导　　师： 江焕峰

学科专业： 081704

授予学位： 硕士

作　　者： ;

机构地区： 华南理工大学

摘　　要： 1,4-二氢吡啶类化合物具有很好的生理活性,在生物、医药方面具有广泛的应用。其中最重要的是作为钙拮抗剂在临床上用于治疗心脑血管和高血压疾病,同时是一种促生长剂类非营养性饲料添加剂,可以促进畜禽和水产动物的生长。另一方面,1,4-二氢吡啶类化合物是重要的化学合成中间体,用于合成各种取代的含氮杂环,并可作为氢源用于还原氨化反应。因此,1,4-二氢吡啶类化合物的合成至今仍是化学界的热点。 由于多组分反应/(MCRs/)可以实现快速大量地合成具有结构多样性和复杂性的化合物并建立相应的化合物库,因此引起了化学家的关注。近几年来,关于MCRs的文献数目迅速增长,新的MCRs不断被发现,MCRs在药物发现、农药化学和天然产物全合成等方面得到广泛的应用。 本论文主要进行了利用多组分反应法来合成多取代1,4-二氢吡啶类化合物的研究。利用易得的炔酮或炔酯、胺、β-二羰基化合物和醛,通过L-脯氨酸催化的一锅煮的多组分反应来实现。该反应经历了氢胺化、Knoevenagel缩合、迈克尔加成、分子内环化历程,得到中等至高收率的多取代1,4-二氢吡啶类化合物。通过对条件的优化,我们确定了扩底的一般条件为:炔酮//炔酯1mmol,胺1mmol,β-二羰基化合物1.5mmol,醛1.2mmol,乙醇3mL,L-脯氨酸10mol/%,室温,反应时间12h。化合物5ckaa的分子结构通过单晶X-射线衍射法确定。通过对炔、胺、β-二羰基化合物、醛的选择研究,证明了该方法适用于多种不同取代基的底物,适用范围广,为多取代1,4-二氢吡啶类化合物的合成提供了方便快捷的路径。本研究共合成了25个1, 4-二氢吡啶类化合物。 本研究的创新点在于:/(1/)使用便宜、无毒的溶剂和催化剂;/(2/)适合众多的底物且底物易得;/(3/)反应条件温和,操作简便。该方法克服了以往方法需要贵金属催化、有害有机溶剂和高温反应的缺点,节约能耗,对环境友好,顺应了绿色化学的发展趋势和要求。 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.

关 键 词： 二氢吡啶 多组分反应 脯氨酸 一锅煮

分 类 号： [O626.32]

领　　域： [理学] [理学]