基于芳基酮醛参与的多组分串级环化反应构建杂环结构体

发布时间：2018-02-07 13:06

本文关键词：多组分反应串级环化反应自分类串级反应芳基酮醛邻氨基苄胺色胺硝基烯烃肉桂醛丁炔二酸二甲酯丙二腈芳乙酮 4-羟基香豆素硫脲二氢吡咯并[2 1-b]喹唑啉二氢中氮茚并[8 7-b]吲哚吡喃酮并[3 2-c]香豆素吡　出处：《华中师范大学》2017年博士论文　论文类型：学位论文

【摘要】：杂环化合物是一类广泛存在于各种天然产物、农药、医药以及功能材料分子中的重要核心骨架。在合成化学领域与医药行业中,对于杂环化合物的合成已成为当前研究的热点。然而从简单易得的起始原料出发直接合成具有多样性与复杂性的杂环化合物是一项十分具有挑战性的研究课题。目前,最具发展前景的合成方法之一是基于多组分串级环化反应来直接构建杂环化合物。多组分反应由于其反应效率高、原子利用率高、操作简便、步骤经济性、汇聚性、产物结构复杂性和多样性等优点广泛应用于有机合成与生物医药合成等领域之中。而串级环化反应是基于一锅中连续发生多个化学键的形成并成环的过程,不仅避免了分步反应的繁琐操作,而且节约了溶剂和试剂的消耗,具有绿色高效、经济环保的优点,因而作为一种最直观有效的合成杂环化合物的方法受到有机合成化学家们的广泛关注。本论文采用芳基酮醛参与的多组分反应作为合成策略,以串级环化反应作为媒介,通过多个单元反应的自组织集成,设计合成一系列具有潜在生物活性和药理活性的含氮、含氧以及含硫杂环化合物。主要包括以下几个部分:第一章,首先概述了多组分串级环化反应的理论,然后总结了近年来国内外多组分串级环化反应在合成杂环化合物方面的研究进展,包括基于人名反应、过渡金属催化、酸/碱介导、小分子催化以及其他条件下的多组分串级环化反应的研究,并对芳基酮醛参与的多组分串级环化反应合成多元杂环或稠环化合物进行了详细的论述。最后,提出了本论文的研究目标和研究思路。第二章,以芳基酮醛、邻氨基苄胺、硝基烯烃三组分作为反应底物,通过缩合、亲核加成、Michael加成、Henry环化、氧化芳构化等有机单元反应的集成,在酸的催化下发生串级双环化反应直接合成了 4,9-二氢吡咯并[2,1-b]喹唑啉衍生物,并且实现了一锅一步连续构建两个环,合成四个键的成键方式。该方法与前期的文献相比,具有反应高效、原料简单易得、条件温和、操作简便等优点。第三章,以芳基酮醛、色胺、硝基烯烃三组分作为反应底物,通过Pictet-Spengler环化、Michael加成、Henry环化、氧化芳构化等有机单元反应的集成,在无金属催化的条件下直接合成了二氢中氮茚并[8,7-b]吲哚衍生物,通过对活泼中间体1-芳甲酰基四氢-β-咔啉的原位捕获首次实现了生物碱类似物的一锅一步直接合成。第四章,在第三章的基础上,以芳基酮醛、色胺作为基本反应底物,生成活泼中间体1-芳甲酰基四氢-β-咔啉后,分别利用肉桂醛、丁炔二酸二甲酯、丙二腈进行原位捕获,通过多样性导向合成的策略,合成一系列不同取代基的二氢中氮茚并[8,7-b]吲哚衍生物,进一步揭示了含有α-氨基酮片段的化合物在合成杂环方面具有十分广泛的应用。第五章,基于sp3 C-H双官能团化反应的迅猛发展,我们设计以芳乙酮作为底物,对甲基sp3C-H进行碘代和Kornblum氧化生成芳基酮醛,并用两分子4-羟基香豆素进行原位捕获,形成双官能团取代的芳乙酮,进而通过酯交换、氧化芳构化等反应直接构建吡喃酮并[3,2-c]香豆素衍生物。相比传统的金属催化sp3 C-H活化并双官能团化的反应而言,此合成方法不需要使用金属催化剂、配体以及其他添加剂,具有反应条件温和、底物适用范围广泛、经济环保等优点。第六章,基于自组织反应网络的研究,我们设计将多组分串级环化反应与自分类反应有机地结合起来,形成一种新颖的多组分自分类串级环化反应,利用芳基酮醛、腈类化合物、硫脲三组分作为反应底物,通过溶剂的调控,使其化学选择性地合成四氢吡咯并[1,2-c]咪唑和四氢吡咯并[1,2-c]噻唑衍生物。第七章,对本博士论文的全部工作进行了总结,并对后期利用多组分串级环化反应策略合成杂环化合物进行了展望。
[Abstract]:Heterocyclic compounds are widely distributed in a variety of natural products, pesticide, medicine and functional materials important core molecules. In synthetic chemistry and pharmaceutical industry, for the synthesis of heterocyclic compounds has become a research hotspot. However, from readily available starting materials of direct synthesis of heterocyclic compounds with diversity and the complexity is a very challenging research topic. At present, one of the most promising synthesis method is a multicomponent cascade cyclization to directly construct heterocyclic compounds based on multicomponent reactions due to its high reaction efficiency, high atom utilization, simple operation steps, economy, convergence. The advantages of product structure complexity and diversity are widely used in organic synthesis and biological medicine synthesis field. The cascade cyclization is a continuous occurrence of multiple chemical bonds based on The formation and loop process, not only to avoid the tedious operation step, but also save solvent and reagent consumption, with a green and efficient, economical and environmental advantages, as a kind of method of the most intuitive and effective synthesis of heterocyclic compounds has attracted wide attention of synthetic organic chemists. This paper uses aryl ketone aldehyde in the multicomponent reaction as a synthetic strategy to cascade cyclization reaction as a medium, through self organization integrated multiple unit responses, design and synthesis of a series of potential biological activity and pharmacological activity of nitrogen, oxygen and sulfur heterocyclic compounds. Mainly includes the following parts: the first chapter firstly summarizes the multicomponent cascade cyclization reaction theory, then summarized the multi-component cascade ring research progress in synthesis of heterocyclic compounds on chemical reactions, including the name should be based on the transition of gold A catalytic, acid / base mediated multicomponent cascade cyclization of small molecular catalysis and other conditions, and the aryl ketone aldehyde in multi-component cascade cyclization to synthesize multiple heterocycles or fused ring compounds are discussed in detail. Finally, this paper puts forward the research objectives and research ideas. In the second chapter, with aryl ketone aldehyde, o-amino benzylamine, nitroalkene three components as substrates, through condensation, nucleophilic addition, Michael addition, Henry cyclization, integrated oxidation aromatization reaction of organic unit, occurrence of cascade double loop reaction in acid under the catalysis of the direct synthesis of 4,9- two pyrrolidine and [2,1-b] quinazoline derivatives, and the realization of the two step continuous construction of a key ring, into synthesis of four key. Compared with the previous methods of the literature, has high efficiency, easily available raw materials, mild conditions, simple operation and other advantages. No. In chapter three, aryl ketone aldehyde, amine, nitro olefin of three components as substrates, the Pictet-Spengler ring, Michael addition, Henry cyclization, integrated oxidation aromatization reaction in organic unit, metal free catalytic conditions for direct synthesis of two hydrogen indolizine and [8,7-b] indole derivatives by in situ 1- of active intermediates arylformyl four hydrogen - carboline alkaloids capture is realized for the first time a similar step direct synthesis. The fourth chapter, on the basis of the third chapter, with aryl ketone aldehyde, tryptamine as the basic substrate, generating active intermediate aroyl 1- four hydrogen acyl beta carboline, respectively using cinnamaldehyde, acetylenedicarboxylate two methyl propylene nitrile, two in situ capture, through the strategy of diversity oriented synthesis, the synthesis of a series of different substituted two hydrogen indolizine and [8,7-b] indole derivatives, further reveals the fragment containing alpha amino ketone The compounds are widely used in the synthesis of heterocycles. The fifth chapter, the rapid development of SP3 C-H bifunctional reaction based on our design based on aromatic acetophenone as substrate of iodine and Kornblum oxidation of aryl ketone aldehyde to methyl sp3C-H, with two molecules of 4- hydroxy coumarin in situ capture, formation bifunctional substituted aryl methyl ketone, then through ester exchange, oxidative aromatization reaction and direct construction of pyrone derivatives. Compared with the traditional [3,2-c] coumarin metal catalyzed SP3 activation of C-H and double functionalization reaction, this method does not require the use of metal catalysts, ligands and other additives, with mild reaction conditions, substrate for a wide range of economic, environmental protection and other advantages. In the sixth chapter, the study of self organization reaction based on network, we design the multi-component cascade cyclization reaction and self classification combination machine Together, the formation of a novel multi component self sorting tandem cyclization reaction with aryl ketone aldehyde, nitriles, thiourea three components as substrates, through the solvent control, the chemical selective synthesis of pyrrolidine and four [1,2-c] imidazole and four hydrogen pyrrolo [1,2-c] thiophene derivatives seventh. Chapter, all the works of this dissertation are summarized, and the later use of multi-component cascade cyclization strategy for synthesis of heterocyclic compounds is prospected.

【学位授予单位】：华中师范大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O626

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