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Synthesis of carboxylic acids, esters and amides

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Hydrocarboxylations

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A user-friendly and operationally simple Ni-catalyzed carboxylation of unactivated primary alkyl bromides and sulfonates with CO₂ at atmospheric pressure is characterized by its mild conditions and remarkably wide scope without the need for air- or moisture-sensitive reagents.
Y. Liu, J. Cornella, R. Martin, J. Am. Chem. Soc., 2014, 136, 11212-11215.

A catalytic carboxylation of unactivated primary, secondary, and tertiary alkyl chlorides with CO₂ at atmospheric pressure features exquisite chemoselectivity, mild conditions and ease of execution.
M. Börjesson, T. Moragas, R. Martin, J. Am. Chem. Soc., 2016, 138, 7504-7507.

A mild Ni-catalyzed reductive coupling enables the synthesis of alkyl esters from readily available alkyl halides and chloroformates. Unactivated primary and secondary alkyl iodides as well as glycosyl, benzyl, and aminomethyl halides provide products in good yields with high functional group tolerance.
M. Zheng, W. Xue, T. Xue, H. Gong, Org. Lett., 2016, 18, 6152-6155.

The merger of photoredox and nickel catalysis enables a direct carboxylation of unactivated secondary alkyl bromides. Site-selectivity is dictated by a kinetically controlled insertion of CO₂ at the initial C(sp³)-Br site by the rapid formation of Ni(I)-alkyl species, thus avoiding undesired β-hydride elimination and chain-walking processes.
J. Davies, J. R. Lyonnet, B. Carvalho, B. Sahoo, C. S. Day, F. Juliá-Hernández, Y. Duan, Á. Velasco-Rubio, M. Obst, P.-O. Norrby, K. H. Hopmann, R. Martin, J. Am. Chem. Soc., 2024, 146, 1753-1759.

A palladium-catalyzed alkoxycarbonylation of secondary alkyl bromides, that proceeds at low pressure (2 atm CO) under mild conditions, deliver esters from across a diverse range of substrates and represent the first catalytic carbonylations of alkyl bromides with carbon monoxide.
B. T. Sargent, E. J. Alexanian, J. Am. Chem. Soc., 2016, 138, 7520-7523.

The presence of LICl enabled an efficient process for the carboxylation of functionalized organozinc reagents with CO₂ in DMF as solvent.
K. Kobayashi, Y. Kondo, Org. Lett., 2009, 11, 2035-2037.

A variety of functionalized organozinc reagents undergo smooth addition reactions at ambient temperature to carbonyl compounds and carbon dioxide in the presence of stoichiometric amounts of MgCl₂. Several reactions were performed on a large scale.
S. Bernhardt, A. Metzger, P. Knochel, Synthesis, 2010, 3802-3810.

The reactivity of sodium methyl carbonate with Grignard and organolithium reagents enables selective syntheses of carboxylic acids, symmetrical ketones, and unsymmetrical ketones.
T. E. Hurst, J. A. Deichert, L. Kapeniak, R. Lee, J. Harris, P. G. Jessop, V. Snieckus, Org. Lett., 2019, 21, 3882-3885.

An efficient cross-coupling reaction of chloroformates with organocopper reagents, derived from Grignard reagents, cuprous bromide and lithium bromide, provides esters in good yields.
D. Bottalico, V. Fiandanese, G. Marchese, A. Punzi, Synlett, 2007, 974-976.

A highly efficient palladium-catalyzed carbonylation of aryl, alkenyl, and allyl halides with phenyl formate affords one-carbon-elongated carboxylic acid phenyl esters in excellent yields. The reaction proceeds smoothly under mild conditions, avoids the use of carbon monoxide, and tolerates a wide range of functional groups including aldehyde, ether, ketone, ester, and cyano groups.
T. Ueda, H. Konishi, K. Manabe, Org. Lett., 2012, 14, 3100-3103.

Chelation-Based Homologation by Reaction of Organometallic Reagents with O-Alkyl S-Pyridin-2-yl Thiocarbonates: Synthesis of Esters from Grignard Reagents
S. Usami, T. Suzuki, K. Mano, K. Tanaka III, Y. Hashimoto, N. Morita, O. Tamura, Synlett, 2019, 30, 1561-1564.

A convenient Ni-catalyzed multicomponent coupling reaction of alkyl halides, isocyanides, and H₂O provides alkyl amides. Bench-stable NiCl₂(dppp) is able to initiate this transformation under mild reaction conditions.
Q. Li, H. Jin, Y. Liu, B. Zhou Synthesis, 2020, 52, 1841-1846.

A deoxygenative amidation reaction of alcohols with carbamoyl chlorides provides amides in very good yields through nickel-photoredox dual catalysis. The reaction is scalable, and the synthetic utility of the reaction was demonstrated by the homologation of alcohols to deliver several important γ-amino alcohols.
L. Wang, Z. Li, Y. Zhou, J. Zhu, Org. Lett., 2024, 26, 2297-2302.

Hypervalent iodine reagents promote a facile and efficient transformation of primary amides to secondary amides. The hypervalent iodine reagent mediates a Hofmann-type rearrangement to an isocyanate intermediate, which is subsequently trapped by an in situ generated carboxylic acid from the hypervalent iodine reagent to provide the corresponding secondary amides.
X. Wang, P. Yang, B. Hu, Q. Zhang, D. Li, J. Org. Chem., 2021, 86, 2820-2826.

A general palladium-catalyzed carbonylative synthesis of acyl fluorides from aryl, heteroaryl, alkyl, and functionalized organic halides proceeds via a synergistic combination of visible light photoexcitation of Pd(0) to induce oxidative addition with a ligand-favored reductive elimination. Subsequent nucleophilic reactions provide highly functionalized carbonyl-containing products.
Y. Liu, C. Zhou, M. Jiang, B. A. Arndtsen, J. Am. Chem. Soc., 2022, 144, 9413-9420.

A copper-catalyzed carbonylative coupling strategy enables the synthesis of acyl fluorides under photoirradiation. Alkyl iodides were transformed in high yields into acyl fluorides by using a commercially available copper precatalyst (CuBr·SMe₂) and a readily available fluoride salt (KF) at ambient temperature and mild CO pressure (6 atm) under blue light irradiation.
P. Tung, N. P. Mankad, Org. Lett., 2024, 26, 3299-3303.

A one-carbon homologation of an alcohol to the extended carboxylic acid, ester, or amide involves a Mitsunobu reaction with an alkoxymalononitrile, followed by unmasking in the presence of a suitable nucleophile. The homologation and unmasking can even be performed in a one-pot process in high yield.
N. Kagawa, A. E. Nibbs, V. H. Rawal, Org. Lett., 2016, 18, 2363-2366.

The reaction of Grignard reagents with alkyl imidazolecarboxylates, which were prepared from alcohols with carbonyl diimidazole, gave the corresponding esters in good to excellent yields.
T. Werner, A. G. M. Barrett, J. Org. Chem., 2006, 71, 4302-4304.

A Ni-catalyzed carboxylation of benzyl halides with CO₂ proceeds under mild conditions at room temperature under atmospheric pressure. The method does not require well-defined and sensitive organometallic reagents and thus is user-friendly and operationally simple.
T. León, A. Correa, R. Martin, J. Am. Chem. Soc., 2013, 135, 1221-1224.

A highly efficient electrochemical desulfonylative carboxylation protocol takes advantage of CO₂ as the abundant C1 building block for the facile preparation of multifunctionalized carboxylic acids, including the nonsteroidal anti-inflammatory drug ibuprofen, under mild reaction conditions.
J.-S. Zhong, Z.-X. Yang, C.-L. Ding, Y.-F. Huang, Y. Zhao, H. Yan, K.-Y. Ye, J. Org. Chem., 2021, 86, 16162-16170.

Visible-light photoredox catalysis realizes an external-reductant-free cross-electrophile coupling of tetraalkyl ammonium salts with carbonyl compounds and CO₂. The byproduct trimethylamine serves as the electron donor. Moreover, this protocol exhibits mild reaction conditions, broad substrate scope, good functional group tolerance, low catalyst loading, and facile scalability.
L.-L. Liao, G.-M. Cao, J.-H. Ye, G.-Q. Sun, W.-J. Zhou, Y.-Y. Gui, S.-S. Yan, G. Shen, D.-G. Yu, J. Am. Chem. Soc., 2018, 140, 17338-17342.

A current-driven nickel-catalyzed reductive carboxylation reaction of racemic propargylic carbonates with CO₂ provides enantioenriched propargylic carboxylic acids, while circumventing the handling of moisture-sensitive organometallic reagents.
Q. Hu, B. Wei, M. Wang, M. Liu, X.-W. Chen, C.-K. Ran, G. Wang, Z. Chen, H. Li, J. Song, D.-G. Yu, C. Guo, J. Am. Chem. Soc., 2024, 146, 14864-14874.

A light-mediated, Cu-catalyzed process provides aliphatic, symmetric acid anhydrides directly by carbonylation of alkyl (pseudo)halides in a single step without any precious metal additives. The transformation requires only simple Cu salts and abundant bases to generate an efficient heterogeneous Cu⁰ photocatalyst in situ.
P. Tung, N. P. Mankad, J. Am. Chem. Soc., 2023, 145, 9423-9427.

A Ni-catalyzed formal aminocarbonylation of primary and secondary unactivated aliphatic iodides with isocyanides provides alkyl amides via a selective monomigratory insertion of isocyanides with alkyl iodides, subsequent β-hydride elimination, and hydrolysis. The reaction features wide functional group tolerance under mild conditions.
W. Huang, Y. Wang, Y. Wang, M. Shrestha, J. Qu, Y. Chen, Org. Lett., 2020, 22, 3245-3250.

A silver-catalyzed decarboxylative cross-coupling between carboxylic acids and isocyanides provides linear amides via a free-radical mechanism. This approach accommodates a diverse array of radical precursors, including aryl, heteroaryl, alkynyl, alkenyl, and alkyl carboxylic acids. Decarboxylative late-stage functionalization of several elaborate pharmaceuticals demonstrated potential applications.
Q. Yan, Q.-J. Yuan, A. Shatskiy, G. R. Alvey, E. V. Stepanova, J.-Q. Liu, M. D. Kärkäs, X.-S. Wang, Org. Lett., 2024, 26, 3380-3385.

The reaction of readily accessible and bench-stable substituted S-phenyl thiocarbamates and Grignard reactants provides secondary amides. Oxidative workup allows recycling of the thiolate leaving group. This amide synthesis is especially suitable for the preparation of challenging amides.
P. Mampuys, E. Ruijter, R. V. A. Orru, B. U. W. Maes, Org. Lett., 2018, 20, 4235-4239.

Pd-catalyzed carbonylation of α-diazocarbonyl compounds or N-tosylhydrazone salts under atmospheric pressure of CO enables an efficient and mild approach toward ketene intermediates. These ketenes can react in situ with various nucleophiles to yield carboxylic acid derivates or in Staudinger cycloadditions to give β-lactam derivatives in good yields with excellent trans diastereoselectivity.
Z. Zhang, Y. Liu, L. Ling, Y. Li, Y. Dong, M. Gong, X. Zhao, Y. Zhang, J. Wang, J. Am. Chem. Soc., 2011, 133, 4330-4341.

A Pd-catalyzed hydrothiocarbonylation of unactivated terminal alkenes provides aliphatic thioesters with exclusive linear selectivity under mild reaction conditions in very good yields, broad substrate scope, and broad functional group tolerance.
W. Yu, J. Han, D. Fang, M. Wang, J. Liao, Org. Lett., 2021, 23, 2482-2487.

A nickel-catalyzed thiocarbonylation of arylboronic acid with sulfonyl chlorides in the presence of Mo(CO)₆ as CO source and reductant provides a broad range of thioesters in good yields with good functional group tolerance.
X. Qi, Z.-P. Bao, X.-T. Yao, X.-F. Wu, Org. Lett., 2020, 22, 6671-6676.

The combination of thiols as nucleophiles and a bidentate ligand enable a palladium-catalyzed thiocarbonylation of styrene derivatives with high regioselectivity toward the more valuable branched isomer. The ambient reaction conditions (temperature, catalyst loading) and the use of a CO surrogate render this transformation a useful method for the synthesis of thioesters.
V. Hirschbeck, P. H. Gehrtz, I. Fleischer, J. Am. Chem. Soc., 2016, 138, 16794-16799.

An efficient Ni-catalyzed reductive carboxylation of brached and linear allylic alcohols with CO₂ provides linear β,γ-unsaturated carboxylic acids as the sole regioisomer with generally high E/Z stereoselectivity. In addition, the carboxylic acids can be generated from propargylic alcohols via a hydrogenation step made possible by a Ni hydride intermediate produced by a hydrogen atom transfer from water.
Y.-G. Chen, B. Shuai, C. Ma, X.-J. Zhang, P. Fang, T.-S. Mei, Org. Lett., 2017, 19, 2969-2972.

In the presence of a Cu(I)/NHC catalyst, highly regioselective reactions of allylboronic pinacol esters with CO₂ (1 atm) give exclusively the more substituted β,γ-unsaturated carboxylic acids in most cases. Various substituted carboxylic acids can be prepared via this method, including compounds featuring all-carbon quaternary centers.
H. A. Duong, P. B. Huleatt, Q.-W. Tan, E. L. Shuying, Org. Lett., 2013, 15, 4034-4037.

A Ni-catalyzed regiodivergent reductive carboxylation of allyl esters with CO₂ is mild, user-friendly, and operationally simple. The reaction is characterized by an exquisite selectivity profile that is dictated by the ligand backbone.
T. Moragas, J. Cornella, R. Martin, J. Am. Chem. Soc., 2014, 136, 17702-17705.

A direct, palladium-catalyzed, carbonylative transformation of allylic alcohols in the presence of formic acid as the CO source provides β,γ-unsaturated carboxylic acids with excellent linear and (E)-selectivity under mild conditions.
F.-P. Wu, J.-B. Peng, L.-Y. Fu, X. Qi, X.-F. Wu, Org. Lett., 2017, 19, 5474-5477.

Cu catalysis enables an efficient and environmentally benign asymmetric dicarboxylation of 1,3-dienes with CO₂ to provide chiral dicarboxylic acids with high regio-, chemo-, and enantioselectivities. The reaction relies on boracarboxylation of 1,3-dienes to give carboxylated allyl boronic ester intermediates and subsequent carboxylation of C-B bonds to give the desired dicarboxylates.
Y.-Y. Gui, X.-W. Chen, X.-Y. Mo, J.-P. Yue, R. Yuan, Y. Liu, L.-L. Liao, J.-H. Ye, D.-G. Yu, J. Am. Chem. Soc., 2024, 146, 2919-2927.

Addition of an allyl copper species to an isocyanate provides access to α-vinyl β-boryl amides in high yields and enantioselectivities. The diversification of these products affords highly useful scaffolds.
S. Byun, A. O. Farah, H. R. Wise, A. Katchmar, P. H.-Y. Cheong, K. A. Scheidt, J. Am. Chem. Soc., 2022, 144, 22850-22857.

A visible-light-driven reductive carboarylation of styrenes with CO₂ and a broad range of aryl iodides and bromides has been achieved in a regioselective manner.
H. Wang, Y. Gao, C. Zhou, G. Li, J. Am. Chem. Soc., 2020, 142, 8122-8129.

In an enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent, the umpoled MAC synthon serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles to provide enantioenriched vinylated α-aryl carbonyl derivatives.
J. C. Hethcox, S. E. Shockley, B. M. Stoltz, Org. Lett., 2017, 19, 1527-1529.

The palladium-catalyzed cross-coupling of allylic and benzylic halides with N,N-dimethylcarbamoyl(trimethyl)silane affords tertiary amides in good to excellent yields.
R. F. Cunico, R. K. Pandey, J. Org. Chem., 2005, 70, 9048-9050.

Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smooth lithium-halogen exchange, the preparation of the corresponding dihalo compounds proved to be highly dependent on the base used to realize the deprotonation, with lithium 2,2,6,6-tetramethylpiperidine emerging as optimal.
V. Pace, L. Castoldi, A. D. Mamuye, W. Holzer, Synthesis, 2014, 46, 2897-2909.

Thiourea-based ligands were evaluated for the palladium-catalyzed bis(methoxycarbonylation) of terminal olefins. The usefulness of these ligands for this reaction is demonstrated by their stability to oxidizing agents, and their superiority in preventing palladium precipitation and double-bond isomerization.
M. Dai, C. Wang, G. Dong, J. Xiang, T. Luo, B. Liang, J. Chen, Z. Yang, Eur. J. Org. Chem., 2003, 4346-4348.

Visible-light photoredox-catalyzed fragmentation of methyl N-phthalimidoyl oxalate allows direct construction of a 1,4-dicarbonyl structural motif by a regioselective conjugate addition of the methoxycarbonyl radical to reactive Michael acceptors.
Y. Slutskyy, L. E. Overman, Org. Lett., 2016, 18, 2564-2567.

A mild, Co₂(CO)₈-catalyzed carbonylative opening of terminal epoxides under 1 atm of carbon monoxide at room temperature in methanol provides β-hydroxy esters in good yields. This transformation tolerates various functional groups.
S. E. Denmark, M. Ahmad, J. Org. Chem., 2007, 72, 9630-9634.

The reaction of chiral 1-aminoalkylepoxides with CO₂, generated from acidic treatment of an aqueous solution of NaHCO₃ at room temperature, efficiently afforded enantiopure cyclic carbonates with total selectivity. Carbonates were readily transformed into the corresponding diols by reaction with LiAlH₄ or by basic hydrolysis.
J. M. Concellón, V. del Solar, S. Carcía-Granda, M. R. Díaz, J. Org. Chem., 2007, 72, 7567-7568.

α-Halonitriles react with alkyllithium, organomagnesium, and lithium dimethylcuprate reagents generating reactive, metalated nitriles. The rapid halogen-metal exchange with alkyllithium and Grignard reagents allows Barbier-type reactions with various electrophiles.
F. F. Fleming, Z. Zhang, W. Liu, P. Knochel, J. Org. Chem., 2005, 70, 2200-2005.

The Brønsted acid catalyzed formal insertion of an isocyanide into a C-O bond of various acyclic and cyclic acetals can be applied to form α-alkoxy imidates. Functional groups, such as nitro, cyano, halogen, ester, and alkoxy groups, are tolerant to the reaction conditions employed. The course of the reaction is highly dependent on the structure of the isocyanide.
M. Tobisu, A. Kitajima, S. Yoshioka, I. Hyodo, M. Oshita, N. Chatani, J. Am. Chem. Soc., 2007, 129, 11431-11437.

Regioselective copper-catalyzed boracarboxylation of vinyl arenes with bis(pinacolato)diboron and carbon dioxide provides boron-functionalized α-aryl carboxylic acids in good yields. The synthetic utility of the transformation was shown through subsequent derivatization of the carbon-boron bond yielding formal hydroxy- and fluorocarboxylation products as well as anionic difluoroboralactones.
T. W. Butcher, E. J. McClain, T. G. Hamilton, T. M. Perrone, K. M. Kroner, G. C. Donohoe, N. G Akhmedov, J. L. Petersen, B. V. Popp, Org. Lett., 2016, 18, 6428-6431.

The cross-coupling reaction of α-oxo acid chlorides with carbamoylsilanes provides vicinal tricarbonyl amides in good yields under mild conditions. The reaction of carbamoylsilanes with oxalyl chloride is accompanied by decarbonylation to give vicinal tricarbonyl amides.
Y. Han, Y. Li, S. Han, P. Zhang, J. Chen, Synthesis, 2019, 51, 2977-2983.

A transition-metal-free direct carboxylation of the ipso-C(sp²)-H bond of diazo compounds proceeds at ambient temperature under atmospheric pressure of carbon dioxide in the presence of a weak base. A series of unsymmetrical 1,3-diester/keto/amide diazo compounds are obtained with good yields and good functional group compatibility.
Q. Liu, M. Li, R. Xiong, F. Mo, Org. Lett., 2017, 19, 6756-6759.

A palladium-catalyzed direct cyanoesterification of cyclopropenes enables a highly atom economic and diastereoselective synthesis of synthetically useful cyclopropanecarbonitriles. The reaction offers mild conditions, good functional group compatibility, and simple operation.
C. Li, R. Yu, S.-Z. Cai, X. Fang, Org. Lett., 2023, 25, 5128-5133.