Organic chemistry

Combinatorial chemistry

Synthon

Surface modification

Catalysis

Lewis acids and bases

Physical chemistry

Alkylation

Chemistry

Trifluoromethyl

Ketone

Alkyl

Bifunctional

Journal of the American Chemical Society

The installation of gem-difluoromethylene groups into organic structures remains a daunting synthetic challenge despite their attractive structural, physical, and biochemical properties. A very efficient retrosynthetic approach would be the functionalization of a single C–F bond from a trifluoromethyl group. Recent advances in this line of attack have enabled the C–F activation of trifluoromethylarenes, but limit the accessible motifs to only benzylic gem-difluorinated scaffolds. In contrast, the C–F activation of trifluoroacetates would enable their use as a bifunctional gem-difluoromethylene synthon. Herein, we report a photochemically mediated method for the defluorinative alkylation of a commodity feedstock: ethyl trifluoroacetate. A novel mechanistic approach was identified using our previously developed diaryl ketone HAT catalyst to enable the hydroalkylation of a diverse suite of alkenes. Furthermore, electrochemical studies revealed that more challenging radical precursors, namely trifluoroacetamides, could also be functionalized via synergistic Lewis acid/photochemical activation. Finally, this method enabled a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds.

Photochemical C–F Activation Enables Defluorinative Alkylation of Trifluoroacetates and -Acetamides