Progress in Synthesis of 1,4-Dihydropyridines

Abstract

1,4-Dihydropyridines (1,4-DHPs) are an important class of heterocyclic compounds, and possess a broad array of biological activities and applications. With the development of green organic synthetic chemistry, some important achievements have been made in the green synthesis of 1,4-DHPs and new synthetic methods, which made up some shortcomings of the traditional synthesis of Hantzch reaction, such as environment friendly, synthesis efficiency, single product structure and lack of reaction type. This review provides the first overview for the green synthesis of Hantzch reaction and new synthetic methods of 1,4-DHPs since 2010. A comprehensive and up-to-date introduction are given for Hantzch reaction under geen solvent, geen catalyst and geen synthetic technology, and the new reaction of synthesis of 1,4-DHPs based on new building blocks. A thorough analysis is provided concerning the feature of improvement of green synthesis of Hantzsch reaction and new synthetic method. Moreover, the substrates, conditions, selectivities and yields have been also described. Finally, a brief discussion relating to developments and potential areas of further research concerning new synthetic methods of 1,4-DHPs and green synthesis, and chiral synthesis, is presented. Keywords 1,4-dihydropyridines; Hantzsch reaction; clean synthesis; enaminone 1,4-二氢吡啶(1,4-DHPs)是一类重要的含氮杂环化 合物, 具有广泛的生理活性和应用价值. 其中最重要的 是临床上作为钙离子通道阻滞剂治疗心脑血管和高血 压等疾病 [1] , 例如, 尼卡地平(Nicardipine, 1)、尼莫地平 (Nimodipine, 2)、尼非地平(Nifedipine, 3)和非洛地平 (Felodipine, 4)等. 作为药物或药物中间体它们还具有抗 人类免疫缺陷病毒(HIV) [1c,2] 、抗菌 [3] 、抗惊厥 [4] 、抗肿 瘤(化合物 5) [5] 、神经保护 [6] 、辐射防护 [7] 等生物活性 [8] , 可用于合成各种各样含氮杂环化合物 [9] . 在合成中, 可 作为氢源应用于众多的有机还原反应(如 Hantzsch 酯, 6) [10] (图 1). 因此, 对 1,4-DHPs 的研究十分活跃, 一直以 来受到科研工作者的广泛关注.1,4-DHPs 的传统合成策略是 Hantzsch 反应的"一 锅法" 合成, 于 1881 年 Hantzsch [11] 最早报道的两分子 β-羰基酸酯、一分子醛和一分子氨发生缩合反应得到 (Scheme 1). 反应经一分子 β-羰基酸酯和醛反应生成 α,β-不饱和化合物, 与另一分子 β-羰基酸酯和氨反应生 成的 β-胺基烯酸酯发生 Micheal 加成反应, 再脱去一分