C-H官能化阻断的不对称去芳构化Heck反应及其串联反应研究

Heck reaction, the cross-coupling of organohalides and olefins to form new alkene derivatives, represents one of the most important carbon-carbon forming reactions. Aromatic compounds are widely utilized as feedstocks in organic synthesis due to their facile accessibility. A number of structurally diverse internal C=C bonds appears inside the aromatic ring. By employing the internal C=C bonds of arenes as coupling reagents, the applicant focused on developing novel asymmetric Heck reactions and domino sequences involving Heck reactions to access chiral alicyclic compounds, which constitutes a new dearmatizing strategy. To avoid the undesired C-H arylation reaction, a functional group attached on the reactive C=C bonds is required to avoid the formation of undesired the C-H functionalization byproducts. Therefore, the aromatic compounds are very limited and only quaternary stereocenters are able to be constructed in previous reports. To address these issues, we will investigate the selective dearomative Heck reactions and related domino sequences of the challenging arenes without a substituent on the reaction cite, including the five member ring heteroaromatics and the six member ring benzenes and naphthalenes. Chiral polycyclic molecules are concisely created based on reaction design, substrate modification, ligand and catalyst optimization, and the success in suppressing the undesired C-H functionalization and side reactions. This project will address three key scientific issues, including how to interrupt the C-H functionalization process, how to break the aromaticity, and how to control the selectivities of the reactions. Detailed study will gain insight on the reaction mechanism, role of the catalysts and their enantiocontrol abilities. This project will help to promote the development of asymmetric Heck reactions.

Heck反应是过渡金属催化卤代烃与烯烃的交叉偶联反应，是最重要的碳碳键形成反应之一。芳香化合物来源广泛，是重要的有机合成原料，其环内含多种类型的碳碳双键。申请人前期以杂芳烃环内碳碳双键为偶联组分，研究和发展了新型不对称Heck反应及相关串联反应，建立了不对称去芳构化新策略和新方法。然而，为消除C-H芳基化副反应，需在参与反应的芳烃环内双键上引入取代基，这大大限制了反应的底物范围，并使研究局限于季碳手性中心的构建。针对这一问题，本项目拟基于反应设计、底物调控、配体和催化剂优化等，有效阻断C-H官能化的竞争过程、抑制副反应，实现反应位点不含取代基的五元杂芳烃底物及苯、萘衍生物的挑战性不对称Heck反应及其串联反应，发展手性环状分子骨架的精准构筑方法。项目将围绕阻断C-H官能化过程、打破芳香性及控制选择性等关键科学问题，探索并揭示催化剂的作用机制及选择性调控规律，进一步推动Heck反应的发展。

Heck反应是过渡金属催化卤代烃与烯烃的交叉偶联反应，是最重要的碳碳键形成反应之一。芳香化合物是重要的有机合成原料，来源广泛、种类繁多，从凯库勒结构看其环内含有多种类型的碳碳双键。近年来，本课题组以杂芳烃环内碳碳双键为偶联组分，研究和发展了新型不对称Heck反应、还原Heck反应及相关串联双官能化反应。研究中为消除芳环C-H键直接芳基化副反应，需在其反应位点处引入取代基，这不但限定了反应的底物范围，还使研究局限于季碳手性中心的构建。为解决这一问题，进一步拓展该类反应的底物范围，本项目围绕阻断C-H官能化过程、打破芳香性及控制选择性等关键科学问题，通过反应和底物设计、取代基调控、配体和催化剂筛选优化等，有效阻断了芳香体系C-H键直接官能化的竞争过程，并抑制卤代烃直接偶联副反应，实现了吲哚、吡咯、萘环及苯环等芳香体系中反应位点处不含取代基的挑战性不对称Heck反应及其串联反应，高效构筑叔碳手性中心及螺环季碳手性中心，发展了手性环状分子骨架的精准构筑方法，探索并揭示催化剂的作用机制及选择性调控规律，进一步推动了Heck反应的发展。此外，项目还基于迁移插入去芳构化策略，通过调控催化剂阻断C-H键官能化，实现了钴催化氮杂缺电子芳烃的去芳构化[3+2]螺环化反应，并在其他类型的去芳构化反应中取得重要进展。项目执行期间，在国内外期刊上发表标注基金的 SCI论文 15篇，其中Acc. Chem. Res. 1篇、J. Am. Chem. Soc. 1篇、Angew. Chem. Int. Ed. 2篇、Nat. Commun. 1篇、ACS Catal. 2篇等，并毕业14名硕博研究生。