Microwave irradiation: Synthesis and characterization of α-ketoamide and bis (α-ketoamide) derivatives via the ring opening of N-acetylisatin

Abstract

Background: The carbonyl group at position 2 of N-acetylisatin behaves as an amide which is more susceptible to nucleophilic attack via ring-opening in the presence of nucleophiles. Because of this behavior, in the present work we describe the microwave synthesis of a series of α-ketoamide and bis-(α-ketoamide) derivatives via the facile ring-opening of N-acylisatin with different amines and diamines. The microwave irradiation afforded the product in less reaction time, higher yield and purity. Reaction of N-acylisatin with methanol under microwave irradiation afforded the α-phenylglyoxyl methyl ester derivatives with excellent yields and purities. Aminolysis of the ester derivatives with piperidine and morpholine afforded the same α-ketoamide derivatives obtained from direct aminolysis of N-acylisatin. The structures of the synthesized compounds were confirmed by FT-IR, NMR, X-ray and elemental analysis.Results: Reaction of N-acetylisatin and N-propoionylsatin with different amines and diamines afforded a series of α-ketoamide and bis-(α-ketoamide) derivatives respectively via the ring opening of N-acylisatins. The reaction was performed under conventional condition as well as microwave irradiation. The microwave irradiation afforded the product in less reaction time, higher yield and purity. Reaction of N-acylisatin with methanol under microwave irradiation afforded the α-phenylglyoxyl methyl ester derivatives in excellent yields and purities as observed from their spectral data. A plausible mechanism involves nucleophilic attack by methanol at C2 carbonyl carbon of N-acetylisatin and subsequent ring opening to generate the α-ketoester. Aminolysis of α-ketoester with amine afforded the same α-ketoamide which is obtained by direct aminolysis of N-acylisatin. The IR, NMR spectra, microanalyses, and single crystal X-ray diffraction confirmed the structures of the synthesized compounds.Conclusions: In conclusion, we have demonstrated that microwave irradiation could be employed efficiently for the synthesis of biologically important α-ketoamide and bis-(α-ketoamide) derivatives. The microwave irradiation has more advantageous over the classical method with regard to reaction time, solvent quantity, and product yield. Reaction of N-acylisatin with methanol under microwave irradiation afforded the α-phenylglyoxyl methyl ester derivatives with excellent yields and purities. Aminolysis of the methyl ester derivatives with amine under microwave irradiation afford the same α-ketoamide derivatives as obtained from direct aminolysis of N-acylisatins. © 2014 El-Faham et al.; licensee Chemistry Central Ltd.