Directed Metalation-Negishi Coupling of bicyclo[1.1.0]butanes with (het)aryl Bromide

Bicyclo[1.1.0]butanes (BCBs) are highly strained, compact molecular motifs that have attracted growing interest in medicinal chemistry due to their potential use as bioisosteres and as reactive elements in targeted covalent inhibitors. In this work, we describe a complementary strategy to Anderson’s previously reported approach for the bridge functionalization of BCBs. Our method relies on sequential deprotonation, formation of a zincate intermediate, and palladium-catalyzed Negishi cross-coupling with widely available (hetero)aryl bromides. Following systematic optimization of the reaction conditions, a diverse range of aryl and heteroaryl substituents was successfully incorporated. This methodology provides efficient access to structurally diverse 1,2,3-trisubstituted BCB derivatives. Furthermore, preliminary reactivity studies with a cysteine mimic demonstrate the electrophilic character of these scaffolds, underscoring their promise for the development of covalent drug candidates and expanding the toolbox for BCB functionalization.