Metal-Catalyzed Fluoroacetyl Carbene Transfer from Sulfonium Salts

Abstract

The synthesis of organofluorine compounds is pivotal in developing innovative pharmaceuticals, materials, and agrochemicals. Fluorinated carbene transfer offers a promising strategy for forming new carbon-carbon and carbon-heteroatom bonds, facilitating one-carbon editing by simultaneously introducing fluorine into target structures. In this study, we introduce a novel fluoroacetyl sulfonium reagent, (2-ethoxy-1-fluoro-2-oxoethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate (1), serving as an effective alternative to the currently unknown 2-diazo-2-fluoroacetate for ethyl fluoroacetyl carbene transfer. This reagent is applied in Doyle-Kirmse and cyclopropanation reactions operating under mild conditions with the use of earth-abundant metal catalysts. This approach enables the efficient synthesis of valuable monofluorinated products.

1

(A) Biologically active molecules containing the fluoroacetyl moiety. (B) Representative example of formal fluoroacetyl carbene transfer. (C) Comparison of acetyl and fluoroacetyl carbene. (D) This work.

1. Synthesis of Sulfonium Salt 1

2. Substrate Scope for the Doyle–Kirmse Reaction

3. Product Functionalization

4. Cyclopropanation Reaction Scope

2

Thermodynamic analysis of potential intermediates of the reaction mechanism using DFT calculations (m06-2x/Def2TZVP using DCM as the solvent).