Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations Peng Yu 2 , Da-Gang Yu 3 , Song Lin 1 , Guo-Quan 3 , Wen Zhang 1 1 Cornell University, USA, 2 Eastern Institute for Advanced Study, China, 3 Sichuan University, China Pyridines and related N-heteroarenes are commonly found in pharmaceuticals, agrochemicals and other biologically active compounds [1,2] . Site-selective C–H functionalization would provide a direct way of making these medicinally active products [3,4,5] . For example, nicotinic acid derivatives could be made by C–H carboxylation, but this remains an elusive transformation [6,7,8] . Here we describe the development of an electrochemical strategy for the direct carboxylation of pyridines using CO 2 . 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 mechanism [9,10] , 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 principle [11] . The scope of the transformation was expanded to a wide range of N-heteroarenes, including bipyridines and terpyridines, pyrimidines, pyrazines and quinolines. References 1. 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). 2. Pozharskii, A. F., Soldatenkov, A. T., Katritzky, A. R. Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications (Wiley, 2011). 3. Nakao, Y. Transition-metal-catalyzed C–H functionalization for the synthesis of substituted pyridines. Synthesis 20 , 3209−3219 (2011). 4. 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). 5. Seregin, I. V., Gevorgyan, V. Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem. Soc. Rev. 36 , 1173−1193 (2007). 6. Khoshro, H., Zare, H. R., Jafari, A. A., Gorji, A. Dual activity of electrocatalytic activated CO 2 toward pyridine for synthesis of isonicotinic acid: An EC’C’C mechanism. Electrochem. Commun. 51 , 69–71 (2015). 7. Fuchs, P., Hess, U., Holst, H. H., Lund, H. Electrochemical carboxylation of some heteroaromatic compounds. Acta Chem. Scand. B 35 , 185−192 (1981). 8. Fu, L., Li, S., Cai, Z.-H., Ding, Y.-Z., Guo, X.-Q., Zhou, L.-P., Yuan, D.-Q., Sun, Q.-F., Li, G. Ligand-enabled site-selectivity in a versatile rhodium (II)-catalysed aryl C–H carboxylation with CO 2 . Nat. Catal. 1 , 469–478 (2018). 9. 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). 10. Mo, Y., Lu, Z., Rughoobur, G., Patil, P., Gershenfeld, N., Akinwnde, A. I., Buchwald, S. L., Jensen, K. F. Microfluidic electrochemistry for single-electron transfer redox-neutral reactions. Science 368 , 1352−1357 (2020). 11. 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).
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