美国芝加哥大学Levin, Mark D.团队报道了氮杂芳烃的碳-氮单原子转变。相关研究成果发表在2023年11月1日出版的《自然》。

当寻找理想的分子来扮演特定的功能角色（例如，药物）时，成功和失败之间的区别通常可以归结为一个原子。用氮原子取代芳香碳原子将有助于发现潜在的药物，但只有间接的方法才能进行这种碳氮转化，通常是通过平行合成。

该文中，研究人员报道了一种能够将杂芳碳原子直接转化为氮原子的转化反应，将喹啉转化为喹唑啉。母体氮杂芳烃的氧化重组产生了一个带有亲电位点的开环中间体，该位点为环的重新闭合和碳基离去基团的排出做好了准备。这种“粘性末端”方法颠覆了现有的原子插入-删除方法，从而避免了逐步骨架编辑中常见的骨架旋转和取代基扰动陷阱。

研究人员展示了广泛的喹啉和相关的氮杂芳烃，所有这些都可以通过用氮原子取代C3碳转化为相应的喹唑啉。机制化实验支持活化中间体的关键作用，并表明了C-to-N嬗变反应发展的更通用策略。

附：英文原文

Title: Carbon-to-nitrogen single-atom transmutation of azaarenes

Author: Woo, Jisoo, Stein, Colin, Christian, Alec H., Levin, Mark D.

Issue&Volume: 2023-11-01

Abstract: When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom1. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines2, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis3. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a ‘sticky end’ approach subverts existing atom insertion–deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.

DOI: 10.1038/s41586-023-06613-4

Source: https://www.nature.com/articles/s41586-023-06613-4