Efficient construction of 3-substituted-quinazolin-4(3H)-ones and theoretical investigation on the reaction pathways

A highly efficient and convenientmethod was developed to synthesize 2,7-dimethyl-3-phenyl-quinazolin-4(3H)-ones from 2-acetamidobenzoic acid, arylamines, arylhydrazines and arylacylhydrazines. Quinazolin-4(3H)-oneswere obtained in good to excellent yields (85-98%) using dropwise POCl 3 as a condensing agent in acetonitrile. Theoretical calculations were performed to explore the competition reaction pathways and the corresponding free energy profiles for the reaction of 2-acetamido-4-methyl-benzoic acid with aniline. The calculations show that the reaction proceeds through three different stages, including the formation of benzoxazin-4-one, diamide and quinazolin-4(3H)-one. The formation of benzoxazin-4-one follows a Vilsmeier-Haack mechanism, in which the POCl3 transfers the 2-acetamido-benzoic acid into an imidoyl chloride, followed by intramolecular attack of the carboxyl oxygen involving addition-elimination sequence. The formation of diamide is initialized by the nucleophilic attack of the aniline nitrogen atom on the carbonyl carbon of benzoxazin-4-one, accompanied by aniline-assisted proton transferring. The formation of quinazolin-4(3H)-one follows an intramolecular nucleophilic addition-elimination mechanism, where the POCl3 helps the elimination of water. The present studies provide insight into themechanism for the formation reactions of quinazolin-4(3H)-ones in the presence of POCl3.