Lewis Acid-Catalyzed Strain-Enabled (3+3) Annulation of Bicyclo[1.1.0]Butanes With Indolylalcohols: Synthesis of Indole-Fused Aza-Bicyclo[3.1.1]Heptanes.

Strain release has long inspired the discovery of unique reactivity, enabling diverse synthetically valuable transformations. Bicyclo[1.1.0]butanes (BCBs), due to their high ring strain, have emerged as versatile building blocks for constructing complex bicyclic architectures. Herein, we report a Lewis acid-catalyzed formal (3 + 3) annulation of BCBs with indolyl alcohols, providing rapid access to indole-fused aza-bicyclo[3.1.1]heptanes. The reaction proceeds under mild conditions, tolerates a broad range of functional groups, and delivers rigid, sp3-rich scaffolds efficiently. Mechanistic studies, including control experiments and computational analysis, indicate a stepwise pathway in which Lewis acid activation of indolyl alcohols generates reactive intermediates, while strain-release of BCBs drives C-C bond formation, followed by C-N bond formation via ring expansion to furnish the fused Aza-bicyclic products.