Multicomponent Reactions Involving Electron-deficient Alkynes For Synthesis Of Nitrogen-containing Spiro And Polycyclic Compounds

Over the past decades, multicomponent reactions (MCRs) have attracted particular attention because of their advantages of atom economy, simpler procedures, lower costs, and high variability. Spirooxindole frameworks are the fundamental skeletons of a large number of bioactive naturally products and medicinally relevant compounds. As a consequence, synthesis of spirocyclic oxindole compounds via MCRs strategy has became one of the hottest research topics in organic chemistry. In this paper we have investigated several MCRs about electron-deficient alkynes with isatins and obtained a series of novel spirooxindole compounds. In addition, several nitrogen-containing polycyclic compounds were obtained unexpectedly through MCRs as well.1. Using Huisgen's 1,4-dipoles as the key substrate, we designed four-component reactions of N-substituted isatin, malononitrile, N-alkylimidazole and but-2-ynedioate, which afforded a series of imidazo[1,2-a]pyridine spirooxindole compounds with high diastereoselectivity in dry THF at room temperature. When imidazole was replaced by thiazole (benzothiazole), three-component reactions of isatylidene malononitrile, thiazole (benzothiazole) and but-2-ynedioate in dry toluene at 120? afforded a series of (benzo)thiazo[3,2-a]pyridine spirooxindoles. To our delight, the obtained diastereoisomers were successfully separated and characterized. The 27 new compounds were identified by NMR, IR, HRMS spectra, and the single crystal structures of six products have been characterized by X-ray diffraction method.2. Three-component reactions of isatin, L-proline and but-2-ynedioate in anhydrous methanol at room temperature afforded a series of spiro[pyrrolizine-3,3'-indolines] deivatives. Initially, reaction of isatin and L-proline generated azomethine ylide, which then underwent a cycloaddition with but-2-ynedioate to give the products. When excess dimethyl but-2-ynedioate were employed in the reactions, the unprecedented seven-membered ring spiro[pyrrolo[1,2-a] azepine-7,3'-indoline] derivatives were obtained at 50?, which were produced by taking part of two equivalent but-2-ynedioate in the reaction course. The 27 new compounds were characterized by NMR, IR, HRMS spectra, and the single crystal structures of four products have been determined by X-ray diffraction method.3. In order to broaden scope of the substrates for synthesis of polycyclic compounds, methyl propiolate was utilized to replace dimethyl but-2-ynedioate in the multicomponent reactions. Depending on reaction conditions and the structure of substituted isatin, the three-component reactions of methyl propiolate, L-proline and substituted isatin not only afforded pyrrolizine and pyrrolo[1,2-a]azepine spirooxindole derivatives, but also yielded three kinds of novel nitrogen-containing polycyclic compounds, (2-(2-oxoindolin-3-ylidene)propylidene)pyrrolidin-1-yl acrylate, azocino[1,2-a]benzo[c][1,5]diazocine and pyrrolo[1',2':1,9]azonino[6,5,4-cd] indolin-2-one. The 18 new compounds were characterized by NMR, IR, HRMS spectra, and the single crystal structures of four products have been determined by X-ray diffraction method.