An Efficient Synthesis of a Variety of Substituted Pyridine-3-Thiols

Authors

  • Oleksandr V. Borysov Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd., Ukraine https://orcid.org/0000-0003-0360-9295
  • Dmytro P. Bohdan Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine

DOI:

https://doi.org/10.24959/ophcj.25.324523

Keywords:

pyridine, thiols, thiobenzoic acid, chromatography, hydrolysis

Abstract

A practical and convenient method for the synthesis of pyridine-3-thiols using substituted 3-iodopyridines as starting compounds has been developed. Based on the use of thiobenzoic acid as a sulfur donor in a two-step procedure, this approach made it possible to synthesize a number of pyridine-3-thiols with F, Cl, Br, CH3, OCH3 substituents at various positions of the pyridine ring. The procedure presented gives high yields of the target products with a purity of 95% and is suitable for synthesis in tens of grams.

Supporting Agency

  • The authors received no specific funding for this work.

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References

  1. Ahmed, I. A. Major Dietary Interventions for the Management of Liver Disease. In Dietary Interventions in Liver Disease; Elsevier, 2019; pp 205 – 212. https://doi.org/10.1016/B978-0-12-814466-4.00017-3.
  2. NNakhaee, S.; Mehrpour, O. Niacin. In Encyclopedia of Toxicology; Elsevier, 2024; pp 755 – 761. https://doi.org/10.1016/B978-0-12-824315-2.00113-5.
  3. Sledge, C. L.; Morgan, B. W. Niacin. In Encyclopedia of Toxicology; Elsevier, 2014; pp 504 – 505. https://doi.org/10.1016/B978-0-12-386454-3.00760-0.
  4. Wittenberg, R. E.; Wolfman, S. L.; De Biasi, M.; Dani, J. A. Nicotinic Acetylcholine Receptors and Nicotine Addiction: A Brief Introduction. Neuropharmacology 2020, 177, 108256. https://doi.org/10.1016/j.neuropharm.2020.108256.
    | |
  5. Xiao, C.; Zhou, C.; Jiang, J.; Yin, C. Neural Circuits and Nicotinic Acetylcholine Receptors Mediate the Cholinergic Regulation of Midbrain Dopaminergic Neurons and Nicotine Dependence. Acta Pharmacol. Sin. 2020, 41 (1), 1 – 9. https://doi.org/10.1038/s41401-019-0299-4.
    | |
  6. Experimental and Clinical Neurotoxicology, 2nd ed.; Spencer, P. S., Schaumburg, H. H., Ludolph, A. C., Eds.; Oxford University Press: New York, 2023.
  7. Wang, J.-G.; Kario, K.; Lau, T.; Wei, Y. Q.; Park, C. G.; Kim, C. H.; Huang, J.; Zhang, W.; Li, Y.; Yan, P.; Hu, D. Use of Dihydropyridine Calcium Channel Blockers in the Management of Hypertension in Eastern Asians: A Scientific Statement from the Asian Pacific Heart Association. Hypertens. Res. 2011, 34 (4), 423 – 430. https://doi.org/10.1038/hr.2010.259.
    | |
  8. Ling, Y.; Hao, Z.-Y.; Liang, D.; Zhang, C.-L.; Liu, Y.-F.; Wang, Y. The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design. DDDT 2021, 15, 4289 – 4338. https://doi.org/10.2147/DDDT.S329547.
    | |
  9. Zhang, H. New Insights into Huperzine A for the Treatment of Alzheimer’s Disease. Acta Pharmacol. Sin. 2012, 33 (9), 1170 – 1175. https://doi.org/10.1038/aps.2012.128.
    | |
  10. Huaman, M. A.; Sterling, T. R. Treatment of Latent Tuberculosis Infection – An Update. Clinics in Chest Medicine 2019, 40 (4), 839 – 848. https://doi.org/10.1016/j.ccm.2019.07.008.
    | |
  11. Thee, S.; Garcia-Prats, A. J.; Donald, P. R.; Hesseling, A. C.; Schaaf, H. S. A Review of the Use of Ethionamide and Prothionamide in Childhood Tuberculosis. Tuberculosis 2016, 97, 126 – 136. https://doi.org/10.1016/j.tube.2015.09.007.
    | |
  12. Weinstock, J.; Wu, J.; Cao, P.; Kingsbury, W. D.; McDermott, J. L.; Kodrasov, M. P.; McKelvey, D. M.; Suresh Kumar, K. G.; Goldenberg, S. J.; Mattern, M. R.; Nicholson, B. Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47. ACS Med. Chem. Lett. 2012, 3 (10), 789–792. https://doi.org/10.1021/ml200276j.
    | |
  13. Zetterberg, F. R.; MacKinnon, A.; Brimert, T.; Gravelle, L.; Johnsson, R. E.; Kahl-Knutson, B.; Leffler, H.; Nilsson, U. J.; Pedersen, A.; Peterson, K.; Roper, J. A.; Schambye, H.; Slack, R. J.; Tantawi, S. Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease. J. Med. Chem. 2022, 65 (19), 12626 – 12638. https://doi.org/10.1021/acs.jmedchem.2c00660.
    | |
  14. Niculescu-Duvaz, D.; Gaulon, C.; Dijkstra, H. P.; Niculescu-Duvaz, I.; Zambon, A.; Ménard, D.; Suijkerbuijk, B. M. J. M.; Nourry, A.; Davies, L.; Manne, H.; Friedlos, F.; Ogilvie, L.; Hedley, D.; Whittaker, S.; Kirk, R.; Gill, A.; Taylor, R. D.; Raynaud, F. I.; Moreno-Farre, J.; Marais, R.; Springer, C. J. Pyridoimidazolones as Novel Potent Inhibitors of V-Raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF). J. Med. Chem. 2009, 52 (8), 2255 – 2264. https://doi.org/10.1021/jm801509w.
    | |
  15. Augeri, D. J.; O’Connor, S. J.; Janowick, D.; Szczepankiewicz, B.; Sullivan, G.; Larsen, J.; Kalvin, D.; Cohen, J.; Devine, E.; Zhang, H.; Cherian, S.; Saeed, B.; Ng, S.-C.; Rosenberg, S. Potent and Selective Non-Cysteine-Containing Inhibitors of Protein Farnesyltransferase. J. Med. Chem. 1998, 41 (22), 4288 – 4300. https://doi.org/10.1021/jm980298s.
    | |
  16. Malwal, S. R.; Chen, L.; Hicks, H.; Qu, F.; Liu, W.; Shillo, A.; Law, W. X.; Zhang, J.; Chandnani, N.; Han, X.; Zheng, Y.; Chen, C.-C.; Guo, R.-T.; AbdelKhalek, A.; Seleem, M. N.; Oldfield, E. Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis. J. Med. Chem. 2019, 62 (5), 2564 – 2581. https://doi.org/10.1021/acs.jmedchem.8b01878.
    | |
  17. Campillo, D.; Belío, Ú.; Martín, A. New Pt→M (M = Ag or Tl) Complexes Based on Anionic Cyclometalated Pt( ii ) Complexes. Dalton Trans. 2019, 48 (10), 3270–3283. https://doi.org/10.1039/C9DT00121B.
    | |
  18. Fortuño, C.; Martín, A.; Mastrorilli, P.; Latronico, M.; Petrelli, V.; Todisco, S. Stable Mixed-Valence Diphenylphosphanido Bridged Platinum(II)–Platinum(IV) Complexes. Dalton Trans. 2020, 49 (15), 4935–4955. https://doi.org/10.1039/D0DT00712A.
    | |
  19. Zabolotna, Y.; Volochnyuk, D. M.; Ryabukhin, S. V.; Horvath, D.; Gavrilenko, K. S.; Marcou, G.; Moroz, Y. S.; Oksiuta, O.; Varnek, A. A Close-up Look at the Chemical Space of Commercially Available Building Blocks for Medicinal Chemistry. J. Chem. Inf. Model. 2022, 62 (9), 2171–2185. https://doi.org/10.1021/acs.jcim.1c00811.
    | |
  20. Fürst, H.; Heltzig, M.; Göbel, W. Beitrag Zur Darstellung Des Pyridin‐3‐sulfochlorids Und Des Pyridin‐3‐thiols. J. Prakt. Chem. 1967, 36 (3–4), 160–164. https://doi.org/10.1002/prac.19670360306.
  21. El-Aal, H. A. K. A.; Khalaf, A. A. Design and Diversity-Oriented Synthesis of Benzo- and Pyrido-Annulated Medium-Sized N,S-Heterocycles via Thio-Michael and Friedel-Crafts Approaches. Arkivoc 2019, 2019 (6), 212–227. https://doi.org/10.24820/ark.5550190.p011.048.
    |
  22. St. Jean, D. J.; Ashton, K. S.; Bartberger, M. D.; Chen, J.; Chmait, S.; Cupples, R.; Galbreath, E.; Helmering, J.; Hong, F.-T.; Jordan, S. R.; Liu, L.; Kunz, R. K.; Michelsen, K.; Nishimura, N.; Pennington, L. D.; Poon, S. F.; Reid, D.; Sivits, G.; Stec, M. M.; Tadesse, S.; Tamayo, N.; Van, G.; Yang, K. C.; Zhang, J.; Norman, M. H.; Fotsch, C.; Lloyd, D. J.; Hale, C. Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles. J. Med. Chem. 2014, 57 (2), 325–338. https://doi.org/10.1021/jm4016747.
    | |
  23. Newman, M. S.; Karnes, H. A. The Conversion of Phenols to Thiophenols via Dialkylthiocarbamates. J. Org. Chem. 1966, 31 (12), 3980–3984. https://doi.org/10.1021/jo01350a023.
  24. Liu, Y.; Kim, J.; Seo, H.; Park, S.; Chae, J. Copper(II)‐Catalyzed Single‐Step Synthesis of Aryl Thiols from Aryl Halides and 1,2‐Ethanedithiol. Adv. Synth. Catal. 2015, 357 (10), 2205–2212. https://doi.org/10.1002/adsc.201400941.
    |
  25. Maślankiewicz, A.; Marciniec, K.; Pawlowski, M.; Zajdel, P. From Haloquinolines and Halopyridines to Quinoline- and Pyridinesulfonyl Chlorides and Sulfonamides. Heterocycles 2007, 71 (9), 1975. https://doi.org/10.3987/COM-07-11088.
    |
  26. Sawada, N.; Itoh, T.; Yasuda, N. Efficient Copper-Catalyzed Coupling of Aryl Iodides and Thiobenzoic Acid. Tetrahedron Lett. 2006, 47 (37), 6595–6597. https://doi.org/10.1016/j.tetlet.2006.07.008.
    |
  27. Ho, D. K. H.; Chan, L.; Hooper, A.; Brennan, P. E. A General and Mild Two-Step Procedure for the Synthesis of Aryl and Heteroaryl Sulfonamides from the Corresponding Iodides. Tetrahedron Lett. 2011, 52 (7), 820–823. https://doi.org/10.1016/j.tetlet.2010.12.050.
    |

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Published

2025-05-15

How to Cite

(1)
Borysov, O. V.; Bohdan, D. P. An Efficient Synthesis of a Variety of Substituted Pyridine-3-Thiols. J. Org. Pharm. Chem. 2025, 23, 43-48.

Issue

Vol. 23 No. 1 (2025)

Section

Original Researches

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