Palladium and copper co-catalyzed chloro-arylation of -difluorostyrenes - use of a nitrite additive to suppress β-F elimination.

The installation of fluorine and fluorinated functional groups in organic molecules perturbs the physicochemical properties of those molecules and enables the development of new therapeutics, agrichemicals, biological probes and materials. However, current synthetic methodologies cannot access some fluorinated functional groups and fluorinated scaffolds. One such group, the -difluorobenzyl motif, might be convergently synthesized by reacting a nucleophilic aryl precursor and an electrophilic -difluoroalkene.

Palladium-Catalyzed Dearomatization of Benzothiophenes: Isolation and Functionalization of a Discrete Dearomatized Intermediate.

A Pd-catalyzed decarboxylative dearomatization reaction of a heterocyclic substrate enables access to an uncommon reaction intermediate that rearomatizes in the presence of amine bases in a net C-H functionalization sequence. The dearomatized benzo[]thiophene intermediate bears an exocyclic alkene that can be functionalized through cycloaddition and halogenation reactions to deliver complex heterocyclic products.

Peroxide-Initiated Hydrophosphinylation of -Difluoroalkenes.

The installation of fluorine and fluorinated functional groups into drug-like scaffolds can perturb the physicochemical, pharmacokinetic, and pharmacodynamic properties of compounds. However, some potentially useful fluorinated substructures reside predominantly outside the realm of the current synthetic methodologies. One such substructure, the α,α-difluorophosphine oxide, might be convergently prepared by the reaction of a -difluorinated alkene with a P-H bond, though such nucleophilic reactions instead proceed through a C-F substitution pathway that delivers monofluorovinyl products.

Cu(II)-Catalyzed Unsymmetrical Dioxidation of -Difluoroalkenes to Generate α,α-Difluorinated-α-phenoxyketones.

A Cu-based catalyst system convergently couples -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-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.