Hydrocyclization/Defluorination of CF-Substituted Acrylamides: Insights from Kinetics of Hydrogen Atom Transfer.

The introduction of F-containing groups into organic molecules can significantly alter their physical and chemical properties. Particularly, gem-difluoroalkenes serve as versatile precursors for a broad variety of organofluorine compounds, commonly used in agrochemicals, pharmaceuticals, and materials science. Based on the kinetics of H• transfer to acrylamide (k = 2.28 × 10 M s at 300 K in toluene), the study describes a nickel-hydride-(or Li[BEtH]) initiated hydrocyclization/defluorination of CF-substituted acrylamides, offering alternative access to 4-fluorovinyl-substituted 2-pyrrolidones (Seletracetam derivatives that are antiepileptic drug candidates). This process proceeds with high yields and remarkable chemo- and regioselectivity. The hydrocyclization/defluorination can be initiated by either H• or H transfer, followed by a 5-exo-trig cyclization and subsequent fluorine elimination. The strategy has been applied in the late-stage functionalization of drug molecules, providing a valuable tool in the synthesis of pharmaceutical compounds.