Mechanistic insights on the Lewis acid-catalyzed three-component cationic Povarov reaction: synthesis of N-propargyl 1,2,3,4-tetrahydroquinolines

Abstract

In this study, the Povarov cationic reaction mechanism was explored using five different Lewis acids as catalysts for the synthesis of N-propargyl-6-methoxy-4-(2′-oxopyrrolidin-1′-yl)-1,2,3,4-tetrahydroquinoline, where the best reaction yield was obtained using InCl₃. The desired product was not obtained in the absence of a catalyst. A comprehensive theoretical analysis at the density functional theory (DFT) level was conducted to study the role of the catalyst and establish a detailed reaction mechanism. Electron localization function (ELF) analyses were performed to elucidate the key bonding events during the reaction stages, highlighting the differences in bond formation among the different catalysts. Our results showed that the presence of an acid catalyst is required for obtaining the intermediary iminium ion. In this sense, the InCl₃ catalyst provides the lowest energy barrier for catalytic interactions, increasing the electrophilic character and, therefore the reactivity of formaldehyde, promoting the formation of iminium ions and subsequently triggering the obtaining of the tetrahydroquinoline compound. In fact, from theoretical analysis, our findings provide evidence of the formation of the tetrahydroquinoline compound through a set of energetically favorable step reactions, ruling out a concerted process. The step involved in this part of the mechanism includes the formation of a Mannich-type adduct, obtained by the nucleophilic addition reaction between the iminium cation and an activated alkene, and a subsequent cyclization via an intramolecular Friedel–Crafts reaction. This defines the cationic Povarov reaction as a domino reaction and invites us to discard the wrong use of the name Aza Diels–Alder or imino Diels–Alder for this type of reaction.