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Synthesis of substituted carboxylic acids, esters and amides


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Arndt-Eistert Synthesis

Kowalski Ester Homologation

Recent Literature

Indium(III) halide catalyzed the coupling of alkyl chlorides with silyl enolates derived from esters, ketones, and aldehydes to give various α-alkylated carbonyl compounds. A one-pot, three-component reactions of aldehyde enolates, alkyl chlorides, and allylsilanes or alkynylsilanes is described.
Y. Nishimoto, M. Yasuda, A. Baba, Org. Lett., 2007, 9, 4931-4934.

Carboindation of various alkenes such as ethylene, 1-alkenes, and cyclic alkenes with indium tribromide enables a regioselective reaction with ketene silyl acetals. The alkylindium product from the carboindation of cyclohexene revealed an anti addition mechanism.
Y. Nishimoto, H. Ueda, Y. Inamoto, M. Yasuda, A. Baba, Org. Lett., 2010, 12, 3390-3393.

A mild, green, and convenient one-pot carbon-chain extension of carboxylic acids with the assistance of microwaves and lithium chloride avoids the use of corrosive reagents, is tremendously faster than previously methods, and was free of configurational isomerization. Notably, LiCl played a dual role in the Krapcho decarboxylation and subsequent ester hydrolysis under neutral conditions.
C. Wang, J. Su, Y. Li, S. Gao, X. Huo, B. Yi, G. Zhao, Synlett, 2023, 34, 1033-1036.

A one-pot, tandem Wittig hydrogenation of aldehydes with stabilized ylides enables a formal C(sp3)-C(sp3) under mild conditions. The reaction is high yielding and broad in scope. Early insights suggest that the chemoselectivity observed in the reduction step is due to partial poisoning of the catalyst.
R. Devlin, D. J. Jones, G. P. McGlacken, Org. Lett., 2020, 22, 5223-5228.

A radical-mediated addition strategy of diazo compounds to diverse alkenes achieves a difunctionalization - either through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT) or formation of azidoalkylation products through an iron catalytic cycle. The methods proceed under mild reaction conditions and show high functional group tolerance.
Y.-L. Su, G.-X. Liu, J.-W. Liu, L. Tram, H. Qiu, M. P. Doyle, J. Am. Chem. Soc., 2020, 142, 13846-13855.

In a borrowing hydrogen methodology, cobalt complexes stabilized with pincer ligands catalyze especially challenging alkylations of unactivated esters and amides with alcohols as alkylating reagents.
N. Deibl, R. Kempe, J. Am. Chem. Soc., 2016, 138, 10786-10789.

An effective and robust iridium pincer complex achieves a selective α-alkylation of tertiary and secondary acetamides involving a borrowing hydrogen methodology. The method tolerates alcohols bearing various functional groups. This presents a convenient and environmentally benign protocol for α-alkylation of amides.
L. Guo, Y. Liu, W. Yao, Y. Leng, Z. Huang, Org. Lett., 2013, 15, 1144-1147.

A manganese-catalyzed C-alkylation of carboxylic acid derivatives with alcohols operates via hydrogen autotransfer and ideally produces water as the only side product. Importantly, aliphatic-, benzylic-, and heterocyclic-containing alcohols can be used as alkylating reagents, eliminating the need for mutagenic alkyl halides.
Y. K. Jang, T. Krückel, M. Rueping, O. El-Sepelgy, Org. Lett., 2018, 20, 7779-7783.

Trialkyl phosphates are inexpensive and stable at room temperature, under air, and are easy to handle. Mild, straightforward and powerful methods for nucleophilic alkylation of various N-, O-, C- and S-nucleophiles using readily available trialkyl phosphates proceed smoothly in excellent yields. Stereoselective transfer of secondary alkyl groups have also been achieved with inversion of configuration.
A. Banerjee, T. Hattori, H. Yamamoto, Synthesis, 2023, 55, 315-332.

Atom-transfer radical (ATR) reaction of alkenes with alkyl bromides under irradiation using a low-pressure Hg lamp give addition/reduction products in good yield. Hydrogen bromide, formed by H-abstraction of a bromine radical from alkenes, is likely to play a key role in the reductive ATR reaction.
S. Sumino, A. Fusano, I. Ryu, Org. Lett., 2013, 15, 2826-2829.

A sterically encumbered bis(oxazoline) ligand backbone enables a Ni-catalyzed enantioselective deaminative alkylation of amino acid and peptide derivatives with unactivated olefins. This protocol is distinguished by its broad scope and generality across a wide number of counterparts, even in the context of late-stage functionalization.
S.-Z. Sun, Y.-M. Cai, D.-L. Zhang, J.-B. Wang, H.-Q. Yao, X.-Y. Rui, R. Martin, M. Shang, J. Am. Chem. Soc., 2022, 144, 1130-1137.

The combination of triphenylphosphine and copper(I) halide catalyzes an atom transfer radical addition reaction of activated organic halides to terminal alkenes under irradiation with 365 nm light using a light-emitting diode.
O. V. Fedorov, S. I. Scherbinina, V. V. Levin, A. D. Dilman, J. Org. Chem., 2019, 84, 11068-11079.

A method for hydrofluoroalkylation of alkenes with trifluoroacetic esters under visible light irradiation affords difluorinated products using readily available trimethyltriazinane as a stoichiometric reducing agent. The cleavage of the C-F bond by a triazinane-derived radical involves a single electron reduction coupled with fluoride transfer.
V. S. Kostromitin, A. O. Sorokin, V. V. Levin, A. D. Dilman, Org. Lett., 2023, 25, 6598-6602.

A photochemically mediated defluorinative hydroalkylation of ethyl trifluoroacetate with a diverse suite of alkenes in the presence of sodium formate enables a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds. Furthermore, trifluoroacetamides can also be functionalized via synergistic Lewis acid/photochemical activation.
M. W. Campbell, V. C. Polites, S. Patel, J. E. Lipson, J. Majhi, G. A. Molander, J. Am. Chem. Soc., 2021, 143, 19648-19654.

Under mild irradiation conditions using violet light-emitting diodes, a catalytic amount of N-(4-mercaptophenyl)pivalamide promotes monoselective defluoroalkylation of trifluoroacetates with a variety of aliphatic alkenes in the presence of a formate salt to provide valuable α,α-difluoro substituted aliphatic carboxylate esters.
C. Liu, N. Shen, R. Shang, Synthesis, 2023, 55, 1401-1409.

A mild Suzuki-Miyaura cross-coupling reaction achieves the synthesis of a broad range of β,γ-alkynyl esters and amides using air-stable potassium alkynyltrifluoroborates as nucleophilic partners. Propargyl esters and amides were obtained in high yields using a low catalyst loading.
G. A. Molander, K. M. Traister, Org. Lett., 2013, 15, 5052-5055.

A general, inexpensive, copper-catalyzed coupling of terminal alkynes with diazo compounds provides ready access to 3-alkynoates. This reaction proceeds efficiently under nonbasic conditions at room temperature and tolerates various functional groups.
A. Suárez, G. C. Fu, Angew. Chem. Int. Ed., 2004, 43, 3580-3582.

Highly substituted α,α-disubstituted β-alkynyl esters are readily prepared from allenyl esters and either alkyl halide, acid chloride, or alkyl chloroformate, mediated by an amide base. This highly efficient and mild process tolerates various functional groups and provides α,α-disubstituted β-alkynyl esters in good to excellent yields.
W. Wang, B. Xu, G. B. Hammond, Org. Lett., 2008, 10, 3713-3716.

A copper-catalyzed highly anti-selective radical 1,2-alkylarylation of terminal alkynes with aryl boronic acids and alkyl bromides providesg facile access to various stereodefined trisubstituted alkenes in high yield under mild reaction conditions. The reaction exhibits high compatibility with a wide range of terminal alkynes and diverse aryl boronic acids.
J.-B. Tang, J.-Q. Bian, Y.-S. Zhang, Y.-F. Cheng, H.-T. Wen, Z.-L. Yu, Z.-L. Yu, Z.-L. Li, Q.-S. Gu, G.-Q. Chen, X.-Y. Liu, Org. Lett., 2022, 24, 2536-2540.

Acrylamide and aromatic aldehydes were found to undergo the Baylis-Hillman reaction at ambient temperature and pressure in an aqueous medium in the presence of a stoichiometric amount of DABCO, to give the corresponding 3-hydroxy-2-methylenepropionamides in excellent yield. A faster, but reversible side reaction gave N-acylhemiaminals, which later disappeared, as the desired Baylis-Hillman adducts were formed as major products over an extended period of time.
C. Yu, L. Hu, J. Org. Chem., 2002, 67, 219-223.

A palladium-catalyzed coupling of aryl halides and ester enolates produced α-aryl esters in high yields at room temperature. The reaction was highly tolerant of functionalities and substitution patterns on the aryl halide. Improved protocols for the selective monoarylation of tert-butyl acetate and the efficient arylation of α,α-disubstituted esters were developed with LiNCy2 as base and P(t-Bu)3 as ligand.
M. Jřrgensen, S. Lee, X. Liu, J. P. Wolkowski, J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 12557-12565.

Iridium catalyzes a branch-selective hydroalkylation of simple aliphatic and aromatic alkenes with malonic amides and malonic esters under neutral reaction conditions. A substrates bearing bromine, chlorine, ester, 2-thienylcarboxylate, silyl, and phthalimide groups are suitable for this hydroalkylation. Selective transformations of hydroalkylated products to 1,3-diamines or monoamides are reported.
T. Sawano, M. Ono, A. Iwasa, M. Hayase, J. Funatsuki, A. Sugiyama, E. Ishikawa, T. Yoshikawa, K. Sakata, R. Takeuchi, J. Org. Chem., 2023, 88, 1545-1559.