镍催化的异腈和硫脲类化合物的新型反应研究
发布时间：2018-11-25 08:11
【摘要】：噻唑类化合物是一类重要的含N、S的杂环化合物,以其独特的化学结构而具有良好的药理活性和生物活性,广泛应用于医药、农药领域。异腈作为C1合成子,代表了一类重要的反应活性物种,广泛应用于含氮杂环的构建。镍具有多种氧化态和温和的氧化加成能力,并且性质稳定、廉价经济,近年来发展了一系列新型的镍催化反应。在第一章,分别对噻唑类化合物的传统合成方法,异腈插入反应的进展以及镍催化反应进行了综述。在第二章,利用镍催化的异腈插入反应建立了一种简单、高效、生态友好的合成三亚胺噻唑化合物的新方法。以环己基异腈和1,3-二苯基硫脲为模型底物,分别从镍催化剂种类、用量,以及溶剂、温度等方面进行了条件探索,并确定最佳条件为:3 mol%的Ni(acac)2为催化剂,丙酮溶剂中,50oC条件下反应1h。反应结束后无需柱层析,抽滤、洗涤即可得到目标产物。在此基础上,利用多样性的异腈和硫脲进行了底物拓展,该方法表现出很好的底物适用性(39 examples;40-93%yields),二芳基、二烷基以及二杂环取代的硫脲都顺利发生了反应;并且不对称硫脲表现出很高的区域选择性。接着进行了一系列机理研究实验:首先,通过单晶衍射分析确定中间体Ni(DPTU)2的结构,并验证其催化活性(1 mol%,93%yield);其次,对照实验结果显示Ni(0)、Ni(II)无氧条件下均不能催化该反应,一则证明该催化循环由Ni(II)启动,再者证明反应过程中需要氧气将还原消除得到的Ni(0)氧化成Ni(II)来完成催化循环;第三,通过XPS对反应过程中镍的价态变化进行了分析佐证;在此基础之上提出了可能的反应机理。最后,对该方法的克级规模反应进行了初步研究,得到产率85%的目标产物。所合成化合物的结构均经IR、1H NMR、13C NMR和HRMS分析确定。该方法的最大特点是:催化剂用量小、低毒廉价,原料经济易得,溶剂绿色,反应高效,原子经济性好,底物范围广,操作简单,可克级规模制备。
[Abstract]:Thiazoles are an important class of heterocyclic compounds containing Nu S, which have good pharmacological and biological activities due to their unique chemical structure, and are widely used in medicine and pesticide fields. Isonitrile, as a C1 synthesizer, represents a class of important reactive species and is widely used in the construction of nitrogen-containing heterocycles. Nickel has a variety of oxidation states and mild oxidation addition ability, and its properties are stable, cheap and economical. In recent years, a series of new nickel catalytic reactions have been developed. In the first chapter, the traditional synthesis methods of thiazole compounds, the progress of isonitrile insertion reaction and nickel catalytic reaction were reviewed. In chapter 2, a simple, efficient and eco-friendly method for the synthesis of triamothiazole compounds was established by nickel catalyzed isonitrile insertion reaction. Using cyclohexylisonitrile and 1-diphenyl thiourea as model substrates, the conditions of nickel catalyst type, dosage, solvent and temperature were studied respectively. The optimum conditions were determined as follows: 3 mol% Ni (acac) _ 2 as catalyst. In acetone solvent, the reaction time was 1 h under 50oC condition. At the end of the reaction, the target product can be obtained without column chromatography, filtration and washing. On this basis, the substrate was expanded by using a variety of isonitrile and thiourea. The method showed good substrate applicability (39 examples;40-93%yields), and the reaction of diaryl, dialkyl and diheterocyclic thiourea was successful. And asymmetric thiourea showed high regioselectivity. Then a series of mechanism experiments were carried out. Firstly, the structure of the intermediate Ni (DPTU) _ 2 was determined by single crystal diffraction analysis, and its catalytic activity (1 mol%,93%yield) was verified. Secondly, the results showed that Ni (0), Ni (II) could not catalyze the reaction. It was proved that the catalytic cycle was initiated by Ni (II). Furthermore, it is proved that oxygen is needed to oxidize Ni (0) to Ni (II) in order to complete the catalytic cycle. Thirdly, the valence state of nickel in the reaction process was analyzed by XPS, and the possible reaction mechanism was put forward. Finally, a preliminary study on the gram scale reaction of this method was carried out, and the target product in 85% yield was obtained. The structures of the synthesized compounds were determined by IR,1H NMR,13C NMR and HRMS. The main characteristics of this method are: small amount of catalyst, low toxicity and low cost, cheap raw material, green solvent, high reaction efficiency, good atomic economy, wide substrate range, simple operation, and can be prepared on a g scale.
【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】：O621.251
本文编号：2355411
[Abstract]:Thiazoles are an important class of heterocyclic compounds containing Nu S, which have good pharmacological and biological activities due to their unique chemical structure, and are widely used in medicine and pesticide fields. Isonitrile, as a C1 synthesizer, represents a class of important reactive species and is widely used in the construction of nitrogen-containing heterocycles. Nickel has a variety of oxidation states and mild oxidation addition ability, and its properties are stable, cheap and economical. In recent years, a series of new nickel catalytic reactions have been developed. In the first chapter, the traditional synthesis methods of thiazole compounds, the progress of isonitrile insertion reaction and nickel catalytic reaction were reviewed. In chapter 2, a simple, efficient and eco-friendly method for the synthesis of triamothiazole compounds was established by nickel catalyzed isonitrile insertion reaction. Using cyclohexylisonitrile and 1-diphenyl thiourea as model substrates, the conditions of nickel catalyst type, dosage, solvent and temperature were studied respectively. The optimum conditions were determined as follows: 3 mol% Ni (acac) _ 2 as catalyst. In acetone solvent, the reaction time was 1 h under 50oC condition. At the end of the reaction, the target product can be obtained without column chromatography, filtration and washing. On this basis, the substrate was expanded by using a variety of isonitrile and thiourea. The method showed good substrate applicability (39 examples;40-93%yields), and the reaction of diaryl, dialkyl and diheterocyclic thiourea was successful. And asymmetric thiourea showed high regioselectivity. Then a series of mechanism experiments were carried out. Firstly, the structure of the intermediate Ni (DPTU) _ 2 was determined by single crystal diffraction analysis, and its catalytic activity (1 mol%,93%yield) was verified. Secondly, the results showed that Ni (0), Ni (II) could not catalyze the reaction. It was proved that the catalytic cycle was initiated by Ni (II). Furthermore, it is proved that oxygen is needed to oxidize Ni (0) to Ni (II) in order to complete the catalytic cycle. Thirdly, the valence state of nickel in the reaction process was analyzed by XPS, and the possible reaction mechanism was put forward. Finally, a preliminary study on the gram scale reaction of this method was carried out, and the target product in 85% yield was obtained. The structures of the synthesized compounds were determined by IR,1H NMR,13C NMR and HRMS. The main characteristics of this method are: small amount of catalyst, low toxicity and low cost, cheap raw material, green solvent, high reaction efficiency, good atomic economy, wide substrate range, simple operation, and can be prepared on a g scale.
【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】：O621.251
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相关期刊论文 前2条
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2 赵娜;张西臣;;硝唑尼特临床应用研究进展[J];中国病原生物学杂志;2010年02期
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