Modular Synthesis of Cyclopropane‐Fused N‐Heterocycles Enabled by Underexplored Diazo Reagents

Abstract

Cyclopropane‐fused N‐heterocycles are featured in various biologically active compounds and represent attractive scaffolds in medicinal chemistry. However, synthesis routes to access structurally and functionally diverse cyclopropane‐fused N‐heterocycles remain underexplored. Leveraging novel α‐diazo acylating agents, we report a general approach for the direct and modular synthesis of cyclopropane‐fused lactams from unsaturated amines. The operationally simple transformation, which proceeds through successive acylation, (3+2) cycloaddition and fragmentation, tolerates a broad range of functional groups and yields a wide spectrum of complex molecular scaffolds, including fused, bridged and spiro ring systems. We demonstrate the utility of this transformation in the concise syntheses of therapeutic agents milnaciprane and amitifadine.