Efficient synthesis, structure, and antimicrobial activity of some novel N- and S-β-d-glucosides of 5-pyridin-3-yl-1,2,4-triazoles

Article abstract of DOI:10.1016/j.carres.2006.06.007

Glucosidation of some 4-amino- and 4-arylideneamino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thiones with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide followed by chromatographic separation gave the corresponding N- and S-β-d-glucosides. The s

Full text of DOI:10.1016/j.carres.2006.06.007

Carbohydrate Research 341 (2006) 2187–2199
Efficient synthesis, structure, and antimicrobial activity of some
novel N- and S-b-D-glucosides of 5-pyridin-3-yl-1,2,4-triazoles
Nasser S. A. M. Khalil
Central Laboratory for Food and Feed, Agricultural Research Center, Giza, Egypt
Received 14 April 2006; received in revised form 3 June 2006; accepted 12 June 2006
Available online 12 July 2006
Abstract—Glucosidation of some 4-amino- and 4-arylideneamino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thiones with
2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide followed by chromatographic separation gave the corresponding N- and S-b-
D-glucosides. The structure of these two regiosiomers was established chemically and spectroscopically. Deamination as well as
deacetylation of some selected nucleosides have been achieved. Antimicrobial screening of 14 selected compounds resulted in their
activity against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus,
Pseudomonas aeruginosa, Bacillus subtilis, and Escherichia coli.
ꢀ 2006 Published by Elsevier Ltd.
Keywords: Synthesis; Glucosidation; 1,2,4-Triazoles; Deamination; Deacetylation; Antibacterial activity; Antifungal activity
1. Introduction
of biological activity of 1,2,4-triazole glycosides15–18
have been stimulated by the finding that Ribavirin
Several base-modified nucleosides have been reported
to act as antiviral and anticancer agents most likely
due to their capability to mimic natural counterparts
and function.1 The synthesis and biological activities
of sugar-modified nucleoside analogs have been active
research areas for many years, since many of these
compounds have found useful application in the chemo-
therapy of cancer and viral infections. A variety of
nucleoside derivatives have been prepared through
the deletion or change in nature of the functional
group present on the heterocyclic base or their sugar
moieties. Such analogs permit the synthesis of oligo-
nucleotides in which a single functional group at a
preselected position has been deleted or otherwise
altered.
(b-D-ribofuranosyl-1,2,4-triazole-3-carboxamide)15
is
remarkable in its broad spectral activity against DNA
and RNA viruses.16,17 Ribavirin has been developed
clinically18 and approved for human use in many phar-
maceutical preparations.
Encouraged by these interesting structures and bio-
logical activities and as a part of our ongoing pro-
gram19–27 addressed to prepare some new biologically
active compounds, we found that it would be of great
interest to synthesize some novel 1,2,4-triazole gluco-
sides to investigate their antibacterial and antifungal
activities.
2. Results and discussion
It has been found that many 1,2,4-triazoles possess a
wide spectrum of activities including antibacterial, anti-
fungal, antiviral, antiinflammatory, anticonvulsant,
antidepressant, antihypertensive, analgesic, and hypo-
glycemic properties.2–14 The synthesis and investigation
In the present work, the reaction of some 4-substituted-
2,4-dihydro-1,2,4-triazol-3-thiones with 2,3,4,6-tetra-O-
acetyl-a-D-glucopyranosyl bromide (4) as well as the bio-
logical activity of the resulting glucosides was studied.
Scheme 1 illustrates our attempt to design suitable start-
ing 4-amino- and/or 4-arylideneamino-5-(pyridin-3-yl)-
2,4-dihydro-[1,2,4]-triazole-3-thiones (2 and/ or 3a–d)
E-mail: nasserkhalil_23@hotmail.com
0008-6215/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.carres.2006.06.007

2188
N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
O
H
N
N
N
N
H
N
SK
N
NH2NH2.H2O
N
N
N
H
SH
S
N
N
S
NH2
NH2
2
1
ArCHO / AcOH
H
N
N
N
N
N
N
H
N
N
N
S
SH
S
N
N
N
N
N
NH2
MeI / DMF / TEA
N
Ar
Ar
3a-d
N
N
SMe
N
N
N
N
H
N
S
9
N
N
4
/ DMF/ TEA
AcO
Ar
N
+
2
O
OAc
N
Ar
/ DMF / TEA
Br
SMe
N
N
HN
AcO
I
4
OAc
10
Ar
N
N
N
N
O
Ar
+
N
Ar
N
NH2
S
N
NH2
S
N
N
N
H
H
S
N
N
N
S
N
N
N
ArCHO
N
AcO
AcO
N
AcO
AcO
AcO
+
O
OAc
O
OAc
O
OAc
OAc
AcO
AcO
AcO
OAc
OAc
7a-d
OAc
OAc
6
8a-d
5
ArCHO
7, 8
a
Ar
C6H5
9, 10 Ar= 4-ClC6H4
b
c
d
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
Scheme 1.
for use in the present objectives. Thus, consecutive
hydrazinolysis and acidification of potassium 3-nicotino-
yldithiocarbazate (1) gave the corresponding 4-amino-5-
(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thione (2).
While 1,2,4-triazole-3-thiones may exist in thione-
thiol tautomeric structures, our investigations showed
that compound 2 has three possible tautomeric struc-
tures, two of them are thione forms (2,4-dihydrothione
and 4,5-dihydrothione) and the third is the thiol form
as indicated by IR and NMR data of compound 2.
Thus, in its solid state, the IR spectrum of compound
2 showed absorption bands at 2924 (CH aliphatic of
the 4,5-dihydrothione tautomeric structure), 2493 (SH
of the thiol tautomeric structure consistent with similar
reported data28), 1338 (C@S of both thione tautomeric
structures consistent with similar reported data29–31),
and 3232 cmꢀ1 (NH of 2,4-dihydrothione tautomeric
structure consistent with similar reported data28). The
1H NMR spectrum of compound 2 showed the predom-
inant 2,4-dihydrothione form in DMSO-d6 as indicated
by the appearance of NH proton signal at d 5.27 (s,
1H, D2O exchangeable).
Condensation of compound 2 with the appropriate
aryl aldehydes gave the corresponding 4-arylidene-

N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
2189
amino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thi-
ones (3a–d). The latter compounds exist similarly in the
three tautomeric forms in the solid state as indicated by
For all the N-glucosides 7a–d, the CH@N and the
anomeric protons appear around d 9.8 and 6.4 more
downfield than those for the S-glucosides 8a–d, which
appear around d 8.6 and 5.4, respectively. Such down-
field shifts in N-glucosyl derivatives are readily
explained by the anisotropic deshielding by the C@S
(similar downfield shifts of the anomeric proton and
the CH@N proton by an adjacent C@S were reported
for pyrimidine35 and 1,2,4-triazole nucleosides).22
1
their IR spectra. On the other hand, the H NMR spec-
tra of these compounds (measured in DMSO-d6) sup-
port the predominant 2,4-dihydrothione structure (NH
signals of these compounds appeared as a singlet at d
14.30–14.38, consistent with similar reported thione
structures31–33). Furthermore, the appearance of the
CH@N proton signal of compounds 3a–d in DMSO-d6
at d 9.61–9.90 confirms their presence in the 2,4-di-
hydrothione form as will be seen later compared to the
CH@N proton signal of compound 9 at d 8.58.
In order to support the latter evidence, methylation of
compound 3d with methyl iodide in N,N-dimethylform-
amide containing triethylamine was conducted to give
the chromatographically separable 3-methylthio deriva-
1
Compounds 2 and 3a–d were used as starting materi-
als to prepare new functionalized 1,2,4-triazole N- and
S-b-D-glucosides. Thus, glucosidation of compounds 2
and/or 3a–d with 1.1 M equiv of 2,3,4,6-tetra-O-acetyl-
a-D-glucopyranosyl bromide (4) afforded a chromato-
graphically separable mixture (94–99% over-all yield)
of two products, namely, 2-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)-4-amino- and/or 4-arylideneamino-5-
(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thiones (5
and/or 7a–d) and 3-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl-1-thio)-4-amino- and/or 4-arylideneamino-5-
(pyridin-3-yl)-4H-[1,2,4]-triazoles (6 and/or 8a–d).
The structures assigned for compounds 5–8 were
based on spectroscopic and chemical evidences. Thus,
the N-b-D-configuration of compounds 5 and 7a–d is
tives 9 and 10. A careful study of the H NMR spectra
of the N-glucosides 7a–d and S-glucosides 8a–d in com-
parison with 4-(4-chlorobenzylideneamino)-3-methyl-
thio-5-(pyridin-3-yl)-4H-[1,2,4]-triazole (9) establishes
their structures. Thus, the appearance of CH@N proton
signal of compound 9 at d 8.58 confirms the assigned
structure of compounds 8a–d and adds another evidence
to the existence of compounds 3a–d in their thione tau-
tomeric form in DMSO-d6 as previously mentioned.
Compounds 7a–d and 8a–d were alternatively synthe-
sized in excellent yields via condensation of compounds
5 and 6 with the appropriate aryl aldehydes.
The proposed mechanism for the formation of com-
pound 10 during methylation of compound 3d is illus-
trated in Scheme 2. Thus, the reaction presumably
proceeds to give first the 3-methylthio derivative 9, which
is then protonated (by the resulting hydroiodic acid)
followed by ring opening and sigmatropic rearrangement
to give an intermediate pyridinium cation. The latter is
attacked by the iodide anion to afford compound 10.
Deamination of compounds 5 and 6 into compounds
11 and 12, respectively (Scheme 3), was achieved almost
quantitatively by the action of nitrous acid in acetic
acid. Compound 11 was alternatively prepared, also in
an excellent yield, via thermolysis of compounds 7a–d.
1
supported by their H NMR data, which revealed the
anomeric proton signal around d 6.4 with a coupling
constant value of 6.6–9.3 Hz consistent with the re-
ported data for N-b-D-glycosides.20–23,25–27,34 The S-b-
D-configuration of compounds 6 and 8a–d is similarly
1
1
assigned from their H NMR data. The H NMR data
of compounds 8a–d showed a signal of the anomeric
proton around d 5.4 with a coupling constant value of
9.9–10.5 consistent with the reported data for S-b-D-
glycosides.22
N
N
N
N
N
N
+
+
NH
NH
SMe
SMe
SMe
+
N
N
N
N
NH
N
N
Ar
Ar
Ar
I
H+
N
N
9
SMe
N
N
HN
I
Ar
10
Scheme 2.

2190
N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
N
N
5
200-220 oC
N
N
Ar
N
N
- ArC
N
SH
N
N
AcO
AcO
H
S
N
AcO
AcO
O
OAc
HONO
O
OAc
OAc
OAc
7a-d
N
H
N
MeOH / NH3
N
S
N
AcO
O
OAc
N
N
N
N
Ar
AcO
H
OAc
N
11
H
S
N
N
S
N
N
HONO
HO
AcO
6
O
O
OH
13
OAc
HO
MeOH / NH3
AcO
OH
OAc
12
MeOH / NH3
N
N
N
N
Ar
H
N
H
N
N
H
S
N
N
N
S
S
N
N
MeOH / NH3
N
HO
HO
HO
8a-d
O
O
O
OH
OH
OH
HO
HO
HO
OH
OH
OH
14
16
15
13, 14 Ar = C6H5
Scheme 3.
The structure of compounds 11 and 12 was inferred
from their correct analytical and spectral data. Thus,
the 1H NMR data of these compounds not only showed
the absence of the NH2 protons at d 5.91–5.45, but also
revealed the presence of the D2O exchangeable NH
proton signal at d 8.3. Further evidence comes from
the disappearance of NH2 bands at 3325–3313, 3229–
3202 cmꢀ1 and the appearance of the characteristic
NH band at 3418–3259 cmꢀ1 in the IR spectra of com-
pounds 11 and 12.
of the acetyl protons at d 1.87–2.04 and the appearance
of the D2O exchangeable OH protons at d 4.43–5.52.
The IR data of these compounds also showed the
absence of the acetyl carbonyl function at 1755–
1747 cmꢀ1 and the appearance of the characteristic
OH band at 3600–3200 cmꢀ1
.
Compounds 5, 6, 7a–d, 8a–d, 9, 11, 13, and 15 have
been evaluated for their antifungal and antibacterial
activities against Aspergillus fumigatus, Penicillium itali-
cum, Syncephalastrum racemosum, Candida albicans,
Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus
subtilis, and Escherichia coli. The inhibitory effects of the
tested compounds against the mentioned organisms
are given in Table 1. The screening results indicate that
Deacetylation of compounds 7a, 8a, 11 and 12
(Scheme 3) via methanolic ammonia treatment led to
the formation of the free nucleosides 13–16. The 1H
NMR data of the latter compounds revealed the absence

N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
2191
all compounds exhibited antifungal and antibacterial
activities. The inhibitory effects of N-glucosides 5 and
7a–c were studied in comparison with similar effects
due to S-glucosides 6 and 8a–d. Thus, compound
6 showed higher inhibitory effect against Aspergillus
fumigatus, Syncephalastrum racemosum, and Staphylo-
coccus aureus as well as lower inhibitory effect against
Penicillium italicum and Bacillus subtilis, compared to
compound 5.
Compound 8a revealed higher inhibitory effect against
Candida albicans, Staphylococcus aureus, Pseudomonas
aeruginosa, and Bacillus subtilis as well as lower inhibi-
tory effect against Penicillium italicum, compared to
compound 7a. Compared to compound 7b, compound
Table 1. Antimicrobial activity of compounds 5, 6, 7a–d, 8a–d, 9, 11, 13, and 15 (at a concentration of 1, 2.5, 5 mg/mL) compared to standard
antimicrobial agents
Test organisms
Compd 5a
Compd 6a
Compd 7aa
1
2.5
5
1
2.5
5
1
2.5
5
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
0
0
0
+
+
0
0
++
+
+
0
+
+
0
+
+
+
+
+
+
+
++
+
0
+
+
+
0
+
0
+
+
+
0
+
+
+
+
++
+
+
+
+
+
0
+
0
+
+
+
0
+
0
++
+
+
+
++
0
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
+
++
0
++
0
++
0
+
0
++
+
++
Escherichia coli
++
Compd 7ba
Compd 7ca
Compd 7da
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
+
+
+
0
+
0
+
+
+
0
+
0
+
+
+
+
++
0
+
0
0
+
0
+
+
+
0
++
+
+
+
++
0
+
+
+
0
+
0
+
+
+
0
+
0
++
+
+
+
++
+
+
+
+
0
+
++
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
+
0
+
+
++
+
++
0
+
0
++
+
++
Escherichia coli
++
Compd 8aa
Compd 8ba
Compd 8ca
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
+
0
+
+
+
0
+
+
+
+
++
0
+
++
+
+
+
++
+
+
+
+
0
+
0
+
+
+
0
+
0
+
+
+
+
++
0
+
+
0
+
0
+
0
0
+
0
+
0
+
0
0
+
+
+
+
+
0
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
+
++
++
0
+
0
+
+
++
Escherichia coli
++
++
+
++
Compd 8da
Compd 9a
Compd 11a
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
+
+
+
0
+
0
+
+
+
0
+
0
+
+
+
0
++
0
+
0
0
+
0
+
0
+
0
++
0
+
0
0
+
+
++
0
++
0
+
+
+
+
+
0
+
+
+
+
+
+
+
++
+
+
++
+
++
+
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
+
0
+
0
+
0
+
+
+
++
++
Escherichia coli
++
+
Compd 13a
Compd 15a
St.b
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
+
+
++
0
+
0
+
+
++
0
++
0
+
+
++
0
++
0
0
0
++
+
+
0
0
0
++
+
+
0
+
+
++
+
++
0
++
++
+++
++
++
++
++
++
+++
+++
+++
++
+++
+++
+++
++
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
++
++
+++
+++
++
+++
+++
++
+
+
+
++
+
++
0
+
0
++
+
++
Escherichia coli
Note: The test was done using the diffusion agar technique. Inhibition values = 0.1–0.5 cm beyond control = +; inhibition values = 0.6–1.0 cm
beyond control = ++; inhibition values = 1.0–1.5 cm beyond control = +++; 0 = not detected.
a 100 lL of each concn was tested (5, 2.5, 1.0 mg/mL); well diameter = 0.6 cm.
b St. = Reference standard; Chloramphenicol was used as a standard antibacterial agent and Terbinafin was used as a standard antifungal agent.

2192
N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
8b exhibited the same inhibitory effect against all the test
organisms. Compound 7c showed higher inhibitory
effect against Aspergillus fumigatus, Candida albicans,
Staphylococcus aureus, Bacillus subtilis, and Escherichia
coli, compared to compound 8c.
Compound 7d showed higher inhibitory effect against
Aspergillus fumigatus, Candida albicans, Pseudomonas
aeruginosa, and Escherichia coli, compared to com-
pound 8d.
From the previous biological results, we can conclude
that the inhibitory effects of N-glucosides 7a–d and
those of S-glucosides 8a–d depend on the substituents
on the aromatic ring.
To see the role of the sugar moiety on the antimicrobial
activity, we compared the inhibitory effect of compound
8d with that of compound 9. Thus, compound 8d showed
higher inhibitory effect against Aspergillus fumigatus,
Penicillium italicum, Bacillus subtilis, and Escherichia coli
as well as lower inhibitory effect against Syncephalastrum
racemosum, compared to compound 9.
We can also compare the inhibitory effect of com-
pound 5 with the similar effect of its deaminated product
11. Thus, compound 11 revealed higher inhibitory effect
against Aspergillus fumigatus, Penicillium italicum,
Syncephalastrum racemosum, Staphylococcus aureus,
Pseudomonas aeruginosa, and Bacillus subtilis as well
as lower inhibitory effect against Escherichia coli, com-
pared to compound 5.
The inhibitory effects of the acylated nucleosides 7a
and 11 can further be compared with their deacylated
analogs 13 and 15, respectively. Thus, compound 13
showed higher inhibitory effect against Syncephalastrum
racemosum, Staphylococcus aureus, and Bacillus subtilis
as well as lower inhibitory effect against Aspergillus
fumigatus and Candida albicans, compared to compound
7a. Compared to compound 15, compound 11 exhibited
higher inhibitory effect against Aspergillus fumigatus,
Penicillium italicum, Pseudomonas aeruginosa, and Bacil-
lus subtilis as well as lower inhibitory effect against Syn-
cephalastrum racemosum.
NMR spectra were recorded at 300 MHz with a Varian
Mercury 300 spectrometer. Mass spectrum of com-
pound 10 was recorded on a GCMS-QP 1000 EX
(70EV) spectrometer. Elemental analyses were carried
out at the Micro Analytical Center, Cairo University,
Giza, Egypt. Antimicrobial screening of compounds 5,
6, 7a–d, 8a–d, 9, 11, 13, and 15 was carried out at the
Medical Mycology Lab., The Regional Center for
Mycology and Biotechnology, Al Azhar University,
Cairo, Egypt. The starting 2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl bromide (4) was prepared as reported.36
TLC was performed on Fluka silica gel 60 F254 alumi-
num sheets, and the products were detected using
254 nm light. Fluka silica gel 60 (70–230 mesh) was used
for column chromatography.
3.1.1. Potassium 3-nicotinoyldithiocarbazate (1). To a
cold solution (0–5 ꢁC) of potassium hydroxide (19.6 g,
349.3 mmol) and nicotinic acid hydrazide (30 g,
219 mmol) in absolute ethanol (470 mL) was added
dropwise while stirring carbon disulfide (15.8 g,
207.8 mmol). The mixture was diluted with 350 mL of
absolute ethanol and stirred overnight. The reaction
mixture was then diluted with 470 mL of ether and the
precipitated solids were collected by filtration, washed
with ether (2 · 120 mL), and dried in an air oven at
105 ꢁC for 1 h. The obtained yellow salt (55.0 g, 100%)
was used in the next step without any further purifica-
tion; mp 258 ꢁC. Anal. Calcd for C7H6KN3OS2
(251.4): C, 33.45; H, 2.41; N, 16.72; S, 25.51. Found:
C, 33.38; H, 2.44; N, 16.57; S, 25.66.
3.1.2.
4-Amino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-tri-
azole-3-thione (2). A suspension of compound 1
(55.1 g, 219.2 mmol) and 99.8% hydrazine hydrate
(102.7 g, 2.05 mol) was heated at reflux temperature
with stirring for 12 h. The color of the reaction mixture
changed to green, hydrogen sulfide was evolved (lead
acetate paper and color), and a homogeneous solution
resulted. The reaction mixture was diluted with
100 mL cold water and acidified with concentrated
hydrochloric acid, and the formed product was collected
by filtration, washed several times with cold water, dried
at room temperature, and recrystallized from N,N-
dimethylformamide to give 22.1 g (52%) of compound
2, colorless crystals, mp 208 ꢁC (dec). IR: 3414, 3232,
3148, 3078, 2924, 2493, 1836, 1647, 1597, 1566, 1508,
1439, 1416, 1338, 1234, 1192, 1161, 1126, 1084, 1045,
999, 980, 930, 806, 741, 698, 633, 602, 509, 474; 1H
NMR (DMSO-d6) d 5.27 (s, 1H, D2O exchangeable
NH), 5.79 (s, 2H, D2O exchangeable NH2), 7.56 (dd,
The present work describes an efficient synthetic
access to N- and S-b-D-glucosides of various function-
alized 1,2,4-triazoles with potential antimicrobial activi-
ties and as starting materials for further synthetic
transformations. It also expands the synthesis as well
as the utility of both base-modified and sugar-modified
nucleosides of possible application in the chemotherapy
of cancer and viral infections.
3. Experimental
3.1. General
1H, JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, JH-5 pyrid.–H-4 pyrid.
8.1 Hz, H-5 pyrid.), 8.37 (td, 1H, JH-4 pyrid.–H-6 pyrid.
1.8 Hz, JH-4 pyrid.–H-2 pyrid. = 2.1 Hz, JH-4 pyrid.–H-5 pyrid.
8.1 Hz, H-4 pyrid.), 8.70 (dd, 1H, JH-6 pyrid.–H-4 pyrid.
=
=
=
=
All melting points are uncorrected. IR spectra were
recorded on a Perkin–Elmer 1430 spectrometer. 1H
1.8 Hz, JH-6
pyrid. = 4.8 Hz, H-6 pyrid.),
pyrid.–H-5

N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
2193
9.15 (dd, 1H, JH-2
pyrid. = 0.9 Hz,
2365, 1635, 1601, 1566, 1508, 1423, 1365, 1304, 1254,
1169, 1095, 1030, 964, 937, 879, 829, 744, 694, 636,
559, 528, 424; 1H NMR (DMSO-d6) d 3.86 (s, 3H,
OCH3), 7.11 (d, 2H, J = 8.8 Hz, ArH), 7.57 (ddd, 1H,
JH-5 pyrid.–H-2 pyrid. = 0.9 Hz, JH-5 pyrid.–H-6 pyrid = 4.8 Hz,
JH-5 pyrid.–H-4 pyrid. = 8.1 Hz, H-5 pyrid.), 7.85 (d, 2H,
pyrid.–H-5
JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.). Anal. Calcd
for C7H7N5S (193.2): C, 43.51; H, 3.65; N, 36.24; S,
16.59. Found: C, 43.55; H, 3.71; N, 36.44; S, 16.39.
3.1.3.
4-Arylideneamino-5-(pyridin-3-yl)-2,4-dihydro-
[1,2,4]-triazole-3-thiones (3a–d). General procedure. To
a solution of compound 2 (1 g, 5.2 mmol) in acetic acid
(10 mL) was added the appropriate aldehyde (5.2 mmol),
and the reaction mixture was heated at reflux tempera-
ture for 2 h. After cooling, the formed product was
collected by filtration and recrystallized from acetic acid.
J = 8.8 Hz, ArH), 8.27 (td, 1H, JH-4
1.8 Hz, JH-4 pyrid.–H-2 pyrid. = 2.1, JH-4 pyrid.–H-5 pyrid.
8.1 Hz, H-4 pyrid.), 8.71 (dd, 1H, JH-6 pyrid.–H-4 pyrid.
1.8 Hz, JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.03
(dd, 1H, JH-2 pyrid.–H-5 pyrid = 0.9 Hz, JH-2 pyrid.–H-4 pyrid.
2.1 Hz, H-2 pyrid.), 9.61 (s, 1H, CH@N), 14.30 (s, 1H,
pyrid. =
pyrid.–H-6
=
=
=
D O exchangeable NH). Anal. Calcd for C15H13N5OS
2
3.1.3.1. 4-Benzylideneamino-5-(pyridin-3-yl)-2,4-dihy-
dro-[1,2,4]-triazole-3-thione (3a). Yield 0.95 g (65%);
pale yellow crystals, mp 272–274 ꢁC. IR: 3414, 3279,
3032, 2874, 2708, 2584, 2365, 1601, 1551, 1504, 1416,
1277, 1223, 1184, 1122, 1080, 1030, 964, 906, 876, 810,
(311.4): C, 57.86; H, 4.21; N, 22.49; S, 10.30. Found:
C, 57.92; H, 4.42; N, 22.32; S, 10.24.
3.1.3.4.
yl)-2,4-dihydro-[1,2,4]-triazole-3-thione
4-(4-Chlorobenzylideneamino)-5-(pyridin-3-
(3d). Yield
1
756, 690, 625, 582, 505; H NMR (DMSO-d6) d 7.56
1.44 g (88%); yellow crystals, mp 248–250 ꢁC. IR:
3469, 3074, 2874, 2827, 2584, 2511, 1589, 1558, 1516,
1481, 1423, 1354, 1304, 1281, 1219, 1169, 1126,
1084, 1034, 1007, 964, 941, 876, 810, 783, 733, 694,
(dd, 1H, JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, JH-5 pyrid.–H-4 pyrid.
8.1 Hz, H-5 pyrid.), 7.52–7.65 (m, 3H, ArH), 7.88 (m,
2H, ArH), 8.26 (td, 1H, JH-4 pyrid. = 1.8 Hz,
=
pyrid.–H-6
1
JH-4 pyrid.–H-2 pyrid. = 2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz,
H-4 pyrid.), 8.71 (dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz,
JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.05 (d, 1H,
JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.), 9.85 (s, 1H,
CH@N), 14.36 (s, 1H, D2O exchangeable NH). Anal.
Calcd for C14H11N5S (281.3): C, 59.77; H, 3.94; N,
24.89; S, 11.40. Found: C, 59.61; H, 3.86; N, 24.97; S,
11.39.
636, 517, 471, 424; H NMR (DMSO-d6) d 7.57 (dd,
1H, JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, JH-5 pyrid.–H-4 pyrid.
=
8.1 Hz, H-5 pyrid.), 7.62 (d, 2H, J = 8.5 Hz,
ArH), 7.90 (d, 2H, J = 8.5 Hz, ArH), 8.25 (td, 1H,
JH-4
=
1.8 Hz, JH-4
=
pyrid.–H-2 pyrid.
pyrid.–H-6 pyrid.
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.72
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 9.03 (d, 1H, JH-2 pyrid.–H-4 pyrid.
=
=
2.1 Hz, H-2 pyrid.), 9.90 (s, 1H, CH@N), 14.38 (s, 1H,
D2O exchangeable NH). Anal. Calcd for C14H10ClN5S
(315.8): C, 53.25; H, 3.19; N, 22.18; S, 10.15. Found:
C, 53.17; H, 3.02; N, 21.97; S, 10.31.
3.1.3.2. 4-(4-Methylbenzylideneamino)-5-(pyridin-3-
yl)-2,4-dihydro-[1,2,4]-triazole-3-thione
(3b). Yield
1.34 g (87%); pale yellow crystals, mp >300 ꢁC. IR:
3445, 3201, 3013, 2870, 2831, 2716, 2592, 2365, 1600,
1599, 1489, 1419, 1381, 1362, 1335, 1300, 1277, 1223,
1173, 1122, 1092, 1041, 968, 906, 879, 810, 694, 636,
513, 444, 420; 1H NMR (DMSO-d6) d 2.40 (s, 3H,
CH3), 7.38 (d, 2H, J = 7.9 Hz, ArH), 7.57 (ddd, 1H,
3.1.4. General procedure for the synthesis of compounds 5
and 6. To a solution of compound 2 (1.93 g, 10 mmol)
in N,N-dimethylformamide (10 mL) and Et3N (1.7 mL,
12 mmol) was added 2,3,4,6-tetra-O-acetyl-a-D-gluco-
pyranosyl bromide (4) (4.93 g, 12 mmol), and the reac-
tion mixture was stirred overnight. The next day, the
reaction mixture was concentrated under reduced pres-
sure, diluted with CH2Cl2 (100 mL), and washed with
water (3 · 100 mL). The organic layer was dried
(Na2SO4), filtered, evaporated under reduced pressure,
and subjected to silica gel (70–230 mesh) column chro-
matography. Compound 5 was eluted first with petro-
leum ether (bp 40–60 ꢁC)!70% ethyl acetate/
petroleum ether (bp 40–60 ꢁC), followed by compound
6 with 80% ethyl acetate/petroleum ether (bp 40–
60 ꢁC)!20% methanol/ethyl acetate. The chromato-
graphically separated crude products were recrystallized
from CH2Cl2/petroleum ether (bp 40–60 ꢁC). Rf values
of the latter compounds were determined on TLC alu-
minum sheets using ethyl acetate/petroleum ether (bp
40–60 ꢁC) [60:40, v/v] as a developing system.
JH-5
pyrid. = 0.9 Hz, JH-5
=
pyrid.–H-6 pyrid.
pyrid.–H-2
4.8 Hz, JH-5
7.78 (d, 2H, J = 7.9 Hz, ArH), 8.25 (td, 1H,
JH-4 pyrid. = 1.8 Hz, JH-4
pyrid. = 8.1 Hz, H-5 pyrid.),
pyrid.–H-4
=
pyrid.–H-2 pyrid.
pyrid.–H-6
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.71
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 9.03 (dd, 1H, JH-2 pyrid.–H-5 pyrid.
=
=
0.9 Hz, JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.), 9.73
(s, 1H, CH@N), 14.35 (s, 1H, D2O exchangeable NH).
Anal. Calcd for C15H13N5S (295.4): C, 61.00; H, 4.44;
N, 23.71; S, 10.86. Found: C, 61.14; H, 4.51; N, 23.64;
S, 10.75.
3.1.3.3. 4-(4-Methoxybenzylideneamino)-5-(pyridin-3-
yl)-2,4-dihydro-[1,2,4]-triazole-3-thione
(3c). Yield
1.31 g (81%); pale yellow crystals, mp 256 ꢁC. IR:
3445, 3067, 2901, 2835, 2716, 2667, 2617, 2588,

2194
N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
3.1.4.1. 2-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranos-
formed precipitate was collected by filtration, washed
with water several times and dried at room temperature.
The precipitate was extracted with CH2Cl2, the solution
was concentrated and the residue subjected to silica gel
(70–230 mesh) column chromatography. Compounds
7a–d were eluted first with petroleum ether (bp 40–
60 ꢁC)!70% ethyl acetate/petroleum ether (bp 40–
60 ꢁC), followed by compounds 8a–d with 80% ethyl
acetate/petroleum ether (bp 40–60 ꢁC)!20% metha-
nol/ethyl acetate. The chromatographically separated
crude products were recrystallized from CH2Cl2/petro-
leum ether (bp 40–60 ꢁC). Rf values of the latter com-
pounds were determined on TLC aluminum sheets
using ethyl acetate/petroleum ether (bp 40–60 ꢁC)
[60:40, v/v] as a developing system.
yl)-4-amino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-
3-thione (5). Yield 2.10 g (40%); colorless crystals, mp
214 ꢁC (Rf = 0.61). IR: 3313, 3229, 3078, 2988, 2920,
2854, 1747, 1651, 1601, 1516, 1435, 1373, 1254, 1227,
1041, 987, 922, 856, 814, 698, 663, 617, 544, 467, 413;
1H NMR (DMSO-d6) d 1.86, 1.96, 1.99, 2.03 (4s, 12H,
0
0
0
00
CH3CO), 4.03 (dd, 1H, JH-6 –H-5 ¼ 2:1 Hz, JH-6 –H-6
¼
12:6 Hz, H-60), 4.20 (dd, 1H, JH-6 –H-5 ¼ 4:8 Hz,
00
0
JH-6 –H-6 ¼ 12:6 Hz, H-600), 4.40 (ddd, 1H, JH-5 –H-6
¼
00
0
0
0
2:1 Hz, JH-5 –H-6 ¼ 4:8 Hz, JH-5 –H-4 ¼ 9:9 Hz, H-50),
0
00
0
0
0
0
0
0
5.05 (dt, 1H, JH-4 –H-2 ¼ 2:7 Hz, JH-4 –H-3 ¼ 6:6 Hz,
JH-4 –H-5 ¼ 9:9 Hz, H-40), 5.65 (dd, 2H, JH-2 –H-4
¼
0
0
0
0
JH-3 –H-1 ¼ 2:7 Hz, JH-2 –H-1 ¼ JH-2 –H-3 ¼ 6:6 Hz, H-20,
0
0
0
0
0
0
H-30), 5.91 (br s, 2H, D2O exchangeable NH2),
0
0
0
0
6.39 (dd, 1H, JH-1 –H-3 ¼ 2:7 Hz, JH-1 –H-2 ¼ 6:6 Hz,
B) An intimate mixture of equimolecular amounts of
each of compounds 5, 6 (104.7 mg, 0.2 mmol) and the
appropriate aryl aldehyde (0.2 mmol) was heated at
160 ꢁC in an oil bath for 5 min. After cooling the prod-
uct was recrystallized from CH2Cl2/petroleum ether (bp
40–60 ꢁC) to give the corresponding arylideneamino
derivatives 7a–d and 8a–d, respectively.
H-10), 7.62 (ddd, 1H, JH-5
pyrid. = 0.9 Hz,
=
pyrid.–H-2
JH-5
= 4.8 Hz, JH-5
pyrid.–H-4 pyrid.
pyrid.–H-6 pyrid.
8.1 Hz, H-5 pyrid.), 8.34 (td, 1H, JH-4 pyrid.–H-6 pyrid.
1.8 Hz, JH-4 pyrid.–H-2 pyrid. = 2.1 Hz, JH-4 pyrid.–H-5 pyrid.
8.1 Hz, H-4 pyrid.), 8.76 (dd, 1H, JH-6 pyrid.–H-4 pyrid.
=
=
=
1.8 Hz, JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.10
(dd, 1H, JH-2 pyrid. = 0.9 Hz, JH-2
pyrid.–H-5
pyrid.–H-4
pyrid. =2.1 Hz, H-2 pyrid.). Anal. Calcd for
C21H25N5O9S (523.5): C, 48.18; H, 4.81; N, 13.38; S,
6.12. Found: C, 48.02; H, 4.92; N, 13.47; S, 5.99.
3.1.5.1.
2-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyrano-
syl)-4-benzylideneamino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,
4]-triazole-3-thione (7a). Yield 1.12 g (51%, A); 100 mg
(82%, B); colorless crystals, mp 181–182 ꢁC (Rf = 0.5).
IR: 3062, 3012, 2970, 2947, 2854, 1747, 1646, 1605,
1578, 1423, 1369, 1319, 1230, 1099, 1065, 1038, 922,
899, 849, 814, 756, 694 644, 617, 544, 498, 451; 1H
NMR (DMSO-d6) d 1.91, 1.98, 2.00, 2.04 (4s, 12H,
3.1.4.2. 3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-
1-thio)-4-amino-5-(pyridin-3-yl)-4H-[1,2,4]-triazole (6).
Yield 3.0 g (57%); colorless crystals, mp 78–80 ꢁC
(Rf = 0.10). IR; 3325, 3202, 3037, 2947, 1751, 1632,
1601, 1574, 1439, 1373, 1230, 1038, 984, 914, 818, 706,
602, 548, 486, 420; 1H NMR (CDCl3) d 1.78, 1.90,
1.93, 2.02 (4s, 12H, CH3CO), 3.69 (ddd, 1H,
0
0
0
00
CH3CO), 4.06 (dd, 1H, JH-6 –H-5 ¼ 2:1 Hz, JH-6 –H-6
¼
12:6 Hz, H-60), 4.23 (dd, 1H, JH-6 –H-5 ¼ 4:8 Hz,
00
0
JH-6 –H-6 ¼ 12:6 Hz,
H-600),
4.44
(ddd,
1H,
00
0
0
00
0
0
0
0
0
0
0
00
0
0
JH-5 –H-6 ¼ 2:4 Hz,
JH-5 –H-6 ¼ 5:1 Hz,
JH-5 –H-4
0
¼
JH-5 –H-6 ¼ 2:1 Hz,
JH-5 –H-6 ¼ 4:8 Hz,
JH-5 –H-4
¼
¼
¼
10:0 Hz; H-50), 4.01 (dd, 1H, JH-6 –H-5 ¼ 5:1 Hz,
9:6 Hz, H-50), 5.09 (t, 1H, JH-4 –H-5 ¼ JH-4 –H-3
0
0
0
0
0
JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.11 (dd, 1H, JH-6 –H-5
¼
9:6 Hz, H-40), 5.68 (t, 1H, JH-3 –H-4 ¼ JH-3 –H-2
0
00
00
0
0
0
0
0
2:4 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600), 4.89-5.00 (m, 3H,
9:6 Hz, H-30), 5.70 (t, 1H, JH-2 –H-1 ¼ 9:3 Hz,
00
0
0
0
H-40, H-30, H-10), 5.14 (dt, 1H, JH-2 –H-4 ¼ 1:0 Hz,
JH-2 –H-3 ¼ 9:6 Hz, H-20), 6.52 (d, 1H, JH-1 –H-2
¼
0
0
0
0
0
0
JH-2 –H-1 ¼ 9:0 Hz, H-20), 5.45 (s, 2H, D2O exchangeable
9:3 Hz, H-10), 7.55–7.69 (m, 4H, ArH, H-5 pyrid.),
0
0
NH2), 7.31 (dd, 1H, JH-5
pyrid. = 4.8 Hz,
7.91 (dd, 2H, J = 1.5, 8.4 Hz, ArH), 8.22 (td, 1H,
pyrid.–H-6
JH-5 pyrid.–H-4 pyrid. = 7.8 Hz, H-5 pyrid.), 8.39 (td, 1H,
JH-4
2.1 Hz, JH-4
8.76 (dd, 1H, JH-6
pyrid. = 1.8 Hz, JH-4
=
pyrid.–H-2 pyrid.
pyrid.–H-6
JH-4
pyrid. = 1.8 Hz, JH-4
=
=
pyrid. = 8.1 Hz, H-4 pyrid.),
pyrid.–H-6
pyrid.–H-5 pyrid.
pyrid.–H-5
7.8 Hz, H-4 pyrid.), 8.55 (dd, 1H, JH-6 pyrid.–H-4 pyrid.
pyrid. = 1.8 Hz,
pyrid.–H-4
1.8 Hz, JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.28
(s, 1H, H-2 pyrid.). Anal. Calcd for C21H25N5O9S
(523.5): C, 48.18; H, 4.81; N, 13.38; S, 6.12. Found: C,
47.99; H, 4.77; N, 13.21; S, 6.28.
JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 8.99 (dd, 1H,
JH-2 pyrid.–H-5 pyrid = 0.9 Hz, JH-2 pyrid.–H-4 pyrid. = 2.1 Hz,
H-2 pyrid.), 9.75 (s, 1H, CH@N). Anal. Calcd for
C H29N5O9S (611.6): C, 54.99; H, 4.78; N, 11.45; S,
28
5.24. Found: C, 55.07; H, 4.68; N, 11.24; S, 5.19.
3.1.5. General procedures for the synthesis of compounds
7a–d and 8a–d. A) To a solution of each of compounds
3a–d (3.6 mmol) in N,N-dimethylformamide (4 mL) and
Et3N (0.6 mL, 4.3 mmol) was added 2,3,4,6-tetra-O-ace-
tyl-a-D-glucopyranosyl bromide (4) (1.77 g, 4.3 mmol),
and the reaction mixture was stirred overnight. The next
day, the reaction mixture was diluted with water and the
3.1.5.2.
2-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyrano-
syl)-4-(4-methylbenzylideneamino)-5-(pyridin-3-yl)-2,4-di-
hydro-[1,2,4]-triazole-3-thione (7b). Yield 1.28 g (57%,
A); 110 mg (88%, B); colorless crystals, mp 180–182 ꢁC
(Rf = 0.74). IR: 3061, 3036, 3012, 2970, 2924, 2854,
1747, 1646, 1605, 1512, 1423, 1369, 1319, 1230, 1099,

N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
2195
1
1067, 1038, 922, 885, 852, 814, 702, 602, 459, 498; H
922, 849, 822, 771, 706, 602, 552, 513, 486 459; 1H
NMR (DMSO-d6) d 1.91, 1.98, 2.00, 2.04 (4s, 12H,
NMR (DMSO-d6) d 1.91, 1.98, 1.99, 2.04 (4s, 12H,
0
0
0
0
0
00
CH3CO), 2.40 (s, 3H, CH3), 4.05 (dd, 1H, JH-6 –H-5
¼
CH3CO), 4.05 (dd, 1H, JH-6 –H-5 ¼ 1:8 Hz, JH-6 –H-6 ¼
2:1 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.23 (dd, 1H,
12:6 Hz, H-60), 4.23 (dd, 1H, JH-6 –H-5 ¼ 4:8 Hz,
0
00
00
0
JH-6 –H-5 ¼ 4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600), 4.42
JH-6 –H-6 ¼ 12:6 Hz, H-600), 4.44 (ddd, 1H, JH-5 –H-6
¼
00
0
00
0
00
0
0
0
1:8 Hz, JH-5 –H-6 ¼ 4:8 Hz, JH-5 –H-4 ¼ 9:9 Hz, H-50),
0
0
0
00
0
00
0
0
(ddd, 1H, JH-5 –H-6 ¼ 2:1 Hz, JH-5 –H-6 ¼ 4:8 Hz,
JH-5 –H-4 ¼ 9:3 Hz, H-50), 5.08 (t, 1H, JH-4 –H-5
¼
5.08 (t, 1H, JH-4 –H-3 ¼ 9:6 Hz, JH-4 –H-5 ¼ 9:9 Hz, H-
0
0
0
0
0
0
0
0
9:3 Hz, JH-4 –H-3 ¼ 9:0 Hz, H-40), 5.67 (t, 1H,
40), 5.68 (t, 1H, JH-3 –H-2 ¼ 9:0 Hz, JH-3 –H-4 ¼ 9:6 Hz,
0
0
0
0
0
0
JH-3 –H-4 ¼ 9:0 Hz, JH-3 –H-2 ¼ 9:1 Hz, H-30), 5.70 (t,
H-30), 5.71 (t, 1H, JH-2 –H-1 ¼ 8:7 Hz, JH-2 –H-3
¼
0
0
0
0
0
0
0
0
1H, JH-2 –H-1 ¼ 8:1 Hz, JH-2 –H-3 ¼ 9:1 Hz, H-20), 6.51
9:0 Hz, H-20), 6.52 (d, 1H, JH-1 –H-2 ¼ 8:7 Hz,
0
0
0
0
0
0
(d, 1H, JH-1 –H-2 ¼ 8:1 Hz, H-10), 7.39 (d, 2H, J =
H-10), 7.61 (dd, 1H, JH-5
pyrid. = 8.1 Hz,
0
0
pyrid.–H-4
8.1 Hz, ArH), 7.61 (ddd, 1H, JH-5
=
=
JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, H-5 pyrid.), 7.65 (d, 2H,
J = 8.4 Hz, ArH), 7.93 (d, 2H, J = 8.4 Hz, ArH), 8.21
pyrid.–H-2 pyrid.
0.9 Hz, JH-5 pyrid.–H-6 pyrid. = 5.1 Hz, JH-5 pyrid.–H-4 pyrid.
7.8 Hz, H-5 pyrid.), 7.80 (d, 2H, J = 8.1 Hz, ArH), 8.21
(td, 1H, JH-4 pyrid.–H-6 pyrid. = 1.5 Hz, JH-4 pyrid.–H-2 pyrid.
1.8 Hz, JH-4 pyrid.–H-5 pyrid. = 7.8 Hz, H-4 pyrid.), 8.76
(td, 1H, JH-4 pyrid.–H-6 pyrid. = 1.8 Hz, JH-4 pyrid.–H-2 pyrid.
2.4 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.77
=
=
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 8.97 (d, 1H, JH-2 pyrid.–H-4 pyrid.
2.4 Hz, H-2 pyrid.), 9.80 (s, 1H, CH@N). Anal. Calcd
for C28H28ClN5O9S (646.1): C, 52.05; H, 4.37; N,
10.84; S, 4.96. Found: C, 51.98; H, 4.31; N, 10.97; S,
4.88.
=
=
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.5 Hz, JH-6 pyrid.–H-5 pyrid.
5.1 Hz, H-6 pyrid.), 8.98 (dd, 1H, JH-2 pyrid.–H-5 pyrid.
=
=
0.9 Hz, JH-2 pyrid.–H-4 pyrid. = 1.8 Hz, H-2 pyrid.), 9.64
(s, 1H, CH@N). Anal. Calcd for C29H31N5O9S (625.7):
C, 55.67; H, 4.99; N, 11.19; S, 5.12. Found: C, 55.54;
H, 4.84; N, 11.17; S, 5.00.
3.1.5.5. 3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-
1-thio)-4-benzylideneamino-5-(pyridin-3-yl)-4H-[1,2,4]-
triazole (8a). Yield 0.94 g (43%, A); 106 mg (87%, B);
pale crystals, mp 92 ꢁC (Rf = 0.10). IR: 3090, 3020,
2951, 2908, 1755, 1651, 1605, 1574, 1431, 1373, 1322,
1219, 1122, 1057, 976, 910, 845, 814, 756, 687, 636,
3.1.5.3. 2-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranos-
yl)-4-(4-methoxybenzylideneamino)-5-(pyridin-3-yl)-2,4-di-
hydro-[1,2,4]-triazole-3-thione (7c). Yield 1.04 g (45%,
A); 109 mg (85%, B); yellow crystals, mp 176 ꢁC
(Rf = 0.78). IR: 3073, 3017 2976, 2939, 2843, 1751,
1601, 1570, 1516, 1423, 1369, 1315, 1259, 1223, 1173,
1
602, 575, 528, 509, 490, 440; H NMR (CDCl3) d 1.87,
1.92, 1.94, 1.97 (4s, 12H, CH3CO), 3.74 (ddd, 1H,
1
1099, 1034, 922, 833, 702, 675, 606 532, 499; H NMR
0
0
0
00
0
0
(CDCl3) d 1.88, 1.95, 1.98, 2.01 (4s, 12H, CH3CO),
JH-5 –H-6 ¼ 1:8 Hz,
JH-5 –H-6 ¼ 4:8 Hz,
JH-5 –H-4
0
¼
9:9 Hz, H-50), 3.96 (dd, 1H, JH-6 –H-5 ¼ 1:8 Hz,
0
0
0
3.81 (s, 3H, CH3O), 3.99 (ddd, 1H, JH-5 –H-6 ¼ 2:1 Hz,
JH-5 –H-6 ¼ 4:8 Hz, JH-5 –H-4 ¼ 9:9 Hz, H-50), 4.13 (dd,
JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.18 (dd, 1H, JH-6 –H-5
¼
0
00
0
0
0
00
00
0
1H, JH-6 –H-5 ¼ 2:1 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.27
4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600), 5.03 (t, 1H,
0
0
0
00
00
0
(dd, 1H, JH-6 –H-5 ¼ 4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600),
JH-4 –H-3 ¼ 9:6 Hz, JH-4 –H-5 ¼ 9:9 Hz, H-40), 5.06 (t,
00
0
00
0
0
0
0
0
1H, JH-3 –H-2 ¼ 9:3 Hz, JH-3 –H-4 ¼ 9:6 Hz, H-30), 5.21
0
0
0
0
0
0
0
0
5.23 (t, 1H, JH-4 –H-3 ¼ 9:6 Hz, JH-4 –H-5 ¼ 9:9 Hz, H-
40), 5.41 (t, 1H, JH-3 –H-2 ¼ 9:3 Hz, JH-3 –H-4 ¼ 9:6 Hz,
(t, 1H, JH-2 –H-1 ¼ 10:5 Hz, JH-2 –H-3 ¼ 9:3 Hz, H-20),
0
0
0
0
0
0
0
0
H-30), 5.86 (t, 1H, JH-2 –H-1 ¼ JH-2 –H-3 ¼ 9:3 Hz, H-20),
5.36 (d, 1H, JH-1 –H-2 ¼ 10:5 Hz, H-10), 7.34 (dd, 1H,
0
0
0
0
0
0
6.26 (d, 1H, JH-1 –H-2 ¼ 9:3 Hz, H-10), 6.92 (d, 2H, J =
8.7 Hz, ArH), 7.35 (dd, 1H, JH-5 pyrid.–H-4 pyrid. = 8.1 Hz,
JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, H-5 pyrid.), 7.74 (d, 2H,
JH-5
pyrid. = 4.8 Hz, JH-5
=
pyrid.–H-4 pyrid.
0
0
pyrid.–H-6
8.1 Hz, H-5 pyrid.), 7.45 (t, 2H, J = 8.0 Hz, ArH),
7.54 (dt, 1H, J = 2.1, 8.0 Hz, ArH), 7.80 (dd, 2H,
J = 8.7 Hz, ArH), 8.21 (td, 1H, JH-4
1.8 Hz, JH-4 pyrid.–H-2 pyrid. = 2.1 Hz, JH-4 pyrid.–H-5 pyrid.
8.1 Hz, H-4 pyrid.), 8.66 (dd, 1H, JH-6 pyrid.–H-4 pyrid.
=
=
=
J = 1.2, 8.0 Hz, ArH), 8.25 (td, 1H, JH-4 pyrid.–H-6 pyrid.
1.8 Hz, JH-4 pyrid.–H-2 pyrid. = 2.1 Hz, JH-4 pyrid.–H-5 pyrid.
8.1 Hz, H-4 pyrid.), 8.60 (dd, 1H, JH-6 pyrid.–H-4 pyrid.
=
=
=
pyrid.–H-6 pyrid.
1.8 Hz, JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.16
(d, 1H, JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.), 9.87
(s, 1H, CH@N). Anal. Calcd for C29H31N5O10S
(641.7): C, 54.28; H, 4.87; N, 10.91; S, 5.00. Found: C,
54.17; H, 4.74; N, 11.00; S, 4.93.
1.8 Hz, JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 8.71
(s, 1H, CH@N), 9.14 (d, 1H, JH-2
=
pyrid.–H-4 pyrid.
2.1 Hz, H-2 pyrid.). Anal. Calcd for C28H29N5O9S
(611.6): C, 54.99; H, 4.78; N, 11.45; S, 5.24. Found: C,
54.84; H, 4.84; N, 11.57; S, 5.34.
3.1.5.4. 2-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranos-
yl)-4-(4-chlorobenzylideneamino)-5-(pyridin-3-yl)-2,4-di-
hydro-[1,2,4]-triazole-3-thione (7d). Yield 1.30 g (56%,
A); 116 mg (90%, B); yellow crystals, mp 178–180 ꢁC
(Rf = 0.75). IR: 3073, 3012, 2975, 2947, 2858, 1751,
1597, 1489, 1423, 1369, 1315, 1227, 1095, 1074, 1038,
3.1.5.6. 3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-
1-thio)-4-(4-methylbenzylideneamino)-5-(pyridin-3-yl)-
4H-[1,2,4]-triazole (8b). Yield 0.91 g (40%, A); 111 mg
(89%, B); pale crystals, mp 118–120 ꢁC (Rf = 0.11). IR:
3098, 3061, 2947, 2888, 2743, 1751, 1642, 1605, 1566,
1435, 1373, 1227, 1086, 1041, 968, 910, 818, 706, 679,

2196
N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
1
0
0
0
00
0
0
644, 602, 563, 513, 482, 455; H NMR (CDCl3) d 1.89,
JH-5 –H-6 ¼ 1:8 Hz,
JH-5 –H-6 ¼ 4:8 Hz,
JH-5 –H-4
0
¼
9:9 Hz, H-50), 3.99 (dd, 1H, JH-6 –H-5 ¼ 1:8 Hz,
0
1.94, 1.96, 1.99 (4s, 12H, CH3CO), 2.39 (s, 3H, CH3),
3.74 (ddd, 1H, JH-5 –H-6 ¼ 1:8 Hz, JH-5 –H-6 ¼ 4:8 Hz,
JH-6 –H-6 ¼ 12:6 Hz,
H-60),
4.21
(dd,
1H,
0
0
0
00
0
00
JH-5 –H-4 ¼ 9:9 Hz, H-50), 3.97 (dd, 1H, JH-6 –H-5
¼
JH-6 –H-5 ¼ 4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600), 5.05 (t,
0
0
0
0
00
0
00
0
1:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.19 (dd, 1H,
1H, JH-4 –H-3 ¼ 9:6 Hz, JH-4 –H-5 ¼ 9:9 Hz, H-40), 5.10
0
00
0
0
0
0
JH-6 –H-5 ¼ 4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600), 5.04 (t,
(t, 1H, JH-3 –H-2 ¼ 9:3 Hz, JH-3 –H-4 ¼ 9:6 Hz, H-30),
00
0
00
0
0
0
0
0
1H, JH-4 –H-3 ¼ 9:6 Hz, JH-4 –H-5 ¼ 9:9 Hz, H-40), 5.08
5.24 (t, 1H, JH-2 –H-1 ¼ 10:2 Hz, JH-2 –H-3 ¼ 9:3 Hz, H-
0
0
0
0
0
0
0
0
(t, 1H, JH-3 –H-2 ¼ 9:3 Hz, JH-3 –H-4 ¼ 9:6 Hz, H-30),
20), 5.40 (d, 1H, JH-1 –H-2 ¼ 10:2 Hz, H-10), 7.38 (dd,
0
0
0
0
0
0
0
0
0
0
5.22
(t,
1H,
JH-2 –H-1 ¼ 10:2 Hz,
JH-2 –H-3
¼
1H, JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, JH-5 pyrid.–H-4 pyrid. =
9:3 Hz, H-20), 5.38 (d, 1H, JH-1 –H-2 ¼ 10:2 Hz, H-10),
8.1 Hz, H-5 pyrid.), 7.47 (d, 2H, J = 8.4 Hz,
ArH), 7.78 (d, 2H, J = 8.4 Hz, ArH), 8.27 (td, 1H,
0
0
7.26 (d, 2H, J = 7.8 Hz, ArH), 7.34 (dd, 1H,
JH-5
pyrid. = 8.1 Hz, JH-5
=
JH-4
pyrid. = 1.8 Hz, JH-4
=
pyrid.–H-2 pyrid.
pyrid.–H-4
pyrid.–H-6 pyrid.
pyrid.–H-6
4.8 Hz, H-5 pyrid.), 7.70 (d, 2H, J = 7.8 Hz, ArH), 8.25
(td, 1H, JH-4 pyrid.–H-6 pyrid. = 1.8 Hz, JH-4 pyrid.–H-2 pyrid.
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.60
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 8.65 (s, 1H, CH@N), 9.16 (d, 1H,
JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.). Anal. Calcd
for C29H31N5O9S (625.7): C, 55.67; H, 4.99; N, 11.19;
S, 5.12. Found: C, 55.71; H, 5.02; N, 11.09; S, 5.17.
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.65
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
=
=
4.8 Hz, H-6 pyrid.), 8.72 (s, 1H, CH@N), 9.15 (d, 1H,
JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.). Anal. Calcd
for C28H28ClN5O9S (646.1): C, 52.05; H, 4.37; N,
10.84; S, 4.96. Found: C, 52.12; H, 4.42; N, 10.81; S,
5.02.
=
3.1.6. General procedure for the synthesis of compounds 9
and 10. To a solution of compound 3d (505 mg,
1.6 mmol) in N,N-dimethylformamide (8 mL) and
Et3N (0.3 mL, 2.1 mmol) was added methyl iodide
(0.12 mL, 1.9 mmol), and the reaction mixture was stir-
red overnight. The next day, the reaction mixture was
dried under reduced pressure, diluted with CH2Cl2
(100 mL) and washed with water (3 · 100 mL). The
organic layer was dried (Na2SO4), filtered, evaporated
under reduced pressure, and subjected to silica gel (70–
230 mesh) column chromatography. Compound 10
eluted first with petroleum ether (bp 40–60 ꢁC)!30%
ethyl acetate/petroleum ether (bp 40–60 ꢁC), followed
by compound 9 with ethyl acetate!20% methanol/
ethyl acetate. The chromatographically separated crude
products were recrystallized from CH2Cl2/petroleum
ether (bp 40–60 ꢁC). Rf values of compounds 9 and 10
were determined on TLC aluminum sheets using ethyl
acetate/petroleum ether (bp 40–60 ꢁC) [60:40, v/v] as a
developing system.
3.1.5.7. 3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-
1-thio)-4-(4-methoxybenzylideneamino)-5-(pyridin-3-yl)-
4H-[1,2,4]-triazole (8c). Yield 1.24 g (54%, A); 110 mg
(86%, B); pale crystals, mp 98–100 ꢁC (Rf = 0.10). IR:
3067, 3008, 2943, 2843, 1751, 1601, 1566, 1516, 1431,
1373, 1311, 1223, 1169, 1034, 968, 910, 837, 814, 752,
1
706, 675, 602, 555, 528, 482; H NMR (CDCl3) d 1.85,
1.90, 1.91, 1.94 (4s, 12H, CH3CO), 3.73 (ddd, 1H,
0
0
0
00
0
0
JH-5 –H-6 ¼ 1:8 Hz,
JH-5 –H-6 ¼ 4:8 Hz,
JH-5 –H-4
¼
10:2 Hz, H-50), 3.79 (s, 3H, OCH3), 3.94 (dd, 1H,
JH-6 –H-5 ¼ 1:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.15 (dd,
0
0
0
00
1H, JH-6 –H-5 ¼ 4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600), 5.00
00
0
00
0
(t, 1H, JH-4 –H-3 ¼ 9:9 Hz, JH-4 –H-5 ¼ 10:2 Hz, H-40),
0
0
0
0
0
0
0
0
5.03 (t, 1H, JH-3 –H-2 ¼ 9:3 Hz, JH-3 –H-4 ¼ 9:9 Hz, H-
30), 5.18 (t, 1H, JH-2 –H-1 ¼ 9:9 Hz, JH-2 –H-3 ¼ 9:3 Hz,
0
0
0
0
H-20), 5.33 (d, 1H, JH-1 –H-2 ¼ 9:9 Hz, H-10), 6.91 (d,
0
0
2H, J = 8.7 Hz, ArH), 7.29 (dd, 1H, JH-5 pyrid.–H-4 pyrid.
=
8.1 Hz, JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, H-5 pyrid.), 7.72 (d,
2H, J = 8.7 Hz, ArH), 8.20 (td, 1H, JH-4 pyrid.–H-2 pyrid.
1.5 Hz, JH-4 pyrid.–H-6 pyrid. = 1.8 Hz, JH-4 pyrid.–H-5 pyrid.
=
=
8.1 Hz, H-4 pyrid.), 8.54 (s, 1H, CH@N), 8.55 (dd, 1H,
3.1.6.1. 4-(4-Chlorobenzylideneamino)-3-methylthio-5-
(pyridin-3-yl)-4H-[1,2,4]-triazole (9). Yield 245 mg
(46%); pale crystals, mp 150–152 ꢁC (Rf = 0.10). IR:
3059, 3022, 2977, 2924, 2854, 1574, 1493, 1450, 1412,
1350, 1315, 1284, 1242, 1180, 1084, 1014, 960, 933,
879, 829, 810, 771, 702, 667, 633, 606, 517, 467; 1H
NMR (CDCl3) d 2.73 (s, 3H, SCH3), 7.34 (ddd, 1H,
JH-6
pyrid. = 1.8 Hz, JH-6
=
pyrid.–H-4
pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 9.11 (d, 1H, JH-2 pyrid.–H-4 pyrid.
=
1.5 Hz, H-2 pyrid.). Anal. Calcd for C29H31N5O10S
(641.7): C, 54.28; H, 4.87; N, 10.91; S, 5.00. Found: C,
54.31; H, 4.97; N, 10.84; S, 5.03.
3.1.5.8. 3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-
1-thio)-4-(4-chlorobenzylideneamino)-5-(pyridin-3-yl)-4H-
[1,2,4]-triazole (8d). Yield 0.94 g (40%, A); 105 mg
(81%, B); pale crystals, mp 110 ꢁC (Rf = 0.13). IR:
3113, 3025, 2943, 2844, 2750, 1751, 1616, 1570, 1488,
1435, 1373, 1227, 1088, 1041, 972, 910, 822, 775, 706,
606, 517, 409, 471; 1H NMR (CDCl3) d 1.90, 1.96,
1.98, 2.03 (4s, 12H, CH3CO), 3.74 (ddd, 1H,
JH-5
pyrid. = 8.1 Hz, JH-5
=
pyrid.–H-6 pyrid.
pyrid.–H-4
4.8 Hz, JH-5 pyrid.–H-2 pyrid. = 0.6 Hz, H-5 pyrid.), 7.41
(td, 2H, JH-2 ArH–H-3 ArH = 8.4 Hz, JH-2 ArH–H-6 ArH
2.1 Hz, JH-2 ArH–H-5 ArH = 1.8 Hz, ArH), 7.76 (td, 2H,
JH-5
JH-3
JH-4
=
ArH = 1.8 Hz, JH-6
ArH = 2.1 Hz,
ArH–H-2
ArH–H-2
ArH–H-2
pyrid.–H-6
ArH = 8.4 Hz, ArH), 8.21 (td, 1H,
pyrid. = 1.8 Hz, JH-4
=
pyrid.–H-2 pyrid.
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.58

N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
2197
(s, 1H, CH@N), 8.61 (dd, 1H, JH-6
1.8 Hz, JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.12
(dd, 1H, JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, JH-2 pyrid.–H-5 pyrid.
0.6 Hz, H-2 pyrid.). Anal. Calcd for C H12ClN5S
(329.8): C, 54.63; H, 3.67; N, 21.23; S, 9.72. Found: C,
54.48; H, 3.61; N, 21.36; S, 9.84.
=
1H NMR (CDCl3) d 1.87, 1.88, 1.89, 1.93 (4s, 12H,
pyrid.–H-4 pyrid.
0
0
CH3CO),
3.96
(ddd,
1H,
JH-5 –H-6 ¼ 2:1 Hz,
JH-5 –H-6 ¼ 4:8 Hz, JH-5 –H-4 ¼ 9:9 Hz, H-50), 4.05 (dd,
0
00
0
0
=
1H, JH-6 –H-5 ¼ 2:1 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.19
0
0
0
00
15
(dd, 1H, JH-6 –H-5 ¼ 4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600),
00
0
00
0
0
0
0
0
5.20 (t, 1H, JH-4 –H-3 ¼ 9:6 Hz, JH-4 –H-5 ¼ 9:9 Hz, H-
40), 5.31 (t, 1H, JH-3 –H-2 ¼ 8:7 Hz, JH-3 –H-4 ¼ 9:6 Hz,
0
0
0
0
H-30), 5.58 (t, 1H, JH-2 –H-1 ¼ 9:3 Hz, JH-2 –H-3
¼
0
0
0
0
3.1.6.2.
4-(4-Chlorobenzylideneamino)-5-(4-iodo-1,
8:7 Hz, H-20), 5.64 (d, 1H, JH-1 –H-2 ¼ 9:3 Hz,
0
0
4-dihydropyridin-4-yl)-3-methylthio-4H-[1,2,4]-triazole
(10). Yield 239 mg (33%); yellow crystals, mp 180–
182 ꢁC (Rf = 0.94). IR: 3391, 3061, 3016, 2924, 2851,
1628, 1581, 1539, 1489, 1416, 1342, 1219, 1180, 1084,
1053, 1011, 895, 868, 822, 756, 706, 671, 644, 505, 459,
413; 1H NMR (CDCl3) d 2.58 (s, 3H, SCH3), 7.33,
7.41, 7.61, 7.73 (4d, 2H each, J = 8.4 Hz, ArH, Pyrid.
H), 8.32 (s, 1H, CH@N), 9.85 (s, 1H, D2O exchangeable
NH); Ms; 408 [Mꢀ(CH3SH, H), 5%]. Anal. Calcd for
C15H13ClIN5S (457.7): C, 39.36; H, 2.86; N, 15.30; S,
7.01. Found: C, 39.16; H, 3.01; N, 15.47; S, 6.94.
H-10), 7.29 (dd, 1H, JH-5
pyrid. = 8.1 Hz,
pyrid.–H-4
JH-5 pyrid.–H-6 pyrid. = 4.8 Hz, H-5 pyrid.), 8.30 (td, 1H,
JH-4 pyrid. = 1.8 Hz, JH-4
=
pyrid.–H-2 pyrid.
pyrid.–H-6
2.1 Hz, JH-4
pyrid. = 8.1 Hz, H-4 pyrid.),
pyrid.–H-5
8.34 (s, 1H, D2O-exchangeable NH), 8.52 (d, 1H,
JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.21 (d, 1H,
JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.). Anal. Calcd
for C21H24N4O9S (508.5): C, 49.60; H, 4.76; N, 11.02;
S, 6.31. Found: C, 49.58; H, 4.70; N, 10.97; S, 6.29.
3.1.7.2. 3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-
1-thio)-5-(pyridin-3-yl)-4H-[1,2,4]-triazole (12). Yield
381 mg (75%, A); colorless crystals, mp 232 ꢁC
(Rf = 0.1). IR: 3418, 3082, 2935, 2854, 2750, 1751,
1616, 1416, 1381, 1234, 1038, 918, 606, 474; H NMR
(CDCl3) d 1.99, 2.00, 2.01, 2.04 (4s, 12H, CH3CO),
3.1.7. Synthesis of compounds 11 and 12. General
procedures
(A) To a cold stirred solution (at 0 ꢁC) of each of com-
pounds 5 and 6 (523 mg, 1 mmol) in acetic acid
(10 mL) was added dropwise, while stirring, a
solution of sodium nitrite (0.6 g in 1 mL water)
over a period of 1 h. The reaction mixture was
kept in the refrigerator overnight, dried under
reduced pressure, diluted with CH2Cl2 (100 mL),
and washed with water (3 · 100 mL). The organic
layer was dried (Na2SO4), filtered, evaporated
under reduced pressure, and the formed residue
was recrystallized from CH2Cl2/petroleum ether
(bp 40–60 ꢁC) to give colorless crystals of com-
pounds 11 and 12. Rf values of compounds 11
and 12 were determined on TLC aluminum sheets
using ethyl acetate/petroleum ether (bp 40–60 ꢁC)
[60:40, v/v] as a developing system.
1
0
0
0
00
3.75 (ddd, 1H, JH-5 –H-6 ¼ 2:1 Hz, JH-5 –H-6 ¼ 4:8 Hz,
JH-5 –H-4 ¼ 9:6 Hz, H-50), 3.98 (dd, 1H, JH-6 –H-5
¼
0
0
0
0
2:1 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-60), 4.12 (dd, 1H,
0
00
JH-6 –H-5 ¼ 4:8 Hz, JH-6 –H-6 ¼ 12:6 Hz, H-600), 5.00 (t,
00
0
00
0
1H, JH-4 –H-3 ¼ 9:6 Hz, H-40), 5.02 (t, 1H, JH-3 –H-2
¼
0
0
0
0
9:3 Hz, JH-3 –H-4 ¼ 9:6 Hz, H-30), 5.19 (t, 1H,
0
0
JH-2 –H-1 ¼ 10:2 Hz, JH-2 –H-3 ¼ 9:3 Hz, H-20), 5.22
0
0
0
0
(d, 1H, JH-1 –H-2 ¼ 10:2 Hz, H-10), 7.29 (dd, 1H,
0
0
JH-5
pyrid. = 8.1 Hz, JH-5
=
=
pyrid.–H-4
pyrid.–H-6 pyrid.
4.8 Hz, H-5 pyrid.), 8.25 (td, 1H, JH-4 pyrid.–H-6 pyrid.
2.1 Hz, JH-4
pyrid. = 8.1 Hz, H-4 pyrid.),
pyrid.–H-5
8.33 (s, 1H, D2O-exchangeable NH), 8.50 (d, 1H,
JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.20 (d, 1H,
JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.). Anal. Calcd
for C21H24N4O9S (508.5): C, 49.60; H, 4.76; N, 11.02;
S, 6.31. Found: C, 49.74; H, 4.65; N, 10.91; S, 6.45.
(B) Each of compounds 7a–d (1 mmol) was heated at
210–220 ꢁC in an oil bath under vacuum in a
micro-distillation system for 15 min. After cool-
ing, the remaining solid was recrystallized from
CH2Cl2/petroleum ether (bp 40–60 ꢁC) to give
colorless crystals of compound 11. The expected
nitriles were collected in the distillates and identi-
3.1.8. Deacetylation of compounds 7a, 8a, 11, and 12.
General procedure. Dry gaseous ammonia was passed
through a solution of each of compounds 7a, 8a, 11,
and 12 (1 mmol) in dry methanol (10 mL) for about
1 h with cooling and stirring, then the reaction mixture
was stirred at room temperature overnight. The result-
ing mixture was then concentrated at reduced pressure
to afford a solid residue, which was washed several times
via boiling in chloroform (100 mL) and decantation.
The residue was dried at room temperature, column
chromatographed (chloroform!20% methanol/chloro-
form), and recrystallized from methanol to give colorless
crystals of compounds 13 and 15 as well as pale crystals
of compounds 14 and 16. Rf values of the latter
1
fied by H NMR.
3.1.7.1. 2-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranos-
yl)-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thione
(11). Yield 431 mg (85%, A); 482 mg (95%, B using
7a); 467 mg (92%, B using 7b); 480 mg (94%, B using
7c); 477 mg (94%, B using 7d); colorless crystals, mp
96-98 ꢁC (Rf = 0.51). IR: 3259, 3082, 2947, 2885, 2739,
1751, 1647, 1605, 1578, 1489, 1439, 1416, 1373, 1223,
1095, 1038, 984, 914, 818, 748, 706, 606, 525, 463, 494;

2198
N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
1
compounds were determined using TLC aluminum
sheets and chloroform/methanol (60:40, v/v) as a devel-
oping system.
629, 555, 525, 478; H NMR (DMSO-d6) d 3.13–3.38
(m, 4H, H-20, H-30, H-40, H-50), 3.45 (dd, 1H,
0
0
00
JH-6 –OH ¼ 5:7 Hz, JH-6 –H-6 ¼ 11:7 Hz), 3.64 (dd, 1H,
JH-6 –H-5 ¼ 2:3 Hz, JH-6 –H-6 ¼ 11:7 Hz, H-600), 4.55 (br,
00
0
00
0
3.1.8.1. 2-b-D-Glucopyranosyl-4-benzylideneamino-5-
(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thione (13).
.Yield 381 mg (86%); pale colorless crystals, mp 172 ꢁC
(Rf = 0.58). IR: 3500–3200, 3256, 3082, 2874, 2519,
2206, 1655, 1601, 1508, 1419, 1350, 1308, 1257, 1215,
1080, 1026, 906, 845, 756, 694, 667, 621, 517, 474, 428;
1H NMR (DMSO-d6) d 3.22–3.52 (m, 4H, H-20, H-30,
1H, D2O-exchangeable OH), 5.00 (d, 1H, J = 5.4 Hz,
0
0
D2O-exchangeable OH), 5.08 (d, 1H, JH-1 –H-2
¼
9:3 Hz, H-10), 5.14 (d, 1H, J = 4.8 Hz, D2O-exchange-
able OH), 5.52 (br, 1H, D2O-exchangeable OH), 7.52
(ddd 1H, JH-5 pyrid.–H-2 pyrid. = 0.9 Hz, JH-5 pyrid.–H-6 pyrid.
4.8 Hz, JH-5 pyrid.–H-4 pyrid. = 8.1 Hz, H-5 pyrid.), 8.29
(td, 1H, JH-4 pyrid.–H-6 pyrid. = 1.8 Hz, JH-4 pyrid.–H-2 pyrid.
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.64
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 9.14 (dd, 1H, JH-2 pyrid.–H-5 pyrid.
0.9 Hz, JH-2 pyrid.–H-4 pyrid. = 2.1 Hz, H-2 pyrid.), 14.24
(br, 1H, D2O-exchangeable NH). Anal. Calcd for
C13H16N4O5S (340.4): C, 45.88; H, 4.74; N, 16.46; S,
9.42. Found: C, 45.77; H, 4.81; N, 16.48; S, 9.49.
=
=
H-40, H-50), 3.73 (dd, 1H, JH-6 –H-5
¼
4:8 Hz,
0
0
JH-6 –H-6 ¼ 12:6 Hz, H-60), 3.97 (ddd, 1H, JH-6 –H-5
¼
=
=
0
00
00
0
4:8 Hz, JH-6 –OH ¼ 5:7 Hz, JH-6 –H-6 ¼ 12:6 Hz, 600), 4.60
00
00
0
(t, 1H, JOH–H-6 ¼ 5:7 Hz, D2O-exchangeable 60-OH),
00
5.08 (d, 1H, J = 5.4 Hz, D2O-exchangeable OH), 5.19
(d, 1H, J = 5.1 Hz, D2O-exchangeable OH), 5.32 (d,
1H, J = 5.4 Hz, D2O-exchangeable OH), 5.79 (d, 1H,
JH-1 –H-2 ¼ 9:3 Hz, H-10), 7.55-7.68 (m, 4H, ArH, H-5
0
0
pyrid.), 7.91 (d, 2H, J = 7.2 Hz, ArH), 8.29 (td, 1H,
3.1.8.4. 3-b-D-Glucopyranosyl-1-thio-5-(pyridin-3-yl)-
4H-[1,2,4]-triazole (16). Yield 238 mg (70%); pale
brown crystals, mp 107 ꢁC (Rf = 0.10). IR: 3600–3200,
3414, 2932, 2858, 2361, 1620, 1520, 1419, 1084, 1045,
613, 474; 1H NMR (DMSO-d6) d 4.00–3.00 (m, 6H,
H-20, H-30, H-40, H-50, H-60, H-600), 4.43 (br, 1H, D2O-
exchangeable OH), 4.65 (br, 1H, D2O-exchangeable
OH), 4.79 (d, 1H, JH-1 –H-2 ¼ 9:3 Hz, H-10), 4.93
(br, 1H, D2O-exchangeable OH), 5.45 (dd, 1H,
J = 5.1, 7.8 Hz, D2O-exchangeable OH), 7.50 (dd, 1H,
JH-4
pyrid. = 1.8 Hz, JH-4
=
pyrid.–H-2 pyrid.
pyrid.–H-6
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.76
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 9.06 (d, 1H, JH-2 pyrid.–H-4 pyrid.
=
=
2.1 Hz, H-2 pyrid.), 9.79 (s, 1H, CH@N). Anal. Calcd
for C20H21N5O5S (443.5): C, 54.17; H, 4.77; N, 15.79;
S, 7.23. Found: C, 53.95; H, 4.71; N, 15.77; S, 7.18.
0
0
3.1.8.2. 3-b-D-Glucopyranosyl-1-thio-4-benzylidenea-
mino-5-(pyridin-3-yl)-4H-[1,2,4]-triazole
(14). Yield
JH-5
pyrid. = 8.1 Hz, JH-5
=
=
=
pyrid.–H-4
pyrid.–H-6 pyrid.
288 mg (65%); pale crystals, mp 102–104 ꢁC
(Rf = 0.10). IR: 3500–3200, 3549, 3414, 3240, 2928,
2361, 2338, 1640, 1616, 1543, 1419, 1381, 1250, 1034,
4.8 Hz, H-5 pyrid.), 8.27 (td, 1H, JH-4 pyrid.–H-6 pyrid.
1.8 Hz, JH-4 pyrid.–H-2 pyrid. = 2.1 Hz, JH-4 pyrid.–H-5 pyrid.
8.1 Hz, H-4 pyrid.), 8.32 (s, 1H, D2O-exchangeable
NH), 8.62 (dd, 1H, JH-6 pyrid. = 1.8 Hz,
JH-6 pyrid.–H-5 pyrid. = 4.8 Hz, H-6 pyrid.), 9.11 (d, 1H,
JH-2 pyrid. = 2.1 Hz, H-2 pyrid.). Anal.
Calcd for C13H16N4O5S (340.4): C, 45.88; H, 4.74; N,
16.46; S, 9.42. Found: C, 45.99; H, 4.77; N, 16.39; S, 9.34.
1
814, 760, 617, 474, 444; H NMR (DMSO-d6) d 4.00-
pyrid.–H-4
3.00 (m, 6H, H-20, H-30, H-40, H-50, H-60, H-600), 4.65
(t, 1H, JOH–H-6 ¼ 5:7 Hz, D2O-exchangeable 60-OH),
0
pyrid.–H-4
4.80 (d, 1H, JH-1 –H-2 ¼ 9:9 Hz, H-10), 5.05 (d, 1H,
J = 5.4 Hz, D2O-exchangeable OH), 5.13 (d, 1H,
J = 5.1 Hz, D2O-exchangeable OH), 5.26 (d, 1H,
J = 5.4 Hz, D2O-exchangeable OH), 7.38 (dd, 1H,
0
0
References
JH-5
pyrid. = 8.1 Hz, JH-5
=
pyrid.–H-6 pyrid.
pyrid.–H-4
4.8 Hz, H-5 pyrid.), 7.58 (m, 3H, ArH), 7.89 (dd, 2H,
J=1.2, 8.1 Hz, ArH), 8.31 (s, 1H, CH@N), 8.38 (td,
1. Towensend, L. B. In Chemistry of Nucleosides and
Nucleotides; Plenum Press: New York, 1991; Vols. 1 and 2.
2. Jones, D. H.; Slack, R.; Squires, S.; Wooldridge, K. R. H.
J. Med. Chem. 1965, 8, 676–680.
1H, JH-4 pyrid.–H-6 pyrid. = 1.8 Hz, JH-4 pyrid.–H-2 pyrid.
=
2.1 Hz, JH-4 pyrid.–H-5 pyrid. = 8.1 Hz, H-4 pyrid.), 8.68
(dd, 1H, JH-6 pyrid.–H-4 pyrid. = 1.8 Hz, JH-6 pyrid.–H-5 pyrid.
4.8 Hz, H-6 pyrid.), 9.15 (d, 1H, JH-2 pyrid.–H-4 pyrid.
2.1 Hz, H-2 pyrid.). Anal. Calcd for C20H21N5O5S
(443.5): C, 54.17; H, 4.77; N, 15.79; S, 7.23. Found: C,
54.41; H, 4.82; N, 15.66; S, 7.17.
=
=
3. Goswami, B. N.; Kataky, J. C. S.; Baruah, J. N. J.
Heterocycl. Chem. 1984, 21, 1225–1229.
4. Holla, B. S.; Kalluraya, B.; Sridhar, K. R. Curr. Sci. 1987,
56, 236–238.
5. Abdou, N. A.; Amin, F. M. Mansoura J. Pharm. Sci.
1990, 6, 25–29.
6. Mishra, R. K.; Tewari, R. K.; Srivastava, S. K.; Bahel, S.
C. J. Indian Chem. Soc. 1991, 68, 110–112.
3.1.8.3.
2-b-D-Glucopyranosyl-5-(pyridin-3-yl)-2,4-
7. Unangst, P. C.; Shurum, G. P.; Connor, D. T.; Dyer, R.
D.; Schrier, D. J. J. Med. Chem. 1992, 35, 3691–3698.
8. Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan,
C. R.; Schrier, D. J.; Dyer, R. D. J. Med. Chem. 1993, 36,
1090–1099.
dihydro-[1,2,4]-triazole-3-thione (15). Yield 299 mg
(88%); colorless crystals, mp 206–208 ꢁC (Rf = 0.5).
IR: 3500–3200, 3364, 3132, 2870, 2704, 1601, 1477,
1439, 1342, 1308, 1242, 1084, 1041, 995, 895, 833, 702,

N. S. A. M. Khalil / Carbohydrate Research 341 (2006) 2187–2199
2199
9. Sugden, J. K.; Yoloye, T. O. Pharm. Acta Helv. 1978, 53,
65–92.
10. Shams El-Dine, Sh. A.; Hazzaa, A. A. B. Pharmazie 1974,
29, 761–763.
11. Misato, T.; Ko, K.; Honma, Y.; Konno, K.; Taniyama, E.
Jpn. Kokai Tokkyo Koho 77 25,028, 1977; Chem. Abstr.
1977, 87, 147054a.
12. Cansiz, A.; Servi, S.; Koparir, M.; Altintas, M.; Digrak,
M. J. Chem. Soc. Pak. 2001, 23, 237–239.
13. Stillings, M. R.; Welbourn, A. P.; Walter, D. S. J. Med.
Chem. 1986, 29, 2280–2284.
23. Mansour, A. K.; Eid, M. M.; Khalil, N. S. A. M.
Nucleosides Nucleotides Nucleic Acids 2003, 22, 21–44.
24. Mansour, A. K.; Eid, M. M.; Khalil, N. S. A. M.
Nucleosides Nucleotides Nucleic Acids 2003, 22, 1805–
1823.
25. Mansour, A. K.; Eid, M. M.; Khalil, N. S. A. M.
Nucleosides Nucleotides Nucleic Acids 2003, 22, 1825–
1833.
26. Mansour, A. K.; Eid, M. M.; Khalil, N. S. A. M.
Molecules 2003, 8, 744–755.
27. Mansour, A. K.; Ibrahim, Y. A.; Khalil, N. S. A. M.
Nucleosides Nucleotides 1999, 18, 2265–2283.
28. Patil, S. A.; Badiger, B. M.; Kudari, S. M. J. Indian Chem.
Soc. 1984, LXI, 713–714.
14. Kane, J. M.; Dudley, M. W.; Sorensen, S. M.; Miller, F. P.
J. Med. Chem. 1988, 31, 1253–1258.
15. Witkowski, J. T.; Robins, R. K.; Sidwell, R. W.; Simon, L.
N. J. Med. Chem. 1972, 15, 1150–1154.
29. Rollas, S.; Buyuktimkin, S.; C¸ evikbas, A. Arch. Pharm.
¨ ¨
16. The Pharmacology of Ribavirin; Smith, R. A., Kirkpatrick,
W., Eds.; Academic Press: London, 1980; pp 133–
156.
(Weinheim) 1991, 324, 189.
30. Mohsen, A.; Omar, M. E.; Osman, S. A. Pharmazie 1973,
28, 30.
17. In Vitro and In Vivo Inhibition of DNA Viruses by
Ribavirin; Sidwell, R. W., Ed.; Academic Press: Orlando,
FL, 1984; pp 19–32.
31. Ragenovic, K. C.; Dimova, V.; Kakurinov, V.; Molnar, D.
G.; Buzarovska, A. Molecules 2001, 6, 815–824.
¨
32. Ergeuc, N.; Ilhan, E.; Otuk, G. Pharmazie 1992, 47,
¨
18. Clinical Applications of Ribavirin; Smith, R. A., Knight,
V., Smith, J. A. D., Eds.; Academic Press: Orlando, FL,
1984; p 222.
59.
33. Rollas, S.; Kalyoncuoglu, N.; Sur-Altiner, D.; Yegenoglu,
¨
Y. Pharmazie 1993, 48, 308.
19. Khalil, N. S. A. M.; Mansour, A. K.; Eid, M. M.
Nucleosides Nucleotides Nucleic Acids 2004, 23, 1889–1910.
20. Khalil, N. S. A. M. Nucleosides Nucleotides Nucleic Acids
2005, 24, 111–120.
34. Cleve, G.; Hoyer, G. A.; Schulz, G.; Vorbrueggen, H.
Chem. Ber. 1973, 106, 3062–3072.
35. Abdou, I. M.; Saleh, A. M.; Zohdi, H. F. Molecules 2004,
9, 109–116.
21. Khalil, N. S. A. M. Nucleosides Nucleotides Nucleic Acids
2005, 24, 1277–1287.
22. Abbas, A. A.; Khalil, N. S. A. M. Nucleosides Nucleotides
Nucleic Acids 2005, 24, 1353–1372.
36. Vogel’s Textbook of Practical Organic Chemistry; 4th ed.
Furniss, B. S., Hannaford, A. J., Rogers, V., Smith, P. W.
G., Tatchell, A. R.; Longman Group Limited: Harlow,
UK, 1978; p 457.