CâH Coupling Reactions between Two (Hetero)arenes

Review pubs.acs.org/CR

Oxidative C−H/C−H Coupling Reactions between Two (Hetero)arenes Yudong Yang, Jingbo Lan, and Jingsong You* Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China ABSTRACT: Transition metal-mediated C−H bond activation and functionalization represent one of the most straightforward and powerful tools in modern organic synthetic chemistry. Bi(hetero)aryls are privileged π-conjugated structural cores in biologically active molecules, organic functional materials, ligands, and organic synthetic intermediates. The oxidative C−H/C− H coupling reactions between two (hetero)arenes through 2-fold C−H activation offer a valuable opportunity for rapid assembly of diverse bi(hetero)aryls and further exploitation of their applications in pharmaceutical and material sciences. This review provides a comprehensive overview of the fundamentals and applications of transition metal-mediated/catalyzed oxidative C−H/ C−H coupling reactions between two (hetero)arenes. The substrate scope, limitation, reaction mechanism, regioselectivity, and chemoselectivity, as well as related control strategies of these reactions are discussed. Additionally, the applications of these established methods in the synthesis of natural products and exploitation of new organic functional materials are exemplified. In the last section, a short introduction on oxidant- or Lewis acid-mediated oxidative Ar−H/Ar−H coupling reactions is presented, considering that it is a very powerful method for the construction of biaryl units and polycylic arenes.

CONTENTS 1. Introduction 2. Oxidative Homocoupling of (Hetero)Arenes 2.1. Homocoupling Reaction without Directing Group 2.1.1. Homocoupling of Arenes 2.1.2. Homocoupling of Heteroarenes 2.2. Homocoupling Reaction with Directing Group 2.3. Polymerization 3. Intermolecular Oxidative Cross-Coupling between Two Arenes 3.1. Arene−Arene Cross-Coupling Reaction without Directing Group 3.2. Arene−Arene Cross-Coupling Reaction with Directing Group 3.2.1. Directed Arene−Arene Cross-Coupling Catalyzed by Palladium 3.2.2. Directed Arene−Arene Cross-Coupling Catalyzed by Rhodium 4. Intermolecular Oxidative Cross-Coupling between an Arene and a Heteroarene 4.1. Non-Directed Arene-Heteroarene Cross-Coupling 4.2. Directed Arene-Heteroarene Cross-Coupling 5. Intermolecular Oxidative Coupling between Two Heteroarenes 5.1. Heteroarene-Heteroarene Coupling without Directing Group 5.1.1. Oxidative Coupling between ElectronRich and Electron-Deficient Heteroarenes

5.1.2. Oxidative Coupling between Two Electron-Deficient Heteroarenes 5.1.3. Oxidative Coupling between Two Electron-Rich Heteroarenes 5.2. Heteroarene-Heteroarene Coupling with Directing Group 6. Intramolecular Oxidative Coupling 7. Oxidative Aromatic Coupling Other than C−H Activation 8. Conclusions Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

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1. INTRODUCTION Bi(hetero)aryl structural features are widely found in pharmaceuticals, agrochemicals, natural products, organic functional materials, ligands, and organic synthetic intermediates.1−8 The bi(hetero)aryl carbon−carbon bond-forming reactions through the merging of two (hetero)aromatic units thus constitute one of the most important subjects in organic chemistry and have attracted great attention.9−12 One of the classic methods to construct bi(hetero)aryl C−C bonds is transition metal-

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Received: August 19, 2016 Published: January 13, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.chemrev.6b00567 Chem. Rev. 2017, 117, 8787−8863

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fragments but instead requires the employment of an oxidant. Thus, this type of reaction is called oxidative C−H/C−H coupling.27,29 Despite many advantages, the development of this concept encounters significant challenges as well. First, the aromatic C− H bonds are generally thought as the inert bond, which possesses a much higher bond dissociation energy than C−X and C−M bonds. Thus, C−H activation processes often require harsh conditions. In addition, because the aromatic compounds typically contain multiple C−H bonds, it is highly challenging to achieve the regioselective C−H activation. In the past decade, many efforts have been focused on the direct oxidative coupling between two aromatic C−H bonds. Several general modes for metal-mediated C−H activation processes, such as electrophilic aromatic substitution (SEAr) process,30,31 concerted-metalation-deprotonation (CMD) process,32−34 and σ-bond metathesis process,35,36 have been proposed in the C−H/C−H oxidative coupling reactions between two (hetero)arenes (Scheme 2). The site-selectivity issues have been partly resolved through the following four strategies: (1) introduction of a directing group (“chelationdirected control”). The incorporated auxiliary group typically contains a Lewis basic heteroatom which could coordinate to the catalyst and bring the metal center close proximate to a specific C−H bond (usually ortho position) to form a five- or sixmembered metallocycle. (2) Utilization of the electronic nature of substrates. For example, when the C−H activation process undergoes a SEAr pathway, the metalation often takes place at the most nucleophilic position, whereas a CMD process favors the most acidic C−H bond. (3) Utilization of the steric effect of substrates. Some C−H bonds could be more accessible to the catalyst due to the steric hindrance. (4) Selection of the catalytic system (“catalytic system-based control”). Regulating and even switching the regioselectivity could be achieved through judicious selection of the catalytic system. The fast development of oxidative C−H/C−H coupling reactions not only enables the biaryl synthesis in a more concise and economical fashion but also refines both the concept and technology in synthetic chemistry. The oxidative C−H/C−H coupling reactions provide a simple and efficient technique to rapidly assemble a diverse set of π-conjugated poly(hetero)aromatic structures. Furthermore, this type of reactions also exhibits the great potential in the synthesis of natural products and the exploration of organic functional materials. Although several reviews related to direct C−H arylation were published in the past few years,18,21,26,27,29,37−40 the topic on oxidative C−H/ C−H coupling reaction between two (hetero)arenes through dual C−H activation has not been summarized systematically and solely. In the current article, we will review the works in this area from early 1960s to June 2016. The topics are arranged based on the patterns of coupling partners, arenes, or heteroarenes. Because some examples require the aid of a directing group, each section will be divided dependent on whether or not a directing group is involved. The subsection is further categorized by transition metal-catalysts. In addition, the applications of oxidative coupling reactions in the exploration of novel organic functional materials and the synthesis of natural products will be briefly discussed in related works as well. Although no C−H activation process is involved in the oxidantor Lewis acid-mediated oxidative Ar−H/Ar−H coupling reactions, a brief introduction on this transformation is still documented in the last section, considering its wide application in the construction of biaryls and polycylic arenes.41−46

Scheme 1. Transition Metal-Catalyzed Coupling Reactions to Access Bi(hetero)aryls

Scheme 2. General Modes for Metal-Mediated C−H Activation Processes

catalyzed cross-coupling reactions between a (hetero)aryl halide and an organometallic reagent, such as Suzuki coupling, Stille coupling, Hiyama coupling, and Negishi coupling reactions (C− X/C−M type) (Scheme 1a).13−16 Although these reactions represent one of the most reliable methods to access (hetero)aryl-(hetero)aryl moieties, it is important to be mindful of the fact that these methods still suffer from some limitations, including (1) prefunctionalization is required for both of the coupling partners and tedious synthetic steps could be needed to access these preactivated substrates and (2) some (hetero)aryl organometallic reagents, halides, and pesudohalides are labile or difficult to synthesize. For example, 2-pyridineboronic acids are typically unstable, thus impeding their use in Suzuki crosscouplings. From the viewpoints of high efficiency and stepeconomy, the replacement of C−X and C−M bonds with C−H bonds as a valid functional group is highly appealing, which provides an opportunity to overcome these limitations to some extent.17−24 In particular, the coupling reaction between two aromatic C−H bonds represents one of the most straightforward and effective methods to forge bi(hetero)aryl structures (C−H/ C−H type) because only a “H2” is released in form (Scheme 1b).25−29 Different from the traditional transition metalcatalyzed cross-coupling reactions, which typically involve a nucleophilic reagent (organometallics) and an electrophilic reagent (organohalide), the coupling between two C−H bonds comprises two nucleophilic hydrocarbons as the coupling 8788


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2. OXIDATIVE HOMOCOUPLING OF (HETERO)ARENES

Scheme 9. Aerobic Oxidative Coupling of Benzene to Biphenyl by a Highly Active Pd-Based Catalyst System

2.1. Homocoupling Reaction without Directing Group

2.1.1. Homocoupling of Arenes. Typically, more than two C−H bonds exist in an aromatic ring, and their bond dissociation Scheme 3. Pd-Mediated Oxidative Homocoupling of Aromatic Compounds Scheme 10. Tandem Palladium-Catalyzed Reductive and Oxidative Coupling of Benzene and Chlorobenzene

Scheme 4. Olefin-Palladium Chloride-Promoted Oxidative Homocoupling of Benzene Derivatives

Scheme 5. PdCl2-Catalyzed Aerobic Oxidation of Arenes to Biaryls in Combination with Zr(IV), Co(II), and Mn(II) Acetates

Scheme 11. Pd(II)-Catalyzed Selective Coupling of p-Xylene in TFA

Scheme 6. Proposed Mechanism of Pd(II)-Catalyzed Aerobic Oxidation of Benzene to Biphenyl

Scheme 7. Selective Synthesis of Biphenyl by the Pd(OAc)2/ MoO2(acac)2/O2/AcOH Catalyst System

energies are highly similar. Therefore, a mixture of biaryl coupling isomers is often obtained if a monosubstituted arene is used as the coupling partner. In addition, because of the low reactivity of aromatic C−H bond, solvent amounts of arene substrates are often requisite in the oxidative homocoupling reactions. Carboxylic acids such as acetic acid and trifluoroacetic acid (TFA) are commonly used as the solvent. Palladiumcatalyzed homocoupling of benzene to synthesize biphenyl is the earliest investigated oxidative C−H/C−H coupling reaction. Up to date, most of the oxidative homocoupling of aromatic

Scheme 8. Oxidation of Benzene to Biphenyl Using a Pd(OAc)2/Molybdovanadophosphoric Acid/O2 System

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Scheme 12. Palldium-Catalyzed Aerobic Oxidative Coupling of o-Xylene Using 2-Fluoropyridine as a Ligand

Scheme 13. Pd(II)-Catalyzed Homocoupling of ElectronDeficient Aromatics

Scheme 16. Pd-Catalyzed Homocoupling of Bromothiophene Derivatives with AgNO3/KF

metric amounts of PdCl2 to synthesize biaryl compounds (Scheme 3).47 CH3 COOH was chosen as the solvent. CH3COONa proved to be essential for this reaction, and no reaction was detected in its absence. Oxygen was found to be beneficial for this reaction, presumably owing to its oxidative ability of Pd(0) to Pd(II). The attempts with monosubstituted benzenes resulted in a mixture of isomeric biphenyls. Later on, Davidson investigated the reaction of Pd(OAc)2 with benzene and toluene in HClO4/CH3COOH. An initial electrophilic aromatic substitution mechanism was suggested.48 The addition of Hg(II)49 or Tl(III)50 as the additive could increase the yields of oxidative couplings of monosubstituted benzenes and improve the selectivity of 4,4′-isomers. In 1970, Fujiwara and co-workers further improved the yields of oxidative homocoupling of benzene derivatives by employment of an olefin-palladium chloride complex/AgNO3 system (Scheme 4).51 A quantitative yield of biphenyl was obtained when the ethylene-palladium complex was used. Neither PdCl2 nor AgNO3 could promote the reaction alone. In the competition experiments, the electron-rich arenes exhibited higher reactivity than the electron-poor ones. Typically, O2 is employed as the oxidant in the Pd(II)catalyzed aerobic biphenyl synthesis. Yoshimoto, Itatani and Iataaki investigated in detail the oxygen partial pressure, effect of ligand, catalyst concentration, isomer distribution, and kinetic isotope effect in the palladium-catalyzed oxidative coupling of aromatic compounds.52−54 To increase the concentration of dioxygen in the reaction medium and accelerate the Pd(II) regeneration process, Sasson and co-workers employed a combination of Zr(OAc)4, Co(OAc)2, and Mn(OAc)2 as dioxygen fixators (Scheme 5).55 In the presence of O2, Mn(II) is first oxidized to Mn(III), which then oxidizes Co(II) to Co(III). Next, binding of Co(III) to dioxygen gives a μperoxocobalt(III) species. The subsequent reaction of Pd(0) with Co(III)−O−O−Co(III) delivers a palladium(II)-peroxo complex, which then reacts with two benzene molecules to give the biphenyl (Scheme 6). The protocol delivered biphenyls in good yield, accompanied by the formation of phenyl acetates as

Scheme 14. Pd-Catalyzed Dimerization of Pyrroles for the Synthesis of 2,2′-Bipyrroles

Scheme 15. Pd-Catalyzed Homocoupling of Heteroarenes

compounds are still accomplished by palladium salts. In 1965, van Helden and Verberg disclosed the first oxidative C−H/C−H coupling of aromatic compounds in the presence of stoichio8790


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Scheme 17. Pd-Catalyzed C−H Homocoupling of Bromothiophenes for the Synthesis of Oligothiophenes

various cocatalysts, including Zr(acac)4, Pr(OAc)3·2H2O, LiOAc·2H2O, Mg(OAc)2·4H2O, Al(acac)3, Be(acac)2, and MoO2(acac)2 (Scheme 7).56 MoO2(acac)2 gave the best selectivity for the biphenyl synthesis up to 88%. However, the yield of biphenyl was rather low. Heteropoly acid (HPA) can be used as a cocatalyst in the palladium-catalyzed oxidative coupling of arenes. In 2002, Ishii and co-workers reported the Pd(OAc)2/HPA-catalyzed aerobic oxidative coupling of benzene (Scheme 8).57 The combination of Pd(OAc)2 and a 1:1 mixture of HPMo11V1 and HPMo12 was the most efficient, giving biphenyl in a 14.3% yield. The formation of phenol was significantly suppressed in this reaction. At almost the same time, Kozhevnikov studied the selectivity between oxidative coupling and hydroxylation using oxygen in the palladium/H5[PMo10V2O40]-catalyzed biphenyl synthesis.58 By simply tuning the amount of water in arene and AcOH/H2O biphasic system, the selectivity for biphenyls reached 74−80% with 16−20% conversion. Water was believed to have at least the following two effects in this transformation: (1) accelerating the deprotonation of the in situ formed Wheland intermediate in the AcOH/H2O medium and (2) increasing the biphenyl/terphenyl ratio. More recently, Zhou and Wang developed an efficient oxidative homocoupling of benzene to synthesize biphenyl by using O2 as the sole oxidant (Scheme 9).59 Only a small amount

Scheme 18. Regioselective Palladium-Catalyzed Oxidative Homocoupling of Indolizines

byproducts. Meanwhile, Yamaji investigated the product distribution of aerobic arene dimerization in the presence of 8791


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Scheme 19. Arylation of Indolizines and Intramolecular Oxidative Coupling Reactions for the Synthesis of Cyclophanes

Scheme 20. Pd(TFA)2-Catalyzed Regioselective Oxidative Homocoupling of Indoles for the Synthesis of 2,3′-Biindoles

Scheme 22. Pd(TFA)2-Catalyzed Regioselective Oxidative Homocoupling of Indoles for the Synsthesis of 3,3′-Biindoles Using AgNO3 as the Oxidant

Scheme 21. Synthesis of C3-Acetoxylated Biindoles Using AgOAc as the Oxidant

stabilize the in situ formed palladium clusters and retard Pd(0) aggregation. Benzylic C−H bond can also be activated in the oxidative coupling of alkyl-substituted benzenes, giving diarylmethanes as the byproducts.61,62 In 2007, Lu and co-workers disclosed a selective synthesis of biaryl and diarylmethane (Scheme 11).63 Pd(OAc)2/TFA/K2S2O8 was employed as the catalytic system. The concentration of TFA exhibited a vital influence on the selectivity of aryl and benzylic C−H activation, which could be attributed to the electrophilicity of the Pd(II) complex. At a low concentration of TFA, the initially generated σ-arylpalladium complex prefers to attack another aryl C−H bond to afford a diaryl Pd(II) intermediate. In contrast, at a high concentration of TFA, the reactivity of initially formed σ-arylpalladium complex is greatly enhanced and thus prefers to attack the sterically lesshindered benzylic C−H bond. The involvement of Pd(IV) species was excluded in this reaction because the stoichiometric coupling could take place in the presence of a Pd(II) complex without any oxidant and base. Palladium-catalyzed oxidative homocouping of o-xylene was reported by Stahl and co-workers (Scheme 12).64 In this work, 2fluoropyridine was proved to be a crucial ligand to enable high

of Pd(OAc)2 (0.07 mol %) was required as the catalyst. TfOH (5.57 mol %) was added to enhance the electrophilicity of the Pd(II) species and promote the regeneration of Pd(II) from Pd(0). The addition of the ligand such as pyridine, 3aminopyridine, 3-cyanopyridine, nicotinic acid, and 2,2′bipyridine significantly inhibited this reaction. It was assumed that the coordination of the Pd(II) center to the nitrogen atom could diminish the electrophilicity of the Pd(II) center. In the oxidative coupling reactions, the regeneration of reactive catalyst typically requires the participation of oxidant and releases wastes. To minimize byproducts and/or wastes released in the catalyst regeneration process, Sasson and co-workers developed a tandem palladium-catalyzed oxidative and reductive coupling of benzene with chlorobenzene, in which the Pd(II) species was regenerated in the Pd(0)-mediated reductive coupling of C6H5Cl (Scheme 10).60 Biphenyl and 4-chlorobiphenyl were obtained in one-pot. Tetrahexylammonium chloride (THAC) was added to 8792


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Scheme 23. Synthesis of a Phenolic Antioxidant 2 Found in Beetroot (Beta Vulgaris)

Scheme 24. Synthesis of 3,3′-Bipyridines

Scheme 26. Cu-Catalyzed Oxidative (Hetero)arene Dimerization Using O2 as the Terminal Oxidant

Scheme 25. Plausible Mechanism for Pd(OAc)2-Catalyzed Regioselective Oxidative Homocoupling of Pyridines to Deliver 3,3′-Bipyridines

Scheme 27. Aerobic Cu(OAc)2-Catalyzed Oxidative Homocoupling of Azoles to Form Bisazoles

electrophilic aromatic substitution. In 2012, Lu and co-workers disclosed the oxidative C−H/C−H coupling between electronpoor aromatic compounds (Scheme 13).65 These reactions were believed to proceed via a SEAr process. Either O2 or K2S2O8 was employed as the optimal oxidant, depending on the substrates tested. The concentrations of arenes and the amounts of TFA should be precisely tuned to improve the reaction efficiency and selectivity. Interestingly, ethyl benzoate exhibited a strong orthodirecting effect and predominately gave the o- rather than marylated products, which should be the major products in a typical electrophilic aromatic substitution. 2.1.2. Homocoupling of Heteroarenes. In addition to arenes, the homocoupling reactions of heteroarenes have also been reported. Compared with arenes, heteroarenes generally have specific reactive sites, and thus the regioselectivity in the oxidative homocoupling of heteroarenes is relatively easy to be

chemo- and regioselectivity. Pyridine derivatives more or less basic than 2-fluoropyridine were less effective in comparison with 2-fluoropyridine. It should be noted that the product of this reaction is highly useful for the synthesis of 4,4′-biphtahlic anhydride, a monomer to prepare the high-performance polyimide resin. Typically, electron-deficient arenes such as nitrobenzene, benzoates, and trifluoromethylbenzene are difficult to undergo 8793


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Scheme 28. Aerobic Cu(II)/Ag(I)-Catalyzed Oxidative Dimerization of Azoles

Scheme 31. Palladium/Heteropolyacid-Catalyzed Oxidative Coupling of Methyl Benzoate

Scheme 32. Pd(OAc)2-Catalyzed Oxidative Coupling Reactions of 2-Arylpyridines at Room Temperature with Oxone as a Terminal Oxidant

Scheme 29. Aerobic Cu-Catalyzed Regioselective Oxidative Homocoupling Reaction of Imidazo[1,2-a]pyridines

controlled. In 1976, Kozhevnikov reported the palladiumcatalyzed homocoupling of furans and thiophenes.66 2,2′Isomers were formed as the major products. The investigation on the effect of substituents indicated that the reactivity of 2substituted furans in the palladium-catalyzed oxidative homocoupling decreased in the following order of substituents: H, CH3, CHO > COOCH3, COOC2H5 > CH(OOCCH3)2 > Scheme 30. Pd(II)-Catalyzed Selective Dimerization of Dimethyl Phthalate to Afford Biphenyltetracarboxylates

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Scheme 33. Proposed Mechanism for Pd(OAc)2-Catalyzed Oxidative Coupling Reactions of 2-Arylpyridines

Scheme 36. Ru-Catalyzed Homocoupling of 2-Arylpyridines

Scheme 34. Ru-Catalyzed Nitrogen-Directed ortho-Selective Homocoupling of Aromatic Compounds in the Presence of Methallyl Acetate as a Hydrogen Scavenger

Scheme 37. Oxidative Homocouplings of ortho-Alkylated Arenes in Combination with ortho-Substituted Aryl Halides as the Sacrificial Oxidant Scheme 35. Proposed Mechanism for Ru-Catalyzed Oxidative Homocoupling of Aromatics

Scheme 38. Rh(I)-Catalyzed Regioselective Dimerization of Aromatic Acids

COOH.67 This order is consistent with the substituent influence in the electrophilic substitution of heteroaromatic compounds. 8795


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Scheme 39. Cu-Mediated Homocoupling of Thiophenecarboxamides

heating the pyrroles in AcOH at 110 °C for 10 h, 2,2′-bipyrroles were obtained in moderate yields. Although a palladium-catalyzed oxidative homocoupling of thiophene with Fe(III) as the oxidant was disclosed by Kozhevnikov as early as in 1977,69 a synthetically useful palladium-catalyzed oxidative homocoupling of thiophenes was not demonstrated until 2004 by Mori and co-workers (Scheme 15).70 In this work, PdCl2(PhCN)2 (3 mol %) was used as the catalyst. AgF served as both the promoter and oxidant in this reaction. Neither palladium nor Ag(I) could promote this reaction alone. DMSO was employed as the solvent. A set of reactive functional groups including CHO, COOEt, COMe, and Br were tolerant under the standard conditions. Benzothiophene and 2-(4-methoxylphenyl)thiazole were also effective substrates. Notably, this reaction could take place even at room temperature. Later, the homocoupling yields of bromothiophenes were improved by a combination of AgNO3 and KF (Scheme 16).71 Considering the wide applications of oligothiophenes in organic functional materials,72−75 several oligothiophenes were synthesized based on this type of homocoupling reactions (Scheme 17). These compounds exhibited the λmax values of UV−vis absorption, ranging from 355−437 nm and the λmax values of emission ranging from 469−542 nm. The regioselective palladium-catalyzed homocoupling of indolizines was also demonstrated by You and co-workers (Scheme 18).76 Treatment of indolizines in the presence of Pd(OAc)2 (5 mol %), Cu(OAc)2 (1.5 equiv), and K2CO3 (2.0 equiv) in DMF afforded the corresponding biindolizines in goodto-excellent yields. Moreover, the arylation of methyl indolizine1-carboxylate with benzene could be achieved using AgOAc as the oxidant, albeit in a low yield with the formation of homocoupled product (Scheme 19, eq 1). To further demonstrate the utility of the methodology, the intramolecular oxidative couplings were carried out under the standard conditions for the synthesis of bridged macrobiindolizines 1, an important type of cyclophanes (Scheme 19, eq 2). This

Scheme 40. Cu-Mediated Homocoupling of Indoles

Scheme 41. Pd-Catalyzed Oxidative Polymerization of Thiophenes

Later on, Itahara disclosed the 2,2′-dimerization of pyrroles in the presence of Pd(OAc)2 in AcOH (Scheme 14).68 Typically, N-aroylation was necessary for the pyrrole substrates. After 8796


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Scheme 42. Synthesis of 5-Alkyl[3,4-c]thienopyrrole-4,6-dione-Based Conjugated Polymers through Pd-Catalyzed Oxidative C− H/C−H Coupling

Scheme 43. Synthesis of Polythiazole-Based Derivatives through Pd-Catalyzed Oxidative C−H/C−H Coupling

protocol represented rare examples for the synthesis of

Biindoles are useful structural skeletons that are often encountered in pharmaceuticals and functional materials. Zhang and co-workers developed a regioselective oxidative homocoupling of indoles to afford 2,3′-biindoles at room

macrocyclic compounds through transition metal-catalyzed C− H functionalization. 8797


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reported a palladium-catalyzed dimerization of pyridines (Scheme 24).84 1,10-Phenanthroline (phen) was employed as the ligand. Unsubstituted pyridine was used as a crucial additive to increase the turnover number (TON). Typically, 3,3′bipyridines were obtained as the major products with the formation of small amounts of 2,3′-bipyridines. Moreover, a significant effect of the acidity of C−H bond on the regioselectivity was observed. For example, 4,4′-bipyridine could be obtained when 2,5-difluoropyrine was used as a substrate, likely owing to the enhanced acidity of the C4 proton caused by C3 fluoro atom. A plausible mechanism involving a CMD process was proposed (Scheme 25). With the assistance of 1,10-phenanthroline, the N-coordinated pyridine 3 dissociates from Pd(OAc)2 and form a π-coordinated palladium intermediate 4, thus facilitating the activation of pyridine C3−H. Subsequently, a similar C−H activation process takes place to give the bipyridine-Pd(II) complex 5, which undergoes reductive elimination to give the desired product. Besides palladium, common and less expensive copper has also been successfully applied to promote the oxidative homocoupling of aromatic compounds. In these reactions, air or O2 is typically employed as the terminal oxidant, thus establishing a more economical and environmentally friendly approach toward bi(hetero)aryls.85−88 In 2009, Daugulis reported an aromatic Glaser-Hay reaction to synthesize bi(hetero)aryls (Scheme 26).85 CuCl2 (1−3 mol %) was used as the catalyst and O2 as the terminal oxidant. Diverse heteroarenes and electron-poor arenes provided the corresponding bi(hetero)aryls in moderate to excellent yields. Notably, this reaction was base-dependent, and thus each reaction substrate required the exact composition of the base. Meanwhile, Qian and Bao reported an aerobic Cu(OAc)2catalyzed oxidative homocoupling of azoles (Scheme 27).86 A set of azoles such as imidazoles, benzimidazoles, thiazoles, oxadiazoles, and benoxazoles were converted to the corresponding biaryls under the standard conditions. Cu(OAc)2 in this reaction could be recovered and recycled. At almost the same time, Mori and co-workers disclosed a Cu(OAc)2/Ag2CO3catalyzed oxidative homocoupling of azoles using O2 as the terminal oxidant (Scheme 28).87 More recently, Cao and co-workers reported the regioselective oxidative homocoupling of imidazo[1,2-a]pyridines (Scheme 29). CuI and O2 proved to be the best catalyst/oxidant combination.88 Other copper salts such as CuCl, CuBr, and

Scheme 44. Synthesis of Regioregular Polybenzodiimidazoles through Cu-Catalyzed Oxidative C−H/C−H Coupling Polymerization

temperature (Scheme 20).77 Pd(TFA)2 and Cu(OAc)2·H2O were used as the catalyst and oxidant, respectively. DMSO was the optimal solvent. Electron-rich and moderately electron-poor indoles coupled with each other in good-to-excellent yields. Interestingly, C3-acetoxylated biindoles were selectively formed when AgOAc was used as the oxidant (Scheme 21). Dioxygen was proved to be crucial for the acetoxylation process. Soon after, Shi and co-workers described the oxidative dimerization of indoles to afford 3,3′-biindoles (Scheme 22).78 In this work, Pd(TFA)2/AgNO3 was chosen as the best catalyst/ oxidant combination. AgNO3 played a crucial role to tune the reaction pathway. However, the exact role of the silver salt was not clear. In addition, MgSO4 was added to regulate the reactivity when NH-free indoles were attempted. It is worth noting that a phenolic antioxidant 2, found in beetroot (Beta vulgaris),79 was readily accessed with this protocol (Scheme 23). Compared with indoles, pyridine generally showed less reactivity in the oxidative homocoupling reaction owing to its relatively low electron density.80−83 Recently, Yu and co-workers

Scheme 45. Rapid Access to 2,2′-Bithiazole-Based Copolymers via Pd-Catalyzed Oxidative C−H/C−H Coupling Reactions of Bis(4-nonylthiazol-5-yl)arenes

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In the investigation of ruthenium-catalyzed oxidative crosscoupling of 2-phenylpyridine with cycloalkanes,94 Li and coworkers found that the dimer of 2-phenylpyridne was formed as the byproduct. After various ruthenium catalysts including RuCl3, Ru3(CO)12, Ru(acac)3, RuCl2(PPh3)3, [Ru(benzene)Cl2]2, and [Ru(p-cymene)Cl2]2 were evaluated, [Ru(p-cymene)Cl2]2 was found to exhibit the highest efficiency (Scheme 36).95 FeCl3 proved to be the most suitable oxidant, and air was thought to act as an extra oxidant in this reaction. The electronic effect of the phenyl substituents did not have a significant impact on the yield, whereas the position of substituents on both the rings greatly influenced this reaction. Typically, the less steric hindered C−H bond was more favorable when two potential reaction sites were available. Using ortho-substituted aryl halides as the sacrificial oxidant, Ackermann and co-workers disclosed a ruthenium-catalyzed N-heteroarene-directed oxidative homocoupling of ortho-alkylated arenes (Scheme 37).96 More recently, Li and co-workers reported the rhodium(I)catalyzed regioselective dimerization of aromatic acids in water (Scheme 38).97 MnO2 was used as the oxidant. This reaction features environmental friendliness, air and water compatibility, and simple operation. Not only homocoupling but also crosscoupling of aromatic acids could proceed smoothly under the standard conditions. In addition, this reaction could be easily performed at the gram-scale level with only 0.4−0.6 mol % rhodium catalyst. A carboxylate directed-dual cyclometalation mechanism was proposed. The directing groups have also been introduced into the heteroarenes to achieve the functionalization of a less reactive position and/or enhance the regioselectivity. In 2014, Hirano and Miura reported a copper-mediated directed homocoupling of thiophenes (Scheme 39).98 The position of substituents showed a significant effect on the yield and regioselectivity. 2Thiophenecarboxamides bearing a substituent at C5 gave lower yields. When 5-aryl-3-thiophenecarboxamides were attempted, the reaction regioselectively occurred at the C2 position. Unfortunately, this reaction failed to extend to other arenecarboxamides such as benzene, furan, and pyrrole. The mechanism investigation indicated that the rate-limiting step could be involved in the disproportionation of Cu(II) species or the second C−H cleavage. In addition, 2,2-biindoles were also obtained regioselectively in the presence of Cu(OAc)2 and AcOH (Scheme 40).

CuCN exhibited less reactivity. The possibility of a radical process was excluded because no significant influence on the yield was observed in the presence of either TEMPO or galvinoxyl. 2.2. Homocoupling Reaction with Directing Group

To increase the regioselectivity of oxidative coupling and enhance the reactivity of aromatic compounds, a directing group is often introduced to favor the activation of a specific C− H bond of substrate (typically ortho position of the directing group). Ester is one of the earliest noted functional groups in the directed coupling reaction between two arenes. In 1986, Shiotani reported the Pd(II)-catalyzed dimerization of dimethyl phthalate (DMP) to afford biphenyltetracarboxylates (Scheme 30).89 In this work, ester was believed to coordinate to the Pd(II) center to direct the C−H metalation process. The steric hindrance of ligand was crucial for the product selectivity. In the presence of 1,10-phenanthroline (phen), 3,4,3′,4′-tetramethyl biphenyltetracarboxylate was formed predominately (Scheme 30a). In contrast, the addition of 2,4-pentanedione (acacH) gave 2,3,3′,4′-tetramethyl biphenyltetracarboxylate as the major product instead (Scheme 30b). Lee and co-workers found a similar ortho-directing effect of carboxylate as well (Scheme 31).90 In the presence of Pd(OAc)2 and vanadium-containing heteropoly acid as an oxidant, 2,2′-biphenic acid dimethyl ester was formed selectively from methyl benzoate. However, rather low conversions were obtained even in the presence of a promoter (15.3% for Hg(OAc)2 and 12.9% for PPh3). Subsequently, Iretskii and co-workers systematically investigated the influence factors in the oxidative coupling of methyl benzoate.91 Electronic properties of the palladium catalyst were found to be crucial in determination of the reactivity and regioselectivity. N-Containing heterocycles can be used as the directing groups in the oxidative C−H/C−H coupling. In 2006, Sanford reported a highly regioselective palladium-catalyzed oxidative homocoupling of 2-arylpyridines at room temperature using oxone as a terminal oxidant (Scheme 32).92 The possibility of Pd(II)/Pd(0) mechanism was precluded in this reaction because the oxidants reported for Pd(II)/Pd(0)-catalyzed oxidative coupling did not deliver the desired product. Further investigation of the mechanism indicated that this reaction underwent two sequential C−H activation processes occurring at Pd(II) and Pd(IV) complexes, respectively (Scheme 33). Notably, this is the first example of Pd(IV)-mediated C−H activation, which opens a door for Pd(II)/Pd(IV)-catalyzed oxidative cross-coupling between two different C−H substrates. Using five-membered N-containing heterocycles such oxazoline as the directing groups, Oi and Inoue demonstrated the ruthenium-catalyzed oxidative homocoupling of aromatic compounds (Scheme 34).93 Methally acetate served as a hydrogen scavenger in this reaction. A substituent at the ortho position of the phenyl ring was typically required. Otherwise, no desired homocoupling product could be observed due to the formation of oligomers through extended coupling at both ortho positions. In the proposed mechanism, the initial directed C−H metalation gives a ruthenacycle complex 6, which then undergoes an oxidative addition with methally acetate to deliver an η1- or η3-allylruthenium(IV) species 7 or 8. The sequential ortho-ruthenation with another molecule of aryl-2-oxazoline and reductive elimination provide the homocoupled product (Scheme 35).

2.3. Polymerization

π-Conjugated polymers widely exist in organic optoelectronic devices, such as organic light-emitting diodes (OLEDs), organic photovoltaics (OPVs), organic field-effect transistors (OFETs), and optical sensors.99−101 Preparation of π-conjugated polymers through transition metal-catalyzed oxidative C−H/C−H coupling polymerization can obviate the end-capping procedures, which are typically performed to eliminate the potential detrimental terminal halides or metal-containing functionalities in the conventional synthetic methods. Currently, the reported examples in this regard mainly focus on the reactions of thiophenes and azoles and typically involve palladium catalysts in conjunction with Cu(OAc)2 or Ag2CO3 as the oxidant. In 2013, Tsuchiya disclosed a palladium-catalyzed oxidative polymerization of thiophenes through double C−H activations.102 Cu(OAc)2 (10 mol %) and O2 were employed as the oxidant combination (Scheme 41, eq 1). The acidity of the additives exhibited a significant influence on the yields and molecular weights of polymers. Only dimer and oligomer were 8799


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Scheme 46. Catalytic Cycle of Cross-Coupling Reaction Illustrating an Inversion of the Reactivity-Selectivity in the Two Metalation Steps (Based on the Palladium Catalysis)

Scheme 47. Pd(II)-Catalyzed Oxidative Arene−Arene Cross-Coupling by Adjusting Concentrations of Arene and TFA

synthesis of polythiazole-based π-conjugated polymers (Scheme 43).105 In 2014, Lan and You demonstrated the Cu-catalyzed oxidative C−H/C−H polymerization of benzodiimidazoles (Scheme 44).106 The resulting polybenzodiimidazoles exhibited high molecular weights, regioregularity, and good thermal stability. The UV−vis spectra of these polymers in CHCl3 gave the absorption maxima ranging from 405 to 428 nm. The similar blue-emitting performances with high quantum yields were observed for these polymers. More recently, Wu and You reported a PdCl2/CuClcocatalyzed oxidative C−H/C−H homopolymerization to prepare 2,2′-bithiazole-based copolymers (Scheme 45).107 A mixture of 1,4-dioxane and DMSO (10:1) was employed as the optimal solvent. The lengths of alkyl chains on the thiazoles

detected in the presence of AcOH. Strong acids facilitated the polymerization and TFA proved to be the most effective, giving poly(3-hexylthiphene) with the highest weight-average molecular weight of 7000. Recently, an ester-directed oxidative polymerization of thiophenes was demonstrated by Thompson (Scheme 41, eq 2).103 The resulted polymers exhibit high molecular weight, good electronic properties, and limited defects. A bench-stable phosphine ligand PCy3-HBF4 could increase the yield and regioregularity. Lu, Li, and Chen described a palladium-catalyzed oxidative C− H/C−H homopolymerization to synthesize a set of 5-alkyl[3,4c]thienopyrrole-4,6-dione-based polymers (Scheme 42).104 These three polymers exhibited a broad UV−vis absorption in the range of 400−700 nm with maximum absorptions at 461, 557, and 543 nm in CHCl3, respectively. Later on, they further developed a palladium-catalyzed oxidative polymerization for the 8800


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exhibited a positive correlation with the molecular weights of polymers.

Scheme 50. Pd-Catalyzed Cross-Coupling of Polyfluoroarenes with Simple Arenes

3. INTERMOLECULAR OXIDATIVE CROSS-COUPLING BETWEEN TWO ARENES 3.1. Arene−Arene Cross-Coupling Reaction without Directing Group

Compared with the oxidative homocoupling reaction, the oxidative cross-coupling between two arenes encounters more Scheme 48. Pd(OAc)2-Catalyzed Oxidative Cross-Coupling of Polyfluoroarenes with Simple Arenes

ature demonstrated by Lu and co-workers in 2006 (Scheme 47).108 A combination of Pd(OAc)2/TFA/K2S2O8 was employed as the catalytic system. The chemoselective oxidative coupling of arenes was achieved by tuning the concentrations of arenes and TFA. A high concentration ratio of relatively electronpoor arene to electron-rich arene was found to favor the crosscoupling over homocoupling. It is believed that the relatively electron-poor Ar with high concentration is preferred to undergo palladation to give a ArPd(II)L species, which subsequently tends to attack the more reactive electron-rich Ar′H to deliver the desired cross-coupled product. Although this cross-coupling reaction is not practical, it provides some valuable information on potential catalytic systems in the oxidative C−H/C−H crosscoupling of simple arenes. More representative examples are the oxidative C−H/C−H cross-coupling between polyfluoroarenes and benzene, in which the two coupling substrates own highly distinct electronic characteristics. In 2010, Su and co-workers developed a Pd(OAc)2-catalyzed oxidative cross-coupling of polyfluoroarenes with simple arenes (Scheme 48).113 In this reaction, Cu(OAc)2 exhibited higher efficiency than other commonly used oxidants such as Ag(I) salts, benzoquinone (BQ), and O2. Carboxylic acids were beneficial to this transformation. PivOH, which often serves as a proton shuttle to promote the C−H bond

challenges. Theoretically, at least three coupled products could be formed, including one cross-coupled product and two homocoupled products. Thus, in addition to the regioselectivity, another vital issue in the cross-coupling reaction between two arenes is to control the chemoselectivity of cross-coupling over homocoupling. To meet this demand, the catalyst has to achieve an inversion of reactivity/selectivity in the two metalation steps of the catalytic cycle, giving the cross-coupled product rather than the homocoupled products (Scheme 46).108−114 Thus, the two substrates with differential π-electronic characteristics are often used as the coupling partners. An early example in this area is the palladium-catalyzed intermolecular cross-coupling of simple arenes at room temperScheme 49. Investigation of Kinetic Isotope Effect

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Scheme 51. Plausible Mechanism for Oxidative Cross-Coupling of Pentafluorobenzene with Arenes

Scheme 52. Pd(OAc)2-Catalyzed Cross-Coupling of Polyfluoroarenes with Simple Arenes in Imidazolium Ionic Liquids

Scheme 53. Arylation of Polyfluoroarenes with Arenes Using Dioxygen as the Sole Oxidant

concerted metalation-deprotonation (CMD) pathway was proposed. Almost meanwhile, Shi and co-workers independently disclosed the cross-coupling of polyfluoroarenes with simple arenes using Ag2CO3 as the oxidant (Scheme 50).114 Diisopropyl sulfide was used as an efficient additive to activate the palladium catalyst and prevent the formation of palladium black. Carboxylic acid was added to suppress the undesired homocoupling reactions and facilitate the deprotonation process. Typically, relatively weak acids such AcOH and PivOH gave better yields than strong acid such as TFA. Mono-, di-, and even triarylation of polyfluoroarenes were observed if multiple reaction sites were available. Mechanism studies revealed that the C−H cleavage of simple arenes was involved in the rate-determining step. H/D exchange experiment indicated that bases such as Ag2CO3 could enable the deprotonation of polyfluorobenzenes alone without the participation of Pd(OAc)2 . On the basis of these

cleavage,115,116 proved to be an optimal additive. Diverse unsymmetrical biaryls were obtained in moderate to high yields. A significant influence of steric factors of substituents on the reactivity and regioselectivity was observed. The reaction of 1,2or 1,3-disubstituted benzenes selectively proceeded at the less hindered C−H position. This observation was consistent with the findings by Sanford117 and Buchwald.118 A kinetic isotope effect (KIE) of 1.3 was found in the intermolecular competition reaction between 2,3,5,6-tetrafluoroanisole and deuterated 2,3,5,6-tetrafluoroanisole, excluding the possibility of C−H cleavage of polyfluorobenzene in the rate-limiting step (Scheme 49, eq 1). However, the primary KIE values of 6.5 and 4.8 were observed for benzene and dichlorobenzene, respectively, indicating that the C−H cleavage of simple arenes might be involved in the rate-determining step (Scheme 49, eq 2). A 8802


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observations, a tentative mechanism was proposed (Scheme 51). Initially, the deprotonation of polyfluorobenzene by Ag2CO3 affords a polyfluorobenzene anion, which subsequently undergoes the palladation to deliver an arylpalladium species 9. Then the carboxylate-assisted palladation of a simple arene affords a biarylpalladium complex, followed by reductive elimination to deliver the desired unsymmetrical polyfluorobiphenyl. Finally, reoxidation of the released Pd(0) to Pd(II) by Ag(I) species completes the catalytic cycle. The synthesis of polyfluorobiphenyls in imidazolium ionic liquids has also been achieved by Laali (Scheme 52).119 In the presence of Pd(OAc)2 (10 mol %) and AcOH (1 mol %), polyfluorobenzenes smoothly coupled with simple arenes in either (bmim)BF4 or (bmim)PF6 at 60−70 °C. Halobenezens, nitrobenzene, cyanobenzne, and ethylbenzene did not work under the standard conditions. It is notable that no additional oxidant and additive were required in this method. In addition, the ionic liquids could be easily recycled and reused. Recently, an aerobic cross-coupling of polyfluorobenzenes with simple arenes using O2 as the sole oxidant was reported by Huang (Scheme 53).120 In the presence of Pd(OAc)2 (10 mol %), PivOH (1.5 equiv), and DL-pGlu-OH (10 mol %), a variety of polyfluorobenzenes and simple arenes could be converted to the desired polyfluorobiaryls in moderate-to-high yields with moderate regioselectivities. Similar to previous reports,114 the diarylation of polyfluorobenzenes such as 1,2,4,5-tetrafluorobenzene was observed as well. It is worth noting that the olefination of polyfluoroarenes with alkenes could also be achieved under the standard conditions.

Scheme 54. Palladium-Catalyzed Cross-Coupling of Benzo[h]quinoline with Arenes

Scheme 55. Proposed Mechanism of BenzoquinonePromoted Palladium-Catalyzed Oxidative Cross-Coupling Reactions

3.2. Arene−Arene Cross-Coupling Reaction with Directing Group

In most cases, the reactions commented in this section are proposed to proceed by the initial chelation-assisted C−H activation to afford a cyclometalated intermediate, which then implements the second C−H activation of another arene molecule without a directing group. Subsequent C−C reductive elimination delivers the cross-coupled product. The regioselectiviy in the first C−H activation process is undoubtedly controlled by the incorporated directing group, and the selectivity issue in the second C−H activation is often circumvented by using either a sterically demanding substrate or a unique catalytic system such as Pd(OAc)2/K2S2O8/TFA. 3.2.1. Directed Arene−Arene Cross-Coupling Catalyzed by Palladium. An early example of the palladiumcatalyzed directed arene−arene cross-coupling is the arylation of benzo[h]quinolines (bzqs) with simple arenes reported by Sanford and co-workers (Scheme 54).117 Solvent amounts of simple arenes were required and benzoquinone (BQ) was used as an essential ligand. Neither homocoupling of bzq nor benzene was observed under the standard conditions. Scheme 56. Stoichiometric Reaction of a Palladacycle Species with Simple Arene

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Scheme 57. Effect of the Benzoquinone Structure on Regioselectivity

Scheme 58. Controlling Site-Selectivity in Pd-Catalyzed Oxidative Cross-Coupling of 1,3-Disubstituted Arene with Cyclometalating Substrate

Scheme 59. Pd-Catalyzed Cross-Coupling of N-Acetanilides with Arenes

Scheme 60. Preparation of 4-Deoxycarbazomycin B through Sequential C−H Activation

Later studies suggest that BQ could promote the reductive elimination of the resulting ArPdAr′ intermediate.121 In a proposed mechanism, initial nitrogen-directed C−H activation of benzo[h]quinoline and subsequent C−H activation of a simple arene coupling partner gives a ArPdAr′ complex. Then coordination of BQ to palldium center and following reductive elimination releases the biaryl product (Scheme 55). Because

electron-rich arenes showed slightly higher reactivity than electron-poor arenes in the reaction with palladium dimer 10, a CMD mechanism for the second C−H activation was excluded (Scheme 56). In addition, the modest electronic effect was inconsistent with an electrophilic aromatic substitution mechanism. Thus, the author suggested a σ-bond metathesis mechanism could be involved. The rate-determining step was found to be dependent on the concentration of quinone promoter (Scheme 57).121,122 Quinone complexation is the rate-determining step at a low concentration of BQ, whereas C−H activation of arene determines the reaction rate at a high concentration of BQ. 8804


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Scheme 63. Pd-Catalyzed Oxidative Ortho-Arylation of OPhenylcarbamates with Arenes

Scheme 61. Pd-Catalyzed Oxidative C−H/C−H Arylation of Anilides with Aryls

Scheme 62. Open-Flask Pd-Catalyzed C−H/C−H CrossCoupling of Indolines with Arenes

Scheme 64. Phenylation of Dimeric Pd Complex 11

Scheme 65. Palladium-Catalyzed ortho-Arylation of Phenylacetamides, Benzamides, and Anilides with Arenes Using Na2S2O8 as an Oxidant

Thus, the regioselectivity of the reaction could be controlled by tuning the electronic character or steric effect of quinone. At a low [BQ] concentration, quinone substitution had a significant effect on the regioselectivity. Alkyl substitution and congested structure enhance the selectivity at the most sterically accessible position. At a high [BQ] concentration, quinone substitution gave an attenuated influence on the regioselectivity because quinone complexation is not the rate-determining step. The steric and electronic nature of carboxylate ligand also affected the selectivity of products. Typically, the sterically large carboxylate ligand increased the selectivity at the least hindered site. In addition, switching the carboxylate to carbonate could reverse the regioselectivity and allow the reaction to predominately take place at the more sterically hindered position (Scheme 58).

Another early example in the directed oxidative cross-coupling between two arenes is the arylation of 1,2,3,4-N-acetyltetrahydriqunolines and acetanilides disclosed by Shi and co-workers (Scheme 59).123 Although this reaction exhibited a relatively wide substrate scope, N-alkylated and free anilines were not effective substrates for this transformation. The steric effect was pronounced in the determination of the regioselectivity of this reaction. The sterically hindered arenes such as o-xylene delivered only a single product of which the least hindered position was arylated. For monosubstituted arenes, a mixture of 8805


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Scheme 66. Reactions of Dimeric Palladium Complexes 12 and 13 with Benzene in the Presence of Na2S2O8 and TFA

Scheme 68. Pd-Catalyzed Para-Selective Oxidative CrossCoupling of Monosubstituted Arenes with Tertiary Benzamides Using K2S2O8 as an Oxidant

m- and p-isomers was delivered. The authors proposed the selectivity of this reaction was most likely controlled by the acetamino directing group in the first C−H activation and by steric effects in the second C−H activation. It is noted that 4deoxycarbazomycin B, a degradation product of carbazomycin B,124 was easily synthesized using this method (Scheme 60). Later on, Buchwald described an efficient synthesis of biaryls via palladium-catalyzed C−H/C−H cross-coupling of pivalanilides with arenes under an oxygen atmosphere (Scheme 61).118 One of the important features of this reaction is the use of molecular oxygen at atmospheric pressure as the sole oxidant, which obviates the requirement of Cu or Ag salts as the cooxidant. Moreover, the amounts of simple arenes were also decreased to only 4−11 equiv. The electronic effect of substituent on the anilide moiety had a strong influence on the yields. Typically, the anilides containing neutral or electrondonating substituents afforded the desired products in good yields. A similar rule was found on the simple arene partners as well. However, it should be mentioned that the steric hindrance seemed to play a more important role than the electronic effect of the substituent on arenes in determination of the regioselectivity, since 1,3-dimethoxybenzene gave no 1,2,3-regioisomer arising

from the coupling of the most electronic-rich carbon. Additionally, the incorporation of the substituent on the anilide was crucial for the mono/bis-selectivity. Unsubstituted pivalanilide gave a mixture of mono/bis-arylated products. Finally, electrondeficient arenes such as 1,3-difluorobenzene and pentafluorobenzne gave notably low conversions, suggesting that a CMD mechanism could not be involved. Besides the oxidative cross-coupling of 1,2,3,4-N-acetyltetrahydriqunolines with simple arenes, the palladium-catalyzed selective C7-arylation of indolines at relatively low temperature was also demonstrated by Oestreich (Scheme 62).125 In the initial reaction condition investigation, a catalytic system comprised of Pd(OAc)2/TFA/Na2S2O8 was noted. However, this reaction system only worked with o-xylene in the simple arenes tested. An extended substrate scope and promising yields were obtained by employment of either Cu(OAc)2/air or O2 as the oxidant instead of Na2S2O8. This reaction was very sensitive to the oxidant and acidic additive. Oxidants such as Ag2CO3 and

Scheme 67. Pd-Catalyzed Para-Selective Oxidative Cross-Coupling of Monosubstituted Arenes with Benzamides Using NFSI as an Oxidant

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were all suitable substrates (Scheme 63).126 Na2S2O8 was used as a unique oxidant in this reaction. A broad scope of o- or msubstituted O-phenylcarbamates irrespective of the electronic nature of their substituents were regioselectively monoarylated to give the desired products in moderate-to-excellent yields. However, the substrates bearing a strong electron-withdrawing functional group such as CF3 exhibited poor reaction efficiencies. Furthermore, O-phenylcarbamates with the electron-neutral or -donating substituent at the para position afforded the 2,6diarylphenol derivatives as the major product. To study the reaction mechanism, a TFA-bridged dimeric palladium complex 11 was synthesized and isolated. This Pd complex smoothly reacted with benzene in the absence of an oxidant or external additive, thus indicating that the second C−H activation might occur via a Pd(II) intermediate (Scheme 64). In addition, a SEAr process for the second C−H activation was proposed based on the competition experiments between electron-rich and electron-neutral arenes. In a following study, the ortho-arylation of phenylacetamides, benzamides, and anilides with simple arenes was achieved using sodium persulfate as the oxidant by the same group (Scheme 65).127 TFA was an indispensable additive in this reaction. Electron-neural and -rich arenes, including benzene, o-xylene, and veratrole, reacted smoothly under the standard conditions. However, in contrast to the arylation of O-phenylcarbamate, electron-deficient arenes were ineffective. N-Isopropyl-2-phenylacetamide and N-cyclohexyl-2-phenylacetamide bearing two reactive ortho C−H bonds delivered the diarylated products via quadruple C−H bond activation. Intramolecular oxidative arylation of benzanilides also occurred under a similar condition to deliver a six-membered lactam product in modest-to-good yields. To probe the reaction mechanism, two dimeric palladium anilide complexes 12 and 13 were prepared by treatment of N(m-tolyl)pivalamide and 1-phenylpyrrolidin-2-one with Pd(OAc)2 in the presence of TFA, respectively. Both Pd complexes could react with benzene to give the corresponding orthoarylated products with addition of Na2S2O8 and TFA (Scheme 66). It is worth noting that no arylation was detected in the absence of Na2S2O8, suggesting that Pd(II) could form either a bimetallic Pd(III) or Pd(IV) complex through the oxidation due to the high redox potential of Na2S2O8 (2.01 eV). This result is

Scheme 69. Mechanochemical C−H/C−H Arylation with Various Arenes

BQ gave only trace amounts of products and even no conversion was detected when PivOH was used instead of TFA. Notably, although alkylated and alkoxylated substrates afforded the crosscoupled products in moderat-to-good yields, the compatibility of other more reactive functional groups was not elucidated extensively. As depicted in Buchwald’s work, electron-deficient arenes represent a challenging class of substrates for oxidative crosscoupling.118 Dong and co-workers demonstrated the palladiumcatalyzed ortho-arylation of O-phenylcarbamates with simple arenes, in which electron-deficient, -neutral, and -rich arenes

Scheme 70. Pd-Catalyzed Oxidative Cross-Coupling of Aldoxime Ethers with Arenes for the Synthesis of Fluorenones

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Scheme 71. Proposed Mechanism for Pd-Catalyzed Cross-Coupling of Aldoxime Ethers with Arenes

Scheme 72. Pd-Catalyzed Oxidative Cyclization of NMethoxybenzamides with Arenes for the Synthesis of Phenanthridinones

Scheme 73. Pd-Catalyzed Ortho-Arylation of Anilides at Room Temperature

Scheme 74. Pd-Catalyzed Ortho-Arylation of Benzaldimines

distinct from a previous report on the bimetallic Pd complex derived from an O-phenylcarbamate, which could involve a Pd(II) intermediate in the second C−H bond activation.126 On the basis of these observations, the author suggested that the reaction mechanism of oxidative cross-coupling varies greatly depending on the directing group and oxidant. Soon later, three dimeric TFA-bridged palladium(II) complexes of N-phenylbenzamides were synthesized and isolated.128 These palladacycles were found to be effective precatalysts for oxidative crosscoupling reactions. As mentioned above, the C−H activation often prefers to take place at the less hindered position on the aromatic ring of 1,2disubstituted arenes. However, the regioselective C−H functionalization of monosubstituted arenes without a directing group is rather troublesome. A breakthrough work in this regard is the palladium-catalyzed para-selective C−H arylation of

monosubstituted arenes demonstrated by Yu and co-workers (Scheme 67).129 Good-to-high yields with excellent pararegioselectivity could be obtained provided that an acidic amide derived from 4-trifluoromethyl-2,3,5,6-tetrafluoroaniline 8808


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Scheme 75. Pd(II)-Catalyzed Direct C−H Alkenylation and Arylation of Arenes Using Removable 2-Pyridylsulfinyl Group as a Directing Group

Scheme 77. Rh(III)-Catalyzed Oxidative C−H/C−H CrossCoupling of Benzamides with Haloarenes

Scheme 76. Removal and Transformation of 2-Pyridylsulfiny Directing Group

Scheme 78. Oxidative Cross-Coupling of 2,2-Dimethyl-1phenylpropan-1-one with Bromobenzenes

was used as the directing group and N-fluorobenzenesulfonimide (NFSI) was employed as the oxidant. The reaction displayed a wide scope of both the benzamides and the monosubstituted arenes, which encompass substituents of different electronic nature. It is believed that the [ArPd(IV)F] species is partially responsible for the para-selectivity. Although F+ reagents were found to be crucial for high paraselectivity in Yu’s work, a para-selective arylation of monosubstituted arenes with tertiary benzamides using K2S2O8, a nonfluoro oxidant, was achieved by Guan (Scheme 68).130 PdCl2/AgOTf/NaOTf/K2S2O8 proved to be the optimal catalyst system. The introduction of DMA and the OTf anion led to a better selectivity. In the absence of either AgOTf or NaOTf, both the catalytic efficiency and selectivity decreased. One reason might be that PdCl2 and extra triflate could in situ form a more electrophilic catalyst species Pd(OTf)2. This reaction also exhibited a good substrate scope. However, both the steric hindrance and electronic nature of the substituents seemed to significantly influence the selectivity and yield. For example, treatment of 3-methylbenzamide with toluene exclusively resulted in the para-selective isomer, while 3,4-dimethylbenza-

mide gave a mixture of isomeric products in lower yields. Moreover, the electron-rich anisole gave rise to a moderate yield of 45%, while the electron-deficient benzotrifluoride afforded a much lower yield of 20%. An electrophilic palladation process was supposed to be involved in the C−H activation of simple arenes because the electron-rich arenes reacted faster than the electron-deficient arenes. A KIE of 3.0 was observed for benzamide, implying the C−H cleavage of benzamide might be involved in the rate-determining step. In addition, a Pd(II)/ Pd(IV) process was proposed and the para-selectivity could to be ascribed to Pd(IV) intermediate. To reduce the molar ratio of benzene substrate used and shorten the reaction time, Xu and co-workers introduced a ball milling technique to promote the C−H/C−H arylation (Scheme 69).131 The mechanochemical condition exhibited broad substrate scopes of both coupling partners. Under the optimized conditions, monosubstituted arenes bearing an electrondonating functional group or a halide gave the desired products in moderate-to-good yields with an excellent para-selectivity, while the arenes with an electron-withdrawing group exhibited a 8809


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Scheme 79. Proposed Catalytic Cycle

Cheng developed a palladium-catalyzed ortho-directed multiple C−H bond functionalization of aromatic aldoxime ethers with arenes for the synthesis of fluorenones,132 a kind of biologically active compounds and structural scaffolds in organic optoelectronic materials (Scheme 70). The reaction was proposed to proceed by sequential chelation-assisted Pd(II)/ Pd(IV)-catalyzed intermolecular arylation of aryl aldoxime ether and Pd(II)-catalyzed intramolecular arylation of in situ formed ortho-arylated aryl aldoxime intermediate (Scheme 71). This tandem process exhibited broad substrate scopes on both coupling partners. However, a lower yield was obtained when the electron-poor fluorobenzene was subjected. Notably, the transformation was highly site-selective even in the case of monosubstituted arenes such as toluene and anisole. In addition, the same group also described a one-pot synthesis of phenanthridinones by palladium-catalyzed oxidative cyclization of N-methoxybenzamides with arenes (Scheme 72).133 These reactions occurred with a broad substrate scope, high yield, and excellent regioselectivity in the presence of Pd(OAc)2/K2S2O8/ TFA, thus providing an opportunity to rapidly assemble a set of phenanthridinone derivatives with diverse substituents. It should be mentioned that this transformation could proceed at room temperature, whereas high temperature is often required in oxidative cross-coupling of two arenes. Another example of room-temperature palladium-catalyzed oxidative C−H/C−H cross-coupling of two arenes is the arylation of anilides described by Song and You (Scheme 73).134 Pd(OAc)2/(NH4)2S2O8/TFA was still employed as the catalytic system. Both electron-rich and electron-deficient arenes were effective for this transformation, but the arenes bearing electron-withdrawing groups such as 1,2-dichlorobenzene furnished the desired products in low yields.

Scheme 80. Directed Cross-Coupling of Arenes with (Hetero)arenes Using a Rhodium(III)/Hexabromobenzene Catalyst System

high meta-selectivity. For disubstituted arenes, the arylation typically took place at the more electronic-favored and less sterically hindered C−H bonds. Both oximes and electron-rich anilides were effective substrates. Notably, only 3.0 to 6.0 equiv of simple arene were required in this transformation. This work represented a highly efficient and selective example for the construction of biaryl skeletons through oxidative C−H/C−H coupling of arenes. 8810


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Scheme 81. Rh-Catalyzed Oxidative Cross-Coupling of Benzyl Thioethers with Carboxylic Acids Controlled by Two Different Directing Groups for the Synthesis of Dibenzo[c,e]oxepin-5(7H)-ones

Scheme 82. Proposed Mechanism

of nBuLi or converted into sulfide and disulfide by using zinc dust and sodium amalgam, respectively (Scheme 76). 3.2.2. Directed Arene−Arene Cross-Coupling Catalyzed by Rhodium. The high reactivity, broad substrate scope, and good functional group compatibility of Rh(III) catalysis render cationic Rh(III) catalysts an attractive alternative in the directed oxidative cross-coupling between two aromatic compounds. However, an apparent weakness of the current

In addition, Gaunt demonstrated the room temperature C−H arylation of benzaldimines by using a bulky aniline component to stabilize the imine group toward hydrolytic cleavage (Scheme 74).135 Zhang reported the Pd(II)-catalyzed direct C−H alkenylation and arylation of arenes by using 2-pyridylsulfiny moiety as the directing group (Scheme 75).136 The 2pyridylsulfinyl group could readily be removed in the presence 8811


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Scheme 83. Pd-Catalyzed Oxidative Cross-Coupling of Indoles with Arenes

While the regioselectivity in one coupling partner could be controlled by the introduction of a directing group, the regioselectivity in another coupling partner is typically realized by the selection of electron-rich, electron-deficient, or bulky substrates. To ensure the regioselectivity of both coupling partners, Shi and co-workers developed a double directing group strategy for the synthesis of dibenzo[c,e]oxepin-5(7H)-ones (Scheme 81).139 Under the optimal conditions comprising [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (40 mol %), AgNO3 (4.0 equiv), and toluene (0.1 M), various benzyl thioethers reacted with aromatic carboxylic acids to provide the corresponding dibenzo[c,e]oxepin-5(7H)-ones in moderate to good yields. Both carboxylic acid and thioether were used as the directing groups in this reaction. The substituents on the S atom of thioethers played a vital role in the reaction efficiency, and the alkyl groups gave better yields than the aromatic groups. The KIE of 2.0 for carboxylic acid and 4.9 for thioether indicated that both the arene C−H activations could be involved in the ratedetermining step. In a plausible mechanism, the initial thioetherdirected C−H rhodation affords a rhodacycle 17, which then undergoes sequential carboxylic acid coordination, ligand exchange, and a second C−H activation to form a Ar− Rh(III)−Ar′ species 18. Following reductive elimination gives the biaryl intermediate 19 and Rh(I). Then rhodium- or silvermediated intramolecular cyclization delivers the final product (Scheme 82). Notably, a mechanism involving the sequential carboxylic acid C−H activation and thioether C−H activation is also possible.

rhodium catalytic system is that it exhibits lower control capacity for regioseletivity than palladium catalysis in the arylation with monosubstituted arenes. The first example of Rh(III)-catalyzed oxidative C−H/C−H cross-coupling of aromatic compounds was disclosed by Glorius in 2012 (Scheme 77).137 In the presence of [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (2.2 equiv), PivOH (1.1 equiv), and CsOPiv (20 mol %), benzamides smoothly reacted with solvent amounts of haloarenes to give the desired products in good-to-high yields. Halides, including bromides, chlorides, and iodides, were all compatible with the rhodium catalytic system. Fluorobenzene, toluene, and benzene gave either no or only trace amounts of the cross-coupled products. Monohaloarenes gave a mixture of m/p products, whereas 3-substituted bromobenzenes furnished a single isomer. Another limitation on the substrate scope is that only m- and p-substituted benzamides appeared to be effective. It is notable that 2,2-dimethyl-1-phenylpropan-1-one was even an effective substrate, giving the corresponding arylated products in moderate yields (Scheme 78). In a tentative mechanism, the initial carbonyl directed C−H rhodation gives a five-membered rhodacycle 14, which then coordinates to bromobenzene in a η2 manner. The following σbond metathesis or CMD process affords a neutral rhodium complex 15. Subsequently, reductive elimination gives the biaryl product (Scheme 79, path a). Alternatively, a pathway involving a rhodium(V) hydride complex 16 is also possible (Scheme 79, path b). Later on, the same group extended this transformation to other simple aromatic compounds such as benzene and anisole by using C6Br6 as both an oxidant and a catalyst modifier (Scheme 80).138 Although highly excessive amounts of simple aromatic coupling partners were still required, the dosage was decreased significantly (typically 20.0 equiv). Heteroaromatic compounds such as thiophenes and furans were also applicable in this transformation.

4. INTERMOLECULAR OXIDATIVE CROSS-COUPLING BETWEEN AN ARENE AND A HETEROARENE 4.1. Non-Directed Arene-Heteroarene Cross-Coupling

In 2007, a breakthrough work in the palladium-catalyzed oxidative cross-coupling of indoles and simple arenes was 8812


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A similar oxidant-controlled phenomenon in the arylation of indoles was reported by DeBoef and co-workers as well (Scheme 87).112 The authors supposed the distinct selectivity was attributed to the formation of different polymetallic clusters in the presence of either Cu(OAc)2 or AgOAc. In contrast to previous reports,109−111 electron-rich arenes such as p-xylene and anisole failed to undergo this transformation under the standard conditions. Besides oxidants, ligands could influence the regioselectivity of oxidative cross-coupling as well. In 2011, Stahl and co-workers reported aerobic oxidative coupling of indoles and benzenes using 4,5-diazafluorene derivatives as ancillary ligands (Scheme 88).140 In the presence of Pd(TFA)2 and 9,9-dimethyl-4,5diazafluorene, C3-arylated indoles were obtained as the major product. In contrast, a catalyst system comprised of Pd(OPiv)2 and 4,5-diazafluoren-9-one predominately gave C2-functionalized products. Moreover, the N-pivalyl indole exhibited higher regioselectivity under the conditions for C2-functionalization while the N-benzenesulfonyl indole showed superior selectivity under the reaction conditions for C3-functionalization. The palladium-catalyzed regioselective oxidative arylation of furan-2-carbonyls with simple arenes was demonstrated by Seayad and co-workers.141 In the presence of Pd(OAc)2 (20 mol %), N,N-dimethyldinaphtho[2,1-d:1′,2′-f ][1,3,2]-dioxaphosphepin-4-amine (MonoPhos, 20 mol %), and N-fluoropyridin1-ium triflate (NFPT, 3.0 equiv), 5-arylated furans were furnished with minor amounts of 4-arylated furans (Scheme 89). Both the electronic characteristics and steric effect of arenes influenced the reaction efficiency and regioselectivity. Typically, electron-rich arenes delivered high yields and excellent regioselectivities, whereas electron-poor arenes afforded moderate yields and regioselectivities. No reaction was detected for the highly electron-deficient pentafluorobenzene. Furthermore, both the steric bulk and the counteranions of F+ oxidants exhibited the influence on the regioselectivity. It is notable that monosubstituted arenes gave rise to poor selectivity while the C−H arylation of monosubstiuted arenes with benzamides gave highly para-selectivity using F+ reagent demonstrated by Yu.129 In addition to the oxidative cross-coupling between simple arenes and electron-rich heteroarenes such as indoles, pyrroles, and furans, the arylation of electron-poor five-membered heteroarenes has also been accomplished by using a Pd(II) catalyst associated with Ag or Cu as the oxidant and PivOH as a pivotal additive. It is noteworthy that O2 is engaged as a cooxidant in most cases. Liu and Zhan reported the oxidative coupling of imidazo[1,2-a]pyridine with simple arenes for the synthesis of arylated imidazo[1,2-a]pyridine derivatives, a kind of structural unit frequently found in pharmaceuticals and biologically active molecules such as alpidem, zolimidine, and zolpidem (Scheme 90).142 A combination of Ag2CO3 and O2 was used as the optimal oxidants. PivOH proved to be an effective additive. The arylation regioselectively occurred at the C3

Scheme 84. Pd-Catalyzed Aerobic Oxidative Coupling for Synthesizing Heterocoupled Biaryls

reported by Fagnou and co-workers (Scheme 83).109 An electrophilic aromatic palladation process and a concerted palladation-deprotonation process were judiciously associated within a single catalytic cycle to achieve the chemoselectivity of cross-coupling over homocoupling. In the presence of Cu(OAc)2 as the oxidant, CsOPiv, PivOH, and 3-nitropyridine, the arylation predominately occurred at the C3 position of indoles to give 3-aryl indoles. No homocoupling products were detected by crude 1H NMR and GC/MS analysis. At almost the same time, DeBoef and co-workers reported the palladium-catalyzed C−H/C−H oxidative coupling of benzofurans and indoles with arenes (Scheme 84).110 The combination of H4PMo11VO40 and O2 was chosen as the optimal oxidant. However, Cu(OAc)2 was found to be a better choice in the case of N-acetylindole and N-methylindole. The NH-free indole gave a complex mixture of products. In addition, the electron-deficient arenes such as nitrobenzene and p-difluorobenzene did not work under the standard conditions. Fagnou and co-workers further elucidated their findings in the C3/C2 regiocontrol in the palladium-catalyzed oxidative crosscoupling of indoles (Scheme 85).111 The employment of Cu(OAc)2 as the oxidant favored the C3 selectivity, whereas AgOAc led to the arylation at the C2 position of indoles. Further investigation indicated that the acetate additives had a strong influence on the selectivity. In the presence of an acetate base, carboxylate-induced cleavage of higher-order Pd clusters might occur and the resulting monomeric Pd complex favored the C2 selectivity. When excess Cu(OAc)2 was added, mixed Pd−Cu clusters might be formed and exhibited the pronounced C3 selectivity. The reaction results also showed that N-pivalyl indole exhibited a higher conversion and C2/C3 selectivity than the Nacetyl analogue. Thus, treatment of indoles/pyrroles with arenes in the presence of Pd(TFA)2 in conjunction with AgOAc and PivOH led to the desired 2-arylated products in moderate to excellent yields with high regioselectivity (Scheme 86).

Scheme 85. Regioselectivity in Oxidative Cross-Coupling Using the Different Oxidant

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Scheme 86. Pd-Catalyzed C2/C3 Selective Cross-Coupling of Indoles with Benzenes

Scheme 87. Pd-Catalyzed Regioselective Cross-Coupling of N-Acetylindoles with Arenes

Scheme 89. Regioselective Oxidative Cross-Coupling of Furan-2-carbonyls with Arenes

Scheme 88. Pd-Catalyzed Regiocontrolled Aerobic Oxidative Coupling of Indoles and Benzenes Using 4,5-Diazafluorene Ligands

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Scheme 90. Pd-Catalyzed Oxidative Cross-Coupling of Imidazo[1,2-a]pyridine Derivatives with Simple Arenes

Scheme 93. Oxidative Cross-Coupling of Benzoxazoles with Simple Arenes

Scheme 94. Synthesis of a Precursor to a Transthyretin Amyloid Fibril Inhibitor

Scheme 91. Pd-Catalyzed C−H Arylation of Caffeine with Arenes

Scheme 95. Pd-Catalyzed C−H/C−H Oxidative CrossCoupling of 4-(5-Methylthiazolo[5,4-d]pyrimidin-7yl)morpholine with (Hetero)arenes

Scheme 92. Pd-Catalyzed C−H Arylation of Azole-4carboxylates with Arenes

catalyzed C−H arylation of xanthines, a kind of important biologically active alkaloids.143 Diverse C8-arylated xanthines were obtained in moderate-to-good yields (Scheme 91).144 Monosubstituted arenes still gave a mixture of isomeric products. Yao reported the oxidative cross-coupling of azole-4carboxylates with arenes.145 Pd(OAc)2/AgOAc was an optimal catalyst/oxidant combination (Scheme 92). Two equiv of PivOH were used as the additive, and solvent amounts of arenes were used. The standard conditions exhibited a broad substrate generality. The highly electron-deficient nitrobenzene could even smoothly react with thiazoles and oxazoles. Notably, the

position of the imidazo[1,2-a]pyridine ring. Both the regioselectivity and efficiency were sensitive to the steric hindrance of simple arenes. Similarly, using Ag2CO3/O2 as the oxidants and PivOH as the additive, Beifuss and co-workers reported the palladium8815


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Scheme 96. Pd-Catalyzed Oxidative Arylation of Various NOxides with Simple Arenes

Scheme 98. Plausible Mechanistic Pathway

Scheme 99. Pd-Catalyzed Oxidative Arylation of Pyridines for the Synthesis of 3-Arylpyridines

Scheme 97. Pd-Catalyzed Oxidative Cross-Coupling of Substituted Quinolines with Chlorobenzenes

Scheme 100. Pd-Catalyzed Oxidative Cross-Coupling of Polyfluoroarenes with Electron-Rich Five-Membered Heteroarenes

products could be readily converted to useful building blocks, thus demonstrating the utility of this methodology. Su and co-workers developed an oxidative cross-coupling of benzoxazoles with simple arenes (Scheme 93).146 In this work, CuBr2 was proposed to work not only as an oxidant but also as a Lewis acid to coordinate to benzoxazole, thus preventing the catalyst poisoning caused by the coordination of benzoxazole to the palladium center. No homocoupling was detected under the optimized conditions. A precursor to a transthyretin amyloid fibril inhibitor was synthesized through this protocol (Scheme 94). A KIE value of 5.6 for the competition experiments between benzene and deuterated benzene and the more reactivity of fluorobenzene than benzene indicated that a CMD process could be involved in the C−H activation of arene. 2-Arylsubstituted thiazolo[5,4-d]pyrimidines are often encountered in biologically active compounds. Sun reported the oxidative C−H/C−H cross-coupling of thiazolo[5,4-d]8816


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Scheme 101. Synthesis of n-Type Organic Semiconductors

Scheme 102. Aerobic Oxidative Cross-Coupling of Fluoroarenes with Heteroarenes

Scheme 104. Au-Catalyzed Oxidative Cross-Coupling between Electron-Poor Polyfluoroarenes and Electron-Rich (Hetero)arenes

Scheme 103. Mild Copper-Mediated Aerobic Oxidative Cross-Coupling of 1,3,4-Oxadiazoles with Polyfluoroarenes arylation even occurred in the absence of benzene through C(sp2)−P/C(sp2)−H bond cleavage, in which PPh3 in the catalyst precursor worked as a phenyl source. Thus, Pd(OAc)2 was employed as the catalyst when substituted arenes were used as the arylating reagent. The oxidative arylation of pyridine and its analogues represents a challenging task owing to the low reactivity of the C−H bonds on these heteroaromtic rings. Chang and coworkers found that the oxidative cross-coupling reaction of pyridine N-oxides with arenes could take place using a catalytic system comprised of Pd(OAc)2 and Ag2CO3 (2.2 equiv) (Scheme 96).148 Treatment of pyridine N-oxides with arenes (40 equiv) regioselectively furnished the ortho-arylated products in moderate-to-good yields with moderate to good mono/ diselectivity, depending on the steric effect. N-Oxides derived from pyrazine, quinoxaline, and quinolines were also effective substrates. In 2013, Huang and co-workers disclosed an oxidative crosscoupling of quinolines with chlorobenzenes (Scheme 97).149 Pd(OAc)2 /Ag2 CO 3 was employed as a catalyst/oxidant combination. DMF was chosen as the optimal solvent. The reaction regioselectively occurred on the C2 position of quinoline. The position and electronic nature of the substituent on the quinoline ring had a stronger influence than the steric effect on the reaction efficiency. However, the substrate scope of

pyrimidine with (hetero)arenes using Pd(PPh3)2Cl2 as the catalyst and Ag2CO3 as the oxidant (Scheme 95).147 PivOH and tetrabutylammonium iodide (TBAI) were employed as the additives. Interestingly, while 4-(5-methylthiazolo[5,4-d]pyrimidin-7-yl)morpholine smoothly reacted with benzene, the 8817


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Scheme 105. Rh-Catalyzed Oxidative Cross-Coupling of NHeteroarene-Substituted Arenes with Various Heteroarenes

Scheme 107. Rh-Catalyzed Oxidative Cross-Coupling of (Hetero)arenes with Thio- and Selenophene Derivatives

Scheme 108. Ortho-C−H Heteroarylation of Aromatic Amines with Heteroarenes Using the Wilkinson Catalyst

Scheme 106. Ru-Catalyzed Oxidative Cross-Coupling of NHeteroarene-Substituted Arenes with Thiophenes

products. In a plausible mechanism, quinoline initially coordinates to the Pd(II) center through nitrogen atom, followed by palladium migration to the C2 to form a quinolinyl palladium intermediate 20. Then palladation of dichlorobenzene and subsequent reductive elimination furnishes the 2-arylated quinoline. The released Pd(0) is reoxidized to Pd(II) by Ag(I)/ O2 to complete the catalytic cycle (Scheme 98). More recently, Yu and co-workers reported the oxidative cross-coupling of pyridines with benzene (Scheme 99).84 Pd(OAc)2 and Phen were used as the catalyst and ligand, respectively. Both solvent amounts of pyridine and benzene were essential for high conversion efficiency. The reaction predominately took place at the C3 position of pyridine. One of the most extensively studied reactions in this section is the oxidative arylation of heteroarenes with polyfluoroarenes. In 2010, Zhang reported the first example of direct Pd(OAc)2catalyzed oxidative cross-coupling of heteroarenes with polyfluoroarenes for the construction of polyfluoroarene-thiophene

arenes was limited. Typically, only chlorine-containing arenes could work under the standard conditions. Bromobenzene, benzene, and toluene gave either no or trace amounts of 8818


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Scheme 109. Synthesis of Extended π-Conjugated Heteroacenes 22 and 23

Scheme 110. Rh-Catalyzed Oxidative Cross-Coupling of O-Methyl Oximes with Heteroarenes

structures,150 a type of structural units existing in organic optoelectronic materials (Scheme 100). Notably, only 2.5 mol % of Pd(OAc)2 was required. Besides thiophenes, furans and indoles were also suitable substrates. Two n-type organic semiconductors were constructed with this method, demonstrating the synthetic application of this protocol (Scheme 101). Later on, the oxidative coupling of polyfluoroarenes with heteroarenes using O2 as the terminal oxidant was also disclosed by the same group (Scheme 102).151 Besides palladium, other transition-metals have also been successfully applied to promote the oxidative cross-coupling of heteroarens with arenes. Bolm and co-workers achieved the copper-mediated aerobic oxidative cross-coupling of 1,3,4oxadiazoles with polyfluoroarenes at room temperature (Scheme 103).152 CuBr and 1,10-phenanthroline were chosen as the mediator and ligand, respectively. tBuOLi was the most effective base. Molecular oxygen and acetonitrile proved to be crucial in

this transformation. Excessive amounts of polyfluoroarenes were required to furnish the cross-coupled products in satisfactory yields. In addition, tri- and difluoroarenes failed to undergo this transformation under the standard conditions. Recently, the first Au-catalyzed oxidative cross-coupling between electron-rich (hetero)arenes and electron-poor polyfluoroarenes via double C−H activation was demonstrated by Larrosa and co-workers (Scheme 104).153 PPh3AuCl was chosen as the catalyst and 1-pivaloyloxy-1,2-benziodoxol-3(1H)-one (PBX) as the oxidant. The presence of AgOPiv was essential for this reaction. DMSO was employed as an additive to likely enhance the solubility of AgOPiv and/or to stabilize the low coordination number Au species in solution. Diverse electronrich (hetero)arenes, including indoles, pyrroles, furans, thiophenes, and anisoles, smoothly reacted with polyfluoroarenes under the standard conditions. A good functional group compatibility was observed in this catalytic system. Although 8819


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Thiophens, furans, oxazoles, and thiazoles were all suitable substrates. Diverse π-conjugated poly(hetero)arenes could be obtained in moderate-to-excellent yields. In this reaction, the acetate anion played a crucial role, presumably as a hydrogen acceptor and/or a ligand for the rhodium catalyst. No significant impact on the yields was observed in the presence of TEMPO. To further demonstrate the utility of this protocol, 3,6di(thiophen-2-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione, a kind of structural moiety frequently appeared in organic functional materials, was used to couple with 2-(o-tolyl)quinoline. The coupled poly(hetero)aryl product 21 shows a strong red emission (λex: 601 nm). The authors also disclosed a ruthenium-catalyzed oxidative cross-coupling of N-heteroarenesubstituted arenes with thiophenes (Scheme 106).154 This is the first example of ruthenium-catalyzed oxidative cross-coupling of arenes and heteroarenes. At almost the same time, Kambe and co-workers independently reported the chelation-assisted oxidative cross-coupling of (hetero)arenes with chalcogenophenes (Scheme 107).155 (Hetero)arenes, including phenylpyridine, N-phenylpyrazole, benzo[h]quinolines, and carbazoles, smoothly reacted with thiophenes to give the desired biaryls in moderate-to-good yields. The attempt with selenophenes was successful as well. In addition to rigid N-heteroaromatic moieties, the conformationally flexible functional groups such as N-pivalyl amides, oxime ethers, and carboxylate can also direct the regioselecive oxidative cross-coupling between arenes and heteroarenes. You and co-workers demonstrated the amide-directed oxidative cross-coupling between aromatic amines and heteroarenes (Scheme 108).156 Less expensive Wilkinson catalyst [Rh(PPh3)3Cl] rather than [RhCp*Cl2]2 was employed as the catalyst precursor. TFA was added to enhance the electrophilicity of the cationic RhIII species, facilitating the C−H activation process. A set of pivalanilides with various functional groups could be heteroarylated in synthetically useful yields regardless of the electronic nature of the substituent on the aromatic ring. A wide substrate scope and a good functional group tolerance were observed for the heteroaromatic partners. Thiophenes, furans, and even caffeine could undergo the cross-coupling with pivalanilides under the standard conditions. One of the highlighted features of this protocol is that the amino moiety

Scheme 111. Rh(III)-Catalyzed Decarboxylative C−H Arylation of Thiophenes Using the Carboxylic Acid as a Traceless Directing Group

5.0 equiv of polyfluoroarenes were typically required, lower substrate ratios (1:1−1.5:1) also gave the desired products in good yields with complete cross-selectivity. In addition, it should be mentioned that the low tendency of Au(I) species to react with organohalides renders this method a highly useful alternative to palladium-catalyzed oxidative coupling reactions. 4.2. Directed Arene-Heteroarene Cross-Coupling

In this section, the oxidative cross-coupling reactions between a heteroarene and an arene bearing a directing group are summarized. Up to now, the transformations in this area have been completed by rhodium (mostly), ruthenium, and copper catalysis. In 2013, You and co-workers reported the rhodiumcatalyzed oxidative cross-coupling of heteroarenes with arenes using N-heteroarenes as the directing group (Scheme 105).154

Scheme 112. Gram-Scale Synthesis for a 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Intermediate

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Scheme 113. Rh(III)-Catalyzed Decarboxylative Ortho-Heteroarylation of Aromatic Carboxylic Acids Using the Carboxylic Acid as a Traceless Directing Group

Scheme 114. Rh(III)-Catalyzed ortho-Heteroarylation of (Hetero)aromatic Carboxylic Acids with Heteroarenes

could be a useful synthetic handle allowing further transformation to highly extended π-conjugated heteroacenes. Two highly extended π-conjugated heteroacenes 22 and 23 were synthesized (Scheme 109). These two heteroacenes exhibited large optical HOMO−LUMO energy gaps estimated from the absorption edges (3.42 and 3.16 eV, respectively) and low-lying HOMO levels defined by cyclic voltammetry (−5.35 and −5.16 eV vs vacuum, respectively). With the assistance of O-methyl oxime as the directing group, You and co-workers achieved the oxidative cross-coupling of heteroarenes with simple arenes (Scheme 110).157 Treatment of oxime ether (1.0 equiv) with heteroarene (1.5 equiv) in the

presence of [RhCp*Cl2]2 (2.5 mol %), Ag2CO3 (2.2 equiv), Cu(TFA)·H2O (20 mol %), and DCE as the solvent, unsymmetrical biaryls could be formed in moderate-to-good yields. The heteroarene scope involves thiophenes, furans, benzothiphene, and benzofuran. Carboxylic acid can serve as both a directing group and a readily removable/convertible functional group,158−161 and thus it has great potential to streamline the synthesis of diverse poly(hetero)arenes. Using carboxylic acid as the traceless directing group, Su and co-workers demonstrated the rhodium-catalyzed decarboxylative C−H arylation of thiophenes (Scheme 111).162 Typically, K2HPO4 was chosen as the optimal 8821


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Scheme 115. Construction of Various Polyheterocycles from ortho-Carboxy-Substituted Bi(hetero)aryls

Scheme 116. Synthesis of the Sensitizer 25

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Scheme 117. Synthesis of 2-(2-Hydroxyphenyl)azoles and Their Photophysical Properties

the key for this oxidative transformation is that the orthodisubstituted products more easily undergo the Ag-promoted decarboxylation than the ortho-monosubstituted precursor carboxylic acids, which is consistent with the computational studies.163 In addition, using the methodology established, an intermediate for a 17β-hydroxysteroid dehydrogenase type 1 inhibitor164 was synthesized in a high yield and a gram-scale from inexpensive and commercially available materials (Scheme 112). Recently, Lan and You further extended the substrate scope of this reaction (Scheme 113).165 Various heteroarenes, including thiophenes, furans, indoles, and azoles, were suitable substrates. A combination of [RhCp*Cl2]2 and AgSbF6 proved to be the optimal catalysts. NMP was used as the solvent. This process offers an efficient alternative to the formal meta-substituted adducts from ortho- and para-substituted aromatic carboxylic acids and the para-heteroarylated adducts from meta-substituted substrates. Lan and You almost simultaneously demonstrated the synthesis of highly functionalized ortho-carboxy-substituted bi(hetero)aryls through a carboxylic acid-directed oxidative cross-coupling of (hetero)aromatic carboxylic acids with heteroarenes (Scheme 114).166 Ag2O and tBuOH proved to be the best oxidant and solvent, respectively, which could efficiently suppress further decarboxylative side reactions. Besides thiophenes, furans and azoles were also applicable. The oxidative protocol enables it to tolerate a broad scope of reactive functional groups, particularly halo groups. The bromo-substituted carboxylic acids as a coupling partner can avoid the late-stage bromination and significantly streamline synthetic routes. By the combination of this oxidative coupling with subsequent intramolecular oxidative lactonization or electrophilic substitution, several polyheterocycles such as cyclopentadithiophen-4one (CPDTO), 5H-dithieno[3,2-b:2′,3′-d]pyran-5-one (DTPO), and seven-ringed bis(styryl)benzene 24 were assembled rapidly (Scheme 115). In addition, an organic sensitizer 25 was easily achieved based on this transformation (Scheme 116). Compound 25 exhibits a broad absorption band covering the range of 300 to 650 nm in EtOH. Furthermore, the

Scheme 118. Cu-Mediated Oxidative Cross-Coupling of 2Arylazines with Azoles Using N-Heteroarene as a Directing Group

base. TEMPO showed a positive effect on the yield, presumably owing to its acceleration effect on the reoxidation of RhI to Rh III as an electron transfer intermediate. An ortho substituent was typically installed to avoid the potential double arylation. Both aromatic and heteroaromatic carboxylic acids were effective substrates. However, the reaction conditions varied depending on the electronic nature of carboxylic acids. It is noteworthy that 8823


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Scheme 119. Cu-Mediated Oxidative Cross-Coupling of Benzamides with 1,3-Azoles

typically required in this reaction. It is notable that a relatively broad scope of functional groups could be tolerant in this reaction. Subsequently, this protocol was extended to the reaction of 1,3-azoles and benzamides bearing an 8-aminoquinoline-based N,N-bidentate directing group (Scheme 119).169 The bidentate directing group was thought to facilitate the cupration of aromatic C−H bond. This reaction also exhibited a broad substrate generality and high functional group tolerance. In addition, the 8-aminoquinoline moiety was readily removed to afford the corresponding esters. Later on, the copper-mediated oxidative cross-coupling of naphthylamines with 1,3-azoles was achieved by the same group (Scheme 120).170 Picolinamide was used as a directing group to facilitate the selective cleavage of peri C−H bond of the naphthyl ring. Both oxazoles and thiazoles were effective substrates. However, the reactions with benzothiazoles, imidazoles, triazoles, and 1,3,4-oxadiazoles resulted in rather low yields (less than 20%). The picolinamide group could be readily removed to afford naphthylamines in a good overall yield. The above-mentioned copper-mediated directed oxidative heteroarylations of aromatic compounds typically involve heteroarenes containing acidic C−H bonds and require the employment of stoichiometric amounts of copper salts. More recently, Shi demonstrated the first copper-catalyzed C−H arylation of electron-rich heteroarenes by using (pyridine-2yl)isopropyl (PIP) as the directing group (Scheme 121).171 In the presence of CuOAc (20 mol %) as the catalyst in conjunction with AgNO3 (4.0 equiv) as the oxidant, oxidative C−H/C−H cross-coupling between benzamides and thiophenes proceeded smoothly to deliver a variety of 2-thienylbenzamides. However, other electron-rich heteroarenes, such as indoles and furans, were

25-based DSSC exhibited a comparable conversion efficiency to N719 under the same fabrication conditions. More recently, Lan and You disclosed the first example of internal oxidative cross-coupling between heteroarenes and phenols through a traceless oxidation directing strategy (Scheme 117).167 The traceless oxidizing directing group serves as both a traceless directing group and an internal oxidant, and thus, it avoids the employment of stoichiometric amounts of an external oxidant and extra steps to remove the undesired directing group in the product. In the presence of [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Ag2CO3 (0.2 equiv), PivOH (2.0 equiv), CsOPiv (0.8 equiv), and DMF as the solvent, N-phenoxyacetamides reacted smoothly with benzoxazoles to afford 2-(2hydroxyphenyl)azoles in moderate-to-high yields. Although Ag2CO3 was not a prerequisite in this reaction, the absence of this species would lead to a diminished yield. Furthermore, the triphenylamine (TPA)-bearing 2-(2-hydroxyphenyl)azoles 26 and 27 exhibit the excited-state intramolecular proton transfer (ESIPT) equilibrium between the enol-form and the keto-form in both solution and solid state and show bright white-light emissions with CIE coordinates of 26 (0.32, 0.38) and 27 (0.34, 0.39) in toluene and 26 (0.30, 0.33) and 27 (0.29, 0.34) in PS films, respectively. Copper-mediated arylation of heteroarenes through dual C− H activation has also been reported. In 2011, Hirano and Miura reported the copper-mediated oxidative cross-coupling of arylazines with azoles using N-heteroarene as a directing group (Scheme 118).168 Cu(OAc)2 proved to be the optimal promoter, and other divalent copper salts such as CuCl2 and Cu(OTf)2 gave no desired product. The addition of PivOH showed a positive effect on the yield. High temperature (up to 170 °C) was 8824


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Scheme 120. Copper-Mediated Oxidative C−H/C−H Coupling of 1-Naphthylamine Derivatives with 1,3-Azoles

Scheme 121. Cu-Catalyzed Oxidative Coupling of Benzamides with Thiophenes Using (Pyridin-2-yl)isopropyl (PIP) as a Directing Group

Scheme 122. Plausible Mechanism

incompetent. A possible mechanism is proposed in Scheme 122. Cu(I) is initially oxidized to Cu(II) species. The subsequent directed C−H cupration affords the aryl−Cu(II) intermediate, followed by oxidation or disproportionation to form the aryl− Cu(III) complex. Following electrophilic aromatic substitution

with thiophene and C−C reductive elimination deliver the desired product. 8825


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Scheme 123. Oxidative Cross-Coupling of Electron-Deficient N-Heteroarenes with Electron-Rich Thiophenes or Furans

Scheme 124. Pd-Catalyzed Oxidative Cross-Coupling of Indoles and Pyrroles with Heteroarenes

5. INTERMOLECULAR OXIDATIVE COUPLING BETWEEN TWO HETEROARENES

inversion of reactivity/selectivity in the two metalation steps, which further achieves the chemoselectivity of cross-couping over homocoupling (“Electronic Differential Principle”). A Pd(II) catalytic system in conjunction with an azine ligand such as pyridine and 2,6-lutidine are often used for the transformations in this section. In 2010, Hu and You demonstrated the first Pd(II)-catalyzed regioselective oxidative C−H/C−H cross-coupling between two heteroaromatic com-

5.1. Heteroarene-Heteroarene Coupling without Directing Group

5.1.1. Oxidative Coupling between Electron-Rich and Electron-Deficient Heteroarenes. The distinctly differential π-electronic properties between two heteroaromatics enable an 8826


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Scheme 125. Oxidative C−H/C−H Cross-Coupling of Electron-Deficient N-Heteroarenes with Electron-Rich Thiophenes, Furans, or Indoles Using Oxygen as the Terminal Oxidant

Scheme 126. Pd-Catalyzed Oxidative Cross-Coupling of Pyridine N-Oxides with Indoles

Scheme 127. Pd-Catalyzed Oxidative C−H/C−H CrossCoupling of Indoles/Pyrroles with Azine N-Oxides

pounds (Scheme 123).172 A diverse set of electron-deficient heteroarenes, including xanthines, azoles, indolizines, and pyridine N-oxides, were effective substrates to couple with either electron-rich thiophenes or furans. Generally, only 2.5 mol % of Pd(OAc)2 was required as the catalyst. Cu(I) was found to be an efficient activator to improve the catalytic efficiency and regioselectivity. The density functional theory (DFT) study supported that a SEAr process could be involved in the initial

palladation of thiophene, and the second C−H activation might undergo a CMD process. You and co-workers next achieved the oxidative C−H/C−H cross-coupling of indoles and pyrroles with heteroarenes (Scheme 124).173 [Pd(dppf)Cl2] and Cu(OAc)2 were used as the catalyst and oxidant, respectively. CuCl was added to 8827


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Scheme 128. Syntheses of Marine Indole Alkaloid Eudistomin U and Dragmacidin D

N-oxide with 2-methyl thiophene could be performed on the gram scale. Palladium-catalyzed oxidative cross-coupling between pyridine N-oxides and N-substituted indoles was also demonstrated by Zhang and Li (Scheme 126).175 The reaction selectively occurred at the C3 position of indole and the C2 position of Noxide. Four equivalents of pyridine and 20 mol % of tetrabutylammonium bromide (TBAB), which might facilitate to stabilize or mediate the Ag2CO3 oxidant, were used as the additive to enhance the reaction efficiency. Under these conditions, more electron-poor N-oxides could undergo oxygen atom transfer to pyridine (an additive in the reaction conditions) to form simple pyridine N-oxide. Thus, a pyridine-free condition should be used in the case of more electron-poor N-oxides.

improve the reaction efficiency and C3/C2 regioselectivity. XPhos was added to prevent the decomposition of N-alkylindoles. Electron-deficient N-heteroarenes, including xanthines, purines, benzothiazoles, benzoxazoles, and N-heteroarene N-oxides, were effective to couple with either indoles or pyrroles under this palladium/copper bimetallic catalytic system. More recently, You and co-workers further disclosed a palladium/copper-catalyzed oxidative C−H/C−H cross-coupling between two heteroarenes by using oxygen as the terminal oxidant for the first time (Scheme 125).174 A wide range of πelectron-rich five-membered heterocycles (e.g., thiophenes, indoles, and furans) could react with N-containing heteroarenes (e.g., purines, indolizines, and azine N-oxides) under the standard conditions to give the desired biheteroarenes in satisfactory yields. Worth noting is that the reaction of quinoline 8828


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Scheme 129. Pd-Catalyzed Heteroarylation of Azines with Heteroarenes

Scheme 130. Pd-Catalyzed Oxidative Cross-Coupling of Benzothiazoles with Thiophenes or Thiazoles

Although the oxidative cross-coupling between azine N-oxides and heteroarenes is an efficient and powerful method to construct azine-containing biheteroaryls, the reaction with unactivated azines instead of activated azine N-oxides is more desired. In 2013, You demonstrated the regioselective oxidative C−H/C−H cross-coupling of pyridines with heteroarenes using a Pd(OAc)2/phen/AgOAc/PivOH catalytic system (Scheme 129).178 A wide array of heteroarenes, including indoles, furans, thiophenes, indazoles, imidazopyridines, and xanthines, could regioselectively couple with pyridines at the C2 position. However, C6-heteroarylation might occur when C3-substituted pyridines were subjected. The C2/C6 selectivity was found to be dependent on the steric and electronic characteristics of the substituent. Interestingly, the reaction of N-methylindole with pyridine selectively occurred at the indole C2 position rather than the C3 position observed in the cross-coupling of indole with pyridyl N-oxide.175,176

At almost the same time, Yamaguchi and Itami disclosed the palladium-catalyzed oxidative C−H/C−H coupling of azine Noxides with indoles or pyrroles (Scheme 127).176 AgOAc (3.0 equiv) and 2,6-lutidine (1.0 equiv) were used as the oxidant and ligand, respectively. 1,4-Dioxane was used as the solvent. This transformation occurred at the C3 position of indole and the C2 position of azine N-oxide and exhibited a good substrate scope for both coupling partners. The regioselectivity of pyrroles could be controlled by manipulating the protecting group at the nitrogen atom. For example, the N-tosyl protecting pyrrole gave the C3-functionalized product, whereas the N-free pyrrole furnished the C2-isomer. In addition, marine indole alkaloid eudistomin U,176 which displays DNA-binding activity and strong antimicrobial properties, and dragmacidin D,177 a potent serine-threonine protein phosphatase inhibitor, were synthesized through C−H/C−H coupling as the core synthetic step (Scheme 128). 8829


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(Scheme 130).179 The added phenanthroline was supposed to coordinate to the palladium center and weaken the coordination to N- and S-atoms of the substrates. As no desired product was obtained in the presence of TEMPO (30 mol %), a radical process was suggested to be involved in this transformation. Biheteroarenes are a type of important structural motifs to construct fluorophores.180−184 The donor−acceptor (D−A) type molecular systems are frequently considered in the discovery of full-color-tunable organic fluorophores. Thus, the direct oxidative C−H/C−H coupling between an electron-rich heteroarene and an electron-deficient heteroarene would offer a facile and straightforward gateway to D−A type HetER−HetED skeletons (Scheme 131). More recently, Gao and You reported a palladium-catalyzed oxidative C−H/C−H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes to construct a large library of biheteroaryl fluorophores (Scheme 132).185 A variety of heteroarenes such as thiophenes, furans, indoles, and pyrroles were effective substrates. A broad scope of functional groups, including aldehyde, acyl, ester, amide, nitro, dimethylamino, and hydroxyl, could be well-tolerated under the standard conditions, thus facilitating further investigation of the relationship between structure and photophysical properties.

Scheme 131. Construction of Biheteroaryl Fluorophores via Direct Oxidative C−H/C−H Cross-Coupling between Electron-Rich and Electron-Deficient Heteroarenes

Yang and co-workers reported the oxidative cross-coupling of benzothiazoles with thiophenes or 2-substituted thiazoles

Scheme 132. Direct Oxidative C−H/C−H Cross-Coupling of 2H-Indazoles with Electron-Rich Heteroarenes

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Scheme 133. Pd-Catalyzed Oxidative C−H/C−H Cross-Coupling between Two Azoles

The resulting donor−acceptor-type biheteroaryl fluorophores (Indazo-Fluors) exhibit full-color-tunable fluorescence, high quantum yields, and large Stokes shifts both in low-polarity and high-polarity solvents. Notably, Indazo-Fluor 28 (FW = 274; λem = 725 nm) is the smallest NIR fluorophore with the emission wavelength over 700 nm in the solid state and Indazo-Fluor 29 proved to be the smallest NIR probe with specific targeting to mitochondria (Scheme 132). The easy access to Indazo-Fluors has highlighted the great appeal of oxidative C−H/C−H crosscoupling reaction in high-throughput screening for organic functional molecules. 5.1.2. Oxidative Coupling between Two ElectronDeficient Heteroarenes. Besides the oxidative cross-coupling between electron-rich and electron-deficient heteroarenes, the reactions between two electron-deficient heteroarenes have also been demonstrated. In this section, the presented examples are mainly focused on the reaction between two azoles. In 2011, Ofial developed the cross-coupling of benzothiazole and benzimidazoles with N-, O-, and S-containing azoles (Scheme 133).186 Treatment of two azoles in the presence of Pd(OAc)2

Scheme 134. Pd-Catalyzed Oxidative Cross-Coupling of 1,3,4-Oxadiazoles with Benzothiazole

Scheme 135. Pd-Catalyzed Oxidative Cross-Coupling between Two Structurally Similar but π-Electronically Differential Azoles

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Scheme 136. Pd-Catalyzed Oxidative C−H/C−H Cross-Coupling between Two Electron-Deficient Heteroaromatic N-Oxides

Scheme 137. Pd-Catalyzed Oxidative C−H/C−H Cross-Coupling between Azine N-Oxides with 1-Benzyl-1,2,3-triazoles

Scheme 138. Pd-Catalyzed Oxidative C−H/C−H Cross-Coupling between Thiazoles and Azine N-Oxides

and Cu(OAc)2·H2O with either KF/AgNO3 or AgF, diverse 2,2′bisheteroaryls were formed regioselectively in moderate-toexcellent yields. Copper salt in this reaction was assumed to reoxidize Pd(0) to Pd(II) and form the catalytically active Cu− Pd species. Ag(I) was thought as a terminal oxidant and was also crucial to restrain the formation of intractable homocoupling. However, the pivotal effect of Ag(I) was not well-understood. In addition, the oxidative cross-coupling of 1,3,4-oxadiazoles with benzothiazole using a Pd(OAc)2/Cu(OAc)2/AgNO3/KF catalytic system was also disclosed by Das and co-workers (Scheme 134).187 You and co-workers described a chemo- and regioselective oxidative cross-coupling of two structurally similar but π-

electronically differential azoles (Scheme 135).188 Homocoupling was significantly suppressed by using a Pd/Cu cocatalytic system. Notably, this reaction could be performed with the 1:1 ratio of two coupling partners even in only 1 h. The negligible effect of TEMPO in this reaction excluded the involvement of radical process. Several reports on the oxidative cross-coupling between azine N-oxides and electron-deficient heteroarenes have been disclosed. Kuang described an efficient protocol for the oxidative cross-coupling between pyridine N-oxides and 2-aryl-1,2,3triazole N-oxides (Scheme 136).189 The resulting N,N′-dioxide products could be easily reduced by Zn or PCl3 to afford the corresponding biheterocycles. The mechanism study indicated 8832


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Scheme 139. Oxidant-Controlled Regioselective Oxidative Cross-Coupling of Pyridines and Benzoxazoles

Scheme 140. Aerobic Cu(OAc)2-Mediated Oxidative Cross-Coupling between Two Azoles

Scheme 141. Cu(II)-Mediated Oxidative Cross-Coupling between Benzoazoles and Azoles

that this reaction could be initiated by the C−H palladation of 1,2,3-triazole N-oxides. Subsequently, the same group further

extended the substrate scope to 1-benzyl-1,2,3-triazoles (Scheme 137).190 8833


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Scheme 142. Cu-Catalyzed Oxidative Cross-Coupling of Benzothiazoles with Thiazoles

Scheme 143. Cu(OAc)2-Catalyzed Oxidative Cross-Coupling between Two Azoles

In 2013, Liu and Li reported the palladium-catalyzed oxidative cross-coupling of electron-deficient thiazoles with azine N-oxides through dual C−H bond activation for the synthesis of 2thiazolylpyridine compounds (Scheme 138).191 Copper(II) pivalate worked as both an oxidant as well as a C−H bond activation promoter in this transformation. Furthermore, the addition of Cu(OPiv)2 was beneficial to the suppression of the homocoupling reaction. The kinetic isotope effect experiments indicated that the cleavage of the C−H bond of pyridine N-oxide could be involved in the determining step. More recently, Itami and co-workers achieved the palladiumcatalyzed oxidative cross-coupling between pyridines and benzoxazoles (Scheme 139).192 In this reaction, organohalide not only worked as the oxidant but also served as the regioselectivity switch. Treatment of pyridines with benzoxazoles in the presence of aryl bromides predominately gave the C3functionalized products, while the employment of benzyl bromide as the oxidant provided the C2-functionalized products. Copper salt is another usually used promoter in the crosscoupling between two electron-deficient heteroarenes. In 2010, Bao and co-workers reported an aerobic Cu(OAc)2-mediated oxidative cross-coupling between two azoles (Scheme 140).86

Scheme 144. Cu(OAc)2-Mediated Formally Dehydrative Cross-Coupling of Azine N-Oxides with Oxazoles

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Scheme 145. Pd(II)-Catalyzed Oxidative C−H/C−H Cross-Coupling between Two Electron-Rich Heteroarenes under Mild Reaction Conditions

Scheme 146. Synthesis of Dye-Sensitizer 30 for Solar Cell and Optical Imaging Agent 31

imidazole and 5-arylthiazole, and between N-benzyl benzimidazole and 5-phenyloxazole or 5-phenylthiazole proceeded smoothly. The addition of TEMPO did not significantly affect the reaction efficiency, thus excluding the possibility of a radical process. Zhang and co-workers reported the copper-catalyzed oxidative cross-coupling of benzothiazoles with thiazoles (Scheme 142).194 Treatment of benzothiazoles (1.0 equiv) with thiazoles

The cross-coupled products were obtained in moderate yields with significant amounts of homocoupling products. Xu, Yu, and Wang reported the copper-mediated oxidative cross-coupling between benzoazoles and azoles (Scheme 141).193 Cu(OAc)2 was essential for this reaction and other investigated copper salts proved to be completely ineffective. The cross-coupling reactions between benzoxazoles and thiazoles, between benzothiazole and 5-arylthiazoles, between N-methyl 8835


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Scheme 147. Rh(III)-Catalyzed Oxidative Cross-Coupling between Two Electron-Rich Heteroarenes

Scheme 148. Copper-Mediated Oxidative Cross-Coupling of Indoles with 1,3-Azoles

Scheme 149. Copper-Catalyzed Oxidative Cross-Coupling of N-(2-Pyrimidyl)indoles or Pyrroles with 1,3-Azoles Using Atmospheric Oxygen as a Terminal Oxidant

azoles were coupled to deliver unsymmetrical bisazoles in xylene under an oxygen atmosphere. Not only benzazoles and azoles but also two nonbenzo-fused azoles smoothly underwent the crosscoupling. It is noteworthy that only equimolar amounts of two coupling partners were employed. Recently, the copper-mediated oxidative cross-coupling of azine N-oxides and oxazoles was demonstrated by Hirano and Miura (Scheme 144).196 In this reaction, the oxygen atom on the azine core was directly removed in situ to afford the azine-oxazole biaryl products. PivOH and pyridine were employed as additive and base, respectively. Cu(OAc)2 was the optimal mediator, and

(2.0−3.0 equiv) in the presence of CuI (10 mol %), Ag2CO3 (2.0 equiv), and tBuOLi (3.0−4.0 equiv) in toluene at 80 °C afforded the cross-coupled 2,2′-bisthiazoles in moderate-to-good yields with excellent regioselectivity. However, oxazoles and benimidazoles were not suitable substrates for this protocol. This transformation could also be extended to the synthesis of 2polyfluoroarylthiazoles. Copper-catalyzed oxidative cross-coupling between two azoles with high chemoselectivity was demonstrated by Lan and You (Scheme 143).195 In the presence of Cu(OAc)2 (20 mol %), Ag2CO3 (1.5 equiv), and pyridine (1.0 equiv), two different 8836


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Scheme 150. Plausible Reaction Mechanism

Scheme 151. Oxidative Cross-Coupling of Indoles/Pyrroles with Electron-Deficient Heteroarenes Using 2-Pyridyl or 2-Pyrimidyl as the Directing Group

different heteroarenes and between two electron-deficient heteroarenes, the cross-coupling reactions between two electron-rich heteroarenes are less developed, presumably partly owing to the intractable homocoupling reaction of electron-rich heteroarenes. To achieve a high chemoselectivity, one of the coupling partners (typically less reactive substrate) is often used in an excess amount. In 2013, Zhang and co-workers demonstrated the oxidative cross-coupling reactions between two electron-rich heteroarenes with similar structure and electronic property (Scheme 145).197 Pd(OAc)2 (2.5 mol %) and Ag2O (3.0 equiv) were used as the catalyst and oxidant, respectively. Ortho-phenyl benzoic acid (oPh-PhCOOH) played a crucial role in enhancing the reaction efficiency. Two thiophenes bearing differential π-electronic properties could be

other Cu(I) and Cu(II) salts such as CuOAc, CuO, Cu2O, CuI, and CuBr gave poor yields. The authors supposed that the inherent acetate ligand and relatively high Lewis acidic nature of Cu(OAc)2 could lead to its unique reactivity. In addition, Cu(OAc)2 was believed to be responsible for the deoxygenation process. Although the yields were moderate, this reaction exhibited a broad substrate scope for both azine N-oxides and oxazoles. The results of H/D exchange experiments indicated that the C−H cupration of oxazole was rapid and reversible, while the C−H metalation of azine N-oxide proceeded sluggishly under the standard conditions. 5.1.3. Oxidative Coupling between Two Electron-Rich Heteroarenes. Compared with the above-mentioned oxidative cross-coupling reactions between two electronic distinctly 8837


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Another example in this area is the Rh(III)-catalyzed oxidative cross-coupling of furans with thiophenes demonstrated by Glorius and co-workers (Scheme 147).198 Treatment of furans (1.0 equiv) with thiophenes (3.0 equiv) in the presence of [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), CsOPiv (20 mol %), CuII(2-ethylhexanoate)2 (3.0 equiv), and tert-AmylOH (2.0 mL) delivered unsymmetrical 2,2′-bisheteroaryls in moderateto-good yields, along with a minor amount of homocoupled bifurans. In addition, the cross-coupling reactions of Nsubstituted indoles and pyrroles with benzofuran and benzothiphene were also successful. It should be noted that CuII(2ethylhexanoate)2 was essential for high yield and chemoselectivity in this reaction. Other copper species such as Cu(OAc)2, Cu2O, and Cu(OH)2 led to a significant decrease in both the yield and chemoselectivity.

Scheme 152. C2/C3 Regioselectivity of C−H Heteroarylation of N,N-Dimethylcarbamoyl Indole with Benzylic Theobromine

5.2. Heteroarene-Heteroarene Coupling with Directing Group

The inherent electronic bias of heteroarene C−H bonds usually leads to the preferential functionalization of more reactive positions, such as C3−H of the indoles, C2−H of thiophenes, furans and pyrroles, and C5 or C2−H of azoles, thus rendering the C−H activation of a nonpreferential site troublesome. In addition, homocoupling often takes place as a side reaction in the oxidative C−H/C−H coupling between two heteroarenes. To overcome the natural selectivity of heteroarenes and to achieve regioselectivity switching, a directing group is typically incorporated to one of the coupling partners. The C2-heteroarylated indole and pyrrole derivatives are a class of important structural motifs in natural products. In 2012, Hirano and Miura demonstrated the copper-mediated crosscoupling of indoles with 1,3-azoles using 2-pyrimidyl as the directing group (Scheme 148).199 A range of indoles and azoles such as oxazoles, benzoxazoles, benzothiazole, and N-methyl-

smoothly coupled to furnish the cross-coupled bisthiophenes in moderate-to-good yields. However, significant amounts of unwanted homocoupled byproducts were still observed in most cases. Furans were also efficient substrates but gave relatively low yields. Worth noting is that the π-conjugated oligomer 30 for dye-sensitized solar cell and an in vivo optical imaging agent 31 for diagnosing Alzheimer’s disease were synthesized based on this protocol (Scheme 146). Thus, this oxidative coupling protocol would be highly useful for the synthesis of new thiophene-based electronic and optoelectronic materials.

Scheme 153. Chelation-Assisted Rh(III)-Catalyzed C2-Selective Coupling of Indoles/Pyrroles with Heteroarenes

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Scheme 154. Synthesis of Extended π-Conjugated Molecules 34 and 35 and Their Photophysical Properties

However, indoles bearing methyl, phenyl, and (2-pyridyl)sulfonyl groups were not suitable for this transformation. In addition, atmospheric oxygen could be used as an effective terminal oxidant (Scheme 149). This catalytic system also exhibited a relatively broad substrate scope and a good functional group tolerance. In the plausible mechanism, the initial carboxylate-assisted cupration of the azole C2−H bond affords a heteroarylcopper species 32, which then reacts with the indole partner through the direction of the 2-pyrimidyl group to give a bis(heteroaryl)copper complex 33. Subsequent O2-promoted reductive elimination delivers the desired product and regenerates the copper(II) species (Scheme 150). The highly electron-withdrawing nature of the 1,3-azolyl moiety in azolylcopper species was thought to facilitate cross-coupling rather than homocoupling. In 2012, You and co-workers reported the palladium-catalyzed regioselective heteroarylation of indoles and pyrroles (Scheme 151).200 A set of azine N-oxides and xanthines coupled smoothly with indoles or pyrroles under the standard conditions. The C2/ C3 selectivity in this reaction could be switched through “chelation-directed control” and “catalytic system-based control” strategies. In the presence of Pd(OAc)2, phen, and AgF as the oxidant, benzylic theobromine reacted with N,N-dimethylcarbamoyl indole to give the C2-heteroarylated product, whereas a catalytic system composed of [Pd(dppf)Cl2], CuCl, X-Phos and Cu(OAc)2·H2O as the oxidant mainly afforded the C3heteroarylated product (Scheme 152). You and Lan further disclosed a chelation-assisted rhodiumcatalyzed C2-selective oxidative cross-coupling of indoles/ pyrroles with heteroarenes (Scheme 153).201 Both electronrich heteroarenes such as thiophenes, benzothiophenes, furans, benzofurans, and indolizines and electron-deficient heteroarenes such as thiazoles, oxazoles, and pyridine N-oxides coupled with indoles or pyrroles in moderate-to-excellent yields. The reaction regioselectively occurred at the C2 position of indoles and pyrroles instead of the commonly preferable C3 site. A variety of functional groups, including free hydroxyl, aldehyde, ketone, ester, chloride, bromide, and iodide, could be tolerant in this reaction. In addition, almost no homocoupling was observed under the standard conditions. It is suggested that the limited coordination number/geometry of metal center and the steric hindrance around metal center could play an important role in the inhibition of homocoupling. This is the first reported catalytic system allowing the oxidative coupling not only between two electron-rich heteroarenes but also between electron-rich and electron-deficient heteroarenes. Two extended π-conjugated molecules 34 and 35 containing 3,6-di(thiophen-2-yl)-2,5dihydro-1,4-diketopyrrolo[3,4-c]pyrrole (DPP) fragment were

Scheme 155. Rh(III)-Catalyzed Amide-Directed Oxidative Cross-Couping of Pyridines with Heteroarenes

Scheme 156. Palladium-Mediated Cross-Coupling Reactions of Ferrocenes with Arenes

benzimidazole were converted to the unsymmetrical biheteroaryls in the presence of Cu(OAc)2 (2.0 equiv) in o-xylene. 8839


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Scheme 157. Synthesis of Planar Chiral Aryl-Substituted Ferrocenyl Oxazolines

Scheme 158. Enantioselective Cross-Coupling Reactions of Ferrocenes with Heteroarenes

synthesized based on this protocol. These two compounds exhibited broad and strong absorptions in the visible region and relatively strong emissions (Scheme 154). Recently, Su and co-workers described an amide-directed rhodium-catalyzed oxidative cross-coupling of pyridines with heteroarenes (Scheme 155).202 N-Phenyl amide proved to be the best directing group in this reaction. In the presence of [RhCp*Cl2]2 (1.5 mol %), AgSbF6 (6 mol %), K3PO4 (1.5 equiv), and Cu(OAc)2 (2.0 equiv), heteroarenes such as thiophenes, furans, thiazoles could regioselectively couple with pyridines in moderate-to-high yields. Ferrocene derivatives are widely used in homogeneous catalysis, organic synthesis, and material science. With the assistance of the oxazoline group, You and co-workers disclosed the palladium-mediated C−H arylation of ferrocenes (Scheme 156).203 A set of monoarylated ferrocenyl oxazolines were obtained in the presence of a stoichiometric amount of Pd(OAc)2. A combination of catalytic amounts of Pd(OAc)2

and excess Cu(OAc)2 mainly gave the diarylated products. It is worth noting that this method could be applied to synthesize planar chiral aryl-substituted ferrocenyl oxazolines from the corresponding chiral substrates (Scheme 157). More recently, the same group developed an enantioselective oxidative C−H/C−H cross-coupling of ferrocenes with heteroarenes (Scheme 158).204 Pd(OAc)2 (10 mol %) was used as the catalyst and monoprotected amino acid Boc-L-Ile-OH (20 mol %) as the chiral ligand. Air oxygen was employed as the oxidant. Dimethyl amino, pyrrolidinyl, piperidinyl, and methyl propylamino were all effective directing groups in this transformation. A high functional group tolerance was achieved for both coupling partners. Diverse heteroarenes, including benzofurans, furans, thiophenes, pyrroles and indoles, were suitable substrates. Moderate-to-high yields and excellent enantioselectivities were obtained. The X-ray crystallographic analysis of single crystals indicated that the configurations of the stereogenic centers of the products were Rp. It should be 8840


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Scheme 159. Cu(II)-Mediated C6-Selective Heteroarylation of Pyridines

Scheme 161. Pd-Catalyzed Intramolecular Oxidative Biaryl Coupling

Scheme 162. Pd-Catalyzed Microwave-Assisted Intramolecular Oxidative Biaryl Coupling

mentioned that this protocol is the first report on the oxidative catalytic asymmetric biaryl coupling reaction via dual C−H bond activation. 2-Pyridones are prevalent structural motifs often encountered in biologically active compounds and natural products.205 In 2014, Hirano and Miura reported the first direct C6-selective heteroarylation of pyridones with the assistance of a pyridine directing group (Scheme 159).206 A diverse set of 1,3-azoles including oxazoles, thiazoles, benzimidazoles, and 1,3,4oxadiazoles were effective substrates under the standard conditions. Although the optimized conditions required stoichiometric amounts of Cu(OAc)2, a Cu(OAc)2/air catalytic system could promote this transformation as well.

Scheme 163. Pd-Catalyzed One-Pot N-Arylation and Oxidative Biaryl Coupling

Scheme 164. Pd-Catalyzed Intramolecular Oxidative Cyclization of Diaryl Ktones for the Synthesis of Fluorenones

6. INTRAMOLECULAR OXIDATIVE COUPLING Intramolecular oxidative coupling is one of the most straightforward and efficient methods to synthesize polycyclic Scheme 160. Ring-Closure Reactions through Intramolecular Oxidative C−H/C−H Coupling between Two (Hetero)aromatic Rings

cyclization of diphenyl ethers and diphenylamines in AcOH or TFA.208 In 1999, Åkermark and co-workers accomplished the aerobic palladium-catalyzed intramolecular oxidative coupling of diaryl amines, benzanilides, and diaryl ethers in AcOH.209 Dioxygen was used as the oxidant in this protocol. Moderate-to-good yields of tricyclic biaryl products were obtained. For more reactive diaryl amines, only Pd(OAc)2 was required as the catalyst. However, less reactive diphenyl ethers and benzanilides required more electrophilic palladium trifluoroacetate together with Sn(OAc)2.

compounds, especially tricyclic bi(hetero)aryl moieties (Scheme 160). Various natural products and their derivatives have been achieved through the intramolecular ring closure reactions. As early as 1974, Itatani and co-workers described the palladiumpromoted intramolecular oxidative coupling of electron-rich diaryl ethers for the synthesis of dibenzofurans.207 Åkermark and co-workers disclosed the palladium-promoted intramolecular 8841


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Scheme 165. Palladium-Catalyzed Intramolecular Oxidative Coupling of Biaryl Sultams

Scheme 167. Pd-Catalyzed Intramolecular Oxidative Arylation of Imidazoles

Scheme 168. Synthesis of Ladder-Type π-Conjugated Molecules

Scheme 166. Pd-Catalyzed Intramolecular Arylation of 1,2,3Triazoles

Later on, Menéndez and co-workers reported a palladiumcatalyzed microwave-assisted intramolecular oxidative biaryl coupling under acid-free condition (Scheme 162).211 Three naturally occurring oxygenated carbazoles, namely murrayafoline A, 2-methoxy-3-methylcarbazole, and glycozolidine, were synthesized by this reaction. Fujii and Ohno almost simultaneously presented a palladium-catalyzed one-pot N-arylation and oxidative biaryl coupling to synthesize carbazoles (Scheme 163).212 Besides electron-rich aryl rings, electron-deficient aryls could also undergo intramolecular oxidative coupling. In 2012, Cheng reported the palladium-catalyzed intramolecular oxidative cyclization of diaryl ketones for the synthesis of fluorenones (Scheme 164).213 Ketones with both the electron-donating and -withdrawing group on the aryl moieties are effective substrates. Laha and co-workers achieved the palladium-catalyzed intramolecular oxidative coupling for the synthesis of annulated biaryl sultams (Scheme 165).214,215 A catalytic system comprised of Pd(OAc)2/AgOAc/tBuOK was employed. A mixture of

In 2008, Fagnou and co-workers further improved the yields of palladium-catalyzed intramolecular oxidative coupling of diaryl amines under air (Scheme 161).210 In this work, PivOH was demonstrated as a better solvent than AcOH for this transformation, leading to greater reproducibility, higher yields, and broader scope. Besides diaryl amines, diaryl ethers and N-benzoyl indoles could also undergo oxidative ring closure reactions to give the corresponding polycycles in good yields. 8842


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Scheme 169. Synthesis of π-Conjugated Compound 36

Scheme 170. Pd-Catalyzed Intramolecular C−H/C−H Coupling for the Synthesis of Condensed Aromatic Compounds

Scheme 171. Pd-Catalyzed Synthesis of Indolo[3,2-c]coumarins

tolerance. A free −NH moiety on sulfonanilide is essential to this cyclization reaction. Other N-substituted substrates failed to

PivOH and AcOH (3:1) was used as the solvent. This reaction exhibited a broad substrate scope and a good functional group 8843


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Scheme 172. Synthesis of Medium-Ring-Containing Indoles by Intramolecular Oxidative Coupling

Scheme 173. Synthesis of Fluorene Derivatives by RhCatalyzed Intramolecular Oxidative Coupling

Scheme 174. Rh- and Ir-Catalyzed Oxidative Cyclization for the Synthesis of Fluorene Derivatives

undergo this transformation. This protocol could be extended to N-arylsulfonyl indoles, affording a diverse set of substituted indole-aryl sultams.215

Intramolecular oxidative coupling between a phenyl ring and a heteroaromatic moiety provides a straightforward alternative to 8844


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Scheme 175. Synthesis of Fluorene Derivatives by RhCatalyzed Intramolecular Oxidative Coupling Using Oxygen as the Terminal Oxidant

Scheme 177. Rh-Catalyzed Intramolecular Arylation of Imidazoles

Scheme 178. Synthesis of Ellipticine by Intramolecular Oxidative Coupling

heteropolycycles, especially π-fused heteroaromatic systems. In 2010, Ackermann and co-workers described a palladiumcatalyzed intramolecular arylation of 1,2,3-triazoles under ambient pressure of air (Scheme 166).216 In a catalytic system comprised of Pd(OAc)2 (5.0 mol %), Cu(OAc)2 (1.0 equiv), and PhMe/PivOH (6/1) as the solvent, a set of heteroannulated phenanthrenes were furnished in moderate-to-excellent yields. Bao and co-workers disclosed an intramolecular oxidative arylation of the C2 position of imidazoles to synthesize imidazole- or benzimidazole-fused isoquinoline polyheteroaromatic compounds (Scheme 167).217 More recently, Kanai and Kuninobu reported the synthesis of heteroatom-containing ladder-type π-conjugated compounds by intramolecular oxidative C−H/C−H cross-coupling (Scheme 168).218 Through the catalysis of Pd(OPiv)2, a set of ortho-

phenylene-, heteroarom- or carbonyl-bridged biaryls could be converted to the corresponding ladder-type π-conjugated compounds. The choice of oxidant was dependent on the nature of substrates. For the substrates with an electron-withdrawing linkage, such as a carbonyl group or phosphine oxide moiety, AgOPiv was used as the oxidant. When the two coupling moieties were linked by an electron-rich group, such as an amino group, a weaker oxidant Cu(OPiv)2 gave higher yields. It is believed that this reaction proceeded through a CMD mechanism. This protocol was applied to construct a large π-conjugated compound 36, which showed blue and light blue fluorescence in the CH3Cl (or THF) solution and in the solid state, respectively (Scheme 169). Almost at the same time, the palladium-catalyzed intramolecular C−H/C−H coupling of 3-

Scheme 176. Rh-Catalyzed Intramolecular Oxidative Coupling of 3-Phenoxybenzoic Acids

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Scheme 179. Synthesis of Carbazomadurin B by Intramolecular Oxidative Coupling

The above-mentioned examples mainly focus on the formation of five- or six-membered rings. The construction of medium-ring biaryls represents a more challenging work. In 2011, Greaney and co-workers reported the intramolecular oxidative C−H coupling for the synthesis of medium-rings (Scheme 172).222 In the presence of Pd(OAc)2 (10 mol %), K2CO3 (1.0 equiv), and Cu(OAc)2 (3.0 equiv), a set of indolecontaining medium-ring biaryls, including seven- and eightmembered rings, were synthesized in moderate-to-excellent yields. In addition to palladium catalysis, rhodium-catalyzed intramoleuclar oxidative coupling of two (hetero)aromatic moieties have also been studied extensively. In 2012, Satoh and Miura reported the rhodium-catalyzed intramolecular oxidative coupling of two arenes to afford fluorene derivatives (Scheme 173).223 Treatment of 1-amino-1,1-diarylalkanes with the combination of RhCl(cod)2 and Cu(OAc)2·H2O in o-xylene could smoothly deliver fluorene derivatives. The amino group was thought to work as a directing group for the C−H activation process. 2,2-Diphenylalkanoic acids were also effective substrates, but [RhCpECl2]2 (CpE = 1,3-bis(ethoxycarbonyl)-2,4,5trimethylcyclopentadienyl) was used as the catalyst instead. Later on, the same group further developed the rhodium- and iridiumcatalyzed oxidative cyclization of 2,2-diphenylalkanoic acids and triarylmethanols using Cu(OAc)2·H2O as the oxidant, respectively (Scheme 174).224 Recently, an intramolecular oxidative cyclization using molecular oxygen as the terminal oxidant was reported as well (Scheme 175).225 Recently, the same group described a rhodium-catalyzed intramolecular oxidative coupling of 3-phenoxybenzoic acids to produce dibenzofuran-1-carboxylic acid derivatives (Scheme 176).226 [Cp*Rh(MeCN)3][SbF6]2 and [RhCl(cod)]2 were proved to have similar activity in this reaction. In addition, Kambe and co-workers achieved the rhodium-catalyzed oxidative intramolecular C−H/C−H coupling between the C2 position of imidazole and a benzene ring (Scheme 177).227 On the basis of the transition metal-mediated/catalyzed intramolecular oxidative cyclization reactions, many natural products and analogues have been synthesized. For example, as early as 1980, Miller reported the synthesis of ellipticine by using a stoichiometric amount of Pd(OAc)2 in a mixture of TFA and AcOH (Scheme 178).228 Knölker and co-workers demonstrated the application of intramolecular C−H/C−H oxidative coupling of diarylamines to synthesize a set of carbazole alkaloids, including carbazomadurin B (Scheme 179),229 clausine L, mukonidine, pityrizazole (Scheme 180),230 and euchrestifoline and girinimbine (Scheme 181).231 Fagnou and co-workers described the synthesis of three naturally occurring tricyclic carbazoles, murrayafoline A, clausenine, and mukonine, through intramolecular oxidative

Scheme 180. Synthesis of Clausine L, Mukonidine, and Pityrizazole by Intramolecular Oxidative Coupling

Scheme 181. Synthesis of Euchrestifoline and Girinimbine by Intramolecular Oxidative Coupling

aryloxythiophenes and 3-aryloxybenzo[b]thiophenes was reported by Satoh and Miura (Scheme 170).219 A set of thieno[3,2b]benzofurans and [1]benzothieno[3,2-b]benzofurans were provided in moderate-to-high yields. It should be noted that the rhodium catalyst system comprised of [RhCp*Cl2]2 and Cu(OAc)2·H2O exhibited much less efficiency than the palladium catalyst system in this transformation. Later, the Pd(TFA)2/AgOAc catalytic system was further used for the synthesis of benzobis- and benzotrisbenzofurans from diaryloxyand triaryloxybenzenes.220 Lan and You reported a palladium-catalyzed intramolecular oxidative coupling of (hetero)aryl carboxylic esters (Scheme 171).221 Moderate-to-good yields were obtained. Associated with the palladium-catalyzed C−H carbonylation of (hetero)arenes with formates, this protocol provided a concise approach to a set of indolo[3,2-c]coumarins. 8846


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Scheme 182. Synthesis of Murrayafoline A, Clausenine, and Mukonine by Intramolecular Oxidative Coupling

Scheme 183. Synthesis of Prodigiosin, Prodigiosene, and Desmethoxyprodigiosin by Intramolecular Oxidative Coupling of Bipyrroles

Bipyrrole structures widely exist in natural products and analogues. In 1988, Boger and co-workers reported the synthesis of prodigiosin, a red pigment isolated from Serratia marcescens, through an intramolecular oxidative coupling strategy (Scheme 183).232 Treatment of 1,1′-carbonyldipyrrole with polymersupported Pd(OAc)2 in acetic acid gave the intramolecular coupled product in a 96% yield. Following transformations of this intermediate gave prodigiosin in a 20% overall yield. In addition, naturally occurring parent pyrrolylpyrromethene, prodigiosene, and desmethoxyprodigiosin were also synthesized based on this protocol.

Scheme 184. Pd-Catalyzed Intramolecular Oxidative Coupling of Bisindolylmaleimides

cyclization of diarylamines with association of Buchwald-Hartwig amination (Scheme 182).210 8847


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Scheme 185. Synthesis of Glycosidated Fluoroindolocarbazole by Rh-Catalyzed Intramolecular Oxidative Cyclization

Wang and co-workers demonstrated the application of intramolecular oxidative coupling of bisindolylmaleimides for the synthesis of rebeccamycin aglycone and related indolo[2,3a]pyrrolo[3,4-c]carbazoles (Scheme 184).233 Pd(OAc)2 (5.0 mol %) was used as the catalyst. CuCl2 (1.0 equiv) was employed as the co-oxidant of air. It is noted that this reaction is very practical and could be performed on more than a 3 kg scale. In addition, the synthesis of glycosidated fluoroindolocarbazole by using a rhodium(III)/copper(II) catalytic system was also demonstrated by Witulski (Scheme 185).234

Scheme 187. FeCl3-Mediated Coupling of Oxygenated Aromatic Compounds

7. OXIDATIVE AROMATIC COUPLING OTHER THAN C−H ACTIVATION The oxidative coupling reactions mentioned above involve the C−H activation processes. However, oxidative aromatic coupling Scheme 186. Mechanism of Oxidative Aromatic Coupling

Scheme 188. MoCl5-Mediated Oxidative Aryl−Aryl Coupling Reaction

reactions could also take place in the presence of an oxidant or a Lewis acid, such as AlCl3, FeCl3, CuCl2, Cu(OTf)2, MoCl5, DDQ, and hypervalent iodine reagents.42−46 These reactions generally do not undergo a C−H activation process and typically require the use of electron-rich (hetero)aromatic compounds as the substrate.235−237 The regioselectivity in these reactions highly depend on the electronic nature of the potential reaction sites. Two mechanisms are often encountered in these reactions

(Scheme 186). One involves a radical cation intermediate and the other contains an arenium cation species. Although these reactions do not involve a C−H activation process, we still would like to give a very brief introduction of this reaction owing to its 8848


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Scheme 189. MoCl5-Mediated Oxidative Trimerization of oDialkoxybenzenes

Scheme 192. Cross-Coupling of Naphthols with Naphthamines

Scheme 193. Cu(II)-Catalyzed Oxidative Homocoupling of 2Naphthols

Scheme 190. MoCl5-Mediated Oxidative Coupling of 9,10Phenanthrenequinones

(HBCs)238−240 and triphenylenes.241,242 In this section, we will not emphasize the mechanism but try to show some common reaction systems and their utilizations and limitations. Oxygenated aromatic compounds are often used as the substrates. The substitution pattern of the substrate has a significant effect on the structure of product and the corresponding yield (Scheme 187). For example, treatment of 1,2-dimethoxybenzenes with FeCl3 /H2 SO 4243 or FeCl3 / Al2O3244 in CH2Cl2 led to the corresponding triphenylene products in high yield. However, the reactions of 1,4dialkoxybenzenes delivered the dimerized products in low yield, partly owing to further coupling of the resulting products.245 When a bromine atom was installed at the C2-site of 1,4-dimethoxybenzene or the C4-position of 1,2-dimethoxybenzene, the corresponding dimers were obtained in high yields. MoCl5 is a Lewis acid widely used in the oxidative coupling of arenes owing to its strong Lewis acid character and high oxidation potential.246 Kovacic and Lange reported the first MoCl5-mediated oxidative coupling reaction of aromatic compounds.247 However, a low yield of the polymer was obtained. Waldvogel and co-workers developed the MoCl5mediated oxidative coupling of phenolic oxygen protected arenes (Scheme 188).248 These reactions were typically completed in 50 min, and the yields were good-to-excellent. In addition, protective groups such as cyclic acetals and ketals, triisopropylsilyl, alkoxycarbonyl methyl, and 2-chloroethyl were compatible under these conditions. Kumar and Manickam reported the oxidative trimerization of o-dialkoxybenzenes to hexaalkoxytriphenylenes (Scheme 189).249 Both symmetrical and unsymmetrical triphenylenes could be obtained in moderate-toexcellent yields. The addition of H2SO4 was proved to have a slightly negative effect on the yield. Although these reactions typically require the use of electron-rich substrates, alkoxyben-

Scheme 191. Highly Selective Oxidative Cross-Coupling between Substituted 2-Naphthols

high efficiency in the synthesis of polycyclic aromatic hydrocarbons (PAHs), such as hexa-peri-hexabenzocoronenes 8849


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Scheme 194. Cu(II)-Catalyzed Cross-Coupling of 2-Naphthol with Tetrafluoronaphthol

phenoxy anion with an electron-deficient group. Later, Kočovský reported the cross-coupling of naphthols with naphthamines under similar conditions (Scheme 192).260 Despite high efficiency, these methods are not catalytic processes. A breakthrough in copper-catalyzed oxidative coupling of 2naphthols was made by Nakajima and Koga (Scheme 193).261 A stable CuCl(OH)·TMEDA complex was used as the catalyst, and O2 or air was employed as the oxidant. Excellent yields were obtained for the substrates with both electron-donating and -withdrawing substituents. Notably, the cross-coupling of 2naphthol with tetrafluoronaphthol was also achieved by using CuCl(OH)·TMEDA as the catalyst (Scheme 194).262 Seminal works on enantioselective oxidative coupling of phenols with naphthols were developed by Wynberg,263 Brussee,264,265 Yamamoto266,267 and Kočovský.268,269 They found that functionalized chiral BINOLs could be synthesized by employment of a stoichiometric amount of chiral copper(II) amine complexes. Nakajima developed an enantioselective catalytic homocoupling of 3-hydroxy-2-naphthoates by using a 270,271 L-proline derived copper catalyst (Scheme 195). Kozlowski and co-workers demonstrated that a 1,5-diaza-cis-decalin copper(II) catalyst system with dioxygen as the oxidant showed high selectivity (Scheme 196).272,273 Later on, a variety of natural products were synthesized on the basis of the chiral diamine/ copper/O2 system (Scheme 197).41,274−282 Canesi283 and Kita284,285 demonstrated stoichiometric amounts of hypervalent iodine reagents could promote the cross-coupling of aromatic compounds. Typically, either HFIP or BF3/CH2Cl2 was used as the solvent to improve the oxidative efficiency of hypervalent iodine reagent. As a representative example, treatment of naphthalenes and electron-rich arenes with stoichiometric amounts of phenyliodine(III) bis(trifluoroacetate) (PIFA) could afford the corresponding crosscoupling products in high yields and selectivity (Scheme 198).284 In the proposed process, naphthalene initially reacts with PIFA to form a π-complex, which then generates a radical cation through a single-electron oxidation process. This radical species could then be attacked by another aromatic molecule. Subsequent oneelectron oxidation and deprotonation would provide the corresponding mixed biaryls (Scheme 199). More recently, Kita and co-workers reported the hypervalent iodine-catalyzed oxidative cross-coupling of phenols using oxone as a terminal oxidant (Scheme 200).286 This reaction features a broad substrate scope, a good functional group tolerance, and mild conditions. In addition, it precludes the overoxidation of the coupling products. The cross-coupling between an arene and a heteroarene or between two heteroarenes mediated by hypervalent iodine reagents has also been demonstrated (Scheme 201).287,288

Scheme 195. Aerobic Oxidative Coupling of 3-Hydroxy-2naphthoates with Chiral Diamine-Copper Complex

Scheme 196. Enantioselective Oxidative Biaryl Coupling Catalyzed by 1,5-Diazadecalin Copper Complex

zenes with electron-withdrawing functional groups could undergo intramolecular oxidative cyclization as well (Scheme 190).250 1,1′-Bis-2,2′-naphthols (BINOL) are a class of biaryl structures widely occurred in natural products and ligands.7,251,252 A broad scope of transition-metals such as Fe(III),253,254 Mn(III),255,256 and Cu(II)257 have been demonstrated as the effective promoters in the 2-naphthol coupling reactions. Among them, copper has proved particularly efficient.258 One of the early examples in the oxidative crosscoupling of substituted 2-naphthols was demonstrated by Závada and co-workers (Scheme 191).259 Treatment of two differently substituted 2-naphthols with excess CuCl2 and tBuNH2 or EtNH2 under strictly anaerobic conditions, a set of cross-coupled products could be afforded in excellent yields and high selectivities. The reaction was proposed to involve two species of different nature. The relatively electron-rich component would undergo a single-electron transfer process to generate a radical species, which could be nucleophilically attacked by a 8850


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Scheme 197. Natural Products Synthesized by Using 1,5-Diaza-cis-decalin Copper(II) Catalyst System

generated and accumulated by low-temperature electrochemical oxidation. This cation is then allowed to react with another arene compound under nonelectrolytic conditions to give the desired cross-coupled product. Under the optimized conditions, naphthalene derivatives reacted with electron-rich (hetero)arenes such as pentamethylbenzene, indoles, and benzothiophens in good yields and high regioselectivities. In the case of phenols, of which the reaction is often complicated by overoxidation and carbon−oxygen bond formation, Waldvogel and co-workers found that electrolysis conditions using borondoped diamond (BDD) electrode as an anode and HFIP as a solvent were highly efficient for the cross-coupling. With this combination, a variety of phenols could undergo electroorganic cross-coupling in good yields and high selectivity.290−292 More recently, they further achieved the synthesis of partially protected nonsymmetric biphenols by using an unprotected phenol and a silyl protected phenol as substrates (Scheme 203).293 To obtain a high chemoselectivity of cross-coupling over homocoupling, the substrates with higher oxidation potential (protected phenols) were used in excess amounts. Triisopropylsilyl (TIPS) was found to be the most suitable protecting group due to its stability under electrolysis conditions, remarkably positive effect on the yields of cross-coupling and readily removal ability. Under identical electrolysis conditions, this partially protected nonsymmetric biphenol synthesis typically gave higher yields than the direct electrochemical cross-coupling of unprotected phenols and phenol-arene cross-coupling.290−292 Furthermore, these oxidative aromatic coupling reactions have proved highly valuable for the synthesis of π-extended polycyclic aromatic products often encountered in organic materials. Hexaperi-hexabenzocoronene (HBC) could be obtained by sequential cyclotrimerization of tolane derivatives through the catalysis of [Co2(CO)8] and intramolecular oxidative cyclization of the resulting hexa(4-alkylphenyl)benzene with Cu(OTf)2/AlCl3/ CS2238 or FeCl3/CH3NO2294 (Scheme 204). Jones and Wong demonstrated that even electron-deficient arenes could undergo intramolecular oxidative coupling to afford the desired fused πconjugated system. 295 Using a DDQ/CF3SO 3H system, hexaphenylbenzene-bearing electron-withdrawing groups such

Scheme 198. PIFA-Mediated Oxidative Cross-Coupling of Arenes

Scheme 199. Proposed Mechanism for Oxidative CrossCoupling

Electroorganic synthesis is also a viable method for oxidative aromatic coupling. Because only electron is used as a reagent and no waste is released, this strategy is highly ecological and atomeconomic. To obviate the homocoupling and overoxidation, Yoshida and co-workers developed a biaryl cross-coupling using “radical-cation pools” strategy (Scheme 202).289 In the absence of another coupling partner, an aromatic radical cation is first 8851


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Scheme 200. Organo-Iodine(III)-Catalyzed Oxidative Phenol-Arene and Phenol−Phenol Cross-Coupling Reaction

Scheme 201. Hypervalent Iodine Reagent-Mediated CrossCoupling of (Hetero)arenes

Scheme 203. Synthesis of Partially Protected Nonsymmetric Biphenols by Anodic Corss-Coupling

Scheme 202. Biaryl Cross-Coupling Using “Radical-Cation Pools”

Scheme 204. Synthesis of Hexa-peri-hexabenzocoronene

as Br, F, and CF3 was readily converted to the desired hexa-perihexabenzocoronen in high yields (Scheme 205). Bis- and oligohexa-peri-hexabenzocoronenes239,240 and even nanographenes296 were successfully prepared using a FeCl3/CH2Cl2 system (Scheme 206). Dyes such as porphyrins297−301 and 4,4difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)302−304 could 8852


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Scheme 205. Synthesis of Electron-Poor Hexa-peri-hexabenzocoronenes

Scheme 206. Synthesis of Bis- and Oligohexa-peri-hexabenzocoronenes

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Scheme 207. Dyes Synthesized by Oxidative Coupling Reactions

be oxidatively coupled to give a set of π-extended molecules with

ties from their precursors, thus providing a novel approach to

the assistance of an appropriate oxidant (Scheme 207). The formed products often exhibited different photophysical proper-

exploit high-performance organic molecules. 8854


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awarded “the national ten thousand talents plan” (2016). He is also a principal scientist for the National High Technology Research and Development Program of China (863 Program) (2013). His research interests focus on developing new concepts and strategies to synthesize π-conjugated frameworks, especially via the transition metal catalyzed C−H functionalization of (hetero)arenes, and exploring their applications in the construction of organic optoelectronic materials.

8. CONCLUSIONS In the past few years, the transition metal-promoted oxidative C−H/C−H coupling reactions between two (hetero)arenes have achieved a significant progress. Diverse biaryl structures and even more complex extended π-conjugated systems have been constructed based on these protocols. Compared with the C−X/ C−M coupling reactions, these oxidative C−H/C−H coupling reactions have exhibited the advantage of high tolerance to reactive functional groups, especially halo groups. This increasingly growing field provides a valuable opportunity to rapidly assemble a large library of poly(hetero)cycles and exploit their applications in optoelectronic materials and pharmaceuticals. The regioselectivity issues in these reactions have been partly resolved by incorporation of a directing group, tuning of steric/electronic effect of substrates, and/or catalytic system. Noble transition metals such as Pd and Rh are still the most widely used catalysts. Exploration of other inexpensive metal catalysts, including Co, Cu, Ni and Fe, would be an important research topic in the future. In addition, high reaction temperature and stoichiometric amounts of metal oxidants are typically required. Thus, the development of milder reaction conditions involving cheaper and less toxic oxidants such as O2 is still highly desired. Furthermore, although the oxidative C−H/ C−H coupling reactions between two (hetero)arenes have exhibited their potentials in the synthesis of natural products and discovery of novel optoelectronic materials, the research in this area is still in its infancy and it is predictable that more and more attention will be focused on this field.

ACKNOWLEDGMENTS This work was financially supported by grants from the National NSF of China (Grants 21432005, 21272160, and 21321061).

ABBREVIATIONS Ac acetyl acac acetylacetonate Ar aryl bmim 1-butyl-3-methylimidazolium Bn benzyl Boc tert-butoxycarbonyl BQ benzoquinone t Bu tert-butyl bzq benzoquinoline CIE Commission Internationale de l’Eclairage CMD concerted-metalation-deprotonation COD cycloocta-1,5-diene Cp* pentamethylcyclopentadienyl CpE 1,3-bis(ethoxycarbonyl)-2,4,5-trimethylcyclopentadienyl CPDTO cyclopentadithiophen-4-one Cy cyclohexyl DavePhos 2 - d i c y c l o h e x y l p h o s p h i n o - 2 ′ - ( N , N dimethylamino)biphenyl DCE 1,2-dichloroethane DMA dimthylacetamide DMF dimethylformamide DMP dimethyl phthalate DMSO dimethyl sulfoxide DPP 3,6-di(thiophen-2-yl)-2,5-dihydro-1,4diketopyrrolo[3,4-c]pyrrole dppb 1,4-bis(diphenylphosphino)butane dppf 1,1′-bis(diphenylphosphino)ferrocene DSSC dye-sensitized solar cell DTPO 5H-dithieno[3,2-b:2′,3′-d]pyran-5-one EDTA ethylenediaminetetraacetic acid ESIPT excited-state intramolecular proton transfer FW formular weight GC/MS gas chromatography/mass spectrometer Glc glucose Gly glycine Het hetero n Hex n-hexyl HOMO highest occupied molecular orbital HPA heteropoly acid Ile isoleucine IMes 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene KIE kinetic isotope effect LUMO lowest unoccupied molecular orbital Me methyl Mes 2,4,6-trimethylphenyl MesBr mesityl bromide MOM methoxymethyl

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Jingsong You: 0000-0002-0493-2388 Notes

The authors declare no competing financial interest. Biographies Yudong Yang was born in Sichuan (China). He received his B.Sc. degree from Beijing University of Chemical Technology in 2007, and Ph.D. under the supervision of Professor Norio Shibata at Nagoya Institute of Technology (Japan) in 2014. Then he returned to China and joined Sichuan University as a lecturer. His current interest focuses on transition-metal catalyzed C−H functionalization and synthesis of heterocycles. Jingbo Lan received his Ph.D. degree in Organic Chemistry from Sichuan University in 2004 and then joined Sichuan University. Since 2011, he has been a full professor. His research interests include synthetic methodology based upon C−H bond functionalization and their applications in the expeditious syntheses of organic functional materials. Jingsong You grew up in Chongqing, China, and later attended Chongqing University. In 1998, he received his Ph.D. from Sichuan University. He then worked as a postdoctoral fellow or a research scientist at National Chung-Hsing University (Taiwan), Institute für Organische Katalyseforschung (Germany), Iowa State University (USA), and University of California, Irvine (USA). In 2004, he joined the chemistry faculty of Sichuan University as a full professor. Now he is a vice dean in the College of Chemistry. He is a winner of the National Science Foundation for Distinguished Young Scholars (2010). He was 8855


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MonoPhos N,N-dimethyldinaphtho[2,1-d:1′,2′-f ][1,3,2]-dioxaphosphepin-4-amine nbd norbornadiene NFSI N-fluorobenzenesulfonimide NFPT N-fluoropyridin-1-ium triflate NMR nuclear magnetic resonance NMP N-methyl-2-pyrrolidone OFET organic field-effect transistor OLEDs organic light-emitting diode OPVs organic photovoltaic pGlu pyroglutamic acid PBX 1-pivaloyloxy-1,2-benziodoxol-3(1H)-one Ph phenyl Phen 1,10-phenanthroline PIFA phenyliodine(III) bis(trifluoroacetate) PIP (pyridine-2-yl)isopropyl Piv pivalyl PS polymer supported i Pr isopropyl r.t room temperature SEAr electrophilic aromatic substitution SET single-electron-transfer TBAB tetrabutylammonium bromide TBAI tetrabutylammonium iodide TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl Tf trifluoromethane sulfonyl TFA trifluoroacetic acid THAC tetrahexylammonium chloride THF tetrahydrofuran TIPBr 2-bromo-1,3,5-triisopropylbenzene TIPS triisopropylsilyl TM transition metal TPA triphenylamine Ts p-toluenesulfonyl X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

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