Oxidative Coupling between Two Hydrocarbons - ACS Publications

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Oxidative Coupling between Two Hydrocarbons: An Update of Recent C−H Functionalizations Chao Liu,† Jiwen Yuan,† Meng Gao,‡ Shan Tang,† Wu Li,† Renyi Shi,† and Aiwen Lei*,†,‡ †

College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, People’s Republic of China ‡ National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, Jiangxi 330022, People’s Republic of China Corresponding Author Notes Biographies Acknowledgments References

1. INTRODUCTION C−C bond formation is a fundamental transformation in organic synthesis. The development of new synthetic methodology could be considered as a way of pursuing a novel method for prolonging the carbon chain. Before the introduction of transition metal catalysis, the development of C−C bond formation was very sluggish and limited. Since its initial discovery, transition metal-catalyzed cross-coupling reactions have emerged as a powerful tool for C−C bond formations during the past 40 years.1 They have not only been studied in academia but also widely applied in chemical industries and many synthetic technologies.2,3 Those classic transformations are mostly based on the bond formations between nucleophiles and electrophiles, which are more or less obtained from the prefunctionalization of their corresponding hydrocarbons. Along with the requirement of green chemistry for atomeconomy and step-economy transformations in modern chemical society for constructing new chemical bonds, more efforts were devoted to develop novel synthetic methodology by directly using hydrocarbons as the nucleophiles to achieve C−H functionalizations, such as the cross-couplings between organohalides and C−H nucleophiles.4 However, organohalides still need to be prepared via prefunctionalization of the corresponding hydrocarbons. The ideal C−C bond formation would be the direct cross-coupling between two hydrocarbons. In this case, a proper oxidant has to be used to accept the redundant electrons. This type of reaction is named oxidative coupling.5 During the past several years, much attention has been paid to developing novel methods for the oxidative coupling between two hydrocarbons. In 2011, several comprehensive reviews were reported to summarize the oxidative couplings between two C−H nucleophiles prior to the year of 2011.5−7 However, this is a “young” and fast-developing area. It is still currently in rapid development. Since then, there has been a tremendous amount of publications on oxidative couplings between two hydrocarbons. However, many challenges remain

CONTENTS 1. Introduction 2. Palladium Catalysis 2.1. Oxidative Coupling between Csp−H and Csp2−H 2.2. Oxidative Coupling between Csp2−H and Csp2−H 2.2.1. Arene−Arene Coupling 2.2.2. Arene−Alkene Coupling 2.2.3. Alkene−Alkene Coupling 2.2.4. Arene−Aldehyde Coupling 2.3. Csp3−H Related Oxidative Cross-Couplings 3. Copper Catalysis 3.1. Oxidative Coupling between Csp−H and Csp2−H 3.2. Oxidative Coupling between Csp−H and Csp3−H 3.3. Oxidative Coupling between Csp2−H and Csp2−H 3.4. Oxidative Coupling between Csp2−H and Csp3−H 3.5. Oxidative Coupling between Csp3−H and Csp3−H 4. Rhodium Catalysis 4.1. Arene−Alkene Coupling 4.2. Arene−Arene Coupling 4.3. Alkene−Alkene Coupling 4.4. Arene−Aldehyde Coupling 5. Ruthenium Catalysis 5.1. Arene−Alkene Coupling 5.2. Alkene−Alkene Coupling 5.3. Alkane-Related Coupling 6. Catalysis with Other Transition Metals 7. Transition-Metal-Free Oxidative Couplings 8. Conclusions Author Information © XXXX American Chemical Society

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Received: August 7, 2014

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DOI: 10.1021/cr500431s Chem. Rev. XXXX, XXX, XXX−XXX

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in this area. As hydrocarbons usually have different reactive C− H bonds, achieving the regioselective C−H functionalization is still challenging. Moreover, the understanding of this concept is superficial and incomplete, and the mechanistic study in this area is still in its primary stage. An in-time summary in this area is highly desirable to provide certain regularity in this area. In this Review, we will summarize the recent advances of this chemistry since the year 2011. Transition metal catalysts combined with oxidants are essential for achieving the direct C−H functionalization. The topics are arranged on the basis of transition metal catalysis. The most applied transition metal catalysts are based on Pd, Cu, Ru, and Rh. Therefore, this Review majorly divides the sections by metal catalysis. It will provide guiding information for the understanding of each transition metal catalysis. As C−H nucleophiles usually have different hybrid carbons, each subsection will be divided by the reaction of Csp−H, Csp2−H, and Csp3−H, respectively.

Pd(OAc)2 was utilized as the catalyst and CuCl2 as the cocatalyst. Two equivalents of Ag2O was used as the oxidant in open air condition. Under nitrogen atmosphere, the reaction failed to afford the desired coupling product. Because of the facile oxidative homocoupling of terminal alkynes, slow addition of terminal alkynes via a syringe pump was necessary to reach moderate to good yields of the cross-coupling products. Similarly, with Pd-complex 4 as the catalyst precursor and silver salt as the oxidant, the oxidative coupling between terminal alkynes and a variety of five-membered heteroarenes was later achieved by Shibahara and Miura (Scheme 2).11 Scheme 2

2. PALLADIUM CATALYSIS Palladium complexes are the most utilized catalysts in C−H functionalizations.8 It might be due to the high electrophilicity of this metal ion and the easy electropalladation of C−H bonds with palladium. Therefore, palladium complexes still dominate the catalytic systems for oxidative couplings between two hydrocarbons. 2.1. Oxidative Coupling between Csp−H and Csp2−H

The Sonogashira coupling is the classic method for constructing Csp−Csp2 bonds, in which aryl halides were applied to couple with terminal alkynes in the presence of palladium and copper catalysts.9 Direct utilization of aromatic C−H to replace C−halide for Csp−Csp2 bond formation would be a more appealing approach. Although it is still a challenging transformation, several achievements have been demonstrated. In 2011, Shi, Larock, and co-workers demonstrated an oxidative coupling of N-substituted sydnones 1 with terminal alkynes for the synthesis of 4-alkynylsydnones 3 (Scheme 1).10

Benzoxazole 5 and benzothiazole 6 as well as thiazole 7, benzimidazole 8, imidazole 9, and imidazo[1,5-a]pyridines 10 (with Pd(OAc)2 as the catalyst precursor) were well tolerated. In this transformation, the terminal alkyne substrates also needed to be added dropwise in a specific period of time. Recently, Su and co-workers reported a palladium-catalyzed oxidative cross-coupling between terminal alkynes and thiophenes (Scheme 3).12 The reaction was conducted with a low catalyst loading (0.2 mol %). In this case, Pd2(dba)3 was used as the catalyst precursor and Ag2CO3 was utilized as the oxidant under N2 protection. No dropwise addition of terminal alkynes was required for this transformation. Other fivemembered heteroarenes such as pyrroles and oxazole were also tested in this transformation. Chang reported an oxidative cross-coupling between terminal alkynes and arene 11, in which a pyridyl group was utilized as the directing group for achieving the cross-coupling (Scheme 4).13 In this case, Pd(acac)2 (10 mol %) was used as the catalyst, and 2 equiv of BQ (1,4-benzoquinone) was utilized as the oxidant. Kinetic isotope effect (KIE) studies showed that the hydrogen/deuterium KIE was significant in both intramolecular (kH/kD = 2.7) and intermolecular (kH/kD = 4.3) reactions (Scheme 5). These values indicate that Csp2−H bond cleavage may be related to the rate-limiting step.

Scheme 1

2.2. Oxidative Coupling between Csp2−H and Csp2−H

Palladium catalysis is majorly effective for the oxidative coupling of aromatic C−H nucleophiles.14−17 Lu and coB


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Scheme 3

Scheme 4

attention has been paid to oxidative cross-couplings between two hydrocarbons. 2.2.1. Arene−Arene Coupling. Along with the development of direct C−H functionalization of hydrocarbons, attention has been turned to focus on site-selective C−H transformations. However, controlling the selectivity is still challenging to date, especially for those simple none-directing monosubstituted arenes.20 Generally, substrates of crosscoupling between two different arenes could be divided into phenyl derivatives and heteroatom arenes. For the crosscoupling between two phenyl derivatives, directing groups are normally required for achieving high site-selectivity. In 2011, Cheng and co-workers reported a palladium-catalyzed cyclization reaction of N-methoxybenzamides 12 with arenes to directly synthesize phenanthridinones 13 (Scheme 6).21 In this transformation, CONHOMe was utilized as the directing group, which has previously been used as directing group for ortho-C−H functionalizations.22,23 Pd(OAc)2 was applied as the catalyst with K2S2O8 as the oxidant. It is worth noting that the reaction proceeded smoothly at 25 °C. The product phenanthridinone was believed to be generated via sequential oxidative C−C and C−N bond formations. The C−C bond forming product 14 was subjected to the reaction conditions to prove the oxidative C−N bond formations. The desired

Scheme 5

workers pioneered the catalytic oxidative cross-coupling between two aromatic C−H nucleophiles in 2006.18 However, the method was far from satisfactory, as both oxidative homocoupling and cross-coupling products were obtained in their reactions. In the next year, Fagnou and co-workers developed a highly selective oxidative cross-coupling between benzene and indole derivatives.19 Since then, considerable C


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Almost at the same time, Yu and co-workers reported a Pdcatalyzed oxidative cross-coupling between two arenes, in which a para-selective C−H arylation of monosubstituted arenes was achieved, and −CONHAr was utilized as the directing group (Scheme 9).24 Oxidant screening exhibited that the F+ type oxidant NFSI is crucial for the high para-selectivity. Other oxidants such as AgOAc or Cu(OAc)2 were ineffective for this cross-coupling. K2S2O8 afforded the coupling product in a good yield, yet with a low regioselectivity. Their previous C−H fluorination paper described the observation of some orthoarylation product with a relatively low para-selectivity, in which benzyltriflamide was utilized as the directing group,25 showing that the directing group is also crucial for the high paraselectivity. Recently, Oestreich and co-workers reported an oxidative arene−arene coupling between indoline 17 and simple arenes to achieve the C7-arylation (Scheme 10).26 Pd(OAc)2 was the choice of catalyst precursor. Na2S2O8 was applied as the terminal oxidant with TFA as the effective additive. An acetyl group at the indoline nitrogen was employed as a directing group. It was shown that the amide group alone is not sufficient to achieve the cross-coupling. An additional substituent at C2 was crucial. The steric repulsion between the C2 substituent and the amide group was believed to force the amide oxygen atom into the proximity of the hydrogen atom at the C7position, thereby facilitating the C−H bond activation. When monosubstituted arene was utilized as the coupling partner, low regioselectivity of the product 18 was obtained in this case. Besides amides, benzo[h]quinolines were also suitable substrates in oxidative arene−arene couplings, in which the coordinating nitrogen is a well-defined directing group.27 In 2011, Sanford and co-workers reported a site-selective palladium-catalyzed oxidative cross-coupling between benzo[h]quinoline and 1,3-disubstituted arenes (Scheme 11).28 Both the concentration and the steric/electronic properties of the quinone promoter were shown to have a significant influence on the site-selectivity. Generally, a high concentration of quinone resulted in a low site-selectivity. The ancillary ligand L leads to a complete reversal in site-selectivity for many arene substrates. It was shown that carboxylate ligands afforded the selective C−H activation of DMB at the meta-position. However, when carbonate was utilized as the ancillary ligand, the selectivity was completely changed to the ortho-position. DFT calculation was further applied to elucidate the origin of site-selectivity, which indicates that the anionic ligand does not induce a mechanism change at the elementary steps, and the predicted selectivity is equivalent for both carbonate and acetate at all steps. With acetate as the L ligand, the reductive elimination step seems to be more selectivity-controlling. With carbonate as the ligand, the C−H activation majorly influences the selectivity.29 In the absence of directing groups, site-selective oxidative C− H/C−H couplings have also been achieved, in which structurespecific aromatic hydrocarbons and heteroarenes were applied as the substrates. In 2011, Itami and co-workers reported an oxidative arene−arene coupling between fluoranthene 19 and simple arenes (Scheme 12). Pd(OAc)2 (10 mol %) was utilized as the catalyst and o-chloranil as the oxidant in the presence of AgOTf as the additive. The reaction took place highly regioselectively at the C3 position of fluoranthene 19.30 At the same time, polyfluoroarenes 20 were utilized to couple with simple arenes by Shi and co-workers (Scheme 13).31 Also, Pd(OAc)2 was used as the catalyst precursor. Ag2CO3 was

Scheme 6

product 15 was obtained in an excellent yield (Scheme 7). A tentative mechanism has been proposed (Scheme 8). The C−C Scheme 7

Scheme 8

bond formation was believed to proceed via a PdII/IV pathway. Persulfate salt was used as the oxidant to oxidize PdII to PdIV intermediate. Electropalladation of another arene then generates intermediate 16 followed by reductive elimination on PdIV species to generate the C−C coupling product 14. The high para-selectivity is very interesting, while no explanation was given in this report. The generated C−C coupling product 14 then entered another catalytic cycle for the intramolecular C−N bond formation. In this catalytic cycle, Pd0/PdII catalysis was proposed. D


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Scheme 9

Scheme 10

Scheme 11

the CHs of heteroarenes have specific site-reactivities, and therefore the site-selective C−H functionalization of heteroarenes is relatively easy-controllable. Moreover, heteroarene units are usually the key skeleton in many medicinal compounds and material sciences.3,32 Consequently, oxidative arene−arene couplings involving heteroarenes were investigated. Five-membered heteroarenes such as pyrrole and thiophene derivatives, and six-membered heteroarenes such as pyridine derivatives were mainly applied as coupling partners in the oxidative cross-couplings.33−39 In 2011, Stahl and co-workers reported a palladium-catalyzed regioselective cross-coupling between indole and benzene (Scheme 14).40 The use of 4,5-diazafluorene derivatives as ancillary ligands allowed the utilization of O2 as the sole oxidant. Different from the initial report on the oxidantcontrolled regioselectivity for the cross-coupling of indole with benzene,19,41 the regioselectivity at the C2 or the C3 position of

Scheme 12

applied as the oxidant. Weak acidic acid such as HOAc was shown to be more effective than strong acidic acid such as TFA. Diisopropyl sulfide (21) was found to be essential to promote the cross-coupling in high yields. The site-selectivity for the simple arenes is poor when it was monosubstituted, such as toluene and anisole, reacting with pentafluorobenzene to afford a mixture of meta/para isomers. As another large family of aromatic compounds, heteroarenes have been applied more in oxidative cross-couplings. Usually, E


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those arenes. Moreover, the regioselectivity is difficult to control. In 2012, Zhang and co-workers reported an oxidative cross-coupling between polyfluoroarenes with thiophene derivatives in the presence of Pd(OAc)2 as the catalyst with 5 mol % of Ag2O as the cocatalyst (Scheme 16).49 In this case, the polyfluoroarenes were required to be 3 equiv to the thiophene substrate. O2 was applied as the terminal oxidant. Both silver salt and O2 were vital to the generation of the desired coupling product. A mixed DMF/DMSO (1:1) system was utilized as the solvent. Besides thiophene derivatives, other heteroarenes like benzothiophene and indole were also suitable substrates for this transformation (24, 25). However, benzofuran (26) afforded a complex mixture. Kinetic isotope effect (KIE) experiments showed that the C− H bond cleavage of polyfluoroarenes is not involved in the ratedetermining step and the C−H bond cleavage of benzothiophene is the rate-determining step in the overall catalytic process. H/D exchange experiments showed that pentafluorobenzene was fully deuterated with D2O under optimized conditions, while no deuteration occurred for benzothiophene. The absence of Pd(OAc)2 also afforded fully deuteration of pentafluorobenzene. However, no deuteration was detected when the reaction was performed without Ag2O (Scheme 17). Therefore, cross-coupling is believed to be initiated from polyfluoroarene, and the silver salt may deprotonate the acidic polyfluoroarene. The oxidative cross-coupling between two different heteroarenes has also been extensively studied, as the biheteroarene skeletons are important building blocks in numerous important organic molecules.3 In 2011, Ofial and co-workers reported an oxidative cross-coupling between benzazoles 27 and azoles 28 by using palladium catalysis (Scheme 18).50 The cross-coupling took place selectively at both C2 positions of the substrates. The combination of Pd(OAc)2, Cu(OAc)2 with AgF or KF/ AgNO3 was found to be optimal to promote the cross-coupling. Condition screening showed that Cu2+, Ag+, and OAc− are critical for the success of the cross-coupling, while the source of those ions is not essential. This transformation is applicable to a

Scheme 13

indole in this report was controlled by properly choosing the neutral and anionic ligands. When ligand 22 and Pd(TFA)2 were utilized as the catalyst, the cross-coupling majorly occurred at the C3 position of indole substrates. However, when ligand 23 and Pd(OPiv)2 were applied as the catalyst, the cross-coupling majorly occurred at the C2 position of indole. For the indole substrates, both N-Piv and N-SO2Ph groups were well tolerated. Although the regioselectivity could be switched by choosing a proper ligand, only moderate selectivity was achieved. Similar to indole derivatives, other heteroarenes like azole-4carboxylates,42 benzoxazoles,43 2-substituted 1,2,3-triazole Noxides,44 xanthines,45 furan-2-carbonyls,46 quinolines,47 and imidazo[1,2-a]pyridine48 have also been respectively applied to couple with simple arenes under palladium catalysis. In those reaction systems, simple arenes were all used as solvents or cosolvents. Pd(OAc)2 was the uniform catalyst precursor. Details are summarized in Scheme 15. The requirement of a large access amount of simple arenes as the coupling partner as well as the solvent limits the scope of Scheme 14

F


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Scheme 15

Scheme 16

Scheme 17

variety of azoles to couple with benzothiazole and benzimidazoles. Imidazoles, oxazoles, and thiazoles are all suitable coupling partners (Scheme 18). Control experiments showed that Ag+ is vital for the selective cross-coupling, as only a trace amount of the homocoupling products 30 and 31 was observed in the presence of silver salt, while in the absence of silver salt, 30 and 31 increased dramatically (Scheme 19). Recently, a

similar catalytic system was applied to the oxidative crosscoupling of 1,3,4-oxadiazoles with benzothiazoles by Das and co-workers.51 The oxidative cross-coupling between benzothiazoles and thiophenes was recently achieved by Yang and co-workers, in which Pd(OAc)2/Phen was found to be the optimal catalyst with AgNO3 as the oxidant in DMSO solvent (Scheme 20).52 Benzothiazole is good coupling partner with thiophene (32), G


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the best among the investigated directing groups. Furthermore, the change of reaction conditions could switch the C2 and C3 selectivities on the cross-coupling between 38 and indole 39 (Scheme 23). A combination of Pd(OAc)2/Phen with AgF as the oxidant afforded a C2-selective product 40, while the combination of PdCl2(dppf)/X-Phos/CuCl with Cu(OAc)2· H2O as the oxidant afforded a C3-selective product 41. A tricky tandem 4-fold C−H activation then was carried out in the same report. Applying the reaction condition of C3selectivity introduced a heteroarene at the C3-position of indole to generate 42. Benzyl was utilized as the indole Nprotecting group. The introduced heteroarene further acted as a directing group to promote the intramolecular oxidative C−H/ C−H cross-coupling of 42 at the C2-position of the indole ring to afford the final product 43 in one pot (Scheme 24). By using N-heteroarenes N-oxide as the substrates, Li, Liu, and co-workers reported its coupling with thiazoles.55 Kuang and co-workers reported a cross-coupling between two different N-heteroarenes N-oxide (44 and 45)56 and a cross-coupling of pyridine N-oxides with five-membered heterocycles.57 Chupakhin and co-workers reported a cross-coupling between Nheteroarenes N-oxide 46 and indoles at C3-position.58 These reactions all selectively occurred at the ortho-position of the Noxide group. Pd(OAc)2 is the choice of catalyst precursor, and dioxane is the general solvent in those reports. Ag+ or Cu2+ salts are the applied oxidants (Scheme 25). As compared to pyridyl N-oxides, the direct cross-coupling of pyridine derivatives is more challenging, which may be due to the strong coordinative property of pyridine to transition metal catalysts. One of the solutions is the introduction of coordinative ligands to prevent the coordination of pyridine substrates. You and co-workers recently achieved an oxidative cross-coupling of pyridine with a variety of heteroarenes (Scheme 26).59 With Pd(OAc)2/AgOAc as the catalyst/oxidant combination, 1,10-phenanthroline (Phen) monohydrate was found to be effective to promote the reaction to generate the cross-coupling products. PivOH was the ideal additive. The reaction selectively occurred at the C2-position of pyridine. Even in the absence of Phen, the reaction selectivity is still predominant at the C2 position of pyridine, albeit in a low yield, indicating that the ligand Phen does not affect the regioselectivity. Several heteroarenes like thiophenes (47), benzothiophenes (48), furans, and indoles were applied as proper coupling partners with pyridine derivatives and other Nheteroarenes such as pyridazine (49) and quinolone (50). Experiments on kinetic isotope effects showed that the C−H activation of pyridine might be involved in the rate-limiting step. Kianmehr later used a similar reaction condition to

Scheme 18

benzothiophene (33), and thiazole (34), while benzimidazole, benzoxazole, and thiazole coupled with thiophenes to afford the products 35, 36, and 37 in low yields. A small KIE value (1.1) for benzothiazole was observed, indicating that the cleavage of its C−H bond is not involved in the rate-limiting step, while a significant KIE (3.0) for benzothiophene was observed. These observations indicated that the C−H breaking benzothiophene might be related to the rate-limiting step. Later, You and co-workers reported a palladium-catalyzed oxidative cross-coupling between two structurally similar azoles (Scheme 21).53 Different from Ofial’s work, both of the substrates are nonbenzofused azoles, which have more closely related structures. PdCl2 was utilized as the catalyst precursor with PPh3 as the ligand. Cu(OAc)2 was the optimal oxidant, and acetate anion was found to be key to the success of this transformation. Furthermore, a catalytic amount of Cu(I) source CuCl was still needed to increase the reaction efficiency. Importantly, the ratio of the two azoles only needs to be 1:1 to achieve high selectivity of cross-coupling products. The same group also reported a palladium-catalyzed oxidative cross-coupling of indoles/pyrroles with a variety of N-heteroarenes N-oxide in the same year. The combination of Pd(OAc)2/dppb as the catalyst, Cu(OAc)2 as the oxidant, and pyridine as the additive promoted the cross-coupling effectively in dioxane at 140 °C (Scheme 22).54 The presence of 2-pyridyl or 2-pyrimidyl as the directing group resulted in the highly selective C2-functionalization on indole or pyrrole rings. However, this standard condition is not suitable for the coupling of indole with xanthines. It was rationalized as the deactivation of the catalyst from the extra coordinations of xanthines nitrogen and oxygen. A rescreening of reaction conditions showed that the N,N-dimethylcarbamoyl group was Scheme 19

H


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Scheme 20

Scheme 21

Scheme 23

Scheme 22

Recently, Zhang and co-workers demonstrated a palladiumcatalyzed oxidative cross-coupling between two electron-rich heteroarenes.61 The work mainly focused on the reaction between two thiophene derivatives (Scheme 28). Pd(OAc)2 was utilized as the catalyst precursor with Ag2O as the oxidant. ortho-Phenyl benzoic acid 53 was found to be superior to other carboxylic acids, such as HOAc and TFA. Various bithiophenes were obtained in moderate to good yields. Furans afforded relatively lower yields with Pd(TFA)2 as the catalyst precursor. Importantly, a useful monomer 54 for organic solar cell and other useful electronic devices were directly synthesized via this protocol in one step. The 54 has also been successfully applied to the synthesis of dye-sensitized solar cell 55 (Scheme 29). As compared to the conventional method, the method provides an efficient and step-economy approach for the thiophene oligomers synthesis. A Pd-catalyzed homocoupling of thiophenes has also been reported to construct thiophene oligomers by Wang,62 in which O2 was used as the sole oxidant with Pd(OAc)2 as the catalyst. The reaction selectively occurred at the C5-position of 2-substituted thiophenes (Scheme 30).

achieve the oxidative coupling between benzofurans 51 and uracil derivatives 52.60 With Pd(OAc)2 as the catalyst and K2S2O8 as the oxidant, the reaction temperature can be lowered to 25 °C (Scheme 27). I


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Scheme 24

Scheme 25

Scheme 26

used as the CN− source. Pd(OAc)2/Cu(OAc)2 was applied as a proper catalyst/oxidant combination. Unlike those transformations with Pd(OAc)2 as the catalyst precursor, Sun and co-workers recently demonstrated an

An oxidative C2−C3 dimerization of indole derivatives has been reported by Kianmehr and co-workers (Scheme 31).63 Meanwhile, cyanation at the C3-position of the dimerization product occurred at the same time. K4[Fe(CN)6]·3H2O was J


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Scheme 27

Scheme 30

Scheme 28 Scheme 31

essential for the success of the coupling. These pioneered studies significantly influenced the following several decades. 2.2.2.1. Directing Group Containing Arene−Alkene Coupling. As compared to the coupling between two arenes, achieving the cross-coupling between arene and alkene is usually less challenging, as the reactivity of arene and alkene is obviously different. However, the site-selectivity on the arene C−H bonds is still a problem. One of the most popular solutions is the introduction of directing groups to control the site-selectivity. Before the year 2011, amide-type or pyridinetype groups were majorly applied as the directing groups.27 In 2011, Arrayas and Zhang, respectively, reported a similar work on the palladium-catalyzed oxidative cross-coupling of 2-pyridyl sulfoxides 66 with alkenes, in which 2-pyridylsulfinyl was utilized as a directing group (Scheme 33).67,68 A variety of olefins and functional groups were well tolerated. Pd(OAc)2 was utilized as the catalyst precursor in both reports, while K2S2O8 or PhI(OAc)2 and AgOAc were applied as the oxidants, respectively. One of the advantages of the 2-pyridylsulfinyl group is that it can be easily removed or converted to its corresponding sulfides.

oxidative cross-coupling between thiazolo[5,4-d]pyrimidine 56 and another heteroarene by using PdCl2(PPh3)2 as the catalyst precursor (Scheme 32).64 Pd(OAc)2 could also promote the coupling although in a relatively low yield. Ag2CO3 was the choice of oxidant with PivOH/TBAI as the additive. A variety of five-membered heteroarenes such as thiophene (57), thiazole (58), and several substituted arenes such as chlorobenzene (59) and anisole (60) were applied to couple with 56. Moderate to good yields were obtained for the coupling products. 2.2.2. Arene−Alkene Coupling. The earliest demonstration on the oxidative cross-coupling between simple arenes and alkenes could trace back to 1967.65,66 At that time, Moritani, Fujiwara, and co-workers reported a coupling between benzene and styrene in the presence of PdCl2. HOAc was found to be Scheme 29

K


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Scheme 32

Scheme 33

Scheme 34

With N-(2-pyridyl)sulfonyl as a directing group, Arrayas and Carretero achieved a diolefination of carbazoles 68 with Pd(OAc)2 as the catalyst (Scheme 34).69 N-Fluoro-2,4,6trimethylpyridinium triflate 70 was utilized as the oxidant. The N-(2-pyridyl)sulfonyl group could be readily removed in a system of Zn/NH4Cl (Scheme 35). Similarly, with the same N(2-pyridyl)sulfonyl directing group, the selective C2-alkenylation of indole derivatives was recently reported by Wang.70 In

this case, Pd(TFA)2 was used as the catalyst with O2 as the sole oxidant. Similarly, with 2-pyridylmethyl ether as the directing group, You and Lan achieved an oxidative ortho-alkenylation of arene 71 (Scheme 36).71 Pd(OAc)2 was still the choice of catalyst precursor, and O2 was the sole oxidant. Specially, the amino acid Boc-Val-OH 73 developed by Yu et al. was effective for promoting this transformation. This 2-pyridylmethyl group could be easily deprotected to release free phenol derivatives via L


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Scheme 35

Scheme 36

system, and AgOAc (4 equiv) was utilized as the oxidant with Li2CO3 (1 equiv) as the additive in DCE at 100 °C. The orthoalkenylation was properly achieved. An in situ workup with TBAF/THF then afforded the final phenol product 76. Alkyl-, methoxy-, chloro-, and fluoro-substituents were well tolerated. It is worthy of note that meta-substituted substrates reacted regioselectively at the sterically less hindered C−H site (78, 79, 81, and 82). Generally, electron-rich phenols gave better yields of the alkenylation products (78, 81). Similarly, Ge and coworkers thereafter utilized benzylic silanol 83 to achieve orthoC−H alkenylation (Scheme 38).79 In this case, Pd(OAc)2 without an extra ligand was applied as the catalyst precursor.

a simple hydrogenation. Recently, Shi reported a similar oxidative cross-coupling between 2-phenoxypyridine and acrylates, in which the 2-pyridyl group was utilized as a directing group and could also be easily removed to release free 2-alkenyl phenol derivatives.72 O2 was also used as the sole oxidant with Pd(OAc)2 as the catalyst. Other N-coordinating directing groups such as imine,73 amide,74 and amino75 have also been developed for various aromatic C−H alkenylations. As compared to sp2-hybrid Nligand, O-ligand has a relatively weak coordination ability to palladium; those weak coordination ligands provide good directing property, yet meanwhile leave the catalyst center electrophilic enough for C−H palladation to occur. Inspired by the report of Yu on tert-alcohol directed C−H alkenylation in 2010,76 silanol was recently developed as a removable directing group for the oxidative C−H alkenylation with olefins.77 Gevorgyan used phenoxyl silanol 74 as the substrate and successfully achieved a one-pot ortho-C−H alkenylation of phenols with olefins (Scheme 37).78 Pd(OAc)2 combined with the (+)menthyl(O2C)-Leu-OH ligand was the optimal catalytic

Scheme 38

Scheme 37

Using free phenolic hydroxyl as a directing group, Sun and co-workers recently achieved an oxidative alkenylation of 2-aryl phenols 84 with acrylates (Scheme 39).80 One equivalent of BQ was used as a proper oxidant, indicating the tolerance of free phenol in the presence of BQ. The reaction was believed to occur via a directed aryl C−H palladation followed by a Hecktype alkenylation process to generate the coupling product. BQ oxidized Pd(0) species to regenerate Pd(II) (Scheme 39). As compared to nitrogen or oxygen ligands, sulfur ligands usually have strong coordination to palladium, which may shut down the C−H activation ability of Pd catalysts. That might be the reason for rare research on this topic. After the report of Daugulis in 2010 with 2-methylthioaniline as a directing group for the arylation of sp3 C−H with aryl iodide,81 Zhang recently demonstrated a palladium-catalyzed oxidative cross-coupling between arenes and olefins with thioether as a directing group.82 With Pd(OAc)2 as the catalyst and AgOAc as the oxidant, a variety of sulfur-involving groups were tested as the directing group for a palladium-catalyzed direct alkenylation of aromatic C−H bond with methyl acrylate (Scheme 40). Benzyl M


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Scheme 39

Scheme 41

PdCl2(PPh3)2 were inactive; yet only PdCl2(CH3CN)2 afforded the coupling product in 16% yield. Currently, most of the directing groups put the reactive site at the ortho-position. In 2012, Yu engineered a directed metaselective C−H alkenylation by utilizing a nitrile-containing template 95 (Scheme 43).85 Pd(OPiv)2 was used as the catalyst with AgOPiv as the oxidant. A set of arenes were selectively meta-alkenylated with olefins. Substituents at the ortho-, meta-, or para-positions of the substrates were well tolerated. Both monosubstituted and disubstituted olefins were suitable substrates for this transformation. Furthermore, template amide 96 linked with hydrocinnamic acid derivatives were also compatible in this reaction; the reaction also selectively occurred at the meta-position of arenes (Scheme 44). The template amide 96 could be easily removed afterward (Scheme 45). Later, computational studies were carried out to rationalize the origin of the selectivity.86 The results supported that a Pdcatalyzed meta-C−H activation occurs via a concerted metalation−deprotonation (CMD) mechanism involving dimeric (Pd−Pd or Pd−Ag dimer) catalytic species. Meanwhile, the role of the N-acyl amino acid ligands was also revealed via computational studies.87 The results indicate that the amino acid acts as both a dianionic bidentate ligand and a proton acceptor. The model reveals the dual roles of amino acids: stabilizing monomeric Pd complexes and serving as the internal base for proton abstraction. The concept was recently further applied in the metaalkenylation of indolines 97 by the same group,64 in which a Ushaped template 99 was utilized. With the template, the reaction selectively occurred at the C6-position of indolines to generate the alkenylation product 98 (Scheme 46), while the selectivity was completely lost in the absence of the template. 2.2.2.2. Nondirecting Group Containing Arene−Alkene Coupling. In the absence of directing groups, substituted arenes usually lose the regioselectivity on C−H functionalization. Therefore, in this case, simple arenes such as benzene are majorly applied to couple with a variety of olefins. In 2012, Hong reported a palladium-catalyzed oxidative cross-coupling of chromones 100 with simple arenes (Scheme 47).88 The C2arylation product 101 was selectively obtained. Pd(TFA)2 was found to be the optimal catalyst with AgOAc as the oxidant and CsOPiv as an additive. Functional groups such as bromo (104) and free hydroxyl (105) were well tolerated. Fluorobenzene resulted in low regioselectivity, affording a mixture of o,m,p-

Scheme 40

thioether afforded the best result (91), while other sulfurcontaining directing groups such as sulfoxide (86), sulfone (87), and thioesters (88, 89) are less effective for this transformation. Moreover, replacing the S atom of benzyl thioether with the O atom resulted in completely no reactivity (90). The transformation tolerates a variety of functional groups on the aromatic rings (Scheme 41). Different from this report, Colobert achieved a sulfoxide-directed oxidative alkenylation of biaryl compounds, while a similar catalytic system was utilized with Pd(OAc)2 as the catalyst and AgOAc as the oxidant in DCE solution.83 Different from those heteroatom-containing directing groups, Cheng recently reported an allylic CC bond directed oxidative ortho-C−H alkenylation in the presence of Pd(OAc)2 as the catalyst with O2 as the oxidant.84 The reaction proceeded well at room temperature. A variety of allylic arenes 92 and olefins 93 were suitable substrates for this transformation (Scheme 42). Other Pd sources such as PdCl 2 and N


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Scheme 42

Scheme 43

Scheme 44

Later, the same group demonstrated a Pd-catalyzed dehydrogenation/oxidative cross-coupling sequence of βheteroatom-substituted ketones 106 with simple arenes

isomers (103). However, nitrobenzene afforded a selective coupling at the meta-position (102). O


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less effective. Various olefins were suitable for this transformation (Scheme 50). Coumarin is an important olefin substrate. It constitutes a major class of naturally occurring compounds and privileged medicinal scaffolds that exhibit a broad range of biological activities. By using a reaction condition similar to their previous report, Hong demonstrated an oxidative cross-coupling of coumarin 115 with unactivated arenes in the presence of Pd(TFA)2 as the catalyst and AgOPiv as the oxidant (Scheme 51).93 The reaction selectively occurred at the C4-position of coumarin. Later, Jafarpour94 and You95 reported a C3-selective oxidative cross-coupling of coumarin with unactivated arenes by using a different catalytic system, in which Pd(OAc)2 was used as the catalyst (Scheme 52). As one of the structurally unique olefins, quinones have also been arylated with simple arenes by You and Song.96 They reported an in situ oxidation of hydroquinones 117 to quinones followed by an oxidative C−H/C−H cross-coupling with simple arenes (Scheme 53). In this case, 5 mol % Pd(acac)2 combined with 3 equiv of Ag2CO3 was effective for generating the desired product. Using 3.5 equiv of DMSO and 2 equiv of PivOH was also essential for this achievement. Several substituted 1,4-hydroquinones were tested and afforded the arylation product in moderate to good yields. It was found that electron-rich arenes reacted faster than electron-deficient ones, suggesting that the C−H bond cleavage of benzene might proceed through an electrophilic palladation pathway. In 2012, Obora reported a Pd-catalyzed chemoselective oxidative cross-coupling between simple arenes and acrylamides with O2 as the sole oxidant. Pd(dba)2 was used as the catalyst precursor with acetylacetone as the ligand in HOAc solution (Scheme 54).97 By simply changing the molar ratio of [Pd]/ acacH, the monoarylation 119 or diarylation 120 products could be respectively obtained. When the ratio was 0.1/0.1, the reaction provided diarylation product selectively. Otherwise, the reaction afforded monoarylation product when the ratio was 0.1/0.4. Monitoring the reaction course showed that monoarylation was initially generated, while it consumed

Scheme 45

(Scheme 48).89 Initially, oxidative dehydrogenation of 106 afforded enaminones and enolones. A sequential oxidative cross-coupling of those enaminones and enolones with arenes occurred to afford the final products. Different from their previous report, Pd(TFA)2 was an ideal catalyst, and a combination of Cu(TFA)2·nH2O (20 mol %) and AgOAc (3 equiv) was found to be the proper oxidant for this transformation. The coupling selectively occurred at the C3position of enaminone with arene (108), while it selectively occurred at the C2-position of enolones (107). With polyfluoroarenes, Zhang achieved a C3-arylation of enaminones.90 Pd(OAc)2 and Ag2CO3 were found to be the proper catalyst/oxidant combination for this transformation. The addition of 5 equiv of iPr2S was required to improve the yield of the product. A variety of polyfluoroarenes and quinolones were suitable substrates for this transformation (Scheme 49). Furthermore, chromones (111) and pyrimidone (112) also underwent the reaction smoothly. Different from Hong’s results, this protocol proceeded selectively at the C3position of chromones (111). With Pd(TFA)2 as the catalyst and AgOAc as the oxidant, Kim achieved a similar arylation of pyrimidine with simple arenes as the solvent.91 Polyfluoroarenes have also been recently applied to couple with various simple olefins under oxidative conditions with Pd(OAc)2 as the catalyst and Ag2CO3 as the oxidant.92 DMSO has been shown to be effective for many Pd-catalyzed C−H functionalizations. However, in this case, PhSMe was found to be better for improving the yield of the coupling product. Other sulfur-containing additives such as SMe2 and PhSOMe were Scheme 46

P


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Scheme 47

Scheme 48

which could be explained by a cis-insertion of the alkene double bond to the aryl−Pd species followed by a β-H elimination process. By simply switching the catalyst precursor to Pd(OAc)2, the method was expanded to the oxidative arylation of α-methylene-γ-butyrolactones 125 (Scheme 57).100 However, due to it containing two types of β-hydrides, a mixture of 126 and 127 was obtained, in which 126 was the major product (Scheme 57). These couplings all afforded trisubstituted alkenes. The catalytic system of Pd(OAc)2 or Pd(TFA)2/ AgOAc with PivOH as the additive then was further expanded to the synthesis of tetrasubstituted alkenes.101,102 Sanford also reported a Pd-catalyzed oxidative cross-coupling of arenes with α,β-unsaturated esters, in which the pyridine ligand effect was carefully studied.103 With Pd(OAc)2 as the catalyst precursor and PhCO3tBu as the oxidant, pyridine was

gradually to afford the diarylation product under the diarylation condition. Several simple arenes were well introduced in this transformation. Later, a similar approach was utilized to synthesize tetrasubstituted olefins starting from disubstituted 121 and trisubstituted olefins 122.98 The combination of a catalytic amount of Pd(OAc)2, Fe(Pc), BQ, and acridine was proved to be an efficient catalytic system. Similar to the previous report, O2 and HOAc were also crucial to achieve the monoarylation or diarylation (Scheme 55). Using Pd(TFA)2 as the catalyst precursor and AgOAc as the oxidant, Kim realized an oxidative cross-coupling between arenes and α,β-unsaturated Weinreb amides (Scheme 56).99 For those Weinreb cinnamamides 123, the reaction proceeded stereoselectively to afford the coupling products 124 with the introduced aryl group at the trans-position of the amide group, Q


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Scheme 49

Scheme 52

Scheme 53

Scheme 50 Scheme 54

Scheme 51

arenes in the presence of 3,5-dichloropyridine as the ligand. Moderate to good yields were obtained (Scheme 58). Recently, with 2-hydroxy-1,10-phenanthroline 128 as a ligand, Duan and co-workers demonstrated a ligand acceleration effect in a palladium-catalyzed oxidative cross-coupling of arenes with acrylates (Scheme 59).104 Pd(OAc)2/Cu(OAc)2 was the optimal catalyst/oxidant combination. Compound 128 was the best ligand for the reaction efficiency. With Phen as the ligand (in the absence of the hydroxyl group as compared to 128), no coupling product was observed. The presence of hydroxyl group was believed to accelerate the dissociation of one acetate ligand at the Pd center to allow its interaction with arene substrates (Scheme 60).

found to affect the reaction rate, yield, and site-selectivity significantly. The Pd/pyridine ratio is also crucial, in which the ideal ratio is 1:0.5 to 1:1. Either a lower or a higher ratio of pyridine resulted in lower chemical yields and longer reaction time. After a ligand screening, 3,5-dichloropyridine was found to be superior to pyridine. Several monosubstituted and 1,2disubstituted olefins then were applied to couple with different R


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Pd(OAc)2. Catalytic amounts of electron-transfer mediators BQ (10 mol %) and Fe(Pc) (2.5 mol %) were employed to lower the energy level between Pd and O2. Various allyl esters and substituted arenes were applied in this transformation. A mixture of linear (L) and branch (B) isomers was obtained in which linear products dominated. With the same catalytic system, the research group also achieved the oxidative coupling between arenes and allyl amides.107 Moreover, they also used saturated substrates 134 as the olefin precursor to achieve its cross-coupling with arenes.108 It was believed that the dehydrogenation of the saturated ketone proceeded first, followed by an oxidative arylation with arenes (Scheme 63). Allylarenes have also been used to couple with simple arenes by Wong and Law (Scheme 64).109 Pd(TFA)2/AgOAc was the optimal catalyst/oxidant combination. The reaction was carried out in simple arene solution at 80 °C under air atmosphere. The coupling reaction afforded a mixture of olefin isomerization products with low selectivity. An intermolecular competition experiment between anisole and fluorobenzene exhibited that electron-rich anisole reacted faster than that of electron-deficient fluorobenzene. The ratio of their corresponding coupling products 136 and 137 is 70:30 (Scheme 65), indicating an electrophilic aromatic substitution pathway for this transformation. 2.2.2.3. Heteroarene−Alkene Coupling. As compared to simple arenes, heteroarenes have different reactive C−H sites, which provide good premise for regioselective C−H functionalizations. Therefore, directing groups are unnecessary in many cases. Furan, pyrrole, thiophene, and their benzo-derivatives are widely applied heterocycles in oxidative cross-couplings. Usually, those types of compounds were generally tested in newly developed protocols. In 2011, Bras and co-workers reported a Pd-catalyzed oxidative cross-coupling of furans and thiophenes with alkenes.110 Pd(OAc)2 was the catalyst precursor with BQ as the oxidant. Notably, the reaction proceeded selectively at the C5-position of substituted furans and thiophenes at room temperature with AcOH/DMSO as the solvent (Scheme 63). Further monitoring of the reaction showed a negative effect of oxidant, as more oxidant resulted in a lower reaction rate. This observation was further investigated by the same group in another report,111 in which a negative effect of the metallic co-oxidants such as AgOAc, Cu(OAc)2, and Mn(OAc)3 was demonstrated. Besides pyrrole and thiophene, indole was used as a substrate in this report. ESI− MS was applied to monitor the reactive intermediates in this transformation.112 The C−H activation of DMSO with Pd intermediate 139 was observed. On the basis of these observations, a possible mechanism was proposed. Initially, the trimer [Pd(OAc)2]3 was disaggregated in the presence of DMSO to form a monomer 138. Further C−H activation of DMSO with the monomer provides intermediate 139 followed by ligand exchange with furan to release DMSO and form a furan-Pd species 140. The following steps are the well-known

Scheme 55

Scheme 56

Ferrocene is a special aromatic compound. With Pd(OAc)2 as the catalyst, the oxidative cross-coupling of ferrocene with electron-deficient olefins was tested by Zakrzewski (Scheme 61).105 The reaction took place in AcOH solution at room temperature for 1 week. In the case of acrylate and cinnamate, the reaction leads to a mixture of monoalkenylated 129 and dialkenylated 130 and 131 ferrocenes, in which the monoalkenylation 129 is the major product. Different from those alkenylations with styrenes or acrylates as the olefin sources, allylic compounds 132 have also been used to couple with simple arenes. Bäckvall recently reported an oxidative cross-coupling between arenes and allyl esters 132 (Scheme 62).106 The reaction proceeds under an ambient pressure of oxygen with a relatively low catalyst loading of Scheme 57

S


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Scheme 58

Scheme 59

Scheme 61

Heck-type alkenylation process with olefin insertion and βhydride elimination to afford the final coupling product (Scheme 66). Other groups have also demonstrated various oxidative couplings of furans, pyrroles, thiophenes, and their benzoderivatives with olefins, in which Pd(OAc)2 was always the choice of the catalyst precursor. Liu reported a Pd-catalyzed oxidative cross-coupling of thiophene and furan with allylic esters 141 in 2011 (Scheme 67),113 in which 1 equiv of Ag2CO3 was used as the oxidant. Xu reported a Pd-catalyzed oxidative cross-coupling of thiophene and furan with allylamines 142 in 2012,114 in which 1 equiv of Ag2CO3 combined with 0.2 equiv of Cu(OAc)2 were applied as the oxidant. In this case, fluoroarenes were also successfully applied as the coupling

partners (Scheme 68). Huang and Lin focused on the oxidative cross-coupling of indole derivatives with olefins,115 in which polyoxometalate H3PMo12O40 was used as a cocatalyst with O2 as the terminal oxidant. DMAP was an effective additive. Free NH indoles were majorly applied, and the reaction proceeded selectively at the C3-position (Scheme 69). Recently, Su used saturated ketones 143 as the olefin source to achieve the alkenylation of those heteroarenes such as pyrrole, thiophene, and indole with Pd(OAc)2 as the catalyst precursor.116 In this case, PCy3 was required as a proper ligand. With Ag2CO3 as the

Scheme 60

T


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Scheme 62

Scheme 63

Scheme 66

Scheme 64

Scheme 67 oxidant, TEMPO was found to be an effective co-oxidant to increase the chemical yield of the coupling product (Scheme 70). Other heterocycles have also been utilized in the oxidative cross-coupling with olefins. Kuang recently reported an oxidative alkenylation of 1,2,3-triazole N-oxides 144 (Scheme Scheme 65

U


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group further expanded the olefination to 4H-pyrido[1,2a]pyrimidin-4-ones 156 by using AgOAc/O2 as the oxidant (Scheme 77).124 Li used 2-pyridones as the heterocycles to react with olefins in the presence of Pd(OAc)2 as the catalyst precursor in 2012.125 Cu(OAc)2 was the proper oxidant for this oxidative coupling. The reaction selectively occurred at the 5-position of unsubstituted 2-pyridones 157. When the 5-position of the substrate was blocked, the alkenylation occurred at the 3position of 2-pyridones 158; in this case, AgOAc was utilized as the oxidant instead of Cu(OAc)2. Those results showed that both 3- and 5-positions were reactive sites. Further utilization of excess olefin to react with 2-pyridone 157 provided dialkenylation product 161 (Scheme 78). As a common heteroarene, pyridine has also been successfully utilized in the oxidative cross-coupling with olefins by Yu and co-workers (Scheme 79).126 With Pd(OAc)2 as the catalyst, a catalytic amount of Ag2CO3 combined with O2 was used as the proper oxidant. Bidentate Phen ligand was added to prevent the N-coordination of pyridine to palladium so as to increase the reactivity of pyridine. The C3-alkenylation dominated the product distribution. A significant isotope effect was observed (kH/kD = 4.0), indicating a mechanism that involves a Pd-mediated C−H cleavage step rather than a Lewis acid-mediated Friedel−Crafts reaction. In 2015, Hajra reported an alkenylation of imidazo[1,2a]pyridines 162.127 Different from the other reports, branched α-vinylated products 163 were obtained instead of the traditional linear β-vinylation. A combination of catalytic amount of Pd(OAc)2 and stoichiometric amount of nBu4NBr was utilized to promote the reaction with O2 as the oxidant. A nucleophilic metalation/β-H elimination mechanism was proposed to explain the unusual selectivity (Scheme 80). 2.2.3. Alkene−Alkene Coupling. The direct crosscoupling between two different alkenes has been rarely reported during the past several years. Until 2004, Ishii reported the first example of oxidative cross-coupling between two different olefins.128 In this report, vinyl acetate 164 was applied as an olefinic substrate to couple with acrylate (Scheme 81). With Pd(OAc)2 as the catalyst precursor, a catalytic amount of H4PMo11VO40 was applied as a co-oxidant with O2 as the terminal oxidant. NaOAc was also used to increase the reaction efficiency. A mixture of E/Z-isomers was obtained. After this report, several other reports on the oxidative crosscoupling between two different olefins were consequently demonstrated. In 2011, a special vinyl ether peracetylated glucal 165 was applied to couple with acrylate by Liu and co-workers (Scheme 82).129 Pd(OAc)2 was found to be the optimal catalyst with 1 equiv of Cu(OTf)2 as the oxidant under 1 atm of O2. The reaction selectively occurred at the β-position of the vinyl ether. The interaction between vinyl ether and Pd catalyst was believed to occur first to form a vinyl-Pd intermediate followed by a Heck-type alkenylation with acrylate to afford the final coupling product. Later, using Cu(OAc)2/AgOAc as the

Scheme 68

71).44 Pd(OAc)2/Ag2CO3 was found to be the ideal catalyst/ oxidant combination. The reaction selectively occurred at the C4-position. The addition of pyridine improved the yield significantly. t-BuOH/dioxane (1:5) as the solvent system provided the best result. Reactions of electron-deficient olefins (145) proceeded better than that of the electron-rich one (146). The Pd(OAc)2/Ag2CO3 combination is also an optimal catalyst/oxidant combination for the cross-coupling of pyridineN-oxides with uracils.117 Recently, Kuang further demonstrated an oxidative olefination of thiazoles with Pd(OAc)2/AgNO3 as the proper catalyst/oxidant combination.118 The olefination selectively occurred at the C2-position of thiazoles (Scheme 72). The addition of Phen (30 mol %) as a ligand was required to increase the reaction efficiency. Acrylates (147), acrylamides (148), and styrenes (149) were all suitable coupling partners of thiazoles. Interestingly, aliphatic alkene 1-octene afforded the branched product 150 in a moderate yield under the standard conditions. A similar oxidative C2-alkenylation of benzoxazole with olefins such as styrenes and acrylates has also been reported by using Pd(TFA)2/AgTFA as the catalyst/oxidant combination with phen as the ligand.119 Later, selective oxidative C5-alkenylation of thiazoles was realized with the retention of acidic C2−H bonds.120 Pd(OAC)2/Cu(OAc)2/ Cs2CO3 was chosen as the catalyst/oxidant/base combination with the addition of 5-nitro-1,10-phen as the ligand (Scheme 73). You achieved an oxidative alkenylation of various Ncontaining heterocycles, including xanthines 151, purine nucleobases 152, and indolizines 153 (Scheme 74).121 With Pd(OAc)2 as the catalyst precursor, 15 mol % of CuCl was required as the cocatalyst. As the oxidant was applied 1.5 equiv of Cu(OAc)2·H2O, and 1 equiv of pyridine was used as an effective additive. DMA was also a crucial solvent. The fluorescent properties of the coupling products were consequently studied. Triazoles 154 are also a suitable coupling partner to react with alkenes.122 In this case, AgOAc was chosen to be the oxidant instead of the previous CuII salt (Scheme 75). Wang used thiazolo[3,2-b]-1,2,4-triazoles 155 as the substrates to couple with olefins.123 Still, Pd(OAc)2 was applied as the catalyst with Cu(OAc)2/O2 as the oxidant. 155 has two reactive CH sites, while the alkenylation selectively occurred at the C5-position (Scheme 76). The same research Scheme 69

V


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Scheme 70

Scheme 71

Scheme 73

oxidant combination, Kapur achieved a Pd-catalyzed oxidative cross-coupling of simple dihydropyrans 167 with unactivated alkenes, in which styrene derivatives and aliphatic alkenes were further applied as coupling partners (Scheme 83).130 Similar to vinyl ether, enamides could also be used as activated olefin substrates. Meanwhile, the amide group could act as a directing group to achieve the C−H palladation of vinyl C−H bond. In 2011, Loh reported a Pd-catalyzed oxidative cross-coupling of enamides with acrylates (Scheme 84).131 A corresponding vinyl-Pd complex 169 was successfully obtained. The complex reacted with tert-butyl acrylate smoothly to afford the coupling product 170. With O2 as the oxidant and NaOAc as an effective additive, a catalytic coupling then was achieved (Scheme 85). The catalytic cycle was believed to occur via the following process (Scheme 86): The alkenyl C−H bond of enamide is first activated by the Pd(II) complex to form a sixmembered palladacycle intermediate 169. Next, a Heck-type alkenylation with the acrylate forms the final product 170 and

releases a Pd(0) species, which was oxidized by O2 to regenerate the Pd(II). Cyclic enamides 171 were later applied to couple with acrylate by Gillaizeau (Scheme 87).132,133 With Pd(OAc)2 as the catalyst, the Cu(OAc)2·H2O/O2 combination as the oxidant was effective for promoting this oxidative crosscoupling in the DMA/HOAc (1:1) solvent system. Chromones134,135 and enaminones136 are two other types of structure unique olefins that have been applied to couple with other olefinic compounds such as acrylates, styrenes, and quinones.135 Pd(OAc)2 was the general catalyst precursor for those transformations. Cu(OAc)2, Ag2CO3, AgOAc, or their mixtures were the choices of the proper oxidants for those different reaction systems. All of those reactions selectively occurred at the α-position of chromones and enaminones 173 (Scheme 88). Recently, the reaction condition of enaminones 174 has been further optimized by using a biomimetic aerobic process with catalytic amount of Cu(OAc)2 and catechol as the electron transfer mediators (Scheme 89).137 The coumarin then was further applied to couple with acrylates and styrenes by Hong and co-workers.138 In this case,

Scheme 72

W


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Scheme 74

further investigated in detail by the same group (Scheme 94).142 To achieve those couplings, Pd(OAc)2 was used as the catalyst and Cu(OAc)2/O2 was the proper oxidant combination. Later, Liu reported an oxidative cross-coupling between styrene derivatives and allylic esters to build up conjugated dienes with Pd(OAc)2 as the catalyst. AgOAc (2.5 equiv) was used as the oxidant (Scheme 95).143 Various aryl and heteroaryl alkenes as well as aliphatic alkenes all gave the desired linear 1,3-butadienes with the tolerance of the traditional leaving groups such as OAc and other carboxylic acid ester groups. Mechanistically, initial olefin insertion to the Pd−O bond of Pd(OAc)2 was proposed to generate intermediate 182, which would precede an elimination of HOAc to give an alkenyl-PdOAc intermediate 183, followed by a Heck-type alkenylation with the allylic ester to give the final product 184. The catalyst is regenerated following oxidation of the low-valent Pd complex. Loh, Xu, and co-workers reported an oxidative cross-coupling of simple alkenes with acrylates by introducing a monoprotected amino acid 185 as an effective ligand to promote the reaction efficiency (Scheme 96).144 Still, Pd(OAc)2/Ag2CO3 is the optimal catalyst/oxidant combination to furnish this reaction. The dimerization of acrylate was observed, and an excess of alkene was necessary to prohibit this dimerization. Both styrenes and aliphatic alkenes were suitable substrates to couple with acrylates, in which styrenes usually provide an excellent E/Z ratio of the coupling product. In the same year, Bäckvall demonstrated a biomimetic aerobic oxidative condition for the cross-coupling of two different alkenes (Scheme 97). This transformation was general for all those olefins applied in those reported results. Similar to the reaction in Scheme 89, both BQ and Fe(Pc) were utilized as the electron-transfer mediators between Pd catalyst and the terminal oxidant O2.145 2.2.4. Arene−Aldehyde Coupling. The direct oxidative cross-coupling of arenes with aldehydes provided a facile approach for the synthesis of diaryl ketones. The activation of aromatic C−H with Pd has been shown to be a welldemonstrated transformation. The direct activation of aldehyde C−H with peroxides has also been disclosed. Therefore, the Pd/peroxide combination was successfully used to promote the

Scheme 75

Scheme 76

Pd(OPiv)2 was used as the catalyst precursor, and O2 (1 atm) was used as the sole oxidant. The reaction also proceeded selectively at the C3-position of the coumarin core (Scheme 90). The C−H palladation of coumarin at the C3-position was believed to occur initially via an electrophilic metalation process, followed by a Heck-type alkenylation to afford the coupling product. Uracils have also been utilized as olefin substrates to couple with electron-deficient alkenes such as acrylates.139 Pd(OAc)2/ AgOAc was again the optimal catalyst/oxidant combination for this transformation. Additive was also important for increasing the reaction efficiency, among which PivOH provided the best results. The alkenylation selectively occurred at the C5-position of uracil 177. An electrophilic palladation pathway was believed to occur, in which uracil’s nucleophilic C5-position was most likely to be first attacked by a Pd(II) species to generate an organopalladium species 178, followed by a Heck-type alkenylation with another olefin (Scheme 91). 4H-Pyrido[1,2-a]pyrimidin-4-ones 179 have also been applied to perform the alkenylation.124,140 With Pd(OAc)2 as the catalyst and O2 as the oxidant, Liang employed PivOH (5 equiv) as the additive, while Cao used AgOAc (0.5 equiv) (Scheme 92). As compared to those special olefins, the cross-coupling between two simple alkenes is more challenging. Loh and coworkers pioneered this coupling in 2009 by using α-substituted styrenes and acrylates as the substrates (Scheme 93).141 The coupling of indenes 181 with electron-deficient olefins was Scheme 77

X


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Scheme 78

Yu148 demonstrated an oxidative cross-coupling of directinggroup-containing anilides with aldehydes, respectively. The reaction selectively occurred at the directed ortho-position of anilides. In the reaction condition of Li and Kwong, Pd(TFA)2 was used as the catalyst and TBHP was used as the oxidant in toluene at 90 °C. Similarly, Li and Wang also used Pd(TFA)2/ TBHP as the catalyst/oxidant combination in toluene at 120 °C, while Yu used Pd(OAc)2 as the catalyst precursor with TBHP as the oxidant. One equivalent of TFA was added as an additive. Toluene was also the choice of solvent. The temperature was 40 °C. The same reaction was later carried out under aqueous conditions by Novak,149 in which sodium dodecyl sulfate was added to increase the solubility of the reactants. Moreover, indolines can also run this type of reaction under similar conditions.150 Generally, the mechanism was believed to proceed via C−H electrophilic cyclopalladation of aryl amides to form a palladacycle 186 followed by an oxidation by acyl radical, which was generated by hydride abstraction from aldehyde. A higher oxidation Pd intermediate was generated. Reductive elimination then afforded the desired product and regenerated Pd(II) species (Scheme 99). Furthermore, with Pd(OAc)2/TBHP as the catalyst/oxidant combination, the oxidative cross-couplings of N-OR benzamide with aldehyde were achieved by Zhao and Huang.151,152 The coupling products further occurred an intramolecular cyclization to generate hydroxyl isoindolonoes 187 (Scheme 100). Besides anilides, N-benzyltriflamides 188 was also used to couple with aldehyde with Pd(OAc)2/TBHP as the catalyst/ oxidant combination (Scheme 101). Because of the presence of a directing group, the reaction selectively occurred at the orthoposition of the N-benzyltriflamide.153 One of the orthopositions needs to be blocked to achieve the monoacylation (189). Without a substituent, diacylation usually occurred (191). Triazoles 192,154 isoxazoles 193,155 pyridine 194,156 and azoxy 195157 have also been used as the N-containing directing groups for the oxidative cross-coupling between arenes and aldehydes (Scheme 102). Pd(OAc)2/TBHP was still the general catalyst/oxidant combination for those transformations with DCE as the solvent. The acylation selectively occurred at the ortho-position of the directing groups. In the absence of a directing group, the oxidative crosscoupling between indoles and aldehyde has also been demonstrated (Scheme 103).158 The acylation selectively occurred at the C3-position of indoles. Pd(OAc)2/TBHP was

Scheme 79

Scheme 80

Scheme 81

C−H/C−H coupling of arenes with aldehyde (Scheme 98). In 2011, Li and Kwong,146 Li and Wang,147 as well as the group of Y


Chemical Reviews

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Scheme 82

Scheme 83

Scheme 87

Scheme 84

Scheme 88

Scheme 85

Scheme 86

2.3. Csp3−H Related Oxidative Cross-Couplings

At the current stage, the Csp3−H activation with Pd catalyst is still a challenging topic. Therefore, very few Pd-catalyzed Csp3−H related oxidative cross-couplings have been disclosed to date. In 2012, Pihko reported an oxidative β-H arylation of keto esters 197 with indole derivatives.160 Pd(TFA)2/tBuOOBz was the optimal catalyst/oxidant combination with i-PrOH/AcOH (4:1) as the solvent at room temperature. The reaction proceeded regioselectively at the C3-position of indole derivatives. With the cyclic keto esters, trans-products were selectively generated (Scheme 105). Two possible mechanisms were proposed for this transformation according to their kinetic studies (Scheme 106). The first possible pathway that occurred was palladation of indole to generate an indole-Pd species 198, which promotes the dehydrogenation of the keto ester followed by a reinsertion process for 199 to afford the final product. The second pathway proceeds the dehydrogenation first to generate 200, followed by a conjugated addition with indole to release the final product. Further mechanistic studies via experimental

still found to be the optimal catalyst/oxidant combination. The reaction was carried out at 140 °C. In this case, PhCl was applied as the solvent. Other solvents such as DMF, DMSO, and DCE were inferior for the product generation. Later, Lan and You achieved the coupling of indoles with formate 196 by switching the oxidant from TBHP to I2.159 In this case, electron-rich arenes performed such a transformation very well (Scheme 104). Z


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Scheme 89

Scheme 90

Scheme 91

Scheme 92

and computational experiments showed that the reaction might proceed via an enone intermediate and the C−C bond formation step could proceed under both acid catalysis and Pd(II) catalysis.161 Later, electron-rich arenes, including phenols, were further applied to couple with β-keto esters to AA


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Scheme 93

Scheme 96

Scheme 94

achieve β-arylation.162 An improved reaction condition with Pd(OAc)2/O2 as the catalyst/oxidant combination in AcOH/ DCE solvent was developed for this reaction. Diphenyl phosphate was found to be an effective cocatalyst for increasing the reaction efficiency of trimethoxybenzene. For the reaction of phenols, Pd(TFA)2/O2 was the optimal catalyst/oxidant combination in TFA/DCE solvent at room temperature. The reaction occurred selectively at the para-positon of phenols (Scheme 107). Furthermore, Yu and co-workers reported a γCsp3−H olefination/cyclization with amide as the directing group.163 With β-keto ester as a nucleophile, Yu achieved a Pdcatalyzed oxidative cross-coupling of anilides in the presence of Mn(OAc)3·2H2O as the oxidant.164 The reaction selectively occurred at the directed ortho-position of anilides 201 and the α-position of β-keto ester 202. It was found that the addition of β-keto ester, Mn(OAc)3·2H2O, and TFA in a batchwise fashion gave the coupling product in a high yield. Various 1,3dicarbonyl compounds were suitable for this reaction and afford the coupling product in good yields (Scheme 108). Moreover, the product could be simply converted to indole via an intramolecular cyclization (Scheme 109). A Pd-catalyzed oxidative cross-coupling of 1,3-dicarbonyl compounds 204 with allylic C−H as the nucleophile was reported by Guo (Scheme 110).165 Pd(OAc)2/PPh3 was the proper catalyst with DMBQ as the oxidant. Similar to those previously reported oxidative allylic alkylation,166 the formation of allylic-Pd followed by a nucleophilic attack with 1,3dicarbonyl compounds was proposed as a proper pathway. As compared to 1,3-dicarbonyl compounds, it is challenging to directly use unactivated ketones as the nucleophile for its

Scheme 97

allylation. Recently, Lei and Luo realized the oxidative crosscoupling of unactivated ketones with allylarenes by using a synergistic Pd/enamine catalysis (Scheme 111).167 Proline was utilized to activate ketone via enamine formation. Pd was demonstrated to activate allylic C−H to form allylic-Pd species, in which Pd(OAc)2/PPh3 was found to be the optimal catalyst precursor. BQ was used as the oxidant with toluene as the solvent. Various ketones were tested in this transformation, and moderate to good yields were obtained. Polyfluorobenzenes have also been used as the nucleophiles to achieve the arylation of allylic C−H compounds. With Pd(OAc)2 as the catalyst, O2 was used as the terminal oxidant. Additive Ag2O (0.1 equiv) was required to increase the chemical yield, and PivOH (0.5 equiv) was required to increase

Scheme 95

AB


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the selectivity toward allylic C−H arylation (Scheme 112).168,169 Recently, Wu and Cui reported an oxidative cross-coupling of quinoline N-oxides 205 with ethers or thioethers,170 in which Pd(OAc)2/TBHP was the optimal catalyst/oxidant combination. The reaction selectively occurred at the C2-position of quinoline N-oxides and the α-position of ethers. CuBr2, NiCl2· 6H2O, and CoCl2 all could promote the coupling to afford the desired product, although in significantly low yields. THF, thioether, and i-PrOH were all suitable substrates for this transformation (Scheme 113). After that, Lee reported an oxidative coupling of phenol/naphthol derivatives with ethers.171 The reaction selectively occurred at the orthoposition of phenolic OH. Apart from the Pd(OAc)2/TBHP catalyst/oxidant combination, a catalytic amount of Cu(OTf)2 was also significant in the transformation (Scheme 114). In 2015, Kozlowski realized a Pd-catalyzed oxidative Csp3− H/Csp3−H coupling without directing groups.172 Phenylglycine azlactones 207 were employed to couple with toluene derivatives in the presence of stoichiometric Pd(OAc)2 (Scheme 115). It was notable that when methyl arenes were replaced by ethyl, propyl, and butyl arenes, C−H activation occurred at the primary CH3 groups. Catalytic reaction can also be achieved by using 2,6-DMBQ as the oxidant. In summary, Pd catalysis still plays the key role in oxidative C−H/C−H coupling due to its well-known C−H activation pathway such as electrophilic palladation and concerted metalation−deprotonation. It can be seen that Pd(OAc)2 is usually the general catalyst precursor. At the current stage, people are still trying to find methods to control the regioselectivity. Although great achievements have been made by using this type of reaction, challenges still remain. Moreover, the mechanism of C−H bond activation is ambiguous, and hence an in-depth mechanistic study is highly required.

Scheme 98

Scheme 99

Scheme 100

3. COPPER CATALYSIS Recently, copper catalysis has attracted more attention in the area of C−H functionalizations. As compared to Pd catalysis, copper is much cheaper and easily available, which would have greater advantages for the industry application of C−H functionalizations. The Glaser−Hay reaction might be one of the oldest copper-catalyzed oxidative coupling reactions.173,174 Because of its complicated mechanism, Cu-catalyzed oxidative C−H functionalizations developed sluggishly during the past decades. Recently, benefited by the development of the CDC reaction,175 Cu-catalyzed oxidative couplings have emerged to be powerful synthetic strategies. Although the substrate scope of different C−H nucleophiles is still limited, more coppercatalyzed oxidative coupling reactions between two C−H nucleophiles have been revealed in recent years.

Scheme 101

3.1. Oxidative Coupling between Csp−H and Csp2−H

Because of the easy generation of homocoupling products of alkynes and inert aromatic Csp2−H bonds, there are only a few reports about Cu-catalyzed oxidative cross-couplings between Csp−H and Csp2−H bonds. In 2013, Jiao and co-workers reported an aerobic direct dehydrogenative annulation of Niminopyridinium 209 ylides with terminal alkynes leading to pyrazolo[1,5-a]pyridine derivatives 210 (Scheme 116).176 In this reaction, CuI was utilized as the catalyst and Ag2CO3/O2 combination as the oxidant. Various kinds of pyrazolo[1,5a]pyridine derivatives have been generated in moderate to good AC


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Scheme 102

Scheme 103

yields. Ag2CO3 was thought to act as a base to promote the cleavage of Csp−H. With the help of a directing group, the copper-mediated tandem oxidative Csp2−H/Csp−H cross-coupling followed by an intramolecular annulation of arenes with terminal alkynes has been developed by You and co-workers, which offers an efficient approach for constructing 3-methyleneisoindolin-1-one scaffold 211 (Scheme 117).177 In this oxidative coupling process, 3 equiv of Cu(OAc)2 acts as both the promoter and the terminal oxidant. Control experiments indicated that the Cu(I)-alkynyl intermediate might serve as a reactive species, while extra Cu(OAc)2 acts as the terminal oxidant. Recently, Yu and co-workers reported the Cu(II)-promoted ortho-alkynylation of arenes or heteroarenes using an amideoxazoline directing group (Scheme 118).178 The combination of 1 equiv of Cu(OAc)2 and 1 equiv of NaOAc was used in this system. A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction.

Scheme 104

AD


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respective Csp2−H bonds, direct oxidative cross-coupling between two Csp2−H bonds utilizing copper catalysis becomes much more challenging. Even so, much progress has been made in this area. In 2011, Miura and co-workers reported a copper-mediated oxidative cross-coupling of directing-group-containing arenes 214 and azoles via dual C−H bond cleavage (Scheme 121).182 In this transformation, Cu(OAc)2 (5 equiv) was used as the promoter and oxidant. PivOH was the effective additive. High temperature (170 °C) forced this reaction to be completed in 2 h in mesitylene. This reaction system shows the high potential of copper salts in direct C−H arylation chemistry and provides a new approach to biaryl motifs. The same group later broadened their protocol to the copper-catalyzed oxidative cross-coupling of directing-groupcontaining indoles 215 with 1,3-azoles to construct indolecontaining biheteroaryls 216 (Scheme 122).183 Cu(OAc)2 (4 equiv) was employed as the promoter and oxidant under N2 atmosphere. Notably, the reaction proceeded smoothly even in the presence of a catalytic amount of copper salts with O2 as the terminal oxidant. Various substituents on both 1,3-azoles and indoles were well tolerated. Moreover, an easily attachable and detachable 2-pyrimidyl directing group is used, allowing for more synthetic diversity. In the next year, the same group demonstrated a coppermediated intermolecular direct biaryl coupling of aryl C−H nucleophiles 217 and 218 with 1,3-azoles (Scheme 123).184,185 The key success of this reaction is the introduction of an amidebased bidentate directing group, which could be easily removed and transformed into other functional groups after the coupling reaction. Similarly, Miura has developed copper-mediated C6selective dehydrogenative heteroarylation of 2-pyridones with 1,3-azoles directed by pyridyl substituent.186 Directing groups play a very important role in the Cucatalyzed oxidative couplings between Csp2−H and Csp2−H bonds; thus it still remains a great challenge to achieve nondirected oxidative coupling reactions. Development of nondirected oxidative coupling reactions seems to be more challenging with copper catalysis. In 2011, Daugulis and coworkers demonstrated a highly regioselective copper-catalyzed cross-coupling of two aromatic compounds using iodine as the oxidant (Scheme 124).187 In this case, 10 mol % CuI was used as the catalyst precursor with 10 mol % phenanthroline as the

Scheme 105

3.2. Oxidative Coupling between Csp−H and Csp3−H

Oxidative coupling between Csp−H and Csp3−H seems to be the more frequent bond formation mode in Cu-catalyzed C−H functionalizations. In 2011, Yu, Bao, and co-workers exploited the Cu(II)-catalyzed oxidative alkynylation reaction of trimethylamine N-oxides with the N-oxide as the internal oxidant to access N,N-dimethylpropargylamines 212 (Scheme 119).179 Cu(acac)2 was used as the catalyst. Both aromatic and aliphatic alkynes were utilized to afford the corresponding products in moderate to excellent yields. Similarly, Su and co-workers reported a solvent-free reaction of tetrahydroisoquinolines 213 with terminal alkynes using a high-speed ball milling technique (Scheme 120).180 DDQ was utilized as an efficient oxidant with copper balls as the promoter. Furthermore, Liu and co-workers established a Cucatalyzed asymmetric oxidative cross-coupling of cyclic carbamates and terminal alkynes with up to 95% ee.181 3.3. Oxidative Coupling between Csp2−H and Csp2−H

Different from palladium catalyst, the electron metalation of aromatic C−H bond with copper salts is usually difficult. Moreover, because of the possible homocouplings of the Scheme 106

AE


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Scheme 107

Scheme 108

Scheme 109

Scheme 111

ligand. K3PO4 was proven to be the optimal base, and pyridine is the effective additive. Control experiments indicated that the reaction might involve an initial iodination of one arene followed by arylation of the most acidic C−H bond of the other coupling component. Cross-couplings of electron-rich arenes with electron-poor arenes proceeded smoothly to afford the corresponding products in good yields. Notably, five- or sixmembered heterocycles and other different functionalities such as fluoride 219, cyano 221, and formyl groups 222 were well tolerated. Typically, a 1:1.5 to 1:3 ratio of coupling components Scheme 110

AF


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Scheme 112

genative cross-coupling of benzothiazoles with thiazoles and polyfluoroarenes under mild conditions was described by Zhang and co-workers (Scheme 125).188 The coupling of benzothiazoles with thiazoles employed CuI as the catalyst, while the coupling of polyfluoroarenes used CuCl as the catalyst together with 225 as the ligand. This protocol provides a straightforward and operationally simple method for the synthesis of the 2,2′-linkage of thiazoles and 2-polyfluoroarylthiazoles. Later, similar works have been reported by You189 and Bolm.190 The Cu-mediated formally oxidative crosscoupling of azine N-oxides and oxazoles has been achieved by Miura, Hirano, and co-workers.191 In 2014, You, Lan, and co-workers have applied their protocol of Cu-catalyzed oxidative C−H/C−H coupling reaction of azoles 226 to polymerization. Cu(OAc)2 was used as the catalyst with AgCO3/O2 as the oxidant, and xylene as the solvent (Scheme 126).192 Recently, Sekar and co-workers reported an efficient chiral copper catalytic system for the asymmetric oxidative homocoupling of 2-naphthol derivatives 227 to synthesize enantiomerically enriched BINOL derivatives (Scheme 127).193 Addition of a catalytic amount of TEMPO (2,2,6,6tetramethylpiperidin-1-yl oxyl) combined with copper-(R)BINAM complex greatly enhanced the reactivity and enantioselectivity of this oxidative coupling and also lowered the reaction temperature to room temperature in CH2Cl2 solvent. A similar work was later reported by Breuning’s group.194 Later, Kozlowski and co-workers broadened this protocol to simple phenols. Copper salen complex 228 was used as the catalyst to promote the oxidative ortho−ortho homocoupling. O2 was applied as the terminal oxidant (Scheme 128).195 Furthermore, the cross-coupling of different phenols could be selectively achieved by using a chromium salen catalyst.

Scheme 113

Scheme 114

is used, in contrast to the existing methodologies that often employ a large excess of arene over the other one. On the other hand, Cu-catalyzed oxidative cross-coupling could also be used to construct C−C bonds between two electron-deficient arenes. In 2012, a copper-catalyzed dehydroScheme 115

AG


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Scheme 116

Scheme 117

Scheme 118

Scheme 120

Scheme 121 In 2013, Lei and co-workers reported the first coppercatalyzed oxidative coupling of alkenes and aldehydes (Scheme 129).196 In this transformation, CuCl2 (20 mol %) was used as the catalyst, and 2.5 equiv of TBHP was utilized as the oxidant. Free radical capture experiment and control experiment indicated that this reaction is likely to proceed through a free radical process. 3.4. Oxidative Coupling between Csp2−H and Csp3−H

this case, CuCl (5 mol %) was used as the catalyst precursor, and THF/H2O(10/1) was employed as the solvent. Air was crucial to promote this oxidative cross-coupling reaction, as no product 230 was observed under the atmosphere of Ar.

Recently, Huo and co-workers developed a CuCl-catalyzed aerobic oxidative coupling of glycine derivatives 229 with indoles utilizing air as the terminal oxidant (Scheme 130).197 In Scheme 119

AH


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Scheme 122

Scheme 123

Scheme 124

In 2012, Todd and co-workers reported a copper-catalyzed oxidative cross-coupling of isochromans 231 with anisoles (Scheme 131).198 A combination of CuCl2 (10 mol %) and DDQ (1.1 equiv) ensured the reaction to proceed efficiently. In this transformation, para C−H of anisole was selectively activated. The reaction greatly expanded the traditional oxaPictet−Spengler reaction.199 Consequently, copper-catalyzed oxidative cross-coupling of heteroarenes with cyclic ethers was

developed under mild conditions by Jiang and co-workers (Scheme 132).200 Cu(OTf)2 (10 mol %) was employed as the catalyst precursor with K2S2O8 (2 equiv) as the terminal oxidant. Further studies about Cu-catalyzed oxidative coupling of olefinic C−H with ether α-C−H was reported soon afterward. Recently, Lei and co-workers achieved a copper-catalyzed oxidative alkenylation of simple ethers to construct allylic ethers AI


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Scheme 125

Almost at the same time, Wei and co-workers described a Cu-catalyzed direct alkenylation of simple alkanes with styrenes (Scheme 134).202 With Cu(OTf)2 as the catalyst and DTBP as the oxidant, a broad range of alkenes underwent cross-coupling with various cycloalkanes and even open-chain alkanes to generate the corresponding alkenylation products in good to excellent yields (234−239). Moreover, different heterocycles were also suitable sources of alkenyl C−Hs (237, 238). When n-hexane was used in the catalytic system, mixed products 239 were obtained due to the existence of three different C−H bonds in n-hexane (1:5:4). The observed significant kinetic isotopic effects for cyclohexane (kH/kD = 5.67) with styrene indicated that the Csp3−H bond cleavage step was probably involved in the rate-limiting step of this transformation. In 2015, a novel copper(II)-catalyzed, regioselective C−H benzylation of enones with toluene via radical triggered oxidative coupling was developed (Scheme 135).203 Cu(tfacac)2 was used as the catalyst together with DTBP as the oxidant, with salicylic acid as the additive. A similar work reported by Duan’s group utilized coumarins and benzylic Csp3−H bonds as the coupling partners.204

Scheme 126

Scheme 127

Scheme 128

3.5. Oxidative Coupling between Csp3−H and Csp3−H

(Scheme 133).201 With DTBP as the oxidant, 10 mol % CuI together with 20 mol % KI were utilized to catalyze this transformation. 1,1-Disubstituted olefins and various kinds of simple ethers could be cross-coupled well to generate the corresponding alkenylation products 232. Notably, open-chain ethers such as diethyl ether (233) were also found to be efficient coupling partners in this reaction. Free radical capture experiment suggested that this reaction probably proceeds through a radical pathway. Later, they developed coppercatalyzed oxidative alkenylation of thioethers via Csp3−H functionalization in similar reaction conditions.191

The Cu-catalyzed oxidative cross-coupling between Csp3−H and Csp3−H represents a challenging topic. Only limited reports have been demonstrated to date. In 2011, a Cu(I)-catalyzed migratory oxidative coupling between nitrones 240 and cyclic ethers or amines was described by Oisaki, Kanai, and co-workers (Scheme 136).205,206 CuOBz (copper benzoate, 5 mol %) together with 6 mol % 1,10phenanthroline were utilized as the catalyst to promote the reaction with TBHP as the terminal oxidant. Twenty mol % NaHCO3 was required as an effective additive. Selective C−C bond-formation proceeded through cleavage of two C(sp3)−H bonds concomitant with CN double bond migration. The reaction provides an alternating nitrone moiety, allowing for further synthetically useful transformations. Further study showed that even in aqueous media, the reaction proceeded efficiently.207 In 2012, Klussmann and co-workers reported a comparative mechanistic study of Cu-catalyzed oxidative coupling of Nphenyltetrahydroisoquinoline 243 with different nucleophiles (Scheme 137).208 Nitromethane 244, dimethyl malonate 245, N-methylpyrrole 246, and indole 247 were tested as suitable nucleophiles. The mechanistic study was based on two different catalyst/oxidant combinations, CuCl2·2H2O/O2 and CuBr/ TBHP (tert-butyl hydroperoxide). The key intermediate in the AJ


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Scheme 129

Scheme 130

Scheme 131

Scheme 134

Scheme 132

Scheme 135

Scheme 133

Scheme 136

aerobic method is shown to be an iminium ion 248, formed through oxidation by copper(II), which can react with a AK


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Scheme 137

Scheme 138

Scheme 139

workers for the selective synthesis of α-etherized α-amino carbonyl compound 251 (Scheme 139).212 In this reaction, only 2 mol % CuCl2 was used as the catalyst to achieve crosscoupling with 1.2 equiv of TBHP as the oxidant under an air atmosphere. In this case, a dual Csp3−H bond oxidative crosscoupling was successfully achieved. Similarly, Huang and coworkers reported a Cu(OAc)2/PivOH-catalyzed oxidative cross-coupling of methylquinoline derivatives with N-aryl glycine esters.213 Meanwhile, Liu, Lou, and co-workers reported a similar work, in which Cu-catalyzed oxidative cross-coupling of cyclic benzylic ethers 252 with α-C−H bonds of carbonyl compounds utilizing Na2S2O8 as the oxidant was developed (Scheme 140).214 Both aldehydes and ketones were used as the appropriate substrates.

nucleophile with sufficient reactivity. In the CuBr/TBHP system, an α-amino peroxide 249 is proposed as an intermediate within the catalytic cycle, which is formed from amine and TBHP by a Cu-catalyzed radical reaction pathway and acts as a precursor of the iminium ion intermediate. Subsequently, different nucleophiles like 5H-oxazol-4-ones209 and nitromethane210 were demonstrated to cross couple with N-aryltetrahydroisoquinoline in the presence of Cu catalyst. Lately, Huang and co-workers developed a dehydrogenative cross-coupling reaction between allylic C−H bonds and the αC−H bond of ketones or aldehydes using 5 mol % Cu(OTf)2 as the catalyst and 1.0 equiv of DDQ as the oxidant (Scheme 138).211 A copper-catalyzed oxidative alkylation of α-amino carbonyl compounds 250 with ethers has been established by Li and coAL


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4.1. Arene−Alkene Coupling

Scheme 140

At the moment when Pd catalysis is dominating the oxidative CH/CH cross-coupling, Rh catalysis and Ru catalysis gradually draw people’s attention in this area and have proved to be successful alternative catalysts in these processes.216 In 2010, Glorius and co-workers developed a novel rhodiumcatalyzed direct oxidative ortho alkenylation of acetanilides utilizing simple styrene derivatives as the alkenyl sources.217 The reaction proceeded smoothly in the presence of only 0.5 mol % [RhCp*Cl2]2 as the catalyst and 2.1 equiv of Cu(OAc)2 as the oxidant. Styrenes and acrylates were all suitable substrates in this transformation. Both electron-rich and electron-deficient styrenes furnished the desired products in moderate to good yields (Scheme 142). Importantly, this method provides a novel strategy for the direct and selective vinylation of acetanilides from ethylene (254). Most recently, Bolm and co-workers achieved the same transformation through a mechanochemical activation strategy with dioxygen as the terminal oxidant.218 In 2010, Bergman and Ellman reported a Rh-catalyzed oxime directed aromatic C−H oxidative alkenylation reaction with unactivated alkenes.219 Similar to Glorius’ work, [RhCp*Cl2]2 (5 mol %) was utilized as the catalyst and Cu(OAc)2 (2.1 equiv) as the terminal oxidant, while a catalytic amount of AgSbF6 was employed as the effective additive to enhance the electrophilicity of rhodium center. Aliphatic alkenes, styrenes, and acrylates are all suitable substrates in this transformation (Scheme 143).

In 2014, Liu and co-workers developed a copper-catalyzed aerobic oxidative coupling of benzylic alcohols and acetonitrile to construct β-ketonitriles 253 (Scheme 141).215 In this case, Scheme 141

CuCl2 (1 mol %) was used as the catalyst with dioxygen as the oxidant and KOH as the base. In the mechanistic proposal, aromatic alcohols were proposed to convert to the corresponding aldehydes followed by the oxidative coupling with acetonitriles. As a non-noble metal, copper is attracting more attention in the area of oxidative C−H/C−H coupling. Similar to the Pd catalysis, directing groups or activated C−H bonds are required in many cases.

Scheme 143

4. RHODIUM CATALYSIS As compared to Pd and Cu catalysis, Rh catalysis is less common in oxidative CH/CH cross-couplings. Currently, only Csp2−H/Csp2−H cross-couplings have been achieved via Rh catalysis.

The ketone and amide directed ortho oxidative alkenylation was reported by Glorius and co-workers in the same year (Scheme 144).220 Similar conditions were used when

Scheme 142

AM


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Scheme 144

Scheme 145

Scheme 146

comparing with their former reports. However, it is the first example of Rh-catalyzed oxidative alkenylations of electron-

poor aromatic C−H bonds. Acetophenones and benzamides were all suitable substrates in this transformation. Notably, AN


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benzamides could cross couple with 1,1- and 1,2-disubstituted olefins to generate the corresponding trisubstituted olefins (259, 260). Lowering the catalyst loading to 0.5 mol % was still effective in the case of acetophenones in this transformation. Later, Rh-catalyzed directing groups containing oxidative cross-coupling between arene and alkenes were extensively studied. Various directing groups such as oxazoline 261,221 triazene 262,222 sulfonic acid 263,223 Weinreb amide 264,224,225 thioether 265,226 tertiary amide 266,227 N-acyl sulfonamide 267,228 phenylphosphine sulfide 268,229 3-thiophene 269,230 and 1,3-dithiane 270231 were subsequently found to be effective in this transformation (Scheme 145). The directing group strategy has also been applied to the oxidative heteroarene−alkene couplings. In 2013, Miura and co-workers reported the carboxylic acid directed orthoalkenylation of thiophenes and furans (Scheme 146, eq 1).232 Shi et al. achieved a pivalamide directed ortho alkenylation of pyridines and quinolones (Scheme 146, eq 2).233 Moreover, regioselective C2 oxidative olefination of N-protected indoles and pyrroles was achieved through the directing group strategy. N,N-Dimethylcarbamoyl protecting group (Scheme 146, eq 3)234 and 2-pyrimidyl protecting group (Scheme 146, eq 4)235,236 were subsequently developed. In 2011, Glorius and co-workers described a Rh(III)catalyzed directed C−H olefination using an oxidizing directing group (Scheme 147).237 In this case, [RhCp*Cl2]2 (1 mol %)

In 2012, Li and co-workers also demonstrated that the azomethine group (273, 274) may act as a potential removable directing group for the generation of formyl heteroarenes.239 The oxidant Cu(OAc)2·H2O is crucial for the success of the reaction. Both acrylates and styrenes were suitable substrates in this transformation (Scheme 149). As for the nondirected oxidative C−H alkenylation reactions, Wang and co-workers reported an oxidative alkenylation of arenes (Scheme 150).240 The reaction proceeded smoothly in the presence of [RhCl(cod)]2 as the catalyst with Cu(OAc)2· H2O/air as the oxidant. One equivalent of trichloroacetic acid was used as the effective additive. However, the arenes need to be utilized as solvents to achieve satisfied reaction efficiency. It was shown that trichloroacetic acid is indispensable, which plays an important role in the cross-coupling process. For the reaction of toluene, mixtures of meta- and para-alkenylation products were generated with poor selectivities (275 and 276). Because of the steric hindrance, ortho-alkenylation product was not observed. In 2014, Yu and co-workers made an improvement of this reaction. The oxidative coupling of 1.0 equiv of simple arenes with acrylates was achieved, by using a bimetallic Rh(II) catalyst [Rh2(OAc)4] (5 mol %) with tricyclohexylphosphine (5 mol %) as the ligand. Cu(TFA)2 and V2O5 were used as the oxidants (Scheme 151).241 Moderate to good yields were obtained with different arenes and acrylates. Notably, reactions of acrylates with disubstituted arenes (277) furnished single regioisomers, while toluene still produced meta-/para-mixtures without selectivities (278).

Scheme 147

4.2. Arene−Arene Coupling

In 2012, Glorius and co-workers achieved a Rh(III)-catalyzed oxidative cross-coupling between two similar heterocycles by using copper(II) salt as the oxidant and CsOPiv as the additive (Scheme 152).242 Structurally similar furans, thiophenes, and pyrroles had been directly used to form 2,2′-bi(heteroaryl) compounds through C−H/C−H oxidative coupling. By using an excess amount (3 equiv) of the less reactive coupling partner, the selective and efficient cross-coupling took place between two different arenes. In the same year, they reported a Rh(III)-catalyzed oxidative cross-coupling between benzamides and halobenzene derivatives (Scheme 153).243 The same Rh(III) catalyst precursor was used along with the same oxidant Cu(OAc)2. C−Cl, C−Br, and C−I bonds were all well tolerated in this transformation. Importantly, the halogen group is crucial for the successful oxidative cross-coupling. Toluene furnished the coupling product in a low yield (279). A mixture of the meta- and para-products was obtained with aryl bromides (280). Delightfully, 1,3-disubstituted bromoarenes led to the regioselective formation of meta-substituted biaryl products with

was employed as the catalyst and CsOAc was used as the additive. The N−O bond in substrate N-methoxybenzamide 271 acts as an internal oxidant. ortho-Alkenylation benzamides were obtained in one step under mild conditions. Later, Lu and co-workers described another oxidizing group directed rhodium(III)-catalyzed C−H olefination for the synthesis of ortho-alkenyl phenols by using 272 as the substrate (Scheme 148).238 Scheme 148

Scheme 149

AO


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Scheme 150

In the next year, You, Lan, and co-workers described a Rh(III)-catalyzed oxidative cross-coupling of indoles/pyrroles with heteroarenes (Scheme 154).245 Ag2CO3 was used as the oxidant, and PivOH was employed as an effective additive. By utilizing N-protected indole or pyrrole as one of the coupling partners, both electron-rich and electron-deficient heteroarenes are suitable substrates in this transformation. This chelationassisted strategy led to the total C2 site-selectivity. Later, the directing group strategy has attracted more attention in the oxidative arene−arene couplings. Directing groups such as pyridinyl and pyrazole 282,246 amide 283,247 pivalamido 284,248 oxime ether 285,249 and carboxylic acid 286250 were subsequently found to be effective in controlling the site-selectivity (Scheme 155).

Scheme 151

4.3. Alkene−Alkene Coupling

moderate to good yields (281). Moreover, the ketone directing group was also suitable for the desired arylation, which afforded the target products in satisfactory yields. Later, the same group reported a similar oxidative cross-coupling of benzamides with simple arenes and heteroarenes. In this case, C6Br6 (2 equiv) was used as an effective additive instead of AgSbF6.244

In 2011, Glorius and co-workers described a Rh-catalyzed olefination of vinylic C−H bonds involving different directing or activating groups (Scheme 156).251 The 1,1- and 1,2disubstituted and even 1,1,2-trisubstituted olefins were successfully converted into the corresponding linear butadienes.

Scheme 152

AP


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Scheme 153

Scheme 154

Scheme 155

AQ


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Scheme 156

Scheme 157

system, the reaction took place favorably to afford highly unsaturated conjugated olefins 289 (Scheme 159).

However, moderate yields along with poor stereoselectivity were obtained. Later, Loh and co-workers described an oxidative crosscoupling reaction of acrylamides with electron-deficient alkenes (Scheme 157).252 Importantly, both Ru and Rh were effective catalysts for this transformation. The reaction afforded (Z,E)dienamides in excellent yields with good stereoselectivity. In 2014, Zhang and co-workers achieved an ester-directed selective olefination of acrylates to afford (Z,E)-dienamides in excellent yields with good stereoselectivity (Scheme 158).253 Besides acrylates, styrenes were also effective in this transformation. Recently, the oxidative coupling between vinyl esters 287 and allenes 288 was also developed.254 By using a similar catalytic

4.4. Arene−Aldehyde Coupling

In 2011, an oxidative ortho-acylation of benzamides with aldehydes was achieved by Kim and co-workers (Scheme 160).255 The combination of [Cp*RhCl2]2 and AgSbF6 was used as the catalyst, in which the corresponding cationic rhodium complex was believed to generate and promote this transformation. Ag2CO3 was the proper oxidant for yielding ortho-monoacylated N,N-diethyl benzamides 290. Later, the same group reported an oxidative cross-coupling of benzamides with aldehydes followed by an intramolecular cyclization to form 3-hydroxyisoindolin-1-one 291 (Scheme 161).256 As compared to their previous report,255 a higher reaction temperature (150 °C) was required for this transformation. As compared to Pd-catalyzed protocols, Rh-catalyzed reactions are more dependent on directed C−H bond activation. This phenomenon might be ascribed to the relatively lower electrophilicity of Rh catalysts when performing C−H bond activation.

Scheme 158

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Scheme 159

5.2. Alkene−Alkene Coupling

Scheme 160

As described in section 4.3, Loh and co-workers has demonstrated that Ru could act as an effective catalyst in the oxidative cross-coupling reaction of acrylamides with electrondeficient alkenes.251 Very recently, the same group developed an efficient Ru-catalyzed oxidative cross-coupling reaction of αsubstituted acrylates with simple acrylates (Scheme 165).275 The same catalyst [RuCl2(p-cymene)]2 was used. AgSbF6 and Cu(OAc)2 were found to be the optimized additive and oxidant in this transformation. Both alkyl and aryl α-substituted acrylates were effective substrates for the synthesis of (Z,E)muconate derivatives. It has been noted that the substituent on the α-position of acrylate influences its reactivity and chemoselectivity. β-Substituted acrylates were not suitable in this transformation.

5. RUTHENIUM CATALYSIS 5.1. Arene−Alkene Coupling

Similar to Rh catalysis, the Ru-catalyzed oxidative aromatic C− H alkenylation also received considerable attention. Dixneuf, Jeganhoman, and Ackermann made significant efforts to the ruthenium-catalyzed ortho C−H activation/alkenylations. Since 2011, directing groups such as pyrrazole 292,257 ketone 293,258,259 anilide and benzylamide 294,260 aldehyde 295,261 ester 296, 262,263 carbamate 297, 264,265 2-pyridyloxy 298,266,267,248sulfonic acid,268 sulfoximine,269 azoxy 299,248 and 1,2,3-triazole270 were subsequently developed (Scheme 162). Different from the Rh catalysis system, styrenes were not effective substrates under Ru catalysis. In most cases, the developed methods were only able to deal with electrondeficient olefins such as acrylates. At the same time, the directing group strategy has also been applied to the oxidative heteroarene−alkene couplings under Ru catalysis. Miura and co-workers reported a rutheniumcatalyzed oxidative vinylation of thiophene-2-carboxylic acids with alkenes (Scheme 163, eq 1).271 Similar to the Rh catalysis, a regioselective alkenylation of indole at the C2-position has been achieved under Ru catalysis by using the amide carbonyl as the directing group (Scheme 163, eq 2).272,273 Importantly, in the case of N-dimethylcarbamoyl as the directing group, styrenes were suitable coupling partners with dioxygen as the terminal oxidant (Scheme 163, eq 3).273 [RuCl2(p-cymene)]2 was generally applied as the catalyst precursor. Li, Wang, and co-workers reported a Ru-catalyzed oxidative alkenylation of N-alkoxyl benzamide,274 in which the amide group was utilized as the directing group (Scheme 164). The N−OMe moiety was an internal oxidant. Therefore, no extra oxidant was required for this transformation. [RuCl2(pcymene)]2 was still the proper catalyst precursor. Direct oxidative alkenylation took place in the case of acrylate, while tandem alkenylation/annulation took place and provided 3,4dihydroisoquinolinone 303 in the case of styrene, for which CF3CH2OH was used as the solvent instead of MeOH.

5.3. Alkane-Related Coupling

In 2008, Li and co-workers described a ruthenium-catalyzed oxidative cross-coupling of 2-phenylpyridine 304 with cycloalkanes (Scheme 166).276 With [RuCl2(p-cymene)]2 as the catalyst and di-tert-butyl peroxide (DTBP) as the oxidant, the reaction furnished ortho-selective products in moderate yields. Both mono- and dialkenylation products were obtained. Interestingly, when Ru3(CO)12 was used as the catalyst with dppb as the ligand, para-selectivities were achieved.277 A wide range of arenes bearing electron-withdrawing substituents were directly functionalized with simple cycloalkanes (Scheme 167). For 2-phenylpyridine 304 in this case, the coupling majorly occurred at the para-position on the phenyl ring to generate 305. Recently, visible-light photoredox catalysis has been extensively studied.278 Ru has been widely used as the core transition metal catalyst. Ru involving visible-light photoredox catalysis has also been used in oxidative C−H/C−H cross-coupling reactions. For example, Wu achieved the oxidative coupling of Csp3−H and Csp3−H bonds by the combination of transition metal catalysis and visible-light photoredox catalysis (Scheme 168).279 Also, the oxidative coupling of aldehydes with C(sp3)− H bonds was achieved by the combination of NHC catalysis and visible-light photoredox catalysis (Scheme 169).280 Similar to Rh catalysis, directing groups are also significant among Ru-catalyzed oxidative C−H/C−H coupling. One potential future direction is to employ Ru photocatalysts to realize the photoinduced oxidative CH/CH cross-coupling reactions.

Scheme 161

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Scheme 162

Scheme 163

Scheme 164

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Scheme 165

Scheme 166

Scheme 169

Scheme 167 ligand 306 as the cooperative catalysts, and TBHP as the terminal oxidant, various optically active coupling products 309 were obtained in moderate to good yields with excellent ee values under mild conditions. In 2014, Chatani and co-workers developed an oxidative coupling reaction between C(sp2)−H compounds 310 and toluene derivatives by Ni(II)-catalysis, in which the 8-aminoquinoline moiety acted as the directing group and heptafluoroisopropyl iodide as the oxidant, and various desired products 311 were obtained smoothly (Scheme 171).282 Bobade and co-workers demonstrated an FeCl2-catalyzed oxidative alkynylation of azoles with terminal alkynes under ligand and solvent-free conditions (Scheme 172).283 With the combination of DTBP/air as the efficient oxidant, different benzoxazoles and benzothiazoles cross-coupled with various terminal alkynes including aliphatic alkynes to generate the desired alkynyl heteroarenes 312 in good yields. Recently, Chen and co-workers described an efficient FeCl2/ DDQ catalytic system that promoted oxidative cross-coupling between the Csp2−H bond and the Csp3−H bond (Scheme 173).284 By using the same catalytic system, Song then reported a cross-coupling reaction of arylmethanes (Csp3−H) with 1,3dicarbonyl compounds (Csp3−H) (Scheme 174).285 In both reports, a radical process was proposed.

6. CATALYSIS WITH OTHER TRANSITION METALS Besides Pd, Cu, Rh, and Ru, there are also a few other transition metals that can promote the oxidative coupling between two hydrocarbons, such as Ni, Fe, Ag, Zn, Mn, and Au, etc. The following part is a brief description of the oxidative coupling between two hydrocarbons promoted by those transition metal catalysts. Recently, Feng reported a chiral NiII−FeII heterobimetallic cooperative catalytic system promoted asymmetric oxidative cross-coupling between two hydrocarbons 307 and 308 (Scheme 170).281 By utilizing NiBr2/Fe(BF4)2·6H2O/chiral Scheme 168

AU


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Scheme 170

Scheme 171

Scheme 172

with arenes. In this transformation, both the rate and the chemoselectivity were significantly enhanced when fluorinated solvents were used (Scheme 176).287 Furthermore, the oxidative cross-coupling of 1,3-dicarbonyl compounds with terminal alkynes has been achieved by Lei and

Licandro and co-workers reported a cyclization of thiophene 313 by the stoichiometric FeCl3, and various substituted dithiophene derivatives 314 were obtained under mild and simple conditions (Scheme 175).286 Pappo and co-workers then developed an iron-catalyzed oxidative coupling of phenols AV


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Scheme 173

treating with nitric acid and Na2CO3. The recycled Ag2CO3 was reused without loss of reactivity. Polysubstituted pyrroles were obtained when changing 1,3-dicarbonyl compounds to βenamino esters 315 (Scheme 178).289 In 2012, Nakamura and co-workers presented a zinc(II)catalyzed redox cross-coupling of propargylic amines 316 and terminal alkynes to afford N-tethered 1,6-enynes 317 (Scheme 179).290 In this reaction, the C−C triple bond of 316 acts as an internal oxidant without the addition of an external oxidant. For manganese promoted organic reactions, radical processes are usually involved.291 Carbonyl compounds and ethers are normally the suitable substrates, due to that those α-CH’s usually have a low bond dissociation energy, allowing the easy generation of their corresponding radicals. In 2013, Liu and Lou reported a manganese dioxide (MnO2) promoted direct coupling of benzylic ethers 318 with simple ketones via oxidative C−H bond activation under air at room temperature (Scheme 180).292 CH3SO3H was an effective additive. Single electron oxidation of α-CH of ethers was believed to occur in this transformation. A manganese-catalyzed intermolecular C−H/C−H oxidative coupling of carbonyls 319 with heteroarenes was developed by Yamaguchi (Scheme 181).293 In this case, the combination of Mn(OAc)2·4H2O/Ph3P was utilized as the catalyst, and NaIO4 was shown to be the superior oxidant. The coupling selectively occurred at the C5-position of 2-substituted pyrroles and thiophenes and the α-position of carbonyl compounds. In 2014, Waldvogel and co-workers established a reliable approach for the oxidative coupling between two Csp2−H compounds by using molybdenum as the promoter (Scheme 182).294 With these MoV reagents, direct access to useful polycyclic arenes was established. Iridium is a very important transition metal catalyst, which has been widely applied to traditional cross-coupling reaction. Recently, more C−H bond activations are achieved by iridium catalysts. In 2014, Hartwig reported an iridium-catalyzed oxidative coupling of furans with unactivated alkenes (Scheme

Scheme 174

Scheme 175

Scheme 176

co-workers. Ag2CO3 was utilized as a crucial promoter. Polysubstituted furans were obtained in one step (Scheme 177).288 Excess silver species could be recycled by filtration and Scheme 177

AW


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Scheme 178

Scheme 179

Scheme 180

Scheme 181

Scheme 182

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Scheme 183

Scheme 184

Scheme 185

183).295 The reaction selectively occurred at the β-position of olefins. In this reaction, a second alkene was an effective hydrogen acceptor. The utilization of ligand 321 not only enhanced the efficiency, but also improved the selectivity of the reaction. Actually, iridium catalysts were more applied to the photocatalytic system. In 2015, MacMillan demonstrated a photoredox-mediated C−H functionalization pathway for the direct α-arylation of cyclic and acyclic ethers with heteroarenes (Scheme 184).296 Iridium catalysts were confirmed to be effective in this reaction. At the same year, Rueping and coworkers developed an ortho-olefination of phenols by iridium and ruthenium cocatalysis (Scheme 185).267 The regeneration of the ruthenium catalyst was accomplished by an IrIII oxidation process. N-Phenyl tetrahydroisoquinoline has been extensively applied in oxidative cross-couplings with other nucleophiles such as nitroalkanes, carbonyl compounds, indole derivatives, and even terminal alkynes. Several catalytic systems have been developed (Scheme 186). Zhu first developed a gold catalysis for this transformation by using complex 323 as the catalyst and air as the sole oxidant.297 Nitroalkanes and different unmodified ketones were the applied nucleophiles in this report. The same group then reported a visible-light-induced gold-catalyzed reaction system with complex 324 as the catalyst. Blue LEDs was the light source. Air was still the choice of oxidant.

Unmodified long-chain methyl ketones, cycloketones, and active methylenes are suitable nucleophiles under the reaction conditions.298,298 Alternatively, Kobayashi used an antimony(V) salt 325 as the catalyst precursor with NHPI (N-hydroxyphthalimide) as the cocatalyst to promote this transformation.299 In this report, different kinds of C−H nucleophiles such as nitromethanes, 1,3-dicarbonyl compounds, and indoles were successfully introduced to couple with tetrahydroisoquinolines, generating the desired Csp3−Csp3 bond formation products in good yields. In 2012, Klussmann and co-workers reported a vanadium catalysis with VO(acac)2 as the catalyst for the coupling of tetrahydroisoquinolines with a broad range of nucleophiles such as nitroalkanes, ketones, indoles, pyrroles, and terminal alkynes. m-CPBA was utilized as the effective oxidant.300 The vanadium catalysis was further expanded to use V2O5 as the catalyst with O2 as the sole oxidant by Prabhu and co-workers in 2012.301 König and co-workers developed a heterogeneous photocatalysis/organocatalysis system for this transformation with CdS as the photocatalyst and L-proline as the organocatalyst.302 O2 was also used as the sole oxidant. Under all of those reaction conditions, a key intermediate 322 was believed to react with the nucleophile to afford the final product. In 2015, Li and co-workers reported a crossdehydrogenative-coupling reaction between tertiary amines and terminal alkynes, in which the synergistic photocatalytic and copper-catalyzed systems cooperate to obtain optically AY


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Scheme 186

Scheme 187

active 1-alkynyl tetrahydroisoquinolines in good yields and excellent enantioselectivities.303 In addition, cobalt also can be utilized to realize this kind of reaction. Wu and co-workers

developed a visible light-mediated cobalt-catalyzed CDC reaction in aqueous medium; the photosensitizer was formed AZ


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Scheme 188

Scheme 189

in recent years,305−307 due to their advantages of no need for removing a trace amount of transition-metal residues. In transition-metal-free oxidative cross-couplings, a radical process was usually involved. Those nucleophiles could easily generate radicals that are normally used as the substrates. NAryl tetrahydroisoquinoline is one of the most frequently applied substrates under various reaction conditions (Scheme 187). Prabhu demonstrated a DDQ/AIBN system with O2 as the oxidant.308 Later, the same group used I2 as the catalyst with O2 as the oxidant.309 Itoh and co-workers then developed a similar I2-catalysis with H2O2 as the oxidant.310,311König311 and Zhou312 used photocatalysis with eosin Y and Rose Bengal as the photocatalyst and O2 as the oxidant to achieve this crosscoupling reaction. Recently, Kobayashi and co-workers used a catalytic amount of sulfuryl chloride (SO2Cl2) under mild aerobic conditions to promote the coupling.313 Huo and coworkers used a catalytic amount of triarylaminium salt as initiator for this oxidative coupling.314 Lou and co-workers used Na2S2O8 as the oxidant to realize the cross-coupling in Scheme 187.315 In 2014, Tokuyama and co-workers found that the C− H functionalization of benzylic C−H bonds in N-aryl tetrahydroisoquinoline could proceed smoothly in the presence of only acetic acid and molecular oxygen, and acetic acid caused a significant acceleration effect.316 Recently, Wang and coworkers also developed a chiral bifunctional thiourea-catalyzed asymmetric oxidative coupling of tertiary amines with α,βunsaturated γ-butyrolactams 328 by DDQ as the oxidant (Scheme 188).316 Other bond formations via transition-metal-free process are scattered. Similar to the functionalization of the sp3 α-C−H bond of nitrogen atom, the C−H functionalization of ethers was also studied. A trityl ion-mediated method to afford the αfunctionalized ethers was reported by Liu and co-workers in 2014 (Scheme 189).317 The trityl salt Ph3CCl showed good

in situ by using a catalytic amount of CoCl2 with dmgH (dimethylglyoxime) as ligand.304 This section shows that metal catalysis other than Pd, Cu, Rh, and Ru is also capable of achieving C−H/C−H coupling, albeit with less examples. It shows the potential of further development of other metals such as Fe, Ni, etc. Currently, the deficiency is that, in most cases, only activated substrates (such as 1,3-diketones, tetrahydroisoquinolines, and isochromans) are suitable substrates in those transformations.

7. TRANSITION-METAL-FREE OXIDATIVE COUPLINGS The above summary shows that many excellent results of C−H bond functionalization have been achieved on the basis of Scheme 190

Scheme 191

transition metal catalysis. On the other hand, transition metalfree cross-coupling reactions have also received much attention BA


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Scheme 192

Scheme 193

Scheme 195

activity. This transition metal-free C−H functionalization of the sp3 α-C−H bond of the oxygen atom of benzopyrans displays a broad scope of nucleophile partners (organoborane and C−H component). This trityl ion-mediated C−H oxidation/ functionalization was believed to undergo a cation intermediate involving an initial single electron transfer (SET). The same group also reported a trity ion-mediated C−H functionalization of benzopyrans in 2014.318 Shirakawa and co-workers also realized α-C−H functionalization of ethers by using t-BuOOtBu as the oxidant.319 Recently, Wang, Liu, and co-workers reported an oxidative cross-coupling of pyridine N-oxides and simple ether in the presence of TBHP (Scheme 190).320 A radical pathway was proposed, in which THF undergoes a hydrogen abstraction from the C−H bond adjacent to the oxygen atom to generate the corresponding free-radical followed by radical addition and oxidation to afford the final product. In 2013, Wu and co-workers developed an I2-promoted domino oxidative cyclization process to construct oxazole derivatives from methyl ketones and benzylic amines (Scheme 191).321 This metal-free and peroxide-free domino oxidative cyclization process involves dual functionalization of two types of C(sp3)−H bonds (sp3 α-C−H of carbonyl and sp3 α-C−H of nitrogen atom). In 2014, they used this system and realized the direct cross-coupling of indoles and methyl ketones to construct indolyl diketones.322 The organocatalyst pyrrolidine was critical in this transformation. The use of inexpensive I2, pyrrolidine, and a broad substrate scope makes this protocol practical (Scheme 192). Afterward, an I2/DMSO system was developed by Meshram and co-workers for the synthesis of 1,2,2-triarylethanones from cross-coupling between aromatic methyl ketones and methoxybenzenes (Scheme 193).323

Hu and co-workers reported a DIAD-mediated metal-free oxidative cross-coupling between tertiary amines and αfluorinated sulfones. β-Fluorinated amines were afforded as the product (Scheme 194).324 This protocol represents a direct fluoroalkylation of C−H bonds with hydrofluorocarbon derivatives. In 2013, Antonchick and co-worker developed an efficient and scalable method for the oxidative cross-coupling of heteroarenes with simple unactivated alkanes.325 This method allows for the selective functionalization of unactivated alkanes (Scheme 195). The reaction selectively occurred at the methylene group of unactivated alkanes. Kita’s group achieved an intermolecular C−H cross-coupling between aromatic ethers using perfluorinated hypervalent iodine(III) compounds FPIFA as a suitable single-electrontransfer (SET) oxidant (Scheme 196).326 The key point of the reaction success is the utilization of hypervalent iodine reagents in the SET oxidation process. In 2013, the same group developed an efficient method for the cross-coupling of phenols with various aromatic compounds.327 Recently, Narayan and Antonchick reported a hypervalent iodine-mediated selective oxidative functionalization of aliphatic C−H bonds of alkanes with chromones or (thio)chromones (Scheme 197).328 The developed methodology is the first report of a direct oxidative functionalization of the C-2 position of (thio)chromones with sp3 C−H bonds. A TEMPO-catalyzed oxidative C−C bond formation with two Csp3−H bonds using molecular oxygen as the terminal oxidant was developed by Jiao and co-workers in 2012 (Scheme 198).329 The protocol proceeded smoothly in relatively mild and neutral conditions, because stoichiometric amounts of oxidants, transition metals, and additives were avoided. Sulfonic acid-catalyzed autoxidative carbon−carbon coupling reaction under elevated partial pressure of oxygen was presented by Klussmann and co-workers (Scheme 199).330

Scheme 194

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Scheme 196

Scheme 197

Scheme 204

Scheme 198

Scheme 205

Scheme 199 Elevation of the partial pressure of oxygen enables the reaction of a broad substrate scope of nucleophiles otherwise showing poor reactivity at ambient pressure. The benzylic C−H bonds of xanthene, acridanes, isochromane, and related heterocycles could be functionalized with ketones, 1,3-dicarbonyl compounds, and aldehydes. The reactions were believed to proceed via autoxidation of the benzylic C−H bonds to the corresponding hydroperoxides followed by a sulfonic acidscatalyzed subsequent nucleophilic substitution. In 2015, Yan and co-workers developed a DDQ and NaNO2catalyzed oxidative coupling of benzylic compound and 1,3dicarbonyls in the presence of O2 and HCOOH (Scheme 200).331 This reaction only needed a catalytic amount of DDQ. It shows high efficiency, and the coupling products are obtained in good to excellent yields within a half hour. An oxidative cross-coupling of aldehydes with heteroarenes such as isoquinoline, quinaxaline, and acridine for the synthesis of heteroaryl ketones was developed by Antonchick and coworkers (Scheme 201).332 In this case, PhI(OCOCF3)2 was used as the oxidant and TMSN3 as the additive. The reaction occurred at room temperature within 2 h. Later in the same year, utilizing TBHP (tert-butyl hydroperoxide) as the oxidant under air atmosphere, Bhanage and co-workers achieved an oxidative cross-coupling between thiazoles and aldehydes (Scheme 202).333 Similar to this report, Wu and co-workers used phenyl 3-phenylpropiolate as the radial acceptor to trap the acyl radical for the synthesis of 3-acyl-4-arylcoumarins in 2015 (Scheme 203).334 In this report, 2 equiv of K2S2O8 was used as the oxidant.

Scheme 200

Scheme 201

Scheme 202

Scheme 203

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Scheme 206

Scheme 207

Scheme 209

Recently, a di-tert-butyl peroxide (DTBP)-promoted αalkylation of α-amino carbonyl compounds by simple alkanes was developed by Cheng and co-workers (Scheme 204).335 The imine and alkyl radical were proposed as the key intermediates of the reaction. The intermolecular KIE value is 8.3, which indicated that the cleavage of the sp3 C−H bond is the ratedetermining step. An aerobic dehydrogenative α-arylation at the tertiary sp3 1,1-diphenylketones with aromatic and heteroaromatic compounds for regioselective synthesis of symmetrical and unsymmetrical benzopinacolones was reported by Jeganmohan and co-workers in 2015 (Scheme 205).336 The reaction was carried out at room temperature in the presence of K2S2O8 in CF3COOH. A carbocation intermediate was proposed. Subsequent α-arylation was achieved at the methane sp3 C− H bond of the substituted ketone. In 2014, the functionalization of α-amino carbonyl compounds (glycine derivatives) was also reported by Huo and co-workers.337 However, utilizing the auto-oxidation of

glycine derivatives, the reaction were performed in the absence of any catalysts and chemical oxidants. Only air or O2 was required. The reaction is highly dependent on the solvent choice, and the highest reaction rate could be afforded in a mixed solvent (MeCN/DCE = 5:1). The condition was not only suitable to the coupling of glycine derivatives and indoles nucleophiles, but also suitable to the synthesis of quinolines using styrenes as the coupling partner (Scheme 206). A catalytic benzoyl peroxide (BPO)-initiated oxidative crosscoupling reaction of N-iminopyridine ylides with simple alkanes and alcohols leads to the corresponding 2-alkylpyridines as reported by Wang and co-workers in 2015 (Scheme 207).338 The intermolecular KIE value for the arene C−H bond was 1.4 and for alkane C−H was 7.3, indicating the cleavage of the sp3 C−H bond was involved as the rate-determining step for this transformation. Wu, Cui, and co-workers developed a base-promoted oxidative cross-coupling of quinolone N-oxides and 1,3-azoles under external oxidant-free conditions. N-Oxides could serve both as an internal oxidant and as a directing group to allow the C−H functionalization at the 2-position (Scheme 208, eq 1).339 The same group also demonstrated the dimerization of

Scheme 208

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Scheme 210

Scheme 211

heteroaromatic N-oxides with N-oxide as the internal oxidant (Scheme 208, eq 2).340 A direct oxidative C−H/C−H cross-coupling of two unactivated aromatic compounds using electrochemical oxidation protocol was reported by Yoshida and co-workers in 2012 (Scheme 209).341 The process consists of two sequential steps. First was the generation and accumulation of a radical cation of an aromatic compounds under electrochemical oxidation. Second was the coupling of the radical cation with another aromatic substrate under nonoxidative conditions; thus nonselective oxidation of the starting materials and oxidation of the products are avoided. No metal complexes and chemical oxidants were needed in the reaction conditions. In 2014, Waldvogel and co-workers reported a metal-free anodic cross-coupling reaction of two different phenols with high selectivity (Scheme 210).342 This protocol employed electrolytes with a high capacity for hydrogen bonding, such as methanol with formic acid or 1,1,1,3,3,3-hexafluoro-2-propanol,; a direct electrolysis in an undivided cell provides mixed 2,2′-biphenols. Recently, Itoh and co-workers reported an aerobic photooxidative direct asymmetric aldol reaction of benzyl alcohol with ketones (Scheme 211).343 Under the irradiation of visible light, using water as the solvent allows the selective oxidation of benzyl alcohol to the corresponding aldehyde, which reacts with enamine generated by ketone with proline-type organocatalyst. However, it was critical to the electron-withdrawing groups on the benzene rings, which become electron poor at the carbonyl carbon of the corresponding benzaldehyde. The transition-metal-free oxidative C−H/C−H couplings are usually based on the SET C−H activation process. Radicals are involved as the intermediates in those transformations. The

reactions normally occurred at the most activated site of the substrates.

8. CONCLUSIONS The oxidative coupling between two hydrocarbons has been widely explored during the past several years. It is a hot and fast-developing area. This Review provides an updated summary of this topic for the last four years. More developed strategies are focused on searching for new types of hydrocarbons in oxidative cross-couplings. Catalytic system is still the key for achieving so many bond formations. Palladium catalysis still dominates the catalytic system for those oxidative couplings. However, more non-noble metal catalysts are becoming popular, such as copper catalysis and iron catalysis. Transition-metal-free oxidative cross-couplings have also drawn much attention at the current stage. Although numerous results have been reported in this blossoming area, many unsolved problems still remain. The reaction conditions are still not mild enough. The reaction efficiency is still very low. Moreover, there is little on mechanistic understandings of C−H functionalizations. It is far from free tailoring of selected C− H bonds. Although it is ideal to use oxidative CH/CH crosscoupling for the synthesis of useful and important molecules, it is still not practical at the current stage. Developing new and applicable methods is highly desirable. Therefore, great chances still remain in oxidative cross-couplings between two hydrocarbons, and further exciting developments are expected. AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. BE


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Biographies

in 2014 on the synthesis of heterocyclic compounds by oxidative crosscouplings. He has been a faculty member at Jiangxi Normal University since July 2014. His research interests are in the area of synthetic methods development and heterocyclic compounds synthesis.

Chao Liu (1985) obtained his B.Sc (2007) and Ph.D. (2012) at Wuhan University under the supervision of Prof. Aiwen Lei. He spent one year (October 2008 to October 2009) as a visiting Ph.D. student in Prof. Todd B. Marder’s group at Durham University, UK. In 2013, he spent three months (June−August) visiting in the group of Prof. Yashihiro Uozumi at IMS, Japan. He started his independent research in 2015 at Lanzhou Institute of Chemical Physics, CAS, and is now focusing on oxo synthesis and selective oxidation.

Shan Tang was born in Xiaogan, Hubei Province, China in 1989. He obtained his B.S. degree (2012) at Wuhan University. He joined Prof. Aiwen Lei’s group during his second year of undergraduate study and started his Ph.D. in September 2012 in the same group. He is currently a fourth year Ph.D. student and works on radical oxidative crosscouplings.

Jiwen Yuan was born in July, 1988 and received his Bachelor’s Degree of Science in 2011 from Nanjing University. He then joined Prof. Lei’s group and received his Master’s Degree from Wuhan University in 2013. After that, he continued working in Prof. Lei’s group as a Ph.D. candidate. His research interest focuses on the metal-free oxidative coupling reactions.

Wu Li obtained his M.Sc. degree at Nanjing Normal University in 2012, under the supervision of Prof. Peipei Sun, and received his Ph.D. degree from Wuhan University in 2015, under the supervision of Prof. Aiwen Lei. His research interests focus on palladium-catalyzed C−H activation and oxidative carbonylation.

Meng Gao was born in Jingzhou, China. After completing his master studies in 2011 at Hubei University, he joined Prof. Aiwen Lei’s research group at Wuhan University. He completed his doctoral study

Renyi Shi was born in 1989 and received his B.Sc. in 2011 from Nanjing University. He has been in Prof. Lei’s group since 2011 and is currently a fifth year Ph.D. student. His research interest focuses on BF


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transition metal-catalyzed oxidative carbonylation and their applications in organic synthesis.

Aiwen Lei (1973) obtained his Ph.D. (2000) under the supervision of Prof. Xiyan Lu at Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (CAS). He then moved to Pennsylvania State University, PA, and worked with Prof. Xumu Zhang as a postdoctoral fellow. He joined Stanford University (2003), working with Prof. James P. Collman as a research associate. He then became a full professor (2005) at the College of Chemistry and Molecular Sciences, Wuhan University, China. His research focuses on novel approaches and understanding toward bond formations.

ACKNOWLEDGMENTS This work was supported by the 973 Program (2012CB725302), the National Natural Science Foundation of China (21390400, 21520102003, 21272180, and 21302148), the Hubei Province Natural Science Foundation of China (2013CFA081), the Research Fund for the Doctoral Program of Higher Education of China (20120141130002), and the Ministry of Science and Technology of China (2012YQ120060). We also appreciate the Program of Introducing Talents of Discipline to Universities of China (111 Program). REFERENCES (1) Meijere, A. d.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd completely rev. and enl. ed.; Wiley-VCH: Weinheim, 2004. (2) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd rev. and enl. ed.; Wiley-VCH: Weinheim, 2004. (3) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51, 8960−9009. (4) Alberico, D.; Scott, M. E.; Lautens, M. Aryl−Aryl Bond Formation by Transition-Metal-Catalyzed Direct Arylation. Chem. Rev. 2007, 107, 174−238. (5) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Bond Formations between Two Nucleophiles: Transition Metal Catalyzed Oxidative CrossCoupling Reactions. Chem. Rev. 2011, 111, 1780−1824. (6) Le Bras, J.; Muzart, J. Intermolecular Dehydrogenative Heck Reactions. Chem. Rev. 2011, 111, 1170−1214. (7) Yeung, C. S.; Dong, V. M. Catalytic Dehydrogenative CrossCoupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds. Chem. Rev. 2011, 111, 1215−1292. (8) Dyker, G. Handbook of C−H Transformations: Applications in Organic Synthesis; Wiley-VCH: Weinheim, 2005. (9) Chinchilla, R.; Najera, C. The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry. Chem. Rev. 2007, 107, 874−922. BG


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