Cu(II)-Catalyzed Unsymmetrical Dioxidation of gem-Difluoroalkenes to Generate alpha,alpha-Difluorinated-alpha-phenoxyketones

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver alpha,alpha-difluorinated-alpha-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of alpha,alpha-difluorinated ketone and alpha,alpha-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 favored relative to the respective nonether variant and that perturbation of the electronic character of the ketone can further encourage the formation of the hydrate. The more facile conversion between ketone and hydrate forms suggests that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.