Molecular Diversity

, Volume 23, Issue 2, pp 307–315 | Cite as

Expedient approach to synthesis of 4-hydroxy-2-(trifluoromethyl) quinolines through an intramolecular cyclization of ethyl 2-cyano-4,4,4-trifluoro-3 (arylamino)but-2-enoate derivatives

  • Ali DarehkordiEmail author
  • Mahdiyeh Talebizadeh
  • Mohammad Anary-Abbasinejad
Original Article


Ethyl 2-cyano-4,4,4-trifluoro-3-(phenylamino)but-2-enoates have been synthesized by reaction of ethyl 2-cyanoacetate with trifluoroacetimidoyl chloride derivatives using sodium hydride in acetonitrile by conventional and microwave irradiation methods. Then, intramolecular cyclization of these products in nitrobenzene under reflux conditions afforded a new series of substituted (trifluoromethyl)quinoline-3-carbonitrile derivatives in quantitative yields.


Trifluoroacetimidoyl chloride Ethyl 2-cyanoacetate 2-Trifluoromethyl quinoline Intramolecular cyclization Microwave irradiation 



We gratefully acknowledge the Vail-e-Asr University of Rafsanjan Faculty Research Grant for financial support.


  1. 1.
    Acharya BN, Thavaselvam D, Kaushik MB (2008) Synthesis and antimalarial evaluation of novel pyridine quinoline hybrids. Med Chem Res 17:487–494. CrossRefGoogle Scholar
  2. 2.
    Assefa H, Kamath S, Buolamwini JK (2003) 3D-QSAR and docking studies on 4-anilinoquinazoline and 4-anilinoquinoline epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. J Comput Aided Mol Des 17:475–493. CrossRefGoogle Scholar
  3. 3.
    Baba A, Kawamura N, Makino H, Ohta Y, Taketomi S, Sohda T (1996) Studies on disease-modifying antirheumatic drugs: synthesis of novel quinoline and quinazoline derivatives and their anti-inflammatory effect. J Med Chem 39:5176–5182. CrossRefGoogle Scholar
  4. 4.
    Bachiller MIF, Perez C, Munoz GCG, Conde S, Lopez MG, Villarroya M, Garcia AG, Franco MIR (2010) Novel Tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of alzheimer’s disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J Med Chem 53:4927–4937. CrossRefGoogle Scholar
  5. 5.
    Bawa S, Kumar S, Drabu S, Kumar R (2010) Structural modifications of quinoline-based antimalarial agents: recent developments. J Pharm Bioallied Sci 2:64–71. CrossRefGoogle Scholar
  6. 6.
    Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AI, Sim GA (1966) Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminata1, 2. J Am Chem Soc 88:3888–3890. CrossRefGoogle Scholar
  7. 7.
    Wang LM, Hu L, Chen HJ, Sui YY, Shen W (2009) One-pot synthesis of quinoline-4-carboxylic acid derivatives in water: ytterbium perfluorooctanoate catalyzed Doebner reaction. J Fluorine Chem 130:406409. Google Scholar
  8. 8.
    Wang Y, Peng C, Liu L, Zhao J, Su L, Zhu Q (2009) Sulfuric acid promoted condensation cyclization of 2-(2-(trimethylsilyl) ethynyl) anilines with arylaldehydes in alcoholic solvents: an efficient one-pot synthesis of 4-alkoxy-2-arylquinolines. Tetrahedron Lett 50:2261–2265. CrossRefGoogle Scholar
  9. 9.
    Wang Y, Ai J, Wang Y, Chen Y, Wang L, Liu G, Geng M, Zhang A (2011) Synthesis and c-Met kinase inhibition of 3, 5-disubstituted and 3, 5, 7-trisubstituted quinolines: identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifluoromethyl) quinoline as a novel anticancer agent. J Med Chem 54:2127–2142. CrossRefGoogle Scholar
  10. 10.
    Wolkenberg SE, Zhao Z, Thut C, Maxwell JW, McDonald TP, Kinose F, Reilly M, Lindsley CW, Hartman GD (2011) Design, synthesis, and evaluation of novel 3, 6-diaryl-4-aminoalkoxyquinolines as selective agonists of somatostatin receptor subtype 2. J Med Chem 54:2351–2358. CrossRefGoogle Scholar
  11. 11.
    Zhao J, Peng C, Liu L, Wang Y, Zhu Q (2010) Synthesis of 2-alkoxy (aroxy)-3-substituted quinolines by DABCO-promoted cyclization of o-alkynylaryl isocyanides. J Org Chem 75:7502–7504. CrossRefGoogle Scholar
  12. 12.
    Zhou T, Lin J, Chen Z (2008) A convenient synthesis of quinolines via ionic liquid-catalysed friedlander annulation. Lett Org Chem 5:47–50. CrossRefGoogle Scholar
  13. 13.
    Zhou W, Zhang L, Jiao N (2009) The tandem reaction combining radical and ionic processes: an efficient approach to substituted 3, 4-dihydroquinolin-2-ones. Tetrahedron 65:1982–1987. CrossRefGoogle Scholar
  14. 14.
    Banks RE, Smart BE, Tatlow JC (eds) (1994) Organofluorine chemistry: principles and commercial applications. Plenum Press, New YorkGoogle Scholar
  15. 15.
    Filler R, Kobayashi Y, Yagupolskii LM (eds) (1993) Organofluorine compounds in medicinal chemistry and biomedical applications. Elsevier, AmsterdamGoogle Scholar
  16. 16.
    Hiyama T (2000) Organofluorine compounds. Chemistry and application. Springer, BerlinCrossRefGoogle Scholar
  17. 17.
    Strekowski L, Lee H (2000) The Friedländer synthesis of 4-perfluoroalkylquinolines. J Fluor Chem 104:281–284. CrossRefGoogle Scholar
  18. 18.
    Kagoshima H, Akiyama T (2000) Mannich-type reaction with trifluoromethylated N, O-hemiacetal: facile preparation of β-amino-β-trifluoromethyl carbonyl compounds. Org Lett 2:1577–1579. CrossRefGoogle Scholar
  19. 19.
    Fuchigami T, Ichikawa S (1994) Electrolytic reactions of fluoroorganic compounds. 14. Regioselective Anodic Methoxylation of N-(Fluoroethyl) amines. Preparation of Highly Useful Fluoroalkylated Building Blocks. J Org Chem 59:607–615. CrossRefGoogle Scholar
  20. 20.
    Hudlicky M (1976) Hydrogenolysis of carbon-fluorine bonds in catalytic hydrogenation. J Fluor Chem 14:189–199. CrossRefGoogle Scholar
  21. 21.
    Welch JT (1987) Tetrahedron report number 221: advances in the preparation of biologically active organofluorine compounds. Tetrahedron 43:3123–3197. CrossRefGoogle Scholar
  22. 22.
    McClinton MA, McClinton DA (1992) Trifluoromethylations and related reactions in organic chemistry. Tetrahedron 48:6555–6666. CrossRefGoogle Scholar
  23. 23.
    Lin P, Jiang J (2000) Synthesis of monotrifluoromethyl-substituted saturated cycles. Tetrahedron 56:3635–3671CrossRefGoogle Scholar
  24. 24.
    Burton DJ, Yang ZY (1992) Fluorinated organometallics: perfluoroalkyl and functionalized perfluoroalkyl organometallic reagents in organic synthesis. Tetrahedron 48:189–275. CrossRefGoogle Scholar
  25. 25.
    Ni C, Hu M, Hu J (2015) Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis. Chem Rev 115:765–825. CrossRefGoogle Scholar
  26. 26.
    Ramezani M, Darehkordi A (2017) Synthesis of new (trifluoromethyl)-1H-benzo [e][1, 2, 4] triazolo [1, 2-a][1, 2, 4] triazine-1, 3 (2H)-diones and (trifluoromethyl) benzo [5, 6][1, 2, 4] triazino [1, 2-b] phthalazine-8, 13-diones. J Fluorine Chem 193:89–97. CrossRefGoogle Scholar
  27. 27.
    Filler R, Kobayashi Y (eds) (1982) Biomedicinal aspects of fluorine chemistry. KodanshaGoogle Scholar
  28. 28.
    Wiesner J, Ortmann R, Jomaa H, Schlitzer M (2003) New antimalarial drugs. Angew Chem Int Ed 43:5274–5293. CrossRefGoogle Scholar
  29. 29.
    Ohnmacht CJ, Patel AR, Lutz RE (1971) Antimalarials. 7. Bis (trifluoromethyl)-. alpha.-(2-piperidyl)-4-quinolinemethanols. J Med Chem 14:926–928. CrossRefGoogle Scholar
  30. 30.
    Schlosser M, Keller H, Si Sumida, Yang J (1997) How 2-anilinovinyl perfluoroalkyl ketones can be mechanistically correlated with their cyclization products 2-(perfluoroalkyl) quinolones. Tetrahedron Lett 38:8523–8526. CrossRefGoogle Scholar
  31. 31.
    Baraznenok IL, Nenajdenko VG, Balenkova ES (1999) 3-Trifloxy-3-trifluoromethylpropeniminium triflate: reaction with aromatic amines-an efficient synthesis of 2-trifluoromethylquinolines. Eur J Org Chem 4:937–941.;2-3 CrossRefGoogle Scholar
  32. 32.
    Cottet F, Marull M, Lefebvre O, Schlosser M (2003) Recommendable routes to trifluoromethyl-substituted pyridine-and quinolinecarboxylic acids. Eur J Org Chem 8:1559–1568. CrossRefGoogle Scholar
  33. 33.
    Darehkordi A, Rahmani F (2016) Synthesis of new α-trifluoromethyl substituted formamidines framework by using N-nucleophiles and N, S bidentate nucleophiles. J Fluorine Chem 190:41–47. CrossRefGoogle Scholar
  34. 34.
    Rahmani F, Darehkordi A (2017) Synthesis of trifluoromethylated pyrroles via a one-pot three-component reaction. Synlett 28:1224–1226. CrossRefGoogle Scholar
  35. 35.
    Darehkordi A, Khabazzadeh H, Saidi K (2005) Facile synthesis of 2, 2, 2-trifluoroacetimidoyl chloride derivatives. J Fluorine Chem 126:1140–1143. CrossRefGoogle Scholar
  36. 36.
    Tamura K, Mizukami H, Maeda K, Watanabe H, Uneyama K (1993) One-pot synthesis of trifluoroacetimidoyl halides. J Org Chem 58:32–35. CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Ali Darehkordi
    • 1
    Email author
  • Mahdiyeh Talebizadeh
    • 1
  • Mohammad Anary-Abbasinejad
    • 1
  1. 1.Department of ChemistryVali-e-Asr UniversityRafsanjanIran

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