TBACN-Promoted Regioselective Cyanofunctionalization and Benzannulation: Enabling Access to Cyanoindolizine Scaffolds via Alkyne Cyclization

Abstract

A novel and regioselective cyanofunctionalization–benzannulation cascade reaction has been developed, utilizing tetrabutylammonium cyanide (TBACN) as a practical and efficient cyanide source. This transformation provides streamlined access to a structurally diverse array of cyano-substituted indolizine scaffolds, which are valuable intermediates in the synthesis of nitrogen-containing heterocycles with potential pharmaceutical applications. The methodology employs readily available N-propargyl pyrrole derivatives as starting materials and proceeds under relatively mild reaction conditions, enabling the synthesis of 20 structurally distinct cyanoindolizine derivatives. The reaction exhibits remarkable regioselectivity in the installation of the cyano group, a feature that was not initially anticipated. This unexpected regioselective outcome was elucidated through a combination of control experiments, by-product analysis, and intermediate isolation, shedding light on the underlying mechanistic pathway. Furthermore, the reaction displays a broad substrate scope, demonstrating high functional group tolerance with respect to both electronic and steric variations on the pyrrole ring and the propargyl substituents. The versatility of the methodology is further highlighted by the potential for downstream transformations of the cyano group into other functional groups, such as amide moieties, which expand the synthetic utility of the obtained scaffolds. Importantly, this work represents the first reported example of a TBACN-mediated benzannulation of propargyl units, marking a significant advancement in the field of heterocyclic chemistry. The strategy not only provides a novel route to access complex indolizine frameworks but also offers valuable mechanistic insights and synthetic opportunities for the design and development of biologically relevant heterocycles.