Review pubs.acs.org/CR

Transition-Metal-Catalyzed Direct Addition of Unactivated C−H Bonds to Polar Unsaturated Bonds Lei Yang and Hanmin Huang* State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China 3. Transition-Metal-Catalyzed Direct Addition of C(sp3)−H Bonds to Polar Unsaturated Bonds via C−H Activation 3.1. Addition of C(sp3)−H to C−C Double Bonds 3.2. Addition of C(sp3)−H to C−O Double Bonds 3.3. Addition of C(sp3)−H to C−N Double Bonds 3.4. Addition of C(sp3)−H to C−N Triple Bonds 3.5. Addition of C(sp3)−H to Carbon Monoxide 4. Conclusions and Perspectives Author Information Corresponding Author Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 2. Transition-Metal-Catalyzed Direct Addition of C(sp2)−H Bonds to Polar Unsaturated Bonds via C−H Activation 2.1. Addition of C(sp2)−H to C−C Double Bonds 2.1.1. Addition of Aryl C−H to C−C Double Bonds 2.1.2. Addition of Olefinic C−H to C−C Double Bonds 2.1.3. Addition of Aldehydic C−H to C−C Double Bonds 2.1.4. Addition of Aldimine C−H to C−C Double Bonds 2.1.5. Addition of Formate C−H to C−C Double Bonds 2.2. Addition of C(sp2)−H to C−C Triple Bonds 2.2.1. Addition of Aryl C−H to C−C Triple Bonds 2.2.2. Addition of Aldehydic C−H to C−C Triple Bonds 2.2.3. Addition of Formate and Formamide C− H to C−C Triple Bonds 2.3. Addition of C(sp2)−H to C−O Double Bonds 2.3.1. Addition of Aryl C−H to Aldehydes and Ketones 2.3.2. Addition of Olefinic C−H to Aldehydes 2.3.3. Addition of Aldehydic C−H to Aldehydes and Ketones 2.4. Addition of C(sp2)−H to C−N Double Bonds 2.4.1. Addition to Imines 2.4.2. Addition to Isocyanates 2.5. Addition of C(sp2)−H to C−N Triple Bonds 2.6. Addition of C(sp2)−H to Carbon Monoxide 2.7. Miscellaneous Examples

A

B B

AL AL AM AN AO AO AS AS AS AS AS AS AS AT

1. INTRODUCTION Transition-metal-catalyzed nucleophilic addition of organometallic reagents to polar unsaturated substrates is one of the most important and powerful bond-forming strategies, and it has a wide range of applications from the synthesis of complex natural products to industrial process.1 Generally, in these transformations, the key step is the generation of active C−M (M = transition metal) nucleophilic species via transmetalation. However, the use of organometallic reagents as nucleophiles to generate the active C−M intermediates often has some drawbacks, including the tedious prefunctionalization steps, anaerobic manipulations, and the unwanted formation of stoichiometric salt wastes, which significantly lowers the atom and step economy and makes such a process environmentally unfriendly.2 An alternative protocol is to replace the organometallic reagents with simple hydrocarbon starting materials and directly add them to polar unsaturated substrates. In this reaction, the key active C−M species are generated in situ via C− H bond activation, which minimizes the number of synthetic manipulations and reduces chemical wastes. In addition to the improved efficiency that can arise when a simple hydrocarbon is used in place of an organometallic compound, this strategy becomes even more attractive when the organometallic species is difficult to prepare or is unstable under reaction conditions. Furthermore, the abundance of unsaturated bonds and the oxidant-free reaction conditions increase the appeal of these reactions and pave the way for large-scale applications. However, the inert nature of unreactive C−H bonds and the requirement

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Received: October 22, 2014

© XXXX American Chemical Society

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Scheme 1

summarize the developments in transition-metal-catalyzed direct addition of unactivated (in this review “unactivated” refers to C− H bonds with pKa > 25, which excludes C−H bonds adjacent to electron-withdrawing groups, such as carbonyl groups and nitriles) C(sp2)−H and C(sp3)−H bonds to polar C−C, C− O, and C−N multiple bonds in polar molecules up to autumn 2014, with an emphasis on the transformations developed through the above two mechanisms. Nevertheless, to highlight the practicability of the C−H addition reactions, this review is not limited to reactions where the C−H unit is added to polar unsaturated bonds. Recent examples of novel annulations initiated by C−H addition and oxidative carbonylation reactions via C−H activation/carbon monoxide (CO) insertion are also discussed. In addition, as an appealing and rapidly developing research area, transition-metal-catalyzed direct addition of benzylic C(sp3)−H bonds of alkylazaarenes to polar multiple bonds, which proceeds via pathways not shown in Scheme 1, is also discussed in this review. The potential synthetic applications and mechanistic aspects of these transformations are also discussed where appropriate. Heck-type reactions,7 hydride transfer reactions,8 direct carboxylation of C−H bonds with CO2,9 and direct addition of C−H bonds to nonpolar multiple bonds are not considered in this review. This review will be divided according to the type of C−H and multiple bonds.

for site-selective functionalization, which are two well-known aspects of each type of C−H functionalization, make such a process extremely challenging. Analogous to the most common transformations via C−H activation,3 the key to success of the C−H addition reactions was the facile occurrence of the C−H bond metalation step, in which an inert C−H bond is converted to a more active C−M species via transition-metal catalysis. There are four general mechanisms for transition-metal-mediated C−H bond metalation:4 (i) oxidative addition with low-valent late transition metals, (ii) σbond metathesis, (iii) electrophilic aromatic substitution with high-valent late transition metals, and (iv) a base-assisted C−H activation mechanism. In light of the general mechanisms for transition-metal-mediated C−H bond metalation, two typical catalytic cycles illustrating the C−H addition reactions are outlined in Scheme 1. Initial C−H bond cleavage provides the C−M species A or A′ by oxidative addition (cycle I) or one of the other generally accepted mechanisms mentioned above (cycle II). The C−M species A or A′ coordinates to the olefin, followed by migratory insertion to give complex C or C′. Reductive elimination from C or protonation of C′ gives the desired product and regenerates the active catalyst. Both of the catalytic cycles feature 100% atom efficiency and fulfill the criteria of sustainable and green chemistry. Over the past few decades, significant efforts have been made in the area of transition-metal-catalyzed direct addition of C−H bonds to unsaturated bonds via C−H activation. In this regard, compared with the well-developed direct addition reactions of C−H bonds to nonpolar multiple bonds pioneered by Murai and co-workers,5 the analogous additions to polar multiple bonds are still in the development stage. However, unsaturated compounds with polar multiple bonds usually contain useful synthetic groups or heteroatoms, which enables such additions to be more powerful in the construction of functionalized complex molecules. Hence, increasing attention has been paid to this research topic.6 The goal of this review is to comprehensively

2. TRANSITION-METAL-CATALYZED DIRECT ADDITION OF C(SP2)−H BONDS TO POLAR UNSATURATED BONDS VIA C−H ACTIVATION 2.1. Addition of C(sp2)−H to C−C Double Bonds

Transition-metal-catalyzed addition of C(sp2)−H bonds to C−C double bonds via C−H bond activation has been demonstrated to be a simple and atom-economical protocol for the construction of C−C bond frameworks. Various C(sp2)−H bonds (e.g., aryl C−H bonds, olefinic C−H, and aldehydic C−H B

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chloride as the catalyst system, a wide range of heterocycles and unactivated alkenes were successfully employed in the reaction. In addition, electron-deficient alkenes acrylonitrile and tert-butyl acrylate also undergo the coupling reaction to give 2-alkylated 4,5-dimethylthiazoles in 59% and 93% yields, respectively. In subsequent reports, Bergman, Ellman, and co-workers found that the alkylation of quinoline and 4,4-dimethyl-2-oxazoline with tert-butyl acrylate proceeded smoothly when using the combination of [RhCl(coe)2]2, PCy3·HCl, or/and PCy3 as the catalyst, giving the desired alkylation products in 53% and 59% yields, respectively.13 The first total synthesis of (+)-lithospermic acid using Rhcatalyzed asymmetric intramolecular alkylation as the key step was realized by Bergman, Ellman, and co-workers (Scheme 5).14

bonds) can participate in this type of addition reaction. The recent advances in this research field are outlined in this section. 2.1.1. Addition of Aryl C−H to C−C Double Bonds. Arenes are one of the most abundant and important bulk chemicals. Among the methods to functionalize arenes, catalytic addition of C−H bonds to alkenes, also known as hydroarylation, is one of the most efficient methods to alkylate arenes. An early example of the catalytic addition of C(sp2)−H bonds to polar C− C double bonds was reported by Yamazaki and co-workers in 1978 (Scheme 2).10 Under an atmosphere of CO (30 atm), Scheme 2

Scheme 5 addition of benzene or monosubstituted benzenes to diphenylketene was realized. The reactions were catalyzed with Rh4(CO)12, affording the corresponding aromatic ketones in 53−68% yields. Control experiments indicated that the use of CO was essential to the catalytic cycle of the reaction. In 1993, an ortho-alkylation of aromatic ketones with olefins via C−H bond activation in the presence of a ruthenium catalyst was reported by Murai and co-workers, 11 which is a representative example of a highly efficient and synthetically useful C−H addition reaction (Scheme 3). This reaction can be Scheme 3

This work provided the first example of the use of a chiral imine as a directing group in C−H bond activation and represented the first application of the C−H addition protocol to natural product synthesis.14a Further efforts to increase the stereoselectivity of this reaction revealed that the nature of the substituents on the aminoindane derivatives was important for obtaining high enantioselectivity.14b In 2004, the first rhodium-catalyzed alkylation of N-benzyl arylketone imines with olefins bearing various functional groups was realized with RhCl(PPh3)3 as the catalyst (Scheme 6).15 Among the electron-deficient alkenes investigated, acrylates and

considered as an ideal pathway for the formation of C−C bonds via C−H bond activation in terms of step and atom economy. Although this catalytic system is not suitable for olefins with polar C−C double bonds (e.g., α,β-unsaturated carbonyl compounds), this seminal paper on the capacity of ruthenium complex to efficiently catalyze C−H addition reactions facilitated by chelation-assisted C−H bond activation, together with that of Yamazaki and co-workers10 documenting Rh-catalyzed C−H addition reactions, paved the way for future investigation. In 2002, Bergman, Ellman, and co-workers described the first alkylation of heterocycles with electron-deficient alkenes in the presence of Rh catalysts (Scheme 4).12 Using 10 mol % of [RhCl(coe)2]2, 15 mol % of PCy3, and 5 mol % of lutidinium

Scheme 6

Scheme 4

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N,N-dimethylacrylamide exhibited good activities for orthoalkylation to give the corresponding ketones after hydrolysis. Interestingly, a competitive reaction of N,N-dimethylacrylamide and 1-hexene with N-benzyl ketimine revealed that N,Ndimethylacrylamide had a much higher reactivity than nonfunctionalized 1-hexene in the presence of the Wilkinson complex. In 2006, Takai, Kuninobu, and co-workers reported [ReBr(CO)3(THF)]2-catalyzed reactions of aromatic ketimines with acrylates via C−H bond activation (Scheme 7).16 Given that

Further studies by Takai, Kuninobu, and co-workers demonstrated that [ReBr(CO)3(THF)]2 could efficiently catalyze addition reactions of the C−H bond of aromatic compounds with α,β-unsaturated carbonyl compounds assisted by nitrogen-containing directing groups (Scheme 9).20 In these reactions, Re2(CO)10 can also be used as a catalyst in some cases. Mechanistic studies suggested that this reaction is triggered by rhenium-catalyzed C−H activation. In 2013, a novel cascade reaction of direct addition of orthoC−H bonds of aromatic ketones to enones followed by an intramolecular aldol condensation was reported (Scheme 10).21 Various aromatic ketones with different substituents reacted smoothly with ethyl vinyl ketone to give the indene derivatives in moderate to good yields in the presence of 5 mol % of [Cp*Rh(CH3CN)3](SbF6)2 and 1 equiv of AgOAc. In general, electron-rich acetophenones gave better yields than electrondeficient acetophenones. Besides ethyl vinyl ketone, low-boilingpoint methyl vinyl ketone can also be used in this cyclization. Notably, this cyclization efficiently occurred in the presence of water and air, providing an operationally simple protocol for the synthesis of indene derivatives. Because of the unique effects of fluorine substituents in molecules, fluorinated compounds play an important role in pharmaceuticals, agrochemicals, and materials science.22 Direct methods for the functionalization of polyfluoroarenes through C−H activation have attracted much attention in recent years.23 In 2010, the effective coupling between pentafluorobenzene and α,β-unsaturated carbonyl derivatives was reported by Zhao and co-workers (Scheme 11).24 In the presence of 1.5 mol % of [(cod)Rh(OH)]2, 3.3 mol % of DPPBenzene, and a mixed solvent of H2O and dioxane, the reaction of pentafluorobenzene and n-butyl acrylate gave the anti-Markovnikov hydroarylation product in high yield with high chemoselectivity (93% combined yield, 17:1 selectivity of hydroarylation product/oxidative arylation product). In addition to pentafluorobenzene, other polyfluoroarenes can also react with a series of α,β-unsaturated carbonyl compounds to provide the corresponding hydroarylation products with high yields and high selectivities. A possible reaction mechanism was then presented. After aromatic C−H activation and subsequent insertion with an activated olefin, the desired hydroarylation product is formed upon protonation. Oxidative arylation byproducts were also detected, which might be generated via β-H elimination after the alkene insertion. Direct 1,4-conjugate addition of heteroarenes, including 2methoxythiophene, 2-methylfuran, furan, and N-methyl pyrroles, to α,β-unsaturated ketones has also been reported (Scheme 12).25 Using 5 mol % of PdCl2 as the catalyst in CH3OH at room temperature, the corresponding Michael adducts were obtained in moderate to excellent yields. In most cases, the monoalkylated product was obtained as the sole product. However, when furan was used as the starting material, the dialkylated product was isolated along with the monoalkylated product. Control experiments showed that a C−H activation mechanism is most likely involved in the reaction. Theoretically, two incompatible proton-transfer steps are generally involved in the 1,4-conjugate addition reaction triggered by transition-metal-catalyzed C−H activation. The first proton transfer occurred in the C−H activation step, in which rapid removal of the generated proton in basic conditions facilitates the reversible arene metalation process. The second proton transfer is the protonation of the metal−enolate, which is preferred in acidic conditions. Therefore, carefully controlled

Scheme 7

aromatic ketimines can form in situ by the reaction of aromatic ketones with anilines, the authors successfully performed the reaction of arylketones with acrylates in the presence of a catalytic amount of rhenium catalyst and an aromatic amine. The reaction was initiated by C−H bond activation of the ketimine, which formed in situ by the reaction of acetophenone with aniline through dehydration. After C−H bond activation, the formed arylrhenium complex underwent the following steps: (i) α,β-unsaturated compound insertion, (ii) intramolecular nucleophilic cyclization, (iii) reductive elimination, and (iv) elimination of aniline to yield the indene product and regenerate the active rhenium species. The elimination of aniline was important to promote the reaction. In 2006, Takai, Kuninobu, and co-workers established a formal [3 + 2] annulation of arylacetylenes and α,β-unsaturated carbonyl compounds for the synthesis of indene derivatives, in which the ketimines were generated in situ via hydroamination of aromatic acetylenes.17 The desired indene derivatives were obtained in 26−97% yields by the ruthenium- and rheniumcatalyzed one-pot reaction in the presence of NH4PF6 (Scheme 8).18 The reaction involves two steps: (i) ruthenium-catalyzed Scheme 8

hydroamination of an aromatic acetylene with aniline, (ii) rhenium-catalyzed reaction of the resulting aromatic ketimine with an α,β-unsaturated carbonyl compound via C−H bond activation, conjugate addition, intramolecular nucleophilic cyclization, and elimination of aniline. Extension of this methodology to hydroarylation of heteroaromatic aldimines with α,β-unsaturated carbonyl compounds was subsequently realized, where a series of desired adducts was obtained in 12− 48% yields in the presence of 3 mol % of Re2(CO)10.19 D

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Scheme 9

Scheme 10

Scheme 13

Scheme 11 desired addition products in good to excellent yields under mild conditions (Scheme 14). Scheme 14

Scheme 12

Intermolecular kinetic competition experiments indicated that the C−H bond metalation step is reversible and an electrophilic deprotonation mechanism is less likely to occur in the reaction. Interestingly, the conjugate addition product can undergo C−C cleavage to give 2-phenylpyridine and chalcone under standard reaction conditions, indicating the reversibility of this C−H activation/addition reaction and giving a feasible approach to promote C−C bond cleavage. A mechanism for this reaction was then proposed (Scheme 15). The reaction is triggered by a rhodium-catalyzed C−H bond activation, wherein the rhodacycle intermediate is produced. Nucleophilic conjugate addition of the rhodacycle intermediate to the chalcone forms an (oxa-π-

base−acid conditions are crucial for this transition-metalcatalyzed C−H activation/conjugate addition reaction. When an acid with an appropriate pKa value is used as solvent, the two proton-transfer events involved in this type of C−H addition are finely balanced. With this consideration in mind, Huang and coworkers developed an efficient and mild rhodium-catalyzed 1,4conjugate addition reaction via C−H activation, in which AcOH was used as the solvent (Scheme 13).26 Using the combination of [Cp*RhCl2]2 and AgSbF6 as the catalyst and AcOH as the solvent, a number of heterocyclic directing groups attached to the arenes and enones were successfully employed in this transformation, affording the E

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Scheme 15

Scheme 17

allyl)rhodium species or a rhodium enolate, which is then protonated by acid to give the product and regenerate the active rhodium catalyst. It is important to note that similar work involving C−H bond activation of arenes with nitrogen-containing heterocyclic directing groups and 1,4-conjugate addition to enones or enals catalyzed by [Cp*Rh(CH3CN)3](SbF6)2 was reported by Li and co-workers (Scheme 16).27 The desired addition products were

Mechanistic studies investigating the role of the base were performed by H/D exchange experiments, and the results suggested that ortho-C−H bond cleavage of pyridine N-oxide occurred through a base-assisted proton abstraction with the aid of metal coordination. A competition experiment with pyridine N-oxide and its deuterated analogue revealed that C−H bond cleavage is the rate-limiting step. In addition, a competitive experiment with 4-phenylpyridine N-oxide and [D5]pyridine Noxide indicated that the reaction did not proceed through innersphere 1,4-conjugate addition. On the basis of these results, a possible mechanism was proposed (Scheme 18). First, the

Scheme 16

Scheme 18

obtained in 57−98% yields in 24−72 h. In this case, however, only aliphatic α,β-unsaturated ketones were used. In 2014, Li and co-workers reported that 4-hydroxycyclohexa-2,5-dienones can also be used as the reaction partners, leading to the synthesis of 3arylated phenols via a sequential C−H bond addition/rearomatization process.28 Chang and co-workers reported the efficient Rh(I)-catalyzed direct addition of heteroarenes to unsaturated alkenes in 2012.29 Using a rhodium(I) complex ligated with DPPE as the catalyst, the addition reactions of various pyridine, quinoline, pyrazine, and pyridazine N-oxides with acrylates proceeded smoothly to produce the desired hydroarylation products in the presence of 25 mol % of CsOAc. Notably, although the hydroarylation of conjugated amides and ketones was highly efficient, that of acrylonitrile was not. It should be noted that various types of azoles, including benzimidazole, benzoxazole, benzothiazole, and thiazole, can smoothly react with tert-butyl acrylate to give the desired alkylated heteroarenes in 72−95% yields (Scheme 17).

[RhCl(cod)]2 precursor and CsOAc undergo anion exchange to give A, which is presumed to be sufficiently active to facilitate the base-promoted proton abstraction and metalation to generate the Rh/heteroaryl species B. Subsequent olefin insertion forms the desired C−C bond, leading to a Rh/alkyl intermediate C. Although protonolysis of C might occur to give desired product F, the results of the controlled experiments ruled out this possibility and indicated that the final protonation step predominantly occurs from isomeric intermediate E, which is generated from C through β-hydride elimination and reinsertion. Given the importance of indoles in natural products and pharmaceuticals, the efficient functionalization of the indole core F

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removable 8-aminoquinoline directing group in the presence of 10 mol % of RuCl2(PPh3)3 and 25 mol % of NaOAc (Scheme 21).35 Under the optimized reaction conditions, the reactions of ortho-substituted amides with methyl vinyl ketone were investigated. The monoalkylated products were exclusively obtained in moderate to good yields when 2 equiv of methyl vinyl ketone was used. In the case of para-substituted amides, dialkylated products were obtained in high yields as the major products when 3 equiv of methyl vinyl ketone was used. However, when meta-substituted amides were subjected to this reaction, the mixture of mono- and dialkylated products was obtained in most cases. Polysubstituted amides with open activated sites at the ortho position were also well tolerated. Scope screening revealed that enones with more sterically hindered double bonds were more reluctant to react with orthosubstituted amides. The synthetic utility of the present methodology was also demonstrated by the facile conversion of the amides into aldehydes and carboxylic acids. Finally, although a series of control reactions using isotopically labeled substrates was conducted to investigate the reaction pathway, the detailed mechanism of the present reaction remains unclear. Carbonyl-directed, ruthenium-catalyzed alkylation of 2aroylbenzo[b]furans with acrylates via C−H activation was reported in 2014 (Scheme 22).36 The selectivity of linear versus branched products in this transformation was catalyst dependent, which was rationalized by the competition between steric and electronic factors. A novel and efficient method for the synthesis of azepinones using benzamides and enals or enones as starting materials was reported by Glorius and co-workers in 2013 (Scheme 23).37 A series of azepinones was obtained in good yields with 2.5 mol % of [Cp*RhCl2]2 and 10 mol % of AgSbF6 as the catalysts in the presence of 2 equiv of PivOH. Various N-substituted benzamides and a number of α,β-unsaturated carbonyl compounds were suitable for this C−H activation/cyclization transformation. Interestingly, the coupling of N-allyloxybenzamide with acrolein under the standard reaction conditions only gave the acyclic 1,4conjugate addition product. The proposed reaction mechanism involved the following steps: regioselective C−H bond cleavage, alkene insertion, protonolysis, nucleophilic addition, protonolysis, and dehydration. Rovis and co-workers reported an interesting rhodiumcatalyzed intramolecular hydroarylation reaction of tethered olefin-containing benzamides.38 In the presence of 1 mol % of [Cp*Rh(CH3CN)3](SbF6)2 and 1 equiv of t-BuCO2H, a series of tethered alkenes could be used for the cyclization, forming the corresponding five- or six-membered products in good to excellent yields. Furthermore, the tethered acrylate could also be used in this reaction to give the corresponding product in good yield (Scheme 24). An efficient Rh(III)-catalyzed coupling reaction for the synthesis of 1,2-oxazepines from N-phenoxyacetamides and α,β-unsaturated aldehydes via C−H activation/[4 + 3] annulation was developed by Duan and co-workers in 2014.39 Interestingly, when an unsaturated ketone such as pent-1-en-3one was used as the coupling partner, only the dialkylated product was obtained. This transformation (Scheme 25) features C−C/C−N bond formation to give seven-membered oxazepine rings at room temperature. Chatani and co-workers reported rhodium-catalyzed intermolecular C−H alkylation of amides containing an 8-aminoquinoline moiety with α,β-unsaturated carbonyl compounds (Scheme 26).40 In the presence of [RhCl(cod)]2 and KOAc, the

via transition-metal-catalyzed C−H activation has attracted much attention from both academia and industry.30 An example of cationic iridium-catalyzed C2-alkylation of N-substituted indole derivatives with various alkenes was reported by Shibata and co-workers in 2012 (Scheme 19).31 Under the optimized Scheme 19

reaction conditions, the corresponding alkylation products were obtained in 27−98% yields with perfect linear selectivity (linear:branched = >99:20:1) and high yield (up to 96%). Mechanistic studies supported a reaction pathway involving the sequence of reversible C−H activation, alkene insertion, C−N bond formation, and N−O bond cleavage. Because of their unique properties, the synthesis and application of cyclopentadienyl−metal complexes have attracted much attention during the past decades.49 Using rheniumcatalyzed C−H bond activation of an olefinic C−H bond as the key step, a novel method for the synthesis of cyclopentadienyl− rhenium (Cp−Re) complexes was developed by Kuninobu et al. (Scheme 32).50 In the presence of 0.5 equiv of Re2(CO)10,

reaction, linear aliphatic alkenes or methyl methacrylate failed to form the desired addition products. A tentative mechanism for this palladium-catalyzed 1,4-conjugate addition was proposed. In this mechanism, alkenyl palladium species are generated by the release of 1 equiv of acid. Then, coordination of the C−C double bond of the acrylate esters to the palladium center occurs, which is followed by carbopalladation and protonation to give the desired product together with regeneration of the palladium catalyst. In addition to the transition-metal catalysts discussed above, the usage of cobalt complexes as catalysts is also possible. Two important papers from the groups of Bergman and Toste showed that cobalt dinitrosyl complexes could promote 1,4-conjugate reactions of unfunctionalized alkenes with enones.53 Although in most cases catalytic turnover was not achieved, a successful intramolecular catalytic transformation example was realized in the presence of 20 mol % of cobalt dinitrosyl complexes (Scheme 35).54 2.1.3. Addition of Aldehydic C−H to C−C Double Bonds. The transition-metal-catalyzed hydroacylation of alkenes with aldehydes, in which an aldehyde is added across a C−C double bond via aldehydic C(sp2)−H bond activation, is an

Scheme 32

various Cp−Re complexes were obtained from α,β-unsaturated ketimines and α,β-unsaturated carbonyl compounds in 36−94% yields. The mechanism of this reaction was proposed to proceed by the following steps: (i) coordination of the ketimine to the rhenium center at the nitrogen atom, (ii) oxidative addition of a specific C−H bond of the ketimine to the rhenium center, (iii) insertion of an α,β-unsaturated carbonyl compound into the rhenium−carbon bond, (iv) intramolecular nucleophilic cyclization, (v) reductive elimination and elimination of aniline to give a cyclopentadiene derivative, and (vi) formation of a Cp−Re complex from the cyclopentadiene derivative and rhenium complex. In this reaction, the rhenium complex acted as both the catalyst for C−H activation and a component of the reactants. In subsequent work, they found that a catalytic amount of Re2(CO)10 or [ReBr(CO)3(THF)]2 was a good catalyst for the addition of an olefin with an N-heterocyclic directing group to α,β-unsaturated carbonyl compounds, affording the γ,δunsaturated carbonyl compounds in good to excellent yields (Scheme 33).51 In 2013, Chen and Pan found that PdCl2 is an efficient catalyst for the 1,4-conjugate addition of alkenes to α,β-unsaturated esters to produce γ,δ-alkenyl esters (Scheme 34).52 Although many aromatic alkenes or acrylate esters were tolerated in this

Scheme 35

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racemic indanones in high yields. The proposed mechanism involved (i) Rh-catalyzed oxidative addition, (ii) migratory insertion, and (iii) reductive elimination. It is noteworthy that the concentration of the substrate played an important role in obtaining high yields. Furthermore, a high yield of 1-indanone was obtained when the 2-vinyl benzaldehyde was added slowly. In contrast, when the substrate was rapidly added with a syringe, the undesired dimer formed as the major product via 2,1migratory insertion. Similar to the intramolecular hydroacylation of polar C−C double bonds, intermolecular hydroacylation reactions have also been well documented in the past decade. The use of a chelationassisted strategy has enormously contributed to the progress of this chemistry. In 2004, a pioneering example of S-chelationcontrolled intermolecular hydroacylation of electron-deficient alkenes was reported by Willis and co-workers (Scheme 39).62 They described an effective hydroacylation reaction of βmethylsulfide-substituted propanal with a range of functionalized electron-deficient alkenes catalyzed by 10 mol % of [Rh(DPPE)]ClO4. The authors proposed the formation of a fivemembered S-chelate-stabilized acylrhodium species to account for the observed reactivity. Subsequent work conducted by Willis and co-workers indicated that synthetically flexible β-thioacetal-substituted aldehydes are able to be used as effective hydroacylation substrates via S-chelate stabilization (Scheme 40).63 The [Rh(DPPE)]ClO4 proved to be an effective catalyst for promoting the reaction. The reaction tolerated a variety of functionalities to give highly functionalized products in good yields. Notably, the thioacetal moiety contained in the products is easily removed by NBS/AgNO3 or Raney Ni to give the corresponding diketones or alkanes in good yields, respectively. Aldehydes containing a β-sulfide group also efficiently underwent hydroacylation with a variety of electron-deficient alkenes, producing ketone-containing linear adducts in good yields with good selectivities.64 An improved catalyst system generated from [RhCl(cod)]2, DPEphos, and AgClO4 that allowed simple alkenes to participate in hydroacylation reaction was designed by Willis, Weller, and co-workers (Scheme 41).65 Mechanistic studies demonstrated that the flexible, hemilabile nature of the DPEphos was responsible for saturation of the vacant coordination site of the metal complex to stabilize the key Rh(III)−acyl−hydride intermediate against reductive decarbonylation. Stoichiometric studies on sequential addition of aldehyde and alkene to precatalyst systems also showed that DPEphos is capable of adjusting its coordination geometry through reversible coordination of the oxygen donor. The proposed S-chelation of the substrate and O-coordination of the ligand to the metal were confirmed by X-ray single-crystal structure analysis. In 2008, Osborne and Willis further extended the substrate scope of hydroacylation to enones. Using 10 mol % of [Rh(DPEphos)]ClO4 as the catalyst, a series of aliphatic, alkenyl, and aromatic enones was successfully hydroacylated to give 1,4diketones, which are useful building blocks for the synthesis of various N-, S-, and O-heterocycles (Scheme 42).66 In contrast, when [Rh(nbd)DPPE]ClO4 was used as the catalyst and CH3CN as an additive, a three-component reductive aldol reaction of aldehydes, enones, and tert-butyl glyoxylate occurred, which was initiated by C−H activation. The influence of hemilabile ligands on the rate and selectivity of the hydroacylation reaction was then investigated.67 The results showed that the overall conversion of the hydroacylation

attractive atom-economical synthetic method for the synthesis of ketones from aldehydes.55 As shown in Scheme 36, the widely Scheme 36

accepted mechanism for this reaction contains three steps: (i) oxidative addition of aldehydic C−H bond to a low-valent metal, (ii) coordination and hydrometalation of the alkene with highvalent acylmetal hydride, and (iii) reductive elimination to give the ketone product and regenerate the low-valent metal catalyst. The main challenge for hydroacylation is the instability of the acylmetal intermediate, which is apt to undergo decarbonylation during the catalytic cycle. One strategy to suppress the decarbonylation is to stabilize the acylmetal intermediate by saturating the coordinative sphere of the metal complex. In this regard, several strategies, such as chelation assistance and performing the reactions under high-pressure CO or ethylene gas, have been devised to stabilize acylmetal hydride species.56 The first intramolecular hydroacylation of 4-enals was reported by Sakai in 1972. Using RhCl(PPh3)3 as the catalyst at room temperature, the desired cyclopentanones were produced in 17−34% yields together with cyclopropanes as byproducts in 20−35% yields.57 In 1976, Miller and co-workers demonstrated that both intermolecular and intramolecular hydroacylation of alkenes could occur in the presence of Wilkinson catalyst when ethylene-saturated CHCl3 was used as the solvent.58 In 1980, Larock and co-workers investigated the intramolecular hydroacylation with a variety of 4,5-unsaturated aldehydes in the presences of ethylene saturated DCM.59 Inspired by these pioneering works, asymmetric intramolecular hydroacylation reactions of alkenes have also been exploited.55 Notably, one early example of asymmetric intramolecular hydroacylation involving aldehydic C−H bond addition to a polar C−C double bond was reported by Bosnich and co-workers (Scheme 37).60 The [Rh(S)-BINAP]ClO4 Scheme 37

complex was found to be a highly efficient chiral catalyst for this asymmetric intramolecular hydroacylation. In these examples, with 4 mol % of catalyst, cyclopentanone derivatives were produced in quantitative yields with up to 99% ee. Morehead and co-workers reported [Rh(R)-BINAP]ClO4catalyzed intramolecular hydroacylation of 2-vinyl benzaldehydes to give chiral indanones in good yields and high enantioselectivities (Scheme 38).61 Unsurprisingly, replacement of [Rh(R)-BINAP]ClO4 with [Rh(DPPE)]ClO4 gave the K

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Scheme 38

Scheme 39

Scheme 42

Scheme 40

In 2012, new rhodium catalysts derived from small-bite-angle diphosphine ligands R12PCH2PR22 (R1, R2 = t-Bu, Cy) were developed by Chaplin et al. (Scheme 43). These new rhodium Scheme 43 Scheme 41

catalysts were bench stable and also exhibited high activity for the intermolecular hydroacylation of a wide variety of alkenes with βS-substituted aldehydes.68 Tanaka and co-workers developed an alternative strategy for stabilization of acylrhodium species by alkene chelation to rhodium instead of S-chelation (Scheme 44). They reported cationic rhodium(I)/DPPB complex-catalyzed intermolecular

is indeed controlled by the hemilabile nature of the chelating phosphine (e.g., DPEphos vs Xantphos), while the course of the reaction can be tuned by changing the bite angle of the phosphine. L

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Scheme 44

hydroacylation of N,N-dialkylacrylamides with both aliphatic and aromatic aldehydes.69 This protocol provided a new versatile method for the synthesis of γ-ketoamides from commercially available substrates with high atom economy. However, methyl acrylate was not a good reaction partner, and only 55% yield of the desired hydroacylation adduct was obtained even when the methyl acrylate was used both as reactant and as solvent. In 2009, highly enantioselective intermolecular hydroacylation of 1,1-disubstituted alkenes with simple aldehydes was achieved by Shibata and Tanaka (Scheme 45).70 It was shown that a

enantioselectivities. Unfortunately, the reaction of benzaldehyde with N,N-diphenylacrylamide was sluggish (38% yield) with only moderate enantioselectivity (64% ee) even when replacing (R,R)-QuinoxP* with (R,R)-Me-Duphos as a ligand. The authors proposed that the strong bidentate coordination of substituted acrylamides to the cationic rhodium might stabilize the acylrhodium intermediate and constructed a rigid chiral environment. The hydroacylation of alkenes with aldehydes can be accelerated by the addition of proper amine ligands. For example, Jun and Jo found the reaction of aliphatic and aromatic aldehydes with acrylic acid derivatives occurred smoothly under the cocatalysis of 5 mol % of RhCl(PPh3)3, 40 mol % of 2-amino3-picoline, and 20 mol % of benzoic acid. Various oxo acid derivatives were obtained in good to excellent yields (Scheme 46).71 Compared with unactivated alkenes, the alkenes containing functional groups were more reactive because of the formation of a metallacyclic complex intermediate with a suitable ring. A novel bifunctional ligand tethering a phosphine to the pyridine ring was synthesized by Breit and co-workers in 2011.72 The ligand was successfully applied to rhodium-catalyzed interand intramolecular hydroacylation of alkenes (Scheme 47). The efficiency of the catalyst system was attributed to the bifunctional P,N ligand, which not only acts as a ligand for generation of active

Scheme 45

cationic rhodium(I)/QuinoxP* complex enabled aliphatic aldehydes to efficiently react with acrylamides. The corresponding γ-ketoamides were obtained in good yields with excellent Scheme 46

M

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as acrylic acid derivatives, as acceptors to facilely produce γ-oxo acid derivatives in good to excellent yields via hydroimination of the alkenes with aldimines in the presence of the Wilkinson catalyst (Scheme 49).76

Scheme 47

Scheme 49

Rh catalyst but also functions as an organocatalyst to activate the aldehydes. Compared with well-known hydroacylation of electrondeficient alkenes, regioselective rhodium-catalyzed hydroacylation of electron-rich olefins has received little attention.73 In the presence of catalytic amounts of Rh(acac)(CO)2 and monodentate phosphine ligand, the hydroacylation of salicylaldehydes and enamides occurred smoothly to give a variety of α-amido ketones in good yields (Scheme 48). The presence of CH3CN Scheme 48 2.1.5. Addition of Formate C−H to C−C Double Bonds. As discussed above, the hydroacylation where an aldehydic C−H bond is activated and then added to electron-deficient alkenes has been extensively studied. However, the analogous hydroesterification of alkenes with formates still remains to be investigated. This is probably because of some inherent limitations, such as the inert formyl C−H bond and the significant tendency for decarbonylation of alkyl formates during the catalytic cycle, resulting in only a few examples being reported.77 The first example of highly efficient and novel chelationassisted hydroesterification of olefins with formates was reported by Chang and co-workers (Scheme 50).78 Using 5 mol % of

facilitated this novel intermolecular hydroacylation reaction through the coordination of nitrile to the rhodium center to stabilize the catalytic intermediates. Further studies revealed that the electron-deficient phosphine P(p-F-Ph)3 was the most effective ligand for the hydroacylation of 1-vinyl-2-pyrrolidinone with salicylaldehydes. A range of enamides, such as 1-vinyl-2pyrrolidinone, N-methyl-N-vinylacetamide, N-methyl-N-vinylacetamide, and N-vinylphthalimide, are also compatible with this catalytic system. The key to the success of this reaction was using the phenolic hydroxyl of the salicylaldehyde as the directing group. 2.1.4. Addition of Aldimine C−H to C−C Double Bonds. An alternative approach to suppress decarbonylation during the hydroacylation is based on conversion of aldehydes to imines, which can more strongly bond to the catalyst. The aldimine can be directly used or generated in situ by the reaction of an aldehyde and an amine. A pioneering study on rhodiumcatalyzed chelation-assisted hydroacylation via C(sp2)−H activation of aldimines was reported by Suggs. In this case, a strained five-membered metallacycle was formed and decarbonylation was escaped for the chelatable aldimine which was prepared from the reaction of 2-amino-3-picoline and aromatic aldehyde.74 Inspired by this work, Jun and co-workers improved this chelation-assisted hydroimination protocol and found that (N-2-pyridyl)aldimines could be generated in situ by performing hydroacylation of aldehydes with alkenes in the presence of 2amino-3-picoline. With this method, a broad range of aldehydes and alkenes was coupled to give ketones in good to excellent yields.75 In the 21st century, the addition of aldimines to alkenes containing activated C−C double bonds has attracted more attention. Willis and co-workers used functionalized olefins, such

Scheme 50

N

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mechanism of the addition reaction was not clear, the observed trans hydroarylation of alkynes was believed to occur under kinetically controlled conditions. Furthermore, reactions of alkynoates with heteroaromatic compounds, such as methylfuran, pyrroles, and indoles, were also investigated by Fujiwara and co-workers. In the presence of 5 mol % of Pd(OAc)2 in AcOH or DCM at room temperature, the desired cis-heteroarylalkenes were produced in moderate to good yields.83 With alkynoates containing less-hindered groups in the C-3 position, such as methyl or n-C5H11, the reactions in AcOH gave diaddition products, while with a relatively bulky group, the reactions gave monoaddition products. Subsequently, a series of β-alkenylpyrroles was obtained through the addition of 2,5substituted pyrroles to alkynoates under similar reaction conditions.84 The intramolecular version of this reaction has also been developed (Scheme 52).85 In the presence of a catalytic amount

Ru3(CO)12 as the catalyst, the hydroesterification of methyl vinyl ketone with 2-pyridylmethyl formate proceeded smoothly, giving the desired linear adduct in good yield. The authors proposed that chelation between the ruthenium and the pyridyl nitrogen involved in the catalytic cycle facilitated the activation of the formyl C−H bond and suppressed undesired decarbonylation. Two six-membered cyclic ruthenium(II) species were proposed as important intermediates. In an effort to improve the reaction conditions of the established Ru-catalyzed hydroesterification, they found that the presence of catalytic amounts of halide salts enabled the reaction to be carried out under milder conditions (70 °C).79 2.2. Addition of C(sp2)−H to C−C Triple Bonds

Aromatic olefins, enones, and conjugated dienes are versatile intermediates in organic synthesis, and various protocols have been developed to produce these compounds.80 Among the established methods, direct addition of C(sp2)−H bonds to C− C triple bonds via C−H activation is recognized as one of the most efficient tools to construct those types of π-conjugated organic molecules. In this section, transition-metal-catalyzed direct additions of C(sp2)−H bonds to functionalized alkynes are presented. 2.2.1. Addition of Aryl C−H to C−C Triple Bonds. In 1979, Hong and co-workers reported an early example of C(sp2)−H addition to C−C triple bonds via C−H activation. They found that Rh4(CO)12 is an effective catalyst for the addition of simple arenes to alkynes.81a Subsequently, a variety of catalytic reactions with this chemistry have been developed.81b−f However, most alkynes used in these reactions were unactivated. Friedel−Crafts-type electrophilic aromatic substitution is generally accepted as the probable pathway for this reaction. In 2000, Fujiwara and co-workers made a breakthrough in direct C(sp2)−H activation/addition to C−C triple bonds. The addition of simple arenes with alkynes (Fujiwara hydroarylation) has been achieved in the presence of Pd(II), Pt(II), or other transition-metal catalysts at room temperature in a TFAcontaining mixed solvent (Scheme 51).82 trans-Hydroarylation

Scheme 52

of Pd(OAc)2 in a mixed solvent containing TFA, various aryl alkynoates and alkynanilides underwent a rapid intramolecular reaction at room temperature to afford coumarins and quinolones in moderate to excellent yields. Up to 1202 turnover numbers (TON) was obtained in the presence of 0.079 mol % of Pd(OAc)2 in 5 h at room temperature. This methodology proved to tolerate a number of functional groups, including bromo and formyl groups. A possible mechanism involving ethynyl chelation-assisted electrophilic metalation of aromatic C−H bonds by in-situ-generated cationic Pd(II) species was proposed. Thereafter, a number of catalytic systems based on Pd(II)/NHC complexes were developed for the addition of electron-rich arenes to propiolic acid esters under acidic conditions.86 However, there is still some controversy about the mechanism of Fujiwara hydroarylation. In fact, the electrophilic arene metalation mechanism proposed by Fujiwara was recently put into question by the experimental work carried out by Tunge and Foresee87a and the theoretical calculations reported by Soriano and Marco-Contelles,87b who both supported an electrophilic aromatic substitution mechanism. Sames and co-workers discovered that PtCl4 is also an efficient catalyst in a similar cyclization reaction for the synthesis of coumarins.88 Using PtCl4 (1−5 mol %) as the catalyst, various arene−ynes with diverse structural features, including propargyl ethers, propargylamines, and alkynoates, cyclized smoothly to form the desired 6-endo products in good to excellent yields. The concise total synthesis of (±)-deguelin was also achieved using platinum-catalyzed 6-endo hydroarylation of an alkynone as the key step.89 Subsequently, a variety of arene−ynes with different linkers between arenes and alkynes have been used in palladium and other transition-metal-catalyzed intramolecular hydroarylation reactions. In most of the studies, a Friedel−Craftstype electrophilic aromatic substitution mechanism was proposed.90 For the direct additions of arenes to alkynes discussed above, it is believed that the most reliable mechanism is via Friedel−Crafts electrophilic aromatic substitution because only electron-rich

Scheme 51

reaction of functionalized alkynes with arenes occurred smoothly to predominantly afford kinetically controlled cis-3-aryl-α,βunsaturated acids, esters, ketones, and aldehydes in most cases. A possible mechanism for the addition reactions was proposed. The electrophilic metalation of aromatic C−H bond by cationic Pd(II) species results in the formation of a σ-aryl-Pd complex A, followed by coordination of alkyne to give B. Trans insertion of C−C triple bonds to the σ-aryl−Pd bond of B gives vinyl−Pd complex C, which then undergoes protonation to give the final product and regenerate the Pd(II) species. The presence of the acid facilitated both the formation of cationic Pd(II) species and the protonation of the vinyl−Pd complex. Although the specific O

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Scheme 53

of these cyclization reactions, a mechanism involving ortho palladation via C−H activation/migratory insertion of a triple bond/protiodepalladation was proposed. Li and co-workers developed a simple and efficient protocol for stereoselective synthesis of (Z)- and (E)-3-(monosubstituted methylene)oxindoles via Pd(OAc)2/DPPF-catalyzed hydroarylation of N-arylpropiolamides (Scheme 55).92 The corresponding oxindoles were obtained in moderate to excellent yields. It is noteworthy that the stereoselectivity of the reaction can be controlled by varying the reaction temperature. To rationalize the stereoselectivity of the products in this transformation, the authors proposed two possible mechanisms. As outlined in Scheme 56, the first pathway involves sequential C− H activation/complexation/addition/protonation/thermodynamic isomerization (path A). Alternatively, a cis-hydropalladation/C−H activation/reductive elimination pathway was also suggested by the authors (path B). 2.2.2. Addition of Aldehydic C−H to C−C Triple Bonds. Although hydroacylation of C−C triple bonds with aldehydes is recognized as a promising method to prepare conjugated enones, compared with hydroacylation of alkenes, hydroacylation of alkynes has received less attention. Pioneering work on transition-metal-catalyzed intermolecular hydroacylation of internal alkynes with aldehydes was reported by Tsuda and coworkers in 1990, in which a Ni(0) complex was found to be an effective catalyst (Scheme 57).93 Subsequently, a series of studies on hydroacylation of alkynes was reported.62−64,94 However, in those cases, simple alkynes were generally used. The hydroacylation of polar alkynes containing electron-deficient C−C triple bonds with aldehydes remains underexplored, and only limited studies with a few cases have been reported. Therefore, the limited examples of hydroacylation of electron-deficient alkynes with aldehydes are not discussed in detail and are just listed in Table 1. 2.2.3. Addition of Formate and Formamide C−H to C− C Triple Bonds. Several examples of the direct addition of formates and formamides to polar C−C triple bonds via C(sp2)−

arenes can be used in the presence of Lewis acids. Therefore, this research topic is only briefly discussed in this section. With the aid of an imine directing group, the C−H bonds of heteroaromatic compounds at the adjacent position to the directing group can add to acetylenes in the presence of [ReBr(CO)3(THF)]2 (Scheme 53).19 Treatment of a furan derivative bearing an imino group at the 3 position with methyl but-2-ynoate produced a mixture of alkenyl furans. The alkenylation reaction occurred not only at the 2 position but also at the 4 position of the furan ring. Reaction of terminal acetylenes with imino furan did not occur under the same conditions. The proposed mechanism involved the following steps: (i) oxidative addition of a C−H bond of an aldimine to a rhenium center, (ii) insertion of acetylene into a rhenium− carbon bond, and (iii) reductive elimination to regenerate the rhenium catalyst. In 2008, the first example of the Pd-catalyzed exclusive 5-exodig hydroarylation of o-alkynyl biaryls via C−H activation was reported by Gevorgyan and Chernyak (Scheme 54).91 In the Scheme 54

presence of 5 mol % of Pd(OAc)2 and 7 mol % of d-i-Prpf, a variety of 9-benzylidene-9H-fluorene derivatives were produced under neutral conditions. On the basis of the observed high values of the kinetic isotope effects and the exclusive cis selectivity Scheme 55

P

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Scheme 56

2.3.1. Addition of Aryl C−H to Aldehydes and Ketones. Functionalized imidazoles are important molecules in the field of biological and medicinal chemistry. The alkylation of imidazoles is one of the most efficient and direct processes to generate functionalized imidazoles and has been extensively used in organic chemistry.97 In 2002, an elegant study of the [Ir4(CO)12]-catalyzed coupling reaction of imidazoles with aldehydes was reported. A variety of 2-alkyl imidazoles were obtained in moderate to excellent yields with diethylmethylsilane as a coreactant (Scheme 60).98 No reaction occurred in the absence of diethylmethylsilane, and addition of a hydrogen acceptor to the reaction system improved the yield. Among the hydrogen acceptors studied, DMAD was the best additive. A possible reaction mechanism was proposed, which included (i) addition of Ir−SiR3 to the aldehyde, (ii) carboiridation of the C− N double bond of the imidazole, (iii) β-hydride elimination, and (iv) regeneration of the active catalyst species Ir−SiR3. Although this is the first example of transition-metal-catalyzed formal direct addition of C−H bonds to aldehydes, the C−H activation step is not involved in the proposed mechanism. In 2007, using the same silyl-capturing strategy, the first manganese complex-catalyzed addition reaction of aromatic C− H bonds to aldehydes using imidazole and imidazoline as directing groups was reported by Kuninobu and Taki (Scheme 61).99 Among the catalysts investigated, [MnBr(CO)5] showed the highest activity. To recycle the manganese complex, 2 equiv of triethylsilane was added. The scope of the optimized catalytic system was broad, and various aromatic, heteroaromatic, and aliphatic aldehydes gave the corresponding silyl ethers in moderate to good yields. Finally, an asymmetric transformation using an aromatic compound with a chiral substituent was established based on this strategy. A mechanism including (i) oxidative addition of a C−H bond of an aromatic compound to a manganese center, (ii) insertion of an aldehyde into the

Scheme 57

H bonds activation have been reported. In 2010, Tsuji and coworkers reported a novel palladium catalytic system for addition of formamides to alkynes (Scheme 58).95 After screening various palladium precursors, phosphine ligands, and additives, the optimized reaction conditions were identified and are summarized in Scheme 58. The reaction proceeded smoothly under the optimized reaction conditions, affording various α,βunsaturated amides in good yields with high regioselectivities and stereoselectivities. A catalytic cycle involving formation of a key Pd(IV) intermediate via oxidative addition of a formyl C−H bond to the Pd(II) catalyst was proposed. Subsequently, hydroesterification of alkynes with aryl formates catalyzed by Pd−Xantphos complexes was also reported by Tsuji and co-workers (Scheme 59).96 A wide range of alkynes including internal alkynes with ester and amide functionalities successfully participated in the hydroesterification reaction. While aryl formates could be used in the reaction, alkyl formates did not react at all. Mechanistic studies showed that the conversion of aryl formates to carbon monoxide and phenol derivatives occurred in the hydroesterification. 2.3. Addition of C(sp2)−H to C−O Double Bonds

The transition-metal-catalyzed addition of C(sp2)−H bonds to aldehydes or ketones via C−H activation is highly intriguing, and these reactions present a green and more straightforward way to add a hydroxyl or an alkoxyl group to a carbon atom. It is therefore not surprising to find that many exciting results have been reported for this type of addition reaction. Q

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Table 1. Various Hydroacylation Reactions of Electron-Deficient Alkynes with Aldehydes

Scheme 58

Scheme 60

manganese−carbon (aryl) bond, and (iii) silyl protection via the formation of H2 was proposed. In 2011, Shi and Li successfully extended the same strategy to the addition of the 3-pyridinyl C−H bond to aldehydes by using the combination of 2 mol % of Ir4(CO)12 and 4 mol % of 1,10phenanthroline (phen) in the presence of HSiEt3 (Scheme 62).100 A variety of 3-substituted pyridine derivatives in addition to pyridine reacted smoothly with aromatic aldehydes to furnish the meta-selective C−H adducts in moderate to good yields. However, aliphatic aldehydes with lower electrophilicity were not compatible with the reaction. Furthermore, 2-substituted pyridines such as 2-methylpyridine and 2,6-lutidine resulted in Scheme 59

R

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Scheme 61

Scheme 63

Scheme 62

this reaction is given in Scheme 63. Cyclometalation gives a fivemembered rhenacycle. Insertion of an aldehyde forms a sevenmembered intermediate followed by intramolecular nucleophilic addition of the alkoxyrhenium moiety to imine, reductive elimination, and elimination of aniline to give the isobenzofuran products. It is interesting to note that the carbon−rhenium bonds show high nucleophilicity, which is a characteristic property of early transition metals, and the rhenium complex can be used as a catalyst for bond formation via reductive elimination, which is usually observed in catalysis involving late transition metals. Given that isobenzofuran derivatives bearing reactive diene moieties can be used in Diels−Alder reactions, three-component coupling of ketimine, benzaldehyde, and cyclooctene initiated by C−H activation was realized. After treating the Diels−Alder adducts in situ with acetic acid, the corresponding naphthalene derivatives were produced in good yields.101b Using the above transformation as a key step, unsymmetric pentacene derivatives with a functional group at the 5 position of the aromatic ring of the pentacene skeletons were also successfully synthesized by Takai and co-workers.102a Moreover, a new type of dehydrative trimerization of aldehydes to give indenone derivatives was achieved by heating a mixture of aryl aldehydes with catalytic amounts of ReBr(CO)5 and Nphenylacetamide in toluene, in which the key step is rheniumcatalyzed C−H bond activation (Scheme 64).102b A simple and straightforward approach to synthesize 3substituted phthalides by rhodium(III)-catalyzed C−H functionalization directed by a carboxyl group was established by Shi and Li in 2012 (Scheme 65).103 Grignard-type arylation of an aldehyde and subsequent intramolecular nucleophilic substitu-

low yields under the same conditions. The proposed mechanism is shown in Scheme 62. An active silyl iridium catalyst is first generated from the combination of Ir precursor, ligand, and silane. Then, oxidative addition of the pyridyl C−H bond to the low-valent Ir species occurs to produce the key Ir(III) intermediate, which is followed by insertion of arylaldehydic CO into the Ir−Si bond and reductive elimination to afford the product along with generation of an iridium hydride species. Finally, the iridium hydride species reacts with hydrosilane to regenerate the active iridium catalyst. As discussed above, although capture of the alcohol products as silyl ethers has been demonstrated as a powerful strategy to obtain high catalytic TONs in such reactions, the use of a superstoichiometric amount of silane significantly decreased the atom economy of the reaction. Therefore, in recent years, the research focus has shifted to the development of efficient C−H addition protocols conducted in the absence of additive. With rational design based on a C−H addition/cyclization process, Kuniobu and Takai used the chelation-assisted strategy to realize the addition reaction of aromatic ketimines with aldehydes in the absence of silanes (Scheme 63).101 A large number of isobenzofuran derivatives can be prepared using this strategy with [ReBr(CO)3(THF)]2 as a catalyst. A plausible pathway for

Scheme 64

S

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Scheme 65

Scheme 67

tion are involved in transformation. Although only aldehydes with electron-withdrawing groups were used in the reaction, this cascade cyclization provides a novel strategy and economical alternative to construct biologically important phthalides in one step. In 2012, using the same C−H addition/cyclization strategy as Shi and Li, Lian et al. developed an excellent method to synthesize phthalides via the direct addition of benzimidates to aldehydes (Scheme 66).104 The combination of [Cp*RhCl2]2

A formal [4 + 1] annulation approach to synthesize N-aryl-2Hindazoles from azobenzenes and aldehydes was developed by Ellman, Lavis, and co-workers in 2013 (Scheme 68).106 The azo moiety served not only as a directing group to promote the Rh(III)-catalyzed C−H activation but also as a nucleophile to trap the alcoholic intermediate. A wide range of aldehydes and azobenzenes participated in the reaction to generate a wide variety of indazoles in 38−81% yields. Moreover, regioselective coupling of asymmetrical azobenzenes was also demonstrated. Mechanistic studies demonstrated that the reaction is initiated by Rh(III)-catalyzed reversible addition of an azobenzene C−H bond to an aldehyde. The resulting alcohol then undergoes intramolecular nucleophilic substitution and rapid aromatization to give the desired 2H-indazole. As discussed above, silane capture and C−H addition/ intramolecular annulation are two important strategies for capturing the hydroxyl group containing intermediates to facilitate the addition of aromatic C−H bond to aldehydes.107 However, it is noteworthy that when using highly electrondeficient aldehydes as the acceptor, direct C−H additions to produce the desired alcohols can be realized in the absence of silane. For example, Rh(III)-catalyzed Grignard-type arylation of electron-deficient aldehydes was realized by Li and co-workers in 2011, wherein nitrogen-containing heterocycle-directed C−H activation is involved (Scheme 69).108 For the aldehydes, as well as ethyl glyoxylate, aromatic aldehydes with electron-withdrawing groups were also found to be good substrates. The reaction can tolerate a wide range of functionalities such as esters, halides, and nitro groups. Interestingly, the reaction can occur efficiently in the presence of water and air. A tentative mechanism involving coordination of rhodium to a nitrogencontaining heterocycle, subsequent electrophilic substitution, sequential aldehyde coordination, nucleophilic addition, and protonation was proposed. A similar study of Rh(III)-catalyzed N-heterocycles-directed aryl C−H bond addition to electron-deficient aldehydes to produce diarylmethanols was reported by Shi and co-workers (Scheme 70).109 The procedure is compatible with water and air. Intra- and intermolecular isotopic studies showed that the C−H cleavage is reversible. A similar reaction of Rh(III)-catalyzed N-nitroso-directed aryl C−H addition to ethyl 2-oxoacetate was reported by Chen et al. in 2014.110 The optimized catalytic system shown in Scheme 71 exhibited high reactivity for a wide range of N-nitrosoanilines, giving the corresponding products in moderate to excellent yields. A mechanism involving N-nitroso-directed electrophilic C−H activation/ortho-rhodation, migratory insertion, and proto-demetalation for product release and catalyst regeneration

Scheme 66

and AgSbF6 is an efficient catalyst system for the reaction to afford the resulting phthalides in good yields. The reaction showed broad substrate scope with a high level of functional group compatibility and is applicable to both aromatic and aliphatic aldehydes. In this reaction, the imidate is a novel directing group that not only enables this C−H bond activation/ addition to aldehydes to proceed well but also captures the alcohol intermediate generated after the C−H addition. It was noted that coupling reactions between benzimidates and aromatic aldehyde could be carried out in air. However, a significant decrease in yield was observed when aliphatic aldehydes were used as the substrates. A novel coupling reaction between two aldehydes for the synthesis of C3-substituted phthalides was reported by Tan et al. in 2013 (Scheme 67).105 The reaction proceeded via imine intermediates by cooperative catalysis of a Rh(III) complex and an aromatic amine. Both homo- and cross-coupling of aldehydes were feasible, and various functionalized aryl and alkyl phthalides were obtained in moderate to high yields. The reaction involved a cascade ortho-C−H activation/insertion/annulation sequence. T

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Scheme 68

reported by Shibata and co-workers.112a The reaction was proposed to occur via a directed intramolecular cyclization− dehydration sequence (Scheme 73). In addition to the acetyl group, ester and amide moieties could also function as directing groups. The reaction was assumed to be initiated by a directed C−H bond cleavage through oxidative addition or an electrophilic metalation mechanism, followed by sequential intramolecular 1,2-addition and dehydration to give the 4-substituted benzoheteroles as the sole regioisomer. In addition, the enantioselective version of this protocol was also achieved by replacing rac-BINAP with (S)-H8-BINAP. In a mechanistic study, Shibata and co-workers found that the value of the intramolecular KIE was approximately 1.1 and the introduction of an electron-withdrawing group on the benzene ring decreased the reactivity.112b From these results, the authors concluded that C−H bond cleavage by electrophilic metalation is more reliable than oxidative addition. Further studies from the same research group demonstrated that the catalyst prepared from [Cp*IrCl2]2, AgSbF6, and Cu(OAc)2 also enabled the reaction, and various multisubstituted benzofurans were obtained in high to excellent yield with perfect regioselectivities at room temperature or 60 °C. In 2013, Shi and co-workers reported Rh-catalyzed intermolecular nucleophilic addition of aromatic C−H bond to ketones (Scheme 74).113 In this case, the directing group had a significant influence on the reactivity. Only the sterically hindered quinolyl directing group could effectively promote the reaction. A C−H activation mechanism through an electrophilic metalation pathway was supported by control experiments. Moreover, a Friedel−Crafts pathway was ruled out because this reaction could not be promoted by simple Lewis acids and Brønsted acids. On the basis of a deuterium-labeling experiment and previous reported data, a reaction pathway involving reversible C−H activation, CO bond insertion, and protonation was proposed. Another Pd(OAc)2-catalyzed C−H addition reaction of azoles to isatins for the construction of 3-substituted-3-hydroxy-2oxindoles was reported by Yang and co-workers (Scheme 75).114 The bidentate nitrogen ligands were found to be useful to promote this reaction. Various substituted N-methylisatins and

Scheme 69

was proposed. Finally, using the obtained C−H addition products as substrates, a formal [2 + 2] cycloaddition/ fragmentation reaction for the construction of indazoles was also achieved. Compared with the well-documented transition-metal-catalyzed direct additions of aryl C−H bonds to aldehydes, the analogous additions of C−H bonds to ketones via C−H activation have received little attention owing to their attenuated reactivity. To date, only limited examples have been reported. Seminal work involving one-step synthesis of benzofurans from phenoxyacetonitriles catalyzed by [(bpy)Pd(μ-OH)]2(OTf)2 or [(bpy)Pd(H2O)2](OTf)2 was reported by Lu and Zhao (Scheme 72).111 Because there was no strong evidence to support the involvement of C−H activation in this transformation, two possible pathways including either a Friedel− Crafts reaction or C−H activation were proposed. Subsequently, using a cationic iridium−BINAP complex as the catalyst, a cascade reaction for the synthesis of 4-substituted benzofurans and indoles from α-aryloxy ketones and α-arylamino ketones was U

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Scheme 70

Scheme 71

Scheme 73

Scheme 72

Scheme 74

different azoles such as benzoxazoles, imidazoles, benzothiazoles, and 2-phenyl-1,3,4-oxadiazole were compatible with the reaction, and the desired addition products were obtained in moderate to excellent yields. Intermolecular KIE experiments (kH/kD = 2.48) indicated that C−H bond cleavage might be the rate-determining step in this transformation. The proposed reaction mechanism is shown in Scheme 75. First, Pd(OAc)2 coordinates with 2,2′-bipyridine to form the activated palladium complex. Then, the activated palladium complex reacts with V

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Scheme 75

benzoxazole by C−H bond activation to produce a dimer, which coordinates with the carbonyl groups of isatin. Finally, migratory insertion of benzoxazole to carbonyl occurs, and subsequent protonation gives the product along with regeneration of the active palladium catalyst. In 2014, Yamamoto and co-workers reported [Ir(cod)2]BArF/(R,R)-Me-BIPAM-catalyzed enantioselective intramolecular hydroarylation of α-ketoamides through C−H activation (Scheme 76).115 Under the optimized reaction conditions, various types of optically active 3-substituted 3-hydroxy-2oxindoles formed in high yields with complete regioselectivity and high enantioselectivities. As shown in Scheme 76, the proposed mechanism initiates with facile C−H activation. The key step for controlling the enantioselectivity is the asymmetric insertion of the carbonyl group of the ketone into the active aryliridium complex. In 2014, Li and co-workers developed Rh(III)-catalyzed directed coupling of arenes with cyclopropenones to produce enones (Scheme 77).116 Using 2.5 mol % of [Cp*RhCl2]2 and 15 mol % of AgSbF6 as the catalyst system, the reaction of 2phenylpyridine and 2,3-diphenylcycloprop-2-enone occurred smoothly under mild conditions to give the desired enone in 91% yield. A series of arenes bearing directing groups such as 2pyridyl, 2-pyrimidyl, N-pyrazyl, and oxime could be used as the substrates. A mechanism involving C−H activation, migratory insertion of the Rh−aryl bond into the carbonyl group, and subsequent β-carbon elimination was proposed. 2.3.2. Addition of Olefinic C−H to Aldehydes. Olefinic C−H bond activation and subsequent addition to aldehydes and ketones offers a direct and high atom-economical synthesis of allylic alcohols.117 The addition of an olefinic C−H bond to aldehydes has continuously received attention during the past years. A novel work in the field of transition-metal-catalyzed direct addition of olefinic C−H bonds to aldehydes was reported in 2009 by Kuniobu and co-workers (Scheme 78).51 They found that the reaction proceeded well when the animidazolyl group

Scheme 76

was used as a directing group in the presence of HSiEt3 and 2.5 mol % of [ReBr(CO)3(THF)]2. Aromatic and aliphatic aldehydes were all compatible with the reaction conditions, and the corresponding silyl ethers were obtained in high yields. W

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Scheme 77

Scheme 79

The selection of the directing group of olefinic substrates and the capture of the alcohol products with HSiEt3 were important to promote the reaction. Moreover, MnBr(CO)5 was also found to be a good catalyst in the reaction. The proposed reaction pathway involves the following sequence of steps: (i) oxidative addition of an alkene to a rhenium or manganese center, (ii) insertion of CO of an aldehyde into the rhenium−carbon or manganese−carbon bond, and (iii) silylation of the alcohol via release H2. The first chelation-assisted direct addition of alkenyl C−H bonds to electron-deficient aryl aldehydes in the absence of silanes was reported in 2012 (Scheme 79).118 Using 5 mol % of [Cp*Rh(CH3CN)3][SbF6]2 as the catalyst and 10 mol % of PivOH as the additive, the reaction exhibited good efficiency with electron-withdrawing groups on the phenyl ring of the aldehydes. However, when benzaldehyde was used as a coupling partner, only 17% yield of the desired adduct was obtained under the optimized reaction conditions. In 2013, using the established C−H addition/annulation strategy, an interesting Rh(III)-catalyzed annulation reaction for the synthesis of substituted furans via C−H bond activation was reported (Scheme 80).119 The reaction conditions were compatible with a number of different substituents on the α,βunsaturated oximes. Using the combination of [Cp*RhCl2]2 and AgSbF6 as the catalyst system, the annulation reactions of α,βunsaturated oximes with ethyl glyoxylate gave the desired 2carboxyethyl-substituted furans in 58−89% yields. Moreover, a broad range of aromatic and aliphatic aldehydes also smoothly underwent the annulation reactions to afford substituted furans in moderate to good yields under the optimized reaction conditions. The annulation was initiated by the Rh(III)-catalyzed addition of an alkenyl C−H bond across the CO bond of an aldehyde with subsequent cyclization and aromatization. 2.3.3. Addition of Aldehydic C−H to Aldehydes and Ketones. Although transition-metal-catalyzed hydroacylation of alkenes and alkynes via an acyl metal hydride species has been well studied, analogous additions of an aldehydic C−H bond to a ketone or an aldehyde are less well developed.120 An early investigation of self-condensation of aldehydes to give esters was undertaken by using ruthenium complexes. The reaction was

Scheme 80

applicable to aliphatic and aromatic aldehydes. The oxidative addition of aldehyde to ruthenium species was proposed to be the initiation step of the catalytic cycle.121 In 1990, a series of [Rh(diphosphine)(solvent)2]+ catalysts was identified as effective catalysts for converting 1,4-dialdehydes and 1,4-keto aldehydes to the corresponding γ-lactones (Scheme 81).122 Among the diphosphine ligands investigated, electronrich diphosphine ligands exhibited the highest reactivity. Because ketones are generally more difficult to reduce (with H−) than aldehydes, significant decarbonylation was observed in the hydroacylation of 1,4-keto aldehydes. Although only moderate yields were obtained, this work represents the first attempt of the

Scheme 78

X

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the latter was a highly enantioselective catalyst. Hammett plot studies and KIE experiments suggested that insertion of the ketone into the rhodium hydride is the rate-limiting step of the catalytic cycle. Density functional theory studies also suggested that the activation energy of ketone insertion is the highest in the three elementary steps, which indicated that ketone insertion was the rate-limiting step. Notably, the presence of the oxygen atom in the substrates seemed to play an important role in suppressing undesired decarbonylation by coordinating to rhodium throughout the catalytic cycle. A chelating sulfur atom also had a similar effect, which was determined by the fact that a thiol ether substrate was also converted into the desired chiral lactone with high yield and excellent enantioselectivity. Moreover, replacement of the oxygen or sulfur atom with a methylene unit virtually stopped the reaction. On the basis of kinetic studies, NMR experiments, and computational modeling, a reasonable mechanism of the intramolecular hydroacylation catalyzed by [Rh((R)-DTBM-SEGPHOS)]BF4 was proposed (Scheme 84). Phthalides are valuable molecules that display a wide range of biological activities.125 In 2009, Dong and co-workers reported an atom-economical approach to obtain chiral phthalides by rhodium-catalyzed enantioselective C−H functionalization (Scheme 85).124c Various chiral phosphine ligands were investigated, and Duanphos gave the best result. Interestingly, the optimization process revealed that the chemoselectivity is significantly affected by the nature of the counterion of the rhodium catalyst. Catalysts with more strongly coordinating counterions, such as NO3−, OMs−, OTf−, and Cl−, showed better selectivity for hydroacylation over decarbonylation. Furthermore, an appropriate choice of counterion was important to control the enantioselectivity. In addition, the authors successfully applied this protocol to the asymmetric synthesis of (S)-(−)-3-n-butylphthalide, which is responsible for the flavor of celery. In 2011, nitrogen-directed rhodium-catalyzed ketone hydroacylation was achieved by Dong and co-workers. Benzoxaze pinones and benzoxazecinones were obtained in 85−91% yields with 50−93% ee and in 84−99% yields with 88−99% ee, respectively (Scheme 86).124d Compared to the ether- and sulfide-tethered analogues, more efficient hydroacylation was

Scheme 81

hydroacylation of aldehydes with ketones via C−H activation. An aldehydic C−H activation/carbonyl/insertion/reductive elimination sequence was thought to be involved in the reaction. Later, a combination of [RhCl(cod)]2 and DPPP also showed good reactivity in delivering o-phthalaldehyde to benzolactone (Scheme 82).123 Scheme 82

From 2008 to 2011, significant contributions were made in this research area by Dong and co-workers.124 In 2008, they reported the first enantioselective Rh(I)-catalyzed intramolecular hydroacylation of 1,6-keto aldehydes derived from salicylaldehydes (Scheme 83).124a In the presence of 5 mol % of [Rh((R)-DTBMSEGPHOS)]BF4, a series of substrates underwent hydroacylation to produce the corresponding chiral benzodioxepinones in high yields with excellent enantioselectivities (up to >99% ee). In 2009, a clear understanding of the mechanism of asymmetric Rh(I)-catalyzed intramolecular hydroacylation was obtained through detailed experimental and theoretical studies. 124b [Rh(DPPP)] 2 (BF 4 ) 2 and [Rh((R)-DTBMSEGPHOS)]BF4 were identified as optimal catalysts for ketones hydroacylation. The former provided rapid and good conversion to benzodioxepinones with no hydroacylated byproducts, and Scheme 83

Y

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Scheme 84

In 2014, Dong and co-workers reported the first enantioselective intermolecular hydroacylation reaction of ketones (Scheme 87).126 By developing a new Rh−Josiphos catalyst, they achieved hydroacylation of α-ketoamides with aliphatic aldehydes. The α-acyloxyamides were formed in good to excellent yields with high enantioselectivities. Kinetic studies revealed a first-order dependence of the rate on the substrates and a second-order rate dependence on the rhodium catalyst. KIE experiments supported C−H bond activation to be turnover limiting. On the basis of the mechanistic and kinetic studies, they proposed a pathway in which rhodium plays a dual role in activating the aldehyde for the hydroacylation reaction.

Scheme 85

2.4. Addition of C(sp2)−H to C−N Double Bonds

Transition-metal-catalyzed direct C−H addition to C−N double bonds has recently emerged as a powerful tool for the transformation of otherwise unreactive C−H bonds to form nitrogen-containing molecules, avoiding tedious and sluggish prefunctionalization steps.127 In recent years, significant advances have been made in this research area. In this section, the direct additions of C(sp2)−H bonds to two types of substrates (imines and isocyanates) are discussed. 2.4.1. Addition to Imines. In 2011, the Rh(III)-catalyzed direct addition of C(sp2)−H bonds to imines to produce secondary amines was successfully achieved by the groups of Bergman128 and Shi.129 The work of Bergman’s group indicated that [Cp*RhCl2]2/AgSbF6 is an efficient catalyst system for the addition of 2-arylpyridines to N-Boc- and N-sulfonylimines (Scheme 88).128a Preliminary mechanism studies using Ntosylimine as the substrate revealed that the addition reaction proceeded via a reversible C−H activation process. A mechanism involving initial electrophilic deprotonation was proposed. Similar but independent work was reported by Shi and coworkers in 2011 (Scheme 89).129a In this case, [Cp*Rh(CH3CN)3][SbF6]2 showed the best catalytic efficiency under the modified reaction conditions. Various N-arylsulfonyl imines

Scheme 86

observed with amines as a coordinating group. Further studies revealed that the coordinating ability of the amine together with its position are all crucial for this transformation. Interestingly, no decarbonylated product was obtained in this N-directed hydroacylation reaction. Z

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Scheme 87

Scheme 89

reaction pathway involving an electrophilic substitution mechanism was proposed. Two possible catalytic cycles were then independently proposed by Bergman128b and Shi129b based on mechanistic studies. Despite the slightly different pathways, the two proposed catalytic cycles involved the same important key steps: (i) cyclorhodation via C−H activation, (ii) ligand exchange, (iii) insertion of the C−N double bond into the Rh−C bond, and (iv) protonation to produce the desired product and regeneration of the active catalyst. Recent work from the research group of Bolm revealed that cyclic imines are also effective substrates in this type of rhodium-catalyzed directed aryl C−H addition reaction.130 In addition to N-heterocycle directing groups, other directing groups have also been used in this type of reaction (Scheme 90).128c Using the combination of [Cp*RhCl2]2 and AgB(C6F5)4 as the catalyst system, the addition of C(sp2)−H bonds of N,Ndialkylbenzamides to a wide range of aromatic N-sulfonylimines proceeded well to form branched amines in good to excellent yields. Moreover, the obtained products could be easily transformed into isoindoline and isoindolinone frameworks.

Scheme 88

Scheme 90

and 2-arylpyridines were investigated, and they all exhibited good reactivities. Notably, the quinolyl unit was also successfully used as a directing group in the reaction. Intra- and intermolecular isotopic studies showed that C−H cleavage is reversible. A AA

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the presence of 10 mol % of [Cp*RhCl2]2 and 40 mol % of AgB(C6F5)4. Pyrrolidinecarboxamide, azo, and quinoline are applicable as directing groups. It is noteworthy that the use of the activating N-perfluorobutanesulfinyl imine substituent was essential to achieve good reactivity and high diastereoselectivity. The highly enantiomerically enriched amines could be obtained in good yields via removal of the sulfonyl group. Although the above-mentioned Cp*Rh(III)-catalyzed reactions are useful and versatile in C(sp2)−H activation reactions, these processes are not economically practical because of the use of a large amount of expensive rhodium (10−20 mol %). Recent studies by Yoshikai’s group and Kanai’s group found that inexpensive low-valent cobalt species showed high catalytic reactivity for aromatic and heteroaromatic C(sp2)−H additions to imines.133,134 Yoshikai found that a cobalt−N-heterocyclic carbene catalyst combined with an appropriate Grignard reagent is an efficient catalyst system for a chelation-assisted direct addition of aromatic C−H bonds to aromatic aldimines (Scheme 93).133a It is noteworthy that unlike the Rh(III)-catalyzed similar

A related rhodium-catalyzed addition reaction of indoles to give a variety of aromatic or alkyl N-sulfonylimines via N,Ndimethylcarbamoyl-directed C−H bond activation has also been reported (Scheme 91).131 This rhodium(III)-catalyzed addition Scheme 91

Scheme 93

reaction exhibited high C2 regioselectivity, functional groups tolerance, and broad substrate scopes and provides an efficient and practical approach to synthesize 2-indolylmethanamine derivatives. Mechanistically, this reaction was initiated by N,Ndimethylcarbamoyl-directed C−H bond activation at the C2 position to form a relatively stable five-membered rhodacycle, followed by coordination of the N-sulfonylimine, nucleophilic addition, and protonation to form the desired product and regenerate the active catalyst. The first Rh(III)-catalyzed asymmetric addition of aromatic C−H bonds to N-perfluorobutanesulfinyl imines assisted by a directing group was reported by Ellman and co-workers in 2014 (Scheme 92).132 The branched chiral amine were prepared in moderate to good yields with excellent diastereoselectivities in Scheme 92

reactions reported by Bergman, Ellman,128 and Shi,129 aldimines bearing Boc and Ts groups were unreactive. Furthermore, with the same catalytic system, self-coupling of an aromatic aldimine was also performed to give an isoindole derivative, which can be intercepted by an aldehyde to afford an indenone. The reaction process was proposed to go via chelation-assisted oxidative addition of the C−H bond to the low-valent cobalt center which was generated from the cobalt precatalyst and t-BuCH2MgBr, followed by reductive elimination of neopentane and subsequent AB

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an electron-donating or an electron-withdrawing substituent showed good reactivities. The reactions also proceeded well with heteroaryl imines. A catalytic cycle based on related Co(III) catalysis involving cobalt-catalyzed C(sp2)−H activation, ligand exchange, imine insertion, and proto-demetalation was proposed. The utility of Cp*Co(III) catalysis was further extended to direct C2-selective nucleophilic addition of indoles to imines by Matsunaga, Kanai, and co-workers (Scheme 95).134 In 2013, they reported a Cp*Co(III) complex-catalyzed addition reaction of indoles (bearing a 2-pyrimidyl directing group) with imines, which gave the desired addition products in 58−93% yields. H/D exchange experiments of N-pyrimidylindole in the presence of CD3OD under Cp*Co(III) catalysis suggested that reversible C2-selective C−H activation and metalation occurred. Similar to the addition of aromatic C(sp2)−H bonds, addition reactions with olefinic C−H bonds have also recently been realized. Shi and co-workers reported Rh(III)-catalyzed olefinic C−H addition to aromatic N-sulfonylaldimines with the assistance of a pyridyl directing group in 2012 (Scheme 96).118 This strategy offers a high atom-economical approach to synthesize various allylic amines. The catalytic reaction was considered to proceed in a way similar to the catalytic addition of aryl C−H bond to imines. In 2013, an elegant work of Rh(III)-catalyzed olefinic C−H bond activation for the synthesis of substituted pyrroles was reported by Ellman and co-workers (Scheme 97).119 In the presence of [Cp*RhCl2]2/AgSbF6, a series of α,β-unsaturated

nucleophilic addition, transmetalation, and protonation to give the final product. Similar to the work of Yoshikai’s group, studies by Matsunaga, Kanai, and co-workers demonstrated that an inexpensive cationic high-valent cobalt complex, [Cp*Co(benzene)](PF6)2, could also serve as an efficient catalyst for the addition of 2arylpyridines to imines (Scheme 94).41 Aryl imines with either Scheme 94

Scheme 95

AC

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Scheme 96

Scheme 98

Scheme 97 [Cp*Rh(OAc)2(H2O)], and a variety of 1,2-disubstituted ferrocenes were obtained in 19−87% yields. In addition to the imino group, the oxazolyl group was also a good directing group. Notably, using a commercially available chiral oxazolyl ferrocene as a substrate, a variety of planar chiral 1,2-disubstituted ferrocenes were produced with excellent diastereoselectivity. However, the yields of the chiral 1,2-disubstituted ferrocenes were only moderate (24−69%).136 Besides imines, pyridinyl and pyrazolic groups have also been shown to be suitable directing groups in this type of reaction (Scheme 99).137 The amidation of 2-arylpyridines with isocyanates via C−H bond activation was realized in the presence of [RuCl2(p-cymene)]2/NaOAc. Various amidated 2arylpyridines were produced in good yields under mild reaction conditions. In addition, an isolated amidated phenylpyrazole was

oximes reacted smoothly with the N-tosyl imine of ethyl glyoxylate in DCE at 90 °C, affording the corresponding pyrroles in reasonable yields. However, N-tosylimines of aromatic aldehydes are not applicable in this reaction. 2.4.2. Addition to Isocyanates. Isocyanates are another type of polar unsaturated organic compounds containing a C−N double bond. The direct addition of C(sp2)−H bonds to isocyanates provides an atom-economical method to synthesize multifarious amides. In 1978, Yamazaki and co-workers reported the first direct addition of benzene to aryl isocyanates,10 in which benzene reacted with phenyl isocyanate in the presence of Rh4(CO)12 to give benzanilide in 42% yield under CO at 220 °C. In 2006, Kuninobu and Takai reported the efficient rheniumcatalyzed addition of aromatic aldimines to isocyanates via C−H bond activation.135a Using 3 mol % of [ReBr(CO)3(THF)]2 as the catalyst, a lot of arylisocyanates reacted well with various aldimines. The desired phthalimidine derivatives were obtained in good to excellent yields. However, primary and secondary alkylisocyanates were not active substrates under the optimized reaction conditions. The mechanism of this reaction was proposed to proceed via the following steps: (i) C−H bond activation, (ii) insertion of the isocyanate, (iii) intramolecular nucleophilic cyclization, and (iv) reductive elimination to give the desired products (Scheme 98). Subsequently, the same group successfully extended this chemistry to the reaction of isocyanates with aldimines derived from heteroaromatic compounds.19,135b In 2012, the direct addition reaction between ferrocenyl aldimines and isocyanates via C(sp2)−H activation was reported by Shibata and co-workers. The reaction was catalyzed by

Scheme 99

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also obtained. Notably, the present catalytic reaction can be extended to cyclohexylisocyanate. An acetate-ligated ruthenium species generated in situ proved to be an active catalyst. Coordination of the 2-phenylpyridine nitrogen to the ruthenium center and subsequent ortho-C−H bond activation forms a fivemembered ruthenacycle along with the release of acetic acid. Selective insertion of isocyanate into the Ru−C bond of ruthenacycle intermediate gives the seven-membered ruthenacycle species, which was followed by protonation to give the final product and regenerate the active Ru(II) species for the next cycle. The 3-methyleneisoindolin-1-one structural motif is widely found in natural products and pharmaceuticals. Traditional methodologies to synthesize these compounds mainly include Wittig reactions, annulations, and designed domino reactions.138 As an alternative straightforward approach to synthesize 3methyleneisoindolin-1-ones, the rhodium-catalyzed tandem annulation of aryl ketone O-methyl oximes with isocyanates triggered by C−H bond activation was reported in 2013 (Scheme 100).139 A wide range of acetophenone oximes

Scheme 101

Scheme 102

Scheme 100

containing different substitutions readily converted to their corresponding products in good to excellent yields. Notably, the reaction also worked well when using 1-isocyanatohexane as the substrate. The notable primary KIE (kH/kD = 3.5) suggested that C−H bond cleavage was most likely involved in the rate-limiting step. The addition of olefinic C(sp2)−H bonds to isocyanates has also been achieved in recent years. For example, an elegant Rh(III)-catalyzed protocol for amidation of anilides and enamides with isocyanates via C−H bond activation was developed by Ellman and Bergman (Scheme 101).140 [Cp*Rh(MeCN)3](SbF6)2 was found to be an effective catalyst for the addition of C−H bonds of anilides and enamides to a wide range of isocyanates, giving valuable N-acyl anthranilamides, enamineamides, and pyrimidin-4-one heterocycles. The regiochemistry observed in this reaction suggested that Rh-mediated C−H bond activation directed by the amide group is involved, which rules out the possibility of a traditional electrophilic aromatic substitution. KIE studies were also consistent with C−H bond activation being the rate-limiting step. Rh(III)-catalyzed addition of olefinic C(sp2)−H bonds to isocyanates and subsequent cyclization to give substituted 5ylidene pyrrol-2(5H)-ones was reported by Hou et al. in 2013 (Scheme 102).141 This approach exhibited high regioselectivity

and was amenable to a wide range of isocyanates as well as α,βunsaturated oximes. This atom-economical reaction provides a simple and straightforward method to produce biologically relevant 5-ylidene pyrrol-2(5H)-ones. A reaction pathway was proposed. A relatively stable five-membered rhodacycle is initially formed by oxime-directed ortho-C−H bond activation. Selective insertion of the isocyanate into the Rh−C bond of the five-membered rhodacycle forms the seven-membered rhodacycle intermediate, which undergoes protonation. Intramolecular nucleophilic addition is followed by elimination of one molecule of methoxyamine to provide the product and regenerate the catalyst. An example of the synthesis of polymer via annulation through aromatic and olefinic C−H bonds activation using an imino group as a directing group was reported by Sueki et al. in 2013 (Scheme 103).142 In this work, a rhenium-catalyzed protocol for AE

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Scheme 103

104).143 In the presence of [Cp*RhCl2]2 and NaOAc, the desired N-substituted phthalimides were produced in 26−91% yields in one step. In general, benzoic acids bearing electron-donating groups on the phenyl ring gave higher yields than those with electron-withdrawing groups. This substituent effect suggests that an aromatic electrophilic substitution (SEAr) mechanism is involved for C−H bond activation. Because the difference in

the synthesis of 3-imino-1-isoindolinones from aromatic imidates and isocyanates was developed. Interestingly, the reaction also proceeded well at the olefinic C−H bond, and the desired cyclic product was obtained in good yield. Furthermore, the imino groups of the imidates are retained after the reaction. A gram-scale reaction was carried out in excellent yield, and double-annulation reactions occurred using a diimidate or diisocyanate substrate. More interestingly, this C− H activation system could be used to synthesize polyimide derivatives, which have high solubility in organic solvents, such as toluene, THF, DCM, and chloroform, via double annulations. This protocol represents the first example of the synthesis of polyimide derivatives with imino groups via C−H bond activation. A reaction mechanism involving (i) oxidative addition, (ii) isocyanate insertion, (iii) intramolecular nucleophilic cyclization, and (iv) reductive elimination/elimination of methanol was proposed. In this catalytic cycle, the elimination of methanol is important to retain the imino group in the product. Synthesis of phthalimides by rhodium-catalyzed cascade cyclization between benzoic acids and isocyanates via C−H activation was reported by Li and co-workers in 2014 (Scheme

Scheme 104

AF

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zero-point energy between C−D and C−H bonds is larger in the transition state than in the ground state, an inverse KIE (the deuterated substrate reacts faster than the nondeuterated substrate) was observed. This inverse KIE of 0.4 indicates that C−H bond activation is the rate-limiting step. This transformation involves cascade amidation of benzoic acid and isocyanate via rhodium-catalyzed direct ortho-C−H activation, followed by intramolecular cyclization. In 2014, Ackermann and co-workers reported a cationic ruthenium(II)-catalyzed cyclization of amides with isocyanates for the synthesis of phthalimides (Scheme 105).144 Using the

Scheme 106

Scheme 105

The reaction was thought to occur by electrophilic metalation of the arene by the Pd(II) catalyst to generate arylpalladium species, coordination of the nitrile to the active arylpalladium species, and then carbopalladation of the nitrile to form the imine−Pd(II) intermediate. The imine−Pd(II) intermediate is protonated by TFA, affording the ketimine and regeneration of the Pd(II) catalyst. The observed preference of ortho and para isomers over the meta isomer in the products from the reaction of toluene is consistent with electrophilic palladation of the arene. The authors subsequently extended this chemistry to the synthesis of xanthones using simple phenols and 2-fluorobenzonitrile as the starting materials (Scheme 107).146b combination of [RuCl2(p-cymene)]2 and AgSbF6 as the catalytic system, a wide range of aromatic benzamides substituted with electron-rich or electron-poor groups as well as acrylamide were coupled with various isocyanates to give the corresponding phthalimides in good yields. Moreover, heteroaromatic amides are also applicable in this protocol, giving the asymmetrically substituted diamides in decent yields. The reaction was proposed to proceed through the mechanistically unique insertion of a cycloruthenated species into the C−N double bond of isocyanate.

Scheme 107

2.5. Addition of C(sp2)−H to C−N Triple Bonds

C−N triple bonds are found in nitriles or isonitriles. The direct addition of C(sp2)−H bond to nitriles and isonitriles provides a highly useful and atom-economical method to produce amides, aromatic ketones, and ketimines. In this section, only the direct addition of C(sp2)−H bond to nitriles will be discussed, because the advances in transition-metal-catalyzed insertion reactions of C−H bonds to isonitriles have been recently reviewed.145 In 2004, Larock reported the first Pd-catalyzed direct addition of simple arenes to nitriles (Scheme 106).146a The simple Pd(OAc)2 catalyst was found to efficiently promote the addition of toluene to benzonitrile in TFA via C(sp2)−H activation. The product was obtained in 68% yield with a 51:16:33 ortho/meta/ para ratio in the presence of DMSO. It is important to note that biarylketimine was obtained as the sole product after the workup when mesitylene and benzonitrile were used. Furthermore, simple aliphatic nitriles, such as acetonitrile, also worked well in this reaction. In addition to intermolecular reactions, intramolecular reactions were also successful, and two typical sevenmembered cyclic ketones were synthesized in decent yields.

3-Acylindoles are widely used as building blocks in organic synthesis.147 As a result, synthetic chemists search for economical and efficient methods to synthesize these molecules.148 Among the established synthetic methods, the direct addition of indoles to nitriles via C(sp2)−H activation is an appealing research topic. However, only a few studies have been reported in this field. In 2013, two similar studies on the addition of C(sp2)−H bonds of indoles to nitriles to give acylindoles were reported.149 Song and You demonstrated that a palladium(II) complex efficiently catalyzed the addition of indoles to nitriles (Scheme 108). 149a A catalyst investigation revealed that [Pd(phen)2(OAc)2] is superior to other palladium species in the reaction of N-methylindole with benzonitrile. Further studies showed that the addition of H2O/AcOH is essential to obtain a perfect product yield, and 1,4-dioxane is the best choice of solvent. The authors found that both N-protected and unprotected indoles were feasible for this addition reaction. In AG

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Scheme 108

Scheme 110

addition to aryl nitriles, aliphatic nitriles also proceeded well to form the desired products. Furthermore, the authors successfully applied this chemistry to the synthesis of indenoindolones in synthetically useful yields (46−62%) in one pot by combining with the palladium-catalyzed intramolecular oxidative coupling of 3-indolylarylketones (Scheme 109).

then, significant advances have been made in this area and a number of reviews on this subject have been published.152 Therefore, only the latest advances in this field are discussed here. The first Pd-catalyzed double C−H activation/carbonylation of diaryl ethers to form xanthones was reported by Lei and coworkers in 2012 (Scheme 111).153 A variety of diaryl ethers were

Scheme 109

Scheme 111

Independent work on palladium-catalyzed addition of free (N−H) indoles to nitriles was reported by Wang and co-workers in 2013 (Scheme 110).149b The addition reaction proceeded well in the presence of Pd(OAc)2/2,2′-bipyridine and D-(+)-camphorsulfonic acid. The desired acylated products were produced in 50−95% yields. However, in contrast to the work of Song and You, no desired products were detected when ortho-substituted aromatic nitrile and phenylacetonitrile were used as substrates. A possible mechanism involving carbopalladation of nitriles and subsequent hydrolysis of ketimines was proposed. Further studies from the same research group revealed that the direct addition of thiophenes to nitriles to give 2-acylthiophenes could be realized under similar reaction conditions.149c

directly carbonylated to xanthones in moderate to good yields using the combination of Pd(OAc)2, K2S2O8, and TFA as the catalyst system. Preliminary mechanistic studies revealed that neither the first C−H cleavage of the diaryl ether with Pd(II) nor the insertion of CO is the rate-determining step. The authors suggested that the second C−H cleavage might be the ratedetermining step. On the basis of the mechanistic studies, a reasonable mechanism involving electrophilic palladation, CO insertion, intramolecular C−H functionalization, and reductive elimination steps was proposed. Later in 2012, Ru 3 (CO) 12 -catalyzed carbonylation of arylacetamides in the presence of ethylene and H2O was reported (Scheme 112).154 The presence of a 2-pyridynylmethyl amine moiety as the bidentate directing group was found to be essential for the success of this reaction. A wide range of functionalities such as methoxy, fluoro, trifluoromethyl, and

2.6. Addition of C(sp2)−H to Carbon Monoxide

CO is one of the most important and simplest C-1 feed stocks for carbonylation chemistry, which has been extensively studied in the past few decades.150 In this respect, catalytic C(sp2)−H activation of hydrocarbons and subsequent insertion of CO is now widely recognized as a very intriguing protocol to prepare carbonyl-containing compounds. Pioneering work on aryl C−H carbonylation was reported by Fujiwara and co-workers.151 Since AH

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Scheme 112

pyridine directing group, other directing groups such as pyrazole and pyrimidine were also effective and produced the desired products in good yields. The synthesis of benzopyranones has received considerable attention because of their importance in the field of natural product synthesis and medicinal chemistry.156 The synthesis of benzopyranones has been achieved through transition-metalcatalyzed C−H carbonylation of 2-phenylphenol derivatives. In this context, Shi and co-workers reported an efficient protocol for the synthesis of dibenzopyranones through Pd-catalyzed C−H carbonylation of 2-phenylphenol derivatives (Scheme 114).157 As expected, a variety of 2-arylphenol could be converted to the desired products in moderate to good yields in the presence of

bromo were tolerated under the reaction conditions. However, to achieve an efficient reaction, high-pressure CO (10 bar) and ethylene (7 bar) as well as a high reaction temperature (160 °C) were required in all cases. The proposed mechanism is shown in Scheme 112. In this mechanism, coordination of ruthenium to the pyridine nitrogen of the amide followed by N−H bond activation leads to the ruthenium hydride complex. The insertion of ethylene followed by C−H bond activation produces the sixmembered metallacycle species with concomitant generation of ethane. The insertion of CO and subsequent reductive elimination affords the final cyclized product along with regeneration of the catalyst. Beller and co-workers reported ruthenium-catalyzed carbonylative coupling of aryl halides with arylpyridines via C−H bond activation (Scheme 113).155 Using 5 mol % of [RuCl2(cod)]n as well as a combination of KOAc and NaHCO3, the aroylation of 2arylpyridines with aryl iodides successfully proceeded with high selectivity in water. Both electron-rich and electron-deficient aryl iodides successfully underwent the transformation. Besides the

Scheme 114

Scheme 113

AI

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thridinones via amine-directed carbonylation has also been realized.160 Zhu and co-workers reported a novel C−H aminocarbonylation reaction using an unprotected amine moiety of an aniline as a directing group (Scheme 117).160a Using 5 mol

Pd(OAc)2 and Cu(OAc)2 under an atmospheric pressure of CO and O2. On the basis of kinetic studies and the results obtained from the investigation of the substrate scope, the authors concluded that the C−H activation step might go through a SEAr mechanism, rather than a concerted metalation−deprotonation process, and C−H activation might be the rate-determining step. In 2013, a similar ruthenium-catalyzed carbonylative C−H cyclization of 2-arylphenols was achieved (Scheme 115).158

Scheme 117

Scheme 115

Various substituted 6H-dibenzo[b,d]pyran-6-ones were obtained in the presence of a catalytic amount of Ru/NHC under a balloon pressure of CO and O 2 . Functional groups such as alkoxycarbonyl, acetyl, and halides were tolerated under the reaction conditions. Control experiments revealed that the C−H metalation step in the catalytic cycle is reversible. A similar palladium-catalyzed oxidative carbonylation reaction of 2-arylphenols under mild conditions was subsequently reported by Chuang and co-workers (Scheme 116).159 Among

% of Pd(CH3CN)Cl2, 1 equiv of Cu(TFA)2, and 1 equiv of TFA in 1,4-dioxane under 1 atm of CO, the aminocarbonylation of Nalkyl- and N-aryl-protected o-phenylanilines proceeded smoothly. The resulting compounds were obtained in 38−91% yields. The proposed reaction mechanism is (i) electrophilic cyclopalladation after chelation, (ii) migratory insertion of coordinated CO, and (iii) reductive elimination to afford the phenanthridinone product and concurrent formation of a Pd(0) species, which can then be reoxidized to the active Pd(II) complex by Cu(TFA)2 in the presence of TFA. Using the pyridyl group in N-aryl-2-aminopyridines as both a directing group and an intramolecular nucleophile, a palladium-catalyzed C(sp2)−H carbonylation reaction to synthesize 11H-pyrido[2,1-b]quinazolin-11-ones was also achieved by Liang et al. in 2014.160b Interestingly, using AgOAc as the oxidant, Chuang and coworkers realized palladium-catalyzed oxidative carbonylation of N-sulfonyl-2-aminobiaryls under TFA-free conditions (Scheme 118).161 This transformation tolerated a variety of substrates and furnished phenanthridinones with up to 94% yield. Zhang and co-workers developed a closely related Pdcatalyzed C−H carbonylation reaction to synthesize phenanthridinones using Cu(TFA)2 as the oxidant in 2013 (Scheme 119).162 The optimized reaction conditions for aminocarbonylation were 3 mol % of Pd(OAc)2 and 1.5 equiv of Cu(TFA)2 in TFE at 70 °C under 1 atm of CO. Using Pd(OAc)2 as the catalyst and Cu(OAc)2 as the oxidant in the presence of KI, C−H carbonylation of N-alkyl anilines to give isatoic anhydrides was achieved under mild reaction conditions by Guan et al. (Scheme 120).163 This new carbonylation reaction displayed high functional group tolerance and generality. Electron-rich substrates were more reactive than the electron-deficient substrates. The addition of pivalic acid was found to be crucial to achieve high yields when using N-alkyl anilines bearing electron-withdrawing groups as substrates. An important intermediate A in the stoichiometric reaction of

Scheme 116

the oxidants investigated, AgOAc gave the best results. The acid−base-free neutral condition is the feature of this work compared to the above two reports. However, the present C−H carbonylation catalytic system was not compatible with substrates equipped with an electron-donating group on the phenolic moiety. In addition to the synthesis of benzopyranones by phenolic hydroxyl-directed C−H carbonylation, the synthesis of phenanAJ

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isatoic anhydride and Pd(0), and (v) reoxidization of Pd(0) by Cu(OAc)2 to regenerate the Pd(OAc)2 catalyst. Carbonylation involving vinyl C−H activation is a developing research area. Two examples of Pd-catalyzed oxidative cyclocarbonylation of 2-vinylphenols and 2-vinylanilines to furnish coumarins and (1H)-quinolinones were reported by Alper and co-workers (Scheme 121).164 However, the C−H activation mechanism is not involved in the preferred reaction pathway.

Scheme 118

Scheme 121

Scheme 119

In 2013, an elegant example of palladium-catalyzed carbonylation of alkenyl C−H bonds of enamides with CO access to 1,3-oxazin-6-ones was developed using Cu(OAc)2 as the oxidant in the presence of DABCO, KI, and Ac2O.165 A reasonable mechanism for this carbonylation was proposed. As shown in Scheme 122, alkenyl C−H activation promoted by Pd(OAc)2 leads to the six-membered vinylpalladium intermediate A. Insertion of CO results in the formation of a seven-membered acylpalladium intermediate B, which transforms into C assisted by DABCO. Reductive elimination of C affords the carbonylation product and Pd(0), which can then be reoxidized by Cu(OAc)2 to regenerate the active catalyst. In 2014, Lee and co-workers reported an efficient phosphaannulation reaction via Pd-catalyzed C−H carbonylation of phosphonic and phosphinic acids. The reaction proceeded smoothly in the presence of Pd(OAc)2/PhI(OAc)2/ AgOAc in DCE at 60 °C under CO atmosphere, affording a broad range of oxaphosphorinanone oxides in 53−86% yields (Scheme 123).166 The intermolecular direct alkoxycarbonylation of arenes with CO and alcohols to form carboxylic esters has also been achieved.167 In 2013, Shi and co-workers reported a Pd(II)catalyzed pyridyl-directed C(sp2)−H alkoxycarbonylation approach to produce aromatic carboxylic esters (Scheme 124).167a Using Pd(OAc)2 as the catalyst, CuBr2 as the oxidant, and NaOAc as an additive, the desired aromatic carboxylic esters formed in modest to good yields with high regioselectivities under an atmospheric pressure of a mixture of CO and O2 (about 4:1, v/v). They then successfully extended this chemistry to Pd(II)-catalyzed oxidative alkoxycarbonylation of 2-phenoxypyridines.167b

Scheme 120

Pd(OAc) 2 with N-methylaniline was isolated and fully characterized by 1H NMR and mass spectroscopy. This carbonylation was believed to proceed through the following mechanism: (i) formation of a dimeric palladium intermediate A by electrophilic palladation, (ii) insertion of CO followed by reductive elimination, (iii) metathesis of N-methylanthranilic acid with Pd(OAc)2 to produce intermediate D and then insertion of CO to afford intermediate E, (iv) nucleophilic attack of the amino group on the acylpalladium moiety to give the

2.7. Miscellaneous Examples

In addition to direct addition of C(sp2)−H bonds to C−X (X = C, N, O) double bonds via C−H activation, the analogous addition to NO bonds has recently been achieved. The first example of this type of transformation was the addition of aryl C−H bonds to nitrosobenzenes directed by nitrogen-containing heterocycles reported by Zhou et al. (Scheme 125).168a As expected, in the presence of 2.5 mol % of [Cp*Rh(CH3CN)3]AK

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Scheme 122

(SbF6)2 and 1 equiv of PivOH in DCE, a variety of N,Ndiarylhydroxylamines were obtained in good to excellent yields at room temperature. Notably, the resulting hydroxylamines were easily reduced to produce valuable diarylamines in excellent yields. The mechanism of this reaction was proposed to proceed via the following series of steps: (i) cyclorhodation, (ii) coordination and subsequent nucleophilic addition (or migratory insertion of NO), and (iii) protonation of rhodacycle to generate the hydroxylamine product together with regeneration of the Rh(III) catalyst. The same research group subsequently reported an unprecedented Rh(III)-catalyzed aryl C(sp2)−H amidation of N-hydroxycarbamates under oxidative conditions. Mechanistically, a reliable reaction pathway was proposed involving in-situ oxidation of N-hydroxycarbamates to generate nitrosoformates, followed by directed addition of aryl C(sp2)−H to nitrosoformates.168b

Scheme 123

Scheme 124

Scheme 125

3. TRANSITION-METAL-CATALYZED DIRECT ADDITION OF C(SP3)−H BONDS TO POLAR UNSATURATED BONDS VIA C−H ACTIVATION 3.1. Addition of C(sp3)−H to C−C Double Bonds

Compared with the direct addition of C(sp2)−H bonds to polar unsaturated bonds via C−H activation, the analogous transitionmetal-catalyzed C(sp3)−H additions are more challenging. In 2010, seminal work (see section 3.3) on the direct addition of the C(sp3)−H bond of 2-alkylazaarenes to aldimines was reported by Huang and co-workers,169 which has sparked the development and application of an expanding body of reactions for direct addition of a C(sp3)−H bond to polar unsaturated bonds. In 2011, the transition-metal-catalyzed direct addition of the benzylic C(sp3)−H of 2-alkylazaarenes to electron-deficient alkenes was realized by Kanai and co-workers (Scheme 126).170 Among the various transition metals investigated, Sc(OTf)3 and Y(OTf)3 showed the best results. The additions of 2alkylazaarenes to enones or α,β-unsaturated N-acylpyrrole took AL

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enantioselectivities. The reaction with acrylates also proceeded well to give the desired adducts. Ethyl acrylate was the best coupling partner and gave the corresponding amine in 99% ee. The structure of the alkyl chain in 2-(alkylamino)pyridine and the directing group play important roles in obtaining high reactivity and selectivity. In 2014, iridium-catalyzed alkylation of C(sp3)−H bonds adjacent to nitrogen in secondary amines was also realized by Lahm and Opatz (Scheme 129).172b The benzoxazol-2-ylamines

Scheme 126

Scheme 129

place smoothly to afford the corresponding products in 60−96% yields with 10 mol % of Sc(OTf)3 or Y(OTf)3 as the catalyst. Furthermore, the resulting products from α,β-unsaturated Nacylpyrrole could be readily transformed into esters or other βsubstituted amides. In addition to enones and α,β-unsaturated N-acylpyrroles, methylenemalononitriles were also found to be efficient electrophiles for such reactions by Huang and co-workers (Scheme 127).171 A series of substituted methylenemalononi-

reacted smoothly with acrylates to afford the alkylated products in good yields in the presence of [Ir(cod)2]BF4 or [Ir(cod)2]BArF when the benzoxazol-2-yl group was utilized as a removable activating and directing group. Notably, when 1,2,3,4-tetrahydroisoquinolines were used as the substrate, the reaction exclusively occurred at the 3 position of the tetrahydroisoquinoline moiety.

Scheme 127

3.2. Addition of C(sp3)−H to C−O Double Bonds

Compared with the previously discussed direct C(sp2)−H activation/addition to aldehydes and ketones, transition-metalcatalyzed direct C(sp3)−H activation/addition to aldehydes and ketones still represents a challenging task for chemists, and only a few studies have been reported. In 2012, an efficient Lewis-acid-catalyzed addition of 2alkylazaarenes to ethyl glyoxylate was reported by Jin et al. (Scheme 130).173 In the presence of 10 mol % of Cu(OTf)2 and Scheme 130 triles participated in the reaction, and the corresponding adducts were obtained in 57−99% yields in the presence of a catalytic amount of Yb(OTf)3. Moreover, a variety of 2-alkylazaarenes also smoothly reacted with 2-benzylidenemalononitrile to afford the desired products in 33−82% yields. In 2012, Shibata and co-workers demonstrated that 2(alkylamino)pyridines could undergo enantioselective alkylation with alkenes using a chiral cationic iridium catalyst (Scheme 128).172a In the presence of [Ir(cod)2]BF4 and (S)-tolBINAP, various chiral amines were obtained with moderate to high Scheme 128 5 mol % of phen, various 2-alkylquinolines and 2-alkylpyridines reacted with ethyl glyoxylate to give the desired addition products in moderate to good yields. However, the addition of 2alkylazaarenes to ethyl pyruvate, aliphatic aldehydes, and aromatic aldehydes failed to form the desired addition products under the same reaction conditions. AM

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alkylazaarenes with N-tosylaldimines bearing an electron-withdrawing or electron-neutral group at the ortho, meta, or para position of the phenyl ring proceeded smoothly to form the corresponding adducts in good to excellent yields. Notably, alkenyl aldimines were also compatible with the conditions. The utility of this protocol was also demonstrated for the synthesis of isoindolinones by intramolecular tandem benzylic addition/ amidination from methyl 2-((tosylimino)methyl)benzoate and 2-methylpyridines (Scheme 133).

This chemistry has been further extended to the synthesis of trifluoromethyl hydroxyl compounds. Yb(OTf)3 was found to be a good catalyst for the reaction of 2-alkylazaarenes with trifluoromethyl carbonyl compounds (Scheme 131).174a In all Scheme 131

Scheme 133

cases, only one product was observed, which excluded the possibility of the formation of a Friedel−Crafts alkylation product. Using Yb(OTf)3 as a catalyst, the direct addition of 2- or 4-methylazaarenes to isatins has also been realized.174b An extensive study of the reactions between 2-methylazaarenes and simple aldehydes was reported by Wang and co-workers in 2014 (Scheme 132).175 They found that these reactions

The intermolecular (kH/kD = 3.6) and intramolecular (kH/kD = 4.1) kinetic isotope effects indicated that the C−H cleavage was the rate-limiting step. The preliminary mechanism of this transformation was then proposed. In the first step, 2,6-lutidine is coordinated to Pd(OAc)2 to form complex A, after which C−H bond cleavage might occur via agostic three-center-two-electron interactions to form the intermediate B, in which the acetate served as an internal base. Intermediate B then reacts with imine to form D, which upon protolysis affords the desired adduct with regeneration of the Pd catalyst (Scheme 134). The first Lewis-acid-catalyzed benzylic addition of 2alkylazaarenes to N-sulfonylaldimines was then reported by Qian et al.178a Using Sc(OTf)3 as the catalyst, the additions of Nsulfonylaldimines to 2-alkylazaarenes occurred smoothly and produced the corresponding addition products in good to excellent yields. In addition, this Sc(OTf)3-catalyzed transformation was employed to synthesize a variety of isoindolinones and isoindolines (Scheme 135). Preliminary mechanistic studies revealed that nucleophilic addition is most likely to be the ratelimiting step in this Lewis-acid-catalyzed protocol. This is different from the above Pd-catalyzed protocol, where it was concluded that C−H cleavage might be the rate-limiting step. Inspired by the success of the palladium- and Lewis-acidcatalyzed additions of 2-alkylazaarenes to aldimines, a novel ironcatalyzed alkenylation reaction of 2-methylazaarenes bearing different substituents was developed by Huang and co-workers (Scheme 136).178b Using Fe(OAc)2 as the catalyst, the alkenylation proceeded smoothly at 120 °C, forming the desired E-isomeric products as the sole products in good to excellent yields. A concerted E2-elimination mechanism was proposed for the formation of (E)-2-alkenylated azaarenes. In 2011, the addition of 2-alkylazaarenes to aldimines was also achieved in the presence of copper catalysts (Scheme 137).179 The adducts were obtained in moderate to excellent yields using the combination of Cu(OTf)2 and phen as the catalytic system. Interestingly, Cu(OTf)2-catalyzed benzylic C−H bond addition of 2-alkylazaarenes to aryl imines can be performed under solvent-free conditions.170b

Scheme 132

occurred smoothly in the presence of LiNTf2 to afford 2(pyridin-2-yl)ethanols in 20−98% yields. Notably, 2-alkenylpyridines were exclusively produced in the form of the E isomers when a catalytic amount of HNTf2 was added. Furthermore, La(pfb)3-catalyzed alkenylation of 2-methylquinolines with aldehydes to give 2-alkenylquinolines was also achieved. 3.3. Addition of C(sp3)−H to C−N Double Bonds

Transition-metal-catalyzed direct addition of C(sp3)−H bonds to the C−N double bonds of imines has been shown to be an efficient protocol to synthesize various functionalized amines. However, most of the examples are limited to the substrates containing activated C(sp3)−H bonds which are generally adjacent to functional groups such as carbonyl or cyano groups.176 In addition, a large amount of external bases is generally needed to obtain high TONs.177 Therefore, very little work has been reported on transition-metal-catalyzed direct addition of unactivated C(sp3)−H bonds to imines. In 2010, Huang and co-workers developed the first catalytic addition of 2-alkylazaarenes to imines through Pd(OAc)2catalyzed C−H bond activation under neutral conditions.178 Addition of nitrogen-containing ligands increased the product yield, and phen proved to be the best ligand. The reactions of 2AN

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Scheme 134

Scheme 135

alkylazaarenes with electron-withdrawing groups such as nitro, cyano, or ester groups are effective in this asymmetric reaction, this work represents the first catalytic enantioselective additions of 2-alkylazaarenes to N-Boc imines.

Scheme 136

3.4. Addition of C(sp3)−H to C−N Triple Bonds

Addition of carbon nucleophiles to the C−N triple bond of nitriles is one of the most attractive transformations of nitriles.181 During the past 20 years, transition-metal-catalyzed addition of C(sp3)−H bonds to nitriles has been well studied. However, most of these transformations are inconsistent with the topic of this review because C(sp3)−H bonds adjacent to polar functional groups such as carbonyl groups or a cyano group are generally regarded as activated C(sp3)−H bonds.177a,182,183 Obviously, compared with direct addition of unactivated C(sp2)−H bond to nitriles, the analogous addition of the C(sp3)−H bond to nitriles is much more challenging, which is an unexploited field and certainly will attracted much attention in the future.

Scheme 137

3.5. Addition of C(sp3)−H to Carbon Monoxide

In addition to the impressive advances that have been made in the catalytic C−H carbonylation of C(sp2)−H bonds, the more challenging C−H carbonylation of unactivated C(sp3)−H bonds has also shown significant progress. The carbonylation of alkanes to acids has been discussed in a recent review.152a Therefore, only the synthesis of aldehydes and the latest results on the synthesis of acids and their derivatives via C(sp3)−H bond activation/ carbonylation are discussed in this section. Carbonylation of alkanes to produce aldehydes in the presence of RhCl(CO)(PMe3)2 under photoirradiation conditions was successfully achieved in 1987 (Scheme 139).184 Because the rhodium complexes remained unchanged after the reaction, the authors declared that the reaction was essentially catalytic, although the reaction was very sluggish.

Diastereoselective and enantioselective addition of 2-alkylazaarenes to N-Boc aldimines was reported in 2012 (Scheme 138).180 A series of chiral adducts was obtained with high diastereoselectivities (from 77:23 to >95:5) and enantioselectivities (from 84% to >99%) in the presence of a chiral Pd(OAc)2− bis(oxazoline) complex. It should be noted that the incorporation of an electron-withdrawing group at a suitable position on the azaarenes was essential to realize an enantioselective transformation under mild conditions. Although only 2AO

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Scheme 138

In 2001, Bitterwolf and co-workers reported the feasibility of the photocatalysis of ethane to propionaldehyde in both singlephase ethane and ethane mixed with CO2 in the presence of RhCl(CO)(PMe3)2. In both cases, propionaldehyde was detected using mass spectrometry and NMR analysis. However, no effort has been made to optimize the reaction to obtain high yield.188 Compared with C(sp3)−H carbonylation of simple alkanes, selective carbonylation of a C(sp3)−H bond in a complicated molecule is more challenging and no relevant studies were reported until the turn of the 21st century. In 2010, Yu and coworkers described a novel Pd(II)-catalyzed β-C(sp3)−H carbonylation reaction of aliphatic N-arylamides under CO (1 atm) atmosphere (Scheme 141).189 The presence of a special acidic directing group was crucial for a successful transformation. Other directing groups, such as carboxylic acids, hydroxamic acids, oxazolines, and pyridines, were unsuitable under the established reaction conditions. Substrates with a quaternary α-carbon atom gave good to excellent yields of the succinimide products. Notably, this carbonylation reaction also worked well with

Scheme 139

The details of the carbonylation of simple alkanes were then reported.185 PMe3 was found to be the optimal ligand in this carbonylation, and the reaction proceeded at ambient temperature under an atmospheric pressure of CO. Other aliphatic alkanes, such as pentane, decane, and 2-methylpentane, were also tolerated under the reaction conditions employed. Among the alkanes investigated, cyclohexane exhibited the lowest reactivity. High terminal selectivity was observed in the carbonylation of nalkanes. A wavelength-dependent product distribution was observed in the carbonylation of decane. In addition, because of its endothermic nature, the reaction required continuous photoirradiation and the use of the alkane as the solvent. The reaction was proposed to start with RhCl(PMe3)2, which was formed by irradiation of RhCl(CO)(PMe3)2. Subsequent oxidative addition of alkanes, CO insertion, and reductive elimination lead to the desired aldehydes. Subsequently, Sakakura and co-workers reported RhCl(CO)(PMe3)2-catalyzed carbonylation of liquefied propane at room temperature to produce butanal upon illumination.186 In 2001, the same group reported the first successful example of the catalytic synthesis of acetaldehyde from methane and CO in dense CO2 (Scheme 140).187 Addition of bezaldehyde was quite effective to promote the reaction. This reaction was also proposed to proceed by an oxidative addition/CO insertion/ reductive elimination process.

Scheme 141

Scheme 140

AP

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substrates containing α-hydrogen atoms. The synthetic utility of this protocol was also demonstrated by converting the succinimide products to 1,4-dicarboxylic acids and 1,4dicarbonyl compounds with two different ring-opening conditions. This carbonylation reaction was considered to proceed via an amide-directed C(sp3)−H cleavage/insertion of CO/ intramolecular C−N reductive elimination sequence. In 2014, based on a newly developed quinoline-based ligand, a sequential and monoselective γ-carbonylation/alkenylation procedure for constructing richly functionalized all-carbon quaternary centers was developed by Yu and co-workers.190 An interesting palladium-catalyzed C(sp3)−H carbonylation for forming four-membered-ring cyclopalladation was also reported by Gaunt and co-workers in 2014 (Scheme 142).191 In this study,

Scheme 143

Scheme 142

In 2011, Jiang and co-workers reported a palladium-catalyzed direct oxidative carbonylation of allylic C−H bonds.193 Under the optimized conditions described in Scheme 145, the desired synthetically useful β-enoic acid esters were produced in good yields with high regioselectivities. The addition of DDQ affected the selectivity and facilitated allylic C−H activation. Preliminary results from deuterium-labeling experiments indicated that the allylic C−H activation process is irreversible and the ratedetermining step. Arylacetic acids and their derivatives are important commodity chemicals and useful synthetic building blocks for agrochemicals and pharmaceutical ingredients.194 In 2012, Huang and coworkers reported the first Pd-catalyzed oxidative carbonylation of benzylic C(sp3)−H bonds for the direct synthesis of arylacetic acid esters via nondirected C(sp3)−H bonds activation (Scheme 146).195a Using 2 mol % of Pd(Xantphos)Cl2 as the catalyst, simple toluenes were smoothly converted to their corresponding arylacetic acid esters in moderate to good yields. Various toluenes with electron-donating or electron-withdrawing functionalities on the aromatic rings were well tolerated. To further demonstrate the usefulness feature of this transformation, a modified procedure with lower catalyst loading (0.167 mol %) was developed and a high TON of 288 was achieved. The mechanism of this reaction was investigated. Radical scavenger experiments suggested that a free radical process is involved in the reaction. Intermolecular KIE experiments (kH/kD = 4.9) indicated that benzylic C−H bond cleavage either occurred before the rate-limiting step or could be involved in the rate-limiting step of this transformation. Accordingly, a tentative mechanism for this benzylic C−H bonds carbonylation reaction was proposed in Scheme 147. First, the alkoxyl radical intermediate formed by homolytic cleavage of DTBP abstracts a benzylic hydrogen atom from toluene to generate a benzyl radical. In the presence of ligands, sequential oxidation of Pd(0) with the two radicals through the SET process provides benzylpalladium complex C, which was characterized by HRMS. Less hindered intermediate D then forms from C through anion exchange. Subsequent CO insertion leads to intermediate E, which undergoes reductive elimination to afford the carbonylation product along with regeneration of the active Pd species. The corresponding tert-butyl ester might also be produced as a minor product through the intermediate F. This new strategy for generation of benzylpalladium intermediate via

a novel C−H carbonylation reaction for the synthesis of βlactams was realized via activation of a C(sp3)−H bond belonging to a methyl group adjacent to a secondary amine. In addition to acyclic amines, piperidine, azepine, morpholine, and piperazine derivatives were also found to be effective substrates, producing the resulting β-lactams in good yields. The results observed during investigation of the reactivity of secondary amines suggested that the C−H palladation step may be reversible under the optimized reaction conditions. Chatani and co-workers developed a Ru3(CO)12-catalyzed carbonylation reaction of C(sp3)−H bonds of aliphatic amides (Scheme 143).192a The regioselective cyclocarbonylation of the C(sp3)−H bonds of aliphatic amides with a 2-pyridinylmethylamine moiety proceeded smoothly to form the corresponding succinimide products in moderate to good yields in the presence of ethylene and water at 160 °C for 5 days. The presence of ethylene as a hydrogen acceptor and the addition of water to generate an active species were critical to the success of this carbonylation reaction. Kinetic experiments indicated that cleavage of the C−H bond is the rate-determining step and irreversible.192b A mono-ruthenium species was proposed as a key catalytic species based on a stoichiometric experiment. The reaction involves several important key steps (Scheme 144): (i) coordination of the pyridyl nitrogen to the ruthenium center followed by oxidative addition of an N−H bond to produce complex B, (ii) insertion of ethylene followed by irreversible C− H bond cleavage to afford ruthenacycle D, (iii) insertion of CO, and (iv) subsequent reductive elimination to give the carbonylative product with regeneration of the mono-ruthenium species. AQ

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Scheme 144

Scheme 145

Scheme 147

Scheme 148 Scheme 146

produce the desired phenylacetamides in 33−85% yields. A series of substituted toluenes bearing different functionalities such as methyl, fluoro, chloro, and methoxy groups was well tolerated. Most importantly, this reaction can also be employed to synthesize 2-arylpropanamides via C−H activation, which are precursors for many important marketed drugs. In 2014, almost the same procedure for Pd-catalyzed oxidative C−H amino-

nondirected C(sp3)−H bonds activation paves the way for the development of new classes of C−H functionalization reactions. This protocol was successfully extended to arylacetamides by the same group (Scheme 148).195b In the presence of 5 mol % of Pd(Xantphos)Cl2, a variety of amines including primary amines and secondary amines smoothly reacted with toluene and CO to AR

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Biographies

carbonylation of toluene was then described by Dyson and coworkers.196

4. CONCLUSIONS AND PERSPECTIVES Transition-metal-catalyzed selective C−H functionalization is one of the most simple and powerful protocols in synthetic organic chemistry. As clearly outlined in this review, over the past decades, the field of transition-metal-catalyzed C−H bond activation and subsequent additions to poplar unsaturated molecules has rapidly expanded to meet the requirements of green and sustainable chemistry, as witnessed by numerous applications in various C−C and C−X bond-forming reactions. For instance, chelation-assisted (i.e., directing groups) C(sp2)− H and C(sp3)−H bond activation/additions has been demonstrated to be one of the most developed methods for the regioselective transformation of C−H bonds to C−C and C−X bonds. Despite significant advances, many challenges still remain. For example, although a variety of transformations involving the direct addition of C(sp2)−H bonds to polar unsaturated molecules have been realized, similar reactions of C(sp3)−H bonds are more challenging, which will require significant effort in the near future. The control of regioselectivity at C−H sites other than at the ortho position of the directing groups for C−H activation/additions will be an interesting target in the future, although some progress on para- and meta-selective C−H functionalization has been achieved.197 In particular, nonchelation-assisted and nondirecting group involved C−H activation/addition reactions are practical and important synthetic protocols. Furthermore, a fascinating challenge is to develop recyclable catalytic systems and highly efficient transition-metal catalyst systems with low catalyst loading, because high catalyst loading (5−40 mol %) is generally required in the current C−H addition reactions. Finally, most of the proposed mechanisms are based on preliminary results and lack solid and thorough experimental and theoretical evidence. Detailed mechanistic studies are necessary. These challenging tasks will certainly attract attention in the future. In fact, there are ample opportunities for the development of new and useful direct C−H addition reactions via C−H activation. Most of the reported C−H additions reactions are limited to 1,2- or 1,4-addition mode. Logically, analogous 1,6addition reactions could be established. The application of C−H additions to synthesis of natural products, pharmaceuticals, and so on under mild conditions is also highly expected.198 Furthermore, highly efficient and enantioselective C−H additions are undoubtedly the ultimate goal in this field. Future advances in the research field will rely on chiral ligand design, substrate design, and mechanistic understanding. Above all, C− H activation/addition will remain a hot research area in the future because of its challenges and advantages. We believe that great advances and exciting results will be achieved in this field in the near future, which will certainly promote the development of organic chemistry in both academia and industry.

Lei Yang was born in Weifang, China. He graduated from Qufu Normal University in Chemistry in 2003 and received his Ph.D. degree in 2008 from the Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, under the supervision of Professor Chungu Xia and Professor Liwen Xu. He is currently an associate professor in Professor Huang’s group at the Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences. His current research interests are focused on the development of homogeneous catalysis and asymmetric synthesis.

Hanmin Huang was born in Hubei, China, and completed his M.S. degree at the Huazhong University of Science & Technology. He obtained his Ph.D. degree in 2003 at the Dalian Institute of Chemical Physics, Chinese Academy of Sciences, under the supervision of Professor Huilin Chen and Professor Zhuo Zheng. He then moved to Nagoya University and worked as a JSPS postdoctoral research fellow with Professor Masato Kitamura. In April 2008, he initiated his independent research in the Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, as a Full Professor financed by the “Hundred Talent program of CAS”. His current research interests are focused on the development of new and efficient synthetic methodologies for green organic synthesis.

ACKNOWLEDGMENTS We thank the Chinese Academy of Sciences and National Natural Science Foundation of China (Grant Nos. 21173241, 21133011, 21222203, and 21372231) for generous and continuous financial support. We thank all of the reviewers for their invaluable suggestions on improvement this manuscript.

AUTHOR INFORMATION Corresponding Author

ABBREVIATIONS Ac acetyl acac acetylacetonate Ac2O acetic anhydride

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. AS

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Ns OAc OMs OPiv OTf p-cymene PG Ph phen PivOH PMP p-Tol rac-BINAP

AcOH Ar atm BArF BF4 BINAP

acetic acid aryl atmosphere tetrakis(pentafluorophenyl)borate tetrafluoroborate 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene Bn benzyl Boc tert-butyloxycarbonyl bpy 2,2′-bipyridine BQ benzoquinone Bu butyl cat catalyst CMD concerted metalation−deprotonation cod 1,5-cyclooctadiene coe cyclooctene Cp* 1,2,3,4,5-pentamethylcyclopentadiene D-CSA D-(+)-camphorsulfonic acid Cy cyclohexyl d days DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DFT density functional theory DG directing group d-i-Prpf 1,1′-bis(di-isopropylphosphino)ferrocene DMAD dimethyl acetylenedicarboxylate DMF dimethylformamide DMSO dimethyl sulfoxide DPEphos 2,2′-oxybis(2,1-phenylene)bis(diphenylphosphine) DPPB 1,4-bis(diphenyphosphino)butane DPPBenzene 1,2-bis(diphenylphosphino)benzene DPPE 1,2-bis(diphenylphosphino)ethane DPPF 1,1′-bis(diphenylphosphino)ferrocene DPPP 1,3-bis(diphenylphosphino)propane dr diastereomeric ratio DTBP di-tert-butyl peroxide ee enantiomeric excess equiv equivalents Et ethyl EWG electron-withdrawing group FcPCy2 (dicyclohexylphosphinyl)ferrocene h hours i-Pr isopropyl IPr·HCl 1,3-bis(2,6-di-isopropylphenyl)imidazolium chloride KIE kinetic isotope effect La(pfb)3 lanthanum pentafluorobenzoate Me methyl (R,R)-Me-Duphos ( − ) - 1 , 2 - b i s ( ( 2 R , 5 R ) - 2 , 5 dimethylphospholano)benzene MS molecular sieves NaBArF sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate nbd 2,5-norbornadiene NBS N-bromosuccinimide n-Bu n-butyl NHC N-heterocyclic carbine NMA N-methylacetamide n-pent n-pentyl n-Pr n-propyl

rt SbF6 SEAr SET SIPr t-Bu TEMPO TFA TFE THF TON Ts Xantphos

4-nitrophenylsulfonyl acetate methanesulfonate pivalate trifluoromethanesulfonate 1-methyl-4-(1-isopropyl)benzene protecting group phenyl 1,10-phenanthroline 2,2-dimethylpropanoic acid p-methoxyphenyl 4-methylphenyl (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene room temperature hexafluoroantimonate aromatic electrophilic substitution single electron transfer 1,3-bis(2,6-diisopropylphenyl)imidazolin-2ylidene tert-butyl 2,2,6,6-tetramethylpiperidine-1-oxyl trifluoroacetate, trifluoroacetic acid trifluoroethanol tetrahydrofuran turnover number tosyl 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

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DOI: 10.1021/cr500610p Chem. Rev. XXXX, XXX, XXX−XXX

Transition-metal-catalyzed direct addition of unactivated C-H bonds to polar unsaturated bonds.

Transition-metal-catalyzed direct addition of unactivated C-H bonds to polar unsaturated bonds. - PDF Download Free
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