IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 Synthesis and Characterization of Some New 1,3- Oxazepine Derivatives Received in : 17 June 2010 Accepted in : 8 February 2011 S. A. Saoud Department of Chemistry,Collge of Education Ibn-Al –Haitham University of Baghdad Abstract In this study, Schiff's bases [S3,S4] were synthezied by condensation of N,N-dimethyl amino benzaldehyde with primary aromatic amine[N-(hydrazinyl methyl)benzamide]. These Sciff's bases were found to react with maleic anhydride and phthalic anhydride to give 1,3- Oxazepine[S5,S6,S7,S8] in good yields. The structures confired by m.p ,T.L.C.,FT.IR and 1H-NMR (of some of them). Key word 1,3 -Oxazepine Introduction Discovery of the activity of 1,3-Oxazepine on the Central Nervous System (CNS)[1], encouraged further searching for new ways to build up this 7-membered heterocyclic ring system[2,3]. Diazepine is a analogue to oxazepine and thiazepile but the difference is nitrogen , oxygen, nitrogen atom . Diazepam (valium) is a substituted benzodiazepine introduced in 1964 which was used for the control of anxiety and tension states, the relief of muscle spasm and for the management of acute agitation during with drawal from alcohol[4]. 1,3-Oxazepine is an antidepressant with a mild sedative component to it is action. The mechanism of it is clinical action in man is not well understood. In animals, amoxapine reduced the uptake of noradrenaline and serotonine and blocked the response of dopamine receptors to dopamine[5]. Synthesis of oxazepine derivatives may occur in various ways; e.g., with the participation of C-6 or C-4 atom of the pyridazinone ring to form differently fused pyridazino ring systems[6], or oxazepine prepared from the reaction of Schiff's bases with maleic and phthalic anhydride to give 1,3-oxazepine-4,7-dione in dry benzene, according to pericyclic reactions[7]. The pericyclic reactions are important class of concerted reactions. A pericyclic reactions are characterized as a change in bonding relationship which takes place as a continuous concerted reorganization of electrons. The word "concerted" specifics that there is a single transition state and thus no intermediate in the process. To maintain continuous smooth electron flow, pericyclic reactions occur through cyclic transition states. Frequently, the cyclic transition states must correspond to an arrangement of the participating orbitals that can maintain a bonding interaction between the reaction components throughout the course of the reaction. Indeed as we shall see later these requirements make pericyclic reactions highly predictable, in terms of such features as relative reactivity , stereo-specificity and regioselectivity[8]. Oxazepine derivatives such as compound (I) is used in chemical weapons as tear gas. Tear gas is the common name for substances which in low concentrations, cause pain to the eyes, flow of tears and difficulty in keeping the eyes open. It is used mainly in military, IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 exercises and riot control[9]. The aim of the work is synthesis new oxazepine derivatives which are expected to have a biological activity like those that have already been reported. Experimental Instruments 1-Melting points were determined with: stuart melting point apparatus and were uncorrected. 2-Thin layer chromatography (T.L.C) Rf <1, was performed on alumina plates. 3-Infrared spectra were recorded with: SHIM ADZU from Ibn-Sina(FT.IR),8400,in KBr disc. 4-1H-NMRwas recorded on fourier transform varian spectrometer , operating at 300 MHz with tetramethylsilane as internal standared in DM SOd6, measurements were made at chemistry department, AL-AL_Bayt university, Jordan. Esterification[10] To a mixture of glycinic acid (14.3g,0.08mol) and anhydrous sodium carbonate (8.5g,0.08mol) in dry acetone (20mL), dimethyl sulphate (10g,0.08mol) was added, then refluxed for 4hr. The reaction was followed by(T.L.C). After cooling the reaction mixture it extracted with ethylacetate (3x) then dried to give syrup product of ester(methyl 2- benzamidoacetate). S1=(Yield 82%,M.P.=syrup),[x = number of extracted]. Synthesis of hydrazide[11] Hydrazine mono hydrate 85% (2g,0.04 mol) was added to methyl ester(S1) (7.7g,0.04 mol) in (10 mL) absolute ethanol with stirring ,then refluxed until the precipitate formed (1.5hrs.). After cooling ,the precipitate was filtered. And recrystallized from ethanol ,N- (hydrazinyl methyl)benzamide S2=( yield 71% ,M.P.(150-152)˚c). Synthesis of Schiff's bases [12] General procedure A mixture of hydrazide compound(S2)(1,9g,0.01 mol.), appropriate aromatic aldehyde (0.01 mol.) and abs. ethanol 98%(25 mL) in the presence of glacial acetic acid (3 drops ) was refluxed in water bath for (4-5)hrs. Table (1) shows the physical properties. Synthesis of 1,3-Oxazepine [13] General procedure A mixture of (0.03 mol.) of imine compound (Schiff̓s bases)(S3,S4)and (0.03 mol.) of selected anhydride dissolved in (25 mL) dry benzene was refluxed in water bath for (4- 5)hrs.The product was recrystallized from dry 1,4-Dioxane . Table (2) shows the physical properties of these compounds. IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 Results and Discussion The reaction of Schiff's bases with anhydrides is pericyclic reaction rather than classical organic reactions. The classical organic reactions involve several steps or rearrangement, with side reactions and relatively low yield, the pericyclic reactions is one step-process, takes place through a single transition state with relatively high yield and frequently no side reaction. The synthesis of compounds was outlined in schem (1) when the glycinic acid was converted to ester (S1) by using dimethyl sulphate and sodium carbonate in dry acetone then the ester was hydrazonlysis with hydrazine hydrate to hydrazide derivative (S2).The condensation reaction of equimolar quantity of primary amine (S2) with the appropriate aromatic aldehydes was major method to prepare of Schiff's bases (S3,S4) the nomenclatures of these compounds are shown in table (3). The synthesized compounds were identified by their M.P and FT.IR. The FT.IR spectra show the disappearance of two absorption band due to (-NH2) str. of hydrazide derivative with appearance band at (1676-1685)cm-1 due to azomethene group (C=N)[14,15]. Moreover, all compounds exhibit significant stretching band near the region (1213,1230,1296) cm -1,this indicated the presence of (-N-N=) group[16]. Schiff's bases are known to react with acid halides and anhydride to give the corresponding addition products [17]. Therefore, it is expected that would react with maleic anhydride or phthalic anhydride and was classified as a 5+2→7, imploying a 5-atoms component plus 2-atoms component leading to 7-membered cyclic ring, but the mechanism (will be outlined below scheme (2)) involves addition of one σ bond (C-O) to one π- bond(C=N) to give 4-membered cyclic transition state which opens into maleic anhydride or phthalic anhydride (5-membered cyclic ring) to give (7-membered cyclic ring)[18]. Schem (2) The suggested mechanism for the formation of the oxazepine derivatives. The compounds [S5,S6,S7,S8] were obtained by the reaction of equimolar amount of imines with select anhydrides in dry benzene, the synthesized compounds were identified by their M.P,FT.IR and 1H-NMR. analysis,the nomenclatures of these compounds are shown in table(3). The FT.IR spectra,figure 1 and 2, showed disappearance band at (1676,1685)cm-1 due to (C=N) of schiff's bases ,while appearance important band due to stretching vibration of (C=O) lactone and (C=O)lactam that is indicater to formation of oxazepine compound, other data are listed in table (4). 1H-NMR sprctrum of compound (S5), showed the following characteristics chemical shifts (DMSO as asolvent) [19]: δ 2.6 s (–N–dimethyl) ; δ 4.09 d (–CH2–) ; δ 7.3 s (–N–CH–) ; δ7.6-7.8 m, (aromatic) ; δ7.8s (–CO–NH–N–) ; δ 8.4 - 8.5t (–CO–NH–CH2–)group. 1H-NMR sprctrum of compound (S8),figure 3, showed the following characteristics chemical shifts (DM SO as asolvent)[19]: δ 2.19 s (–CH3) ; δ 4.09 d (–CH2–) ; δ 6.9 d of d (CH=CH) ; δ 7.3 s (–N–CH–) ; δ7.5-7.9 m (aromatic) ; δ8.1 s (–CO–NH–N–) ; δ 8.6 - 8.8 t (– CO–NH–CH2–). R=Ph-CO-NH-CH2-CO-NH- Ar=[4-N(CH3)2Ph],[4-CH3Ph] IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 All these reactions show the difference between classical organic reaction and pericyclic reaction. Reference 1- Hussein, F.A. and Najim, S.T. (2002) synthesis and characterization of 2,3-diaryl-2,3- dihydrobenz [1,2-e][1,3] oxazepine-4,7-diones, Irq.J. chem., 28(1):13-25. 2- Abed ,A.H. (2001) Irq.J. chem., 3(1), pp.480-492. 3- Hussein, F.A. and Obaid, H.A. (2001), Irq.J. chem.,synthesis and characterization of 2- aryl-3-(p-methoxy phenyl)-2,3-dihydro-1,3-oxazepine-4,7-diones(1), 27(3):751-763. 4- Wilson, C.O. and Gisvold, O. (1966)"Test Book of Organic Medicinal and Pharmaceutical Chemistry",5 th ,Ed.,Pitman Medical Publishing Co.LTD, London coppy right by J.B.Lippin cott company. 5- Huan-Ming chen and Ramachandra S.Hosmane,(2000), ,6-amino-2-phenylimidazo[4,5- e][1,3]diazepine-4,8(1H,5H)-dione, J. M olecules 5:M164. 6- Elias, O.and Laszio ,K. H.(2000) "International Electronic Conference on synthetic Chemistry"2 nd ed.,printed and bound in great Britain. 7- Hussein, F.A. and Abed Abaid, H. (2002) synthesis and characterization of 2-aryl-3- phenyl-2,3-dihydro-1,3-oxazepine-1,4-diones, Irq.J. chem., 27(3):943. 8- Francis, A.Carey and Richard (1983)"Advanced Organic Chemistry",part A:Structures and Mechanisms,2 nded.,Longman plenum press,New York, J.Sundberg p-243. 9- Tear Gases, Internet,(2002),AFOA Briefing Book on Chemical Weapons. 10- Saoud,S.A. (2007),M .Sc.thesis ,College of Ibn-al-Haitham ,Baghdad University . 11- Mustafa, I.F. (1997), synthesis and characterization of some oxadiazole and triazole derivatives Mu'tah Journal for Research and studies, 12(3): 153-165. 12- Mahmoud ,M.G. ; Al-Rnbaiy,Z.M.; Al-Knbaisy, R.K.; Al-Najafi,M.M. and Al- Gumaily,H. M. (2004), IBN AL-HAITHAM.J.For pure and Appl.sci., synthesis antimicrobial evaluation of 2-amino-5-thiol-1,3,4-thiadiazole derivatives, 17(1:103-110. 13- Hussein,F.A. ; Mahmoud M. J. and Taufig, M. T. (2006),Al-mustansirya J.Sci.,synthesis of substituted 1,3-oxazepines and 1,3-diazepines via Schiff bases , 17(1): 14- Sharba, A.; AL-Bayati,R.; Aouad ,M. and Rezki,N. (2005), synthesis of oxadiazoles, thiadiazoles and triazoles derivative from benzo[6] thiophene , J.Molecules,10:1161- 1168. 15- Sharba,A.; AL-Bayati ,R. ; Rezki ,N. and Aouad,M. (2005), synthesis of thiodiazole and triazoles derivative from cyclopropan dicarboxylic acid, J.Molecules, 10:1153-1160. 16- Nadia,A.S. (2005),Ph.D.,Thesis, College of Science, AL-Nahrain University ,Iraq. 17- V.Ram, (1988), Chemotherapeutical agents, VII. Synthesis and pesticidal activities of sulphides and sulphones derived from bis[4-aryl-1,2,4-triazoline-5-thione-3-yl] alkane and 5-phenyl-1,3,4-oxadiazole-2-thione, J.Heterocyclic chem., 25: 253-256. 18- Maysoon,T.T.,Ph.D., (2004), Thesis,College of Education Ibn-al-Haitham, university of Baghdad, Iraq. 19- Al-Smad M. and Ratrout, S. (2004) new 1,2,3-selenadiazoles and thiadiazole derivatives, J.M olecules 9:957-967. IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 Table (1): The physical properties of Schiff's bases. Comp . No. Structural formula colour Molecular formula Molecular weight M.P. ˚C Yiel d % S3 Red C18H20O2N4 324 174- 175 82 S4 Yellow C17H17O2N3 295 135- 136 78 Table (2): The physical proper ties of 1,3-Oxazepine. Comp. No. Structural formula colour Molecular formula Molecular weight M.P. ˚C Yield % S5 Orange C25H22O5N4 472 148- 149 75 S6 Yellow C21H20O5N4 422 Syrup 81 S7 Yellow C24H19O5N3 443 156- 157 78 S8 Yellow C20H17O5N3 393 syrup 85 Table (3): The nomenclatures of compounds (S 2-S 8) Comp. No. nomenclatures S2 N-(hydrazinyl methyl)benzamide S3 N-((2-(4-(dimethylamino)benzylidene)hydrazinyl)methyl)benzamide S4 N-((2-(4-methyl benzylidene)hydrazinyl)methyl)benzamide S5 N-((3-(4-(dimethylamino)phenyl)-1,5-dioxobenzo[e][1,3]oxazepin-4- (1H,3H,5H)-ylamino)methyl)benzamide S6 (Z)-N-((2-(4-(dimethylamino)phenyl)-4,7-dioxo-1,3-oxazepin-3(2H,4H,7H)- ylamino)methyl)benzamide S7 N-((1,5-dioxo-3-p-tolybenzo[e][1,3]oxazepin-4(1H,3H,5H)- ylamino)methyl)benzamide S8 (Z)- N-((4,7--dioxo-2-p-tolyl-1,3-oxazepin-3(2H,4H,7H)- ylamino)methyl)benzamide IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 Table (4): FT.IR data of 1,3-oxazepine derivatives. Comp. No. C=O Lactam cm -1 C=O Lacton cm -1 C-O Lacton cm -1 C-N str. cm-1 C=C str. cm-1 S5 1715 1678 1276 1176 1639-1531 S6 1724 1724 1232 1172 1643-1539 S7 1710 1700 1278 1170 1643-1546 S8 1732 1720 1230 1138 1643-1543 Schem(1) IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 Fig.(1):FT.IR of compound (S 6) Fig.(2):FT.IR of compound (S 5) IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.24 (1) 2011 Fig (3) : 1H-NMR of compound (S 8) 2011) 1( 24المجلد مجلة ابن الھیثم للعلوم الصرفة والتطبیقیة دیدةــــازبین الجـــــــــــاوكس-3,1تقات ــــــخیص بعض مشــــیر وتشـــــــتحض 2010حزیران 17 :استلم البحث في 2011شباط 8 :قبل البحث في شیماء عبد سعود د، یة التربیة ابن الهیثمكل، قسم الكیمیاء جامعة بغدا الخالصة مـع امـین مثیـل بنزالدیهایـد-4و، مثیـل امینـو بنزالدیهایـد ثنـائي-تكـاثف ن مـن ت قواعد شـفحضر في هذه الدراسة مـع انهدریـد المالیـك و انهدریـد الفثالیـك العطـاء المحضـرة قواعـد شـف تعلـو ف.] بنزامایـد )لمثیـل هایـدرازینی(-ن [حلقـي اولـي ،طة درجـة االنصــهار ابوسـشخصـت المركبـات المحضــرة . نسـبة منتــوج جیـدةب [S5,S6,S7,S8] نوكسـازبیأ-3,1مركبـات .1H-NMR الرنین النووي المغناطیسيطیف و ، FT.IR طیف االشعة تحت الحمراءو ،صفائح الكروموتوكرافیة الرقیقة و أوكسازبین-3,1 :لمفتاحیةالكلمات ا