Regioselectivity in the glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol

Article abstract of DOI:10.1016/j.carres.2009.01.026

The glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (1) and its 3-benzylsulfanyl and 3-methylsulfanyl derivatives with different glycosyl halides 2-4 has been studied in presence of base. The S-glycosides 5-7 were obtained in the

Full text of DOI:10.1016/j.carres.2009.01.026

Carbohydrate Research 344 (2009) 725–733
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Carbohydrate Research
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Regioselectivity in the glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-
4H-1,2,4-triazole-3-thiol
a,
El Sayed H. El Ashry a, , Ahmed A. Kassem , Hamida M. Abdel-Hamid a,à
,
*
Farida Louis a, Sherine A. N. Khattab a, Mohamed R. Aouad b
a Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
b Chemistry Department, Faculty of Science, University of Science and Technology–Mohamed Boudiaf-USTO-MB BP:1505 ELM’NOUAR, ORAN 31000, Algeria
a r t i c l e i n f o
a b s t r a c t
Article history:
The glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (1) and its 3-benzylsulfa-
nyl and 3-methylsulfanyl derivatives with different glycosyl halides 2–4 has been studied in presence
of base. The S-glycosides 5–7 were obtained in the presence of triethylamine, whereas the respective
S,N4-bis(glycosyl) derivatives 8–10 were synthesized in the presence of potassium carbonate; the S,N2-
bis(glycosyl) isomer 11 could also be isolated in the case of the galactosyl analog. Similarly, after protect-
ing 1 as 3-benzyl(methyl)sulfanyl derivatives 12 or 13, the N4-glycosyl analogs 14–19 as well as minor
amounts of S,N2-bis(galactosyl) isomers 20 and 21 were formed. The theoretical calculations using
AM1 semiempirical methods agreed with the experimental results. Microwave irradiation (MWI) led
to higher yields in much less time than the conventional methods, and no change in regioselectivity
has been noticed.
Received 29 November 2008
Received in revised form 22 January 2009
Accepted 29 January 2009
Available online 5 February 2009
Keywords:
Thioglycoside
Selective glycosylation
Glycosyl halide
Benzo[b]thiophene
1,2,4-Triazole
Ó 2009 Elsevier Ltd. All rights reserved.
Microwave irradiation
1. Introduction
which the glycosyl moieties have been used as carriers for the het-
erocycle, having the triazole ring linked to the benzothiophene
Glycosylsulfanyl heterocycles have attracted much attention
because of their biological activity and in particular because of
their inhibition of the activity of enzymes.1–6 They have excellent
chemoselectivity in glycosylation processes as both donors and
acceptors,7 particularly via reaction processes that involve active
and latent glycosylation8 protocols. Thus, these compounds serve
as useful intermediates for the synthesis of oligosaccharides.6–14
On the other hand, the 1,2,4-triazole nucleus is found in many
drug structures such as anastrozole, estazolam, ribavirin, and tria-
zolam. In addition, these compounds show antiseptic, analgesic,
and anticonvulsant properties.15 Considerable attention has been
devoted to the synthesis of benzothiophene derivatives that pos-
sess diverse pharmacological properties, such as antibiotic, analge-
sic, antiallergic, anti-inflammatory, diuretic and enzyme inhibition
activities.16,17
ring, as in 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole. The
effects of base and microwave irradiation (MWI) on the glycosyla-
tion with various glycosyl halides have been investigated as a con-
tinuation of our previous work using microwave technology.18–27
Microwave-assisted organic reactions constitute an emerging tech-
nology that makes experimentally and industrially important
organic syntheses more effective and more ecofriendly than
conventional reactions.28–32
2. Results and discussion
The optimum conditions have been determined for the selective
glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-
3-thiol (1),33 which is readily available34 from MWI-assisted
synthesis, as well as of its 3-benzylsulfanyl- and methylsulfanyl
derivatives 1234 and 13,33 which are prepared by both conven-
tional and MWI methods. Coupling of 1 with one or two equiva-
lents of glycosyl halides 2–4 takes place in the presence of
triethylamine with acetone as solvent to give the S-glycosyl com-
pounds 5–7 in 77–80% yield (Scheme 1). More efficiently, MWI of
a mixture of the reactants provided 5–7 in higher yields (90–
93%) within 3–4 min with no change in regioselectivity.
On the basis of these findings, it is interesting to report the syn-
thesis and spectroscopic analysis of a new series of compounds in
* Corresponding author. Tel.: +20 34246601, fax: +20 34271360.
E-mail address: Eelashry60@hotmail.com (E.S.H. El Ashry).
On leave to Chemistry Department, Faculty of Science, King Khaled University,
Abha, Saudi Arabia.
The 1H NMR spectra of 5–7 confirmed that a monoglycosylation
of 1 had taken place by showing one exchangeable proton in the
à
On leave to Chemistry Department, Faculty of Science, King Abdelaziz University,
Jeddah, Saudi Arabia.
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.01.026

726
E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
Cl
4
3
9
8
N
N
5
6
2
SH
Et3N
O
N
H
S
7
K2CO3
O
1
Cl
Cl
N
N
, DMF
N
N
S
HNEt3
S
K
N
H
S
N
H
S
B
A
R2
AcO
R1
OAc
AcY
O
X
2 Y = O, X = Br, R1 = OAc, R2 = H
3 Y = NH, X = Cl, R1 = OAc, R2 = H
1
R2 = OAc
4
Y = O, X = Br, R = H,
R2
Cl
S
AcO
AcY
R1
OAc
N
N
O
S
N
H
5 Y = O, R1 = OAc, R2 = H
Y = NH, R = OAc, R2 = H
1
6
7
Y = O, R1 = H, R2 =OAc
O
K2CO3,
, DMF
R2
OAc
Cl
AcO
a
Cl
AcO
AcO
N
K
R1
OAc
N
AcY
N
N
a
O
S
O
S
OAc
N
S
N
S
K
2-4
2-4
R2
Cl
AcO
a
AcO
AcO
OAc
R1
OAc
AcY
N
N
O
S
b
N
S
O
O
OAc
AcO
AcO
AcO
R2
Cl
YAc
AcO
N
N
b
a
O
S
OAc
R1
OAc
N
11
S
8 Y = O, R1 = OAc, R2 = H
9 Y = NH, R1 = OAc, R2 = H
Y= O, R1 = H, R2 = OAc
10
Scheme 1.
downfield region at 12.08–14.62 ppm due to the NH-proton of the
triazole ring. The anomeric protons of 5–7 were assigned to the
pyranosyl) analogs, along with the recovery of some starting mate-
rial 1. Under the same reaction conditions, but using 2.2 equiv of
glycosyl halides 2 or 3, the S,N4-bis(glycopyranosyl) derivatives 8
and 9, respectively, were obtained. On the other hand, reaction of
0
0
doublet at 5.27–5.46 ppm with J1 ,2 9.9–10.7 Hz, confirming the
b-configuration. The heteromultiple bond correlation 1H–1H DQF-
COSY and 1H–13C HMQC experiments facilitated the spectral
assignment of 5–7 (Section 4).
1 with tetra-O-acetyl-a-D-galactopyranosyl bromide (4) afforded
a mixture of S,N4- 10 and S,N2-bis(galactopyranosyl) 11 derivatives
as major and minor products, respectively, in 75% overall yield,
which were separated by column chromatography (RfN-4 > RfN-2).
Improvement of the yields of the bis(glycosides) to 89–92% and
Reaction of 1 with 1.1 equiv of glycosyl halides 2–4 in the pres-
ence of K2CO3 did not afford the expected S-glycopyranosyl
products only, but they were accompanied by the S,N4-bis(glyco-

E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
727
significant reduction in reaction times to 4–5 min were achieved
under microwave irradiation (MWI), but with no recognized
change in the ratio of isomers.
The structures of compounds 8–11 were established on the ba-
sis of their elemental analyses and spectral data, which indicated
the presence of two glycosyl residues and the absence of the signal
of an NH-triazole. The 1H NMR spectra of 8–11 showed the pres-
ence of two doublets in the region 5.51–5.70 and 5.48–6.03 ppm
In order to assign the site of glycosylation, we have initiated a
study of the tautomerism in 5-(3-chlorobenzo[b]thien-2-yl)-4H-
1,2,4-triazole-3-thiol (1),34 which indicated the preference of the
thiol tautomer. In the present work, the theoretical approach has
been considered for the tautomers 5–7 and the transition state
by means of the semiempirical AM1 method. The computations
were carried out with the MOPAC7 package.35 Thus, the heat of for-
mation, dipole moment, the highest occupied molecular orbital
energies (EHOMO), the lowest unoccupied molecular orbital energies
(ELUMO), and the charge density on triazole heteroatoms, as well as
the relative stabilities, have been calculated (Tables 1 and 2).
On the basis of the regioselective alkylation of 1,34 we could as-
sume that the glycosylation of 1 would give, due to the higher
nucleophilic properties and the lower electronegativity of the sul-
fur atom,36 the S-glycosylated products 5–7, which could be the
precursors for the bis(glycosylated) products 8–11. Further, reac-
tion of 5–7 in presence of potassium carbonate could generate
one or more of the equilibrated anionic transition states, which
upon reaction with glycosyl halides 2–4 gave the corresponding
bis(glycosylated) derivatives 8–11 (Scheme 3). Since this glycosyl-
ation occurred from a nucleophilic substitution, we have analyzed
the charge density distribution in the tautomers, their anionic
forms and the calculated relative stabilities (Scheme 3). The transi-
tion states and tautomers of 5–7 have the negative charge more
localized at the N4 atom, followed by N2 and then N1 (Tables 1
and 2), thus explaining the favored regioselective glycosylation at
N4, and to minor extent at N2 such as S,N2-bis(galactopyranosyl)
11. Moreover, the calculated relative stability (Tables 1 and 2)
based on the energy difference for possible alkylation on N4, N2
and N1 also coincides with the experimental results.
with J1 ,2 9.2–10.7 Hz for H-10a and H-10b, confirming that the gly-
cosyl residues were in the b-configuration. The heteromutiple
bond correlation facilitated the spectral assignment. In the 1H
NMR spectrum of compound 9, there are eight signals in the
upper-field region corresponding to the methyl groups of the two
acetamido and six acetoxy groups. The two anomeric protons cor-
related with 83.3 and 84.5 ppm for C-10a and C-10b, respectively.
Resonances for the other proton and carbon atom were in their
appropriate positions (Section 4).
0
0
In order to help in assigning the H-10 in the 1H NMR of S,N4- and
S,N2-bis(glycosides), latent glycosylations of the S-protected 12
and 13 with glycosyl halides 2–4 were carried out in presence of
K2CO3 under MWI for 4–6 min to give the respective glycosides
14–19 in 86–90% yield (Scheme 2); conventional methods required
longer times (18–21 h) to give 71–76% yields of the same products.
It has also been found that the galactosyl derivatives gave in addi-
tion, the minor galactosyl derivatives at N2 20 and 21.
Attempted use of the chemical shifts of H-10 of both the S- and
N-glycosides for differentiation was not reliable because of their
close values. Thus, the spectra showed the anomeric protons as
doublets at 5.50–5.51 ppm for 18 and 19, and 5.46–5.45 ppm for
20 and 21; the thioglycoside showed them at 5.51–5.70 ppm.
R2
Cl
AcO
N
N
R1
OAc
AcY
SR
+
O
N
H
S
X
2 Y = O, X = Br, R1 = OAc, R2 = H
12 R = CH2Ph
13 R = CH3
1
Y = NH, X = Cl, R = OAc, R2 = H
3
4
Y = O, X = Br, R1 = H, R2 = OAc
K2CO3
O
OAc
Cl
AcO
N
N
SR
+
O
N
S
Cl AcO
O
YAc
N
N
AcO
R2
SR
N
S
R1
OAc
14 Y = O, R = CH2Ph, R1 = OAc, R2 = H
15 Y = O, R = CH3, R1 = OAc, R2 = H
16 Y = NH, R = CH2Ph, R1 = OAc, R2 = H
20
21
R = CH2Ph
R = CH3
Y = NH, R = CH3, R1 = OAc, R2 = H
17
18
1
Y = O, R = CH2Ph, R = H, R2 = OAc
19 Y = O, R = CH3,
R1 = H, R2 = OAc
Scheme 2.

728
E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
Table 1
Calculated (AM1) heat of formation (kcal), relative stability (kcal), dipole moments, (l, Debye), HOMO orbital energies (EHOMO, eV) and charge density on triazole heteroatoms for
the tautomers 5–7
Tautomer No.
Heat of formation (
D
Hf, kcal)
l
(Debye)
EHOMO (eV)
ꢀ8.509
ELUMO (eV)
ꢀ0.933
Charge density on triazole heteroatoms
Relative stabilitya (RS, kcal)
5a
ꢀ254.133
2.887
5.977
5.277
4.777
5.398
8.576
4.829
7.767
2.634
ꢀ0.181 (N-4)
ꢀ0.091 (N-2)
ꢀ0.039 (N-1)
ꢀ0.168 (N-4)
ꢀ0.167 (N-2)
ꢀ0.047 (N-1)
ꢀ0.130 (N-4)
ꢀ0.104 (N-2)
ꢀ0.153 (N-1)
ꢀ0.178 (N-4)
ꢀ0.097 (N-2)
ꢀ0.048 (N-1)
ꢀ0.099 (N-4)
ꢀ0.134 (N-2)
ꢀ0.028 (N-1)
ꢀ0.121 (N-4)
ꢀ0.116 (N-2)
ꢀ0.155 (N-1)
ꢀ0.180 (N-4)
ꢀ0.087 (N-2)
ꢀ0.038 (N-1)
ꢀ0.097 (N-4)
ꢀ0.132 (N-2)
ꢀ0.028 (N-1)
ꢀ1.841 (5a–5b)
ꢀ3.618 (5a–5c)
5b
5c
6a
6b
6c
7a
7b
7c
a
ꢀ252.292
ꢀ250.515
ꢀ214.017
ꢀ211.823
ꢀ208.940
ꢀ258.733
ꢀ254.186
ꢀ252.575
ꢀ8.441
ꢀ8.545
ꢀ8.583
ꢀ8.211
ꢀ8.492
ꢀ8.575
ꢀ8.217
ꢀ8.635
ꢀ0.777
ꢀ1.114
ꢀ1.090
ꢀ0.518
ꢀ1.211
ꢀ1.082
ꢀ0.524
ꢀ1.083
ꢀ1.777 (5b–5c)
ꢀ2.194 (6a–6b)
ꢀ5.077 (6a–6b)
ꢀ2.883 (6b–6c)
ꢀ4.547 (7a–7b)
ꢀ6.158 (7a–7c)
ꢀ1.611 (7b–7c)
ꢀ0.112 (N-4)
ꢀ0.072 (N-2)
ꢀ0.152 (N-1)
RS = The difference in the heat of formation between each of two possible tautomers.
Table 2
Calculated (AM1) heat of formation (kcal), relative stability (kcal), dipole moments, (
the transition states (TS) TS 5–7
l
, Debye), HOMO orbital energies (EHOMO, eV) and charge density on triazole heteroatoms for
TS of tautomer No.
Heat of formation (
D
Hf, kcal)
l
(Debye)
EHOMO (eV)
ꢀ4.619
ELUMO (eV)
Charge density on triazole heteroatoms
Relative stabilitya (RS, kcal)
TS 5a
ꢀ305.670
ꢀ305.436
ꢀ304.828
ꢀ267.928
ꢀ267.553
ꢀ265.985
ꢀ311.560
ꢀ308.385
ꢀ307.215
14.026
14.378
14.794
9.255
2.351
ꢀ0.118 (N-4)
ꢀ0.116 (N-2)
ꢀ0.093 (N-1)
ꢀ0.115 (N-4)
ꢀ0.105 (N-2)
ꢀ0.095 (N-1)
ꢀ0.129 (N-4)
ꢀ0.096 (N-2)
ꢀ0.097 (N-1)
ꢀ0.111 (N-4)
ꢀ0.096 (N-2)
ꢀ0.090 (N-1)
ꢀ0.116 (N-4)
ꢀ0.137 (N-2)
ꢀ0.095 (N-1)
ꢀ0.141 (N-4)
ꢀ0.122 (N-2)
ꢀ0.091 (N-1)
ꢀ0.116 (N-4)
ꢀ0.111 (N-2)
ꢀ0.093 (N-1)
ꢀ0.112 (N-4)
ꢀ0.113 (N-2)
ꢀ0.094 (N-1)
ꢀ0.234 (5a–5b)
ꢀ0.842 (5b–5c)
TS 5b
TS 5c
TS 6a
TS 6b
TS 6c
TS 7a
TS 7b
TS 7c
a
ꢀ4.701
ꢀ4.729
ꢀ4.836
ꢀ4.952
ꢀ4.733
ꢀ4.667
ꢀ4.626
ꢀ4.780
2.321
2.296
2.202
2.165
2.143
2.325
2.367
2.226
ꢀ0.608 (5a–5c)
ꢀ0.375 (6a–6b)
ꢀ1.943 (6a–6b)
9.601
ꢀ1.568 (6b–6c)
9.731
13.847
14.947
9.387
ꢀ3.175 (7a–7b)
ꢀ4.345 (7b–7c)
ꢀ1.170 (7b–7c)
ꢀ0.139 (N-4)
ꢀ0.098 (N-2)
ꢀ0.095 (N-1)
RS = The difference in the heat of formation between each of two possible TS.

E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
729
R
N
Cl
Cl
N
N
N
SR
SR
N
N
S
S
Transition states (TS)
Products
8-11
H
N
1
2
Cl
Cl
N NH
Cl
N
N
N
SR
SR
SH
N
H
N
N
4
S
S
S
1
5a-7a
5b-7b
Tautomeric
forms
Reactant
Cl
HN
N
SR
N
S
5c-7c
R2
AcO
R1
OAc
AcY
R =
O
1
Y = O, R = OAc, R2 = H
5, 8
6, 9
Y = NH, R1 = OAc, R2 = H
7, 10, 11 Y = O, R1 = H, R2 =OAc
Scheme 3.
On the other hand, AM1 optimization of the structure of tau-
tomers 5–7 could justify the possibility of intramolecular hydrogen
bonding between the mobile hydrogen atom of the triazole ring
and the chlorine atom. Since the benzothiophene and triazole rings
are not planar, the N–HꢁꢁꢁCl distance was found to be smaller in
case of tautomer 5c (2.00 Å) when compared to tautomers 5a
(4.99 Å) and 5b (4.87 Å) (Table 3). Accordingly, the tendency of
intramolecular H-bonding seems to be higher in case of 5c, and
hence its proton-donating power is weakened (i.e., becoming less
acidic), thus diminishing the possibility of its alkylation (Fig. 1).
The preferential formation of S,N4-bis(glycopyranosyl) more
than S,N2-bis(glycopyranosyl) is presumably due to the higher
acidity of N4–H. After the introduction of the glycosyl residue on
the sulfur atom, the second glycosyl residue will be directed to
N4. In case of the galactosyl derivative, the higher reactivity of
the donor could be a reason for further galactosylation at N2. Such
isomers from other sugars were undetectable. The difference in the
effect of the triethylamine and potassium carbonate in the glyco-
sylation steps can be due to the extent of abstraction of a proton
from N4–H or N2–H.
3. Conclusions
In conclusion, regioselective glycosylation of 5-(3-chloro-
benzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (1) with glycosyl ha-
lides 2–4 to give the corresponding S-glycosides 5–7 took place in
presence of triethylamine. In the presence of potassium carbonate,
the respective S,N4-bis(glycosyl) derivatives 8–10 were obtained;
the galactopyranosyl analogue gave, in addition, minor products
of S,N2-bis(glycosyl) isomer 11. MWI led to higher yields in much
less time than the conventional methods, and no change in
regioselectivity has been noticed.
Table 3
Selected bond length (Å) and angles (°)
Tautomer No.
Bond length NHꢁꢁꢁCl
Bond angle
C(15)–C(14)–C(1)–N(5)
Tetrahedral angle
Cl(16)–C(15)–C(14)
C(1)–C(14)–C(15)–Cl(16)
C(15)–Cl(16)–H(6)–N(5)
5a
5b
5c
6a
6b
6c
7a
7b
7c
4.987
4.872
2.000
5.092
4.861
2.000
4.951
4.861
2.000
125.7
126.2
126.4
125.8
126.3
126.3
125.6
126.3
126.3
41.2
ꢀ0.4
1.5
34.6
4.3
ꢀ3.9
43.7
7.2
ꢀ3.2
1.6
0.0
0.0
1.3
0.0
0.0
1.7
0.0
0.0
—
—
3.8
—
—
ꢀ7.8
—
—
ꢀ6.4

730
E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
Figure 1.
The AM1 computational data are in agreement with the result-
HMQC experiments. Chemical shifts (d) are given in ppm relative
to the signal for TMS as internal standard. Elemental analyses
were performed in the Microanalyses unit at the Faculty of Sci-
ence, Cairo University. Numbering of the ring systems in deriva-
tives follows that of the starting material 1 regardless of IUPAC
rules.
ing isomeric ratio distribution observed in the experimental data,
where the glycosylation occurred predominantly at the N4 and to
lesser extent at the N2 atom, which was noticed in the case of
galactopyranosyl derivatives.
4. Experimental
4.2. General procedure: reaction of 5-(3-chlorobenzo[b]thien-
2-yl)-4H-1,2,4-triazole-3-thiol (1) with glycosyl halides 2–4 in
the presence of Et3N
4.1. General methods and materials
Melting points were determined with a Melt-Temp apparatus,
and are uncorrected. TLC was performed on Baker-Flex silica gel
1B-F plates using EtOAc–hexane as the developing solvent, and
the spots were detected by UV light absorption. Irradiation was
done in a domestic microwave oven EM-230M (1200 W output
power under ‘defrost’ setting). The irradiation was done, unless
otherwise stated, in a closed Teflon cylindrical vessel that was
placed at the center of a rotating plate inside the oven. The vessel
was supported by a frame for safety. The vessel had an outside
diameter of 6.5 cm and a length of 6.0 cm, whereas the space in-
side the vessel was 3.0 cm in width and 2.0 cm in length. An addi-
tional 2.0 cm in length inside the vessel was used for the screw
cap that was tightened. The oven was set in the defrost mode
with fixed output power. 1H NMR and 13C NMR spectra were re-
corded on a Jeol spectrometer (500 MHz). The assignment of 1H
NMR spectra was based on chemical shift correlation DQFCOSY
spectra, while the assignment of 13C NMR spectra was based on
4.2.1. Conventional method (CM)
A mixture of compound 1 (1 mmol) and Et3N (1 mmol, 0.14 mL)
in dry acetone (25 mL) was stirred for 1 h, then glycosyl halides 2–
4 (1.1 mmol) were added. Stirring was continued overnight with 2,
whereas with 3 and 4, the reaction mixture was heated under re-
flux for 2 and 3 h, respectively. The mixture was filtered, the solids
were washed with acetone, the filtrate was evaporated under re-
duced pressure, and the crude product was recrystallized from
EtOH to give the S-glycosides 5–7.
4.2.2. Microwave irradiation (MWI) method
A mixture of compound 1 (0.5 mmol), Et3N (0.5 mmol, 0.07
mL), and glycosyl halides 2–4 (0.55 mmol) in dry acetone (5
mL) in a closed Teflon vessel was irradiated for 3–4 min. The
reaction mixture was cooled and processed as described above
to give 5–7.

E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
731
4.2.3. 5-(3-Chlorobenzo[b]thien-2-yl)-3-(2,3,4,6-tetra-O-acetyl-
Stirring was continued overnight, and then the reaction mixture
was heated under reflux for 2–4 h. The mixture was filtered, the
solids were washed with acetone, the filtrate was evaporated un-
der reduced pressure, and the crude product was recrystallized
from EtOH to afford 8 and 9 from 2 and 3, respectively, whereas
10 and 11 from 4 were separated by column chromatography using
30:70 hexane–EtOAc as eluant, and the products were recrystal-
lized from EtOH.
b-
D-glucopyranosylsulfanyl)-4H-1,2,4-triazole (5)
Colorless plates; yield: CM (80%), MW (93%); mp 214–215 °C;
TLC, Rf 0.18 (1:1 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz): d
0
0
2.01, 2.03, 2.07, 2.09 (4 ꢂ s, 12H, 4 ꢂ CH3CO), 3.86 (ddd, 1H, J5 ,6
4.6, J5 ,6 2.3, J5 ,4 9.9 Hz, H-50), 4.22 (dd, 1H, J6 ,5 4.6, J6 ,6 12.2
0
00
0
0
0
0
0
00
Hz, H-60), 4.28 (dd, 1H, J6 ,5 2.3, J6
,
12.2 Hz, H-600), 5.14 (dd, 1H,
00
0
00
0
6
J4 ,3 9.2, J4 ,5 9.9 Hz, H-40), 5.17 (dd, 1H, J2 ,3 9.2 Hz, J2 ,1 9.9 Hz,
0
0
0
0
0
0
0
0
H-20), 5.27 (d, 1H, J1 ,2 9.9 Hz, H-10), 5.31 (t, 1H, J3 ,4 9.2 Hz, H-30),
7.43–7.48 (m, 2H, H-5, H-6 benzothiophene), 7.82 (dd, 1H, J 2.3, J
6.1 Hz, H-4 benzothiophene), 7.87 (dd, 1H, J 2.3, J 6.1 Hz, H-7 ben-
zothiophene), 12.08 (s, 1H, D2O exchangeable, NH). 13C NMR
(CDCl3, 125.7 MHz): d 20.7, 20.8 (4 ꢂ CH3CO), 61.9 (C-60), 68.1
(C-40), 69.9 (C-200), 73.6 (C-30), 76.3 (C-50), 83.3 (C-10), 120.0 (C-9),
122.6 (C-4), 122.7 (C-7), 125.5 (C-5), 126.1 (C-8), 126.9 (C-6),
137.0 (C-3), 137.6 (C-2), 169.5, 169.6, 170.2, 171.1 (4 ꢂ CH3CO).
Anal. Calcd for C24H24ClN3O9S2: C, 48.20; H, 4.04; N, 7.03. Found:
C, 48.12; H, 4.10; N, 6.81.
0
0
0
0
4.3.2. Microwave irradiation (MWI) method
A mixture of compound 1 (0.5 mmol), potassium carbonate (1
mmol, 0.138 g), and glycosyl halides 2–4 (1.1 mmol) in dry acetone
(5 mL) and a few drops of DMF in a closed Teflon vessel were irra-
diated for 4–5 min. The reaction mixture was cooled and processed
as described above to give 8–11.
4.3.3. 5-(3-Chlorobenzo[b]thien-2-yl)-4-(2,3,4,6-tetra-O-acetyl-
b-D-glucopyranosyl)-3-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosylsulfanyl)-4H-1,2,4-triazole (8)
4.2.4. 3-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-
nosylsulfanyl)-5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole
(6)
D
-glucopyra-
Colorless crystals; yield: CM (77%), MW (92%); mp 172–173 °C,
Rf 0.10 (1:1 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz): d 1.87,
1.97, 1.99, 2.01, 2.02, 2.04, 2.07, 2.08 (8 ꢂ s, 24H, 8 ꢂ CH3CO),
3.87 (ddd, 1H, J5 a,6 a 2.3, J5 a,6 a 4.6, J5 a,4 a 9.9 Hz, H-50a), 3.98
0
0
0
00
0
0
Colorless plates; yield: CM (78%), MW (92%); mp 222–223 °C,
Rf 0.68 (1:5 hexane–EtOAc). 1H NMR (DMSO-d6, 500 MHz): d 1.79,
1.88, 1.92, 1.95 (4 ꢂ s, 12H, NCH3CO, 3 ꢂ CH3CO), 3.90–3.93 (m,
(ddd, 1H, J5 b,6 b 2.3, J5 b,6 b 4.6, J5 b,4 b 9.9 Hz, H-50b), 4.10 (dd, 1H,
0
0
0
00
0
0
J6 a,5 a 2.3, J6 a,6 a 12.2 Hz, H-60a), 4.17 (dd, 1H, J6 b,5 b 2.3, J6 b,6 b
0
0
0
00
0
0
0
00
1H, H-50), 3.98 (dd, 1H, J6 ,5 1.5, J6 ,6 12.2 Hz, H-60), 4.09 (ddd,
12.2 Hz, H-60b), 4.28 (dd, 1H, J6 a,5 a 4.6, J6 a,6 a 12.2 Hz, H-600a),
0
0
0
00
00
0
00
0
1H, J2 ,3 9.9, J2 ,1 10.7, J2 ,NH 9.2 Hz, H-20), 4.18 (dd, 1H, J6 ,5 5.3,
4.32 (dd, 1H, J6 b,5 b 4.6, J6 b,6 b 12.2 Hz, H-600b), 5.14 (dd, 1H, J4 a,3 a
0
0
0
0
0
00
0
00
0
00
0
0
0
,
6
12.2 Hz, H-600), 4.92 (t, 1H, J4 ,3 J4 ,5 9.9 Hz, H-40), 5.19 (dd,
9.2, J4 a,5 a 9.9 Hz, H-40a), 5.20 (dd, 1H, J2 a,1 a 10.7, J2 a,3 a 9.9 Hz, H-
00
J6
0
0
0
0
0
0
0
0
0
0
0
1H, J3 ,2 9.9 Hz, H-30), 5.46 (d, 1H, J1 ,2 10.7 Hz, H-10), 7.49–7.54
(m, 2H, H-5, H-6 benzothiophene), 7.84 (dd, 1H, J 1.5, J 6.9 Hz,
H-4 benzothiophene), 8.06 (dd, 1H, J 1.5, J 7.6 Hz, H-7 benzothio-
20a), 5.29 (dd, 1H, J4 b,3 b 9.2, J4 b,5 b 9.9 Hz, H-40b), 5.32 (dd, 1H,
0
0
0
0
0
0
0
0
J3 a,2 a 9.9, J3 a,4 a 9.2 Hz, H-30a), 5.37 (t, 1H, J3 b,2 b = J3 b,4 b 9.2 Hz,
0
0
0
0
0
0
0
0
H-30b), 5.58 (d, 1H, J1 a,2 a 10.7 Hz, H-10a), 5.65 (d, 1H, J1 b,2 b 9.2
0
0
0
0
phene), 8.24 (d, 1H, JNH,2 9.2 Hz, D2O exchangeable, NHAc), 14.62
Hz, H-10b), 5.82 (t, 1H, J2 b,1 b = J2 b,3 b 9.2 Hz, H-20b), 7.41–7.46 (m,
2H, H-5, H-6 benzothiophene), 7.79 (dd, 1H, J 1.5, J 6.9 Hz, H-4 ben-
zothiophene), 7.89 (dd, 1H, J 1.5, J 6.9 Hz, H-7 benzothiophene). 13C
NMR (CDCl3, 125.7 MHz): d 20.4, 20.6, 20.7 (8ꢂCH3CO), 61.4 (C-
60b), 61.7 (C-60a), 67.4 (C-40b), 68.0 (C-40a), 69.6 (C-20a), 69.8 (C-
20b), 73.1 (C-30b), 73.8 (C-30b), 74.9 (C-50b), 76.7 (C-50a), 84.1 (C-
10a), 84.3 (C-10b), 120.8 (C-9), 122.6 (C-4), 122.8 (C-7), 125.2 (C-
5), 125.8 (C-8), 126.6 (C-6), 137.4 (C-3), 137.6 (C-2), 168.4, 169.3,
169.4, 169.6, 170.1, 170.3, 170.7 (8 ꢂ CH3CO). Anal. Calcd for
C38H42ClN3O18S2: C, 49.16; H, 4.56; N, 4.53. Found: C, 48.97; H,
4.65; N, 4.54.
0
0
0
0
0
(s, 1H, D2O exchangeable, NH). 13C NMR (DMSO-d6, 125.7 MHz): d
20.8, 20.9, 23.1 (4 ꢂ CH3CO), 52.5 (C-20), 62.3 (C-60), 68.8 (C-40),
73.6 (C-30), 75.6 (C-50), 84.1 (C-10), 119.9 (C-9), 122.5 (C-4),
123.7 (C-7), 126.3 (C-5), 126.8 (C-8), 127.3 (C-6), 136.9 (C-3),
137.2 (C-2), 169.8, 170.1, 170.4 (4 ꢂ CH3CO). Anal. Calcd for
C24H25ClN4O8S2: C, 48.28; H, 4.22; N, 9.38. Found: C, 48.05; H,
4.44; N, 9.25.
4.2.5. 5-(3-Chlorobenzo[b]thien-2-yl)-3-(2,3,4,6-tetra-O-acetyl-
b-
D
-galactopyranosylsulfanyl)- 4H-1,2,4-triazole (7)
Colorless crystals; yield: CM (77%), MW (90%); mp 200–201 °C,
Rf 0.50 (1:2.5 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz): d 1.98,
2.04, 2.08, 2.15 (4 ꢂ s, 12H, 4 ꢂ CH3CO), 4.06–4.09 (m, 1H, H-50),
4.3.4. 4-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-
nosyl)-3-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-
anosylsulfanyl)-5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole
(9)
D
-glucopyra-
-glucopyr-
D
4.13–4.20 (m, 2H, H-60, H-600), 5.16 (dd, 1H, J3 ,2 9.9, J3 ,4 3.1 Hz,
0
0
0
0
H-30), 5.29 (d, 1H, J1 ,2 9.9 Hz, H-10), 5.36 (t, 1H, J2 ,3 9.9 Hz, H-20),
0
0
0
0
5.48 (d, 1H, J4 ,3 3.1 Hz, H-40), 7.42–7.47 (m, 2H, H-5, H-6 benzo-
thiophene), 7.81 (dd, 1 H, J 2.3, J 6.9 Hz, H-4 benzothiophene),
7.86 (dd, 1H, J 2.3, J 6.9 Hz, H-7 benzothiophene), 12.18 (s, 1H,
D2O exchangeable, NH). 13C NMR (CDCl3, 125.7 MHz): d 20.6,
20.7, 20.8 (4 ꢂ CH3CO), 61.7 (C-60), 67.3 (C-40, C-20), 71.7 (C-30),
75.2 (C-50), 83.8 (C-10), 120.0 (C-9), 122.6 (C-4), 122.7 (C-7),
125.5 (C-5), 125.9 (C-8), 126.9 (C-6), 137.1 (C-3), 137.5 (C-2),
169.8, 170.1, 170.3, 170.7 (4 ꢂ COCH3). Anal. Calcd for
C24H24ClN3O9S2: C, 48.20; H, 4.04; N, 7.03. Found: C, 48.34; H,
4.29; N, 6.88.
Colorless crystals; yield: CM (76%), MW (90%); mp 116–118 °C;
Rf 0.16 (1:5 hexane–EtOAc); 1H NMR (CDCl3, 500 MHz): d 1.80,
1.94, 2.01, 2.03, 2.04, 2.06, 2.07, 2.08 (8 ꢂ s, 24H, 2 ꢂ NCH3CO,
0
0
0
0
0
00
0
0
6 ꢂ CH3CO), 3.84 (ddd, 1H, J5 a,6 a 2.3, J5 a,6 a 5.3, J5 a,4 a 9.2 Hz, H-
50a), 4.01 (ddd, 1H, J5 b,6 b 2.3, J5 b,6 b 4.6, J5 b,4 b 9.9 Hz, H-50b),
0
0
0
00
0
0
4.12 (dd, 1H, J6 a,5 a 2.3, J6 a,6 a 12.2 Hz, H-60a), 4.18 (dd, 1H, J6 b,5 b
0
0
0
00
0
0
2.3, J6 b,6 b 12.2 Hz, H-60b), 4.22 (dd, 1H, J6 a,5 a 5.3, J6 a,6 a 12.2 Hz,
0
00
00
0
00
0
H-600a), 4.26 (dd, 1H, J6 b,5 b 4.6, J6 b,6 b 12.2 Hz, H-600b), 4.40 (ddd,
00
0
00
0
1H, J2 a,1 a 9.9, J2 a,3 a 9.9, J2 a,NHa 7.7 Hz, H-20a), 4.56 (ddd, 1H, J2 b,1 b
0
0
0
0
0
0
0
9.9, J2 b,3 b 9.9, J2 b,NHb 7.7 Hz, H-20b), 5.16 (dd, 1H, J4 a,3 a 9.9, J4 a,5 a
0
0
0
0
0
0
0
9.2 Hz, H-40a), 5.22 (t, 1H, J3 a,2 a = J3 a,4 a 9.9 Hz, H-30a), 5.41 (t,
0
0
0
0
0
0
0
0
0
0
4.3. General procedure: reaction of 5-(3-chlorobenzo[b]thien-
2-yl)-4H-1,2,4-triazole-3-thiol (1) with glycosyl halides 2–4 in
presence of K2CO3
1H, J3 b,2 b = J3 b,4 b 9.9 Hz, H-30b), 5.53 (d, 1H, J1 a,2 a 9.9 Hz, H-10a),
5.64 (t, 1H, J4 b,3 b = J4 b,5 b 9.9 Hz, H-40b), 6.03 (d, 1H, J1 b,2 b 9.9
0
0
0
0
0
0
Hz, H-10b), 6.49 (d, 1H, JNHb,2 b 7.7 Hz, D2O exchangeable, NHAc),
0
7.42–7.53 (m, 2H, H-5, H-6 benzothiophene), 7.69 (dd, 1H, J 3.1, J
0
4.3.1. Conventional method (CM)
8.4 Hz, H-4 benzothiophene), 7.80 (d, 1H, JNHa,2 a 7.7 Hz, D2O
A mixture of compound 1 (1 mmol) and potassium carbonate (2
mmol, 0.276 g) in dry acetone (25 mL) and 5 drops of DMF were
stirred for 1 h, then glycosyl halides 2–4 (2.2 mmol) were added.
exchangeable, NHAc), 7.89 (dd, 1H, J 1.5, J 6.9 Hz, H-7 benzothio-
phene). 13C NMR (CDCl3, 125.7 MHz): d 20.7, 20.8 (8ꢂCH3CO),
53.6 (C-20a), 54.5 (C-20b), 62.0 (C-60a), 62.1 (C-60b), 68.2 (C-40b),

732
E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
68.4 (C-40a), 71.4 (C-30b), 73.4 (C-30a), 74.5 (C-50b), 76.3 (C-50a),
83.3 (C-10a), 84.5 (C-10b), 120.4 (C-9), 122.6 (C-4), 122.7 (C-7),
125.4 (C-5), 125.9 (C-8), 126.10 (C-6), 136.0 (C-3), 137.5 (C-2),
170.5, 170.7, 170.8, 171.0, 171.1 (8 ꢂ CH3CO). Anal. Calcd for
C38H44ClN5O16S2: C, 49.27; H, 4.79; N, 7.56. Found: C, 48.85; H,
5.02; N, 7.45.
umn chromatography to afford the respective derivatives, which
were recrystallized from EtOH.
4.4.2. Microwave irradiation (MWI) method
A mixture of compound 12 or 13 (0.5 mmol), potassium carbon-
ate (0.5 mmol, 0.069 g), and glycosyl halides 2–4 (0.55 mmol) in
dry acetone (5 mL) in a closed Teflon vessel was irradiated by
MW for 4–6 min. The reaction mixture was cooled and processed
as described above to give 14–21.
4.3.5. 5-(3-Chlorobenzo[b]thien-2-yl)-4-(2,3,4,6-tetra-O-acetyl-
b-
anosylsulfanyl)-4H-1,2,4-triazole (10) and 5-(chlorobenzo[b]-
thien-2-yl)-2-(2,3,4,6-tetra-O-acetyl-b- -galactopyranosyl)-3-
-galactopyranosylsulfanyl)-4H-1,2,4-
D-galactopyranosyl)-3-(2,3,4,6-tetra-O-acetyl-b-D-galactopyr-
D
4.4.3. 3-Benzylsulfanyl-5-(3-chlorobenzo[b]thien-2-yl)-4-
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-4H-1,2,4-triazole
(2,3,4,6-tetra-O-acetyl-b-
D
triazole (11)
(14)
Yield of the crude: CM (75%), MW (89%); eluant: 30:70 hexane–
EtOAc; the first fraction gave colorless crystals of 10 in 68% yield;
mp 118–119 °C; Rf 0.43 (1:2.5 hexane–EtOAc). 1H NMR (CDCl3,
500 MHz): d 1.88, 1.90, 1.99, 2.00, 2.05, 2.08, 2.14, 2.27 (8s, 24H,
8 ꢂ CH3CO), 4.11–4.18 (m, 6H, H-50a, H-50b, H-60a, H-60b, H-600a,
Colorless crystals; yield: CM (76%), MW (90%); mp 198–200
°C; Rf 0.33 (1:1 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz): d
0
0
1.82, 2.01, 2.03, 2.05 (4s, 12H, 4 ꢂ CH3CO), 3.92 (ddd, 1H, J5 ,6
2.3, J5 ,6 5.3, J5 ,4 9.9 Hz, H-50), 4.16 (dd, 1H, J6 ,5 2.3, J6 ,6 12.2
0
00
0
0
0
0
0
00
Hz, H-60), 4.25 (dd, 1H, J6 ,5 5.3, J6 ,6 12.2 Hz, H-600), 4.55, 4.62
00
0
00
0
H-600b), 5.20 (dd, 1H, J3 b,2 b 9.9, J3 b,4 b 3.1 Hz, H-30b), 5.21 (dd, 1H,
(2d, 2H, J 13.0 Hz, CH2Ph), 5.26 (dd, 1H, J4 ,3 = J4 ,5 9.9 Hz, H-40),
0
0
0
0
0
0
0
0
J3 a,2 a 9.9, J3 a,4 a 3.1 Hz, H-30a), 5.43 (dd, 1H, J2 a,1 a 10.7, J2 a,3 a 9.9
5.36 (dd, 1H, J3 ,2 9.2, J3 ,4 9.9 Hz, H-30), 5.51 (d, 1H, J1 ,2 9.9 Hz,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Hz, H-20a), 5.49 (d, 1H, J4 a,3 a 3.1 Hz, H-40a), 5.51 (d, 1H, J4 b,3 b 3.1
H-10), 5.90 (dd, 1H, J2 ,1 9.9, J2 ,3 9.2 Hz, H-20), 7.27–7.34 (m, 3H,
3 Ph-H), 7.42–7.48 (m, 4H, 2 Ph-H, H-5, H-6 benzothiophene),
7.82 (dd, 1H, J 1.5, J 6.9 Hz, H-4 benzothiophene), 7.91 (dd, 1H,
0
0
0
0
0
0
0
0
Hz, H-40b), 5.59 (d, 1H, J1 b,2 b 9.2 Hz, H-10b), 5.70 (d, 1H, J1 a,2 a
0
0
0
0
10.7 Hz, H-10a), 5.95 (dd, 1H, J2 b,1 b 9.2, J2 b,3 b 9.9 Hz, H-20b),
7.42–7.47 (m, 2H, H-5, H-6 benzothiophene), 7.81 (dd, 1H, J 1.5, J
6.9 Hz, H-4 benzothiophene), 7.90 (dd, 1H, J 1.5, J 6.9 Hz, H-7 ben-
zothiophene). 13C NMR (CDCl3, 125.7 MHz): d 20.4, 20.6, 20.7, 20.8
(8 ꢂ CH3CO), 61.1 (C-60a), 61.3 (C-60b), 66.8 (C-20a), 67.1 (C-20b),
67.3 (C-40a, C-40b), 71.1 (C-30a), 71.7 (C-30b), 73.8 (C-50a), 75.3 (C-
50b), 84.8 (C-10a), 85.6 (C-10b), 120.5 (C-9), 122.6 (C-4), 122.7 (C-
7), 125.2 (C-5), 126.0 (C-8), 126.6 (C-6), 137.4 (C-3), 137.6 (C-2),
168.4, 169.9, 170.0, 170.1, 170.2, 170.4 (8ꢂCH3CO). Anal. Calcd
for C38H42ClN3O18S2: C, 49.16; H, 4.56; N, 4.53. Found: C, 49.08;
H, 4.69; N, 4.48.
0
0
0
0
J
1.5,
J
6.9 Hz, H-7 benzothiophene). Anal. Calcd for
C31H30ClN3O9S2: C, 54.10; H, 4.39; N, 6.11. Found: C, 54.06; H,
4.65; N, 5.72.
4.4.4. 5-(3-Chlorobenzo[b]thien-2-yl)-3-methylsulfanyl-4-
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-4H-1,2,4-triazole
(15)
Colorless crystals; yield: CM (74%), MW (88%); mp 186–188 °C;
Rf 0.27 (1:1 hexane–EtOAc). 1H NM (CDCl3, 500 MHz): d 1.89, 2.04,
2.06, 2.08 (4 ꢂ s, 12H, 4 ꢂ CH3CO), 2.80 (s, 3H, SCH3), 3.97 (ddd, 1H,
J5 ,6 2.3, J5 ,6 4.6, J5 ,4 9.9 Hz, H-50), 4.21 (dd, 1H, J6 ,5 2.3, J6 ,6 12.2
0
0
0
00
0
0
0
0
0
00
The second fraction gave 11; colorless crystals (3% yield); mp
112–114 °C; Rf 0.37 (1:2.5 hexane–EtOAc). 1H NM (CDCl3, 500
MHz): d 1.88, 1.97, 1.98, 2.00, 2.01, 2.04, 2.16 (7 ꢂ s, 24 H,
8 ꢂ CH3CO), 4.19 (m, 6H, H-50a, H-50b, H-60a, H-60b, H-600a, H-
Hz, H-60), 4.29 (dd, 1H, J6 ,5 4.6, J6 ,6 12.2 Hz, H-600), 5.28 (t, 1H,
00
0
00
0
J4 ,3 = J4 ,5 9.9 Hz, H-40), 5.41 (dd, 1H, J3 ,2 9.2, J3 ,4 9.9 Hz, H-30),
0
0
0
0
0
0
0
0
5.57 (d, 1H, J1 ,2 9.2 Hz, H-10), 5.92 (dd, 1H, J2 ,1 = J2 ,3 9.2 Hz, H-
20), 7.40–7.47 (m, 2H, H-5, H-6 benzothiophene), 7.80 (dd, 1H, J
1.5, J 6.9 Hz, H-4 benzothiophene), 7.90 (dd, 1H, J 1.5, J 6.9 Hz,
H-7 benzothiophene). Anal. Calcd for C25H26ClN3O9S2: C, 49.06;
H, 4.28; N, 6.87. Found: C, 49.04; H, 4.35; N, 6.80.
0
0
0
0
0
0
600b), 5.08 (dd, 1H, J3 b,2 b 9.9, J3 b,4 b 3.1 Hz, H-30b), 5.18 (dd, 1H,
0
0
0
0
J3 a,2 a 9.9, J3 a,4 a 3.1 Hz, H-30a), 5.43 (dd, 1H, J2 a,1 a 10.7, J2 a,3 a
0
0
0
0
0
0
0
0
9.2 Hz, H-20a), 5.45 (d, 1H, J4 b,3 b 3.1 Hz, H-40b), 5.48 (2d, 2H,
0
0
J4 a,3 a 3.1, J1 b,2 b 9.2 Hz, H-40a, H-10b), 5.51 (d, 1H, J1 a,2 a 10.7
0
0
0
0
0
0
Hz, H-10a), 6.00 (dd, 1H, J2 b,1 b 9.2, J2 b,3 b 9.9 Hz, H-20b), 7.55–
7.59 (m, 2H, H-5, H-6 benzothiophene), 7.87–7.90 (m, 1H, H-4
benzothiophene), 7.96–7.98 (m, 1H, H-7 benzothiophene). 13C
NMR (CDCl3, 125.7 MHz): d 20.5, 20.6, 20.7, 20.8 (8 ꢂ CH3CO),
61.1 (C-60a), 61.4 (C-60b), 66.9 (C-20a), 67.3 (C-40a, C-40b), 67.6
(C-20b), 71.4 (C-30a), 72.0 (C-30b), 73.9 (C-50a), 74.7 (C-50b), 84.3
(C-10a), 84.5 (C-10b), 120.0 (C-9), 122.7 (C-4), 123.3 (C-7), 124.2
(C-8), 126.1 (C-5), 127.6 (C-6), 136.1 (C-3), 138.6 (C-2), 168.3,
169.6, 170.0, 170.3, 170.4 (8 ꢂ CO). Anal. Calcd for
C38H42ClN3O18S2: C, 49.16; H, 4.56; N, 4.53. Found: C, 49.10; H,
4.33; N, 4.28.
0
0
0
0
4.4.5. 4-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyr-
anosyl)-3-benzylsulfanyl-5-(3-chlorobenzo[b]thien-2-yl)-4H-
1,2,4-triazole (16)
Colorless plates; yield: CM (74%), MW (89%); mp: 248–250 °C,
TLC Rf 0.57 (1:1 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz): d
1.74, 2.00, 2.04, 2.06 (4s, 12H, NCH3CO, 3 ꢂ CH3CO), 4.00 (ddd,
1H, J5 ,6 2.3, J5 ,6 4.6, J5 ,4 10.7 Hz, H-50), 4.15 (dd, 1H, J6 ,5 2.3,
0
0
0
00
0
0
0
0
J6 ,6 12.2 Hz, H-60), 4.26 (dd, 1H, J6 ,5 4.6, J6 ,6 12.2 Hz, H-600),
0
00
00
0
00
0
4.43 (ddd, 1H, J2 ,1 9.9, J2 ,3 9.9, J2 ,NH 7.7 Hz, H-20), 4.54, 4.57 (2d,
0
0
0
0
0
2H, J 13.0 Hz, CH2Ph), 5.19 (t, 1H, J3 ,2 = J3 ,4 9.9 Hz, H-30), 5.59 (d,
0
0
0
0
0
0
0
1H, JNH,2 7.7 Hz, D2O exchangeable, NHCH3CO), 5.83 (dd, 1H, J4 ,3
9.9, J4 ,5 10.7 Hz, H-40), 6.14 (d, 1H, J1 ,2 9.9 Hz, H-10), 7.26–7.33
(m, 3H, 3 Ph-H), 7.43–7.49 (m, 4H, 2 Ph-H, H-5, H-6 benzothio-
phene), 7.83 (dd, 1 H, J 1.5, J 8.4 Hz, H-4 benzothiophene), 7.91
(dd, 1H, J 1.5, J 6.9 Hz, H-7 benzothiophene). Anal. Calcd for
C31H31ClN4O8S2: C, 54.18; H, 4.55; N, 8.15. Found: C, 54.52; H,
4.77; N, 8.02.
0
0
0
0
4.4. General procedure: reaction of 5-(3-chlorobenzo[b]thien-
2-yl)-3-benzylsulfanyl-4H-1,2,4-triazole (12) and 5-(3-chloro-
benzo[b]thien-2-yl)-3-methylsulfanyl-4H-1,2,4-triazole (13)
with glycosyl halides 2–4
4.4.1. Conventional method (CM)
A mixture of compound 12 or 13 (1 mmol) and potassium car-
bonate (1 mmol, 0.138 g) in dry acetone (25 mL) was stirred for 1 h,
then glycosyl halides 2–4 (1.1 mmol) were added. Stirring was con-
tinued overnight, then the mixture was heated under reflux for 2–
5 h. The mixture was filtered, and the solids were washed with ace-
tone. The acetone was evaporated under reduced pressure, and the
crude product was recrystallized from EtOH or subjected to col-
4.4.6. 4-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyr-
anosyl)-5-(3-chlorobenzo[b]thien-2-yl)-3-methylsulfanyl-4H-
1,2,4-triazole (17)
Colorless crystals; yield: CM (72%), MW (87%); mp 178–180
°C; Rf 0.52 (1:2 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz): d
1.80, 2.06, 2.07, 2.08 (4 ꢂ s, 12H, NCH3CO, 3 ꢂ CH3CO), 2.77 (s,

E.S.H. El Ashry et al. / Carbohydrate Research 344 (2009) 725–733
733
3H, SCH3), 4.04 (ddd, 1H, J5 ,6 2.3, J5 ,6 4.6, J5 ,4 10.7 Hz, H-50),
0
0
0
000
0
0
Acknowledgments
4.23 (dd, 1H, J6 ,5 2.3, J6 ,6 12.2 Hz, H-60), 4.30 (dd, 1H, J6 ,5
0
0
0
00
00
0
4.6, J6 ,6 12.2 Hz, H-600), 4.50 (ddd, 1H, J2 ,1 = J2 ,3 9.9, J2 ,NH 7.7
00
0
0
0
0
0
0
The authors thank the AvH foundation for the continued sup-
port, and thank Professor V. Whittmann at Konstanz University
for his discussion.
Hz, H-20), 5.22 (t, 1H, J3 ,2 = J3 ,4 9.9 Hz, H-30), 5.75 (d, 1H, JNH,2
0
0
0
0
0
0
0
0
0
7.7 Hz, D2O exchangeable, NHAc), 5.84 (dd, 1H, J4 ,3 9.9, J4 ,5
10.7 Hz, H-40), 6.17 (d, 1H, J1 ,2 9.9 Hz, H-10), 7.41–7.48 (m,
2H, H-5, H-6 benzothiophene), 7.81 (dd, 1H, J 1.5, J 6.9 Hz, H-
4 benzothiophene), 7.90 (dd, 1H, J 1.5, J 6.9 Hz, H-7 benzothio-
phene). Anal. Calcd for C25H27ClN4O8S2: C, 49.14; H, 4.45; N,
9.17. Found: C, 49.52; H, 4.77; N, 8.98.
0
0
References
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4.4.7. 3-Benzylsulfanyl-5-(3-chlorobenzo[b]thien-2-yl)-4-
D-galactopyranosyl)-4H-1,2,4-triazole
(18) and 3-benzylsulfanyl-5-(3-chlorobenzo[b]thien-2-yl)-2-
(2,3,4,6-tetra-O-acetyl-b-
(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)- 4H-1,2,4-triazole
(20)
Yield of the crude product: CM (73%), MW (87%); eluant: 85:15
hexane–EtOAc, the first fraction gives 18, colorless crystals in 62%
yield; mp 80–81 °C; TLC Rf 0.310 (2:1 hexane–EtOAc). 1H NMR
(CDCl3, 500 MHz): d 1.85, 2.00, 2.01, 2.14 (4 ꢂ s, 12H, 4 ꢂ CH3CO),
4.11–4.19 (m, 3H, H-50, H-60, H-600), 4.55, 4.64 (2d, 2H, J 13.0 Hz,
CH2Ph), 5.19 (dd, 1H, J3 ,2 9.9, J3 ,4 3.1 Hz, H-30), 5.49 (d, 1H, J4 ,3
0
0
0
0
0
0
12. El Ashry, E. S. H.; Awad, L. F.; Abdel-Hamid, H.; Atta, I. A. J. Carbohydr. Chem.
2005, 24, 745–753.
13. Pastuch, G.; Wandzik, I.; Szeja, W. Tetrahedron Lett. 2000, 41, 9923–9926.
3.1 Hz, H-40), 5.50 (d, 1H, J1 ,2 9.9 Hz, H-10), 6.05 (t, 1H, J2 ,1 = J2 ,3
0
0
0
0
0
0
9.9 Hz, H-20), 7.26–7.34 (m, 3H, 3Ph-H), 7.42–7.49 (m, 4H, 2Ph-H,
H-5, H-6 benzothiophene), 7.81 (d, 1H, J 7.7 Hz, H-4 benzothio-
phene), 7.91 (dd, 1H, J 3.1, J 6.9 Hz, H-7 benzothiophene). Anal.
Calcd For C31H30ClN3O9S2: C, 54.10; H, 4.39; N, 6.11. Found: C,
54.29; H, 4.59; N, 5.97.
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The second fraction gave 20; white crystals in 6% yield; mp 72–
74 °C; TLC Rf 0.243 (2:1 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz):
d 1.83, 1.97, 2.04, 2.17 (4 ꢂ s, 12H, 4 ꢂ CH3CO), 4.06–4.18 (m, 3H,
H-50, H-60, H-600), 4.39, 4.50 (2d, 2H, J 13.0 Hz, CH2Ph), 5.09 (dd,
1H, J3 ,2 9.9, J3 ,4 3.1 Hz, H-30), 5.45 (d, 1H, J4 ,3 3.1 Hz, H-40), 5.46
0
0
0
0
0
0
(d, 1H, J1 ,2 9.9 Hz, H-10), 5.98 (t, 1H, J2 ,1 = J2 ,3 9.9 Hz, H-20),
7.24–7.33 (m, 3H, 3 Ph-H), 7.45–7.57 (m, 4H, 2 Ph-H, H-5, H-6 ben-
zothiophene), 7.89 (dd, 1H, J 3.1, J 6.9 Hz, H-4 benzothiophene),
7.97 (dd, 1H, J 3.1, J 6.9 Hz, H-7 benzothiophene). Anal. Calcd for
C31H30ClN3O9S2: C, 54.10; H, 4.39; N, 6.11. Found: C, 54.27; H,
4.40; N, 6.00.
0
0
0
0
0
0
21. El Ashry, E. S. H.; Ramadan, E.; Abdel-Hamid, H.; Hagar, M. Synth. Commun.
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229–232.
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Heterocycl. Chem. 2006, 90, 1–127; (c) El Ashry, E. S. H.; Kassem, A. A. ARKIVO
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4.4.8. 5-(3-Chlorobenzo[b]thien-2-yl)-3-methylsulfanyl-4-
(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)-4H-1,2,4-triazole
(19) and 5-(3-chlorobenzo[b]thien-2-yl)-3-methylsulfanyl-2-
(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)-4H-1,2,4-triazole
(21)
Yield of the crude: CM (71%), MW (86%); eluant: 85:15 hexane–
EtOAc; the first fraction gives 19; colorless crystals in 60% yield;
mp 60–61 °C; Rf 0.30 (2:1 hexane–EtOAc). 1H NMR (CDCl3, 500
MHz): d 1.90, 2.01, 2.05, 2.22 (4 ꢂ s, 12H, 4 ꢂ CH3CO), 2.80 (s,
25. El Ashry, E. S. H.; Rashed, N.; Awad, L. F.; Ramadan, E.; Abdel-Maggeed, S. M.;
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2005.; (b) Van der Eycken, E.; Kappe, C. O. Microwave-assisted Synthesis of
Heterocycles; Springer: Heidelberg, 2006; (c) Kappe, C. O.; Stadler, A.
Microwave-assisted Combinatorial Chemistry. In Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002; pp 405–433; (d)
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3H, SCH3), 4.16–4.21 (m, 3H, H-50, H-60, H-600), 5.23 (dd, 1H, J3 ,2
0
0
9.9, J3 ,4 3.1 Hz, H-30), 5.52 (d, 1H, J4 ,3 3.1 Hz, H-40), 5.55 (d, 1H,
0
0
0
0
J1 ,2 9.2 Hz, H-10), 6.07 (dd, 1H, J2 ,1 9.2, J2 ,3 9.9 Hz, H-20), 7.40–
7.46 (m, 2H, H-5, H-6 benzothiophene), 7.80 (dd, 1H, J 1.5, J 7.7
Hz, H-4 benzothiophene), 7.89 (dd, 1H, J 1.5, J 7.7 Hz, H-7 benzo-
thiophene). Anal. Calcd for C25H26ClN3O9S2: C, 49.06; H, 4.28; N,
6.87. Found: C, 49.28; H, 4.25; N, 6.76.
0
0
0
0
0
0
The second fraction gave 21; white crystals in 5% yield; mp 53–
54 °C; Rf 0.18 (2:1 hexane–EtOAc). 1H NMR (CDCl3, 500 MHz): d
1.87, 1.96, 2.03, 2.18 (4 ꢂ s, 12H, 4 ꢂ CH3CO), 2.64 (s, 3H, SCH3),
4.05–4.08 (m, 3H, H-50, H-60, H-600), 5.08 (dd, 1H, J3 ,2 9.9, J3 ,4 3.1
0
0
0
0
Hz, H-30), 5.45, 5.47 (2d, 2H, J1 ,2 9.9, J4 ,3 3.1 Hz, H-10, H-40), 6.01
0
0
0
0
(dd, 1H, J2 ,1 9.9, J2 ,3 9.9 Hz, H-20), 7.55–7.57 (m, 2H, H-5, H-6 ben-
zothiophene), 7.88 (dd, 1H, J 3.1, J 6.9 Hz, H-4 benzothiophene),
7.96 (dd, 1H, J 3.1, J 6.9 Hz, H-7 benzothiophene). Anal. Calcd for
C25H26ClN3O9S2: C, 49.06; H, 4.28; N, 6.87. Found: C, 48.98; H,
4.20; N, 6.79.
0
0
0
0
35. Stewart, J. P. MOPAC, Version 7.00, QCPE Program.
36. Handbook of Heterocyclic Chemistry; Katritzky, A. R., Bird, W. C., Boulton, C. W.,
Cheeseman, G. W. H., Lagowski, J. M., Lwowski, W., Mckillop, A., Potts, K. T.,
Rees, C. W., Eds.; Pergamon Press: Oxford, 1985; p 357.