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Organic Chemistry International
Volume 2012 (2012), Article ID 284947, 4 pages
Synthesis and Reactions of 3-(2-Chloromethyl-carbonylamino)tetrachloroquinazolin-2,4-dione
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, Arish, Egypt
2Chemistry Department, Faculty of Science, South Valley University, Qena 83523, Egypt
Received 16 April 2012; Accepted 4 June 2012
Academic Editor: Cyril Parkanyi
Copyright © 2012 M. A. Hassan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A series of tetrachloroquinazolin-2,4-dione derivatives were synthesized using appropriate synthetic route and characterized by IR, 1H NMR, MS, and elemental analysis. The synthesized compounds were evaluated for their preliminary in vitro antibacterial activity towards Salmonella typhi, Staphylococcus aureus, and Bacillus cereus.
Pyrimidine and quinazoline derivatives have occupied a unique position in medicinal chemistry; the pyrimidine ring is present in a large number of biological important compounds  such as alkaloids, drugs, and agrochemicals. Furthermore, pyrimidine and condensed pyrimidines have received much attention over the years because of their interesting biological and pharmacological properties as sedatives  and antibacterial [3–8], antimalarial , analgesic [2, 4, 7], anti-inflammatory [2, 3, 7], anticonvulsant , antipyretic , antiparasitic , antifungal [6, 9], antitoxic , antiviral [8, 10, 11], anticancer [12–15], and DNA-binding activities . This encouraged us to develop new synthetic route for the synthesis of new quinazoline derivatives by introducing a heterocyclic moiety directly or through side chain in position 3 starting with 3-(2-chloromethylcarbonylamino)tetrachloro-quinazolin-2,4-dione 2. We anticipated that these novel heterocyclic compounds would possess certain pharmacological activities.
2. Results and Discussion
The reaction sequences employed for synthesis of the target compounds are shown in Scheme 1, and their physical properties are depicted in Table 1. The key intermediate in the present study, 3-(2-chloromethylcarbonylamino)tetrachloroquinazolin-2,4-dione 2, was prepared by the reaction of 3-aminotetrachloroquinazolin-2,4-dione  1 with chloroacetyl chloride. Reaction of the starting compound 2 with potassium isothiocyanate gave 3. It was expected that the imino group could be hydrolyzed but ammonia odour was not detected during the reaction. The preparation of 4a,b was achieved by the reaction of compound 2 with urea and/or thiourea under basic condition. Compound 5 was synthesized by heating compound 2 with piperidine in dioxane.
Formation of compounds 4a and 4b may proceed according to the mechanism shown in Scheme 3.
3. Biological Activity
Salmonella typhi, Staphylococcus aureus, and Bacillus cereus were obtained from the Faculty of Veterinary Medicine, Pathology Department. The three kinds of selected bacteria were grown on the appropriate media.
The two most active compounds tested are compounds 2 and 5. The activity of these compounds against all microorganisms tested showed positive reactions as indicated by zone of inhibition (Table 2); this may be due to four and five chlorine atoms , respectively. Compound 1 has approximately the same antibacterial activity against Staph. areus and Bacillus cereus. Compound 1 did not show any inhibition activity against Salmonella typhi. However, 1 showed a moderate antibacterial effect compared to other compounds, and this may be due to the tetrachloro pyrimidine [19–21].
4.1. Chemical Protocols
Melting points were uncorrected and determined on an electric melting point apparatus (Kofler). The IR spectra (KBr) were recorded on a Shimadzu 408 spectrometer. The 1H-NMR spectra were recorded using 200 MHz varian EM 390 spectrometer; chemical shifts are reported in ppm with TMS as an internal standard and are given in δ units. Electron impact mass spectra were obtained at 70 ev using a GCMS sp.1000 Shimadzu. Elemental analyses were carried out at the Microanalysis Unit at Cairo University. The purity of the compounds was detected by TLC.
4.1.1. Synthesis of 3-(2-Chloromethylcarbonylamino)tetrachloroquinazolin-2,4-dione (2)
To a stirred solution of 3-aminotetrachloroquinazolin-2,4-dione 1 (0.31 gm, 1 mmol) in DMF (10 mL), chloroacetyl chloride (1 mL) was added dropwise at room temperature. The reaction mixture was stirred for 2 h and then diluted with cold water. The solid formed was filtered off and crystallized by benzene/ethanol to give 2 as white crystalline material (0.35 gm, 89% yield), m.p. 320–322 C. FT.IR (KBr) (cm−1): 3211 (NH), 3021 (CH aliph.), 1741 and 1700 (C=O’s). 1HNMR (200 MHz, DMSO-d6) δ (ppm): 4.04 (s, 2H, CH2), 11.2 (s, 1H, NH), 11.58 (s, 1H, NH).
4.1.2. Synthesis 5,6,7,8-Tetrachloro-3-(2-imino-4-oxo-thiazolidin-3-yl)(1H,3H)-quinazolin-2,4-dione (3)
3-(2-Chloromethylcarbonylamino)tetrachloroquinazolin-2,4-dione 2 (0.39 gm, 1 mmol) was heated under reflux with potassium isothiocyanate in acetone (25 mL) for 6 h. After cooling, the solid formed was filtered off and crystallized by ethanol to give 3 as white crystalline material (0.24 gm, 58% yield), m.p. 286–288 C. FT.IR (KBr) (cm−1): 3200 (NH), 1740 and 1660 (C=O’s). 1HNMR (200 MHz, DMSO-d6) δ (ppm): 4.37 (s, 2H, CH2), 9.44 (s, 1H, C=NH), 10.9 (s, 1H, NH).
4.1.3. General Procedure for the Synthesis of (4a and 4b)
To a solution of 3-(2-chloromethylcarbonylamino)tetrachloroquinazolin-2,4-dione 2 (0.39 gm, 1 mmol) in absolute ethanol (20 mL), urea and/or thiourea (1 mmol) was added in presence of piperidine as a catalyst, and the reaction mixture was heated under reflux for 6 h. After cooling, the precipitate formed was filtered off and crystallized from benzene to give 4a-b.
Pale yellow crystals (0.27 gm, 67% yield), m.p. 306–308 C. FT.IR (KBr) (cm−1): 3211 (NH), 3021 (CH aliph.), 1751 and 1695 (C=O’s). 1HNMR (200 MHz, DMSO-d6) δ (ppm): 4.37 (s, 2H, CH2), 11.1 (s, 1H, NH), 11.43 (s, 1H, NH).
White crystalline material (0.27 gm, 66% yield), m.p. 300–302 C. FT.IR (KBr) (cm−1): 3308 (NH), 1746 and 1669 (C=O’s), 1200 (C=S). 1HNMR (200 MHz, DMSO-d6) δ (ppm): 4.38 (s, 2H, CH2), 11.11 (s, 1H, NH), 11.41 (s, 1H, NH). MS: m/z (%) 412 (M), 414 (M + 2), 416 (M + 4).
4.1.4. Synthesis of 2-(Piperidine-1-yl)-N-(5,6,7,8-tetrachloro-2,4-dioxo-1,3-dihydro-2H,4H-quinazolin-3-yl)acetamide (5)
A mixture of 3-(2-chloromethylcarbonylamino)tetrachloroquinazolin-2,4-dione 3 (0.39 gm, 1 mmol) and piperidine (3 mmol) in dioxane (20 mL) was heated under reflux for 6 h. After cooling, the precipitate formed was filtered off and crystallized from benzene/ethanol to give 5 as white crystalline material (0.31 gm, 70% yield), m.p. 190–192 C. FT.IR (KBr) (cm−1): 3405, 3196 (NH’s), 2960 (CH2 aliph.), 1751 and 1700 (C=O’ s). 1HNMR (200 MHz, DMSO-d6) δ (ppm): 1.5–1.7 (m, 6H, 3CH2), 2.99 (t, 4H, 2CH2), 4.4 (s, 2H, CH2–CO), 9.06 (s, 1H, C=NH), 11.2 (s, 1H, NH).
The authors are thankful to Dr. W. M. Salem, Lecturer of microbiology, Faculty of Science at Qena, South Valley University for his help, advice, and guidance in the microbiological studies in this work.
- S. Ostrowski, J. Swat, and M. Makosza, “A preparative method for synthesis of 4,5,6-trichloropyrimidine,” Arkivoc, vol. 1, no. 6, pp. 905–908, 2000.
- E. A. Bakhite, S. M. Radwan, and A. M. Kamal El-Dean, “Synthesis of novel pyridothienopyrimidines, pyridothienopyrimidothiazines, pyridothienopyrimidobenzthiazoles and triazolopyridothienopyrimidines,” Journal of the Chinese Chemical Society, vol. 47, no. 5, pp. 1105–1113, 2000.
- M. I. Younes, H. H. Abbas, and S. A. M. Metwally, “Synthesis of ethyl-5-amino-1-(5-ethyl-5H-1,2,4-triazino [5,6-b]indol-3-yl)-1H-pyrazole-4-carboxylate and pyrazolo[3,4-d]pyrimidine derivatives,” Pharmazine, vol. 46, no. 2, pp. 98–100, 1991.
- J. L. Rideout, T. A. Krenitsky, E. Y. Chao, G. B. Elion, R. B. Williams, and V. S. Latter, “Pyrazolo[3,4-d]pyrimidine ribonucleosides as anticoccidials. 3. Synthesis and activity of some nucleosides of 4-[(arylalkenyl)thio]pyrazolo[3,4-d]pyrimidines,” Journal of Medicinal Chemistry, vol. 26, no. 10, pp. 1489–1494, 1983.
- J. L. Rideout, T. A. Krenitsky, G. W. Koszalka et al., “Pyrazolo[3,4-d]pyrimidine ribonucleosides as anticoccidials. 2. Synthesis and activity of some nucleosides of 4-(alkylamino)-1H-pyrazolo[3,4-d]pyrimidines,” Journal of Medicinal Chemistry, vol. 25, no. 9, pp. 1040–1044, 1982.
- M. G. Marie, D. M. Aly, and M. M. Mishrikey, “A new synthesis of pyrazolo[1,5-c]pyrimidines from acetylenic β-diketones,” Bulletin of the Chemical Society of Japan, vol. 65, no. 12, pp. 3419–3422, 1992.
- F. Gatta, F. Perotti, L. Gradoni et al., “Synthesis of some 1-(dihydroxypropyl)pyrazolo[3,4-d]-pyrimidines and in vivo evaluation of their antileishmanial and antitrypanosomal activity,” European Journal of Medicinal Chemistry, vol. 25, no. 5, pp. 419–424, 1990.
- B. G. Ugarkar, H. B. Cottam, P. A. Mekernan, R. K. Robins, and G. R. Revankar, “Synthesis and antiviral/antitumor activities of certain pyrazolo[3,4-d]pyrimidine-4(5H)-selone nucleosides and related compounds,” Journal of Medicinal Chemistry, vol. 27, no. 8, pp. 1026–1030, 1984.
- G. M. Makara, W. Ewing, Y. Ma, and E. Wintner, “Synthesis of bicyclic pyrimidine derivatives as ATP analogues,” Journal of Organic Chemistry, vol. 66, no. 17, pp. 5783–5789, 2001.
- D. J. Miller, K. Ravikumar, H. Shen, J. K. Suh, S. M. Kerwin, and J. D. Robertus, “Structure-based design and characterization of novel platforms for ricin and shiga toxin inhibition,” Journal of Medicinal Chemistry, vol. 45, no. 1, pp. 90–98, 2002.
- E. R. El-Bendary and F. A. Badria, “Synthesis, DNA-binding, and antiviral activity of certain pyrazolo[3,4- d]pyrimidine derivatives,” Archiv der Pharmazie, vol. 333, no. 4, pp. 99–103, 2000.
- J. Balzarini and C. McGuigan, “Bicyclic pyrimidine nucleoside analogues (BCNAs) as highly selective and potent inhibitors of varicella-zoster virus replication,” Journal of Antimicrobial Chemotherapy, vol. 50, no. 1, pp. 5–9, 2002.
- A. M. Shalaby, O. A. Fathalla, E. M. M. Kassem, and M. E. A. Zaki, “Synthesis of new 5-N-pyrazolyl amino acids, pyrazolopyrimidines and pyrazolopyridines derivatives,” Acta Chimica Slovenica, vol. 47, no. 2, pp. 187–203, 2000.
- E. I. Al-Afaleq and S. A. Abubshait, “Heterocyclic o-aminonitriles: preparation of pyrazolo[3,4-d]-pyrimidines with modification of the substituents at the 1-position,” Molecules, vol. 6, no. 7, pp. 621–638, 2001.
- P. J. Bhuyan, H. N. Borah, K. C. Lekhok, and J. S. Sandhu, “Studies on uracils: a facile one-pot synthesis of pyrazolo[3,4-d]pyrimidines,” Journal of Heterocyclic Chemistry, vol. 38, no. 2, pp. 491–493, 2001.
- M. A. Hassan, A. M. M. Younes, M. M. Taha, and A. H. Abdel-Monsef, “Synthesis and reactions of 3-aminotetrachloroquinazolin-2,4-dione,” European Journal of Chemistry, vol. 2, no. 4, pp. 514–518, 2011.
- R. A. Finch, G. R. Revankar, and P. K. Chan, “Structural and functional relationships of toyocamycin on NPM-translocation,” Anti-Cancer Drug Design, vol. 12, no. 3, pp. 205–215, 1997.
- K. J. Ryan and C. G. Ray, Sherris Medical Microbiology, McGraw Hill, 4th edition, 2004.
- C. D. Selassie, R. L. Li, M. Poe, and C. Hansch, “On the optimization of hydrophobic and hydrophilic substituent interactions of 2,4-diamino-5-(substituted-benzyl)pyrimidines with dihydrofolate reductase,” Journal of Medicinal Chemistry, vol. 34, no. 1, pp. 46–54, 1991.
- G. C. Cheng, “3 some pyrimidines of biological and medicinal interest-I,” Progress in Medicinal Chemistry, vol. 6, no. C, pp. 67–134, 1969.
- D. B. Mc Nair-Scott, T. L. V. Ulbrich, M. L. Rogers, E. Chu, and C. Rose, “Effect of substituted pyrimidines on growth and biosynthesis of microorganisms,” Cancer Research, vol. 19, pp. 15–19, 1959.