无金属体系下偶联反应在杂环合成中的探索与应用
发布时间：2018-11-08 19:16
【摘要】：“无过渡金属催化的偶联反应”,由于该类反应能够高效地构建C-C键或CX(杂)键,引起了有机化学家的大量关注并得到了长足的发展。结合本组的实际研究工作和一贯坚持的高原子经济性和绿色化学的理念,我们围绕着无金属、高效性和绿色可持续三个基本点开展了以下的探索工作并取得了一些成果。其主要内容如下:(1)TEA/DMF体系促进的分子间环化反应在TEA(三乙胺)/DMF(N,N-二甲基甲酰胺)体系的促进下,一步构建CC键和C-N键。这一碱催化的串联环化过程适用于多种3-(杂)芳基-3-卤代丙烯醛类化合物与1,2,3,4-四氢异喹啉(及其衍生物)之间进行反应,并以高收率获得相应的吡咯[2,1-a]异喹啉类化合物(产率高达97%)。机理控制实验揭示出该过程并不经历自由基中间体,依据所有的实验结果,我们谨慎提出了可能的机理,该过程很可能经历了亚胺中间体,进而完成最后的偶联反应;或者,该过程还有可能经过先亲核加成再消除的途径来进行。(2)TBAC/TBHP体系促进的分子间环化反应在TBAC(四丁基氯化铵)/TBHP(叔丁基过氧化氢)体系的促进下,一步构建两根C-C键。在简单的K2HPO4存在的条件下,TBAC和TBHP催化了2-异氰基联苯(及其衍生物)与DMF间的反应,对应产物可以以中等到优秀的产率得到(产率高达86%)。这是我们初次通过一个可能的自由基环化过程来构建啡啶-6-羧酸酰胺类化合物。虽然,这一部分的工作仍有欠佳之处,但是,这它却为之后的自由基偶联工作积累了宝贵的经验。(3)TBAB/TBHP体系促进的分子间环化反应在TBAB(四丁基溴化铵)/TBHP体系的促进下,一步构建C-C键和C-S键。这一简单的反应适用于多种2-异氰基联苯与硫醇类(亦或苯硫酚类)化合物进行反应,对应的6-芳基(烷基)噻啡啶可以以中等到优秀的产率获得(产率高达86%)。此外,根据一系列机理控制实验的结果和HRMS检测到的被TEMPO捕获的巯基自由基,我们知道了这是一个自由基类型的反应,并且该反应是一个直接活化S-H键的过程,进而我们给出了一个可能的机理。(4)NH4I/TBHP体系促进的分子间环化反应在NH4I/TBHP体系的促进下,一步构建C-C键和C-N键。与第一部分工作不同,我们希望这一反应可以通过自由基途径来完成。考虑到无金属体系下N-自由基中心构建及其他的一些困难,基于我们现有的经验,我们正在着手探索通过自由基偶联的手段合成6-氨基取代的啡啶类化合物。经过筛选,我们以糖精作为最优氮源,以之与2-异氰基联苯进行反应,NH4I/TBHP是目前的最优的催化体系,该体系下产率可达46%,后续优化和探索工作仍在进行中。
[Abstract]:"Coupling reaction without transition metal catalysis", which can efficiently construct C-C bond or CX bond, has attracted a lot of attention of organic chemists and has been greatly developed. Combined with the practical research work and the concept of high atom economy and green chemistry, we have carried out the following exploration work around the three basic points of metal-free, high efficiency and green sustainability, and obtained some achievements. The main contents are as follows: (1) the intermolecular cyclization promoted by TEA/DMF system was promoted by TEA (triethylamine) / DMF (NN- dimethylformamide) system, and the CC bond and C-N bond were constructed in one step. This alkali-catalyzed series cyclization process is suitable for the reaction between a variety of 3- (hetero-aryl-3-haloacrolein) compounds and 1t2O3H _ 3N _ 4-tetrahydroisoquinoline (and its derivatives). The corresponding isoquinoline compounds (yield as high as 97%) of pyrrole [2o 1-a] were obtained in high yield. The mechanism control experiment revealed that the process did not undergo free radical intermediates. According to all the experimental results, we carefully proposed a possible mechanism, this process probably experienced the imine intermediate, and then completed the final coupling reaction. Alternatively, the process may be carried out by nucleophilic addition and then elimination. (2) the intermolecular cyclization promoted by the TBAC/TBHP system is promoted by the TBAC (tetraDing Ji ammonium chloride) / TBHP (tertiary Ding Ji hydrogen peroxide) system. Two C-C bonds are constructed in one step. In the presence of simple K2HPO4, TBAC and TBHP catalyze the reaction between 2-isocyanobyls (and their derivatives) and DMF, and the corresponding products can be obtained in medium to excellent yields (up to 86%). This is the first time we have synthesized enkephalin-6-carboxylic acid amides through a possible radical cyclization process. Although there are still some shortcomings in this part of the work, however, It has accumulated valuable experience for the later free radical coupling work. (3) the intermolecular cyclization promoted by TBAB/TBHP system was promoted by TBAB (tetraDing Ji ammonium bromide) / TBHP system, and C-C bond and C-S bond were constructed in one step. This simple reaction is suitable for a variety of 2-isocyanated biphenyls to react with mercaptan (or phenylthiophenols) compounds, corresponding to which 6-aryl (alkyl) pyruvorphine can be obtained in medium to excellent yields (up to 86%). In addition, based on the results of a series of mechanism control experiments and the sulfhydryl radical trapped by TEMPO detected by HRMS, we know that this is a free radical type reaction, and that the reaction is a process of direct activation of S-H bond. Furthermore, a possible mechanism is given. (4) the intermolecular cyclization promoted by NH4I/TBHP system is promoted by NH4I/TBHP system, and C-C bond and C-N bond are constructed in one step. As opposed to the first part of the work, we hope that this reaction can be done through the free radical pathway. Considering some difficulties in the construction of N- radical centers in metal-free systems and based on our existing experience, we are exploring the synthesis of 6-amino-substituted enkephaline compounds by means of free radical coupling. After screening, we used saccharin as the optimal nitrogen source and reacted with 2-isocyanobenzene. NH4I/TBHP is the best catalytic system at present. The yield of the system can reach 46%. The further optimization and exploration are still under way.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.251
[Abstract]:"Coupling reaction without transition metal catalysis", which can efficiently construct C-C bond or CX bond, has attracted a lot of attention of organic chemists and has been greatly developed. Combined with the practical research work and the concept of high atom economy and green chemistry, we have carried out the following exploration work around the three basic points of metal-free, high efficiency and green sustainability, and obtained some achievements. The main contents are as follows: (1) the intermolecular cyclization promoted by TEA/DMF system was promoted by TEA (triethylamine) / DMF (NN- dimethylformamide) system, and the CC bond and C-N bond were constructed in one step. This alkali-catalyzed series cyclization process is suitable for the reaction between a variety of 3- (hetero-aryl-3-haloacrolein) compounds and 1t2O3H _ 3N _ 4-tetrahydroisoquinoline (and its derivatives). The corresponding isoquinoline compounds (yield as high as 97%) of pyrrole [2o 1-a] were obtained in high yield. The mechanism control experiment revealed that the process did not undergo free radical intermediates. According to all the experimental results, we carefully proposed a possible mechanism, this process probably experienced the imine intermediate, and then completed the final coupling reaction. Alternatively, the process may be carried out by nucleophilic addition and then elimination. (2) the intermolecular cyclization promoted by the TBAC/TBHP system is promoted by the TBAC (tetraDing Ji ammonium chloride) / TBHP (tertiary Ding Ji hydrogen peroxide) system. Two C-C bonds are constructed in one step. In the presence of simple K2HPO4, TBAC and TBHP catalyze the reaction between 2-isocyanobyls (and their derivatives) and DMF, and the corresponding products can be obtained in medium to excellent yields (up to 86%). This is the first time we have synthesized enkephalin-6-carboxylic acid amides through a possible radical cyclization process. Although there are still some shortcomings in this part of the work, however, It has accumulated valuable experience for the later free radical coupling work. (3) the intermolecular cyclization promoted by TBAB/TBHP system was promoted by TBAB (tetraDing Ji ammonium bromide) / TBHP system, and C-C bond and C-S bond were constructed in one step. This simple reaction is suitable for a variety of 2-isocyanated biphenyls to react with mercaptan (or phenylthiophenols) compounds, corresponding to which 6-aryl (alkyl) pyruvorphine can be obtained in medium to excellent yields (up to 86%). In addition, based on the results of a series of mechanism control experiments and the sulfhydryl radical trapped by TEMPO detected by HRMS, we know that this is a free radical type reaction, and that the reaction is a process of direct activation of S-H bond. Furthermore, a possible mechanism is given. (4) the intermolecular cyclization promoted by NH4I/TBHP system is promoted by NH4I/TBHP system, and C-C bond and C-N bond are constructed in one step. As opposed to the first part of the work, we hope that this reaction can be done through the free radical pathway. Considering some difficulties in the construction of N- radical centers in metal-free systems and based on our existing experience, we are exploring the synthesis of 6-amino-substituted enkephaline compounds by means of free radical coupling. After screening, we used saccharin as the optimal nitrogen source and reacted with 2-isocyanobenzene. NH4I/TBHP is the best catalytic system at present. The yield of the system can reach 46%. The further optimization and exploration are still under way.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.251
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