Chemistry - 254 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Synthesis and Characterization of Some Amides Containing Isoxazoline Ring Kh. F. Ali , Dh. F Hussein and J. H. Tomma Department of Chemistry , College of Education Ibn Al- Haitham University of Baghdad , Baghdad – Iraq . Received in : 8 May 2012 Accepted in : 7 August 2012 Abstract This work involves synthesis of amides containing isoxazoline unit starting with chalcone; 4-[3-(3‾-nitrophenyl)-2-propene- 1-one]-aniline[I]. 4-Aminoacetophenone was reacted with 3-nitrobenzaldehyde in basic medium giving chalcone [I] by claisen-schemidt reaction. The chalcone [I] was reacted with hydroxylamine hydrochloride giving isoxazoline [II] in NaOH basic medium. The amides with structural formula [III]a-h were prepared by the reaction of amino compounds ; isoxazoline [II] with different acid chlorides in dry pyridine and using DMF as a solvent at 40C. All the synthesized compounds have been characterized by melting points , FTIR and 1HMNR (of compound [III]a) spectroscopy. Key words: isoxazoline , amides Introduction Chalcones constitute an important class of natural products belonging to the flavonoid family , which have been reported to possess a wide spectrum of biological activities[1,2]. Chalcones are also key precursors in the synthesis of many biologically important heterocycles. The classical synthesis of the isoxazolins involves the base-catalyzed condensation of substituted aromatic ketone and substituted aldehydes to give α,β-unsaturated ketones (chalcone), which on cyclization with hydroxylamine hydrochloride in alkaline medium give the corresponding isoxazoline derivatives[3-5]. Isoxazoline derivative remains a main focus of medicinal chemists, due to their diverse pharmacological activity. Isoxazoline derivatives have been reported to possess a good biological activity [3,6-9]. The amides containing heterocyclic unit show good antibacterial activity [10,11] . Depending on the above finding , we decided to synthesize novel amides derived from aromatic amine containing isoxazoline unit. Experimental Materials : All the chemicals were supplied from Merck , 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(S), 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. General procedures Chemistry - 255 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 New amides [III]a-g were synthesized according to Scheme 1. Preparation of (chalcone) 4-[3-(3`-nitrophenyl)-2-propene- 1-one]-aniline [I] Equimolar quantities of 4-amino acetophenone (0.01mol) and 3- nitrobenzaldehyde (0.01mol) were dissolved in 5mL of alcohol. Sodium hydroxide solution (0.02 mol) was added slowly and the mixture becomes cold. Then the mixture was poured slowly into 400mL of ice water with constant stirring and kept in refrigerator for 24 hrs [12] .The precipitate obtained was filtered ,washed and recrystallized from chloroform . C H O NH2CCH3 CH NH2CCH O N NH2 NH2OH . HCl O OH Scheme 1 NO2 NO2 O NO2 [I] [II] R= CH3, C2H5, C3H7, C4H9, C7H15, Ph , p-CH3OC6H4- or p-CH3OC6H4CO2C6H4- O N NHCOR NO2 [III] RCOCl Py DMF NaOH Synthesis of 4-[5-(3`-nitrophenyl)-4,5-dihydroisoxazol-3-yl ] aniline [II] A mixture of chalcone[I] (0.02mol), hydroxylamine hydrochloride (1.39gm , 0.02mol) and sodium hydroxide solution (0.5gm NaOH in 25mL of water) in ethanol (60mL) was refluxed for 6hrs. The mixture was concentrated under vaccum and poured into ice water . The precipitate obtained was filtered , washed and recrystallized from ethanol [13] . Synthesis of 3-(4-substituted phenylamido)-5-(3`- nitrophenyl)-4,5-dihydroisoxazol. [III]a-h. 2-Amino-1,3,4-oxadiazoles [III] (0.001mol) was dissolved in 5ml of dry pyridine . The different acid chlorides ( 0.0022mol) were added slowly. The mixture was stirred for 3hrs at 4 0C . The reaction mixture was poured into 50 ml of 10% HCl , the solid which separated was filtered , washed well with water , dried in air , recrystalized from ethyl acetate .The physical properties were listed in Table 1 Chemistry - 256 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Results and discussion The chalcones [I] is synthesized by claisen-schmidt condensation of 4-amino acetophenone and 3-nitrobenzaldehyde by base catalyzed followed by dehydration to yield the desire chalcones. The mechanism of this reaction may be outlined as follows [14]. H2N C CH2 H OH H2OH2N C CH2 O O + NO2 C CH2N C CH2 O H O CH CH2 NH2 OO NO2 CH2 CH2 C NH2 OO CH CH2 C NH2 OH O OH NO2NO2 H2O CH C NH2 OH O -H2O CH CH C NH2 OH CH NO2NO2 scheme 2 The structural assignments of the chalcones [I] based on melting points and FTIR spectroscopy. The FTIR spectrum , Figure 1 indicated the appearance of two bands at 3425cmˉ¹ and 3221cmˉ¹ which could be attributed to asymmetric and symmetric stretching vibration of NH2 group,a week band at 3086cmˉ¹ due to stretching vibration of (=C-H) group, Three peaks at 1651cmˉ¹ , 1632cmˉ¹ 1608cmˉ¹ due to of C=O , C=C (CH=CH) and C=C(aromatic) stretching vibrations,respectively. This compound [II] was synthesized from the reaction of chalcones [I] with hydroxylamine hydrochloride in alkaline medium , the mechanism of this reaction may be outlined as follows [15] . Chemistry - 257 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 O NH2 NH2OH O NH2 NH2 O NH2 O NH2 O NH2 NO CH2 NH2 NO OHCH2 H -H2O O N NH2 [C] H [D] [A] [B] H O2NO2N O2N O2N O2N O2N Scheme 3 CH CH2 C CH C P.T CH C [E] CH CH C CH CH C Proton Transfer H O The structure of the isoxazoline [II] have been characterized by melting point and FTIR. The FTIR spectra of isoxazoline [II] ,Figure 2 showed the disappearance of two absorption bands of the CH=CH and C=O group in the starting material [I] together with appearance of new absorption bands for C=N and C-O (cyclic ether) groups around 1610 cmˉ¹ and 1178 cmˉ¹, respectively . The new amides [III] were synthesized by reaction aromatic primary amine [II] and different acid chlorides ( aliphatic or aromatic ) in dry DMF and pyridine at low temperature . These amides were identified by their melting points , FTIR and ¹HNMR spectroscopy . FTIR absorption-spectra as in Figure 3 of compound [III]c showed the disappearance of absorption bands due to NH2 group of the starting materials together with appearance of new absorption bands in the region (3390-3302)cmˉ¹ and (1685-1660)cmˉ¹ which is assigned to NH and C=O (amid) stretching, respectively. The other data of functional groups which are characteristic of these compounds are given in Table 2. 1HMNR spectrum of compound [III]a , Figure 4 showed the following signals: eight aromatic protons appeared as multiplet in the region δ 6.90-8.8 ppm , a singlet signal at δ 9.9 ppm that could be attributed to NH proton. One proton of CH(isoxazoline) appeared as doublet at δ 6.32-6.38 ppm while the two protons of CH2 of isoxazoline appears as doublet of doublet at δ4.17-4.28ppm , three protons singlet appears at δ 2.02 ppm that are attributed to CH3 group . Chemistry - 258 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 References 1-Vays, K.; Nimavat, K.; Jani, G. and Hathi,M., (2009) , “ Synthesis and Antimicrobial Activity of Coumarin Derivatives Metal Complexes An in Vitro Evaluation” , Orbital , 1(2) : 183-192. 2- Dawne, B.; Konda, Sh.; Shaikh, B. and Bhosale, R., (2009) , “ Animproved procedure for synthesis of some new 1,3-diaryl-2-propen-1-ones using PEG-400 as a recyclable solvent and their antimicrobial evaluation ” ,Acta Pharm. , 59 :473-482. 3- Swamy ,P. and S. Agasimundin , Y. (2008) “ Synthesis and Antimicrobial Screening of Certain Substituted Chalcones and Isoxazolines bearing Hydroxy benzofuran” , Rasayan J. Chem, 1(2) : 421- 428. 4- Al-Issa , S. and Hattab, A.A. ,(2008) ,“ Comparative study-reaction of 2`-Hydroxy chalcones with Hydroxyl amine Hydrochloride in different reaction medium”, J. Saudi Chem. Soc., 12(4) : 537-542. 5- Sharma, P. ; Sharma, S. ; Singh ,S. and Suresh , B. (2009) “ Synthesis of Some New Isoxazoline Derivatives” , as Possible Anti-Candida Agents ” , Acta Poloniae Pharmaceutica- Drug Research, 66(1) : 101-104. 6- Desai, J.; Desai, C. and Desai, K., (2008) ,“ A convenient , Rapid and Eco- Friendly Synthesis of isoxazoline Heterocyclic Moiety Containing Bridge at 2°- Amine as Potential Pharmaological Agent ” , J. Iran. Chem. Soc., 5(1) : 67- 73. 7- Singhal, M. ; Verma, B.; Jhala, Y. and Dulawat, S., (2005) , “ An efficient synthesis of some new fluorine containing acetyl pyrazoline and isoxazole derivatives and their antibacterial activity ” , Indian J. Heterocycl. Chem., 14 :343. 8- Prajapati, A.; Bardia, R. ; Rao, T. and Verma, V. , (2007) , “An efficient synthesis of some new fluorine containing acetyl pyrazoline and isoxazole derivatives and their antibacterial activity” , J. Inst. Chemists , 79 : 7 . 9- Caramella, P. and Gruenanger , P.,(1984), “1,3-Dipolar Cycloaddition Chemistry” , (Ed.), Vol. 1, Padwa, A., Wiley Interscience, New York , 337. 10- Zareef , M.; Iqbal , R. ; Mirza , B.; Kham, K.; Manan , A.; Asim , F. and Kan, Sh. , (2008), “ Synthesis and Antimicrobial Activity of Some Derivatives of Acylhydrazine Including Novel Benzendiazasulfonamides ” , ARKIVOC ,(ii) : 141-152. 11- Kushwaha, N.; Saini, R. and Kushwaha, S. (2011) “ Synthesis of Some Amid Derivatives and Their Biological Activity ” , International J. of Chem Tech Research , 3(1) : 203-209. 12- Kalirajan , R.; Sivakumar , S.; Jubie , S. ; Gowramma, B. and Suresh, B. (2009) “ Synthesis and Biological Evaluation of Some Heterocyclic Derivatives of Chalcones” , International J. of Chem Tech Research , 1(1) : 27-34. 13- Abd El-Fattah, O .; Fathalla , M.; Kassem , E. ; Ibrahem N. and Kamel , M. (2008) “Synthesis and anticancer of some new quinazolin-4-one derivatives and evaluation Chemistry - 259 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 of their antimicrobial and Anti-inflammatory effects” ,Acta Poloniae Pharm-Drug Res. ,65(1) :11-20. 14- Carey , F. (2006) “Organic Chemistry” Sixth Edition , University of Virginia . 15- Shah ,T. and Desai , V. (2007) “Synthesis and antibacterial studies of some novel Schiff isoxazoline derivatives ” , J.Serb. Chem. So.,72(5) : 443-449. Table(1): The physical properties of new compounds [III] and compounds [IV]. Com p No. Nomenclature Structural formula Molecular formula M. P 0C Yiel d % Color [III]a 3-(4- methylbenzamido)- 5-(3`-nitrophenyl)- 4,5-dihydroisoxazol O N O2N NHCOCH3 C17H15N3 O4 140 86 Pale yello w [III]b 3-(4- ethylbenzamido)-5- (3`-nitrophenyl)-4,5- dihydroisoxazol O N O2N NHCOC2H5 C18H17N3 O4 gumm y 75 yello w [III]c 3-(4- propylbenzamido)-5- (3`-nitrophenyl)-4,5- dihydroisoxazol O N O2N NHCOC3H7 C19H19N3 O4 145 69 yello w [III]d 3-(4- butylbezamido)-5- (3`-nitrophenyl)-4,5- dihydroisoxazol O N O2N NHCOC4H9 C20H21N3 O4 118- 120 84 brown [III]e 3-(4- heptylbenzamido)-5- (3`-nitrophenyl)-4,5- dihydroisoxazol O N O2N NHCOC7H15 C23H27N3 O4 152 68 Glow yello w [III]f 3-(4- phenylbenzamido)- 5-(3`-nitrophenyl)- 4,5-dihydroisoxazol O N O2N NHCO C22H17N3 O4 120 80 Pale yello w [III]g 3-[4-(4`-ansoyl)- benzamido]-(3`- nitrophenyl)-4,5- dihydroisoxazol O N O2N NHCO OCH3 C23H19N3 O5 85-88 86 yellow [III]h 3-{4-[4`- (4 ̏ - ansoyl)-Carboxy phenyl]- benzamido}-5-(3`- nitrophenyl)-4,5- dihydroisoxazol O NO2N NHCO OCH3CO2 C30H23N3 O7 220- 222 89 yello w Chemistry - 260 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Table (2): Characteristic FTIR absorption bands of amides [III]a-h. Comp. No. νNH νC-H aliph νC=O amid νC=N endocyc. νC=C arom. νC-O endocyc. νNO2 [III]a 3320 2931-2854 1684 1630 1599 1092 1530,1317 [III]b 3315 2965-2874 1670 1625 1597 1082 1524,1310 [III]c 3302 2959-2872 1666 1622 1597 1098 1530,1312 [III]d 3365 2954-2889 1660 1625 1599 1090 1530,1310 [III]e 3319 2955-2895 1665 1628 1600 1094 1524,1314 [III]f 3339 2955-2895 1670 1634 1601 1099 1528,1319 [III]g 3381 2920-2846 1680 1620 1606 1120 1510,1319 [III]h 3390 2965-2900 1685 1624 1600 1116 1515,1318 Fig. (1) : FTIR spectrum of chalcone [I] Chemistry - 261 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Fig. (2) : FTIR spectrum of compounds [II] Fig. (3) : FTIR spectrum of compound [III]c Chemistry - 262 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 Fig.(4) : 1HNMR spectrum of compound [III]a Chemistry - 263 مجلة إبن الهيثم للعلوم الصرفة و التطبيقية 2012 السنة 25 المجلد 3 ددالع Ibn Al-Haitham Journal for Pure and Applied Science No. 3 Vol. 25 Year 2012 تحضير وتشخيص بعض االميدات تحوي على حلقة االيزوكسازولين ضحى فاروق حسين ، جمبد هرمز توما ،خالد فهد علي قسم الكيمياء ، كلية التربية ابن الهيثم ، جامعة بغداد 2012آب 7قبل البحث في 2012آيار 8في : ملتسا ثحبلا الخالصة نيتروفنيل - 3(-3[-4حتوي على حلقة االيزوكسازولين باستخدام جديدة تضمن هذا البحث تحضير اميدات يت نايتروبنزالديهايد -3أمينو اسيتوفينون َمع - 4] من تفاعلI[a,bمادة اساسية ، يحضر الجالكون انلين ك ]اون-1-بروبين-2-) ] مع هايدروكسيل أمين هايدروكلورايد مؤديا الى a,b]Iشمدت. يتفاعل الجالكون -في وسط قاعدي بواسطة تفاعل كاليسين ة الغير متجانسة ] من تفاعل مركبات االمين الحلقيIII[ a-h] .حضرت االميدات الجديدة IIتكوين مشتقات االيزوكزازولين [ ثنائي مثيل فورماميد البيريدين الجاف وباستخدام ] مع كلوريدات الحوامض الكاربوكسيلية المتنوعة في IIايزوكزازولين [ .0C 4عند درجة حرارة شخصت جميع المركبات المحضرة في هذا البحث من خالل قياس درجات أنصهارها باالضافة الى الطرق a[III]. للمركب المتمثلة بطيف األشعة تحت الحمراء وطيف الرنين النووي المغناطيسي البروتوني الطيفية االيزوكزولين و االميدات الكلمات المفتاحية :