Recent Advances in Multicomponent Reactions for Pyrrolidine Derivative Synthesis: Catalytic, Catalyst-Free, and Azomethine Ylide Approaches

Abstract: Pyrrolidine derivatives, as privileged nitrogen-containing heterocycles, are widely recognized for their broad spectrum of biological activities and their prevalence in pharmaceuticals and natural products. The efficient and sustainable synthesis of these frameworks remains a central challenge in organic and medicinal chemistry. Multicomponent reactions (MCRs) have emerged as powerful tools for the rapid and atomeconomical construction of pyrrolidine scaffolds, offering significant advantages over traditional stepwise approaches. This review comprehensively summarizes recent advances (2018-2024) in the synthesis of pyrrolidine derivatives via MCRs, focusing on catalyst-based, catalyst-free, and azomethine ylide-mediated strategies. Special attention is given to enabling techniques such as ultrasound and microwave irradiation, as well as the use of various catalysts and green solvents. The scope, efficiency, and limitations of each method are critically analyzed, alongside a discussion of their merits and demerits in terms of yield, selectivity, operational simplicity, and environmental impact. Collectively, these developments highlight the growing industrial and pharmaceutical relevance of MCRs for pyrrolidine synthesis and provide valuable insights for future research in heterocyclic chemistry and drug discovery.