JWang's串联反应的扩展
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摘要
氮桥头芳杂五环并吡啶类化合物,由于其具有与吲哚或嘌呤结构上的相似性与差异性,近年来受到了药物化学家和有机化学家越来越多的重视。
我们小组在对抗高血压药物洛沙坦进行结构改造的过程中,意外的发现了一个新型的串联反应(JWang's串联反应),并成功的运用此反应合成了系列咪唑并[1,5-a]吡啶类化合物。此法原料易于制备,反应条件温和,后处理简单,产率较高并且在吡啶环4位上引入了其他方法难以得到的酯基。该反应本身是由N烯丙基化、去质子、电子转移、分子内缩合等多步反应组成的一连串反应在同一条件下按顺序进行的一个组合反应,反应类型前所未有,又有许多优点,本论文将此反应扩展到了其它氮桥头芳杂五环并吡啶类化合物的合成上,为系列氮桥头芳杂五环并吡啶类化合物的合成建立了有效的通用方法。
在第二章我们系统的研究了此串联反应的最佳反应条件及反应机理,成功的合成了中氮茚类化合物。从原料吡咯出发,经一步改进的Vilsmeier-Haack反应得到取代的2-吡咯甲醛,然后与γ-溴代巴豆酸乙酯经过SN2反应,脱质子,电子对转移,亲核加成,脱水消除五步反应得到了20个中氮茚系列化合物。
在第三章中,以苯乙酮为起始原料,与草酸二乙酯反应,再和水合肼缩合得到吡唑甲酯,接着用LiAlH4还原,PCC氧化得到吡唑甲醛,最后,与溴代巴豆酸乙酯经过五步反应得到了12个吡唑并[1,5-a]吡啶系列化合物,并且分离得到了4个未环合的中间体,进一步验证了反应机理。
第四章中,第一部分首先由咪唑出发,通过与三苯基氯甲烷反应,得到1位由三苯甲基保护的咪唑,接着用丁基锂锂代后与取代的苯甲醛反应得到羟苄基咪唑,再进一步用三氧化铬氧化得到苯甲酰基咪唑,最后与溴代巴豆酸乙酯经过五步反应得到了16个咪唑并[1,2-a]吡啶系列化合物。第二部分由邻二甲苯经过乙酰化、成肟、贝克曼重排、硝化、还原和脱乙酰化得到4,5-二甲基邻苯二胺,然后与α-羟基酸,接着用三氧化铬氧化得到2-酰基苯并咪唑,最后与溴代巴豆酸乙酯经过五步反应得到了10个吡啶并[1,2-a]苯并咪唑系列化合物,并对其光学性质进行了测试,发现了部分新颖的具有较好光学性质的化合物,为以后的修饰改造工作打下了基础。
最后,第五章中,我们成功的将JWang's串联反应应用到了[1,2,4]三氮唑并[1,5-a]吡啶类化合物的合成中,除得到预想产物外,还意外发现了一个酰基化试剂(5-苯甲酰基-1,2,4-三氮唑),并得到了2位苯甲酰基取代的[1,2,4]三氮唑并[1,5-a]毗啶类化合物,酰基化试剂的衍生工作正在进行。
生物活性测试表明,部分氮桥头芳杂五环并吡啶化合物具有较好活性,为进一步修饰改造打下了基础。
This dissertation explores the tandem Wang's reaction and its application towards the synthesis of indolizines. This tandem reaction proceed by an intermolecular SN2 reaction, deprotonation, and then electron pair transfer, cyclization, followed by elimination to form the desired final products. The synthetic utility of this reaction has been demonstrated by its successful application in the synthesis of pyrazolo[1,5-a]pyridines, imidazo[1,2-a]pyridines, pyrido[1,2-a]benzimidazoles and [1,2,4]triazolo[1,5-a]pyridine.
The first part of this study presents the development of the tandem reaction with respect to both its reaction condition and scope. The reaction proceeds smoothly under very mild conditions at room temperature in moderate to good yields.
Aimed with a highly efficient method for the preparation of N-bridged heterocyclic compounds, the second part of this study describes the application of the novel tandem reaction to the synthesis of pyrazolo[1,5-a]pyridines, imidazo[1, 2-a]pyridines, pyrido[1,2-a]benzimidazoles and [1,2,4]triazolo[1,5-a]pyridine. Fortunately, the expected products were obtained in good yield under the same reaction conditions.
我们小组在对抗高血压药物洛沙坦进行结构改造的过程中,意外的发现了一个新型的串联反应(JWang's串联反应),并成功的运用此反应合成了系列咪唑并[1,5-a]吡啶类化合物。此法原料易于制备,反应条件温和,后处理简单,产率较高并且在吡啶环4位上引入了其他方法难以得到的酯基。该反应本身是由N烯丙基化、去质子、电子转移、分子内缩合等多步反应组成的一连串反应在同一条件下按顺序进行的一个组合反应,反应类型前所未有,又有许多优点,本论文将此反应扩展到了其它氮桥头芳杂五环并吡啶类化合物的合成上,为系列氮桥头芳杂五环并吡啶类化合物的合成建立了有效的通用方法。
在第二章我们系统的研究了此串联反应的最佳反应条件及反应机理,成功的合成了中氮茚类化合物。从原料吡咯出发,经一步改进的Vilsmeier-Haack反应得到取代的2-吡咯甲醛,然后与γ-溴代巴豆酸乙酯经过SN2反应,脱质子,电子对转移,亲核加成,脱水消除五步反应得到了20个中氮茚系列化合物。
在第三章中,以苯乙酮为起始原料,与草酸二乙酯反应,再和水合肼缩合得到吡唑甲酯,接着用LiAlH4还原,PCC氧化得到吡唑甲醛,最后,与溴代巴豆酸乙酯经过五步反应得到了12个吡唑并[1,5-a]吡啶系列化合物,并且分离得到了4个未环合的中间体,进一步验证了反应机理。
第四章中,第一部分首先由咪唑出发,通过与三苯基氯甲烷反应,得到1位由三苯甲基保护的咪唑,接着用丁基锂锂代后与取代的苯甲醛反应得到羟苄基咪唑,再进一步用三氧化铬氧化得到苯甲酰基咪唑,最后与溴代巴豆酸乙酯经过五步反应得到了16个咪唑并[1,2-a]吡啶系列化合物。第二部分由邻二甲苯经过乙酰化、成肟、贝克曼重排、硝化、还原和脱乙酰化得到4,5-二甲基邻苯二胺,然后与α-羟基酸,接着用三氧化铬氧化得到2-酰基苯并咪唑,最后与溴代巴豆酸乙酯经过五步反应得到了10个吡啶并[1,2-a]苯并咪唑系列化合物,并对其光学性质进行了测试,发现了部分新颖的具有较好光学性质的化合物,为以后的修饰改造工作打下了基础。
最后,第五章中,我们成功的将JWang's串联反应应用到了[1,2,4]三氮唑并[1,5-a]吡啶类化合物的合成中,除得到预想产物外,还意外发现了一个酰基化试剂(5-苯甲酰基-1,2,4-三氮唑),并得到了2位苯甲酰基取代的[1,2,4]三氮唑并[1,5-a]毗啶类化合物,酰基化试剂的衍生工作正在进行。
生物活性测试表明,部分氮桥头芳杂五环并吡啶化合物具有较好活性,为进一步修饰改造打下了基础。
This dissertation explores the tandem Wang's reaction and its application towards the synthesis of indolizines. This tandem reaction proceed by an intermolecular SN2 reaction, deprotonation, and then electron pair transfer, cyclization, followed by elimination to form the desired final products. The synthetic utility of this reaction has been demonstrated by its successful application in the synthesis of pyrazolo[1,5-a]pyridines, imidazo[1,2-a]pyridines, pyrido[1,2-a]benzimidazoles and [1,2,4]triazolo[1,5-a]pyridine.
The first part of this study presents the development of the tandem reaction with respect to both its reaction condition and scope. The reaction proceeds smoothly under very mild conditions at room temperature in moderate to good yields.
Aimed with a highly efficient method for the preparation of N-bridged heterocyclic compounds, the second part of this study describes the application of the novel tandem reaction to the synthesis of pyrazolo[1,5-a]pyridines, imidazo[1, 2-a]pyridines, pyrido[1,2-a]benzimidazoles and [1,2,4]triazolo[1,5-a]pyridine. Fortunately, the expected products were obtained in good yield under the same reaction conditions.
引文
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