Visible-Light-Induced Regio- and Stereoselective C(sp2)-H Trifluoromethyl-Bicyclopentylation of Enamides with BCP-Thianthrenium Salt via Oxidative Radical/Polar Crossover

Abstract 1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) represent privileged scaffolds in medicinal chemistry as pharmaceutical bioisosteres of benzene rings owing to their enhanced metabolic and pharmacokinetic properties. Herein, we demonstrate an unprecedented and practical photoredox-catalyzed direct C(sp2)-H trifluoromethyl-bicyclopentylation of enamides with bench-stable BCP-thianthrenium salt under environmentally friendly and transition-metal-free conditions, delivering a broad array of geometrically-defined E-configured enamides bearing the pharmaceutically prominent CF3-BCP entity in a regio- and stereoselective manner. The transformation proceeded through the Giese addition of structurally rigid CF3-BCP alkyl radical to electron-rich enamides and the ensuing oxidative radical/polar crossover followed by β-H elimination. The synthetic utility of this methodology was further highlighted by its scalability and its capacity for streamlined late-stage functionalization, enabling access to various synthetically and biologically important organic intermediates and heterocycles.