IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL. 24 (1) 2011 Synthesis and Characterization of Some New 1,3- Oxazepine Derivatives Received in : 17 June 2010 Accepte d in : 8 February 2011 S. A. Saoud Departme nt of Chemistry,Collge of Education I bn-Al –Haitham Unive rsity of Baghdad Abstract In this st udy , Schiff's bases [S3,S4] were sy nthezied by condensation of N,N-dimethy l amino b enzaldehy de with p rimary aromatic amine[N-(hy draziny l methy l)benzamide]. These Sciff's b ases were found to react with maleic anhydride and p hthalic anhydride to give 1,3- Oxazep ine[S5, S6,S7, S8] in good y ields. The structures confired by m.p ,T.L.C.,FT.IR and 1 H-NM R (of some of them). Key word 1,3 -Oxazepine Introduction Discovery of the activity of 1,3-Oxazep ine on the Central Nervous Sy st em (CNS)[1], encouraged further search ing for new way s to build up this 7-membered heterocyclic r ing system[2,3]. Diazep ine is a analogue to o xazep ine and thiazep ile but t he difference is nitrogen , oxy gen, nitrogen atom . Diazep am (valium) is a substituted benzodiazep ine introduced in 1964 which was used for the control of anxiety and tension st ates, t he relief of muscle sp asm and for the management of acute agitation durin g with drawal from alcohol[4]. 1,3-Oxazep ine is an antidepressant with a mild sedative comp onent to it is action. The mechan ism of it is clinical action in man is not well understood. In animals, amoxapine reduced the uptake of noradrenaline and serotonine and block ed the resp onse of dop amine receptors to dop amine[5]. Sy nthesis of oxazep ine derivatives may occur in various way s; e.g., with the p articip ation of C-6 or C-4 atom of the p y ridazinone ring to form diff erently fused py ridazino ring sy st ems[6], or oxazep ine p rep ared from the reaction of Schiff's bases with maleic and p hthalic anhydride to give 1,3-o xazep ine-4,7-dione in dry benzene, accordin g to p ericyclic reactions[7]. The p ericyclic reactions are important class of concerted reactions. A p ericyclic reactions are char acterized as a change in bonding relationship which takes p lace as a continuous concerted reor ganization of electrons. The word "concerted" sp ecifics that t here is a single transition state and thus no intermediate in the p rocess. To maintain continuous smooth electron flow, p ericyclic reactions occur through cyclic transition st ates. Frequently , the cy clic transition st ates must corresp ond to an arrangement of the particip ating orbitals that can maintain a bonding interaction between the reaction co mponents throughout the course of the reaction. Indeed as we shall see later these requirements make p ericyclic reactions high ly p redictable, in terms of such features as relative reactivity , stereo-sp ecificity and regioselectivity [8]. Oxazep ine derivatives such as comp ound (I) is used in chemical weapons as tear gas. Tear gas is the common n ame for substances which in low concentrations, cause p ain to the eyes, flow of tears and difficulty in keeping the ey es op en. It is used mainly in military , IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL. 24 (1) 2011 exercises and r iot control[9]. The aim of the work is sy nthesis new oxazep ine derivatives which are exp ected to have a biological activity like those that have already been reported. Experime ntal Instruments 1-M elting p oints were determined with: st uart melting p oint app aratus and were uncorrected. 2-Thin layer chromatography (T.L.C) Rf <1, was p erformed on alumina plates. 3-Infrared sp ectra were recorded with: SHIM ADZU from Ibn-Sina(FT .IR),8400,in KBr disc. 4- 1 H-NM Rwas recorded on fourier transform varian sp ectrometer , op erating at 300 M Hz with tetramethy lsilane as internal st andared in DM SOd 6 , measurements were mad e at chemist ry department, AL-AL_Bayt university , Jordan. Este rifi cation[10] To a mixture of glycinic acid (14.3 g,0.08mol) and anhydrous sodium carbonate (8.5g,0.08mol) in dry acetone (20mL), dimethy l sulp hate (10g,0.08mol) was added, then reflu xed for 4hr. The reaction was followed by (T.L.C). Aft er cooling the reaction mixture it extracted with ethy lacetate (3x) then dried to give sy rup p roduct of ester(methy l 2- benzamidoacetate). S1=(Yield 82%,M .P.=sy rup ),[x = number of extracted]. S ynthesis of hydrazide[11] Hy drazine mono hy drate 85% (2g,0.04 mol) was added to methy l ester(S1) (7.7g,0.04 mol) in (10 mL) absolute ethanol with st irrin g ,then reflu xed until the p recipitate formed (1.5hrs.). Aft er cooling ,the p recipitate was filtered. And recryst allized from ethanol ,N- (hy draziny l methy l)benzamide S2=( y ield 71% ,M .P.(150-152)˚c). S ynthesis of S chiff's bases [12] General procedure A mixture of hy drazide comp ound(S2)(1,9g,0.01 mol.), app rop riate aromatic aldehyde (0.01 mol.) and abs. ethanol 98%(25 mL) in the p resence of glacial acetic acid (3 drop s ) was refluxed in water bath for (4-5)hrs. Table (1) shows the physical prop erties. Sy nthesis of 1,3-Oxazep ine [13] General procedure A mixture of (0.03 mo l.) of imine compound (Schiff̓s bases)(S3, S4)and (0.03 mol.) of selected anhydride dissolved in (25 mL) dry benzene was r eflu xed in water bath for (4- 5)hrs.T he p roduct was recry stallized from dry 1,4-Dioxane . Table (2) shows the p hysical p rop erties of these compounds. IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL. 24 (1) 2011 Results and Discussion The reaction of Schiff's b ases with anhydrides is p ericyclic reaction rather than classical organic r eactions. The classical or ganic reactions involve several st eps or rearrangement, with side reactions and relatively low y ield, the p ericyclic reactions is one st ep -p rocess, takes p lace through a sin gle transition st ate with relatively high y ield and frequently no side reaction. The sy nthesis of comp ounds was outlined in schem (1) when the glycinic acid was converted to ester (S1) by using dimethy l sulp hate and sodium carbonate in dry acetone then the ester was hy drazonly sis with hy drazine hy drate to hy drazide derivative ( S2).The condensation reaction of equimolar quantity of p rimary amine (S2) with the app rop riate aromatic aldehy des was major method to p rep are of Schiff's bases (S3, S4) the nomen clatures of these comp ounds are shown in table (3). The sy nthesized comp ounds were identified by their M .P and FT.IR. The FT.IR sp ectra show t he disappearance of two absorption band due to (-NH2) str. of hy drazide derivative with app earance band at (1676-1685)cm -1 due to azomethene group (C=N)[14,15]. M oreover, all comp ounds exhibit sign ificant st retching band near the region (1213,1230,1296) cm -1 ,this indicated the p resence of (-N-N=) group [16]. Schiff's b ases are known to react with acid h alides and anhydride to give the corresp onding addition p roducts [17]. Therefore, it is exp ected that would react with maleic anhydride or p hthalic anhydride and was classified as a 5+2→7, imp loy ing a 5-atoms comp onent p lus 2-atoms comp onent leadin g to 7-membered cyclic ring, but the mechanis m (will be outlin ed below scheme (2)) involves addition of one σ bond (C-O) to one π- bond(C=N) to give 4-member ed cyclic transition state which op ens into maleic anhydride or p hthalic anhydride (5-membered cyclic ring) to give (7- membered cyclic rin g)[18]. Schem (2) The suggested mechanism for the formation of the oxazep ine deriv atives. The comp ounds [S5,S6, S7, S8] were obtained by the reaction of equimolar amount of imines with select anhydrides in dry benzene, the sy nthesized comp ounds were identified by their M .P,FT.IR and 1 H-NMR. analysis,the nomenclatures of these comp ounds are shown in table(3). The FT.IR sp ectra,figure 1 and 2, showed disappearance band at (1676,1685)cm -1 due to (C=N) of schiff's bases ,while ap p earance imp ortant band due to stretching vibration of (C=O) lactone and (C=O)lactam that is indicater to formation of oxazep ine comp ound, other data are list ed in table (4). 1 H-NM R sp rctrum of comp ound (S5), showed the following characterist ics chemical shifts (DM SO as asolvent) [19]: δ 2.6 s (–N–dimethy l) ; 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 . 1 H-NM R sp rctrum of comp ound (S8),figure 3, showed the following characterist ics 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. S CI. VOL. 24 (1) 2011 All these reactions show t he difference between classical organic reaction and p ericyclic reaction. Re ference 1- Hussein, F.A. and Najim, S.T. (2002) sy nthesis and characterization of 2,3-diaryl-2,3- dihydrobenz [1,2-e][1,3] oxazep ine-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.,sy nthesis and characterization of 2- aryl-3-(p-methoxy p heny l)-2,3-dihy dro-1,3-oxazep ine-4,7-diones(1), 27(3):751-763. 4- Wilson, C.O. and Gisvold, O. (1966)"T est Book of Organic M edicinal and Pharmaceutical Chemistry ",5 th ,Ed.,Pitman M edical Publishin g Co.LTD, London cop py right by J.B.Lippin cott company . 5- Huan-M ing chen and Ramach andra S.Hosmane,(2000), ,6-amino-2-phenylimidazo[4,5- e][1,3]diazep ine-4,8(1H,5H)-dione, J. M olecules 5:M 164. 6- Elias, O.and Lasz io ,K. H.(2000) "Int ernational Electronic Conference on sy nthetic Chemistry "2 nd ed.,p rinted and bound in great Britain. 7- Hussein, F.A. and Abed Abaid, H. (2002) sy nthesis and characterization of 2-ary l-3- p heny l-2,3-dihy dro-1,3-oxazep ine-1,4-diones, Irq.J. chem., 27(3):943. 8- Francis, A.Carey and Richard (1983)"Advanced Or ganic Chemist ry ",p art A:Structures and M echanisms,2 nd ed.,Lon gman p lenum press,New York, J.Sundber g p -243. 9- Tear Gases, Int ernet,(2002),AFOA Briefing Book on Chemical Weap ons. 10- Saoud,S.A. (2007),M .Sc.thesis ,College of Ibn-al-Haitham ,Baghdad University . 11- M ust afa, I.F. (1997), synthesis and characterization of some oxadiazole and triazole derivatives M u'tah Journal for Research and st udies, 12(3): 153-165. 12- M ahmoud ,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 p ure and App l.sci., sy nthesis antimicrobial ev aluation of 2-amino-5-thiol-1,3,4-thiadiazole derivatives, 17(1:103-110. 13- Hussein,F.A. ; M ahmoud M . J. and Taufig, M . T. (2006),Al-mustansiry a J.Sci.,sy nthesis of substituted 1,3-oxazep ines and 1,3-diazepines via Schiff b ases , 17(1): 14- Sharba, A.; AL-B ayati,R.; Aouad ,M . and Rezki,N. (2005), sy nthesis of oxadiazoles, thiadiazoles and triazoles derivative fro m benzo[6] thiophene , J.M olecules,10:1161- 1168. 15- Sharba,A.; AL-B ayati ,R. ; Rezki ,N. and Aouad,M . (2005), sy nthesis of thiodiazole and triazoles derivative from cy clop rop an dicarboxy lic acid, J.M olecules, 10:1153-1160. 16- Nadia,A.S. (2005),Ph.D.,T hesis, College of Science, AL-Nahr ain University ,Iraq. 17- V.Ram, (1988), Ch emotherap eutical agents, VII. Sy nthesis and pesticidal activities of sulp hides and sulp hones derived from bis[4-aryl-1,2,4-triazoline-5-thione-3-y l] alkane and 5-phenyl-1,3,4-oxadiazole-2-thione, J.Heterocy clic chem., 25: 253-256. 18- M ay soon,T.T.,Ph.D., (2004), Thesis,College of Education Ibn-al-Haitham, university of Baghd ad, 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. S CI. VOL. 24 (1) 2011 Table (1): The physical propertie s of S chiff's bases. Comp . No. Structural formula colour M olecular formula M olecular 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 tie s of 1,3-Oxazepine. Comp. No. Structural formula colour M olecular formula M olecular weight M .P. ˚C Yield % S5 Orange C25H22O5N4 472 148- 149 75 S6 Yellow C21H20O5N4 422 Sy rup 81 S7 Yellow C24H19O5N3 443 156- 157 78 S8 Yellow C20H17O5N3 393 sy rup 85 Table (3): The nomenclatures of compounds (S 2-S 8) Comp. No. nomenclatures S2 N-(hy drazinyl methy l)benzamide S3 N-((2-(4-(dimethy lamino)benzy lidene)hy draziny l)methy l)benzamide S4 N-((2-(4-methy l benzylidene)hy draziny l)methy l)benzamide S5 N-((3-(4-(dimethy lamino)p heny l)-1,5-dioxobenzo[e][1,3]oxazep in-4- (1H,3H,5H)-y lamino)methy l)benzamide S6 (Z)-N-((2-(4-(dimethy lamino)p henyl)-4,7-dioxo-1,3-o xazep in-3(2H,4H,7H)- y lamino)methy l)benzamide S7 N-((1,5-dioxo-3-p -tolybenzo[e][1,3]oxazep in-4(1H,3H,5H)- y lamino)methy l)benzamide S8 (Z)- N-((4,7--dioxo-2-p -toly l-1,3-oxazep in-3(2H,4H,7H)- y lamino)methy l)benzamide IBN AL- HAITHAM J. FOR PURE & APPL. S CI. 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 st r. cm -1 C=C st r. 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. S CI. VOL. 24 (1) 2011 IBN AL- HAITHAM J. FOR PURE & APPL. S CI. 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. S CI. VOL. 24 (1) 2011 Fig (3) : 1 H-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 جامعة بغداد، یة التربیة ابن الهیثمكل، قسم الكیمیاء 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 FT طیف االشعة تحت الحمراءو ،صفائح الكروموتوكرافیة الرقیقة و .IR ، الرنین النووي المغناطیسيطیف و 1 H-NM R. أوكسازبین-3,1 :لمفتاحیةالكلمات ا