Hydrocyclization/Defluorination of CF ₃ ‐Substituted Acrylamides: Insights from Kinetics of Hydrogen Atom Transfer

Abstract 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 _H = 2.28 × 10 ⁻⁴ M ⁻¹ s ⁻¹ at 300 K in toluene), the study describes a nickel‐hydride‐(or Li[BEt ₃ H]) initiated hydrocyclization/defluorination of CF ₃ ‐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.