Synthesis of acyl fluorides

Recent Literature

The use of the bench-stable, solid reagent (Me₄N)SCF₃ enables a convenient, highly efficient, and selective transformation of aliphatic and aromatic carboxylic acids to acyl fluorides at room temperature. This base- and additive-free method offers high functional group tolerance and facile product purification via filtration.
T. Scattolin, K. Deckers, F. Schoenebeck, Org. Lett., 2017, 19, 5740-5743.

Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor reagent) is a new deoxofluorinating agent that is much more thermally stable than DAST (C₂H₅)₂NSF₃. It is effective for the conversion of alcohols to alkyl fluorides, aldehydes and ketones to the corresponding gem-difluorides, and carboxylic acids to the trifluoromethyl derivatives with, in some cases, superior performance compared to DAST.
G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic, H. Cheng, J. Org. Chem., 1999, 7048-7054.

XtalFluor-E promotes a deoxofluorination reaction of carboxylic acids to provide a wide range of acyl fluorides in good yields after a simple filtration through a pad of silica gel. This transformation is assisted by a catalytic amount of NaF and occurs at room temperature in EtOAc. A sequential deoxofluorination/amidation is also possible.
M. Gonay, C. Batisse, J.-F. Paquin, J. Org. Chem., 2020, 85, 10253-102604.

Sulfur mediates a synthesis of acyl fluorides from carboxylic acids using Selectfluor. A broad range of acyl fluorides are accessible from carboxylic acids while avoiding the formation of acid anhydrides. ¹⁹F NMR spectra suggest that a S₈-fluoro-sulfonium cation and a neutral S₈-difluoride are generated in situ as reactive species in this deoxyfluorination reaction.
E. M. Mahmoud, S. Mori, Y. Sumii, N. Shibata, Org. Lett., 2023, 25, 2810-2814.

3,3-Difluoro-1,2-diphenylcyclopropene (CpFluor), a bench-stable fluorination reagent, can be used for an efficient deoxyfluorination of (hetero)aryl, alkyl, alkenyl, and alkynyl carboxylic acids to the corresponding acyl fluorides under neutral conditions. A synthesis of acyl fluorides with in-situ formed CpFluor, as well as a one-pot amidation reaction are also described.
X. Wang, F. Wang, F. Huang, C. Ni, J. Hu, Org. Lett., 2021, 23, 1764-1768.

Aminodifluorosulfinium tetrafluoroborate salts act as efficient deoxofluorinating reagents when promoted by an exogenous fluoride source and, in most cases, exhibited greater selectivity by providing less elimination byproduct as compared to DAST and Deoxo-Fluor. Aminodifluorosulfinium tetrafluoroborates are storage-stable, and unlike DAST and Deoxo-Fluor do not react violently with water.
F. Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F. LaFlamme, A. L'Heureux, Org. Lett., 2009, 11, 5050-5053.

A deoxyfluorination reaction of carboxylic acids using potassium fluoride (KF) and highly electron-deficient fluoroarenes provides acyl fluorides good yields.
S. Mao, J. H. Kramer, H. Sun, J. Org. Chem., 2021, 86, 6066-6074.

The combination of trichloroisocyanuric acid and cesium fluoride provides acyl fluorides directly from three different functional group precursors: carboxylic acids, aldehydes, or alcohols. It can be applied to the late-stage functionalization of natural products and drug molecules.
Y. Liang, Z. Zhao, A. Taya, N. Shibata, Org. Lett., 2021, 23, 847-852.

A pyridinium trifluoromethoxide salt (PyOCF₃) can be formed at room temperature from the reaction of 2,4-dinitro(trifluoromethoxy)benzene with 4-dimethylaminopyridine. PyOCF₃ undergoes slow release of fluorophosgene and fluoride for deoxyfluorination reactions. A wide substrate scope and high functional group tolerance are demonstrated for the synthesis of acid fluorides.
A. V. R. D. Lisboa, G. Duran-Camacho, A. K. Ehrlacher, M. R. Lasky, M. S. Sanford, Org. Lett., 2023, 25, 9025-9029.

A fast and simple method for deoxyfluorination of carboxylic acids employs commodity chemicals (PPh₃, NBS, fluoride) to afford products in excellent yields under mild conditions. The protocol offers scalability, high functional group tolerance, chemoselectivity, and easy purification of products.
S. B. Munoz, H. Dang, X. Ispizua-Rodriguez, T. Mathew, G. K. S. Prakash, Org. Lett., 2019, 21, 1659-1663.

A series of acyl fluorides was conveniently synthesized at 100 mmol scale using phase-transfer-catalyzed halogen exchange between acyl chlorides and aqueous bifluoride solution. The procedure consists of vigorous stirring at room temperature, followed by extraction and distillation. Isolated acyl fluorides display excellent purity and can be transformed into sterically hindered amides and esters.
M. Tryniszewski, M. Barbasiewicz, Synthesis, 2022, 54, 1446-1460.

Deoxo-Fluor is a versatile and mild reagent for acyl fluoride generation and subsequent one-flask amide coupling. The conversion of acids to amides and Weinreb amides and the use of Deoxo-Fluor as peptide-coupling reagent have been explored. Products were isolated after facile purification in good yields.
J. M. White, A. R. Tunoori, B. J. Turunen, G. I. Georg, J. Org. Chem., 2004, 69, 2573-2576.

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 near-stoichiometric amount of N-Formylsaccharin, an easily accessible crystalline compound, has been employed as an efficient CO source in a mild Pd-catalyzed fluorocarbonylation of aryl halides to afford the corresponding acyl fluorides in high yields. The acyl fluorides obtained could be readily transformed into various carboxylic acid derivatives such as carboxylic acid, esters, thioesters, and amides in a one-pot procedure.
T. Ueda, H. Konishi, K. Manabe, Org. Lett., 2013, 15, 5370-5373.

Activated ketones such as α-oximinoketones can serve as starting materials for the preparation of acyl fluorides via a pull-and-push-driven fluorinative C-C bond cleavage. The use of diethylaminosulfur trifluoride (DAST) derivatives led to a highly efficient and chemoselective reaction. The method is mild, fast, and scalable.
D. Kim, H. N. Lim, Org. Lett., 2020, 22, 7465-7469.

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The combination of readily accessible starting materials provide a surrogate for toxic difluorophosgene (COF₂) gas that enables a synthesis of carbamoyl fluorides. This protocol does not require the use of pre-functionalized substrates, the preparation of light-, temperature-, and/or moisture-sensitive chemicals, or the application of explosive fluorinating reagents.
D. Cadwaller, T. R. Tiburcio, G. A. Cieszynski, C. M. Le, J. Org. Chem., 2022, 87, 11457-11468.

A rearrangement of in situ-generated amidoximes enables a practical and modular synthesis of fluoroformamidines. High yields in just 60 s at room temperature highlight the efficiency of this protocol. Furthermore, fluoroformamidines proved to be useful intermediates in the synthesis of diverse ureas and carbamimidates.
J. A. Vogel, K. F. Miller, E. Shin, J. M. Krussman, P. R. Melvin, Org. Lett., 2024, 26, 1277-1281.