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Recent Advances in Intramolecular C─N Bond Formation for Pyrrolidine Synthesis
Rasma Kroņkalne1, Māris Turks1
1Institute of Chemistry and Chemical Technology, Faculty of Natural Sciences and Technology, Riga Technical University, Riga, Latvia.
Abstract:
Pyrrolidines constitute a privileged class of nitrogen heterocycles that are ubiquitous in pharmaceuticals, bioactive molecules, and functional materials, thereby continuing to stimulate the development of efficient and versatile synthetic strategies. Among these, intramolecular C─N bond formation represents one of the most fundamental and broadly applicable approaches for the construction of pyrrolidine frameworks. Despite its central importance, a systematic overview focusing specifically on this ring-closing paradigm has been lacking. This review summarizes key advances reported between 2013 and 2025 in the synthesis of pyrrolidines via intramolecular C─N bond formation, focusing specifically on examples featuring a polar ring-closure step N: → C(+/δ+). The discussion is organized according to the ring-formation mechanism, encompassing transition-metal-catalyzed and metal-free cyclization of alkenyl and alkynyl amines, tandem annulation processes, intramolecular nucleophilic additions to carbonyl compounds, nucleophilic substitution reactions, and regioselective C(sp3)-H activation of aliphatic amines, including Hofmann-Löffler-Freytag-type transformations. By highlighting mechanistic features, substrate scope, and synthetic utility, this review aims to provide a comprehensive and practical reference for the design of new pyrrolidine syntheses based on intramolecular C─N bond formation.
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