Triplet Carbene Insertion Enables Modular Access to C2-Substituted Bicyclo[1.1.1]pentanes

Bicyclo[1.1.1]pentanes (BCPs) play crucial roles as saturated bioisosteric replacements of planar benzene rings. As strategic three-dimensional alternatives to ortho- or meta-substituted arenes, C2-substituted BCPs provide access to an underexplored chemical space. The pursuit of efficient and broadly applicable synthetic routes for these scaffolds remains a significant challenge, primarily due to the unique topological features of BCP cores. Here, we report a robust and modular strategy for the direct synthesis of C2-substituted BCPs from readily available bicyclo[1.1.0]butanes (BCBs) and diazo compounds. Leveraging homolytic cleavage of the central bond in BCBs, a triplet energy transfer-initiated carbene insertion process occurs, to form 1,4-biradical species, which are ultimately converted to the target BCPs via rapid radical recombination. This methodology establishes a modular platform for systematic access to the C2-functionalized BCP architectures, enabling expeditious diversification of the three-dimensional skeletons. Its practicability has been further demonstrated through the collective replacement of the phenyl moiety with bioisosteric BCP in 15 bioactive molecules.