Medicinal Chemistry Research

, Volume 23, Issue 3, pp 1569–1580

Eco-friendly synthesis and antimicrobial activities of substituted-5-(1H-indol-3-yl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione derivatives

  • G. Thirupathi
  • M. Venkatanarayana
  • P. K. Dubey
  • Y. Bharathi Kumari
Original Research


l-Tyrosine is an efficient catalyst for the condensation of substituted indole-3-aldehydes 1(ad), N-methyl indole-3-aldehydes 4(a–d), and N-ethyl indole-3-aldehydes 6(a–d) with meldrum’s acid (2) containing a cyclic active methylene group to produce 3(ad), 5(ad), and 7(ad), respectively, in water at room temperature for 30 min. The antimicrobial activities of 3(ad), 5(ad), and 7(ad) have been studied.


Anti-bacterial activities Anti-fungal activities Indole-3-aldehyde Meldrum’s acid l-Tyrosine Water 


  1. Brown RCF, McMullen GL (1974) Methyleneketenes and methylenecarbenes: a new phenolic ring synthesis: 2-naphthol from o-tolualdehyde. Aust J Chem 27:2385–2391CrossRefGoogle Scholar
  2. Brown RCF, East wood FW, Harrington KJ (1974) Methyleneketenes and methylenecarbenes: formation of arylmethyleneketenes and alkylideneketenes by pyrolysis of substituted 2,2-dimethyl-1,3-dioxan-4,6-diones. Aust J Chem 27:2373–2384CrossRefGoogle Scholar
  3. Cabello JA, Campelo JM, Garcia A, Luna D, Marians JM (1984) Knoevenagel condensation in the heterogeneous phase using AlPO4–Al2O3 as a new catalyst. J Org Chem 49:5195–5197CrossRefGoogle Scholar
  4. Darvatkar NB, Deorukhkar AR, Bhilare SV, Salunkhe MM (2006) Ionic liquid mediated Knoevenagel condensation of meldrum’s acid and aldehydes. Synth Commun 36:3043–3051CrossRefGoogle Scholar
  5. Desai UV, Pore DM, Mane RB, Solabanavar SB, Wadgaonkar PP (2004) One-pot synthesis of mono alkylated and mixed, dialkylated meldrum’s acid derivatives. Synth Commun 34:25–32CrossRefGoogle Scholar
  6. Fildes D, Caignaert V, Villemin D, Jaffres PA (2001) Potassium exchanged zirconium hydrogen phosphate Zr (O3POK)2: a heterogeneous basic catalyst Knovenagel reaction with out solvent. Green Chem 3:52–56CrossRefGoogle Scholar
  7. Formentin P, Garcia H, Leyva A (2004) Assessment of the suitability of imidazolium ionic liquids as reaction medium for base-catalysed reactions case of Knoevenagel and Claisen-Schmidt reactions. J Mol Catal A 214:137–142CrossRefGoogle Scholar
  8. Frankel S, Reitman S, Sonnenwirth AC (1970) Gradwohl’s clinical laboratory methods and diagnosis: textbook on a laboratory procedure and their interpretation. 7th edn. 2, p 1406–1458 Google Scholar
  9. Freeman F (1980) Properties and reactions of ylidenemalononitriles. Chem Rev 8:329–350CrossRefGoogle Scholar
  10. Hu Y, Chen ZC, Le ZC, Zheng QG (2004) Organic reactions in ionic liquids: gewald synthesis of 2-aminothiophenes catalyzed by ethylenediammonium diacetate. Synth Commun 34:3801–3806CrossRefGoogle Scholar
  11. Huang X, Xie L (1986) One-pot synthesis of mono substituted isopropylidene malonates. Synth Commun 16:1701–1707CrossRefGoogle Scholar
  12. Ibrahim M, Abdel-Hamed AM, El-Gohary M (2011) A new approach for the Synthesis of bioactive heteroaryl thiazolidine-2,4-diones. J Brazilian Chem Soc 22:1130–1139CrossRefGoogle Scholar
  13. Jones G (1967) The Knovenagel condensation reaction in organic reactions, vol 15. Wiley, New York, pp 204–599Google Scholar
  14. Kadam AJ, Desai UV, Mane RB (1999) Synthesis of deuterium labelled acids. J Label Compd Radio Pharm 42:835–842CrossRefGoogle Scholar
  15. Kaspady Md, Narayanaswamy VK, Raju M, Rao GK (2010) Synthesis, antibacterial activity of 2,4-disubstituted oxazoles and thiazoles as bioisosteres. Lett Drug Des Discov 6:21–28CrossRefGoogle Scholar
  16. Knoevenagel E (1898) Dry media reaction procedure for synthesis of α, β-unsaturated acids, α-cyanoacrylonitriles and α-cyanoacrylates via Knoevenagel condensation using NaHSO4 SiO2 catalyst. Berichte 31:2585–2596Google Scholar
  17. Kraus GA, Krolski ME (1986) Synthesis of a precursor to quassimarin. J Org Chem 51:3347–3350CrossRefGoogle Scholar
  18. Malamas MS, Sredy J, Gunawan I (2000) New azolidinediones as inhibitors of protein tyrosine phosphatase with antihyperglycemic properties. J Med Chem 43:995–1010CrossRefPubMedGoogle Scholar
  19. Martins L, Vieira KM, Rios LM, Cardoso D (2008) Basic catalyzed Knoevenagel condensation by FAU zeolites exchanged with alkylammonium cations. Catal Today 133:706–710CrossRefGoogle Scholar
  20. Mc Nab H (1978) Meldrum’s acid. Chem Soc Rev 7:345–358CrossRefGoogle Scholar
  21. Miroslav S, Daniel P, Marta A, Andres F, Carmen C, Fernando A, Mercedes A (2009) Total synthesis and antiproliferative activity screening of (±)aplicyanins A, B and E and related analogues. J Med Chem 52:6217–6223CrossRefGoogle Scholar
  22. Murugan R, Anbazhagan S, Sriman Narayanan S (2009) Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives. Eur J Med Chem 44:3272–3279CrossRefPubMedGoogle Scholar
  23. Nakamura S, Hirao H, Ohwada T (2004) Rational for the acidity of meldrum’s acid: consistent relation of C–H acidities to the properties of localized reactive orbital. J Org Chem 69:4309–4316CrossRefPubMedGoogle Scholar
  24. Narsaiah AV, Nagaiah K (2003) An efficient Knoevenagel condensation catalyzed by LaCl3·7H2O in heterogeneous medium. Synth Commun 2003(33):3819Google Scholar
  25. Narsaiah AV, Basak AK, Visali B, Nagaiah K (2004) An eco-friendly synthesis of electrophilic alkenes catalyzed by dimethylaminopyridine under solvent-free conditions. Synth Commun 34:2893–2901CrossRefGoogle Scholar
  26. Navneet Ch, Pawan K, Chetan S, Kamal R, Aneja Pawan KS (2012) Synthesis and biological evaluation of some novel thiazolyl hydrazine methylidene ferrocenes as antimicrobial agents. Lett Drug Des Discov 9:63–68CrossRefGoogle Scholar
  27. Oguchi M, Wada KH, Honma H (2000) Molecular design, synthesis and hypoglycemic activity of a series of thiazolidine-2,4-diones. J Med Chem 43:3052–3066CrossRefPubMedGoogle Scholar
  28. Prajapati D, Lekhok KC, Sandhu JS, Ghosh AC (1996) Lithium bromide as a new catalyst for carbon–carbon bond formation in the solid state. J Chem Soc Perkin Trans 1(9):959–960CrossRefGoogle Scholar
  29. Rao PS, Ratnam RV (1991) Zinc chloride as a new catalyst for Knoevenagel condensation. Tetrahedron Lett 32:5821–5822CrossRefGoogle Scholar
  30. Rao PS, Venkataratnam RV (1993) Anhydrous zinc chloride catalysis in carbonyl methylene condensations: synthesis of arylidene acetonitriles and arylidene heterocycles. Ind J Chem B 32:484–486Google Scholar
  31. Ravichandran V, Harish R, Suresh Kumar K, Ram Kishore A (2011) Synthesis and evaluation of antimicrobial activity of thiazolidinone derivatives. Lett Drug Des Discov 8:82–86CrossRefGoogle Scholar
  32. Reddy TI, Verma RS (1997) Rare-earth exchanged NaY zeolite promoted Knoevenagel condensation. Tetrahedron Lett 38:1721–1724CrossRefGoogle Scholar
  33. Rodriguez I, Iborra S, Corma A, Rey F, Jorda JL (1999) MCM-41-quaternary organic tetraalkylammonium hydroxide composites as strong and stable bronsted base catalysts. Chem Commun 35:593–594CrossRefGoogle Scholar
  34. Santamarta F, Verdia P, Tojo EA (1978) Simple, efficient and green procedure for Knoevenagel reaction in [MMIm][MSO4] ionic liquid. Catal Commun 9:1779–1781Google Scholar
  35. Tara LSK, Gordon WG (2001) Diels–alder reactions of 2- and 3-nitroindoles. A simple hydroxycarbazole synthesis. Tetrahedron Lett 42:4783–4785CrossRefGoogle Scholar
  36. Texier-Boullet F, Foucod A (1982) Knoevenagel condensation catalyzed by aluminium oxide. Tetrahedron Lett 23:4927–4930CrossRefGoogle Scholar
  37. Thirupathi G, Venkatanarayana M, Dubey PK, Bharathi Kumari Y (2012a) Facile and green syntheses of substituted-5-arylidene-2,4-thiazolidine diones using l-tyrosine as an eco-friendly catalyst in aqueous medium. Der Pharma Chemica 4:2009–2013Google Scholar
  38. Thirupathi G, Venkatanarayana M, Dubey PK, Bharathi Kumari Y (2012b) l-Tyrosine catalyzed Knoevenagel condensation: facile synthesis of cyanoacrylo nitriles cyanoacrylates and cyanoacrylamides in solvent free condition under grindstone method. Der Pharma Chemica 14:1897–1901Google Scholar
  39. Thirupathi G, Venkatanarayana M, Dubey PK, Bharathi Kumari Y (2012c) l-Tyrosine as an eco-friendly and efficient catalyst for Knoevenagel condensation of arylaldehydes with meldrum’s acid in solvent free condition under grindstone method. Org Chem Int 1:1–4Google Scholar
  40. Thirupathi G, Venkatanarayana M, Dubey PK, Bharathi Kumari Y (2013) Facile and green syntheses of unsymmetrically substituted 3-(1-benzyl-1H-indol-3-yl)-2-(1-ethyl-1H-indole-3-carbonyl) acrylonitrile and study of their antimicrobial activities. Chem Sci Trans 2:197–207CrossRefGoogle Scholar
  41. Thorat MT, Jagdale MH, Mane RB, Salunkhe MM, Wadgaonkar PP (1987) Clay-catalysed Knoevenagel condensation. Curr Sci 56:771–772Google Scholar
  42. Tietze LF, Beifuss U (1991) Comprehensive organic synthesis. In: Trost BM, Fleming I, Heathcock CH (eds). Oxford, Pergamon, p 341–392Google Scholar
  43. Tran UPN, Le KKA, Phan NTS (2011) Expanding applications of metal organic frameworks: zeolite imidazolate framework ZIF-8 as an efficient heterogeneous catalyst for the Knoevenagel reaction. ACS Catal 1:120–127CrossRefGoogle Scholar
  44. Venkatanarayana M, Dubey PK (2012) l-Proline-catalyzed Knoevenagel condensation: a facile, green synthesis of (e)-ethyl-2-cyano-3-(1H-indol-3-yl)acrylates and (e)-3-(1H-indol-3-yl)acrylonitriles. Synth Commun 42:1746–1759Google Scholar
  45. Yadav JS, Reddy BVS, Basak AK, Visali B, Narsaiah AV, Nagaiah K (2004) Phosphane-catalyzed Knoevenagel condensation: a facile synthesis of cyanoacrylates and cyanoacrylonitriles. Eur J Med Chem 67:546–551Google Scholar
  46. Yang DH, Yang BH, Chen BC, Chen SY (2006) A convenient synthesis of 5-arylidene thiazolidine-2,4-diones on potassium fluoride-aluminium oxide. Org Prep Proced Int 38:81–85CrossRefGoogle Scholar
  47. Zidar N, Tomasic T, Sink R (2010) Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of murD ligase. J Med Chem 53:6584–6594CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • G. Thirupathi
    • 1
  • M. Venkatanarayana
    • 1
  • P. K. Dubey
    • 1
  • Y. Bharathi Kumari
    • 1
  1. 1.Department of Chemistry, College of Engineering HyderabadJawaharlal Nehru Technological University HyderabadHyderabadIndia

Personalised recommendations