酰胺氢协助策略：芳基自由基形成新方法及其应用

Aryl radicals could hardly be generated directly from sp2 C-H bonds due to their large bond dissociation energy. Instead, active pre-functionalized arenes generally serve as radical precursors for arene functionalization. Cationic aryl radicals could be formed directly from arenes through single-electron transfer (SET). However, this strategy is limited to certain aromatic ethers, and alkoxy groups are difficult to remove. Recently, we disclosed a novel protocol for aryl radical generation, which is assisted by the removable amide group. The hydrogen abstraction from the amidyl N-H bonds could occur easily, and the resultant anilidyl radicals have resonance structures of N-radicals and C-radicals. The later ones could be captured as well during reaction, accomplishing aromatic C-H functionalization. Such amide-assisted radical strategy, using which might deliver a new class of reactions, might serve as a powerful complement to traditional electrophilic aromatic substitution and modern C-H activation. In this project, a series of radical aromatic C-H functionalization reactions, which are difficult to realize through conventional methods, would be developed via this strategy using anilides as substrates. Specifically, 1) ortho-sulfonylation using sulfonylhydrazides; 2) ortho-cyanoalkylarylation with nitriles; 3) ortho-oxygenation with NHPI or HOBt. Mechanisms of these reactions will be thoroughly investigated by a combination of experimental and DFT theoretical study, providing conclusive evidences for the amide-assisted radical pathway and ruling out the electrophilic aromatic substitution and the C-H activation mechanisms.

芳基自由基一般由预官能团化的活泼芳香前体生成，不能由C-H键直接得到。单电子转移（SET）能够从芳烃直接产生阳离子自由基，但该策略目前主要局限于部分芳香醚，而烷氧基难移除。最近，我们发现了一个全新的芳基自由基生成方法，即引入方便移除的酰胺基团，通过酰胺氮自由基共振得到芳基碳自由基。碳自由基被捕获便能实现芳烃的C-H键官能团化。该酰胺氢协助自由基策略是传统亲电芳香取代和现代C-H键活化反应的有力补充，并将为现代化学补充一类新反应。本项目拟以该策略为研究对象和工具，以酰基苯胺为底物，发展过去难实现的自由基芳烃C-H键官能团化反应。具体包括：1）邻位磺酰化；2）邻位氰烷基化；3）使用NHPI和HOBt的邻位氧合反应；4）在实验基础上，结合理论计算对反应历程进行深入研究，找到酰胺氢协助自由基历程的确切证据，排除亲电芳香取代和C-H键活化等机理。

芳基自由基一般由预官能团化的活泼芳香前体生成，不能由C-H键直接得到。单电子转移（SET）能够从芳烃直接产生阳离子自由基，但该策略此前主要局限于部分芳香醚，而烷氧基难移除。我们发现了一个全新的芳基自由基生成方法，即引入方便移除的酰胺基团，通过酰胺氮自由基共振得到芳基碳自由基，碳自由基被捕获便能实现芳烃的C-H键官能团化。该酰胺氢协助自由基策略是传统亲电芳香取代和现代C-H键活化反应的有力补充，并将为现代化学补充一类新反应。本项目以该策略为研究对象和工具，以酰基苯胺为底物，发展过去难实现的自由基芳烃C-H键官能团化反应，包括硝基化、硒化等，并将研究内容拓展到酰胺基团协助的烯烃双官能团化/环化反应。实验中捕获到了酰胺N-自由基，找到了酰胺氢协助自由基历程的确切证据，排除了亲电芳香取代和C-H键活化等机理。