Metal-Catalyzed Decarboxylative CâH Functionalization - Chemical

Review pubs.acs.org/CR

Metal-Catalyzed Decarboxylative C−H Functionalization Ye Wei,†,‡,∥ Peng Hu,†,§,∥ Min Zhang,† and Weiping Su*,† †

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China ‡ College of Pharmacy, Third Military Medical University, Chongqing 400038, China § School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China ABSTRACT: C−H bond activation and decarboxylation are two significant processes in organic synthesis. The combination of these processes provides a novel synthetic strategy, that is, decarboxylative C−H bond functionalization. Considerable attention has been focused on such an active research field. This review offers an overview of the utility of decarboxylative C−H bond functionalization in the synthesis of various organic compounds, such as styrenes, chalcones, biaryls, and heterocycles, covering most of the recent advances of the decarboxylative functionalization of Csp−H, Csp2−H, and Csp3− H bonds, as well as their scopes, limitations, practical applications, and synthetic potentials.

CONTENTS 1. Introduction 2. Decarboxylative Csp−H Bond Functionalization 3. Decarboxylative Csp2−H Bond Functionalization 3.1. Nonchelation-Assisted Reactions 3.1.1. Functionalization of Heteroarene C−H Bonds 3.1.2. Functionalization of C−H Bonds of Benzene Rings 3.1.3. Functionalization of Acyl C−H Bonds 3.2. Chelation-Assisted Reactions 3.2.1. Decarboxylative C−H Bond Arylation 3.2.2. Decarboxylative C−H Bond Acylation 3.2.3. Decarboxylative C−H Bond Alkynylation/Annulation 4. Decarboxylative Csp3−H Bond Functionalization 5. Decarboxylative C−H Bond Functionalization via Stepwise Reactions and Miscellaneous 5.1. Carboxyl Group as a Traceless Directing Group for ortho C−H Bond Functionalization 5.2. Tandem Reactions, Oxidative Decarboxylation Reactions and Other Reactions 6. Conclusion and Perspective Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments References

1. INTRODUCTION In recent years, transition metal-catalyzed inert C−H bond functionalization1−4 has emerged as a cutting-edge research topic in catalysis and has already attracted considerable attention from the chemistry community. Such a synthetic strategy offers a concise route to directly transform C−H bonds into various valuable C−C and C−heteroatom bonds (e.g., C−halide, C−O, C−N, and C−S), which would streamline the synthetic processes and reduce the formation of unwanted byproducts (Scheme 1a). Among the methods for C−C bond formation, catalytic dehydrogenative cross-coupling of two C−H bonds represents an ideal strategy in view of atom- and step-economy.5 However, the known reactions generally suffer from high reaction temperature, low chemoselectivities and/or regioselectivities, and narrow substrate scopes. Considering these limitations and the shortcomings of the above-mentioned organic halides and organometallic reagents, synthetic chemists have been seeking new coupling partners for the formation of C− C bonds via C−H bond functionalization. Carboxylic acids are commercially available in large structural diversities at low cost, and they can be readily prepared by means of numerous well-established methods (Scheme 2).6 Moreover, these compounds are generally stable to air and moisture, easy to store, and simple to handle. As such, carboxylic acids are highly attractive raw starting materials in organic synthesis. One of the most fascinating transformations of carboxylic acids is decarboxylation,7,8 in which the C−CO2H group undergoes C−C bond cleavage to liberate one equivalent of carbon dioxide along with the generation of an active carbon species (e.g., a carbon radical or a C−M species). In this context, palladium,9,10 copper,11

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Special Issue: CH Activation Received: August 3, 2016 Published: March 7, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.chemrev.6b00516 Chem. Rev. 2017, 117, 8864−8907

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Scheme 1. Synthetic Methods for C−C Bond Construction

Scheme 2. Known Methods for the Synthesis of Carboxylic Acids

Scheme 3. (a) Aryl-Metal Species Derived from Decarboxylation and (b) Their Applications in C−C Bond Formation via C−H Bond Activation

silver,12,13 gold,14,15 and rhodium16 are capable of inducing the decarboxylation of the benzoic acids to form the corresponding aryl-metal species, some of which have been isolated and characterized (Scheme 3a). It has been known that the carboxylic acids are promising alternatives to organic halides and organometallic reagents for C−C bond (Scheme 1b). Naturally, synthetic chemists try to apply the in situ generated aryl-metal species derived from decarboxylation into the C−H bond functionalization, thus taking full advantage of both C−H bond activation and decarboxylation to develop a novel synthetic strategy, that is, decarboxylative C−H bond cross-coupling

reaction (Schemes 1c and 3b). Mechanistically, two modes for decarboxylation of carboxylic acids have been established for decarboxylative C−H bond functionalization reactions: one is the redox-neutral decarboxylation to form nucleophilic organometallic intermediate in which the oxidation state of metal ions that mediate decarboxylation does not change; the other one is the oxidative decarboxylation to form radical intermediates in which metal ions promoting decarboxylation undergo change in the oxidation state. Considerable progresses of transition metalcatalyzed decarboxylative C−C bond formation have been established over the past few years,7,8,17−22 including those 8865


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Scheme 4. Cu-Catalyzed Decarboxylative Alkynylation

Scheme 5. Proposed Mechanism for Cu-Catalyzed Decarboxylative Alkynylation

involving C−H bond functionalization;17,19−22 and lots of new reactions and efficient catalysts have been successfully exploited. In order to facilitate the chemists to understand the recent advance of decarboxylative C−H bond functionalization, we herein present a comprehensive review that contains the synthetic potential, scope, and limitations. Until now, there is no exact definition of decarboxylative C−H bond functionalization. Normally, decarboxylative C−H bond cross-coupling reactions refer to these reactions in which carboxylic acids undergo decarboxylation to generate reaction intermediates that then couple with C−H bonds of the other coupling partners to form new C−C bonds. Nevertheless, to give a wider spectrum of the field, other kinds of reactions involving both decarboxylation and C−H bond transformation are also discussed in the review, including applying carboxyl group as a traceless directing group for ortho aryl C−H bond functionalization, and oxidative decarboxylation reactions involving C−H bond transformations. In addition, the review only focuses on metal-promoted reactions, while metal-free examples are not considered. Generally, this review covers relevant publications in the recent ten years; however, some early literatures are also included to provide necessary backgrounds. This review is introduced mainly according to the hybridization of the C−H bond coupling partners (Csp−H, Csp2−H, and Csp3−H) as thread. Section 2 discusses the alkynylation reactions of amino acids and propiolic acids with terminal alkynes. Section 3 provides a survey of decarboxylative C−H bond functionalization of (hetero)arenes and formamides, which includes alkylation, arylation, acylation, alkenylation, and alkynylation. Section 4 introduces the work on decarboxylative C−H bond functionalization of hydrocarbons. Section 5 discusses the other kind of reactions containing procedures of both decarboxylation and C−H bond transformation, which include the examples of multiple-step reactions

performed in tandem manners, applying the carboxyl group as a traceless directing group for ortho aryl C−H bond functionalization and some other miscellaneous reactions. Note that this review does not cover the decarboxylative Heck-type reactions (decarboxylative cross-coupling of carboxylic acids and olefins to produce substituted alkenes) that could be regarded as formal C−H functionalization because the related examples have already been discussed in the previous reviews.8,17,19,20 We hope that this review would be a handy reference for the chemists interested in using the decarboxylative C−H bond functionalization for C−C bond construction.

2. DECARBOXYLATIVE CSP−H BOND FUNCTIONALIZATION Alkynes are versatile synthetic intermediates, from which a vast array of useful molecules can be prepared.23 Generally, terminal alkynes can be deprotonated by alkyllithiums or Grignard reagents because of their acidic C−H bonds. The resulting alkynyl anion can react with a spectrum of electrophiles to deliver target produces. However, the use of strong bases usually results in poor functional group compatibility and/or unsatisfactory reaction selectivity. Nevertheless, the deprotonation process of terminal alkynes can also occur under milder reaction conditions in the presence of a transition metal that coordinates with the unsaturated C−C triple bond to enhance the acidity of the terminal C−H bond. The in situ formed transition organometallic acetylides, such as copper, silver, nickel acetylide intermediates, can be utilized as coupling partners to take part in various reactions, including the decarboxylative couplings. An example regarding the decarboxylative Csp−H bond functionalization was disclosed by Liang and Li in 2009.24 In this protocol, readily available α-amino acids reacted with terminal alkynes catalyzed by a copper(I) bromide to give rise to various 8866


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Scheme 6. Decarboxylative Alkynylation for the Synthesis of N-Heterocycles

Scheme 7. Cu-Catalyzed Conjugated Diyne Synthesis

Scheme 8. Ag-Catalyzed Alkylation of Quinoline and 4-Cyanopyridine

products were obtained in synthetically useful to moderate yields (up to 57%), this method presents a good complement to the Cadiot−Chodkiewicz reaction toward the synthesis of unsymmetric diynes.

nitrogen-containing compounds in moderate to good yields, except for the noncyclic amino acid that showed poor reactivity (Scheme 4). The combination of CuBr and peroxide was thought to trigger the α-amino acids to occur oxidative decarboxylation to form an organocopper intermediate, which then reacts with terminal alkynes to provide the target products (Scheme 5). Later on, Liang, Yao, and Li as well as Seidel developed coppercatalyzed three-component couplings for the synthesis of alkynylated pyrrolidine and piperidine derivatives (Scheme 6).25,26 In these reactions, an aldehyde or ketone was thought to react with the α-amino acid to generate an azolidin-5-one derivative that could undergo decarboxylation to form an azomethine ylide.27 The reactive azomethine ylide was then captured by the terminal alkynes to form a new Csp3−Csp bond. Another type of decarboxylative alkynylation was Cu-catalyzed cross-couplings between propiolic acids and terminal alkynes, which was reported by Yu and Jiao in 2010 (Scheme 7).28 The reactions employed air as the oxidant and were amenable to many propiolic acids bearing aryl, heteroaryl, and styryl groups. With respect to the alkynes, most of them were aryl alkyne derivatives, and in limited cases, the substrates with an alkenyl or an alkyl groups could also be applied. Although all the coupled

3. DECARBOXYLATIVE CSP2−H BOND FUNCTIONALIZATION Aromatic compounds, such as anilines, phenols, pyridines, thiophenes, and alkylbenzenes, represent a highly important class of organic compounds. The synthetic transformations of such large quantity of chemicals using transition metal-catalyzed decarboxylative C−H functionalization obviously can provide a large amount of structurally divergent derivatives. In this part, we will review the cross-couplings between various (hetero)arenes and carboxylic acids with or without the assistance of a directing group. 3.1. Nonchelation-Assisted Reactions

3.1.1. Functionalization of Heteroarene C−H Bonds. 3.1.1.1. Alkylation of Heteroarene C−H Bonds. An early example of the decarboxylative functionalization of heteroarene C−H bonds can be traced back to the alkylation of 8867


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Scheme 9. Proposed Mechanism for Nucleophilic Radical Addition to ProtonatedPyridines (Minisci Reaction)

Scheme 10. Preparation of Agonist of Thyrotropin-Releasing Hormone Receptor 2

Scheme 11. Ag-Catalyzed Alkylation of Purine Nucleosides

form a radical cation. This intermediate is finally transformed into the target product through deprotonation and oxidation steps. By applying the Minisci reaction, a series of interesting and useful molecules that relate to medicinal chemistry and material science have successfully been prepared. Jain has utilized this strategy to selectively introduce a cycloalkyl group into a protected histidine with cyclopropyl carboxylic acid. The resulting compound is a precursor of a potent agonist for thyrotropin-releasing hormone receptor 2 (Scheme 10).30 Another example regarding the application of Minisci reaction for the synthesis of biologically active molecules was recently disclosed by Qu and Guo (Scheme 11).31 They found that AgNO3/(NH4)2S2O8 enabled the decarboxylative alkylation of purine nucleosides to occur at room temperature. The reactions exclusively took place at the C6−H position of purines. The kinetic isotope effect (KIE) experiment indicated that the C−H bond cleavage was not a rate-limiting step. The alkylation reaction might proceed through the radical process

heteroaromatic bases under acidic reaction conditions, which utilized silver nitrate as the catalyst, and carboxylic acids as the alkylating agents (Scheme 8). This pioneering work was presented in 1971 by Minisci.29 The reaction resembles the well-known Friedel−Crafts alkylation while exhibiting opposite reactivity and selectivity since more electron-poor heteroarenes react faster. Generally, these reactions use readily available starting materials and take place under mild reaction conditions, showing good functionality, compatibility, and synthetically useful yields. Nowadays, the silver-catalyzed alkylation of electron-deficient aromatic heterocycles via oxidative decarboxylation of alkyl carboxylic acids has evolved into a useful tool for the construction of C−C bonds and is often referred as Minisci reactions. The generally accepted processes start with the oxidation of a Ag(I) salt into a Ag(II) species by persulfate anion (Scheme 9). Subsequently, the reactive Ag(II) species triggers the decarboxylation of alkylcarboxylic acids to produce a carboncentered radical, which then reacts with protonated pyridines to 8868


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Scheme 12. Preparation of Cyclohexane-Centered Tripodal Carbohydrate Receptors

Scheme 13. Cu-Catalyzed Decarboxylative Alkylation of Indoles with α-Amino Acids

Scheme 14. Decarboxylative C3−H Arylation of Indoles

since the addition of the radical scavenger TEMPO totally inhibited the reaction. Recently, Miller utilized the Minisci reaction to synthesize some novel tripodal receptors which can be applied in molecular recognition of monosaccharides in polar and apolar solvents (Scheme 12).32 Cis-1,3,5-cyclohexanetricarboxylic acid reacted with 4-cyanopyridine under the classic reaction conditions of

Minisci reaction, affording a trisubstituted cyclohexane in 24% yield. This compound exhibits the highest binding affinity for noncovalent binding of an α-glucopyranoside in chloroform. Liang and Li in 2009 reported five examples regarding the decarboxylative alkylation of indoles with α-amino acids (Scheme 13).24 The C2-substituted indoles show moderate reactivity, yet the C3-substituted one is totally unreactive. 8869


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arylated indoles (Scheme 16).34 The authors found that the addition of propionic acid and tetramethylene sulfoxide (TMSO) is beneficial to the formation of the target products. Note that this method is suitable for both ortho-substituted electron-rich and -poor benzoic acids, and the C2 and C3 selectivity can be governed by the electronic properties of the ortho substituents on the benzoic acids. Thus, electron-poor benzoic acids result in C3 arylated products, whereas electronrich ones lead to C2 arylated products. Two reaction pathways were speculated with respect to the formation of C2 and C3 arylated indoles (Scheme 17). In the case of electron-rich benzoic acids, the Pd salt triggers the decarboxylation to generate an aryl-Pd(II) intermediate A (path A), which then electrophilically attacks the C3 position of indoles to form a new palladium species B. Such a species produces the C2 arylated products C through the sequence of palladium migration from C3 to C2 position and reductive elimination. Contrarily, the decarboxylation of an electron-poor benzoic acid is promoted by silver salt to form an arylsilver intermediate D (path B), which then complexes with an arylpalladium species E generated from Pd(II) catalyst and indoles to transfer the aryl fragment from silver to palladium via a Pd/Ag bimetallic transition state. The coordination of the Ag(I) species to the C N double bond in complex F is postulated to inhibit the migration of aryl fragment from C3 to C2 position, thus C3 arylated products G are finally observed through reductive elimination. In both pathways, the Ag(I) salt also acts as an oxidant to oxidize the Pd(0) into Pd(II). Tan subsequently reported the decarboxylative C−H bond arylation of thiazoles and benzoxazoles with benzoic acids catalyzed by a palladium catalyst (Scheme 18).35 Although a slightly higher catalyst loading (20 mol % of PdCl2) is required, this method enables ortho-substituted electron-rich and -poor benzoic acids to couple with many azole derivatives, affording the corresponding products in moderate yields. The authors suggested a mechanism starting from Pd-mediated decarboxylation, followed by a carbopalladation into the CN double bond to form a palladium species. Then β-H elimination delivers the arylated products and HPdX. The latter generates a Pd(0) species, which can be oxidized and regenerates the Pd(II) catalyst (Scheme 19). The similar decarboxylative C−H arylation of benzoxazoles was also reported by Hoover recently.36 Compared to Tan’s work,35 this approach employed inexpensive CuCl as the catalyst (Scheme 20). Nevertheless, an obvious limitation of this method is that only 2-nitrobenozic acids are suitable for the transformation. In addition, the use of stoichiometric amounts of oxidant is another issue. More recently, Maiti expanded the substrate scope of this type of transformation using molecular oxygen as the oxidant.37 This method is amenable to 2nitrobenozic acids, polyfluorobenzoic acids, oxazoles, thioazoles, imidazoles, thiophenes, and furans. The authors thought that O2 is mainly involved in the formation of aryl-Cu(III) species. Besides copper salts, the similar transformation could also be realized in the presence of nickel(II) under higher reaction temperature (160−170 °C), which was recently revealed by Zhang and Lu38 as well as Kalyani.39 Greaney extended the decarboxylative C−H arylation to heteroaromatic acids for the rapid assembly of heterobiaryl scaffolds (Scheme 21). 40 The authors find that bis(dicyclohexylphosphino)ethane (dcpe) is beneficial to the reaction. As a base/oxidant, CuCO3 is superior to the commonly used Ag2CO3. Thus, with Pd(OAc)2 as the catalyst, they realized

3.1.1.2. Arylation of Heteroarene C−H Bonds. In spite of the numerous merits of the Minisci reaction, a major limitation is that the carboxylic acid substrates are restricted to alkylcarboxylic acids, which means that a spectrum of aromatic carboxylic acids cannot be used as the cross-coupling partners under the classical conditions. Presumably, aromatic carboxylic acids are hard to undergo decarboxylation to generate aryl radicals, or such radicals are too reactive to be captured by heteroarenes. In order to explore the use of the aromatic carboxylic acids as starting materials for the C−H bond functionalization, much effort has been devoted to develop new catalytic systems. To this end, Larrosa established a bimetallic catalytic system containing Pd/ Ag to realize direct C−H arylation of indoles with benzoic acids as the aryl donors (Scheme 14).33 In the presence of Pd(MeCN)2Cl2 as a catalyst and Ag2CO3 as an oxidant, a variety of benzoic acids bearing ortho electron-withdrawing substituents (e.g., Cl, NO2, and F) reacted with N-protected indoles in moderate yields. It should be mentioned that the reactions showed excellent regioselectivity demonstrated by the exclusive formation of the C-3 arylated products. In order to make sense of the roles of Pd and Ag salts in the processes of C−H activation and decarboxylation, some control experiments were conducted. The protodecarboxylation of benzoic acids occurred smoothly in the presence of excess Ag2CO3, while the reactions did not occur at all with a substoichiometric quantity of Pd(MeCN)2Cl2. Besides, the cross-coupling reactions only happened with both Pd(MeCN)2Cl2 and Ag2CO3. Thus, these results revealed that the silver salt rather than the palladium salt is responsible for the decarboxylation process, and both metals are necessary for the C−H arylation. On the basis of these results, the authors gave a possible mechanism depicted in Scheme 15. Pd-catalyzed C3−H Scheme 15. Proposed Mechanism for Decarboxylative C3−H Arylation of Indoles

bond activation of indole generates an aryl-palladium species, which reacts with an aryl-silver intermediate derived from Agmediated decarboxylation to form a diaryl-palladium complex. Such an intermediate then furnishes the biaryl products through reductive elimination. The reduced Pd(0) species can be oxidized into Pd(II) species by Ag2CO3. Later on, Su developed a Pd-catalyzed regioselective C−H arylation method for the concise preparation of C2 and C3 8870


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Scheme 16. Pd-Catalyzed Regioselective C−H Arylation of Indoles

Scheme 17. Proposed Mechanism for Pd-Catalyzed Regioselective C−H Arylation

thiophenes, the authors found that both 2:18 ratio (volume ratio) of DMSO/DME and 4:16 ratio of DMSO/DME gave lower yields than the optimal 3:17 ratio of DMSO/DME. A number of functional groups are tolerated in the reactions, such as ketone, chloro, bromo, aldehyde, and ester substitutes. These transformations proceed through a similar reaction mechanism, in which the palladium salt and silver salt are responsible for ortho C−H bond activation and decarboxylation, respectively (Scheme 25). Very recently, Su developed a protocol that realized the direct arylation of pyridines with various benzoic acids catalyzed by a silver salt (Scheme 26).43 This is the first example of Minisci-type reaction of benzoic acids, thus significantly expanding the substrate scope of Minisci-type reaction. Depending upon the silver salts used (e.g., AgNO3, AgTFA, and Ag2SO4), various benzoic acids, including the ones without substituents at ortho positions of carboxyl group, reacted with pyridine and its derivatives smoothly. Moreover, the reactions tolerated various

the decarboxylative coupling reactions between various oxazoles and oxazole- or thiazole-carboxylic acids. With regard to the possible mechanism, two catalytic cycles were speculated (Scheme 22). On one hand, Cu mediates the decarboxylation of the heteroaromatic acid, forming an arylcopper species. On the other hand, the acidic C−H bond of the oxazole undergoes deprotonation in the presence of CO32−, generating an arylpalladium species, which then reacts with the formed arylcopper species, involving a transmetalation step, to give a new palladium intermediate. Then, reductive elimination offers the heterobiaryl product and Pd(0), which can be oxidized to Pd(II) by Cu(II). On the basis of the Pd/Ag bimetallic catalytic system, Su recently developed decarboxylative C−H arylation of thiophenes and furans (Schemes 23 and 24).41,42 The catalytic system contains Pd(OAc)2 or Pd(TFA)2, PCy3, and Ag2CO3. Besides, the ratio of a mixed solvent containing DMSO and DME can affect the result. For example, regarding the C−H arylation of 8871


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Scheme 18. Pd-Catalyzed C−H Arylation of Azoles

with the exception of 4-tert-butylpyridine that exclusively reacted with 3-bromobenzoic acid at the C2 position. 3.1.1.3. Acylation of Heteroarene C−H Bonds. Not only aromatic carboxylic acids but also α-oxoglyoxylic acids can take part in the transition metal-catalyzed decarboxylative C−H bond functionalization. In that case, the α-oxoglyoxylic acids act as the acyl source toward the synthesis of ketones. Recently, Zhang realized the C3−H bond acylation of free (N−H) indoles by means of Cu-catalyzed sp2 C−H bond functionalization (Scheme 27).44 The desired products were obtained in moderate to good yields. Besides, Zhang and Ge achieved the acylation of azoles with αoxoglyoxylic acids through Ni-catalyzed sp2 C−H bond functionalization (Scheme 28).45 This approach displayed good functional group compatibility and produces the desired products in moderate to excellent yields. The proposed mechanism is similar to those decarboxylative C−H bond (hetero)arylation reactions,33−35,40 involving processes of Nicatalyzed C−H bond activation and Ag-mediated decarboxylation. The decarboxylative C−H acylation of azoles was also realized by Sun, Li, and Lu,46 who used Co(ClO4)2·6H2O as the catalyst. Similar to the work of Zhang and Ge, the reactions also proceeded at high temperature (170 °C).

Scheme 19. Proposed Mechanism for Pd-Catalyzed Decarboxylative C−H Arylation of Azoles

functional groups, such as nitro, trifluoromethyl, cyano, mesyl, and bromo groups. Nevertheless, this method, similar to the classic Minisci reaction, showed unsatisfactory regioselectivity, Scheme 20. Cu-Catalyzed C−H Arylation of Benzoxazoles

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Scheme 21. Pd-Catalyzed C−H Heteroarylation of Azoles

Scheme 22. Proposed Mechanism for Pd-Catalyzed Decarboxylative C−H Heteroarylation of Azoles

Scheme 23. Pd-Catalyzed C−H Arylation of Thiophenes

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Scheme 24. Pd-Catalyzed C−H Arylation of Furans

Scheme 25. Proposed Mechanism for Pd-Catalyzed Decarboxylative C−H Arylation of Thiophenes and Furans

Scheme 26. Ag-Catalyzed C−H Arylation of Pyridines

3.1.1.5. Alkynylation of Heteroarene C−H Bonds. α,β-Ynoic acids can be used as alternatives to bromoalkynes and terminal alkynes in the C−H bond functionalization for the synthesis of aryl alkynes. Lee disclosed a method for the alkynylation of benzoxazoles with α,β-ynoic acids, using PdCl2 as the catalyst and Ag2O/O2 as the oxidant (Scheme 30).48 However, such a method displays low functional group tolerance regarding both heteroarenes and α,β-ynoic acids. 3.1.2. Functionalization of C−H Bonds of Benzene Rings. Undoubtedly, simple arenes such as benzene, toluene,

3.1.1.4. Alkenylation of Heteroarene C−H Bonds. Acrylic acids are also attractive coupling partners for the decarboxylative C−H bond alkenylation to prepare styrene derivatives. CouveBonnaire and Hoarau developed a Pd/Cu bimetallic catalytic system to construct heteroarylated monofluoroalkenes from heteroarenes and α-fluoroacrylic acids (Scheme 29).47 1,3,4Oxadiazoles and 1,3-diazoles were suitable substrates for the reaction. The Pd and Cu salts were considered to be responsible for the C−H bond activation and decarboxylation, respectively. 8874


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Scheme 27. Cu-Catalyzed C3−H Acylation of Indoles

Scheme 28. Ni-Catalyzed C−H Acylation of Azoles

Scheme 29. Pd/Cu-Mediated Decarboxylative Fluoroalkenylation of Heteroarenes

and xylene are highly attractive substrates toward the preparation of substituted aromatic compounds via C−H bond functionalization because of their broad availability and low cost. Yet, most

of the C−H bond functionalization reactions concerning simple arenes show unsatisfactory results, especially the low regioselectivity, which are attributed to, in a large part, their low 8875


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Scheme 30. Pd-Catalyzed Decarboxylative Alkynylation of Benzoxazoles

Scheme 31. Pd-Catalyzed (a) Intermolecular and (b) Intramolecular Decarboxylative Arylation Reactions

reactivity and multiple reactive sites. Thus, the application of simple arenes for the decarboxylative C−H functionalization to construct the cross-coupling compounds with high efficiency and excellent selectivity remains a challenging goal. An early example regarding the decarboxylative C−H arylation of simple arene was reported by Crabtree in 2008,49 in which anisole and 2,6-dimethoxybenzoic acid were utilized as the coupling partners (Scheme 31a). The reaction took place at 200 °C (microwave) with Pd(OAc)2 as a catalyst, 2-di-tertbutylphosphino-2′,4′,6′-tri-isopropylbiphenyl (tBu-XPhos) as a ligand and Ag2CO3 as an oxidant in DMF/DMSO, affording a mixture of meta- and para-arylated products in a ratio of 3/1. Besides the desired products, large quantities of 1,3-dimethoxybenzene was formed, which was generated by protodecarboxylation of 2,6-dimethoxybenzoic acid. With this catalytic system, the authors also described an example of intramolecular decarboxylative C−H arylation using 2-phenoxybenzoic acid as the substrate (Scheme 31b). Similar to the intermolecular arylation, a moderate yield of the desired product was obtained accompanying with large amounts of the protodecarboxylated product. Subsequently, Glorius demonstrated that the Pd-catalyzed intramolecular decarboxylative C−H arylation was amenable to various 2-phenoxybenzoic acids (Scheme 32).50 With this method, a variety of dibenzofurans bearing synthetically useful functional groups were prepared in moderate to good yields. Presumably, the use of more electrophilic Pd(TFA)2 as the catalyst in comparison with Pd(OAc)2 used in Crabtree’s work, and 1,4-dioxane as a cosolvent plays major roles in prohibiting the formation of protodecarboxylation byproduct. Similar to most of the examples regarding decaboxylative C−H arylation, these intramolecular reactions were proposed to proceed through steps of decarboxylation, transmetalation, C−H activation, and reductive elimination to offer the final products

Scheme 32. Pd-Catalyzed Intramolecular Decarboxylative Arylation Reactions

(Scheme 33). The authors suggested that Pd or Ag salts were responsible for the decarboxylation step. Another example for intermolecular decarboxylative C−H arylation of simple arenes was achieved with fluorobenzenes and benzoic acids, which was first disclosed by Tan35 in 2010. In their work, highly electron-deficient pentafluorobenzene and 1,2,4,5tetrafluoro-3-methoxybenzene showed moderate reactivities, using 20 mol % of PdCl2 as the catalyst. The similar transformation was subsequently extensively investigated by Su51 in 2011. In Su’s work, the authors employed Pd(TFA)2/ PCy3 as the catalyst system, and Ag2CO3 as the oxidant, allowing a wide spectrum of aromatic carboxylic acids, including heteroaromatic carboxylic acids to undergo decarboxylative coupling with an array of fluorobenzenes (Scheme 34). This approach provides a promising alternative to the traditional cross-coupling for the synthesis of the fluorobiphenyls that are of great importance in pharmaceutical52 and material applica8876


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Scheme 33. Proposed Mechanism for Pd-Catalyzed Intramolecular Decarboxylative Arylation of 2-Phenoxybenzoic Acids

Scheme 34. Pd-Catalyzed Decarboxylative Reactions between Fluoroarenes and Carboxylic Acids

tions.53 The authors performed a series of experiments to gain insight of the decarboxylation step. They found that the palladium complex containing PCy3 enabled the decarboxylation of electron-rich carboxylic acids and silver salt could promote the decarboxylation of both electron-rich and -deficient ones. Two possible reaction pathways were suggested as shown in Scheme 35. As an example for the construction of fluorobiphenyls, Luo recently explored an approach capable of decarboxylative coupling with perfluorobenzoic acids and benzene, toluene, chlorobenzene, or xylene, applying a Pd/Ag bimetallic system (Scheme 36).54 The major disadvantages of this method lie in the narrow substrate scope with both fluorobenzoic acids and simple arenes as well as low reactivity. In Su’s work mentioned above concerning the Ag-catalyzed decarboxylative arylation (Scheme 26),43 besides the pyridine derivatives, some simple arenes, such as benzene, dichlorobenzene, and benzotrifluoride, could also be arylated with various benzoic acids to generate the biphenyls (Scheme 37). Similar to the decarboxylative arylation of pyridines, the reactions with respect to simple arenes were also affected by the silver salts used, including Ag2SO4, AgNO3, and AgTFA. Although synthetically useful yields could be obtained, the regioselectivity is

Scheme 35. Proposed Mechanism for Pd-Catalyzed Decarboxylative C−H Arylation of Fluoroarenes

unsatisfactory. For example, the reaction between benzotrifluoride and 2-chloro-4-nitrobenzoic acid gave a mixture of C2, C3, and C4-substituted products in a ratio of 1:2.5:1.5. 8877


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Scheme 36. Pd-Catalyzed Decarboxylative Reactions between Perfluorobenzoic Acids and Simple Arenes

Scheme 37. Ag-Catalyzed C−H Arylation of Simple Arenes

Scheme 38. Synthesis of α-Ketoamides through Decarboxylative Cross-Coupling of Formamides and α-Oxocarboxylic Acids

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Scheme 39. Pd-Catalyzed Decarboxylative C−H Arylation with Acylperoxides as Arylating Reagents

3.1.3. Functionalization of Acyl C−H Bonds. Decarboxylative acyl C−H founctionalization reactions are rare. Wang reported a CuBr2-catalyzed decarboxylative acylation reaction between formamides and α-oxocarboxylic acids, resulting in αketoamides, which are core structures for many natural products and pharmaceuticals (Scheme 38).55 By using CuBr2 as the catalyst and DTBP (di-tert-butyl peroxide) as the oxidant, the reaction enjoys a good substrate scope; both N-alkylformamides and N,N-dialkylformamides were suitable substrates.

radical scavenger, reduced the substrate conversion, supporting the presence of aryl radicals in the reactions. Scheme 40. Stoichiometric Reaction of Palladacycle with Bezoyl Peroxide

3.2. Chelation-Assisted Reactions

Functional groups possessing heteroatoms, such as N, O, and S, are usually utilized as directing groups to assist transition metalcatalyzed inert C−H bond functionalization. On one hand, the use of directing groups can locate the transition metals at a proximal distance to the C−H bond which is desired to be activated, thus enhancing the chemo- and/or regioselectivities of the related reactions. On the other hand, directing groups may stabilize the organometallic intermediates generated by C−H bond cleavage, such as palladacycle and rhodacycle species, which can participate in the subsequent transformations to give rise to the desired products. Moreover, the introduction of directing groups can also provide opportunities for the synthesis of structurally diverse and complex compounds by means of further synthetic transformations. Considering these merits of directing groups, various directing groups have successfully been explored in the decarboxylative C−H bond functionalization. 3.2.1. Decarboxylative C−H Bond Arylation. Yu demonstrated that aryl acylperoxides are surrogates to benzoic acids for the decarboxylative arylation of aromatic C−H bonds (Scheme 39).56 In Yu’s work, a wide range of arenes showed good reactivity toward the Pd-catalyzed decarboxylative arylation reactions, which were aided by various directing groups, such as pyridine, oxazole, and oxime. Nevertheless, it should be noted that the acylperoxides are commercially limited and potentially dangerous if they are not stored or handled properly. The authors also figured out that the aryl acylperoxides with bulky or electrondonating groups were poor substrates. For example, reaction of 4-methoxybenzoic peroxyanhydride with 2-phenylpyridine afforded an arylcarboxylation product in 90% yield. A stoichiometric reaction between a cyclometalated compound and benzoyl peroxide was performed to investigate the reaction mechanism, which suggested that the palladacycle generated from C−H bond activation might be involved in the transformation (Scheme 40). Besides, the addition of ascorbic acid, a

Recently, Shi developed a useful method to construct heterobiaryls from benzamides and 2-thiophenecarboxylic acids improved by CuOAc and AgNO3 (Scheme 41).57 In this work, 2(pyridine-2-yl)propan-amine (PIP-amine), developed by the same group, was employed as a bidentate directing group for the aryl C−H bond activation. Significantly, the reactions were competent to heterocyclic C−H arylation, such as pyridine, thiophene, and furan. Despite the good functionality compatibility, large quantities of CuOAc, AgNO3, and Li2CO3 were required to obtain synthetically useful yields. When 3thiophenecarboxylic acid was used as a coupling partner under the standard reaction conditions, 2-arylated thiophene was formed as the sole product and no 3-arylated thiophene was observed. In addition, thiophene can also participate in the reaction to produce the 2-arylated thiophene. Thus, they stated that the reaction likely proceeded through a tandem process constituting of protodecarboxylation and oxidative dehydrogenative coupling. Besides, the synthetic utility of the PIP-amine group was further demonstrated by the reactions of intramolecular cyclization, ortho C−H alkynylation, and ortho C−H hydroxylation (Scheme 42). 3.2.2. Decarboxylative C−H Bond Acylation. Since early work demonstrated that the decarboxylation of α-oxocarboxylic acids could be realized, catalyzed by transition metals under mild reaction conditions,58 decarboxylation of α-oxocarboxylic acids was combined with chelation-assisted C−H bond activation to explore new synthetic methods to access ketones. Generally, the transition metal-catalyzed decarboxylative aryl C−H acylation with α-oxocarboxylic acids utilizes Pd(II) salts, 8879


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Scheme 41. Cu/Ag-Mediated C−H Arylation with 2-Thiophenecarboxylic Acids

Scheme 42. Synthetic Transformations

Scheme 43. General Reaction Pathway for Pd-Catalyzed Decarboxylative C−H Acylation

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Scheme 44. Room Temperature Pd-Catalyzed Decarboxylative Acylation between Anilides and α-Oxocarboxylic Acids

Scheme 45. Pd-Catalyzed Decarboxylative Acylation of Arenes with α-Oxocarboxylic Acids

Scheme 46. Pd-Catalyzed Decarboxylative Acylation of Benzoic Acids

afford a palladacycle complex, which undergoes ligand exchange with α-oxocarboxylic acids to furnish a new palladium(II) species. Such a species subsequently undergoes decarboxylation

such as Pd(OAc)2 and Pd(TFA)2 as the catalyst, and the possible reaction pathway is outlined in Scheme 43. With the assistance of a directing group, the palladation of sp2 C−H bond occurs to 8881


Chemical Reviews

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Scheme 47. Pd-Catalyzed Decarboxylative Acylataion of Cyclic Enamides with α-Oxocarboxylic Acids

Scheme 48. Pd-Catalyzed Decarboxylative Acylation of Oximes

ylative C−H bond functionalization reactions to synthesize ketones, using Pd(PhCN)2Cl2 as the catalyst, (NH4)2S2O8 and Ag2O as the oxidants, with pyridine or oxazole as the directing groups (Scheme 45).61 In contrast to their work on the acylation of anilides, this method displayed a relatively narrow substrate scope and high reaction temperature (120 °C). The same group recently realized the decarboxylative C−H bond coupling between two different types of carboxylic acids, in which the carboxyl substitute of benzoic acid was explored as the directing group for sp2 C−H bond activation and the αoxocarboxylic acids were used as the acylating reagents (Scheme 46).62 A series of 2-benzoylbenzoic acids were prepared in moderate to good yields with this method, including the one bearing sterically crowded 2,4,6-trimethyl group. Contrary to their work on the acylation of anilide and pyridine derivatives, the addition of a persulfate salt, such as K2S2O8, Na2S2O8, or (NH4)2S2O8, failed to afford the target products. Importantly, this method can be applied for the synthesis of pitofenone, an antispasmodic used in Spasmalgon.

to deliver an acylpalldium(II) complex, which undergoes reductive elimination to form the desired product and a Pd(0) salt. The latter can be oxidized into Pd(II) to fulfill the catalytic cycle. In accordance with the above-mentioned reaction mechanism, Ge developed a protocol to realize the ortho C−H bond acylation of anilides with α-oxocarboxylic acids in the presence of Pd(TFA)2 and (NH4)2S2O8 (Scheme 44).59 An obvious feature of this method is the mild reaction conditions. In this case, a variety of useful functionalities, such as bromide, nitro, chloro, and trifluoromethyl groups are compatible. Both phenylglyoxylic acids and aliphatic α-oxocarboxylic acids are suitable reagents for the acylation reactions. The possible process of the reaction might include ortho palladation of the acetanilides, decarboxylation, and reductive elimination steps. A similar method for the ortho C−H bond acylation of acetanilides was reported by Saxena afterward, in which the iron peroxo complex Fe(III)EDTA-H2O2 was employed as the oxidant.60 The Ge group also reported another example of applying αoxocarboxylic acids as the coupling partners for the decarbox8882


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Scheme 49. Investigation of Solvent for the Acylation of N,N-Diethyl-2-phenylacetamide

Scheme 50. Pd-Catalyzed Decarboxylative Acylation of Phenylacetamides

ketoximes underwent ortho acylation smoothly, with the exception of the m-F substituted one that reacted with phenylglyoxylic acid to give rise to two regioisomer products with a 2:1 ratio. The authors stated that the steric effect of the substituents likely hampered either the formation of the palladacycle or the proximity of the α-oxocarboxylic acids into the palladacycle. Furthermore, aldoximes were also suitable for this type of transformation while low yields were obtained. The decarboxylative acylation of aldoximes with α-oxocarboxylic acids were subsequently investigated by Tan using the similar catalytic system, significantly expanding the substrate scope of the aldoximes.65 However, aliphatic α-oxocarboxylic acids showed no reactivity in the work of Kim and Tan. Kim also applied the Pd(II)/(NH4)2S2O8 combination for the preparation of ortho arylated phenylacetamides from phenylacetamides and α-oxocarboxylic acids.66 The ratio of mono- and bis-arylated products is sensitive to the solvent used (Scheme 49). The use of diethylene glycol dimethyl ether (diglyme) or THF as the solvent favors the formation of the mono product,

Guo and Duan also used amide as a directing group for the acylation of olefinic C−H bonds with Pd(OAc)2 as a catalyst at room temperature (Scheme 47).63 With this method, only 4chromanone-derived enamides were suitable substrates for the C−H acylation. In the case of tetralone-derived enamide, only a trace quantity of desired product was obtained, presumably because this substrate was unstable under the conditions. Besides, the reactions were not amenable to aliphatic αoxocarboxylic acids. The addition of TEMPO, a radical scavenger, did not influence the yield, precluding the existence of a free radical in the reactions. The reaction likely begins with the formation of a cyclic vinylpalladium intermediate by olefinic C−H activation. Then, α-oxocarboxylic acid reacts with the palladacycle complex to deliver the target product through decarboxylation and reductive elimination processes. Another type of directing group used in the decarboxylative C−H acylation was explored by Kim in 2013,64 who utilized Omethyl oximes as the directing group to facilitate C−H acylation (Scheme 48). With Pd(OAc)2 as the catalyst, various O-methyl 8883


Chemical Reviews

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Scheme 51. Pd-Catalyzed Decarboxylative Acylation of Carbamates

Scheme 52. Pd-Catalyzed Decarboxylative C2-Acylation of Indoles

the formation of the palladacyle complex generated from C−H cleavage.68 Besides, N-substituted indolines could also participate as the substrates to generate C7-acylated indolines in the presence of Pd(II)/(NH4)2S2O8.69 Zhu recently demonstrated that the method of decarboxylative C−H acylation can be applied for the synthesis of 2-aroylindoles that are prevalent in pharmaceutically important compounds.70 The authors installed a pyrimidyl group to the N atom of indoles as a director to assist the C−H bond cleavage (Scheme 52).71 The reactions utilized Pd(OAc)2 as the catalyst, and Ag2O/ K2S2O8 as the oxidants. In addition, they figured out that the use of mixed solvents of 1,4-dioxane, HOAc, and DMSO was crucial to the acylation process. With this method, a series of 2aroylindoles were prepared in moderate to good yields. The pyrimidyl director can be removed from the acylated products to

albeit leading to low yields (entries 1 and 2). Chloro-containing solvents such as DCM and DCE were studied with DCE to be optimal, showing 75% yield and excellent bis-selectivity (entries 4 and 5). With Pd(TFA)2 as the catalyst, (NH4)2S2O8 as the oxidant, and DCE as the solvent, phenylacetamides with electron-donating and -withdrawing functionalities could react with various α-oxocarboxylic acids (Scheme 50). The reaction involving para methoxy-substituted phenylacetamide favored the generation of bis-arylated product, while meta substituted ones favored the monoarylated products because of the steric hindrance. The same group also realized ortho acylation of O-phenyl carbamates with α-oxocarboxylic acids (Scheme 51).67 The use of a catalytic amount of TfOH (20 mol %) is crucial for this transformation and no desired product was observed in the absence of such an additive. Presumably, TfOH is beneficial to 8884


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Scheme 53. Pd-Catalyzed Decarboxylative Acylation of 2-Aryloxypyridines

Scheme 54. Stoichiometric Reactions of Palladacycle Complex

Scheme 55. Pd-Catalyzed Decarboxylative Acylation of Azoxybenzenes

give rise to the corresponding N−H 2-aroylindoles by NaOEt in DMSO. Introduction of an aroyl group into the ortho position of 2aryloxypyridines for indirect preparation of 2-hydroxy aromatic ketones was recently reported by Zhang, using pyridine as the directing group (Scheme 53).72 Note that heterocyclic αoxocarboxylic acids showed moderate reactivity in the reactions.

The pyridine group of the acylated products can be removed to furnish 2-hydroxy aromatic ketones. For example, phenyl(2(pyridin-2-yloxy)phenyl)methanone was transformed to (2hydroxyphenyl) (phenyl)methanone in 82% yield by treatment with MeOTf and Na/NaOH. The mechanistic studies revealed that a palladacyle intermediate was involved in the reaction, 8885


Chemical Reviews

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Scheme 56. Pd-Catalyzed Decarboxylative Acylation of Azobenzenes

Scheme 57. Pd-Catalyzed Decarboxylative Acylation of 2-Aryl-4H-benzo[d][1,3]oxazin-4-one

(Scheme 57).75 It was found that phenylglyoxylic acids bearing electron-donating groups at the aromatic ring resulted in the target products in good yields, while phenylglyoxylic acids with electron-withdrawing groups showed moderate reactivity. Taking advantage of the coordination ability of nitroso group with palladium salt, Wang developed a method for the preparation of acylated N-nitrosoanilines (Scheme 58).76 The reactions tolerate various functional groups, such as chloro, bromo, iodo, and ester groups. The different alkyl groups on the N-nitroso group influence the reactivity of the substrates. For example, the yield is decreased by 20% when changing the methyl group to isopropyl group, as shown in Scheme 58. Chu and Sun more recently realized the decarboxylative acylation of 1,2,3,4-tetrahydroquinolines at room temperature (Scheme 59).77 This method generally shows good reaction efficiency and acceptable functional group compatibility. However, the highly electron-withdrawing CF3 group on the benzene ring of the tetrahydroquinolines inhibited the reaction. In addition, the thiophene and furan derived α-oxoarylacetic acids display rather poor and no reactivity, respectively.

supported by a stoichiometric reaction between 2-phenoxypyridine palladacycle and phenylglyoxylic acid (Scheme 54). Wang recently reported a Pd-catalyzed method for the synthesis of acylated azoxybenzenes with α-oxocarboxylic acids, using azoxy functionality as a directing group (Scheme 55).73 Numerous ortho acylated azoxybenzenes were obtained in synthetically useful to high yields. The target products can be easily converted into the corresponding indazoles under 1 atm of H2 with a Pd/C catalyst at room temperature. Using the similar reaction conditions for azoxybenzenes acylation, the ortho C−H acylation of azobenzenes were also explored by Wang (Scheme 56).74 Nevertheless, the aliphatic αoxocarboxylic acids, such as 2-oxopropanoic acid showed no reactivity. Besides, all the azobenzenes used are limited to symmetric azobenzene derivatives. Through further synthetic transformations, the acylated products can be converted into the corresponding indazoles in good yields. More recently, Ranu demonstrated that cyclic imine could act as a directing group in the Pd-catalyzed decarboxylative ortho C−H acylation of 4H-benzo[d][1,3]oxazin-4-one derivatives 8886


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Scheme 58. Pd-Catalyzed Decarboxylative Acylation of N-Nitrosoanilines

Scheme 59. Pd-Catalyzed Decarboxylative Acylation of Tetrahydroquinolines

3.2.3. Decarboxylative C−H Bond Alkynylation/Annulation. More recently, Niu and Song reported the Co(II)catalyzed decarboxylative C−H activation/annulation for the synthesis of isoquinolones and isoindolinones (Scheme 60).78 The reactions show reasonable functional group compatibility and low to moderate product yields. The experimental results regarding the formation of isoindolinones suggest that the ortho alkynylated compound derived from decarboxylative C−H alkynylation might be the intermediate of the reaction.

A study with wider hydrocarbon substrate scope of this area was reported by Liu group in 2012.79 Vinylic carboxylic acids were found to undergo decarboxylative olefination of sp3 C−H bonds with vast scope of substrates, including alcohol, ether, amine, amide, toluene, and even normal alkane (Scheme 62). The reaction probably proceeded through a radical pathway, and copper powder was used as the catalyst and tert-butyl hydroperoxide (TBHP) as the oxidant. At the same time, the Mao group reported a similar reaction independently, improved by CuO (10 mol %) and di-tert-butyl peroxide (DTBP).80 However, the hydrocarbon reactants were majorly focused on toluene derivatives. Later on, this group reported the same reaction with higher efficiency, catalyzed by Fe3O4.81 Interestingly, they found that the 70−80 nm Fe3O4 nanoparticle catalyst could be recycled and 75% isolated yield of the product could be obtained even after the eighth reaction cycle. In 2013, Pan and Han reported one similar decarboxylative alkenylation of cycloalkanes with arylvinyl carboxylic acids, promoted by

4. DECARBOXYLATIVE CSP3−H BOND FUNCTIONALIZATION Examples of decarboxylative functionalization of Csp3−H bonds are limited. Liang and Li reported in 2009 three examples of decarboxylative cross-coupling of α-amino acids with nitromethane to construct Csp3−Csp3 bonds, and moderate to good yields were obtained (Scheme 61).24 8887


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Scheme 60. Co-Catalyzed Decarboxylative C−H Alkynylation/Annulation Cascade Reaction to Form Isoquinolones and Isoindolinones

Scheme 61. Cu-Catalyzed Decarboxylative Alkylation of Nitromethane with α-Amino Acids

Scheme 62. Cu-Catalyzed Decarboxylative Olefination of sp3 C−H Bond

resulted in only phenylethanone derivatives, as shown in Scheme 63. In most cases, both directions enjoyed moderate to good yields of products. However, the carboxylic acid substrates were limited to arylvinyl carboxylic acids. In 2016, the Zhang group presented one reaction to produce pyrrolidones via copper-catalyzed decarboxylative Csp3−H functionalization/cyclization in a tandem manner (Scheme 64).84 The well-known auxiliary 8-aminoquinoline was applied to direct the activation of β sp3 C−H bond of the amide substrate. Alkynyl carboxylic acids were used as the second reaction partner. This is the first example of decarboxylative crosscoupling of unactivated Csp3−H bond. The reaction enjoys good functional group tolerance and useful to excellent yields can be obtained. E/Z isomer ratios of the products can be controlled by the treatment with p-toluenesulfonic acid after the reaction. However, the amide substrates are restricted to the ones without a hydrogen at the α position and only C−H bonds of methyl group can be activated. The reaction probably undergoes coppercatalyzed sp3 C−H activation first followed by alkynylation. After that, silver-catalyzed cyclization and p-toluenesulfonic acid treatment provide the final product, as shown in Scheme 65.

Fe(acac)3 and di-tert-butyl peroxide (DTBP).82 Generally, good to excellent yields were observed. However, all of these four examples suffer from the limited scope of carboxylic acids substrates: only aryl vinylcarboxylic acids can be applied. In addition, large excess of hydrocarbon compounds are usually required both as the reactants and the solvents. The reactions are performed through radical pathways, thus poor selectivities are always shown when hydrocarbon compounds with different sp3 C−H bonds are tested, especially in the case of unactivated alkanes. In 2014, the Wen group reported one example of nickel- and manganese-catalyzed decarboxylative cross coupling of arylvinyl carboxylic acids andcyclic ethers (Scheme 63).83 The reaction gave different products when different catalysts were used: manganese acetate produced the normal decarboxylative crosscoupling products (alkylated styrene derivatives), while nickel

5. DECARBOXYLATIVE C−H BOND FUNCTIONALIZATION VIA STEPWISE REACTIONS AND MISCELLANEOUS In this part, reactions involving decarboxylation and C−H functionalization not presented before will be reviewed, majorly including examples of multiple-step reactions performed in tandem manners and applying carboxyl group as a traceless directing group for ortho C−H bond functionalization of arenes. 8888


Chemical Reviews

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Scheme 63. Selective Ni- and Mn-Catalyzed Decarboxylative Cross-Coupling of Arylvinyl Carboxylic Acids with Cyclic Ethers

Scheme 64. Pyrrolidone Synthesis via Copper-Catalyzed Tandem Decarboxylative Csp3−H Functionalization/Cyclization

Scheme 65. Proposed Mechanism of Copper-Catalyzed Tandem Decarboxylative Csp3−H Functionalization/Cyclization

5.1. Carboxyl Group as a Traceless Directing Group for ortho C−H Bond Functionalization

However, the meta- and para-substituted adducts may be also accessed by using a removable ortho-directing group, for example, a carboxyl group. When considering the readily availability and the rich source of carboxylic acids, the advantages of using benzoic acids to achieve meta-, para-, and even multiple position-substituted arenes are obvious (Scheme 66b): no requirement of special-prepared directing group or ligand; because the directing group will be moved after the C−H functionalization step, the products with different substitutes at meta and para positions can be produced, as compared to the

Regioselectivity of C−H bond functionalization attracts considerable attention in recent years. Specially, after some years’ continuous successes in the development of directed ortho C−H functionalization of substituted benzenes, chemists move their enthusiasms to search for methods enabling meta and para C−H functionalization on aromatic rings selectively (Scheme 66a). Huge efforts devoted to decarboxylative C−H functionalization reaction have led to a significant progress in this area. 8889


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moderate to good yields are obtained. However, the reaction is a two-step, one-pot process. [(Cp*RhCl2)2] acts as the catalyst to improve the ortho-olefination step, after which a stoichiometric amount of AgOAc and base are required for decarboxylation under higher temperature of 160 °C. 1,3- and 1,4-Distyrylbenzenederivatives can also be generated through substrate control. Further research shows better substrate scope together with satisfactory yields.87 Heteroarene carboxylic acids, such as thiophenecarboxylic acids, indole carboxylic acids, and benzofuran carboxylic acids, all can be applied as substrates to produce olefin-functionalized heteroarenes in one step, with [(Cp*RhCl2)2] as the catalyst, Cu(OAc)2·H2O as the additive, and DMF as the solvent. Generally good isolated yields (63%− 84%) are obtained. The first formal meta C−H arylation directed by the traceless carboxyl group was presented by Larrosa in 2011 (Scheme 69).88 Ortho-substituted benzoic acids and iodoarenes are applied as the reactants. The reaction is improved by the Pd(OAc)2/ Ag2CO3 system, using stoichiometric HOAc as an additive. A wide range of substitutes are compatible, and moderate to good yields are provided. Specially, outstanding regioselectivities are shown, and in all cases the desired products are generated as the sole isomers, which is superior as compared with other directed meta C−H arylation reactions. In addition, the authors find that the palladium salts but not the silver salts catalyze the decarboxylation of ortho-arylated benzoic acid intermediates, with complete chemoselectivities over the corresponding orthosubstituted substrates. This result is in accordance with the hypothesis that Pd-catalyzed decarboxylation can be influenced by steric factors.89 In 2013, the Gooßen group reported one carboxylate directed ortho C−H alkoxylation reaction of benzoates with borate esters, followed by decarboxylation, to construct aryl ethers as the final products (Scheme 70).90 The reaction is promoted by the catalytic system Cu(OAc)2/Ag2CO3, using 1 atm of O2 as the final oxidant. Cu(OAc)2 is suggested as the C−H alkoxylation catalyst via a Cu(I)/Cu(II)/Cu(III) cycle; while Ag2CO3 acts as the decarboxylation catalyst. A broad range of functional groups are survived and generally moderate to good yields can be provided. Both monosubstituted phenyl ethers, meta- and parasubstituted phenyl ethers, even multiple-substituted aromatic ethers can be produced. In addition, chiral alkoxide can be

Scheme 66. Different Pathways for meta and para Aromatic C−H Functionalization

directed meta and para C−H bond functionalization reactions, of which further steps are required to transform the directing groups. In this part, we will review the work of using carboxyl functionality as the traceless directing group for decarboxylative C−H bond functionalization in recent years. Satoh and Miura presented the first example of applying carboxyl group as a removable directing group to improve vinylation of heteroaromatic compounds, including indole, pyrrole, furan, and thiophene carboxylic acids (Scheme 67).85 Both C3-vinylated indoles and synthetically harder C2-vinylated indoles can be produced selectively by using the relevant C2- and C3-substituted indole carboxylic acids, respectively. Though the performance of the functional group tolerance is not satisfactory, the reaction shows a unique application of carboxyl group as a removable directing group (also more frequently called traceless directing group), which gives rise to various new methods to construct new chemical bonds efficiently. Later in 2010, the Satoh and Miura group extended the olefination reaction to benzoic acid system, resulting in metasubstituted stilbenes (Scheme 68).86 Good substrate scope and

Scheme 67. Vinylation of Heterocyclic Compounds Directed by a Removable Carboxyl Group

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Scheme 68. Synthesis of Stilbenes via ortho-Olefinationand Decarboxylation of Benzoic Acids

Scheme 69. Application of Carboxyl as a Traceless Directing Group for Formal meta-Selective Direct Arylation

Scheme 70. Application of Carboxylate Group as a Traceless Directing Group for Aryl Ethers Synthesis through C−H Alkoxylation

transformed to the corresponding ether product with retention of configuration. The authors also presented an example of 8891


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Scheme 71. Tandem Arylation/Decarboxylation of Salicylic Acid

Scheme 72. Formal meta-Arylation of Phenols Through a Tandem C−H Functionalization/Decarboxylation Process

Scheme 73. Application of Carboxyl as a Traceless Directing Group for N-Aryl Benzamides Synthesis through C−H Amidation

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Scheme 74. Application of Carboxyl as a Traceless Directing Group for C−H Cross-Coupling/Cyclization of α-Keto Carboxylic Acids with Internal Alkynes

Scheme 75. Introduction of meta-Amino Groups by Directed C−H Amidation and Tandem Decarboxylation

with tandem C−H arylation/decarboxylation were also described.92 Shi and Li reported in 2015 an example of using carboxyl as a traceless directing group to form the less common metasubstituted N-aryl benzamides via a tandem C−H amidation/ decarboxylation of benzoic acids with isocyanates (Scheme 73).93 The reaction is catalyzed by the [Cp*RhCl2]2/Cu2O system, applying K2HPO4 as a base. Methoxy, chloro, and bromo groups are compatible in the reaction and synthetically useful to good yields of the desired products can be obtained. However, the reaction suffers from the inferior performance of the osubstituted benzoic acid substrates, which results in low yields of the corresponding products. Another limitation is that only phenyl isocyanates can be applied. The same reaction can also be catalyzed by the less expensive ruthenium.94 In 2015, Li and Wang reported a C−H cross-coupling/ cyclization reaction between α-keto carboxylic acids anddisubstituted alkynes, using carboxyl as a traceless directing group, catalyzed by [Ru(p-cymene)Cl2]2 (Scheme 74).95 Treated with stoichiometric Cu(OAc)2, the reaction uses O2 (from air) as the source of one of the oxygen atoms of the ester group, proved by the 18O2 labeling experiment. CO2, as the direct evidence of decarboxylation, is also detected by FT-IR. The reaction enjoys a broad scope of functional groups, and moderate to good yields of

combining the synthesis of borate ester reagent with the decarboxylative C−H alkoxylation in a one-pot process, providing the relevant product successfully. In 2014, the Larrosa group found that salicylic acid can undergo a tandem C−H arylation/decarboxylation reaction with iodoarenes, improved by PEPPSI-IPr/Ag2CO3 (Scheme 71).91 On the basis of the result and also because salicylic acid derivatives can be produced by carboxylation of phenols with CO2, the authors develop a one-pot procedure to synthesize meta-arylated phenols through a three-step process, as shown in Scheme 72. Phenols first mix with KOH at 50 °C for 10 min and then treat with 25 atm of CO2 at 190 °C for 2 h, which will generate the carboxylated phenols in situ. After that, the coupling reagents iodoarenes, catalysts, and additives are added, the desired products are generated after 16 h at 130 °C. The reaction enjoys a vast scope of functional groups of both phenols and iodoarenes, and the isolated yields are generally synthetically useful to moderate. The reaction is completely meta-selective, and no other isomer is observed. CO2 is used as the source of the carboxylate group, which is performed as a traceless directing group and transformed to CO2 again after decarboxylation. The method presents a new pathway of highly selective metaaromatic C−H functionalization based on the transformation of CO2. The details of the C−H arylation of salicylic acid derivatives 8893


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Scheme 76. Carboxyl as a Traceless Directing Group for the Rhodium(III)-Catalyzed Decarboxylative C−H Arylation of Thiophenes

Scheme 77. Formal para-C−H Bond Functionalization of meta-Substituted Benzoic Acids Using Carboxyl as a Traceless Directing Group

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Scheme 78. C−H Hydroarylation of Internal Alkynes Using Carboxyl as a Traceless Directing Group

Scheme 79. Synthesis of Acenes through Tandem C−H Functionalization/Decarboxylation Using Carboxyl as a Traceless Directing Group

isocoumarin derivatives can be produced. In addition, both diphenyl-substituted and dialkyl-substituted alkynes can be applied as substrates. The Chang group reported a formal meta- and para-aromatic C−H bond amidation reaction of benzoic acids with sulfonyl

azides, using carboxyl as a traceless directing group, enabled by a two-step, one-pot process (Scheme 75).96 For the meta amidation, Pd(OAc)2 is applied as the decarboxylation catalyst, while in the case of para amidation, the Cu 2 O/1,10phenanthrolinecatalyst system is required and the decarbox8895


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Scheme 80. Decarboxylative Cross Couplings of Benzoic Acids with Diarylacetylenes to Construct Naphthalene Derivatives

through a hydroarylation/protodecarboxylation sequence because the ortho-vinylated benzoic acids can not undergo decarboxylation to afford the protodecarboxylative products under the standard reaction conditions. The decarboxylative hydroarylation strategy was also reported by Zhao more recently, who used Ru(p-cymene)2(OAc)2 as the catalyst and 1,4dioxane/mesitylene/heptane as the solvent.101 This catalytic system displays lower reaction temperature (80 °C) and broader substrate scope, as compared to Gooßen’s method. In addition, Zhao’s hydroarylation method shows good regioselectivity with respect to unsymmetrical aryl-alkyl alkynes. Note that both Gooßen and Zhao’s methods are not amenable to terminal alkynes. Very recently, the Hong group developed a method to synthesize acenes from diaryl acetic acids and acrylates through a tandem C−H functionalization/decarboxylation process (Scheme 79).102 The reaction is catalyzed by Pd(OAc)2, applying O2 as the terminal oxidant. The tandem transformation begins with the carboxyl directed aromatic C−H vinylation, followed by an intramolecular C−H cyclization and decarboxylative aromatization. Linearly fused polycyclic aromatic hydrocarbons are very important structures for medicinal and material research. The presented method provides a convenient and straightforward way to construct anthracene derivatives, polyacenes, and heteroacenes in moderate to excellent yields, bearing a broad range of substitutes.

ylation step is performed in DMA. Both meta and para amidation reactions occur smoothly with a variety of substitutes in moderate to good yields and exact regioselectivities. In 2015, the Su group presented a work of formal metaarylation of aromatic carboxylic acids with thiophenes through C−H/C−H cross-coupling, enabled by application of carboxyl as a traceless directing group (Scheme 76).97 The reaction is improved by the [(Cp*RhCl2)2]/Ag2CO3 system, and TEMPO is found to benefit the outcome of the products. A broad range of functional groups are compatible from both sides of the coupling partners, and moderate to good yields are provided. In addition, both electron-rich and electron-deficient aromatic carboxylic acids are suitable substrates, including heterocyclic compounds. Besides thiophenes, benzofuran can also act as the reactant for the transformation. Furthermore, extended π-conjugated systems bearing thiophene subunits, which are important for material science, can be quickly constructed through the method in moderate to good yields. The similar reaction was also reported by the Lan and You group later, and some different heteroarenes were tested.98 Recently, the Zhang group presented the research of using carboxyl as a traceless directing group to form para-substituted arenes, applying meta-substituted benzoic acids as the substrates (Scheme 77).99 In all, three types of functionalization are described: arylation with iodobenzenes, benzoylation with benzoylformic acids, and hydroxylation with oxygen. Generally, the reactions are performed via a two-step process without isolation of the benzoic acid intermediates: the first step is palladium-catalyzed aromatic C−H bond functionalization; the second step is copper-catalyzed decarboxylation. The reactions usually enjoy a good substitute tolerance and synthetically useful to good yields can be obtained. Though the reaction conditions are based on the relevant reported research, the results show good examples of applying carboxyl as a traceless group to enable various C−H functionalization efficiently to form many interesting structures in excellent regioselectivity. In 2016, the Gooßen group described an Ru-catalyzed C−H hydroarylation of internal alkynes applying carboxyl as a traceless directing group (Scheme 78).100 Both meta- and para-vinylated benzenes bearing various functional groups can be formed in moderate to excellent yields. Heterocyclic compounds also act as suitable substrates. However, alkyl-substituted alkynes show low reactivity under the present reaction conditions. The authors considered that this type of transformation may not proceed

5.2. Tandem Reactions, Oxidative Decarboxylation Reactions and Other Reactions

The Satoh and Miura group reported some pioneer work of decarboxylative cross coupling of benzoic acids with alkynes via regioselective C−H bond activation. By using benzoic acids and alkynes as substrates, naphthalene derivatives could be formed selectively, catalyzed by an iridium catalyst ([Cp*IrCl2]2).103 A new benzene ring could be constructed via reactions between two molecular alkynes and one molecular benzoic acid, accompanying by decarboxylation, which represented a new example of aromatic homologation, as compared to the cross coupling reactions of aryl halogens with alkynes. When osubstituted benzoic acid, for example, 2-methylbezoic acid was tested, and the same product was provided as in the case of applying 4-methylbezoic acid (Scheme 80), probably due to the steric hindrance reason. The reaction was only efficient to diarylacetylenes, while dialkylacetylenes led to very low yields of corresponding products (10−20% GC/MS yields). A proposed 8896


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substrates for the reaction, and highly substituted heterocyclic compounds were produced in moderate to high yields, catalyzed by Pd(OAc)2. Besides diarylacetylenes, dialkylacetylenes also worked well as the reactants. However, when N-phenyl indole carboxylic acids were applied, the 5,6-diarylindolo[1,2-a]quinolines were formed predominantly, through a two C−H bond activation and decarboxylation process. The three reactions reviewed above are good methods to construct highly substituted π-conjugated compounds, which may potentially have interesting properties for material science and biology research. However, unsymmetric alkynes are not used in these methods. In 2010, the Glorius group reported one palladium-catalyzed intermolecular formal [4 + 2] annulation of 2-phenylbenzoic acids with alkynes, and both symmetrical and unsymmetric alkynes were studied (Scheme 84).107 It was found that pyridine derivatives played an essential role to improve the reaction, and acridine presented the best performance. A variety of alkynes and 2-phenylbenzoic acids were examined, and moderate to high yields of the desired products were observed, despite the enhanced steric hindrance of the reactants. Interestingly, when unsymmetric alkynes and substituted 2phenylbenzoic acids were chosen as the reactants, good regioselectivity was shown (≥10:1). The method may be useful for material science for the synthesis of polycyclic aromatic hydrocarbons. The mechanistic investigations have also been performed to reveal that two of four proposed reaction pathways were in agreement with the experimental results (Scheme 85). Path A started by decarboxylation to generate an aryl-Pd(II) species, followed by alkyne insertion, Pd(II) promoted C−H activation, and final product formation by reductive elimination. Path B involves carboxyl-directed C−H palladation, alkyne insertion, decarboxylation, and reductive elimination. On the basis of currently understanding of decarboxylative crosscoupling reaction, we thought that the reaction likely occurred by way of path A. Under the given reaction conditions, benzoic acids bearing two ortho substituents are prone to undergo silverpromote decarboxylation to generate aryl-silver species and subsequent transmetalation to give aryl-palladium species. Migratory insertion of triple bond of unsymmetrical alkyne into the C−Pd bond of aryl-palladium species should selectively occur at the more electron-deficient sp-carbon atom bonding to the phenyl group due to nucleophilic addition of an aryl fragment to triple bond, rationalizing the origin of the observed regioselectivity. The Su group reported in 2010 an example of palladiumcatalyzed decarboxylative cross-coupling reaction of benzoic

mechanism was presented in Scheme 81. After C−H addition with one molecule of diarylacetylene and decarboxylation, an Ir Scheme 81. Proposed Mechanism of Ir-Catalyzed Decarboxylative Aromatic Homologation

intermediate with a five-membered ring was formed. If 2substituted benzoic acid was used as the substrate, isomerization of the Ir intermediate would happen and the species with less steric hindrance would be formed, resulting in the more favored 1,2,3,4,6-functionalized naphthalenes. The ability of the iridium catalyst [Cp*IrCl2]2 to improve decarboxylative aromatic homologation was also discussed by Kudinov.104 Later in 2009, the Satoh and Miura group found that the reactions between N-phenylanthranilic acids and diarylacetylenes could construct 4-ethenylcarbazoles, by applying [RhCl(cod)]2/C2H2Ph4 (1,2,3,4-tetraphenyl-1,3-cyclopentadiene) as the catalyst system (Scheme 82).105 Air was used as the terminal oxidant for the oxidative coupling reaction. When the reactants extended to heterocyclic carboxylic acids, condensed heteroaromatic compounds could be formed (Scheme 83).106 Indole-, pyrrole-, benzofuran-, and furancarboxylic acids were all suitable

Scheme 82. Decarboxylative Cross-Coupling of N-Phenylanthranilic Acids with Alkynes

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Scheme 83. Decarboxylative Cross-Coupling of Heterocyclic Carboxylic Acids with Alkynes

Scheme 84. Palladium-Catalyzed Intermolecular [4 + 2] Annulation of 2-Phenylbenzoic Acids with Alkynes

to good yields can be obtained. Furthermore, 2-substituted quinolines can be produced in a one-pot process by applying 2nitrobenzoic acids and propiophenones as substrates, involving a selective hydrogenative cyclization after the optimized decarboxylative cross-coupling procedure. In 2013, the Satoh and Miura group reported a decarboxylative cyclization reaction to construct fluorene derivatives, applying 2,2-diarylacetic acids as substrates, which can readily be produced by arylation of phenylacetates (Scheme 88).110 [CpERhCl2]2 (CpE = 1,3-bis(ethoxycarbonyl)-2,4,5-trimethylcyclopentadienyl) was found to be the best catalyst, while Cu(OAc)2·H2O the suitable oxidant. The method presented a simple pathway from readily available compounds to fluorenes. However, just low to moderate yields were obtained, and limited functional groups were studied. In the same article, the authors also investigated the dehydrogenative cyclization of triarylmethanols to form fluorene derivatives, showing better yields and functional group tolerance. In the decarboxylative reaction, C−H cross-coupling and decarboxylation happened independently. An intermolecular

acids and nitroethanes, resulting in exclusively (E)-β-nitrostyrenes (Scheme 86).108 The reaction is probably a result of in situ dehydrogenation of nitroethanes to nitroethylenes, followed by decarboxylative Heck coupling. The method offers a rapid entry to (E)-β-nitrostyrenes, and both electron-rich, -deficient benzoic acids and heterocyclic carboxylic acids are suitable substrates. The authors also found that Pd(II) and Ag(I) salts are responsible for the decarboxylation of electron-rich and -deficient benzoic acids, respectively. Another example of combination of decarboxylation and dehydrogenation was presented by Su in 2012. Propiophenones were found to undergo decarboxylative cross-coupling reactions with aryl carboxylic acids, leading to the Heck products chalcones, which performed as an important class of biologically active compounds (Scheme 87).109 In addition, because acyclic arylvinyl ketones are not commercially available and the methods to prepare them are not step- and atom-efficient, the presented example offers a better choice for chalcone construction. The reaction enjoys good functional group tolerance, and moderate 8898


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protodecarboxylation happened (protodecarboxylation is easier with an ortho substitute) and provided the final product. In 2013, Guo and Duan reported a silver-catalyzed decarboxylative acylarylation of acrylamides with α-oxocarboxylic acids, producing substituted oxindoles (Scheme 90).112 The reaction was oxidized by the strong oxidant K2S2O8 in water or mixture of acetone and water (1:1 ratio) at relatively gentle conditions (50 °C). A very good functional group tolerance was shown, including both electron-donating and -withdrawing groups, even some sensitive substitutes, such as hydroxyl and iodo groups. In addition, both aromatic and aliphatic αoxocarboxlic acids were good reactants for the reaction. Generally, moderate to excellent isolated yields were observed. Intramolecular and intermolecular kinetic isotope effect (KIE) experiments (kH/kD = 1.0) and the fact that the reaction was suppressed by the radical scavenger TEMPO both indicated a radical process for the transformation. And also it is well-known that Ag(I)/K2S2O8 can easily generate radicals through decarboxylation. On the basis of these observations, the author suggested a radical mechanism as shown in Scheme 91. When changing the acrylamide substrates from 2,2-disubstituted olefins to 1,2-disubstituted olefins, six-membered rings could be formed, resulting in 3-acyl-4-arylquinolin-2(1H)-ones, which were found in many natural products and pharmaceutically active compounds as the structural motifs, under the similar reaction conditions (Scheme 92).113 The methods also enjoyed a good functional group tolerance and provided moderate to excellent yields of the desired products. The Duan group reported the same reaction independently.114 The Song group reported in 2014 an example of aerobic oxidative decarboxylation of arylacetic acids and α-hydroxyphenylacetic acids to produce aromatic aldehydes and ketones (Scheme 93).115 The reaction was catalyzed by Cu(OAc)2, and O2 was used as the terminal oxidant. Arylacetic acids bearing different kinds of substitutes all reacted smoothly, and moderate to excellent yields were obtained. In addition, heterocyclic substrates also performed well. As proposed, phenylacetic acid is probably first decarboxylated by Cu, forming a benzyl-cooper species, which is then oxidized to generate the aldehyde product. When ammonia in water was used under similar conditions, primary amides were generated as the products (Scheme 94).116 The reaction also enjoyed a broad substitute tolerance and good performance of yields. By studying some mechanism reactions, the authors suggested a proposed mechanism as shown in Scheme 95: phenylglyoxylic acid is first generated by oxidation,

Scheme 85. Mechanism Insight of Intermolecular [4 + 2] Annulation of 2-Phenylbenzoic Acids with Alkynes

example is shown in Scheme 89.111 Decarboxylation crosscoupling of heterocyclic compounds can be catalyzed by a Pd(OAc)2/Ag2O system. The carboxylic acid group is not used as a directing group for the reaction, while the reaction seems to undergo electrophilic palladation on indole substrate, followed by C−H functionalization with pyridine N-oxide, after which

Scheme 86. Synthesis of Nitrostyrenes through Decarboxylative Cross-Coupling of Benzoic Acids and Nitroethanes

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Scheme 87. Formation of Chalcones through Decarboxylative Cross-Coupling of Aryl Carboxylic Acids and Propiophenones

Scheme 88. Cyclization of 2,2-Diarylacetic Acids through Intramolecular Dehydrogenation and Decarboxylation

Scheme 89. Cross-Coupling of Heterocyclic Compounds via Dual C−H Activation and Decarboxylation

from the limited alkylation reagents, of which only two types were investigated. Wan and Hao recently reported a Ag-catalyzed decarboxylative cyclization method for the synthesis of gem-difluoromethylenated phenanthridines (Scheme 97).118 Under the relatively gentle reaction conditions, various difluoroaetates, including thiophene-derived and sterically hindered ones, were reacted with biarylisonitriles to afford the corresponding products in moderate to good yields. Nevertheless, the reactions were limited to aryl difluoroacetates. For example, potassium trifluoroacetate showed no reactivity to the reaction.

following copper-catalyzed decarboxylation. Further reaction with ammonia and water generates benzamide as the product. In 2015, the Wang group reported an example of Ir(III)improved aromatic C−H bond alkylation with diazomalonates via metal carbene migratory insertion (Scheme 96). Plenty of arenes bearing different types of carbamoyl directing groups can be applied, including kinds of heterocyclic compounds.117 When diazomalonate with one tert-butyl group and one methyl group is tested, the C−H coupling is followed by decarboxylation, resulting in products substituted by a CH2CO2Me group ortho to the directing group, while in the case of applying the diazomalonate with two tert-butyl groups, the substitute is −CH2CO2H. The reaction enjoys a broad scope of substitutes, most of which can be further functionalized by various methods. With good performance also shown in yields of products, generally, good to excellent yields can be obtained. The selectivity of the reaction can easily be controlled by the amount of diazomalonates used, and both monoalkylation and dialkylation can be achieved. However, the reaction suffers

6. CONCLUSION AND PERSPECTIVE Since Myers published the pioneering work on catalytic decarboxylative Heck-type reaction of aryl carboxylic acids in 2002, over the past 14 years, hundreds of new decarboxylative cross-coupling reactions have been developed partially because of the ready availability of starting materials and green processes 8900


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Scheme 90. Synthesis of Oxindoles via Decarboxylative Acylarylation of Acrylamides with α-Oxocarboxylic Acids

reactions represent one of the most important topics in the context of decarboxylative cross-coupling reactions. To date, the major interest in the decarboxylative C−H bond functionalization area has focused on the Csp2−H bond functionalization to construct Csp2−Csp2 bonds. In these reactions, a broad range of aryl carboxylic acids participate in decarboxylative C−H bond functionalization reactions of various (hetero)arenes. Silvercatalyzed decarboxylative alkylation of electron-deficient aromatic heterocycles via oxidative decarboxylation of alkyl carboxylic acids, that is, Minisci reaction, represents a classic method for construction of Csp2−Csp3 bonds. Recently, the Minisci-type reaction of aryl carboxylic acids has been achieved to provide a synthetically useful approach to C−H bond arylation of pyridines and electron-deficient benzenes. Decarboxylative ortho-C−H functionalization via carboxyl-directed C−H bond functionalization and subsequent decarboxylation has been

Scheme 91. Proposed Mechanisms of Decarboxylative Acylarylation of Acrylamides with α-Oxocarboxylic Acids

with unharmful CO2 as the byproduct. Driven by the development of diverse C−H bond functionalization reactions, the catalytic decarboxylative C−H bond functionalization

Scheme 92. Synthesis of 3-Acyl-4-arylquinolin-2(1H)-ones via Decarboxylative Acylarylation of Acrylamides with αOxocarboxylic Acids

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Scheme 93. Synthesis of Aromatic Aldehydes via Decarboxylative Oxidation of Arylacetic Acids

Scheme 94. Synthesis of Primary Amides via Decarboxylative Ammoxidation of Arylacetic Acids

Scheme 95. Proposed Mechanism of Synthesis of Primary Amides via Decarboxylative Ammoxidation of Arylacetic Acids

Scheme 96. Decarboxylative Aromatic C−H Bond Functionalization via Metal Carbene Migratory Insertion

traditional reactions with organometallic reagents, as exemplified by reactions of electron-deficient benzoic acids. In spite of remarkable progress in this area, great space remains for improvement of the current methods for decarboxylative C− H bond functionalization reactions. Generally, the established decarboxylative C−H bond functionalization reactions occurred at high temperatures (≥120 °C), and aryl carboxylic acids participating in the decarboxylative cross-coupling reaction via redox-neutral decarboxylation must contain substituents on ortho-positions. Although silver-catalyzed decarboxylative C−H

established to enable facile syntheses of multisubstituted benzenes, many of which are traditionally synthesized by multistep synthetic routes. Both Csp−H and Csp 3 −H functionalization reactions using carboxylic acids as coupling partners have also appeared. These achievements in the development of decarboxylative C−H bond functionalization reactions clearly showcase the potential of carboxylic acids to serve as versatile reagents in place of organometallic reagents. In some cases, the products obtained from decarboxylative C−H bond functionalization reactions are difficult to generate from 8902


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Scheme 97. Synthesis of Gem-Difluoromethylenated Phenanthridines

benzoic acids. Importantly, active metal catalysts for decarboxylation, in combination with active catalysts for the C−H bond activation may allow the decarboxylative C−H bond functionalization reactions to occur under mild conditions and therefore make it possible to achieve the regioselective or enantioselective decarboxylative C−H bond functionalization reaction. As catalytic C−H bond functionalization reactions advance, diverse decarboxylative C−H bond functionalization reactions can be imaged. For example, it has been established that a radical intermediate formed via cleavage of the C−H bond is rapidly bonded to the metal center of the catalyst in a Cu-catalyzed enantioselective C−H bond cyanation reaction,121 indicating that alkyl radical intermediates generated from oxidative decarboxylation of alkyl carboxylic acid may be trapped by metal catalysts to access selective C−H bond alkylation. Organic water two-phase reaction system can be designed to realize the decarboxylative C−H bond functionalization of electron-rich arenes via oxidative decarboxylation, in which oxidative decarboxylation occurs in the water phase to prevent oxidation of electron-rich arenes in the organic phase. To date, the decarboxylative C−H bond functionalization reactions have been based on only Pd- or Ag- or Cu-promoted redox-neutral decarboxylation mode and Ag-promoted oxidative decarboxylation mode. To develop the diversity of decarboxylative C−H bond functionalization reactions, new decarboxylation modes are required. Since directing group-assisted C−H bond activation mode is well-established, it is possible to achieve a directing group-assisted metal-promoted decarboxylation mode, especially for alkyl carboxylic acids. The great potential of broadly available carboxylic acids to serve as versatile reagents is a driven force to push forward the development of decarboxylative C−H bond functionalization reactions. Eventually, the near future will witness that decarboxylative C−H bond functionalization reactions evolve into powerful tools for construction of C−C bonds.

bond functionalization reaction via oxidative decarboxylation has no requirement for ortho-substituted aryl carboxylic acids, such a reaction gives low selectivity due to formation of the radical intermediate. Similarly, Minisci reaction of alkyl carboxylic acids also lacks regioselectivity in formation of Csp2−Csp3 bonds and is limited to electron-deficient pyridine derivatives due to oxidative decarboxylation. In the decarboxylative Csp−H bond functionalization reaction, only amino acids (majorly cyclic amino acids) and propiolic acids could be used as coupling partners. As for the decarboxylative Csp3−H bond functionalization reaction, only arylvinyl carboxylic acids, propiolic acids, and α-amino acids have been investigated as the substrates for functionalizations of activated Csp3−H bond adjacent to nitrogen or oxygen atom, the benzylic Csp3−H bond, and the Csp3−H bond bearing an auxiliary coordinating group. Obviously, the development of decarboxylative C−H bond functionalization reaction will benefit from the advance in the field of C−H bond functionalization. On the other hand, highly reactive catalyst systems for decarboxylation of carboxylic acids are required to overcome the current limitations of decarboxylative C−H bond functionalization reaction and even other decarboxylative cross-coupling reactions. The redox-neutral decarboxylation processes of aryl carboxylic acids promoted by Pd(II),9,10 Ag(I),12,13 or Cu(I)11 all occur at high temperatures, which might be a barrier toward achieving many mild decarboxylative cross-coupling reactions. Recently, in their theoretical and experimental study of the mechanism of Pd/Cu catalyzed decarboxylative cross-coupling reaction with aryl bromides, Gooßen and co-workers disclosed that the transmetalation step has a comparably high energy barrier as the decarboxylation step and therefore demonstrated that introducing a bidentate ligand into a reaction system to facilitate transmetalation from Cu species to Pd species led to a decrease in reaction temperature.119 Su and co-workers reported that an electron-donating carbene ligand could enhance the reactivity of Pd catalyst toward decarboxylation of electron-deficient benzoic acids.120 These previous studies indicate that ligands are promising to enhance catalytic activity of metal catalysts for the decarboxylation step and subsequent transmetalation step. Active metal catalysts supported by ligands may enable expansion of the substrate scope of bezoic acids beyond ortho-substituted

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Peng Hu: 0000-0001-7864-3514 8903


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from the NSFC (no. 21302220), the State Key Laboratory of Structural Chemistry (no. 20150009), and Chongqing Natural Science Foundation (no. cstc2016jcyjA0008). P.H. thanks the financial support from Sun Yat-sen University.

Weiping Su: 0000-0001-5695-6333 Author Contributions ∥

Y.W. and P.H. contributed equally to this work.

Notes

The authors declare no competing financial interest.

REFERENCES

Biographies

(1) Ackermann, L.; Vicente, R.; Kapdi, A. R. Transition-MetalCatalyzed Direct Arylation of (Hetero)Arenes by C−H Bond Cleavage. Angew. Chem., Int. Ed. 2009, 48, 9792−9826. (2) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions. Chem. Rev. 2010, 110, 1147−1169. (3) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Bond Formations between Two Nucleophiles: Transition Metal Catalyzed Oxidative Cross-Coupling Reactions. Chem. Rev. 2011, 111, 1780−1824. (4) Yeung, C. S.; Dong, V. M. Catalytic Dehydrogenative CrossCoupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds. Chem. Rev. 2011, 111, 1215−1292. (5) Li, C.-J. Cross-Dehydrogenative Coupling (CDC): Exploring C−C Bond Formations beyond Functional Group Transformations. Acc. Chem. Res. 2009, 42, 335−344. (6) Hegedus, L. S.; Wade, L. Preparation of Carboxylic Acids, Acid Halides and Anhydrides. In Compendium of Organic Synthetic Methods; John Wiley & Sons: Hoboken, NJ, 1977; Vol. 3, pp 8−32. (7) Gooβen, L. J.; Rodríguez, N.; Gooβen, K. Carboxylic Acids as Substrates in Homogeneous Catalysis. Angew. Chem., Int. Ed. 2008, 47, 3100−3120. (8) Rodríguez, N.; Goossen, L. J. Decarboxylative Coupling Reactions: A Modern Strategy for C−C-Bond Formation. Chem. Soc. Rev. 2011, 40, 5030−5048. (9) Myers, A. G.; Tanaka, D.; Mannion, M. R. Development of a Decarboxylative Palladation Reaction and Its Use in a Heck-type Olefination of Arene Carboxylates. J. Am. Chem. Soc. 2002, 124, 11250− 11251. (10) Tanaka, D.; Romeril, S. P.; Myers, A. G. On the Mechanism of the Palladium(II)-Catalyzed Decarboxylative Olefination of Arene Carboxylic Acids. Crystallographic Characterization of Non-Phosphine Palladium(II) Intermediates and Observation of Their Stepwise Transformation in Heck-like Processes. J. Am. Chem. Soc. 2005, 127, 10323−10333. (11) Gooßen, L. J.; Deng, G.; Levy, L. M. Synthesis of Biaryls via Catalytic Decarboxylative Coupling. Science 2006, 313, 662−664. (12) Gooßen, L. J.; Linder, C.; Rodriguez, N.; Lange, P. P.; Fromm, A. Silver-Catalysed Protodecarboxylation of Carboxylic Acids. Chem. Commun. 2009, 7173−7175. (13) Cornella, J.; Sanchez, C.; Banawa, D.; Larrosa, I. Silver-Catalysed Protodecarboxylation of ortho-Substituted Benzoic Acids. Chem. Commun. 2009, 7176−7178. (14) Cornella, J.; Rosillo-Lopez, M.; Larrosa, I. A Novel Mode of Reactivity for Gold(I): The Decarboxylative Activation of (Hetero)Aromatic Carboxylic Acids. Adv. Synth. Catal. 2011, 353, 1359−1366. (15) Dupuy, S.; Lazreg, F.; Slawin, A. M. Z.; Cazin, C. S. J.; Nolan, S. P. Decarboxylation of Aromatic Carboxylic Acids by Gold(I)-NHeterocyclic Carbene (NHC) Complexes. Chem. Commun. 2011, 47, 5455−5457. (16) Sun, Z.-M.; Zhao, P. Rhodium-Mediated Decarboxylative Conjugate Addition of Fluorinated Benzoic Acids: Stoichiometric and Catalytic Transformations. Angew. Chem., Int. Ed. 2009, 48, 6726−6730. (17) Satoh, T.; Miura, M. Transition-Metal-Catalyzed Regioselective Arylation and Vinylation ofCarboxylic Acids. Synthesis 2010, 2010, 3395−3409. (18) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Transition Metal-Catalyzed Decarboxylative Allylation and Benzylation Reactions. Chem. Rev. 2011, 111, 1846−1913. (19) Shang, R.; Liu, L. Transition Metal-Catalyzed Decarboxylative Cross-CouplingReactions. Sci. China: Chem. 2011, 54, 1670−1687. (20) Cornella, J.; Larrosa, I. Decarboxylative Carbon-Carbon BondForming Transformations of (Hetero)aromatic Carboxylic Acids. Synthesis 2012, 44, 653−676.

Ye Wei was born in 1982 in China. He earned his B.Sc. degree in 2005 from Huaqiao University and his Ph.D. degree in 2010 from Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, under the guidance of Prof. Weiping Su. After a two-year postdoctoral appointment with Prof. Naohiko Yoshikai at Nanyang Technological University, he went back to China to join the College of Pharmacy at Third Military Medical University as an Associate Professor. He was promoted to Professor in 2015. Wei’s research interests are primarily focused on atom- and step-economic synthetic methods, with an emphasis on the transition-metal-mediated novel organic transformations to construct heterocyclic scaffolds. Peng Hu was born and raised in China. He completed his undergraduate study at Hubei University in 2006. After one year’s study at Graduate University of Chinese Academy of Sciences, he joined the group of Prof. Weiping Su at Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, where he worked on transition metal catalyzed cross-coupling reactions and received his Ph.D. degree in 2011. Being a research associate in the Su group for one year, he moved to Weizmann Institute of Science as a postdoctoral fellow, working with Prof. David Milstein. From March 2014 to February 2016, he joined Prof. Thorsten Bach’s research group as a Humboldt postdoctoral fellow in Technische Universität München and studied palladium-catalyzed cross-coupling reactions via C−H bond functionalization. Since March 2016, he is a visiting scientist of the Milstein group, working on hydrogen storage and efficient hydrogenation/dehydrogenation reactions. He was offered an independent position by Sun Yat-sen University, and his interests include environmentally benign catalytic reactions and sustainable energy systems. Min Zhang was born in 1984 in Henan, China. She received her B.Sc. from Xinyang Normal University in 2007 and obtained her Ph.D. at Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences with Prof. Weiping Su in 2012. After a doctoral study, she joined Prof. Weiping Su’s group and is currently an associate professor. Her research interests focus on the development of new synthetic methodologies based on C−H bond activation. Weiping Su graduated from Anhui Education Institute in 1987 and earned his Ph.D. degree at Fujian Institute of Research on the Structure of Matter (FJIRSM) in 1999 under the supervision of Prof. Maochun Hong. After one year of working as an assistant professor at FJIRSM, he moved to the United States to do postdoctoral studies with Prof. Richard H. Holm at Harvard University (2000−2001), Prof. Jin Li at Rutgers University (2001−2002), and Prof. John G. Verkade at Iowa State University (2002−2005). Then, he joined the faculty at FJIRSM in 2006. His research interest includes synthetic methodology, discoveries of metal complex-based homogeneous catalysts and nanoparticle-based recyclable catalysts, and the structure−property relationships of catalysts.

ACKNOWLEDGMENTS W.S. acknowledges the financial support from the NSFC (Grants 21431008, 21332001, and u1505242) and the CAS/SAFEA International Partnership Program for Creative Research Teams are greatly appreciated. Y.W. acknowledges the financial support 8904


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