Multicomponent Reactions For Synthesis Of Heterocyclic Spirooxindoles

The spirooxindole system is the core structure of many pharmacological agents and natural alkaloids. The target of this paper is to develop new multicomponent reactions for the synthesis of heterocyclic spirooxindole compounds. On the basis of survey and analysis of the known synthetic methods of the various spirooxindoles and in continuation of our recent research work on developing multicomponent reactions, we successfully investigated several multicomponent reactions with cheap and readily available starting materials under mild conditions for the synthesis of diverse heterocyclic spirooxindole compounds having a wide range of biological and pharmaceutical property.1. The polyfunctionalized spiro[indoline-3,4’-pyrrolo[3,4-b]pyridines] were efficiently synthesized by the three-component reaction of 3-benzyl-l-methyl-1H-pyrrole-2,5-dione, isatins and malononitrile (ethyl cycanoacetate) in ethanol in the presence of triethylamine. Smilarily, 3-arylamino-l-methyl-1H-pyrrole-2,5-dione can also be used in the reaction. This reaction not only provided convenient synthetic method for versatile spirooxindole system, but also developed new potential applications of reactive N-methyl-2-maleimide in synthetic and combinatorial chemistry. All of 26 new compounds have been characterized by IR, NMR, LC-MS, HRMS spectra, and the single crystal structures of three products were determined by X-ray diffraction method.2. The one-pot four-component reaction of benzohydrazide (2-picolinohydrazide), acetylenedicarboxylate, isatin and malononitrile (ethyl cyanoacetate) in the presence of triethylamine as base afforded functionalized 1-benzamide spiro[indoline-3,4’-pyridines] in good yields.1H NMR spectra indicated that an equilibrium of cis/trans-conformations exists in the obtained products. In addition, the domino four-component reaction of hydrated hydrazine, dimethyl acetylenedicarboxylate, isatines and malononitrile or ethyl cycanoacetate in ethanol in the presence of triethylamine resulted in the polysubstituted spiro[indoline-3,4’-pyrano[2,3-c]pyrazole] derivatives in satisfactory yields. Under similar conditions, the four-component reaction containing acenaphthenequinone also resulted in the spiro[acenaphthyl-3,4’-pyrano[2,3-c]pyrazole] in good yields. All of 29 new compounds have been identified by IR, NMR, LC-MS, HRMS spectra, and the single crystal structures of four products were determined by X-ray diffraction method.3. The three-component reaction of N-methyl-2-maleimide, isatin, indanedione in ethanol in the presence of triethylamine afforded the polysubstituted Spiro [indeno [2,1-e] pyrrolo [3,4-b] pyridin-10,31 indoline] derivatives in satisfactory yields. In addition, when 5,5-dimethyl-cyclohexanedione was used in the reaction, the functionalized spiro compounds were also obtained in satisfactory yields. All of 13 new compounds have been identified by IR, NMR, LC-MS, HRMS spectra, and the single crystal structures of two products were determined by X-ray diffraction method.