IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 Synthesis o f 1,2,3 –Trisubstituted- 1,2,3- Trihydro-1,3- Diazepine-4,7-Diones (part3) F.A. Hussein, M. J. Mahmoud, and M. T. Tawfiq Departme nt of Chemistry, College of Education I bn AL-Haitham Unive rsity of Baghdad Abstract 1,3- Oxazep ines, benz [1,2-e] [1,3]-oxazep ines, and 3- nitrobenz [1,2-e] [1,3] - oxazep ines were reacted with ammonia derivatives, H2N-Z .. to give 1,3 – diazepine -4,7- dione, benzodiazep ine - 4,7- dione, and 3 – nitrobenzo -1,3- diazepine - 4,7- dione, resp ectively. Introduction The st arting imidazole diest er [1] reacts with guanidine hy drochloride to y ield 1,3- diazepine derivatives [2] (1): The reaction of 1- ( 2 - aminomethy lphenyl) p y rrole hy drochloride [3] with carbony l comp ounds gives diazep ines [4] in a ring closure reaction(2) Compound[4] was oxidized by manganes dioxide in toluene to give 4H- p y rrolobenzodiazepine [5] (2). Me O O O O N N H Me H2N H N N O O N N H .. . . .. .. . . . . Guanidine.H CI Me ONa,MeOH R.T.48h rs HCI(IM) [1] [2] dimethyl-2-phenyl 1H-imidazole-4,5- dicarbo xylate. 6-amino-2-Phenylimidazo[4,5-e] [1,3]diazepine-4,8(1H,5H) -dione. N R1 H + CH2NCl R2 N + NH2 Cl R1 R2 + O = C [3] [4] IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 M any of the diazepines show interesting sedatives, muscle relaxant, and anticonvulsant p rop erties in animals (2). Several clinical useful drugs were found which contain a hetrocy clic moity fused onto the seven membered ring, like p y rrolobenzodiazepines which are now accessible by several routes (2). Aim of the work Sy nthesis new diazepines derivatives which are exp ected to have a biological activity in the medical field. Experimental Part Material and S olvents: 1. 1,3-Oxazep ine -4,7- diones (II),(III) and (IV) p repared as p art 1 (3). 2. Ammonia derivatives H2N-Z . 3. Dry benzene (M erck 99). 4. Ethanol (M erck 99.7-100). 5. Dioxane. The instruments: 1. M elting p oints were determined with: Strut M elting p oint Ap p aratus and were uncorrected. 2. IR. Sp ectra were recorded with: PYE UNICAM SP3-300 Infrared Sp ectrop hotometer (KBr disc) in the range (4000-200)cm -1 . 3. FT IR Sp ectra, Were recorded with: SHIM ADZU FT IR-8400S Infrared Sp ectrop hotometer (KBr disc). 4. Elemental Analysis (C.H.N.) was carried with: Perkin Elmer B-240 Elemental Analyzer. Experimental: Sy nthesis of :2- st y ry l -3- aryl -1,2,3-trihydro [1,3]- diazepine - 4,7- dione -1- thiocarbamide (VIIIf) , 2 – st y ry l – 3 – aryl - 1,2,3, - trihydrobenzo [1,2-e] [1,3] –diazepine - 4,7- dione -1- thiocarbamide (1Xf), 1- Hy droxy - 2- st y ry l-3-(p-nitrop henyl) - 1,2.3 – trihydrobenzo [1,2-e] [1,3] – diazepine - 4,7- dione (1Xb) ,1-amino -2- st y ry l -3- (p - methy lphenyl) - 1,2,3 - trihy drobenzo [1,2-e] [1,3] - diazepine 4,7-dione (1Xd), 2 – sty ry l -3- N N R1 R2 [4] .. N + NH2 Cl R1 R2 .. o xi. [5] R1 = CCl3, C6H5-CH=CH2, CH3, C2H5,CH3CO,CO2C2H5 R2 = H,CH3,CO2C2H6 IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 (2,4-dibromop henyl) - 1,2,3 – trihydrobenzo -[1,2-e] [1,3] – diazepine - 4,7 – dione - 1- thiocarbamide (1Xf), 1- hy droxy -2- st y ry l -3- (p -methy lphenyl) - 1,2,3-trihydro -3- nitrobenzo [1,2-e] [1,3] – diazepine - 4,7-dione (Xd) ,1- formamidino-2- st y ry l -3- (p - methoxy p henyl) - 1,2,3 – trihydro -3- nitrobenzo [1,2-e][1,3]- diazepine-4,7-dione (Xe), 2- st y ry l -3- (2,4-dibromop henyl)-1,2,3- trihydro -3- nitrobenzo [1,2-e][1,3]-diazep ine -4,7- dione -1- thiocarbamide (Xf). A mixture of (0.0015 mole) of 2-st y ry l -3- aryl -2,3- dihydro [1,3]-oxazep ine -4, 7- dione (II) and (0.0015 mole) of thiourea (or guanidine hy drochloride + Na2CO3) susp ended in (20 mL) of dry benzene (or absolute ethanol) was heated and refluxed in water bath for 3hrs, the solvent was evap orated leaving light y ellow cryst als of 2-st y ry l -3- aryl-1,2,3-trihy dro [1,3]-diazepine -4,7- dione-1-thiocarbamide (VIII) filtered and recry st allized from dioxane. This exp eriment was repeated by using other 1,3-oxazep ines with ammonia derivatives in order to obt ain different diazep ine derivatives (IX) and (X). Discussion In a p revious p aper (3) sy nthesis of 1,3 - oxazep ine - 4, 7- dione (II) benzo [1,2- e][1,3]- oxazep ine -4,7- dione (III) and 3- nitrobenzo [1,2-e][1,3] oxazep ine-4,7- dione (IV) was described. These oxazep ines were found to be good st arting comp ounds for the sy nthesis of another class of heterocylic comp ounds (4) by the reaction with ammonia derivatives H2N-Z as shown below(4,5,6): IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 The mechanism (7) involves the addition of the amine to the carbony l group of the lactone forming the dipolar intermediate (A) which undergoes cleavge to give another dipolar intermediate (B). Intermediate (B) undergoes hy drogen transfer from nitrogen to oxy gen to give the open chain hy droxy l amide (C) in which both maintain their configuration throughout the course of the reaction that p ermits the elimination of H2O and the reclosure of the st ructure to give 1,3-diazepine-4, 7-dione (D). O C O (II) O C O C O C O (II I) O C O C O (IV) NO2 (X) (IX) N C O C O Br C O C O (VII I) C O C O Br NO2 C 6H5 - C H = C H - CH N Ar C6 H5 - CH = CH CH N Ar C6H5 - CH = CH CH N Ar C 6H5 - C H = CH - CH N Ar C6 H5 - CH = CH CH N Ar C6H5 - CH = CH CH N Ar Z - N H2N - Z Where Z = -OH ( hydroxyl am ino), - NH2 (hydrazine), -CSNH2 (t hiourea) , and - C(NH)NH2(gua nidine). Ar = C H3 , OC H3 , NO2 , Scheme 1 Z- Z-N C N Ar H and Ar CH OH O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 The resulting diazepines VIII, IX and X are identified by their m.ps,elemental analysis (tables 1,3,6,8,11) and IR, FTIR sp ectra (tables 2,4,5,7,9,10,12). It is noticeable that the IR sp ectra of the exp ected p roducts show the app earance of (NH, OH) absorp tion bands at (3580,3320)cm -1 , resp ectively (8). This value indicates t hat t he alcoholic p art of the lactam (c) maintains its configuration throughout the course of the reaction of the 1,3-oxazep ine-4,7-diones with ammonia derivatives, Scheme 2. Re ferences 1. Huan-M ing Chen and Ramachandra ,S. Hosmane.,(2000), M olecules, 5, M 164. 2. Sternbach, L.H.; Reeder E.; Keller O., and M etlesics hesics W., (1961), J. org. Chem., 26,4488. 3. Hussein, F.A.; M ahmoud M . J. and Tawfiq. M . T., (2006), Al-M ust ansirya J.Sci., 17 (1):42. 4. Hussein, F. A. and Abid ,O.H., (2001), Iraqi Journal of Chemist ry , 27 (3) : 943. 5. Sood, K. Romesh, Bhadti S. Vishweshwar, Huan-M ing Chen and Ramachanrda S. Hosmanre., (2001), M olecules., 6, M 246. 6. Cheesman G. W. H., Green berg S.C., (1979), J. Heterocyclic Chem., 16,241. 7. M orrison R. and Boyed R.(1987)" Organic Chemistry ", 5 th ed., Allyn and Bacon, Inc. New York, P. (874 and 882). 8. John R. Dy er,(1965)"Ap p lication of Absorp tion Sp ectroscop y of Organic Compounds", p rentice –Hill, Inc., London,P.35. C6H5 HC C6H5 CH C H H C O C O (B) (II) CH N C O C6H 5 OC H C O Ar N HC C O (D) Ar CH HC N C6H5 OC C6H5 HC N CO Ar HC CH O H C CH O C O (A) (C) HO C N CH C O Ar N C O A r + Z - NH2 Z - NH2 Z NH2 Z NH Z- H2O Scheme 2 IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 Table :(1) M.F., M.Ps, Yie lds %, and Elemental Analysis of 2-styryl-3-(2,4- dibromophe nyl )-1,2,3-trihydro [1,3]-diazepine-4, 7-dione -1- thi ocarbamide (VIIIf). Table: (2) IR absor ption bands (cm -1 ) of 2-styryl -3- (2,4- dibromophe nyl )- 1,2,3- trihydro [1,3]-diazepine -4, 7-dione-1-thiocarbamide (VIIIf). Table:(3) M.F., m.ps, yields %, and Elemental Anal ysi s of 2-styryl-3-(2,4- dibromophe nyl )-1,2,3-trihydrobenz o [1,2-e][1,3]-diazepine -4,7-dione -1-thi ocarbamide (IXf).&2-styryl-3-(2,4-dibromophe nyl )-1,2,3-trihydro-3-nitrobenz o[1,2,e][1,3]-diazepine- 4,7-dione -1-thi ocarbamide(Xf). Comp. M.F. Color m.p(c ° ) Yield (%) Calc. Found C% H% N% C% H% N% VIIIf C2 0 H15 O2 N3 SBr2 Light y ellow 192-193 68 45.96 2.87 8.04 45.47 2.97 8.41 C o m p . N H s tr . C -H s tr . A ll y li c = C H s tr . V in y li c C -H s tr . A r o m a ti c C = O s tr . Ia ct a m C = S s tr . C = C s tr . V in y li c C = C s tr . A r o m a ti c C -N s tr . N -H b en d. C -H b en d. A ll y li c = C H b en d. C -B r VIIIf 3470Asym . 3345 Sym . 3195 3120 3040 1690 1260 1495 1625 1145 1590 1280 830 575 Comp . M.F. Color m.p(c ° ) Yield (%) Calc. Found C% H% N% C% H% N% IXf C2 4 H17 O2 N3 SBr2 Light brown 170-171 58 50.349 2.97 7.342 50.11 3.11 7.66 Xf C2 4 H16 O4 N4 SBr2 Da rk y ellow 158-159 62 46.67 2.59 9.07 46.59 2.26 9.54 CHCH HC N C N C O OC S NH2 Br Br (VIIIf) CHCH HC N C N C C S H2N Br Br (IX f) O O CHCH HC N C N C C S H2N Br Br N O2 ( Xf) O O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 Table:(4)IR absorption bands (cm -1 ) of 2-styryl -3-(2,4-dibromophe nyl )-1,2,3- trihydrobenz o [1,2-e][1,3]-diazepine -4,7-dione -1-thi ocarbamide(IXf). & 2-S tyryl-3-(2-4-dibromophe nyl )-1,2,3-trihydro-3-nitrobenz o[1,2-e][1,3]-diazepine -4,7- dione -1-thi ocarbamide(Xf). Table:(5) FTIR a bsorption bands (cm -1 ) of 2-S tyryl -3-(2,4-dibromophe nyl )-1,2,3- trihydro-3-nitrobenz o [1,2,e][1,3]-diazepine-4,7-dione -1-thi ocarbamide(Xf) Table:(6) M.F., m.ps, Yields%, Elemental Anal ysi s of 1-Hydroxy-2-styryl-3-(p- ni trophe nyl )-1,2,3-trihydrobenz o[1,2-e][1,3]diazepine -4,7-dione (IXb). & 1-Hydroxy-2- styryl-3-(p-methyl phe nyl )-1,2,3-trihydro-3-nitrobenz o[1,2-e][1,3]diazepine -4,7- dione (Xd). C o m p . N -H s tr . C -H s tr . A ll y li c = C H s tr . V in y li c C -H s tr . A r o m a ti c C = O s tr . Ia ct a m C = S s tr . C = C s tr . V in y li c C = C s tr . A r o m a ti c C -N s tr . C -N O 2 A r o m a ti c N -H b en d . C -H b en d . A ll y li c C is -C H b en d. V in y li c C -B r IXf 3580 Asym . 3480 Sym . 3195 3120 3040 1710 1260 1510 1585 1170 - 1590 1280 830 575 Xf 3585 Asym . 3440 Sym . 3195 3120 3040 1735 1260 1490 1625 1170 1560 ,1360 1630 1280 835 570 C o m p . N -H s tr . C -H s tr . A ll y li c = C H s tr . V in y li c C -H s tr . A r o m a ti c C = O s tr . Ia ct a m C = S s tr . C = C s tr . V in y li c C = C s tr . A r o m a ti c C -N s tr . C -N O 2 A r o m a ti c N -H b en d . C -H b en d . A r o m a ti c. = C H b en d. V in y li c C -H b en d . A ll y li c C -B r A ll y li c Xf 3479 Asym . 3372 Sym . 3168 3145 3112 1733 1255 1493 1559 1153 1537, 1355 1620 830, 790 840 1320 541 Comp. M.F. Color m.p(c ° ) Yield (%) Calc. Found C% H% N% C% H% N% IXb C23 H17O5 N3 Da rk y ellow Ove r 270 64 66.50 4.09 10.12 66.62 3.96 9.74 Xd C24 H19O5 N3 Brown Ove r 270 61 67.13 4.42 9.79 67.31 4.17 9.57 CHCH HC N C N C CH 3 HO NO2 ( Xd) O O CHCH HC N C N C NO 2 HO (IXb) O O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 Table:(7) IR absorption bands (cm -1 ) of 1-Hydroxy -2-styrl-3-(p-ni trophe nyl )-1,2,3- trihydrobenz o [1,2-e][1,3]-diazepine -4,7-dione (IXb). & 1-Hydroxy-2-styrl-3-(p-methylphe nyl )-1,2,3-trihydro-3-nitrobenz o [1,2-e][1,3]diazepine -4,7-dione (Xd) Table:(8) M.F., m.ps, Yie lds% and Elemental Analysis of 1-Amino-2-styryl-3- (p- methylphe nyl)-1,2,3-trihydrobenz o[1,2-e][1,3]-diazepine-4,7-dione(IXd). Comp. M.F. Color m.p(C°) Yield (% ) Calc. Found C% H% N% C% H% N% IXd C24H21O2N3 Light brown Over 270 59 75 .19 5.4 8 10 .96 75.26 5.8 3 10 .6 Table:(9) IR absorption bands (cm -1 ) of 1-Amino-2-styryl -3-(p-methyl phe nyl )-1,2,3- trihydrobenz o[1,2-e][1,3]-diazepine -4,7-dione (IXd) C o m p . N -H s tr . C -H s tr . A ll y li c = C H s tr . V in y li c C -H s tr . A r o m a ti c C -H s tr . C = O s tr . L a ct a m C = C s tr . V in y li c C = C s tr . A r o m a ti c C -N s tr . N -H b en d . C -H b en d . A r o m a ti c C -H b en d . A ll y li c = C H b en d. v in y li c IXd 3530 Asym . 3420 Sym . 3245 3165 3060 2830 1670 1475 1530 1140 1550 840,750 1345 840 Table :(10) FTIR a bsorption bands (cm -1 ) of 1- Amino -2-styryl-3-(p-methylphenyl )- 1,2,3-trihydrobenz o-[1,2-e][1,3]-diazepine-4,7-dione(IXd) C o m p . N -H s tr . C -H s tr . A ll y li c = C H s tr . V in y li c C -H s tr . A r o m a ti c C -H s tr . C = O s tr . L a ct a m C = C s tr . V in y li c C = C s tr . A r o m a ti c C -N s tr . N -H b en d . C -H b en d . A r o m a ti c C -H b en d . A ll y li c = C H b en d . v in y li c IXd 3527 Asym . 3398 Sym . 3255 3178 3064 2825 1676 1488 1552 1147 1565 849, 761 1363 835 C o m p . O -H s tr . C -H s tr . A ll y li c = C H s tr . V in y li c C -H s tr . A r o m a ti c C = H s tr . a li ph a ti c C = O s tr . L a ct a m C = C s tr . V in y li c C = C s tr . A r o m a ti c C -N s tr . C -N O 2 A r o m a ti c C -H b en d . A r o m a ti c C -H b en d . A ll y li c = C H b en d . v in y li c IXb 3570 3195 3120 3040 - 1680 1510 1650 1170 1570, 1350 - 1280 830 Xd 3570 3195 3120 3045 2875 1645 1525 1640 1165 1570, 1340 820, 780 1265 830 CHCH HC N C N C CH 3 H2N ( IXd) O O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL.23 (2) 2010 Table:(11) M.F., m.ps, yi elds% and Elemental Anal ysis of 1-Formamidino -2-styryl-3- (p-methoxyphenyl)-1,2,3-trihydro-3-nitrobezno[1,2-e][1,3]-diazepine-4,7-dione(Xe) Comp. M.F. m.p(C ° ) Yiel d (%) Cal c. Found C% H % N% C% H % N% Xe C25H21O5 N5 Over 270 62 63.69 4.45 14.86 63.75 4.38 15.24 CHCH HC N C N C O CH 3 NO2 HN H 2N (Xe) O O IHJPAS Table: (12) IR absor ption bands (cm -1 ) of 1-Formamidino -2-styryl-3- (p- methoxyphenyl)-1,2,3- trihydro-3-ni trobenzo [1,2-e][1,3] –diazepine -4,7-dione(Xe). C om p . N -H s tr . C -H s tr . A ll y li c = C H s tr . V in y li c C -H s tr . A ro m a ti c C -H s tr . A li p ha ti c C = O s tr . L a c ta m C = C s tr . V in y li c C = C s tr . A ro m a ti c C -O s tr . E th er C -N s tr . C - N o 2 N -H b en d . C -H b en d . A ro m a ti C -H b en d . A ll y li c C i s C -H b en d . V in y li c X e 3540 ,34 0 0 31 75 31 50 3050 2880 17 20 1480 16 30 1135 1150 15 70 , 13 60 1580 825 12 80 835 IHJPAS 2010) 2( 32المجلد مجلة ابن الهیثم للعلوم الصرفة والتطبیقیة -دایازیبین -3، 1-ثالثي ھیدرو -3، 2، 1 –ثالثي التعویض -3، 2، 1تحضیر ).الجزء الثالث( دایونات -7، 4 میسون طارق توفیق، مھند جمیل محمود، فھد علي حسین جامعة ، ابن الھیثم -ة كلیة التربی، الكیمیاءقسم الخالصة ع [e-2,1] [3,1]نتروبنـز -3اوكسـازیبین و – [e-2,1][3,1]بنـز ، اوكسازیبین -3,1تم مفاعلة اوكسـازیبین ـم H2N-Z مشـتقات االمونیـا .. ون -4,7دایـازیبین -3، 1فأعطـت زو -3دایـون و -7,4-بنزودایـازیبین ، داـی -3,1-نتروبـن . دایون على التوالي -7,4-دایازیبین IHJPAS