Enantioconvergent Copper-Catalysed Difluoromethylation of Alkyl Halides.

Stereochemical-controlled hydrogen bond donors play essential roles in the pharmaceutical industry. Consequently, organic molecules that bear difluoromethyl (CF 2 H) groups at chiral centers are emerging as pivotal components in pharmaceuticals due to their distinct hydrogen-bonding property. However, a general approach for introducing CF 2 H groups in an enantioselective manner remained elusive. Here, we show that enantioconvergent difluoromethylation of racemic alkyl electrophiles, through alkyl radical intermediates, represents a new strategy for constructing CF 2 H-containing stereocenters. This strategy is enabled by using copper catalysts bound with a chiral diamine ligand bearing electron-deficient phenyl groups, and a nucleophilic difluoromethyl-zinc reagent. This method allows for the high-yield conversion of a diverse range of alkyl halides into their alkyl-CF 2 H analogs with excellent enantioselectivity (up to 99% e.e.). Mechanistic studies, supported by DFT calculations, revealed a route involving asymmetric difluoromethylation of alkyl radicals and crucial non-covalent interactions in the enantio-determining steps.