Rapid access to 3-substituted bicyclo[1.1.1]pentanes

The prevalence of benzene rings in pharmaceutical scaffolds has prompted efforts to identify structural bioisosteres with improved in vivo properties. Notably, investigators have leveraged bicyclo[1.1.1]pentanes (BCPs)—C(sp³)-enriched, 1,4-disubstituted phenyl bioisosteres—to tune the pharmacokinetic profiles of lead compounds. Although 3-arylated BCPs have been widely implemented to confer resistance to oxidative degradation and hydrogen atom transfer (HAT) processes, the analogous 3-alkylated BCPs remain underexplored as bioisosteric “benzylic” C–H motifs. Current methods for installing 3-alkylated BCP motifs are heavily reliant on lengthy de novo synthesis and the preparation of reactive [1.1.1]propellane feedstocks, limiting their adoption in drug-discovery programs. In this report, we disclose a mild, unified method for the preparation of both alkyl- and aryl-substituted BCPs from bench-stable precursors. This method, which proceeds via dual copper-photoredox catalysis, is capable of installing BCP functionalities onto a range of saturated motifs, aryl-containing residues, and medicinally relevant heterocycles.