Chemistry - 276 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Synthesis and Characterization of Novel Compounds Containing of Imidazolidinone and Oxazepine Rings T. R. Muhsen , J. H. Tomma and A. J. A. Mukhlus Department of Chemistry , College of Education Ibn Al- Haitham, University of Baghdad Abstract The compound 3-[4̄-(4˭-methoxy benzoyloxy) benzylideneamino]-2-thioxo- imidazolidine-4-one [III] was prepared from the cyclization of thiosemicarbazone [II] with ethyl α -chloroacetate in the presence of fused sodium acetate. Treatment the later compound with acetic anhydride yielded the corresponding 1-Acetyl-3-[ 4̄- (4˭- methoxy benzoyloxy) benzylideneamino] – 2 – thioxo -imidazolidine-4-one [IV]. 1,3-Oxazepine derivatives [V]a-d and [VI]a-d are obtained from the reaction of compounds[III] and [IV] with different acid anhydrides, in dry benzene. The FTIR and 1HNMR spectroscopy are indicated a good evidence for the formation of the synthesized compounds. Some of the synthesized compounds have been screened against E.coli , Staph. aureus , Psenudomonsaeruginosa and Bascillus cereus . They exhibited moderate to weak antibacterial activity unless compound [V]d did not show any biological activity. Key words: imidazolidenone, oxazepine Introduction 2-Thioxo-imidazolidin-4-one are imidazolidine ring that contain two groups thion(C=S) and carbonyl (C=O) at position, 2 and 4, respectively. It is well known that 2- thioxo-4-imidazolidinone derivatives display a wide range of biological properties.[1,2] Various methods are used for the preparation of 2-thioxo-imidazolidin-4-one among these; Treatment of arylisothiocyanate with amino acid under different conditions [3, 4]. Also, 2-thioxo-imidazolidin-4-One can be prepared by reaction of thiosemicarbazone with ethylα - chloroacetate in the presence of CH3CO2Na under reflux [1]. 1, 3-Oxazepine is non-homologuos seven member rings, that contains oxygen at position 1 andnitrogen at position 3. Oxazepine is used in the medical field and has been much chemical and biological studied. Many workers synthesized and studies the oxozepine derivatives mentioned as in the literates [5-8]. The aim of this work is to synthesis and characterization a novel compound containing imidazoliden-4-One and 1, 3-Oxazepine units in the same molecule. Experimental Materials: All the chemicals were supplied from Fluke, GCC and Aldrich Chemicals Co. and used as received. Techniques: FTIR spectra were recorded using potassium bromide discs on a Shimadzo (Ir prestige-21) . 1HNMR spectra were carried out by company: Bruker , model: ultra-shield 300 MHz , origin : Switzerland and are reported in ppm(δ), DMSO was used as a solvent with TMS as an internal standard . Measurements were made at chemistry department, Al- albyat University; uncorrected melting points were determined by using Hot-Stage, Gallen Kamp melting point apparatus. Chemistry - 277 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 General procedures The new compounds [II]-[VI] were synthesized according to scheme 1. N S N NH C O N HO CHO MeO- CO2 CHO NH2 NH NH2CS CO2 CH S CO2 CH NH C NH2 C CH3CO2Na [I] [II] [III] COCl MeO MeO (CH 3 CO) 2 O N N NCOCH3 C O CO2 CH S C [IV] MeO N NH C O CO2 S C [V] MeO A N NCOCH3 C O CO2 S C [VI] MeO A HC O N C O C O H C O N CO C O H C O N CO C O H C O N CO C O, ,A= dry benzene MeO Pyridine , DMF CL-CH2-CO2-Et or Scheme 1 dr y be nz en e an hy dr id es anhydrides Synthesis of 4-(4`-methoxy benzoyloxy) benzaldehyde [I] Anisoyl chloride (0.01mol) was added to a stirred solution of 4-hydroxy benzaldehyde (0.01mol) and dry pyridine (1mL) in dry dimethyl formamide (DMF) (10 mL) at (5-10°C). Stirring was continued for 3hrs at the same temperature. The resulting mixture was poured into 100 mL of 10% HCl . The precipitate was filtered and washed with solution of 10% NaHCO3 and water for several times [9] ,dried and recrystallized from ethanol . m.p 90 0C , yield 95%. Synthesis of 4-(4-̄methoxy benzoyloxy)benzaldehyde thiosemicarbazone [II] Chemistry - 278 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 A mixture of aromatic aldehyde [I] (0.001 Mole) , thiosemicarbazide ( 0.001 Mole) in ethanol ( 3mL ) was heated under reflux for 4hr, then cooled .The yellow solid formed was filtered ,dried and purified by recrystallization from ethanol to give compound [II]. m.p 200 0C , yield72%. Synthesis of 3-[4̄-(4˭-methoxy benzoyloxy) benzylideneamino]-2-thioxo-imidazolidine-4- one [III] A mixture of compound [II] (0.001mole), ethyl chloro acetate (0.001mole) and fused acetate (0.003mole) in ethanol was heated under reflux for 4hrs , then cooled and poured into water. The resulting pale yellow solid was filtered off, washed with water, dried and recrystallized by ethanol to give compound [III] . m.p 238 0C , yield 77%. Synthesis of 1-Acetyl-3-[ 4̄- (4˭- methoxy benzoyloxy) benzylideneamino] – 2 – thioxo - imidazolidine-4-one [IV] A solution of [III] (0.01mole) in acetic anhydride (25mL)was heated under reflux for 4hrs, then cooled and poured onto ice-water .The resulting orange product was filtered off ,washed with water, dried and recrystallized by ethanol to give compound [IV] . m.p 2250C , yield 58% . Synthesis of 1,3-oxazepine derivatives [V]a-d and [VI]a-d A mixture of (0.001mol) of Schiff bases [III] or [IV] and (0.001mole) of appropriate acid anhydrides in dry benzene (5mL) was refluxed for 6 hrs , the solvent was removed and the resulting colored crystalline solid recrystallized from ethanol. The physical data of all synthesized 1,3-oxazepines are listed in Table (1) . Result and discussion Thiosemicarbazone [II] were synthesized by refluxing equimolars of aromatic aldehyde [I] and thiosemicarbazide in ethanol . This compound was identified by its melting point and FTIR spectroscopy. FTIR absorption-spectrum showed the disappearance of aldehydic (C=O) absorption band at 1695 cm-1 together with appearance of new absorption stretching band at1699 cm-1 which is assigned to C=N stretching[10]. The spectrum showed many peaks in the region 3445- 3105cm-1 which could be attributed to asymmetric and symmetric stretching vibration of NH and NH2 groups and two sharp peaks at 1722cm-1 and 1186cm-1 due to ester and thion groups , respectively. Compound [III] was synthesized from the reaction of thiosemicarbazone [II] with ethyl chloroacetate in fused sodium acetate; the suggested mechanism of this reaction may be shown as follows Scheme 2. N S O N O N S S N N CH2 NH C C O S Ar CH NH C CH CNH2 Ar CH NH C CH C NH Ar CH N C CH2 NH C O H - EtOH Ar CH O-Et Cl -HCl Schem 2 2 OEt 2 OEt + Ar = MeO CH3CO2Na N S Ar CH HN C CH2 NH C OEt O N S Ar CH N C CH2 NH C OEtH O CO2 Chemistry - 279 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 The structure of the imidazolidenone [III] was identified by its melting point , FTIR and ¹HNMR spectroscopy. The FTIR spectrum of this compound showed the disappearance of absorption bands of the NH2 group ,in the thiosemecarbazone and appearance a sharp new absorption stretching bands at 1634 cm-1 due to C=O group of imidazolidenone ring. Also showed a weak stretching band at 3069 cm-1 and a sharp peak at1200 cm-1 could be attributed to NH and C=S groups, respectively. The 1HNMR spectrum of compound [III]a shows the following signals : eight aromatic protons appeared as pair of doublet at δ 7.12-8.28 ppm ,two sharp singlet at δ 8.44 ppm and δ 11.9 ppm that could be attributed to the one proton of CH=N and one proton of NH, respectively. The spectrum shows also two sharp singlet at δ 3.88 ppm an δ 3.23 ppm due to the three protons of OCH3 and two protons of CH2 groups, respectively. Treatment the later compound with acetic anhydride yielded the corresponding 1- Acetyl-3-[ 4̄- (4˭- methoxy benzoyloxy) benzylideneamino] – 2 – thioxo -imidazolidine-4-one [IV]. The FTIR spectrum indicated the disappearance the characteristic stretching band of the NH group with appearance a good band at 1720 cm-1 due to N-acetyl (N-C=O) stretching vibration. The 1HNMR of this compound show the following features: two pairs of doublet of doublets in the region δ6.79-8.09 ppm which can be attributed to eight protons of two p- substituted benzene rings having different substituents at positions I,4 . A sharp singlet at δ 8.79 ppm that could be attributed to the one proton of CH=N. The spectrum shows a quartet signal and a triplet signal at δ 4,31-4.49 ppm and δ 2.05-2.22 ppm due to two protons of CH2 and three protons of NCOCH3 groups, respectively . Besides a sharp singlet at δ 3.87 ppm for the three protons of OCH3. The 1,3-oxazepine derivatives were obtained by addition reaction of Schiff bases with different anhydrides in dry benzene, The new 1,3-oxazepine derivatives [V] and [VI] were synthesized by refluxing compound [III] or [VI] with different anhydride (maleic, 2,3,5,6-tetrahydrophthalic , phthalic or naphthalic anhydride) in presence of dry benzene. The characteristic FTIR absorption bands of these compounds were confirmed from the disappearance of band due to C=N of Schiff bases and other peaks characterized of cyclic anhydride of the starting materials together with appearance two bands characteristic of two carbonyl groups of oxazepine ring. The spectral data of FTIR for new oxazepine compounds are listed in Table(2). The 1HNMR spectrum of compound [VI]d (in DMSO) shows a singlet signal of N- CH proton absorbed at δ 7.22 ppm, the aromatic ring protons appear as multiplet in the region (δ 6.79-8.56) ppm , a singlet signals at δ3.87 ppm and 3.83 for OCH3 protons absorbed . The spectrum shows a quartet signal and a triplet signal at δ 4.31-4.49 ppm and δ 2.05-2.22 ppm due to two protons of CH2 and three protons of NCOCH3 groups, respectively Biological Activity The antibacterial activity of the synthesized compounds was performed according to the agar diffusion method [11]. The prepared compounds were tested against E.coli , Staph. aureus , Psenudomonsaeruginosa and Bascillus cereus. Each compounds was dissolved in DMSO to give concentration 1ppm. The plates were then incubated at 37 0C and examined after 24 hrs. The zones of inhibition formed were measured in millimeter and are represented by (-), (+) and (+ +) depending upon the diameter and clarity as in Table (3). Chemistry - 280 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 References 1.Nasser,A.; Idhayadhulla, A. ; Kumar, R. and Selvin, J. (2010) Synthesis of Some 2-Thioxo- imidazolidin-4-one Derivatives and its Antimicrobial Activity,E-Journal of Chemistry, 7(4):1320-1325. 2. Ma, Ch.; Zheng , P. and Li, J.(2006)Solid-state Synthesis and Characterization of 2- Thioxo-4-imidazolidinone Derivatives”, Journal of the Chinese Chemical Society, 53: 633- 636. 3. Savjani , G. and Gajjar, A .(2011)Pharmaceutical Importance and Synthetic Strategies for Imidazolidine-2-thione and imidazole-2-thione derivatives, Pakistan J.of Biological Sciences , 14(24):1076-1089. 4. Luis , J.; Filh1, J.; Lira, B.; Medeiros , I.; Morais , L.; Santos , A.; Oliveira, C.; and Athayde-Filho, P. (2010) Synthesis of New Imidazolidin-2,4-dione and 2- Thioxoimidazolidin-4-ones via C- Phenylglycine Derivatives , Molecules 15:128-137. 5. Bilgiç, S., Bilgiç, O., Bilgiç, M., Gündüz, M. and Karakoç, N. (2009) Synthesis of 2-Aryl- 1,2-dihydronaphtho[1,2-f][1,4]-oxazepin-3(4H)-one. Part I”, ARKIVOC, xiii, 185-192. 6.Al-Jamali, N. M., (2008), “Synthesis, Characterization of New 1,3-Oxazepine, Diazepine, Thiazepine derivatives and Open Ring of Thio Compounds”, Ph.D. Thesis, College of Education Ibn –Al Haitham , University of Baghdad. 7. Tawfiq, M. T. (2004) Synthesis of Substituted 1,3-Oxazepines and 1,3-Diazepines Via Schiff Bases, Ph.D. Thesis, College of Education Ibn –Al Haitham, University of Baghdad. 8.Tomma, J. ; Ali, E. ; Tomi, I.; Al-Witry, Z. ; Hassan, H. (2011) Synthesis and Characterization of New Heterocyclic compound” ,Mustansiriyah Journal of Science, 22(2):35-44. 9. Al- Dujaili , A. and Tomma ,J.(2002) Synthesis and Liquid-Crystalline Properties Of some New 1,3,4-Thiadiazol Imines Derivatives” , J. Iraqi Journal of Chemistry , 28(2):405-413. 10. Mostafa, T. (2010) Synthesis and Modification of some Heterocyclic Compounds with Potential Biological Activity Coupled on Poly (Maleic Anhydride –Methyl Methacrylate) ” , Journal of American Science 6(8):512-524. 11- Tomma , J. ; Raheema, A. and Rouil ,I. (2005) Synthesis and Antibacterial Activity of Some Novel Schiff- Bases Compounds Containing Oxadiazole Ring, Ibn Al-Haitham J. for Pure and Appl. Sci., 18(1):41-49. Chemistry - 281 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Table (1): Physical data of oxazepine compounds. Comp. No. Nomenclature Structural formula Molecular formula M. P 0C Yie ld % Color [V]a 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-(2-thioxo-imidazol -idine-4-one-3-yl)-2,3- dihydro-1,3-oxazepine-4,7- diones CO2CH3O NH O S NHC O N C OCO C22H17N3O 7S 228-230 54 Off white [V]b 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-(2-thioxo-imida zolidine-4-one-3-yl)-2,3- dihydro-5,6- cyclohexane[1,2e]-1,3- oxazepine-4,7-diones CH3O N H C O C O C O CO2 N N H C S C O C26H23N3O 7S 252-256 70 Off white [V]C 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-(2-thioxo- imidazolidine-4-one-3-yl)-2,3- dihydro-benz[1,2e]1,3-- oxazepine-4,7-diones N H C C O C O N N C S C O CH3O O CO2 H C26H19N3O 7S 206-208 61 yellow [V]d 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-(2-thioxo-imida zolidine-4-one-3-yl)-2,3- dihydro-naphth[2,3e]-1,3- oxazepine-4,7-diones N H C O C O C O CO2CH3O N N H C S C O C30H21N3O 7S 195-198 82 yellow Pale [VI]a 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-[1-acetyl (2-thioxo- imidazolidine-4-one-3-yl)-2,3- dihydro-1,3-oxazepine-4,7- diones CO2CH3O N O S NHC O N C OCO C C H3 O C24H19N3O 8S 178-180 57 yellow [VI]b 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-[1-acetyl (2-thioxo- imidazolidine-4-one-3-yl)-2,3- dihydro-5,6- cyclohexane[1,2e]-1,3- oxazepine-4,7-diones N H C C O C O N N C S C O O CH3O O CO2 C CH3 C28H25N3O 8S 172-176 59 Yellow dark [VI]C 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-[1-acetyl (2-thioxo- imidazolidine-4-one-3-yl)-2,3- dihydro-benz[1,2e]-1,3- oxazepine-4,7-diones N H C C O C O N N C S C O O CH3O O CO2 C CH3 C28H21N3O 8S 205-209 68 Glow yellow [ VI]d 2-[4̄-(4˭-methoxy benzoyloxy) phenyl]-3-[1-acetyl (2-thioxo- imidazolidine-4-one-3-yl)-2,3- dihydro-naphth[2,3e]-1,3-- oxazepine-4,7-diones N H C C O C O N N C S C O O CH3O O CO2 C CH3 C32H23N3O 8S 234 63 yellow Chemistry - 282 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Table (2) : FTIR spectral data of oxazepine compounds. Comp. No. νNH νC-H Aliph. νC=O lactone,lactome of oxazepine νC=O amid exocyclic νC=O imidazolidinone νC=C arom. [V]a 3069 2976,2843 1770 , 1710 - 1634 1598 [V]b 3098 2966,2862 1765 , 1695 - 1634 1597 [V]c 3078 2960,2843 1765 , 1695 - 1633 1599 [V]d 3067 2989,2842 1771 , 1726 - 1634 1599 [VI]a - 2958,2840 1732 , 1697 1705 1637 1604 [VI]b - 2942,2825 1728 , 1695 1719 1655 1605 [VI]c - 2940,2854 1768 , 1690 1721 1654 1604 [VI]d - 2926,2852 1770 , 1684 1701 1640 1605 Table (3) : Biological activities of some of synthesized compounds. Comp. No. Staphylococcus aureus(G+) Bascillus cereus (G+) Escherichichia coli(G-) Psenudomonsaeru ginosa(G-) [II] + + + + + + _ [III] _ + + + _ [IV] + + + + [V]d _ _ _ _ [V]a + + + + _ [VI]c _ ++ _ _ Key to symbols : Moderately active = + +(11-15) mm and slightly active = + (5-10) Chemistry - 283 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 العدد Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 تحضير وتشخيص مركبات جديدة تحتوي على حلقتي االيميدازولدينون واالكسازبيين طالب رشيد محسن ، جمبد هرمز توما ، عبد الجبار عبد القادر مخلص جامعة بغداد ،كلية التربية ابن الهيثم ،قسم الكيمياء الخالصة مع اثيل كلورو اسيتات بوجود خالت [II]من الغلق الحلقي للثايوسيميكاربازون [III]ون -4-يميدازولدينحضراال . حضرت مشتقات [VI]الصوديوم المنصهرة تمت معاملة المركب االخير مع انهيدريد الخليك لينتج المركب المقابل ات متنوعة على التوالي في البنزين الجاف. أثبتت مع انهيدريد [IV]و [III]من تفاعل المركب [VI]و [V]االوكسازبين . درست NMR H 1وطيف الرنين النووي المغناطيسي FTIRصحة التراكيب للمركبات المحضرة باستعمال طيف ,E.coli , Staph. Aureuالفعالية البايولوجية لبعض من المركبات المحضرة ضد انواع من البكتريا Psenudomonsaeruginosa Bascillus cereus وبينت النتائج ان اغلب المركبات اظهرت فعالية بايولوجية ضد اي فعالية ضد هذه االنواع من البكتريا d[V]البكتريا المستخدمة تراوحت بين المتوسطة الى الضعيفة ولم يظهر المركب االوكسازبين ،االيميدازولدين الكلمات المفتاحية :