BF3-enabled unusual (3 + 2) cycloaddition of bicyclobutanes with aldimine ester: access to 2-azabicyclo[2.1.1]hexanes

Abstract

Cycloaddition reactions involving bicyclobutanes (BCBs) have garnered significant interest in the synthesis of bicyclic frameworks, particularly due to their utility as saturated bioisosteres for benzenoid rings in contemporary drug discovery. Despite these advancements, the cycloaddition of BCBs with N-alkyl (hetero)aryl imines to construct 2-azabicyclo[2.1.1]hexanes (2-aza-BCHs) has remained an unresolved challenge. In this work, we disclose a BF₃-enabled, unusual (3 + 2) cycloaddition between BCBs and aldimine esters, providing access to previously elusive 2-aza-BCH derivatives. This transformation not only introduces a novel strategy for cycloadditions involving BCBs and N-alkyl (hetero)aryl imines but also underscores the distinctive reactivity of aldimine esters as CN two-atom synthons in cycloaddition chemistry. To further demonstrate the synthetic potential of this methodology, we conducted a scaled-up reaction and performed diverse synthetic modifications of the products, yielding a range of valuable nitrogen-containing bridged bicyclic scaffolds.