【作者】 周中振；

【导师】 杨光富；

【作者基本信息】 华中师范大学 ， 有机化学， 2007， 博士

【摘要】 黄酮类化合物具有广泛的生物活性，许多黄酮类化合物已被应用于医药和农药领域。为了寻找高活性黄酮类化合物，人们在不断从植物体内分离新型黄酮类化合物的同时也对其结构进行改造。二十世纪九十年代以来，农药发展进入了一个新的时代，即以杂环化合物为主的时代。杂环化合物由于其广谱、高效、低毒的生物活性而引起各国化学家的重视。因而，本论文在前人研究基础上将噻唑、吡唑和哒嗪等杂环引入类黄酮骨架中，设计合成了233个新型类黄酮类杂环化合物，同时对黄酮类化合物的合成方法进行了探索。具体内容如下所示：（1）基于活性亚结构拼接原理，将噻唑酮引入黄酮骨架结构中，利用微波辅助液相组合平行合成技术，以3-醛基色酮、伯胺和巯基乙酸为原料，合成了一个具有杀虫活性的2-（4-氧代-4H-色烯-3-）噻唑-4-酮类化合物库。与常规加热方法相比，微波辅助液相组合平行合成技术大大缩短反应时间，提高了反应收率。生物活性测试结果显示2-（4-氧代-4H-色烯-3-）噻唑-4-酮类衍生物在杀菌和除草方面表现出较弱的抑制活性，但在杀虫方面表现出良好的抑制活性。在250mg.L^-1的浓度下，所测试的化合物当中有5个化合物对朱砂叶螨表现出70％以上的杀虫活性。其中化合物I-2 c对朱砂叶螨的抑制率达到90.5％。同时，对中间体色酮酰腙类化合物也进行了生物活性测试。实验结果显示，这一类化合物在杀菌和杀虫方面表现出一定的抑制活性。（2）基于活性亚结构拼接的原理，将杂环吡唑酮引入苯并吡喃环中，利用微波辅助多步液相组合平行合成手段，以3-羧基色酮为原料，快速产生了一个结构多样性的具有杀虫活性的苯并吡喃[4,3-c]吡唑-3（2H）-酮类化合物库。与常规平行合成相比，微波辅助多步液相组合平行合成将反应时间由16h缩短至13min，并提高了产物收率。生测实验结果显示，在250 mg.L^-1的浓度下，这类化合物对朱砂叶螨表现出良好的杀虫活性，即使当浓度降低至100mg.L^-1的情况下仍有部分化合物表现出一定的抑制活性。（3）以苯并吡喃[4，3-c]吡唑-3（2H）-酮类化合物为先导进行结构修饰，并设计合成了四个系列化合物，并对其进行了生物活性筛选。生测结果显示，仅Ⅳ系列化合物对朱砂叶螨表现出较好的抑制活性。Ⅲ系列化合物和Ⅵ系列化合物虽然杀虫活性较弱，但都表现出一定的杀菌活性。（4）建立了3-羟基-2-芳甲酰基苯并呋喃类衍生物的合成新方法：以2-溴苯乙酮与水杨酸酯为原料，在无水碳酸钾作用下，一步关环合成3-羟基-2-芳甲酰基苯并呋喃类衍生物。与以往合成方法相比，此方法缩短了反应步骤，提高了产物收率。（5）建立了苯并吡喃4-酮-3-甲酸乙酯类化合物的合成新方法：以邻羟基苯甲酰乙酸乙酯和原甲酸甲酯为原料一步关环以较好的分离收率得3-酯基色酮。（6）在苯并吡喃稠杂环系列晶体体系上研究了由分子内氢键所导致的晶体分子构象的变化对固态超分子结构的影响。通过对晶体结构分析，取代基的类型对分子间π-π共轭有较大的影响：当在N上引入吸电子取代基时，分子间π-π共轭相互作用减弱；当N上取代基是推电子取代基时，分子间π-π共轭相互作用增强。同时，晶体分子构型对固态超分子结构也存在很大的影响。当取代基与呋喃环呈反式构型，且取代基为推电子基取代基时，晶体分子间往往形成相互包合的二聚体。这种现象仍需要大量的实验去证实。（7）利用微波辅助有机合成技术，首次报道了黄烷酮以N-溴代丁二酰亚胺（NBS）为溴化试剂在偶氮双异丁氰（AIBN）催化下高选择性转化为3-溴黄酮或黄酮。这种方法具有收率高、反应时间短（10min）和适用性强等特点，是合成3-溴黄酮和黄酮类衍生物较为理想的方法。（8）首次报道了微波辅助下以离子液体为反应介质，在噻唑盐和Et₃N催化下的分子内Stetter反应。反应基本在5-20min内结束，并以很好的分离收率得到产物。与常规方法相比，微波辅助下在室温离子液体中进行的分子内Stetter反应缩短了反应时间，提高了反应收率。此外，室温离子液体回收再用的结果显示，室温离子液体连同催化剂完全能够回收再用。并在此基础上，我们发展了一种环境友好的高效的合成苯并二氢吡喃-4-酮类衍生物的新方法。更多还原

【Abstract】 Flavonoids are widely distributed diverse groups of plant secondary metabolites with widespread biological activities. Many of them have been used as medicine and pesticide. In order to search highly biological activities flavonoids, the reformation of the structure goes on in parallel with the separation of new flavonoids form plants. Since 1990s, pesticide has entered into a new period, heterocyclic compounds era. Heterocyclic compounds attracted significant interest of chemists due to its widespread and highly biological activities. For the low activities of flavonoids, we designed and synthesized six series of 233 novel heterocyclic flavonoids by introduction of thiazole, pyrazole and pyridazine in order to search new lead compounds with highly activities. At the same time, we explored the efficient methods for the preparation of flavonoids. It may be summarized as follows:（1） On the basis of the principle of combination of active groups, it is the first report about the application of liquid-phase combinatorial parallel synthesis under microwave irradiation to construct a library of 2-（4-oxo-4H-1-benzopyran-3-yl）-4-thiazolidinones with insecticidal activity by fusing a thiazolidinone to the flavonoid skeleton, using 3-formyl chromone, primary amine and mercaptoacetic acid as reactants. Compared with an identical library generated by conventional parallel synthesis, the microwave-assisted parallel synthesis approach dramatically decreased the reaction time, and substantially increased the product yields.The bioassay showed that they not exhibit obviously herbicidal activity and fungicidal activity but insecticidal activity. Five of them exhibited beyond 70% inhibition of Tetranychus cinnabarnus in 250 mg.L^-1. The best one was compound 2-9 c which exhibited 90.5 % inhibition of Tetranychus cinnabarnus. At the same time, the biological activities of N’-（（4-oxo-4H- chromen-3-yl） methylene） acyl hydrazone derivatives were also studied. The results showed that they exhibited middling fungicidal activity and insecticidal activity.（2） On the basis of the principle of combination of active groups, it is the first report that a rapid library-generation via liquid-phase multiple-parallel synthesis of 2-（substituted）benzyl-1-benzopyrano [4,3-c] pyrazol-3-ones with insecticidal activity by fusing a pyrazol-3-one to the flavonoid skeleton under microwave irradiation was successfully performed using chromenone-3-carboxylic acids as starting materials. Compared with an identical library generated by conventional parallel synthesis, microwave-assisted parallel synthesis dramatically decreased reaction time from an average of 16 h to 13 min, and the yields of products and intermediates were improved in most cases. A bioassay indicated that the compounds of the library exhibited excellent insectidal activity aginst T cinnabarinus at the dosage of 250 mg.L^-1, and some compounds still exhibited insecticidal activity when the dosage was reduced to 50 mg.L^-1. This showed that 2-（substituted） benzyl-1-benzopyrano [4, 3-c] pyrazol-3-ones might be used as lead structures for further optimization. （3） Benzopyrano- [4,3-c] pyrazol-3-ones was identified as lead compounds for further studies. And four series of 115 novel heterocyclic flavonoids was designed and synthesized. But, the bioassay indicated only IV series compounds showed middling insecticidal activity. III and VI series compounds showed feeble insecticidal activity but middling fungicidal activity.（4） We developed a new efficient methods for the preparation of （3-hydroxybenzofuran-2-yl） （phenyl） methanone derivatives. （3-Hydroxybenzofuran-2-yl） （Phenyl） methanone derivatives were synthesized in a one step substitution cylization reaction of 2-bromo-1-phenylethanone and methyl 2-hydroxybenzoate in the presence of potassium carbonate. Compared with old methods, it reduces the steps and substantially increased the product yields.（5） We developed a new efficient methods for the preparation of methyl 4-oxo-4H-chromene-3-carboxylate derivatives. Methyl 4-oxo-4H-chromene-3- carboxylate derivatives were synthesized in excellent yields via a one step cylization reaction of ethyl 3-（2-hydroxyphenyl）-3- oxopropanoate and triethyl orthoformate.（6） On the base of a serier of crystal VI, the effects of substituents on molecule configuration and the structure of solid supermolecule crystals were studied. The properties of substituents have tremendous influence on the aromaticπ-πstacking interactions. The aromaticπ-πstacking interactions was weakened by introducing the electron drawing substituents. However, the aromaticπ-πstacking interactions was strengthened by introducing the donating drawing substituents. At the same time, the molecular configurations also have tremendous influence on the structure of solid supermolecule crystals. When the donating drawing substituents shows trans configurations with furan ring, the molecules generates an dimer embosomed with each other by aromaticπ-πstacking interactions. The phenomena shall be demonstrated later by a mass of experiments.（7） We presented the first report of a highly selective transformation of flavanones to 3-bromoflavones or flavones by using N-bromosuccinimide （NBS） as a brominating reagent in the presence of catalytic amount of 2, 2’-azobis （isobutyronitrile） （AIBN） under microwave irradiation. The combination of excellent yields, shorter reaction time （10 min）, and high levels of functional group compatibility makes this an attractive synthetic approach to 3-bromoflavones and flavones.（8） We presented the first report of microwave-assisted intramolecular Stetter reaction using imidazolium-type room temperature ionic liquids （RTILs） as solvents, with thiazolium salts and Et₃N as catalysts. The features such as excellent yields, shorter reaction time （5 20 min）, and recyclable and reusable ionic liquid and catalyst make this method an environmentally benign and highly efficient procedure for the preparation of chromanone derivatives.更多还原