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学科主题: 药物化学
题名:
钯催化的C-H键官能团化和CO-羰基化策略在杂环与羰基化合物合成中的应用
作者: 任龙
答辩日期: 2013-12-30
导师: 焦宁
专业: 药物化学
授予单位: 北京大学
授予地点: 北京大学药学院
学位: 硕士
关键词: 钯催化、C-H 键官能团化、CO、羰基化、吡咯、吲哚、异氰酸酯、氨 基甲酸酯、二芳基甲酮
其他题名: Syntheses of Heterocycles and Carbonyls via Palladium Catalyzed C-H Functionalization and CO-Carbonylation
分类号: R914.5
摘要: 传统的钯催化偶联方法需要使用芳环预先被卤化或拟卤化的底物。而直接的钯催化C-H键官能团化偶联则不再需要预先活化的底物,避免了大量卤素副产物的产生,更加符合化学反应的原子经济性、环境友好性及可持续性发展要求。 CO是“C1化学”或构建羰基结构的重要碳源。钯催化的CO-羰基化反应灵活多样,应用广阔。使用易得CO气体参与的羰基化反应合成,避免了高能耗羰基化合成试剂的大量使用和浪费,为产物结构中羰基的引入提供了一条捷径。硕士研究生阶段,我们将这两个钯催化反应策略应用到了以下三个课题的研究之中。 课题一: 2, 3-二氢-1H-吡咯[1,2-a]并吲哚是许多生物活性分子及药物的核心骨架。这种骨架具有天然的生源性,早期被发现于微生物的代谢产物丝裂霉素(一种抗肿瘤抗生素)中。随后,许多含有此骨架结构的生物活性分子被相继发现或合成出来。该结构较特殊,具吲哚五元环与另一五元环通过C-N键骈合的情况,合成具有挑战性,通常需要进行多步合成。通过采用分子内胺氢化与碳氢键官能团化串联关环策略,我们发展了一种钯催化由简单氮炔基取代芳胺直接构建此类骈合吲哚结构的氧化环化方法学。该方法利用氧气为唯一氧化剂,为含有此类结构母核的药物或生物活性分子的合成提供了一条更为简洁的合成路线。 课题二: 异氰酸酯的反应活性高,转化多样,应用广泛,是有机合成中的重要中间体。氨基甲酸酯作为它的重要转化产物之一,被广泛地应用于生物医药、农业及材料等各个领域。生物医药研究中,大量生物活性分子被报道具有氨基甲酸酯类结构,其中有许多已被开发成为上市药物。然而异氰酸酯本身的合成研究却相对滞后。一般需要使用到大量环境友好性差的高能耗合成试剂,且常常伴随有大量反应废弃物的产生。另一些金属催化的方法则需要苛刻的反应条件,转化的可控性较差。 利用CO将有机叠氮直接羰基化是生成异氰酸酯的一种更为快捷的方法。过去这类反应的报道都具有较大的方法局限性。我们组利用钯催化的CO-羰基化策略,常压下实现了有机叠氮向异氰酸酯的高效转化;并以之为中间体与醇现场一锅法制得了氨基甲酸酯。发展了从有机叠氮向氨基甲酸酯的直接合成方法。本法对有机叠氮化物和羟基化物均有宽广的适用性,对各种活性官能团都具有很好的兼容性,且只需2 mol%的PdCl2盐作催化剂,反应在一个大气压CO下进行,无需其他配体或添加剂。方法的实用性还体现在它可用以顺利地构建含氨基甲酸酯结构的大环化合物。体系温和中性,使得此法可被用于氨基甲酸酯类生物活性分子的系列修饰。 课题三: 二芳基甲酮是一类重要的化学结构,它广泛地存在于各种生物活性分子、天然提取物、功能分子及高级材料之中;同时也是有机化学中常用的碳碳键形成砌块和转化中间体。传统的二芳基甲酮合成方法需要过量的路易斯酸,或使用高能活泼金属试剂。金属催化CO-羰基化反应的广泛应用为二芳基甲酮合成提供了更为简洁高效的方法选择,避免了芳香酰基化物的预先制备和使用。芳基硼酸具有易得、无毒且对空气和湿度都很稳定等优点,使用方便。我们利用廉价环境友好的氧气氧化的钯催化CO-羰基化策略,发展了芳基硼酸高化学选择性合成对称二芳基甲酮的方法学。本方法仅需2.5 mol%的简单催化剂PdCl2(PPh3)2,且具有广阔的底物适用性和较好的官能团兼容性。
英文摘要: Aromatic (Pseudo)Halides are needed in traditional palladium catalyzed couplings. Whereas, the couplings via direct Pd catalyzed C-H functionalization skip over those pre-activated substrates, avoiding large-scale outputting of halides wastes, thus makes this strategy much more satisfiable for the requirements of atom-economy, environmental friendliness and sustainability. CO is an important carbon source for “C1 chemstry” or carbonyl building. Pd-catalitc CO-carbonylation reactions are versatile and widely used. Applying the readily available CO involved carbonylation reaction spares the using and wasting of “energetic” carbonylation reagents. This strategy gives a short cut for carbonyl assembling into the products. The two strategies have been applied in three research subjects bellow during my graduate study. Subject 1: 2,3-Dihydro-1H-pyrrolo[1,2-a]indole is a core structure of many bioactive molecules and pharmaceuticals. It was early found to be naturally originated in microbial metabolites, mitomycin antibiotics. Afterward, large numbers of bioactive compounds containing this skeleton have also been discovered and synthesized. This special indole structure with two ?ve-membered rings fused together by a C-N bond as a bridge makes the synthesis more challenging and usually need multiple steps. A Pd catalyzed aerobic oxidative approach to this indole structure from simple N-alkynyl anilines through tandem intramolecular hydroamination and aryl C-H functionalization cyclization process has been developed. Molecular oxygen was used as the sole oxidant, providing a more convenient route for the synthesis of bioactive molecules and pharmaceuticals containing this structure. Subject 2: Isocyanate is a valued building block for organic synthesis for its high reactivity, multiple transformability and wide applications. As one of its important transformation, carbamate has been broadly used in various fields, such as medicine, agriculture and materials. In pharmaceutical research, large numbers of bioactive molecules have been reported possessing a carbamate scaffold, and many of which have been developed into marketed drugs. The synthesis of isocyante, however, is relatively reluctant. Lots of environmentally unfriendly energy-intensive reagents are needed in isocyanate synthesis, bringing forth large quantities of chemical waste. Other metal catalytic methods require harsh conditions or have poor conversion controlling. There is a straight approach to isocyanate through direct carbonylation of organic azides by carbon monoxide. However, various method limitations still remained in reported works. Employing Pd catalyzed CO-carbonylation strategy, isocyanate has been formed from organic azides under an ambient pressure, and served as an intermediate to react with alcohols in situ to synthesize carbamate in one pot. Thus a synthesis of carbamates directly from organic azides has been developed in our group. This methodology has broad scope for both organic azides and hydroxides, and general compatibility for diverse functional groups. Only 2 mol% PdCl2 salt serve as the catalyst and the reaction procedes under an ambient CO, no need for any ligand or additives in this reaction. Its applicability is attributed as well to the ability of synthesizing carbamate macrocycles. The mild and neutral condition makes the reation a method for serial modification of bioactive carbamates. Subject 3: Diarylmethanone is an important chemical structure, exists widely in bioactive molecules, natural extracts, functional molecules, and advanced materials, and also is an often-used building block and transformable intermediate in organic chemistry. Traditional synthesis of diarylmethanone needs either excessive Lewis acids or reactive organometal reagents. The burgeoning strategy of metal catalytic CO-carbonylation provides a conveniently efficient route for diarylmethanone synthesis, evading the pre-preparation and use of aryl acid derivatives. Aryl boronic acids are readily available, nontoxic, air- and moisture-stable, and easy to use. Utilizing cheaper and more environmentally friendly O2 as oxidant for Pd catalyzed CO-carbonylation strategy, a highly chemical selective protocal has been developed for the synthesis of symmetric diarylmethanone from aryl boronic acid in our group. This protocol costs only 2.5 mol% simple catalyst PdCl2(PPh3)2, presenting a broad substrate scope and tolerant for various functional groups.
语种: 中文
出处: http://xuewei.bjmu.edu.cn/simpsearch.action?keyword=钯催化的C-H键官能团化和CO-羰基化策略在杂环与羰基化合物合成中的应用&dbid=72
相关网址: 查看原文
内容类型: 学位论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/107271
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作者单位: 北京大学药学院

Recommended Citation:
任龙. 钯催化的C-H键官能团化和CO-羰基化策略在杂环与羰基化合物合成中的应用[D]. 北京大学药学院. 北京大学. 2013.
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