过渡金属催化吲哚苯环区域选择性官能团化研究

发布时间：2018-11-06 12:12

【摘要】：吲哚及其衍生物是天然产物及药物活性分子的重要骨架,吲哚环的官能团化一直都是有机合成领域的热门研究方向。由于吲哚当中吡咯环上电子云密度较高,较易进行反应,近年来已经有大量关于吲哚C2和C3位官能团化的工作见诸报道。然而关于吲哚苯环区域官能团化反应的研究,在有机合成界尚属少见。有鉴于此,本论文发展了一系列过渡金属催化体系,通过不同反应条件与导向基团的调控,高区域选择性地得到了吲哚苯环区域各位置官能团化产物。本论文具体的研究内容包括如下几部分:第一部分:我们从过渡金属催化的角度出发,以一类大位阻二叔丁基磷氧作为导向基团,利用Pd(OAc)_2作为催化剂,芳基硼酸作为芳基源,2-氯吡啶作为配体,银盐和铜盐作为氧化剂,完美地克服了 2,3号位的优先顺序问题,首次成功实现了吲哚7号位高选择性的直接芳基化。该反应体系底物范围广,区域选择性高,极有望拓展到其他吲哚C7位C-H官能团化反应体系,为接下来的课题研究打下了基础。第二部分:利用之前开发的二叔丁基磷氧作为导向基团,以CuO作为催化剂,二芳基高碘化物作为芳基源,在不加任何配体和添加剂的作用下,高区域选择性地实现了吲哚6号位的直接芳基化。该反应底物对不同官能团耐受性好,区域选择性高,产率普遍优异。我们设计了一个连续合成反应,其高产率和高区域选择性说明了该反应体系的应用价值。第三部分:通过在吲哚C3位引入特戊酰基作为导向基团,以Pd(PPh_3)_2C1_2为催化剂,芳基碘化物为芳基源,Ag_2O为氧化剂,DBU为碱,在溶剂HFIP当中高区域选择性地实现了吲哚4号位的直接芳基化。该反应区域选择性高,底物范围广,同时导向基团易脱除。在克级反应实验当中,反应仍然具有很好的区域选择性和产率。通过一个天然产物分子的合成示例,证明了该反应策略在分子合成中的应用价值。第四部分:利用之前开发的二叔丁基磷氧官能团化的吲哚作为底物,以P(p-CF_3C_6H_4)_3AuNTf_2作为催化剂,α-苯基酯重氮化合物为卡宾前体,HNTf_2为添加剂,高区域选择性地实现了吲哚苯环区域的直接烷基化。底物拓展表明该反应体系具有良好的区域选择性。
[Abstract]:Indole and its derivatives are important skeletons of natural products and drug active molecules. The functionalization of indole ring has always been a hot research direction in organic synthesis. Due to the high electron cloud density of pyrrole ring in indole, there have been a lot of reports on indole-C2 and C3 functionalization in recent years. However, studies on the regional functionalization of indole ring are rare in organic synthesis. In view of this, a series of transition metal catalytic systems were developed in this paper. Through the regulation of different reaction conditions and guided groups, the functionalized products of various positions in the indole ring region were obtained selectively in the high region. The specific research contents of this thesis are as follows: the first part: from the point of view of transition metal catalysis, we use Pd (OAc) _ 2 as the catalyst with a large hindrance of tert-Ding Ji as the guiding group. Aryl boric acid as aryl source, 2-chloropyridine as ligand, silver salt and copper salt as oxidant, which perfectly overcome the priority of 2,3 sites, and successfully realized the highly selective direct arylation of indole 7 site for the first time. This reaction system has a wide range of substrates and high regioselectivity, which is expected to be extended to other C-H functionalized reaction systems at indole C _ 7 position, which will lay a foundation for further research. The second part: using the second tert-Ding Ji as the guiding group, CuO as the catalyst and the diaryl polyiodide as the aryl source, without any ligands and additives. The direct arylation of indole 6 site is realized selectively in high region. The substrate has good tolerance to different functional groups, high regional selectivity and excellent yield. A continuous synthetic reaction was designed, and its high yield and high region selectivity showed the application value of the reaction system. The third part: by introducing tervalyl group as the guiding group at indole-C3 site, using Pd (PPh_3) _ 2C1_2 as catalyst, aryl iodide as aryl source, Ag_2O as oxidant, DBU as base, The direct arylation of indole 4 site was achieved in high region selectivity in solvent HFIP. The region selectivity of the reaction is high, the substrate range is wide, and the guided group is easy to be removed. The reaction still has good regioselectivity and yield. The application value of this reaction strategy in molecular synthesis is proved by an example of the synthesis of natural product molecules. The fourth part: using indoles as substrate, using P (p-CF_3C_6H_4) _ 3AuNTf_2 as catalyst, 伪 -phenyl ester diazo compound as carbene precursor and HNTf_2 as additive. The direct alkylation of indole ring was realized selectively in high region. The substrate expansion shows that the reaction system has good regioselectivity.
【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.251

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