Copper-Catalyzed Ring-Opening of N -Chlorocyclopropylamides for Modular Access to γ -Functionalized Enamides

Abstract

Enamides are privileged structural motifs in pharmaceuticals, natural products, and synthetic intermediates. However, general and modular methods for accessing highly functionalized allylic enamides remain limited. Herein, we report a copper-catalyzed ring-opening functionalization of readily available N-chlorocyclopropylamides with diverse nucleophiles, providing efficient access to a broad range of γ-functionalized (E)-enamides. Under mild conditions, N-chlorocyclopropylamides undergo single-electron transfer (SET) to generate nitrogen-centered radicals, which trigger strain-driven β-scission of the cyclopropane ring. The resulting distonic radical intermediates are intercepted by copper species, ultimately delivering alkylated, phosphorylated, acyloxy, aryloxy, and thio-substituted enamides with >20:1 E/Z-selectivity. Gram-scale synthesis and diverse downstream derivatizations, including late-stage functionalization of pharmaceuticals, further demonstrate the synthetic utility of this method. Mechanistic studies support a radical-based mechanism involving aminyl radical-triggered ring opening and copper-mediated radical coupling. This strategy leverages the dual reactivity of the N–Cl bond and the strain-release reactivity of cyclopropanes, offering a versatile platform for the rapid assembly of complex enamide scaffolds.