C3 Selective chalcogenation and fluorination of pyridine using classic Zincke imine intermediates

Kwong, H. L. et al. Chiral pyridine-containing ligands in asymmetric catalysis. Coord. Chem. Rev. 251, 2188–2222 (2007).Article 
CAS 

Google Scholar 
Kallitsis, J. K., Geormezi, M. & Neophytides, S. G. Polymer electrolyte membranes for high-temperature fuel cells based on aromatic polyethers bearing pyridine units. Polym. Int. 58, 1226–1233 (2009).Article 
CAS 

Google Scholar 
Zafar, M. N. et al. Pyridine and related ligands in transition metal homogeneous catalysis. Russ. J. Coord. Chem. 42, 1–18 (2016).Article 
CAS 

Google Scholar 
Guan, A. Y., Liu, C. L., Sun, X. F., Xie, Y. & Wang, M. A. Discovery of pyridine-based agrochemicals by using Intermediate Derivatization Methods. Bioorg. Med. Chem. 24, 342–353 (2016).Article 
CAS 
PubMed 

Google Scholar 
Stolar, M. & Baumgartner, T. Functional conjugated pyridines via main-group element tuning. Chem. Commun. 54, 3311–3322 (2018).Article 
CAS 

Google Scholar 
Tahir, T. et al. Pyridine Scaffolds, Phenols and derivatives of azo moiety: current therapeutic perspectives. Molecules 26, 4872 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Bhutani, P. et al. U.S. FDA approved drugs from 2015–June 2020: a Perspective. J. Med. Chem. 64, 2339–2381 (2021).Article 
CAS 
PubMed 

Google Scholar 
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 
Blatchford, J. W. et al. Photoluminescence in pyridine-based polymers: role of aggregates. Phys. Rev. B. 54, 9180–9189 (1996).Article 
ADS 
CAS 

Google Scholar 
Altaf, A. A. et al. A Review on the medicinal importance of pyridine derivatives. J. Drug Des. Med. Chem 1, 1–11 (2015).
Google Scholar 
Lou, X. Y. & Yang, Y. W. Pyridine-conjugated pillar arene: from molecular crystals of blue luminescence to red-emissive coordination nanocrystals. J. Am. Chem. Soc. 143, 11976–11981 (2021).Article 
CAS 
PubMed 

Google Scholar 
De, S. et al. Pyridine: the scaffolds with significant clinical diversity. RSC Adv. 12, 15385–15406 (2022).Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Murakami, K., Yamada, S., Kaneda, T. & Itami, K. C–H functionalization of azines. Chem. Rev. 117, 9302–9332 (2017).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 
Bull, J. A., Mousseau, J. J., Pelletier, G. & Charette, A. B. Synthesis of pyridine and dihydropyridine derivatives by regio- and stereoselective addition to N-activated pyridines. Chem. Rev. 112, 2642–2713 (2012).Article 
CAS 
PubMed 

Google Scholar 
Dolewski, R. D., Hilton, M. C. & McNally, A. 4-Selective pyridine functionalization reactions via heterocyclic phosphonium salts. Synlett 29, 8–14 (2018).Article 
CAS 

Google Scholar 
Zhou, F. Y. & Jiao, L. Recent developments in transition-metal-free functionalization and derivatization reactions of pyridines. Synlett 32, 159–178 (2021).Article 
CAS 

Google Scholar 
Li, C. & Yan, Z. Regioselective synthesis of 4-functionalized pyridines. Chem 10, 628–643 (2024).Article 
CAS 

Google Scholar 
Kim, M., Koo, Y. & Hong, S. N-functionalized pyridinium salts: a new chapter for site-selective pyridine C–H functionalization via radical-based processes under visible light irradiation. Acc. Chem. Res. 55, 3043–3056 (2022).Article 
CAS 
PubMed 

Google Scholar 
Olah, G. A. Mechanism of electrophilic aromatic substitutions. Acc. Chem. Res. 4, 240–248 (1971).Article 
CAS 

Google Scholar 
Galabov, B., Nalbantova, D., Schleyer, P. & Schaefer, H. F. Electrophilic aromatic substitution: new insights into an old class of reactions. Acc. Chem. Res. 49, 1191–1199 (2016).Article 
CAS 
PubMed 

Google Scholar 
Wasa, M., Worrell, B. T. & Yu, J. Q. Pd0/PR3-Catalyzed Arylation of nicotinic and isonicotinic acid derivatives. Angew. Chem. Int. Ed. 49, 1275–1277 (2010).Article 
CAS 

Google Scholar 
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 
Ye, M. et al. Ligand-promoted C3-selective arylation of pyridines with Pd catalysts: Gram-scale synthesis of (±)-preclamol. J. Am. Chem. Soc. 133, 19090–19093 (2011).Article 
CAS 
PubMed 

Google Scholar 
Zhang, T. et al. A directive Ni catalyst overrides conventional site selectivity in pyridine C–H alkenylation. Nat. Chem. 13, 1207–1213 (2021).Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Li, B. J. & Shi, Z. J. Ir-catalyzed highly selective addition of pyridyl C–H bonds to aldehydes promoted by triethylsilane. Chem. Sci. 2, 488–493 (2011).Article 
CAS 

Google Scholar 
Murphy, J., Liao, M., Hartwig, X. & Meta, J. F. halogenation of 1,3-disubstituted arenes via Iridium-catalyzed. arene borylation. J. Am. Chem. Soc. 129, 15434–15435 (2007).Article 
CAS 
PubMed 

Google Scholar 
Larsen, M. A., Hartwig, J. F. & Iridium-catalyzed, C. –H. borylation of heteroarenes: scope, regioselectivity, application to late-stage functionalization, and mechanism. J. Am. Chem. Soc. 136, 4287–4299 (2014).Article 
CAS 
PubMed 

Google Scholar 
Cheng, C. & Hartwig, J. F. Iridium-catalyzed silylation of aryl C–H bonds. J. Am. Chem. Soc. 137, 592–595 (2015).Article 
CAS 
PubMed 

Google Scholar 
Wübbolt, S. & Oestreich, M. Catalytic Electrophilic C–H silylation of pyridines enabled by temporary dearomatization. Angew. Chem. Int. Ed. 54, 15876–15879 (2015).Article 

Google Scholar 
Xie, F. et al. Direct reductive quinolyl β-C–H alkylation by multispherical cavity carbon-supported cobalt oxide nanocatalysts. ACS Catal 7, 4780–4785 (2017).Article 
CAS 

Google Scholar 
Wright, J. S., Scott, P. J., Steel, P. G. & Iridium-catalysed, C. −H. borylation of heteroarenes: balancing steric and electronic regiocontrol. Angew. Chem. Int. Ed. 133, 2830–2856 (2021).Article 
ADS 

Google Scholar 
Wright, J. S., P. Scott, J., Steel, P. G. & Iridium-catalysed, C. −H. borylation of heteroarenes: balancing steric and electronic regiocontrol. Angew. Chem. Int. Ed. 60, 2796–2821 (2021).Article 
CAS 

Google Scholar 
Zhou, J., Li, B., Hu, F. & Shi, B. F. Rhodium(III)-catalyzed oxidative olefination of pyridines and quinolines: multigram-scale synthesis of naphthyridinones. Org. Lett. 15, 3460–3463 (2013).Article 
CAS 
PubMed 

Google Scholar 
Fischer, D. F. & Sarpong, R. Total synthesis of (+)-complanadine a using an iridium-catalyzed pyridine C−H functionalization. J. Am. Chem. Soc. 132, 5926–5927 (2010).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Hoque, M. E., Bisht, R., Haldar, C. & Chattopadhyay, B. Noncovalent interactions in Ir-catalyzed C–H activation: L-shaped ligand for para-selective borylation of aromatic esters. J. Am. Chem. Soc 139, 7745–7748 (2017).Article 
CAS 
PubMed 

Google Scholar 
Trouvé, J., Zardi, P., Al-Shehimy, S., Roisnel, T. & Gramage-Doria, R. Enzyme-like supramolecular iridium catalysis enabling C−H bond borylation of pyridines with meta-Selectivity. Angew. Chem. Int. Ed. 60, 18006–18013 (2021).Article 

Google Scholar 
Cao, H., Cheng, Q. & Studer, A. meta-Selective C−H functionalization of pyridines. Angew. Chem. Int. Ed. 62, e202302941 (2023).Article 
CAS 

Google Scholar 
Chakraborty, S. & Biju, A. T. Directing group-free regioselective meta-C−H functionalization of pyridines. Angew. Chem. Int. Ed. 62, e202300049 (2023).Article 
CAS 

Google Scholar 
Zhou, X. Y., Zhang, M., Liu, Z., He, J. H. & Wang, X. C. C3-Selective trifluoromethylthiolation and difluoromethylthiolation of pyridines and pyridine drugs via dihydropyridine intermediates. J. Am. Chem. Soc. 144, 14463–14470 (2022).Article 
CAS 
PubMed 

Google Scholar 
Zhang, M. et al. C3-Cyanation of pyridines: constraints on electrophiles and determinants of regioselectivity. Angew. Chem. Int. Ed. 62, e202216894 (2023).Article 
CAS 

Google Scholar 
Tian, J. J., Li, R. R., Tian, G. X. & Wang, X. C. Enantioselective C3-allylation of pyridines via tandem borane and palladium catalysis. Angew. Chem. Int. Ed. 62, e202307697 (2023).Article 
CAS 

Google Scholar 
Liu, Z. et al. Asymmetric C3-allylation of pyridines. J. Am. Chem. Soc. 145, 11789–11797 (2023).Article 
CAS 
PubMed 

Google Scholar 
Liu, Z. et al. Borane-catalyzed C3-alkylation of pyridines with imines, aldehydes, or ketones as electrophiles. J. Am. Chem. Soc. 144, 4810–4818 (2022).Article 
CAS 
PubMed 

Google Scholar 
Cao, H., Cheng, Q. & Studer, A. Radical and ionic meta-C–H functionalization of pyridines, quinolines, and isoquinolines. Science 378, 779–785 (2022).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Guo, S. M., Xu, P. & Studer, A. meta-selective copper-catalyzed C–H arylation of pyridines and isoquinolines through dearomatized intermediates. Angew. Chem. Int. Ed. 63, e202405385 (2024).Sun, G. Q. et al. Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations. Nature 615, 67–72 (2023).Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Boyle, B. T., Levy, J. N., Lescure, L., de., Paton, R. S. & McNally, A. Halogenation of the 3-position of pyridines through Zincke imine intermediates. Science 378, 773–779 (2022).Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Selingo, J. D. et al. A General Strategy for N-(Hetero)arylpiperidine synthesis using Zincke Imine. intermediates. J. Am. Chem. Soc. 146, 936–945 (2024).Article 
CAS 
PubMed 

Google Scholar 
Nguyen, H. M. H. et al. Synthesis of 15N-pyridines and higher mass isotopologs via Zincke imine intermediates. J. Am. Chem. Soc. 146, 2944–2949 (2024).Article 
CAS 
PubMed 

Google Scholar 
Tolchin, Z. A. & Smith, J. M. 15NRORC: an azine labeling protocol. J. Am. Chem. Soc. 146, 2939–2943 (2024).Article 
CAS 
PubMed 

Google Scholar 
Conboy, A. & Greaney, M. F. Synthesis of benzenes from pyridines via N to C switch. Chem 10, 1–10 (2024).Article 

Google Scholar 
Benjamin, J. H., Uhlenbruck, B. J. H. & Josephitis, C. M. A deconstruction–reconstruction strategy for pyrimidine diversification. Nature 631, 87–93 (2024).Article 

Google Scholar 
Tieqiao Wang, T. & Li, C. Skeletal editing of pyridine and quinoline N-Oxides through nitrogen to carbon single atom swap. CCS Chem. https://doi.org/10.31635/ccschem.024.202404133 (2024).Falcone, N. A. & He, S. N-Oxide-to-carbon transmutations of azaarene N-Oxides. Org. Lett. 26, 4280–4285 (2024).Article 
CAS 
PubMed 

Google Scholar 
Wang, H. & Greaney, M. F. Regiodivergent arylation of pyridines via Zincke intermediates. Angew. Chem. Int. Ed. 63, e202315418 (2023).Article 

Google Scholar 
Yan, M., Lo, J. C., Edwards, J. T. & Baran, P. S. Radicals: reactive intermediates with translational potential. J. Am. Chem. Soc. 138, 12692–12714 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Zhang, L., Yan, J., Ahmadli, D., Wang, Z. & Ritter, T. C. Enantioselective total synthesis of (+)-alterbrassicicene. J. Am. Chem. Soc. 145, 20182–20188 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Joalland, B., Shi, Y., Kamasah, A., Suits, A. G. & Mebel, A. M. Roaming dynamics in radical addition–elimination reactions. Nat. Commun. 5, 4064 (2014).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Hu, C., Mena, J. & Alabugin, I. V. Design principles of the use of alkynes in radical cascades. Nat. Rev. Chem. 7, 405–423 (2023).Article 
PubMed 

Google Scholar 
Ruffoni, A., Mykura, R. C., Bietti, M. & Leonori, D. The interplay of polar effects in controlling the selectivity of radical reactions. Nat. Synth. 1, 682–695 (2022).Article 
ADS 

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 
Guillemard, L., Kaplaneris, N., Ackermann, L. & Johansson, M. J. Catalytic enantioselective Minisci-type addition to heteroarenes. Nat. Rev. Chem. 5, 522–545 (2021).Article 
CAS 
PubMed 

Google Scholar 
Oláh, J., Alsenoy, C. V. & Sannigrahi, A. B. Condensed fukui functions derived from stockholder charges:  assessment of their performance as local reactivity descriptors. J. Phys. Chem. A. 106, 3885–3890 (2002).Article 

Google Scholar 
Bartholomew, G. L., Carpaneto, F. & Sarpong, R. Keletal editing of pyrimidines to pyrazoles by formal carbon deletion. J. Am. Chem. Soc. 144, 22309–22315 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Bartholomew, G. L. et al. 14N to 15N isotopic exchange of nitrogen heteroaromatics through skeletal editing. J. Am. Chem. Soc. 146, 2950–2958 (2024).Article 
CAS 
PubMed 

Google Scholar 
Wei, Y. F., Gao, W. C., Chang, H. H. & Jiang, X. F. Recent advances in thiolation via sulfur electrophiles. Org. Chem. Front. 9, 6684–6707 (2022).Article 
CAS 

Google Scholar 
Song, S. & Zhang, Y. Cs2CO3-catalyzed aerobic oxidative cross-dehydrogenative coupling of thiols with phosphonates and arenes. Angew. Chem. Int. Ed. 56, 2487–2491 (2017).Article 
CAS 

Google Scholar 
Li, S. et al. C3-selective C–H thiolation of quinolines via an N-arylmethyl activation strategy. Org. Chem. Front. 10, 2324–2331 (2023).Article 
ADS 
CAS 

Google Scholar 
Morofuji, T., Nagai, S. & Watanabe, A. Inagawa, & Kano, K. N. Streptocyanine as an activation mode of amine catalysis for the conversion of pyridine rings to benzene rings. Chem. Sci. 14, 485–490 (2023).Article 
CAS 
PubMed 

Google Scholar 
Purser, S., Moore, P. R. & Swallow, S. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).Article 
CAS 
PubMed 

Google Scholar 

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