Organocatalysis in Inert CâH Bond Functionalization - Chemical

Review pubs.acs.org/CR

Organocatalysis in Inert C−H Bond Functionalization Yan Qin,†,‡,§ Lihui Zhu,†,‡,§ and Sanzhong Luo*,†,‡ †

Key Laboratory for Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China ABSTRACT: As two coexisting and fast-growing research fields in modern synthetic chemistry, the merging of organocatalysis and C−H bond functionalization is well foreseeable, and the joint force along this line has been demonstrated to be a powerful approach in making inert C−H bond functionalization more viable, predictable, and selective. In this review, we provide a comprehensive summary of organocatalysis in inert C−H bond functionalization over the past two decades. The review is arranged by types of inert C−H bonds including alkane C−H, arene C−H, and vinyl C−H as well as those activated benzylic C−H, allylic C−H, and C−H bonds alpha to the heteroatom such as nitrogen and oxygen. In each section, the discussion is classified by the explicit organocatalytic mode involved.

CONTENTS 1. Introduction 1.1. Organocatalysis 1.2. Inert C−H Bond Functionalization 1.3. Working Modes of Organocatalysis in Inert C−H Bond Functionalization 1.3.1. Synergistic Catalysis 1.3.2. Metal and Organic Cooperative Catalysis (MOCC) 1.3.3. Sequential Catalysis for Remote C−H Bond Functionalization 1.3.4. Direct Organocatalytic C−H Bond Activation 2. sp3 C−H Bond Functionalization 2.1. α-Functionalization of Amines 2.1.1. Aminocatalysis 2.1.2. NHC Catalysis 2.1.3. Thiourea Catalysis 2.1.4. Phase-Transfer Catalysis 2.1.5. Brønsted Acid Catalysis 2.1.6. Organic Lewis Acid Catalysis 2.1.7. Photoredox Organocatalysis 2.1.8. TBAI/TBHP Catalysis 2.1.9. Electroorganic Catalysis 2.1.10. Miscellaneous Catalysis 2.2. α-Functionalization of Alcohols and Ethers 2.2.1. Aminocatalysis 2.2.2. Photoredox Organocatalysis 2.2.3. TBAI/TBHP Catalysis 2.2.4. Miscellaneous Catalysis 2.3. β-C−H Functionalization of Carbonyl Compounds 2.3.1. Aminocatalysis 2.3.2. NHC Catalysis 2.4. Benzyl C−H Bond Functionalization 2.4.1. Aminocatalysis © 2017 American Chemical Society

2.4.2. Brønsted Acid Catalysis 2.4.3. H-Bonding Catalysis 2.4.4. Photoredox Organocatalysis 2.4.5. TBAI/TBHP Catalysis 2.4.6. Iodoarene Catalysis 2.4.7. Electroorganic Catalysis 2.4.8. Miscellaneous Catalysis 2.5. Allylic C−H Bond Functionalization 2.5.1. Aminocatalysis 2.5.2. Brønsted Acid Catalysis 2.5.3. TBAI/TBHP Catalysis 2.5.4. Electroorganic Catalysis 2.5.5. Miscellaneous Catalysis 2.6. Alkane C−H Bond Functionalization 3. sp2 C−H Bond Functionalization 3.1. Aldehyde C−H Bond Functionalization 3.1.1. Aminocatalysis 3.1.2. Lewis Acid Catalysis 3.1.3. Photoredox Organocatalysis 3.1.4. TBAI/TBHP Catalysis 3.2. Alkene C−H Bond Functionalization 3.2.1. Aminocatalysis 3.2.2. Lewis Acid Catalysis 3.2.3. Miscellaneous Catalysis 3.3. Arene C−H Bond Functionalization 3.3.1. Brønsted Acid Catalysis 3.3.2. Photoredox Organocatalysis 3.3.3. TBAI/TBHP Catalysis 3.3.4. Frustrated Lewis Pairs (FLPs) Catalysis 3.3.5. Iodoarene Catalysis 3.3.6. Norbornene Catalysis

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Special Issue: CH Activation Received: September 28, 2016 Published: February 13, 2017 9433

DOI: 10.1021/acs.chemrev.6b00657 Chem. Rev. 2017, 117, 9433−9520

Chemical Reviews 3.3.7. Electroorganic Catalysis 3.3.8. Lewis Acid Catalysis 3.3.9. Miscellaneous Catalysis 4. Conclusion and Outlook Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments References

Review

energy/electron transfer.6 Though organocatalysis in principle is generally believed to operate mostly with reactive C−H bonds (pKa < 30), a clear-cut borderline is hard to define. In this review, we would follow the usually considered inert C−H bond domain. For simplicity, we intend to state that the following areas will not be discussed. Aminocatalysis with α-C−H of carbonyl compounds together with its vinylogous versions such as dienamine, trienamine, or aromatic enamine reaction,7 Nheterocyclic carbene (NHC)-catalyzed umpolung reactions of aldehydes (aldehyde C−H functionalization),8 and the typical Friedel−Crafts reactions (arene C−H functionalization)9 will not be covered in this review. A large portion of the literature on the use of organic radical initiators or radical precursors in free radical chain reactions, e.g., homolytic aromatic substitution,10 will also be excluded, and these contents have been reviewed elsewhere. However, mechanistic complexity in many radical processes made the selection rather difficult, and in this regard catalysis with organic iodines is still included as this chemistry involves manifold mechanistic scenarios. Moreover, we will not discuss dehydrogenations reactions without new C−C/C−X bond formation.11 A number of excellent reviews covering the above-mentioned materials have been published, and the interested reader is directed to these for further reading.

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1. INTRODUCTION 1.1. Organocatalysis

Organocatalysis has evolved over the last two decades into an enabling strategy in chemical synthesis.1 The use of small chiral organic molecules, capable of activating and transforming another organic molecule, has rapidly gained tremendous growth due to the inherent nonmetal feature, mild reaction conditions, and broad functional group tolerance. Organocatalysis has now become a major catalytic method paralleling metal2 and enzymatic catalysis,3 and new territory for C−C/C−X bond formations continues to be unlocked in this area. One of the recent prominent advances is inert C−H bond functionalization. With its origins deeply rooted in organometallic chemistry, direct functionalization of the inert C−H bond is dominated by the transition-metal catalysis and the application of organocatalysis is largely lagging behind. As two coexisting and fast-growing research fields in modern synthetic chemistry, the merging of organocatalysis and C−H bond functionalization is well foreseeable, and the joint force along this line has been demonstrated to be a powerful approach in making inert C−H bond functionalization more viable, predictable, and chemo- and stereoselective. Hence, we strongly believe a comprehensive review in this area, i.e., organocatalysis in inert C−H bond functionalization, was well overdue and is highly desirable. There are reviews on “metal-free” or “nonmetal” C−H bond functionalization,4 and we cover herein only the examples where explicit organocatalytic cycles are involved.

1.3. Working Modes of Organocatalysis in Inert C−H Bond Functionalization

Organocatalysis in C−H functionalization spans all of the major types of organocatalysts (Figure 1). The joint force along this line has provided viable solutions to the selectivity issues associated with inert C−H bond functionalization. Parallel to these efforts, distinctive organocatalytic C−H activation modes have also been uncovered, which complement or even bypass the prevalent transition-metal catalysis. Figure 1 illustrates all organocatalysts that have been explored in C−H bond functionalization reactions, and they can be briefly categorized into four types on the basis of their working modes. 1.3.1. Synergistic Catalysis. In this mode, a separate and well-established organocatalytic cycle is merged with the C−H activation process to provide selectivity control for the C−C/C− X bond formation (Scheme 2). A number of organocatalytic intermediates such as enamine, iminium ion, Breslow intermediate, as well as noncovalent H-bonding and ion-pair interactions have been successfully employed to couple with C− H activation intermediates, and the organocatalysts normally do not participate in the C−H bond activation steps. In particular, the synergistic bi/multicatalytic cycle has become a powerful approach to achieve enantioselective C−H functionalization reactions.12 Enantioselective control in these reactions follows the typical organocatalytic modes involving weak interactions such as H bonding, steric effect, and ion-pair or charge interaction. There has also been a new trend in utilizing classical oranocatalysts such as chiral amines, amino acids, or chiral phosphoric acid as a chiral ligand in transition-metal-catalyzed C−H bond functionalization.13 1.3.2. Metal and Organic Cooperative Catalysis (MOCC). An organocatalytic motif or strategy can also be integrated successfully into the typical metal-catalyzed process, resulting in cooperative C−H activation. The so-called metal and organic cooperative catalysis (MOCC) or catalytic (transient) directing group from the viewpoint of C−H bond activations enables direct activation of a specific C−H bond in a highly predictable and selective manner.14 Aminocatalysis is the most successful component in MOCC catalysis, and its first

1.2. Inert C−H Bond Functionalization

Inert C−H bonds functionalization is considered atom and step economic by directly installing new C−C/C−X bonds from ubiquitous C−H bonds without preactivation of the substrates. Despite the revolutionary progress witnessed over the past two decades, transforming a specific C−H bond efficiently and selectively in a practical manner remains a challenging issue. The reasons are twofold: (1) C−H bonds are abundant and strong and (2) often harsh conditions are required. A brief survey on known bond energies of major organic compounds reveals all the C−H bond energies are large relative to C−C/C−X bonds, and they are also less differentiated thermodynamically (Scheme 1).5 It should also be pointed out that “inert”, “unreactive”, or “latent” are loosely defined terms. Inertness is typically valued by considering only the pKa of a particular C−H bond. However, an acidic C−H moiety with a lower pKa may be homolytically strong with a larger BDE or vice versa (Scheme 1, e.g., C(sp3)−H in 1propene vs acetaldehyde). Moreover, the renaissance of photocatalysis recently may further blur the borderline between “inert” and “reactive”, as an inert C−H bond in its ground state may become extremely active once excited via photoinduced 9434


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Scheme 1. pKa and Bond Dissociation Energy of Major C−H Bonds

functionalization.21 On this basis, the past few years have witnessed dramatic advances on the use of organic molecules as viable electron mediators to facilitate C−H bond activation and functionalization, echoing the blossom of modern photocatalysis and electrocatalysis. Typical examples include DDQ22 and hypervalent iodine23 as SET catalysts and organic dyes as organic photoredox catalysts24 and electroorganic catalysts.25 The multivarious mechanistic scenario associated with these C−H activation processes regarding the order of electron and hydrogen transfer as well as the manner of how the C−H is cleaved also adds diversity to the following functionalization reactions and shows tremendous potential in organocatalyst design. The following sections are organized by type of inert C−H bonds. In each section, our discussions will be categorized by the type of organocatalysts.

application by Jun in hydroacylation reaction was reported in 1997,15 even before aminocatalysis was revived in the gold rush of organocatalysis. Later, Dong16 and Yu17 elegantly employed a similar aminocatalytic strategy in vinyl C−H and sp3 C−H bond activation, respectively. In Yu’s work the use of chiral amino acid can even achieve excellent enantioselectivity in the C−H arylation reactions. Another notable MOCC was investigated by Kanai and co-workers,18 wherein a urea H-bonding motif was rationally designed to guide a meta-selective C−H borylation reaction (Scheme 3). 1.3.3. Sequential Catalysis for Remote C−H Bond Functionalization. Organocatalytic active intermediates, such as enamine/iminium and Breslow intermediate from NHC, are formed reversibly with sufficient kinetic stability for direct physical characterization, a feature distinctive from many transient catalytic active transition-metal species. Hence, these organocatalytic intermediates can be further manipulated efficiently, mostly via a redox process due to their favorable electronic properties for remote site C−H activation and functionalization. A frequently encountered strategy is the remote C−H functionalization of carbonyl compounds beyond the typical α-functionalization. Both enamine/iminium and NHC Breslow intermediates are amenable to this sequential catalysis to enable selective β-C−H or even γ-C−H functionalization reactions of carbonyl compounds (Scheme 4).19 1.3.4. Direct Organocatalytic C−H Bond Activation. It is known that single electron transfer (SET) can significantly weaken a σ bond (Scheme 5). Bordwell and Cheng determined the pKa of toluene radical cation to be ca. −20, roughly 1060 times more acidic than its parent toluene (pKa 43)!20 In classical photochemistry and electrochemistry, a single electron-transfer pathway has been a dominant process for bond activation and

2. SP3 C−H BOND FUNCTIONALIZATION 2.1. α-Functionalization of Amines

Nitrogen-containing compounds are important structural motifs in natural products as well as in pharmaceutical compounds. Direct organocatalytic functionalization of α-C(sp3)−H bonds has been developed in recent years, especially for nitrogencontaining heterocycles.26 2.1.1. Aminocatalysis. 2.1.1.1. Oxidative Cross-Coupling Reactions. The cross-dehydrogenative coupling (CDC), pioneered by the Murahashi group27a and the Li group27b to construct new C−C or C−X (X = N, O, P, S, B, or Si) bonds via direct activation of C−H or X−H bonds, is considered a powerful and unique strategy for the α-functionalization of amines under oxidative conditions without preactivation.27 One 9435


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Figure 1. Organocatalysts for C−H bond functionalization.

Scheme 2. Synergistic Catalysis in C−H Bond Functionalization

Scheme 3. Metal−Organic Cooperative Catalysis in C−H Bond Activation

major mechanistic scenario for CDC reactions is to proceed via iminium ion intermediates, generated in situ by the loss of two

electrons and one hydrogen. The reactive iminium ion can be intercepted by a nucleophile to form a new C−C or C−X bond 9436


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first employed to make the direct CDC reaction possible with acetone as demonstrated by Klussmann in 2009.29 The reaction proceed via a synergistic coupling of the in situ-generated enamine and iminium ion intermediate, derived from acetone and tertiary amine, respectively (Scheme 7). Proline catalysis can also be successfully coupled with ruthenium-based photoredox catalyst. The reactions worked particularly well with cyclic tertiary amines, especially N-aryl tetrahydroisoquinolines and N-

Scheme 4. Sequential Catalysis for Remote C−H Bond Formation

Scheme 8. Chiral Amine in Oxidative Mannich Reaction of Tertiary Amines with Acetone

Scheme 5. Organocatalytic Electron/Hydrogen Transfer for Direct C−H Activation substituted pyrrolidines. Unfortunately, no enantioselectivity was observed in these examples.30 A pure organocatalytic CDC reaction involving proline catalysis and organic photoredox catalyst has also been reported in moderate to high yields with air as the sole oxidant.31,32 When chiral amine catalysts were used (Scheme 8), the reaction afforded the desired adduct with poor yield and 20:1 after 9443


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Scheme 26. Redox-Neutral Indole Cascade Annulation

Scheme 27. Redox-Neutral 1,5-Hydride Shift/Isomerization Reaction

Scheme 28. Asymmetric 1,5-Hydride-Transfer/Ring-Closure Reaction of Benzylidenemalonate

Scheme 30. Synthesis of Chiral Cyclic Aminals via 1,5Hydride Transfer

Scheme 29. Mechanistic Study of the Asymmetric tertAminocyclization Scheme 31. Asymmetric Binary Acid-Catalyzed tertAminocyclization

conjugated anion via azomethine ylide intermediates I−III to deliver pyrroles. A similar reaction could also be utilized in the synthesis of N-alkyl indoles from indoline and aldehyde (Scheme 32b).62 In 2011, Xue and co-workers provided new sights on the 1,3-H shift mechanism based on detailed computational studies. The acidic additive such as acetic acid may engage in N,O-acetal formation to facilitate an intramolecular H shift, instead of the previously proposed intermolecular proton shuttle. A concerted

Besides 1,5-hydrogen transfer, formal 1,3-H transfer has also been reported to facilitate redox-neutral α-C−H functionalization of amines via an azomethine ylide intermediate. In 2009, Tunge reported the condensation of 3-pyrroline with aldehydes to form N-alkylpyrroles in the presence of a catalytic amount of benzoic acid (Scheme 32a).61 Considering that a 1,3-H shift is orbital-symmetry forbidden, Seidel and co-workers proposed a sequential proton transfer mediated by benzoic acid and its 9444


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Scheme 32. Redox Isomerization via an Azomethine Ylide Intermediate

Scheme 33. Evidence for Azomethine Ylide Intermediate

Scheme 34. Redox-Neutral α-Cyanation of Amines

H shift was proposed to be involved in the productive pathway (Scheme 32c).63 The [3 + 2] cycloaddition of pyrrolidine with aldehyde 33a possessing a pendant dipolarophile was reported to proceed via an azomethine ylide intermediate in this redox-neutral reaction cascade (Scheme 33).60 Polycyclic heterocycles with four new contiguous stereogenic centers was formed with excellent diastereoselectivity. Later, milder conditions were explored for the generation of reactive azomethine ylide, and difficult substrates such as tetrahydroisoquinoline, piperidine, morpholine, and thiomorpholine could be incorporated to undergo the [3 + 2] reaction to afford the desired polycyclic products.64 This verification of azomethine ylide has spurred the future development of related transformations. In 2012, Seidel described α-cyanation of amines in a redox-neutral fashion.65

α-Aminonitrile 34a, which was not easily accessible by Stetter reactions, could be obtained from a novel α-aminonitrile isomerization (Scheme 34a), a direct α-cyanation of pyrrolidine with available cyanohydrin (Scheme 34b), or even a one-pot three-component reaction of pyrrolidine, benzaldehyde, and TMSCN (Scheme 34c) catalyzed by Brønsted acid under microwave irradiation. These redox-neutral transformations involved a reductive N-alkylation followed by an oxidative αfunctionalization. The same strategy was applied to the redox9445


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Scheme 35. Redox-Neutral C−P Bonds Formation

Scheme 36. Redox-Mannich Reaction

neutral formation of C−P bonds in the α-position of amines from three-component reaction of cyclic secondary amine, aldehyde, and phosphine oxide (Scheme 35).66 Recently, Seidel and Chen reported a redox-Mannich reaction, unlike the classic three-component Mannich reaction, to prepare ring-substituted β-amino ketone (Scheme 36).67 A carboxylic acid catalyst was required for this reaction, and slow addition of ketone and aldehyde gave rise to a higher yield. When using nitroalkane as the nucleophile, the desired aza-Henry-type product was obtained in excellent yields (Scheme 36).

substituted piperidines as synthetic drugs, such as quillifoline (Scheme 39, 39a and 39b). Unfortunately, no desired product was detected with piperidine substrates (Scheme 39, 39c). In the catalytic cycle, chiral Brønsted acid interacted with the boronate via the transesterification to form a chiral nucleophile I. In the presence of 2,2,2-trifluoroethanol, acyliminium II could be stabilized as N-acyl hemiaminal adduct III, which underwent coupling with the arylation reagents in the form of an “ate” complex V to generate α-functionalized product (Scheme 40). Liu and Tan recently reported an unactivated alkene as hydrogen acceptor initiating the enantioselective functionalization of C−H bonds adjacent to heteroatoms.70 By employing a combination of copper salt with a chiral phosphoric acid, CF3containing N,O-aminals were obtained with excellent regio-, chemo-, and enantioselectivity through a cascade C−CF3 formation/1,5-H shift/C−H functionalization process (Scheme 41). Control experiments suggested that chiral Brønsted acid played multiple roles in controlling the stereoselectivity and enhancing the reaction rate via activation of Togni’s reagent. A mechanism was proposed that a •CF3 radical is generated from activation of Togni’s reagent with copper(I) and the phosphoric acid (PA) (Scheme 41). 2.1.6. Organic Lewis Acid Catalysis. Stable carbocations have been used as important reagents and catalysts in organic synthesis.71 In 2016, Luo and co-workers disclosed that the tritylium salt, [Ph3C][BArF], generated in situ could act as organic Lewis acid and promote the three-component redoxneutral α-arylation of tetrahydroisoquinoline, aldehyde, and indole to afford the desired α-substituted N-heterocyclic products in good yields (Scheme 42).72 2.1.7. Photoredox Organocatalysis. In recent years, a photoinduced electron-transfer (PET) strategy, an essential step in the conversion of solar energy into chemical energy in photosystems, has been successfully employed in formation of iminium cation species (Scheme 43).73,74 In early the 1990s, a photoinduced cyanation of alkaloids catalyzed by N,N′-dimethyl2,7-diazapyrenium-bis(tetrafluoroborate) (DAP+, 2BF4−) cat-19 was described with TMSCN as nucleophile.73 Various α-

Scheme 37. Redox-Neutral α-Sulfenylation

Synthesis of ring-fused N,S-acetals was nicely demonstrated by the Seidel group from redox-neutral transformation of amines with thiosalicylaldehydes in the presence of acetic acid.68 A range of secondary amines including morpholine, thiomorpholine, and even open-chain dibenzylamine was found to undergo αsulfenylation in moderate to good yields (Scheme 37). Computational studies suggested that a catalytic amount of acetic acid as an additive facilitated the key proton-transfer step. 2.1.5.2. Oxidative Cross-Coupling Reactions. Liu and coworkers reported the first asymmetric oxidative alkenylation and arylation of α-C−H bonds of N-heterocycles.69 Carbamoyl tetrahydro-β-carbolines as substrates proceeded smoothly with a range of styrenyl boronates to give α-alkenylation products under mild conditions by using tartaric acid derived cat-16 as organocatalysts (Scheme 38, 38a and 38b). Enantioselective αarylation products were also obtained with electron-rich aryl boronates by switching cat-16 to cat-17, whereas electrondeficient aryl boronate failed to deliver the desired product (Scheme 38, 38c and 38d). Carbamoyl tetrahydropyridines 39 also worked for the α-alkenylation and arylation to furnish 2,49446


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Scheme 38. Enantioselective Oxidative C−H Alkenylation and Arylation of N-Heterocycles

Scheme 39. Enantioselective Oxidative C−H Alkenylation and Arylation of N-Heterocycles

Scheme 40. Proposed Mechanism of Enantioselective Oxidative C−H Alkenylation

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Scheme 41. Enantioselective Radical Functionalization of C−H bonds

Scheme 42. Redox-Neutral α-C(sp3)−H Arylation of Amines

Scheme 45. Photocyanation of Hydrazines

Scheme 43. Generation of Iminuim Ion by PET Strategy

with TMSCN using methylene blue (MB) as the photosensitizer (Scheme 45).75 With water as a second nucleophile, cyanation products were further transformed into the corresponding lactams. Voltammetric investigations showed that hydrazines are more easily oxidized than tertiary amines (0.77 vs 1.02 V, vs SCE); no further oxygenation was observed under the conditions. Cyanoarenes, such as 1,4-dicyanonaphthalene (DCN), 9,10dicyanoanthracene (DCA), and 1,4-dicyanobenzene (p-DCB), have been widely used as PET catalysts due to their strong photooxidative ability.76 In the early 1990s, Pandey and co-workers developed a series of cyanoarenes-catalyzed aerobically oxidized C−H functionalization of pyrrolidine and piperidine derivatives with alcoholic OH or allylsilane as nucleophiles (Scheme 46).77 In these transformations, methyl viologen (MV2+) was employed as electron relay reagent to match the potentials of oxygen and cyanoarenes (Scheme 47). In 2014, Jiang and co-workers systematically developed a dicyanopyrazine-derived organic photoredox catalyst which has absorption maxima locating in the visible-light area due to the push−pull chromophores (dicyanopyrazine, DPZ). They successfully employed the catalyst in the CDC reaction of Naryltetrahydroisoquinolines.78 Later, process-controlled CDC

Scheme 44. Photocyanation of Tertiary Amines

aminonitriles were obtained in good to excellent yields (75− 95%) under mild conditions (Scheme 44).74 In 2000, Cocquet and co-workers reported a photocyanation reaction of N-arylaminopiperidines or N-arylaminopyrrolidines 9448


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Scheme 49. Asymmetric C(sp3)−H Olefination of Tetrahydro-β-carbolines

Scheme 46. DCN-Catalyzed Oxidative C−H Functionalization of Amines

Scheme 47. Catalytic Role of Cyanoarenes and Methyl Viologen

Scheme 50. Photocatalytic CDC Reaction of NAryltetrahydroisoquinolines

Scheme 48. Four Diverse Aerobic Radical Cascade Reactions of N-Aryltetrahydroisoquinolines

been demonstrated. König and Hari described Eosin Y-catalyzed cross-dehydrogenative-coupling reactions of tetrahydroisoquinoline derivatives with nitroalkanes, dialkyl malonates, and dialkyl phosphonates in moderate to good yields (Scheme 50).81a However, nitroalkanes and dialkyl malonates must be used in a large excess as solvent to ensure complete conversion. Also, C−S bond formation was achieved with NH4SCN as a sulfur source.81b,82 Later, Wu and Tong also reported these reactions using TBA-Eosin Y as a photocatalyst in dilute solution.31 Rose Bengal was an efficient photocatalyst to afford the CDC product with a higher yield.32a Moreover, α-cyano- and α-trifluoromethylated tertiary amines could also be obtained with the combination of graphene oxide and Rose Bengal.32b Subsequently, a direct oxidative α-trifluoromethylation and αalkynylation of N-aryl tetrahydroisoquinolines was developed by using Rose Bengal as catalyst.83 Trifluoromethyl tetrahydroisoquinoline could be accessed with TMSCF3 as nucleophile in

couplings were realized with the same organocatalyst, and four diverted reaction pathways were achieved by simply modifying the reaction conditions (Scheme 48).79 In 2016, Jiang and Tan disclosed an enantioselective aerobic oxidative C(sp3)−H olefination of N-tetrahydro-β-carbolines (THCs) as well as aryltetrahydroisoquinolines (THIQs).80 A triple-catalytic system, composed of dicyanopyrazine-derived chromophore (DPZ) as the photoredox organocatalyst, cat-20 as a chiral Lewis base catalyst, and NaBArF as an inorganic salt cocatalyst, was efficient as employed for the synthesis of valuable α-substituted THCs and THIQs (Scheme 49). Eosin Y and Rose Bengal are well-known dye molecules and have been widely employed as photoredox organocatalysts in organic synthesis.24 In the past few years, several examples of oxidative α-C−H bond functionalization of tertiary amines have

Scheme 51. Photocatalytic Alkynylation and αTrifluoromethylation of N-Aryltetrahydroisoquinolines

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good yield. α-Alkynylation was also realized in the presence of CuCl and using alkyne as the nucleophilic partner (Scheme 51).

Scheme 54. Photoredox Ugi-Multicomponent Reaction

Scheme 52. Photocatalytic CDC Reaction of NAryltetrahydroisoquinoline with Diazo Compound

highly valuable α-amino amides in good yields within the continuous flow devices (Scheme 54).86b Scheme 55. Photocatalytic C-3 Formylation of Indole

In 2014, Zhou and co-workers utilized diazo compounds as nucleophiles for the first time in the CDC reaction of tertiary amines.84 β-Amino-α-diazocarbonyl products were obtained in moderate to high yields without nitrogen extrusion (Scheme 52a). The products could be transformed into ring-enlarged benzoazepines, and interestingly, the use of either CuI or Ru2(OAc)4 could tune the regioselectivity (Scheme 52b). More recently, Wu and Tong advanced the photomediated CDC reaction under oxidant-free conditions to deliver the desired adducts along with hydrogen gas evolution, formulating a new type of transformation called cross-coupling hydrogen evolution (CCHE).85a By combining Eosin Y with a graphenesupported RuO2 nanocomposite (G-RuO2), the desired cross-

A novel visible-light-promoted indole C-3 formylation reaction catalyzed by Rose Bengal was developed very recently.87 TMEDA was first oxidized to an iminium ion and then attacked by indole substrates to afford C-3-substituted indole, which was further photooxidized into iminium ion to give 3-formyl-Nmethylindole after hydrolysis and the C−N bond cleavage (Scheme 55). Besides iminium cation species, α-amino radical could also be furnished after a single electron transfer and deprotonation to undergo radical addition with electron-deficient alkenes. Scheme 56. Photocatalytic Cyclization of N,NDimethylanilines with Maleimides

Scheme 53. Photocatalytic Cross-Coupling Hydrogen Evolutions

Recently, a visible-light-mediated synthesis of tetrahydroquinolines from N,N-dimethylanilines and maleimides was developed using Eosin Y as catalyst under ambient air.88 The α-amino radical species underwent radical addition to maleimide, followed by cyclization to give the corresponding tetrahydroquinoline (Scheme 56). A similar reaction was also reported with [Ru(bpy)3]3+ as photocatalyst.89 Bodipys cat-21, a class of fluorescent dyes, have a strong absorption of visible light (ε > 77 000 M−1 cm−1) with a longlived triplet excited state (τT is up to 84.6 ms). The iodo-Bodipys have been used as new type of photocatalyst for a number of CDC reactions (Scheme 57).90a The reaction was found to proceed much faster than that with Ru(bpy)3Cl2 or Ir(ppy)3. A C60-Bodipy derivative was also used for oxidation/[3 + 2]

coupling products were obtained along with a quantitative yield of H2 without the use of any sacrificial oxidants in water. G-RuO2 played a crucial role for H2 evolution that acted as an electron and a proton acceptor. Considering the high cost of G-RuO2, an earth-abundant Co(dmgH)2Cl2 complex was then identified as a substitute to capture the electrons and protons in a follow-up study (Scheme 53).85b Continuous-flow and microfluidic vortex fluidic devices (VFDs) were effective in photocatalytic CDC reactions involving these dye molecules.86 Considerably shorter reaction times and higher yields were achieved compared with the batch conditions. N,N-Dimethylanilines were successfully reacted with different isocyanides in the Ugi-multicomponent reaction resulting in 9450


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radical-type conjugate addition to electron-deficient alkenes. In 1999, Hoffman and co-workers reported an example of

Scheme 57. Bodipy-Catalyzed the Oxidation/[3 + 2] Cycloaddition/Oxidative Aromatization Tandem Reaction

Scheme 59. Photocatalyzed Conjugate Addition of Tertiary Amines to Electron-Deficient Alkenes

cycloaddition/oxidative aromatization of tetrahydroisoquinoline and N-phenylmaleimide to produce the highly functionalized pyrrolo[2,1-a]isoquinolines.90b In addition, when activated

photoinduced addition of N-methylpyrrolidine 59 to unsaturated carbonyl compounds in the presence of benzophenone.93 Electron donating substituents on the benzophenones suppressed undesirable side reactions to afford high yields of the desired products. 4,4′-Dimethoxybenzophenone was identified as the optimal photosensitizer in the overall reaction (Scheme 59). Though conjugate additions of α-amino alkyl radicals to enones were well developed, successful examples of enantioselective versions were rare. The Bach group developed a chiral photoredox organocatalyst cat-22 to realize enantioselective intramolecular conjugate addition.94 The chiral photocatalyst has two key elements, the catalytic benzophenone unit and a bridgehead lactam. The photosensitive benzophenone unit not

Scheme 58. Photocatalytic CDC/Dehydrogenation/6πCyclization/Oxidation Cascade Reaction

Scheme 60. Photocatalytic Enantioselective Cyclization of αAmino Alkyl Radical

alkyne was employed as dipolarophile, the desired product was obtained in moderate yield without NBS (Scheme 57). The same reaction could also be achieved in the presence of Rose Bengal and NBS.91 Recently, Brasholz and co-workers reported an interesting photocatalytic cascade reaction between N-aryltetrahydroisoquinolines and nitroalkanes (Scheme 58).92 The red dye 1,5diaminoanthraquinone (1,5-AAQ) was chosen as the optimal photoredox catalyst under aerobic conditions. The initially formed CDC product was not stable and further oxidized via a PET process by the excited anthraquinone catalyst AQ* to give amine radical cation, which was converted into iminium ion II via H abstraction by superoxide radical anion (Scheme 58). Basemediated deprotonation led to the formation of nitroenamine III. This active intermediate then underwent photoinduced conrotatory 6π-electrocyclic ring closure to azomethine ylide IV. Rearomatization of ylide IV followed by catalytic oxidation led to the final product in moderate yield. α-Amino alkyl radicals generated by HAT or ET/PT pathway by photosensitizer such as aromatic ketones could undergo

only served as photoinduced hydrogen abstractor but also acted as a stereocontrolling device inducing the desired enantiofacial differentiation in the cyclization step; meanwhile, the bridgehead lactam binded with the substrate by a bidentate hydrogen bond to give a chiral product avoiding the use of stoichiometric chiral auxiliary (Scheme 60). Chiral spirocyclic pyrrolizidine 60b was obtained in 64% yield with 70% ee. 2.1.8. TBAI/TBHP Catalysis. The utilization of tetrabutylammonium iodide (TBAI) as an organocatalyst combined with excess tert-butyl hydroperoxide (TBHP) has become an powerful and efficient approach for oxidative C(sp3)−H functionalization in the past few years.95 This elegant oxidative system provides a simple method for generating radical species t9451


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Scheme 63. TBAI/TBHP-Catalyzed α-Oxygenation of Secondary Amines

Scheme 61. Oxidation System of TBAI and TBHP

BuO• and t-BuOO• along with iodine (Scheme 61a and 61b). These active radical species could initiate the reaction by abstracting a hydrogen atom to form a carbon radical (Scheme 61c). Besides, NaI, KI, NIS, and even I2 may be suitable to initiate the radical process in parallel experiments, which indicates the conversion between I− and I2 during the reaction. This metal-free catalytic system shows comparable activity with transition metals in C−H functionalization, while their advantages are obvious in view of sustainable and environmentally friendly development. On the other hand, hypoiodite [R4N]+[IO]− or [R4N]+[IO2]− has been proposed as the real active catalyst by Ishihara and coworkers in a similar TBAI/oxidant system.96 In the presence of chiral quaternary ammonium iodide as organocatalyst, the enantioselective variant of oxidative transformations could also be achieved. These active species have been considered to induce the homolysis of C−H bonds, especially on α-oxyl C−H (section 2.2) or benzyl C−H bonds (section 2.4), to yield radical intermediates. In some cases, TBHP is not suitable due to the nucleophilicity of the emerging t-BuO− anion.97 Other oxidants, such as Oxone (KHSO5/KHSO4/K2SO4) and H2O2, are chosen as co-oxidants for their non-nucleophilic character. In these oxidative systems, the real oxidant species is often proposed as [IO]+ or [IO2]3+. A TBAI-catalyzed C3-formylation of indoles with Nmethylaniline as a formylation reagent was reported by the Wang group in 2012.98 By employing TBHP as a cheap and environmentally benign co-oxidant, N-methylaniline was oxidized to imine species followed by nucleophilic addition to

Scheme 64. Domino Synthesis of 3-Aroylindoles

treatment with Grignard reagents (Scheme 63). However, when N-benzhydryl-3-methylbenzamide and N-benzyl-N-methylbenzamide were used as substrates, only acylimine and oxyl product was obtained. Similar catalysis could also been applied to an oxidative annulation of o-alkynyl-N,N-dialkylamine for the synthesis of 3-aroylindoles (Scheme 64).101 By using nontoxic PhCH2CN as the cyano source, Wan and co-workers utilized the oxidative system of TBAI/TBHP to Scheme 65. TBAI/TBHP-Catalyzed α-Cyanation of N,NDimethylaniline

Scheme 62. Formylation of Indoles with N-Methylaniline

indole for the generation of a cross-dehydrogenative-coupling product. The CDC product was not stable under this reaction condition and underwent a second oxidation and hydrolysis to afford the corresponding 3-formylindole. This methodology could be applied to N-H and N-substituted indoles, avoiding the use of toxic phosphorus oxychloride and transition metal (Scheme 62). The selective C3-formylation of indoles could also be achieved with hexamethylenetetramine (HMTA), generating formylating species in situ under a catalytic amount of silica-supported ceric ammonium nitrate (CAN−SiO2).99 This solid-supported reagent then could be recycled and reused. Recently, Yu and Shen accomplished an oxidative α-C−H functionalization of N-benzylbenzamides to tert-butylperoxyamido acetal.100 The acetal products were obtained in good yields and could be further transformed into α-substituted amides by

realize cyanation of N,N-dimethylaniline.102 Under the developed conditions, a range of substituted tertiary amines was tolerated to afford the corresponding α-amino nitrile products in good yields (Scheme 65). TBAI was proposed to initialize the generation of tBuO• or tBuOO• radical species that facilitate C− H bond cleavage and the following C−C bond formation. 2.1.9. Electroorganic Catalysis. Electroorganic chemistry has become a useful alternative tool to provide radical ions for the oxidation of organic molecules.25 The employment of organocatalysts, or organic redox mediator in electroorganic chemistry, is an environmentally benign strategy for oxidative transformations. To date, organic redox mediators used in electroorganic reactions have been rather limited; successful examples include N-oxyl radicals, triarylamines, and triarylimidazoles, with 9452


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Scheme 66. Br−/TEMPO-Mediated Electrochemically Oxidative C−H Functionalization

N-Hydroxyphthalimide (NHPI) and its derivatives are precursors of electron-deficient phthalimide N-oxyl radical (PINO), which has a strong tendency for abstraction of hydrogen atom from simple alkanes to furnish the corresponding alkyl radicals.105 In recent years, this class of compounds has been

which the oxidation could be carried out under milder conditions compared to a direct electronic pathway.25i In 2012, the Little group disclosed an example of electrochemical oxidation of amines, isochromanes, and xanthenes mediated by a bromide ion/TEMPO (2,2,6,6-tetramethyl-1piperidinyloxy) dual-redox catalyst system (Scheme 66).103 This transformation was conducted in a two-phase electrolytic medium. The electronic oxidation of Br− to hypobromite (−OBr) occurred in the basic aqueous medium, while the electron transfer between TEMPO+ and substrates took place in the organic phase. TEMPO+ was the direct active oxidant that oxidized the substrate to form the corresponding cation radical, which underwent deprotonation, a further oxidation, and hydrolysis to yield the corresponding product. 2.1.10. Miscellaneous Catalysis. DDQ (2,3-dichloro-5,6dicyano-1,4-benzoquinone) is a classical oxidant that has been widely employed in various oxidation reactions. Given its high cost and the difficulty to remove the byproduct DDHQ, use of DDQ in a catalytic amount is highly desirable. In 2013, Prabhu

Scheme 68. Sb(V)/NHPI-Catalyzed CDC Reaction of NAryltetrahydroisoquinoline with Nucleophiles

widely used as organocatalysts in C−H bond functionalization, and the topic has been reviewed extensively prior to 2007.105c Hence, in this review we will only discuss the examples published after 2007. A catalyst system of antimony(V)/NHPI cocatalysts for the cross-dehydrogenative-coupling reaction has been efficiently developed by the Kobayashi group recently (Scheme 68).106 In this process, the antimonate anion initiated the reaction by a single electron oxidation of THIQ substrate, and subsequently, the PINO radical generated in situ facilitated the α-hydrogen abstraction to form the iminium ion in the presence of oxygen. This catalyst system tolerated a variety of tertiary arylamines and nucleophiles with comparable performance to many other catalytic systems. In 2015, a novel aerobic oxidation of primary amines into the corresponding oximes was developed with the catalytic system of 3-methyl-4-oxa-5-azahomoadamantane cat-23 in aqueous sol-

Scheme 67. DDQ-Catalyzed CDC Reaction of NAryltetrahydroisoquinoline with Nucleophiles

Scheme 69. Aerobic Oxidation of Primary Amine to (E)Oxime

reported the first cross-dehydrogenative-coupling reactions mediated by a catalytic amount of DDQ using molecular oxygen as the co-oxidant and AIBN as an additive.104 In this report, the CDC reactions of THIQ 67a with simple ketone proceeded smoothly to give Mannich-type products in the absence of amine catalyst (Scheme 67a, 67b). Under the same reaction conditions, 4-hydroxycoumarin derivative and phosphonate were also good nucleophiles to react with 67a to form C−C and C−P bonds (Scheme 67b and 67c). 9453


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ution.107 This process tolerated a range of substituted arylamines to yield the corresponding (E)-type oximes in good yields (Scheme 69). Control experiments indicated that 1-methyl-2azaadamantane N-oxyl radical is the real catalyst generated in situ in the presence of acetaldoxime and dioxygen. This N-O radical species initiated the reaction by abstracting a hydrogen atom from the primary amine to form a α-aminobenzyl radical, which was then captured by O2. The formed α-aminobenzyl hydro-

of amines to produce secondary imines using a simple o-quinone catalyst without the assistance of any metals.109 In this report, imine products underwent further oxidation with additional substrates to furnish an oxidative trimerization adduct, imidazolinone, at elevated temperature (Scheme 71). Less loading of catalyst was found to favor the trimerization process, presumably as a result of balancing the imine formation. Recently, the Clift group described the α-functionalization of primary amines through sequential quinone-catalyzed amine oxidation/nucleophilic addition (Scheme 72).110 A commercially available 2,6-di-tert-butyl-p-benzoquinone (DTBQ) was employed to mediate the aerobic oxidation of benzylamine to the corresponding N-protected imines, which then reacted with appropriate nucleophiles such as organolithium reagents or Grignard reagents to furnish α-branched amines 72 at low temperature. In 2016, the MacMillan group presented a successful α-C−H arylation reaction of amines and ethers by employing the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis (Scheme 73).111 In the triple catalytic cycles, the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 was excited to Ir(III)* (I) under irradiation of visible light, which underwent single electron transfer (SET) with a tertiary amine to produce Ir(II) (II) and amine radical cation (III), which acted as HAT organocatalyst abstracting the hydrogen atom of the sp3C−H bond α to the heteroatom to afford the radical intermediate (IV) for subsequent Ni-mediated cross coupling.

Scheme 70. Synthesis of 2-Aryl Quinazolines

2.2. α-Functionalization of Alcohols and Ethers

Alcohols and ethers are the most common structural motifs spread across bioactive natural products and synthetic pharmaceuticals.112 Alcohols have been widely used as reaction medium in organic chemistry. Over 20% of the top 200 smallmolecule pharmaceuticals and 75% of new chemicals contain at least one α-substituted ether moiety. Therefore, the development of efficient synthetic methods for α-functionalization of oxygen atoms is vital for the discovery of biologically interesting agents. 2.2.1. Aminocatalysis. The direct functionalization of the C(sp3)−H bond α to oxygen via CDC reaction has been a powerful method for the synthesis of α-substituted ethers. However, progress along this line has been rather slow compared to their amino counterpart, likely a result of the inherent higher oxidation potential impeding the generation of oxocarbenium intermediates.113 Nevertheless, introduction of aminocatalysis in this reaction has been shown to deliver superior stereocontrol for the α-C(sp3)−H functionalization of ethers. In 2014, Liu and Lou et al. developed the first one-pot enantioselective CDC reaction of cyclic benzylic ethers with aldehydes.114 The reaction produced α-substituted isochroman 74a with up to 92% yield and 96% ee (Scheme 74). In this report, addition of H2O and LiOTf was extremely crucial for stabilizing the oxocarbenium intermediate and hence increasing its electrophilicity. This one-

peroxide was converted to the product (E)-oxime after dehydration. By using the 4-hydroxy-TEMPO radical as the catalyst, oxidative synthesis of 2-aryl quinazolines was reached by a onepot reaction of benzylamine with 2-aminobenzoketones or 2aminobenzaldehydes (Scheme 70).108 4-Hydroxy-TEMPO was believed to abstract a benzylic hydrogen to initiate the reaction. Quinones are widely used as cofactors in biological oxidation processes in the living systems. The development of bioinspired quinone catalysts has been extensively explored, and progress has been achieved in the combination of quinones and metal catalysis for a number of transformations.22c In 2015, Luo and co-workers developed a bioinspired organocatalytic aerobic C−H oxidation Scheme 71. Synthesis of Imidazolinone via Trimerization

Scheme 72. Quinone-Catalyzed Oxidation/Nucleophilic Addition of Primary Amines

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Scheme 73. Photoredox-Mediated Cross-Coupling Reaction

Scheme 74. Organocatalytic Enantioselective Cross-Coupling Reaction of Ethers

nium phosphate (or TBAP), which acted as a hydrogen-bonding catalyst, efficient α-C-alkylation of alcohols was accomplished to afford a radical addition adduct 76 with methyl acrylate. This photocatalyzed, H-bond-assisted C−H activation strategy enabled highly selective transformation in the presence of multiple types of C−H bonds, such as allylic, benzylic, α-CO, and α-ether C−H bonds (Scheme 76). In this process, photoinduced single electron transfer generated quinuclidine radical cation III as the HAT catalyst, which then abstracted α-H to give the α-oxyl radical VI for subsequent radical addition to acrylates (Scheme 77). Control experiments revealed that TBAP plays dual roles in accelerating C−H abstraction and enhancing the rate of radical addition to Michael acceptors, likely via H bonding with the alcohol oxygen. 2.2.2. Photoredox Organocatalysis. In 1999, Albini and co-workers reported the conjugate addition of 1,3-dioxolane with

pot strategy could also be applied to the coupling of alkenyl boronate esters. The alkenylation of isochroman was catalyzed by a chiral Brønsted acid to afford the product 74b in 62% yield and 61% ee. Tu and co-workers presented an elegant enantioselective ether version of tert-aminocyclization reaction by using a chiral secondary amine catalyst cat-26 (Scheme 75).115 A range of chiral spiroethers with various substituents was accessed from tetrahydrofuran and tetrahydropyran derivatives with good enantioselectivities. The counterion of the aminocatalyst was found to be critical, and the switch to SbF6− led to enhanced catalytic activity. Recently, Macmillan demonstrated an inspiring example of αC(sp3)−H functionalization of alcohols via the HAT process.116 By synergistically combining three distinct catalysts, a [Ir] photoredox catalyst, a HAT catalyst, and tetra-n-butylammo9455


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α,β-unsaturated ketone. A Yang cyclization was subsequently followed to yield 2-hydroxycyclobutanone ketals. 1,3-Dithiane, 1,3-dithiolane, and 1,3-oxathiane rings could all be employed in similar reactions to give cyclobutane products.118 In 2009, Albini and co-workers again extended this photoirradiated hydrogen abstraction to alcohol substrates using a flow reactor system.119 By employing disodium benzophenondisulfonate (BPSS) as a water-soluble photocatalyst, alkyl radicals derived from i-PrOH reacted with α,β-unsaturated aldehydes and acids to form lactols and lactones in a mixed aqueous solution under solar light irradiation (Scheme 79). 1,3-Dioxolane was also used as a substrate in the reactions. 9-Mesityl-10-methylacridinium perchlorate (Acr + -Mes· ClO4−) and its derivatives are electron donor−acceptor dyad molecules, which afford the charge-separated states (Acr•-Mes·+) upon visible-light excitation (λ > 450 nm). This type of photocatalyst, known as the Fukuzumi catalyst, has strong oxidizing capabilities in the excited state (Ered = +2.06 V vs SCE, MeCN) that can oxidize alkyl aromatic compounds to generate the radical cation of the aromatic ring upon irradiation of visible light.120 Recently, Tung and Wu applied the combination of this organic photocatalyst with their cobaloxime complex (Co(dmgBF2)2·2MeCN, dmg = dimethylglyoxime) into the crosscoupling hydrogen-evolution (CCHE) transformation of isochromans with β-keto esters under mild condition.120c The desired cross-coupling product was obtained along with H2 in good yield without using any sacrificial oxidants (Scheme 80). More recently, they also applied a similar system in direct hydroxylation and aminations of benzene.121 The use of Eosin Y has also been found to promote an oxidative α-alkynylation of ether with t-BuOOH as oxidant. In this process, photopromoted energy transfer with excited Eosin Y facilitated hemolysis of t-BuOOH to tert-butoxy radical t-BuO•, which could abstract the α-hydrogen atom of tetrahydrofuran to yield α-oxy radical.122 This long-lived α-oxy radical underwent subsequent radical addition to alkyne, affording a mixture of Z/E vinyl tetrahydrofuran product (Scheme 81). 2.2.3. TBAI/TBHP Catalysis. In 2011, Wan and co-workers described the catalytic formation of α-acyloxy ethers involving CDC reaction of ether and carboxylic acid (Scheme 82).123 The combination of catalytic amounts of TBAI with excess TBHP as oxidant was efficient for generating tert-butoxyl radical t-BuO•, which participates directly for abstracting α-H to an α-oxyl radical. An oxocarbenium intermediate generated from further oxidation of the radical was proposed as the active intermediate, which was then intercepted by a number of nucleophiles including carboxylic acid, amide, and tetrazoles (Scheme 83).124 The strong oxidation power of TBAI/TBHP could enable in-situ oxidation of benzyl alcohols, styrenes, and phenylacetylenes into benzoic acids, which then participate in C−O bond formation with oxocarbenium intermediate derived from ethers (Scheme 84).125 2.2.4. Miscellaneous Catalysis. It is known that DDQ could mediate a CDC-type reaction of ethers. Efforts have been put to pursue catalytic use of DDQ in this reaction. Liu and Floreancig found that MnO2 can be used as inexpensive oxidant for regenerating DDQ from its reduced hydroquinone form.126 Oxidative cyclizations and cross-dehydrogenative coupling were realized in the presence of a catalytic amount of DDQ and excess MnO2 as terminal oxidant (Scheme 85). Though slower than the stoichiometric reaction, the corresponding products were easier to purify with comparable yields.

Scheme 75. Asymmetric 1,5-Hydride-Transfer/Cyclization of Ethers

Scheme 76. Photocatalytic H-Bond-Assisted C(sp3)−H Activation

Scheme 77. Proposed Mechanism for C-Alkylation of Alcohols

α,β-unsaturated ketones in the presence of benzophenone (BQ) or anthraquinone (AQ) as photosensitizer (Scheme 78).117 Upon irradiation of UV light, benzophenone catalyst first abstracted a hydrogen from 1,3-dioxolane to generate an αoxygen alkyl radical, which then underwent radical addition to 9456


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Scheme 78. Photocatalytic Conjugate Addition of 1,3-Dioxolane with α,β-Unsaturated Ketones

Scheme 79. Solar-Light-Initiated Conjugate Addition of iPrOH with α,β-Unsaturated Carbonyl Compounds

Scheme 81. Photocatalyzed Vinylation of Tetrahydrofuran with Alkynes

Scheme 82. TBAI-Catalyzed Oxidative Esterification of Ethers with Carboxylic Acids

Another similar example of C−H bond functionalization of isochroman was described by Muramatsu and Nakano recently by using substoichiometric amounts of DDQ with [bis(trifluoroacetoxy)iodo]benzene (PIFA) as the terminal oxidant.127 A range of aryl and alkyl Grignard reagents, even amides, were shown to be tolerant to afford α-functionalized products under this reaction condition (Scheme 86). An oxidative dehydrogenative coupling of isochroman with simple acetophenone was disclosed to construct a C−C bond by using catalytic amounts of CBr4 as a radical mediator under air atmosphere (Scheme 87a).128a Control experiments manifested that 2-bromo-1-phenylethan-1-one should be involved as an important intermediate to form bromine radical in this CBr4 catalytic process. Very recently, the same group developed a CBr4-promoted double-oxidative dehydrogenative cyclization/ acidic ring-opening/aromatization tandem reaction of glycine derivatives with dioxane (Scheme 87b).128b Complex quinolone derivatives were furnished with a double-oxidative dehydrogenative cyclization strategy. MacMillan and co-workers developed a synergistic photoredox/thiol combined catalytic system for direct α-C−H arylation of benzyl ethers.129 Benzyl ether is known to have a relatively weak benzylic C−H bond with small BDE, amenable to the HAT process.130 Mechanistically, a photoredox cycle with Ir(ppy)3 would generate thiyl radical IV from mercaptoacetate cat-27 via a proton-coupled electron-transfer (PCET) process

for benzylic hydrogen abstraction. Then a HAT cycle proceeded between R−S• radical IV and benzyl ethers to regenerate the thiol catalyst while forming a α-benzyl radical for subsequent bond formation (Scheme 88). The power of this synergistic photoredox and thiol catalysis has been demonstrated in the C− H arylations of benzyl ethers with cyanobenzenes (Scheme 89). Free benzylic alcohols were also used as a substrate in the reactions to form arylated products in good yields. It was worth noting that aldehyde additive (octanal) is critical in facilitating the transformation by in-situ forming a hemiacetal intermediate required for the selective C−H functionalization. In addition, allylic C−H substrate, 2,5-dihydrofuran, was compatible under

Scheme 80. Photocatalyzed Cross-Coupling Hydrogen Evolution of Isochromans and β-Keto Esters

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Scheme 83. TBAI-Catalyzed Amination of Ethers

Scheme 84. TBAI-Catalyzed Oxidative Esterification of Ether with Aryl Alkenes and Alkynes

Scheme 86. DDQ-Catalyzed Oxidative Cross-coupling Reaction of Isochromans

Scheme 85. DDQ-Catalyzed Oxidative Cross-Coupling Reaction of Ethers

Scheme 87. CBr4-Mediated Oxidative Dehydrogenative Reaction

this condition, resulting in the formation of an arylation adduct in excellent yield as a single regioisomer. The similar photoredox/thiol catalytic system could also be applied in a direct coupling of benzyl ethers with secondary aldimines.131 In this case, the α-benzylic ether radical (via oxidation) and α-amino radical anion (via reduction) coupled with each other to afford β-amino ethers (Scheme 90). Unlike Ir(ppy)3, the excited species of Ir(ppy)2(dtbbpy)PF6 served as an oxidant and could be quenched by the thiol catalyst to produce [IrII], which then reduced the N-aryl imine via a single-electrontransfer event to afford the α-amino radical anion. Very recently, Wang and co-workers adopted this catalytic system to realize the direct α-C−H arylation reaction of N-acyl-protected tetrahydroisoquinolines with electron-deficient benzonitriles using triphenylsilanethiol as the HAT catalyst.132

2.3. β-C−H Functionalization of Carbonyl Compounds

Within the realm of organic synthesis, the carbonyl moiety represents one of the most prevalent functional groups that has been widely used in organic transformations.133 Direct α-C−H and ipso functionalization are two standard textbook transformations of carbonyl compounds as a result of their highly polar nature as well as the strong α-acidity (Scheme 91a).134 βFunctionalization of carbonyl compounds is mainly restricted to the conjugate addition to the corresponding α,β-unsaturated carbonyl compounds. Direct β-C−H functionalization of 9458


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Scheme 88. Proposed Mechanism for Benzylic C−H Arylation

Scheme 90. Cross-Coupling of Benzylic Ether with Schiff Base

Scheme 91. (a) Direct ipso- and α-Carbonyl Functionalization; (b) Direct β-Carbonyl Functionalization

saturated carbonyl compounds has remained an unaddressed challenge in carbonyl chemistry and attracted considerable attention in the past few years. Mechanistically, there are four approaches to achieve β-C−H functionalization of carbonyls depending on the nature of how the C−H bond is cleaved (Scheme 91b): (1) 2 e− oxidation to form α,β-unsaturated carbonyl compound to be intercepted by another nucleophile; (2) β-proton abstraction to give β-carbonyl anion in the presence of strong base; (3) single-electron oxidation to afford β-carbon radicals; (4) metal-assisted C−H functionalization via a C−M intermediate. 2.3.1. Aminocatalysis. 2.3.1.1. Oxidative Enamine Catalysis. In 2011, Wang and co-workers described the βfunctionalization of saturated aldehydes by oxidative enamine catalysis.135 In this report, they chose o-iodoxybenzoic acid

(IBX)136 as optimal oxidant for selectively oxidizing the in-situgenerated enamine to α,β-unsaturated aldehyde-derived iminium ion, which underwent nucleophilic conjugate addition by fluorobis(phenylsulfonyl)methane (FBSM) to give Michael adducts with moderate to good yields and high enantioselectiv-

Scheme 89. Direct Arylation of Benzylic Ethers

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Scheme 92. Enantioselective Cascade Oxidation-Michael Reaction of Aldehydes with FBSM

Scheme 93. Enantioselective Cascade Oxidation-Michael Reaction of Aldehydes with Nitromethane

Scheme 94. Enantioselective Cascade Oxidation-Michael Reaction of Aldehydes with Malonate

ities (Scheme 92).137 Aminocatalyst was sacrificed under the oxidative conditions, which accounted for the requirement of high catalyst loading. At the same time of Wang’s publication, Hayashi reported a one-pot, enantioselective oxidative coupling of saturated aldehydes and nitromethane with DDQ as the oxidant (Scheme 93).138 Both Wang and Hayashi’s work shared a similar oxidation and conjugation sequence by an identical aminocatalyst cat-2. In both cases, the reactions showed quite broad tolerance of phenylpropanals. Under Hayashi’s condition, heteroaromatic substrate, such as β-furylpropanal, and 5-phenylpent-4-enal could be applied. In a following work, Hayashi developed an improved catalytic system for oxidation of aldehyde into α,βunsaturated aldehyde by using MnO2 as a terminal oxidant.139 Subsequently, Xu and co-workers elegantly demonstrated the Saegusa oxidation-Michael cascade reaction for asymmetric βC−H functionalization of saturated aldehyde by the combination of chiral amine with Pd(OAc)2.140 This process avoided the use of a stoichiometric amount of expensive oxidants with molecular oxygen as the sole oxidant and hence is environmentally benign (Scheme 94). The reaction worked well with a number of β-

phenylpropanals as substrates with moderate yields and excellent enantioselectivities. On the contrary, aliphatic aldehydes were not accepted as substrate for this reaction. On the basis of asymmetric oxidative enamine catalysis, Enders and co-workers reported a two-component four-step domino Scheme 95. Two-Component Four-Step Synthesis of Polyfunctionalized Cyclohexene Derivatives

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Scheme 96. (a) Enantioselective β,γ-C−H Functionalization of Aldehydes; (b) Saugusa-Type Oxidation of Enamine

Scheme 97. Direct β- or γ-Arylation of Ketones

reaction.141 Two molecules of saturated aldehydes were involved, and one participated in enamine-Michael addition to nitrostyrene, while the other underwent enamine oxidation to iminium for a cascade Michael addition and aldol condensation to afford highly substituted cyclohexenes with excellent enantioselectivity. An oxindole-derived Michael acceptor could also be used as a substrate to afford a spirocyclic compound with excellent enantioselectivity (Scheme 95). In 2015, Gong and co-workers developed a metal−aminecocatalyzed enantioselective β,γ-C−H functionalization of

aldehydes with quinone derivatives employing molecular oxygen as an oxidant (Scheme 96a).142 3-Phenylbutanal worked out well in this combination catalysis system (Scheme 96a, 96a), while other aliphatic aldehyde gave rather poor yields with good enantioselectivity (Scheme 96a, 96b). When electron-rich quinones were employed, [Cu(OTf)]2C6H6 was used as Lewis acid to activate quinones for good yields (Scheme 96a, 96c and 96d). The mechanism of this transformation involved initial Saugusa-type oxidation of enamine intermediate into a dien9461


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Scheme 98. C−H Arylation of Aliphatic Aldehydes Enabled by a Transient Directing Group

Scheme 99. Photoredox Organocatalytic Activation Strategy for Direct β-Arylation of Carbonyl Compounds

Scheme 100. Proposed Mechanism of Photoredox C−H β-Arylation

amine for a typical [4 + 2] cyclization to furnish the final adduct after elimination of catalyst (Scheme 96b). By combining aminocatalysis with palladium catalysis, Yu developed a metal organic cooperative strategy for remote C−H functionalization of ketones. The aminocatalyst, once covalently connected with ketone moiety, can serve as a transient directing group for typical Pd-mediated C−H functionalization. In this

regard, Yu17 beautifully demonstrated that a simple amino acid would facilitate inert β- or γ-C−H arylations by imine formation to transiently deliver the palladium catalytic center via coordinating with the carboxylic moiety (Scheme 97). β- or γArylation of a wide range of ketones proceeded smoothly under the reaction condition to afford products in moderate to good 9462


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Scheme 101. Direct β-Arylation of Ketones and Aldehydes

yields. Aliphatic aldehydes were not suitable substrates under this reaction condition. Ge and co-workers further expanded this strategy to aliphatic aldehyde substrate in 2016 (Scheme 98).143 By employing 3aminopropanoic acid cat-28 as organocatalyst, the β-arylation product 98 of aliphatic aldehyde proceeded smoothly with moderate yield. 2.3.1.2. Photoredox Catalysis. In 2013, Macmillan and coworkers disclosed an elegant 5π-electron (5πe−) activation mode for the direct β-arylation of saturated aldehyde and ketone by synergistic combination of photoredox catalysis with organocatalysis (Scheme 99).144 In this synergistic catalytic cycle, Ir(ppy)3-mediated PET oxidized the in-situ-formed enamine intermediate V into a radical cation, which upon β-deprotonation leads to a 5π-electron β-enaminyl radical VII ready for new C−C bond formation (Scheme 100). The strategy has been successfully demonstrated in the β-arylation reaction with electron-poor cyanoarenes (Scheme 101), and the reaction worked well for both cyclohexanones and aldehydes as substrates (Scheme 101a, 101) with a different optimal aminocatalyst identified in each case. A catalytic asymmetric version has been briefly explored, with 50% ee achieved by employing a chiral cinchona-derived primary amine catalyst cat-31 (Scheme 101b). The Macmillan group further realized the direct β-coupling of cyclic ketones with aryl ketones by the synergistic photoredox/ aminocatalysis.145 The nucleophilic β-enaminyl 5π-electron species would be intercepted by a ketyl radical, generated by single electron reduction, to form a γ-hydroxyketone adduct 102.

Scheme 102. Homo-Aldol Reaction of Ketones

Cyclic ketones worked particularly well as substrates with benzophenones being the other reaction partner (Scheme 102, 102a and 102b). By changing photoredox catalyst Ir(ppy)3 to Ir(MeO-ppy)3, aryl−alkyl ketones could also be employed as a substrate for this homoaldol reaction (Scheme 102, 102c and 102d). The 5π-electron β-enaminyl activation mode was successfully applied to saturated aldehydes in β-radical Michael addition to acrylates (Scheme 103).146 A broad array of acrylates could be employed as a substrate (Scheme 103, 103a−d), and functional groups on the aldehyde part were also well tolerated in the reaction (Scheme 103, 103e−h). Recently, the same group developed a direct β-Mannich reaction of cyclic ketones with imines to yield γ-aminoketone 9463


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Scheme 103. Direct β-Alkylation of Ketones and Aldehydes

Scheme 104. Direct β-Alkylation of Ketones

aldehyde or other prefunctionalized aldehydes. Directly activating the β-C−H bond of a simple saturated carbonyl compound is highly desirable in terms of reaction economy in NHC catalysis. In a manner similar to oxidative enamine catalysis, the electron-rich Breslow intermediate from NHC catalysis might also undergo facile oxidation to give an advanced intermediate for further reaction (Scheme 105, C). In 2013, Chi and coworkers reported such an oxidative NHC catalysis for the oxidative annulation of saturated aldehydes and 1,3-dicarbonyls.148 The overall reaction proceeded in two sequential oxidative steps: oxidation of Breslow intermediate (I) to NHC-bound ester intermediates (II) and further oxidation of the ester enolate intermediate (III) to an NHC-bound α,β-unsaturated enone (IV). This α,β-unsaturated enone (IV) could react with stabilized enolate derived from 1,3-dicarbonyls to give cyclic enol γ-lactones (Scheme 106) with excellent enantioselectivities. This reaction required diquinone 106a as oxidant, and in some cases LiCl as an additive could facilitate the conversion. Unfortunately, only β-aryl propionaldehydes worked well, and no reactivity was observed for nonaromatic substituted aldehydes, likely a result of a less acidic β-C−H bond compared with aryl-substituted ones. Later, the Chi group developed the first NHC-catalyzed β-C− H functionalization of a saturated carboxylic ester. In the catalytic cycle, NHC coupled with the active phenol ester to form a NHCbound enolate (II) (Scheme 107). Because of the highly electron-withdrawing and conjugated nature of the triazolium moiety, the triazolium-bounded enolate II may undergo βdeprotonation to give a homoenolate III with β-carbon as a nucleophilic center. Experimentally, this homoenolate has been found to couple successfully with enone, trifluoroketone, and hydrazone to afford cyclopentene, δ-lactone, and δ-lactam, respectively, in a highly enantioselective manner (Scheme 108).149 In all three reactions, β-aryl substitution seems to be essential for the reaction to occur. Esters with a β-alkyl substituent afforded products in low yields. To resolve this problem, the Chi group utilized anhydrides as alternatives of esters under catalysis of a bulkier NHC.150 The desired five-ring cyclic products could be obtained with benzylidene diketones as electrophiles in good yields and with good to excellent enantioselectivities (Scheme 109, 109a−c), while no product formed if a R1 or R2 group in the diketone was replaced with an

products 104 (Scheme 104).147 By employing the synergistic strategy, the 5π-electron β-enaminyl radical underwent direct radical−radical coupling with a persistent α-amino radical, formed by single-electron reduction of imine, to furnish γScheme 105. Activation Mode of Aldehyde through NHC Catalysis

aminoketones. Various ketone- and aldehyde-derived imines underwent coupling with cyclohexanone to form the corresponding γ-aminoketones with high levels of efficiency. 2.3.2. NHC Catalysis. Intensive efforts in the past decades have established N-heterocyclic carbene (NHC) as a powerful catalytic strategy, not only for umpolung catalysis with aldehydes but also for nucleophilic catalysis in α- or β-C−H functionalization of aldehydes/esters via a Breslow intermediate (Scheme 105, A and B).8 The extended Breslow intermediate, referred to as homoenolate (B), is normally generated from α,β-unsaturated 9464


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Scheme 106. NHC-Catalyzed Enantioselective β-Functionalization of Aldehydes

Scheme 107. Catalytic Cycle of Enantioselective β-Functionalization of Carboxylic Esters

The Chi group later expanded the scope of β-C−H functionalization of ester to o-tosylamino enones.151 Under similar reaction conditions, esters could react with o-tosylamino enones to afford multicyclic oxoquinoline-type heterocycles (Scheme 111) which have interesting biological activities. Recently, Yao and co-workers extended Chi’s catalysis with active ester to free carboxylic acids, wherein an active ester

aliphatic group (Scheme 109, 109d and 109e). Also, simple chalcone and isatin were suitable electrophiles to give the corresponding chiral cyclopentene and spiro-lactone products. The only flaw of this strategy was that an excess amount of anhydride is required because of facile hydrolysis of anhydrides under basic reaction conditions (Scheme 110). 9465


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Scheme 108. NHC-Catalyzed Enantioselective β-Functionalization of Carboxylic Esters

Scheme 109. NHC-Catalyzed Enantioselective β-Functionalization of Carboxylic Anhydrides

Scheme 110. NHC-Catalyzed Enantioselective β-Functionalization of Carboxylic Anhydrides

2.4. Benzyl C−H Bond Functionalization

species was in-situ generated by reacting with the typical peptide coupling reagent HATU.

152

2.4.1. Aminocatalysis. Cozzi and co-workers first reported an enantioselective α-benzylation of aldehydes with highly conjugate benzyl derivatives under oxidative conditions by using MacMillan-type aminocatalyst.153 Other than xanthene, 1,3,5cycloheptatriene, flavanoids, and indole derivatives could all be applied as substrates, and the corresponding products were

The reaction was applied to the

coupling with isatin to afford spirocyclic oxindolo-γ-butyrolactones in high yields with excellent enantioselectivities (Scheme 112). 9466


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Scheme 111. NHC-Catalyzed Enantioselective β-Functionalization of Esters

Scheme 112. NHC-Catalyzed Enantioselective β-Functionalization of Carboxylic Acids

anodic oxidation, thus obviating the use of stoichiometric amounts of DDQ.154

Scheme 113. Catalytic Stereoselective Benzylic C−H Functionalization

Scheme 114. Enantioselective Benzylic C−H Functionalization

In 2012, Xiao reported a similar transformation catalyzed by diarylprolinol silyl ether catalyst.155 Though the products were obtained with low yields, the reaction demonstrated high enantioselectivity for the oxidative coupling of aldehyde and xanthene. The Jiao group developed a successful example of asymmetric oxidative α-benzylation of aldehydes by using dioxygen as oxidant.156 The MacMillan catalyst employed in this case acted not only as enamine catalyst but also as acid promoter to facilitate benzyl C−H bond activation as Klussmann previously reported.157,158 The reaction tolerated a range of aldehydes as substrates to afford benzylation products in moderate to good yields with excellent ee values (Scheme 114). In an impressively recent advance, Yu and co-workers expanded their aminocatalyst/palladium combined catalytic strategy in the benzylic C−H arylation reaction with iodobenzene.17 In this case, benzaldehydes would react with amino acid to guide palladium-mediated C−H arylation into the benzylic position. When using a chiral amino acid as the transient directing group, enantioselective C−H arylation was achieved with excellent enantioselectivity (Scheme 115).

obtained in the reactions with moderate yields and high enantioselectivity (Scheme 113). The highly conjugated benzyl compounds ensure the formation of stabilized cationic or radical intermediates that serve as active benzylation species under DDQ oxidations. It is worth mentioning that the asymmetric coupling of aldehydes and xanthene could be successfully conducted in the presence of amine catalyst cat-26 by utilizing 9467


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Scheme 115. Direct Benzylic C−H Arylation

parallel oxidation process to furnish the desired cross-coupling products other than autoxidation.157 2.4.3. H-Bonding Catalysis. In 2015, Zhou and co-workers utilized quinine-based squaramide catalyst cat-37 as hydrogenbonding catalyst to facilitate the oxidative cascade reaction between 2-alkyl-substituted phenols and malononitriles for the enantioselective synthesis of 2-amino-4H-chromenes 117 (Scheme 117).159 In this case, MnO2 was employed as equivalent oxidant to oxidize the benzylic C−H bond, forming o-quinone methides (Scheme 117, I). The cascade Michael addition− cyclization process then proceeded under catalysis of the hydrogen-bonding catalyst with excellent enantioselectivity. Very recently, the Melchiorre group developed a photoenolization/Diels−Alder reaction of 2-alkyl benzophenones 118 and maleimides using a chiral thiourea−amine catalyst, a derivative of natural cinchona alkaloids (Scheme 118).160 In this process, 2-alkyl benzophenone 118 was photoactivated to form a hydroxy-o-quinodimethane intermediate, which then reacted with maleimide in typical [4 + 2] cycloaddition. Control experiments and mechanistic studies indicated that the chiral thiourea−amine acts as a bifunctional catalyst: (a) the thiourea moiety serves as a chiral catalyst to activate maleimide by hydrogen bonding, thus increasing its dienophilic character, while (b) the quinuclidine moiety quenches the triplet state of benzophenone via an electron-transfer process to suppress the background racemic reaction. The cooperation of these two effects contributed to the high stereoselectivities. 2.4.4. Photoredox Organocatalysis. Fukuzumi and coworker described an oxygenation of p-xylene using 9-mesityl-

Scheme 116. Autoxidative Coupling of Xanphene with Carbonyl Compounds

2.4.2. Brønsted Acid Catalysis. Xanphene is known to undergo facile autoxidation under aerobic conditions due to its weak benzylic C(sp3)−H bond.156 Recently, a strong Brønsted acid such as methanesulfonic acid was found to promote the heterolytic cleavage of the autoxidation intermediates such as peroxide-like I or II to benzylic carbocation III and facilitate the subsequent C−C bond formation with various ketones and 1,3dicarbonyl compounds under neat conditions (Scheme 116). The reaction also worked well with N-substituted acridines and N-phenyltetrahydroisoquinoline. Further mechanism studies revealed the in-situ-generated H2O2 may initialize another

Scheme 117. Enantioselective C−H Oxidation/Michael Addition/Cyclization Cascade

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Scheme 118. Enantioselective Photoenolization/Diels−Alder Reaction

Scheme 119. Photocatalytic Oxygenation of p-Xylene Using [Me2Acr+-Mes]ClO4−

generated hydrogen peroxide degraded RFT under irradiation, which led to low yields and poor selectivities. In 2015, Mühldorf and Wolf found that Sc(OTf)3 can act as an additive and could enable the oxygenation of alkyl benzenes Scheme 121. Photocatalytic Oxygenation of Benzylic sp3 C− H Bonds by RFT and a Non-Heme Iron Catalyst

2,7,10-trimethylacridinium ion (Me2Acr+-Mes) as an efficient photoredox organocatalyst in oxygen-saturated acetonitrile.161 The reaction afforded p-tolualdehyde and H2O2 in quantitative yields without the formation of further oxygenated product (Scheme 119). This photocatalytic oxygenation also worked well with durene and mesitylene as substrates but not with toluene. With aqueous hydrochloric acid as an additive, further oxidation of benzaldehydes afforded carboxylic acids as the main products.162 The author suggested that Cl− undergoes a single electron transfer with Mes•+ to give Cl• radical, which abstracts the formyl hydrogen atom of benzaldehyde. The benzyl C−H oxidation could also be achieved using anthraquinone-2,3Scheme 120. Photocatalytic Oxygenation of Benzylic sp3 C− H Bonds to Ketones

bearing electron-withdrawing substituents, but this Sc(OTf)3/ RFT oxidative system did not work well with other benzylic substrates.166a Very recently, the same group developed the efficient photooxidation of alkyl benzenes to ketones and carboxylic acids using the catalytic system of riboflavin tetraacetate and the biomimetic nonheme iron complex [Fe(TPA)(MeCN)2](ClO4)2 (TPA = tris(2-pyridylmethyl)amine) (Scheme 121).166b The iron catalyst was responsible for alkyl benzene oxygenation as well as H2O2 disproportionation, leading to high efficiency. Pandey and co-workers developed a photoredox catalytic protocol for benzyl C−O formation via C−H activation.167,168 In the presence of 1,4-dicyanonaphthalene (DCN) under irradiation with a 450 W lamp (>300 nm), alkylarene was oxidized to arene radical cation intermediate I, which upon deprotonation and further oxidation leads to benzylic carbocation II for C−O bond formation (Scheme 122). The corresponding cyclic ethers were obtained in moderate to good yield. For ester-substituted substrates, a second cycle of electron−proton−electron (E−P− E) transfer occurred to generate the unexpected cyclic

dicarboxylic acid as photocatalyst to give methyl ester products in methanol.163 Recently, Lei and co-worker developed a simple and mild route of aerobic oxidation of benzylic sp3 C−H bonds.164 Under the irradiation of visible light, a variety of benzylic sp3 C−H bonds could be oxidized into the ketone products using 1.0 mol % of Me2Acr+-Mes as photoredox organocatalyst (Scheme 120). In addition, the result of 18O2-labeling experiments revealed that the carbonyl oxygen of benzophenone was exchanged with water under the visible-light conditions. In 2010, research from the König group revealed that toluene derivatives could be oxidized to ketones and alcohols as product mixtures using riboflavin tetraacetate (RFT) as photocatalyst under the irradiation of blue light.165 Moreover, benzyl C−H substrate, benzyl methyl ether, and acylated benzyl amines were transformed directly into the corresponding methyl ester and benzylimides under this condition. However, the in-situ9469


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Scheme 122. Photocatalytic Benzylic C−H Functionalization for C−O Bond Formation

Scheme 123. Visible-Light-Promoted Direct Benzylic C−H Amination

Scheme 124. Visible-Light-Catalyzed Benzylic C−H Mono- and gem-Difluorination

photocatalyst systems for fluorinating the sp3 C−H bonds under visible-light irradiation.169 Mono- and gem-difluorination were controlled expediently just by switching diarylketone photocatalysts. 9-Fluorenone catalyzed benzylic C−H monofluorination to form product 124a, while xanthone as catalyst forms gem-difluorination 124b without explicit mechanistic explanation (Scheme 124). Two types of Selectfluor salts were chosen as fluorine atom donors, and the formation of cationic Nradicals was proposed to play a vital role in regenerating the photocatalyst. A continuous-flow protocol was also adopted in this photoinduced benzylic C−H fluorination. By using Selectfluor as the fluorine source and xanthone as photoorganocatalyst, the corresponding fluorinated products were obtained in shorter times.170 It was known that acetophenone absorbed weakly between 375 and 400 nm at high concentrations. Chen further developed an acetophenone-catalyzed fluorination of unactivated C(sp3)−

hemiacetals with water as the source of oxygen. This protocol also could be employed for direct transformation of arylalkyls into the corresponding aryl ketones (Scheme 122, 122d). However, formation of the C−N bond failed under the same condition due to the competitive electron-transfer process between amines and alkyl aryl groups. In 2015, Pandey and Laha developed a successful crossdehydrogenative benzylic C−H amination by using DCA (9,10dicyanoanthracene) as a photoredox catalyst under aerobic conditions (Scheme 123).168 The methoxy group present in the amide substrate was necessary for generating the desired product. Aminated products were obtained with a wide range of benzyl C−H bonds in moderate yields and excellent regioselectivity. Diarylketones promoting C−H functionalization are mostly carried out with high-energy UV irradiation, thus normally requiring the presence of excess stoichiometric amounts of ketones. In 2013, Chen and co-workers developed new 9470


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by arylketones,169,171 photoinduced electron transfer was proposed in this case to generate radical cation intermediates in the key radical forming step. Electronically and sterically diverse benzylic fluorides were obtained in moderate yields (Scheme 127). 2.4.5. TBAI/TBHP Catalysis. Benzyl esters are important functional groups in organic synthesis that are often employed as the protecting groups in amino acids and their derivatives.153 Traditional methods for preparing benzyl esters mainly rely on esterification of benzyl alcohols, carboxylic acids, and acyl chlorides. In recent years, oxidative coupling reactions of common C−H substrates to synthesize benzyl esters have been developed by using transition metals, such as palladium,174a−e copper,174f rhodium,174g and platinum.174h However, very few examples of organocatalytic oxidative esterifications were reported under metal-free conditions. In 2012, the Fu group presented a direct esterification from carboxylic acids and alkylarenes catalyzed by combination of TBAI and TBHP (Scheme 128a).175 In this reaction, toluene was first oxidized to benzaldehyde which served as acyl donors to form 128a. Large kinetic isotope effects (kH/kD = 9/1) were observed in the deuterium experiment, which indicated that cleavage of the benzyl C−H bond was involved in the rate-determining step. Later, it was found that aromatic aldehydes as coupling partners could also react with alkylarenes smoothly to afford benzyl esters under the same catalytic system (Scheme 128b).176 The Fu group then demonstrated the direct oxidative esterification of alcohols with toluene derivatives.177 In this course of the reaction the use of 1.2 equiv of NaH2PO4 as additive could improve the efficiency in some instances. In 2013, Patel and co-workers reported the synthesis of benzylic esters with alkylbenzenes as self-coupling partners (Scheme 128c).178 Various functional groups were tolerated under the reaction conditions. In the above examples, hypoiodites ([IO]− or [IO2]− generated in situ) were proposed as the real catalytic species to initiate a homolytic cleavage of the benzylic C−H bond to give a benzyl radical. The benzylic radical was further oxidized by the hypoiodite species to a benzyl cation. Control experiments in the presence of a catalytic amount of I2 or KI and TBHP as oxidant could not afford the desired products, which excluded I2 as the hydrogen abstractor. With catalytic amounts of nBu4NI in the presence of TBHP, C−O bond formation was achieved to synthesize alkyloxyamines, as reported by Lv and co-workers.179a In particular, Nhydroxyphthalimide (NHPI) was utilized as a stoichiometric reactant, generating N-oxyl radical (PINO) in situ, which was

Scheme 125. Visible-Light-Promoted Unactivated C(sp3)−H Fluorination

Scheme 126. Visible-Light-Promoted Selective C(sp3)−H Fluorination

H bonds upon irradiation of short violet light (375−400 nm) by a household CFL (Scheme 125).171 At the same time, Tan and coworkers also studied a photocatalyzed fluorination of unactivated C(sp3)−H bonds in the presence of anthraquinone (AQ).172 By employing Selectfluor as fluorine source, site-selective fluorinaScheme 127. UV-Light-Promoted Benzyl C−H Fluorination

tion was achieved with a range of secondary C−H bonds, most distal to electron-withdrawing groups (EWG) (Scheme 126). Lectka and co-workers employed 1,2,4,5-tetracyanobenzene (TCB) as a photocatalyst to catalyze benzyl C−H fluorination under UV-light irradiation.173 Unlike the HAT process initiated

Scheme 128. TBAI-Catalyzed Benzylic Acyloxylation of Alkylarenes

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Scheme 129. TBAI-Catalyzed C−O Bond Formation for Synthesis of Alkyloxyamines

Scheme 132. Domino Synthesis of Imidazo[1,5c]quinazolines Scheme 130. TBAI-Catalyzed Benzylic C−H Amination

then coupled with benzylic and allylic radicals (Scheme 129). Moreover, direct fluorination and nitration of benzyl C−H bonds could also be achieved under the catalysis of NHPI.179c,d Other than C−O bond formation, direct C−N bond formation through benzylic C−H activation has also been developed under this metal-free system of TBAI/TBHP.180a A

and formamide could be used as the nitrogen source. Control experiments indicated that Lewis acid plays an important role in the transformation of toluene to benzyl alcohol, which is then further oxidized to aldehyde.182c The in-situ-forming hemiaminal undergoes further oxidation to produce amide product. No aromatic C−H amination products were detected. In 2014, Li and co-workers reported an efficient method for the synthesis of imidazo[1,5-c]quinazolines from readily available 4-methylquinazolines and benzylamines via a tandem reaction amination of sp3 C−H bonds under catalysis of the TBAI/TBHP system (Scheme 132).183a The method could be carried out on a gram scale in high isolated yield. In a continued study, the double amination of sp3 C−H bonds of methylarenes with 2-aminobenzamide was developed for the synthesis of quinazolinones.183b 2.4.6. Iodoarene Catalysis. Hypervalent iodine as oxidant is known to promote benzylic C−H bond oxidation, a fundamental

Scheme 131. TBAI-Catalyzed Benzylic C−H Imidation

Scheme 133. Oxidation of Benzylic and Alkane C−H Bonds wide range of benzylic C−H substrates and N-heterocycles, e.g., 1H-benzotriazole, benzotriazoles, benzimidazoles, and tetrazoles, were tolerated to afford amination products in high yields (Scheme 130).180b The reactions were easily scaled up to the gram scale. A recoverable and reusable 1-butylpyridinium iodide, a type of heterocyclic ionic liquid, has also been developed for the benzylic C−H amination with azoles.181 With Lewis acid as cocatalyst, aromatic amides could be synthesized from alkylarene with N-substituted formamides,182a primary amines,182b and ammonia182c via oxidative C−H activation (Scheme 131). The cheap feedstock chemicals such as toluene were used as acyl donors after oxidation to benzaldehyde, and both free amine including aqueous ammonia

transformation in organic synthesis. A catalytic example was realized using 2-iodoxybenzenesulfonic acid (IBS) as a catalyst which could be regenerated in situ from sodium 2-iodobenzenesulfonate with oxone as the terminal oxidant.184 The addition of tetra-n-butylammonium hydrogen sulfate (nBu4NHSO4) as a phase-transfer catalyst accelerated the reaction effectively. Methylene C−H bonds were oxidized to a ketone product, while benzoic acids were the major products obtained from 9472


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Scheme 134. (a) Iodoarene-Catalyzed Stereospecific Intramolecular Benzyl C−H Amination.; (b) Chemoselectivity between sp3 and sp2 C−H Amination

Scheme 135. DFT-Computed Free Energies in TFE for the Reaction between Benzamide and PhI(OAc)2

Scheme 136. DDQ-Mediated Benzyl C−H Oxidation

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Scheme 137. Triarylimidazole-Mediated Benzyl C−H Oxidation

toluene derivatives (Scheme 133). Simple alkanes, such as cyclohexane, could be oxidized under this condition, but the observed selectivity was often low. Shi and co-workers first reported an intramolecular benzylic C−H amination using iodoarene as precatalyst and m-CPBA as oxidant.185 Cyclic substrates with five- to seven-membered rings were compatible in this reaction and afforded the desired products in 70−95% yields (Scheme 134a, 134a−c). Acyclic tertiary C−H bonds were also tolerated under this mild condition (Scheme 134a, 134d−f). However, reactions of the secondary C−H bonds afforded a trace amount of product with fully decomposed starting material (Scheme 134a, 134g). Competitive sp2 C−H amination was observed with sp3 and sp2 C−H amination products in a ratio of 42/58, showing catalysis was less differentiable in this regard (Scheme 134b). DFT calculations were performed to elucidate the mechanistic details (Scheme 135). This reaction was proposed to involve an iodonium cation intermediate II and proceeded via a concerted C−H activation/C−N bonding transition state (TSa) without the involvement of a carbocation intermediate. 2.4.7. Electroorganic Catalysis. DDQ as an oxidant has been widely employed in the oxidation of benzyl C−H bonds. In the early 2000s, Utley and Rozenberg reported electrochemical oxidation of toluene derivatives and 2-benzylnaphthalenes to the corresponding aldehydes and ketones in the presence of a catalytic amount of DDQ (Scheme 136).186 The reduced dihydroquinone (H2DDQ) could be electrochemically regenerated in aqueous acetic acid (with Eo = 0.44 V vs SCE). Chiba and co-workers realized the electrochemical synthesis of natural euglobals from the cycloaddition between generated quinone methide and terpenes using DDQ as the redox mediator (Scheme 136).187 Triarylimidazoles as electroorganic mediators are capable of accessing a reasonable range of potentials, which were efficient for the oxidation of benzyl C−H bonds under mild conditions (Scheme 137).188 At the anode, the triarylimidazole was oxidized to cation radical, which then accepted an electron from the substrate to give a new cation radical and regenerate the mediator. Upon further deprotonation and oxidation, a benzyl cation was generated for subsequent bond formation, especially for the oxygenation of benzyl alcohols and benzyl ethers in large scale. 2.4.8. Miscellaneous Catalysis. It is well known that benzylic C−H bonds can be oxidized using a catalytic amount of NHPI via a radical mechanism under oxygen atmosphere.189 An initial report for catalytic benzylic oxidation was given in 1995 by Ishii and co-workers, where substituted benzyl derivatives were directly transformed to ketones via NHPI-catalyzed aerobic oxidation, and following reports by the same group proved that toluene derivatives could be oxidized to benzoic acid under the assistance of metal salt such as Co(OAc)2 (Scheme 138).190

Scheme 138. NHPI-Catalyzed Benzylic C−H Bond Oxidation

Scheme 139. Catalytic Cycle of NHPI-Catalyzed Benzylic C− H Bond Oxidation

In these transformations, NHPI was initially transformed to PINO by the Co−peroxy radical generated from Co(II) under aerobic conditions to initiate the catalytic cycle. The generated PINO radical could abstract benzylic hydrogen from toluene to form benzyl radical, and a typical HAT cycle was then established by PINO/O2 to facilitate benzylic oxygenation (Scheme 139). Benzoic acid was obtained via Co(III)-mediated oxidation of Scheme 140. Oxidative C−C Coupling of Benzylic C−H Bonds with 1,3-Dicarbonyl Compounds

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Scheme 141. Hydroxylation of α-Phenylethyl Phosphonate

Scheme 144. Synthesis of Aromatic Nitriles from Methyl Arenes through Ammoxidation

benzyl hydroperoxy. On the basis of this knowledge, Correia and Li reported an aerobic oxidative cross-dehydrogenative-coupling Scheme 142. Benzylic C−H Bond Nitrooxylation

through ammoxidation is of great significance in industrial manufacture.196 In 2013, Wang and co-worker developed a novel ammoxidation of methyl arenes with tert-butyl nitrite (TBN) under the catalysis of Pd(OAc)2 and NHPI under nitrogen atmosphere (Scheme 144).197 TBN acted as the nitrogen source as well as the oxidant, reacting with NHPI to generate PINO radical and NO species. Benzyl radical formed in situ coupled with NO radical to form nitrosomethyl arene intermediate.198 Detailed mechanistic studies indicated the aldoxime is the key intermediate in this transformation, which was converted into nitrile in the presence of palladium.199 Under this condition, a variety of substituted methyl arenes were tolerated to furnish nitrile products smoothly, while a high loading of NHPI at slightly elevated temperatures was needed for toluene derivatives bearing strongly election-withdrawing substituents, such as NO2, CO2Me, and Ac. Moreover, there was only one methyl group that

reaction of benzylic C−H bonds and carbonyl compounds in the presence of catalytic amounts of FeCl2, CuCl, and NHPI (Scheme 140).191 By employing a catalytic system of CuCl, NHPI, and PPh3, α-C−H bond of α-phenylethyl phosphonate could be oxygenated to generate α-hydroxy phenylethyl phosphonate 141a, which is a valuable synthetic intermediate in pharmaceutical chemistry (Scheme 141).192 Scheme 143. NDNPI-Catalyzed Fluorination of Benzyl C−H Bonds

Scheme 145. TEMPO-Catalyzed Oxidative C−C Coupling of N-Substituted Acridines with Various Nucleophiles

Inoue and co-workers have introduced a nitrooxy group at the benzylic positions in the presence of NHPI catalyst and cerium(IV) ammonium nitrate (CAN) reagent system (Scheme 142).193 The nitrooxy group acted as a surrogate for the OH group as well as an excellent leaving group for further substitution reactions. A variety of benzylic substrates bearing electron-deficient functionalities, such as acyloxy, tosyloxy, ketone, ester, or amide groups, were compatible to give benzyl nitrates at room temperature. In 2013, Inoue and co-workers developed a metal-free fluorination of benzyl C−H bonds with Selectfluor by employing a catalytic amount of cat-41 (Scheme 143).194 Selectfluor acted as an oxidant to generate N-oxyl radical in situ and was trapped by the resulting benzyl carbon radical to form a C−F bond. This transformation proceeded with high functional group tolerance to yield fluorinated products with good chemoselectivities. Moreover, C−H bonds of alkanes, such as cyclododecane, 2oxaadamantan-1-ol, and adamantane derivatives, were suitable substrates to afford monofluorides in moderate yields. Aromatic nitriles are a class of useful materials in the synthesis of pharmaceuticals, natural products, and industrial products.195 The preparation of aromatic nitriles from available methyl arenes

could be transformed into a cyano group with substrates bearing two or more methyl groups. The same research group further extended the substrate scope to allyl arenes in this reaction.200 By employing a similar catalytic system, allyl arenes were converted into the corresponding alkenyl nitriles in moderate to good yields. In 2012, Jiao developed a TEMPO-catalyzed oxidative CDC reaction with acridine derivatives using molecular oxygen as the oxidant.201 A number of stabilized enolates such as nitroalkanes, ketones, malonates, and malononitrile could be used as nucleophiles to react with N-substituted acridines to construct 9475


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catalyzed C−H activation of allylarenes provided a new strategy for the allylic alkylation for unactivated ketones (Scheme 147a). The reactions of allylbenzene proceeded well with five- to sevenmembered cyclic ketones to furnish the corresponding allylation products in moderate to good yields (Scheme 147a, 147a−c). Acyclic ketones showed poor reactivity in this system with only 21% yield (Scheme 147a, 147d). The reaction also worked with

new C−C bonds (Scheme 145). The reaction was proposed to proceed via acridine hydroperoxyl or hydroxyl radical intermediates. The isolation of acridinone byproduct was rationalized to disprove a benzylic cation mechanism. However, Scheme 146. Oxidative Coupling of Allylarenes with Diketones

Scheme 148. Enantioselective Oxidative Coupling of Allylarenes with Aldehydes

efforts to synthesize and characterize the radical intermediates have been all in vain. Recently, Yan reported a successful example of oxidative coupling between benzylic compounds and 1,3-dicarbonyls with the DDQ/NaNO2/O2 oxidative system.202 DDQ could oxidize the benzyl and allylic C−H bond to form benzylic or allylic cation, which then reacted with dicarbonyl compounds to form CDC reaction products. NO released in situ from NaNO2 in the presence of excess amounts of HCOOH was oxidized to NO2 by dioxygen, which then regenerated the catalyst DDQ. The coupling products were obtained with high efficiency as shown below (Scheme 146). 2.5. Allylic C−H Bond Functionalization

5α-cholestan-3-one to give the allylic adduct in 50% yield with high regioselectivity (Scheme 147b). Unfortunately, no enantioselectivity was achieved in this catalytic system. At the same time, Gong and co-workers accomplished the first asymmetric oxidative allylation of aldehydes with terminal alkenes by the combined catalytic system of palladium, amine, and chiral phosphoric acid catalyst.205 A chiral counteranion strategy was shown to play a critical role in controlling the stereochemistry of C−H oxidative coupling. A range of αbranched aromatic aldehydes and terminal alkenes was tolerated

2.5.1. Aminocatalysis. Tsuji−Trost allylic alkylation is a fundamental C(sp3)−C(sp3) bond formation reaction via transient palladium(II) π-allyl intermediates with prefunctionalized allylic substrates.203 The oxidative Tsuji−Trost reaction has recently been pursued directly using allylic hydrocarbons for C(sp3)−C(sp3) bond formation. The first oxidative allylic alkylation of unactivated ketones was realized by Lei and Luo et al. under synergistic Pd/enamine catalysis.204 The combination of catalytic nucleophilic enamine activation with Pd-

Scheme 147. Oxidative Coupling of Allylarenes with Unactivated Ketones

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In 2014, Wang and co-workers reported nBu4NI/TBHPcatalyzed direct amination of allylic C−H with anilines.208 The reactions were limited to cyclohexene and cyclopentene as allylic substrates and aniline bearing electron-withdrawing groups, such as cyano, nitro, and acetyl substitution (Scheme 151). The reactions could be expanded to imidations with phthalimides, imidazoles, triazoles, and sulfonamides (Scheme 152).209 In 2013, the Li group described the allylic sulfonylation of αmethylstyrenes with sulfonylhydrazides by using TBAI as the catalyst with TBHP as oxidant (Scheme 153a).210 The coupling of styrene with TsNHNH2 could also take place to form olefin sulfone 153b in lower yield (Scheme 153b). It was proposed that sulfonyl radicals generated from sulfonylhydrazides underwent addition to α-methylstyrene derivatives followed by H abstraction with tert-butoxyl or tert-butylperoxy radicals to afford allylic sulfones. 2.5.4. Electroorganic Catalysis. Electroorganic chemistry (EOC) has become one of the most attractive and powerful methods in organic synthesis in recent times that could replace stoichiometric reagents with electrical current.25 In previous reports, NHPI-mediated electrochemical allylic C−H oxidation only gave low yields of enones.211 Very recently, Baran and coworkers reported a successful example of electrochemical allylic C−H oxidation in the presence of a catalytic amount of cat-43 (Scheme 154).212 In this work, simple operations were performed in large-scale industrial settings without a substantial environmental impact, while precious metals, such as platinum and gold, were avoided by using inexpensive carbon electrodes. A broad scope of enones was furnished in large scale (demonstrated on 100 g) with high chemoselectivity. 2.5.5. Miscellaneous Catalysis. In 2015, the MacMillan group reported direct arylation of nonfunctionalized allylic C−H bonds by the synergistic merging of photoredox catalysis and hydrogen-atom-transfer catalysis.213 SET with Ir(ppy)3 helped to generate thiyl radical from thiol precatalyst cat-44 for allyic H abstraction. The resulted allylic radical would then couple with an aryl anionic radical generated from another photoinduced electron transfer to give the arylation adduction. Both cyclic and acyclic alkenes could be applied in the reactions (Scheme 155a, 155a−f), and the reaction also tolerated a number of electrondeficient cyanoarenes (Scheme 155a, 155g−i). This protocol was also suitable for arylation of benzyl C−H bonds (Scheme 155b); however, only allylic C−H-functionalized product formed when both olefinic and benzylic substrates were combined in the same vessel.

Scheme 149. Intramolecular Enantioselective Allylation

to undergo the asymmetric allylic alkylation to afford products with good enantioselectivities (Scheme 148). 2.5.2. Brønsted Acid Catalysis. Chai and Rainey reported a cascade of Pd(II)/chiral phosphoric acid-catalyzed intramolecScheme 150. TBAI-Catalyzed Esterification of Allylic C−H Bonds

ular allylic C−H bond activation and semipinacol rearrangement reaction.206 Cyclobutanol substrates underwent migratory ring expansion via a semipinacol rearrangement with the nascent πallylpalladium species to furnish the corresponding spirocyclic indenes products with good diastereoselectivity (Scheme 149). Chiral phosphoric acid served as a counteranion/anionic ligand to deliver enantioselective control for the reaction. 2.5.3. TBAI/TBHP Catalysis. TBAI catalysis has also been shown to be a powerful approach in C−O bond formation via allylic C−H functionalization. In 2012, Wan and co-workers reported the oxidative coupling of allylic hydrocarbons with readily available carboxylic acid in the presence of TBAI and TBHP (Scheme 150). The reaction worked with tetrasubstituted

2.6. Alkane C−H Bond Functionalization

Methodologies for the selective oxyfunctionalization of industrial feedstocks such as alkanes have significant importance for the synthesis of value-added chemicals. In this area, Du Bois and coworkers developed an oxaziridine-mediated catalytic hydroxylation of unactivated tertiary C−H bonds.214−216 In 2005, they developed their first-generation benzoxathiazine catalysts.214 In this report, DFT calculation was conducted at first to evaluate the oxidizing potential of benzoxathiazine oxaziridines. By employing urea·H2O2 as the O source and bis(3,5-bis(trifluoromethyl)phenyl) diselenide (Ar2Se2) as a suitable cocatalyst, oxaziridine catalyst cat-46 was regenerated with minimal byproduct formation. This unique oxidative catalytic system could be applied to the oxidation of saturated and unsaturated aliphatic substrates via O atom transfer (Scheme 156a). The hydroxylation of tertiary C−H bonds, especially distal to the electronwithdrawing group, was strongly preferred (Scheme 156b,

Scheme 151. TBAI-Catalyzed Amination of Allylic C−H Bonds

alkenes, a rather difficult substrate in allylic C−H oxidation, to provide the allylic esters in good yields for the first time.207 Mechanically, TBAI was proposed to facilitate the generation of tert-butoxyl and tert-butylperoxy radical, which then underwent H abstraction to generate allylic and acyloxyl radicals, and the two free radicals cross-coupled to give the desired allylic ester. 9477


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Scheme 152. TBAI-Catalyzed Amination of Allylic C−H Bonds

Scheme 153. TBAI-Catalyzed Sulfonylation of Styrene Derivatives

Scheme 154. Electrochemical Allylic C−H Oxidation

Bois and Adams developed an improved reaction protocol in the presence of cat-44 with Oxone as oxidant in an aqueous fluoroalcohol solvent mixture.216 The choice of fluoroalcohol solvent was uniquely efficacious for this transformation, which both concentrates the reactants and mitigates the deleterious impact of H2O on oxaziridine stability (Scheme 158). It is well known that dioxiranes are highly chemoselective stoichiometric reagents for C(sp3)−H hydroxylation. Recently, the first ketone-catalyzed C−H hydroxylation was reported by generating dioxirane in situ with H2O2 as oxidant.217 p-Fluorine phenyl trifluoromethyl ketone was chosen as the most efficient organocatalyst with a tendency for hydroxylation of tertiary over secondary C−H bonds (Scheme 159). Substrates other than adamantane were oxidized with moderate yields only. N-Hydroxyphthalimide (NHPI) was used as a precursor of the electron-deficient phthalimide N-oxyl radical (PINO) to abstract hydrogen from simple alkanes to generate alkane radicals with the company of transition metals or other redox additives.105

156a−c). In addition, this system performed extremely well for epoxidation reactions of olefins (Scheme 156b, 156d and 156e). Due to the high, indiscriminating reactivity of the oxidant, only a modest efficiency of C−H hydroxylation was achieved with their first-generation oxaziridine system. Computational and experimental studies suggested that an electron-withdrawing group para to the phenolic oxygen should lower the activation energy of oxaziridine intermediate.215 Additionally, the use of polar solvents or hydrogen-bond donor additives could help to stabilize the transition structure. A pentafluorophenyl group introduced at the para position (cat-47) was found to improve the yield effectively (Scheme 157). Roles of acetic acid were not only responsible for generating the corresponding oxaziridine via peracetic acid but also as a cosolvent to help solubilize apolar substrates. Owing to long reaction times as well as the need for superstoichiometric amounts of H2O2, more facile reaction condition was required for C−H hydroxylation. Recently, Du 9478


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Scheme 155. Photocatalytic Arylation of Allylic C−H Bonds

Scheme 156. Catalytic Hydroxylation of Unactivated Tertiary C−H Bonds and Epoxidation of Olefins

Halogenated organic molecules are fundamental building blocks in organic synthesis. Lectka and co-workers reported a fluorination of a series of sp3 C−H bonds with Selectfluor using a polycomponent catalytic system involving NHPI, an anionic phase-transfer catalyst (KB(C6F5)4), and a copper(I) bisimine complex.219 Under this mild condition, only monofluorinated

With a dialkyl azodicarboxylate as the trapping agent of the resultant carbon radical, a C(sp3)−H amination was achieved for aliphatic C−H bonds as well as benzylic and propargylic C−H bonds (Scheme 160).218 The hydrazine compounds were obtained in good efficiency, which could be further converted to the corresponding carbamates or amines. 9479


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Scheme 157. Catalytic Hydroxylation of Unactivated Tertiary C−H Bonds

Scheme 161. C(sp3)−H Bond Fluorination Using a Polycomponent Catalytic System



Scheme 162. Photocatalytic Bromination of C(sp3)−H Bond products were obtained in moderate to good yields with cycloalkanes, linear alkanes, adamantane, α-methylstyrenes, and benzylic substrates (Scheme 161). In some cases, the addition of KI as additive was required to maintain the oxidation state of Cu(I) catalyst by forming a diiodide Cu(I) complex and to aid the production of PINO radical. The abstraction of alkane C−H bonds could also be reached by employing photosensitizer, diarylketone derivatives. In 2006, Doohan and Geraghty developed the photocatalyzed addition of cycloalkanes to electron-deficient alkynes using a silicasupported benzophenone.220 Vinyl cycloalkanes were obtained as mixtures of E/Z isomers with a UV lamp (Scheme 162). In 2013, a photocatalytic bromination of aliphatic and benzylic sp3 C−H bonds was established with easy-to-handle CBr4 as the source of bromine upon irradiation of a household lamp (Scheme 163).221 Experimental and computational studies indicated morpholine is essential to act as reductive quenchers in visible-light photoredox catalysis. It was noted that water may remove excess bromides to facilitate the process.

Scheme 163. Photocatalytic Bromination of C(sp3)−H Bond

In 2016, Ge and co-workers reported a site-selective C−H bond activation via a metal−organic cooperative catalysis strategy. By utilizing glyoxylic acid cat-49 as an organic catalyst to serve as a transient directing group, the sp3 γ-C−H bond of aliphatic amines could be efficiently activated, generating

Scheme 160. Catalytic Radical Amination of C(sp3)−H Bonds

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Scheme 164. sp3 C−H Bond Arylation of Primary Amine Using a Transient Directing Group

Scheme 165. [Rh(PPh3)Cl] and Aminopyridine-Catalyzed Intermolecular Hydroacylation

Scheme 166. Mechanism of Amine-Directed Transition-Metal Catalysis

arylated products 164 in moderate yields (Scheme 164a).222a In the same year, Yu and co-workers also reported a C−H bond functionalization of the sp3 γ-C−H bond employing 2hydroxynicotinaldehyde cat-50 as organocatalyst to achieve arylation reaction in moderate to good yields (Scheme

164b).222b In these transformations, aldehyde reacts with primary amine to form a imine intermediate I which would coordinate with the palladium center to act as a directing group in the following transformations. 9481


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Scheme 167. Intermolecular Hydroacylation to Alkynes

Scheme 168. Intramolecular Hydroacylation to Alkynes

3. SP2 C−H BOND FUNCTIONALIZATION

the addition of aniline could significantly enhance the reaction rate by accelerating the imine formation step via transamination with aniline (Scheme 166). In the following report, Jun further expanded the hydroacylation of alkynes (Scheme 167).226 The reaction was optimized by increasing the loading of aminocatalyst to 40 mol % and adding 20 mol % of benzoic acid as weak acid additive to enhance the formation of imine intermediate. Both branched and linear products could be obtained, and the nature of the aldehydes has a profound effect on the regioselectivity. With aromatic aldehydes, only branched products were furnished. The use of a bulky alkyne together with an aliphatic aldehyde was shown to yield only a linear product (Scheme 167, 167d).

3.1. Aldehyde C−H Bond Functionalization

In this section, typical aldehyde umpolung reactions by NHC or other nucleophilic catalysis will not be discussed. This type of umpolung catalysis has been reviewed extensively;8 interested readers are referred to these for further information. 3.1.1. Aminocatalysis. Direct hydroacylation of alkenes and alkynes with aldehydes is one of the most straightforward approaches for the synthesis of ketones. However, the typical transition-metal-catalyzed approaches suffer from deacylation by pathways, which limit the synthetic applicability.223a On the basis of known hydroacylation with aldimine,224 Jun and co-workers pioneered the cooperative use of transition metal and aminocatalyst for hydroacylation reaction with aldehydes. The so-called metal−organic cooperative catalysis (MOCC) took advantage of the in-situ imine formation of aminocatalyst, e.g., 2-aminopyridine, which also directed the C−H activation in a typical chelation manner.223b In 1997, Jun and co-workers first reported the Rh(I) and 2-aminopyridine-catalyzed intermolecular hydroacylation reaction with aldehydes (Scheme 165).15 2-Amino-3picoline cat-51 was identified as the optimal organocatalyst to facilitate this reaction. The presence of a 3-methyl group in the pyridine ring would limit the free rotation of the pyridinyl moiety, thus facilitating metal chelation and C−H activation via cyclometalation (intermediate II, Scheme 166). Alkene was then coordinated with rhodium metal center; migratory insertion of hydrogen and reductive elimination through intermediates III and IV gave the hydroacylation adduct, which upon release of aminocatalyst and rhodium afforded the final ketone product.225 Control experiments verified the critical role of aminocatalyst in the reaction. In the absence of aminocatalyst, no hydroacylation product was obtained with decarbonylation dominating in the overall process. In the whole cycle, imine formation turned out to be rate determining. In this context, further studies revealed that

Scheme 169. Asymmetric Catalysis of Intramolecular Hydroacylation

In 2012, Douglas and co-workers studied an intramolecular hydroacylation approach to synthesize macrocyclic rings (Scheme 168).227 This cooperative amine/Rh catalysis overcame the limitations of sole transition-metal catalysis wherein a heteroatom shall be placed adjacent to the aryl ring to facilitate coordination to the metal center in order to prevent decarbon9482


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Scheme 170. Asymmetric Roskamp−Feng Reaction

Scheme 171. Asymmetric Insertion of Diazoester into Aryl−CHO Bonds

and excellent enantioselectivities with both substituted benzaldehydes and aliphatic aldehydes (Scheme 170). Various α-alkyl diazoesters were also well tolerated. The reaction is a formal C− H bond insertion reaction of aldehydes via a 1,2-hydride shift (Scheme 171a, path a), accompanied by a 1,2-R-group migration side pathway to give byproduct 170′ in a formal C−C bond insertion manner (Scheme 171a, path b). Later, the side pathway was further developed to provide functionalized acyclic allcarbon α-quaternary aldehydes in good yields with excellent enantioselectivities by slightly modifying the organic Lewis acid (Scheme 171b).230 The Ryu group further expanded the Roskamp reaction to diazos from α-ketoamides (Weinreb amide).231 The obtained ketone products were in-situ reduced in order to avoid racemization (Scheme 172). This protocol worked well with benzaldehyde, and the reactions with aliphatic aldehydes showed diminished enantioselectivities. In addition, diazos from unfunctionalized ketone could also be employed as a reaction

ylatoin. Both six- and seven-membered rings were adopted in this process, generating a β-tertiary carbon center with moderate to good yields. A catalytic asymmetric version has also been attempted with chiral ligands, showing unfortunately lower enantioselectivity (Scheme 169). When a 5-chiral benzoxazolesubstituted aminopicoline was utilized, the reaction gave 82% yield and 31% ee, showing promising results in further catalyst development along this line in the future. 3.1.2. Lewis Acid Catalysis. Apart from the typical NHC or transition-metal-catalyzed hydroacylation with aldehydes,223 Lewis-acid-catalyzed Roskamp reaction has been a useful synthetic alternative to construct β-keto carbonyl compounds via hydroacylation of alkyl diazoesters with aldehydes. On the basis of the organic Lewis-acid catalysis with oxazaborolidinium ion, e.g., cat-55,228 Ryu and co-workers described the first example of asymmetric formal insertion of diazoester into the C(O)−H bond of aldehydes catalyzed by cat-55 or cat-56 at −95 °C.229 Chiral α-alkyl-β-ketoesters were obtained in high yields 9483


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Scheme 172. Asymmetric Roskamp−Feng Reaction

Scheme 175. Photooxidative Amidation of Aldehydes

hemiaminal intermediate to amide,237 a range of amide products was obtained in moderate to good yields (Scheme 175). Recently, Wong and co-workers reported a photooxidative amidation of aldehydes with amines catalyzed by Rose Bengal.238 Tertiary amides were obtained from electron-deficient substituted benzaldehydes and cyclic secondary amines in moderate yields (Scheme 176). Under the mild conditions, the delicate endoperoxide bridge remained unchanged after the amidation. 3.1.4. TBAI/TBHP Catalysis. In 2011, the Wan group demonstrated a metal-free aldehyde C−H oxidation involving acyl radical species to synthesize tert-butyl peresters with TBHP under a catalytic amount of nBu4NI.239 A variety of substituted aryl aldehydes were applied as substrates under the optimized conditions (Scheme 177a). tert-Butyl peresters could be further transformed into allylic esters by Cu-catalyzed Kharasch− Sosnovsky reaction in one pot (Scheme 177b). In 2012, Barbas and co-workers developed a cross-coupling reaction of aldehydes with N-hydroxyimides, hexafluoroisopropyl alcohol, or sulfonimides using catalytic amounts of nBu4NI or nBu4NBr (Scheme 178).240 The reaction mainly worked with aromatic aldehydes. The obtained N-hydroxyimide esters and Nfluorobenzenesulfonimide could undergo amine displacement with free amines to form imide products without any other additives. Acetal or aminal species were proposed as reactive intermediates in this report, which is distinctive from Wan’s mechanism wherein acyl radical was hypothesized. Subsequently, Wan and co-workers depicted the synthesis of amides based on their acyl radical protocol.241 N,N-Dimethylformamide (DMF) underwent oxidative deacylation to generate aminyl radical in situ, and subsequent radical−radical crosscoupling with acyl radical afforded amide products in good yields (Scheme 179). Mechanism studies excluded the possibility of nucleophilic addition of an amine to an aldehyde and oxidation of the resulting carbinolamine, because only a trace amount of amide was obtained when dimethylamine is used instead of DMF. Benzylic alcohols instead of benzaldehydes could be applied in the imidation reaction (Scheme 180a).242 Primary amides were also accessible from benzylic alcohols and aldehydes when ammonium bicarbonate (NH4HCO3) was used as nitrogen donor (Scheme 180b).243 In this reaction, hemiaminals were invoked as the key intermediates which underwent dehydrogenation to afford the corresponding primary amides. Tertiary amines could be used as a nitrogen source to react with aldehydes in the presence of simple TBAI catalyst.244 In this transformation, the oxidation of tertiary amine proceeded to afford secondary amine at first, which was then reacted with aldehyde to give amide under oxidative conditions. Very recently, with the employment of N-chloramines as nitrogen source, a solvent-free oxidative amidation of aldehydes and alcohols has been demonstrated (Scheme 180c).245 Under ball-milling conditions, the reactions could be conducted at 50 °C or even room temperature. A direct acylation of NH-sulfoximines was

Scheme 173. Photocatalyzed Conjugate Addition of α,βUnsaturated Ketones

partner instead of a α-diazoester to access enantioenriched acyclic α-tertiary aryl ketones (Scheme 172).232 3.1.3. Photoredox Organocatalysis. Photoredox organocatalysis has been applied to oxidative amidation of aldehydes with amines, which is an atom- and step-efficient pathway for the Scheme 174. Photocatalyzed Acylation of 1,4Naphthoquinone

synthesis of amide without the use of transition metals and expensive chemical oxidants and harsh conditions.233 The aldehyde C−H bonds could be abstracted by benzophenone derivatives upon irradiation of UV light.234 The generating acyl radicals were used for conjugate addition of α,β-unsaturated ketones to form the 1,4-diketones (Scheme 173). In 2002, Mattay and co-workers utilized a “photo Friedel− Crafts acylation’’ of 1,4-naphthoquinone with aliphatic and aromatic aldehydes to access naphthohydroquinones in moderate to good yields (Scheme 174).235 However, 5 days were needed for completion. In 2014, by employing phenazine ethosulfate cat-60 as the organic photocatalyst, aerobic oxidative amidation of aromatic aldehydes was achieved at a low catalytic loading.236 The phenazinium cation was proposed to undergo a single electron transfer and proton transfer from amine to generate phenazyl radical, which disproportionated to give the doubly reduced hydrophenazine at basic condition. Subsequently, the reduced hydrophenazine was oxidized with O2 to regenerate photocatalyst along with H2O2. As H2O2 was efficient for oxidizing the 9484


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Scheme 176. Photooxidative Amidation of Aldehydes

Scheme 177. TBAI-Catalyzed Esterification of Aldehydes

Scheme 179. TBAI-Catalyzed Amidation of Aldehydes

Scheme 178. TBAI-Catalyzed Esterification and Amination of Aldehydes

Scheme 180. TBAI-Catalyzed Amidation of Aldehydes

catalytic cycle, IN3 was generated via a formal reductive elimination of intermediate I, which was formed by IBA-N3 and TBAI (Scheme 181). Homolysis of a I−N3 bond gave two distinct reactive radical species, iodine and azide radical. H abstraction of aldehydes with iodine radical produced an acyl radical, coupling with azide radical to afford acyl azides in decent yields. 3.2. Alkene C−H Bond Functionalization

Due to the π-nature of the alkene bond, many addition− elimination transformations with olefinic bonds can be regarded as formal C−H bond functionalization reactions. Therefore, we limited our discussions to those with explicit C−H bond activation or C−H bond cleavage as the key product-determining steps. The typical Heck-type processes as well as electron-tuning alkene functionalization reactions, such as reactions with

achieved with aldehydes for the generation of N-acylsulfoximines using TBAI/TBHP oxidative system.246 The labile and explosive acyl azides could also be safely prepared following TBAI oxidative protocols with azidobenziodoxolone (IBA-N3) as the azido source.247 In the proposed 9485


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out DFT studies on the mechanistic details of this reaction, reaching a cooperative aminocatalytic and rhodium catalytic cycle as illustrated in Scheme 184. The success of aminocatalysis with azaindoline has been ascribed to its ease for imine formation as well as the fixed geometry setting a favorable coordinating sphere for enamine C−H bond activations (as in intermediate II) and the accompanying bond formations (intermediates III and IV). In 2015, Dong and co-workers reported an Conia−ene intramolecular alkylation with the same cooperative catalytic strategy.252 2-Aminopyridine was determined as the identified optimal aminocatalyst. Either cyclic or acyclic ketones were applicable to this process, leading to the formation of a fivemembered ring in moderate yield with good functional group tolerance (Scheme 185). The amino/Rh cooperative catalysis was also applicable to the coupling of enamine intermediate with alkyne.253 After hydrolysis by concentrated HCl (aq), the reaction afforded α,β-enones 186 instead of the expected β,γ-enone products in the presence of aminocatalyst cat-61 (Scheme 186). On the other hand, the use of a stoichiometric amount of 2aminopyridine to generate substituted enamine 187′ produced the expected β,γ-enone products 187 with the hydrolysis under rather weak acidic condition (Scheme 187). In 2016, Dong and co-workers reported a combined amine/ Pd(OAc)2 catalysis for direct arylation reactions of cyclopentanones.254 Both aminocatalyst and palladium have been proved to be essential for the reaction. The reaction was proposed to proceed via enamine C−H bond activation; however, no coordinating moiety on the aminocatalyst was required in this case, a feature different from amine/Rh cooperative catalysis. The identified optimal aminocatalyst involved two components, secondary amine pyrrolidine and primary amine cat-62, where the latter was believed to enhance the imine formation of substrate with pyrrolidine via transamination (Scheme 188). 3.2.2. Lewis Acid Catalysis. 3.2.2.1. Nucleophilic Addition of Simple Alkenes to Unsaturated Carbonyls. Due to the associated cationic by pathways, alkenes have been seldom used directly as nucleophiles for conjugate addition to α,β-enones. The control of selective β-proton elimination of the cationic intermediates would be the main challenge to achieve this reaction. In 2013, Okamoto and Ohe developed a direct conjugate addition of styrene derivatives to β-silylenones by using Me3SiOTf as organocatalyst under simple and mild reaction conditions (Scheme 189, 189a−d).255 The generated TfOH was the real catalyst of this transformation to cause the scission of a C(sp2)−Si bond when Me3SiOTf was used as a

Scheme 181. TBAI-Catalyzed Azidation of Aldehyde C−H Bonds

enamine, enamide, or aromatic enamines, are also excluded.248−250 3.2.1. Aminocatalysis. Enamine is a versatile nucleophilic intermediate in many organocatalytic transformations. Recently, it has been shown that the enamine C−H bond may undergo further metal insertion to give enamine C−M species for subsequent bond formation, significantly expanding the domain of aminocatalysis. In 2012, Dong and co-workers successfully demonstrated the feasibility of such amino/transition-metal cooperative catalysis in the direct alkylation reactions with alkenes.251a Though the overall transformation is a α-C−H functionalization of carbonyls, the inherent mechanism involves enamine C−H bond activation as the key step. 2-Aminopyridine, previously utilized in Jun’s studies, has also been shown to work concertedly with Rh(I) to facilitate the alkylations of 1,2cyclopentadiones. This transformation required a stoichiometric amount of 2-aminopyridine as in-situ-installed directing group to lower the energy barrier of the C−H activation step to furnish the essential C−Rh intermediate 182a, and then migratory insertion to alkene and reductive elimination delivered α-alkylated 1,2diketones in moderate to good yields after further hydrolysis (Scheme 182). In 2014, the same group further extended the same strategy for the alkylation of simple cyclopentanones.251b 7-Azaindoline was identified as the optimal aminocatalyst, and the combination of [Rh(coe)2Cl2] and 7-azaindoline cat-61 enabled the direct αcoupling of cyclopentanones and ethylene under both pH and redox-neutral conditions with good yields and moderate diastereoselectivity (Scheme 183). Wang and co-workers carried

Scheme 182. Rh(I)-Catalyzed Alkylation of Enamine Generated from 1,2-Diketones

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Scheme 183. Catalytic Aminopyridine-Directed Alkylation of Ketones

Scheme 184. DFT-Calculated Catalytic Cycle of Aminopyridine-Directed Alkylation

Scheme 185. Intramolecular Alkylation of Ketones

catalyst precursor. β-Silyl group of enones was important for the reaction efficiency, which stabilizes the cationic intermediate via an γ-silicon effect (Scheme 190, I). With 1,1-diphenylethylene as nucleophile, simple enones without silicon substituents could be used as reaction partners for strongly stabilized diphenylmethyl cation intermediate formed (Scheme 189, 189e and 189f).

Recently, the Luo group successfully utilized a conjugate addition of simple alkenes to α,β-enones under catalytic amounts of FeCl3 and sodium phosphate (cat-63).256 This strategy was useful for a range of styrene derivatives and enones to afford vinylation products in high yields (Scheme 191). In the transformation, the anionic phosphate played a dual role as 9487


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Scheme 186. Catalytic Aminopyridine-Directed Alkenylation of Ketones

Scheme 187. β,γ-Enone Formation Utilizing Equivalent Catalyst and Weak Acid

Scheme 188. Palladium-Catalyzed α-Arylation of Cyclopentanones

Scheme 190. Catalytic Cycle of Direct Conjugate Addition of Simple Alkenes to α,β-Enones

Scheme 189. Catalytic Direct Conjugate Addition of Simple Alkenes to α,β-Enones

Scheme 191. Catalytic Direct Conjugate Addition of Simple Alkenes to α,β-Enones

ligand of a Lewis acid, which tunes the Lewis acidity of the metal center, and meanwhile as counteranion to stabilize the carbocation intermediate I through an ion-pair effect, thereby facilitating selective β-proton elimination. A labeling experiment showed that the β-proton elimination is the rate-determining step. 3.2.2.2. Insertion Reaction of Diazoester. In 2013, Ryu and co-workers reported the first example of boron Lewis-acidscatalyzed C(sp2)−H functionalization of cyclic enones with diazoacetates.257 With a newly designed N-protonated oxazaborolidinium ion or simple BF3·Et2O as catalyst, insertion of the carbon atom of diazoacetates proceeded smoothly to afford βfunctionalized cyclic enones from simple cyclic enones in a single step and with high yields (Scheme 192, with cat-64). A range of α-aryl- or allyl-substituted diazoacetates showed excellent

reactivity with the six-membered cyclic enones (Scheme 192, with cat-64, 192a−d), while diminished yields were obtained with five- and seven-membered cyclic enones (Scheme 192, with cat-64, 192e, and 192f). Acyclic enones did not yield the βfunctionalized enones but produce 2-pyrazolines as major products.258 In addition, a labeling competitive experiment proved that the insertion reaction proceeded in an intramolecular hydride-transfer manner. 9488


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Scheme 192. Catalytic Carbon Insertion into the β-Vinyl C−H Bond of Cyclic Enones

Scheme 193. Oxidative Dimerization of Silylallenes Catalyzed by CuCl/NHPI

3.3. Arene C−H Bond Functionalization

Later, the same group also realized the enantioselective transformation of carbon insertion into the β-vinyl C−H bond of cyclic enones by using chiral oxazaborolidinium ions cat-65 with a 1-naphthyl substituent at the boron center.259 For various sized cyclic enones, β-functionalized products were obtained in good yield with high enantioselectivities (Scheme 192). 3.2.3. Miscellaneous Catalysis. Silylallenes are important building blocks that have been employed in a variety of transformations.260 NHPI catalysis via PINO radical was shown to abstract an allenic C(sp2)−H hydrogen to generate an unexpected propargylic radical, which then dimerized to give a diyne adduct (Scheme 193).260c Minor elimination product or radical trapping adduct was obtained in a few cases, adding evidence to the involvement of the propargylic radical in the reaction pathway.

Organic molecules have recently been identified to promote biaryl coupling via arene C−H bond functionalization.261 Further mechanistic studies reveal a homolytic aromatic substitution (HAS) process in these reactions.10 The promoting role of organic molecules has been much debated and was believed to serve as radical initiator or radical precursor to facilitate the radical chain cycle. Hence, most of the organic additives have been proved to be sacrificed, not undergoing catalytic turnover.262 Therefore, detailed discussion of this type of reaction will be excluded in this section. 3.3.1. Brønsted Acid Catalysis. An asymmetric arylation of diazo compounds with aniline derivatives was achieved with the combination of an achiral dirhodium complex and a chiral spiro 9489


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Scheme 194. Asymmetric Arylation of Anilines with α-Aryl-αdiazoacetates

Metal-free porphyrins have been reported to act as electron mediators even in the absence of light irradiation. Very recently, Kanai and co-workers described that 5,10,15,20-tetrakis(4diethylaminophenyl)porphyrin worked as an effective organic promoter for the C−H arylation of coumarins with aryl diazonium salts.269 3-Arylcoumarin derivatives were prepared in good yields under mild conditions (Scheme 198). Photoredox catalysis with Eosin Y has also been applied in the synthesis of phenanthrenes with biaryldiazonium salts by the Zhou group.270a Under visible-light irradiation, the [4 + 2] benzannulation reaction between biaryldiazonium salts and alkynes proceeded smoothly to give 9-substituted and 9,10disubstituted phenanthrenes (Scheme 199). Recently, Studer and co-workers used biarylamines as starting material for the same coupling reactions.270b The biarylamines were transformed into the corresponding diazonium salts with isoamyl nitrite. The oxidative degradation of hydrazines for free radical transformation has also been explored in photoredox catalysis.271a The use of Eosin B as catalyst was efficient for generation of aryl and alkyl radical species from hydrazines upon visible-light irradiation in the open air, which were then trapped by 2isocyanobiphenyls to furnish 6-substituted phenanthridine products 200 in good yields (Scheme 200). In the same year, a one-pot arylative cyclization of 2-isocyanobiphenyls with arylamines was reported by the Zhu group in the presence of a catalytic amount of BPO as promoter under basic conditions.271b Very recently, the Gu group reported a visible-light-catalyzed synthesis of aryl ketones from aryldiazonium salts, CO, and arenes.272 The phenyl radical generated in situ could be rapidly trapped by CO to give a benzoyl radical I, which resulted in a benzylidyneoxonium ion II after back electron transfer to Eosin Y+•. The desired aryl ketone was formed by Friedel−Crafts-type coupling of II with arene (Scheme 201). In 2015, the activation of ethyl bromofluoroacetate was proceeding under the catalysis of Eosin Y upon the irradiation of visible light. Indoles and anilines were adopted as nucleophiles to form two C−C bonds, furnishing bisindolyl and bisanilinoyl acetate derivatives (Scheme 202).273 The unsymmetrical diarylacetates featuring indoles and N-substituted anilines were also synthesized in this reaction. Very recently, König and co-workers reported the direct arylation of simple arenes and heteroarenes with perfluoroaryl bromides by a photoredox process (Scheme 203, 203a)274a Valuable polyfluorinated biaryl compounds were synthesized under mild conditions. NEt3 was chosen as a sacrificial reductant to transfer a single electron to initiate Eosin Y. The generated Eosin Y radical anion reduced polyfluorinated bromoarene into a bromide anion and the polyfluorinated aryl radical, which reacted with arenes to afford biaryl products. Later, the reaction has been extended to brominated and chlorinated heteroarenes using rhodamine 6G as photocatalyst.274b Arylated pyrroles were obtained in good yields from a wide range of heteroaryl

phosphoric acid (SPA) cat-66.263 α-Diarylacetates were obtained in good yields with high enantioselectivities (Scheme 194). Preliminary mechanistic studies suggested that the arylation reaction proceeded via a stepwise process: Rh-mediated arene C−H insertion followed by a stereogenerating 1,2-proton shift. A proton shuttle mediated by SPA was proposed to account for the observed stereoselectivity. 3.3.2. Photoredox Organocatalysis. As a powerful singleelectron oxidative photocatalyst discussed in section 2.1.7, 1,4dicyanonaphthalene (DCN) could also be used to directly oxidize electron-rich arene to form a radical cation for subsequent bond formation. In 1986, Pandey and co-workers first reported a DCN-catalyzed photoinduced electron-transfer (PET) process in transforming cinnamic acids to corresponding coumarins as single products in 60−80% yield under irradiation of UV light (Scheme 195a).264a Later in 1988, the same group reported a similar process for the synthesis of 2H-benzopyran product (Scheme 195b).264b After the initial report, Pandey and co-workers reported an oxidative annulation reaction of silyl enol ethers with electron-rich aromatics to generate α-arylated ketones in moderate yields (Scheme 196).265 Aryl diazonium salts can easily undergo homolysis to generate aryl radical because of their relatively high reduction potentials.266 Organic photoredox catalysis has recently been applied in the reaction with aryldiazonium salts. Upon irradiation of visible light in the presence of Eosin Y, aryl radical from aryl diazonium salt could undergo homolytic aromatic substitution with heteroarenes such as pyrrole, furan, and thiophene.267 A wide range of diazonium salts and heterocycles were tolerated to give the desired arylation products with good yields under mild conditions (Scheme 197). The reaction could also be conducted directly with anilines following an in-situ diazotization by tBuONO.268 The aryl diazoniums-based C−H arylation bears close resemblance with the tBuOK-promoted strategies for C−H arylation.10 Scheme 195. DCN-Catalyzed Oxidative Aromatic Substitution

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Scheme 196. DCN-Catalyzed Direct Aromatic Annulation with Silyl Enol Ethers

Scheme 197. Direct Arylation of Heteroarenes C−H Bonds with Aryl Diazonium Salts

Scheme 201. Carbonylation of Arenes with Aryl Diazonium Salts

Scheme 198. Direct Arylation of Coumarins with Aryl Diazonium Salts

Scheme 202. Photocatalytic Activation of Ethyl Bromofluoroacetate

Scheme 199. [4 + 2] Benzannulation of Biaryldiazonium Salts with Alkynes Scheme 203. Photocatalytic Perfluoroarylation of Brominated Arenes and Heteroarenes

Scheme 200. Oxidative Cyclization of 2-Isocyanobiphenyls with Hydrazines

bromides/chlorides bearing electron-withdrawing groups (Scheme 203, 203b). In 2014, Ghosh and König et al. reported photoreduction of aryl halides as well as reductive arylation reactions by perylene diimides N,N-bis(2,6-diisopropylphenyl)perylene-3,4,9,10-bis(dicarboximide) (PDI) organic photocatalyst upon irradiation with blue light (Scheme 204).275 There were two photoexcitation processes in the catalytic cycle: excited PDI was first

reductively quenched to PDI•− radical anion, which was further photoexcited to be able to reduce aryl halides. The resulted 9491


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PhNO2 as oxidant, sulfinyl radicals could be generated from various sodium aryl sulfinates. Sulfinyl radicals then attacked the olefin to furnish vinyl sulfones along with reduction of nitrobenzene to aniline. Under photoredox catalysis by Eosin Y, sulfinic acids could also be oxidized to the corresponding sulfonyl radicals with the assistance of TBHP. Addition of sulfonyl radical to 3-phenylpropiolate initialized a radical addition to arene, leading to the production of 3-sulfonated coumarin product (Scheme 206).277a The same product could also be obtained by switching sulfinic acid to sulfonylhydrazide, utilizing TBAI as the catalyst and TBHP as the oxidant277b Moreover, the TBAI-TBHP catalytic system was applied to an oxidative arylsulfonylation of α,βunsaturated imides with sulfonylhydrazides, providing an efficient method for the synthesis of isoquinoline-1,3(2H,4H)dione derivatives.277c In the same year, they extended the photoredox-catalyzed synthesis of organic sulfones to sulfonated oxindoles from N-arylacrylamides and arylsulfinic acids.278 A range of sulfonated oxindoles was obtained via this cascade C−S/ C−C bond-formation process in water (Scheme 207). In 2014, Scaiano and co-workers reported the first radical trifluoromethylation of electron-rich heterocycles with Tongi’s reagent utilizing methylene blue (MB) as photoredox organocatalyst upon the irradiation of visible light.279 Electron-rich heterocycles, such as indoles, pyrroles, and thiophenes, proceeded smoothly to give the corresponding products with moderate to high efficiency (Scheme 208). In addition, this mild condition was also suitable for hydrotrifluoromethylation of terminal alkenes and alkynes. TMEDA served as the electron donor in this process. One-step direct oxygenation of benzene is the most straightforward approach and also the most dreamed process to phenol production in both academia and industry. In previous work, phenol could be obtained in only low yields using heterogeneous inorganic catalysts under high-temperature conditions. In 2011, the Fukuzumi group reported the selective oxygenation of benzene to phenol using 3-cyano-1-methylquinolinium ion (cat-68, λ = 330 nm) as photocatalyst in oxygensaturated MeCN.280 With the strong oxidizing ability of cat-68 at the singlet excited state (Ered = 2.72 V vs SCE),281 the QuCN+ ion was capable of oxidizing benzene (Eox = 2.32 V vs SCE)282 to radical cation via a SET process, which could react with water to furnish phenol. After 5 h of irradiation, phenol was formed in 51% yield with 98% selectivity (Scheme 209). No further oxygenation of phenol was observed, which was rationalized by considering that the back electron transfer of phenol radial cation is much faster than the electron transfer from phenol to QuCN+. Subsequently, the same authors performed an oxygenation of benzene with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) as photocatalyst and tert-butyl nitrite (TBN) as additive under visible-light irradiation (Scheme 210).283 Electron-transfer oxidation of benzene could be achieved by visible-light-excited DDQ with a very strong oxidizing ability. TBN acted as a recycling reagent to regenerate DDQ from DDQH2 under aerobic conditions. The reaction reached 98% conversion to furnish a 93% yield of phenol under homogeneous and ambient condition after irradiation for 30 h. Under this condition, halogenated benzenes (F, Cl, and Br) also underwent photooxygenations to give the corresponding phenol products, albeit in low yields. The dehydrogenative lactonization of 2-arylbenzoic acids is an atom-economic approach to prepare benzo-3,4-benzocoumarins. Very recently, the Gonzalez-Gomez group developed a photo-

Scheme 204. Photoinduced Reduction of Aryl Halides to Aryl Radicals

Scheme 205. Visible-Light-Mediated Synthesis of Vinyl Sulfones

ArX•− underwent facile homolysis to give aryl radical, which then abstracted a hydrogen atom to give reduced arenes or coupled with pyrroles to give arylation products. In this reaction, Et3N was sacrificed for both electron and hydrogen. The reaction was well applied to aryl chloride, bromide, and iodides. Recently, the König group further developed a photocatalytic pathway for preparing vinyl sulfones from aryl sulfinates (Scheme 205).276 Utilizing Eosin Y as photocatalyst and Scheme 206. Oxidative Cyclization of Phenyl Propiolates with Sulfinic Acids

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Scheme 207. Visible-Light-Catalyzed Synthesis of Sulfonated Oxindoles

Scheme 208. Photocatalytic Radical Trifluoromethylation

Scheme 210. Photocatalytic Direct Oxygenation of Benzene to Phenol

redox organocatalyzed dehydrogenative lactonization of 2arylbenzoic acids with (NH4)2S2O8 as terminal oxidant.284 Fukuzumi photocatalyst [Acr+-Mes]ClO4− was shown to promote the oxidative generation of benzoyloxy radicals that underwent oxygen radical addition to arene, leading to the desired benzocoumarins after further oxidation (Scheme 211). In 2016, Gilmour and Metternich reported the cascade E → Z isomerization and cyclization of (E)-cinnamic acids.285 The same group previously disclosed that (−)-riboflavin could catalyze the E → Z isomerization of activated olefins via an energy-transfer pathway (ET).286 They merged the two activation modes of (−)-riboflavin, energy transfer and single electron transfer (SET), in one reaction to mimic the biosynthesis of coumarin derivatives. Under UV-light irradiation, a range of (E)-cinnamic acids proceeded E → Z isomerization to afford Z isomers, which underwent a SET/deprotonation step with (−)-riboflavin to give coumarin products (Scheme 212). A second batch of photocatalyst (5 mol %) after 12 h was required for high productivity. The mechanism regarding the SET process remains elusive at this moment. Recently, Nicewicz and co-workers described a C−H amination methodology by using the combination of organic photoredox catalysis with TEMPO as cocatalysts under aerobic conditions.287 The coupling of N-heterocyclic nucleophiles with a variety of substituted arenes was successfully achieved to give amination products (Scheme 213a). In the presence of weak benzylic C−H bonds, the use of 1 equiv of TEMPO and strictly excluding O2 would help to suppress benzylic oxidation, leading to sole production of arene C−H adducts. Moreover, aniline could be forged directly by using an ammonium salt (H4N+H2NCO2−) as the nitrogen source. In this transformation, the photogenerated arene cation radical was proposed as the key intermediate for amine addition (Scheme 213b). The role of TEMPO was to aromatize radical intermediate II directly by H-

Scheme 211. Photocatalytic Dehydrogenative Lactonization of 2-Arylbenzoic Acids

atom abstraction. Dioxygen (O2) served as the terminal oxidant for the regeneration of the photoredox catalyst and TEMPO. Recently, the Wu and Tung group reported a breakthrough on the direct aromatic C−H amination and hydroxylation via an hydrogen-evolution cross-coupling strategy by the combined catalysis of QuCN + ClO 4 − or QuH + ClO 4 − and Co− (dmgBF2)2(CH3CN)2.121 The amination and hydroxylation of benzene were realized with ammonia (or Boc-protected amine) and water as the coupling partners, while an equivalent amount of hydrogen was liberated as the only side product (Scheme 214).

Scheme 209. Photocatalytic Direct Oxygenation of Benzene to Phenol

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Scheme 212. (−)-Riboflavin-Mediated Isomerization/Cyclization of (E)-Cinnamic Acids

Scheme 213. Photocatalytic Amination of Arene C−H Bonds

Scheme 214. Photocatalyzed Benzene C−H Amination and Hydroxylation via Hydrogen-Evolution Cross-Coupling

Scheme 216. Photocatalytic Bromination of Arene C−H Bonds

Scheme 215. Photocatalyzed N-Arylation Reaction undergo arene C−H amination and intramolecular hydroamination. By employing electron-rich arenes as coupling partners, new C−N bonds were furnished with high functional group tolerance in moderate to good yields (Scheme 215). In 2011, Fukuzumi and co-workers described an oxidative bromination of arenes and heteroarenes by the use of Acr+-Mes as a photocatalyst and HBr as a Br source under aerobic conditions.289 Arene radical cations produced by photoinduced Scheme 217. Photocatalytic Fluorination of Arene C−H Bonds

Carbonyl-substituted benzenes and phenyl halides were compatible with the mild and green reaction conditions. Leonori developed an efficient route for the generation of amidyl radicals from electron-poor aryloxy−amides via a photoredox SET reduction−fragmentation process using Eosin Y as the photocatalyst.288 The resulting amidyl radicals could 9494


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electron transfer reacted with Br− efficiently to form Br adducts. Monobrominated products were obtained with high selectivity in oxygen-saturated acetonitrile without overbromination (Scheme 216). Subsequently, the same group reported a unique

functionalization. Nagano and co-workers reported the TBAIcatalyzed intramolecular oxidative coupling of N-arylenamines to provide 1H-indole derivatives in good to excellent yields293 (Scheme 219). In 2011, Nachtsheim and co-workers described the amination of benzoxazoles to generated 2-aminooxazoles, which was also the first example of an iodide-catalyzed oxidative amination of heteroarenes (Scheme 220a).294a Initial mechanistic experiments indicated that an I2−I+ redox process was involved in the reaction pathway to form N-iodomorpholine in situ, which then could react with benzoxazole to yield the desired amination adduct. Besides secondary amines, primary amines and aqueous NH3 were tolerated under this condition (Scheme 220b and 220c).294b However, this oxidation system did not work with benzothiazole and 1-methyl-1H-benzoimidazole. Another example of constructing 2-aminooxazoles was achieved by employing N,N-dialkylformamide as nitrogen source.295 Decarboxylative

Scheme 218. Photocatalytic Thiocyanation of Heterocycles

photocatalytic fluorination of benzene under photoirradiation of the 3-cyano-1-methylquinolinium ion (QuCN+) with tetraethylammonium fluoride tetrahydrofluoride (TEAF·4HF) as a fluorine source.290 Under this mild condition, monofluorinated benzene was furnished without overfluorination (Scheme 217). Visible-light-driven photoredox processes could also be applied to the carbon−sulfur bond-forming reactions.291,292 In 2014, an efficient visible-light-induced C-3 thiocyanation of indoles has been developed by Li and co-workers with Rose

Scheme 221. TBAI-Catalyzed Sulfonylation and Diazotization of Indoles

Scheme 219. Intramolecular CDC Reaction of NArylenamines aminations proceeded smoothly in the presence of nBu4NI/ TBHP. In 2014, the Little group disclosed that the use of excess TBHP could be avoided when reactions were carried out under constant current conditions in a simple undivided cell.296 Wan and co-workers reported an oxidative sunfonylation reaction by TBAI/TBHP catalysis.297 Interestingly, dual sulfonylation and diazotization occurred when sulfonyl hydrazides reacted with indole to furnish novel 3-sulfonyl-2sulfonyldiazenyl-1H-indole products.298 In this process, sulfonyl hydrazide acted as the source of both sulfonyl and azo moiety. The reaction afforded only sulfonyldiazenyl adduct when 3methylindole was used as a substrate (Scheme 221). Iminoxyl radicals are useful heteroatom-centered radicals, which could undergo cyclization to afford heterocycles. In 2014, the Han group reported the cascade reaction of β,γ-unsaturated

Bengal as the photocatalyst under aerobic conditions (Scheme 218a).291 The thiocyanate anion (SCN−) was oxidized to thiocyanate radical by a SET process. A similar thiocyanation of imidazoheterocycles was reported using Eosin Y as a photoredox catalyst to give 3-(thiocyanato)imidazo[1,2-a]pyridine derivatives (Scheme 218b).292 3.3.3. TBAI/TBHP Catalysis. The oxidative system of TBAI and TBHP was also extremely efficient for C(sp2)−H bonds

Scheme 220. TBAI-Catalyzed Intermolecular Amination of Heteroarene C−H Bonds

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then underwent a four-center sigma-bond metathesis with HBpin to produce the final borylation adducts (Scheme 223). DFT calculation has been utilized to verify the mechanism, and a

Scheme 222. TBAI-Catalyzed Iminoxyl Radical-Participated Cascade Reaction

Scheme 225. B(C6F5)3-Catalyzed Intramolecular Synthesis of Benzofused Siloles

ketoximes with 2-arylphenylisonitriles to give isoxazolinefunctionalized phenanthridines under the TBAI-TBHP catalytic Scheme 223. Calculated Mechanism of FLP-Catalyzed C−H Borylation of Heteroarenes

C−H activation step was found to be rate determining. The reaction worked smoothly with a range of electron-rich pyrroles to give borylation products on the most electron-rich position (Scheme 224, 224a−c). However, the presence of the electronwithdrawing groups inhibited the reaction completely, suggesting the electron-rich nature is critical for the reaction to proceed. In addition, thiophene and furan derivatives could also be incorporated in the reaction (Scheme 224, 224d−h). In 2014, Ingleson and co-workers developed an intramolecular dehydrosilylation reaction catalyzed by a frustrated Lewis base of B(C6F5)3 and 2,6-dichloropyridine (Scheme 225).301 In the catalytic cycle, B(C6F5)3 activated Si−H for electrophilic Scheme 226. B(C6F5)3-Catalyzed Silylation of Aromatic C−H Bonds

system (Scheme 222).299 The process was initiated by oxidation of β,γ-unsaturated ketoxime to iminoxyl radical, followed by a cascade radical cyclization/addition/cyclization sequence. 3.3.4. Frustrated Lewis Pairs (FLPs) Catalysis. Recently, the Fontaine group developed an elegant example of dehydrogenative borylation of heteroarenes using frustrated Lewis pairs (FLPs) cat-69 as a catalyst.300 The reaction was suggested to proceed via Lewis acid/base cooperative activation of arene C−H bond to give a borylated intermediate III, which

silylation of the arene and 2,6-dichloropyridine (Cl2-py) facilitated deprotonation of the silylated arenium cation to afford benzofused silole. In 2016, the Hou group reported a boron-catalyzed intermolecular aromatic C−H silylation with hydrosilanes.302 By using B(C6F5)3 as catalyst, electron-rich aromatic compounds such as N,N-disubstituted anilines reacted with a range of hydrosilanes to forge C−Si bonds at the para position with release of H2 (Scheme 226). Moreover, metal-sensitive chlorohydrosilanes such as PhSiH2Cl and Ph2SiHCl could also be used as silylation agents under this metal-free condition. Zhang and co-workers developed a B(C6F5)3-catalyzed arene C−C bond formation very recently.303 Unprotected phenols

Scheme 224. FLP-Catalyzed Borylation of Heteroarene C−H Bonds

Scheme 227. B(C6F5)3-Catalyzed Ortho-Selective Substitution of Phenols with α-Aryl Diazo Esters

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Scheme 228. Intramolecular C−C Bond-Forming Spirocyclization of Phenols

Scheme 229. Cross-Biaryl Coupling of Two Arene C−H Bonds

Scheme 230. Cross-Coupling of Phenols

reacted with α-aryl diazo esters at the ortho positions to give a variety of useful diaryl acetates under mild conditions with high site selectivity (Scheme 227). Mechanism studies suggested that hydrogen bonding between the phenol −OH group and the catalyst F atom helped to direct the ortho-C−H substitution. 3.3.5. Iodoarene Catalysis. The catalytic utilization of hypervalent iodine reagents has gained increasing addition in developing environmentally benign C−H functionalization processes with arenes.304 Hypervalent iodine reagents are normally used in a stoichiometric amount. In 2008, the Kita group developed a regenerating system for biphenol oxidative coupling reactions for the synthesis of galanthamine-type alkaloids with a catalytic amount of iodoarene at low temperature.305 This new H2O2/trifluoroperacetic acid anhydride

(TFAA) system was efficient for generating hypervalent iodine by forming an active oxidant, bis(trifluoroacetyl) peroxide (Scheme 228a). Five- to seven-membered spirodienones were obtained in moderate to good yields (Scheme 228b). Kita and co-workers further developed an intermolecular oxidative biaryl coupling.306 By using specific 2,2′-diiodobiphenyl cat-71 as organocatalyst, cross-biaryl coupling of Nmethanesulfonyl anilides with unfunctionalized aromatic hydrocarbons was achieved to furnish the corresponding products in good yields (Scheme 229). The reaction may involve a trivalent iodine species, but the detailed mechanism awaited further studies. The presence of an electron-donating methoxy group in the catalyst was believed to accelerate the oxidative regeneration of the catalytic active species with mCPBA. 9497


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catalyst and MeCO3H as oxidant.311 In this transformation, four C−H bonds were stereoselectively functionalized to afford optically active spirooxindoles (Scheme 233). It was noted that tertiary amide rather than secondary amide or carboxylic acid in chiral organoiodine catalyst played a key role in stereocontrol. A range of 4-substituted N1,N3-diphenylmalonamides was well tolerated to provide the corresponding products in moderate yields with good enantioselectivities. However, a strong electrondonating substituent (−OMe) led to significantly diminished yield and enantioselectivity. DFT calculation studies identified an iodonium intermediate with a vital trifluoroacetate counterion in this process.312 In the following year, the Gong group accomplished an enantioselective dearomatizing spirocyclization of 1-hydroxy-Naryl-2-naphthamide derivatives.313 Though chiral hypervalent iodines have been frequently used in the enantioselective dearomatization of phenols, especially forming C−O and C−N bonds,314 it was for the first time creation of an all-carbon stereogenic center was demonstrated stereoselectively through C(sp2)−H functionalization in good yield with high enantioselectivity (Scheme 234). In 2016, Du and co-workers developed an enantioselective cascade C−O and C−C bond formation for the synthesis of chiral spirofurooxindoles via a similar strategy.315 In 2014, Martin and co-workers reported an Ar−I-catalyzed CDC reaction for C−O bond formation to synthesize benzolactones.316 The reaction proceeded to give benzolactone products in moderate to good yields under mild conditions. An unexpected regioselectivity pattern was observed by switching the iodoarene catalyst (Scheme 235). The mechanism for this switching phenomenon is still unclear. Moreover, this protocol could also be applied to a C(sp3)−H functionalization scenario. Iodobenzene has also been reported to promote an intramolecular oxidative cyclization with phenol ether to give spirofuran or benzopyran via a hypervalent iodine-mediated SET pathway (Scheme 236).240 Similar oxidative cyclization has been utilized in the synthesis of benzoxazoles and benzothiazoles from anilides and thioanilides, respectively (Scheme 237).317 Direct aryl C−H amination provides a sustainable approach for synthesizing aryl C−N bonds, which are significant scaffolds in pharmaceuticals, natural products, and optoelectronic materials. Hypervalent iodine species have also been reported to promote oxidative C−N bond formation with arenes and heteroarenes. These reactions may involve a distinctive ligandexchange mode, wherein the N−H bond is acidic enough to undergo ligand exchange on the iodine(III) center, resulting in cationic nitrogen for aromatic electrophilic substitution.

In 2016, the Kita group extended this biaryl coupling to crosscoupling of phenols (Scheme 230).307 With iodoarene cat-72 as the optimal catalyst, two different phenol derivatives were crosscoupled efficiently in high yields. Oxone was employed as a Scheme 231. Synthesis of 3,3-Disubstituted Oxoindoles via Bromocarbocyclization

terminal oxidant in this case with 18-crown-6 added as phasetransfer additives. A novel organocatalytic bromocarbocyclization with NBS as bromide source was developed to prepare C3-disubstituted oxoindole derivatives.308 The ring-closure process occurred via a 5-exo-trig mode with excellent diastereoselectivity, and a trivalent iodine species was proposed to mediate the electrophilic cyclization. Considering the atom-economic issue, an approach of generating electrophilic Br+ species in situ was achieved by using nontoxic oxone as terminal oxidant and KBr as brominating reagent (Scheme 231). Chiral hypervalent iodines have been developed as organocatalysts for the oxidative enantioselective reactions in recent years.309 An important example was presented by Ishihara and co-workers in 2010 and 2014 in utilizing quaternary ammonium (hypo)iodite (Scheme 232, cat-74) as organocatalyst to facilitate an enantioselective oxidative cycloetherification of ketones.96b,310 This transformation employed H2O2, TBHP, or cumene hydroperoxide (CHP) as co-oxidant to generate dihydrobenzofuran and chroman derivatives with good enantioselectivity under mild conditions (Scheme 232). In 2014, the Gong group established the asymmetric intramolecular C(sp2)−H/C(sp3)−H oxidative cross-coupling of N1,N3-diphenylmalonamides for the first time by using C2symmetric chiral organoiodine compound cat-75 as an organo-

Scheme 232. Quaternary Ammonium (Hypo)iodite-Catalyzed Oxidative Cycloetherification of Ketones

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Scheme 233. Asymmetric Direct C(sp2)−H/C(sp3)−H Oxidative Cross-Coupling Reaction

electrochemical conditions, avoiding the use of stoichiometric amounts of mCPBA.320 Subsequently, a similar hypervalent iodine-mediated amination reaction has also been employed in the synthesis of a series of nitrogen-containing heterocycles such as 1,2-disubstituted benzimidazoles,321a N-aryl-substituted 1H-indazoles,321b and pyrido[1,2-a]benzimidazoles321c (Scheme 239). Notably, an anodic oxidation could be employed for the purpose of regenerating hypervalent iodine species in this reaction under electrochemical conditions, thus avoiding the use of stoichiometric amounts of mCPBA (Scheme 240).320 Hypervalent iodine catalysis can also be utilized for intermolecular amination of arenes. Aminations with Nmethoxybenzamide proceeded smoothly in the presence of catalytic amounts of cat-81.322 The presence of a N-methoxy group was essential for stabilizing the nitrenium cations to achieve a cross-amination process (Scheme 241, 241a−d). In addition, hydrazination of nonprefunctionalized arenes was also achieved under the same conditions with N-(1,3-dioxoisoindolin-2-yl)acetamide (Scheme 241, 241e−g). Hydrazinated analogues of vitamin P and ibuprofen were obtained in 92% and 71% yields, respectively. Recently, 3-aminopyridines were successfully employed for aminations with simple arenes under hypervalent iodine catalysis. No protection of the primary amine was required in this case, likely due to the electron-deficient nature of the pyridine moiety.

Scheme 234. Enantioselective Dearomatizing Spirocyclization

Moraoda and Togo reported an iodobenzene-catalyzed cyclization of 2-aryl-N-methoxyethanesulfonamide via oxidative C−N bond formation (Scheme 238a).318a A recyclable ionic liquidsupported iodobenzene cat-80 performed equally well in the reaction.318b The reaction also worked well with N-acetaminobiphenyl to give N-acetylcarbazole 238b via intramolecular C−N formation, and an intermolecular version has also been developed with a stoichiometric amount of (diacetoxy)iodobenzene.319 These transformations could also be achieved using anodically generated hypervalent iodine species under

Scheme 235. ArI-Catalyzed C−H Functionalization/C−O Formation

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Scheme 236. Oxidative Intramolecular Cyclization of Vinylogous Esters

Scheme 237. Syntheses of Benzoxazoles and Benzothiazoles

Scheme 238. Intramolecular Amination of Arene C−H Bonds

Scheme 240. Synthesis of Tetrahydropyrroloiminoquinone Alkaloids

Scheme 239. Intramolecular Amination of Unactivated Arene C−H Bonds Scheme 241. Intermolecular Amination and Hydrazination of Unactivated Arene C−H bonds

The desired amination products were obtained in moderate yields in most cases (Scheme 242).323 An oxidative imidation of acetanilides was realized with LiNTf2 as the nitrogen source.324 The use of a catalytic amount of iodotoluene showed a more diminished yield than that with a stoichiometric amount of PhI(OAc)2 (Scheme 243). Imidation products were obtained with exclusive para regioselectivity.

Interestingly, a novel annulative transformation was realized by the functionalization of benzamide derivatives with alkynes.325 9500


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reacting with hypervalent iodine. The chlorination then followed a typical electrophilic substitution pathway (Scheme 245). 3.3.6. Norbornene Catalysis. The Catellani reaction is an exquisite example of metal and organic cooperative catalysis involving palladium and norbornene (NBE). The reaction was discovered by Marta Catellani in 1997 and has since been developed as a powerful method for ortho and ipso functionalization of aryl halides including ortho C−H functionalization. The reaction has recently been evolved to enable metaC−H activation and functionalization.327 In the Catellani reaction, norbornene plays a key role as the transient orthodirecting group to facilitate a number of C−C and C−N bond formations via a sequence of directed ortho−C−H activation (Scheme 246).328 In most cases, a superstoichiometric amount of norbornene was required in order to enhance the reaction efficiency. In a few noted cases, a catalytic amount of norbornene was able to promote the reaction effectively. On the other hand, new norbornene derivatives have been explored to address the unsolved reactivity.329 In 2013, Dong and co-workers disclosed the first Pd/NBEcatalyzed o-arene amination by using benzoyloxyamines as the nitrogen source with isopropanol as a reductant (Scheme 247).330 Recently, the same group reported the o-arene acylation of aryl iodides via the Catellani-type C−H functionalization to afford aromatic ketones (Scheme 248). In this reaction, isopropyl carbonate anhydrides served as both an acyl source and a hydride donor.329b 3.3.7. Electroorganic Catalysis. In 2007, Amatore employed a catalytic amount of benzoquinone or hydroquinone as redox mediator in an electrochemical process for oxidative Heck reaction (Scheme 249).331 The electrochemically recycled benzoquinone oxidized Pd(0) to Pd(II), thus facilitating the oxidative Heck cycle. In 2016, Xu and co-workers developed an efficient electrocatalytic generation of amidyl radicals to prepare nitrogencontaining heterocycles by employing inexpensive ferrocene ([Cp2Fe]) as the redox catalyst.332 In the olefin hydroamidation,332a they found the cyclization of substrate 250 furnished polycyclic indoline product following an oxidative termination (Scheme 250). In the following work,332b an intramolecular electrochemical coupling of (hetero)arylamines with tethered alkynes was achieved to prepare highly functionalized indoles as well as azaindoles with high chemo- and regioselectivities (Scheme 251). In these two reports, H2 was the only cathode byproduct. In 2016, by using a catalytic amount of perylene bisimide (PDI) as the redox mediator, the electroreductive coupling of aryl halides and pyrroles was developed to achieve the arylation of pyrroles through C−H bond activation in [EMIM]NTf2/ DMSO (Scheme 252).333 At the cathode, PDI could be reduced to generate the PDI radical anion, followed by SET to aryl halide to yield ArX•−. This unstable radical anion underwent cleavage of the Ar−X bond to give the aryl radical Ar•, which coupled with pyrrole to afford the coupling products. The electrochemical approach has the advantage of alleviating the use of a sacrificial reductant as required in the photoredox catalysis.24 3.3.8. Lewis Acid Catalysis. Very recently, the Stephan group reported a C−C bond coupling reaction of benzyl fluorides with arenes using an electrophilic organofluorophosphonium catalyst, [(C6F5)3PF][B(C6F5)4].334 They elucidated that the Lewis acidity of this fluorophosphonium cation is derived from the positive charge and the σ* orbital on phosphorus. The highly electrophilic phosphonium cation

Scheme 242. Intermolecular Amination of Unactivated Arene C−H bonds

Scheme 243. Iodine(III)-Mediated/Catalyzed Para-Selective Imidation of Anilide

Scheme 244. Oxidative Annulation of Benzamide Derivatives with Alkynes

Isoquinolones, a class of important heterocyclic scaffolds, were synthesized directly via cascade C−C and C−N bond formation in the presence of iodobenzene and peracetic acid. In this Scheme 245. Chlorination of Arene C−H Bonds

annulation process, PhI(OAc)2 (formed in situ) oxidized benzamide to form nitrenium ion II, followed by addition to alkyne and an intramolecular Friedel−Crafts process, leading to the desired isoquinolone (Scheme 244). A PhI-mCPBA oxidative catalytic system has also been reported to promote an interesting oxidative chlorination of electron-rich arenes.326 The chloride source LiCl was in-situ transferred to active chlorinating intermediate PhI(OTs)Cl by 9501


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Scheme 246. Mechanism of Pd/NBE-Catalyzed Catellani Reaction

Scheme 247. Pd/NBE-Catalyzed Arene (a) C−H Amination

Scheme 248. Pd/NBE-Catalyzed Arene (b) C−H Acylation via Catellani Reaction

first formed by homolysis of NHPI by oxidation of oxygen, would trigger the formation of benzyl radical from toluene. The formed benzyl radical could be trapped by oxygen to give eventually an active hydroxyl radical from a peroxide intermediate 255a. The formed hydroxyl radical would then add to the Pd center to facilitate the oxygenation cycle (Scheme 255). A similar catalytic system has also been applied in the arene C−H acylation reaction.337 Acyl radical, generated in situ from toluene or benzaldehyde, was employed to add to the Pd center to facilitate the transformation (Scheme 256). It is worth mentioning that the conditions of this transformation were quite similar to that of the previously reported hydroxylation reaction, which were both catalyzed by Pd(II) and NHPI with oxygen as the terminal oxidant. The authors rationalized the results by invoking a counteranion effect as well as variations on the reaction conditions such as reaction temperature and concentration of reactants.

activated the benzyl fluoride to generate the fluorophosphorane and a benzyl carbocation, which underwent electrophilic aromatic substitution with arenes. Silane served as a hydrogen donor and regenerated the phosphonium catalyst (Scheme 253). A range of 1,1-diarylalkanes was obtained in moderate to good yields with electron-rich and electron-poor arenes as well as heterocycles. In addition, competing reactions showed excellent selectivity for the C−F bond in the presence of benzyl chlorides and benzyl bromides. 3.3.9. Miscellaneous Catalysis. N-Hydroxyphthalimide (NHPI) has been utilized extensively in allylic and benzylic oxidations,105 but the application in sp2 C−H bond functionalization is rather limited. Most work in these areas has used oxygen to recycle NHPI and PINO (phthalimido-N-oxyl).335 In 2013, Jiao and co-workers first reported Pd(II)- and NHPIcocatalyzed aerobic hydroxylation of aryl sp2 C−H bond in moderate yield with pyridine as the directing group (Scheme 254).336 In these transformations, PINO intermediate, which was 9502


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Scheme 249. Electrochemical Pd/Benzoquinone-Catalyzed Heck-Type Reaction

Scheme 250. Electrocatalytic Olefin Hydroamidation

Scheme 252. Electroreductive Arylation of Pyrroles

Scheme 251. Electrocatalytic Synthesis of Highly Functionalized (Aza)indoles

Scheme 253. C−C Coupling of Benzyl Fluorides

Very recently, Sajiki and co-workers reported pyridine N-oxide as cocatalyst in Pd/C-catalyzed intramolecular C−H amination (Scheme 257).338 This reaction proceeded via single electron transfer between the Pd(II) amide complex and the aromatic ring, followed by an intramolecular nucleophilic addition to give carbazoles. Pyridine N-oxide was proposed to promote the oxidation of Pd(0) to Pd(II) in DMSO under oxygen atmosphere. In the presence of catalytic amounts of copper(II) triflate, an aerobic oxidative C−H functionalization of glycine derivatives

with olefins was developed to prepare substituted quinolones (Scheme 258).339 In this process, NHPI was employed as a cheap and nontoxic organocatalyst for C−H functionalization initiated by a hydrogen abstraction. A broad range of glycine derivatives and simple alkenes exhibited good performance to give the quinolone products in moderate to high yields. 9503


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Scheme 254. Pd(II) and NHPI Cocatalyzed Aerobic Hydroxylation

Scheme 256. Pd(OAc)2 and NHPI Cocatalyzed Acylation of Arenes

Scheme 257. Pd/C and Pyridine N-Oxide Cocatalyzed Intramolecular C−H Amination

Ascorbic acid (vitamin C) was initially found to promote hemolysis of aryl diazonium ions to generate aryl radicals via the SET process under metal-free conditions, with no heating or irradiation required. The metal-free direct C−H arylation of (hetero)arenes could be achieved in good efficiency with anilines and tBuONO as nitrosating agent.340 Besides, the arylation of unactivated benzene was accomplished to give biphenyl products in moderate to good yields (Scheme 259). However, Colleville and co-workers later found that the use of ascorbic acid as a radical promoter is not necessary in these transformations by detailed mechanistic studies.341 With in-situ monitoring, they identified a triazene intermediate as a precursor of the reactive aryl radical. The Meerwein arylation of alkenes with aryl diazonium salts has gained increasing attention in recent years.342 In 2014, a benzoyl peroxide (BPO) was found to promote carboarylation reaction of alkenes with anilines as described in the presence of tBuONO.343 This process underwent a radical C−H cyclization to construct the pharmaceutically interesting 3,3-disubstituted oxindole scaffold (Scheme 260). The C−H borylation of arenes generates organoboronates, which are important synthetic reagents in a variety of organic transformations.344 In 2015, Kanai and co-workers reported a meta-selective aromatic C−H borylation using a newly designed catalytic system, in which a bipyridine-derived ligand was tethered to a known organocatalytic motif, a urea moiety.18 The urea group seems to have a directing effect for meta-C−H activation and functionalization by H bonding with substrate (Scheme 261). This new type of catalytic system was generally applied for meta-selective C−H borylation of aromatic amides, esters, phosphonates, phosphoric diamide, and phosphine oxides. More recently, Phipps and co-workers utilized a

noncovalent ion-pair interaction to achieve meta-selective borylation reaction.345 Spin-center shift refers to elimination of a leaving group (e.g., hydroxyl group) adjacent to the radical center, resulting in 1,2radical center shift. This type of radical process is widely disseminated in biological processes such as biosynthesis of DNA and has also shown significant potential in synthetic chemistry, particularly in photochemical processes.346 Recently, Jin and MacMillan took advantage of this spin-center shift to achieve a powerful direct alkylation of heterocycles using alcohols as radical precursors by the merger of photoredox and thiol hydrogen-atom transfer catalysis (Scheme 262).347 A wide variety of heteroaromatics, such as isoquinoline, quinolone, phthalazine, and pyridine, were alkylated in excellent efficiencies under mild reaction conditions (Scheme 263, 263a−i). Commercially available alcohols as latent alkylating agents delivered the alkylated isoquinoline products in high yields. Tetrahydrofuran was also a competent alkylating agent in this alkylation transformation, resulting in a pendent hydroxylsubstituted product after tetrahydrofuran ring opening. Control experiments have verified the spin-center shift elimination pathway.

4. CONCLUSION AND OUTLOOK Though dominated by transition-metal catalysis, organocatalysis in inert C−H bond functionalization has started to show significant potential in this area. As summarized in this review, the use of organocatalysis has been widely explored in direct

Scheme 255. Proposed Hydroxy Radical Formation Process

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Scheme 258. Aerobic Oxidative C−H Functionalization of Glycine Derivatives with Olefins

Scheme 259. Direct C−H Arylation of Benzene with Anilines Nitrosated in Situ

Scheme 260. BPO-Promoted Meerwein Carboarylation of Alkenes with Anilines

Scheme 261. Meta-Selective C−H Borylation of Aromatic Compounds

Scheme 263. Direct Alkylation of Heteroarene C−H Bonds with Alcohols

Scheme 262. Direct Alkylation of Heteroarene C−H Bonds with Alcohols via a Spin-Center Shift Process

bonding catalysis, as well as ion-par interaction, can be employed to deliver stereoselective and , most desirably, enantioselective control for inert C−H functionalization reactions. The organocatalytic intermediates, such as enamine or Breslow intermediate, could also be further manipulated via acid/base or redox processes to achieve remote C−H functionalization. Deeply rooted in the classical radical chemistry and photochemistry, organocatalytic electron transfer and H transfer has become a powerful and enabling strategy in inert C−H functionalization, largely complementing or even bypassing the metal-catalyzed processes. The marriage of organocatalysis and transition-metal

functionalization of virtually all types of C−H bonds including alkane C−H, arene C−H, and vinyl C−H as well as those activated benzylic C−H, allylic C−H, and C−H bonds alpha to a heteroatom such as nitrogen and oxygen. The well-established organocatalytic cycle, such as aminocatalysis, NHC catalysis, H9505


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2011CB808600, 2012CB821600), Chinese Academy of Sciences (QYZDJ-SSW-SLH023) for generous financial support. S. L. is supported by National Program for Support of Top-notch Young Professionals, CAS Youth Innovation Promotion Association and CAS one-hundred talented program (D).

catalysis has been particularly fruitful in the development of a catalytic transient directing group, capitalizing on the aminocatalytic strategy as well as typical H-bonding catalysis. Further developments along this line are anticipated and highly warranted in the coming days. As a renaissance of the traditional photochemistry and electrochemistry, organocatalytic C−H activation and functionalization via single electron transfer or hydrogen transfer have become enabling and powerful strategies in organic synthesis. Further success along this line relies mainly on the design of photoorganocatalyst and electroorganocatalysts with precisely tunable redox properties as well as sufficient redox and photostability. In addition, de novo design of bioinspired organocatalysts on the basis of enzymatic C−H functionalization processes is also an unexplored field with enormous potential. Lastly, as mechanistic studies generally lag behind the pace in methodology development, coherent mechanistic scenarios would certainly lay the basis for the development of organocatalytic C−H functionalization with improved efficiency and stereoselectivity.

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AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Sanzhong Luo: 0000-0001-8714-4047 Author Contributions §

Y.Q. and L.Z.: These authors contributed equally to this review.

Notes

The authors declare no competing financial interest. Biographies Yan Qin was born in 1990 in Henan, China. She graduated from Zhengzhou University in 2011 with a major in Chemistry. She received her Ph.D. degree from the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) under the supervision of Prof. Sanzhong Luo and Prof. Jin-Pei Cheng in July 2016. Her work focused on the C−H oxidation of amines using bioinspired ortho-quinone catalysts. After receiving her Ph.D. degree, she joined the Ningbo Institute of Industrial Technology, Chinese Academy of Sciences as a postdoctoral researcher. Lihui Zhu was born in 1989 in Shandong, China. He graduated from Shanxi University in 2011 and started his Ph.D. program at the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) in 2013 under the supervision of Prof. Sanzhong Luo. He is currently working on aminecatalyzed remote C−H functionalization reactions. Sanzhong Luo was born in 1977 in Henan, China. He graduated from Zhengzhou University in 1999 and then spent his graduate studies successively at Nankai University, the Chinese Academy of Sciences (CAS), and the Ohio State University (USA) and received his Ph.D. degree from the CAS in 2005 under the supervision of Prof. Jin-Pei Cheng. He was a visiting scholar at Stanford University in 2009 (with B. M. Trost). He started his independent career in July 2005 at the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) and became Full Professor there in 2011. His laboratory focuses on asymmetric catalysis and synthesis, emphasizing the development of new catalysts and catalytic modes by drawing inspiration from nature.

ACKNOWLEDGMENTS We thank National Natural Science Foundation of China (NSFC 21390400, 21572232, 21672217 and 21521002) and the Ministry of Science and Technology (973 Program 9506


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