基于芳炔參與的新型反應研究
發(fā)布時間：2018-10-05 07:56
【摘要】：色烯類衍生物是一類在自然界中廣泛存在的雜環(huán)類骨架化合物,具有廣泛生理活性和藥理活性。特別的,2-亞胺-3-甲酰胺-2H-色烯類衍生物是一類非肽類小分子抑制劑,對一些特定酶具有良好的生物活性抑制性能,這使得其可以作為一種被用于治療阿茲海默、癌癥等疾病的藥物;此外,2-亞胺-3-甲酰胺-2H-色烯類衍生物還可以作為小分子熒光分子探針,具有低毒性以及特異性標記活體細胞器的特點。苯炔是一種高活性反應中間體,參與的反應類型眾多,包括:親核加成反應、σ鍵插入反應、環(huán)加成反應和多組分偶聯(lián)反應等。由于苯炔不能單獨分離得到,一般是利用苯炔前體原位生成活性中間體參與化學反應。然而通常苯炔產生的條件復雜、苛刻,限制了苯炔化學的發(fā)展。直到1983年,kobayashi合成了一種新的苯炔前體三氟甲磺酸-2-(三甲基甲硅烷基)苯基酯,在氟源作用下,可以溫和定量的生成高活性苯炔,使得苯炔作為一種關鍵的有機合成子,在天然產物和藥物中間體的制備過程中的得到了廣泛應用。本文開發(fā)建立了一種直接合成2-亞胺-2H-色烯骨架的新方法,以苯炔前體、烯酮N,S-縮醛、DMF(氮氮二甲基甲酰胺)為合成子,三組分一鍋法合成目標化合物。在課題確立之初,通過對原料配料比、氟源種類、溶劑、溫度、加料方式等方面的優(yōu)化,得到了最優(yōu)條件:苯炔前體、烯酮N,S-縮醛配料比2:1,KF作為氟源,DMF(c=0.2 M)為溶劑,90 oC為最佳反應溫度,苯炔前體以滴加的方式(100 uL/9 h)參與反應;值得注意的是目標產物2-亞胺-2H-色烯骨架化合物可直接通過乙醇重結晶析出,無需柱層析純化,節(jié)省了試劑成本,節(jié)約實驗人員時間。利用建立的方法成功拓展了19個底物,均能以較好的收率獲得目標化合物,部分產率高達96%;此外我們亦拓展合成了生物活性骨架2-亞胺-3-甲酰胺-2H-色烯化合物,以較為可觀產率得到了7個目標化合物。根據(jù)實驗數(shù)據(jù),我們提出了一個反應機理:在氟離子作用下,Kobayashi苯炔前體生成苯炔中間體,與DMF的羰基發(fā)生一個[2+2]π鍵加成反應,生成的四元雜環(huán)由于張力較大,不穩(wěn)定,開環(huán),生成一個鄰亞甲基醌型(o-QM)中間體;而后o-QM中間體被烯酮N,S-縮醛捕獲,生成一個類似[4+2]環(huán)加成產物;最終脫掉一分子二甲胺和甲硫醇得到目標化合物。所有合成的新化合物的結構都已通過IR、1H NMR、13C NMR及HRMS進行表征(部分含氟化合物3d、3e、3k和3l亦通過19F NMR表征),并且通過化合物3a的單晶數(shù)據(jù)確定了目標化合物結構。
[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.
【學位授予單位】：青島科技大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O621.3
本文編號：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.
【學位授予單位】：青島科技大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：O621.3
【參考文獻】
相關博士學位論文 前1條
1 張鐵欣;苯炔參與的串聯(lián)或多組分反應研究[D];浙江大學;2011年
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