Isaac Scientific Publishing

Modern Organic Chemistry Research

One-Pot Synthesis of Novel Derivatives of Dithioxopyrido[2,3-d:6,5-d’]dipyrimidine-4,6-diones Using Hap-Encapsulated γ-Fe2O3Supported Sulfonic Acid Nanocatalyst

Download PDF (740.8 KB) PP. 1 - 10 Pub. Date: February 1, 2018

DOI: 10.22606/mocr.2018.31001


  • Manouchehr Mamaghani*
    Department of Chemistry, Faculty of Science, University of Guilan, PO Box 41335-1914, Rasht, Iran.
  • Laya. Moslemi
    Department of Chemistry, Faculty of Science, University of Guilan, PO Box 41335-1914, Rasht, Iran.
  • Abed Badrian
    Department of Basic Science, Research Institution for Educational Studies, OERP, PO Box 15875-4874, Tehran-Iran.


A series of novel dithioxopyrido[2,3-d:6,5-d’]dipyrimidine-4,6-dione derivatives were synthesized through a one-pot three-component approach using HAp-encapsulated-γ-Fe2O3[γ- Fe2O3@HAP-SO3H] catalyzed condensation of 6-amino-2,3-dihydro-2-thioxopyrimidin-4(1H)-one and various substituted aryl aldehydes at 110 oC in DMF. In this protocol the use of nanocatalyst provided a green, useful and rapid method to generate the products in short reaction times and good to excellent yields (70–95%) and the catalyst is easily separated by applying an external magnetic field.


Pyrido[2,3-d]pyrimidines, three-component, dipyrimidine, [γ-Fe2O3@HAP-SO3H], nanocatalyst.


[1] B. Karami, S. J. Hoseini, Kh. Eskandari, A. Ghasemi and H. Nasrabadi, “Synthesis of xanthene derivatives by employing Fe3O4 nanoparticles as an effective and magnetically recoverable catalyst in water”, Catalysis Science & Technology, vol. 2, pp. 331-338, 2012.

[2] H. Ebrahimzadeh, E. Moazzen, M. M. Amini and O. Sadeghi, “Novel magnetic ion imprinted polymer as a highly selective sorbent for extraction of gold ions in aqueous samples”, Analytical Methods, vol. 4, pp. 3232-3237, 2012.

[3] M. Esmaeilpour, A. R. Sardarian and J. Javidi, “Schiff base complex of metal ions supported on superparamagnetic Fe3O4@SiO2 nanoparticles: An efficient, selective and recyclable catalyst for synthesis of 1,1- diacetates from aldehydes under solvent-free conditions”, Applied Catalysis, A, vol. 445‐446, pp. 359-367, 2012.

[4] K. K. Senapati, C. Borgohain and P. Phukan, “Synthesis of highly stable CoFe 2O4 nanoparticles and their use as magnetically separable catalyst for Knoevenagel reaction in aqueous medium”, Journal of Molecular Catalysis A Chemical, vol. 339, no. 1, 24-31, 2011.

[5] D. Habibi, S. Kaamyabi and H. Hazarkhani, “Fe3O4 nanoparticles as an efficient and reusable catalyst for the solvent-free synthesis of 9,9-dimethyl-9,10-dihydro-8H-benzo-[a]xanthen-11(12H)-ones”, Chinese Journal of Catalysis, vol. 36, no. 3, pp. 362-366, 2015.

[6] A. Hu, G. T. Yee and W. Lin, “Magnetically recoverable chiral catalysts Immobilized on magnetite nanoparticles for asymmetric hydrogenation of aromatic ketones”, Journal of the American Chemical Society, vol. 127, no. 36, pp. 12486–12487, 2005.

[7] C. W. Lim and I. S. Lee, “Magnetically recyclable nanocatalyst systems for the organic reactions”,Nano Today, vol. 5, pp. 412-434, 2010.

[8] S. Rostamnia, K. Lamei, M. Mohammadquli, M. Sheykhan and A. Heydari, “Nanomagnetically modified sulfuric acid (γ-Fe2O3@SiO2-OSO3H): An efficient, fast, and reusable green catalyst for the Ugi-like Groebke-Blackburn- Bienaymé three-component reaction under solvent-free conditions”, Tetrahedron Letters, vol. 53, no. 39, pp. 5257-5260, 2012.

[9] Y. Zhang, Y. Zhao and C. Xia, “Basic ionic liquids supported on hydroxyapatite-encapsulated γ-Fe2O3 nanocrystallites: An efficient magnetic and recyclable heterogeneous catalyst for aqueous Knoevenagel condensation”, Journal of Molecular Catalysis A: Chemical, vol. 306, no.1–2, pp. 1-148, 2009.

[10] L. Ma’mani, M. Sheykhan and A. Heydari, “Nanosilver embedded on hydroxyapatite-encapsulated γ-Fe2O3: Superparamagnetic catalyst for chemoselective oxidation of primary amines to N-monoalkylated hydroxylamines”, Applied Catalysis A: General, vol. 395, no. 1–2, pp. 34-38, 2011.

[11] L. Ma’mani, M. Sheykhan, A. Heydari, M. Faraji and Y. Yamini, “Sulfonic acid supported on hydroxyapatiteencapsulated- γ-Fe2O3 nanocrystallites as a magnetically Br?nsted acid for N-formylation of amines”, Applied Catalysis A: General, vol. 377, no.1–2, pp. 64–69, 2010.

[12] M. Khoobi, L. Ma’mani, F. Rezazadeh, Z. Zareie and A. Foroumadi, “One-pot synthesis of 4H-benzo[b]pyrans and dihydropyrano[c]chromenes using inorganic–organic hybrid magnetic nanocatalyst in water”, Journal of Molecular Catalysis A: Chemical, vol. 359, pp. 74-80, 2012.

[13] A. Rahmati, “Synthesis of 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo [3,4-b] pyridine-5-carbonitrile via a one-pot, three-component reaction”, Tetrahedron Letters, vol.51, no. 22, pp. 2967-2970, 2010.

[14] D. Q. Shi, S. H. Shi, Z. B. Kim and S. J. Huang, “A novel and efficient one-pot synthesis of furo[3′,4′:5,6]pyrido[2,3-c]pyrazole derivatives using organocatalysts”, Tetrahedron, vol. 64, no. 10, pp. 2425–2432, 2008.

[15] A. D. Broom, J. L. Shim and G. L. Anderson, “Pyrido[2,3-d]pyrimidines. IV. Synthetic studies leading to various oxopyrido[2,3-d]pyrimidines” The Journal of Organic Chemistry, Vol. 41, no. 7, pp. 1095-1099, 1976.

[16] E. M. Grivsky, S. Lee, C. W. Sige, D. S. Duch and C. A. Nichol, “Synthesis and antitumor activity of 2,4- diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d] pyrimidine ”, Journal of Medicinal Chemistry, vol. 23, no. 3, pp. 327–329, 1980.

[17] J. Matsumoto and S. Minami, “Pyrido[2,3-d]pyrimidine antibacterial agents. 3. 8-Alkyl- and 8-vinyl-5,8-dihydro- 5-oxo-2-(1-piperazinyl)pyrido[2,3-d]pyrimidine-6-carboxylic acids and their derivatives”, Journal of Medicinal Chemistry, vol. 18, no. 1, pp. 74–79, 1975.

[18] A. M. Thompson, G. W. Rewcastl, A. J. Bridge, D. W. Fry, A. J. Kraker, W. A. Denny and A. McMichael, “Tyrosine kinase inhibitors. 7. 7-amino-4-(phenylamino)- and 7-amino-4-[(phenylmethyl)amino]pyrido[4,3- d]pyrimidines: a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor”, Journal of Medicinal Chemistry, Vol. 38, no. 19, pp 3780–3788, 1995.

[19] N. R. Mohamed, M. M. T. El-Saidi, Y. M. Ali and M. H. Elnagdi, “Utility of 6-amino-2-thiouracil as a precursor for the synthesis of bioactive pyrimidine derivatives”, Bioorganic & Medicinal Chemistry, vol. 15, no. 18, pp. 6227–6235, 2007.

[20] A. Pastor, R. Alajarin, J. J. Vaquero, J. Alvarez-Builla, M. Fau de Casa-Juana, C. Sunkel, J. G. Priego, I. Fonseca and J. Sanz-Aparicio, “Synthesis and structure of new pyrido [2, 3-d] pyrimidine derivatives with calcium channel antagonist activity”, Tetrahedron, vol. 50, no. 27, pp. 8085–8098, 1994.

[21] A. B. A. Elgazzar, A. E. M. Gafaar, H. N. Hafez and A. S. Aly, “Novel syntheses and reactions of polynuclear heterocyclic derivatives derived from thioxopyridopyrimidine, with a new ring system”, Phosphorus, Sulfur, and Silicon and the Related Elements, vol.181, no. 8, pp. 1859-1883, 2006.

[22] M. S. Youssouf, P. Kaiser, G. D. Singh, S. Singh, S. Bani, V. K. Gupt, N. K. Satti, K. A. Suri and R. K. Johri, “Anti-histaminic, anti-inflammatory and bronchorelaxant activities of 2, 7-dimethyl-3-nitro-4H pyrido [1,2-a] pyrimidine-4-one”, International Immunopharmacology, vol. 8, no. 7, pp. 1049-1055, 2008.

[23] A. B. A. El-Gazzar, M. M. Youssef, A. A. Abu-Hashem and F. A. Badria, “Synthesis and anti-oxidant activity of novel pyrimido [4, 5-b] quinolin-4-one derivatives with a new ring system”, Phosphorus, Sulfur, and Silicon and the Related Elements, vol. 182, no. 9, pp. 2009-2037, 2007.

[24] M. R. Mahmoud, E. A. A. El-Bordany, N. F. Hassan and F. S. M. Abu El-Azm, “Utility of nitriles in synthesis of pyrido[2,3-d]pyrimidines, thiazolo[3,2-a]pyridines, Pyrano[2,3-b]benzopyrrole, and Pyrido[2,3- d]benzopyrroles”, Phosphorus, Sulfur, and Silicon and the Related Elements, vol. 182, no. 11, pp. 2507-2521, 2007.

[25] J. Bulicz, C. G. Daniela, D. C. G. Bertarelli, D. Baumert, F. Fülle, C. E. Müller and D. Heber, “Synthesis and pharmacology of pyrido[2,3-d]pyrimidinediones bearing polar substituents as adenosine receptor antagonists”, Bioorganic & Medicinal Chemistry, vol. 14, no. 8, pp. 2837-2849, 2006.

[26] J. I. Degraw, P. H. Christie, W. T. Colwell and F. M. Sirotnak, “Synthesis and antifolate properties of 5,10- ethano-5,10-dideazaaminopterin”, Journal of Medicinal Chemistry, vol. 35, no. 2, pp 320–324, 1992.

[27] A. D. Broom, J. L. Shim and G. J. Anderson, “Pyrido[2,3-d]pyrimidines. IV. Synthetic studies leading to various oxopyrido[2,3-d]pyrimidines”, The Journal of Organic Chemistry, vol. 41, no. 7, pp. 1095-1099, 1976.

[28] I. Devi, J. L. Borah and P. L. Bhuyan, “A novel three-component one-pot synthesis of pyrano[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines using microwave heating in the solid state”, Tetrahedron Letters, vol. 44, no. 45, pp. 8307-8310, 2003.

[29] Y. Gao, S. J. Tu, T. J. Li, X. J. Zhang, S. L. Zhu, F. Fang, D. Q. Shi, “Effective synthesis of 7-amino-6-cyano- 5‐aryl‐5H‐pyrano[2,3‐d] pyrimidine‐2,4(1H,3H)- diones Under Microwave Irradiation”, Synthetic Communications, Vo. 34, no. 7, pp. 1295-1299, 2004.

[30] J. Quiroga, M. Alvarado, B. Insuasty, M. Nogueras, A. Sanchez and J. Cobo, “Synthesis of 6-cyanopyrido[2,3- d]pyrimidinones in the reaction of 6-amino-4-pyrimidinones with arylidene derivatives of malonodinitrile”, Journal of Heterocyclic Chemistry, vol. 35, no. 6, pp. 1309–1311, 1998.

[31] S. Abdolmohammadi and S. Balalaie, “An Efficient Synthesis of Pyrido[2,3-d]pyrimidine Derivatives via One- Pot Three-Component Reaction in Aqueous Media”, International Journal of Organic Chemistry, vol. 2 no. 1, 1-8, 2012.

[32] X.-S. Wang, Z.-S. Zeng, D.-Q. Shi, X.-Y. Wei and Z.-M. Zong, “KF‐Alumina catalyzed one‐pot Synthesis of pyrido[2,3‐d]pyrimidine derivatives”, Synthetic Communications, Vol. 34, no.23, pp. 4331-4338, 2004.

[33] X.-S. Wang, Z.-S. Zeng, D.-Q. Shi, S. Tu, S.-J.; X. –Y. Wei and Z.-M. Zong, “Three‐Component, one‐pot Synthesis of pyrido[2,3‐d]pyrimidine derivatives catalyzed by KF‐alumina”, Synthetic Communications, vol. 36, no. 14, pp.1921-1927, 2005.

[34] M. Syamala, “Recent Progress in Three-Component Reactions. An Update”, Organic Preparations and Procedures International, vol. 41, no. 1, pp. 1-68, 2009.

[35] D. Shi, S. Ji, L. Niu, J. Shi and X. Wang, “One-pot synthesis of pyrido[2,3-d]pyrimidines via efficient threecomponent reaction in aqueous media”, Journal of Heterocyclic Chemistry, vol. 44, no.5, pp. 1083–1090, 2007.

[36] D-Q. Shi, Y. Zhou and H. Liua, “An efficient synthesis of pyrido[2,3-d]pyrimidine derivatives in ionic liquid”, Journal of Heterocyclic Chemistry, vol. 47, no. 1, pp. 131–135, 2010.

[37] M. Mamaghani, F. Shirini, M. Sheykhan and M. Mohsenimehr, “Synthesis of a copper(II) complex covalently anchoring a (2-iminomethyl)phenol moiety supported on HAp-encapsulated-a-Fe2O3 as an inorganic–organic hybrid magnetic nanocatalyst for the synthesis of primary and secondary amides” Royal Society of Chemistry Advances, vol. 5, pp. 44524–44529, 2015.

[38] M. Mamaghani, F. Shirini, N. O. Mahmoodi, A. Azimi-Roshan and H. Hashemlou, “A green, efficient and recyclable Fe+3@K10 catalyst for the synthesis of bioactive pyrazolo[3,4-b]pyridin-6(7H)-ones under "on water", conditions”, Journal of Molecular Structure, vol. 1051, pp. 169–176, 2013.

[39] M. Mamaghani, Z. Taati, M. Rasoulian, J. Yousefizad, N. Toraji, M. Mohsenimehr and R. Hossein Nia, “[Fe2O3@HAp-SO3H] an efficient nanocatalyst for the synthesis of highly functionalised 2-thioxopyrido[2,3- d]pyrimidines”, Journal of Chemical Research, vol. 40, pp. 29–34, 2016.

[40] R. Hossein Nia, M. Mamaghani, K. Tabatabaeian, F. Shirini and M. Rassa, “An expeditious regioselective synthesis of novel bioactive indole-substituted chromene derivatives via one-pot three-component reaction”, Bioorganic and Medicinal Chemistry Letters, vol. 22, pp. 5956–5960, 2012.

[41] P. Crepaldi, B. Cacciari, M. C. Bonache, K. Varani, P. A. Borea, Iv. Kügelgen, K. Hoffmann, M. Pugliano, C. Razzari and M. Cattaneo, “6-Amino-2-mercapto-3H-pyrimidin-4-one derivatives as new candidates for the antagonism at the P2Y12 receptors”, Bioorganic and Medicinal Chemistry, vol. 17, no. 13, pp. 4612-4621, 2009.