Teng-Fei Xiao, Ming-Ming Li, Dong Xie, Yu-Cheng Gu, Pan-Pan Zhou*, Guo-Qiang Xu* & Peng-Fei Xu*
https://doi.org/10.1007/s11426-025-3052-7
Abstract
Bicyclo[1.1.1]pentanes (BCPs) have emerged as valuable saturated bioisosteres of arenes in drug discovery. While 1,3-disubstituted BCPs are increasingly accessible, the pharmaceutical value of 2-substituted BCPs as replacements for MIMIC ortho-/meta-substituted arene rings, modular access to these scaffolds remains elusive. Here we report a visible-light-mediated σ-bond insertion strategy that exploits triplet energy transfer catalysis to convert readily available bicyclo[1.1.0]butanes (BCBs) into 2-substituted BCPs. The reaction proceeds via triplet carbene intermediates that engage in regioselective insertion into the central C–C σ-bond of BCBs. Mechanistic studies, supported by radical trapping experiments, Stern-Volmer analysis, light-dependence assays, and density functional theory (DFT) calculations, reveal a radical mechanism. The key challenges in this transformation include: controlling the highly reactive radical intermediates; achieving regioselective addition to the highly strained BCB (strain energy: 53.8 kcal/mol), and reconstructing the highly strained BCP ring (strain energy: 54.4 kcal/mol) during radical coupling.