Three-Step Synthesis of 1-Azabicyclo[1.1.0]butanes from Azetidinone and Theoretical Study of Their Stability

Highly strained small-ring heterocycles have recently attracted considerable attention as three-dimensional alternatives to planar aromatic motifs in medicinal chemistry. Among these, 1-azabicyclo[1.1.0]butanes (ABBs) represent an exceptionally compact nitrogen-containing scaffold with potential utility as precursors to heterocyclic bioisosteres. Nevertheless, general and modular synthetic approaches to ABBs remain scarce. Herein, we report a concise three-step route to C3-substituted ABBs from readily accessible azetidinones. Central to this strategy is an intramolecular 3-exo-tet cyclization triggered by deprotonation with organolithium reagents, proceeding efficiently at low temperature. The method accommodates a broad range of aryl substituents with diverse electronic properties. In addition, vinyl chloride-containing substrates undergo tandem cyclization and elimination, enabling direct access to previously unreported alkynyl-substituted ABBs. Although ABB formation is highly efficient, the resulting compounds exhibit limited stability, leading to rapid decomposition during purification. To clarify the factors governing this behavior, density functional theory (DFT) calculations were performed. Comparison of strain and protonation energies across a series of ABB derivatives revealed that differences in intrinsic ring strain are minimal and cannot account for the observed instability. Instead, protonation energy calculations suggest that protonation promotes heterolytic cleavage of the central C-N bond, generating a benzylic cation whose stability is strongly influenced by substituent electronics. A pronounced linear correlation between calculated protonation energies and Hammett σ parameters supports a dominant role of resonance stabilization.