IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.23 (2) 2010 Synthesis of 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 Department of Chemistry, College of Education Ibn AL-Haitham University of Baghdad Abstract 1,3- Oxazepines, benz [1,2-e] [1,3]-oxazepines, and 3- nitrobenz [1,2-e] [1,3] - oxazepines were reacted with ammonia derivatives, H2N-Z .. to give 1,3 – diazepine -4,7- dione, benzodiazepine - 4,7- dione, and 3 – nitrobenzo -1,3- diazepine - 4,7- dione, respectively. Introduction The starting imidazole diester [1] reacts with guanidine hydrochloride to yield 1,3- diazepine derivatives [2] (1): The reaction of 1- ( 2 -aminomethylphenyl) pyrrole hydrochloride [3] with carbonyl compounds gives diazepines [4] in a ring closure reaction(2) Compound[4] was oxidized by manganes dioxide in toluene to give 4H- pyrrolobenzodiazepine [5] (2). Me O O O O N N H Me H2N H N N O O N N H .. . . .. .. . . . . Guanidine.HCI MeONa,MeOH R.T.48hrs HCI(IM) [1] [2] dimethyl-2-phenyl 1H-imidazole-4,5- dicarboxylate. 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. SCI. VOL.23 (2) 2010 Many of the diazepines show interesting sedatives, muscle relaxant, and anticonvulsant properties in animals (2). Several clinical useful drugs were found which contain a hetrocyclic moity fused onto the seven membered ring, like pyrrolobenzodiazepines which are now accessible by several routes (2). Aim of the work Synthesis new diazepines derivatives which are expected to have a biological activity in the medical field. Experimental Part Material and Solvents: 1. 1,3-Oxazepine -4,7- diones (II),(III) and (IV) prepared as part 1 (3). 2. Ammonia derivatives H2N-Z. 3. Dry benzene (Merck 99). 4. Ethanol (Merck 99.7-100). 5. Dioxane. The instruments: 1. Melting points were determined with: Strut Melting point Apparatus and were uncorrected. 2. IR. Spectra were recorded with: PYE UNICAM SP3-300 Infrared Spectrophotometer (KBr disc) in the range (4000-200)cm -1. 3. FTIR Spectra, Were recorded with: SHIM ADZU FTIR-8400S Infrared Spectrophotometer (KBr disc). 4. Elemental Analysis (C.H.N.) was carried with: Perkin Elmer B-240 Elemental Analyzer. Experimental: Synthesis of :2- styryl -3- aryl -1,2,3-trihydro [1,3]- diazepine - 4,7- dione -1- thiocarbamide (VIIIf) , 2 – styryl – 3 – aryl - 1,2,3, - trihydrobenzo [1,2-e] [1,3] –diazepine - 4,7- dione -1- thiocarbamide (1Xf), 1- Hydroxy - 2- styryl-3-(p-nitrophenyl) - 1,2.3 – trihydrobenzo [1,2-e] [1,3] – diazepine - 4,7- dione (1Xb) ,1-amino -2- styryl -3- (p- methylphenyl) - 1,2,3 - trihydrobenzo [1,2-e] [1,3] - diazepine 4,7-dione (1Xd), 2 – styryl -3- N N R1 R2 [4] .. N +NH2 Cl R1 R2 .. oxi. [5] R1 = CCl3, C6H5-CH=CH2, CH3, C2H5,CH3CO,CO2C2H5 R2 = H,CH3,CO2C2H6 IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.23 (2) 2010 (2,4-dibromophenyl) - 1,2,3 – trihydrobenzo -[1,2-e] [1,3] – diazepine - 4,7 – dione - 1- thiocarbamide (1Xf), 1- hydroxy -2- styryl -3- (p-methylphenyl) - 1,2,3-trihydro -3- nitrobenzo [1,2-e] [1,3] – diazepine - 4,7-dione (Xd) ,1- formamidino-2- styryl -3- (p- methoxyphenyl) - 1,2,3 – trihydro -3- nitrobenzo [1,2-e][1,3]- diazepine-4,7-dione (Xe), 2- styryl -3- (2,4-dibromophenyl)-1,2,3- trihydro -3- nitrobenzo [1,2-e][1,3]-diazepine -4,7- dione -1- thiocarbamide (Xf). A mixture of (0.0015 mole) of 2-styryl -3- aryl -2,3- dihydro [1,3]-oxazepine -4, 7- dione (II) and (0.0015 mole) of thiourea (or guanidine hydrochloride + Na2CO3) suspended in (20 mL) of dry benzene (or absolute ethanol) was heated and refluxed in water bath for 3hrs, the solvent was evaporated leaving light yellow crystals of 2-styryl -3- aryl-1,2,3-trihydro [1,3]-diazepine -4,7- dione-1-thiocarbamide (VIII) filtered and recrystallized from dioxane. This experiment was repeated by using other 1,3-oxazepines with ammonia derivatives in order to obtain different diazepine derivatives (IX) and (X). Discussion In a previous paper (3) synthesis of 1,3 - oxazepine - 4, 7- dione (II) benzo [1,2- e][1,3]- oxazepine -4,7- dione (III) and 3- nitrobenzo [1,2-e][1,3] oxazepine-4,7- dione (IV) was described. These oxazepines were found to be good starting compounds for the synthesis of another class of heterocylic compounds (4) by the reaction with ammonia derivatives H2N-Z as shown below(4,5,6): IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.23 (2) 2010 The mechanism (7) involves the addition of the amine to the carbonyl group of the lactone forming the dipolar intermediate (A) which undergoes cleavge to give another dipolar intermediate (B). Intermediate (B) undergoes hydrogen transfer from nitrogen to oxygen to give the open chain hydroxyl amide (C) in which both maintain their configuration throughout the course of the reaction that permits the elimination of H2O and the reclosure of the structure to give 1,3-diazepine-4, 7-dione (D). O C O (II) O C O C O C O (III) O C O C O (IV) NO2 (X) (IX) N C O C O Br C O C O (VIII) C O C O Br NO2 C6H5 - CH = CH - CH N Ar C6H5 - CH = CH CH N Ar C6H5 - CH = CH CH N Ar C6H5 - CH = CH - CH N Ar C6H5 - CH = CH CH N Ar C6H5 - CH = CH CH N Ar Z - N H2N - Z Where Z = -OH (hydroxyl amino), - NH2 (hydrazine), -CSNH2 (thiourea), and -C(NH)NH2(guanidine). Ar = CH3 , OCH3 , NO2 , Scheme 1 Z- Z-N C N Ar H and Ar CH OH O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. SCI. 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 spectra (tables 2,4,5,7,9,10,12). It is noticeable that the IR spectra of the expected products show the appearance of (NH, OH) absorption bands at (3580,3320)cm -1, respectively (8). This value indicates that the alcoholic part of the lactam (c) maintains its configuration throughout the course of the reaction of the 1,3-oxazepine-4,7-diones with ammonia derivatives, Scheme 2. References 1. Huan-Ming Chen and Ramachandra ,S. Hosmane.,(2000), Molecules, 5, M164. 2. Sternbach, L.H.; Reeder E.; Keller O., and Metlesics hesics W., (1961), J. org. Chem., 26,4488. 3. Hussein, F.A.; Mahmoud M. J. and Tawfiq. M. T., (2006), Al-Mustansirya J.Sci., 17 (1):42. 4. Hussein, F. A. and Abid ,O.H., (2001), Iraqi Journal of Chemistry, 27 (3) : 943. 5. Sood, K. Romesh, Bhadti S. Vishweshwar, Huan-Ming Chen and Ramachanrda S. Hosmanre., (2001), Molecules., 6, M246. 6. Cheesman G. W. H., Green berg S.C., (1979), J. Heterocyclic Chem., 16,241. 7. Morrison R. and Boyed R.(1987)" Organic Chemistry", 5 th ed., Allyn and Bacon, Inc. New York, P. (874 and 882). 8. John R. Dyer,(1965)"Application of Absorption Spectroscopy 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 C6H5 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 Ar + Z - NH2 Z - NH2 Z NH2 Z NH Z- H2O Scheme 2 IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.23 (2) 2010 Table :(1) M.F., M.Ps, Yields %, and Elemental Analysis of 2-styryl-3-(2,4- dibromophenyl)-1,2,3-trihydro [1,3]-diazepine-4, 7-dione -1- thiocarbamide (VIIIf). Table: (2) IR absorption bands (cm-1) of 2-styryl -3- (2,4- dibromophenyl)- 1,2,3- trihydro [1,3]-diazepine -4, 7-dione-1-thiocarbamide (VIIIf). Table:(3) M.F., m.ps, yields %, and Elemental Analysis of 2-styryl-3-(2,4- dibromophenyl)-1,2,3-trihydrobenzo [1,2-e][1,3]-diazepine-4,7-dione-1-thiocarbamide (IXf).&2-styryl-3-(2,4-dibromophenyl)-1,2,3-trihydro-3-nitrobenzo[1,2,e][1,3]-diazepine- 4,7-dione-1-thiocarbamide(Xf). Comp. M.F. Color m.p(c°) Yield (%) Calc. Found C% H% N% C% H% N% VIIIf C20H15O2N3SBr2 Light yellow 192-193 68 45.96 2.87 8.04 45.47 2.97 8.41 C om p . N H s tr . C -H s tr . A ll yl ic = C H s tr . V in yl ic C -H s tr . A r om at ic C = O s tr . Ia ct am C = S s tr . C = C s tr . V in yl ic C = C s tr . A r om at ic C -N s tr . N -H b en d. C -H b en d. A ll yl ic = 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 C24H17O2N3SBr2 Light brown 170-171 58 50.349 2.97 7.342 50.11 3.11 7.66 Xf C24H16O4N4SBr2 Dark yellow 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 (IXf) O O CHCH HC N C N C C S H2N Br Br NO2 (Xf) O O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.23 (2) 2010 Table:(4)IR absorption bands (cm -1) of 2-styryl -3-(2,4-dibromophenyl)-1,2,3- trihydrobenzo [1,2-e][1,3]-diazepine-4,7-dione-1-thiocarbamide(IXf). & 2-Styryl-3-(2-4-dibromophenyl)-1,2,3-trihydro-3-nitrobenzo[1,2-e][1,3]-diazepine-4,7- dione-1-thiocarbamide(Xf). Table:(5) FTIR absorption bands (cm-1) of 2-Styryl -3-(2,4-dibromophenyl)-1,2,3- trihydro-3-nitrobenzo [1,2,e][1,3]-diazepine-4,7-dione-1-thiocarbamide(Xf) Table:(6) M.F., m.ps, Yields%, Elemental Analysis of 1-Hydroxy-2-styryl-3-(p- nitrophenyl)-1,2,3-trihydrobenzo[1,2-e][1,3]diazepine-4,7-dione(IXb). & 1-Hydroxy-2- styryl-3-(p-methylphenyl)-1,2,3-trihydro-3-nitrobenzo[1,2-e][1,3]diazepine-4,7- dione(Xd). C om p . N -H s tr . C -H s tr . A ll yl ic = C H s tr . V in yl ic C -H s tr . A r om at ic C = O s tr . Ia ct am C = S s tr . C = C s tr . V in yl ic C = C s tr . A r om at ic C -N s tr . C -N O 2 A r om at ic N -H b en d . C -H b en d . A ll yl ic C is -C H b en d. V in yl ic 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 om p . N -H s tr . C -H s tr . A ll yl ic = C H s tr . V in yl ic C -H s tr . A r om at ic C = O s tr . Ia ct am C = S s tr . C = C s tr . V in yl ic C = C s tr . A r om at ic C -N s tr . C -N O 2 A r om at ic N -H b en d . C -H b en d . A r om at ic . = C H b en d. V in yl ic C -H b en d . A ll yl ic C -B r A ll yl ic 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 H17O5N3 Dark yellow Over 270 64 66.50 4.09 10.12 66.62 3.96 9.74 Xd C24 H19O5N3 Brown Over 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 NO2 HO (IXb) O O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.23 (2) 2010 Table:(7) IR absorption bands (cm -1) of 1-Hydroxy -2-styrl-3-(p-nitrophenyl)-1,2,3- trihydrobenzo [1,2-e][1,3]-diazepine-4,7-dione(IXb). & 1-Hydroxy-2-styrl-3-(p-methylphenyl)-1,2,3-trihydro-3-nitrobenzo [1,2-e][1,3]diazepine-4,7-dione(Xd) Table:(8) M.F., m.ps, Yields% and Elemental Analysis of 1-Amino-2-styryl-3- (p- methylphenyl)-1,2,3-trihydrobenzo[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 5.48 10 .96 75.26 5.83 10 .6 Table:(9) IR absorption bands (cm -1) of 1-Amino-2-styryl -3-(p-methylphenyl)-1,2,3- trihydrobenzo[1,2-e][1,3]-diazepine-4,7-dione(IXd) C om p . N -H s tr . C -H s tr . A ll yl ic = C H s tr . V in yl ic C -H s tr . A r om at ic C -H s tr . C = O s tr . L ac ta m C = C s tr . V in yl ic C = C s tr . A r om at ic C -N s tr . N -H b en d . C -H b en d . A r om at ic C -H b en d . A ll yl ic = C H b en d. vi ny li c IXd 3530 Asym. 3420 Sym. 3245 3165 3060 2830 1670 1475 1530 1140 1550 840,750 1345 840 Table :(10) FTIR absorption bands (cm -1) of 1-Amino -2-styryl-3-(p-methylphenyl)- 1,2,3-trihydrobenzo-[1,2-e][1,3]-diazepine-4,7-dione(IXd) C om p . N -H s tr . C -H s tr . A ll yl ic = C H s tr . V in yl ic C -H s tr . A r om at ic C -H s tr . C = O s tr . L ac ta m C = C s tr . V in yl ic C = C s tr . A r om at ic C -N s tr . N -H b en d . C -H b en d . A r om at ic C -H b en d . A ll yl ic = C H b en d . vi ny li c IXd 3527 Asym. 3398 Sym. 3255 3178 3064 2825 1676 1488 1552 1147 1565 849, 761 1363 835 C om p . O -H s tr . C -H s tr . A ll yl ic = C H s tr . V in yl ic C -H s tr . A r om at ic C = H s tr . al ip h at ic C = O s tr . L ac ta m C = C s tr . V in yl ic C = C s tr . A r om at ic C -N s tr . C -N O 2 A r om at ic C -H b en d . A r om at ic C -H b en d . A ll yl ic = C H b en d . vi ny 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 CH3 H2N (IXd) O O IHJPAS IBN AL- HAITHAM J. FOR PURE & APPL. SCI. VOL.23 (2) 2010 Table:(11) M.F., m.ps, yields% and Elemental Analysis 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 (%) Calc. 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 OCH3 NO2 HN H2N (Xe) O O IHJPAS Table: (12) IR absorption bands (cm-1) of 1-Formamidino -2-styryl-3- (p- methoxyphenyl)-1,2,3- trihydro-3-nitrobenzo [1,2-e][1,3] –diazepine -4,7-dione(Xe). C om p . N -H s tr . C -H s tr . A ll yl ic = C H s tr . V in yl ic 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 ac ta m C = C s tr . V in yl ic 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 yl ic C i s C -H b en d . V in yl ic X e 3540 ,340 0 3175 3150 3050 2880 1720 1480 1630 1135 1150 1570 , 1360 1580 825 1280 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