双环吡咯及双环吡啶酮类杂环化合物的合成研究
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摘要
含氮杂环化合物是一类非常重要的化合物,因具有良好的生物活性和广泛的用途等特点而备受化学家们的关注。近年来,已有许多含氮杂环化合物被开发成医药和农药产品。多数杂环农药对哺乳动物、禽类和鱼类的毒性低,而对害虫和病菌具有高选择性。
双环吡咯类杂环化合物具有抗肿瘤、抗菌、镇痛消炎等突出的生物活性,如酪蛋白激酶2抑制剂、5-羟色胺拮抗剂等均含有双环吡咯结构单元。双环吡啶酮类化合物亦具有抗肿瘤、抗炎、止痛等突出的生物活性,同时双环吡啶酮结构又是药物常见的结构单元,如喜树碱、石杉碱甲等天然产物骨架中都含有双环吡啶酮结构。本文主要研究内容如下：
1.从简单易得的取代苯乙酮1出发合成二甲缩硫醚2,产物再与乙二胺、1,3-丙二胺或1,4-丁二胺反应合成了一系列的杂环烯酮缩胺3。
2.用易得原料丁炔二酸二乙酯或丙炔酸乙酯5和碘在CHCl3作溶剂回流制得二碘代丁烯酸二乙酯或二碘代丙烯酸乙酯6,该反应具有操作简单、收率高等优点。
3.建立了以杂环烯酮缩胺3与二碘代烯酸酯6在PdCl2/Cs2CO3催化下简捷高效合成双环吡咯和双环吡啶类杂环化合物的新方法。以71-93%的产率合成了20个新的双环吡咯类化合物7a～7t,以43～62%的产率合成7个新的双环吡啶酮类杂环化合物8a～8b,9a～9e。
4.所合成的化合物均未见文献报道,所有产物结构均已得到IR、1HNMR,13C NMR和MS等波谱数据的证实。其中,我们还对化合物7g进行了单晶衍射分析,确证了该类化合物的结构。
5.本文还对并环吡咯类化合物及双环吡啶酮类化合物的合成和应用进展进行了综述。
N-heterocycles are the important compounds with good biological activities and extensive properties causing attention of chemists. In recent few years, there are many N-containing heterocycles were developed into medicines and pesticides. Most N-heterocyclic pesticides have low toxicity to mammals, birds and fish, and with high selectivity to insects and bacteria.
Bicyclic pyrroles have excellent biological activities such as anticancer, antibacterial, analgesic, anti-inflammatory, and so on. For instance, bicyclic pyrroles used as protein kinase CK2inhibitors and5HT4-receptor antagonists. Bicyclic pyridones have excellent biological activities including anticancer, analgestic, antiphlogistic activities. They were frequently found in pharmacophores like camptothecin and huperzine. The main research contents and results as follows:
1. The benzoyl substituted mercaptals2were synthesized by acetophenone derivatives1. Compound2reacted with ethane-1,2-diamine, propane-1,3-diamine or butane-1,4-diamine to obtain the heterocyclic ketene aminals3.
2. In this thesis, cheap and.easily attained diethyl but-2-ynedioate or ethyl propiolate S and iodine were used as raw materials. Ethyl2,3-diiodoacrylate or diethyl2,3-diiodofumarate6were synthesized with good yields in CHCl3and under reflux conditions. The synthetic method has the advantages of very simple and efficient.
3. A method of synthesis novel bicyclic pyrroles/pyridones have been constructed by cyclic condensation of heterocyclic ketene aminals (HKAs)3with Ethyl2,3-diiodoacrylate or diethyl2,3-diiodofumarate6in the presence of PdCl2/CszCO3as catalyst. The method has the advantages of very simple and efficient. Twenty novel bicyclic pyrroles7a-7t were synthesized with71-93%, seven novel bicyclic pyridones8a-8b and9a-9e were synthesized with43-62%.
4. All the structures of the target compounds were characterized by IR,1H NMR,13C NMR and HRMS, The structure of7g was characterized by X-ray. The target compounds had not been reported in literatures.
5. The synthesis and applications of bicyclic pyrrole/pyridones were also reviewed in this thesis.
双环吡咯类杂环化合物具有抗肿瘤、抗菌、镇痛消炎等突出的生物活性,如酪蛋白激酶2抑制剂、5-羟色胺拮抗剂等均含有双环吡咯结构单元。双环吡啶酮类化合物亦具有抗肿瘤、抗炎、止痛等突出的生物活性,同时双环吡啶酮结构又是药物常见的结构单元,如喜树碱、石杉碱甲等天然产物骨架中都含有双环吡啶酮结构。本文主要研究内容如下：
1.从简单易得的取代苯乙酮1出发合成二甲缩硫醚2,产物再与乙二胺、1,3-丙二胺或1,4-丁二胺反应合成了一系列的杂环烯酮缩胺3。
2.用易得原料丁炔二酸二乙酯或丙炔酸乙酯5和碘在CHCl3作溶剂回流制得二碘代丁烯酸二乙酯或二碘代丙烯酸乙酯6,该反应具有操作简单、收率高等优点。
3.建立了以杂环烯酮缩胺3与二碘代烯酸酯6在PdCl2/Cs2CO3催化下简捷高效合成双环吡咯和双环吡啶类杂环化合物的新方法。以71-93%的产率合成了20个新的双环吡咯类化合物7a～7t,以43～62%的产率合成7个新的双环吡啶酮类杂环化合物8a～8b,9a～9e。
4.所合成的化合物均未见文献报道,所有产物结构均已得到IR、1HNMR,13C NMR和MS等波谱数据的证实。其中,我们还对化合物7g进行了单晶衍射分析,确证了该类化合物的结构。
5.本文还对并环吡咯类化合物及双环吡啶酮类化合物的合成和应用进展进行了综述。
N-heterocycles are the important compounds with good biological activities and extensive properties causing attention of chemists. In recent few years, there are many N-containing heterocycles were developed into medicines and pesticides. Most N-heterocyclic pesticides have low toxicity to mammals, birds and fish, and with high selectivity to insects and bacteria.
Bicyclic pyrroles have excellent biological activities such as anticancer, antibacterial, analgesic, anti-inflammatory, and so on. For instance, bicyclic pyrroles used as protein kinase CK2inhibitors and5HT4-receptor antagonists. Bicyclic pyridones have excellent biological activities including anticancer, analgestic, antiphlogistic activities. They were frequently found in pharmacophores like camptothecin and huperzine. The main research contents and results as follows:
1. The benzoyl substituted mercaptals2were synthesized by acetophenone derivatives1. Compound2reacted with ethane-1,2-diamine, propane-1,3-diamine or butane-1,4-diamine to obtain the heterocyclic ketene aminals3.
2. In this thesis, cheap and.easily attained diethyl but-2-ynedioate or ethyl propiolate S and iodine were used as raw materials. Ethyl2,3-diiodoacrylate or diethyl2,3-diiodofumarate6were synthesized with good yields in CHCl3and under reflux conditions. The synthetic method has the advantages of very simple and efficient.
3. A method of synthesis novel bicyclic pyrroles/pyridones have been constructed by cyclic condensation of heterocyclic ketene aminals (HKAs)3with Ethyl2,3-diiodoacrylate or diethyl2,3-diiodofumarate6in the presence of PdCl2/CszCO3as catalyst. The method has the advantages of very simple and efficient. Twenty novel bicyclic pyrroles7a-7t were synthesized with71-93%, seven novel bicyclic pyridones8a-8b and9a-9e were synthesized with43-62%.
4. All the structures of the target compounds were characterized by IR,1H NMR,13C NMR and HRMS, The structure of7g was characterized by X-ray. The target compounds had not been reported in literatures.
5. The synthesis and applications of bicyclic pyrrole/pyridones were also reviewed in this thesis.
引文
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