於有氧環境利用銅催化進行一鍋化環化-酮基化反應合成咪唑併[1,2-a]苯併咪唑及1H-吡咯-1-基-1H-苯併[d]咪唑-5-羧酸乙酯

Abstract

本論文共分做三部份，第一部分是利用銅催化於有氧的環境下一鍋化進行環化和酮基化反應合成benzoimidazo[1,2-a]imidazolones，第二部分是單一銅催化於有氧的環境下進行環化和酮基化反應合成1H-pyrrol-1-yl-1H-benzo[d]imidazole-5-carboxylates，第三部分是合成Rosoxacin。 第一部分：以兩種銅金屬催化末端炔加成到來自於2-aminobenzimidazole與芳香醛形成的亞胺上，並在氧氣系統下伴隨著分子內環化合成benzoimidazo[1,2-a]imidazolones，此產物上新形成的羰基是來自於氧氣，而本實驗室成功研究出一種高效合成benzoimidazo[1,2-a]imidazolones的方法，此方法是藉由2-aminobenzimidazole、芳香醛和末端炔在一鍋化有氧氣條件下得到了新穎的氧化5-exo-dig環化-酮基化聯繼，此部分的結果已發表在Chem. Comm. 2016, 52, 6621-6624。 第二部分：在第一部分研究中得到了吡咯環的副產物，並進一步研究此副產物如何形成，並使其成為主要產物，以單一銅金屬催化末端炔加成到亞胺上形成炔丙胺，於有氧氣條件下炔丙胺再一次與末端炔反應形成中間體44，最後伴隨著分子內環化，合成1H-pyrrol-1-yl-1H-benzo[d]imidazole-5-carboxylates，而此產物上新形成的羰基是來自於氧氣，此研究結果在合成1H-pyrrol-1-yl-1H-benzo[d]imidazole-5-carboxylates提供了新穎的合成方法。 第三部分：在電腦輔助模擬計算下，舊藥Rosoxacin在IRAK4 (interleukin-1 receptor-associated kinase 4)有良好的生物活性，而IRAK4是一種蛋白激酶，所以我們就以3-pyridin-4-ylaniline和乙氧基丙二酸酯(ethoxymethylenemalonate ester)在聚磷酸下合環，再以鹼水解得到產物Rosoxacin。

This thesis is divided into three parts, the first part is copper-catalysed aerobic oxidative carbocyclization- ketonization, one-pot synthesis of imidazo[1,2-a]benzimidazole, the second part is a single copper-catalysed aerobic oxidative carbocyclization- ketonization, one-pot synthesis of 1H-pyrrol-1-yl-1H-benzo [d] imidazole-5-carboxylates, the third part is a synthetic Rosoxacin. Part 1: Two copper metal-catalyzed alkyne-terminal addition to the imine derived from 2-aminobenzimidazole with an aromatic aldehyde formed in an oxygen system and accompanied by intramolecular cyclization synthesis benzoimidazo [1,2-a] imidazolones, on this product carbonyl newly formed from oxygen, our laboratory successfully developed a highly efficient synthesis benzoimidazo [1,2-a] imidazolones method, this method is by 2-aminobenzimidazole, aromatic aldehyde and terminal acetylene in one-pot of there oxygen conditions of the novel oxidation 5-exo-dig cyclization - ketonization, the results of this section have been published in Chem Comm 2016, 52, 6621-6624. Part 2: Obtained in the first part of the study of the side-products of the pyrrole ring, and further study of how the formation of this side-product, and make it the main product formed propargylamine single copper metal-catalyzed alkyne-terminal addition to the imine to oxygen conditions under propargylamine again with a terminal alkyne to form intermediate 44, along with the final intramolecular cyclization, synthesizing 1H-pyrrol-1-yl-1H-benzo [d] imidazole-5-carboxylates, and the newly formed on this product carbonyl from oxygen, this results in the synthesis of 1H-pyrrol-1-yl-1H-benzo [d] imidazole-5-carboxylates provides novel synthetic methods. Part 3: In the computer-aided simulation, old drugs Rosoxacin in IRAK4 (interleukin-1 receptor-associated kinase 4) has a good biological activity, IRAK4 is a protein kinase, so we have to 3-pyridin-4-ylaniline and ethoxy malonate (ethoxymethylenemalonate ester) in polyphosphate rings, then alkaline hydrolysis to give the product Rosoxacin.