Catalytic Enantioselective Synthesis of Difluorinated Alkyl Bromides

We report an iodoarene-catalyzed enantioselective synthesis of beta,beta-difluoroalkyl bromide building blocks. The transformation involves an oxidative rearrangement of alpha-bromostyrenes, utilizing HF-pyridine as the fluoride source and m-CPBA as the stoichiometric oxidant. A catalyst decomposition pathway was identified, which, in tandem with catalyst structure-activity relationship studies, facilitated the development of an improved catalyst providing higher enantioselectivity with lower catalyst loadings. The versatility of the difluoroalkyl bromide products was demonstrated via highly enantiospecific substitution reactions with suitably reactive nucleophiles. The origins of enantioselectivity were investigated using computed interaction energies of simplified catalyst and substrate structures, providing evidence for both CH-pi and pi-pi transition state interactions as critical features.