Strain‐Release Driven Epoxidation and Aziridination of Bicyclo[1.1.0]butanes via Palladium Catalyzed σ‐Bond Nucleopalladation

The development of preparative methods for the synthesis of four‐membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and aziridines containing a cyclobutane motif. In a two‐step one‐pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross‐coupled with an aryl triflate through C−C σ‐bond alkoxy‐ or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring‐opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three‐dimensional structures into target molecules. Strained spirocyclic epoxides and aziridines were synthesized via three‐component coupling between in situ generated 1‐lithio bicyclo [1.1.0]butane, a broad variety of ketones, aldehydes and N‐tosyl imines, and aryl triflates. The key step involves a highly diastereoselective palladium‐catalyzed C−C σ‐bond alkoxyarylation (or aminoarylation) of bicyclo [1.1.0]butyl carbinolate intermediates.