Rh(III)催化非典型[4+2]环化构建中环内酰胺及多芳基乙烯分子骨架

Rhodium(III)-catalyzed direct C-H functionalization/cycloaddition has become one of the most powerful synthetic tools to prepare complex cycles from simple starting materials. Among them, [4+1] and [4+2]-annulations have been well developed for the synthesis of five- and six-membered heterocycles. In contrast, only a few examples on the synthesis of medium-sized rings and other functional organic molecules have been reported, which are mainly achieved by unusual [4+2]-annulations. In this project, a couple of directing groups assisted Rh(III)-catalyzed C-H functionalization has been proposed for the preparation of some bio-interesting skeletons containing medium-sized-ring lactams and polyarylethylenes in convenient and efficient ways. Firstly, Rh(III)-catalyzed [4+3] and [4+2+2] cyclization reactions have been designed to access to seven- and eight-membered lactams that are difficult to be obtained by conventional methods. Secondly, Rh(III)-catalyzed C-H activation/β-H elimination tandem process will be conducted, with the aim to develop a novel and highly efficient route to synthesize the anti-cancer agent tamoxifen and tetrasubstituted alkenes which features the property of aggregation induced enhanced emission(AIE). This project can enrich and enlarge the application scope of the current Rh(III)-catalyzed C-H functionalization methodology and has great significance for the synthesis of novel bio-interesting compounds and fluorescent materials.

Rh(III)催化的C-H键活化/环化构建环状分子已成为有机合成方法学研究的热点领域之一。其中通过[4+1]、[4+2]环化分别构建五元、六元杂环的研究已比较成熟，然而对于具有更高合成难度与价值的中环内酰胺及其它功能有机分子的合成还有待进一步研究。本项目拟开展Rh(III)催化的非典型[4+2]环化反应研究，实现一些具有中环结构的潜在生物活性分子及荧光分子核心骨架的简洁合成，具体包括：探索Rh(III)催化的[4+3]和[4+2+2]环加成反应机制，用于合成传统方法较难制备的七元和八元环内酰胺；打破以往合成多芳基乙烯对于McMurry偶联的依赖，运用Rh(III)催化C-H活化/β-H消除机制，合成抗乳腺癌药物他莫昔芬及具有聚集诱导荧光增强性质（AIE）的四苯基乙烯分子骨架。本项目以中环内酰胺和多芳基乙烯为研究对象，将建立高效的合成策略，对新药研发和荧光材料的合成具有积极意义。

近十几年来，Rh(III)催化已成为构建新的C-C、C-N及C-O键的强有力工具之一。然而目前的相关研究集中于烯烃或炔烃独立参与的传统[4+2]环化反应，合成结构单一的五元环或六元环产物。而对于具有更高合成难度与价值的中环内酰胺及利用β-H消除构建多取代烯烃的合成探索仍不多见。本项目拟开展Rh(III)催化的非典型[4+2]环化反应研究，为一些潜在生物活性分子及荧光分子核心骨架提供简洁的合成方法，具体包括：（1）在温和的反应条件下从简单的原料出发，巧妙地完成了Rh（III）催化的三组分（乙酰氨基酚、醛和水合肼）反应得到多芳基取代的他莫昔芬类似物；（2）使用邻羟基苯乙烯作为反应物实现烯基C-H活化得到烯基取代的环戊烯胺骨架，反应快速，起始原料容易合成并且原子经济性100%; (3) 发现了Rh(III)接力催化醛、2-氨基吡啶和活化的烯烃作用一步实现异吲哚酮的合成。金属催化剂铑分别参与了两个分步反应。值得一提的是该方法可推广至合成抗抑郁药物帕秦克隆及帕戈隆的合成；（4）利用最近几年复兴起来的电化学合成技术，首次实现了Rh(III)催化电氧化条件下的苯甲酰胺的邻位烯基化反应。此外，自由基化学也已成为快速搭建新的碳碳、碳氧及碳氮键的方法，申请人在这方面也进行了一些研究，实现了芳基烷基偶氮类化合物、氟烷基以及磷酰基取代的螺[5.5]分子骨架和氨基取代杂环的合成。至项目立项以来作为第一作者或通讯作者已在权威期刊Angew. Chem. Int. Ed. Chem., Chem. Eur. J., Org. Lett., J. Org. Chem等发表论文七篇，其中SCI一区4篇，二区2篇，三区1篇。申请发明专利6项。