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 to utilize 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 through the synthesis of a diverse range of valuable building blocks – including highly sought-after bridge arylated BCP derivatives which are prepared via a novel electrocatalytic cross-coupling procedure.