Abstract
BackgroundThe 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.ResultsReaction 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.ConclusionsIn 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.
Highlights
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
In continuation of our earlier work [11,12], we present the reaction of N-acetyl- and N-propionylisatin in methanol with different amines and diamines under microwave irradiation to afford α-ketoester, series of α-ketoamide and bis-(α-ketoamide) derivatives in excellent yields and purities
Isatin and its derivatives undergo nucleophilic attack at the carbonyl group at position 2 and/or 3. The chemoselectivity of these reactions depends on the nature of the substituent attached to the isatin nucleus, on the nature of the nucleophiles, and the nature of the group attached to the nitrogen atom of the isatin nucleus [15]
Summary
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 carbonyl group at position 2 of N-acetylisatin behaves as an amide carbonyl group which is opposed to the conventional amide carbonyl functionality in isatin [15] Because of this behavior, N-acetylisatin is more susceptible to nucleophilic attack via ring-opening in the presence of nucleophiles, such as amines and alcohols. This ring-opening reaction led to numerous synthetic methods for preparation of α-ketoamides [16,17,18,19,20,21,22], which are of interest in organic and medicinal chemistry [23,24,25,26,27].
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