Sustainable synthesis of 1-thiol-3-alkyl bicyclo[1.1.1]pentanes via electron donor–acceptor complex photoactivation: a metal- and additive-free strategy for bioisostere design

Abstract

Bicyclo[1.1.1]pentane (BCP) is a key scaffold in drug design for mimicking aromatic groups and improving pharmacokinetics, yet efficient synthesis of C,S-disubstituted BCPs remains challenging. We report a visible-light-driven, metal- and additive-free multicomponent reaction via electron donor–acceptor (EDA) complex activation. Using S-aryl/alkyl benzenethiosulfonates and iodides, this strategy simultaneously constructs Csp³-C and Csp³–S bonds on BCP in one step (420 nm LED, NMP or DMC), achieving diverse substrates (up to 76% yield). Mechanistic studies confirm a radical-relay pathway initiated by EDA formation. Scalable continuous-flow synthesis and derivatization to sulfoxides/sulfones enhance pharmaceutical utility. This method provides a sustainable platform for sulfur-functionalized BCPs, advancing bioisostere design.