Year: 2025
Type: article
Abstract: 2-Pyrrolidone derivatives are valuable heterocycles with significant biological relevance, yet their synthesis through multicomponent reactions (MCRs) remains mechanistically ambiguous, particularly due to the difficulty of distinguishing them from isomeric aryl-substituted furanones. In this work, we combine electron impact mass spectrometry (EI-MS), Direct Analysis in Real Time mass spectrometry (DART-MS), and single-crystal X-ray diffraction to unambiguously confirm the exclusive formation of 2-pyrrolidone products in the reaction of anilines, benzaldehydes, and diethyl acetylenedicarboxylate. EI-MS provided a diagnostic fragmentation profile inconsistent with furanone structures, while X-ray analysis validated the pyrrolidone core. Time-resolved DART-MS enabled the detection of key long-lived intermediates-such as imines, hydrated alkyne adducts, and pyrrolidone-type species-supporting a stepwise mechanism involving acid-catalyzed imine formation, alkyne hydration, nucleophilic addition to an iminium ion, and final lactamization. Complementary experiments employing diethyl oxaloacetate, together with DFT calculations, further substantiated the pivotal role of alkyne hydration and the β-nucleophilic attack governing cyclization. Citric acid emerged as the most effective catalyst due to its dual activation of the aldehyde and iminium intermediates, while competing enamine formation rationalizes differences in isolated yields across the series. Overall, this study provides the first experimentally supported mechanism for this MCR and establishes a robust analytical framework for the structural and mechanistic elucidation of pyrrolidone-forming reactions.
Source: ACS Omega
Institution: Universidad Nacional Autónoma de México
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $1,935
Awards: G4471378619, G5211874954
OpenAlex ID: W7117301162