Strain-Release-Driven Annulation of Quinazoline-Derived Azomethine Imines with Crotonate Sulfonium Salts for the Synthesis of Nitrogen-Rich Three-Dimensional Cage-like Molecules: Insights from Experiment and Theoretical Calculations

Abstract

Quinazoline-derived azomethine imines (QAIs) are valuable building blocks for constructing nitrogen-containing heterocycles through [3 + n] annulation reactions. We recently communicated a new type of annulation reaction of QAIs─a sulfonium salt-mediated cascade reaction that converts QAIs into nitrogen-rich three-dimensional cage-like molecules. Herein, we present a full mechanistic account of this transformation through combined experimental and computational studies. Theoretical calculations reveal an unexpected strain-release-driven pathway that revises the initially proposed mechanism. The cascade proceeds through a rate-determining intramolecular nucleophilic addition that forms a strained three-membered aziridine ring, followed by ring cleavage and reorganization via a seven-membered benzodiazepine intermediate, ultimately leading to the cage-like product. The diastereoselectivity is rationalized by conformational analysis of the key intermediates. Furthermore, computational analysis reveals that the suppression of the conventional [3 + 3] annulation pathway is due to the thermodynamic instability of six-membered ring formation.