Enantioconvergent copper-catalysed difluoromethylation of alkyl halides

Abstract

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.