Lewis Acid Catalyzed Michael Addition Of Indoles And α-Picolines With Maleimides

Various indolylsuccinimide and pyridylmethylsuccinimide derivatives are ubiquitous structural features of many alkaloid natural products and drug candidates. Their derivatives are important intermediates in organic synthesis and in pharmaceutical chemistryRecently, Michael addition of indoles with electron-deficient α,β-unsaturated carbonyl compounds constitute powerful methods for direct C-C bond formation for functionalization of these biologically important motifs. However, the Michael addition of indoles and α-picolines to maleimide was not reported until now.In our group, An etc investigated the conjugate addition of indole to maleimide in dichloroethane using ZnBr2as catalyst. The result demonstrated that ZnBr2is a more effective catalyst for electron-rich indoles. This protocol is unsuitable for electron-deficient indoles. In continuation of our efforts in developing selective, efficient and mild synthetic methodologies for the preparation of heterocycle derivatives. Therefore, this paper mainly includes the following parts.1) We studied the Michael addition of maleimide to indole containing electron-withdrawing groups such as nitro and halogen group. In this reaction, using boron trifluoride etherate as a catalyst, maleimides were treated with indoles to give3-indolylsuccinimides in dichloroethane with79～94%yield. Zinc triflate, Zinc bromide and Yttrium triflate did not play a catalytic role in this reaction. Four3-indolylsuccinimides were obtained. Their structures were confirmed by IR,1H NMR,13C NMR and HRMS analysis.2) Next step, we turned our attention to study the Michael addition of2-methylpyridines and maleimides. Effect of Lewis acid catalysts, such as Zinc triflate, Yttrium triflate, aluminum trichloride, bismuth nitrate and zinc bromide, on the reaction yield was discussed. The result suggested that zinc bromide serve as a effective catalyst in chlorobenzene under reflux. The yield is preferably up to90%.3) To further illustrate the utility of this method,2-methylquinoline was used instead of a-picoline as the substrate. With zinc bromide as a catalyst, thirteen3-pyridylmethyl and related3-quinolylmethylsuccinimides were synthesized. Eleven of them were not reported in the literature. Their structures were confirmed by H NMR, C NMR and HRMS analysis.