The polarity reversal strategy facilitates the para-selective C-H functional grouping reaction of aromatic hydrocarbons

On April 27, 2023, the research group of Gao Hongyin, School of Chemistry and Chemical Engineering, Shandong University, and Yu Zhixiang, School of Chemistry, Peking University, made new progress in the field of selective C-H functional reaction in aromatic hydrocarbon regions. The research results were published in the journal Nature Synthesis under the title “Regioselective umpolung para-C–H functionalization of arylhydroxylamines”.

Xi Zhenguo, a master’s student of Shandong University, is the first author of the paper, Professor Gao Hongyin (reaction methodology development and mechanism research) and Professor Yu Zhixiang of Peking University (reaction mechanism research) are the co-corresponding authors of the paper, Liu Xijia, a postdoctoral fellow in the research group of Professor Yu Zhixiang of Peking University, provided theoretical calculation support, and Guo Zhaoquan and Gao Zhiwei, master’s students of Shandong University, made certain contributions. Shandong University and Peking University are the co-authors of the paper.

The regionally selective aromatic C-H functional group reaction has a wide range of applications in the field of synthetic chemistry, materials science and pharmaceutical industry. Different from the well-developed ortho or meta-C-H functional reactions of aromatic hydrocarbons, the para-C-H bond functional grouping reaction of aromatic hydrocarbons is less studied and is particularly challenging. Since the para-C-H bond is relatively far from the guide group, special guide groups and catalytic systems are generally required to react under more harsh reaction conditions. Therefore, it is of great significance to develop a low-cost, mild-conditioned, and universally applicable reaction strategy to realize the para-C-H functionalization reaction of aromatic hydrocarbons.

Professor Gao Hongyin’s research group developed a polarity reversal strategy based on aryl hydroxylamine substrate, and realized the selective C-H bond functionalization reaction of hydroxylamine para. They used easy-to-prepare sulfonylfluimidazole salts (which can be prepared at near the equivalent yield of kilograms) as the activation reagent, and reacted with hydroxylamine substrates to achieve its polarity reversal and generate electrophilic active intermediatesIB, and then captured by various external nucleophiles (water, alcohols, thiophylphenols, etc.) to achieve the efficient construction of a series of para-functional aniline compounds. The reaction has a high degree of chemical selectivity and regional selectivity, simple and mild reaction conditions, a wide range of substrates, and high synthesis efficiency. This strategy can be successfully applied to the late functional modification of many active drug molecules or natural product molecules. Through a large number of control experiments, ultra-low temperature nuclear magnetic resonance, in situ infrared and DFT calculations, the authors conducted in-depth discussions on the reaction mechanism, and elucidated the tandem reaction mechanism of O-fluorosulfonylation, polarity reversal after N-O bond breakage, and subsequent capture by nucleophiles. They also preliminarily verified the synthetic application potential of the method by the gram-scale preparation reaction and subsequent transformation of the product. This polarity inversion strategy opens a new mode of hydroxylamine substrates to participate in the reaction, laying the foundation for the introduction of more types of nucleophiles into the reaction system, and then constructing more valuable nitrogen-containing functional molecules.

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In recent years, Professor Gao Hongyin’s research group has focused on the study of tandem rearrangement reactions driven by weak bond breakage[2,3]-,[3,3]-Rearrangement reaction or polarity reversal strategy, developed a series of novel synthesis methods of nitrogen-containing functional molecules, and realized the efficient construction of indole, biaryl compounds and functionalized arylamine compounds with diverse structures. The relevant research results were published in Nat. Synth.,Angew. Chem. Int. Ed.,ACS Catal.,Chem. SCI. and other international authoritative journals. The above research was funded and supported by the National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and the “Qilu Young Scholars” start-up fund of Shandong University. Professor Yu Zhixiang’s research group has been committed to studying the mechanism of organic chemical reactions, developing new chemical reactions and synthesizing natural products and drug molecules based on new reactions in the research group. Yu Zhixiang’s research group has published a number of original and high-impact scientific research results in these fields. (Source: Science Network)

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