Dibromocarbene Addition to Bicyclo[1.1.0]butanes: A Facile Route to Substituted Bicyclo[1.1.1]pentanes

Strained, multicyclic hydrocarbons are increasingly important structural motifs for drug discovery. In particular, substituted bicyclo[1.1.1]pentanes (BCPs) have risen to prominence as bioisosteres for the ubiquitous benzene ring. Despite their favorable pharmacokinetic properties, synthetic strategies towards BCPs suffer from significant drawbacks – namely an overreliance on [1.1.1]propellane – an operationally challenging starting material which complicates scale-up and hampers widespread adoption of these motifs. In this work, the synthesis of 2,2-dibromo BCPs is described, presenting a class of novel substituted BCPs and circumventing the need for [1.1.1]propellane-based precursors. Scalable access to these compounds is demonstrated in a simple and inexpensive process, and their applicability for medicinal chemistry campaigns is highlighted, including through development of an electrochemical method for BCP bridge arylation to afford direct access to valuable BCP building blocks.