A Simple Preparative Synthesis of Isomeric 2-Chloroquinolinecarboxylic Esters





2-chloroquinoline, esters, oxidation, quinolone-2, chlorination


A simple two-stage method for the synthesis of isomeric esters of 2-chloroquinoline-5-, 6-, 7-carboxylic acids by successive oxidation and chlorination reactions of methyl quinoline-5-, 6-, 7-carboxylates has been developed. The target compounds have been obtained in acceptable yields using readily available reagents, simple transformations, and purification methods. Quinoline-8-carboxylic acid ester is unreactive under these conditions. The ester of 2-chloroquinoline-8-carboxylic acid has been obtained with an overall yield of 55%, starting from 8-methylquinoline. The multi-stage process is paid off by the fact that several transformations occur in one reaction cycle. All the methods developed can be used for the synthesis of target compounds on a multigram scale. Intermediate 2(1H)-oxoquinoline carboxylates are promising compounds in the synthesis of functionalized and condensed heterocycles.

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  • The authors received no specific funding for this work.


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  1. Hamama, W. S.; Ibrahim, M. E.; Gooda, A. A.; Zoorob, H. H. Recent advances in the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs. RSC Adv. 2018, 8 (16), 8484 - 8515. https://doi.org/10.1039/C7RA11537G.
  2. Lee, B. S.; Lee, J. H.; Chi, D. Y. Novel Synthesis of 2-Chloroquinolines from 2-Vinylanilines in Nitrile Solvent. J. Org. Chem. 2002, 67 (22), 7884 - 7886. https://doi.org/10.1021/jo016196i.
  3. El-Sayed, O. A.; Al-Bassam, B. A.; Hussein, M. E. Synthesis of Some Novel Quinoline-3-carboxylic Acids and Pyrimidoquinoline Derivatives as Potential Antimicrobial Agents. Arch. Pharm. 2002, 335 (9), 403 - 410. https://doi.org/10.1002/1521-4184(200212)335:9<403::AID-ARDP403>3.0.CO;2-9.
  4. Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Quinolines and structurally related heterocycles as antimalarials. J. Med. Chem. 2010, 45 (8), 3245 - 3264. https://doi.org/10.1016/j.ejmech.2010.04.011.
  5. Abdou, W. M.; Khidre, R. E.; Shaddy, A. A. Synthesis of Tetrazoloquinoline-Based Mono- and Bisphosphonate Esters as Potent Anti-Inflammatory Agents. J. Heterocycl. Chem. 2013, 50 (1), 33 - 41. https://doi.org/10.1002/jhet.968.
  6. Abdou, W. M.; Khidre, R. E.; Kamel, A. A. Elaborating on Efficient Anti-Proliferation Agents of Cancer Cells and Anti-Inflammatory-Based N-Bisphosphonic Acids. Arch. Pharm. 2012, 345 (2), 123 - 136. https://doi.org/10.1002/ardp.201100080.
  7. Selvi, S. T.; Nadaraj, V.; Mohan, S.; Sasi, R.; Hema, M. Solvent free microwave synthesis and evaluation of antimicrobial activity of pyrimido[4,5-b]- and pyrazolo[3,4-b]quinolines. Bioorg. Med. Chem. 2006, 14 (11), 3896 - 3903. https://doi.org/10.1016/j.bmc.2006.01.048.
  8. Dine, I.; Mulugeta, E.; Melaku, Y.; Belete, M. Recent advances in the synthesis of pharmaceutically active 4-quinolone and its analogues: a review. RSC Adv. 2023, 13 (13), 8657 - 8682. https://doi.org/10.1039/D3RA00749A.
  9. Kumar, G.; Saroha, B.; Kumar, R.; Kumari, M.; Kumar, S. Recent Advances in Synthesis and Biological Assessment of Quinoline-Oxygen Heterocycle Hybrids. ChemistrySelect 2021, 6 (20), 5148 - 5165. https://doi.org/10.1002/slct.202100906.
  10. Shvekhgeimer, M. G. A., The Pfitzinger Reaction. (Review). Chem. Heterocycl. Comp. 2004, 40 (3), 257 - 294. https://doi.org/10.1023/B:COHC.0000028623.41308.e5.
  11. Mandal, S.; Bhuyan, S.; Jana, S.; Hossain, J.; Chhetri, K.; Roy, B. G. Efficient visible light mediated synthesis of quinolin-2(1H)-ones from quinoline N-oxides. Green Chem. 2021, 23 (14), 5049 - https://doi.org/10.1039/D1GC01460A.
  12. Pachupate, N. J.; Vaidya, P. D. Catalytic wet oxidation of quinoline over Ru/C catalyst. Journal of Environmental Chemical Engineering 2018, 6 (1), 883 - https://doi.org/10.1016/j.jece.2017.12.014.
  13. Abe, H.; Sato, A.; Tokishita, Sh.-i.; Ohta, T.; Ito, H. Synthesis of Fluorescence Pyriproxyfen Analogues as Juvenile Hormone Agonists. Heterocycles 2011, 83 (7), 1649 - 1658. https://doi.org/10.3987/COM-11-12232.
  14. Qiao, K.; Wan, L.; Sun, X.; Zhang, K.; Zhu, N.; Li, X.; Guo, K. Regioselective Chlorination of Quinoline N-Oxides and Isoquinoline N-Oxides Using PPh3/Cl3CCN. J. Org. Chem. 2016, 2016 (8), 1606 - 1611. https://doi.org/10.1002/ejoc.201501567.
  15. Friedlaender, P.; Ostermaier, H. Ueber das Carbostyril. II. Chem. Ber. 1882, 15 (1), 332-338. https://doi.org/10.1002/cber.18820150179.
  16. Chakrabartty, S. K.; Kretschmer, H. O. Sodium hypochlorite as a selective oxidant for organic compounds. J. Chem. Soc., Perkin Trans. 1 1974, 0, 222 - 228. https://doi.org/10.1039/P19740000222.
  17. Decker, H. Ueber die Einwirkung von Alkalien auf Jodalkylate der Chinolin- und Acridinreihe. Journal für Praktische Chemie 1892, 45 (1), 161 - 200. https://doi.org/10.1002/prac.18920450120.
  18. Fischer, O. Einwirkung von Phosphorpentachlorid auf N- Alkyl-Pyridone und-Chinolone. Chem. Ber. 1898, 31 (1), 609 - 612. https://doi.org/10.1002/cber.189803101127.
  19. Yang, J.; Gustavsson, A.-L.; Haraldsson, M.; Karlsson, G.; Norberg, T.; Baltzer, L. High-affinity recognition of the human C-reactive protein independent of phosphocholine. Org. Biomol. Chem. 2017, 15 (21), 4644 - 4654. https://doi.org/10.1039/C7OB00684E.
  20. Xu, W.; Nagata, Y.; Kumagai, N. TEtraQuinolines: A Missing Link in the Family of Porphyrinoid Macrocycles. J. Am. Chem. Soc. 2023, 145 (4), 2609 - 2618. https://doi.org/10.1021/jacs.2c12582.




How to Cite

Ishkov, Y. V.; Veduta, V. V.; Fedko, N. F.; Bohdan, N. M. A Simple Preparative Synthesis of Isomeric 2-Chloroquinolinecarboxylic Esters. J. Org. Pharm. Chem. 2023, 21, 11-17.



Original Researches