基于芳炔参与的新型反应研究
发布时间：2018-10-05 07:56
【摘要】：色烯类衍生物是一类在自然界中广泛存在的杂环类骨架化合物,具有广泛生理活性和药理活性。特别的,2-亚胺-3-甲酰胺-2H-色烯类衍生物是一类非肽类小分子抑制剂,对一些特定酶具有良好的生物活性抑制性能,这使得其可以作为一种被用于治疗阿兹海默、癌症等疾病的药物;此外,2-亚胺-3-甲酰胺-2H-色烯类衍生物还可以作为小分子荧光分子探针,具有低毒性以及特异性标记活体细胞器的特点。苯炔是一种高活性反应中间体,参与的反应类型众多,包括:亲核加成反应、σ键插入反应、环加成反应和多组分偶联反应等。由于苯炔不能单独分离得到,一般是利用苯炔前体原位生成活性中间体参与化学反应。然而通常苯炔产生的条件复杂、苛刻,限制了苯炔化学的发展。直到1983年,kobayashi合成了一种新的苯炔前体三氟甲磺酸-2-(三甲基甲硅烷基)苯基酯,在氟源作用下,可以温和定量的生成高活性苯炔,使得苯炔作为一种关键的有机合成子,在天然产物和药物中间体的制备过程中的得到了广泛应用。本文开发建立了一种直接合成2-亚胺-2H-色烯骨架的新方法,以苯炔前体、烯酮N,S-缩醛、DMF(氮氮二甲基甲酰胺)为合成子,三组分一锅法合成目标化合物。在课题确立之初,通过对原料配料比、氟源种类、溶剂、温度、加料方式等方面的优化,得到了最优条件:苯炔前体、烯酮N,S-缩醛配料比2:1,KF作为氟源,DMF(c=0.2 M)为溶剂,90 oC为最佳反应温度,苯炔前体以滴加的方式(100 uL/9 h)参与反应;值得注意的是目标产物2-亚胺-2H-色烯骨架化合物可直接通过乙醇重结晶析出,无需柱层析纯化,节省了试剂成本,节约实验人员时间。利用建立的方法成功拓展了19个底物,均能以较好的收率获得目标化合物,部分产率高达96%;此外我们亦拓展合成了生物活性骨架2-亚胺-3-甲酰胺-2H-色烯化合物,以较为可观产率得到了7个目标化合物。根据实验数据,我们提出了一个反应机理:在氟离子作用下,Kobayashi苯炔前体生成苯炔中间体,与DMF的羰基发生一个[2+2]π键加成反应,生成的四元杂环由于张力较大,不稳定,开环,生成一个邻亚甲基醌型(o-QM)中间体;而后o-QM中间体被烯酮N,S-缩醛捕获,生成一个类似[4+2]环加成产物;最终脱掉一分子二甲胺和甲硫醇得到目标化合物。所有合成的新化合物的结构都已通过IR、1H NMR、13C NMR及HRMS进行表征(部分含氟化合物3d、3e、3k和3l亦通过19F NMR表征),并且通过化合物3a的单晶数据确定了目标化合物结构。
[Abstract]:Chromene derivatives are a class of heterocyclic skeleton compounds widely existing in nature, which have a wide range of physiological and pharmacological activities. As a class of non-peptide small molecular inhibitors, the special 2-imide-3-formamide -2H-chromene derivatives have good bioactivity inhibition to some specific enzymes, which makes them as a kind of treatment for Alzheimer's disease. In addition, 2-imide-3-formamide -2H-chromene derivatives can also be used as small molecular fluorescent probes with the characteristics of low toxicity and specific labeling of organelles in vivo. Phenyne is a highly active intermediate, which involves in many kinds of reactions, including nucleophilic addition reaction, 蟽 bond insertion reaction, cycloaddition reaction and multicomponent coupling reaction. Because benzenes can not be separated from each other, the active intermediates are usually produced from the precursors of benzene acetylene in situ to take part in the chemical reaction. However, the complex and harsh conditions usually restrict the development of phenylacetylene chemistry. It was not until 1983 that Kobayashi synthesized a new phenyl ester, trifluoromethylsulfonate-2- (trimethylmethylsilyl) phenyl ester. It has been widely used in the preparation of natural products and pharmaceutical intermediates. In this paper, a new method for the direct synthesis of 2-imine-2H-chromene skeleton has been developed. The target compound is synthesized by three-component one-pot method with the precursor of phenylacetylene, ketene, N-dimethylformamide (DMF) as the synthesizer. At the beginning of the project, the optimum conditions were obtained by optimizing the ratio of raw materials, fluorine sources, solvents, temperature, feeding methods, and so on. The optimum reaction temperature was 2: 1 KF as fluorine source and 90 oC as solvent, and the precursor of phenyne participated in the reaction by drip (100 uL/9 h). It is worth noting that the target product 2-imide-2H-chromene skeleton compounds can be precipitated directly through ethanol recrystallization, without column chromatography purification, thus saving reagent cost and experimenter time. By using the established method, 19 substrates were successfully expanded, and the target compounds were obtained in good yields, some of which were as high as 96. In addition, we also extended the synthesis of biologically active skeleton 2-imine-3-formamide -2H-chromene compounds. Seven target compounds were obtained in considerable yield. Based on the experimental data, we proposed a reaction mechanism: Kobayashi benzyngene precursor was synthesized into phenylacetylene intermediate under the action of fluorine ion, and a [22] 蟺 bond addition reaction occurred with the carbonyl group of DMF. The resulting quaternary heterocyclic ring was ring opening due to high tension and instability. An intermediate of o-methylene quinone (o-QM) was formed, and then the intermediate of o-QM was captured by ketene NNS-acetal to form a product similar to [42] cycloaddition. Finally, the target compound was obtained by removing a molecule of dimethylamine and methylmercaptan. The structures of all the new compounds have been characterized by IR,1H NMR,13C NMR and HRMS (some fluorine compounds 3d3e3k and 3l have also been characterized by 19F NMR), and the structure of the target compounds has been determined by the single crystal data of compound 3a.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.3
本文编号：2252600
[Abstract]:Chromene derivatives are a class of heterocyclic skeleton compounds widely existing in nature, which have a wide range of physiological and pharmacological activities. As a class of non-peptide small molecular inhibitors, the special 2-imide-3-formamide -2H-chromene derivatives have good bioactivity inhibition to some specific enzymes, which makes them as a kind of treatment for Alzheimer's disease. In addition, 2-imide-3-formamide -2H-chromene derivatives can also be used as small molecular fluorescent probes with the characteristics of low toxicity and specific labeling of organelles in vivo. Phenyne is a highly active intermediate, which involves in many kinds of reactions, including nucleophilic addition reaction, 蟽 bond insertion reaction, cycloaddition reaction and multicomponent coupling reaction. Because benzenes can not be separated from each other, the active intermediates are usually produced from the precursors of benzene acetylene in situ to take part in the chemical reaction. However, the complex and harsh conditions usually restrict the development of phenylacetylene chemistry. It was not until 1983 that Kobayashi synthesized a new phenyl ester, trifluoromethylsulfonate-2- (trimethylmethylsilyl) phenyl ester. It has been widely used in the preparation of natural products and pharmaceutical intermediates. In this paper, a new method for the direct synthesis of 2-imine-2H-chromene skeleton has been developed. The target compound is synthesized by three-component one-pot method with the precursor of phenylacetylene, ketene, N-dimethylformamide (DMF) as the synthesizer. At the beginning of the project, the optimum conditions were obtained by optimizing the ratio of raw materials, fluorine sources, solvents, temperature, feeding methods, and so on. The optimum reaction temperature was 2: 1 KF as fluorine source and 90 oC as solvent, and the precursor of phenyne participated in the reaction by drip (100 uL/9 h). It is worth noting that the target product 2-imide-2H-chromene skeleton compounds can be precipitated directly through ethanol recrystallization, without column chromatography purification, thus saving reagent cost and experimenter time. By using the established method, 19 substrates were successfully expanded, and the target compounds were obtained in good yields, some of which were as high as 96. In addition, we also extended the synthesis of biologically active skeleton 2-imine-3-formamide -2H-chromene compounds. Seven target compounds were obtained in considerable yield. Based on the experimental data, we proposed a reaction mechanism: Kobayashi benzyngene precursor was synthesized into phenylacetylene intermediate under the action of fluorine ion, and a [22] 蟺 bond addition reaction occurred with the carbonyl group of DMF. The resulting quaternary heterocyclic ring was ring opening due to high tension and instability. An intermediate of o-methylene quinone (o-QM) was formed, and then the intermediate of o-QM was captured by ketene NNS-acetal to form a product similar to [42] cycloaddition. Finally, the target compound was obtained by removing a molecule of dimethylamine and methylmercaptan. The structures of all the new compounds have been characterized by IR,1H NMR,13C NMR and HRMS (some fluorine compounds 3d3e3k and 3l have also been characterized by 19F NMR), and the structure of the target compounds has been determined by the single crystal data of compound 3a.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.3
【参考文献】
相关博士学位论文 前1条
1 张铁欣;苯炔参与的串联或多组分反应研究[D];浙江大学;2011年
，本文编号：2252600
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