Advances in transition-metal catalyzed C–H bond activation of amidines to synthesize aza-heterocycles

Abstract

Amidine compounds, as important nitrogen analogues of isoelectronic carboxylic acids, are found throughout biologically active molecules and serve as the most attractive precursors for the synthesis of N-containing compounds. In this review, the advancements in the synthesis of aza-heterocycles via transition-metal catalyzed C–H bond activation of amidines have been summarized through diverse annulation reactions. Amidines act as two-electron donors via the more basic and less sterically crowded imino lone pair and coordinate with transition-metals, in which N–H imine could act as both directing group and intramolecular nucleophile, electrophile or proton acceptor. The mechanisms of different annulation pathways will be highlighted in this review along with a discussion of more recent developments in the field.

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1 Introduction

Aza-heterocycles, as common fragments of the vast majority of clinical drugs and candidates of medicinal targets, have made notable contributions to the quality of human life.^1,2 Therefore, the diversity of aza-heterocyclic structures, as well as the important biological and pharmaceutical applications, motivated researchers to develop efficient, atom economical and selective transformations to access aza-heterocycles. Amidines, as important nitrogen analogues of isoelectronic carboxylic acids, are found throughout biologically active molecules and among the most attractive precursors for the synthesis of N-containing compounds (Scheme 1a).³ The molecular structure confirmation of amidines dates back to 1858, reported by Gerhardt, through the reaction of aniline with N-phenylbemimidyl chloride and named.⁴ Subsequently, Shriner noted that there were five general types of amidines classified according to the number and distribution of the substituents at the nitrogen atoms, including (i) unsubstituted, (ii) monosubstituted, (iii) symmetrical disubstituted, (iv) unsymmetrical disubstituted and (v) trisubstituted (Scheme 1b).⁵ Especially, amidines contain an amino nitrogen atom with a free electron pair, which conjugate with the π-electrons of the C=N double bond. It combines the properties of an azomethine-like C=N double bond with an amide like C–N single bond with a partial double bond character as indicated by the resonance form (Scheme 1b(ii)).⁶ For more than 160 years, amidines have proven to be irreplaceable building blocks and ranked as one of the most important classes of nitrogen reagents in organic chemistry because of their versatile chemical properties.⁷ For example, they are strongest neutral organic bases due to the ability of their protonated forms to delocalise charge over two nitrogen atoms.⁸ These bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) have been widely used in numerous organic reactions and have often been shown to be advantageous when compared with other organic bases (Scheme 1c).

Scheme 1 Examples of drug molecules containing amidine, bases and the general types of amidines.

Transition-metal catalyzed C–H bond activation has gained great attention in the past decade and become one of the most reliable tools for synthesis of N-heterocycles.^9,10 Among this family, the directing groups (DGs) are generally required to resolve the regio-selectivity and improve the catalytic activity of metal.¹¹ For example, the pyridines¹² and oximes¹³ are used as DGs to realized C–H bond activation through coordinating with transition-metal. However, a single reaction sits will bring chemical trace left in the products, which leads to undesired waste-products. Based on that, the commercially available amidines have attracted intensive interest as DGs to synthesize N-heterocycles, because amidines act as two-electron donors via the more basic and less sterically crowded imino lone pair and coordinate with transition-metal, in which N–H imine could act as both directing group and intramolecular nucleophile or electrophile. However, multiple activity reaction sites of different substitutive amidines not only presented a challenge for the synthetic chemistry but also offered the opportunity to obtain an array of different N-heterocyclic compounds. Generally, according to the principal resonance structures of amidines, the transition-metal catalyzed C–H bond activation of amidines takes the following mainly four chemical transformations (Scheme 2): (a) the N–H imine acts as intramolecular nucleophilic group to promote the [5 + n] annulation progress; (b) the metal-X (X = C, N) or nucleophilic reagent undergoes migratory insertion into the C=N bond (acting an electrophilic group) or the N–H imine acts as intramolecular nucleophilic group, leading [4 + n] annulation progress; (c) nucleophilic reagent undergoes migratory insertion into the C=N bond, resulting in [3 + 3] annulation and the cleavage of C–N bond; (d) the N–H imine is used as the proton acceptor to promote intramolecular proton transfer (IPT) process. Based on its recent advances, it would be timely to provide a comprehensive review of the plethora of transformations in the field of C–H functionalization.

Scheme 2 The strategies of C–H bond activation of amidines.

The previous reviews¹⁴ mainly summarized the preparation, structural studies and synthetic application of amidines. In this review, we summarize and unify the development of the transition-metal catalyzed C–H bond activation of amidines to synthesize heterocyclic compounds since 2008. The critical goal of our review is to draw attention to this burgeoning research area, and stimulate further interest from the synthetic community in discovering novel reactivities as well as multidisciplinary application. We feature the recent development of transition-metal catalyzed C–H bond activation of amidines to synthesize N-heterocycles through diverse annulation models.

2 The [5 + n] annulation of amidines in C–H activation

2.1 The [5 + 0] annulation of amidines

The earliest [5 + 0] annulation of amidines developed in the 1960s was a milestone in organic synthesis chemistry, which has been successfully applied in the selective synthesis of benzimidazoles.¹⁵ Then, organic chemists have made significant efforts to gain insight into the mechanism of this transformation^16,17 until C–H activation comes into view. As early as 2008, Buchwald group¹⁸ firstly reported an efficient copper-catalyzed C–H functionalization/C–N bond-forming approach, providing benzimidazoles in good yields from N-phenylbenzamidines (Scheme 3). Various benzimidazoles could be easily obtained with high step economy. This method could be extended to the preparation of N-methylated 2-phenylbenzimidazoles. Meanwhile, the bulky tert-butyl group was also compatible in this transformation, affording the corresponding products in 83–89% yields. However, the functionalized amidines without ortho substituents showed less reactivity to give the desired benzimidazole, primarily underwent decomposition, which seemed to inhibit the catalytic cycle.

Scheme 3 Cu-catalyzed intramolecular annulation of N-phenylbenzamidines.

On the basis of the previous reports,¹⁹ the possible reaction pathways were proposed in Scheme 4. First, the Cu(OAc)₂ presumably led to a Cu–N adduct 3 with copper either in oxidation state II or III. Subsequently, the N-aryl ring attacked the amidine moiety in a fashion similar to an electrophilic aromatic substitution to form 4 with concurrent release of a reduced copper species in pathway A. The rearomatization of intermediate 4 provides the product 2. In pathway B, the N-phenyl ring attacks the copper center in 3 to give a metallacycle 5, which underwent rearomatization and reductive elimination of the metal to form 2. Pathway C involves a copper nitrene. A concerted insertion of the nitrogen into a C–H bond or an electrocyclic ring closure and a final [1,3]-shift of a hydrogen would then lead to 2.

Scheme 4 The possible reaction pathways for the conversion of 1 into 2.

One year later, Shi and co-workers²⁰ developed a novel method to construct the core structure of 1H-benzo[d]imidazole through Pd^II-catalyzed C–H activation of N-phenylbenzamidines under mild reaction conditions (Scheme 5). This transformation contains a broad substrate scope, with various functional groups being well-tolerated. The detailed mechanism studies indicated that a palladacycle monomer or dimer is the key intermediate for this transformation and thiourea (tetramethylthiourea, TMTU) was first used to prompt the efficiency of C–H activation. Based on a series of control experiments, a possible reaction mechanism was depicted in Scheme 5. Initially, the Pd^II coordinated with imino-group to deliver the palladacycle intermediate 9. In Path a, after the decomposition of the dimeric palladacycle to produce the monomer 10 in the presence of TMTU, the acetate played a role as a base to in removing the proton of the imine group to generate intermediate 11. The intermediate 11 underwent reductive elimination to yield the desired product 8 and Pd⁰ specie, which was oxidized to the Pd^II by copper salt for the next catalytic cycle. In Path b, the palladacycle dimer 9 may also go through the direct deprotonation and reductive elimination to finish this catalytic cycle according to its observed weak reductive elimination activity.

Scheme 5 Pd-catalyzed intramolecular C–H activation of N-phenylbenzamidines.

In 2012, Zhu group²¹ discovered a novel Cu-catalyzed N-arylation of amidines with aryl boronic acids to synthesis of benzimidazoles (Scheme 6). Unprotected amidines were compatible in this transformation, affording the corresponding products in moderate yields. Meanwhile, the N-arylated amidine 16 was generated in situ in a one-pot manner to carry out annulation reactions avoiding prefunctionalization of amines prior to the reaction.

Scheme 6 Cu-catalyzed N-arylation of amidines with aryl boronic acids.

2.2 The [5 + 1] annulation of amidines

Inspired by Wasers work,²² Ohno group²³ deduced that the amidine group in N-phenylbenzamidine not only serves as a directing group for copper-catalyzed C–H alkynylation, but also forms substituted quinazoline through [5 + 1] cyclization as a nucleophilic group (Scheme 7). Otherwise, nitrogen alkynylation²⁴ might promote tautomerization–electrocyclization cascade²⁵ of 20b to give the same quinazoline 19.

Scheme 7 Cu-catalyzed [5 + 1] annulation reactions of N-phenylbenzamidines with alkyne.

The challenges of this strategy include predominant alkyne introduction over benzimidazole formation and and regioselective cyclization or alkynylation in the presence of two nitrogen atoms. After exploring appropriate alkyne sources for the reaction, they successfully developed a novel synthesis of quinazolines through copper-catalyzed alkynylation and [5 + 1] cyclization of N-phenylbenzamidine in 2010 (Scheme 7). This reaction was synthetically useful since functionalized quinazolines can be directly constructed from ortho-unsubstituted amidines, readily prepared from commercially available anilines. Meanwhile, the reaction of 19 with TBAF in THF–AcOH (20 : 1) at room temperature led to efficient cleavage of the TIPS group to give known quinazoline 21 in 76% yield.

Subsequently, the transition-metal catalyzed C–H bond activation/[5 + 1] annulation of amidines has been made significant progress. In 2011, Zhu group²⁶ developed an efficient synthesis of quinazoline-4-(3H)-ones from N-phenylbenzamidine through palladium-catalyzed intramolecular C(sp²)–H carboxamidation (Scheme 8). No atoms except protons in substrates were lost during the process. In addition, the control experiments suggested that the C–H bond activation was reversible and deuterium–hydrogen exchange occurred during the reaction. In this reaction, initial chelation of the amidine nitrogen with palladium(II) forms intermediate 24, followed by reversible cyclopalladation. The coordinated CO inserts into the C–Pd bond in intermediate 26, generating a seven-membered palladacycle 26. Reductive elimination leads to the product 23 and releases Pd(0), which is reoxidized by CuO under the aid of HOAc.

Scheme 8 Pd-catalyzed intramolecular C–H carboxamidation of N-arylamidines.

At the same year, they²⁷ found that the similarity of CO and isonitriles in terms of their coordination to transition metal suggested that an equivalent C–H isonitrile insertion process should be viable. Based on that, they achieved palladium-catalyzed intramolecular C–H amidination by isonitrile insertion provided direct access to 4-aminoquinazolines (Scheme 9).

Scheme 9 Pd-catalyzed intramolecular C–H amidination of N-arylamidines.

After these work, various kinds of C₁ synthons were applied to this system to construct nitrogen-heterocycle derivatives. In 2013, Zhang group²⁸ used solvents (including DMSO, DMF, DMA, NMP, TMEDA) as methyl one carbon synthons to synthesize quinazolines through direct oxidative amination of N–H bonds and methyl C(sp³)–H bonds followed by intramolecular C–C bond formation reactions (Scheme 10). In this reaction, the oxidation of CuX with the oxidant (such as selectfluor) provided the Cu(III) complex 34, which underwent a C–N bond formation reaction via nitrene insertion into the C(sp³)–H bond of DMSO to give the intermediate 35. Finally, in the present of H⁺, the cleavage of the C–S bond gave an iminium species 36, which underwent an electrophilic addition reaction or electrocyclization with the aromatic ring to provide di-hydroquinazolines. Subsequently, aromatic aldehydes or benzyl alcohol were found to be one carbon synthon for the synthesis of quinazoline derivatives via reactions of N-phenylbenzamidines by Zhang.²⁹ The CuO nanoparticles were used as efficient catalysts, and reaction showed high generality and functional group tolerance (Scheme 11).

Scheme 10 Cu-catalyzed [5 + 1] annulation reactions of amidines with various one carbon synthons.

Scheme 11 Cu-catalyzed oxidative coupling of amidines with aromatic alcohols.

Besides Cu and Pd, the [5 + 1] annulation reaction with N-phenylbenzamidine could also occur through Rh(III)-catalyzed C–H activation. However, this required an appropriate C₁ synthon in reaction system and avoided the metal-X (X = C, N) undergoing migratory insertion into the C=N bond (acting an electrophile), causing NH to be removed through subsequent elimination. In 2018, the catalytic [5 + 1] annulation/5-exocyclization reaction of amidines with diynes was reported by Du (Scheme 12).³⁰ Significantly, this reaction represented the first example of using diyne as a one-carbon reaction partner in C–H functionalization. The diynes were employed as new one-carbon units that efficiently enable insertion of six-membered metallacycles in situ and accelerate implementation of subsequent cascade reactions by another alkyne group, thereby providing a favorable driving force for resisting well-established [n + 2] annulations. Initially, the C–H activation at the amidine led to six-membered 43, which then would undergo ligand exchange to deliver the intermediate 44. The intermediate 44 generated 45 has a lower barrier, and migratory insertion of 45 generated intermediate 46. Two distinct pathways can be speculated after the formation of intermediate 46. In path a, reductive elimination of intermediate 46 gave the intermediate 47 with release of the Cp*Rh(I). Then demetalation of intermediate 47 led to the formation of desired products, which proceeded with isomerization to yield the final [5 + 1] products. Alternatively, for unsymmetrical diynes bearing the Me-group at one alkyne terminus, continuous migration insertion and a 1,4-rhodium shift of 46 followed by the subsequent β-H elimination generates dehydrogenation product in path b.

Scheme 12 Rhodium(III)-catalyzed cascade [5 + 1] annulations of amidines with diynes.

In 2020, Wu group³¹ used cyclopropenone as coupling partner to realize rhodium-catalyzed [5 + 1] annulation reaction of N-arylamidines (Scheme 13). The reaction featured mild reaction conditions, wide substrate scope and high atom-economy. Cyclopropenones were employed as appealing reaction partners with the release of the ring strain being the driving force. Interestingly, C-benzyl imidamides underwent not only the C–H activation/annulation, but also the attached oxidation to develop 2-benzoyl quinazolines. In addition, the synthetic practicality has been highlighted in several derivatization reactions, including the alkene functionalizations by reduction and oxidation. A plausible mechanism was proposed by author. First, a six-membered rhodacyclic intermediate 55 was generated via coordination of 50 to the active catalyst and following cyclometalation. Subsequently, oxidative addition for the C–C bond cleavage in cyclopropenone occurs through the transition state 56 to form the Rh(V) intermediate 57. The followed reductive elimination led to the formation of acyl arene in intermediate 58. The final product 52 was obtained by way of cyclocondensation with the release of H₂O and the rhodium(I) species can be reoxidized by the action of Ag(I) and/or O₂ to complete the catalytic cycle.

Scheme 13 Rhodium(III)-catalyzed [5 + 1] annulations of N-arylamidines with cyclopropenones.

Different from the conventional transition metal-catalyzed thermal annulation reactions, metal photocatalysis oxidative C_sp²–H annulation at room temperature (RT) is very challenging and complementary, which has been proven to follow the principles of green chemistry. In 2021, Hwang group³² reported the visible light-initiated copper-catalyzed oxidative C_sp²–H annulation of amidines with terminal alkynes to form 2,4-disubstituted quinazolines using molecular O₂ as an oxidant at RT (Scheme 14). This method was applicable for the synthesis of anticancer compounds from simple commercially available starting materials. The green metrics and eco-scale evaluations signify that the current photochemical process was simple, cost-effective and environmentally benign.

Scheme 14 Visible light-initiated copper-catalyzed aerobic oxidative C_sp²–H annulation of amidines with terminal alkynes.

Based on the mechanistic investigations, a possible reaction mechanism was depicted. Under visible light irradiation, in situ generated Cu(I)-phenylacetylide 62 absorbed blue light and become photochemically excited triplet state 63. This photoexcited state 63 then underwent a SET process by donating an electron to molecular O₂ and generated a Cu(II) complex 64, as well as a superoxide anion radical. In the next stage, the basic nature of the copper-superoxo radical anion had propensity to abstract acidic NH proton 59 to form a nitrogen-centered radical 65, which further reacts with Cu(II)-phenylacetylide complex 64 and forms Cu^III-complex species 66. This intermediate Cu^III-complex 66 underwent reductive elimination and generated Cu(I)-coordinated ynamine intermediate 67. Intermediate 67 then underwent Friedel–Crafts-type cyclization (6-exo-dig cyclization) to form cyclized intermediate 68 and subsequent aromatization to form compound 69, which upon photo-oxidation by Cu(II) superoxo forms product 61.

2.3 The [5 + 2] annulation of amidines

Compared with the C–H activation/[5 + 0] or [5 + 1] annulation reactions with the amidines, the [5 + 2] annulation reaction is more hard to achieve due to the fact that the formation of an eight-membered metallacycle intermediate required in the envisioned [5 + 2] annulation is energetically unfavorable. Meanwhile, the substrate is requested to provide C₂ synthon in reaction. With these challenges in mind, an efficient approach for the synthesis of 1,3-benzodiazepines has been developed via rhodium(III)-catalyzed annulative coupling between N-aryl amidines with propargylic esters by Fan group³³ in 2020 (Scheme 15). Of note, this was the first example in which N-aryl amidines serving as a C₅ synthon underwent a regioselective [5 + 2] annulation with propargyl esters acting as a C₂ synthon to afford valuable seven-membered heterocyclic system. This protocol featured broad substrate scope, good tolerance of a wide range of functional groups and facile operation process. In addition, the cytotoxicity of selected products against several human cancer cell lines was tested, which demonstrated their good potential for pharmaceutical applications. In this reaction, the insertion of the triple bond into the C–Rh bond generated an eight-membered rhodacycle 75, which underwent a reductive elimination to give the intermediate 76 and released the Rh(I) species. The Rh(I) species was then oxidized back to the active Rh(III) catalyst by Cu(II)/air. Finally, the intermediate 76 took part in a deacetylation process, most likely under the promotion of Rh(III) as a Lewis acid catalyst via the formation of intermediate 77 to give product 72.

Scheme 15 Rh(III)-catalyzed [5 + 2] annulation of N-aryl amidines with propargylic esters.

In 2023, Cui group³⁴ developed Ru(II)-catalyzed regioselective [5 + 2] annulation of N-aryl amidines with alkynyl cyclobutyl acetates to construct 5-cyclobutylidenebenzo[d][1,3] diazepines (Scheme 16). The method featured excellent regioselectivity, high step economy and good functional group tolerance. In this reaction, cheaper and earth abundant ruthenium was used as catalyst and the introduced cyclobutyl group would facilitate the subsequent biotransformation.

Scheme 16 Ru(II)-catalyzed [5 + 2] annulation of N-aryl amidines with alkynyl cyclobutyl acetates.

3 The [4 + n] annulation of amidines in C–H activation

3.1 The [4 + 1] annulation of amidines

Recently, the metal-catalyzed annulation reaction has been increasingly employed for synthesis of nitrogen-heterocycles, especially by Rh^III,³⁵ Ru^II,³⁶ Co^III,³⁷ and Ir^III-catalyzed³⁸ C–H activation in the presence of a DG. For these metals, amidines exhibited different chemical properties from copper and palladium-catalyzed C–H activation reactions, which afforded the opportunity to manipulate an array of different heterocyclic compounds. The amidines were used in a series of [4 + 1] annulation reactions, in which the metal-X (X = C, N) or nucleophilic reagent underwent migratory insertion into the C=N bond (acting an electrophilic group) and the cleavage of C=N bond.

In 2016, Li group³⁹ developed the firstly ruthenium(II)-catalyzed intermolecular coupling between aryl imidamides and diazo compounds by C–H activation, which enabled the synthesis two classes of indole derivatives by [4 + 1] annulation under mild conditions (Scheme 17). Derivatizations of 3H-indole 84a were performed to further showcase the synthetic utility of these compounds.⁴⁰ Interestingly, the intermediate 91 was formed by Ru–C(alkyl) migratory insertion into the C=N bond. In path A, the intermediate 91 underwent protonolysis, intramolecular nucleophilic addition and subsequent elimination of one molecule of amide to generate product 83. In path B, the intermediate 91 underwent elimination of ammonia with assistance of Ru^II or acetic acid, furnishing 3H-indole 84 as the final product. This change in selectivity was likely caused by the reduced electro-philicity of the ester carbonyl group.

Scheme 17 Ru(II)-catalyzed C–H activation of imidamides and divergent couplings with diazo compounds.

At the same year, they reported⁴¹ a redox-neutral approach to synthesize unprotected indoles via Rh(III)-catalyzed C–H activation in similar reaction system (Scheme 18). This reaction proceeded under relatively mild conditions with broad substrate scope. The metal–C underwent migratory insertion into the C=N bond (acting an electrophile), causing NH to be removed through subsequent elimination in the case of HOAc. Meanwhile, a rhodacyclic intermediate was isolated to favor the plausible mechanism.

Scheme 18 Rh(III)-catalyzed C–H activation/[4 + 1] annulation of imidamides with α-diazo-β-ketoesters.

Subsequently, Dong group⁴² revealed an efficient approach for the synthesis of unique 3H-indole derivatives from N-phenylamidines with pyridotriazoles via a rhodium-catalyzed highly selective C–H bond activation and annulation reaction (Scheme 19). In this transformation, the pyrido-triazoles were employed as a powerful carbene precursor coordinating with the metal by releasing of N₂ to afford the rhodium carbene 99. The intermediate 99 provided seven-membered rhodacyclic species 100 by migratory insertion. Thereafter the Rh–C(alkyl) bond underwent migratory insertion into the C=N bond to intermediate 101, which underwent elimination of the active Rh(III) catalyst and one molecule of NH₃ with the assistance of acid upon protonolysis and intramolecular protonolysis to afford product 98. The reaction tolerated diverse functional groups and conveniently afforded various 3H-indoles in moderate to excellent yields. In addition, the ester group could be removed in the present of NaBH₄ to afford 2,3-disubstituted indole 102, which suggested that this current protocol could be a practicability synthetic method and a late-stage modification tool.

Scheme 19 Rh(III)-catalyzed cascade annulation between N-phenylbenzimidamides and pyridotriazoles.

In 2021, Fan group⁴³ developed Rh(III)-catalyzed coupling and spirocyclization of N-aryl amidines with diazo oxindoles to construct 3-spiroox-indole 3H-indoles (Scheme 20a). In this reaction, the newly formed C(sp³)–Rh bond underwent a nucleophilic addition onto the C–N double bond of the amidine moiety to accomplish spirocyclization to form intermediate 107. The protonation of 107 with HOAc afforded intermediate 108, which underwent the elimination of ammonia to afford product. This novel spirocyclization features easily accessible substrates with a broad scope and generality, and formation of multiple bonds with high efficiency. Subsequently, Cui group⁴⁴ developed the Ru(II)-catalyzed selective C–H bond activation/[4 + 1] spirocyclization starting from easily available N-aryl amidines and diazopyrazolones (Scheme 20b). A series of spiropyrazolones could be easily obtained under mild reaction conditions with high step and atom economy.

Scheme 20 Transition metal-catalyzed [4 + 1] spirocyclization of N-aryl amidines with diazo compounds.

In addition, sulfoxonium ylides as a convenient and safe carbene precursor reagent, have been widely used in transition-metal-catalyzed C–H activation.⁴⁵ Interestingly, the sulfoxonium ylided can be used as the C₂ (ref. 46) unit or C₁ (ref. 47) unit according to the different reaction conditions. In 2019, Wu group⁴⁸ reported their work on additive-controlled selective synthesis of indoles and quinazolines by using N-arylamidines and sulfoxonium ylides as the starting materials (Scheme 21). In this process, the oxidants were shown to play a key role in selectively controlling the [4 + 1] and [5 + 1] annulation. In Ar atmosphere, the reaction predominantly gave the indoles through [4 + 1] annulation because sulfoxonium ylide was used as internal oxidant. Changing to O₂ and copper salt system, the preference of the annulation was switched to [5 + 1] annulation because the Cp*Rh(I) need to be reoxidized for catalytic cycle. Initially, the rhodacyclic intermediate 116 coordinated of sulfoxonium ylides 113 to generate a Rh(III) alkyl species 117, and the α-elimination of DMSO from 117 afforded a reactive rhodium α-oxo carbene species 118. Subsequently, in pathway a, the intermediate 118 was proposed to undergo migratory insertion of the Rh–C bond to generate a seven-membered rhodacyclic intermediate 119, which undergo Rh–C(alkyl) migratory insertion into the C–N bond to afford intermediate 120. Finally, the product 114 was released from 120 by elimination of the active Rh(III) catalyst and one molecule of ammonia from 120 upon protonolysis and intramolecular protonolysis. In pathway b, the reductive elimination from intermediate 119′ formed partially reduced quinazoline 121. Subsequently, the oxidation of 121 afforded the quinazoline product 115. On the other hand, the resulting Cp*Rh(I) can be reoxidized to the starting Rh(III) species by the action of Cu(II) and/or O₂ to complete the catalytic cycle.

Scheme 21 Rh(III)-catalyzed selective C–H activation/annulation of N-arylamidines and sulfoxonium ylides.

Subsequently, Cui group found that Ir(III)-catalyzed C–H activation of arens bearing a protic directing group preferred to couple with carbene compounds occurred under redox-neutral conditions to furnish various heterocycles. Different from ionic radius and catalytic activity of Ru and Rh, it can improve the selectivity of reaction of N-phenylbenzamidine and promote the reaction to occur. Hence, they⁴⁹ reported a convenient and straightforward approach to synthesis 1,2-disubtituted benzimidazoles via Ir(III)-catalyzed C–H activation of N-phenylbenzamidine and organic azides in 2017 (Scheme 22). The TsN₃ took part in the reaction by removing N₂ as the precursor of the nitrogen carbene, which coordinated with metal to generate iridium carbene species 125. The Ir–Ar bond was proposed to undergo migratory insertion into the carbene unit to generate intermediate 126. The Ir–N(TsN₃) bond then underwent migratory insertion into the C=N bond to afford amide species 127. Finally, the product 124 was eventually formed from 127 by elimination of the active Ir(III) catalyst and one molecule of NH₃ from 127 upon protonolysis and intramolecular protonolysis. The products could be easily obtained in up to 99% yield and with good functional group tolerance.

Scheme 22 Ir-catalyzed [4 + 1] annulation of imidamides with sulfonyl azides.

However, the organic azide was unstable chemical reagent. To solve this limitation, Cui group used N-hydroxycarbamates instead of organic azides as amination reagents. Soon after, they⁵⁰ successfully developed a novel method to synthesize 2-alkylbenzimidazole through the direct C–H amination of imidamides with hydroxylamines catalyzed by Rh(III) (Scheme 23). Various 2-alkylbenzimidaoles were conveniently afforded in good to excellent yields under relatively mild conditions employing readily available N-hydroxycarbamates as a nitrogen source.

Scheme 23 Rh(III)-catalyzed [4 + 1] annulation of imidamides with hydroxylamines.

According to the property of C=N bond of imidamides (acting an electrophile), causing NH to be removed through subsequent elimination, various cyclization reactions of imidamides involving different nucleophiles were reported. In 2018, Liu group⁵¹ demonstrated that the easily accessible α-halogenated ketones could be used as one-carbon reaction partners for direct construction of 3-acylindoles via Rh(III)-catalyzed annulation of N-phenylamidines (Scheme 24). This strategy featured high regioselectivity and wide substrate tolerance. In particular, the methodology could provide a short synthesis route for pravadoline 138, which demonstrated the practicability of this protocol. Meanwhile, the intermediate 139 was isolated and characterized, suggesting that C–H alkylation took place before C=N bond cleavage. The key intermediate 139 could be further converted into the desired product 137 under standard conditions with Rh-catalyzed system.

Scheme 24 Rh(III)-catalyzed [4 + 1] annulation of N-phenylamidines with α-halogenated ketones.

Soon afterwards, Cui group⁵² developed an efficient and practical method to construct benzimidazole derivatives via Rh(III)-catalyzed sequential C–H amination by using anthranil⁵³ as bifunctional aminating reagent (Scheme 25). This procedure could proceed smoothly with a low catalyst loading, avoid the external oxidants, and offer high-value products as versatile building blocks for further transformation, especially for heterocycle synthesis. In addition, the title product 142b could be easily further converted into imidazo[4,5-c]acridines 144, which was observed with unique fluorescent properties. According to the result of the control experiment, the NH of N-phenyl pivalimid amide might play as a directing group to sequential C–H aminations in the catalytic cycle, and compound 143 was a byproduct, but not the key intermediate in this reaction.

Scheme 25 Rh(III)-catalyzed sequential C–H amination/annulation cascade reactions of imidamides with anthranils.

In 2020, an efficient and practical Rh(III)-catalyzed C–H activation/annulation to construct benzimidazo[1,2-a]quinolines from readily imidamides and anthranils in [BMIM]BF₄ was reported by Wu group (Scheme 26).⁵⁴ Anthranils were as a new type of bifunctional aminating agent to expose carbonyl group after breaking the N–O bond. Subsequently, the product was obtained from the intramolecular Knoevenagel condensation of intermediate 148 at high temperature without extra additives.

Scheme 26 Rh(III)-catalyzed C–H activation cascade reaction between imidamides and anthranils.

Based on that, Fan group⁵⁵ achieved a Rh(III)-catalyzed [4 + 1] annulation of N-arylpivalimidamides with dioxazolones (Scheme 27). It was the first example in which N-acylbenzimidazoles were synthesized through simultaneous formation of the imidazoyl moiety and introduction of the N-acyl group. The dioxazolone as a masked amidating reagent followed by an intramolecular N-nucleophilic addition and ammonia elimination to afford product. In addition, the chemistry transformations illustrated the synthetic utility of the products.

Scheme 27 Rh(III)-catalyzed C–H activation/[4 + 1] annulation reaction of N-arylpivalimidamides with dioxazolones.

3.2 The [4 + 2] annulation of amidines

Different from other DGs, the N-phenylbenzamidine is essentially bifunctional with two N–H bonds. In addition, the low thermostability of benzamidines might cause complications, which is difficult to achieve the C–H activation at the C-phenyl ring. In 2011, Li group⁵⁶ firstly achieved the synthesis of N-substituted 1-aminoisoquinolines via Rh(III)-catalyzed oxidative coupling of N-aryl and N-alkyl benzamidines with alkynes (Scheme 28). C–H activation occurred at C-phenyl ring with excellent regio-selectivity. The exposed amino group avoided the use of other ammoniation reagent, which provided a new strategy for synthesis of amino heterocyclic compounds.

Scheme 28 Rh(III)-catalyzed oxidative coupling of N-aryl benzamidines with alkynes.

Interestingly, they unconsciously discovered the incorporation of two alkynes units with N-phenylbenzamidine, even though only 1.05 equiv alkyne was provided (Scheme 28b). Simple optimization by providing an excess of alkynes and Cu(OAc)₂ afforded this product in 73% yield. They reasoned that the isolation of the 2-fold oxidative coupling product is due to steric assistance. After the formation of the 1-(phenyl-amino)isoquinoline intermediate, the steric repulsion between the o-Me and the N-phenyl group renders these two groups distal to each other, leading to a conformation that is exactly favorable for C–H activation. With this conformational assistance, the isoquinoline ring nitrogen coordinated to the Rh(III) to give an intermediate in which the ortho C–H bond in the N-phenyl ring is pointed favorable to the metal center, leading to cyclometalation and eventually C–C and C–N formation.

Subsequently, in order to improve the selectivity, Ackermann group⁵⁷ changed the N-aryl to N-alkyl benzamidines, and reported a ruthenium(II)-catalyzed oxidative C–H-bond functionalization on easily accessible N-alkyl benzamidines with alkynes and alkenes (Scheme 29). Notably, this strategy proved to be widely applicable and enabled annulations of alkynes and alkenes to provide expedient access to diversely substituted 1-aminoisoquinolines and novel 1-iminoisoindo-lines, respectively. The desired product 164 was obtained through an intramolecular aza-Michael addition of intermediate 166, followed by dehydrogenation of the thus obtained intermediate 167.

Scheme 29 Ruthenium(II)-catalyzed oxidative C–H bond functionalization of aryl amidines with alkynes and alkenes.

Under this strategy, a cobalt(III)-catalyzed C–H/N–H bond functionalization for the synthesis of 1-aminoisoquinolines from amidines and diazo compounds was developed by them in 2016 (Scheme 30).⁵⁸ The byproducts of N₂ and H₂O in the reaction made the process environmentally benign and the in situ formed cationic cobalt(III) catalyst provided access to structurally diverse isoquinolines under the assistance of carboxylates cobalt intermediate.

Scheme 30 Cobalt(III)-catalyzed synthesis of isoquinolines through C–H functionalization with diazo compounds.

It was not difficult to find that the Rh was more inclined to react with N-phenylbenzamidine than other metals, and the experimental results also confirmed this. For example, Shang⁵⁹ and Li group⁶⁰ developed a Rh-catalyzed annulative coupling between N-phenylbenzamidine with cyclic 2-diao-1,3-diketones or sulfoxonium ylides to synthesize 1-aminoisoquinoline derivatives (Scheme 31a and b). These methodologies featured a broad substrate scope, and involved the formation of two new σ bonds (C–C and C–N) in a single operation under redox-neutral conditions.

Scheme 31 Rh(III)-catalyzed annulative coupling between N-aryl amidines with cyclic 2-diazo-1,3-diketones and sulfoxonium ylides.

Interestingly enough, in 2019, Zhou group⁶¹ developed a catalyst-controlled highly selective synthetic strategy to produce phosphoryl-indoles and phosphoryl-isoquinolines through a selective C–H bond activation of N-phenylbenzimidamide and the subsequent divergent couplings with diazophosphonate compounds (Scheme 32). Different C–H activation pathways of the substrate N-phenylbenzimidamide by altering the Rh(III)/Ru(II) catalyst systems prepared diverse privileged scaffolds. The H/D exchange experiment indicated that the C–H activation process preferred to occur on the C-phenyl ring under the Rh(III) catalytic system, while C–H activation preferred to occur on the N-phenyl ring under the Ru(II) catalytic system. In Ru(II) catalytic system, a Ru–C(alkyl) migratory insertion into the C=N bond could give the species 181, which underwent further protonolysis, intramolecular nucleophilic addition, and subsequent elimination of CH₃CONH₂ to give the target product 179. This protocol might find wider application in the discovery of lead compounds in the future, and verified the importance of the Rh in the occurrence of the C–H activation in C-phenyl ring.

Scheme 32 Highly selective C–H bond activation of N-arylbenzimidamide and divergent couplings with diazophosphonate compounds.

In addition, the para-methoxybenzyl (PMB)-substituted benzamidine furnished the product through a twofold C–H/N–H-bond functionalization with two alkynes (Scheme 33a),⁵⁷ thereby high-lighting the ability of the 1-aminoisoquinolines themselves to serve as useful substrates for directed C–H-bond transformations. In 2020, Du group⁶² reported a tandem process of multiple C–H activation and intermolecular highly meta-selective C–H amination between N-phenylbenzimidamide and alkynes (Scheme 33b). Initially, assisted by the N=C group, the ortho C–H bond of the C-phenyl ring of 187 was activated to generate a five-membered rhodacycle 190. Subsequently, 190 underwent alkyne insertion, followed by reductive elimination, to form 193 as well as Cp*Rh(I). Reoxidation of Rh(I) to Rh(III) by Mn(OAc)₃·2H₂O completed the catalytic cycle. Separately and simultaneously, assisted by the N–C group, the ortho C–H bond of the C-phenyl ring was activated to furnish another five-membered rhodacycle intermediate 194. After that, coordination of alkyne to rhodacycle intermediate 194 and insertion of alkyne into the Rh–C bond afforded a seven-membered rhodacycle intermediate 196. Reductive elimination of 196 leaded to the formation of 197 and regenerates Cp*Rh(I). Then 197 and 193 underwent steric-effect-controlled intermolecular meta C–H amination to form intermediate 198. In the final stage of this cascade reaction, an intramolecular C–H amination delivered the product.

Scheme 33 Rhodium-catalyzed multiple C–H activation/highly meta-selective C–H amination between amidines and alkynes.

In 2021, Li group⁶³ developed Mn-catalyzed [4 + 2] annulation of aryl amidines with vinylene carbonate for the synthesis of 1-aminoisoquinolines (Scheme 34). The vinylene carbonate was used as a acetylene surrogate through removing CO₂ in the transition-metal-catalyzed coupling reactions. In addition, the protocol obviates the need for any oxidants and shows good functional group tolerance and high atom efficiency.

Scheme 34 Mn(II)-catalyzed [4 + 2] annulation of N-aryl amidines with vinylene carbonate.

At the same year, Cui group⁶⁴ reported Rh(III)-catalyzed [4 + 2] annulation of N-arylbenzamidines with 1,4,2-dioxazol-5-ones for the synthesis of 4-aminoquinazolines (Scheme 35). This strategy proceeded with excellent regioselectivity, broad substrate scope and high step economy, and two C–N bonds were formed in reaction. In addition, the benzimidazo-[1,2-c]quinazolines 205 could also be synthesized via a phenyl-iodine diacetate (PIDA)-mediated intramolecular C–H cyclo-amination of 204a.

Scheme 35 Rh(III)-catalyzed [4 + 2] annulation of N-arylbenzamidines with 1,4,2-dioxazol-5-ones.

Subsequently, Cui group⁶⁵ explored Rh(III)-catalyzed C–H bond activation/annulation reactions of propargyl alcohols with N-arylbenzamidines to synthesize 1-aminoisoquinolines through a noncovalent interaction (Scheme 36). The hydroxyl group in 207 might provide binding affinity for Rh, and PhCOO⁻ facilitated the formation of the intramolecular hydrogen bonding with 206 and 207, which guided the regioselective migratory insertion. Only one isomer was obtained in this transformation, and the reactions proceeded with a broad substrate scope and high atom economy. In addition, the hydroxyl could be removed to afford the olefins.

Scheme 36 Rh(III)-catalyzed [4 + 2] annulation of N-arylbenzamidines with propargyl alcohols.

In 2022, a Rh(III)-catalyzed [4 + 1 + 1] spirocyclization of N-aryl amidines with diazo homophthalimides and O₂ to construct the hitherto unreported spiro[benzo[d][1,3]oxazine-4,4′-isoquinoline] derivatives has been developed by Fan group⁶⁶ (Scheme 37). Interestingly, the intermediate 214 reacted with oxygen in air and further transformed into 215, which underwent intramolecular O-nucleophilic addition and elimination of ammonia to afford product 213. In addition, this novel protocol featured easily obtainable substrates bearing diverse functional groups, structurally and pharmaceutically valuable products, and mild reaction conditions, is cost-free and clean, and has an abundant oxygen source and a sustainable reaction medium.

Scheme 37 Rh(III)-catalyzed [4 + 1 + 1] annulation of N-aryl amidines with diazo homophthalimides.

4 The [3 + 3] annulation of amidines in C–H activation

Different from imine, the C–N bond of imidamides was difficult to cleave due to the high stability. When NH of imidamides took part in nucleophilic attack instead of imine, the other substrate needed to provide sufficiently long chain of electrophilic point, which avoided forming an intermediate with macrocyclic tension with imine.

Cyclopropanols, as the β-aryl ketone precursor, can serve as a readily available C₃ synthon for the construction of cyclic compounds.^67,68 To realize cyclization of β-aryl ketone precursor, a bifunctional nucleophilic directing group that attacked the resulting carbonyl group needs to be employed. In 2017, Li group⁶⁹ disclosed a Rh(III)-catalyzed annulative coupling between cyclopropanlos and imidamides for the synthesis of 2-substituted quinolines, where cyclopropanlos acted as a C₃ synthon (Scheme 38). With the assistance of a bifunctional imidamide directing group, the reaction occurred via sequential C–H/C–C cleavage and C–C/C–N bond formation. According to the proposed mechanism, intramolecular nucleophilic addition of 220 generated a hemiaminal 221, dehydration of which delivered an N-protected 1,4-dihydroqquinoline intermediate 222. Nucleophilic deprotection of 222 furnished the intermediate 223, which was readily oxidized even by Cu(I) species to eventually furnish the product.

Scheme 38 Rh(III)-catalyzed [3 + 3] annulation of imidamides with cyclopropanol.

In 2024, Fan group⁷⁰ developed Rh(III)-catalyzed cascade reactions of N-aryl amidines with two CF₃-ynones for the synthesis of CF₃- and alkynyl-substituted quinoline derivatives (Scheme 39). In this cascade procedure, the CF₃-ynone played multiple roles by acting not only as an alkenylating reagent but also as an alkynylating reagent and a source of the CF₃ group. Initially, under the promotion of Cu(II), CF₃-ynones 225 underwent detrifluoroacetylation to form an alkynyl copper species 230, which was then trapped by intermediate 229 to give intermediate 231. From intermediate 231, 231′ was formed through equilibration. Subsequently, a reductive elimination reaction took place with 231′ to furnish intermediate 232, which underwent intramolecular N-nucleophilic addition to give intermediate 233. The intermediate 233 underwent intermolecular O-nucleophilic addition to form intermediate 234. Finally, an aromatization driven ring-opening reaction of the 1,3-oxazetidine moiety took place to give product 226.

Scheme 39 Rh(III)-catalyzed [3 + 3] cascade annulation reactions of N-aryl amidines with CF₃-ynones.

5 The intramolecular proton transfer process of amidines in C–H activation

Intramolecular proton transfer is an important process in chemical reactions and biological transformations.⁷¹ In particular, the translocation of reactive carbanion centers can be achieved through 1,n-proton transfer in either a direct or an assisted manner (via the protonation/deprotonation mechanism).⁷² However, these pathways rely on intramolecular carbon-to-carbon proton transfers, achieving the intramolecular proton transfer through transition metal-catalyzed C–H bond activation process is still a challenge due to the system incompatibility.

In 2023, Cui group⁷³ developed Rh(III)-catalyzed divergent C–H bond functionalization of N-aryl amidines with iodonium ylides. Carbazolones and zwitterionic salts were diversely constructed through intermolecular annulation and intramolecular proton transfer under the different reaction conditions (Scheme 40). Except for the coordination with metal, N-aryl amidines were used as the proton acceptor for the first time, affording the ammonium zwitterionic salts, which affords a remarkable and meaningful expansion in the area of multi-function directing groups. In path A, the intermediate 242 took enol-isomerization to give intermediate 243, which underwent intramolecular proton transfer progress to afford a new carbon anion and ammonium 237. In addition, the intermediate 241 might also undergo enol-isomerization to form O–Rh–N specie 242′ and followed by proton transfer process to afford 243 and the active catalyst species. In path B, the intramolecular nucleophilic addition of intermediate 242 afforded intermediate 244 with the help of K₃[Fe(CN)₆], followed by elimination of water to yield intermediate 245. Finally, nucleophilic deprotection of intermediate 245 furnished the product 238.

Scheme 40 Rh(III)-catalyzed divergent C–H functionalization of N-aryl amidines with iodonium ylides.

6 Conclusion

In this review, we have presented the progress of the transition-metal catalyzed C–H activation of amidines to synthesize heterocyclic compounds in the past decade. A wide range of original procedures for synthesizing various classes of N-heterocyclic systems have been developed on the basis of amidines and their derivatives through diverse annulation strategies. Different from other DGs, multiple activity reaction positions of amidines presented a difficult challenge. Although much progress has been achieved in this field, there are problems and demands for more applications of amidines in organic synthesis. For example, it is still difficult to achieve the C–H activation at the meta- or para-position of amidines. Meanwhile, transition-metal-catalyzed C–H activation of amidines to construct large and small ring compounds is very limited. Recently reported methods pave the way for the future of this exciting field where many more discoveries are surely waiting to be uncovered. In summary, the field of amidines chemistry is growing because of its high efficiency in the preparation of N-heterocycles. The potential of these amidine compounds is far from being fully realized. We hope that this review will be a spur for other researchers to join the field and we look forward to monitoring the literature as the synthetic opportunities that exist for this transformation are exploited.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Author contributions

Jie Ren and Yijia Xiong contributed equally. Jie Ren: investigation, literature curation, formal analysis, writing – original draft; Yijia Xiong: investigation, formal analysis literature curation, writing – original draft; Qian Li: literature curation; Bin Wang: investigation; Guanglu Wang: investigation, formal analysis; Bingyang Wang: investigation, formal analysis; Huimin Liu: writing – review & editing; Xuepeng Yang: supervision, writing – review & editing.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We greatly acknowledge partial financial support from the National Natural Science Foundation of China (22401268), the Key Program for Natural Science Foundation of Henan Province (242300421202), and Zhengzhou University of Light Industry.

Notes and references

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Footnote

† Jie Ren and Yijia Xiong contributed equally.

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