Methanol‐Mediated One‐Pot Transformation of Benzonitriles to Five and Six‐Membered Heterocycles: Synthesis and Mechanistic Approach

Abstract Herein we describe a facile methodology for the synthesis of heterocyclic molecules such as 2‐aryl‐substituted imidazolines, oxazolines and 1,4,5,6‐tetrahydropyrimidines, under one‐pot and metal‐free conditions. A series of electron‐poor substituted benzonitriles were used as starting materials with different available diamines and amino alcohols, producing the desired products in good to high yields within methanol and in the absence of catalyst or additives. This methodology can be easily scaled up to laboratory size of 3 mmol for both five‐ and six‐membered heterocycles. Detailed mechanistic and theoretical studies supported the dual role of methanolic media as solvent and as mediated agent. To shed light on the reaction mechanism, DFT mechanistic studies suggest a distinction in the first step, with the activation of the nitrile by methanol, and the formation of a benzimidamide and/or a benzimidate (observed by NMR) as intermediates. This facile synthetic procedure provides a green, metal‐free, and mild protocol for the synthesis of a series of imidazoline, oxazoline and tetrahydropyrimidine derivatives.