAS; (b) U. Gruntz, A. A. Ikizler, A. R. Katritzky, D. H. Kenny and B. P. Leddy, J. Chem. Soc., Perkin Trans. 1, 1979, 436 Search PubMed; (c) A. R. Katritzky, U. Gruntz, D. H. Kenny, M. C. Rezende and H. Sheikh, J. Chem. Soc., Perkin Trans. 1, 1979, 430 RSC; (d) A. R. Katritzky, U. Gruntz, N. Mongelli and M. C. Rezende, J. Chem. Soc., Chem. Commun., 1970, 133 Search PubMed; (e) A. R. Katritzky, G. Liso, E. Lunt, R. C. Patel, S. S. Thind and A. Zia, J. Chem. Soc., Perkin Trans. 1, 1980, 849 RSC; (f) A. R. Katritzky, M. F. Abd-el-Megeed, G. Lhommet and C. A. Ramsden, J. Chem. Soc., Perkin Trans. 1, 1979, 426 RSC.
  13. J. Grimshaw, S. Moore and J. Trocha-Grimshaw, Acta Chem. Scand. Ser. B, 1983, 37, 485 CrossRef.
  14. C. H. Basch, J. Liao, J. Xu, J. J. Piane and M. P. Watson, J. Am. Chem. Soc., 2017, 139, 5313 CrossRef CAS PubMed.
  15. F. J. R. Klauck, M. J. James and F. Glorius, Angew. Chem., Int. Ed., 2017, 56, 12336 CrossRef CAS PubMed.
  16. For selected reviews, see: (a) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322–5363 CrossRef CAS PubMed; (b) L. Marzo, S. K. Pagire, O. Reiser and B. König, Angew. Chem., Int. Ed., 2018, 57, 10034–10072 CrossRef CAS PubMed; (c) T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem., 2010, 2, 527–532 CrossRef CAS PubMed; (d) N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116, 10075–10166 CrossRef CAS PubMed; (e) M. H. Shaw, J. Twilton and D. W. C. MacMillan, J. Org. Chem., 2016, 81, 6898–6926 CrossRef CAS PubMed; (f) J. W. Tucker and C. R. J. Stephenson, J. Org. Chem., 2012, 77, 1617–1622 CrossRef CAS PubMed.
  17. (a) K. Zeitler, Angew. Chem., 2009, 121, 9969–9974 CrossRef; (b) J. Xuan and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828–6838 CrossRef CAS PubMed . For selected reviews, see: ; (c) M. Parasram and V. Gevorgyan, Chem. Soc. Rev., 2017, 46, 6227 RSC; (d) L. Ravindar, L. Revathi, W.-Y. Fang, K. P. Rakesh and H.-L. Qin, Adv. Synth. Catal., 2018, 360, 4652–4698 CrossRef; (e) R. Kancherla, K. Muralirajan, A. Sagadevan and M. Rueping, Trends Chem., 2019, 1, 510–523 CrossRef; (f) R. C. McAtee, E. J. McClain and C. R. J. Stephenson, Trends Chem., 2019, 1, 111–125 CrossRef.
  18. For recent reviews on photoredox C–C and C–X couplings see: (a) D. Maiti and T. Patra, Chem. – Eur. J., 2017, 23, 7328–7401 CrossRef PubMed; (b) Y. Jin and H. Fu, Asian J. Org. Chem., 2017, 6, 368–385 CrossRef CAS; (c) J. Schwarz and B. König, Green Chem., 2018, 20, 323 RSC; (d) W.-J. Xiao, C.-J. Zhu, L.-Q. Lu, Y. Chen and D.-G. Yu, Sci. China: Chem, 2018, 62, 24–57 Search PubMed ; For a review on deborylative couplings, see:; (e) J. W. B. Fyfe and A. J. B. Watson, Chem, 2017, 3, 31–55 CrossRef CAS.
  19. For a review, see: F.-S. He, S. Ye and J. Wu, ACS Catal., 2019, 9, 8943–8960 CrossRef CAS.
  20. J. Grimshaw, S. Moore and J. T. Grimshaw, Acta Chem. Scand., Ser. B, 1983, 37, 485–489 CrossRef.
  21. (a) K. Teegardin, J. I. Day, J. Chan and J. Weaver, Org. Process Res. Dev., 2016, 20, 1156–1163 CrossRef CAS PubMed; (b) D. Ravelli and M. Fagnoni, ChemCatChem, 2012, 4, 169–171 CrossRef CAS; (c) T.-Y. Shang, L.-H. Lu, Z. Cao, Y. Liu, W.-M. He and B. Yu, Chem. Commun., 2019, 55, 5408–5419 RSC; (d) G. Kachkovskyi, C. Faderl and O. Reiser, Adv. Synth. Cat., 2013, 355, 2240–2248 CrossRef CAS; (e) D. A. Koch, B. J. Henne and D. E. Bartak, J. Electrochem. Soc., 1987, 134, 3062–3067 CrossRef CAS.
  22. F. J. R. Klauck, M. J. James and F. Glorius, Angew. Chem., Int. Ed., 2017, 56, 12336–12339 CrossRef CAS PubMed.
  23. (a) Y. Jin, H. Yang and H. Fu, Chem. Commun., 2016, 52, 12909–12912 RSC; (b) S. B. Lang, K. M. O’Nele, J. T. Douglas and J. A. Tunge, Chem. – Eur. J., 2015, 21, 18589–18593 CrossRef CAS PubMed; (c) J. Schwarz and B. König, Green Chem., 2016, 18, 4743–4749 RSC; (d) A. Noble, S. J. McCarver and D. W. C. Macmillan, J. Am. Chem. Soc., 2015, 137, 624–627 CrossRef CAS PubMed; (e) A. Noble and D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 11602–11605 CrossRef CAS PubMed; (f) Z. Zuo, H. Cong, W. Li, J. Choi, G. C. Fu and D. W. C. MacMillan, J. Am. Chem. Soc., 2016, 138, 1832–1835 CrossRef CAS PubMed; (g) Z. Zuo and D. W. C. Macmillan, J. Am. Chem. Soc., 2014, 136, 5257–5260 CrossRef CAS PubMed; (h) L. Chu, C. Ohta, Z. Zuo and D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 10886–10889 CrossRef CAS; (i) M. Jiang, H. Yang and H. Fu, Org. Lett., 2016, 18, 1968–1971 CrossRef CAS PubMed; (j) M. Jiang, Y. Jin, H. Yang and H. Fu, Sci. Rep., 2016, 6, 26161 CrossRef CAS PubMed; (k) Y. Jin, M. Jiang, H. Wang and H. Fu, Sci. Rep., 2016, 6, 20068 CrossRef PubMed.
  24. X. Jiang, M. M. Zhang, W. Xiong, L. Q. Lu and W. J. Xiao, Angew. Chem., Int. Ed., 2019, 58, 2402–2406 CrossRef CAS PubMed.
  25. (a) V. P. Ananikov, D. G. Musaev and K. Morokuma, Organometallics, 2005, 24, 715–723 CrossRef CAS; (b) L. Firmansjah and G. C. Fu, J. Am. Chem. Soc., 2007, 129, 11340–11341 CrossRef CAS PubMed.
  26. Z. K. Yang, N. X. Xu, C. Wang and M. Uchiyama, Chem. – Eur. J., 2019, 25, 5433–5439 CrossRef CAS PubMed.
  27. Z. F. Zhu, M. M. Zhang and F. Liu, Org. Biomol. Chem., 2019, 17, 1531–1534 RSC.
  28. Concomitantly to this report, Watson's and Martin's groups reported a very similar approach using stoichiometric manganese as the reducing agent; (a) R. Martin-Montero, V. R. Yatham, H. Yin, J. Davies and R. Martin, Org. Lett., 2019, 21, 2947–2951 CrossRef CAS PubMed; (b) J. Liao, C. H. Basch, M. E. Hoerrner, M. R. Talley, B. P. Boscoe, J. W. Tucker, M. R. Garnsey and M. P. Watson, Org. Lett., 2019, 21, 2941–2946 CrossRef CAS PubMed.
  29. J. Yi, S. O. Badir, L. M. Kammer, M. Ribagorda and G. A. Molander, Org. Lett., 2019, 21, 3346–3351 CrossRef CAS PubMed.
  30. J. Jin and D. W. C. MacMillan, Angew. Chem., Int. Ed., 2015, 54, 1565–1569 CrossRef CAS PubMed.
  31. M. J. James, F. Strieth-Kalthoff, F. Sandfort, F. J. R. Klauck, F. Wagener and F. Glorius, Chem. – Eur. J., 2019, 25, 8240–8244 CrossRef CAS PubMed.
  32. E. Arceo, I. D. Jurberg, A. Álvarez-Fernández and P. Melchiorre, Nat. Chem., 2013, 5, 750 CrossRef CAS PubMed.
  33. (a) For selected examples on EDA-mediated reactions, see: J. Sun, Y. He, X. An, X. Zhang, L. Yu and S. Yu, Org. Chem. Front., 2018, 5, 977–981 RSC; (b) Y. Z. Cheng and S. Y. Yu, Org. Lett., 2016, 18, 2962–2965 CrossRef CAS PubMed; (c) M. Silvi, E. Arceo, I. D. Jurberg, C. Cassani and P. Melchiorre, J. Am. Chem. Soc., 2015, 137, 6120–6123 CrossRef CAS PubMed; (d) M. Nappi, G. Bergonzini and P. Melchiorre, Angew. Chem., Int. Ed., 2014, 53, 4921–4925 CrossRef CAS PubMed; (e) E. Arceo, A. Bahamonde, G. Bergonzini and P. Melchiorre, Chem. Sci., 2014, 5, 2438–2442 RSC . For a comprehensive review on EDA-mediated reactions, see: ; (f) C. G. S. Lima, T. M. Lima, M. Duarte, I. D. Jurberg and M. W. Paixao, ACS Catal., 2016, 6(3), 1389–1407 CrossRef CAS.
  34. M. Ociepa, J. Turkowska and D. Gryko, ACS Catal., 2018, 8, 11362–11367 CrossRef CAS.
  35. K. Goliszewska, K. Rybicka-Jasińska, J. A. Clark, V. I. Vullev and D. Gryko, ChemRxiv, 2019 DOI:10.26434/chemrxiv.8966048.v1.
  36. (a) B. Giese, Angew. Chem., Int. Ed. Engl., 1983, 22, 753 CrossRef; (b) B. Giese, J. A. Gonzalez-Gomez and T. Witzel, Angew. Chem., Int. Ed. Engl., 1984, 23, 69 CrossRef; (c) Y. Zhang and W. Wang, Catal. Sci. Technol., 2012, 2, 42–53 RSC; (d) K. J. Romero, M. S. Galliher, D. A. Pratt and C. R. J. Stephenson, Chem. Soc. Rev., 2018, 47, 7851–7866 RSC.
  37. For selected reviews on allylation, see: (a) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921–2944 CrossRef CAS PubMed; (b) J. D. Weaver, A. Recio, A. J. Grenning and J. A. Tunge, Chem. Rev., 2011, 111, 1846–1913 CrossRef CAS PubMed.
  38. M. M. Zhang and F. Liu, Org. Chem. Front., 2018, 5, 3443–3446 RSC.
  39. (a) X.-W. Lan, N.-X. Wang and Y. Xing, Eur. J. Org. Chem., 2017, 5821–5851 CrossRef CAS; (b) R. Giri and S. KC, J. Org. Chem., 2018, 83, 3013–3022 CrossRef CAS PubMed; (c) R. K. Dhungana, S. KC, P. Basnet and R. Giri, Chem. Rec., 2018, 18, 1314–1340 CrossRef CAS PubMed.
  40. F. J. R. Klauck, H. Yoon, M. J. James, M. Lautens and F. Glorius, ACS Catal., 2019, 9, 236–241 CrossRef CAS.
  41. J. Wu, P. S. Grant, X. Li, A. Noble and V. K. Aggarwal, Angew. Chem., Int. Ed., 2019, 58, 5697–5701 CrossRef CAS PubMed.
  42. (a) A. Noble, R. S. Mega, D. Pflästerer, E. L. Myers and V. K. Aggarwal, Angew. Chem., Int. Ed., 2018, 57, 2155–2159 CrossRef CAS PubMed; (b) A. Fawcett, J. Pradeilles, Y. Wang, T. Mutsuga, E. L. Myers and V. K. Aggarwal, Science, 2017, 357, 283–286 CrossRef CAS PubMed; (c) M. Silvi, C. Sandford and V. K. Aggarwal, J. Am. Chem. Soc., 2017, 139, 5736–5739 CrossRef CAS.
  43. J. Wu, L. He, A. Noble and V. K. Aggarwal, J. Am. Chem. Soc., 2018, 140, 10700–10704 CrossRef CAS PubMed.
  44. F. Sandfort, F. Strieth-Kalthoff, F. J. R. Klauck, M. J. James and F. Glorius, Chem. – Eur. J., 2018, 24, 17210–17214 CrossRef CAS.
  45. (a) M. Moir, J. J. Danon, T. A. Reekie and M. Kassiou, Expert Opin. Drug Discovery, 2019, 1–13 Search PubMed; (b) T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal and S. W. Krska, Chem. Soc. Rev., 2016, 45, 546–576 RSC.

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