銅金屬催化合成胍與苯併咪唑

Abstract

本論文共分為三個部分：第一與第二部分著重在 cyanamide 化合物的合成應用，以合成 guanidine 與 benzimidazole 化合物為目標。第三部分則是以研究基因修飾核苷酸 5-hydroxymethylcytidine 化合物的合成方法為主。 在論文第一部分，我們以苯環上具不同取代基的 N-phenylcyanamide 化合物，在一價碘化銅做為催化劑，Xantphos做為配體，與各種一級與二級胺類化合物進行反應，可以合成出一系列的具有雙取代基的 guanidine 化合物。我們的研究提供一個簡便的方法合成 N-alkyl-N’-arylguanidine 化合物。 論文的第二部分，我們以 o-bromophenylcyanamide 化合物，在一價碘化銅做為催化劑、1,10- phenanthroline 做為配體，和各種一級與二級胺類化合物進行反應，合成環外胺基具取代的 2-aminobenzimidazole 化合物。同時，我們設計一系列中間物反應，證實銅催化合成 2-aminobenzimidazole 化合物的反應機構與區位選擇性。 論文的第三部分，我們由 cytidine 合成醣上具保護基的 5-cyanocytidine 化合物，希望使用 DIBAL 試劑還原 5-位置的 cyano 官能基，合成 5-hydroxymethylcytidine 化合物。雖然成功合成預期產物，但產率並不佳。因此我們更換合成策略，希望在鹼基 cytosine 5-號位置引進乙烯基，進行氧化裂解的方式合成產物。所以我們以 5-iodouracil 化合物做為模型進行，Heck 反應進行碳-碳鍵的生成，並將成功的實驗條件套用至 5-iodocytidine 化合物，亦成功的合成醣上具保護基 (E)-5-(2’-Methoxycarbonylvinyl)cytidine 產物。This thesis contains three parts: In the first and second parts of the thesis , we investigated the utilitzation of copper(I) iodide-catalyzed reaction of N-substituted cyanamides to systhsize a wide variety of N,N’-disubstituted guanidine and 2-aminobenzimidazole derivatives. At the same time, In the third part, the synthetic approach of an epigenetic DNA base 5-hydroxymethyl-2’-deoxycytidine (5-hmdC), was studied. In the first part, N-alkyl-N’-arylguanidines could be effectively synthesized through the reaction of N-arylcyanamides with various primary and secondary alkylamines, under the catalysis of copper (I) iodide and xantphos in DMF. This methodology provides a facile access to versatile N,N’-disubstituted guanidine derivatives from N-arylcyanamides. In the second part, the synthesis of 2-aminobenzimidazole derivatives from the reation of o-bromophenylcyanamides with various primary and secondary alkylamines, under the catalysis of copper (I) iodide and 1,10-phenanthroline in 1,4-dioxane was reported. This methodology provides a direct access to 2-aminobenzimidazole derivatives. Mechanistic investigation including intermediate studies helped establish a catalytic cycle and the regiochemistry was addressed based on the porposed mechanism. In the last part, sugar-protected 5-cyanocytidine was successfully prepared from cytidine. The reduction of the 5-cyano group to form 5-hydroxymethylcytidine achieved only in a very low yield. Although the synthesis of 5-hydroxymethylcytidine, was accomplished, more efficient synthetic approach is yet to be developed.