Amine-promoted three-component cycloaddition of bicyclo[1.1.0]butanes with hydroxylamine and polyformaldehyde: expedient access to 2-oxa-3-azabicyclo[3.1.1]heptanes

Abstract

Bicyclo[3.1.1]heptanes are generally considered important bioisosteres for meta-substituted arenes. Herein, we have developed an amine-promoted synthesis of C4-unsubstituted 2-oxa-3-azabicyclo[3.1.1]heptanes via a formal dipolar [4π + 2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with nitrones generated in situ from hydroxylamines and polyformaldehyde. This synthesis featured mild reaction conditions with excellent functional group tolerance. Notably, mono-substituted and disubstituted BCBs exhibited different regioselectivities during cycloaddition reactions. Computational density functional theory (DFT) calculations provided insights into the mechanistic aspects of this selective cycloaddition, further highlighting the potential of this synthetic approach.