Regioselective Synthesis of 2‑Aryl-5-cyano-1-(2-hydroxyaryl)‑1<i>H</i>‑imidazole-4-carboxamides Self-Assisted by a 2‑Hydroxyaryl Group

The reactivity of the diaminomaleonitrile-based imines containing hydroxyphenyl substituents with diverse aromatic aldehydes has been explored for the synthesis of novel highly substituted nitrogen heterocycles, which are considered privileged scaffolds in drug discovery. We report here a simple and efficient method for the regiocontrolled synthesis of a variety of 2-aryl-5-cyano-1-(2-hydroxyaryl)-1H-imidazole-4-carboxamides from 2-hydroxybenzylidene imines and aromatic aldehydes. Computational studies on the reaction path revealed that the regioselectivity of the reaction toward the formation of imidazole derivatives instead of 1,2-dihydropyrazines, most likely via a diaza-Cope rearrangement, is driven by the 2-hydroxyaryl group in the scaffold. The latter group promotes the intramolecular abstraction and protonation process in the cycloadduct intermediate, triggering the evolution of the reaction toward the formation of imidazole derivatives.本研究针对含羟苯基取代基的二氨基马来腈（diaminomaleonitrile）衍生亚胺与多种芳香醛的反应活性开展探索，以制备新型高度取代的氮杂环（nitrogen heterocycles）——这类骨架在药物发现领域被公认为优势骨架（privileged scaffolds）。本文报道了一种简便高效的区域可控合成方法，可通过2-羟基亚苄基亚胺与芳香醛的反应，制备一系列2-芳基-5-氰基-1-(2-羟芳基)-1H-咪唑-4-甲酰胺类化合物。针对该反应路径的计算研究显示，反应优先生成咪唑衍生物而非1,2-二氢吡嗪（1,2-dihydropyrazines），其区域选择性大概率通过二氮杂-Cope重排（diaza-Cope rearrangement）实现，且该选择性由骨架中的2-羟芳基基团驱动。该2-羟芳基基团可促进环加成中间体（cycloadduct intermediate）的分子内质子夺取与质子化过程，进而触发反应朝着生成咪唑衍生物的方向进行。