A General Protocol for C−H Difluoromethylation of Carbon Acids with TMSCF2Br

An efficient method for the selective C‐difluoromethylation of carbon acids with the reagent TMSCF₂Br 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 TMSCF₂Br.