A General Protocol for C-H Difluoromethylation of Carbon Acids with TMSCF₂ Br

An efficient method for the selective C-difluoromethylation of carbon acids with the reagent TMSCF₂ Br has been developed. A variety of structurally diverse sp³ - and sp-hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, β-ketoesters, malonates, and other activated C-H nucleophiles, could be efficiently and selectively transformed into the corresponding C-difluoromethylated products under mild conditions. This protocol is also effective for the late-stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF₂ Br.