Carbon-to-nitrogen single-atom transmutation of azaarenes.
Carbon-to-nitrogen single-atom transmutation of azaarenes.
复制标题
氮杂芳烃的碳氮单原子嬗变。
DOI：
10.1038/s41586-023-06613-4
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发表时间：
2023
期刊：
影响因子：
64.8
通讯作者：
Levin,MarkD
中科院分区：
文献类型：
--
作者：
Woo,Jisoo;Stein,Colin;Christian,AlecH;Levin,MarkD
当寻找理想的分子来填补特定的功能作用(例如，药物)时，成败之间的差异通常可以归结为单个原子。用氮原子取代芳香碳原子将使发现潜在的药物成为可能，但只有间接的手段才能实现这种C到N的转化，通常是通过平行合成。在这里，我们报告了一种转化，使杂芳烃碳原子能够直接转化为氮原子，将喹啉转化为喹唑啉。母体氮芳烃的氧化重组得到了开环的中间体，其带有为环重新闭合和碳基离开基团的排出而准备的亲电中心。这种“粘性末端”方法颠覆了现有的原子插入-删除方法，因此避免了在逐步骨架编辑中常见的骨架旋转和取代基扰动陷阱。我们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碳来转化为相应的喹唑啉。机械实验支持激活的中间体的关键作用，并表明了发展C-到-N转化反应的更一般的策略。
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 atom. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis. 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.