Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 60 Synthesis, Characterization and 1, 3-Dipolar Cycloaddition of Novel Sugar-Derived Nitrones with -ArylmaleimidesMohammed Al-Ghorbani, Usama Al- Timari, Taha Fadhland Shaukath Ara KhanumDepartment of Chemistry, Yuvaraja’s College, University of Mysore, Mysore, Karnataka, INDIA Department of Chemistry, College of health medical technology, Baghdad, IRAQ Department of Chemistry, College of Science and Education University of Aden, YEMENAvailable online at: www.isca.in, www.isca.me Received 28th January 2014, revised 7th February 2014, accepted 12th March 2014Abstract The chiral N-D-ribosylnitrones 5-10 have been synthesized in four steps respectively, in the fourth step, D-ribosyloxime (4) condensed with substituted benzaldehyde in cool condition. The heterocyclization of Z- nitrone 6 with substituted N-arylmaleimide by 1,3-dipolar cycloaddition were afforded new heterocyclic system of isoxazolidine derivatives 11-16 and 11'-16' as a mixture of diastereoisomers, the new isoxazolidines 11-16 have been separated purely and characterized by H NMR, mass spectra and elemental analysis. Keywords: -sugar Nitrone, 1,3-dipolar cycloaddition , isoxazolidines. IntroductionThe utility of nitrones in synthetic organic chemistry has been widely illustrated1-3. Cycloadducts of nitrones are attractive intermediates for the synthesis of several classes of bioactive compounds as well as natural products4–8. The main reactions of nitrones involving such compounds are nucleophilic addition, and 1,3-dipolar cycloaddition to olefins and acetylenes. Both of these processes have been used as key steps in the preparation of diverse target molecules containing nitrogen. The 1,3-dipolar cycloaddition reaction between a nitrone and an olefin gives the isoxazolidine skeleton. Isoxazolidines containing two heteroatoms can be considered as masked forms of several functional group combinations. The introduction of a sugar moiety into nitrone can both improve the solubility of nitrone in water and reduce their toxicity towards living cell. Still the sugar moiety is a most useful chiral moiety in asymmetric chemistry, in view of their potential medicinal significance and pharmaceutical applications, the development of the synthetic procedures and utilities of glycosyl nitrone are of very importance. The stereochemistry of the 5-membered ring depends mainly on configuration of a nitrone and olefin since cycloadditions proceed regiospecifically and lead to the diastereoselective formation of products. The N, O bond of these adducts can be readily cleaved to produce acyclic molecules with stereocontrolled configuration at chirality centers. Here we present a very efficient and stereoselective synthesis of the new nitrones 5-10 and an overview 1,3-dipolar cycloaddition of nitrone 6 to substituted N-arylmaleimides. Material and Methods All the chemicals were purchased from Aldrich Chemical Co. and used without further purification. Melting points were determined on SMP1 melting point apparatus and are uncorrected. All reactions were monitored by thin layer chromatography, which was performed on aluminium-backed silica gel Merck 60 F254 plates, with detection by the exposure to iodine vapour. Column chromatography was performed on silica gel (lachema, 230-400 mesh). The H and 13C-NMR spectra were obtained using a Varian VXR 300 spectrometer at 300 MHz, the chemical shifts are reported in ppm scale. The coupling constants () are given in Hz. The elemental analysis of the compounds was performed on a Perkin Elmer 2400 Elemental Analyzer. Elemental data for C and H were measured within ±0.4% of the theoretical values. General procedure for synthesis of sugar-derived-nitrones (5-10): The nitrones (5-10) were synthesized from D-ribose in four steps. Preparation of D-ribosyloxime (2): Powdered hydroxylamine hydrochloride (20 g, 0.28 mol) in dry methanol 100 ml was neutralized with a sodium methoxide solution (prepared from 20 g sodium and 30 ml methanol). The solution was cooled in an ice-bath, the residue was filtered and washed with dry methanol (50 ml). The methanolic hydroxylamine solution was refluxed in a water-bath and powdered anhydrous D-ribose (30 g, 0.2 mol) was added slowly, the solution was evaporated, dried and recrystallisation from methanol. Preparation of 2,3 -Di-O-isopropylidine--D-ribosyloxime (3): D-ribose oxime (10 g, 60 mmol) was added to a dry acetone 200 ml containing concentrated sulphuric acid 1ml and copper sulphate anhydrous 5 g was added to the solution. The reaction mixture was stirred overnight at RT. When TLC shows completion of the reaction the suspended copper sulphate was removed by filtration. The acetone solution was diluted with Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 61 chloroform (50ml), the chloroform layer was separated, washed with water (30 ml), dried over anhydrous MgSO, and evaporated to dryness. Preparation of 5-O-Acetyl -2,3-di-O-isopropylidine-D-ribosyl oxime (4): 2,3–Di-O–isopropylidine-–D–ribosyloxime (7 g, 34 mmol) was dissolved in dry pyridine 80 ml and cooled to 0 C. A solution of acetic anhydride 1 ml in dry chloroform 70 ml was added at 0C. The reaction mixture was set a side overnight at room temperature. When TLC shows completion of the reaction, the reaction mixture was worked up as above to give pale yellow syrup. Preparation of D-ribose derived nitrones (5-10)10: 5-O-Acetyl-2,3–di-O-isopropylidine--D-ribosyloxime (0.5 g, 2 mmol) was dissolved in absolute ethanol 20 ml and cooled to 10 C with stirring, substituted benzaldehyde (2mmol) dissolved in ethanol and added drop wise during 10-15 min. stirring for (2-4 hr) at room temperature, when TLC shows completion of the reaction, the crude nitrone product was filtered, the solvent was evaporated and the combined crude solids were dried and then crystallized by ethanol. Compound (6) is taken as a representative example to explain characterization data. C-(4-Chlorophenyl)-N-(5-Acetyl-2,3-di-O-isopropylidine-D-ribosyl)-nitrone(6): Yield 60%; mp 114-116 oC; R 0.55;H-NMR (300 MHz, CDCl, ppm): 1.32 (3H, s, CH), 1.54 (3H, s, CH), 2.20 (3H, s, COCH), 3.73 (2H, m, ACOCH,), 4.25 (1H, m, ribosyl), 4.55 (1H, d, ribosyl), 4.60 (1H, d, ribosyl), 5.30 (1H, d, ribosyl), 6.90 (1H, s, N=CH), 7.17-7.28 (m, 4H, Ar-H). Anal. Cal. For C1720ClNO: C, 57.71; H, 5.70; Found C, 57.73; H 5.90%. General procedure for synthesis of N-sugar isoxazolidines (11-16)11: Nitrone (6) (50 mg, 0.13 mmol) was dissolved in dry toluene 25 ml, and the corresponding maleimides (0.13 mmol) were heated at 110C under reflux for 4-7 hr, the reaction mixture, which followed by TLC (CHCl : MeOH, 8:2) to indicate the completion of reaction, was concentrated under vacuum. The resulting syrup residue was purified by column chromatography (chloroform) and then crystallized from chloroform-petroleum ether. Yellow solid crystals were obtained. 2-(5-Acetyl-2,3-di-O-isopropylidine--D-ribosyl)-3-(4-chlorophenyl)-5-phenyl-4,6-dioxo-2,3,3a,4,6,6a-hexahydro-pyrrolo[3,4-d] isoxazole (11): Yield 30%; mp 170-172 oC; R0.60; H-NMR (300 MHz,CDCl, / ppm) 1.32 (3H, s, CH), 1.57 (3H, s, CH), 2.11 (3H, s, COCH), 3.46 (1H, s, isoxazolidine), 3.69 (2H, m, AcOCH), 3.89 (1H, d, isoxazolidine), 4.38 (1H, m, ribosyl), 4.57 (1H, d, ribosyl), 4.63 (1H, d, ribosyl), 4.98 (1H, d, 3a-6a = 7.4Hz, isoxazolidine), 5.32 (1H, d, ribosyl), 7.27-7.88 (9H, m, Ar-H); Anal. Cal. For 2727ClN: C, 61.54; H, 5.16; Found C, 61.44; H, 5.08%. 13C-NMR (300 MHz, CDCl): 26.16 (CH), 26.71 (CH), 50.00 (C-3a), 67.54 (C-3), 75.01 (C-6a), 76.35 (C-3), 77.68 (C-2), 82.50 (C-4), 83.39 (C-5), 105.30 (C-1), 112.44 (C-Me), 122.922, 125.25, 127.37, 127.70, 127.77, 127.81, 128.04, 128.20, 129.01, 129.97, 132.28, 132.35, 132.45, 132.50, 134.29 (aromat.C), 170.00 (C=O), 170.48 (C=O), 174.10 (C=O). 2-(5-Acetyl-2,3-di-O-isopropylidine--D-ribosyl)-3,5-di-(4-chlorphenyl)-4,6-dioxo-2,3,3a,4,6,6a-hexahydro-pyrrolo[3,4-d]isoxazole (12): Yield 35%; mp 125-127 oC; R 0.65; 1H-NMR (300 MHz, CDCl/ ppm): 1.33 (3H, s, CH), 1.55 (3H, s, CH), 2.22 (3H, s, COCH), 3.52 (1H, s,isoxazolidine), 3.70 (2H, m, ACOCH), 3.92 (1H, d, isoxazolidine), 4.25 (1H, m, ribosyl), 4.52 (1H, d, ribosyl), 4.54 (1H , d, ribosyl), 4.90 (1H, d, 3a-6a = 9Hz, isoxazolidine), 5.32 (1H, d, ribosyl), 7.17-7.64 (8H, m, Ar-H); Anal. Cal. For C2726Cl: C, 57.76.; H, 4.67; Found C, 57.72; H, 4.63%. 2-(5-Acetyl-2,3-di-O-isopropylidine--D-ribosyl)-3-(4-chlorphenyl)-5-(2,6-dichlorophenyl)-4,6-dioxo-2,3,3a,4,6,6a-hexahydro-pyrrolo[3,4-d]isoxazole (13): Yield 27%; mp 130-132 oC; R 0.70; H-NMR (300 MHz, CDCl, / ppm): 1.37 (3H, s, CH), 1.58 (3H, s, CH), 2.19 (3H, s, COCH), 3.56 (1H, s, isoxazolidine), 3.87 (2H, m, ACOCH), 3.97 (1H, d, isoxazolidine), 4.25 (1H, m, ribosyl), 4.54 (1H, d, ribosyl), 4.61 (1H , d, ribosyl), 4.90 (1H, d, 3a-6a = 8.7 Hz, isoxazolidine), 5.34 (1H, d, ribosyl), 7.35-7.86 (7H, m, Ar-H); Anal. Cal. For 2725Cl: C, 54.42; H, 4.23; Found C, 54.30; H, 4.20%. 2-(5-Acetyl-2,3-di-O-isopropylidine--D-ribosyl)-3-(4-chlorphenyl)-5-(4-nitrophenyl)-4,6-dioxo-2,3,3a,4,6,6a-hexahydro-pyrrolo[3,4-d]isoxazole (14): Yield 35%; mp 140-143 oC; R 0.75; H-NMR(300 MHz, CDCl, / ppm): 1.29 (3H, s, CH), 1.51 (3H, s, CH), 2.32 (3H, s, COCH), 3.51 (1H, s, isoxazolidine), 3.66 (2H, m, ACOCH), 3.90 (1H, d, isoxazolidine), 4.23 (1H, m, ribosyl), 4.48 (1H, d, ribosyl), 4.61 (1H , d, ribosyl), 5.07 (1H, d, 3a-6a = 8.3, Hz isoxazolidine), 5.34 (1H, d, ribosyl), 7.10-7.57 (8H, m, Ar-H); Anal. Cal. For 2726ClN: C, 56.70; H, 4.58; Found C, 56.57; H, 4.55%. 2-(5-Acetyl-2,3-di-O-isopropylidine--D-ribosyl)-3-(4-chlorphenyl)-5-(4-bromophenyl)-4,6-dioxo-2,3,3a,4,6,6a-hexahydro-pyrrolo[3,4-d]isoxazole (15) : Yield 40%; mp 165-167 oC; R 0.65;H-NMR(300 MHz, CDCl, / ppm): 1.34 (3H, s, CH), 1.49 (3H, s, CH), 2.23 (3H, s, COCH), 3.52 (1H, s, isoxazolidine), 3.65 (2H, m, ACOCH), 3.89 (1H, d, isoxazolidine), 4.36 (1H, m, ribosyl), 4.50 (1H, d, ribosyl), 4.76 (1H , d, ribosyl), 4.76 (1H, d, 3a-6a = 7.8 Hz, isoxazolidine), 5.42 (1H, d, ribosyl), 7.12-7.87 (8H, m, Ar-H); Anal. Cal. For 2726BrClN: C, 53.53; H, 4.33; Found C, 53.57; H, 4.34%. 2-(5-Acetyl-2,3-di-O-isopropylidine--D-ribosyl)–3-(4-chlorphenyl)-5-(4-fluorophenyl)-4,6-dioxo-2,3,3a,4,6,6a-hexahydro-pyrrolo[3,4-d]isoxazole (16): Yield 30%; mp 190-193; R 0.55;H-NMR(300 MHz, CDCl, / ppm): 1.32 (3H, s, CH), 1.55 (3H, s, CH), 2.25 (3H, s, COCH), 3.54 (1H, s, isoxazolidine), 3.56 (2H, m, ACOCH), 3.90 (1H, d, isoxazolidine), 4.26 (1H, m, ribosyl), 4.52 (1H, d, ribosyl), 4.58 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 62 (1H , d, 3a-6a = 8.2 Hz, isoxazolidine), 4.73 (1H, d, ribosyl), 5.37 (1H, d, ribosyl), 7.24-7.68 (8H, m, Ar-H); Anal. Cal. For 2726ClFN: C, 59.51; H, 4.81; Found C, 59.55; H, 4.99 %. Results and Discussion The chiral - sugar derived nitrones 5-10 have been synthesized from protected D-ribosyloxime and substituted benzaldehyde (scheme 1). All nitrones 5-10 have stable crystalline compounds and diastereomerically pure. The structure and configuration of nitrone was determined by the analyses of their spectral data. It has been reported that nitrone has pure product in the Z-configuration, This consideration is in accord with Vasellas results that the N-glycosylaldehydonitrones possess a Z-configuration12-13The structure of nitrone was confirmed by H NMR and mass spectroscopy. The phenyl ring protons are observed as a multiple and (N=CH) proton as singlet with chemical shifts of 7.17-7.28 and 6.90 ppm, respectively. The 1,3-dipolar cycloadditions of -D-ribosylnitrone with -aryl maleimides by refluxing a toluene solution to provide the corresponding cycloadducts, isoxazolidines 11-16 and 11'-16' as a mixture of diastereoisomers have shown in (scheme 2) and the obtained results are presented in (table 1. The structures of isoxazolidines 11-16 were confirmed by H NMR and mass spectroscopy. For example in 11, the isoxazolidine ring protons are observed as singlet, doublet and doublet with chemical shifts of 3.46, 3.89 and 4.98 ppm, 3a-6a= 7.4Hz, respectively. Analysis of11by elemental analysis also conformed. CHO+NAcOCHNHOHAcOCHNHOHHOCHNaOMeHOOHOH N H O H dry MeOHD-RiboseNHOH.ClAcO / Py5, X = H6, X = 4-Cl7, X = 2,6-diCl8, X = 4-NO9, X = 4-Br10, X = 4-F 5 - 1 0 Ac = CHCOAceton / H +anhyd. CuSOScheme-1 Synthesis of nitrones 5-10 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 63 AcOHArCHAcOHArCH11-1611'-16'2'3'4'5'1'3a6a+NAcOCHCldry toluene11, X = H12, X = 4-Cl13, X = 2,6-diCl14, X = 4-NO15, X = 4-Br16, X = 4-FScheme-2 Reaction of nitone 6 with -aryl maleamides The diastereomeric 11'-16' were inability of separating by column chromatography because of extremely unstable and unsuitable for isolation in appreciable chemical purity and yield, which only the preponderant isomers 11-16 were isolated in a pure state. Induction of three asymmetric centers at C, C3a and 6a positions of the newly developed isoxazolidine derivatives have made this synthesis highly attractive. The development of diastereomers can be rationalized by an exo approach of nitrone which has configuration for the formation of major cycloadducts 11-16 exo transition state). The minor cycloadducts 11'-16' has also endo approach of Z-nitrone (endotransition state) (figure 1 . The distinction between the arrangements of H-3, H-3a and H-6a atoms is based on spectroscopic data using the 3-3a and 3a-6a coupling constants. The bridgehead protons H-3a and H-6a, which have always cisarrangement, is indicated by coupling constant 3a-6a = 9Hz. H-NMR analysis of the major isoxazolidines 11-16 indicate that each diastereomer has H-3, H-3a are characteristic for theexo-addition, For example in 12 the signals for the H-6a and H-3a appear as doublets at = 4.90 and 3.92 ppm respectively, with coupling constant at 3a-6a = 9 Hz. In the H-3, H-3a, the proton H-3 and H-3a fails to display coupling since = 90C. This feature of the NMR spectrum is indicating for the formation of major cycloadducts exo-addition14-15 NH A r RibArArArRib e x o e n d o Figure-1 Two possible N-arylmaleimides approaches to nitrone 6 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 64 Figure-2 H-NMR spectra of compound 6 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 65 Figure-3 H-NMR Spectra of compound 11 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 66 Figure-4 13CNMR spectra of compound 11 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(3), 60-67, March (2014) Res. J. Chem. Sci. International Science Congress Association 67 Conclusion A series of novel isoxazolidine derivatives 11-16 were synthesized by 1,3- dipolar cycloaddition of nitrone 6 with N-arylmaleimide substituted and characterized by H NMR, mass spectroscopy and elemental analysis. The development of diastereomers can be rationalized by an exo approach of nitrone 6 which has Z-configuration for the formation of exo addition as a pure major cycloadducts 11-16. References1.Tufariello J., In 1,3- Dipolar Cycloaddition Chemistry, John Wiley & Sons: New York., , 9 (1984) 2.Colacino E., Nun P., Colacino F.M., Martinez J and Lamaty F., Solvent-free synthesis of nitrones in a ball-mill, Tetrahedron, 64, 5569–5576, (2008) 3.Bloch R., Addition of organomatallic reagents to C=N bonds: reactivity and selectivity, Chem. Rev, 98, 1407–1438, (1998)4.Chunsheng C., Zhinian L., Jinyan S., Tao L. and Baoyan Z., Synthesis of isoxazolidines by 1,3-dipolar cycloaddition and their bioactivity, Front. Chem. 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