Monofluorinated C1 Synthon Strategy for the Construction of Fluoromethylene-Linked Bicyclo[1.1.1]Pentane Derivatives

Abstract

Fluoroalkyl-substituted bicyclo[1.1.1]pentanes (BCPs) have emerged as an attractive scaffold in drug discovery. Herein, the modular construction of fluoromethyl-linked BCPs is reported. Fluoroiodomethyl phenyl sulfoxide is found to be a synthetic equivalent of a formal fluoromethylene radical cation synthon, which, under metal-free conditions and violet light irradiation (400 nm), enables an atom-transfer radical addition reaction to [1.1.1]propellane. This straightforward approach provides access to novel bicyclo[1.1.1]pentane-substituted fluoromethyl sulfonium reagents. The electrophilic properties of these sulfonium salts allow nucleophilic displacement under mild conditions, enabling the introduction of the fluoromethyl bicyclopentyl group into diverse natural products and drug molecules with good functional group tolerance.