Preparation of glycosyl thiourea derivatives from glycosyl azides using sulfamic acid and sodium iodide in one-pot

Article abstract of DOI:10.1016/j.carres.2016.09.002

Novel one-pot reaction conditions have been developed for the preparation of glycosyl thiourea derivatives directly from glycosyl azides mediated by a combination of sulfamic acid and sodium iodide. The reaction conditions were clean, non-toxic and the products were isolated in good to excellent yield.

Full text of DOI:10.1016/j.carres.2016.09.002

Accepted Manuscript
Preparation of glycosyl thiourea derivatives from glycosyl azides using sulfamic acid
and sodium iodide in one-pot
Arin Gucchait, Manas Jana, Kuladip Jana, Anup Kumar Misra
PII:
S0008-6215(16)30284-1
10.1016/j.carres.2016.09.002
CAR 7252
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 2 August 2016
Revised Date: 2 September 2016
Accepted Date: 3 September 2016
Please cite this article as: A. Gucchait, M. Jana, K. Jana, A.K. Misra, Preparation of glycosyl thiourea
derivatives from glycosyl azides using sulfamic acid and sodium iodide in one-pot, Carbohydrate
Research (2016), doi: 10.1016/j.carres.2016.09.002.
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ACCEPTED MANUSCRIPT
Preparation of glycosyl thiourea derivatives from glycosyl azides
using sulfamic acid and sodium iodide in one-pot
Arin Gucchait, Manas Jana, Kuladip Jana and Anup Kumar Misra*
Bose Institute, Division of Molecular Medicine, P-1/12, C.I.T. Scheme VII-M, Kolkata-700054,
India
Abstract: Novel one-pot reaction conditions have been developed for the preparation of
glycosyl thiourea derivatives directly from glycosyl azides mediated by a combination of
sulfamic acid and sodium iodide. The reaction conditions were clean, non-toxic and the products
were isolated in good to excellent yield.
Keywords: Carbohydrate; azide; thiourea; reduction; sulfamic acid; sodium iodide;
isothiocyanate.
1.
Introduction
Thiourea derivatives are important class of molecules having versatile chemical and biological
applications.1 They have been used in therapeutics as antioxidant,2 anti-bacterial,3 anti-
inflammatory,4 anti-parasitic,5 anti-HIV,6 anti-tubercular,7 rodenticide,8 anti-cancer agents,9 anti-
fungal agents10 etc. Thiourea derivatives have been used as agrochemicals such as insect growth
regulator,11 and herbicides.12 They have also wide applications in the chemical synthesis of
heterocycles and other organic molecules.13,14 In the recent past, thiourea derivatives have been
applied as organocatalysts and ligands in a variety of asymmetric organic reactions.15,16 In
addition, they have been applied as chemical sensors for the detection of heavy metals17 and in
polymer synthesis.18
1

ACCEPTED MANUSCRIPT
Glycosyl thiourea derivatives have been used for the preparation of several biologically
important molecules such as glycoconjugates,19 thioureidosugar derivatives,20 nucleosides,21
spiroglycosides,22 glycoclustures and dendrimers,23 bridged thiourea calix sugar derivatives24 etc.
A number of glycosyl thiourea derivatives have been found promising as antiviral, antibacterial
and antitumor agents.25 Because of the increasing therapeutic importance, several glycosyl
thiourea derivatives have been synthesized using the reaction of glycosyl isothiocyanates with
aryl/alkyl amines or reaction of glycosyl amines with aryl/alkyl isothiocyanates (Scheme 1).26-29
However, the reported methods for the preparation of glycosyl thiourea derivatives suffer from
several shortcomings such as, handling of unstable glycosyl halide for the preparation of
glycosyl isothiocyanate derivatives, chemical and thermal instability of glycosyl amine derived
from the reduction of glycosyl azides, operational complication for the preparation of glycosyl
amines,27,29 poor yield in the thiophosgene mediated conversion of amino group into
isothiocyanato group,28 hazardous reaction conditions29 etc. Therefore, there is a strong need to
develop a high yielding, reproducible, user friendly reaction condition for the preparation of
glycosyl thiourea derivatives. During our synthetic studies on carbohydrates we were interested
to prepare a series of glycosyl thiourea derivatives. It was envisaged that development of a one-
pot reaction condition for the reduction of azido group followed by reaction with an appropriate
aryl/alkyl isothiocyanate could furnish satisfactory yield of the glycosyl thiourea derivative in a
clean reaction condition. Prompted by a recent report of Shankaraiah et al.30 for the preparation
of podophyllotoxin-thiourea congeners, in which azide derivative was reacted with aryl
isothiocyanates in the presence of a combination of sulfamic acid and sodium iodide, it was
decided to prepare glycosyl thiourea derivatives directly from glycosyl azides avoiding the
problems associated with the preparation of glycosyl amines or isothiocyanate derivatives.
Earlier, sulfamic acid has been used in various organic transformations because of its
organocatalytic property.31 We report herein a convenient one-pot synthesis of glycosyl thiourea
2

ACCEPTED MANUSCRIPT
conjugates by the reaction of glycosyl azides with aryl isothiocyanates in the presence of a
combination of sulfamic acid and sodium iodide (Scheme 2). It is presumed that on treatment
with a combination of sulfamic acid and sodium iodide, the glycosyl azide reduced to form
glycosyl amine in situ which immediately reacts with aryl isothiocyanate to furnish glycosyl
thiourea derivatives.
AcO
Reduction
AcO
AcO
S
O
O
RNCS
O
O
R
NH2
N
H
N
N3
H
Unstable
Thiophosgene
AgSCN or
KSCN or
TMSNCS
AcO
AcO
AcO
S
O
O
RNH2
R
NCS
N
N
H
Low yielding
Br
H
Scheme 1: Conventional approaches for the preparation of glycosylthiourea derivatives.
AcO
AcO
S
O
ArNCS (1.5 equiv.)
O
Ar
N3
N
N
Sulfamic acid (3.0 equiv.)
H
H
NaI (4.0 equiv.), RT, 8-10 h
Scheme 2: Preparation of glycosyl thiourea derivatives directly from glycosyl azides.
2.
Results and discussion
In a set of initial experiments, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl azide (1) (1 mmol) was
allowed to react with 4-fluoro-benzylisothiocyanate in the presence of a varied quantity of
sulfamic acid and sodium iodide at room temperature in a variety of solvents such as, THF,
CH3CN, DMF etc. After a series of optimization, it was observed that use of 3.0 equiv. of
sulfamic acid and 4.0 equiv. of sodium iodide in acetonitrile resulted in the formation of 4-
fluorophenyl 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) thiourea (5) in 70% yield in 8 h at
room temperature. Following similar reaction condition a series of per-O-acetylated glycosyl
azide derivatives were reacted with a series of aryl isothiocyanates to furnish a variety of per-O-
3

ACCEPTED MANUSCRIPT
acetylated glycosyl aryl thiourea derivatives in very good yield (Table 1). Although in the earlier
report less amount of reagents were used for this transformation, in this case reducing the
quantity of sulfamic acid or sodium iodide led to incomplete conversion of the starting material
even after 24 h presumably due to the fact that sodium iodide got decomposed under the reaction
condition. A scaled up synthesis of compound 10 was also carried out with similar yield as in
small scale preparation. All products were unambiguously characterized by their spectral
analysis. In order to evaluate the medicinal potential of the compounds it is necessary to have
their deprotected version. Therefore, representative thiourea derivatives (10, 12 and 16) were
subjected to the transesterification with dilute sodium methoxide following the reaction
conditions reported by Somsak et al.32 Gratifyingly, quantitative yield of de-O-acetylated
thiourea derivatives were achieved without formation of any by product besides the possibility
of the reactivity of thiourea functionality with sodium methoxide. Presumably, the azide group
was reduced to amine functionality in the presence of the combination of sulfamic acid and
sodium iodide, which reacted with aryl isothiocyanates to give the thiourea derivatives.
Table 1: Preparation of glycosyl thiourea derivatives by Sulfamic acid and Sodium iodide
mediated reaction of glycosyl azides with aryl isothiocyanates in acetonitrile.
Sl.
No.
1
Glycosyl azide
Product
Time
(h)
8
Yield
(%)
70
Ref
OAc
OAc
O
32
F
S
O
AcO
AcO
AcO
AcO
N3
N
N
H
H
OAc
OAc
1
1
5
m.p. 190-191 °C [EtOH]; [α]D25 + 20 (c
1.0, CHCl3); [Lit. m.p.: 191–193 °C; [α]D
+18 (c 0.29, CHCl3)].
OAc
8
70
33
2
F
S
O
AcO
AcO
N
H
N
H
OAc
6
m.p. 187-188 °C [EtOH]; [α]D25 + 16 (c
1.0, CHCl3).
4

ACCEPTED MANUSCRIPT
OAc
S
8
72
32
3
1
CF3
O
AcO
AcO
N
H
N
H
OAc
7
m.p. 110-112 °C [EtOH]; [α]D25 + 28 (c
1.0, CHCl3); [Lit. m.p.: 112–114 °C; [α]D
+32 (c 0.15, CHCl3)].
Cl
9
8
66
68
--
4
5
1
1
OAc
O
Cl
S
AcO
AcO
N
H
N
H
OAc
8
OAc
O
34
Cl
S
AcO
AcO
N
H
N
H
OAc
9
m.p. 127-128 °C [EtOH]; [α]D25 − 10 (c
1.0, CHCl3); [Lit. m.p.: 128–130 °C; [α]D
− 12.3 (c 1.8, CHCl3)].
OAc
NO2
S
8
74
72
(5 g
scale)
33
35
6
7
1
1
1
O
AcO
AcO
N
H
N
H
OAc
10
m.p. 96-98 °C [EtOH]; [α]D25 + 16 (c 1.0,
CHCl3)
OAc
CH3
S
10
56
O
AcO
AcO
N
H
N
H
OAc
11
m.p. 76-78 °C [EtOH]; [α]D25 − 4 (c 1.0,
CHCl3)
OAc
O
8
8
62
65
36
37
8
9
Cl
Cl
S
AcO
AcO
N
H
N
H
OAc
12
m.p. 176-178 °C [EtOH]; [α]D25 − 14 (c
1.0, CHCl3); [Lit. m.p.: 178 °C].
OAc
OAc
O
Cl
AcO
AcO
AcO
AcO
AcO
AcO
S
O
N
H
N
H
N3
2
2
13
[α]D25 − 6 (c 1.0, CHCl3)
OAc
O
8
8
60
68
--
--
10
11
Cl
AcO
AcO
AcO
Cl
S
N
H
N
H
14
S
N3
HN
N
H
CF3
O
AcO
O
AcO
338
AcO
OAc
AcO
OAc
15
5

ACCEPTED MANUSCRIPT
Cl
S
8
58
--
12
3
3
HN
N
H
Cl
O
AcO
AcO
AcO
OAc
16
S
10
10
58
62
--
--
13
14
HN
N
H
CH3
O
AcO
OAc
17
Cl
3
Cl
S
HN
N
H
O
AcO
AcO
OAc
18
S
8
8
76
64
--
--
15
16
3
3
HN
N
NO2
H
O
AcO
AcO
AcO
AcO
OAc
19
S
HN
N
H
F
O
OAc
20
AcO
AcO
AcO
OAc
O
10
68
--
17
OAc
O
OAc
OAc
O
NO2
S
O
O
AcO
O
AcO
N
N
AcO
OAc
N3
OAc
H
H
OAc
OAc
21
4
3.
Conclusion
In summary, a straightforward convenient one-pot reaction condition has been developed for the
preparation of glycosyl thiourea derivatives in excellent yield directly from glycosyl azides
mediated by a combination of sulfamic acid and sodium iodide avoiding the use of toxic
reagents. Further utilization of glycosyl thiourea derivatives in the organic transformations are in
progress in our laboratory.
6

ACCEPTED MANUSCRIPT
4.
Experimental
4.1.
General methods: All reactions were monitored by thin layer chromatography over
silica gel coated TLC plates. The spots on TLC were visualized by warming ceric sulphate (2%
Ce(SO4)2 in 2N H2SO4) sprayed plates in hot plate. Silica gel 230-400 mesh was used for
1
column chromatography. H and 13C NMR spectra were recorded on Brucker Avance 500 MHz
spectrometers using CDCl3 as solvent and TMS as internal reference unless stated otherwise.
Chemical shift value is expressed in δ ppm. Assignment of the protons and carbons in the
carbohydrate ring was carried out using 1D 1H, 13C and 13C DEPT NMR spectra and 2D COSY,
HSQC NMR spectra. ESI-MS were recorded on a Micromass mass spectrometer. Commercially
available grades of organic solvents of adequate purity are used in all reactions.
4.2.
General experimental condition for the preparation of glycosyl thiourea derivatives
To a solution of glycosyl azide (1.0 mmol) and aryl isothiocyanate (1.2 mmol) in dry CH3CN (5
mL) were added sulfamic acid (100 mg, 3.0 mmol) and sodium iodide (600 mg, 4.0 mmol) and
the reaction mixture was allowed to stir at room temperature for appropriate time mentioned in
Table 1. The solvents were removed under reduced pressure and the crude reaction mixture was
diluted with CH2Cl2 (50 mL). The organic layer was successively washed with 5% Na2S2O3 (50
mL), water (50 mL), dried (Na2SO4) and concentrated. The crude product was purified over SiO2
column chromatography using hexane-EtOAc to give pure products. Spectral data of the isolated
products, which are not reported earlier, are presented below.
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-N′-(2,3-dichlorophenyl)thiourea (8): Yellow
25
1
oil; [α]D − 6 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz): δ 7.52 (br s,1 H, NH), 7.47 - 7.30
(m, 3 H, Ar-H), 6.78 (d, J = 7.5 Hz, 1 H, NH), 5.68 (t, J = 8.5 Hz, 1 H, H-1), 5.33 (t, J = 9.5 Hz,
1 H, H-3) 5.02 (t, J = 10.0 Hz, 1 H, H-4), 4.88 (t, J = 9.5 Hz, 1 H, H-2), 4.34 (dd, J = 12.0 Hz,
5.5 Hz, 1 H, H-6a), 4.08 (d, J = 12.0 Hz,1 H, H-6b), 3.87 - 3.80 (m, 1 H, H-5), 2.06, 2.05, 2.03,
7

ACCEPTED MANUSCRIPT
13
2.00 (4 s, 12 H, 4 CH3CO); C NMR (CDCl3, 125 MHz): δ 182.5 (CS), 171.3, 170.4, 169.6,
169.4 (4 C, 4 CH3CO), 134.9 - 126.6 (6 C, Ar-C), 83.1 (C-1), 73.7 (C-5), 72.6 (C-3), 70.6 (C-2),
68.3 (C-4), 61.6 (C-6), 20.7, 20.6, 20.5, 20.4 (4 C,4 CH3CO). ESI-MS: 573.0 [M+Na]+; Anal.
Calcd. for C21H24Cl2N2O9S (550.06): C, 45.74; H, 4.39%; found: C, 45.60; H, 4.56%.
N-(2,3,4,6-Tetra-O-acetyl-β-D-mannopyranosyl)-N′-(2,3-Dichlorophenyl)thiourea
(14):
Yellow oil; [α]D25 − 14 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 8.40 (br s, 1 H, NH), 7.66
- 7.22 (m, 3 H, Ar-H), 7.17 (d, J = 7.5 Hz, 1 H, NH), 5.87 (br s, 1 H, H-1), 5.38 (br s, 1 H, H-2),
5.09 - 5.04 (m, 2 H, H-3, H-4), 4.23 - 4.21 (m, 1 H, H-6a), 3.98 (d, J = 12.5 Hz, 4.5 Hz, 1 H, H-
13
6b), 3.60 - 3.57 (m, 1 H, H-5), 2.06, 1.98, 1.97, 1.94 (4 s, 12 H, 4 CH3CO); C NMR (CDCl3,
125 MHz): δ 181.7 (CS), 170.4, 170.0, 169.4, 169.3 (4 CH3CO), 133.4 - 127.4 (6 C, Ar-C), 80.8
(C-1), 74.0 (C-2), 71.4 (C-3), 69.8 (C-4), 65.4 (C-5), 62.2 (C-6), 20.9, 20.7, 20.5, 20.4 (4
CH3CO). ESI-MS: 573.0 [M+Na]+; Anal. Calcd. for C21H24Cl2N2O9S (550.06): C, 45.74; H,
4.39%; found: C, 45.57; H, 4.60%.
N-(2,3,4-Tri-O-acetyl-α- -rhamnopyranosyl)-N′-(4-trifluoromethylphenyl)thiourea (15):
L
Yellow oil; [α]D25 + 26 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 8.86 (br s, 1 H, NH), 7.63
- 7.45 (m, 4 H, Ar-H), 6.79 (br s, 1 H, NH), 5.94 (d, J = 9.0 Hz, 1 H, H-1), 5.42 (br s, 1 H, H-2),
5.07 (dd, J = 10.0 Hz, 3.0 Hz, 1 H, H-3), 4.91 (t, J = 10.0 Hz, 1 H, H-4), 3.70 - 3.64 (m, 1 H, H-
13
5), 2.14, 2.03, 1.97, (3 s, 9 H, 3 CH3CO), 1.18 (d, J = 6.5 Hz, 3 H, CCH3); C NMR (CDCl3,
125 MHz): δ 180.7 (CS), 170.0, 169.4, 169.3 (3 CH3CO), 126.7 - 124.4 (6 C, Ar-C), 80.4 (C-1),
72.2 (C-3), 71.0 (C-4), 70.4 (C-2), 70.1 (C-5), 20.8, 20.6, 20.4, (3 CH3CO), 17.4 (CCH3). ESI-
MS: 515.1 [M+Na]+; Anal. Calcd. for C20H23F3N2O7S (492.12): C, 48.78; H, 4.71%; found: C,
48.60; H, 4.86%.
N-(2,3,4-Tri-O-acetyl-α-
L
-rhamnopyranosyl)-N′-(2,4-dichlorophenyl)thiourea (16): Yellow
25
1
oil; [α]D − 9 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz): δ 8.32 (br s, 1 H, NH), 7.64 - 7.24
8

ACCEPTED MANUSCRIPT
(m, 3 H, Ar-H), 6.90 (br s, 1 H, NH), 5.80 (br s, 1 H, H-1), 5.4 (br s, 1 H, H-2), 5.04 (dd, J =
10.0 Hz, 2.0 Hz, 1 H, H-3), 4.91(t, J = 10.0 Hz, 1 H, H-4), 3.68 - 3.64 (m, 1 H, H-5), 2.10, 2.02,
13
1.94 (3 s, 9 H, 3 CH3CO), 1.18 (d, J = 5.5 Hz, 3 H, CCH3); C NMR (CDCl3, 125 MHz): δ
181.4 (CS), 170.0, 169.4, 169.3 (3 CH3CO), 133.0 - 127.7 (6 C, Ar-C), 80.7 (C-1), 72.2 (C-3),
71.3 (C-4), 70.2 (C-2), 70.0 (C-5), 20.8, 20.7, 20.4 (3 CH3CO), 17.4 (CCH3). ESI-MS: 515.0
[M+Na]+; Anal. Calcd. for C19H22Cl2N2O7S (492.05): C, 46.26; H, 4.49%; found: C, 46.10; H,
4.66%.
N-(2,3,4-Tri-O-acetyl-α- -rhamnopyranosyl)-N′-(4-methylphenyl)thiourea (17): Yellow oil;
L
[α]D25 − 3 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 8.25 (br s, 1 H, NH), 7.21 - 7.09 (m, 4
H, Ar-H), 6.37 (br s, 1 H, NH), 5.95 (d, J = 9.5 Hz, 1 H, H-1), 5.37 (br s, 1 H, H-2), 5.07 (dd, J =
10.0 Hz, 3.0 Hz, 1 H, H-3), 4.91 (t, J = 10.0 Hz, 1 H, H-4), 3.68 - 3.63 (m, 1 H, H-5), 2.38 (s, 3
13
H, Ar-CH3), 2.15, 2.04, 1.95 (3 s, 9 H, 3 CH3CO), 1.2 (d, J = 5.5 Hz, 3 H, CCH3); C NMR
(CDCl3, 125 MHz): δ 180.8 (CS), 169.2 - 169.1 (3 CH3CO), 138.9 - 125.7 (6 C, Ar-C), 80.5 (C-
1), 72.0 (C-3), 71.1 (C-4), 70.0 (C-2, C-5), 20.6, 20.4, 20.3 (3 CH3CO), 17.5 (CCH3), 14.2 (Ar-
CH3). ESI-MS: 461.1 [M+Na]+; Anal. Calcd. for C20H26N2O7S (438.14): C, 54.78; H, 5.98%;
found: C, 54.60; H, 6.20%.
25
N-(2,3,4-Tri-O-acetyl-α-
L
-rhamnopyranosyl)-N′-(2,3-dichlorophenyl)thiourea (18): [α]D
−
1
7.6 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz): δ 8.37 (br s, 1 H, NH), 7.61 - 7.35 (m, 3 H, Ar-
H), 6.94 (br s, 1 H, NH), 5.87 (br s, 1 H, H-1), 5.44 (br s, 1 H, H-2) 5.08 (dd, J = 10.0 Hz, 3.0
Hz, 1 H, H-3), 4.93 (t, J = 10.0 Hz, 1 H, H-4), 3.69 - 3.66 (m, 1 H, H-5), 2.11, 2.04, 1.96 (3 s, 9
13
H, 3 CH3CO), 1.22 (d, J = 5.5 Hz, 3 H, CCH3); C NMR (CDCl3, 125 MHz): δ 181.2 (CS),
170.0, 169.4, 169.3 (3 CH3CO), 136.0 - 125.4 (6 C, Ar-C), 80.7 (C-1), 72.2 (C-3), 71.3 (C-4),
70.2 (C-2), 70.0 (C-5), 20.8, 20.7, 20.5 (3 CH3CO), 17.4 (CCH3). ESI-MS: 515.0 [M+Na]+;
Anal. Calcd. for C19H22Cl2N2O7S (492.05): C, 46.26; H, 4.49%; found: C, 46.10; H, 4.66%.
9

ACCEPTED MANUSCRIPT
N-(2,3,4-Tri-O-acetyl-α-
L
-rhamnopyranosyl-N′-(4-nitrophenyl)thiourea (19): [α]D25 + 6.3 (c
1
1.0, CHCl3); H NMR (CDCl3, 500 MHz): δ 9.09 (br s, 1 H, NH), 8.10 - 7.58 (m, 4 H, Ar-H),
7.23 - 7.21 (m, 1 H, NH), 5.93(d, J = 8.5 Hz, 1 H, H-1), 5.45 (d, J = 2.5 Hz, 1 H, H-2), 5.06 (dd,
J = 10.0 Hz, 3.0 Hz, 1 H, H-3), 4.96 (t, J = 10.0 Hz, 1 H, H-4), 3.71 - 3.66 (m, 1 H, H-5), 2.16,
2.06, 1.97 (3 s, 9 H, 3 CH3CO), 1.22 (d, J = 5.5 Hz, 3 H, CCH3); 13C NMR (CDCl3, 125 MHz): δ
180.5 (CS), 170.4, 169.8, 169.5 (3 CH3CO), 144.2 - 122.6 (6 C, Ar-C), 80.2 (C-1), 72.3 (C-3),
71.5 (C-4), 70.1 (C-2), 70.0 (C-5), 20.8, 20.7, 20.5, (3 CH3CO), 17.5 (CCH3). ESI-MS: 492.1
[M+Na]+; Anal. Calcd. for C19H23N3O9S (469.12): C, 48.61; H, 4.94%; found: C, 48.45; H,
5.10%.
N-(2,3,4-Tri-O-acetyl-α- -rhamnopyranosyl)-N′-(4-fluorophenyl)thiourea (20): Yellow oil;
L
[α]D25 − 12 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 8.54 (br s, 1 H, NH), 7.30 - 7.05 (m,
4 H, Ar-H), 6.46 (br s, 1 H, NH), 5.93 (d, J = 9.0 Hz, 1 H, H-1), 5.37 (d, J = 2.5 Hz, 1 H, H-2),
5.06 (dd, J = 10.0 Hz, 3.5 Hz, 1 H, H-3), 4.88 (t, J = 10.0 Hz, 1 H, H-4), 3.70 - 3.60 (m, 1 H, H-
13
5), 2.02, 1.98, 1.95, (3 s, 9 H, 3 CH3CO), 1.18 (d, J = 6.0 Hz, 3 H, CCH3); C NMR (CDCl3,
125 MHz): δ 181.0 (CS), 169.6, 169.3, 169.2 (3 CH3CO), 132.0 - 116.7 (6 C, Ar-C), 80.5 (C-1),
72.1 (C-3), 71.2 (C-4), 70.1 (C-2), 70.0 (C-5), 20.6, 20.5, 20.4 (3 CH3CO), 17.4 (CCH3). ESI-
MS: 465.1 [M+Na]+; Anal. Calcd. for C19H23FN2O7S (442.12): C, 51.58; H, 5.24%; found: C,
51.40; H, 5.40%.
N-[2,3,4,6-Tetra-O-acetyl-β-
D
-galactopyranosyl)-(1→4)-2,3,6-tri-O-acetyl-β- -
D
25
1
glucopyranosyl]-N′-(4-nitrophenyl)thiourea (21): Yellow oil; [α]D + 6 (c 1.0, CHCl3); H
NMR (CDCl3, 500 MHz): δ 8.90 (br s, 1 H, NH), 7.95 (d, J = 9.0 Hz, 2 H, Ar-H), 7.62 (d, J =
8.5 Hz, 2 H, Ar-H), 7.08 (s, 1 H, NH), 5.66 (t, J = 9.0 Hz, 1 H, H-1), 5.30-5.28 (m, 2 H, H-4B,
H-2A), 5.11 (t, 1 H, H-3A), 4.99 (dd, J = 3.0 Hz, 1 H, H-2B), 4.71 (t, J = 11.0 Hz, 1 H, H-3B),
4.56 (d, J = 7.5 Hz, 1 H, H-1B), 4.18 - 4.10 (m, 4 H, H-6abB, H-6abA), 4.05 (t, J = 9.0 Hz, 1 H, H-
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5B), 3.88 (t, J = 5.5 Hz, 1 H, H-4A), 3.80 (t, J = 8.5 Hz, 1 H, H-5A), 2.18, 2.14, 2.11, 2.09, 2.07,
13
2.04, 2.03, (7 s, 21 H, 7 COCH3); C NMR (CDCl3, 125 MHz): δ 182.1 (CS), 170.6, 170.3 (2
C), 169.9, 169.7, 169.5, 169.4 (7 COCH3), 146.0, 143.1, 131.6, 130.0, 129.3, 126.8 (Ar-C),
100.1 (C-1B), 81.1 (C-1A), 76.4 (C-5A), 73.8 (C-5B), 73.4 (C-3A), 71.0 (C-4A), 70.8 (C-3B), 70.1
(C-2A), 69.2 (C-2B), 67.5 (C-4B), 62.7 (C-6B), 61.3 (C-6A), 22.5, 21.1, 20.9 (2 C), 20.8, 20.7 (2
C), (7 COCH3). ESI-MS: 838.2 [M+Na]+; Anal. Calcd. for C33H41N3O19S (815.21): C, 48.59; H,
5.07%; found: C, 48.45; H, 5.25%.
General method for the de-O-acetylation of glycosyl thiourea derivatives: A solution of per-
O-acetylglycosyl thiourea derivative (100 mg) in 0.05 M CH3ONa (5 mL) was allowed to stir at
room temperature for 2 h. The reaction mixture was neutralized with Dowex X8 (H+) resin,
filtered and concentrated under reduced pressure. The crude product was passed through a short
pad of SiO2 using EtOAc as eluant to give pure de-O-acetylated products in quantitative yield.
25
N-(β-
D
-Glucopyranosyl-N′-(4-nitrophenyl)thiourea (10a): glassy syrup; [α]D + 5 (c 1.0,
CH3OH); 1H NMR (D2O, 500 MHz): δ 8.31 (d, J = 9.0 Hz, 2 H, Ar-H), 7.68 (d, J = 9.0 Hz, 2 H,
Ar-H), 5.65-5.60 (br s, 1 H, H-1), 3.95-3.91 (dd, J = 12.0, 2.0 Hz, 1 H, H-6a), 3.81-3.74 (dd, J =
12.0, 5.0 Hz, H-6b), 3.64-3.58 (m, 2 H, H-2, H-5), 3.53 (t, J = 9.0 Hz, 1 H, H-3), 3.46 (t, J = 9.0
13
Hz, 1 H, H-4); C NMR (D2O, 125 MHz): δ 181.9 (CS), 146.3-121.3 (Ar-C), 83.8 (C-1), 78.8,
77.9, 72.9, 70.1, 63.1; ESI-MS: 382.0 [M+Na]+; Anal. Calcd. for C13H17N3O7S (359.08): C,
43.45; H, 4.77%; found: C, 43.25; H, 5.00%.
25
N-(β-
D
-Glucopyranosyl-N′-(2,3-dichlorophenyl)thiourea (12a): glassy syrup; [α]D − 8 (c
1.0, CH3OH); 1H NMR (D2O, 500 MHz): δ 9.16 (br s, 1 H, NH), 8.46 (br s, 1 H, NH), 8.02-7.80
(m, 3 H, Ar-H), 5.82-5.78 (m, 1 H, H-1), 4.27-4.11 (m, 2 H, H-6ab), 3.95-3.73 (m, 4 H, H-2, H-3,
H-4, H-5); 13C NMR (D2O, 125 MHz): δ 183.8 (CS), 133.9-128.1 (Ar-C), 84.1 (C-1), 77.7,
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76.8, 72.3, 69.7, 61.0; ESI-MS: 405.0 [M+Na]+; Anal. Calcd. for C13H16Cl2N2O5S (382.02): C,
40.74; H, 4.21%; found: C, 42.53; H, 4.45%.
25
N-(α-
L
-Rhamnopyranosyl)-N′-(2,4-dichlorophenyl)thiourea (16a): glassy syrup; [α]D + 9
(c 1.0, CH3OH); 1H NMR (D2O, 500 MHz): δ 8.03-7.80 (m, 3 H, Ar-H), 5.96 (br s, 1 H, H-1),
4.40 (br s, 1 H, H-2), 4.06 (dd, J = 9.5, 3.5 Hz, 1 H, H-3), 3.92-3.85 (m, 1 H, H-5), 3.77 (t, J =
10.5 Hz, 1 H, H-4), 1.69 (d, J = 6.5 Hz, 3 H, CCH3); 13C NMR (D2O, 125 MHz): δ 182.6 (CS),
133.9-128.1 (Ar-C), 82.0 (C-1), 73.9, 73.4, 72.0, 70.1, 17.0 (CCH3); ESI-MS: 389.0 [M+Na]+;
Anal. Calcd. for C13H16Cl2N2O4S (366.02): C, 42.52; H, 4.39%; found: C, 42.33; H, 4.60%.
Acknowledgements
A.G. and M.J. thank CSIR, New Delhi for providing Junior and senior research fellowships
respectively. This work was supported by SERB, New Delhi (Project No. EMR/2015/000282).
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Graphical abstract
Preparation of glycosyl thiourea derivatives from glycosyl
azides using sulfamic acid and sodium iodide in one-pot
Arin Gucchait, Manas Jana, Kuladip Jana
and Anup Kumar Misra*
AcO
AcO
S
ArNCS
O
O
Ar
N3
Sulfamic acid
NaI, RT, 8-10 h
56-76%
N
N
H
H
Ar = aryl
15

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Research Highlights
•
•
•
•
Glycosyl thiourea derivatives were prepared directly from glycosyl azides.
Sulfamic acid and sodium iodide has been used for the reduction of azide group.
Non-metallic and non-hazardous reaction condition.
Aryl isothiocyanates reacted with in situ generated glycosyl amine derivatives.