Synthesis of α-fluorocarboxylic acids and derivatives

Recent Literature

A Ag-catalyzed decarboxylative fluorination reaction provides an unprecedented route to either gem-difluoroalkanes or α-fluorocarboxylic acids from malonic acid derivatives by the judicious selection of base and solvent. This reaction features the use of readily available starting materials, tunable chemoselectivity and good functional group compatibility.
Z. Wang, C.-Y. Guo, C. Yang, J.-P. Chen, J. Am. Chem. Soc., 2019, 141, 5617-5622.

The reaction of ketene acetals with AcOF made directly from fluorine provides α-fluorocarboxylic esters and acids in good yields. This route circumvents the problems associated with nucleophilic fluorinations such as eliminations and rearrangements. Even α-fluoro derivatives of α- and β-branched carboxylic acid derivatives can be isolated in good yield.
S. Rozen, A. Hagooly, R. Harduf, J. Org. Chem., 2001, 66, 7464-7468.

An unbalanced ion pair promoter consisting of a bulky and charge-delocalized cation and a small and charge-localized anion, greatly accelerates nucleophilic fluorinations with KF. An inexpensive and commercially available ion-exchange resin can easily be converted into a recycable polymer-supported ion pair promoter, which can also be used in continuous flow conditions.
W. Li, Z. Lu, G. B. Hammond, B. Xu, Org. Lett., 2021, 23, 9640-9644.

A divergent strategy for the fluorination of phenylacetic acid derivatives is induced by a charge-transfer complex between Selectfluor and 4-(dimethylamino)pyridine. In the presence of water, decarboxylative fluorination through a single-electron oxidation is dominant. Non-aqueous conditions result in the clean formation of α-fluoro-α-arylcarboxylic acids.
A. Madani, L. Anghileri, M. Heydenreich, H. M. Möller, B. Pieber, Org. Lett., 2022, 24, 5376-5380.

Planar chiral [2.2]paracyclophane-based isothiourea catalysts catalyze a highly efficient enantioselective fluorination of carboxylic acids to provide a broad range of optically active α-fluoroesters in high yield and excellent enantioselectivity.
S. Yuan, C. Liao, W.-H. Zheng, Org. Lett., 2021, 23, 4142-4146.

A copper-catalyzed H-F insertion into α-diazocarbonyl compounds provides complex α-fluorocarbonyl derivatives under mild conditions using potassium fluoride (KF) and hexafluoroisopropanol. The method is readily adapted to radiofluorination with [¹⁸F]KF.
E. E. Gray, M. K. Nielsen, K. A. Choquette, J. A. Kalow, T. J. A. Graham, A. G. Doyle, J. Am. Chem. Soc., 2016, 138, 10802-10805.

A catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide (NFSI) and C₆F₅ONa furnishes tertiary α-fluoroesters. Mechanistic studies suggest that the addition of an external nucleophile (C₆F₅ONa) is critical for turnover, releasing the catalyst from an N-acylated intermediate.
S. Y. Lee, S. Neufeind, G. C. Fu, J. Am. Chem. Soc., 2014, 136, 8899-8902.

By altering the amount of Selectfluor, a highly selective mono- and difluorination of 1,3-dicarbonyl compounds provides various 2-fluoro- and 2,2-difluoro-1,3-dicarbonyl compounds in very good yields. This practical and convenient fluorination can be performed in aqueous media without any catalyst and base.
L. Tang, Z. Yang, J. Jiao, Y. Cui, G. Zou, Q. Zhou, Y. Zhou, W. Rao, X. Ma, J. Org. Chem., 2019, 84, 10449-10458.

An isothiourea-catalyzed fluorination of alkynyl-substituted acetic acids provides a broad range of optically active tertiary α-alkyl fluorides in high enantioselectivity (up to 97% ee). Furthermore, this methodology can be scaled up to a Gram scale without loss of enantioselectivity.
S. Yuan, W.-H. Zheng, J. Org. Chem., 2022, 87, 713-720.

Related

A efficient copper-catalyzed cross-coupling of allyl phosphate with 2-fluoro-2-(trimethylsilyl)acetate provides a series of monofluoroalkylation products in high yields.
Y. Liu, R. Chen, L. Lu, D. Yin, F. Yan, X.-X. Li, H. Xiao, S. Fun, S. Fun, Y.-S. Feng, J. Org. Chem., 2023, 88, 7469-7476.

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.