TiO2 Nanoparticles: A Potent ‎Heterogenous Nanocatalyst Mediated ‎One-Pot Tandem Approach for the ‎Environmentally Friendly Synthesis of 3,4-‎Dihydropyrimidin-2-(1H)-One/Thione ‎Derivatives Under Solvent-Free Conditions

Document Type : Research Paper


Young Researchers and Elite Club, Shiraz Branch, Islamic Azad University, Shiraz, Iran.‎


   This procedure has developed the use of TiO2 nanoparticles as an environmentally friendly and highly efficient heterogenous nanocatalyst for the eco-safe, facile and one-pot three-component Biginelli synthesis of biologically active corresponding 3,4-dihydropyrimidin-2-(1H)-one/thione derivatives under solvent-free conditions. This eco-friendly protocol provides high to excellent yields, short reaction times, clean reaction, simplicity and easy work up and mild conditions compared to the traditional method of synthesis. Furthermore, environment-friendly, readily available, low-cost and non-toxic nanocatalyst made this protocol economic and sustainable.


  1. Prakash, O., Kumar, R., Parkash, V., (2008). “Synthesis and antifungal activity of some new 3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromones”, Eur. J. Med. Chem., 43: 435-440.
  2. Sujatha, K., Shanmugam, P., Perumal, P. T., Muralidharan, D., Rajendran, M., (2006). “Synthesis and cardiac effects of 3,4-dihydropyrimidin-2(1H)-one-5 carboxylates”, Bioorg. Med. Chem. Lett.,  16: 4893-4897.
  3. Wisen S., Androsavich, J., Evans, C. G., Chang, L., Gestwi cki, J. E., (2008). “Chemical modulators of heat shock protein 70 (Hsp70) by sequential, microwave-accelerated reactions on solid phase”, Bioorg. Med. Chem. Lett., 18: 60-65.
  4. Heys, L., Moore, C. G., Murphy, P., (2000). “The guanidine metabolites of Ptilocaulis spiculifer and related compounds; isolation and synthesis”, Chem. Soc. Rev., 29: 57-67.
  5. Ashok, M., Holla, B. S., Kumara, N. S., (2007). “Convenient one pot synthesis of some novel derivatives of thiazolo[2,3-b]dihydropyrimidinone possessing 4-methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities”, Eur. J. Med. Chem., 42: 380-385.
  6. Hurst, E. W., Hull, R., (1960). “Two new synthetic substances active against viruses of the psittacosis-lymphogranuloma-trachoma group”, J. Med. Pharm. Chem., 3: 215-219.
  7. Magerramow, A. M., Kurbanova, M. M., Abdinbekova, R. T., Rzaeva, I. A., Farzaliev, V. M., Allokhverdiev, M. A., (2006). “Synthesis and antioxidative properties of some 3, 4-dihydropyrimidin-2 (1H) ones (-thiones) ”, Russ. J. Appl. Chem., 79: 787-790.
  8. Bahekar, S. S., Shinde, D. B., (2004). “Synthesis and anti-inflammatory activity of some [4, 6-(4-substituted aryl)-2-thioxo-1, 2, 3, 4-tetrahydro-pyrimidin-5-yl]-acetic acid derivatives”, Bioorg. Med. Chem. Lett., 14: 1733-1736.
  9. Chitra, S., Pandiarajan, K., (2009). “Calcium fluoride: an efficient and reusable catalyst for the synthesis of 3, 4-dihydropyrimidin-2(1H)-ones and their corresponding 2(1H) thione: an improved high yielding protocol for the Biginelli reaction”, Tetrahedron Lett., 50: 2222-2224.
  10. Liu, C. J., Wang, J. D., (2009). “Copper(II) Sulfamate: An Efficient Catalyst for the One-Pot Synthesis of 3,4-Dihydropyrimidine-2(1H)-ones and thiones”, Molecules., 14: 763-770.
  11. Kumar, A., Maurya, R. A. (2007). “An efficient bakers, yeast catalyzed synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones”, Tetrahedron Lett., 48: 4569-4571.
  12. Lal, J., Sharma, M., Gupta, S., Parashar, P., Sahu, P., Agarwal, D. D., (2012). “Hydrotalcite: A novel and reusable solid catalyst for one-pot synthesis of 3, 4-dihydropyrimidinones and mechanistic study under solvent free conditions”, J. Mol. Catal. A. Chem., 352: 31-37.
  13. Litvic, M., Vecani, I., Ladisic, Z. M., Lovric, M., Voncovic, V., Filipan-Litvic, M., (2010). “First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multi gram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction”, Tetrahedron., 66: 3463-3471.
  14. Ahmad, B., Khan, R. A., Habibullah, A., Keshai, M., (2009). “An improved synthesis of biginelli-type compounds via phase-transfer catalysis”, Tetrahydron Lett., 50: 2889-2892.
  15. Kamal, A., Krishnaji, T., Azhar, M. A., (2007). “Copper (II) tetrafluoroborate as a mild and efficient catalyst for the one-pot synthesis of 3, 4-dihydropyrimidin-2(1H)-ones under solvent-free conditions”, Catal. Commun., 8: 1929-1993.
  16. Zhang, Y., Wang, B., Zhang, X., Huang, J., Liu, C., (2015). “An Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Thiones Catalyzed by a Novel Brønsted Acidic Ionic Liquid under Solvent-Free Conditions”, Molecules., 20: 3811-3820.
  17. Attri, P., Bhatia, R., Gaur, J., Arora, B., Gupta, A., Kumar, N., C hoi, E. H., (2017). “Triethylammonium acetate ionic liquid assisted one-pot synthesis of dihydropyrimidinones and evaluation of their antioxidant and antibacterial activities”, Arab. J. Chem., 10: 206-214.
  18. Aswin, K., Mansoor, S. S., Logaiya, K., Sudhan, P. N., Ahmed, R. N., (2014). “Facile synthesis of 3, 4-dihydropyrimidin-2 (1H)-ones and-thiones and indeno [1, 2-d] pyrimidines catalyzed by p-dodecylbenzenesulfonic acid”, J. Taib. Uni. Sci. (JTUSCI)., 8: 236-247.
  19. Safaei-Ghomi, J., Tavazo, M., Mahdavini, G. H., (2018). “Ultrasound promoted one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones using dendrimer-attached phosphotungstic acid nanoparticles immobilized on nanosilica”, Ultrason. Sonochem., 40:  230–237.
  20. Maleki, A., Paydar, R., (2016). “Bionanostructure-catalyzed one-pot three-component synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives under solvent-free conditions”, React. Funct. Polym., 109: 120-124.
  21. Bakherad, M., Javanmardi, M., Doosti, R., Tayebee, R., (2017). “A Highly Efficient and Green Catalytic Synthesis of 3,4-dihydro-pyrimidin-2-(1H)-ones (Thiones) Using 3-sulfonic Acid-1-imidazolopyridinium Hydrogen Sulfate under Solvent-free Conditions”, Croat. Chem. Acta., 90: 53–58.
  22. Fu, R., Yang, Y., Ma, X., Sun, Y., Li, J., Gao, H., Hu, H., Zeng, X., Yi, J., (2017). “An Efficient, Eco-friendly and Sustainable One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Directly from Alcohols Catalyzed by Heteropolyanion-Based Ionic Liquids”, Molecules., 22: 1531-1543.
  23. Ghazavi, N., Mosslemin, M., Mohebat, R., (2018). “Sulfonic acid functionalized pyridinium chloride [pyridine‐SO3H]Cl: novel homogeneous catalyst for  solvent-free synthesis of dihydropyrimidinone derivatives”, Bulg.
    Chem. Commun
    ., 49: 249-255.
  24. Maleki, A., Zand, P., Mohseni, Z., (2016). “Fe3O4@PEG-SO3H rod-like morphology along with the spherical nanoparticles: novel green nanocomposite design, preparation, characterization and catalytic application”, RSC. Adv., 6: 110928-110934.
  25. Nami, N., Lale Mohammadi, S., (2017). “One-Pot Facile Synthesis of New 1, 2, 4-‎Triazolidine Derivatives Using Sodium ‎Borohydride and Fe3O4 Magnetic ‎Nanoparticles (MNPs)”, Int. J. Nanosci. Nanotechnol., 13: 347-357.
  26. Maleki, A., Kari, T., (2018). “Novel Leaking-Free, Green, Double Core/Shell, Palladium-Loaded Magnetic Heterogeneous Nanocatalyst for Selective Aerobic Oxidation”, Catal. Lett., 148: 2929-2934.
  27. Keshipour, S., Kalam Khalteh, N., (2017). “Pd and Fe3O4 Nanoparticles Supported on ‎N-(2-Aminoethyl)Acetamide Functionalized ‎Cellulose as an Efficient Catalyst for ‎Epoxidation of Styrene”, Int. J. Nanosci. Nanotechnol., 13: 219-226.
  28. Maleki, A. Aghaei, M., Ghamari, N., Kamalzare, M., (2016). “Efficient Synthesis of 2, 3-Dihydroquinazolin-4(1H)-ones in the Presence of Ferrite/Chitosan as a Green and Reusable Nanocatalyst”, Int. J. Nanosci. Nanotechnol., 12: 215-222.
  29. Maleki,A., Rahimi, J., Demchuk, O. M. Wilczewska, A. Z., Jasiński, R., (2018). “Green in water sonochemical synthesis of tetrazolopyrimidine derivatives by a novel core-shell magnetic nanostructure catalyst”, Ultrason. Sonochem., 43: 262-271.
  30. Khorshidi, A. R., Shariati, Sh., (2016). “OSO3H Functionalized Mesoporous MCM-41 Coated on Fe3O4 Nanoparticles: an Efficient and Recyclable Nano-Catalyst for Preparation of 3,2′-Bisindoles”, Int. J. Nanosci. Nanotechnol., 12: 139-147.
  31. Mirzaei, M., Ahadi, H., Shariaty-Niassar, M., Akbari, M., (2015). “Fabrication and Characterization of Visible Light active Fe-TiO2 Nanocomposites as Nanophotocatalyst”, Int. J. Nanosci. Nanotechnol., 11: 289-293.
  32. Maleki, A., Jafari, A. A., Yousefi, S., (2017). “Green cellulose-based nanocomposite catalyst: Design and facile performance in aqueous synthesis of pyranopyrimidines and pyrazolopyranopyrimidines”, Carbohydr. Polym., 175: 409-416.
  33. Bamoniri, A., Pourali, A.R., Nazifi, S. M. R., (2014). “Nano Silica/ HIO4 as a Green and Reusable Catalyst for Synthesis of 2-Naphthol Azo Dyes under Grinding Conditions”, Int. J. Nanosci. Nanotechnol., 10: 197-203.
  34. Mohamadpour, F., Maghsoodlou, M. T., Heydari, R., Lashkari, M., (2016). “Saccharin: a green, economical and efficient catalyst for the one‑pot, multi‑component synthesis of 3,4‑dihydropyrimidin‑2‑(1H)‑one derivatives and 1H‑pyrazolo [1,2‑b] phthalazine‑5,10‑dione derivatives and substituted dihydro‑2‑oxypyrrole”, J. Iran. Chem. Soc.,  13: 1549-1560.
  35. Mohamadpour, F., Maghsoodlou, M. T., Heydari, R., Lashkari, M., (2017). “Tartaric acid: A naturally green and efficient di-functional Brønsted acid catalyst for the one-pot four-component synthesis of polysubstituted dihydropyrrol-2-ones at ambient temperature”, Iran. J. Sci. Technol. Trans. Sci., 41: 843-849.
  36. Maghsoodlou, M. T., Heydari, R., Mohamadpour, F., Lashkari, M., (2017). “Fe2O3 as an Environmentally Benign Natural Catalyst for One-Pot and Solvent-Free Synthesis of Spiro-4H-Pyran Derivatives”, Iran. J. Chem. Chem. Eng., 36: 31-38.
  37. Mohamadpour, F., Maghsoodlou, M. T., Heydari, R. Lashkari, M., (2016). “Copper (II) acetate monohydrate: an efficient and ecofriendly catalyst for the one-pot multi-component synthesis of biologically active spiropyrans and 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives under solvent-free conditions”, Res. Chem. Intermed., 42: 7841-7853.
  38. Maghsoodlou, M. T. Heydari, R. Lashkari, M. Mohamadpour, F., (2017). “Clean and one-pot synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones/tiones derivatives using maleic acid as an efficient and environmentally benign nature di-functional Brønsted acid catalyst under solvent-free conditions”, Indian. J. Chem., 56 B: 160-164.
  39. Mohamadpour, F., Lashkari, M., (2018). “Three-component reaction of β-keto esters, aromatic aldehydes and urea/thiourea promoted by caffeine: A green and natural, biodegradable catalyst for eco-safe Biginelli synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/tiones derivatives under solvent-free conditions”, J. Serb. Chem. Soc., 83: 673-684.
  40. Biginelli, P., (1893). “Aldehyde-urea derivatives of aceto- and oxaloacetic acids”, Gazz. Chim. Ital., 23: 360-413.
  41. Russowsky, D., Lopesa, F. A., da Silvaa, V. S. S., Cantoa, K. F. S., Montes D’Oca, M. G., Godoi, M. N., (2004). “Multicomponent Biginelli's synthesis of 3,4-dihydropyrimidin-2(1H)-ones promoted by SnCl2.2H2O”, J. Braz. Chem. Soc., 15: 165-169.
  42. Lu, J., Bai, Y. J., Guo, Y. H., Wang, Z. J., Ma, H. R., (2002). “CoCl2·6H2O or LaCl3·7H2O Catalyzed Biginelli Reaction. One‐Pot Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones”, Chin. J. Chem., 20: 681-687.