Cu(II)-Catalyzed Unsymmetrical Di-oxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-Phenoxyketones

A Cu-based catalyst system convergently couples gem -difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone’s sp 3 -hybridized hydrate form is energetically favoured relative to the respective non-ether variant, and that perturbation of the electronic character of the ketone can further encourage formation of the hydrate. The more facile conversion between ketone and hydrate forms suggest that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.