Ethyl 3-bromopropanoate mediated tandem Knoevenagel-aldol annulation: a new strategy for the synthesis of indolizines

Abstract

A simple, efficient, and straightforward methodology has been developed for the synthesis of poly-functionalised indolizines via a tandem Knoevenagel-aldol annulation. The transformation proceeds through ethyl 3-bromopropanoate as a unique bifunctional reagent that enables tandem methylene substitution, intramolecular condensation, and subsequent aromatisation in a single synthetic sequence. A range of 2-substituted pyrroles and phenacyl bromides were successfully converted into 8-substituted ethyl 5-benzoylindolizine-7-carboxylates in good to excellent yields (64-88%) under mild, metal-free conditions. This strategy represents the first demonstration of ethyl 3-bromopropanoate as a dual-reactive partner in heterocyclic synthesis, providing a sustainable and catalyst-free route to indolizine scaffolds of medicinal interest. The method tolerates a broad substrate scope, exhibits high reproducibility, and delivers atom-economical access to functionalised pyridine-fused frameworks, establishing it as a practical and versatile alternative to existing multistep or metal-assisted procedures.