基于重氮对芳环C–H键插入的不对称催化三组分反应研究

Diazo compounds are widely used as precursors of metal carbenes under transition metal catalysis, which have been involved in a variety of C–H functionalizations. However, compared with the well-developed sp3 C–H functionalizations, aromatic sp2 C–H functionalizations via metal carbenes are less developed owing to undesired ring expansions and poor regioselectivities. Very recently, inspired by the booming development of directing-group-assisted aromatic C–H functionalizations under transition metal catalysis, several groups developed a new strategy for aromatic C–H functionalization with diazo compounds by employing rhodium(III) catalysts. This strategy offers new opportunities for developing different types of diazo compounds-involved aromatic C–H functionalizations. However, current achievements within this context are limited to transformations that are terminated with protonolysis of the key alkyl-rhodium intermediates. Therefore, in this project, we will explore new terminating ways; for example, introduce electrophiles such as imines to trap the alkyl-Rh intermediates, and therefore develop new transformations via directing-group-assisted aromatic C–H functionalizations with diazo compounds. Meanwhile, we will introduce chiral phosphoric acid as a cooperative catalyst to active the imine component and therefore to realize efficient catalytic asymmetric control for this transformation. Mechanism studies including intra/intermolecular KIE experiments and HR LC/MS detection of the key intermediates will be conducted to gain some insights about the mechanism of this transformation. Finally, with this established catalytic cycle, we will further choose other electrophiles such as active aldehyde/ketone or isocyanate to develop new types of three-component reactions.

重氮化合物经由金属卡宾实现的C–H 键官能团化是有机化学中的重要研究领域。然而，相比sp3 C–H键官能团化的广泛发展，重氮化合物对芳环sp2 C–H键的官能团化由于受到扩环副反应及区域选择性等问题而较少研究。近年来，基于导向基团辅助的芳环C–H键官能团化是有机化学中的研究热点，这一催化模式最近被运用到了三价铑催化的重氮对芳环C–H键的插入反应中，为重氮化合物对芳环C–H键的官能团化提供了一种新思路。然而，在此催化模式下，目前工作仅实现了对历程中的关键烷基铑中间体发生质子化进而终止反应。为此，本项目将探索该烷基铑中间体新的转化途径，拟采用亚胺对其进行亲电捕捉，实现由芳烃、重氮和亚胺出发的新型三组分反应；采用手性磷酸为协同催化剂，实现不对称催化控制；通过KIE实验及检测关键中间体的生成等对该反应开展机理研究；基于此催化机制，发展其他亲电试剂如活泼醛酮、异氰酸酯等参与的新型三组分反应。

本项目以重氮卡宾对芳环碳氢键的不对称官能团化为研究目标，围绕重氮卡宾参与的新型多组分反应模式、新型协同催化体系的发展、多样性目标分子为导向的合成设计这三个方面开展了深入和持续的研究，取得了一些重要的研究进展。.实现了几类吲哚化合物的C3位碳氢键的高效官能团化，同时，以合成含氮或含氧杂环化合物为导向，实现了不同类型的多样性导向的杂环化合物的高效合成，部分化合物表现出了一些初步的生物活性；基于项目开展过程中针对重氮酰胺类化合物的反应活性研究，实现了一例不需要金属参与的高效构建3-卤代氧化吲哚类化合物构建的方法；成功实现了亲电试剂对硫叶立德的捕捉，并实现了该转化的不对称控制。采用亚胺为亲电试剂，通过二价铑金属催化剂和手性磷酸催化剂的协同作用，实现了该转化，得到了一类多取代的含硫化合物；围绕重氮化合物对芳香碳氢键的官能团化，实现了一例通过分子内的亲电试剂对活泼两性离子中间体捕捉的反应，可以高效的实现芳基碳氢键的官能团化。这些研究进展丰富了重氮化合物参与的多组分反应的反应模式、为相关的新反应的发现、新类型不对称反应的发现提供了反应基础。