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.

Graphical abstract: 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

Supplementary files

Article information

Article type
Paper
Submitted
24 Apr 2025
Accepted
04 Jul 2025
First published
11 Jul 2025

Green Chem., 2025, Advance Article

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

R. Xu, B. Cao, Y. Wang, J. Zhang, Y. Huang and W. Li, Green Chem., 2025, Advance Article , DOI: 10.1039/D5GC02067K

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