Bicyclo[2.1.1]hexanes and related bridged bicyclic molecules can serve as alternatives to arene groups in drug development (i.e., as bioisosteres). Methods for the synthesis of such ring systems are, thus, useful. One possible path is the formal (3+2)-cycloaddition of bicyclobutanes and alkenes.

Corey R. J. Stephenson, University of British Columbia, Vancouver, Canada, and colleagues have developed a method for the synthesis of bicyclo[2.1.1]hexanes via a formal (3+2) cycloaddition of allylated cyclopropanes (general reaction pictured). The team used allylated cyclopropanes with a 4-nitrobenzimine substituent, which were subjected to LED light at 390 nm in a toluene solution for 10 min.

Under these conditions, the desired functionalized bicyclo[2.1.1]hexanes were obtained as a mixture of diastereomers in mostly high to excellent overall yields. The protocol shows a good functional group tolerance due to the mild conditions. The bicyclic imine products obtained via this approach can easily be further functionalized. They can, for example, be hydrolyzed, hydrolyzed and then acylated, or further converted via a photo-induced ring opening and formal (4+2)-cycloadditions.

• Bicyclo[2.1.1]hexanes via Intramolecular Formal (3+2)‐Cycloaddition,
  Corey R. J. Stephenson, Alexander S. Harmata, Elene Tatunashvili, Abigail Chang, Tao Wang,
  Angew. Chem. Int. Ed. 2024.
  https://doi.org/10.1002/anie.202413695