Catalytic Enantioselective Synthesis of Difluorinated Alkyl Bromides

We report an iodoarene-catalyzed
enantioselective synthesis of
β,β-difluoroalkyl bromide building blocks. The transformation
involves an oxidative rearrangement of α-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−π and π–π
transition state interactions as critical features.