Copper-Catalyzed Propargylic Double Substitution Enables Cascade [1 + 5] Annulation

Abstract Sequential functionalization of a single propargylic precursor remains a longstanding challenge in transition-metal-catalyzed propargylic substitution. Herein, we report the first copper-catalyzed propargylic double substitution through sequential dual σ-site functionalization of readily available propargylic esters. The resulting strategy enables an efficient cascade [1 + 5] annulation with 2-(1H-indol-2-yl)phenols, allowing propargylic esters to serve as unprecedented C1 synthons for the synthesis of structurally diverse indole-fused polycyclic frameworks. The reaction proceeds under mild conditions with broad substrate scope and excellent functional group tolerance. Control and deuterium-labeling experiments support a mechanism involving propargylic C–H bond cleavage and sequential interception of two electrophilic allenylidene-derived intermediates. This work establishes a new reaction mode for propargylic substitution chemistry and expands the synthetic potential of propargylic esters.