2011) 1( 24المجلد مجلة ابن الھیثم للعلوم الصرفة والتطبیقیة ارثرواسكوربیك-Dبتیورات لحامض ر مشتقات من الباتحضیر 2010أیلول 15:استلم البحث في 2010تشرین الثاني 9 :قبل البحث في رمیز رسمیة محمود، انباسمة محسن سرح، در مخلصعبد الجبار عبد القا بغداد جامعة ، ابن الهیثم-كلیة التربیة، قسم الكیمیاء لخالصةا ه المشـتقات ذللحصـول علـى هـ.ارثرواسـكوربیكD-تحضیر مشتقات جدیـدة مـن البـاربتیورات لحـامض ا البحثذیتضمن ه مـادة )3(ربیك حـامض االسـكو L-التـي حضـرت مـن تفاعـل ) 4(حـامض االسـكوربیك L--ایزوبروبیلیدینO--6,5تم اختیار C-3 و C-2تمــت اسـترة مجـامیع الهیدروكســیل فـي المواقـع . مـع االســیتون الجـاف بوجـود غــاز كلوریـد الهیـدروجین اولیـة ) 5(التحلـل المـائي للمركـب ). 5(تـم الحصـول علـى المركـب ،اذزیادة من كلورید البنزویل بوجود البیریـدین الجـاف عمالباست ببرایـودات الصــودیوم لینــتج ) 6(بعــدها تمــت اكسـدة المركــب ). 6(اعطــى المركـب ،اذ %)65(حــامض الخلیـك المعباسـت ان تفاعـــل ). 8(ي یتفاعــل مـــع ثنــائي مثیــل المالونـــات بوجــود هیدروكســید البوتاســـیوم لیعطــي المالونــات ذالــ) 7(االلدیهایــد علــى ) 11(و ) 10(و ) 9(د اعطـى المركبــات مــع الیوریــا والثایویوریـا والكوانــدین هایدروكلورایــ) 8(التكـاثف الحلقــي للمركـب . التوالي FT)واطیــاف االشـعة تحـت الحمــراء TLC)( طة كروماتوغرافیـا الطبقـة الرقیقـةاشخصـت المركبـات المحضـرة بوســ IR) نـوويواطیـاف الـرنین ال U.V-Vis)( طة اطیاف االشعة فوق البنفسجیة والمرئیـةاه المركبات تم تشخیصه بوسذوبعض من ه ) ( المغناطیسي 1 HNM R واطیاف كاربون الرنین النووي المغناطیسي).( 13 CNM R .اتنالمالو ، حامض االسكوربیك، ثرواسكوربیكحامض االر ، الباربتیورات :لمفتاحیةاالكلمات IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL. 24 (1) 2011 Synthesis o f Barbiturate Derivatives of D-Erythroascorbic Acid Received in : 15 September 2010 Accepte d in : 9 November 2010 A-J.A. Muk hlis, B. M. Sarhan, R. M. Rumez Departme nt of Chemistry , College of Education- Ibn-Al-Haitham , Unive rsity of Baghdad Abstract The aim of this work is t he sy nthesis of new derivatives of barbiturate of D-ery throascorbic acid. To obtain these derivatives, the 5,6-O-isop rop y lidene-L-ascorbic acid (4) was chosen, which was p repared from the reaction of L-ascorbic acid (3) as a st arting material with dry acetone in the p resence of hy drogen chloride. The esterification of hy droxy l group s at C-2 and C-3 p ositions with excess of benzoy l chloride in dry p y ridine was obtained comp ound (5). Hy drolysis for comp ound (5) in acetic acid (65%) gave the comp ound (6). Oxidation of the p roduct (6) with sodium p eriodate results an Aldehyde (7), which was reacted with dimethy l malonate in the p resence of p otassium hy droxide to give the malonate (8). The cyclocondensation reaction for comp ound (8) with urea, thiourea and guanidine hy drochloride gave the following comp ounds (9), (10) and (11) resp ectively. All these comp ounds were characterised by Thin Layer Chromatography (TLC) and FT IR sp ectra and some were characterised by (U.V-Vis) sp ectra, 1 HNM R sp ectra and 13 CNM R sp ectra. Key words: barbiturate, ery throascorbic acid, ascorbic acid, malonate. Introduction Barbituric acid was discovered in the mid-19th century , with the first medical barbiturate, barbitone (1), being sy nthesized in 1903. Phenobarbitone (2) was introduced as a p harmaceutical in 1912. Therap eutically , these drugs are used as sedatives, anaesthetics and anticonvulsants. Phenobarbitone is also used in the treatment of epilepsy [1]. M ost of the known barbiturate comp ounds p ossess low solubility in water, therefore, researches claimed sy nthesis of new carbohy drate derivatives containing barbiturate,[2],[3] these derivatives have high solubility in water in addition of p ossessing p ossible biological activity . Khalafi-Nezhad et al.[4] p repared barbituric acid derivative from reaction barbituric acid with different aromatic aldehyde on basic alumina was p erformed in a conventional microwave oven in the absence of solvent. Recently , Kidwai et al.[5] reported the p reparation of barbituric acid derivatives by heating reactants with microwave irradiation and confirm all the compounds sy nthesized were found to p ossess good antifungal activity . (1) (2) N N O OO H H C H 2 CH 3 C H 2C H 3 N N O OO C6H 5 H H CH2 CH3 IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL. 24 (1) 2011 Experime ntal M elting p oints were determined by electrothermal Stuart melting p oint app aratus and are uncorrected. IR sp ectra (in KBr) were recorded on Shimadzu FT infrared sp ectrop hotometer. 1 H and 13 CNM R sp ectra were recorded on Ultra Shield (300 M Hz ) sp ectrop hotometer with tetramethy l silane as internal st andard. Electronic sp ectra were obtained using a (U.V-Vis) sp ectrop hotometer ty p e Shimadzu, (160A).Thin layer chromatography (TLC) was p erformed on aluminum p lates coated with lay er of silica gel, sup p lied by M erck. The sp ots were detected by iodine vap or. S ynthesis of 5,6-O-isopropylidene -L-ascorbic acid (4) Dry hy drogen chloride was rapidly bubbled with st irring for 20 minutes into a (250ml) flask containing (10g, 57mmol) of p owdered L-ascorbic acid (3) and (100ml) of dry acetone. Aft er addition of (80ml) n-hexane, st irring and cooling in an ice-water, the sup ernatant was decanted. The p recipitate was washed four times with (154ml) of acetone-hexane mixture (4:7) (v/v), cooling in an ice-water and removal of sup ernatant after each addition. The last p recipitate was dried under reduced p ressure to give (4) (11.7g, 95.35%) as a white cryst alline residue, m.p (206-208˚C). Rf (0.68) (benzene: methanol, 5:5) (v/v). FT IR (KBr, cm -1 ): 3240, 3062 (O-H), 2993 (C-Hali.), 2908 (C-Hac e.), 1751 (C=Olac .), 1662 (C=C), 1431 (-CH-asy m ), 1388 (-CH-sy m ), 1141-900 (C-O), 767 δ(O-H) (O.O.P.). S ynthesis of 2,3-O-dibenzoyl-5,6-O-isopropylidene-L-ascorbic acid (5) To a cold solution of (4) (10g , 46mmol) in p y ridine (50ml), benzoy l chloride was added as drop wise (15ml , 129mmol) with st irring .The resulting mixture was st irred for 2 hours , then kep t in dark p lace at room temp erature for 22 hours. The mixture was p oured into ice-water and st irred for 20 minutes, the sup ernatant was decanted. Extraction with chloroform (150 ml). The chloroform lay er was washed with water, dilute hy drochloric acid (5%) (2 × 100ml.), water, saturated aqueous sodium hy drogen carbonate (100ml) and water. Dried over anhydrous magnesium sulfate. Chloroform was evap orated gave a brown sy rup . The sy rup was p recipitated from chloroform: p etroleum ether (60-80˚C) (1:5) (v/v) to give (5) (15g, 76.5%) as a pale brown solid, m.p (83-85˚C). Rf (0.73) (benzene: methanol, 5:5) (v/v). FT IR (KBr, cm -1 ): 3062 (C-Har .), 2985 (C-Hali.), 2931 (C- Hac e.), 1751 (C=Olac .), 1662 (C=Oest.), 1627 (C=Cali.), 1600 (C=Car .), 1261-1118 (C-O), 900- 600 δ(C-H) (O.O.P.). S ynthesis of 2,3-O-dibenzoyl-L-ascorbic acid (6) Compound (5) (10g , 23.6mmol) was dissolved in (65%) acetic acid (30ml) , absolute methanol (10ml) and st irred for 48 hours at room temp erature. The TLC showed that the reaction was complete (benzene: methanol, 6:4). Benzene (40ml) was added to the solution and evap orated the organic solvent (repeat this p rocess four times).The residue was solid, recry st allized from chloroform and then diethy l ether to y ield (6) (7g, 77.7%) as a white cryst als, m.p (115-116˚C), Rf (0.35). FT IR (KBr, cm -1 ): 3406 (O-H), 3074 (C-Har .), 2939 (C-Hali.), 1716 (C=Oest.), 1600 (C=Car .), 1273-1118 (C-O), 900-600 δ(C-Har .) (O.O.P.). S ynthesis of pentul osono-γ-lactone-2,3-enedibenzoate (7) To the stirred solution of sodium p eriodate (5.6g) in dist illed water (60ml) at (0˚C), a solution of (6) (10g, 26mmo l) in absolute ethanol (60ml) was added drop wise. Aft er 15 minutes, ethy lene glycol (0.5ml) was add ed as drop wise, st irring was continued at room temp erature for 1 hour. The mixture was filtered and water (40ml) was added to the filtrate. Extraction with ethy l acetate (3×50ml), the extracts dried by anhydrous magnesium sulfate. Evap oration and the residue recry st allized from benzene to y ield the p ure p roduct (7) (4g, 44.4%) as a white cryst als, m.p (110-112˚C). Rf (0.63) (benzene: methanol, 6:4) (v/v). FT IR (KBr, cm -1 ): 3080 IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL. 24 (1) 2011 (C-Har .), 2839, 2677 (C-Hald.), 1689 (C=Oald.), 900-600 δ(C-Har .) (O.O.P.). 1 HNM R (CDCl3): δ(4.97) p p m (s, 1H, H4), δ (7.28-8.17) p p m (m, 10H, aromatic), δ(11.4) p p m (br, 1H, CHO.). 13 CNM R (CDCl3): δ(172.44) p p m (C=O), δ(133.83) p p m (C-3), δ(133.47) p p m (C-2), δ(130.23-128.03) p p m (Car .), δ(77.46) p p m (C-4). The signal of aldehydic carbony l was disapp eared due to it which showed out of t he scale.[6] S ynthesi s of 5-C-dimethyl malonyl -pentulose -γ-l actone-2,3-ene dibenz oate (8) The mixture of p otassium hy droxide (1.9g, 34mmol) and dimethy l malonate (3.9ml, 34mmol) was st irred for 30 minutes, a solution of (7) (10g, 28.4mmol) in absolute ethanol (60ml) was added. Aft er st irring for 24 hours at room temp erature, the TLC showed that the reaction was comp lete (benzene: methanol, 4:6) and the resulting mixture was filtered then the solvent was evap orated, the combined residue was washed with chloroform and then p etroleum ether (60- 80˚C) to give (8) (10g, 72.7%) as a white cryst als, m.p (dec.240˚C), Rf (0.65). FT IR (KBr, cm -1 ): 3402 (O-H), 3055 (C-Har .), 2904 (C-Hali.), 1720 (C=Oest.), 1581 (C=Cali.), 1450(C=Car .), 1400-1000 (C-O), 900-600 δ(C-Har .) (O.O.P.). 1 HNM R (DM SO): δ(2.50) p p m (DM SO), δ(2.72) p p m (d, 1H, CH malonate), δ(3.16) p p m (s, 1H, OH), δ(3.56-3.58) p p m (s, 6H, 2CH3 malonate), δ(7.14-8.86) p p m (m, 10H, aromatic). 13 CNM R (CDCl3): δ(168.82) p p m (C=O), δ(135.26) p p m (C-3), δ(131.55) p p m (C-2), δ(129.58,128.40) p p m (Car .), δ(51.63) p p m (C-4), δ(44.67) p p m (C-5), δ(40.78-39.11) p p m (C-6 and carbon 2CH3 malonate). S ynthesi s of pentul ose -γ-l actone-2,3-ene dibenz oate barbituric acid (9) or thiobarbituric acid (10) or azhydrobarbituric acid (11) To the solution of sodium methoxide (30.9mmol of sodium metal dissolved in absolute methanol (20ml)), dry urea or thiourea or guanidine hy drochloride (15.5mmol) was added, st irring at room temp erature for 1 hour. The comp ound (8) (5g, 10.3mmol) in absolute methanol (30ml) was added, st irring was continued at room temperature for 48 hours. T he TLC showed that t he reaction was comp lete (benzene: methanol, 4:6). The solvent was evap orated; the combined residue was washed with hot absolute ethanol to give (9), (10), and (11) resp ectively. The p hy sical p rop erties for p repared comp ounds showed in Table (1). The FT IR, 1 HNM R and 13 CNM R sp ectra data are given in Tables (2), (3) and (4). Results and Discussion L-ascorbic acid (3) is one of the natural antioxidant p resent in biological sy st em because of its activity to att ack the free radicals and other reactive oxy gen sp ecies, as the literatures p oints to the great role which ascorbic acid p lay s to p revent a number of disease and its imp ortance in food industry .[7],[8] One st rategy allows the sy nthesis of comp ounds (9), (10) and (11) in (6) st eps st arting from L-ascorbic acid, scheme (1). The first st ep emp loys the p rotection of the hy droxy l group s at C-5 and C-6 p ositions in L- ascorbic acid with acetal formation leading to comp ound (4) using dry acetone in acidic media, following Salomon[9] method. This is followed by esterification of the hy droxy l group s at C-2 and C-3 p ositions with excess of benzoy l chloride in dry p y ridine. The FTIR sp ectra for comp ound (4) and (5) were confirmed the formation of comp ound (5) by disapp earance of the bands for (O-H) of comp ound (4) and exhibited the band at (1662) cm -1 for (C=O) of the est er in comp ound (5) sp ectrum. In order to p repare aldehyde (7), the acetal moiety was cleaved under acidic condition[10] (65% acetic acid) for comp ound (5) to give (6) and oxidation of the p roduct with sodium p eriodate to result (7), which gave a p ositive Tolen’s test by the formation of a silver mirror.[11],[12] The FTIR sp ectra for compound (6) and (7) confirmed the formation of comp ound (7) by disapp earance of the bands for (O-H) of comp ound (6) and exhibited the band at (1689) cm -1 for (C=O) in compound (7) sp ectrum. The st ructure of (7) was confirmed IBN AL- HAITHAM J. FOR PURE & APPL. S CI. VOL. 24 (1) 2011 by 1 HNM R which exhibited a si gn al at δ(11.4) pp m for (CHO) and was characterised by 13 CNM R and (U.V-Vis) sp ectrum which showed one p eak at (295) nm (33898 cm -1 ) (εm ax = 156 molar -1 cm -1 ) assi gned to (n π*) transition. The other st ep was the formation of comp ound (8) from the reaction of an aldehyde (7) with dimethy l malonate. The FTIR sp ectrum of (8) showed the bands at (3402) cm -1 and (1720) cm -1 due to (O-H) and (C=O) of the ester resp ectively and disap p earance of the band for (C=O) aldehydic. The st ructure of (8) was confirmed by the disapp eared of a signal at δ(11.4) p p m for (CHO) by 1 HNM R and was characterised by 13 CNM R and (U.V-Vis) sp ectrum which showed one peak at (297) nm (33670 cm -1 ) (εm ax = 102 molar -1 cm -1 ) assigned to (n π*) transition. In order to obtain our target comp ounds (9), (10) and (11), the cyclocondensation reaction of malonate (8) with urea, thiourea and guanidine hy drochloride in alkaline media (sodium methoxide) leads to these comp ounds. All FT IR sp ectra for these comp ounds exhibited disapp earance of the band at (1720) cm -1 for (C=O) of the ester for comp ound (8) and disp lay ed of the bands at (1662, 1597, 1643) cm -1 due to (C=O in CHCONH) for comp ounds (9), (10) and (11) resp ectively. The FT IR sp ectra of (9), (10) and (11) showed the bands at (1627) cm -1 , (1153) cm -1 and (1597) cm -1 due to (C=O in HNCONH), (C=S) and (C=N) resp ectively. The st ructures of these comp ounds were confirmed by 1 HNM R and 13 CNM R, which showed disapp earance of the signals at δ(3.56-3.58)p p m and δ(40.78-39.11) p p m from 1 HNM R and 13 CNM R sp ectra for comp ound (8). The (U.V-Vis) sp ectra data are given in Table (5). O O OHHO HO HO (3) O O O OH3C H3C HO OH (4 ) O O O OH3 C H3C (5) OBzBzO O O HO HO (6) OBzBz O O O OBZBZO C H O (7) O O OBZBZO HO HC CO2CH3 CO2 CH3 (8) NHHN OO X O O OBZBZO H O Acetone HCl(g) BzCl Py. AcOH 6 5% NaIO4CH2(CO2CH3)2 KOH Urea or thiourea or guanidine hydro chloride CH3ONa (9), X = O (10), X = S (11), X = NH 1 23 4 5 6 S cheme (1) the scheme of prepared compounds IBN AL- HAITHAM J. FO R PURE & APPL. SCI. VO L.24 (1) 2011 Re ferences 1. Cole, M . D. (2003) “ The Analysis of Controlled Substances”, John Wiley and Sons, Ltd. Chapter 9: 139,140. 2. Al-Qase, A. H. J.(2000) M . Sc. Thesis, College of Education / Ibn-Al-Haitham, University of Baghdad 3. Fay ad,A. A. (2008)Ph. D. T hesis, College of Education / Ibn-Al-Haitham, University of Baghdad 4. Khalafi-Nezhad ,A. and Hashemi,A. (2001) “ M icrowave Enhanced Knoevenagel Condensation of Barbituric Acid with Aromatic Aldehydes on Basic Alumina”, Iran. J. Chem. & Chem. Eng. 20 (1):9-11. 5. Kidwai,M . ; Thakur ,R. and M ohan,R. (2005) “Ecofriendly Sy nthesis of Novel Antifungal (Thio) Barbituric Acid Derivatives” Acta Chim. Slov., 52: 88-92. 6. Carey , F. A. (2006) “Organic Chemistry”, 6 th Ed., the M cGraw-Hill Companies, Inc., New York, p p . 767. 7. Beifuss,U.; Kunz ,O. and Aguado,G. P. (1999) Synlett, 147-149. 8. Beifuss,U. ; Kunz ,O. and Voss, G. (2000 )“Regioselective Sy nthesis of 3-O-Alky l Ethers of Ascorbic Acid without Protecting Group s in a Single Step”, Tetrahedron, , 56:357- 363. 9. Salomon,L. L. (1963) Exp erientia, , 19 (12): 619. 10. Gazivoda,T.; Witt ine, K.; Lovric,I. ; M akuc, D.; Plavec, J.; Cetina, M . ; M rvos-Sermek, D.; Suman,L. ; Kralj,M .; Pavelic, K. ; M intas ,M . and Raic-M alic S. (2006)“Synthesis, st ructural studies, and cytost atic evaluation of 5,6-di-O-modified L-ascorbic acid derivatives”, Carbohy dr. Res., , 341 (4):433-442. 11. Vogel, A. I. (1989) “ Vogel's Textbook of Practical Organic Chemistry ”, 5 th Ed., John Wiley and Sons, Inc., New York, , p p . 1219. 12. Fieser ,L. F. and Williamson,K. L. (1983) “Organic Exp eriments”, 5 th Ed., D. C. Heath and Comp any, the United States of America, , pp . 160-161. Table (1) :Physical propertie s for prepared compounds (9), (10) and (11) Comp . No. Formula M olecular weight (g/mol) Weight of p roduct (g) Yield % M .p ˚C or dec. Physica l state Rf 9 C23H16O10N2 480 3.57 72 210(dec.) White solid 0.52 10 C23H16O9N2 S 496 3 60 225(dec) Yellow solid 0.60 11 C23H17O9N3 479 4.25 86 205(dec.) Pale- y ellow solid 0.33 IBN AL- HAITHAM J. FO R PURE & APPL. SCI. VO L.24 (1) 2011 Table (2): Infrared spectra data ( wa ve number ύ) cm -1 of the compounds (9), (10) and (11) Compound υ(N-H) and υ(O-H) υ(C=O) in (CHCONH, HNCONH) υ(C=N) υ(C-N) υ(C=S) 9 3471(s) 1662(s) 1627(s) - 1346(w) - 10 3383(s) 1597(s) - 1392(s) 1153(m) 11 3421(br) 1643(m) 1597(s) 1334(w) - Where: s = st rong, m = medium, w = weak, br = broad Table (3): 1 HNMR data for the compounds (9), (10) and (11) measured in D2O with tetramethyl silane (TMS ) as internal standard and che mical shift in ppm (δ) Compound Functional group δ(pp m) 9 d, 1H, CH malonate 3 d, 1H, lactone ring H4 4.70-4.78 m, 10H, aromatic 7.25-7.73 10 d, 1H, CH malonate 3 t, 1H, CH-OH 3.22 d, 1H, lactone rin g H4 4.69 m, 10H, aromatic 7.32-7.76 11 d, 1H, CH malonate 3 t, 1H, CH-OH 3.23 d, 1H, lactone rin g H4 4.70-4.78 m, 10H, aromatic 7.34-7.77 IBN AL- HAITHAM J. FO R PURE & APPL. SCI. VO L.24 (1) 2011 Table (4): 13 CNMR data for the compounds (9), (10) and (11) measured in CDCl3 and chemical shift in ppm (δ) Compound Functional group δ(pp m) 9 C=O in HNCONH 177.53 C=O in CHCONH 175.65 C=O in est er, lactone ring 164.53 C-3 136.14 C-2 131.63 C, aromatic 131.24-127.85 C-4 61.24 C-5, C-6 47.85 10 C=O 161.70 C-3 136.00 C-2 131.20 C, aromatic 128.73, 128.25 11 C=NH 177.43 C=O in CHCONH 175.76 C=O in est er, lactone ring 163.31 C-3 136.18 C-2 131.25 C, aromatic 128.75, 128.29 C-4 48.88 C-5, C-6 47.71 Table (5): Electroni c spectra data for the compounds (9), (10) and (11) Compound λm ax nm Wave numb er cm -1 εm ax molar -1 cm -1 Assignment 9 294 34013 66 n π* 10 257 291 38910 34364 140 195 π π* n π* 11 232 297 43103 33670 15 192 π π* n π*