四川大学余达刚团队报道了电化学反应器决定了N-异芳烃羧化反应的位点选择性。相关研究成果发表在2023年1月5日出版的《自然》。

吡啶和相关的N-杂芳烃通常存在于药物、农用化学品和其他生物活性化合物中。位点选择性的C–H功能化将提供制备这些药物活性产物的直接方法。例如，烟酸衍生物可以通过C–H羧化制备，但这仍然是一个难以实现的转变。

该文中，研究人员描述了利用CO₂直接羧基化吡啶的电化学策略的发展。电解装置的选择导致不同的位置选择性：分开的电化学电池导致C5羧化，而不分开的电池促进C4羧化。建议通过成对的电解机制运行未分离的电解池反应，其中阴极和阳极事件在改变位点选择性方面发挥关键作用。具体而言，阳极生成的碘优先通过氢原子转移与C4羧化途径中的关键自由基阴离子中间体反应，从而通过Curtin Hammett原理转移反应选择性。转化的范围扩大到广泛的N-杂芳烃，包括双吡啶和三联吡啶、嘧啶、吡嗪和喹啉。

附：英文原文

Title: Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations

Author: Sun, Guo-Quan, Yu, Peng, Zhang, Wen, Zhang, Wei, Wang, Yi, Liao, Li-Li, Zhang, Zhen, Li, Li, Lu, Zhipeng, Yu, Da-Gang, Lin, Song

Issue&Volume: 2023-01-05

Abstract: Pyridines and related N-heteroarenes are commonly found in pharmaceuticals, agrochemicals, and other bioactive compounds1,2. Site-selective C–H functionalization would provide a direct way of making these medicinally-active products3,4,5. For example, nicotinic acid derivatives could be made by C–H carboxylation, but this remains an elusive transformation6,7,8. Here, we describe the development of an electrochemical strategy for the direct carboxylation of pyridines using CO2. The choice of electrolysis setup gives rise to divergent site selectivity: a divided electrochemical cell leads to C5-carboxylation, whereas an undivided cell promotes C4-carboxylation. The undivided cell reaction is proposed to operate via a paired electrolysis mechanism9,10, wherein both cathodic and anodic events play critical roles in altering the site selectivity. Specifically, anodically-generated iodine preferentially reacts with a key radical anion intermediate in the C4-carboxylation pathway via hydrogen-atom transfer, thus diverting the reaction selectivity via the Curtin-Hammett principle11. The scope of the transformation was expanded to a wide range of N-heteroarenes including bi- and terpyridines, pyrimidines, pyrazines and quinolines.

DOI: 10.1038/s41586-022-05667-0

Source: https://www.nature.com/articles/s41586-022-05667-0