多氟芳烃类化合物被广泛地应用于药物化学，材料化学和农药领域。而多氟联芳烃类化合物作为其中重要的一类，其合成受到了化学家的广泛关注。以脱羧，Suzuki-Miyaura和脱氢为代表的交叉偶联反应是合成多氟联芳烃类化合物的重要方法。然而，上述制备多氟联芳烃类化合物的方法仍存在较为明显的不足。第一：受限于多氟芳烃亲核试剂相应试剂的反应活性和商业可得性，很难同时将19种不同的多氟芳基引入芳烃（改变氟芳基亲核试剂上氟原子的个数和分布方式，存在19种不同的氟芳基）。第二：对于复杂芳烃，特别是药物分子的区域选择性多氟芳基化无法实现（图1）。
图1 多氟联芳烃类化合物的合成方法及限制
为了解决上述限制，作者设想可以利用相同或相近的催化条件将多种催化反应融合在一起，进而充分的发挥不同氟芳基亲核试剂的优点，完成19种氟芳基的引入。虽然非活化的芳香烃具有来源广泛的优点，但对于复杂芳烃尤其是药物分子的高区域选择性氟芳基化反应是难以实现的。因此，作者考虑采用德国马普研究所Tobias Ritter教授团队发展的定位选择性噻蒽化反应作为芳烃底物的原位活化手段，实现单一位点选择性的（多）氟芳基化反应。相关成果在国际Top期刊Org. Chem. Front.（DOI：10.1039/D2QO00991A）上发表。该工作实验部分由河南科技学院化学化工学院研究生王跃辉完成，第一作者为化工学院青年教师梁磊，通讯作者为牛红英教授。
图2 反应设计
牛红英/梁磊团队主要致力于有机合成方法学的研究工作，擅于通过发展新方法完成目标分子的高效合成。近年来在《Organic Letters》,《Chemical Communication》和《Organic Chemistry Frontiers》等国际知名期刊上发表论文10余篇，获授权发明专利多项。上述工作受到国家自然科学基金、河南省科技攻关项目、河南科技学院人才引进等项目的资助与支持。
[CN], 2022 — In an outstanding advancement in the field of organic chemistry, the research team led by Professor Hong-Ying Niu and young scholar Lei Liang from Henan University of Technology has made significant strides in the synthesis of polyfluorinated biphenyl compounds, a key category of polyfluorinated aromatic compounds widely used in pharmaceuticals, material science, and pesticides. Their groundbreaking work is published in the top international journal Org. Chem. Front. (DOI: 10.1039/D2QO00991A).
The synthesis of polyfluorinated biphenyl compounds has garnered widespread attention due to their critical applications. Traditional methods, such as decarboxylation, Suzuki-Miyaura, and dehydrogenative cross-coupling reactions, have been essential for synthesizing these compounds. However, these methods faced notable limitations, particularly in integrating different polyfluorophenyl groups into aromatic compounds due to the reactivity and availability of polyfluorophenyl nucleophilic reagents, and achieving region-selective polyfluorophenylation in complex aromatics, especially in drug molecules.
Addressing these challenges, the Niu/Liang team envisioned combining various catalytic reactions under similar or close conditions, leveraging the advantages of different fluorophenyl nucleophilic reagents to introduce 19 types of fluorophenyl groups. Despite the broad availability of non-activated aromatic hydrocarbons, achieving high regioselectivity in complex aromatics, especially in pharmaceutical molecules, remained a challenge. To overcome this, the team adopted the regioselective thianthrene chemistry developed by Professor Tobias Ritter's group at the Max Planck Institute in Germany for in-situ activation of aromatic substrates, enabling selective (poly)fluorophenylation at a single site.
The experimental part of this significant study was conducted by graduate student Yue-Hui Wang from the College of Chemistry and Chemical Engineering at Henan University of Technology. The first author of the paper is Lei Liang, a young faculty member of the Chemical Engineering College, and the corresponding author is Professor Hong-Ying Niu.
The Niu/Liang team, primarily engaged in organic synthetic methodology research, excels in developing new methods for the efficient synthesis of target molecules. In recent years, they have published over ten papers in internationally renowned journals, including Organic Letters, Chemical Communication, and Organic Chemistry Frontiers, and have obtained multiple authorized invention patents. Their work has been supported by the National Natural Science Foundation, Henan Provincial Science and Technology Tackle Key Project, and talent introduction projects of Henan University of Technology.
This breakthrough not only marks a significant advancement in organic synthesis but also opens new avenues for the practical application of polyfluorinated biphenyl compounds in various fields.
Org. Chem. Front. 2022, 9, 5832-5839 https://pubs.rsc.org/en/journals/journalissues/qo#!recentarticles