Enantioconvergent copper-catalysed difluoromethylation of alkyl halides.

Stereochemically controlled hydrogen bond donors play essential roles in the pharmaceutical industry. Consequently, organic molecules that bear difluoromethyl (CF2H) groups at chiral centres are emerging as pivotal components in pharmaceuticals owing to their distinct hydrogen-bonding property. However, a general approach for introducing CF2H groups in an enantioselective manner has remained elusive. Here we show that enantioconvergent difluoromethylation of racemic alkyl electrophiles, through alkyl radical intermediates, represents a strategy for constructing CF2H-containing stereocentres. This strategy is enabled by using copper catalysts bound with a chiral diamine ligand bearing electron-deficient phenyl groups, and a nucleophilic CF2H-zinc reagent. This method allows the high-yield conversion of a diverse range of alkyl halides into their alkyl-CF2H analogues with excellent enantioselectivity. Mechanistic studies reveal a route involving asymmetric difluoromethylation of alkyl radicals and crucial non-covalent interactions in the enantiodetermining steps. This copper-catalysed difluoromethylation process opens an avenue for the efficient preparation of CF2H-containing pharmaceuticals.