500 Letters in Organic Chemistry, 2011, 8, 500-503 Microwave-Assisted Synthesis of Novel Tetra-O-acetyl--D-glucopyranosyl Thiosemicarbazones of Substituted Isatins Nguyen D Thanh* and Nguyen T.K Giang Faculty of Chemistry, College of Science, Hanoi National University, 19 Le Thanh Tong, Hanoi, Vietnam Received February 08, 2011: Revised April 25, 2011: Accepted April 25, 2011 Abstract: Some new substituted isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazones were synthesized by reaction between 2,3,4,6-tetra-O-acetyl--D-glucopyranosyl thiosemicarbazide and corresponding substituted isatins using conventional and microwave-assisted heating method It is shown that the latter gave higher yields of products Keywords: Glucopyranosyl, isatin, microwave-assisted, monosaccharide, thiosemicarbazide, thiosemicarbazones INTRODUCTION Thiosemicarbazone derivatives of saccharides [1] are interesting because they show significantly biological activities, such as antimicrobial, anti-inflammatory, antioxidant, etc [1, 2] Isatin (indol-2,3-dione) is a resourceful endogenous heterocyclic molecule identified in human being and rat tissues Numerous isatin derivatives exhibit biological activities The mode of action and chemistry of novel representative is the subject of continuous investigation [1–3] and reviews [4, 5] Several of its derivatives were reported to exhibit a wide range of promising pharmacodynamic profile like anticonvulsant [5], anti-HIV [6], cytotoxic, [7] tuberculostatic [8], and anti-microbial [9] At millimolar concentrations, isatin has been found to inhibit different enzymes, an effect that may contribute to its anti-infective actions [10] Isatin has been preferred because during initial screening it has shown activity in the MES test [11] In previous papers, we have synthesized some peracetated glycopyranosyl thiosemicarbazides with several different aromatic carbonyl compounds [12] Based on these findings, we described the synthesis of some compounds featuring monosaccharide moiety fused onto the isatin moiety with the aim of obtaining more potent pharmacologically active compounds We reported here in the preparation of substituted isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazones RESULTS AND DISCUSSION Required 5- and 7-substituted isatins 2a-g were synthesized according to references [13] Seven new substituted isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazones 3a-g were obtained by condensation of 2,3,4,6tetra-O-acetyl--D-glucopyranosyl thiosemicarbazide [12, 14] with corresponding substituted isatins 2a-g in the presence of glacial acetic acid as catalyst (Scheme 1) *Address correspondence to this author at the Faculty of Chemistry, College of Science, Hanoi National University, 19 Le Thanh Tong, Hanoi, Vietnam; Tel: +84-04-38261853; Fax: +84-04-38241140; E-mail: nguyendinhthanh@hus.edu.vn 1570-1786/11 $58.00+.00 We realized that the precursor, tetra-O-acetyl--Dglucopyranosyl thiosemicarbazide 1, could be soluble easily in methanol, ethanol, toluene, benzene or dioxane, but all obtained isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl) thiosemicarbazones 3a-g are hardly soluble in methanol, ethanol, toluene, benzene or dioxane, but easily soluble in DMF, DMSO, they only could be soluble in heating Therefore, reaction reagents were dissolved in hot absolute methanol or ethanol and were irradiated then in microwave reactor for 5–7 At the end of the reaction process the precipitate appeared could be observed The reaction yields were 60–74% Experimental results are given in Table IR spectra of these thiosemicarbazones showed characteristic absorptions in the range of 3359–3335 and 3265– 3167 cm1 (NH bond), 1751–1746, 1227–1216 and 1050– 1037 cm1 (ester), 1375–1372 cm1 (C=S), and 1625–1616 cm1 (C=N bond) The assignments of 1H and 13C were confirmed using HMBC and HSQC methods in case of compound 3a The H NMR spectra of the substituted isatin (2,3,4,6-tetra-O-acetyl-D-glucopyranosyl)thiosemicarbazones 3a-g showed resonance signals in range at = 12.77–12.44 ppm (proton NHb), = 11.99–11.21 ppm (proton NH of isatin), = 9.90–9.52 ppm in doublet with J = 9.5–9.0 Hz (proton NHa), protons in isatin ring have chemical shifts in range at =8.63–6.91 ppm, and protons in glucopyranose ring have resonance signals in range at = 6.06–4.14 ppm Methyl groups in acetate ester have chemical shifts in range at = 2.02–1.93 ppm The anomeric configuration of 3a-g was confirmed on the basis of the coupling constant J1,2 = 9.5 Hz in agreement with the 1,2-trans-diaxial relationships between protons H-1 and H-2 (Table 2) The 13C NMR spectrum of compound 3a-g showed resonance signals at 179.09–178.01 ppm (carbon atom in C=S group), = 169.99–169.11 ppm (carbon atoms in C=O bond of acetyl groups), = 162.49–162.19 ppm (C=O lactam), = 147.73–104.28 ppm (carbon atoms in isatin ring), = 81.89–61.13 ppm (glucopyranose ring) and = 20.71–18.49 ppm (methyl carbons in acetyl groups) [12] In summary, we reported for the first time a microwaveassisted and efficient method for the synthesis of (2,3,4,6tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazones of substituted isatins © 2011 Bentham Science Publishers Microwave-Assisted Synthesis of Novel Tetra-O-acetyl- -D-glucopyranosyl OAc Letters in Organic Chemistry, 2011, Vol 8, No R1 O AcO AcO H N + O H N OAc EtOH, AcOH Conventional or MW heating N H NH2 S R1 OAc O AcO AcO O Ha N OAc S R2 501 3a-g 2a-g R2 Hb N N NH O Scheme Synthetic pathway of substituted isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazones Table Reaction Conditions for Reaction of Substituted Isatin with Tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazide R1 Entry Microwave-assisted heating R2 Conventional heating Yield (%) Reaction time (min) Yield (%) Reaction time (hr) 3a H H 84 74 3b Cl H 82 62 3c Br H 89 69 3d Br Br 89 69 3e NO2 H 80 60 3f Cl NO2 81 61 3g Br NO2 85 65 General Methods for Synthesis of Substituted Isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazones (3a-g) OAc AcO O Ha N AcO OAc Hb N N NH S O Fig (1) Long range proton-carbon connectivity network found in the HMBC spectrum of isatin (2,3,4,6-tetra-O-acetyl--Dglucopyranosyl)thiosemicarbazone 3a; arrows point from H to C; double arrows indicate both H···C correlations MATERIALS AND METHODS Melting points were determined by open capillary method on STUART SMP3 instrument (BIBBY STERILINUK) and were uncorrected IR spectra (KBr disc) were recorded on an Impact 410 FT-IR Spectrometer (Nicolet, USA) 1H and 13C NMR spectra were recorded on Bruker Avance Spectrometer AV500 (Bruker, Germany) at 500.13 MHz and 125.77 MHz, respectively, using DMSO-d6 as a solvent and TMS as an internal standard MS spectra were recorded on mass spectrometer LTQ Orbitrap XLTM (ThermoScientific, USA) using ESI method All the starting benzaldehydes were purchased from commercial suppliers (Merck-Germany) and used with no further purification All other solvents and reagents were used as received or purified by standard protocols Tetra-O-acetyl--glucopyranosyl isothiocyanates were prepared by the reaction of tetra-O-acetyl-glucopyranosyl bromide (prepared from D-glucose) [15] with lead thiocyanate in dried toluene [16] A suspension mixture of (2,3,4,6-tetra-O-acetyl--Dglucopyranosyl)thiosemicarbazide (1 mmol) and substituted isatin (1 mmol) and glacial acetic acid (0.05 mL) in hot absolute methanol or ethanol (5 mL) was irradiated under reflux for 30 minutes in domestic microwave oven [17] After irradiating for 2-3 minutes, the suspension mixture turned into a clear solution The irradiation was continued in given time At the end of reaction process, the precipitate was appeared The reaction mixture was cooled to room temperature; the color precipitate was filtered with suction The crude product was recrystallized from hot 95% ethanol or hot mixture of toluene and ethanol (1:1 in volume) to afford the title compounds of isatin (2,3,4,6-tetra-O-acetyl-D-glucopyranosyl) thiosemicarbazones 3a-g Isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazone (3a) M.p 251–252 °C [] D25 = +34.0 (c = 0.23, CHCl3) IR (KBr): = 3335, 3265 (NH),1750 (C=O ester), 1731 (C=O lac1 tam), 1625 (CH=N), 1373 (C=S), 1225, 1037 (COC ester) H NMR (500.14 MHz, DMSO-d6): = 12.77 (s, 1H, NHb), 11.21 (s, 1H, NH isatin), 9.52 (d, J = 9.0 Hz, 1H, NHa), 7.72 (d, J = 7.5 Hz, 1H, H-4’), 6.94 (d, J = 8.0 Hz, 1H, H-5’), 7.12 (dt, 7.5, 0.5 Hz, 1H, H-6’), 7.39 (dt, J = 7.5,1.0 Hz, 1H, H-7’), 5.99 (t, J = 9.0 Hz, 1H, H-1), 5.33 (t, J = 9.25 Hz, 1H, H-2), 5.44 (t, J = 9.5 Hz, 1H, H-3), 4.98 (t, J = 9.75 Hz, 1H, H-4), 4.14 (dq, J = 9.5, 2.5 Hz, 1H, H-5), 4.23 (dd, J = 12.5, 4.5 Hz, 1H, H-6a), 4.01 (d, J = 12.5, 1.65 Hz, 1H, H6b), 2.01–1.93 (s, 12H, 4CH3 CO) 13C NMR (125.76 MHz, DMSO-d6): = 179.01 (C=S), 169.84–169.21 (4COCH3), 162.44 (C=O lactam), 133.25 (C-3’), 121.24 (C-4’), 119.61 (C-4a’), 111.09 (C-5’), 122.30 (C-6’), 131.66 (C-7’), 142.65 502 Letters in Organic Chemistry, 2011, Vol 8, No (C-7a’), 81.79 (C-1), 70.88 (C-2), 72.68 (C-3), 67.77 (C-4), 72.40 (C-5), 61.13 (C-6), 20.40–20.18 (4CH3 CO) MS (+ESI): m/z (%) = 551.21 (20) [M+H]+, 573.16 (100) [M+Na]+ 5’-Chloroisatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl) thiosemicarbazone (3b) = +40.0 (c = 0.24, CHCl3) IR M.p 202–203 °C (KBr): = 3558, 3259 (NH),1748 (C=O ester),1709 (C=O lac1 tam),1619 (CH=N),1375 (C=S), 1227, 1043 (COC ester) H NMR (500.14 MHz, DMSO-d6): = 12.61 (s, 1H, NHb), 11.32 (s, 1H, NH isatin), 9.67 (d, J = 9.5 Hz, 1H, NHa), 7.82 (s, H-4’), 7.42 (dd, J = 8.5, 1.5 Hz, 1H, H-6’), 6.95 (d, J = 8.0 Hz, 1H, H-7’), 6.03 (t, J = 9.0 Hz, 1H, H-1), 5.32 (t, J = 9.25 Hz, 1H, H-2), 5.46 (t, J = 9.0 Hz, 1H, H-3), 4.99 (t, J = 9.5 Hz, 1H, H-4), 4.19 (d, J = 10.0 Hz, 1H, H-5), 4.24 (dd, J = 12.5, 4.5 Hz, 1H, H-6a), 4.01 (d, J = 11.5 Hz, 1H, H-6b), 2.01–1.93 (s, 12H, 4CH3CO) 13C NMR (125.76 MHz, DMSO-d6): = 179.00 (C=S), 169.99–169.23 (4COCH3), 162.33 (C=O lactam), 132.13 (C-3’), 121.63 (C-4’), 112.69 (C-4a’), 126.60 (C-5’), 130.95 (C-6’), 120.93 (C-7’), 141.37 (C-7a’), 81.86 (C-1), 71.00 (C-2), 72.72 (C-3), 67.68 (C-4), 72.48 (C-5), 61.67 (C-6), 20.53–20.31 (4CH3 CO) MS (+ESI): m/z (%) = 607.03/609.05 (100/40) [M+35Cl]+/ [M+37Cl]+ [] D25 5’-Bromoisatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl) thiosemicarbazone (3c) = +36.0 (c = 0.22, CHCl3) IR M.p 197–198 °C (KBr): = 3343, 3215 (NH), 1746 (C=O ester), 1709 (C=O lactam), 1624 (CH=N), 1372 (C=S), 1216, 1050 (COC ester) H NMR (500.14 MHz, DMSO-d6): = 12.64 (s, 1H, NHb), 11.33 (s, 1H, NH isatin), 9.77 (d, J = 9.0 Hz, 1H, NHa), 7.99 (d, J = 1.5 Hz, 1H, H-4’), 7.54 (dd, J = 8.0, 2.0 Hz, 1H, H6’), 6.91 (d, J = 8.0 Hz, 1H, H-7’), 5.98 (t, J = 9.0 Hz, 1H, H-1), 5.34 (m, 1H, H-2), 5.42–5.35 (m, 1H, H-3), 4.40 (t, J = 9.5 Hz, 1H, H-4), 4.35 (d, J = 9.5 Hz, 1H, H-5), 4.09–4.07 (m, 2H, H-6a & H-6b), 2.01–1.93 (s, 12H, 4CH3CO) 13C NMR (125.76 MHz, DMSO-d6): = 179.09 (C=S), 169.98– 169.35 (4COCH3), 162.19 (C=O lactam), 133.66 (C-3’), 123.82 (C-4’), 122.05 (C-4a’), 114.18 (C-5’), 131.90 (C-6’), 113.07 (C-7’), 141.69 (C-7a’), 82.36 (C-1), 68.64 (C-2), 71.97 (C-3), 67.48 (C-4), 70.72 (C-5), 61.32 (C-6), 20.49– 18.49 (4CH3CO) MS (+ESI): m/z (%) = 650.97/652.94 (100/98) [M+79Br]+/[M+81Br]+ [] D25 5’,7’-Dibromomoisatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazone (3d) = +38.0 (c = 0.20, CHCl3) IR M.p 243–245 °C (KBr): = 3359, 3167 (NH), 1748 (C=O ester), 1688 (C=O lactam), 1616 (CH=N), 1372 (C=S), 1224, 1040 (COC ester) H NMR (500.14 MHz, DMSO-d6): = 12.56 (s, NHb), 11.67 (s, NH isatin), 9.75 (d,J = 9.0 Hz, NHa), 7.96 (s, H-4’), 7.82 (dd, J = 8.5, 1.5 Hz, H-6’), 6.03 (t, J = 9.25 Hz, H-1), 5.32 (t, J = 9.25 Hz, H-2), 5.46 (t, J = 9.25 Hz, H-3), 4.99 (t, J = 9.75 Hz, H-4), 4.19 (d, J = 9.5 Hz, H-5), 4.24 (dd, J = 12.5, 4.5 Hz, H-6a), 4.01 (d, J = 11.5 Hz, H-6b), 2.01–1.93 (4CH3CO) 13C NMR (125.76 MHz, DMSO-d6): = 178.99 (C=S), 169.98–169.19 (4COCH3), 162.33 (C=O lactam), 135.10 (C-3’), 131.67 (C-4’), 114.45 (C-4a’), 104.28 (C-5’), 122.71 (C-6’), 123.51 (C-7’), 141.08 (C-7a’), 81.88 (C-1), 70.99 (C-2), 72.72 (C-3), 67.65 (C-4), 72.50 (C-5), 61.66 (C[] D25 Thanh and Giang 6), 20.53–20.32 (4CH3CO).MS (+ESI): m/z (%) = 728.86/730.83/732.85 (52/100/54) [M+79Br+79Br]+/ 79 81 + 81 81 + [M+ Br+ Br] /[M+ Br+ Br] 5’-Nitroisatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl) thiosemicarbazone (3e) M.p 251–253 °C [] D25 = +45.0 (c = 0.22, CHCl3) IR (KBr): = 3632, 3102 (NH), 1751 (C=O ester), 1710 (C=O lactam), 1626 (CH=N), 1347 (C=S), 1212, 1049 (COC ester) H NMR (500.14 MHz, DMSO-d6): = 12.59 (s, 1H, NHb), 11.83 (s, 1H, NH isatin), 9.90 (d, J = 9.0 Hz, 1H, NHa), 8.63 (d, J = 2.5 Hz, 1H, H-4’), 8.30 (dd, J = 8.5, 2.5 Hz, 1H, H6’), 7.13 (d, J = 9.0 Hz, 1H, H-7’), 6.06 (t, J = 9.25 Hz, 1H, H-1), 5.35 (t, J = 9.25 Hz,1H, H-2), 5.47 (t, J = 9.5 Hz, 1H, H-3), 5.01 (t, J = 9.75 Hz, 1H, H-4), 4.19 (dq, J = 10.0, 2.0 Hz, 1H, H-5), 4.24 (dd, J = 12.5, 5.0 Hz, 1H, H-6a), 4.01 (dd, J = 12.25, 1.75 Hz, H-6b), 2.02–1.93 (s, 12H, 4CH3CO) 13C NMR (125.76 MHz, DMSO-d6): = 178.01 (C=S), 169.93–169.14 (4COCH3), ), 162.88 (C=O lactam), 131.45 (C-3’), 116.69 (C-4’), 120.71 (C-4a’), 142.76 (C-5’), 127.34 (C-6’), 111.30 (C-7’), 147.73 (C-7a’), 81.97 (C-1), 70.94 (C-2), 72.72 (C-3), 67.64 (C-4), 72.53 (C-5), 61.65 (C6), 20.49–20.28 (4CH3CO) MS (+ESI): m/z (%) 593.90 (100) [M–H]+ 5’-Chloro-7’-nitroisatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazone (3f) M.p 256-258 °C [] D25 = +45.0 (c = 0.22, CHCl3) IR (KBr): = 3365, 3101 (NH), 1742 (C=O ester), 1710 (C=O lactam), 1633 (CH=N), 1375 (C=S), 1243, 1041 (COC ester) H NMR (500.14 MHz, DMSO-d6): = 12.44 (s, 1H, NHb), 11.99 (s, 1H, NH isatin), 9.85 (d, J = 9.0 Hz, 1H, NHa), 8.16 (d, J = 2.25 Hz, 1H, H-4’), 8.23 (d, J = 2.25 Hz, 1H, H-6’), 6.05 (t, J = 9.25 Hz, 1H, H-1), 5.31 (t, J = 9.25 Hz,1H, H-2), 5.48 (t, J = 9.5 Hz, 1H, H-3), 5.00 (t, J = 9.75 Hz, 1H, H-4), 4.20 (dq, J = 10.0, 2.0 Hz, 1H, H-5), 4.25 (dd, J = 12.25, 4.75 Hz, 1H, H-6a), 4.02 (d, J = 11.0 Hz, H-6b), 2.01–1.93 (s, 12H, 4CH3CO) 13C NMR (125.76 MHz, DMSO-d6): = 178.96(C=S), 169.90–169.11(4COCH3), 162.60(C=O lactam), 136.60(C-3’), 129.41(C-4’), 125.38(C-4a’), 113.13(C-5’), 126.07(C-6’), 132.01(C-7’), 126.07(C-7a’), 81.87(C-1), 70.97(C-2), 72.64(C-3), 67.61(C-4), 72.50(C-5), 61.60(C-6), 20.71–20.25(4CH3CO) MS (+ESI): m/z (%) = 652.00/653.96 (100/42) [M+35Cl]+/[M+37Cl] + 5’-Bromo-7’-nitroisatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazone (3g) M.p 260–261 °C [] D25 = +45.0 (c = 0.22, CHCl3) IR (KBr): = 3358, 3093 (NH), 1744 (C=O ester), 1720 (C=O lactam), 1627 (CH=N), 1373 (C=S), 1229, 1040 (COC ester) H NMR (500.14 MHz, DMSO-d6): = 12.45 (s, 1H, NHb), 11.99 (s, 1H, NH isatin), 9.86 (d, J = 9.5 Hz, 1H, NHa), 8.27 (s, 1H, H-4’), 8.34 (d, J = 1.5 Hz, 1H, H-6’), 6.05 (t, J = 9.25 Hz, 1H, H-1), 5.32 (t, J = 9.25 Hz,1H, H-2), 5.48 (t, J = 9.5 Hz, 1H, H-3), 5.00 (t, J = 9.5 Hz, 1H, H-4), 4.20 (dq, J = 10.0, 2.0 Hz, 1H, H-5), 4.25 (dd, J = 12.25, 4.75 Hz, 1H, H6a), 4.01 (dd, J = 11.0, 1.5 Hz, H-6b), 2.02–1.93 (s, 12H, 4CH3CO) 13C NMR (125.76 MHz, DMSO-d6): = 178.95(C=S), 169.90–169.11(4COCH3), 162.49(C=O lactam), 136.95(C-3’), 129.32(C-4’), 125.60(C-4a’), 113.13(C5’), 127.02(C-6’), 132.32(C-7’), 128.72(C-7a’), 81.89(C-1), 70.96(C-2), 72.65(C-3), 67.61(C-4), 72.50(C-5), 61.60(C-6), Microwave-Assisted Synthesis of Novel Tetra-O-acetyl- -D-glucopyranosyl Letters in Organic Chemistry, 2011, Vol 8, No 20.48–20.25(4CH3CO) MS (+ESI): m/z (%) = 695.91/ 697.94 (100/98) [M+79Br]+/[M+81Br]+ (b) Verma M.; Pandeya S.N.; Singh K.N.; Stables J.P Anticonvulsant activity of Schiff bases of isatin derivatives Acta Pharm., 2004, 54, 49–56; (c) Sharma P.P.; Pandeya S.N.; Roy R.K.; Anurag; Verma K.; Gupta S Synthesis and anticonvulsant activity of some novel isatin Schiff’s bases Int J ChemTech Res., 2009, 1, 758-763 Pandeya S.N.; Sriram D.; Clercq E.D.E.; Pannecouque C.; Witvrouw M Anti-HIV activity 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Acta Chim Slov., 2010, 466-469 Ghosh S.; Misra A.K.; Bhatia G.; Khan M.M.; Khanna A.K Syntheses and evaluation of glucosyl aryl thiosemicarbazide and glucosyl thiosemicarbazone derivatives as antioxidant and antidyslipidemic agents Bioorg Med Chem Lett., 2009, 19, 386-389 Lemieux R.L In: Methods in Carbohydrate Chemistry; Whistler R.L and Wolfrom M.L., Eds; Academic Press: New York, 1963; Vol 2, pp 221-223 Bama K.G.; Rajani K.B Synthesis, Antimicrobial & antifungal activities of some 2-arylimino-4-(tetra-O-acetyl--Dglucopyranosyl)-4-thiazolidinones Indian J Chem., 1988, 27B, 1157-1159 Nguyen D.T; Nguyen T.T.M Synthesis of N-tetra-O-acetyl--Dglucopyranosyl-N'-(4',6'-diarylpyrimidine-2'-yl)thioureas Carbohydr Res., 2009, 344, 2399-2405 ACKNOWLEDGEMENTS [6] Financial support for this work was provided by Vietnam's National Foundation for Science and Technology Development (Project code: 104.01-2010.50) [7] SUPPLEMENTARY MATERIAL [8] Supplementary material is available on the publishers 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NH O Scheme Synthetic pathway of substituted isatin (2,3,4,6-tetra-O-acetyl--D-glucopyranosyl )thiosemicarbazones Table Reaction Conditions for Reaction of Substituted Isatin with Tetra-O-acetyl--D-glucopyranosyl)thiosemicarbazide