Efficient Synthesis of Heterocycles - American Chemical Society

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Copper-Catalyzed C−H Functionalization Reactions: Efficient Synthesis of Heterocycles Xun-Xiang Guo,*,† Da-Wei Gu,† Zhengxing Wu,‡ and Wanbin Zhang*,‡ †

Chem. Rev. 2015.115:1622-1651. Downloaded from pubs.acs.org by KAROLINSKA INST on 01/28/19. For personal use only.

Shanghai Center for Systems Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China ‡ School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China 3.1.2. Via Cu-Catalyzed Hydrazone Csp2−H Functionalization 3.1.3. Via Cu-Catalyzed Alkenyl Csp2−H Functionalization 3.1.4. Via Cu-Catalyzed Csp3−H Functionalization 3.1.5. Via Cu-Catalyzed Aryl Csp2−H and Imine Csp2−H Functionalization 3.2. Synthesis of Six-Membered N,O-Heterocycles 3.2.1. Via Cu-Catalyzed Csp3−H Functionalization 3.2.2. Via Cu-Catalyzed Aryl Csp2−H and Csp3− H Functionalization 4. Synthesis of O-Heterocycles 4.1. Synthesis of Five-Membered O-Heterocycles 4.1.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization 4.2. Synthesis of Six-Membered O-Heterocycles 4.2.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization 4.2.2. Via Cu-Catalyzed Aryl C sp2 −H and Formyl Csp2−H Functionalization 5. Synthesis of N,S-Heterocycles 5.1. Synthesis of Five-Membered N,S-Heterocycles 5.1.1. Via Cu-Catalyzed Csp3−H Functionalization 5.2. Synthesis of Six-Membered N,S-Heterocycles 5.2.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization 6. Conclusion Author Information Corresponding Authors Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Synthesis of N-Heterocycles 2.1. Synthesis of Five-Membered N-Heterocycles 2.1.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization 2.1.2. Via Cu-Catalyzed Hydrazone Csp2−H Functionalization 2.1.3. Via Cu-Catalyzed Csp3−H Functionalization 2.1.4. Via Cu-Catalyzed Csp−H Functionalization 2.1.5. Via Cu-Catalyzed Aryl C sp2 −H and Alkenyl Csp2−H Functionalization 2.1.6. Via Cu-Catalyzed Aryl C sp2 −H and Formyl Csp2−H Functionalization 2.1.7. Via Cu-Catalyzed Aryl Csp2−H and Csp3− H Functionalization 2.1.8. Via Cu-Catalyzed Aryl Csp2−H and Csp−H Functionalization 2.2. Synthesis of Six-Membered N-Heterocycles 2.2.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization 2.2.2. Via Cu-Catalyzed Alkenyl Csp2−H Functionalization 2.2.3. Via Cu-Catalyzed Csp3−H Functionalization 2.2.4. Via Cu-Catalyzed Aryl Csp2−H and Csp3− H Functionalization 2.3. Synthesis of Other N-Heterocycles 2.3.1. Synthesis of Three-Membered N-Heterocycles via Cu-Catalyzed Csp3−H Functionalization 2.3.2. Synthesis of Four-Membered N-Heterocycles via Cu-Catalyzed Csp3−H Functionalization 3. Synthesis of N,O-Heterocycles 3.1. Synthesis of Five-Membered N,O-Heterocycles 3.1.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization

© 2014 American Chemical Society

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1. INTRODUCTION Heterocycles are some of the most important structural motifs found in naturally occurring compounds. The synthesis of heterocycles has attracted considerable attention because of their important physiological and biological activities.1

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dx.doi.org/10.1021/cr500410y | Chem. Rev. 2015, 115, 1622−1651

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Transition-metal-catalyzed C−H functionalizations are some of the most convenient and efficient procedures available for the construction of complex heterocycles from simple starting materials. Over the past few years, novel methodologies utilizing transition-metal-catalyzed C−H functionalizations have been developed.2 Such methods provide significant benefits toward the synthesis of a variety of heterocycles. Copper salts, which are inexpensive and possess low toxicity, have been widely used in organic reactions. Reviews relating to Cu-catalyzed3 and Cu-mediated4 organic reactions have previously been published; in particular, two important reviews have recently appeared. Kozlowski and co-workers reported a comprehensive overview of Cu-catalyzed aerobic organic reactions.3a Stahl and co-workers reported recent trends and mechanistic insights relating to Cu-catalyzed aerobic oxidative C−H functionalizations.3f Recently, the use of Cu-catalyzed C− H functionalization reactions has gained significant traction, and a range of these methodologies relating to the construction of heterocycles have been successfully developed. A series of important structural motifs including N-heterocycles, N,Oheterocycles, O-heterocycles, and N,S-heterocycles (Scheme 1) have been synthesized using a number of Cu-catalyzed C−H (Csp−H, Csp2−H, and Csp3−H) functionalization reactions (Scheme 2).

Scheme 2. Reported Types of C−H Functionalization for the Synthesis of Heterocycles

Scheme 1. Some Typical Heterocycles Synthesized via CuCatalyzed C−H Functionalizations

mechanistic studies in this field is lacking. Although mechanistic studies are limited, we would like to promote discussion about the possible mechanisms involved in C−H functionalization reactions for the synthesis of heterocycles. Therefore, we have attempted to categorize such reactions according to whether the reaction mechanism is thought to occur via a one-electron process, a two-electron process, or a combination of one- and two-electron processes in terms of the transformation of copper oxidation states. The one-electron process is often used to explain Cucatalyzed C−H functionalizations. One common process is the CuII/CuI catalytic cycle initiated via one-electron oxidation by CuII (Scheme 3). First, CuII abstracts one electron from the substrate to afford a radical intermediate. The radical intermediate can then go through several transformations

The mechanism of Cu-catalyzed C−H functionalizations can be quite complex when the different oxidation states of copper (Cu0, CuI, CuII, and CuIII) in different reaction conditions are considered. Early studies proposed that such reactions proceed via a single-electron transfer (SET) mechanism with an electron-rich substrate.3c,f,k In 2006, Yu and co-workers5 reported a series of important Cu-catalyzed C−H functionalizations. Simultaneously, Chatani and co-workers6 developed a Cu-catalyzed C−H amination of 2-phenylpyridines. Since these developments, increasing arrays of Cu-catalyzed C−H functionalizations involving an organometallic mechanism have been developed.3f,7 This mechanism mentioned by Stahl and co-workers3f shows similarities to Pd-catalyzed C−H activations involving a metalation−deprotonation mechanism. Even so, it is very difficult to provide a general mechanistic scheme for such reactions because research involving

Scheme 3. Proposed Mechanism of a One-Electron Process in Cu-Catalyzed C−H Functionalizations for the Synthesis of Heterocycles

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involving cyclization and oxidation processes to afford the heterocycle product (Scheme 3, path A). In other cases the radical intermediate can proceed via radical transformation and then undergoes similar processes involving cyclization and oxidation to afford the heterocycle product (Scheme 3, path B). The generated CuI is subsequently oxidized by oxidants to regenerate the CuII catalyst, which can be used in the next catalytic cycle. A second CuII/CuI catalytic cycle involves the cyclization of the substrate to form a CuII intermediate in the presence of a CuII species. The intramolecular electron transfer of the CuII intermediate then gives a radical intermediate, which following a series of transformations affords the heterocycle product. Finally, an alternative CuII/CuI catalytic cycle involves one-electron oxidation of the substrate by a radical species, which is formed via CuII and an oxidant (particularly organic peroxides); the formed radical intermediate then undergoes a series of transformations to afford the heterocycle product. Cu-catalyzed C−H functionalizations occurring through the two-electron process have gained increasing attention. A common mechanistic process has been proposed using a CuI/CuIII catalytic cycle. The process involving a CuI/CuIII catalytic cycle for the synthesis of heterocycles is shown in Scheme 4. First, CuI and a halogenated substrate form an

Scheme 5. Proposed Mechanism of a Combination of Oneand Two-Electron Processes in Cu-Catalyzed C−H Functionalizations for the Synthesis of Heterocycles

membered and other ring size heterocycles. The syntheses of fused ring systems are arranged according to the step in which the new ring in the fused heterocycles is formed via C−H functionalization. Furthermore, each subsection is further separated according to whether the heterocyclic ring system is prepared via a Cu-catalyzed Csp−H, Csp2−H, or Csp3−H functionalization. For some typical reactions, the detailed mechanism will be described in the following text. The syntheses of heterocycles via Cu-mediated C−H functionalizations8 and with copper salts as cocatalysts9 are not covered in the present review.

Scheme 4. Proposed Mechanism of a Two-Electron Process in Cu-Catalyzed C−H Functionalizations for the Synthesis of Heterocycles

2. SYNTHESIS OF N-HETEROCYCLES Nitrogen-containing heterocycles are some of the most important heterocycles used by the chemical community. Most investigations involving the synthesis of heterocycles via Cu-catalyzed C−H functionalization reactions have been directed toward the synthesis of nitrogen-containing species. 2.1. Synthesis of Five-Membered N-Heterocycles

2.1.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization. The first example of the synthesis of five-membered Nheterocycles via Cu-catalyzed aryl Csp2−H functionalization was reported by Brasche and Buchwald in 2008 (Scheme 6).10 The

III

organocopper intermediate involving oxidative addition and C−H functionalization. Then reductive elimination of the organocopperIII intermediate affords the heterocycle product and CuI species to close the catalytic cycle. Another twoelectron process has also been proposed using the CuI/CuIII catalytic cycle, in which the organocopperIII intermediate is formed by CuI and the substrate in the presence of strong oxidants involving C−H functionalization. This process is a potential strategy for the synthesis of heterocycles using the Cu-catalyzed C−H functionalizations, although currently it has mainly been studied in intermolecular C−H functionalizations. The combination of one- and two-electron processes should be paid more attention in Cu-catalyzed C−H functionalizations. This process has been proposed to occur via a CuI/CuII/ CuIII catalytic cycle (Scheme 5), in which the key step is the formation of an organocopperIII intermediate. First, the substrate and CuII form a CuII intermediate involving C−H functionalization. The organocopperIII intermediate is then formed by a CuII disproportionation. Reductive elimination of the organocopperIII intermediate affords the heterocycle product and CuI species, which is oxidized to CuII to take part in the next catalytic cycle. The present review aims to report the recent advances in the synthesis of heterocycles via Cu-catalyzed C−H functionalization reactions. These results are organized according to the different heteroatoms involved in the formation of heterocycles, i.e., N-heterocycles, N,O-heterocycles, O-heterocycles, and N,Sheterocycles. Each section is divided into smaller subsections according to the size of the heterocyclic ring, i.e., five- and six-

Scheme 6. Cu-Catalyzed Synthesis of Benzimidazoles

intramolecular reaction of amidines 1 afforded the corresponding benzimidazoles 2 in high yields in the presence of a copper catalyst and by using molecular oxygen as an oxidant. Although the exact mechanism is unclear, three possible pathways are shown in Scheme 7 based on the formation of an intermediate Cu−N adduct from the reaction of amidine and Cu(OAc)2. Similarly, Jiang and co-workers developed a Cu-catalyzed aryl Csp2−H functionalization of 3 for the synthesis of fivemembered N-heterocycles of indazoles 4 (Scheme 8).11 1624


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Scheme 7. Proposed Mechanism for the Cu-Catalyzed Synthesis of Benzimidazoles

Scheme 10. Proposed Mechanism for the Cu-Catalyzed Synthesis of 10a,11-Dihydro-10H-indolo[1,2-a]indoles

Scheme 8. Cu-Catalyzed Synthesis of Indazoles

Scheme 11. Cu-Catalyzed Enantioselective Synthesis of Hexahydro-1H-benz[f ]indoles

In 2009, Sherman and Chemler reported the synthesis of the N-heterocycles 10a,11-dihydro-10H-indolo[1,2-a]indoles 6 (Scheme 9).12 The compounds 6 were prepared by Cu-

Chang and co-workers. The Cu-catalyzed intramolecular reaction of N-substituted amidobiphenyls 10 afforded carbazoles 11 in moderate to high yields using hypervalent iodine(III) as the oxidant (Scheme 12).14 Although the

Scheme 9. Cu-Catalyzed Synthesis of 10a,11-Dihydro-10Hindolo[1,2-a]indoles

Scheme 12. Cu-Catalyzed Synthesis of N-Substituted Carbazoles

catalyzed intramolecular carboamination of alkenes 5 using 3 equiv of MnO2 as the oxidant. A proposed mechanism for this reaction is shown in Scheme 10. The substrate is cyclized to form a CuII intermediate in the presence of a CuII species via a syn-aminocupration process. Intramolecular electron transfer of CuII intermediate then generates a radical intermediate, which undergoes a series of transformations and an oxidation to afford the product. This novel method for the Cu-catalyzed carboamination of alkenes was applied to the synthesis of enantiomerically enriched N-heterocycles hexahydro-1H-benz[f ]indoles 8 via the intramolecular reaction of 7 using a chiral bisoxazoline ligand 9 (Scheme 11).13 These reactions involved an intramolecular Cu-catalyzed aryl Csp2−H functionalization. A new synthetic method for the formation of carbazoles via a Cu-catalyzed aryl Csp2−H functionalization was described by

formation of carbazoles 11 took place under both Cu-catalyzed and metal-free conditions, the yields of carbazoles 11 were much lower under metal-free conditions. The combination of copper species and hypervalent iodine(III) species greatly improved product yields. Very recently, using a less expensive and abundant MnO2 as a terminal oxidant at 200 °C with microwave irradiation, Hirano, Miura, and co-workers developed an efficient picolinamide-directed, Cu-catalyzed synthesis of carbazoles 13 via aryl Csp2−H functionalization (Scheme 13).15 The key requirement for the reaction of a Cu1625


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Scheme 13. Cu-Catalyzed Synthesis of Carbazoles

Scheme 15. Cu-Catalyzed Synthesis of Pyrido[1,2a]benzimidazoles

catalyzed intramolecular C−H amination of 2-aminobiphenyls 12 is the introduction of the picolinamide-based directing group, which is spontaneously removed after the coupling event. Using Cu-catalyzed intramolecular heteroaromatic Csp2− H functionalization, Fu and co-workers developed an efficient method for the synthesis of imidazobenzimidazoles (Scheme 14).16 The Cu-catalyzed intramolecular reaction of 2-(1H-

Scheme 16. Cu-Catalyzed Synthesis of Purine-Fused Polycycles

Scheme 14. Cu-Catalyzed Synthesis of Imidazobenzimidazoles


imidazol-1-yl)-N-alkylbenzenamines 14 using molecular oxygen as the oxidant afforded the corresponding imidazobenzimidazoles 15 in high yields. A Cu-catalyzed aryl Csp2−H functionalization with heteroaromatic compounds for the synthesis of N-heterocycles was developed by Maes and co-workers (Scheme 15).17 The intramolecular C−H amination of N-arylpyridin-2-amines 16 using Cu(OAc)2·H2O as the catalyst and molecular oxygen as the oxidant provided pyrido[1,2-a]benzimidazoles 17 in moderate to good yields. It was found that an acidic additive was important for this reaction and that the type of acid determined selectivity. Using a similar procedure, Guo, Fossey, and co-workers developed a Cu-catalyzed synthesis of purine-fused polycycles (Scheme 16).18 The multiheterocyclic purine nucleosides 19 were prepared in good yields by the Cu-catalyzed intramolecular aryl Csp2−H activation/amination reaction of 6anilinopurine nucleosides 18 using PhI(OAc)2 as an oxidant. The synthesis of five-membered N-heterocycles by a Cucatalyzed aryl Csp2−H functionalization has also been utilized in intermolecular reactions. Bao and co-workers reported the Cucatalyzed one-pot synthesis of benzimidazoles (Scheme 17).19

The benzimidazoles 21 were obtained in moderate to good yields by the Cu-catalyzed addition of nucleophiles to arylcarbodiimides 20 using molecular oxygen as an oxidant. This reaction proceeds via a Cu-catalyzed intermolecular nucleophilic addition followed by intramolecular C−H functionalization/C−N bond formation. A one-pot reaction for the synthesis of benzimidazoles via a Cu-catalyzed aryl Csp2−H functionalization was developed by Neuville, Zhu, and co-workers (Scheme 18).20 The Cucatalyzed one-pot reaction of benzamidines 22 with aryl 1626


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reaction of conjugated N-tosyl amides 28 and Togni’s reagent 26 provided trifluoromethylated oxindoles 29 in moderate to good yields. To understand the mechanism of this transformation, control experiments were performed. Radical inhibition experiments show the reaction may occur via a radical mechanism, as evidenced by the poor yields obtained for the reaction in the presence of a radical inhibitor (2,6-di-tertbutyl-4-methyl phenol (BHT) or (2,2,6,6-tetramethylpiperidin1-yl)oxyl (TEMPO)). A crossover experiment suggests that the aryl migration is an intramolecular process in this transformation. On the basis of this experimental evidence, the reaction is proposed to proceed via a Cu-catalyzed trifluoromethylation/1,4-aryl migration/desulfonylation/C−N bondformation process, with an amidyl radical intermediate involved in the reaction (Scheme 21). Recently, another novel reaction


boronic acids 23 gave substituted benzimidazoles 24 in moderate to good yields. This one-pot reaction consists of an intermolecular C−N bond formation and an intramolecular aryl Csp2−H functionalization/C−N bond-forming procedure. Recently, Sodeoka and co-workers described the Cucatalyzed synthesis of trifluoromethylated five-membered Nheterocycles via aryl Csp2−H functionalization (Scheme 19).21 The Cu-catalyzed carbotrifluoromethylation of N-protected allylanilines 25 with Togni’s reagent 26 gave trifluoromethylated indoline derivatives 27 in good yields.

Scheme 21. Proposed Mechanism for Cu-Catalyzed Synthesis of Trifluoromethylated Oxindoles

Scheme 19. Cu-Catalyzed Synthesis of Trifluoromethylated Indoline Derivatives

for the synthesis of trifluoromethylated oxindoles via Cucatalyzed aryl Csp2−H functionalization was described by Liang, Lipshutz, and co-workers (Scheme 22).23 The Cu-catalyzed Scheme 22. Cu-Catalyzed Synthesis of Trifluoromethylated Oxindoles

The synthesis of trifluoromethylated oxindoles via Cucatalyzed aryl Csp2−H functionalization was developed by Nevado and co-workers (Scheme 20).22 The Cu-catalyzed Scheme 20. Cu-Catalyzed Synthesis of Trifluoromethylated Oxindoles

trifluoromethylation of N-arylacrylamides 30 gave trifluoromethylated oxindoles 31 in good yields using the inexpensive and stable Langlois’ reagent (CF3SO2Na) as the source of CF3 radical. This reaction was performed under mild reaction conditions using water as the reaction medium, at room temperature, and in air. Interestingly, the aqueous medium containing the water-soluble copper catalyst can be recycled in the present reaction. The use of a copper catalyst and diaryliodonium salts for the formation of 3,3-disubstituted oxindoles was described by Zhou, Li, and co-workers24 and Fu and co-workers.25 For example, the Cu-catalyzed reaction of N-arylacrylamides 30 1627


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with diaryliodonium salts 32 afforded a variety of functionalized 3,3-disubstituted oxindoles 33 in moderate to good yields (Scheme 23).

Scheme 25. Cu-Catalyzed Synthesis of Dihydroimidazoles

Scheme 23. Cu-Catalyzed Synthesis of 3,3-Disubstituted Oxindoles

A Cu-catalyzed Csp3−H functionalization by Ge and coworkers has been developed. They reported an efficient Cucatalyzed intramolecular dehydrogenative cyclization reaction for the formation of N-heterocycles (Scheme 26).29 The Scheme 26. Cu-Catalyzed Synthesis of Pyrazoles 2.1.2. Via Cu-Catalyzed Hydrazone Csp2−H Functionalization. 1,2,3-Triazoles and 1,2,4-triazoles are very important classes of heterocycles and are commonly utilized in the pharmaceutical industry because of their distinct biological properties. The development of efficient procedures for the synthesis of such molecules is thus highly desired. In 2012, Guru and Punniyamurthy reported a Cu-catalyzed hydrazone C−H functionalization for the synthesis of substituted 1,2,3triazoles 35 and 1,2,4-triazoles 36 from bisarylhydrazones 34 (Scheme 24).26 These two different triazoles were prepared selectively from a common starting material. Scheme 24. Cu-Catalyzed Synthesis of Substituted 1,2,3- and 1,2,4-Triazoles pyrazoles 40 were prepared in good yields from the intramolecular reaction of N,N-disubstituted hydrazones 39. Interestingly, the addition of dimethylsulfide (DMS) as the cosolvent greatly improved the reaction efficiency. A sequence of Csp3−H functionalization, cyclization, and aromatization has been proposed for this reaction. Hajra and co-workers reported a novel method for the synthesis of imidazo[1,2-a]pyridines from commercially available compounds (Scheme 27).30 The Cu-catalyzed reaction of 2-aminopyridines 41 and ketones 42 afforded imidazo[1,2a]pyridines 43 in good yields. The key step of this reaction proceeds via a Cu-catalyzed oxidative intramolecular C−H amination of imines from the reaction of 2-aminopyridines 41 and ketones 42. Additionally, a new CuI/air catalytic system Scheme 27. Cu-Catalyzed Synthesis of Imidazo[1,2a]pyridines

2.1.3. Via Cu-Catalyzed Csp3−H Functionalization. The Cu-catalyzed Csp3−H functionalization for the synthesis of fivemembered N-heterocycles was developed. An amidine-directed Cu-catalyzed Csp3−H functionalization was described by Chiba and co-workers.27,28 The synthesis of dihydroimidazoles 38 was realized from the intramolecular amination of C−H bonds of N-alkylamidines 37 using Cu(OAc)2 as a catalyst and PhI(OAc)2 as an oxidant (Scheme 25). 1628


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was developed to synthesize imidazo[1,2-a]pyridines 43 from the same starting materials.31 Very recently, the reaction of 2aminopyridines 41 and ketones in the presence of a heterogeneous CuCl2/nano-TiO2 catalytic system was also reported for the formation of imidazo[1,2-a]pyridines 43.32 The synthesis of imidazoheterocycles via Cu-catalyzed aerobic oxidation has also been described by Zhang, Su, and co-workers (Scheme 28).33 The Cu-catalyzed reaction of 2-

Scheme 30. Proposed Mechanism for Cu-Catalyzed Synthesis of Polysubstituted Pyrroles

Scheme 28. Cu-Catalyzed Synthesis of Imidazoheterocycles

catalyzed oxidative dehydrogenation of the amine followed by a [3 + 2]-cycloaddition and oxidation gives the desired product. In this case, the reaction appears to be a Cu-catalyzed Csp3−H functionalization if judged from the generated products. However, this reaction actually involves a Cu-catalyzed oxidative dehydrogenation step. The following examples in this section all involve a Cu-catalyzed oxidative dehydrogenation process. A Cu-catalyzed oxidative dehydrogenation for the synthesis of substituted imidazoles was described by Cai, Wang, and Ji (Scheme 31).35 The reaction of ketones 52 and benzylamines aminopyridine derivatives 44 and arylketones 42 or unsaturated ketones 45 using molecular oxygen as the oxidant gave aryl- or alkenyl-substituted imidazoheterocycles (46 or 47) in good yields. This method was applied to the gram-scale preparation of the commercially available drug Zolimidine from readily available starting materials. Lu, Wang, and co-workers reported a novel method for the preparation of polysubstituted pyrroles (Scheme 29).34 The reaction of α-diazoketones 48, nitroalkenes 49, and amines 50 in the presence of CuOTf as the catalyst and air as the oxidant provided polysubstituted pyrroles 51 in moderate yields. As shown in Scheme 30, the initial step in the reaction sequence is the reaction of the α-diazoketone and amine. Subsequently, Cu-

Scheme 31. Cu-Catalyzed Synthesis of Substituted Imidazoles

Scheme 29. Cu-Catalyzed Synthesis of Polysubstituted Pyrroles

53 using CuI as the catalyst and molecular oxygen as the oxidant provided imidazoles 54 in moderate to good yields. A plausible mechanism is proposed in Scheme 32. The enamine intermediate is generated by the tautomerization of an imine, which is formed via the reaction of the ketone and the benzylamine. Subsequently, oxidation followed by attack with benzylamine and dehydration under Lewis acid (BF3·Et2O) affords a diimine intermediate. Finally, annulation, proton elimination, and further oxidation give the desired product. The application of a Cu-catalyzed oxidative dehydrogenation of benzylamines toward the synthesis of benzimidazoles was developed by Zhou and co-workers (Scheme 33).36 2Substituted benzimidazoles 2 were obtained in high yields by Cu-catalyzed oxidative condensation of o-phenylenediamines 1629


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Scheme 32. Proposed Mechanism for Cu-Catalyzed Synthesis of Substituted Imidazoles

Scheme 35. Cu-Catalyzed Synthesis of 3-Aroylindoles

Scheme 36. Proposed Mechanism for Cu-Catalyzed Synthesis of 3-Aroylindoles Scheme 33. Cu-Catalyzed Synthesis of Benzimidazoles

Scheme 37. Cu-Catalyzed Synthesis of Isatins

55 and benzylamines 53 with air as the oxidant. A key step in this reaction was the formation of an imine intermediate via oxidative dehydrogenation of benzylamine 53 with the copper complex and molecular oxygen (Scheme 34). Scheme 34. Proposed Mechanism for Cu-Catalyzed Synthesis of Benzimidazoles

The intramolecular oxidative C−H amination of 2′-aminoacetophenones 58 in the presence of CuI as the catalyst and molecular oxygen as the oxidant provided isatins 59 in moderate to good yields. A possible pathway is shown in Scheme 38. Oxidation of 2′-aminoacetophenone generates the 2′-aminophenyloxalaldehyde intermediate. The intramolecular cyclization of 2′-aminophenyloxalaldehyde forms the 2hydroxyindolin-3-one derivative, which is subsequently oxidized by CuI/O2 to give the desired product. Recently, a similar

Patel and co-workers reported the synthesis of 3-aroylindoles 57 via a Cu-catalyzed intramolecular oxidative functionalization of o-alkynylated N,N-dimethylamines 56 using tert-butyl hydroperoxide (TBHP) as an oxidant (Scheme 35).37 The reaction process involves Cu-catalyzed oxidative dehydrogenation followed by C−C and C−O bonds formation to give the desired product. As shown in Scheme 36, an aminyl radical cation species is formed from the substrate in the presence of copper salt and peroxide. The abstraction of a proton radical followed by cyclization, ketonization, and further oxidation gives the desired product. Cheng and co-workers developed a Cu-catalyzed intramolecular oxidation for the synthesis of isatins (Scheme 37).38

Scheme 38. Proposed Mechanism for Cu-Catalyzed Synthesis of Isatins

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CuII−N adduct. Oxidation of the CuII intermediate generates a CuIII intermediate (the formation of the CuIII intermediate is most likely to occur via the disproportionation of CuII). Subsequently, reductive elimination, intramolecular 5-endo-digcyclization, and protonation give the desired product and generate a CuI intermediate, which is reoxidized by molecular oxygen to regenerate the CuII species to close the catalytic cycle. 2.1.5. Via Cu-Catalyzed Aryl Csp2−H and Alkenyl Csp2− H Functionalization. A novel method to synthesize indoles by Cu-catalyzed aryl Csp2−H and alkenyl Csp2−H functionalization was developed. The Cu-catalyzed intramolecular cyclization of N-aryl enaminones 64 provided multisubstituted indoles 65 in good yields when using CuI and 1,10-phenanthroline as the catalyst and air as the oxidant (Scheme 42).41

reaction was described by Ilangovan and Satish.39 The tertiary amines 60 can also be used for the synthesis of isatins 59 using a catalytic system consisting of Cu(OAc)2·H2O, NaOAc, and air. In this reaction, intramolecular C−N bond cleavage and C− N bond formation occur in a single step (Scheme 39). Scheme 39. Cu-Catalyzed Synthesis of Isatins

Scheme 42. Cu-Catalyzed Synthesis of Multisubstituted Indoles

2.1.4. Via Cu-Catalyzed Csp−H Functionalization. The synthesis of five-membered N-heterocycles via Cu-catalyzed Csp−H functionalization is relatively rare. In 2013, Li and Neuville reported the Cu-catalyzed synthesis of 1,2,4trisubstituted imidazoles 63 from the reaction of amidines 61 and terminal alkynes 62 (Scheme 40).40 The 1,2,4-trisubScheme 40. Cu-Catalyzed Synthesis of 1,2,4-Trisubstituted Imidazoles

2.1.6. Via Cu-Catalyzed Aryl Csp2−H and Formyl Csp2− H Functionalization. Li and co-workers described a novel reaction for the synthesis of isatins via a Cu-catalyzed aryl Csp2− H and formyl Csp2−H functionalization (Scheme 43).42 The Scheme 43. Cu-Catalyzed Synthesis of Isatins

stituted imidazoles 63 were prepared in moderate to good yields using molecular oxygen as the oxidant. As shown in Scheme 41, the catalytic cycle is initiated by the formation of a Scheme 41. Proposed Mechanism for Cu-Catalyzed Synthesis of 1,2,4-Trisubstituted Imidazoles

intramolecular C−H oxidation/acylation of formyl-N-arylformamides 66 using a copper catalyst and molecular oxygen as the oxidant provided isatins 59 in moderate to good yields. Recently, Zhou and co-workers developed an oxidative cascade coupling reaction for the synthesis of oxindoles via a Cu-catalyzed aryl Csp2−H and formyl Csp2−H functionalization (Scheme 44).43 The reaction of N-arylacrylamides 30 and aldehydes 67 proceeded to afford the corresponding oxindoles 68 in good yields using a combination of CuCl2 as a catalyst 1631


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The direct C−H functionalization of pyridines is an economic and useful synthetic method for the synthesis of Nheterocycles. In 2013, Fu and co-workers47 and Jiang and coworkers48 reported an efficient protocol for the construction of imidazo[1,2-a]pyridines via a Cu-catalyzed functionalization of the Csp2−H bond of pyridines and Csp3−H bonds (Scheme 47).

Scheme 44. Cu-Catalyzed Synthesis of Oxindoles

Scheme 47. Cu-Catalyzed Synthesis of Imidazo[1,2a]pyridines

and TBHP as an oxidant. The initial step was proposed to generate an acyl radical from the reaction of TBHP and aldehydes 67 in the presence of copper species. Subsequently, addition followed by cyclization formed the desired products 68. 2.1.7. Via Cu-Catalyzed Aryl Csp2−H and Csp3−H Functionalization. The application of Cu-catalyzed aryl Csp2−H and Csp3−H functionalization to construct fivemembered N-heterocycles was reported by Taylor and coworkers (Scheme 45).44 The 3,3-disubstituted oxindoles 70 Scheme 45. Cu-Catalyzed Synthesis of Oxindoles For example, the Cu-catalyzed aerobic cyclization of pyridines 73 and ketone oxime esters 76 provided imidazo[1,2-a]pyridines 75 in good yields using 20 mol % of CuI as a catalyst and a catalytic amount of Li2CO3 as a base. As shown in Scheme 48, the oxidative addition of CuI to the oxime ester Scheme 48. Proposed Mechanism for Cu-Catalyzed Synthesis of Imidazo[1,2-a]pyridines

were prepared in high yields by an intramolecular double C−H functionalization of anilides 69 in the presence of a Cu(OAc)2· H2O catalyst and air. This method is applicable to a wide range of substrates tolerating a variety of functional groups. Roy, Majumdar, and co-workers described the formation of five-membered N-heterocycles via a Cu-catalyzed heteroaromatic Csp2−H and Csp3−H functionalization (Scheme 46).45,46 The intramolecular reaction of compounds 71 with 20 mol % of Cu(OTf)2 catalyst under air afforded pyrrolopyrimidines 72 in good yields.

forms a CuIII-imino species. Insertion of pyridine into the Cu− N bond generates a N-pyridine imino intermediate. Tautomerization and intramolecular H-abstraction lead to a sixmembered copper ring intermediate. Reductive elimination and oxidative aromatization give the desired product and regenerate the CuI species. Recently, an efficient synthesis of oxindoles via Cu-catalyzed intermolecular C−H functionalization was developed by Liu and co-workers (Scheme 49).49 The oxindoles 78 were obtained in good yields via the Cu-catalyzed oxidative alkylarylation of acrylamides 30 with simple alkanes 77. A possible CuI/CuII catalytic cycle is shown in Scheme 50. The reaction, which involves a free-radical cascade process results in the selective functionalization of Csp3−H and Csp2−H/C−C

Scheme 46. Cu-Catalyzed Synthesis of Pyrrolopyrimidines

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Scheme 49. Cu-Catalyzed Synthesis of Oxindoles

Scheme 52. Proposed Mechanism for Cu-Catalyzed Synthesis of Pyrazolo[1,5-α]pyridines

copper acetylide species; (ii) dehydrogenation of the substrate; and (iii) elimination of the benzoyl moiety in this reaction.

Scheme 50. Proposed Mechanism for Cu-Catalyzed Synthesis of Oxindoles

2.2. Synthesis of Six-Membered N-Heterocycles

2.2.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization. Representing an important class of six-membered N-heterocyclic species, phenanthridine derivatives are of great interest to the chemical community because of their potent biological activities and optoelectronic properties. In 2010, Chiba and coworkers reported a Cu-catalyzed aryl Csp2−H functionalization for the synthesis of phenanthridine derivatives 83 (Scheme 53).51 The facile synthetic method for the preparation of Scheme 53. Cu-Catalyzed Synthesis of Phenanthridine Derivatives

bonds. This novel protocol represents an efficient C−H functionalization strategy for the construction of bioactive heterocycles. 2.1.8. Via Cu-Catalyzed Aryl Csp2−H and Csp−H Functionalization. A direct Cu-catalyzed C−H functionalization of pyridine derivatives utilizing Csp−H functionalization was developed for the synthesis of N-heterocycles. Using this method, Jiao and co-workers described an efficient synthesis of pyrazolo[1,5-α]pyridines (Scheme 51).50 The oxidative annuScheme 51. Cu-Catalyzed Synthesis of Pyrazolo[1,5α]pyridines

phenanthridine derivatives 83 was realized from the reaction of biaryl-2-carbonitriles 82 and Grignard reagents via Cu-catalyzed C−N bond formation under an O2 atmosphere. The reaction proceeds via N−H imine formation by the nucleophilic addition of a Grignard reagent to biaryl-2-carbonitrile 82, followed by Cu-catalyzed intramolecular aryl Csp2−H functionalization. The synthesis of nitrogen-bridgehead azolopyridine derivatives via Cu-catalyzed heteroaromatic Csp2−H functionalization was developed by Xi and co-workers (Scheme 54).52 The reaction of 1,4-dihalo-1,3-dienes 85 with azoles 84 using CuI as the catalyst provided nitrogen-bridgehead azolopyridine derivatives 86 in moderate to good yields. This coupling reaction proceeds via a Cu-catalyzed domino N−H/C−H bond functionalization. An unusual procedure for the formation of six-ring-fused heterocycles via Cu-catalyzed Csp2−H functionalization was disclosed by Zou, Zhang, and co-workers (Scheme 55).53 The Cu-catalyzed oxidative dimerization of 2-arylindoles 87 with molecular oxygen as the oxidant afforded six-ring-fused heterocycles 88 containing indole and quinoline skeletons.

lation of N-iminopyridinium ylides 79 with terminal alkynes 80 gave the corresponding pyrazolo[1,5-α]pyridines 81 in moderate to good yields when molecular oxygen was used as the oxidant. A possible mechanism for the reaction is shown in Scheme 52 according to mechanistic studies. The first step involves formation of a copper acetylide species from the alkyne with the copper catalyst assisted by a silver complex under basic conditions. Subsequent steps include C−H functionalization, reductive elimination, 5-endo-cyclization, protonation, and rearomatization to give the desired products. It is found that the base plays three roles: (i) assisting in the formation of a 1633


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of 89 in the presence of 20 mol % CuI using air as an oxidant under neutral conditions afforded N-aryl acridones 90 in good yields. Control experiments showed that the reaction proceeded smoothly to afford the desired product when a stoichiometric amount of an electron-transfer scavenger (1,4dinitrobenzene), a radical clock (diallyl ether), or a radical inhibitor (hydroquinone) was added. These results suggest that a radical process is not present in this transformation. During this time, two similar reactions relating to the synthesis of sixmembered acridones from the intramolecular amination of 2aminobenzophenones were also reported using CuI/2,2′bipyridine (bpy)/O255 and CuTc/PPh3/PivOH/O256 reaction conditions. Interestingly, under the reaction conditions of CuI/ bpy/O2,55 only a trace amount of the desired product was obtained by addition of 5 mol % of BHT, which is a known inhibitor of radical reactions. This evidence supports that the catalytic reaction occurs via a radical mechanism. The application of Cu-catalyzed heteroaromatic Csp2−H functionalization to construct six-membered N-heterocycles was achieved by Qiao and co-workers (Scheme 57).57 The

Scheme 54. Cu-Catalyzed Synthesis of Nitrogen-Bridgehead Azolopyridine Derivatives

Scheme 55. Cu-Catalyzed Synthesis of Fused N-Heterocycles

Scheme 57. Cu-Catalyzed Synthesis of 5-Substituted Imidazo/Benzimidazo[2,1-b]quinazolinones

Molecular oxygen was discovered to be not only an oxidant but also a reactant. This reaction provides a novel route to the preparation of fused N-heterocycles. Zhou, Deng, and co-workers developed Cu-catalyzed intramolecular aryl Csp2−H functionalization for the synthesis of Naryl acridones 90 (Scheme 56).54 The intramolecular amination

intramolecular aerobic oxidative reaction of (1H-imidazol-1yl)[2-(alkylamino)phenyl]methanones and (1H-benzimidazol1-yl)[2-(alkylamino)phenyl]methanones 91 using 20 mol % of CuCl as the catalyst and air as the oxidant provided 5substituted imidazo/benzimidazo[2,1-b]quinazolinones 92 in moderate to good yields. A range of functional groups are tolerant to the reaction conditions. The Cu-catalyzed heteroaromatic Csp2−H functionalization has been extended to intermolecular reactions. For example, Chen, Bao, and co-workers reported a Cu-catalyzed one-pot synthesis of azoquinazolinones 95 (Scheme 58).58 The Cucatalyzed reaction of 2-halobenzamides 93 and N-heterocycles 94 using molecular oxygen as the oxidant gave azoquinazolinones 95 in moderate to good yields. This reaction occurs via a sequential Cu-catalyzed N-arylation and an intramolecular heteroaromatic Csp2−H functionalization process. Fu, Hu, and co-workers also described a one-pot, two-step reaction for the synthesis of indoloimidazoquinoline derivatives 98 (Scheme 59).59 The compounds 98 were prepared in good yields by the Cu-catalyzed one-pot reaction of 2-(2-bromophenyl)-1Hindoles 96 and imidazoles 97. A novel three-component synthesis of N-polyheterocycles was developed by Qian and co-workers (Scheme 60).60 The reaction of bis(2-bromophenyl)methanone 99, terminal alkynes 62, and 2-azidoacetamides 100 with CuI as the catalyst

Scheme 56. Cu-Catalyzed Synthesis of N-Aryl Acridones

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addition/C−N coupling/cyclization/C−H arylation mechanism. This efficient reaction creates three new rings and five new bonds (two C−C and three C−N bonds) from three different copper catalytic cycles in a cascade of four types of reactions. For this reaction, the Cu-catalyzed heteroaromatic Csp2−H functionalization is a key step, leading to the formation of the six-membered N-heterocycles. Recently, an efficient method for the synthesis of polycyclic benzimidazoles 104 was reported (Scheme 61).61 The reaction of bis(o-haloaryl)-

Scheme 58. Cu-Catalyzed Synthesis of Azoquinazolinones

Scheme 61. Cu-Catalyzed Synthesis of Polycyclic Benzimidazoles

Scheme 59. Cu-Catalyzed Synthesis of Indoloimidazoquinoline Derivatives

carbodiimides 102 and azoles 103 occurs via a Cu-catalyzed domino addition/double cyclization process to give polycyclic benzimidazoles 104. A key step is the formation of the sixmembered N-heterocycles via Cu-catalyzed heteroaromatic Csp2−H functionalization (Scheme 62). Scheme 62. Proposed Mechanism for Cu-Catalyzed Synthesis of Polycyclic Benzimidazoles Scheme 60. Cu-Catalyzed Synthesis of N-Polyheterocycles

A Cu-catalyzed aryl Csp2−H functionalization with 3,3diarylacrylamides was applied to the synthesis of six-membered N-heterocycles. Cacchi and co-workers developed a simple protocol for the construction of 4-aryl-2-quinolones (Scheme 63).62 The 4-aryl-2-quinolones 106 were prepared in moderate to good yields by Cu-catalyzed intramolecular cyclization of 3,3-diarylacrylamides 105 using air as the oxidant and KOtBu as the base. Using a similar Cu-catalyzed intramolecular C−H functionalization/C−N bond-forming process, Tan, Yu, and coworkers developed a simple protocol for the synthesis of

provided N-polyheterocycles 101 in moderate to good yields. The reaction proceeds via a Cu-catalyzed domino cyclo1635


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Scheme 65. Cu-Catalyzed Synthesis of N-Heterocycles

Scheme 63. Cu-Catalyzed Synthesis of 4-Aryl-2-quinolones

Scheme 66. Proposed Mechanism for Cu-Catalyzed Synthesis of N-Heterocycles

phenanthridin-6(5H)-ones 108 from readily available substrates of 2-phenylbenzamides 107 (Scheme 64).63 Scheme 64. Cu-Catalyzed Synthesis of Phenanthridin6(5H)-ones

Scheme 67. Cu-Catalyzed Synthesis of Quinolines

2.2.2. Via Cu-Catalyzed Alkenyl Csp2−H Functionalization. A procedure for the construction of six-membered Nheterocycles via a Cu-catalyzed alkenyl Csp2−H functionalization has been developed by Fu and co-workers. In 2011, they reported an intramolecular synthesis of fused N-heterocycles (Scheme 65).64 The intramolecular amination of substituted 3methylene isoindolin-1-ones 109 in the presence of a copper catalyst gave the corresponding N-heterocycles 110 in high yields. The use of acid was found to be of particular importance as the reaction failed to provide any of the desired products in the absence of acid. A possible mechanism is shown in Scheme 66. A Cu−N adduct intermediate formed from the reaction of 109 and Cu(O2CCF3)2 was proposed for this reaction. Intramolecular addition of the alkenyl CC bond, followed by oxidation, provides the desired product and regenerates the CuII species. Chiba and co-workers described an efficient reaction for the synthesis of six-membered N-heterocycles via Cu-catalyzed oxidative functionalization of alkynes (Scheme 67).65 The intramolecular reaction of N-(2-alkynylaryl)enamine carboxylates 111 using a copper catalyst and molecular oxygen as an oxidant provided quinolines 112 in good yields. A plausible

mechanism for this reaction is shown in Scheme 68. The reaction proceeds through a sequence of intramolecular carbocupration of the alkyne followed by isomerization, elimination, and further oxidation to give the desired product. 2.2.3. Via Cu-Catalyzed Csp3−H Functionalization. An intramolecular Cu-catalyzed Csp3−H functionalization for the synthesis of quinolinones was developed by Li and co-workers (Scheme 69).66 The Cu-catalyzed oxidative cyclization of N-(2ethynylaryl)acetamides 113 using molecular oxygen as an oxidant provided quinolinones 114 in good yields. 1636


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yields. The recyclability of the catalyst was tested four times in the present reaction. Fu and co-workers developed a simple method for the synthesis of quinazolinones via Cu-catalyzed oxidative dehydrogenation (Scheme 71).68 The reaction of substituted 2-

Scheme 68. Proposed Mechanism for Cu-Catalyzed Synthesis of Quinolines

Scheme 71. Cu-Catalyzed Synthesis of Quinazolinones

Scheme 69. Cu-Catalyzed Synthesis of Quinolinones halobenzamides 117 and benzylamines 53 using CuBr as the catalyst and air as an oxidant provided quinazolinones 118 in moderate to good yields. The domino reaction undergoes sequential Cu-catalyzed Ullmann-type coupling, aerobic oxidation, an intramolecular nucleophilic addition, and a further oxidation process. This novel method tolerates various functional groups in the starting materials. Recently, a similar method for the synthesis of quinazolinones via Cu-catalyzed aerobic oxidation was reported (Scheme 72).69 The quinazoScheme 72. Cu-Catalyzed Synthesis of Quinazolinones Involving C−C Bond Cleavage

Cu-catalyzed oxidative dehydrogenation methodology has been used to construct six-membered N-heterocycles. For example, Wang and co-workers reported the use of a heterogeneous catalyst based on copper oxide nanoparticles attached to a kaolin support (CuO NPs) to synthesize quinazolines (Scheme 70).67 The Cu-catalyzed reaction of 2aminobenzophenones 115 and benzylamines 53 using TBHP as the oxidant provided quinazoline derivatives 116 in high

linones 118 were prepared by using α-substituted arylmethanamines 119 as starting materials instead of benzylamines 53. This reaction proceeds through a Cu-catalyzed domino reaction involving C−C bond cleavage (Scheme 73).

Scheme 70. Cu-Catalyzed Synthesis of Quinazolines

Scheme 73. Proposed Mechanism for Cu-Catalyzed Synthesis of Quinazolinones

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An efficient construction of six-membered N-heterocycles via Cu-catalyzed oxidative dehydrogenation was described by Zou, Zhang, and co-workers (Scheme 74).70 The Cu-catalyzed

Scheme 76. Proposed Mechanism for Cu-Catalyzed Synthesis of N-Fused Heterocycles

Scheme 74. Cu-Catalyzed Synthesis of Indolo[1,2c]quinazolines

reaction of 2-(2-halophenyl)-1H-indoles 120 and benzylamines 53 using air as an oxidant provided indolo[1,2-c]quinazolines 121 in moderate to good yields. The reaction proceeds via Cucatalyzed sequential intermolecular N-arylation and intramolecular aerobic oxidative C−H amination. Readily available α-amino acids have been used as a nitrogen source in the Cu-catalyzed oxidative dehydrogenation for the construction of six-membered N-heterocycles. Fu and coworkers reported a novel synthesis of N-fused heterocycles via Cu-catalyzed aerobic oxidation (Scheme 75).71 The H-

Scheme 77. Cu-Catalyzed Synthesis of Tetrahydroisoquinolino[2,1-a]quinazolinones

Scheme 75. Cu-Catalyzed Synthesis of N-Fused Heterocycles

Scheme 78. Cu-Catalyzed Synthesis of 2-Hetarylquinazolin4(3H)-ones

indolo[1,2-c]quinazolines 124 were prepared in good yields by a Cu-catalyzed domino C−H functionalization procedure via the reaction of indoles 122 and α-amino acids 123. As shown in Scheme 76, this reaction proceeds via a Cu-catalyzed Narylation, aerobic oxidation dehydrogenation, intramolecular cyclization, and dissociation of formic acid. In addition, this method was applied to the synthesis of tetrahydroisoquinolino[2,1-a]quinazolinones 126 from the reaction of N-substituted benzamides 93 and 1,2,3,4-tetrahydroisoquinolines 125 (Scheme 77).72 Recently, the synthesis of 2-hetarylquinazolin-4(3H)-ones via Cu-catalyzed oxidative amination has been described by Zhou, Yin, and co-workers (Scheme 78).73 The reaction of 2-

aminobenzamides 127 and substituted (2-azaaryl)methanes 128 in the presence of CuCl as a catalyst with molecular oxygen as an oxidant afforded 2-hetarylquinazolin-4(3H)-ones 129 in moderate to good yields. This reaction proceeds via a tandem 1638


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oxidation−amination−cyclization transformation procedure, and three Csp3−H and three N−H bonds cleavages are involved in the reaction (Scheme 79).

Scheme 81. Proposed Mechanism for Cu-Catalyzed Synthesis of Tetrahydroquinolines

Scheme 79. Proposed Mechanism for Cu-Catalyzed Synthesis of 2-Hetarylquinazolin-4(3H)-ones

Scheme 82. Cu-Catalyzed Synthesis of Cinnolines

2.2.4. Via Cu-Catalyzed Aryl Csp2−H and Csp3−H Functionalization. As an efficient synthetic methodology, the Cu-catalyzed double functionalization of aryl Csp2−H and Csp3−H bonds has been applied to the synthesis of sixmembered N-heterocycles. In 2011, Hirano, Miura, and coworkers developed a Cu-catalyzed oxidative direct cyclization of N-methylanilines with electron-deficient alkenes for the synthesis of tetrahydroquinolines (Scheme 80).74 Under a CuCl2/

Deuterium-labeling experiments were performed to probe the reaction mechanism. The value of the kinetic isotope effect (kH/kD = 1.2/1) suggests that the cleavage of the aryl Csp2−H bond might not be involved in the rate-determining step. This reaction was proposed to proceed via Cu-catalyzed Csp3−H oxidation, cyclization, and aromatization processes (Scheme 83). The six-membered N-heterocycles of cinnolines were prepared efficiently via a Cu-catalyzed aerobic dehydrogenative coupling reaction from aryl Csp2−H bond and Csp3−H bonds. On the basis of their previous results of Cu-catalyzed synthesis of oxindoles,44 Taylor and co-workers recently

Scheme 80. Cu-Catalyzed Synthesis of Tetrahydroquinolines

Scheme 83. Proposed Mechanism for Cu-Catalyzed Synthesis of Cinnolines

air catalyst system, the reaction of N-methylanilines 130 with maleimides 131 provided the corresponding tetrahydroquinolines 132 in moderate to good yields. The proposed reaction mechanism is shown in Scheme 81: the initial single electron transfer from the N-methylaniline to CuII complex, followed by deprotonation, provides the α-amino radical. Then electrophilic radical addition to the maleimide and cyclization onto the aromatic ring generate the corresponding cyclohexadienyl radical, which is rearomatized by the second single electron transfer/proton elimination, giving the product. In 2012, Ge and co-workers reported a novel synthesis of cinnolines 134 via a Cu-catalyzed intramolecular aerobic dehydrogenative cyclization of N-methyl-N-phenylhydrazones 133 with molecular oxygen as the oxidant (Scheme 82).75 1639


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reported the Cu-catalyzed synthesis of six-membered Nheterocycles by aryl Csp2−H and Csp3−H functionalization (Scheme 84).76 1,2,3,4-Tetrahydroquinolines 136 and 3,4-

as the oxidant. A possible mechanism for this reaction is proposed in Scheme 86. The oxidation of 139 in the presence Scheme 86. Proposed Mechanism for Cu-Catalyzed Synthesis of Acridones

Scheme 84. Cu-Catalyzed Synthesis of 1,2,3,4Tetrahydroquinolines and 3,4-Dihydro-1H-quinolin-2-ones

of a copper salt and molecular oxygen affords 1-arylindoline2,3-dione, which upon treatment with pyridine and water at high temperature results in the formation of a Friedel−Crafts intermediate. From this intermediate, the reaction can take two possible pathways to yield the target product. One pathway involves dehydration, decarboxylation, oxidation, and isomerization. The other route involves elimination of pyridinium formate. An efficient Cu-catalyzed annulation of amidines was designed to synthesize substituted quinazolines by Xiong, Zhang, and co-workers (Scheme 87).79 The intermolecular

dihydro-1H-quinolin-2-ones 138 were efficiently prepared in the presence of copper(II) 2-ethylhexanoate as a catalyst with air as an oxidant. A synthesis of acridones using a Cu-catalyzed C−C bond cleavage and intramolecular cyclization approach was developed independently by Zhou and co-workers77 and Fu and coworkers78 (Scheme 85). The Cu-catalyzed intramolecular cyclization of 1-[2-(arylamino)aryl]ethanones 139 occurred to give acridones 140 in good yields using air or molecular oxygen

Scheme 87. Cu-Catalyzed Synthesis of Quinazolines

Scheme 85. Cu-Catalyzed Synthesis of Acridones

annulations of amidines 1 and various one-carbon synthons 141, such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), or tetramethylethylenediamine (TMEDA), in the presence of selectfluor as the oxidant provided quinazolines 142 or 143 in moderate to good yields. This reaction proceeds through a direct oxidative amination of N−H bonds and methyl Csp3−H bonds followed by intramolecular C−C bond formation (Scheme 88). 1640


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Liu and co-workers81 and Huang and co-workers.82 For example, the alkyl-substituted phenanthridines 148 (or 150) were prepared by a Cu-catalyzed free-radical addition/ cyclization of isocyanides 147 with simple alkanes 77 or alcohols 149 using dicumyl peroxide (DCP) as an oxidant (Scheme 91). A Cu-catalyzed dual C−H functionalization using

Scheme 88. Proposed Mechanism for Cu-Catalyzed Synthesis of Quinazolines

Scheme 91. Cu-Catalyzed Synthesis of Phenanthridine Derivatives

Recently, the use of peroxides as the oxidant in the Cucatalyzed double functionalization of aryl Csp2−H and Csp3−H bonds has been applied to the synthesis of six-membered Nheterocycles. For example, Duan and co-workers developed Cucatalyzed tandem oxidative cyclization of cinnamamides 144 with benzyl hydrocarbons 145 for the formation of functionalized dihydroquinolinones 146 using tert-butyl peroxybenzoate (TBPB) as an oxidant (Scheme 89).80 Moreover, not only Scheme 89. Cu-Catalyzed Synthesis of Dihydroquinolinones

TBHP as an oxidant for the synthesis of polycyclic amines was described by Seidel and co-workers (Scheme 92).83 The reaction of N-phenyl 1,2,3,4-tetrahydroisoquinoline 151 with alkenes 152 in the presence of copper catalyst afforded polycyclic amines 153 in moderate to good yields. 2.3. Synthesis of Other N-Heterocycles

2.3.1. Synthesis of Three-Membered N-Heterocycles via Cu-Catalyzed Csp3−H Functionalization. A novel synthesis of three-membered N-heterocycles via Cu-catalyzed

benzyl hydrocarbons 145 but also ethers, alcohols, and alkanes are suitable for these reaction conditions. A tandem intermolecular radical addition and an intramolecular 6-endotrig-cyclization process were proposed for the mechanism of this reaction (Scheme 90). The formation of alkyl-substituted phenanthridine derivatives via Cu-catalyzed aryl Csp2−H and Csp3−H bond functionalizations was reported independently by

Scheme 92. Cu-Catalyzed Synthesis of Polycyclic Amines

Scheme 90. Proposed Mechanism for Cu-Catalyzed Synthesis of Dihydroquinolinones

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Csp3−H functionalization was reported by Chan and co-workers (Scheme 93).84 2,2-Diacyl aziridine derivatives 156 were

Scheme 95. Proposed Mechanism for Cu-Catalyzed Synthesis of β-Lactam Derivatives

Scheme 93. Cu-Catalyzed Synthesis of 2,2-Diacyl Aziridine Derivatives

coordination of the substrate to the CuII species and ligand exchange with the base. Oxidation of the alkyl/CuII complex affords an alkyl/CuIII species. β-Lactam derivatives and CuI species are obtained via reductive elimination of the alkyl/CuIII complex. The CuII species is regenerated via oxidation of the CuI species with duroquinone.

obtained in good yields via the reaction of 2-alkyl-substituted 1,3-dicarbonyl compounds 154 with 2 or 3 equiv of PhINTs 155 in the presence of a Cu(OTf)2 catalyst. Interestingly, the product selectivity can be controlled by a slight modification of the reaction conditions. The aziridination products were obtained with 2 or 3 equiv of 155. However, the use of 1.2 equiv of 155 only provided amination products. 2.3.2. Synthesis of Four-Membered N-Heterocycles via Cu-Catalyzed Csp3−H Functionalization. Recently, Kuninobu, Kanai, and co-workers85 and Ge and co-workers86 independently developed an efficient reaction for the synthesis of four-membered N-heterocycles via a Cu-catalyzed Csp3−H functionalization. For example, the intramolecular amidation of N-(quinolin-8-yl)pivalamide derivatives 157, which contain an 8-aminoquinolinyl group as the directing group, in the presence of 20 mol % of CuCl as a catalyst and duroquinone as an oxidant under air, provided the β-lactam derivatives 158 in high yields (Scheme 94). Deuterium-labeling experiments show no apparent H−D exchange in this reaction. The observed secondary kinetic isotope effect suggests that the cleavage of the Csp3−H bond should not be involved in the ratedetermining step. A possible mechanism for this reaction is shown in Scheme 95. An alkyl/CuII species is formed by the

3. SYNTHESIS OF N,O-HETEROCYCLES 3.1. Synthesis of Five-Membered N,O-Heterocycles

3.1.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization. Oxazole five-membered N,O-heterocycles are found throughout nature and in biologically active molecules. Ueda and Nagasawa reported a Cu-catalyzed aryl Csp2−H functionalization for the synthesis of 2-arylbenzoxazoles (Scheme 96).87,88 The CuScheme 96. Cu-Catalyzed Synthesis of 2-Arylbenzoxazoles

Scheme 94. Cu-Catalyzed Synthesis of β-Lactam Derivatives

catalyzed intramolecular coupling of benzanilides 159 provided 2-arylbenzoxazoles 160 in moderate to good yields using 20 mol % Cu(OTf)2 as a catalyst and molecular oxygen as an oxidant. The value of the kinetic isotope effect (kH/kD = 1/1) in an intramolecular competition experiment using ortho-deuterium-labeled substrate suggests that cleavage of the C−H bond is not involved in the rate-determining step. The observed higher reactivities of electron-rich anilides compared to electron-deficient anilides, and lower reactivities of an electron-withdrawing halogen substituent at the meta-position compared to the para-position, imply that an electrophilic aromatic substitution process is involved in the reaction. Using a Cu-catalyzed intramolecular heteroaromatic Csp2−H functionalization, Takemura, Kuninobu, and Kanai developed an efficient synthesis of five-membered N,O-heterocycles (Scheme 97).89 The alkoxylation of azoles 161 provided the corresponding N,O-heterocycles 162 in moderate to good yields using CuCl as a catalyst and (tBuO)2 as the oxidant. 3.1.2. Via Cu-Catalyzed Hydrazone Csp2−H Functionalization. A synthetic procedure for the synthesis of five1642


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A possible mechanism involving a CuII/CuI catalytic cycle is shown in Scheme 100. The enamide radical cation is formed

Scheme 97. Cu-Catalyzed Alkoxylation of Azoles

Scheme 100. Proposed Mechanism for Cu-Catalyzed Synthesis of 2,5-Disubstituted Oxazoles

from the reaction of the enamide with CuBr2. Subsequent cyclization and oxidation provides the desired product. The CuBr2 catalyst is regenerated via the oxidation of the reduced copper species with K2S2O8 and tetra-n-butylammonium bromide (TBAB). 3.1.4. Via Cu-Catalyzed Csp3−H Functionalization. The Cu-catalyzed Csp3−H functionalization was applied to the synthesis of five-membered N,O-heterocycles. In 2012, Chiba and co-workers developed a novel reaction for the synthesis of dihydrooxazoles 168 via a Cu-catalyzed Csp3−H functionalization (Scheme 101).92 The Cu-catalyzed C−H oxygenation of

membered N,O-heterocycles via Cu-catalyzed hydrazone Csp2− H functionalization has been developed. In 2011, Patel and coworkers described a novel intramolecular synthesis of 2,5substituted 1,3,4-oxadiazoles 164 via a Cu-catalyzed hydrazone Csp2−H functionalization (Scheme 98).90 The Cu-catalyzed intramolecular C−H functionalization of N-arylidenearoylhydrazide derivatives 163 afforded the target products 164 in good yields using air as an oxidant.

Scheme 101. Cu-Catalyzed Synthesis of Dihydrooxazoles Scheme 98. Cu-Catalyzed Synthesis of 2,5-Substituted 1,3,4Oxadiazoles

3.1.3. Via Cu-Catalyzed Alkenyl Csp2−H Functionalization. Cheung and Buchwald reported an efficient reaction for the preparation of 2,5-disubstituted oxazoles (Scheme 99).91 The intramolecular oxidative cyclization of enamides 165 in the presence of copper catalyst and K2S2O8 as the oxidant gave 2,5disubstituted oxazoles 166 in good yields. The reaction proceeds by a Cu-catalyzed alkenyl Csp2−H functionalization.

N-alkylamidines 167 under an oxygen atmosphere provided dihydrooxazoles 168 in moderate to good yields. A radical mechanism has been proposed for the reaction (Scheme 102). Wang and co-workers described a Cu-catalyzed synthesis of polysubstituted oxazoles 170 from readily available starting materials (Scheme 103).93 The Cu-catalyzed reaction of benzylamines 53 and β-diketones 169 provided polysubstituted

Scheme 99. Cu-Catalyzed Synthesis of 2,5-Disubstituted Oxazoles

Scheme 102. Proposed Mechanism for Cu-Catalyzed Synthesis of Dihydrooxazoles

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Scheme 103. Cu-Catalyzed Synthesis of Polysubstituted Oxazoles

Scheme 106. Proposed Mechanism for Cu-Catalyzed Synthesis of 2-Arylbenzoxazoles

membered metallacycle intermediate can be oxidized by Cu(OTf)2 to give a CuIII intermediate, which undergoes reductive elimination to provide the desired product.

oxazoles 170 in good yields. The reaction procedure is initiated by the reaction of benzylamine and a β-diketone derivative in the presence of iodine. Oxidation followed by intramolecular cyclization and further oxidation afforded the desired oxazole (Scheme 104).

3.2. Synthesis of Six-Membered N,O-Heterocycles

3.2.1. Via Cu-Catalyzed Csp3−H Functionalization. A novel synthesis of six-membered N,O-heterocycles via Cucatalyzed Csp3−H functionalization was reported by Zhang and co-workers (Scheme 107).96 The Cu-catalyzed intramolecular

Scheme 104. Proposed Mechanism for Cu-Catalyzed Synthesis of Polysubstituted Oxazoles

Scheme 107. Cu-Catalyzed Synthesis of 4H-3,1Benzoxazines

3.1.5. Via Cu-Catalyzed Aryl Csp2−H and Imine Csp2−H Functionalization. An efficient method for the synthesis of 2arylbenzoxazoles via a Cu-catalyzed dual functionalization of an aryl Csp2−H bond and imine Csp2−H bond was developed by Punniyamurthy and co-workers (Scheme 105).94,95 The CuScheme 105. Cu-Catalyzed Synthesis of 2-Arylbenzoxazoles reaction of N-o-tolylbenzamides 172 in the presence of selectfluor as the oxidant afforded 4H-3,1-benzoxazines 173 in good yields. A possible mechanism is shown in Scheme 108. The initial step is the formation of the active CuI species, which can be formed via either the reduction of the CuII species by the nucleophile or the disproportionation of the CuII species. A CuI intermediate is formed from the substrate and copper species. Scheme 108. Proposed Mechanism for Cu-Catalyzed Synthesis of 4H-3,1-Benzoxazines

catalyzed intramolecular cyclization of bisaryloxime ethers 171 using molecular oxygen as the oxidant provided 2-arylbenzoxazoles 160 in good yields. A possible mechanism for this reaction involves a Lewis acid assisted C−H functionalization followed by C−O/C−N bond formation. As shown in Scheme 106, a six-membered metallacycle intermediate is formed from the coordination of the substrate to Cu(OTf)2. Reductive elimination gives the desired product. Alternatively, the six1644


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Oxidative addition of selectfluor gives a CuIII intermediate. Intramolecular hydrogen atom abstraction (HAA) then generates a benzyl radical with a CuII center. Cyclization leads to the desired product and CuI species. In this reaction, the selective functionalization of a benzylic Csp3−H bond over an aryl Csp2−H bond was realized by the copper catalyst. 4H-3,1-Benzoxazines can also be prepared via another efficient reaction. Chiba and co-workers described the C−H oxygenation of N-(2-isopropylphenyl)amidines 174 to give 4H3,1-benzoxazines 173 in moderate to good yields (Scheme 109).92 A Cu-catalyzed Csp3−H functionalization is involved in this reaction, and the mechanism of the present reaction is similar to that shown in Scheme 102.

by the addition of 1 equiv of radical scavenger (BHT or thiophenol) suggests that a radical process may be involved in the present reaction. On the basis of this information, a reaction mechanism is proposed in Scheme 111, an iminium salt Scheme 111. Proposed Mechanism for Cu-Catalyzed Synthesis of Dihydro-1,3-oxazines


intermediate formed in the presence of the CuII species with O2. Subsequent formation of the desired product can occur via endo-[4 + 2]-cycloaddition (path a). The pathway involving an intramolecular cyclization of the iminium salt without disturbing the chiral center (path b) is also possible as observed by the partial retention of enantiomeric purity of the product when using chiral substrates in the reaction. Recently, the formation of dihydrooxazinones via a Cucatalyzed oxidative dehydrogenation was described by Maiti and co-workers (Scheme 112).98 The Cu-catalyzed intra-

Maycock and co-workers developed a new method for the synthesis of six-membered N,O-heterocycles via Cu-catalyzed oxidative dehydrogenation (Scheme 110).97 The benzo- or Scheme 110. Cu-Catalyzed Synthesis of Dihydro-1,3oxazines

Scheme 112. Cu-Catalyzed Synthesis of Dihydrooxazinones

molecular dehydrogenative coupling of salicylamides 177 afforded dihydrooxazinones 178 in good yields. Interestingly, the site of (sp3)C−O bond formation in salicylamides 177 can be predicted based on electronic differences between the amide N-substituents. 3.2.2. Via Cu-Catalyzed Aryl Csp2−H and Csp3−H Functionalization. A Cu-catalyzed aryl Csp2−H and Csp3−H functionalization was developed for the construction of sixmembered N,O-heterocycles. Bi, Zhang, and co-workers described a novel method for the synthesis of 4H-3,1benzoxazines 180 (Scheme 113).99 The Cu-catalyzed dehydrogenative cross-coupling reaction of N-para-tolylamides 179

naphtho-2,3-dihydro-1,3-oxazines 176 were obtained in good yields through the Cu-catalyzed intramolecular oxidation of substituted tertiary aminophenols/naphthols 175 using air as the oxidant. Control experiments showed that it is the formation of a conformationally rigid system via the chelation of the copper complex with the nitrogen and the phenolic OH group in the substrate that direct the dehydrogenative oxidation. The dehydrogenative oxidation occurs at the carbon in close proximity to the phenolic OH group. The loss of the pyrrolidine moiety from the substrate and the formation of an oxabutadiene intermediate are likely steps in the reaction sequence. The observed formation of trace amounts of product 1645


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catalyst. Very recently, an asymmetric version of these reactions was developed by Zurek, Chemler, and co-workers.101 A synthesis of five-membered O-heterocycles via Cucatalyzed aryl Csp2−H functionalization was developed by Zhu and co-workers (Scheme 115).102 The intramolecular


Scheme 115. Cu-Catalyzed Synthesis of Dibenzofurans

using selectfluor as an oxidant gave 4H-3,1-benzoxazines 180 in good yields. Mechanistic studies suggest that this reaction may involve a Cu-catalyzed intermolecular C−H activation of the aryl Csp2−H and benzylic methyl Csp3−H bond, followed by intramolecular C−O bond formation.

oxidative Csp2−H cycloetherification of o-arylphenols 186 with 30 mol % CuBr as the catalyst and air as an oxidant afforded dibenzofurans 187 in moderate to good yields. A Cu-catalyzed aryl Csp2−H functionalization for the synthesis of five-membered O-heterocycles has been used in intermolecular reactions. Recently, Jiang and co-workers developed a Cu-catalyzed synthesis of benzofurans from readily available starting materials (Scheme 116).103 The polysub-

4. SYNTHESIS OF O-HETEROCYCLES 4.1. Synthesis of Five-Membered O-Heterocycles

4.1.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization. In 2012, Chemler and co-workers reported the synthesis of fivemembered O-heterocycles via a Cu-catalyzed aryl Csp2−H functionalization (Scheme 114).100 The Cu-catalyzed intra-

Scheme 116. Cu-Catalyzed Synthesis of Benzofurans

Scheme 114. Cu-Catalyzed Synthesis of Tetrahydrofurans

stituted benzofurans 190 were prepared in high yields via the reaction of phenols 188 and alkynes 189 using Cu(OTf)2 as a catalyst and molecular oxygen as an oxidant. The reaction pathway is envisaged to proceed via a Cu-catalyzed intermolecular nucleophilic addition and intramolecular Cucatalyzed aryl Csp2−H functionalization. 4.2. Synthesis of Six-Membered O-Heterocycles

4.2.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization. Benzolactones, six-membered O-heterocycles, are important structural motifs found in a variety of naturally occurring and biologically active compounds, and they possess a diverse array of pharmacological properties. Therefore, a direct and efficient synthesis of benzolactones is greatly desired. In 2013, GallardoDonaire and Martin reported an efficient Cu-catalyzed synthesis of benzolactones (Scheme 117).104 The intramolecular C−H hydroxylation of 2-arylbenzoic acids 191 afforded benzolactones 192 in moderate to good yields using Cu(OAc)2 as the catalyst and (PhCO2)2 as the oxidant. This

molecular carboetherification/C−H functionalization of 4pentenols 181 and 184 using MnO2 as the oxidant provided the corresponding fused-ring tetrahydrofurans 183 and bridged-ring tetrahydrofurans 185, respectively, in high yields. This reaction involves a primary carbon radical intermediate and radical addition to the aryl ring in the presence of a copper 1646


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Scheme 117. Cu-Catalyzed Synthesis of Benzolactones

Scheme 120. Cu-Catalyzed Synthesis of Trifluoromethylated Coumarins

reaction proceeds via a Cu-catalyzed aryl Csp2−H functionalization with benzoic acids. Hu and co-workers developed a Cu-catalyzed synthesis of chromeno[2,3-d]imidazol-9(1H)-ones (Scheme 118).105 The

lated coumarins 197 were obtained in moderate to good yields from Cu-catalyzed reactions of propiolates 196 with Togni’s reagent 26. A radical mechanism was proposed for this reaction. 4.2.2. Via Cu-Catalyzed Aryl Csp2−H and Formyl Csp2− H Functionalization. A Cu-catalyzed dual C−H functionalization was used for the construction of six-membered Oheterocycles. In 2012, Wang and co-workers reported a Cucatalyzed one-step preparation of xanthones (Scheme 121).107

Scheme 118. Cu-Catalyzed Synthesis of Chromeno[2,3d]imidazol-9(1H)-ones

Scheme 121. Cu-Catalyzed Synthesis of Xanthones

Cu-catalyzed reaction of 3-iodochromones 193 and amidines 194 using air as an oxidant provided chromeno[2,3-d]imidazol9(1H)-ones 195 in moderate to good yields. As shown in Scheme 119, the key step of this reaction consists of intramolecular cycloetherification via a Cu-catalyzed heteroaromatic Csp2−H functionalization. Recently, Lu, Ding, and co-workers described the Cucatalyzed direct trifluoromethylation of propiolates for the construction of trifluoromethylated coumarins (Scheme 120).106 The six-membered O-heterocycles of trifluoromethy-

The Cu-catalyzed reaction of phenols 188 with aryl aldehydes 198 using air as an oxidant afforded the xanthones 199 in moderate to good yields. The reaction is envisaged to proceed via a Cu-catalyzed dual functionalization of the aryl Csp2−H bond of the phenol and the formyl Csp2−H bond of the aldehyde. Intramolecular cyclization then gives the desired product.

Scheme 119. Proposed Mechanism for Cu-Catalyzed Synthesis of Chromeno[2,3- d]imidazol-9(1H)-ones

5. SYNTHESIS OF N,S-HETEROCYCLES 5.1. Synthesis of Five-Membered N,S-Heterocycles

5.1.1. Via Cu-Catalyzed Csp3−H Functionalization. An efficient method for the synthesis of five-membered N,Sheterocycles via a Cu-catalyzed oxidative dehydrogenation of a Csp3−H bond was described by Liang and co-workers (Scheme 122).108 The reaction of N-benzyl-2-iodoanilines 200 and potassium sulfide in the presence of CuBr as a catalyst with air as an oxidant afforded benzothiazoles 201 in good yields. As shown in Scheme 123, the copper species acts as a catalyst for traditional cross-coupling and oxidative cross-coupling reac1647


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Scheme 122. Cu-Catalyzed Synthesis of Benzothiazoles

Scheme 125. Cu-Catalyzed Synthesis of Sultams

Scheme 123. Proposed Mechanism for Cu-Catalyzed Synthesis of Benzothiazoles

6. CONCLUSION This review has summarized important reactions relating to the synthesis of heterocycles via copper-catalyzed C−H functionalizations. Significant advances concerning the synthesis of N-, N,O-, O-, and N,S-heterocycles via copper-catalyzed C−H functionalization reactions have been achieved in a relatively short period of time. Even so, it is clear that several important frontiers still exist for further research in this field: (1) The most successful examples for the synthesis of heterocycles via copper-catalyzed C−H functionalization rely on large amounts of copper catalyst (generally 10−20 mol % of copper catalyst). The discovery of new copper catalysts is therefore required to overcome this problem. (2) The reported examples often require harsh reaction conditions (high temperatures and long reaction times). The development of mild reaction conditions is thus highly desired. (3) Although some types of oxidants, such as peroxides, selectfluor, PhI(OAc)2, MnO2, and K2S2O8, are commonly used for C−H functionalization reactions, more environmentally friendly oxidants, such as molecular oxygen, are greatly desired. (4) Reactions concerning the asymmetric synthesis of heterocycles via copper-catalyzed C−H functionalizations are rare. It is especially difficult to directly induce chirality in the C−H functionalization step; therefore, success examples of such reactions have not yet been reported. The development of versatile asymmetric catalytic approaches for the preparation of different chiral heterocycles thus still remains a challenge in this area of research. (5) The C−H functionalization of unactivated alkanes has only been reported this year. This is a noteworthy achievement as it provides additional efficient pathways to the synthesis of heterocycles. However, greater developments in this area of research are still required. (6) Finally, a more detailed mechanistic understanding, especially of reactions involving organocopper intermediates, is strongly desired to promote the discovery of efficient and highly selective catalytic systems.

tions. The Cu-catalyzed double C−S bonds formation from a traditional cross-coupling reaction and an oxidative crosscoupling reaction provides an efficient procedure for the synthesis of benzothiazoles 201. 5.2. Synthesis of Six-Membered N,S-Heterocycles

5.2.1. Via Cu-Catalyzed Aryl Csp2−H Functionalization. Zeng and Chemler developed an efficient method for the synthesis of six-membered N,S-heterocycles (Scheme 124).109 Scheme 124. Cu-Catalyzed Enantioselective Carboamination of Alkenes

The enantiomerically enriched N,S-heterocycles 203 were prepared by a Cu-catalyzed asymmetric intramolecular carboamination of alkenes 202 using 3 equiv of MnO2 as the oxidant. This reaction involves an intramolecular Cu-catalyzed aryl Csp2−H functionalization. Recently, Matsunaga, Kanai, and co-workers described a novel Cu-catalyzed intermolecular carboamination of alkenes (Scheme 125).110 The reaction of alkenes 152 with Nfluorobenzenesulfonimide 204 in the presence of Cu(CH3CN)4BF4 as a catalyst provided six-membered N,Sheterocycles of sultams 206 in moderate to good yields.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. 1648


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Biographies

Zhengxing Wu was born in Shandong province, China, in 1987. He received his B.S. degree in 2009 from Donghua University. He is currently studying towards a Ph.D. degree at Shanghai Jiao Tong University under the supervision of Prof. Wanbin Zhang. His current research interests are focused on transition metal-catalyzed synthesis of heterocycles.

Xun-Xiang Guo received his M.S. degree in 2004 under the supervision of Prof. Qi-Lin Zhou at East China University of Science and Technology. He moved to Kyoto University (Japan), where he obtained his Ph.D. degree under the supervision of Prof. Tamio Hayashi in 2008. He continued his studies as a postdoctoral fellow with Prof. Shu̅ Kobayashi at the University of Tokyo (Japan). In 2010, he joined the faculty at Shanghai Jiao Tong University. Currently, he is an associate professor at the same university. His research interests are focused on copper-catalyzed synthesis of heterocycles, asymmetric catalysis, and the synthesis of biologically active compounds.

Wanbin Zhang received his B.S. and M.S. degrees from East China University of Science and Technology (ECUST) in 1985 and 1988, respectively. From 1994 to 1997, he undertook Ph.D. studies at Osaka University under the supervision of Prof. Isao Ikeda. He then worked as an assistant professor at Osaka University until 2001 and then as a research fellow at the Speciality Chemicals Research Center of the Mitsubishi Chemical Corporation. Since 2003, he has worked as a professor in the School of Chemistry and Chemical Engineering at Shanghai Jiao Tong University. In 2013 he was promoted to the position of distinguished professor. Professor Zhang’s current research interests include synthetic organic chemistry, asymmetric catalysis and synthesis, and process studies of pharmaceuticals and their intermediates.

ACKNOWLEDGMENTS This work was supported by the Natural Science Foundation of China (21172142, 21172143, 21232004, and 21472123) and Shanghai Jiao Tong University. REFERENCES (1) For selected reviews on synthesis of heterocycles, see: (a) Nawrat, C. C.; Moody, C. J. Angew. Chem., Int. Ed. 2014, 53, 2056. (b) Synthesis of Heterocycles via Metal-Catalyzed Reactions that Generate One or More Carbon−Heteroatom Bonds; Wolfe, J. P., Ed.; Springer: Berlin, 2013. (c) Garella, D.; Borretto, E.; Stilo, A. D.; Martina, K.; Cravotto, G.; Cintas, P. Med. Chem. Commun. 2013, 4, 1323. (d) Ball, C. J.; Willis, M. C. Eur. J. Org. Chem. 2013, 425. (e) Liu, T.; Fu, H. Synthesis 2012, 44, 2805. (f) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937. (g) Hashmi, A. S. K. Pure Appl. Chem. 2010, 82, 657. (h) Minakata, S. Acc. Chem. Res. 2009, 42, 1172. (2) For selected recent reviews: (a) Zhao, C.; Crimmin, M. R.; Toste, F. D.; Bergman, R. G. Acc. Chem. Res. 2014, 47, 517. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (c) Girard, S. A.; Knauber, T.; Li, C.J. Angew. Chem., Int. Ed. 2014, 53, 74. (d) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726. (e) Mousseau, J. J.; Charette, A. B. Acc. Chem. Res. 2013, 46, 412. (f) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (g) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236. (h) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (i) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (j) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (k) Engle, K. M.; Mei, T.S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (l) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (m) Lyons, T.

Da-Wei Gu was born in Shanghai, China, in 1990. He received his B.S. degree in 2013 from School of Chemistry and Chemical Engineering at Shanghai Jiao Tong University. Then he continued his studies at the same university under the supervision of Prof. Xun-Xiang Guo. His current research interests are focused on the copper-catalyzed synthesis of heterocycles.

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