基于自由基的烯烃氢官能团化/串联环化可控合成氮杂环的反应研究

The construction of azacycle with high functional group compatibility under mild condition has been the spotlight and challenge in current organic chemistry. Most of general methods for the preparation of azapolycyclic compounds are focused on the metal-catalyzed coupling. The construction of azacycle with high functional group compatibility under mild condition has been the spotlight and challenge in current organic chemistry. Most of general methods for the preparation of azapolycyclic compounds are focused on the metal-catalyzed coupling. However, this method has been greatly restricted for the lack of special directing group, expensive metal catalyst et.al. Therefore, it is remarkably significant to develop some novel and efficient methods for the synthesis of azapolycyclic compounds with diverse functional groups. This proposal is intended to construct these compounds through radical hydrofunctionalization of olefins/tandem cyclization reaction. The free radical species formed under Fe(III)/PhSiH3 to functionalize olefins to form new alkyl radicals or the anti-Markovnikov alkyl radical formed under catecholborane, which are captured by ynamine, N-cyanoamide, thiourea to achieve the series cyclization. Our project will provide novel methods for the preparation of azapolycyclic compounds through radical hydrofunctionalization of olefins/tandem cyclization reaction, and the radical mechanism will be studied systematically. Finally, the current methods developed herein will also be used to synthesize pharmaceuticals and natural product molecules. The applicant is a first-named author of 5 papers published in Org. Lett. and Adv. Syn. Catal., and is fairly skilled in scientific research. We hope to propose new methodologies to enrich and expand researches on radical tandem reaction with simple available raw materials, and provide novel approaches and theoretical support for full synthesis of natural products.

温和条件下高官能团兼容性的氮杂环构建，是目前有机化学界研究的热点和难点。目前成环过程需要特殊的导向基、昂贵的金属催化剂等缺点，制约了它的发展，因此发展结构多样性的氮杂环类化合物的新合成方法具有重大意义。本项目拟通过自由基的烯烃氢官能团化/串联环化的反应模式来构建氮杂环：烯烃在Fe(III)/PhSiH3体系下形成烷基自由基物种或者在儿茶酚硼烷参与下形成反马氏烷基自由基物种，被炔胺、N-氰基酰胺、硫脲等捕获，实现串联环化，得到氮杂环，并深入揭示其反应机理，为氮杂环化合物的制备提供一种新颖、高效实用的方法，并在此基础上进行药物分子或类天然产物分子的全合成，实现类天然产物分子的成药性改造。申请人读博期间以第一作者在Org. Lett.等杂志上发表5篇论文，有较好的科研基础，该项目的成功实施，将建立一种原料简单易得、原子经济性好的方法，丰富并拓展自由基串联反应的研究。

氮杂环由于其有特殊的药理活性，因此对于氮杂环类骨架的简洁、高效的设计合成一直是有机合成的热点和难点。发展结构多样性的氮杂环类化合物的新合成方法具有重大的意义，本项目从6个部分展开：(1)以N-2-氯甲基苯基-4-甲基苯磺酰胺原位形成不饱和亚胺中间体为原料，采用温和的反应条件，和亚甲胺叶立德发生[4+3]环加成反应，合成得到含有1,2,4-三氮杂卓环结构骨架的氮杂环化合物。 (2).用四甲基氟化铵(TMAF)作为碱，原位形成不饱和亚胺中间体，然后被烯醇硅醚捕获，以较高收率得到2-对甲苯磺酰胺基取代的二氢色酮。(3).通过炔丙基硫盐在碱作用下原位形成联烯中间体，然后和靛红酸酐反应，简洁高效的构建了一系列含硫的喹诺酮类药物结构母核。(4).炔丙基硫盐在碱作用下原位形成联烯中间体之后，和N-叶立德在碱性条件下合成吡咯并[2,1-a]喹啉，吡咯并[2,1-a]酞嗪和吲哚利嗪类结构母核。(5).利用巴豆酸酯的硫盐作为多组分反应的原料，利用多组分反应，成功的构建了取代环丙烷和茚并[1,2-b]氧西平类杂环化合物。(6).利用巴豆酸酯硫盐和靛红衍生的Morita-Baylis-Hillman酯发生[3 + 2]环化反应：合成螺环类化合物。