Microwave-assisted synthesis of acetophenone (per-O-acetylated-β-D-glucopyranosyl)-thiosemicarbazones

Article abstract of DOI:10.1155/2010/760180

Thirteen new substituted acetophenone (2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)- thiosemicarbazones (3) were synthesized by reaction of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl thiosemicarbazide (1) and substituted acetophenones (2). The reaction was pe

Full text of DOI:10.1155/2010/760180

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2010, 7(3), 899-907
http://www.e-journals.net
Microwave-Assisted Synthesis of Acetophenone
(per-O-acetylated- -D-glucopyranosyl)-
thiosemicarbazones
β
NGUYEN DINH THANH*, NGUYEN THI KIM GIANG and LE THE HOAI
Faculty of Chemistry,
College of Science, Hanoi National University,
19 Le Thanh Tong, Ha Noi 10000, Viet nam.
nguyendinhthanh@hus.edu.vn
Received 3 November 2009; Accepted 2 January 2010
Abstract−Thirteen new substituted acetophenone (2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-thiosemicarbazones (3) were synthesized by reaction of
2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl
thiosemicarbazide
(1)
and
substituted acetophenones (2). The reaction was performed using microwave-
assisted method. The compounds (3) have remarkable antibacterial and
antifungal activities against Escherichia coli, Staphylococcus epidermidis and
Candida albicans.
Keywords: Glucopyranosyl thiosemicarbazide, Thiosemicarbazones, Microwave-assisted method,
Acetophenone.
Introduction
Thiosemicarbazones are a class of small molecules that have been evaluated over the
last 50 years as antivirals and as anticancer therapeutics, as well as for their parasiticidal
action against Plasmodium falciparum and Trypanasoma cruzi which are the causative
agents of malaria and Chagas’s disease, respectively1. The chemistry of
thiosemicarbazide derivatives of saccharides is interested2-4. These compounds arouse
interest as versatile intermediates for preparing various (e.g., heterocyclic) derivatives
as well. Thiosemicarbazones can be used for making electrodes5, or complexes
formation of metallic ions6. Thiosemicarbazones exhibit various biological activities
such as antituberculosis7, antimicrobial8, anti-inflammatory9, antiviral, anticonvulsant10,
antihypertensive11, local anesthetic12, anticancer13, hypoglycemic14 and cytotoxic
activities, among others15.

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N. DINH THANH et al.
A number of glucosyl thiosemicarbazide derivatives showed significant in vivo anti-
microorganisms and in vitro antioxidant activity, which could be used as leads for the
development of effective anti-atherosclerotic agents16. On the other hand, these molecules
can also serve as phosphane-free multidentate ligands for transition-metal catalysis and they
are efficient ligands for palladium-catalyzed coupling reactions in air17. In the past, some
papers have been published for the synthesis of aldehyde/ketone 4-(per-O-acetylated-β-D-
glucopyranosyl)-thiosemicarbazones and their corresponding deacetylated analogues18. The
main synthetic step for the synthesis of these molecules is being the reaction of a glucosyl
thiosemicarbazide with a carbonyl compound.
Continuing our studies on the synthesis and the reactivity of peracetated
glycopyranosyl isothiocyanates and thiosemicarbazides19, we report here a systematic study
for the synthesis and spectral characterization of a series of aromatic ketone 4-(
glucopyranosyl)-thiosemicarbazones using microwave-assisted method20.
β-D-
Experimental
All the starting materials and reagents were purchased from commercial suppliers and used after
further purification. 2,3,4,6-Tetra-O-acetyl- -D-glucopyranosyl isothiocyanate was prepared by
the reaction of per-O-acetylated-
-D-glucopyranosyl bromide (prepared from D-glucose)21a with
lead thiocyanate in dried toluene21b and 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl thiosemicarbazide
were synthesized by known method18b,22
β
β
.
Physical measurements
Melting points were determined by open capillary method on STUART SMP3 instrument
(BIBBY STERILIN-UK) and are 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 solvent and TMS as an internal standard. The chemical
shifts are expressed in δ ppm scale down field from TMS and proton signals are indicated as
s = singlet, d = doublet, t = triplet and m = multiplet. HRMS spectra were recorded on mass
spectrometer AutoSpec Premier (WATERS, USA) using EI 70 eV.
General procedure for synthesis of substituted acetophenone 2,3,4,6-tetra-O-acetyl-
β
-D-glucopyranosyl thiosemicarbazones (3a-m)
A suspension mixture of (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazide 1
(1 mmol) and corresponding substituted acetophenone 2 (1 mmol) and glacial acetic acid
(0.05 mL) in absolute methanol (5 mL) was irradiated with reflux for 5-7 minutes in
microwave oven. The suspension mixture became clear solution after irradiating in 3-4
minutes. After reaction the mixture was cooled to room temperature, the colorless
crystals were filtered with suction. The crude product was recrystallized from ethanol or
ethanol/toluene to yield corresponding acetophenone (2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-thiosemicarbazones 3.
4-Nitroacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-thiosemicarbazone (3a)
White solid, mp 217-218 °C; yield 77%;
−58.0 (c 1.0, CHCl3); IR (KBr, cm−1): 3354,
1
3318, 1744, 1229.0, 1034, 1370, 1582; H NMR (DMSO-d6): 11.01 (s, 1H, H-2”), 8.81
δ
(d,1H, J=9.0 Hz, H-4”), 8.22 (m. 4H, H-2’ & H-6’, H-3’ & H-5’), 5.95 (t, 1H, J=9.25
Hz, H-1), 5.45 (t, 1H, J=9.5 Hz, H-3), 5.35 (t, 1H, J=9.25 Hz, H-2), 4.98 (t, 1H, J=9.5 Hz,
H-4), 4.22 (dd, J=12.25, 4.75 Hz, 1H, H-6a), 4.10 (ddd, J=9.95, 4.75, 2.25 Hz, 1H, H-5), 3.99

Microwave-Assisted Synthesis of Thiosemicarbazones
901
(dd, J=12.25, 2.5 Hz, 1H, H-6b), 2.39 (s, 3H, CH3C=N), 1.99-2.01 (s, 12H, 4×CH3CO); 13C
NMR (DMSO-d6): 179.7 (C=S), 169.3-169.9 (4×C=O), 147.6 (C=N), 147.1 (C-4’), 143.5
δ
(C-1’), 127.9 (C-3’ & C-5’), 123.2 (C-2’ & C-6’), 81.4 (C-1), 70.8 (C-2), 72.5 (C-3), 72.2
(C-5), 68.0 (C-4), 61.7 (C-6), 20.2-20.4 (4×CH3CO), 14.3 (CH3C=N); HRMS: 568.1432
(M+), calcd. for C23H28N4O11S=568.1475 Da.
3-Nitroacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-thiosemicarbazone (3b)
White solid, mp 196-197 °C, lit.18e mp 184-186 °C; yield 78%;
IR (KBr, cm−1): 3325, 3246, 1749.0, 1372, 1617, 1226, 1045; 1H NMR (DMSO-d6):
−78.0 (c 1.0, CHCl3);
10.98
δ
(s, 1H, H-2”), 8.77 (d, 1H, J=9.0 Hz, H-4”), 8.56 (s, 1H, H-2’), 8.44 (d, J=8.0 Hz, 1H, H-4’),
8.27 (t, J=7.5 Hz, 1H, H-6’), 7.71 (t, J=8.0 Hz, 1H, H-5’), 5.94 (t, 1H, J=9.0 Hz, H-1), 5.44
(t, 1H, J=9.5 Hz, H-3), 5.29 ( t, 1H, J=9.0 Hz, H-2), 4.98 (t, 1H, J=9.5 Hz, H-4), 4.22 (dd,
J=12.5, 5 Hz, 1H, H-6a), 4.09 (ddd, J=7, 3.75, 2 Hz, 1H, H-5), 4.00 (dd, J=11.25, 1.5 Hz,
1H, H-6b), 2.41 (s, 3H, CH3C=N), 1.95-2.00 (s, 12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ
179.6 (C=S), 169.3-169.9 (4×C=O), 148.1 (C-3’), 147.6 (C=N), 139.1 (C-1’), 133.0 (C-2’),
129.7 (C-4’), 123.9 (C-6’), 121.3 (C-5’), 81.4 (C-1), 72.4 (C-3), 72.2 (C-5), 70.8 (C-2), 68.0
(C-4), 61.7 (C-6), 20.3-20.5 (4×CH3CO), 14.5 (CH3C=N); HRMS: 568.1316 (M+), calcd. for
C23H28N4O11S=568.1475 Da.
4-Chloroacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-thiosemicarbazone(3c)
White solid, mp 199-201 °C; yield 85%;
1
−86.5 (c 1.0, CHCl3); IR (KBr, cm−1): 3323, 3298,
1749.0, 1614, 1370, 1225, 1098; H NMR (DMSO-d6): δ 10.83 (s, 1H, H-2”), 8.67 (d, 1H,
J=9.25 Hz, H-4”), 7.97 (t, 2H, J=8.6 Hz, H-2’ & H-6’), 7.47 (d, 2H, J=8.6 Hz, H-2’ & H-6’),
5.93 (t, 1H, J=9.0 Hz, J1,2=9.25 Hz, H-1), 5.43 (t, 1H, J=9.5 Hz, H-3), 5.31 (t, 1H, J=9.25 Hz,
J=9.5 Hz, H-2), 4.97 (t, 1H, J=9.75 Hz, H-4), 4.21 (dd, J=12.25, 4.75 Hz, 1H, H-6a), 4.07 (ddd,
J=10, 4.75, 2.25 Hz, 1H, H-5), 3.99 (dd, J=12.25, 2.25 Hz, 1H, H-6b), 2.32 (s, 3H, CH3C=N),
1.94-2.00 (s, 12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ 179.4 (C=S),169.3-169.9 (4×C=O),
148.5 (C=N), 136.1 (C-4’), 134.3 (C-1’), 128.6 (C-3’ & C-5’), 128.2 (C-2’ & C-6’), 81.3 (C-1),
72.5 (C-3), 72.1 (C-5), 70.8 (C-2), 68.0 (C-4), 61.7 (C-6), 20.2-20.5 (4×CH3CO), 14.3
(CH3C=N); HRMS: 557.1230/559.1209 (M+), calcd. for C23H28ClN3O9S=557.1235/559.1205 Da.
4-Bromoacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazone(3d)
White solid, mp 205-206 °C, lit.18e mp 186-88 °C; yield 90%;
−98.7 (c 1.0, CHCl3); IR
(KBr, cm−1): 3354, 3318, 1749.0, 1602, 1373, 1230, 1041; 1H NMR (DMSO-d6):
10.84 (s,
δ
1H, H-2”), 8.67 (d, 1H, J=9.0 Hz, H-4”), 7.88 (d, 2H, J=8.3 Hz, H-2’ & H-6’), 7.59 (d, 2H,
J=8.3 Hz, H-2’ & H-6’), 5.94 (t, 1H, J=9.0 Hz, J1,2=9.0 Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-
3), 5.32 (t, 1H, J=9.0 Hz, J=9.1 Hz, H-2), 4.98 (t, 1H, J=9.5 Hz, H-4), 4.22 (dd, J=12.25,
4.75 Hz, 1H, H-6a), 4.08 (ddd, J=10, 5.75, 2 Hz, 1H, H-5), 3.99 (d, J=11.5 Hz, 1H, H-6b),
2.32 (s, 3H, CH3C=N), 1.95-2.00 (s, 12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ 179.4
(C=S), 169.3-169.9 (4×C=O), 148.5 (C=N), 136.5 (C-4’), 131.1 (C-3’ & C-5’), 128.8 (C-2’
& C-6’), 123.1 (C-1’), 81.3 (C-1), 72.5 (C-3), 72.2 (C-5), 70.8 (C-2), 68.0 (C-4), 61.7 (C-6),
20.3-20.5 (4×CH3CO), 14.2 (CH3C=N); HRMS: 601.0568/603.0494 (M+), calcd. for
C23H28BrN3O9S=601.0729/ 603.0709 Da.
Acetophenone (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-thiosemicarbazone(3e)
White solid, mp 208-209 °C; yield 77%;
1
−45.5 (c 1.0, CHCl3); IR (KBr, cm−1): 3354,
3318, 1743, 1620, 1371, 1234, 1039; H NMR (DMSO-d6): δ 10.81 (s, 1H, H-2” ), 8.63 (d,
1H, J=9.5 Hz, H-4”), 7.93 (m, 2H, H-2’ & H-6’), 7.42 (m, 3H, H-3’, H-4’ & H-5’), 5.94

902
N. DINH THANH et al.
(t, 1H, J=9.5 Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-3), 5.31 (t, 1H, J=9.5 Hz, H-2), 4.98 (t, 1H,
J=9.87 Hz, H-4), 4.21 (dd, J=12.0, 5.0 Hz, 1H, H-6a), 4.07 (ddd, J5,4=9.87, 4.75, 2.25 Hz,
1H, H-5), 4.00 (dd, J=11.25, 2.5 Hz, 1H, H-6b), 2.34 (s, 3H, CH3C=N), 1.99-2.00 (s, 12H,
4×CH3CO); 13C NMR (DMSO-d6):
δ 179.3 (C=S), 169.-169.9 (4×C=O), 149.7 (C=N), 137.6
(C-1’), 129.5 (C-4’), 128.2 (C-2’ & C-6’), 126.7 (C-3’ & C-5’), 81.3 (C-1), 72.4 (C-3), 72.1
(C-5), 70.7 (C-2), 68.1 (C-4), 61.8 (C-6), 20.2-20.5 (4×CH3CO), 14.4 (CH3C=N); HRMS:
523.1556 (M+), calcd. For C23H29N3O9S=523.1624 Da.
4-Methylacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazone(3f)
White solid, mp 200-201 °C; yield 83%;
3305, 1748, 1600, 1378, 1225, 1039; 1H NMR (DMSO-d6):
−66.4 (c 1.0, CHCl3); IR (KBr, cm−1): 3356,
δ
10.76 (s, 1H, H-2”), 8.59 (d, 1H,
J=9.3 Hz, H-4”), 7.82 (d, 2H, J=8.2 Hz, H-2’ & H-6’), 7.23 (d, 2H, J=8.1 Hz, H-2’ & H-6’),
5.93 (t, 1H, J=9.3 Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-3), 5.30 (t, 1H, J=9.3 Hz, H-2), 4.98 (t,
1H, J=9.5 Hz, H-4), 4.21 (dd, J=12.5, 5 Hz, 1H, H-6a), 4.19 (dd, J=12.25, 2.25 Hz, 1H, H-6b),
4.06 (ddd, J5,4=10.0, 4.75, 2.25 Hz, 1H, H-5), 2.32 (s, 3H, CH3C=N), 2.31 (s, 3H, ArCH3),
1.99-2.00 (s, 12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ 179.2 (C=S), 169.3-169.9 (4×C=O),
149.8 (C=N), 139.3 (C-1’), 134.5 (C-4’), 128.8 (C-2’ & C-6’), 126.7 (C-3’ & C-5’), 81.2 (C-
1), 72.5 (C-3), 72.1 (C-5), 70.7 (C-2), 68.1 (C-4), 61.8 (C-6), 20.8 (ArCH3), 20.2-20.8
(4×CH3CO), 14.3 (CH3C=N); HRMS: 537.1770 (M+), calcd. for C24H31N3O9S=537.1781 Da.
4-Methoxyacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazone (3g)
White solid, mp 190–191 °C, lit.18f mp 192-198 °C; yield 78%;
(KBr, cm−1): 3390, 3332, 1745, 1608, 1378, 1223, 1038;1H NMR (DMSO-d6):
−48.0 (c 1.0, CHCl3); IR
10.73 (s, 1H,
δ
H-2”), 8.58 (d, 1H, J=9.0 Hz, H-4”), 7.89 (d, 2H, J=8.9.0 Hz, H-2’ & H-6’), 6.95 (d, 2H,
J=8.9.0 Hz, H-3’ & H-5’), 5.93 (t, 1H, J=9.5 Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-3), 5.30 (t, 1H,
J=9.5 Hz, H-2), 4.98 (t, 1H, J=9.5 Hz, H-4), 4.21 (dd, J=12.5, 5.0 Hz, 1H, H-6a), 4.06 (ddd,
J=10.0, 4.75, 2.0 Hz, 1H, H-5), 3.99 (dd, J=12.5, 2.0 Hz, 1H, H-6b), 3.81(s, 3H, OCH3), 2.30
(s, 3H, CH3C=N), 1.99-2.00 (s, 12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ 179.0 (C=S),
&
169.3-169.9 (4×C=O), 160.5 (C4’), 149.7 (C=N), 129.6 (C1’), 128.4 (C2’ & C6’), 113.6 (C3’
C5’), 81.2 (C1), 72.5 (C3), 72.1 (C5), 70.8 (C2), 68.1 (C4), 61.8 (C6), 55.2 (OCH3), 20.3-20.5
(4×CH3CO), 14.2 (CH3C=N); HRMS: 553.1712 (M+), calcd. for C24H31N3O10S=553.1730 Da.
4-Ethoxyacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-thiosemicarbazone(3h)
White solid, mp 184-185 °C; yield 86%;
1604, 1374, 1227, 1039; 1H NMR (DMSO-d6):
−79.2 (c 1.0, CHCl3); IR (KBr): 3375, 3318, 1748,
10.71 (s, 1H, H-2”), 8.58 (d, 1H, J=9.5 Hz, H-
δ
4”), 7.87 (d, 2H, J=8.9.0 Hz, H-2’ & H-6’), 6.94 (d, 2H, J=8.9.0 Hz, H-2’ & H-6’), 5.94 (t, 1H, J
=9.5 Hz, J1,2=9.2 Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-3), 5.31 (t, 1H, J=9.3 Hz, J=9.5 Hz, H-2),
4.99 (t, 1H, J=9.5 Hz, J=9.75 Hz, H-4), 4.21 (dd, J=12.5, 5.0 Hz, 1H, H-6a), 4.07 (ddd,
J5,4=10.25 Hz, J=6.5 Hz, J=2.5 Hz, 1H, H-5), 4.05 (q, 2H, J=7.0 Hz, OCH2), 3.40 (dd, J=12.25,
2.25 Hz, 1H, H-6b), 1.34 (t, 3H, J=7.0 Hz, OCH2CH3), 2.30 (s, 3H, CH3C=N), 1.99-2.01 (s,
12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ 179.0 (C=S), 169.9-169.3 (4×C=O), 159.8 (C-4’),
149.7 (C=N), 129.5 (C-1’), 128.3 (C-3’ & C-5’), 114.0 (C-2’ & C-6’), 81.3 (C-1), 72.5 (C-3),
72.2 (C-5), 70.8 (C-2), 68.1 (C-4), 63.2 (OCH2CH3), 61.8 (C-6), 20.5–20.2 (4×CH3CO), 14.5
(CH3C=N), 14.2 (OCH2CH3); HRMS: 567.1885 (M+), calcd. for C25H33N3O10S=567.1887 Da.
3-Nitro-4-methylacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-
thiosemicarbazone (3i)
White solid, mp 223-224 °C; yield 81%;
−67.3 (c 1.0, CHCl3); IR (KBr, cm−1): 3325, 3246,

Microwave-Assisted Synthesis of Thiosemicarbazones
1621, 1748, 1370, 1222, 1046; 1H NMR (DMSO-d6):
903
δ
10.92 (s, 1H, H-2”), 8.73 (d, 1H, J=9.1
Hz, H-4”), 8.35 (d, J=1.5 Hz, 1H, H-2’), 8.20 (d, J=8.0 Hz, 1H, H-5’), 7.54 (d, J=8.0 Hz, 1H, H-
6’), 5.92 (t, 1H, J=9.2 Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-3), 5.28 (t, 1H, J=9.25 Hz, H-2), 4.98 (t,
1H, J=9.5 Hz, H-4), 4.22 (dd, J=12.25, 4.75 Hz, 1H, H-6a), 4.08 (ddd, J=9.0, 3.5, 2.25 Hz, 1H,
H-5), 4.01 (dd, J=11.5, 2.0 Hz, 1H, H-6b), 2.65 (s, 3H, ArCH3), 2.52 (s, 3H, CH3C=N), 1.95-2.01
(s, 12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ 179.5 (C=S), 169.3-169.9 (4×C=O), 149.5 (C-3’),
147.5 (C=N), 136.6 (C-1’), 133.2 (C-2’), 132.5 (C-6’), 130.8 (C-4’), 121.9 (C-5’), 81.4 (C-1),
70.7 (C-2), 72.4 (C-3), 72.2 (C-5), 68.1 (C-4), 61.7 (C-6), 20.3-20.5 (4×CH3CO), 18.8 (ArCH3),
14.3 (CH3C=N); HRMS: 582.1663 (M+), calcd. for C24H30N4O11S=582.1632 Da.
3-Nitro-4-methoxyacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-
thiosemicarbazone (3j)
White solid, mp 222-223 °C; yield 77%;
1
−78.6 (c 1.0, CHCl3); IR (KBr, cm−1): 3340,
1747, 1617, 1379, 1226, 1037; H-NMR (DMSO-d6): 10.85 (s, 1H, H-2”), 8.71 (d, 1H,
δ
J=9.0 Hz, H-4”), 8.33 (d, J=2.5 Hz, 1H, H-2’), 8.21 (dd, J=8.75, 2.25 Hz, 1H, H-6’), 7.37
(d, J=9.0 Hz, 1H, H-5’), 5.90 (t, 1H, J=9.0 Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-3), 5.27 (t,
1H, J=9.25, H-2), 4.97 (t, 1H, J=9.75 Hz, H-4), 4.22 (dd, J=12.25, 4.75 Hz, 1H, H-6a), 4.06
(ddd, 1H, J=10.0 Hz, 4.75 Hz, 2.25 Hz, H-5), 3.99 (d, 1H, J=11.0 Hz, 2.0 Hz, 1H, H-6b),
3.97 (s, 3H, OCH3), 2.33 (s, 3H, CH3C=N), 1.98-2.00 (s, 12H, 4×CH3CO); 13C NMR
(DMSO-d6):
δ 179.4 (C=S), 169.3-169.9 (4×C=O), 152.3 (C-4’), 147.6 (C=N), 139.7 (C-1’),
132.2 (C-3’), 122.7 (C-2’), 129.8 (C-5’), 113.8 (C-6’), 81.4 (C-1), 72.4 (C-3), 72.2 (C-5),
70.7 (C-2), 68.1 (C-4), 61.7 (C-6), 56.9 (OCH3), 20.3-20.5 (4×CH3CO), 14.2 (CH3C=N);
HRMS: 598.1598 (M+), calcd. for C24H30N4O12S=598.1581 Da.
3-Nitro-4-ethoxyacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-
thiosemicarbazone (3k)
White solid, mp 203-204 °C; yield 78%;
3203, 1750, 1622, 1373, 1238, 1042; 1H NMR (DMSO-d6):
−98.0 (c 1.0, CHCl3); IR (KBr, cm−1): 3340,
10.85 (s, 1H, H-2”), 8.70 (d, 1H,
δ
J=9.5 Hz, H-4”), 8.32 (d, 1H, H-5’), 8.19 (m, 1H, H-2’), 7.37 (s, 1H, H-6’), 5.91 (t, 1H, J=9.25
Hz, H-1), 5.44 (t, 1H, J=9.5 Hz, H-3), 5.27 (t, 1H, J=9.5 Hz, H-2), 4.97 (t, 1H, J=9.5 Hz, H-4),
4.28 (q, 2H, J=7.0 Hz, OCH2CH3), 4.22 (dd, J=12.5, 5.0 Hz, 1H, H-6a), 4.07 (ddd, J=10.0,
4.75, 2.25 Hz, 1H, H-5), 3.98 (dd, J=12.25, 2.25 Hz, 1H, H-6b), 2.49 (s, 3H, CH3C=N), 1.95-
2.00 (s, 12H, 4×CH3CO), 1.35 (t, 3H, J=7.0 Hz, OCH2CH3); 13C NMR (DMSO-d6):
δ 179.5
(C=S), 169.3-169.9 (4×C=O), 151.4 (C-4’), 149.7 (C-3’), 147.6 (C=N), 139.9 (C-1’), 128.4
(C-5’), 122.6 (C-2’), 114.6 (C-6’), 81.4 (C-1), 72.4 (C-3), 68.1 (C-4), 72.2 (C-5), 70.7 (C-2),
61.7 (C-6), 65.3 (OCH2CH3), 20.3-20.5 (4×CH3CO), 14.3 (CH3C=N), 14.2 (OCH2CH3);
HRMS: 612.1737 (M+), calcd. for C25H32N4O12S=612.1741 Da.
3-Nitro-4-chloroacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-
thiosemicarbazone (3l)
White solid, mp 215-216 °C; yield 83%;
1747, 1611, 1370, 1223, 1043; 1H NMR (DMSO-d6):
−88.8 (c 1.0, CHCl3); IR (KBr, cm−1): 3332, 3239,
δ
(ppm) 10.97 (s, 1H, H-2”), 8.81 (d, 1H, J=9.0
Hz, H-4”), 8.50 (d, J=2.0 Hz, 1H, H-2’), 8.22 (dd, J=8.75, 2.25 Hz, 1H, H-6’), 7.79 (d, 1H, J=9.0 Hz,
H-5’), 5.90 (t, 1H, J=9.0 Hz, H-1), 5.43 (t, 1H, J=9.5 Hz, H-3), 5.28 (t, 1H, J=9.5 Hz, H-2), 4.97 (t,
1H, J=9.5 Hz, H-4), 4.22 (dd, J=12.25, 4.75 Hz, 1H, H-6a), 4.07 (ddd, J=6.25, 5.0, 2.5 Hz, 1H, H-5),
3.99 (dd, 1H, J=11.5, 2.0 Hz, H-6b), 2.35 (s, 3H, CH3C=N), 1.93-2.00 (s, 12H, 4×CH3CO); 13C NMR
(DMSO-d6):
δ 179.7 (C=S), 169.3-169.9 (4×C=O), 148.2 (C-4’), 146.5 (C=N), 138.4 (C-3’), 131.4

904
N. DINH THANH et al.
(C-1’), 131.2 (C-5’), 125.1 (C-2’), 122.9 (C-6’), 81.5 (C-1), 72.5 (C-3), 72.3 (C-5), 70.7 (C-2), 68.1
(C-4), 61.7 (C-6), 20.3-20.5 (4×CH3CO), 14.193 (CH3C=N); HRMS: 602.1076/604.1046
[M+/(M+2)+], calcd. for C24H2735ClN4O11S/C24H2737ClN4O11S =602.1086/604.1056 Da.
3-Nitro-4-bromoacetophenone(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-
thiosemicarbazone (3m)
White solid, mp 204-205 °C; yield 85%;
1
−89.0 (c 1.0, CHCl3); IR (KBr, cm−1): 3327,
1750, 1620, 1374, 1226, 1035; H-NMR (DMSO-d6): 10.96 (s, 1H, H-2”), 8.80 (d, 1H,
δ
J=9.0 Hz, H-4”), 8.46 (d, J=2 Hz, 1H, H-2), 8.11 (dd, J=8.5, 2.0 Hz, 1H, H-6’), 7.91 (d,
J=8.5 Hz, 1H, H-5), 5.90 (t, 1H, J=9.0 Hz, H-1), 5.43 (t, 1H, J=9.5 Hz, H-3), 5.28 (t, 1H,
J=9.5 Hz, H-2), 4.97 (t, 1H, J=9.5 Hz, H-4), 4.07 (ddd, J=10.0, 4.75, 2.25 Hz, 1H, H-5),
4.22 (dd, J=12.5, 4.5 Hz, 1H, H-6a), 3.98 (dd, J=12.5, 2.0 Hz, 1H, H-6b), 2.35 (s, 3H,
CH3C=N), 1.93-2.00 (s, 12H, 4×CH3CO); 13C NMR (DMSO-d6):
δ 179.7 (C=S), 169.4-
170.0 (4×C=O), 150.3 (C-4’), 146.6 (C=N), 138.4 (C-3’), 134.3 (C-1’), 131.3 (C-5’), 122.8
(C-2’), 113.3 (C-6’), 81.5 (C-1), 72.3 (C-5), 72.5 (C-3), 70.7 (C-2), 68.1 (C-4), 61.7 (C-6),
20.3-20.5 (4×CH3CO), 14.2 (CH3C=N); HRMS: 646.0589/648.0557 [M+/(M+2)+], calcd. for
C24H2779BrN4O11S/C24H2781BrN4O11S =646.0580/648.0560 Da.
Results and Discussion
The synthesis of the title compound is outlined in Scheme 1. Condensation of 4-(tetra-O-acetyl-
6-8
β
acetophenone 4-(tetra-O-acetyl-
-D-glucopyranosyl)thiosemicarbazide (1)1c,
with a number of acetophenones afforded
β
-D-glucopyranosyl)-thiosemicarbazones (3). This syntheses
was carried out using minimum amount of solvent (methanol) comparing conventional heating
methods (3-5 mL volume vs. 20-30 mL, respectively). Reaction time was from 40 to 50 minutes
depending substituent’s nature: withdrawing substituents need shorter reaction time than
donating ones (Table 1). In the first period of reaction when reaction was starting to irradiate
about 10-15 minute, the pasty mixture of reagents in methanol was dissolved and the reaction
became homogenous. In the final period of reaction, the solid product appeared and precipitated
out. The solid thiosemicarbazones (3) were filtered by suction and recrystallized from ethanol or
ethanol/toluene (1:1 in volume)11,12. These compounds can be dissolved in ethanol, toluene,
chloroform, DMF and had high melting points. Compounds 3b, 3d and 3g have been already
reported in references18, so other remaining acetophenone 4-(tetra-O-acetyl-
β-D-
glucopyranosyl)-thiosemicarbazones (3) have been synthesized for the first time. All the
products were characterized by IR, 1H NMR and 13C NMR, and mass spectra.
OAc
OAc
O
NH2NH2.H2O
CH2Cl2
O
AcO
AcO
AcO
AcO
NCS
NH
C
S
NH NH2
OAc
OAc
MeOH,
R
CH3COOH
O
C
Microwave
Irradiation
CH3
OAc
O
R
AcO
AcO
NH
C
S
NH
N
C
OAc
CH3
Scheme 1.

Microwave-Assisted Synthesis of Thiosemicarbazones
905
The IR spectra of compounds 3 showed characteristic absorptions in the range of
3323–3390 cm−1 and 3298–3332 cm−1 (N−H bond), 1743–1749, 1223–1234 cm−1 and
1038−1098 cm−1 (ester), 1370–1378 cm−1 (C=S), and 1620-1600 cm−1 (C=N bond). In the
1H NMR spectra of 3, the aromatic proton H-1 is represented as a triplet at the range 5.90–
5.95 ppm due to the coupling with the N(4”)−H and the H-2. The coupling constant JH-1,H-2
(9.0–9.5 Hz) is an evidence which confirms the β configuration in compounds 312-18. The
NH proton of the thioamide functionality of compounds 3 appeared at 10.71−10.98 ppm (singlet)
for N(2”)H and 8.77−8.58 ppm (doublet, JNH,H-1=9.0−9.5 Hz) for N(4”)H. The 13C-NMR spectra
showed the thiocarbonyl carbon atom with chemical shift at δ=179.0−179.7 ppm18.
Table 1. Substituted acetophenone (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazones
(3a-m).
Microwave
Irradiation Time,min
Microwave
Irradiation Time, min
Entry
R
Entry
R
4-NO2
3-NO2
4-Cl
6
6
6
6
8
8
8
4-OC2H5
8
7
7
7
7
7
3a
3b
3c
3d
3e
3f
3h
3i
3-NO2-4-Me
3- NO2-4-OMe
3- NO2 -4-OEt
3- NO2-4-Cl
3- NO2 -4-Br
3j
4-Br
H
3k
3l
4-CH3
4-OCH3
3m
3g
a ) lit.18e: mp 184-186 °C; b) lit.18e: mp 186-88 °C; c) lit.18f: mp 192-198 °C.
It has previously been found that thiosemicarbazone derivatives relating to the
stereochemistry of the C=N bond, can exist in the E or Z form or as a mixture of E/Z
isomers, usually with the E form being the major isomer23. E/Z-Isomeric ratios is depended
on the substituents’ nature and its position on the thiosemicarbazone moiety and the solvent.
The correct configuration then can be determined by 1H NMR spectroscopy, as the N(4”)H
on NH−N=C group appears at δ=9–12 ppm for the E form, and δ=14–15 ppm for the Z
form23. Thiosemicarbazones 3 had remarkable anti-microorganism activities (Table 2). In
amount of compounds 3 was 20 µg/mL, the biological activities were insignificant for E.
coli, S. epidermidis and C. albicans. In higher amount (40 µg/mL and 60 µg/mL) most these
compounds had significant biological activities for those microorganisms
.
Table 2. Exploration of biological activities of thiosemicarbazones 3a-m.
Diameter of antibacterial ring, mm
S. epidermidis
Entry
R
E. coli
C. albicans
40 µg/mL 60 µg/mL 40 µg/mL 60 µg/mL 40 µg/mL 60 µg/mL
4-NO2
3-NO2
4-Cl
20
20
20
15
20
20
20
20
20
20
20
20
20
20
20
20
18
20
20
20
20
20
20
20
20
20
24
23
25
20
23
23
23
20
20
24
25
20
24
28
26
30
25
26
25
26
26
25
27
30
26
28
20
20
18
18
20
20
20
20
20
18
20
20
21
25
25
23
24
25
25
25
25
25
23
25
26
26
3a
3b
3c
3d
3e
3f
4-Br
H
4-CH3
4-OCH3
4-OC2H5
3g
3h
3i
3-NO2-4-Me
3- NO2-4-OMe
3- NO2 -4-OEt
3- NO2-4-Cl
3- NO2 -4-Br
3j
3k
3l
3m

906
N. DINH THANH et al.
Conclusion
We have developed a highly efficient method for the synthesis of (2,3,4,6-tetra-O-acetyl-
β-D-glucopyranosyl)-thiosemicarbazones of acetophenones under microwave-assisted
heating conditions.
Acknowledgments
Financial support for this work was provided by Scientific Research Fund-Hanoi National
University (Grant QGTD.08.03).
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