氮自由基参与的不同含氮化合物的可控合成研究

Being with a broad ubiquity in nature, N-containing compounds are generally accepted as one of important scaffolds with remarkable molecular complexities and potential bioactivities. Due to its wide applications and promising bioactivities, it’s a hot yet challenging topic in modern organic synthesis that N-containing building blocks are smuggled in the targeted molecules under mild conditions. To date, numerous established protocols could be employed to form C-N bonds, although the majority of them use halides as starting materials or precious metal as catalyst. Therefore, it is highly desirable that direct aminations of C-H bonds are developed under mild condition in absence of precious metal.. In this project, we would like to explore nitrogen radical-based reactions with a wish to form diverse C-N bonds with a broad generality and selectivity. Furthermore, these our developed methodologies will be applied into the controllable synthesis of various N-heterocyclic compounds with a range of potential bioactivities, and also into rapid and efficient synthesis of some commercial available medicines such as Tegafur and Letrozole. It is believed that high chemical reactivity supports realization of generality of C-N bonds formation. Meanwhile, it is possible that selective formation of C-N bonds in one molecule is achieved by controlling reactivity of nitrogen radical.

含氮化合物广泛存在于生物体中，而且具有许多显著的多样性和潜在的生物活性。由于含氮化合物广泛的应用和潜在的生物活性，如何高效、快速地将含氮基团引入到有机分子中是当前有机合成化学研究的热点、难点之一。迄今为止，许多简单便捷的方法可用于形成C-N键，但是这些方法大多采用卤代烃及其类似物为原料或者依赖贵重金属为催化剂。因此，避免使用贵重金属，在温和条件下研究C-H键的直接胺化反应具有十分重要的理论和实际意义。. 本项目拟以氮自由基为氮源，利用氮自由基的高反应活性及对氮自由基反应活性的调控来研究C-N键的形成反应，以解决在温和条件下C-N键形成反应中的普适性和同一分子中不同C-N键形成的选择性。并且，将已经发展的不同类型C-N键的选择性形成运用于不同具有潜在生物活性的含氮化合物的可控合成及一些含氮上市药物如替加氟和来曲唑的高效、快速合成。

本项目发展了产生酰胺氮自由基的2种不同方式：廉价金属铜盐催化和无金属oxone氧化法，并分别研究了通过2种不同方式产生的酰胺氮自由基对炔键和芳烃的分子内的加成反应，实现了不同含氮骨架化合物的可控合成。而且，还将发展的基于氮自由基的合成方法学用于甘茶酚、石斛碱、B型流感抗体等活性化合物的全合成中。在研究中，本项目还发现酰胺氮自由基在一定条件下可以异构为亚胺氧自由基。本项目还研究了亚胺氧自由基对分子内炔键的区域选择性加成反应，并实现了异香豆素类化合物和苯并呋喃酮类化合物的可控合成。此外，本项目还研究了原位产生的烯基自由基对分子芳烃的区域选择性性加成反应，通过烯基自由基对分子内芳烃的区域选择性加成反应实现了香豆素和N-杂螺环三烯酮化合物的选择性合成。