摘要/Abstract

以3-氰基/酯基吲哚为代表的3-吸电子基团取代吲哚结构存在于多种生物活性分子中, 常作为优势骨架构建类药性化合物库用于新药发现. 本文设计并发展了一种基于亚胺氯化物活性中间体的串联反应, 从邻卤苯乙腈/酯和酰胺出发, 在碱和CuBr催化下, 一锅法构建结构多样性3-吸电子基团取代吲哚骨架的新合成方法. 该反应原料简单易得、反应快速(5 min完成)、产率高、底物适用范围广并可克级放大, 具有原子经济性和步骤经济性, 是基于优势骨架的多样性导向的合成方法学(privileged substructure-based DOS)案例的重要补充.
关键词: 一锅法合成, 亚胺氯化物, 3-吸电子基团取代吲哚, 类药性优势骨架
Indole scaffold is widely present in pharmaceutical and pesticide products, dyes and natural products. The indole skeleton substituted by the electron withdrawing group at position 3 is an important class of bioactive indole derivatives. Among them, 3-cyanoindole is a key module in the construction of privileged scaffold-based combinatory library and diversity-oriented synthesis for drug discovery. For these reasons, the design and synthesis of these scaffolds have received considerable attention in organic synthesis and have been extensively studied. However, the cyano group on the indole was introduced directly in previously reported methods. Due to the high toxicity of cyanide, the application of these reactions is limited. Imidoyl chloride, a highly reactive synthon, which was successfully used as a module for the construction of quinolones, quinazolines, benzimidazoles and other drug-like privileged scaffolds by our group. By making use of the imidoyl chloride as the active intermediate to mediate a cascade reaction to form the heterocycle, we developed a new one-pot synthesis to construct the 3-cyano or carboxylate-indole derivatives. The reaction proceeded via two sequential steps: initial formation of imidoyl chloride starting from N-substituted arylamide and thionyl chloride, followed by 2-bromo-arylnitrile carbanion nucleophilic addition, elimination and Ulmann reaction. This synthetic methodology is featured with cheap and readily available starting materials, high reaction yields, high functional group tolerance and broad substrate scope. This reaction is a direct synthesis not requiring prefunctionalization, and highly atom- and step-economic. It’s worth noting that it’s the first time building 3-cyanoindole scaffold commenced with the substrates bearing cyano group, which is of great importance for avoiding potential safety hazards.
Key words: one-pot synthesis, imidoyl chloride, 3-electron withdrawing group substituted indoles, drug-like privileged scaffold


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