Electrochemical reactor dictates site selectivity in N

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Nature volume 615, pages 67–72 (2023)Cite this article

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Pyridines and related N-heteroarenes are commonly found in pharmaceuticals, agrochemicals and other biologically active 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 the 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 through a paired-electrolysis mechanism9,10, in which 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 through hydrogen-atom transfer, thus diverting the reaction selectivity by means of the Curtin–Hammett principle11. The scope of the transformation was expanded to a wide range of N-heteroarenes, including bipyridines and terpyridines, pyrimidines, pyrazines and quinolines.

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All data supporting the findings of this work are available in the paper and its Supplementary Information.

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We thank X. Wang from the Analytical & Testing Center at Sichuan University, J. Li and D. Deng from the comprehensive training platform of the Specialized Laboratory in the College of Chemistry at Sichuan University and the analytical facilities at Cornell University (supported by National Science Foundation grant CHE-1531632) for compound characterization. This work was financed by the National Natural Science Foundation of China (22225106 and 21822108 to D.-G.Y.), Sichuan Science and Technology Program (20CXTD0112 to D.-G.Y.), the ‘973’ Project from the MOST of China (2015CB856600 to D.-G.Y.), Fundamental Research Funds from Sichuan University (2020SCUNL102 to D.-G.Y.), National Institute of General Medical Sciences (R01GM130928 to S.L.), Eli Lilly and Company (to S.L.) and Cornell University (to S.L.). S.L. is grateful to the Sloan Foundation for a Sloan Research Fellowship. Electron spin resonance data were collected and analysed at the National Biomedical Center for Advanced ESR Technology (ACERT) (P41GM103521) with assistance from S. Chandrasekaran. We thank M. Frederick for helpful discussions, P. Milner and S. Meng for the use of gas chromatography, C. Wagen and E. Jacobsen for the use of the Karl Fischer titrator, I. Keresztes for help with NMR analysis, J. Martinez Alvarado for graphic design of Fig. 2, J. Ho for manuscript editing and W. Guan for reproducing experiments.

These authors contributed equally: Guo-Quan Sun, Peng Yu, Wen Zhang

Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, People's Republic of China

Guo-Quan Sun, Wei Zhang, Li-Li Liao, Zhen Zhang, Li Li & Da-Gang Yu

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

Peng Yu, Wen Zhang, Yi Wang, Zhipeng Lu & Song Lin

Beijing National Laboratory for Molecular Sciences, Beijing, People's Republic of China

Da-Gang Yu

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G.-Q.S., P.Y. and Wen Zhang contributed equally to this work. G.-Q.S., P.Y., Wen Zhang, Wei Zhang, L.-L.L., Z.Z. and L.L. performed synthetic experiments. P.Y., G.-Q.S. and Wen Zhang performed mechanistic experiments. Y.W. and Z.L. conducted DFT calculations and electroanalytic experiments. S.L. and D.-G.Y. supervised the project.

Correspondence to Da-Gang Yu or Song Lin.

The authors declare no competing interests.

Nature thanks Ki Tae Nam and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Sun, GQ., Yu, P., Zhang, W. et al. Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations. Nature 615, 67–72 (2023). https://doi.org/10.1038/s41586-022-05667-0

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Received: 18 August 2022

Accepted: 16 December 2022

Published: 05 January 2023

Issue Date: 02 March 2023

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

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Electrochemical reactor dictates site selectivity in N