吡啶氮参与分子内烯烃碳胺化和双胺化反应

Intramolecular cyclization employing pyridine as nitrogen nucleophile is the one of the most straightforward and powerful approaches for N-heterocycles. However, intramolecular carboamination and diamination of alkenes using pyridine as nitrogen nucleophile and their asymmetric studies are still highly important challenges that remain unmet. These difficulties can be attributed to the following factors including deactivation of catalyst due to strong coordination ability of substrate, construction of C-N bond via intramolecular reaction of pyridine and C=C bond, and stereoselectivity in the asymmetric reaction. To address these challenging issues, we propose the strategies of substrate design and regulation of catalyst activation. The reasonable substrate design overcomes strong coordination ability of substrates. The regulation of catalyst solves the problems of construction of C-N bond and stereoselectivity in the asymmetric reaction. We propose to develop intramolecular trifluoromethylamination, aminoarylation/aminoalkylation, aminoalkynylation and diamination of alkenes employing pyridine as nitrogen nucleophile. Base on the successful former works, we schedule the exploration of their asymmetric transformation. Some of these proposals have been proved to be possible in the preliminary research.

吡啶氮作为亲核试剂参与分子内环化反应是合成含氮杂环化合物最为直接有效的方法之一。然而，吡啶氮参与分子内烯烃碳胺化、双胺化及其不对称反应仍然是极具挑战性的课题，主要难点有：(1) 吡啶氮原子的强配位作用易导致催化剂中毒失活；(2) 分子内吡啶氮与烯烃的碳-氮键选择性构建；(3) 不对称反应的立体选择性问题。针对上述困难，本研究项目拟采用底物设计和催化剂调控策略，实现吡啶氮参与分子内烯烃碳胺化和双胺化反应。通过底物设计削弱其配位能力和调控吡啶碳氮双键环外异构能力；调控催化剂活性及其空间立体环境实现碳-氮键的构建和不对称反应的立体选择性控制。计划开展吡啶氮参与分子内烯烃三氟甲基胺基化、芳基/烷基胺基化、炔基胺基化和双胺化反应。在此基础上，进一步探索其不对称版本反应。目前，初步的实验结果已经证明了该项目可行性。

含氮杂环化合物是生物碱的核心结构单元，广泛存在于天然产物和生理活性化合物中。因此，对其高效的催化合成已经成为现代有机化学的一个研究重点。其中，以简单易得的含氮芳香化合物的氮原子作为亲核试剂参与不饱和键的官能团化反应是构建含氮杂环化合物的最为直接且有效的方法之一。本项目基于底物设计和催化剂调控策略，采用手性胺作为催化剂，实现了2-羟基吡啶与MBH酯的不对称N-烯丙基化反应。采用二苯基环己基膦作为催化剂，实现了2-羟基吡啶、吲哚、吡咯和咪唑等含氮芳香化合物的N-环丙烷化反应，合成了一些列环丙胺化合物。采用三苯基膦作为催化剂，实现了吲哚、吡唑和咪唑等氮芳香化合物与炔酮的极性反转偶联反应，构建N-烯基取代的吲哚、吡唑和咪唑等含氮芳香化合物。项目执行期间共发表论文5篇，申请中国发明专利1件。

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