Phthalimidine Synthesis via the Direct Condensation between Phthalide and Primary Amine in the Presence of Catalytic Amount of InCl3

Abstract

Background: We previously reported the 1:1 condensation reaction between ophthalaldehyde and primary amine in the presence of 1,2,3-1H-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries to provide phthalimidines (2,3-dihydroisoindol-1-ones) under mild reaction conditions in good isolated yields. However, this reaction was found to proceed via dissymmetrization of equi-oxidation stage functionalities (carbonyl groups herein), which would give rise to regioisomer(s) whenever the orientation of substituents in the target molecule phthalimidine was dissymmetrical. In order to overcome such defects, we focused on phthalide, which possessed identical electronic structure with that of target molecule phthalimidine. Thus, the condensation between a phthalide derivative and a primary amine would eliminate a water molecule, but does not accompany with any kind of redox paths. Therefore, dissymmetrical trends possessed by the phthalide derivative should transfer directly to the resulting phthalimidine, and as a result the formation of possible regioisomer(s) can completely be prevented. This strategy has existed as the oldest method of phthalimidine synthesis, however, Lewis acid catalysts utilized in the past were not appropriate to extend its scope. In this report, we demonstrate an improved method of phthalimidine synthesis along this line using InCl3 as a catalyst, which would allow the synthesis of this class to accommodate with the contemporary standard of organic syntheses. Keywords: Catalytic, direct condensation, InCl3 (Indium chloride), lewis acid, phthalide, phthalimidine.