Electrochemical reactor dictates site selectivity in N

Mar 31, 2023

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.

Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

Article CAS PubMed Google Scholar

Pozharskii, A. F., Soldatenkov, A. T. & Katritzky, A. R. Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications (Wiley, 2011).

Nakao, Y. Transition-metal-catalyzed C–H functionalization for the synthesis of substituted pyridines. Synthesis 20, 3209–3219 (2011).

Article Google Scholar

Stephens, D. E. & Larionov, O. V. Recent advances in the C–H-functionalization of the distal positions in pyridines and quinolines. Tetrahedron 71, 8683–8716 (2015).

Article CAS PubMed PubMed Central Google Scholar

Seregin, I. V. & Gevorgyan, V. Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem. Soc. Rev. 36, 1173–1193 (2007).

Article CAS PubMed PubMed Central Google Scholar

Khoshro, H., Zare, H. R., Jafari, A. A. & Gorji, A. Dual activity of electrocatalytic activated CO2 toward pyridine for synthesis of isonicotinic acid: an EC′C′C mechanism. Electrochem. Commun. 51, 69–71 (2015).

Article CAS Google Scholar

Fuchs, P., Hess, U., Holst, H. H. & Lund, H. Electrochemical carboxylation of some heteroaromatic compounds. Acta Chem. Scand. B 35, 185–192 (1981).

Article Google Scholar

Fu, L. et al. Ligand-enabled site-selectivity in a versatile rhodium(II)-catalysed aryl C–H carboxylation with CO2. Nat. Catal. 1, 469–478 (2018).

Article CAS Google Scholar

Llorente, M. J., Nguyen, B. H., Kubiak, C. P. & Moeller, K. D. Paired electrolysis in the simultaneous production of synthetic intermediates and substrates. J. Am. Chem. Soc. 138, 15110–15113 (2016).

Article CAS PubMed Google Scholar

Mo, Y. et al. Microfluidic electrochemistry for single-electron transfer redox-neutral reactions. Science 368, 1352–1357 (2020).

Article ADS CAS PubMed Google Scholar

Seeman, J. I. Effect of conformational change on reactivity in organic chemistry. Evaluations, applications, and extensions of Curtin-Hammett Winstein-Holness kinetics. Chem. Rev. 83, 83–134 (1983).

Article CAS Google Scholar

Guo, P., Joo, J. M., Rakshit, S. & Sames, D. C–H arylation of pyridines: high regioselectivity as a consequence of the electronic character of C–H bonds and heteroarene ring. J. Am. Chem. Soc. 133, 16338–16341 (2011).

Article CAS PubMed PubMed Central Google Scholar

Cheng, C. & Hartwig, J. F. Rhodium-catalyzed intermolecular C–H silylation of arenes with high steric regiocontrol. Science 343, 853–857 (2014).

Article ADS CAS PubMed Google Scholar

Zhu, R.-Y., Farmer, M. E., Chen, Y.-Q. & Yu, J.-Q. A simple and versatile amide directing group for C–H functionalizations. Angew. Chem. Int. Ed. 55, 10578–10599 (2016).

Article CAS Google Scholar

Arockiam, P. B., Bruneau, C. & Dixneuf, P. H. Ruthenium(II)-catalyzed C–H bond activation and functionalization. Chem. Rev. 112, 5879–5918 (2012).

Article CAS PubMed Google Scholar

Brückl, T., Baxter, R. D., Ishihara, Y. & Baran, P. S. Innate and guided C–H functionalization logic. Acc. Chem. Res. 45, 826–839 (2012).

Article PubMed Google Scholar

Proctor, R. S. J., Davis, H. J. & Phipps, R. J. Catalytic enantioselective Minisci-type addition to heteroarenes. Science 360, 419–422 (2018).

Article ADS CAS PubMed Google Scholar

Liu, Q., Wu, L., Jackstell, R. & Beller, M. Using carbon dioxide as a building block in organic synthesis. Nat. Commun. 6, 5933 (2015).

Article ADS PubMed Google Scholar

Tortajada, A., Juliá-Hernández, F., Börjesson, M., Moragas, T. & Martin, R. Transition‐metal‐catalyzed carboxylation reactions with carbon dioxide. Angew. Chem. Int. Ed. 57, 15948–15982 (2018).

Article CAS Google Scholar

Ye, J.-H., Ju, T., Huang, H., Liao, L.-L. & Yu, D.-G. Radical carboxylative cyclizations and carboxylations with CO2. Acc. Chem. Res. 54, 2518–2531 (2021).

Article CAS PubMed Google Scholar

Zhang, L. & Hou, Z. N-Heterocyclic carbene (NHC)–copper-catalysed transformations of carbon dioxide. Chem. Sci. 4, 3395–3403 (2013).

Article ADS CAS Google Scholar

Boogaerts, I. I. F. & Nolan, S. P. Carboxylation of C–H bonds using N-heterocyclic carbene gold(I) complexes. J. Am. Chem. Soc. 132, 8858–8859 (2010).

Article CAS PubMed Google Scholar

Liu, X.-F., Zhang, K., Tao, L., Lu, X.-B. & Zhang, W.-Z. Recent advances in electrochemical carboxylation reactions using carbon dioxide. Green Chem. Eng. 3, 125–137 (2022).

Article Google Scholar

Luo, J. & Larrosa, I. C–H carboxylation of aromatic compounds through CO2 fixation. ChemSusChem 10, 3317–3332 (2017).

Article CAS PubMed PubMed Central Google Scholar

Dhawa, U., Choi, I. & Ackerman, L. in CO2 as a Building Block in Organic Synthesis (ed. Das, S.) 29–57 (Wiley, 2020).

Ye, M., Gao, G.-L. & Yu, J.-Q. Ligand-promoted C-3 selective C–H olefination of pyridines with Pd catalysts. J. Am. Chem. Soc. 133, 6964–6967 (2011).

Article CAS PubMed Google Scholar

Fosu, S. C., Hambira, C. M., Chen, A. D., Fuchs, J. R. & Nagib, D. A. Site-selective C–H functionalization of (hetero)arenes via transient, non-symmetric iodanes. Chem. 5, 417–428 (2019).

Article CAS PubMed Google Scholar

Proctor, R. S. J. & Phipps, R. J. Recent advances in Minisci-type reactions. Angew. Chem. Int. Ed. 58, 13666–13699 (2019).

Article CAS Google Scholar

Lewis, J. C., Bergman, R. G. & Ellman, J. A. Rh(I)-catalyzed alkylation of quinolines and pyridines via C–H bond activation. J. Am. Chem. Soc. 129, 5332–5333 (2007).

Article CAS PubMed PubMed Central Google Scholar

Hilton, M. C. et al. Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates. Science 362, 799–804 (2018).

Article ADS CAS PubMed PubMed Central Google Scholar

O’Hara, F., Blackmond, D. G. & Baran, P. S. Radical-based regioselective C–H functionalization of electron-deficient heteroarenes: scope, tunability, and predictability. J. Am. Chem. Soc. 135, 12122–12134 (2013).

Article PubMed PubMed Central Google Scholar

Nakao, Y., Yamada, Y., Kashihara, N. & Hiyama, T. Selective C-4 alkylation of pyridine by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 132, 13666–13668 (2010).

Article CAS PubMed Google Scholar

Kim, J. H. et al. A radical approach for the selective C–H borylation of azines. Nature 595, 677–683 (2021).

Article ADS CAS PubMed Google Scholar

Fier, P. S. & Hartwig, J. H. Selective C–H fluorination of pyridines and diazines inspired by a classic amination reaction. Science 342, 956–960 (2013).

Article ADS CAS PubMed Google Scholar

Gao, Y., Cai, Z., Li, S. & Li, G. Rhodium(I)-catalyzed aryl C–H carboxylation of 2-arylanilines with CO2. Org. Lett. 21, 3663–3669 (2019).

Article CAS PubMed Google Scholar

Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical methods since 2000: on the verge of a renaissance. Chem. Rev. 117, 13230–13319 (2017).

Article CAS PubMed PubMed Central Google Scholar

Wiebe, A. et al. Electrifying organic synthesis. Angew. Chem. Int. Ed. 57, 5594–5619 (2018).

Article CAS Google Scholar

Novaes, L. F. T. et al. Electrocatalysis as an enabling technology for organic synthesis. Chem. Soc. Rev. 50, 7941–8002 (2021).

Article CAS PubMed PubMed Central Google Scholar

Ackermann, L. Metalla-electrocatalyzed C–H activation by earth-abundant 3d metals and beyond. Acc. Chem. Res. 53, 84–104 (2020).

Article CAS PubMed Google Scholar

Jiao, K.-J., Xing, Y.-K., Yang, Q.-L., Qiu, H. & Mei, T.-S. Site-selective C–H functionalization via synergistic use of electrochemistry and transition metal catalysis. Acc. Chem. Res. 53, 300–310 (2020).

Article CAS PubMed Google Scholar

Kärkäs, M. D. Electrochemical strategies for C–H functionalization and C–N bond formation. Chem. Soc. Rev. 47, 5786–5865 (2018).

Article PubMed Google Scholar

Horn, E. J. et al. Scalable and sustainable electrochemical allylic C–H oxidation. Nature 533, 77–81 (2016).

Article ADS CAS PubMed PubMed Central Google Scholar

Wang, F. & Stahl, S. S. Electrochemical oxidation of organic molecules at lower overpotential: accessing broader functional group compatibility with electron–proton transfer mediators. Acc. Chem. Res. 53, 561–574 (2020).

Article CAS PubMed PubMed Central Google Scholar

Yan, Y., Zeitler, E. L., Gu, J., Hu, Y. & Bocarsly, A. B. Electrochemistry of aqueous pyridinium: exploration of a key aspect of electrocatalytic reduction of CO2 to methanol. J. Am. Chem. Soc. 135, 14020–14023 (2013).

Article CAS PubMed Google Scholar

Wang, P. et al. Electrochemical arylation of electron-deficient arenes through reductive activation. Angew. Chem. Int. Ed. 58, 15747–15751 (2019).

Article CAS Google Scholar

Hori, Y. in Modern Aspects of Electrochemistry (eds Vayenas, C. G., White, R. E. & Gamboa-Aldeco, M. E.) 89–189 (Springer, 2008).

Dunwell, M. et al. The central role of bicarbonate in the electrochemical reduction of carbon dioxide on gold. J. Am. Chem. Soc. 139, 3774–3783 (2017).

Article CAS PubMed Google Scholar

Montoro, R. & Wirth, T. Direct iodination of alkanes. Org. Lett. 5, 4729–4731 (2003).

Article CAS PubMed Google Scholar

Murray, P. R. D. et al. Photochemical and electrochemical applications of proton-coupled electron transfer in organic synthesis. Chem. Rev. 122, 2017–2291 (2022).

Article CAS PubMed Google Scholar

Sore, H. F., Galloway, W. R. & Spring, D. R. Palladium-catalysed cross-coupling of organosilicon reagents. Chem. Soc. Rev. 41, 1845–1866 (2012).

Article CAS PubMed Google Scholar

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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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