Morimoto Tatsuya, Nishimoto Yoshio, Suzuki-Osborne Taku, Chong Su-Gi, Okamoto Kazuhiro, Yoneda Tomoki, Kikuchi Azusa, Yokogawa Daisuke, Atobe Mahito, Shida Naoki
Department of Chemistry and Life Science, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan.
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
J Am Chem Soc. 2025 Jul 23;147(29):25635-25641. doi: 10.1021/jacs.5c06798. Epub 2025 Jul 14.
The synthesis of polysubstituted (hetero)aromatic compounds is essential in various fields, including pharmaceuticals, where such compounds are fundamental to many approved drugs. In this study, we present a novel electrochemical method for single-carbon insertion targeting various (hetero)aromatic compounds, with a particular focus on pyridines. In this process, the electrochemical oxidation of pyrrole derivatives produces a radical cation intermediate, which then undergoes nucleophilic attack by diazo compounds to yield polysubstituted pyridine derivatives. Notably, the insertion position is influenced by the electronic properties of -protecting groups, allowing for unprecedented -selective insertion through the introduction of electron-withdrawing groups. Insights from spectroscopy and theoretical calculations suggest the involvement of distonic radical cation intermediates, facilitating carbon-atom migration on the aromatic ring and enabling insertion at different positions. This study expands the chemical toolkit for synthesizing polysubstituted (hetero)aromatic compounds and introduces a new concept for single-carbon insertion chemistry.
多取代（杂）芳族化合物的合成在包括制药在内的各个领域都至关重要，在制药领域，此类化合物是许多已批准药物的基础。在本研究中，我们提出了一种新颖的电化学方法，用于针对各种（杂）芳族化合物进行单碳插入，尤其侧重于吡啶。在此过程中，吡咯衍生物的电化学氧化产生一个自由基阳离子中间体，然后该中间体受到重氮化合物的亲核攻击，生成多取代吡啶衍生物。值得注意的是，插入位置受保护基电子性质的影响，通过引入吸电子基团可实现前所未有的选择性插入。光谱学和理论计算的结果表明，存在双自由基阳离子中间体，这有助于芳环上碳原子的迁移，并能在不同位置进行插入。本研究扩展了合成多取代（杂）芳族化合物的化学工具集，并引入了单碳插入化学的新概念。
