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Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations

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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.

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Correspondence to Da-Gang Yu or Song Lin.

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Sun, GQ., Yu, P., Zhang, W. et al. Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations. Nature (2023). https://doi.org/10.1038/s41586-022-05667-0

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  • DOI: https://doi.org/10.1038/s41586-022-05667-0

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