Chemical Papers

, Volume 73, Issue 1, pp 27–37 | Cite as

One-pot synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinates and arylmethylene-bis-3,3′-quinoline-2-ones

  • Ashraf A. AlyEmail author
  • Essmat M. El-Sheref
  • Aboul-Fetouh E. Mourad
  • Momtaz E. M. Bakheet
  • Stefan Bräse
  • Martin Nieger
Original Paper


In this investigation an efficient synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinic acid derivatives was achieved by one-pot reaction of one equivalent of aromatic amines with two equivalents of diethyl malonate in diphenyl ether and catalyzed with triethylamine. In case of applying the previous condition with aromatic amines and diethyl malonate in a ratio of 2:1, no quinolone structure was obtained, whereas N1,N3-bis(4-bromophenyl)malonamide, as an example, was obtained in 95% yield. Under the same previous condition, arylmethylene-bis-3,3′-quinoline-2-ones were in one pot synthesized via the reaction of equal equivalents of aromatic amines and diethyl malonate together with half equivalent of the corresponding aromatic aldehydes. The structure of the obtained compounds was proved by IR, NMR and mass spectra and X-ray structure analyses.

Graphical abstract


Bis-(quinolin-3-yl)succinates N1,N3-bis(4-bromophenyl)malonamide arylmethylene-bis-3,3′-quinoline-2-ones One-pot synthesis X-ray 



Authors thank the DFG-funded Transregio 3MET (TRR88), Karlsruhe Institute of Technology; Karlsruhe, Germany for 1 month of financial support for Professor Aly to enable him to carry out the analyses.


  1. Abass M, Mostafa BB (2005) Synthesis and evaluation of molluscicidal and larvicidal activities of some novel enaminones derived from 4-hydroxyquinolinones: part IX. Bioorg Med Chem 13:6133–6144. CrossRefGoogle Scholar
  2. Abass M, Hassanin HM, Allimony HA, Hassan H (2015) Substituted quinolinones 27. Regioselective synthesis of pyrazolo-, oxazolo-, and triazepinoquinoline derivatives. Chem Heterocycl Compd 51:1023–1029. CrossRefGoogle Scholar
  3. Ahmed N, Brahmbhatt KG, Sabde S, Mitra D, Singh IP, Bhutani KK (2010) Synthesis and anti-HIV activity of alkylated quinoline 2,4-diols. Bioorg Med Chem 18:2872–2879. CrossRefGoogle Scholar
  4. Al-Trawneh SA, Zahra JA, Kamal MR, El-Abadelah MM, Zani F, Incerti M, Cavazzoni A, Alfieri RR, Petronini PG, Vicini P (2010) Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents. Bioorg Med Chem 18:5873–5884. CrossRefGoogle Scholar
  5. Aly AA, El-Sheref EM, Mourad Aboul-Fetouh E, Brown AB, Bräse S, Bakheet ME, Nieger M (2018) Synthesis of spiro[indoline-3,4′-pyrano[3,2-c]quinolone]-3′-carbonitriles. Monatsh Chem 149(149):635–644. CrossRefGoogle Scholar
  6. Bhat SI, Trivedi DR (2014) A highly efficient and green cascade synthesis of 3-methyl-substituted-4- hydroxy-1-methylquinolin-2(1H)-ones under solvent- and catalyst-free conditions. RSC Adv 4:11300–11304. CrossRefGoogle Scholar
  7. Cagir A, Jones SH, Gao R, Eisenhauer BM, Hecht SM, Luotonin A (2003). A naturally occurring human DNA topoisomerase I poison. J Am Chem Soc 125:13628–13629. CrossRefGoogle Scholar
  8. Chattaway FD, Mason FA (1910) XXXVIII.—Halogen derivatives of malonanilide, ethyl malonanilate, and malonanilic acid. J Chem Soc Trans 97:339–345. CrossRefGoogle Scholar
  9. Chen YL, Fang KC, Sheu JY, Hsu SL, Tzeng CC (2001) Synthesis and antibacterial evaluation of certain quinolone derivatives. J Med Chem 44:2374–2377. CrossRefGoogle Scholar
  10. El-Sheref EM, Aly AA, Mourad Aboul-Fetouh E, Brown AB, Bräse S, Bakheet ME (2018) Synthesis of pyrano[3,2-c]quinoline-4-carboxylates and 2-(4-oxo-1,4-dihydroquinolin-3-yl)fumarates. Chem Pap 72:181–190. CrossRefGoogle Scholar
  11. Eswaran S, Adhikari AV, Chowdhury LH, Pal NK, Thomas KD (2010) New quinoline derivatives: synthesis and investigation of antibacterial and antituberculosis properties. Eur J Med Chem 45:3374–3383. CrossRefGoogle Scholar
  12. Hashim J, Glasnoc TN, Kremsner JM, Kappe CO (2006) Symmetrical bisquinolones via metal catalyzed cross-coupling and homocoupling reactions. J Org Chem 71:1707. CrossRefGoogle Scholar
  13. Igarashi J, Kobayashi Y (2005) Improved synthesis of quinine alkaloids with the Teoc protective group. Tetrahedron Lett 46:6381–6384. CrossRefGoogle Scholar
  14. Junichiro Y, Atsushi DY, Kenichiro I (2012) C–H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew Chem Int Ed 51:8960–9009. CrossRefGoogle Scholar
  15. Ma Z, Hano Y, Nomura T, Chen Y (2004) Novel quinazoline–quinoline alkaloids with cytotoxic and DNA topoisomerase II inhibitory activities. Bioorg Med Chem Lett 14:1193–1196. CrossRefGoogle Scholar
  16. Madhu B, Sekar BR, Reddy CH, Dubey PK (2017) Effect of heterocyclic ring system on formation of dimeric quinolones under catalyst-free conditions: a green approach. Res Chem Intermed 43:6993–7012. CrossRefGoogle Scholar
  17. Michael JP (2005) Quinoline, quinazoline and acridone alkaloids. Nat Prod Rep 2:627–646. CrossRefGoogle Scholar
  18. Musiol R, Jampilek J, Buchta V, Silva L, Niedbala H, Podeszwa B, Palka A, Majerz-Maniecka K, Oleksyn B, Polanski J (2006) Antifungal properties of new series of quinoline derivatives. Bioorg Med Chem 14:3592–3598. CrossRefGoogle Scholar
  19. Panda SS, Bajaj K, Meyers MJ, Sverdrup FM, Katritzky AR (2012) Quinine bis-conjugates with quinolone antibioticsand peptides: synthesis and antimalarial bioassay. Org Biomol Chem 45:8985–8993. CrossRefGoogle Scholar
  20. Parson S, Flack HD, Wagner T (2013) Use of intensity quotients and differences in absolute structure refinement. Acta Crystallogr B69:249–259. Google Scholar
  21. Sankaran M, Kumarasamy C, Chokkalingam U, Mohan PS (2010) Synthesis, antioxidant and toxicological study of novel pyrimido quinoline derivatives from 4-hydroxy-3-acyl quinolin-2-one. Bioorg Med Chem Lett 20:7147–7151. CrossRefGoogle Scholar
  22. Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr A64:112–122. CrossRefGoogle Scholar
  23. Sheldrick GM (2015) Crystal structure refinement with SHELXL. Acta Crystallogr C 71:3–8. CrossRefGoogle Scholar
  24. Slater AF, Cerami A (1992) Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167–169. CrossRefGoogle Scholar
  25. Tarushi A, Polatoglou E, Kljun J, Turel I, Psomas G, Kessissoglou DP (2011) Interaction of Zn(II) with quinolone drugs: structure and biological evaluation. Dalton Trans 40:9461–9473. CrossRefGoogle Scholar
  26. Thi HTN, Lee C-Y, Teruya K, Ong W-Y, Dohura K, Go M-L (2008) Antiprion activity of functionalized 9-aminoacridines related to quinacrine. Bioorg Med Chem 16:6737–6746CrossRefGoogle Scholar
  27. Turski WA, Nakamura M, Todd WP, Carpenter BK, Whetsell WO Jr, Schwarcz R (1988) Identification and quantification of kynurenic acid in human brain tissue. Brain Res 454:164–169. CrossRefGoogle Scholar
  28. Vennerstrom JL, Holmes TJ (1987) Prostaglandin-H synthase inhibition by malonamides. Ring-opened analogues of phenylbutazone. J Med Chem 30:434–437. CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  • Ashraf A. Aly
    • 1
    Email author
  • Essmat M. El-Sheref
    • 1
  • Aboul-Fetouh E. Mourad
    • 1
  • Momtaz E. M. Bakheet
    • 1
  • Stefan Bräse
    • 2
  • Martin Nieger
    • 3
  1. 1.Chemistry Department, Faculty of ScienceMinia UniversityEl-MinyaEgypt
  2. 2.Institute of Organic Chemistry, Karlsruhe Institute of TechnologyKarlsruheGermany
  3. 3.Department of ChemistryUniversity of HelsinkiHelsinkiFinland

Personalised recommendations