Recent advances in copper-mediated chelation-assisted functionalization of unactivated C–H bonds

Abstract

Transition metal-catalyzed direct functionalization of C–H bonds has recently emerged as a powerful strategy for the construction of carbon–carbon and carbon–heteroatom bonds. Among various metals employed, base metal copper has attracted significant attention owing to its relatively low cost, abundance, and versatile reactivity. This review aims to comprehensively summarize the recent advances in copper-mediated (both stoichiometric and catalytic) chelation-assisted functionalization of unactivated C–H bonds.

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Wei-Hao Rao

Wei-Hao Rao was born in Henan Province, China in 1985. He received his B.S. degree in 2008 and M.S. degree in 2011 from Henan Normal University. Then he pursued his Ph.D. degree in the laboratory of Prof. Bing-Feng Shi in the Department of Chemistry, Zhejiang University. After receiving the PhD, he then joined the College of Chemistry and Chemical Engineering, Xinyang Normal University. His current research is focused on C–H bond activation.

Bing-Feng Shi

Bing-Feng Shi received his B.S. degree from Nankai University in 2001 and a Ph.D. degree from Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the guidance of Professor Biao Yu in 2006. After being a postdoctoral fellow at the University of California, San Diego (2006–2007), he moved to The Scripps Research Institute working with Professor Jin-Quan Yu as a research associate. In 2010, he joined the Department of Chemistry at Zhejiang University as a professor. His research focus is on transition-metal-catalyzed C(sp^3)–H functionalization and its application in the synthesis of natural products.

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1. Introduction

Since the pioneering work of Ullmann and Goldberg,¹ copper-mediated cross-coupling reactions have been extensively applied in organic synthesis (Scheme 1a).² Traditionally, these methods rely on the use of prefunctionalized starting materials (such as organohalides/pseudohalides, or organometallic compounds), which require tedious synthetic operation, and thus reduce the overall efficiency of these transformations. To avoid these disadvantages, transition metal-catalyzed direct functionalization of C–H bonds has recently proved to be one of the most efficient and straightforward complements, since it obviates the prefunctionalization of the starting materials, which makes the reaction more step- and atom-economical.³ Among the various transition metals employed, base metal copper has attracted significant attention owing to its relatively low cost, abundance, and versatile reactivity.^2,4 Early developed methods based on copper-mediated direct functionalization of C–H bonds are only scoped to electronically activated (hetero)aryl C–H bonds, C–H bonds adjacent to a heteroatom, and benzylic C(sp³)–H bonds. These elegant examples have appeared in several relevant reviews and will not be discussed in this review.⁴

Scheme 1 Copper-mediated cross-coupling and C–H functionalization.

To address the difficulty in the functionalization of unactivated C–H bonds and the issue of regioselectivity, directing groups have been introduced into C–H functionalization.³ In 2006, the Yu group^5a and the Chatani group^5b independently reported copper-mediated pyridyl-directed C–H functionalization of 2-arylpyridines (Scheme 2). Recently, the 8-aminoquinoline (AQ) bidentate auxiliary, which was first introduced by Daugulis,⁶ has been used in copper-mediated C–H functionalization. Inspired by these elegant studies, significant advances have recently been made in copper-mediated (both stoichiometric and catalytic) chelation-assisted functionalization of unactivated C–H bonds, which provide practical benefits towards the construction of carbon–carbon and carbon–heteroatom bonds. This review aims to comprehensively summarize recent advances in this area and serve as a handy reference for those interested in using copper-mediated C–H functionalization in organic synthesis (Scheme 1b). For clarity, this review is classified by the type of bond formation, including C–C, C–N, C–O, and other carbon–heteroatom bonds formation.

Scheme 2 Copper-mediated pyridyl-assisted functionalization of C(sp²)–H bonds.

2. Carbon–carbon bond formation

2.1 Arylation

Copper-mediated diaryl compound synthesis was first demonstrated by the dehydrogenative homocoupling of two identical arenes.^5a,7 The cross-coupling with other arylation partners was first demonstrated by Miura and co-workers, where a Cu(OAc)₂-mediated pyridyl- or pyrimidyl-directed dehydrogenative heteroarylation of C(sp²)–H bonds was achieved (Scheme 3).^8a They found that the choice of copper(II) acetate was critical to the success of this reaction and other divalent copper salts completely failed to give the heteroarylated products. PivOH could dramatically improve the reaction efficiency. Good tolerance of a wide spectrum of functional groups was also observed. However, the coupling partner was limited to 1,3-azoles and caffeine containing acidic C–H bonds. Another drawback is the use of unremovable directing groups, such as pyridine and pyrimidine. To overcome these drawbacks, the same research group further developed a copper-mediated dehydrogenative heteroarylation of benzamides using 8-aminoquinoline as the directing group, which could be easily introduced and removed as a protecting group (Scheme 4a).^8b Moreover, the oxidative dehydrogenative heteroarylation of amides bearing a picolinamide (PA) auxiliary was accomplished by the same group under nearly identical conditions in 2013 (Scheme 4b).^8c

Scheme 3 Copper-mediated pyridine or pyrimidine-directed oxidative heteroarylation of C(sp²)–H bonds with 1,3-azoles.

Scheme 4 Copper-mediated dehydrogenative heteroarylation of C(sp²)–H bonds with 1,3-azoles.

These heteroarylation reactions were enabled by excess copper salts, which hampered its synthetic application. In the related investigations of copper-mediated C6-selective dehydrogenative heteroarylation of 2-pyridones with 1,3-azoles, Miura and co-workers disclosed that in certain cases, the dehydrogenative heteroarylation in the presence of catalytic copper acetate (20 mol%) could be feasible with molecular oxygen in air as an efficient terminal oxidant (Scheme 5a).^8d Notably, the 2-pyridyl auxiliary could be readily removed at room temperature, affording the desired heteroarylated 2-pyridone 12 with a free N–H group (Scheme 5b).

Scheme 5 Copper-catalyzed pyridine-directed heteroarylation of 2-pyridones with 1,3-azoles.

In 2014, Dai and Yu reported a copper-catalyzed arylation of aromatic amides with arylboron reagents using a readily removable amide-oxazoline directing group (Scheme 6).^9a Both the benzamides (13) and the arylboron reagents (14) tolerate a broad range of functional groups. To demonstrate the synthetic utility, the arylated product 15a was further transformed into its thioester 16. The thioester can then be converted to the aldehyde 17a and carboxylic acid 17b in good yields (Scheme 6b). Very recently, Tan and co-workers reported a copper-mediated arylation of benzamides with arylboronic acids using the AQ directing group.^9b

Scheme 6 Copper-catalyzed oxa-directed arylation of C(sp²)–H bonds with ArBpin.

Recently, our group has developed a removable PIP (2-pyridinylisopropyl) bidentate directing group,¹⁰ which has shown to be effective in base-metal catalyzed C–H functionalization.¹¹ In 2015, we reported the copper-catalyzed, PIP-directed arylation of benzamides using aromatic carboxylic acids as arylation reagents (Scheme 7).^12a Kinetic isotope effects disclosed that either C–H cleavage was the turnover-limiting step or the turnover-limiting step occurred prior to C–H cleavage, and reactions with radical scavengers suggested that radical intermediates might not be involved in the reaction. Further mechanistic studies revealed that the reaction proceeded via a protodecarboxylative/dehydrogenative arylation sequence other than direct decarboxylative arylation. Enlightened by these results, we finally realized a copper-catalyzed dehydrogenative arylation of benzamides with thiophenes using PIP as a bidentate directing group (Scheme 8a).^12b Notably, the reaction was scalable and tolerated a wide range of functional groups. The PIP directing group could be easily removed by a nitrosylation/hydrolysis sequence (Scheme 8b).

Scheme 7 Copper-catalyzed protodecarboxylative/dehydrogenative arylation of C(sp²)–H bonds with 2-thiophenecarboxylic acids.

Scheme 8 Copper-catalyzed oxidative dehydrogenative arylation of C(sp²)–H bonds with thiophenes.

Although several examples of direct arylation of aryl C–H bonds have been developed through the copper-mediated chelation-assisted strategy, the strategy was limited to the arylation of C(sp²)–H bonds. Recently, the Ge group described a copper-mediated dehydrogenative arylation of aminoquinoline amides 24 with polyfluoroarenes as the coupling partners (Scheme 9).¹³ However, the scope of aliphatic amides 24 was limited to substrates possessing the quaternary carbon center adjacent to a carbonyl group.

Scheme 9 Copper-mediated oxidative dehydrogenative arylation of C(sp³)–H bonds with polyfluoroarenes.

2.2 Alkynylation

Aryl alkynes are among the most important structural motifs in natural products, pharmaceuticals, and materials.¹⁴ Undoubtedly, the oxidative coupling of aryl C–H bonds with terminal alkynes would be an ideal strategy to access these compounds from the viewpoint of atom- and step-economy.¹⁵ In a pioneering study of the mechanism and applications of aryl-Cu(III) complexes, Wang and co-workers reported the first C(aryl)–C(alkynyl) bond formation via the cross-coupling of alkynyllithium reagents with several structurally well-defined aryl-Cu(III) intermediates 2 (Scheme 10).^16a This transformation provides an unique synthetic route to access alkynylated azacalixaromatics, which can serve as key building blocks to various tailor-made functional macrocyclic host molecules for supramolecular chemistry. It is worth noting that the seminal studies regarding the structurally well-defined aryl-Cu(III) species by Wang, Stahl and Ribas have greatly deepened the mechanistic insights.¹⁶

Scheme 10 Copper-mediated alkynylation of C(sp²)–H bonds with terminal alkynes.

In 2014, Yu and Dai reported the synthesis of aryl alkynes via a copper-mediated dehydrogenative alkynylation of C(sp²)–H bonds with the assistance of an amide-oxazoline group (Scheme 11a).^17a The method demonstrated good generality to both benzamides and terminal alkynes, and both aromatic amides and heteroaromatic amides could be alkynylated under mild reaction conditions, thus providing an alternative pathway to traditional Sonogashira coupling. In the same year, our group independently described a Cu(OAc)₂-catalyzed oxidative annulation of benzamides bearing a PIP auxiliary with terminal alkynes (Scheme 11b).^17b As expected, an external oxidant was necessary for the catalytic cycle, and screening experiments showed that Ag₂CO₃ as the terminal oxidant was an effective ingredient. Also, the presence of Et₃N as a co-base was beneficial for the transformation since it might facilitate the deprotonation of the terminal alkyne. A broad range of (hetero)aromatic amides could even be alkynylated. However, the terminal alkyne was limited to TIPS-alkyne 31. We rationalized that a copper-mediated basic-ligand-enabled concerted metalation/deprotonation (CMD) rather than a copper-mediated electrophilic aromatic substitution (S_EAr) pathway was likely involved in the alkynylation.

Scheme 11 Copper-mediated alkynylation of C(sp²)–H bonds with terminal alkynes.

2.3 Trifluoromethylation

In 2014, the first copper-mediated ortho-trifluoromethylation of benzamides with TMSCF₃ employing the amide-oxazoline directing group was reported by Yu and Dai (Scheme 12).¹⁸ Stoichiometric Cu(OAc)₂ and excess Ag₂CO₃ were essential to the success of this transformation. Nevertheless, excess N-methyl morpholine oxide (NMO) as the oxidant was necessary. Various electron-rich and electron-deficient benzamides underwent trifluoromethylation efficiently to deliver the trifluoromethylated products. It was worth noting that this protocol was compatible with a variety of heterocycles, including pyridines, pyrroles, benzofurans and quinolone-derived substrates. The significant isotope effects and negligible effect of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) on the reaction rendered a radical pathway unlikely. Preliminary mechanistic studies suggested that a copper-mediated C–H activation pathway rather than an electrophilic aromatic substitution (S_EAr) or radical pathway was involved in the reaction (Scheme 12b). Oxazoline-directed cupration of benzamide 13a with Cu(OAc)₂via C–H activation followed by disproportionation of Cu(II) species with Cu(OAc)₂ afforded a chelated copper(III) species 35. Subsequent transmetallation of this Cu(III) species with TMSCF₃ generated the Cu(III)–CF₃ intermediate 36 which underwent reductive elimination to afford the desired product 33a.

Scheme 12 Copper-mediated ortho-trifluoromethylation of C(sp²)–H bonds with TMSCF₃.

2.4 Tandem C–H functionalization/annulation

In 2014, copper-mediated tandem alkynylation/annulation of arenes with terminal alkynes was first reported by You and co-workers (Scheme 13a).^19a After a short screening of copper salts, copper acetate proved to be the best choice, giving the desired oxidative annulation products in moderate to high yields. The protocol featured a wide substrate scope, high functional group tolerance and exclusive chemo-, regio- as well as stereoselectivity. Moreover, they found that ortho-alkynyl benzamide 38a could be transformed into the corresponding annulation product 39a in the presence of either Cu(OAc)₂ or CuOAc, indicating that the domino reaction might proceed via an oxidative alkynylation/intramolecular annulation sequence (Scheme 13b). Shortly after, the Huang and Yu group independently reported the same tandem oxidative alkynylation/annulation reaction.^19b

Scheme 13 Copper-mediated AQ-directed tandem oxidative alkynylation and annulations of arenes with terminal alkynes.

In 2014, Liu and co-workers reported a copper-mediated annulation of benzamides with ethyl cyanoacetate using AQ as the directing group (Scheme 14).²⁰ A number of isoquinolinone compounds 40 were synthesized via this tandem C(sp²)–C(sp³)/C(sp³)–N bond formation sequence. Apart from ethyl cyanoacetate, a variety of cyano substrates, such as cyano substituted amides, phosphonates, and methylsulfonyls, could also be used as coupling partners.

Scheme 14 Copper-mediated annulation of benzamides with cyano substrates.

Since the amide-oxazoline directing group has demonstrated versatile reactivity in copper-mediated C–H functionalization, the Yu group rationalized that the same directing group might promote the coupling of aromatic C–H bonds with malonates under copper catalysis (Scheme 15).²¹ As expected, after extensive screening of reaction parameters, the desired products could be obtained in moderate to high yields with Cu(OAc)₂ and Ag₂CO₃ as the optimal catalyst and oxidant respectively. As such, this method presents an alternative tool for the construction of isoindolinone scaffolds 42. Interestingly, the reaction of benzamide 43 with 3-oxobutanoate 44 produced methyl 3,6-dimethyl-1-oxo-1H-isochromene-4-carboxylate 45via the enolate O-acylation following oxidative C–H coupling (Scheme 16).

Scheme 15 Copper-catalyzed coupling of aromatic C–H bonds with malonates.

Scheme 16 Coupling of the benzamide derivative with 3-oxobutanoate.

Although a variety of carbon-based nucleophiles mentioned above have been developed as the coupling partners for copper-mediated C–H bond functionalization, the use of accessible alkenes as the coupling partners remained a great challenge. In 2015, Miura et al. reported the copper-mediated oxidative coupling of benzamides bearing 8-aminoquinoline with maleimides (Scheme 17).^22a Cy₂NMe was crucial for the success of this reaction. Based on the observations of the reaction in the absence of Cy₂NMe, they proposed that Cy₂NMe not only facilitated the C–H cleavage of benzamides, but also accelerated other critical elementary steps. A plausible reaction pathway was proposed as shown in Scheme 18.

Scheme 17 Copper-mediated oxidative coupling of benzamides with maleimides.

Scheme 18 Plausible mechanism.

Recently, a copper-catalyzed formal [4 + 1] cycloaddition of benzamides and isonitriles via AQ-directed C–H cleavage has also been developed by Miura and co-workers (Scheme 19).^22b The corresponding 3-iminoisoindolinones 54 were exclusively delivered in good yields. The use of diphenyl sulfide as an additive demonstrated a unique acceleration effect on the transformation. Although the exact role of Ph₂S remained to be elucidated, the authors considered that the presence of diphenyl sulfide could suppress the formation of inactive, isonitrile-overcoordinated copper species.

Scheme 19 Copper-catalyzed 8-aminoquinoline-directed [4 + 1] cycloaddition of benzamides and isonitriles.

More recently, a copper-catalyzed AQ-directed tandem oxidative alkynylation/annulation of aliphatic amides for the synthesis of pyrrolidones was demonstrated by Zhang and co-workers (Scheme 20a).²³ A wide range of alkynyl carboxylic acids were used as coupling partners. Consistent with previous reports, high selectivity of β-methyl groups over methylene groups was observed. The use of TBAI as an additive could significantly improve the efficiency, and preliminary results support that TBAI acts as a phase transfer catalyst. Interestingly, they also found that terminal alkynes could also be used in this transformation, albeit with less efficiency (Scheme 20b).

Scheme 20 Copper-catalyzed AQ-directed oxidative alkynylation/annulation of C(sp³)–H bonds with alkynyl carboxylic acids or terminal alkynes.

2.5 Cyanation

Aryl nitriles are important structural motifs, due to their ubiquitous presence in bioactive organic molecules and chemical transformations. Therefore, the synthesis of aryl nitriles has attracted much attention.²⁴ In 2006, Yu's group reported the first Cu-mediated ortho-cyanation of 2-phenylpyridine (Scheme 21a).^5a Besides the use of TMSCN as a normal “CN” source, they also found that nitromethane (CH₃NO₂) could also work as a “CN” source. However, the mechanism of the cyanation with CH₃NO₂ as the cyanide anion surrogate is still unclear. In 2009, Wang disclosed that the aryl-Cu(III) complex 27a reacted with KCN at ambient temperature to afford the corresponding cyano-functionalized tetraazacalix[1]arene[3]pyridine 57a in an almost quantitative yield (Scheme 21b).^16b

Scheme 21 Copper-mediated ortho-cyanation of C(sp²)–H bonds with TMSCN, MeNO₂ or KCN.

Several examples of copper-mediated pyridyl-directed cyanation of C(sp²)–H bonds with various cyanide anion surrogates were reported in the following years.²⁵ In 2012, Wang et al. used benzyl nitrile as a safe and operational benign cyanide anion surrogate for aerobic copper-mediated cyanation of 2-arylpyridines (Scheme 22).^25a In the study, several by-products including benzaldehyde, benzoic acid, N,N-dimethylbenzamide, cis-/trans-2,3-diphenylfumaronitrile, and the free cyanide anion were detected in the reaction mixture and these by-products were considered to be generated from the aerobic C–H oxidation step of benzyl nitrile catalyzed by copper salt. Moreover, the authors proposed that the cyanation step proceeded via a single electron transfer (SET) pathway.

Scheme 22 Copper-mediated cyanation of C(sp²)–H bonds with benzyl nitrile.

The Chang group employed a NH₄I/DMF system as the combined source of a cyano unit for copper-mediated ortho-cyanation of 2-arylpyridines (Scheme 23).^25b They proposed that ammonium iodide played a dual role: as a source of iodide for the formation of iodine and as a donor of the “N” unit of the cyano moiety. It was believed that 2-arylpyridines might undergo iodination through a radical-cation pathway leading to the iodinated intermediates 57, which underwent subsequent cyanation to furnish the desired cyanated products 56. The cyanide anion is postulated to be generated from the copper-mediated reaction of ammonia and DMF.^26a,b

Scheme 23 Copper-mediated ortho-cyanation of 2-arylpyridines with NH₄I and DMF.

The Jiao group reported a Pd-catalyzed direct cyanation of indoles and benzofurans employing DMF as both the reagent and solvent in 2011.^27a Unlike Chang and Cheng's work,²⁶ they found that both the “C” and “N” units of the cyano group are derived from DMF. Inspired by these results, Jiao and co-workers successfully achieved copper-mediated cyanation of 2-arylpyridines employing DMF as both the reagent and solvent, providing a complementary strategy to access aryl nitriles (Scheme 24a).^27b Although the mechanism is not clear yet, preliminary studies suggested that the mechanism of the present protocol was totally different from that of Chang's reactions.^25b

Scheme 24 Copper-catalyzed ortho-cyanation of 2-arylpyridines: (a) DMF as a cyanide source; (b) AIBN as a free-radical “CN” source.

In 2013, Han et al. reported a copper-mediated pyridyl-directed C(sp²)–H cyanation using azobisisobutyronitrile (AIBN) as a free-radical “CN” source (Scheme 24b).^27c The ¹⁸O-labeled experiments confirmed that acetone was mainly generated by the reaction of O₂ and AIBN. They also observed the formation of acetyl acetone cyanohydrin 60a by analysis of the reaction mixture with ESI-MS. X-ray photoelectron spectroscopic (XPS) analyses revealed the reduction of Cu(OAc)₂ to the Cu(I) species by AIBN with or without 2-phenylpyridine 5a. Based on these results, the generation of the cyano group was proposed as shown in Scheme 24b.

In 2013, Shen et al. reported a copper-catalyzed cyanation of the aromatic C–H bond using acetonitrile as a cyanide source (Scheme 25a).^27d The authors hypothesized that hexamethyldisilane may only serve as a Lewis acid to activate the C–CN bond cleavage of acetonitrile to afford the copper cyanide species, which subsequently reacted with the aromatic C–H bond to yield a new aromatic C–CN bond.

Scheme 25 Copper-catalyzed cyanation with MeCN.

In the same year, Zhu and co-workers also reported a copper-mediated C2-cyanation of indoles employing acetonitrile as the cyanide source (Scheme 25b).^27e The presence of either the pyridine or pyrimidine auxiliary in the substrates was crucial for the C2-selectivity.

3. Carbon–nitrogen bond formation

3.1 Intermolecular amination

In 2006, Yu's group and Chatani's group independently developed an aerobic copper-mediated C(sp²)–H bond amination using pyridine as the directing group (Scheme 26).⁵ Subsequently, several different protocols for the copper-mediated ortho-amination of 2-phenylpyridines have been developed.²⁸ These precedents indicated that copper-mediated direct amination of unactivated C–H bonds was feasible with the assistance of a suitable directing group. Furthermore, the reaction of well-defined Cu(III) complexes with N-nucleophiles to form C–N bonds has been well established.¹⁶

Scheme 26 Pioneering work on copper-mediated pyridyl-directed amination of C(sp²)–H bonds by Yu and Chatani.

On the basis of these precedents, the Daugulis group realized the copper-catalyzed C–H amination using the removable bidentate AQ directing group (Scheme 27a).^29a The amination of both electron-rich and electron-deficient benzamides proceeded smoothly to provide the corresponding products in moderate to high yields. Notably, the amination selectively delivered mono-functionalization products at the less sterically hindered position. Secondary amines possessing various functional groups, such as ester, ether, cyano, and NHBoc, were all compatible with this reaction, affording the amination products in excellent yields. Primary amines were also able to serve as the coupling partner, albeit in lower to moderate yields. They further presented that α,α-disubstituted benzylamines could also be aminated with the assistance of the PA auxiliary under the optimized conditions, albeit in moderate yields (Scheme 27b). Although this transformation showed good functional group tolerance and substrate scope, it still limited to the use of silver salt as a cocatalyst and NMO as a terminal oxidant. Moreover, only primary and secondary aliphatic amines were effective coupling partners. To overcome these limitations, a general method using Cu(OAc)₂ or Cu₂(OH)₂CO₃ as the catalyst and oxygen from air as the sole oxidant was recently reported by Daugulis and co-workers.^29b Notably, primary and secondary aliphatic and aromatic amines, N-heteroarenes, such as indoles, pyrazole, and carbazole, sulphonamides, as well as electron-deficient aromatic and heteroaromatic amines were tolerated under the reaction conditions (Scheme 27c).

Scheme 27 Copper-catalyzed direct amination of unactivated C(sp²)–H bonds.

In 2014, the Carretero and Chen group independently reported a copper-catalyzed PA-directed amination of aniline derivatives at room temperature (Scheme 28).³⁰ Although the amine partners were limited to cyclic secondary amines, a broad range of anilines bearing various functional groups were tolerated. The PA directing group could be removed under basic conditions. Mechanistic studies revealed that an aromatic substitution-type pathway mediated by SET might be involved in the reaction.

Scheme 28 Copper-catalyzed PA-directed amination of anilines via a SET pathway.

In 2014, a copper-mediated amidation and amination of (hetero)arenes with a broad range of sulfonamides, amides, and anilines was reported by Yu's group (Scheme 29).^31a The amide-oxazoline was used as a removable directing group in this transformation. While the stoichiometric copper in the reaction was necessary, exceptional compatibility with heterocyclic arenes and amine donors was observed in the reaction, which should be practically attractive to medicinal chemists. A related copper-catalyzed AQ-directed amination of benzamides with pyrroles, indoles, pyrazoles and carbazoles via dehydrogenative coupling has recently been reported by Punniyamurthy.^31b

Scheme 29 Copper-mediated amidation and amination of C(sp²)–H bonds.

Organic azides have been proven to be an efficient and convenient amino source in transition metal-catalyzed C–H amination reactions.³² Zhu and co-workers recently described several examples of copper-mediated formation of aromatic C–N bonds with azides (Scheme 30).³³ They disclosed that when TMSN₃ was used as a nitrogen source, the free amino group could be directly introduced into the aromatic ring, thus providing a redox-neutral access to the primary amino group (Scheme 30a).^33a Notably, a key intermediate for the synthesis of inhibitors of phosphate transport protein was prepared in 62% isolated yield with this protocol. Moreover, the copper-catalyzed amidation of C(sp²)–H bonds could be achieved, when TsN₃ was used as an amino source (Scheme 30b). Indazoles were obtained with amidine or imine as the directing group via tandem C–N/N–N bond formation. Mechanistic investigations indicated that an aryl-Cu(III) intermediate rather than a copper nitrenoid intermediate via an inner-sphere pathway was involved in the process.

Scheme 30 Copper-mediated formation of C–N bonds with organic azides as amino donors.

3.2 Intramolecular amination

Inspired by the seminal work of Buchwald on benzimidazole synthesis via copper-catalyzed intramolecular C–H amination,^34a a number of heterocycles were synthesized via a related S_EAr pathway.³⁴ These elegant studies have recently been reviewed and will not be discussed here.^34k

The first chelation-assisted amination of unactivated C(sp³)–H bonds was independently reported by Kanai and Ge in 2014. Biologically important β-lactams were successfully synthesized via the Cu-catalyzed AQ-directed intramolecular C(sp³)–H amination (Scheme 31a and b).^35a,b,36 Shortly after, the You group reported a copper-catalyzed AQ-directed intramolecular C(sp³)–H amination using oxygen as the sole external oxidant (Scheme 31c).^35c To increase the practicality of these reactions, the removal of 5-methoxy-8-aminoquinoline was demonstrated to give β-lactams with a free NH group. The reactions were proposed to proceed via reductive elimination of a Cu(III) intermediate.

Scheme 31 The synthesis of β-lactams via copper-catalyzed intramolecular C(sp³)–H amination.

Miura et al. reported a copper-catalyzed PA-directed intramolecular amination of C(sp²)–H bonds for the synthesis of carbazoles under microwave irradiation (Scheme 32a).^37a Interestingly, the PA directing group could be spontaneously detached after the formation of C–N bonds. In 2015, they successfully extended this protocol to the construction of indoline scaffolds (Scheme 32b).^37b In some cases, the use of excess Cu(OAc)₂ was superior to the combination of catalytic Cu(OAc)₂ and excess MnO₂ as the terminal oxidant.

Scheme 32 The synthesis of carbazoles and indolines via copper-catalyzed intramolecular C(sp²)–H amination.

3.3 Azidation

Organic azides are an important class of compounds and have been extensively applied in organic synthesis as building blocks or as “masked amines”.³⁸ Despite their importance, the synthesis of organic azides via copper-mediated C–H azidation has been less studied. In 2012, the Jiao group reported the first copper-catalyzed C–H azidation of anilines with TMSN₃ directed by the amino group under rather mild conditions (Scheme 33a).^39a The amino group can be converted into various groups, such as Cl, Br, I, CN, OH or H, by the Sandmeyer reaction. The azidation reaction was proposed to proceed via a SET pathway. In 2014, Hao reported an analogous ortho-azidation of anilines using azido-benziodoxolone 84 catalyzed by Cu(OAc)₂ (Scheme 33b).^39b

Scheme 33 Copper-catalyzed ortho-azidation of anilines.

In 2015, a copper-catalyzed pyridyl-directed ortho-azidation using benzotriazole sulphonyl azide as the azidating reagent in the solvent 1,2,3-trichloropropane (TCP) was reported by Narula and co-workers.^39c A SET pathway was also proposed for this azidation reaction (Scheme 34).

Scheme 34 Copper-catalyzed ortho-azidation of 2-arylpyridines.

The above mentioned azidation reactions all proceeded through a SET mechanism without involving an organometallic C–H activation step. In 2014, Wang and co-workers reported the first copper-catalyzed azidation via an organometallic C–H activation pathway through an arylcopper(III) intermediate (Scheme 35).⁴⁰ Stoichiometric reactions of the isolated arylcopper(II) species 87 and arylcopper(III) species 27 with sodium azide clearly indicated that the arylcopper(III) was an active species in this azidation protocol. Thus, an unprecedented Cu(II)–ArCu(II)–ArCu(III)–Cu(I) catalytic cycle was proposed for this reaction.

Scheme 35 Copper-catalyzed azidation of azacalix[1]arene[3]pyridines.

3.4 Nitration

In 2011, Bi and Liu reported a copper-catalyzed ortho-nitration of 2-arylpyridines with AgNO₃ using oxygen as an oxidant (Scheme 36).⁴¹ Mechanistic studies revealed that the reaction proceeded through a four-centered transition state, with simultaneous cleavage of the ortho-C–H bond and the N–O bond of the nitrate anion on the 2-arylpyridine-coordinated copper(II) intermediate.

Scheme 36 Copper-mediated ortho-nitration of 2-arylpyridines.

In 2014, the Gooßen group reported a copper-mediated ortho-nitration of (hetero)arenes with the assistance of the removable AQ directing group (Scheme 37a).^42a The reactions of both electron-rich and electron-deficient benzamides with AgNO₂ proceed smoothly in the presence of NMO as the oxidant and propylene carbonate (PC) as the solvent. In contrast to the previous pyridyl-directed nitration,⁴¹ isotope-labeling experiments and control experiments with TEMPO as the radical scavenger revealed that C–H bond activation was the rate-determining step and a radical pathway was not involved in the process. Shortly after, the Tan group reported the copper-mediated AQ-directed nitration of aryl C–H bonds using sodium nitrite as the nitration agent. Notably, good selectivity can be achieved by simply tuning the reaction conditions (Scheme 37b).^42b

Scheme 37 Copper-mediated ortho-nitration of (hetero)arene amides.

4. Carbon–oxygen bond formation

4.1 Intermolecular carbon–oxygen bond formation

In 2006, the Yu group described the first example of Cu(OAc)₂-catalyzed ortho-acetoxylation of 2-arylpyridines in HOAc/Ac₂O using O₂ as the terminal oxidant.^5a A SET mechanism for the reaction was proposed. The direct oxygenation of a structurally well-defined aryl-Cu(III) complex 27a with various carboxylates at room temperature was reported by Wang in 2009.^16b In 2009, Ohno and co-workers reported a Cu(OAc)₂-mediated ortho-functionalization of C(sp²)–H bonds using tetrahydropyrimidine as the directing group, where the ortho-hydroxylation of aromatic C–H bonds followed by cyclization with triphosgene was described (Scheme 38).⁴³ Shortly after, Cheng et al. used anhydrides^44a or acyl chlorides^44b as the coupling partners for copper-catalyzed acyloxylation of 2-arylpyridines (Scheme 39). In sharp contrast to Yu's SET mechanism, this reaction was considered to proceed through an organometallic C–H activation, followed by the reductive elimination of a key RCO₂–Cu(III)–Ar intermediate 95. More recently, our group also reported a copper-catalyzed PIP-directed acyloxylation of the C(sp²)–H bond with sterically bulky benzoic acids.^44c

Scheme 38 Copper-catalyzed ortho-hydroxylation of aromatic C–H bonds followed by cyclization with triphosgene.

Scheme 39 Copper-catalyzed aerobic acyloxylation of C(sp²)–H bonds.

In 2013, the Gooßen group reported a copper-catalyzed carboxylate-directed ortho-alkoxylation of benzoates with B(OR)₃ (Scheme 40a).⁴⁵ Interestingly, concomitant decarboxylation was observed in the process. The presence of silver carbonate was crucial for the success of this reaction, not only for the decarboxylation, but also for the alkoxylation process. Inspired by the copper-mediated pyridyl-directed phenoxylation by Yu^5a and the observation of facile C–O reductive elimination from the copper(III) center,^16b,e,f the bimetallic copper/silver system was further extended to the regiospecific dehydrogenative cross-coupling of arenes and alcohols with the assistance of pyridine, pyrimidine or pyrazole (Scheme 40b).⁴⁶ These reactions were proposed to go through Ar–Cu(III)–OR intermediates 100 and 103.

Scheme 40 (a) Copper-catalyzed carboxylate-directed alkoxylation with concomitant protodecarboxylation; (b) copper-catalyzed dehydrogenative alkoxylation with alcohols.

Although copper(II)-mediated C–H oxidation has been well investigated, the mechanisms of many of these reactions remain unclear. In an instructive study, Stahl and co-workers gave clear evidence for the involvement of a basic ligand induced, rate-limiting organometallic C–H activation step in the Cu(OAc)₂-mediated AQ-directed methoxylation reactions based on the experimental and computational studies (Scheme 41).⁴⁷

Scheme 41 Cu(OAc)₂-mediated AQ-directed methoxylation and mechanistic studies.

The Daugulis group reported the etherification of benzamides directed by 8-aminoquinoline with Cu₂(OH)₂CO₃ as the catalyst and air as the oxidant (Scheme 42a).⁴⁸ The aryloxylation could be achieved in the presence of K₂CO₃ and DMF; while C–H alkoxylation occurred when tetramethylguanidine (TMG) was used as a base and pyridine as a solvent. They found that PA is also an efficient directing group for this protocol. In 2015, a copper-catalyzed PIP-directed methoxylation of C(sp²)–H bonds with MeOH was achieved by our group (Scheme 42b).⁴⁹ The reaction employed Cu₂(OH)₂CO₃ as the catalyst, KOCN as the base and air as the oxidant. Selective mono-methoxylation of both aromatic and heteroaromatic amides has been accomplished under the optimized conditions.

Scheme 42 Copper-catalyzed directed etherification of C(sp²)–H bonds.

Recently, Song et al. reported a copper-mediated mono- and diaryloxylation of benzamides using a N,O-bidentate auxiliary OP (Scheme 42c).^50a Selective mono- or diaryloxylation could be tuned by simply switching the amounts of ingredients and solvents. Next, they employed the identical auxiliary for CuCl-mediated C–H alkoxylation of (hetero)arenes with alcohols (Scheme 42c).^50b The use of pyridine substantially improved the reaction efficiency to give a superior result. Notably, besides primary alcohols, secondary alcohols including isopropanol and HFIP could also serve as coupling partners.

In 2014, our group reported the efficient synthesis of phenol derivatives via copper-mediated PIP-directed hydroxylation of (hetero)arenes (Scheme 43a).⁵¹ The method employed Ag₂CO₃ as the oxidant and tetrabutylammonium iodide (TBAI) as the additive. Notably, the procedure could also proceed smoothly at the gram scale and was compatible with a wide range of functional groups. Further mechanistic studies showed that a basic ligand-enabled, irreversible, rate-determining concerted-metalation–deprotonation (CMD) C–H cleavage was likely involved in the process. Later on, an aerobic copper-mediated hydroxylation of C(sp²)–H bonds with the assistance of the amide-oxazoline directing group was reported by Yu and Dai (Scheme 43b).⁵² Dioxygen was used as the sole oxidant and water was found to remarkably facilitate the reaction. Significant KIEs and the results of the reaction with TEMPO as the radical scavenger indicated that a copper-mediated C–H cleavage step rather than an S_EAr or a radical pathway was involved in the process. More recently, Jana reported the hydroxylation of benzamides with copper(II) acetate monohydrate and a pyridine ligand directed by AQ (Scheme 43c).^7c

Scheme 43 Copper-mediated directed hydroxylation of C(sp²)–H bonds.

In 2014, the Kanai group and the Ge group independently reported for the first time that direct acetoxylation of methyl C(sp³)–H bonds of aliphatic amides was enabled by the AQ directing group in the presence of copper salt as the catalyst and silver salt as the oxidant (Scheme 44).⁵³

Scheme 44 Copper-mediated AQ-directed acetoxylation of methyl C(sp³)–H bonds. Conditions A: Cu(OAc)₂ (50 mol%), AgOAc (3.0 equiv.), KH₂PO₄ (1.5 equiv.). Conditions B: CuI (40 mol%), Ag₂O (4.0 equiv.), KH₂PO₄ (2.0 equiv.), HOAc.

The Zhang group achieved the copper-mediated etherification of methyl C–H bonds of aliphatic amides with organosilanes employing the same AQ directing group (Scheme 45).⁵⁴ The reaction proceeded in a tandem way of the first oxidation of β-C(sp³)–H bonds and subsequent arylation/vinylation to give the etherification products 118 or 119. Isotope-labeling experiments revealed that Cu(OAc)₂ served as the source of oxygen in the aryloxylation products. A plausible mechanism was proposed as shown in Scheme 46.

Scheme 45 Copper-mediated aryloxylation and vinyloxylation of methyl C(sp³)–H bonds with organosilanes.

Scheme 46 Proposed mechanism.

Recently, the Baran group reported a scalable, high yielding, and site-specific oxidation of the steroidal C12-position with copper and molecular oxygen by the improvement of Schönecker's oxidation protocol.^55a–d This protocol has been previously applied in the total synthesis of cyclopamine^55e and (+)-cephalostatin 1.^55f These reactions proceed through an inner-sphere way, which was mechanistically different from the topic of this review.

4.2 Intramolecular carbon–oxygen bond formation

In 2008, Nagasawa et al. reported a copper-catalyzed intramolecular oxidative C–O coupling of benzanilides for the synthesis of 2-arylbenzoxazoles.⁵⁶ In 2012, Zhu et al. reported the synthesis of dibenzofurans via Cu-catalyzed oxidative C(sp²)–H cycloetherification of o-arylphenols.⁵⁷ However, a nitro group at the para- or meta-position was necessary to the successful cycloetherification. In 2013, Martin and Gevorgyan independently reported the copper-catalyzed intramolecular esterification of C(sp²)–H bonds (Scheme 47).⁵⁸

Scheme 47 Copper-catalyzed intramolecular esterification of C(sp²)–H bonds.

5 Carbon–sulfur bond formation

Since Yu reported the first example of copper-mediated direct thioetherification of 2-phenylpyridine,^5a several methods of C–S bond formation based on the strategy of copper-mediated auxiliary-directed C–H functionalization have been developed in the following years. In 2010, the Qing group reported that widely available DMSO was able to work as a methylthiolation reagent for copper-mediated methylthiolation of 2-arylpyridines (Scheme 48).⁵⁹ The presence of excess CuF₂ was found to be essential to the successful transformation based on their consideration that the organic sulfur compound could deactivate copper salt through the binding effect.

Scheme 48 Copper-mediated methylthiolation of 2-arylpyridines with DMSO.

In 2012, the Daugulis group reported the copper-mediated AQ-directed sulfenylation of C(sp²)–H bonds (Scheme 49a).⁶⁰ Disulfide compounds acted as both an effective thiolating reagent and oxidant. DMSO was selected as the solvent based on the consideration that it was able to in situ regenerate RSSR by oxidizing the resulting RSH. Both electron-rich and electron-deficient benzamides were compatible with this protocol, providing the thiolated products in good yields. Nevertheless, the direct sulfenylation of benzylamines bearing the PA directing group could also be accomplished under almost identical conditions (Scheme 49b).

Scheme 49 Copper-mediated sulfenylation of C(sp²)–H bonds with disulfides.

Liang et al. described a copper-catalyzed AQ-directed thiolation of benzamides with aryl and aliphatic thiols using Ag₂CO₃ as the oxidant (Scheme 50).⁶¹ The protocol exhibited broad substrate generality and primary, secondary and tertiary thiols all could serve as thiolation reagents.

Scheme 50 Copper-catalyzed thiolation of C(sp²)–H bonds with aryl and aliphatic thiols.

The above mentioned methods still suffer from shortages of the use of odorous sulfur sources and the formation of undesired toxic byproducts. As such, identifying a useful and operationally convenient sulfur source to increase the practicality of this class of reactions was highly appealing. The use of elemental sulfur (S₈) as a low-cost and non-odorous sulfur source in copper-mediated sulfenylation of C(sp²)–H bonds has been recently realized by our group (Scheme 51).⁶² TBAI as the additive was found to be crucial for the success of this transformation. Moreover, the reaction was scalable, and tolerated a variety of functional groups and even several heteroarenes to afford various benzoisothiazolones in moderate to excellent yields. Additionally, the synthetic transformation of the resulting benzoisothiazolones has been performed.

Scheme 51 Copper-mediated C–S/N–S bond formation with elemental sulfur.

The copper-mediated direct sulfonylation of C(sp²)–H bonds with aryl sulfinate salts was developed independently by Tan and our group.⁶³ As described by Tan et al., the reaction required stoichiometric Cu(OAc)₂ and proceeded under air with the assistance of 8-aminoquinoline (Scheme 52).^63a In contrast, we employed our newly developed PIP group as the auxiliary, and the sulfonylation of C–H bonds could take place in the presence of a catalytic amount of Cu(OAc)₂. However, Ag₂CO₃ as the terminal oxidant was necessary in the transformation (Scheme 53).^63b Both the methods specifically furnished mono-sulfonylated products, which was quite different from previous copper-mediated auxiliary-directed C–H thiolation reactions.

Scheme 52 Copper-mediated AQ-directed sulfonylation of C(sp²)–H bonds.

Scheme 53 Copper-catalyzed PIP-directed sulfonylation of C(sp²)–H bonds.

6 Carbon–halogen bond formation

In the seminal study by Yu and co-workers, they found that the reaction of 2-arylpyridines 5 with catalytic copper acetate (20 mol%) in Cl₂CHCHCl₂ gave the corresponding chlorinated products 129 in good yields (Scheme 54). Analysis of the reaction mixture using ¹H NMR and pH measurements revealed that the Cl⁻ anion was provided by Cl₂CHCHCl₂. Bromination or iodination occurred when Br₂CHCHBr₂ or iodide was used as the halogen source, respectively. Inspired by this work, various halogen sources, such as benzoyl chloride, lithium halides and NXS, have been used by Cheng,^44b Shen,^64a,b and Han,^64c respectively. In 2011, the copper-catalyzed ortho-chlorination of 2-arylpyridines with an acyl chloride was described by Cheng's group (Scheme 54).^44b Shen et al. discovered that cheap and easy-to-handle LiX (X = Cl, Br) could serve as the halogen sources for copper-catalyzed ortho-halogenation of 2-phenylpyridines (Scheme 54).^64a,b However, toxic CrO₃ was used as the terminal oxidant. In 2014, Han developed a mild protocol for copper-mediated highly selective mono- and di-halogenation of 2-arylpyridines (Scheme 54).^64c Acyl hypohalites, generated in situ from the readily available carboxylic acid and N-halosuccinimides (NXS; X = Br, Cl), were crucial for the good selectivity.

Scheme 54 Copper-mediated halogenation of 2-arylpyridines with various halogen sources.

In 2012, Wang and co-workers reported the regioselective halogenation of azacalix[1]arene[3]pyridines at the lower rim position of the benzene ring with alkali metal halides as the halogen source. The reaction proceeded through the copper(II)-mediated aryl C–H activation, which gave structurally well-defined aryl-Cu(III) intermediates, followed by a subsequent carbon–halogen reductive elimination (Scheme 55).⁶⁵ It is worth noting that the cost-effective and operation friendly potassium fluoride is used as the fluorine source, providing an effective method to access fluoroarenes.

Scheme 55 Copper-mediated halogenation of azacalix[1]arene[3]pyridines.

In 2013, the Daugulis group reported the copper-catalyzed fluorination of C(sp²)–H bonds directed by AQ and PA directing groups (Scheme 56).⁶⁶ The reaction employed CuI as the catalyst and AgF as the nucleophilic fluoride source. Selective mono- or difluorination of benzamide substrates could be achieved by tuning the reaction temperature and the amounts of CuI catalyst, oxidant, and AgF.

Scheme 56 Copper-catalyzed fluorination of C(sp²)–H bonds.

An easily removable N-(2-pyridyl)sulfonyl auxiliary for the selective halogenation of C(sp²)–H bonds of anilines under copper catalysis was developed by Carretero's group (Scheme 57).⁶⁷ortho-Mono-halogenation of anilines could be achieved with the CuX₂–NXS (X = Cl, Br) system. The one-step removal of the 2-pyridylsulfonyl auxiliary under mild reductive conditions afforded the free primary amine in high yield.

Scheme 57 Copper-catalyzed halogenation of protected anilines with NXS.

In 2015, the ortho-halogenation of benzamides with NXS (X = Cl, Br, I) under copper catalysis was developed by our group using the removable PIP group (Scheme 58).⁶⁸ A wide range of functional groups could be tolerated. The PIP auxiliary could be easily removed to give ortho-halogenated benzoic acids.

Scheme 58 Copper-catalyzed PIP-directed halogenation of C(sp²)–H bonds with NXS.

7 Carbon–phosphorus bond formation

The ability of 8-aminoquinoline to enable phosphorylation of benzamides under copper catalysis was demonstrated by Yu and co-workers in 2014 (Scheme 59).⁶⁹ They showed that both aromatic and heteroaromatic benzamides were suitable substrates for phosphorylation with H-phosphonates. It is noteworthy that the protocol exclusively delivered the mono-phosphorylated products.

Scheme 59 Copper-catalyzed AQ-directed phosphorylation of C(sp²)–H bonds.

8 Conclusions

In this review, we have summarized recent advances in copper-mediated chelation-assisted functionalization of unactivated C–H bonds. Several N-based monodentate groups and amide-based bidentate groups⁷⁰ have been developed to serve as effective directing groups for copper-mediated functionalization of C–H bonds and could remarkably facilitate a variety of transformations, including the formation of carbon–carbon, carbon–nitrogen, carbon–oxygen, carbon–sulfur, carbon–halogen, and carbon–phosphorus. From a synthetic point of view, these reactions provide novel and efficient tools for constructing various synthetically useful compounds. However, the detailed mechanism of copper-mediated auxiliary-directed functionalization of C–H bonds remains to be elucidated, and the functionalization of C(sp³)–H bonds remains underdeveloped. As such, more efforts will continue to be devoted to the development of this area.

Acknowledgements

Financial support from the National Basic Research Program of China (2015CB856600), the NSFC (21572201, 21422206, and 21272206) and the Fundamental Research Funds for the Central Universities (2015XZZX004-03) is gratefully acknowledged.

Notes and references

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Footnote

† Current address: College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang 464000, China.

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