Synthesis Of Multisubstituted 1,4-dihydropyridines Via Multicomponent Reactions

1,4-Dihydropyridines have exhibited a broad range of biological activities, and have been widely applied in biologic and curatorial fields, especially in clinical practice for the treatment of cardio-cerebral vascular disease and high blood pressure as a calcium channel blocker. They can also improve the growth of livestocks and aquatic products as the non-nutritional additives. Meanwhile, they have been recognized as versatile synthetic intermediates that provide ready access to a variety of substituted nitrogen-containing heterocycles, and widely employed as a hydride source for reductive amination. Thus, the synthesis of 1,4-dihydropyridines is of continuing interest.Multicomponent reactions(MCRs) have attracted chemists for the rapid assembly of large numbers of organic molecules with structural diversity and complexity, and the establishment of the corresponding compound libraries. In recent years, the number of the literatures on MCRs increased rapidly, and new MCRs were constantly discovered. MCRs have been widely applied in drug discoverty, chemical pesticides, total synthesis of natural products, etc.In this paper, we present an efficient access to highly functionalized multisubstituted 1,4-dihydropyridines via L-proline-catalyzed one-pot MCRs of alkynoates or alkynones, amines,β-dicarbonyl compounds and aldehydes. The MCR process involves hydroamination / Knoevenagel condensation / Michael-type addition / intramolecular cyclization processes and leads to the formation of highly functionalized multisubstituted 1,4-dihydropyridines in moderate to good yields. After optimizing the reaction conditions, we determined the general conditions to extend substrates: alkynoate/alkynone (1.0 mmol), amine (1.0 mmol),β-dicarbonyl compound (1.5 mmol), aldehyde (1.2 mmol), ethanol (3 mL), L-proline (10 mol%), RT, 12 h. The molecular structure of 5ckaa was confirmed by single-crystal X-ray diffraction. With the optimized conditions, we find that this method is suitable for a variety of different substituentd substrates, providing an easy access to diverse multisubstituted polyfunctional 1,4-dihydropyridines. 25 examples of 1,4-dihydropyridines are given in this paper.The notable advantages of this method are mild reaction conditions, the use of inexpensive, non-toxic solvent and catalyst, and the easy availability of staring materials. This method avoids the use of expensive metal precursors, harmful organic solvents and high-temperature reaction conditions. It's energy saving and environmentally friendly, conforming to the development trend and requirements of green chemistry.