untitled European Journal of Chemistry 2 (4) (2011) 514‐518 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2011 EURJCHEM DOI:10.5155/eurjchem.2.4.514‐518.479 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis and reactions of 3‐aminotetrachloroquinazolin‐2,4‐dione Mamdouh Adly Hassan, Ahmed Mohamed Mosalem Younes, Mohamed Mobark Taha and Abou‐Bakr Haredy Abdel‐Monsef* Chemistry Department, Faculty of Science, South Valley University, Qena‐83523, Egypt *Corresponding author at: Chemistry Department, Faculty of Science, South Valley University, Qena‐83523, Egypt. Tel.: +20.96.5211281; fax: +20.96.5211279. E‐mail address: bakooos2004@yahoo.com (A.H. Abdel‐Monsef). ARTICLE INFORMATION ABSTRACT Received: 21 June 2011 Received in revised form: 31 July 2011 Accepted: 31 July 2011 Online: 31 December 2011 KEYWORDS N‐phenylsulphonyloxytetrachlorophthalimide was obtained by treatment of N‐hydroxy tetrachlorophthalimide with benzenesulphonyl chloride. Also, the titled compound 3 was obtained by reaction of compound 2 with hydrazine hydrate via Lossen rearrangement. Compound 3 used as starting material for the synthesis of new pyrimidine and quinazolinedione derivatives containing four chlorine atoms which have pharmacological activity. Quinazolinedione Hydrazine hydrate Anti‐inflammatory Tetrachloroquinazolindione N‐Phenylsulphonyloxytetrachlorophthalimide 3‐(N‐acetylamino)tetrachloroquinazolindione 1. Introduction Owing to the importance of tetrachlorophthalimides as good α‐glucosides inhibitors that decrease glucose level [1,2] in blood and their use as potentially valuable for various diseases, we aimed in the present study to synthesize another class of new tetrachloroheterocyclic compounds such as tetrachloro quinazolindione derivatives. It has been recently shown that pyrimidines and quinazolindiones are important compounds posses pharmacological activity including use as anticonvul‐ sant, electroshock, pentylenetetrazole induced seizures in mice [3], sedative, hypotensive [4], antinflammatory, antigonisys [5,6], vasodilator [7‐9], contractile smooth muscles and posses inhibitory activity toward the calcium independent phosphor‐ diesteras enzyme [10]. This encouraged us to synthesize quinazolinedione derivatives containing four chlorine atoms in benzene ring starting with tetrachlorophthalic anhydride which may possess greater certain pharmacological activities. 2. Experimental 2.1. Instrumentation Melting points were uncorrected 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 by 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 GC‐MS sp.1000 Shimadzu. Elemental analyses were carried out at Microanalysis Unit at Cairo University; purity of the compounds was detected by TLC. 2.2. Synthesis 2.2.1. N‐phenylsulphonyloxytetrachlorophthalimide (2) Benzenesulphonyl chloride was added dropwisely with stirring in ice bath to a solution of N‐hydroxytetrachloro phthalimide (6.3 g, 20 mmol) in pyridine (15 mL) [11]. The reaction mixture was vigorously stirred for 15 min., the solid formed was acidified with cold dilute hydrochloric acid (1:1), and the solid formed was filtered off and dried. The target product was crystallized from petroleum ether (80‐100) and benzene (3:1) to give N‐phenylsulphonyloxytetrachlorophthal‐ imide (3 g, 6.8 mmol) 2 in yield 35 % as yellow crystals (Scheme 1). M.p.: 244 oC. FT‐IR (KBr, cm‐1): 1808 and 1750 (C=O), 1360 and 1180 (SO2‐O‐). 1H NMR (300 MHz, DMSO‐d6, ppm): 7.70‐ 8.11 (m, 5H, Ph‐SO2). MS (m/z, %): 439 (1.01%) correspond to the molecular formula (C14H5Cl4NO5S) in addition to the characteristic peaks for compounds containing four chlorine atoms [13] at (M+2), (M+4) and (M+6). Anal. calcd. for C14H5Cl4NO5S: C, 38.12; H, 1.14; N, 3.18. Found: C, 38.31; H, 1.16; N, 3.18%. 2.2.2. 3‐aminotetrachloroquinazolin‐2,4‐dione (3) A mixture of N‐phenylsulphonyloxytetrachlorophthalimide, 2, (4.41 g, 10 mmole) and hydrazine hydrate in dry benzene (40 mL) using Dean & starks' apparatus was refluxed for 2 hours [12]. After cooling; the solid formed was filtered off and crystallized from water to give 3‐aminotetrachloroquinazolin‐ 2,4‐dione (2.4 g, 7.6 mmole) 3 in yield 76 % as white crystal (Scheme 2). M.p.: 274 oC. FT‐IR (KBr, cm‐1): 3457 (NH), 3313 and 3206 (NH2), 1726 and 1675 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 5.62 (s, 2H, NH2) and also showed the disappearance of NH signal in DMSO‐d6 while FT‐IR spectrum revealed the presence of a band for νNH at 3457 cm‐1. Hassan et al. / European Journal of Chemistry 2 (4) (2011) 514‐518 515 Scheme 1 Scheme 2 Anal. calcd. for C8H3Cl4N3O2: C, 30.52; H, 0.96; N, 13.34. Found: C, 30.75; H, 0.97; N, 13.34 %. 2.2.3. 3‐(N‐acetylamino)tetrachloroquinazolin‐2,4‐dione (4) To a solution of 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.315 g, 1 mmole) in dry pyridine (10 mL), acetylchloride (1 mL) was added drop wisely at room temperature. The reaction mixture was stirred for 2 hours, and a cold diluted HCl (1:1) was added to the reaction mixture and the solid formed was filtered off and crystallized from benzene/ethanol to give 3‐(N‐acetylamino)tetrachloroquinazolin‐2,4‐dione (0.29 g, 0.81 mmole) 4 in yield 81 % as white crystal (Scheme 3). M.p.: 306 oC. FT‐IR (KBr, cm‐1): 3200 (NH), 1780 and 1750 (C=O) (imide carbonyl). 1H NMR (200 MHz, DMSO‐d6, ppm): 1.93 (s, 3H, CH3), 10.6 (S, 1H, NH), 11.4 (S, 1H, NH). Anal. calcd. for C10H5Cl4N3O3: C, 33.65; H, 1.41; N, 11.77. Found: C, 33.86; H, 1.42; N, 11.98%. 2.2.4. 3‐(phenylsulphonylamino)tetrachloroquinazolin‐2,4‐ dione (5) 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) in dry pyridine (10 mL) was cooled in ice bath; benzenesulphonyl chloride was added drop wisely. The reaction mixture with stirred at room temperature for 4 hours. A cold diluted HCl (1:1) was added to the reaction mixture and the solid formed was filtered off and crystallized from benzene/ethanol to give 3‐(phenylsulphonylamino)tetrachloro quinazolin‐2,4,dione (0.27 g, 0.59 mmole) 5 in yield 59 % as yellow crystal (Scheme 3). M.p.: 300 oC. FT‐IR (KBr, cm‐1): 3200 (NH), 1810, 1750 (C=O), 1360, 1180 (SO2). 1H NMR (200 MHz, DMSO‐d6): 7.30‐7.90 (m, 5H, Ar‐H), 9.75 (s, 1H, NH), 11.40 (s, 1H, NH). Anal. Calcd. for C14H7Cl4 N3O4S. C, 36.95; H, 1.55; N, 9.23. Found: C, 37.23; H, 1.56; N, 9.34 %. 2.2.5. 3‐(2‐thiophenecarbonylamino)tetrachloroquinazolin‐ 2,4‐dione (6) A solution of 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) in dry pyridine (10 mL) was cooled in ice bath; 2‐thiophenecarbonyl chloride was added drop wisely with stirring for 4 hours. A cold diluted HCl (1:1) was added to the reaction mixture and the solid formed was filtered off and crystallized from benzene/ethanol to give 3‐(2‐thiophene‐ carbonylamino)tetrachloroquinazolin‐2,4‐dione (0.28 g, 0.729 mmole) 6 in yield 67 % as white crystal (Scheme 3). M.p.: 308 oC. FT‐IR (KBr, cm‐1): 3200 (NH), 1740 and 1680 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 7.26‐7.28 (dd, 1H, HX), 7.96 (dd, 1H, HM), 7.98‐8.02 (dd, 1H, HA), 11.34 (s, 1H, NH), 11.55 (s, 1H, NH). MS (m/z, %): 423 (0.59 %) (M+) in addition to the characteristic peaks for compounds containing four chlorine atoms at m/z = 425 (0.66 %) (M+2), 427 (0.41 %) (M+4) and 429 (0.08 %) (M+6). Anal. calcd. for C13H5Cl4N3O3S: C, 36.74; H, 1.18; N, 9.88. Found: C, 36.98; H,1.19; N 10.05 %. 2.2.6. 3‐(2‐chloromethylcarbonylamino)tetrachloro quinazolin‐2,4‐dione (7) To a stirred solution of 3‐aminotetrachloroquinazolin‐2,4‐ dione 3 (0.31 g, 1 mmole) in DMF (10 mL), chloroacetylchloride (1 mL) was added drop wisely at room temperature. The reaction mixture was stirred for 2 hours, and then dilute with cold water. The solid formed was filtered off and crystallized from benzene/ethanol to give 3‐(2‐chloromethylcarbonyl‐ amino)tetrachloroquinazolin‐2,4‐dione (0.35 g, 0.89 mmole) 7 in yield 89 % as white crystal (Scheme 3). M.p.: 320 oC. FT‐IR (KBr, cm‐1): 3211 (NH), 3021 (CH Aliph.), 1741 and 1700 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 4.04 (s, 2H, CH2), 11.2 (s, 1H, NH), 11.58 (s, 1H, NH). Anal. calcd. for C10H4Cl5N3O3: C, 30.69; H, 1.03; N, 10.73. Found: C, 30.81; H, 1.02; N 10.90%. 2.2.7. 3‐(N‐benzamido)tetrachloroquinazolin‐2,4‐dione (8a) A solution of 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) in dry pyridine (10 mL) was cooled in ice bath; benzoylchloride was added drop wisely with stirring for 4 hours. A cold diluted HCl (1:1)was added to the reaction mixture and the solid formed was filtered off and crystallized from benzene/ethanol to give 3‐(N‐benzamido)tetrachloro quinazolin‐2,4‐dione (0.32 g, 0.76 mmole) 8a in yield 78 % as white crystal (Scheme 3). M.p.: 310 oC. FT‐IR (KBr, cm‐1): 3200 (NH), 3000 (CH arom.), 1740 and 1660 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 7.30‐8.00 (m, 5H, Ar‐H), 11.30 (s, 1H, NH), 11.40 (s, 1H, NH). Anal. calcd. for C15H7Cl4N3O3. C, 42.99; H, 1.68; N, 10.03. Found: C, 43.20; H, 1.66; N 10.07%. 2.2.8. 3‐[(N‐(4‐bromobenzamido)tetrachloroquinazolin‐2,4‐ dione (8b) A mixture of 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) and p‐bromobenzoylchloride (0.21 g, 1 mmole) in dry pyridine (10 mL) was heated under reflux for 1/2 hour. After cooling, the reaction mixture was poured into cold diluted HCl (1:1). The solid formed was filtered off and crystallized from benzene/ethanol to give 3‐[(N‐(4‐bromo benzamido)tetrachloroquinazolin‐2,4‐dione (0.28 g, 0.56 mmole) 8b in yield 56 % as white crystal (Scheme 3). M.p.: 314 oC. 516 Hassan et al. / European Journal of Chemistry 2 (4) (2011) 514‐518 Scheme 3 FT‐IR (KBr, cm‐1): 3200 (NH), 3000 (CH Arom.), 1740 and 1660 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 7.70‐7.90 (two doublet 4H, A2B2 Arom.), 10.65 (s, 1H, NH), 11.47 (s, 1H, NH). Anal. calcd. for C15H6BrCl4N3O3: C, 36.18; H, 1.21; N, 8.44. Found: C, 36.28; H, 1.22; N 8.68%. 2.2.9. 3‐arylidineaminotetrachloroquinazolin‐2,4‐diones (9a‐d) 3‐Aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) was heated under reflux for 10‐12 hours with the appropriate aromatic aldehydes namely benzaldehyde, p‐nitrobenzaldehyde, p‐chlorobenzaldehyde and thiophenecarbaldehyde (1 mmole) in absolute ethanol (20 mL) and in prescence of pipridine as a catalyst. After cooling; the reaction mixture was filtered off and crystallized from appropriate solvent to give the arylidine derivatives, 9a‐d, respectively (Scheme 4). 3‐(Benzylidene‐amino)‐5,6,7,8‐tetrachloro‐1H‐quinazoline‐ 2,4‐dione (9a): Yield: 77 % as yellow crystal. M.p.: 360 oC. FT‐IR (KBr, cm‐1): 3221 (NH), 1731,1685 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 7.54‐7.95 (m, 5H, arom. H), 8.6 (s, 1H, CH=N), 11.45 (s, 1H, NH). Anal. calcd. for C15H7Cl4N3O2: C, 44.71; H, 1.75; N, 10.42. Found: C, 44.94; H, 1.76; N 10.59%. 3‐(Nitrobenzylidene‐amino)‐5,6,7,8‐tetrachloro‐1H‐ quinazoline‐2,4‐dione (9b): Yield: 64 % as brown silky. M.p.: 360 oC. FT‐IR (KBr, cm‐1): 3389 (NH), 1726, 1623 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 8.24‐8.42 (two d, 4H, A2B2 arom.), 8.93 (s, 1H, CH=N), 11.20 (s, 1H, NH). Anal. calcd. for C15H7Cl4N3O2: C, 40.22; H, 1.35; N, 12.51. Found: C, 40.51; H, 1.36; N 12.65 %. 3‐(Chlorobenzylidene‐amino)‐5,6,7,8‐tetrachloro‐1H‐ quinazoline‐2,4‐dione (9c): Yield: 60 % as yellow crystal. M.p.: 272 oC. 1H NMR (200 MHz, DMSO‐d6, ppm): 7.63‐7.90 (two d, 4H, A2B2 arom.), 8.79 (s, 1H, CH=N), 11.4 (s, 1H, NH). Anal. calcd. for C15H6Cl5N3O2: C, 41.19; H, 1.38; N, 9.60. Found: C, 41.29; H, 1.39; N 9.89%. 5,6,7,8‐Tetrachloro‐3‐[(thiophen‐2‐ylmethylene)‐amino]‐1H‐ quinazoline‐2,4‐dione (9d): Yield: 74 % as yellow crystal. M.p.: 320 oC. FT‐IR (KBr, cm‐1): 3493 (NH), 3108‐3032 (CH aliph), 1751, 1695 (C=O). 1H NMR (200 MHz, DMSO‐d6): 7.30 (dd, 1H, HX), 7.78 (dd, 1H, HM), 7.96 (dd, 1H, HA), 8.8 (s, 1H, CH=N), 11.22 (s, 1H, NH). Anal. calcd. for C13H5Cl4N3O2S : C, 38.17; H, 1.23; N, 10.27. Found: C, 38.38; H, 1.24; N 10.51%. 2.2.10. N‐(5,6,‐7,8‐tetrachloro‐2,4‐dioxo‐1,4‐dihydro‐2H‐ quinazolin‐3‐yl)‐malonamic acid ethyl ester (10) A mixture of 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) and diethylmalonate was refluxed for 6 hours. After cooling; the reaction mixture was filtered off and crystallized from benzene/ethanol to give N‐(5,6,7,8‐ tetrachloro‐2,4‐dioxo‐1,4‐di‐hydro‐2H‐quinazolin‐3‐yl)malon‐ amic acid ethyl ester (0.34 g, 0.75 mmole) 10 in yield 78 % as white crystal (Scheme 4). M.p.: 310 oC. FT‐IR (KBr, cm‐1): 3200 (NH), 1740 and 1660 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 1.18 (t, 3H, CH3), 3.50 (s, 2H, CH2‐CO), 4.13 (q, 2H, CH2‐ O), 10.90 (s, 1H, NH), 11.44 (s, 1H, NH). Anal. calcd. for C13H9Cl4N3O5: C, 36.39; H, 2.11; N, 9.79. Found: C, 36.69; H, 2.12; N 9.98%. 2.2.11. 3‐(ethoxymethylidineamino)tetrachloroquinazolin‐ 2,4‐dione (11) Triethylorthoformate is added to 3‐aminotetrachloro quinazolin‐2,4‐dione 3 (0.31 g, 1 mmole). The mixture was refluxed for 6 hours, and then allowed to stand overnight. The precipitated product was collected and crystallized from benzene to give 3‐(ethoxymethylidineamino)tetrachloro quinazolin‐2,4‐dione (0.27 g, 0.72 mmole) 11 in yield 72 % as yellow crystal (Scheme 4). M.p.: 182 oC. FT‐IR (KBr, cm‐1): 3293 (NH), 1741 and 1660 (C=O). 1H NMR (200 MHz, DMSO‐d6, ppm): 1.37 (two interfered triplets for the two isomeric CH3 protons), 4.39 two quartets for CH2 (Z), 4.55 for CH2 (E) in integration ratio (2:3), respectively, 7.98 (s, 1H, CH (Z)), 8.20 (s, 1H, CH (E)), 11.22 (s, 1H, NH). Anal. calcd. for C11H7Cl4N3O3: C, 35.61; H, 1.90; N, 11.33. Found: C, 35.85; H, 1.91; N 11.52%. Hassan et al. / European Journal of Chemistry 2 (4) (2011) 514‐518 517 Scheme 4 2.2.12. N‐phenylthiocarbamoyl‐N‐tetrachloroquinazolin‐2,4‐ dione‐N'‐pheny‐lthiourea (12) Heating of 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) with phenylisothiocyanate in absolute ethanol (20 mL) under reflux for 6 hours gave after cooling a solid product which was filtered off and crystallized from benzene to give N‐ phenylthiocarbamoyl‐N‐tetrachloroquinazolin‐2,4‐dione‐N'‐ phenylthiourea (0.37 g, 0.62 mmole) 12 in yield 63 % as white crystal (Scheme 4). M.p.: 210 oC. FT‐IR (KBr, cm‐1): 3231, 3185, 3129 (NH), 1731 and 1695 (C=O).1H NMR (200 MHz, DMSO‐d6, ppm): 6.90‐7.57 (m, 10 H, aromatic), 9.80 (s, 1H, HN‐CS), 11.20 (s, 1H, quinazoline NH). Anal. calcd. for C22H13Cl4N5O2S2: C, 45.15; H, 2.24; N, 11.96. Found: C, 45.41; H, 2.25; N 12.15%. 2.2.13. N‐phenyl‐N'‐[(1H,3H)‐5,6,7,8‐tetrachloroquinazolin‐ 2,4‐dion‐3‐yl]urea (13) When a mixture of 3‐aminotetrachloroquinazolin‐2,4‐dione 3 (0.31 g, 1 mmole) and phenyl thiocyanate in dry pyridine (10 mL) was refluxed for 10 hours. After cooling; the reaction mixture was poured into ice‐water and the solid formed was filtered off and crystallized from benzene to give N‐phenyl‐N'‐ [(1H,3H)‐5,6,7,8‐tetrachloro‐quinazolin‐2,4‐dion‐3‐yl]urea (0.25 g, 0.57 mmole) 13 in yield 57 % (Scheme 4). M.p.: 194 oC. FT‐IR (KBr, cm‐1): 3200 (NH), 1740 and 1660 (C=O).1H NMR (200 MHz, DMSO‐d6, ppm): 6.98‐7.50 (m, 5 H, aromatic), 8.70 (s, 1H, NH), 10.90 (s, 1H, NH), 11.80 (s, 1H, NH). Anal. calcd. for C15H8Cl4N4O3: C, 41.51; H, 1.85; N, 12.91. Found: C, 41.78; H, 1.86; N 13.18%. 2.2.14. Antibacterial studies Sallmonela typhi, staphylococcus aureus, bacillus cereus and bacillus subtilis were obtained from the Faculty of Veterinary Medicine, Pathology Department, Qena, Egypt. All the bacteria were grown on the desired media until the desired growth was obtained. Disc diffusion test [14]: Whatman paper No. 1 filter paper was used to make sterile disc in order to screen for the antibacterial activity of Sallmonela typhi, Staphylococcus aureus, Bacillus cereus and Bacillus subtilis. This filter paper was punctured to the shape of commercial antibiotic disc and discs were autoclaved at 121 °C for 15 min. The suspension of bacteria culture was prepared according to the MacFarland standard 0.5 and was lawned onto the Mueiller Hinton agar plates to produce the bacteria field. A sterile of punctured filter papers was placed on the bacteria field by sterile forceps and the solubilized extract then was pipetted out onto the surface of filter paper on the bacteria field. Tetracycline and DMF was used as a positive and negative control. The concentration of the compounds tested was 50 mg/mL. Finally, the plate was incubated at 37 °C and the zone inhibition is observed after 24‐ 48 h and measured as mm. 3. Results and discussion 3.1. Synthesis As a part of our program aimed to synthesize new pyrimidine derivatives as potential pharmaceuticals and/or agrochemicals, we report here the synthesis of new tetrachloroheterocyclic compounds such as tetrachloro quinazolindione derivatives. Treatment of N‐hydroxytetra chlorophthalimide with benzenesulphonyl chloride gave compound 2, which identified as N‐phenylsulphonyloxytetra‐ chlorophthalimide (Scheme 1). The main fragmentation routes for compound 2 are shown in Scheme 5. Treatment of N‐phenylsulphonyloxytetrachlorophthalimide 2 with excess hydrazine hydrate in dry benzene afforded 3‐ aminotetrachloroquinazolin‐2,4‐dione, 3 (Scheme 3). The reaction of N‐phenylsulphonyloxytetrachlorophthalimide, 2, with hydrazine may proceed according to the following mechanism (Scheme 6). The reaction of compound 3 with different acid chlorides was intensively investigated. Several 3‐substituted 518 Hassan et al. / European Journal of Chemistry 2 (4) (2011) 514‐518 tetrachloroquinazolin‐2,4‐diones, 4, 5, 6, 7, 8a and 8b were prepared via treatment of 3‐aminotetrachloroquinazolin‐2,4‐ dione 3 with acid chlorides namely acetylchloride, benzene sulphonylchloride, 2‐thiophenecarbonyl‐chloride, chloroacetyl chloride, benzoylchloride and p‐bromobenzoylchloride (Scheme 3). The reactions of compound 3 with different aldehydes, diethylmalonate, triethylorthoformate, phenyl isothiocyanate and phenyl thiocyanate were intensively investigated. Several 3‐arylidineaminotetrachloroquinazolin‐2,4‐diones 9a‐d have been prepared via treatment of 3‐aminotetrachloroquinazolin‐ 2,4‐dione, 3, with different aldehydes, namely benzaldehyde, p‐nitrobenzaldehyde, p‐chlorobenzaldehyde and thiophene carbaldehyde (Scheme 4). Also, 3‐aminotetrachloroquinazolin‐ 2,4‐dione, 3, reacted with diethylmalonate, triethylortho‐ formate, phenyl isothiocyanate and phenyl thiocyanate to give N‐(5,6,‐7,8‐tetrachloro‐2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐ yl)‐malonamic acid ethyl ester, 10, 3‐(ethoxymethylidine‐ amino)tetrachloroquinazolin‐2,4‐dione, 11, N‐phenylthio carbamoyl‐N‐tetrachloroquinazolin‐2,4‐dione‐N'‐phenyl‐ thiourea, 12, and N‐phenyl‐N'‐[(1H,3H)‐5,6,7,8‐tetrachloro quinazolin‐2,4‐dion‐3‐yl]urea, 13, respectively (Scheme 4). Scheme 5 3.2. Antibacterial Assays The compound 3 exhibited anti‐bacterialactivity against Staph. areus (8 mm), Bacillus cereus (15 mm) and Bacillus subtilis (9 mm). On the other hand this compound didn't show any inhibition activity against Salmonella typhi. This may be due to four chlorine [15] atoms and pyrimidine ring [16‐18]. The activity of compound 7 against all microorganisms tested showed positive reactions as indicated by zone of inhibition 7, 9, 18, 10 mm, respectively, this may be due to and five chlorine atoms, respectively. The compound 8a showed the most activity against bacteria such as Bacillus Subtilis (29 mm) which is 2 mm more than the zone around tetracycline disc (27 mm); this may be due to presence of (HN‐CO‐Ph). The Compound 8b has antimicrobial effect due to presence of bromine atom [19]. The Compound 9b has antimicrobial effect due to presence of (NO2) group. The compounds 9d and 10 showed most activity against Bacillus Subtilis (18 mm and 19 mm, respectively). This may be due presence of (HN‐CO) group in two compounds. Scheme 6 Acknowledgements The authors are grateful to Dr. Yousif Hassn Ebied for his help. References [1]. Agrawal, J. P.; Chouk M. P. Res. Ind. J. 1982, 27, 19‐21. [2]. Sou, S.; Mayumi, S.; Takahashi, H.; Yamasaki, R.; Kadoya, S.; Sodeoka, M.; Hashimoto, Y. Bioorg. 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