金属催化的串联反应：多取代三氮唑及氧化吲哚衍生物的高效合成

发布时间：2018-06-26 19:38

  本文选题：金属催化 + 全取代三氮唑　； 参考：《山东大学》2017年博士论文

【摘要】：1,2,3-三氮唑在有机化合物中是一类非常重要的骨架,其在医药、生物化学以及材料化学领域也有广泛的应用。近年来,有研究表明三氮唑也可作为配体或导向基团用于碳氢键活化,也可以作为卡宾的前驱体应用到有机合成中。最初,三氮唑的合成是利用1,3-Huisgen环加成,但是这类反应通常需要高温,并且反应时间较长,选择性不好。2002年,Sharpless、Fokin和Meldal等人报道了铜催化的叠氮和炔的环加成反应(CuAAC),此反应可以高效的合成单一构型的产物1,4-二取代1,2,3-三氮唑。CuAAC反应具有高效、反应条件温和、优良的化学选择性及区域选择性、良好的官能团兼容性等优点,因此成为click反应最具代表性的反应之一。尽管CuAAC反应在过去的十几年中被广泛的关注,但是,这类反应只能利用端炔作为底物与叠氮环加成合成1,4-二取代1,2,3-三氮唑。若是非端炔利用此反应条件与叠氮环加成则会因为活化能垒较高而导致反应活性降低,并且反应选择性差。化学家们利用1,4-二取代三氮唑作为底物,利用碳氢键活化过程可以合成全取代三氮唑化合物,但是碳氢键活化过程需要比较苛刻的条件。因此,本论文以金属催化的串联反应为手段,发展了一系列合成全取代三氮唑化合物以及氧化吲哚衍生物,四氢吡咯等五元含氮杂环化合物的方法,具体内容如下:第一章,利用Cu/Pd双金属催化叠氮、炔和芳基卤化物的反应,一锅法合成了全取代三氮唑。传统的铜催化的叠氮和端炔的环加成反应只能得到1,4-二取代三氮唑,而全取代三氮唑的合成具有很大的挑战。利用CuAAC反应的中间体5-Cu三氮唑与反应体系中原位生成的芳基钯物种发生转金属化再进行还原消除可高效构建全取代三氮唑。此反应不仅条件温和、选择性好、底物范围广,而且可以应用于一些具有生物活性的天然产物和氨基酸的进一步修饰中。第二章,利用Cu催化的click反应合成了稳定的5-Sn三氮唑,并对其应用进行了深入研究。CuAAC反应的中间体5-Cu三氮唑被三正丁基甲氧基锡捕获生成较为稳定的5-Sn三氮唑。金属三氮唑在以往的文献中也有报道,但是往往都不能分离得到,为了增加其稳定性需要加入特定的配体,使其应用受到了很大的限制。而5-Sn三氮唑对空气、湿度和光都不敏感,可以在4℃下保存数周,应用范围广泛,可以通过Stille偶联反应进一步修饰,也可以与硫三氟甲基试剂和三氟甲基试剂反应得到氟化的三氮唑化合物。第三章,Pd催化的不饱和酰胺的分子内芳基化反应合成3,3-二取代氧化吲哚衍生物。这类化合物是一类重要的结构单元,在天然产物和活性药物化合物中都广泛存在。通过Pd催化的不饱和酰胺的分子内芳基化/硼化反应得到含硼的氧化吲哚衍生物。在研究中发现,将反应溶剂替换而其他反应条件不变时,可以得到还原Heck产物。控制实验结果表明,还原Heck产物是由硼化的氧化吲哚化合物转化得到的。第四章,Au催化的未活化炔烃的直接四功能化反应构建四氢吡咯类化合物。近年来,碳碳双键的直接双功能化反应受到了科学家的青睐。通过过渡金属催化或高价卤化物活化可以实现双键的氧胺化、双氧化以及双胺化等反应。将此推及到炔烃,以Au为催化剂成功构建了四氢吡咯类化合物。
[Abstract]:1,2,3- three azoles are a very important class of organic compounds in organic compounds. They are also widely used in the fields of medicine, biochemistry and material chemistry. In recent years, studies have shown that three azoles can also be used as ligands or guiding groups for hydrocarbon activation, and can also be used as precursors of CABBEEN to organic synthesis. Initially, three nitrogen The synthesis of azoles is the use of 1,3-Huisgen ring addition, but this kind of reaction usually requires high temperature, and the reaction time is long. The selective poor.2002 years, Sharpless, Fokin and Meldal et al. Reported the copper catalyzed azide and alkyne cycloaddition reaction (CuAAC). This reaction can efficiently synthesize the single configuration product 1,4- two instead of 1,2,3- three azoles.Cu The AAC reaction has the advantages of high efficiency, mild reaction conditions, good chemical selectivity and regioselectivity, good functional group compatibility and so on. Therefore, the reaction of the click reaction is one of the most representative reactions. Although the CuAAC reaction has been widely concerned in the past decade, this kind of reaction can only be used as a substrate and azide ring. 1,4- two substituted 1,2,3- three azoles. If non terminal alkynes use this reaction condition and the addition of azide ring, the reaction activity is reduced because of the higher activation energy barrier, and the reaction selectivity is poor. The chemists use the 1,4- two to replace three azoles as the substrate, and use the hydrocarbon bond activation process to synthesize the completely substituted three azoles. The activation process of hydrocarbon bonds requires more stringent conditions. Therefore, in this paper, a series of methods for synthesizing total substituted three azoles and five membered nitrogenous heterocyclic compounds, such as four hydrogen pyrrole, are developed by means of metal catalyzed series reaction. The specific contents are as follows: the first chapter, using Cu/Pd bimetallic catalysis The reaction of nitrogen, alkyne and aryl halides has been prepared by one pot synthesis of three azoles. Traditional copper catalyzed azide and endyne cycloaddition reactions can only get 1,4- two to replace three azoles, while the synthesis of total substituted three azoles has great challenge. The intermediate 5-Cu three azoles using the intermediate of CuAAC reaction and the in situ aryl palladium in the reaction system The total substitution of three azoles can be constructed by metallization and reduction. The reaction is not only mild, selective, and wide, but also can be used in the further modification of some natural products and amino acids with biological activity. The second chapter, the stable 5-Sn three azoles are synthesized by the click reaction catalyzed by Cu. The intermediate 5-Cu three azazole, the intermediate of the.CuAAC reaction, is captured by tri n-butyl methoxy to produce more stable 5-Sn three azazole. Metal three azazole is also reported in the previous literature, but it is often inseparable. In order to increase its stability, it needs to be added to a specific ligand, so that its application has been applied. 5-Sn three azazole is not sensitive to air, humidity and light. It can be preserved at 4 for weeks and is widely used. It can be further modified by Stille coupling reaction, and can be reacted with sulfur three fluoromethyl and three fluoromethyl reagents to get fluorinated three azolides. Third chapter, Pd catalyzed unsaturated amides. 3,3- two substituted indole derivatives are synthesized by intron arylation reaction. These compounds are an important class of structural units, which exist widely in natural products and active drug compounds. The oxidation indole derivatives containing boron are obtained by the intramolecular arylation / boriding reaction of unsaturated amides catalyzed by Pd. In the study, the reaction was found to be a reaction. Heck products can be reduced by solvent replacement and other reaction conditions. Control results show that the reduction of Heck products is obtained by the conversion of boronizing indole compounds. The fourth chapter, the direct four functionalization of Au catalyzed by unactivated alkynes, to construct four hydrogen pyrroles. In recent years, the direct dual function of carbon carbon double bonds The reaction has been favored by scientists. Through transition metal catalysis or high valent halide activation, the reactions of double bonds, such as oxygen amination, dioxidation and diamination, are applied to alkynes, and four pyrroles have been successfully constructed with Au as a catalyst.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O626
，

本文编号：2071180