铜催化C-H键活化构建新型N-烯基苯并咪唑衍生物

发布时间：2018-05-15 04:15

本文选题：铜催化 + 氮烯基苯并咪唑衍生物　；参考：《西南大学》2017年硕士论文

【摘要】：氮烯基结构存在于许多天然产物和医药分子中,显示出广泛的生物活性。在自然界中发现了许多具有生物活性的氮烯基天然产物的存在,如(±)-ξ-Clausenamide、(+)-SB-204900就是从芸香料黄皮中提取出来的天然有机分子并具有许多药理作用。由于烯胺衍生物的特殊结构,特别是氮烯基苯并咪唑,在有机反应中常用作复杂化合物的原料和重要的医药中间体。在高分子化学中,该类化合物也可作为聚合过程的反应单体。其中氮烯基吡咯烷酮(NVP)就用于构建具有经济重要性的聚合物。烯胺衍生物含有双键和氮原子,可与多种过渡金属进行配位,因此也是许多金属络合物的核心配体。不仅如此,烯胺衍生物可以用于合成传统方法难以制备的多取代氮杂环化合物。经研究发现,氮烯基唑类化合物已经应用于金属的分离、极性化合物的提取、化妆品和染料的提纯等。另外,氮烯基咪唑类衍生物在医药和农药领域也被发现具有较好的抗真菌和抗寄生虫方面作用。寻找到一种简便适用的方法合成具有潜在生物活性的新型氮烯基苯并咪唑类衍生物也是科研工作者正在努力的方向。C-H键活化被称为有机化学领域中的“圣杯”,而实现碳氢键的高选择性活化也是化学科研工作者的追求目标。特别是过渡金属参与C-H键活化的体系中,对反应底物具有较好官能团容忍性,绝大多数文献中报道的反应对卤素、酰胺、硝基和酯基等均适用,因而一直是有机化学的热门领域。随着对过渡金属催化C-H键活化的深入研究,反应催化剂由价格昂贵的Ru、Ir、Rh和Pd等过渡金属转变为使用相对廉价的Cu催化剂,并且反应条件也越来越温和。在有机合成中,较多结构复杂化合物的合成路线需要多步反应,而传统方法则涉及繁杂的纯化分离过程。从绿色化学和经济的角度看,减少不必要的后处理,尽可能地避免中间体的分离过程完全顺应了时代要求。而串联反应即为在一个反应体系中不进行任何操作,反应原料进行了多个反应结合的过程。因为其具有操作简便、无需分离中间体、收率好且高效等优点,相比于传统方法充分展示出优越性而一直活跃于有机化学的研究前沿。因此,我们实现了N-烯基苯并咪唑的C-N键通过苯并咪唑和缺电子烯烃的分子间串联氮杂迈克尔加成反应,及Cu(II)和碘化锂共同作用下苯并咪唑酯发生分子内α位C-H键的碘化和脱卤化氢的形式α,β-脱氢过程。该方法对唑类具有较好的官能团容忍性,对苯环上含有甲基、酯基、硝基、卤素及大的共轭环均适用。这些官能团还可以进行衍生反应,便于化合物的结构修饰而得到更多结构新颖且存在潜在生物活性的含唑类化合物。但是,对于苯并咪唑的2位、丙烯酸酯的α或β位存在的位阻效应,对反应影响较大,目标产物的分离产率显著降低。该方法首次报道了在温和条件下,苯并咪唑衍生物分子间和分子内酯α位碳氢键的选择性碘化的串联反应。该过程并非自由基反应,包括通过铜盐催化sp3 C-H的活化得到α-碘酯中间体,有效地合成了二十多个新型唑类化合物。我们对所有化合物的高分辨质谱、氢谱、碳谱及红外光谱进行解析,证实了化合物的分子结构。另外,我们还成功培养出了4a的单晶,经过X-射线单晶衍射进一步确认了其空间立体构型。在反应机理的探讨时,我们发现一个重要的中间体—α-碘代酯,并进一步证实了该反应其中的一个过程为苯并咪唑和丙烯酸酯发生迈克尔加成反应,然后再进行Cu催化的C-H键活化生成α-碘代酯中间体,最后发生脱卤代氢得到目标产物。在控制实验对比过程中,我们发现Cu盐虽在酯的α-H活化中起到重要作用,但对后续反应影响较小,而在脱卤代氢的过程中碱的作用是不可忽略的。并且在我们报道在温和条件下生成碘酯的方案,亦可以运用到许多医药反应中得到关键中间体。由于多数苯并咪唑衍生物具有生物活性,因此,我们也对合成的氮烯基化苯并咪唑衍生物进行了抗菌活性测试。对比我们课题组先前做的苯并咪唑迈克尔加成产物的抗微生物活性实验对比研究发现,部分化合物脱氢后的抗微生物活性明显增强,甚至个别化合物对微生物测试的MIC值低于参考药物。与此同时,我们还发现化合物4i的抗微生物活性普遍较好,具有中等或者强的抑菌活性,有望进一步开发和研究作为抑菌药物合成的备选之一。
[Abstract]:The nitrogeny structure exists in many natural products and pharmaceutical molecules, showing a wide range of biological activities. In nature, many natural products of biologically active nitrogeny are found, such as (+) - -Clausenamide, (+) -SB-204900 is a natural organic molecule extracted from the yellow skin of Brassica and has many pharmacological effects. Due to the special structure of alkene derivatives, especially nitrogenyl benzimidazole, they are used as raw materials and important pharmaceutical intermediates for complex compounds in organic reactions. In polymer chemistry, this kind of compounds can also be used as reaction monomers in the polymerization process. Among them, nitrogenyl pyrrolidone (NVP) is used for the construction of economic importance. Enamine derivatives contain double bonds and nitrogen atoms, which can be coordinated with a variety of transition metals and are therefore the core ligands of many metal complexes. Not only that, the alkene derivatives can be used to synthesize the multi substituted heterocyclic compounds that are difficult to be prepared by traditional methods. Separation, extraction of polar compounds, the purification of cosmetics and dyes. In addition, nitrogenyl imidazole derivatives have also been found in the fields of medicine and pesticides with good antifungal and antiparasitic effects. A simple and convenient method for synthesis of new nitrogenyl benzimidazole derivatives with potential bioactivity is also found. .C-H key activation is known as the "Holy Grail" in the field of organic chemistry, and the high selective activation of hydrocarbon bonds is also the goal of the chemical researchers. Especially, in the system of C-H bond activation, the transition metal has a good functional group tolerance to the reaction substrate. Most of the documents are reported in the literature. The reaction of the channel is suitable for halogens, amides, nitro and ester groups, and has been a hot field in organic chemistry. With the in-depth study of the activation of C-H bonds catalyzed by transition metals, the reaction catalysts are converted from expensive Ru, Ir, Rh and Pd to the relatively cheap Cu catalysts, and the reaction conditions are becoming more and more mild. In organic synthesis, the synthetic route of more complex compounds requires a multistep reaction, while the traditional method involves a complex process of purification and separation. From a green chemical and economic point of view, the reduction of unnecessary post-processing and as much as possible to avoid the separation process of intermediates are fully aligned with the requirements of the times. There are no operations in the system, and the reaction materials are combined with multiple reactions. Because they have the advantages of simple operation, no separation of intermediates, good yield and high efficiency, we have been active in the research frontier of organic chemistry compared with the traditional methods. Therefore, we have realized the C- of N- alkyl benzimidazole. N bonds through the intermolecular tandem azo Michael addition reaction of benzimidazole and the absence of electronic olefin, and Cu (II) and lithium iodide in the form of intramolecular alpha C-H bond iodization and dehalogenated hydrogen in the form of alpha, beta dehydrogenation process. This method has good functional group tolerance to the azoles and contains methyl and ester groups on the benzene ring. Nitro, halogens and large conjugated rings are all applicable. These functional groups can also be derivatized to facilitate the structural modification of the compounds to obtain more novel and potentially bioactive compounds. However, the 2 position of benzimidazole, the presence of the alpha or beta of acrylate, has a larger effect on the reaction. The separation yield of the products is significantly reduced. This method is the first time to report a series reaction of selective iodization of the alpha hydrogen bond between the benzimidazole derivatives and the benzimidazole derivatives under mild conditions. This process is not a free radical reaction, including the activation of SP3 C-H through copper salts as an intermediate of alpha iodide, which effectively syntheses more than 20 new compounds. The high resolution mass spectra, hydrogen, carbon and infrared spectra of all the compounds have been analyzed to confirm the molecular structure of the compound. In addition, we have also successfully cultured the single crystal of 4A, and further confirmed its spatial stereotactic by X- ray single crystal diffraction. The essential intermediate, alpha iodate, further confirmed that one of the processes was the Michael addition reaction of benzimidazole and acrylate, and then activated by the C-H bond catalyzed by Cu to generate the intermediate of alpha iodate and finally dehalogenation of hydrogen to obtain the target product. In the control experiment, we found the Cu salt. Although it plays an important role in the activation of the ester's alpha -H, it has little effect on the subsequent reaction, and the effect of alkali is not negligible in the process of dehalogenation of hydrogen. And in our report, the scheme of producing iodine ester under mild conditions can also be used in many pharmaceutical reactions to obtain key intermediates. As a result, we also tested the antibacterial activity of the synthetic benzimidazole derivatives. Comparison of the anti microbial activity experiments of the benzimidazole Michael addition products previously done by our group found that the anti microbiological activity of some compounds was obviously enhanced after dehydrogenation, even to a few compounds. The MIC value of biological tests is lower than that of the reference drugs. At the same time, we also found that the anti microbial activity of the compound 4I is generally good, with moderate or strong antibacterial activity. It is expected to further develop and study as one of the alternatives for the synthesis of antibacterial drugs.

【学位授予单位】：西南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626.23

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