A novel and convenient synthesis of thiazol-2(3H)-imine-linked glycoconjugates

Article abstract of DOI:10.1055/s-2008-1067121

A novel and convenient synthetic approach for the preparation of thiazol-2(3H)-imine-linked glycoconjugates, which involves the cyclization of l-benzoyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl)thiourea with a variety of carbonyl compounds bearing an α-H in the presence of [hydroxy(tosyloxy)iodo]benzene (HTIB) and triethylamine, has been developed. The methodology has advantages such as avoiding the use of lachrymatory and toxic bromine, simplicity of procedure, mild reaction conditions, and high yields. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067121

1994
SHORT PAPER
A Novel and Convenient Synthesis of Thiazol-2(3H)-imine-Linked Glyco-
conjugates
T
hiazol-2(3
H
)-imi
u
ne-Linked G
o
lycoconjugat
-
es Bin Zhou,*a Yue-Qing Guan,a Chao Shen,b Qian Wang,a Xiao-Ming Liu, Peng-Fei Zhang,*b Li-Li Lia
a
College of Chemical and Environmental Engineering, Shandong University of Science and Technology,
Qingdao, Shandong 266510, P. R. of China
Fax +86(532)86057718; E-mail: gbzhou_zju@sdust.edu.cn
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, P. R. of China
Fax +86(571)88484468; E-mail: pfzhang@hznu.edu.cn
b
Received 4 March 2008; revised 7 April 2008
es of inflammation, immune response, tumor metastasis,
and bacterial and viral infections. During our research, we
developed a novel route, which utilizes the work of Singh
et al.,10 for the synthesis of thiazol-2(3H)-imine-linked
Abstract: A novel and convenient synthetic approach for the prep-
aration of thiazol-2(3H)-imine-linked glycoconjugates, which in-
volves the cyclization of 1-benzoyl-3-(2,3,4,6-tetra-O-pivaloyl-b-
D-glucopyranosyl)thiourea with a variety of carbonyl compounds
bearing an a-H in the presence of [hydroxy(tosyloxy)iodo]benzene glycoconjugates from the cyclization of 1-aroyl-3-glyco-
(HTIB) and triethylamine, has been developed. The methodology
sylthiourea with carbonyl compounds in the presence of
[hydroxy(tosyloxy)iodo]benzene (HTIB)11 and triethyl-
has advantages such as avoiding the use of lachrymatory and toxic
bromine, simplicity of procedure, mild reaction conditions, and
amine. To the best of our knowledge, it is the first example
high yields.
of the preparation of thiazol-2(3H)-imine-linked glyco-
conjugates.
Key words: thiazol-2(3H)-imine, glycoconjugate, [hydroxy(tosyl-
oxy)iodo]benzene, synthesis
In this paper, we would like to report a novel and conve-
nient procedure for the synthesis of thiazol-2(3H)-imine-
linked glycoconjugates, which includes a-tosyloxylation
In recent years, thiazolidene and its derivatives have re-
of carbonyl compounds with [hydroxy(tosyloxy)io-
ceived considerable attention because of their bioactivity
do]benzene, followed by treatment with 1-benzoyl-3-gly-
and many applications in organic and medicinal chemis-
cosylthiourea at ambient temperature (Scheme 1).
try.1–6 For example, Masuda’s group has reported that a
As shown in Scheme 1, the reaction of 2,3,4,6-tetra-O-
pivaloyl-b-D-glucopyranosylamine (1)12 with benzoyl
isothiocyanate proceeded smoothly in acetone at room
temperature to afford the desired product, 1-benzoyl-3-
(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyranosyl)thiourea (2),
in 92% yield.13
series of thiazolidenebenzenesulfonamide derivatives are
a novel class of non-nucleoside HIV-1RT inhibitors.2,3
Therefore, the preparation of these compounds has be-
come increasingly important. Our considerable current re-
search interests focus on the synthesis of glycoconjugates,
which exert important effects on many complex biologi-
cal events,7–9 including cellular recognition in the process-
OPiv
OPiv
O
S
C
O
C
O
O
PivO
PivO
PivO
PivO
Ph
C N C S
H
H
N
N
Ph
NH2
OPiv
OPiv
1
2
O
C
OPiv
N
Ph
1) PhI(OH)OTs, R1COCH2R2
2) Et3N
O
PivO
PivO
N
S
OPiv
R1
R2
3a–e
a: R1 = Me, R2 = H
b: R1 = Et, R2 = H
c: R1 = Ph, R2 = H
d: R1 = 4-O2NC6H4, R2 = H
e: R1 = Me, R2 = Ac
Scheme 1 Synthesis of thiazol-2(3H)-imine-linked glycoconjugates
SYNTHESIS 2008, No. 13, pp 1994–1996
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067121; Art ID: F20807SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Thiazol-2(3H)-imine-Linked Glycconjugates
1995
Esquire 3000 plus spectrometer. 1H and 13C NMR spectra of sam-
ples in CDCl3 were recorded on a Bruker Avance 400 spectrometer
using TMS as internal standard. Elemental analyses were performed
on Carlo-Erba 1106.
Hypervalent iodine reagents have received much attention
due to their low toxicity, ready availability, easy handling,
and reactivities similar to those of heavy metal reagents14–17
and they have been found to be an effective reagent for the
one-step conversion of enolizable ketones into the corre-
sponding a-tosyloxy ketones.18 As part of our programme
directed towards the use of hypervalent iodine reagents in
organic synthesis, we have reported a one-pot procedure
for the synthesis of imidazoles.11 Hence, we utilized [hy-
droxy(tosyloxy)iodo]benzene instead of bromine for the
synthesis of thiazol-2(3H)-imine derivatives following
the reported procedure of Singh et al.10 When 1-benzoyl-
3-(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyranosyl)thiourea
(2) was reacted with acetone in the presence of [hy-
droxy(tosyloxy)iodo]benzene and triethylamine, the reac-
tion was found to be complete within a short period of
time under extremely mild conditions to obtain the ex-
pected product, 1-benzoyl-4-methyl-3-(2,3,4,6-tetra-O-
pivaloyl-b-D-glucopyranosyl)thiazol-2(3H)-imine (3a);
its structure was confirmed by 1H and 13C NMR, IR, MS,
and elemental analysis.
1-Benzoyl-3-(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyranosyl)thio-
urea (2)
A soln of benzoyl isothiocyanate (2 mmol) in acetone (10 mL) was
added to 2,3,4,6-tetra-O-pivaloyl-D-glucopyranosylamine (1; 1.03
g, 2 mmol) and the mixture was refluxed; the reaction was moni-
tored by TLC. After 1.5 h, the reaction was complete and the solvent
was removed under reduced pressure and the residue was recrystal-
lized (95% EtOH) to give 2 as a solid; yield: 92%; mp 209–211 °C.
IR (KBr): 3416, 3238, 2971, 2874, 1737, 1681, 1525, 1482, 1396,
1369, 1321, 1281, 1143, 1093, 985, 919, 798, 718, 614 cm–1.
1H NMR (CDCl3): d = 11.09 (d, J = 4.4 Hz, 1 H), 9.03 (s, 1 H), 7.83
(t, J = 3.6 Hz, 2 H), 7.63 (t, J = 3.8 Hz, 1 H), 7.51 (t, J = 4.2 Hz, 2
H), 5.87 (t, J = 4.6 Hz, 1 H), 5.47 (t, J = 4.6 Hz, 1 H), 5.17–5.29 (m,
2 H), 4.22 (q, J = 0.8 Hz, 1 H), 4.13 (q, J = 2.6 Hz, 1 H), 3.90–3.94
(m, 1 H), 1.11–1.27 (m, 36 H).
13C NMR (CDCl3): d = 182.73, 178.08, 177.19, 176.95, 176.40,
166.04, 133.77, 131.28, 129.14, 127.53, 82.91, 74.50, 72.29, 70.15,
67.61, 61.67, 38.70–38.86, 26.92–27.13.
To further demonstrate the scope of the reaction, the cy- MS (ESI): m/z = 679.1 [M + H]+.
clizations of 1-benzoyl-3-(2,3,4,6-tetra-O-pivaloyl-b-D-
glucopyranosyl)thiourea (2) and a variety of carbonyl
compounds bearing a-H in the presence of [hydroxy(tosyl-
oxy)iodo]benzene and triethylamine were carried out at
room temperature and the corresponding thiazol-2(3H)-
imine-linked glycoconjugates 3b–e were obtained in
yields of 80% or higher. The results are listed in Table 1.
Anal. Calcd for C34H50N2O10S: C, 60.16; H, 7.42; N, 4.13. Found:
C, 60.57; H, 7.48; N, 4.05.
1-Benzoyl-4-methyl-3-(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyr-
anosyl)thiazol-2(3H)-imine (3a); Typical Procedure
Into a 50-mL 3-neck flask, thiourea 2 (0.678 g, 1 mmol), Et3N (1
mmol), and acetone (5 mL) were added, then a soln of HTIB (1
mmol) in acetone (5 mL) was added dropwise. When the reaction
was complete, the mixture was filtered and concentrated in vacuo to
give the crude product, which was recrystallized (EtOH) to give
pure 3a as a solid. yield: 90%; mp 181–183 °C.
Table 1 Results of Cyclizations of 1-Benzoyl-3-(2,3,4,6-tetra-O-
pivaloyl-D-glucopyranosyl)thiourea with HTIB/Carbonyl Com-
pounds
In the synthesis of 3b–e, CHCl3 was used instead of acetone as the
solvent and the molar ratio of 2–HTIB–Et3N was 1:1:1.
Entry R1
R2
Product Time
(h)
Yield Mp
(%)
90
87
82
86
85
(°C)
IR (KBr): 3459, 2974, 2874, 2361, 1743, 1605, 1571, 1474, 1397,
1339, 1279, 1242, 1135, 1039, 918, 759, 716 cm–1.
1
2
3
4
5
Me
H
3a
3b
3c
3d
3e
1.0
1.5
3.5
2.5
3.0
181–183
162–163
155–158
96–98
1H NMR (CDCl3): d = 8.29 (d, J = 3.4 Hz, 2 H), 7.50 (q, J = 4.4 Hz,
3 H), 6.97 (d, J = 4.8 Hz, 1 H), 6.26 (s, 1 H), 5.57–5.66 (m, 2 H),
5.36 (t, J = 4.8 Hz, 1 H), 4.29 (q, J = 7.6 Hz, 1 H), 4.17 (d, J = 6.4
Hz, 1 H), 4.07 (d, J = 5.0 Hz 1 H), 2.65 (s, 3 H), 0.88–1.23 (m, 36
H).
13C NMR (CDCl3): d = 177.68, 177.18, 177.00, 176.15, 173.86,
170.93, 136.34, 134.35, 131.71, 129.20, 128.12, 106.07, 83.20,
75.44, 72.39, 69.42, 66.76, 60.87, 38.67–38.81, 26.68–27.09,
15.31.
Et
H
Ph
H
4-O2NC6H4
Me
H
Ac
174–177
In conclusion, we have developed a novel and convenient
method for the synthesis of thiazol-2(3H)-imine-linked
glycoconjugates, which has advantages such as avoiding
the use of lachrymatory and toxic bromine reagent, sim-
plicity of procedure, and higher yields. Further work is
currently on-going to extend our synthetic protocol and
study the biological activity and applications of deprotect-
ed thiazol-2(3H)-imine-linked glycoconjugates.
Anal. Calcd for C37H52N2O10S: C, 61.99; H, 7.31; N, 3.91. Found:
C, 62.03; H, 7.27; N, 4.04.
1-Benzoyl-4-ethyl-3-(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyrano-
syl)thiazol-2(3H)-imine (3b)
Solid; yield: 87%; mp 162–163 °C.
IR (KBr): 2975, 2937, 2874, 1744, 1603, 1571, 1472, 1398, 1367,
1343, 1315, 1275, 1230, 1135, 1036, 905, 760, 722 cm–1.
1H NMR (CDCl3): d = 8.29 (q, J = 4.8 Hz, 2 H), 7.47–7.52 (m, 3 H),
7.00 (d, J = 4.6 Hz, 1 H), 5.59–5.62 (m, 2 H), 5.36 (s, 1 H), 4.06–
4.28 (m, 3 H), 2.53 (s, 2 H), 2.19 (s, 2 H), 2.04 (s, 1 H), 1.36 (t,
J = 7.2 Hz, 1 H), 0.85–1.27 (m, 36 H).
13C NMR (CDCl3): d = 177.62, 177.07, 176.96, 176.13, 173.59,
168.85, 140.62, 136.45, 131.55, 129.15, 128.03, 103.96, 82.86,
Chemicals and solvents were either purchased or purified by stan-
dard techniques. Analytical TLC was performed on a Merck pre-
coated TLC (silica gel 60 F254) plate. Melting points were recorded
on an X4-Data microscopic melting point apparatus and are uncor-
rected. IR spectra were recorded on a Nicolet 380 FT-IR spectro-
photometer using KBr discs. ESI-MS were acquired on a Bruker
Synthesis 2008, No. 13, 1994–1996 © Thieme Stuttgart · New York

1996
G.-B. Zhou et al.
SHORT PAPER
75.31, 72.43, 69.34, 66.69, 60.87, 38.62–38.78, 26.58–27.05,
21.35, 11.58.
1H NMR (CDCl3): d = 8.28 (d, J = 3.6 Hz, 2 H), 7.50–7.58 (m, 3 H),
7.07 (t, J = 4.6 Hz, 1 H), 5.64 (t, J = 4.4 Hz, 2 H), 5.38 (d, J = 4.8
Hz, 1 H), 4.18–4.28 (m, 2 H), 4.06 (d, J = 5.2 Hz, 1 H), 3.02 (s, 3
H), 2.49 (s, 3 H), 0.87–1.23 (m, 36 H).
13C NMR (CDCl3): d = 190.41, 177.67, 177.03, 176.98, 176.03,
174.51, 167.82, 143.38, 135.57, 132.30, 129.34, 128.27, 118.38,
83.29, 75.61, 72.26, 69.22, 66.46, 60.64, 38.63–38.82, 30.51,
26.65–27.05, 14.10.
Anal. Calcd for C38H54N2O10S: C, 62.44; H, 7.45; N, 3.83. Found:
C, 62.48; H, 7.41; N, 3.81.
1-Benzoyl-4-phenyl-3-(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyr-
anosyl)thiazol-2(3H)-imine (3c)
Solid; yield: 82%; mp 155–158 °C.
IR (KBr): 2985, 2909, 1694, 1636, 1596, 1577, 1512, 1485, 1471,
1449, 1393, 1358, 1321, 1293, 1225, 1161, 1127, 1095, 1070, 1009,
988, 905, 878, 719, 688 cm–1.
Anal. Calcd for C39H54N2O11S: C, 61.72; H, 7.17; N, 3.69. Found:
C, 61.76; H, 7.10; N, 3.77.
1H NMR (CDCl3): d = 9.99 (d, J = 4.0 Hz, 1 H), 8.13 (t, J = 4.4 Hz,
2 H), 7.85 (t, J = 4.2 Hz, 2 H), 7.43–7.60 (m, 6 H), 5.50 (t, J = 9.6
Hz, 1 H), 5.29 (d, J = 4.4 Hz, 1 H), 5.19 (t, J = 9.6 Hz, 1 H), 4.96 (s,
1 H), 4.17 (d, J = 0.8 Hz, 2 H), 4.13 (d, J = 2.6 Hz, 1 H), 1.08–1.17
(m, 36 H).
13C NMR (CDCl3): d = 189.84, 178.03, 177.03, 176.86, 176.29,
168.78, 158.54, 140.14, 133.15, 132.29, 131.30, 128.89, 128.35,
128.05, 126.96, 81.00, 79.08, 73.95, 72.06, 69.98, 67.75, 62.03,
38.63–38.74, 26.85–27.05.
Acknowledgment
This work was supported by the Natural Science Foundation of
Shandong Provincial Education Department (J07WC06), the Natu-
ral Science Foundation of Zhejiang Province (No. R406378) and
the National Natural Science Foundation of China (No. 20662005).
References
(1) Boschelli, D. H.; Connor, D. T.; Kuipers, P. J.; Wright, C. D.
Bioorg. Med. Chem. Lett. 1992, 2, 705.
(2) Masuda, N.; Osamu, Y.; Fujii, M.; Ohgami, T. Bioorg. Med.
Chem. 2004, 12, 6171.
(3) Masuda, N.; Osamu, Y.; Fujii, M.; Ohgami, T. Bioorg. Med.
Chem. 2005, 13, 949.
(4) Gaja, M. A.; Knapp, J. S. J. Appl. Microbiol. 1997, 83, 327.
(5) Grizik, S. I.; Krichevskii, E. S.; Kuleshova, E. F.; Solov’eva,
N. P. Pharm. Chem. J. 1993, 27, 617.
Anal. Calcd for C42H54N2O10S: C, 64.76; H, 6.99; N, 3.60. Found:
C, 64.71; H, 7.05; N, 3.67.
1-Benzoyl-4-(4-nitrophenyl)-3-(2,3,4,6-tetra-O-pivaloyl-b-D-
glucopyranosyl)thiazol-2(3H)-imine (3d)
Solid; yield: 86%; mp 96–98 °C.
IR (KBr): 3323, 2973, 2874, 1744, 1625, 1601, 1525, 1477, 1398,
1343, 1283, 1228, 1145, 1036, 986, 868, 721 cm–1.
1H NMR (CDCl3): d = 7.93 (q, J = 17.0 Hz, 2 H), 7.51 (t, J = 7.2
Hz, 4 H), 7.34 (d, J = 3.8 Hz, 1 H), 7.19 (q, J = 10.6 Hz, 2 H), 6.51
(d, J = 4.4 Hz, 1 H), 5.52 (t, J = 9.4 Hz, 1 H), 5.10–5.20 (m, 3 H),
4.21 (d, J = 5.6 Hz, 1 H), 4.13 (q, J = 9.0 Hz, 1 H), 3.94 (t, J = 5.0
Hz, 1 H), 0.78–1.36 (m, 36 H).
13C NMR (CDCl3): d = 188.01, 178.39, 177.93, 176.85, 176.39,
168.68, 154.38, 140.41, 137.47, 132.56, 130.57, 129.81, 129.13,
128.09, 125.35, 122.76, 83.92, 74.10, 71.80, 70.51, 67.61, 61.72,
38.67–38.91, 26.89–27.06.
(6) Hara, T.; Hairavama, F.; Arima, H.; Yamaquchi, Y.
J. Inclusion Phenom. Macrocyclic Chem. 2006, 56, 135.
(7) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2355.
(8) Giannis, A. Angew. Chem., Int. Ed. Engl. 1994, 33, 178.
(9) Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek,
R. A. Science 2001, 291, 2370.
(10) Singh, C. B.; Murru, S.; Kavala, V.; Patel, B. K. Org. Lett.
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(11) Zhang, P. F.; Chen, Z. C. Synthesis 2001, 2075.
(12) Zhou, G. B.; Zhang, P. F.; Pan, Y. J. Tetrahedron 2005, 61,
5671.
Anal. Calcd for C42H53N3O12S: C, 61.22; H, 6.48; N, 5.10. Found:
C, 61.16; H, 6.53; N, 5.12.
(13) Zeng, R. S.; Zou, J. P.; Zhi, S. J.; Chen, J.; Shen, Q. Org.
Lett. 2003, 5, 1657.
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(15) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271.
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4-Acetyl-1-benzoyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-b-D-
glucopyranosyl)thiazol-2(3H)-imine (3e)
Solid; yield: 85%; mp 174–177 °C.
IR (KBr): 3466, 2975, 2937, 2875, 1745, 1680, 1652, 1608, 1571,
1472, 1395, 1366, 1334, 1282, 1228, 1169, 1128, 1074, 923, 892,
719, 666, 584 cm–1.
Synthesis 2008, No. 13, 1994–1996 © Thieme Stuttgart · New York