Synthesis of 5-aryl-3-glycosylthio-4-phenyl-4H-1,2,4-triazoles and their acyclic analogs under conventional and microwave conditions

Article abstract of DOI:10.1080/07328300802030795

Under microwave irradiation (MWI), 4-phenyl-5-substituted-4H-1,2,4- triazole-3-thiol derivatives 7 and 8 were synthesized in a good yield by intramolecular cyclization of the aroyl phenyl thiosemicarbazides 5 and 6. The respective triazolylglycosides (Str-glycosides) 12-17 were obtained by reaction of triazoles 7 and 8 with glycosyl halides 9-11 in dry acetone in the presence of potassium carbonate as base under both conventional and MWI conditions. Alkylation of 7 and 8 with haloalchols 18-20 in boiling ethanolic solution containing sodium ethoxide as a base gave the corresponding alkylated analogs 21-26. MWI conditions led to higher yield in shorter reaction time than the conventional method. Treatment of 26 with tosyl chloride gave the unexpected product 29 and not 27 or 28. Oxidation of 26 with sodium metaperiodate afforded triazole 8 and not the aldehyde 30. Attempted glycosylation and alkylation of the phenolic OH group in triazole 8 were unsuccessful; this was proved by theoretical calculations using the AM1 semi-empirical method. (Chemical Equation Presented). Copyright Taylor & Francis Group, LLC.

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Synthesis of
5‐Aryl‐3‐Glycosylthio‐4‐Phenyl‐4H‐1,2,4‐Triazoles
and Their Acyclic Analogs Under Conventional
and Microwave Conditions
Prof. El Sayed H. El‐Ashry a b , Nagwa Rashed a , Laila F. Awad a , El Sayed
Ramadan a , Somia M. Abdel‐Maggeed a & Nagat Rezki a
a Faculty of Science, Chemistry Department, Alexandria University,
Alexandria, Egypt
b International Center for Chemical and Biological Sciences (HEJ Research
Institute), University of Karachi, Karachi, Pakistan
Version of record first published: 28 May 2008.
To cite this article: Prof. El Sayed H. El‐Ashry , Nagwa Rashed , Laila F. Awad , El Sayed Ramadan , Somia M.
Abdel‐Maggeed & Nagat Rezki (2008): Synthesis of 5‐Aryl‐3‐Glycosylthio‐4‐Phenyl‐4H‐1,2,4‐Triazoles and Their
Acyclic Analogs Under Conventional and Microwave Conditions, Journal of Carbohydrate Chemistry, 27:2,
70-85
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Journal of Carbohydrate Chemistry, 27:70–85, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802030795
Synthesis of 5-Aryl-3-
Glycosylthio-4-Phenyl-4H-
1,2,4-Triazoles and Their
Acyclic Analogs
Under Conventional
and Microwave
Conditions
El Sayed H. El-Ashry,1,2 Nagwa Rashed,1 Laila F. Awad,1
El Sayed Ramadan,1 Somia M. Abdel-Maggeed,1 and
Nagat Rezki1†
1Faculty of Science, Chemistry Department, Alexandria University, Alexandria, Egypt
2International Center for Chemical and Biological Sciences (HEJ Research Institute),
University of Karachi, Karachi, Pakistan
Under microwave irradiation (MWI), 4-phenyl-5-substituted-4H-1,2,4-triazole-3-thiol
derivatives 7 and 8 were synthesized in a good yield by intramolecular cyclization of
the aroyl phenyl thiosemicarbazides 5 and 6. The respective triazolylglycosides (Str-
glycosides) 12–17 were obtained by reaction of triazoles 7 and 8 with glycosyl halides
9–11 in dry acetone in the presence of potassium carbonate as base under both conven-
tional and MWI conditions. Alkylation of 7 and 8 with haloalchols 18–20 in boiling etha-
nolic solution containing sodium ethoxide as a base gave the corresponding alkylated
analogs 21–26. MWI conditions led to higher yield in shorter reaction time than the
conventional method. Treatment of 26 with tosyl chloride gave the unexpected
product 29 and not 27 or 28. Oxidation of 26 with sodium metaperiodate afforded
triazole 8 and not the aldehyde 30. Attempted glycosylation and alkylation of the
Received August 7, 2007; accepted November 8, 2007.
†Nagat Rezki is on leave from the ministry of high education and scientific research,
Algeria.
Address correspondence to Prof. El Sayed H. El-Ashry, Faculty of Science, Chemistry
Department, Alexandria University, Alexandria, Egypt. E-mail: eelashry60@hotmail.com
70

Synthesis of 5-Aryl-3-glycosylthio-4-phenyl-4h-1,2,4-triazoles
71
phenolic OH group in triazole 8 were unsuccessful; this was proved by theoretical
calculations using the AM1 semi-empirical method.
Keywords 1,2,4-Triazole, Thioglycoside, Alkylation, Microwave irradiation (MWI),
AM1 semi-empirical calculation, Hydrogen bonding
INTRODUCTION
Carbohydrates play significant roles in the molecular recognition process.[1–3]
These conclusions have been based on molecular biology studies, which
required model glycosides to be available by synthesis to understand their
mechanisms. Thus, considerable efforts have been devoted to the synthesis of
glycosides,[4–11] of which thioglycosides,[5,8] trichloroacetimidates,[9] glycosyl
halides,[10] and modifications thereof [10,11] have been extensively used as
glycosyl donors. The glycosylthio-derived heterocycles have been recently
reviewed.[5] Although they are widely used as glycosyl donors in glycosidation
reactions,[5,12–17] a divergent use of some glycosylthio heterocycles as glycosyl
acceptors and, subsequently, as donors have recently attracted much attention
for stereoselective synthesis of oligosaccharides.[5] Moreover, they are promis-
ing candidates as potential therapeutics and enzyme inhibitors.[5,17,18] Conse-
quently, the modification in the heterocyclic ring would lead to a change of the
capability of donor ability of the glycosidic bond and give a better chance for
selecting which heterocycles should be used in glycosyl donors or acceptors.
Continuing our program for the synthesis of glycosylated heterocycles[5,11,19]
and their acyclic analogs,[18,20] the selected heterocycle is a functionalized
1,2,4-triazole ring, a ring of great spectrum of therapeutic importance such
as anti-inflammatory, anticonvulsant, and antifungal properties.[21] The meth-
odology for effecting the sequence of reactions utilized microwave irradiation
(MWI), which have been used by us[22] and others.[23]
RESULTS AND DISCUSSION
The synthesis of 1,2,4-triazoles started with methyl benzoate (1) or methyl sali-
cylate (2) that was converted to the acid hydrazides 3 or 4 in 99% and 98% yield,
respectively, by MWI for 2 min in a closed Teflon vessel; conventional heating
for 4 h was required. When 3 or 4 reacted with phenyl isothiocyanate in
ethanol under MWI for 2.5 to 3.0 min, the corresponding aroyl-phenylthiosemi-
carbazide 5 and 6 were obtained. The dehydrative cyclizations of 5 and 6

El S. H. El-Ashry et al.
72
were achieved by 4% aqueous sodium hydroxide to give the corresponding
1,2,4-triazoles 7 and 8, respectively. Improvements of the yields and shorter
reaction times have been achieved under the MWI condition.
The conversion of triazoles 7 and 8 into the respective triazolylglycosides,
STr-glycosides 12–17 were carried out by the reaction with the glycosyl
halides 9–11 in the presence of potassium carbonate (Sch. 1). Under conven-
tional conditions, the coupling required stirring for overnight and then
heating for 2 to 4 h, whereas these reactions were achieved by MWI for 2.5 to
3.5 min to give better yields (Table 1).
1
The H NMR spectra of compounds 12–17 showed characteristic signals
corresponding to the aromatic protons at dH 6.45 to 7.63 ppm, whereas the
singlet corresponding to the phenolic OH for compound 12 was assigned at
dH 11.61 ppm. Their anomeric protons were assigned as doublet in the range
0
0
of dH 4.82 to 5.64 ppm with J1 ,2 9.9 to 10.7 Hz confirming the b-configuration.
1
The 2D NMR spectra (1H-1H DQFCOSY and H-13C HMQC) facilitated the
spectral assignment of the sugar protons of compounds 12, 13, and 15. Thus,
the anomeric proton H-10 of compound 13 was resonated as doublet at dH
5.54 ppm and its carbon at dc 83.8 ppm. In the 1H NMR spectrum of
Scheme 1

Synthesis of 5-Aryl-3-glycosylthio-4-phenyl-4h-1,2,4-triazoles
73
Table 1: Comparative data of conventional and MW methods for the synthesis of
compounds 3–26.
Conventional method
Microwave method
Time (min) Yield (%)
1.0 99
Compound No.
Time (h)
Yield (%)
3
4
5
6
7
4
4
6
6
4
89
86
86
89
76
74
78
76
81
80
80
79
86
82
78
84
79
78
1.0
2.5
3.0
4.5
4.0
2.5
3.0
3.0
3.0
3.5
3.0
2.0
2.5
3.0
3.0
4.0
4.0
98
95
98
90
92
92
90
89
94
92
92
90
98
96
92
95
92
8
4
12
13
14
15
16
17
21
22
23
24
25
26
18
18
20
18
19
20
2
3
4
3
4
4
compound 15 there are four signals in the upper region corresponding to the
acetamido and three acetoxy groups. The anomeric proton appeared at dH
5.62 ppm as a doublet with J1 ,2 10.7 Hz correlated with dc 85.4 for C-10,
0
0
which are characteristic of a b anomer (Experimental).
The S-acyclic analogs have been also synthesized from the 1,2,4-triazoles 7
and 8 by alkylation with the haloalcohols 18–20 in boiling ethanol as solvent
and sodium ethoxide as basic catalyst for 2 to 4 h to give the corresponding
alkylated analogs 21–26. Improvements of the yields (92%–98%) in shorter
reaction time (2–4 min) were achieved when reactions were carried out
under MWI.
The structure of 21–26 was established on the basis of their elemental
analyses and spectral data, which confirmed the success of the alkylation by
the appearance of one exchangeable proton at dH 4.57 to 5.19 ppm, which
was assigned to the OH proton of the acyclic side chain for the compounds
21–24 instead of the thiol proton of their precursors. Moreover, their 1H
NMR spectra also showed the characteristic triplet corresponding to the
SCH2 protons at dH 3.15 to 3.25 ppm with J 6.9 Hz, whereas the CH2O
protons were assigned to the quartet at dH 3.67 and 3.44 ppm for compounds
22 and 23; that of 24 was overlapped with solvent signal. At lower frequency
a pentet corresponding to C-2 protons was assigned to the dH 1.75 to
1.82 ppm for compounds 23 and 24.

El S. H. El-Ashry et al.
74
The 1H NMR spectra of compound 25 showed two characteristic D2O
exchangeable signals at dH 4.75 and 5.11 ppm due to two OH protons, which
confirmed the success of the thiol alkylation. The SCH2 protons were
assigned to two doublet of doublets at dH 3.15 and 3.31 ppm, whereas the
terminal methylene protons appeared as multiplet at dH 3.32 to 3.41.
Various attempts to glycosylate or alkylate the phenolic OH in 8, in
addition to the S-alkylation, have failed and only S-alkylation or S-glycosyla-
tion occurred, these results being later confirmed by theoretical calculations.
Treatment of 26 with tosyl chloride in pyridine at 08C did not give the
expected tosyl derivative 27. No reaction occurred after 7 d at 08C or even at
rt for 10 d. On heating the reaction mixture at reflux temperature for 6 h, a
product was obtained that was characterized by spectral and elemental
analysis to be 29 instead of 27 or 28. The elemental analysis of 29 showed
the absence of sulfur element and agreed with the molecular formula
1
C14H11N3O2. The H NMR spectrum of 29 showed only characteristic signals
corresponding to the nine aromatic protons as well as two exchangeable
signals at d 9.93 and 11.21 corresponding to NH and phenolic OH protons,
respectively.
The unexpected hydrolytic cleavage of the C-S bond in 26 may be rational-
ized by the occurrence of an intramolecular rearrangement of the presumably
formed 27, which under the influence of base gave the anion 27a that acts as
internal nucleophile, attack C-5 with subsequent C-O bond formation a
charge on the nitrogen in the spiro intermediate 27b, and then cleavage of
the O-alkyl residue to give 27c which via the attack of sulfur anion at the
b-carbon form 29 (Sch. 2). Moreover, oxidation of 26 with sodium metaperio-
date resulted in the formation of the starting material 8 rather than the for-
mation of the aldehydes 30. Although the product is not the anticipated one
under such conditions of reactions of reaction, it is not surprising. Oxidation
of the sulfur atom to give the oxide or dioxide derivative can be considered,
which let such group readily cleaved to give 8 (Figure 1).
The two tautomeric thiole/thione forms for the 1,2,4-triazoles 7 and 8 may
be postulated. The 1,2,4-triazole ring was found to exist in thione or thiol form
due to the mobility of the hydrogen atom between the sulfur and nitrogen
atoms of the ring. In order to determine which form is predominate, a theoreti-
cal study of the tautomerism has been investigated by means of semi-empirical
AM1 methods, which were carried out with the MOPAC7 program package.[24]
The heat of formation, dipole moment, highest occupied molecular orbital
energies (EHOMO), lowest unoccupied molecular orbital energies (ELUMO), and
the charge density on triazole heteroatoms as well as the relative stability of
the tautomers have been taken into account (Table 2).
The relative stability (RS) calculations from the gas phase AM1 method for
the triazole 7 and 8 favored the predominance of the thiol form 7a and 8a over
thione form 7b and 8b with relative stability energy, RS ¼ 7.042,

Synthesis of 5-Aryl-3-glycosylthio-4-phenyl-4h-1,2,4-triazoles
75
Scheme 2
7.513 kcal mol21, respectively. Moreover, the thiol form 8a (DHf ¼ 96.603
.
kcal mol21) was found to be more stable than the thiol form 7a (DHf ¼ 140.180
.
21
kcal mol ) with relative stability energy RS ¼ –33.477 kcal mol21. This
could be attributed to the hydrogen bonding between the OH phenolic and N-1
triazole atom, which provides higher stability to 8a. This conclusion has been
theoretical confirmed by AM1 optimization of the structure of 8a, which
revealed that the phenolic benzene ring and the triazole ring are planar with
dihedral angles of –2.2 and –9.7 degrees corresponding to N(11)-H(21)-O(20)-
C(4) and N(11)-C(7)-C(5)-C(4), respectively. Thus, the possibility of hydrogen
bonding O-HꢀꢀꢀꢀꢀN(11) became more evident, where the N(11) acts as acceptor,
due to the fact that AM1-calculated O-HꢀꢀꢀꢀꢀN(11) hydrogen bonding distances
.
.
˚
is 2.090 A, a distance that permit such bonding to take place.
This tendency of intramolecular hydrogen bonding decreases the acidity of
the phenolic hydrogen atom to be abstracted under the basic catalysts required

El S. H. El-Ashry et al.
76
Figure 1
in the glycosylation and alkylation processes. These theoretical conclusions
agreed with the experimental results where several attempts to prepare O-sub-
stituted phenolic moieties on triazole 8 by reaction with either alkyl halides or
sugar halides under different reaction conditions were unsuccessful.
EXPERIMENTAL
Melting points were determined with a Melt-temp apparatus and are uncor-
rected. TLC was performed on Baker-Flex silica gel 1B-F plates using ethyl
acetate-hexane as developing solvent and the spots were detected by UV
light absorption. Irradiation was done in a domestic microwave oven EM-
230M (1200-watt output power under defrost temperature). The irradiation
was done, unless otherwise stated, in a closed Teflon cylindrical vessel, which
was placed at the center of a rotating plate inside the oven. The vessel was
supported by a frame for safety. The vessel has an outside diameter 6.5 cm
and a length of 6.0 cm, whereas the space inside the vessel was 3.0 cm wide
and 2.0 cm length. More 2.0 cm in the length inside the vessel was used for
the screw of the cover in order to be tight. The oven was adjusted on the
defrost mode with the fixed output power. 1H NMR and 13C NMR spectra
1
were recorded on Jeol spectrometer (500 MHz). The assignment of H NMR
spectra was based on chemical shift correlation DQFCOFY spectra, while the
assignment of 13C NMR spectra was based on HMQC experiments. Chemical
shifts (d) are given in ppm relative to the signal for TMS as internal
standard. Elemental analyses were performed in the unit of Microanalyses
at Faculty of Science, Cairo University.

Table 2: Calculated (AM1) heat of formation (kcal mol21), dipole moments (m, Debye), HOMO orbital energies (EHOMO, eV),
.
LUMO orbital energies (ELUMO, eV), charge density on triazole heteroatoms, and relative stability (kcal mol21) for the reactant
.
tautomers.
Heat of
Relative
Tautomer
no.
formation (DHf)
Dipole moment
Debye
EHOMO
(eV)
ELUMO
(eV)
Charge density on
triazole heteroatoms
stabilitya (RS)
21
21
.
.
kcal mol
kcal mol
7a
7b
8a
8b
140.180
147.222
96.603
4.806
4.694
4.640
3.821
–8.587
–8.539
–8.857
–8.696
–0.601
–0.532
–0.585
–0.506
(S) 0.218
(7b–7a) 7.042
(N1) 20.063
(N2) 2 0.094
(N4) 20.101
(S) 20.198
(N1) 20.045
(N2) 20.242
(N4) 20.173
(S) 0.224
(N1) 20.052
(N2) 20.099
(N4) 20.096
(S) 20.183
(N1) 20.033
(N2) 20.099
(N4) 20.179
(8b–8a) 7.513
(8a–7a) –43.577
104.116
aRS ¼ DHf (thione) – DHf (thiol); minus sign indicates that thione is more stable and vice versa.

El S. H. El-Ashry et al.
78
Preparation of Acid Hydrazide Derivatives 3, 4; General
Procedure
Microwave Method (MW)
A solution of 1 or 2 (1.6 mmol), ethanol (5 mL), and 2.5 equivalent of hydra-
zine hydrate in a closed Teflon vessel was irradiated for 1 min by MW. The
reaction mixture was cooled, and then 5 mL of ice water was added to the
solution where a formed precipitate was recrystallized from ethanol to give 3
and 4, respectively.
Benzoylhydrazine (3). Colorless crystals; mp 115–1168C (Lit[25] mp 113–
1178C).
o-Hydroxybenzoyl hydrazine (4). Colorless crystals; mp 1498C (Lit[26] mp
1528C).
4-Aroyl-1-phenylthiosemicarbazides 5, 6; General
Procedure
A solution of 3 or 4 (1 mmol), ethanol (5 mL), and phenyl isothiocyanate
(1.2 mmol) in a closed Teflon vessel was irradiated for 2.5 to 3.0 min by MW.
The reaction mixture was cooled to 08C and the precipitate was recrystallized
from ethanol to give 5 and 6, respectively.
1-Benzoyl-4-phenylthiosemicarbazide (5). Colorless needles; mp 1638C
(Lit[25] mp: 1658C).
1-(o-Hydroxybenzoyl)-4-phenylthiosemicarbazide (6). Colorless crystals;
mp: 192–1948C (Lit[27] mp 1968C).
5-Aryl-4-phenyl-4H-1,2,4-triazole-3-thiol 7, 8; General
Procedure
Conventional Method (CM)
A solution of 5 or 6 (1 mmol) and 4% aqueous sodium hydroxide (5 mL) in a
closed Teflon vessel was irradiated for 4.0 to 4.5 min by MW. The mixture was
cooled and acidified with diluted HCl and the precipitate was recrystallized
from ethanol to give triazoles 7 and 8, respectively.
4,5-Diphenyl-4H-1,2,4-triazole-3-thiol (7). Colorless crystals; mp: 281–
2828C (Lit[25] mp 279–2808C).
5-(o-Hydroxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiol (8). Colorless
crystals; mp 2718C (Lit[28] mp 2738C).

Synthesis of 5-Aryl-3-glycosylthio-4-phenyl-4h-1,2,4-triazoles
Preparation of Glycosyl-STr 12–17; General Procedure
Conventional Method (CM)
79
A solution of compounds 7 or 8 (1 mmol) and potassium carbonate (1 mmol)
in dry acetone (10 mL) was stirred for 1 h, and then glycosyl halides 9–11
(1.1 mmol) were added. Stirring was continued for overnight, and then the
reaction mixture was refluxed for 2 to 4 h, then filtered, washed with
acetone, evaporated under reduced pressure, and recrystallized from ethanol
or purified by column chromatography (Table 1).
Microwave Method (MW)
A solution of compounds 7 or 8 (1 mmol) and potassium carbonate (0.5 mmol)
and glycosyl halides 9–11 (0.55 mmol) in dry acetone (5 mL) in a closed Teflon
vessel was irradiated by MW for 2.5 to 3.5 min. The reaction mixture was
cooled and processed as described above to give the same products (Table 1).
4,5-Diphenyl-3-(20,30,40,60-tetra-O-acetyl-b-D-glucopyranosylthio)-4H-1,2,
4-triazole(12). Colorless crystals; mp 1238C; TLC, Rf 0.24 (2:1 Hexane/EtOAc);
1H NMR (500 MHz, CDCl3) d ¼ 1.97, 1.99, 2.00, 2.01 (4s, 12H, 4 CH3CO), 3.80
(ddd, 1H, J5 ,6 ¼ 2.3, J5 ,6 ¼ 4.6, J5 ,4 ¼ 6.1 Hz, H-50), 4.09 (dd, 1H, J6 ,5 ¼ 2.3,
0
0
0
00
0
0
0
0
J6 ,6 ¼ 12.2 Hz, H-60), 4.24 (dd, 1H, J6 ,5 ¼ 4.6, J6 ,6 ¼ 12.2 Hz, H-600), 5.11
0
00
0
0
0
00
(2dd, 2H, J4 ,3 ¼ 9.9, J4 ,5 ¼ 6.1, J2 ,1 ¼ 9.9, J2 ,3 ¼ 9.9 Hz, H-20, H-40), 5.27
0
0
0
0
0
0
0
0
(t, 1H, J3 ,2 ¼ J3 ,4 ¼ 9.9 Hz, H-30), 5.58 (d, 1H, J2 ,1 ¼ 9.9 Hz, H-10), 7.25–7.44
(m, 10H, Ar-H); 13C NMR (125.7 MHz, CDCl3) d ¼ 20.6, 20.7 (4 CH3CO), 61.6
(C-60), 67.8 (C-40), 70.0 (C-20), 73.8 (C-30), 76.2 (C-50), 84.3 (C-10), 110.0, 118.1,
118.7, 127.6, 128.2, 128.6, 129.9, 130.1, 149.6, 155.6 (Ar-C), 169.5, 169.6, 170.6
(CH3CO); Anal. Calcd for C28H29N3O9S (583.61): C, 57.62; H, 5.01; N, 7.20.
Found: C, 57.49; H, 5.33; N, 7.29.
0
0
0
0
0
0
5-(o-Hydroxyphenyl)-4-phenyl-3-(20,30,40,60-tetra-O-acetyl-b-D-gluco-
pyranosyl-thio)-4H-1,2,4-triazole (13). Colorless plates; mp: 146–1488C;
1
TLC, Rf 0.22 (2:1 Hexane/EtOAc); H NMR (500 MHz, CDCl3) d ¼ 1.97, 1.99,
0
00
0
00
2.00, 2.01 (4s, 12H, 4 OAc), 3.82 (dddd, 1H, J5 ,6 ¼ 2.3, J5 ,6 ¼ 4.6,
J5 ,4 ¼ 9.2 Hz, H-50), 4.11 (dd, 1H, J6 ,5 ¼ 2.3, J6 ,6 ¼ 12.2 Hz, H-600), 4.25 (dd,
0
0
0
0
0
00
1H, J6 ,5 ¼ 4.6, J6 ,6 ¼ 12.2 Hz, H-600), 5.08 (t, 1H, J4 ,3 ¼ 9.9 Hz, H-40), 5.12
00
0
00
0
0
0
(dd, 1H, J2 ,1 ¼ 10.7, J2 ,3 ¼ 9.2 Hz, H-20), 5.25 (t, 1H, J3 ,2 ¼ J2 ,3 ¼ 9.2 Hz,
0
0
0
0
0
0
0
0
H-30), 5.54 (d, 1H, J1 ,2 ¼ 10.7 Hz, H-10), 6.47–6.54 (m, 2H, Ar-H), 7.05 (d, 1H,
J ¼ 6.9, Ar-H), 7.17–7.21 (m, 3H, Ar-H), 7.54–7.62 (m, 3H, Ar-H), 11.61
(s, 1H, D2O exchangeable, OH); 13C NMR (125.7 MHz, CDCl3) d ¼ 20.6, 20.7 (4
CH3CO), 61.6 (C-60), 68.1 (C-40), 69.9 (C-20), 73.7 (C-30), 76.3 (C-50), 83.8 (C-10),
110.0, 118.1, 118.7, 125.6, 127.8, 130.5, 130.9, 131.7, 134.0 (Ar-C), 169.5, 169.5,
170.0, 170.6 (CH3CO); Anal. Calcd for C28H29N3O10S (599.61): C, 56.09; H,
4.87; N, 7.01. Found: C, 56.00; H, 5.06; N, 6.93.
0
0

El S. H. El-Ashry et al.
80
4,5-Diphenyl-3-(20-acetamido-20-deoxy-30,40,60-tri-O-acetyl-b-D-glucopyra-
nosyl-thio)-4H-1,2,4-triazole (14). Colorless crystals; mp: 152–1548C; TLC,
1
Rf 0.67 (1:1 Hexane/EtOAc); H NMR (500 MHz, CDCl3) d ¼ 1.97, 1.99, 2.02,
2.04 (4s, 12H, 3 OAc, NAc), 3.82–3.90 (m, 1H, H-50), 4.09 (dd, 1H, J6 ,5 ¼ 2.3,
0
0
J6 ,6 ¼ 13.0 Hz, H-60), 4.23 (dd, 1H, J6 ,5 ¼ 5.3, J6 ,6 ¼ 13.0 Hz, H-600), 4.27
0
00
00
0
0
00
(ddd, 1H, J2 ,1 ¼ 10.7, J2 ,3 ¼ 9.2, J2 ,NH ¼ 8.4 Hz, H-20), 5.14 (dd, 1H,
0
0
0
0
0
J3 ,2 ¼ 9.2, J3 ,4 ¼ 9.9 Hz, H-30), 5.29 (t, 1H, J4 ,3 ¼ J4 ,5 ¼ 9.2 Hz, H-40), 5.58
0
0
0
0
0
0
0
0
(d, 1H, J1 ,2 ¼ 10.7 Hz, H-10), 7.01 (d, 1H, JNH,2 ¼ 8.4 Hz, D2O exchangeable,
NHAc), 7.02 (d, 2H, J ¼ 6.9, Ar-H), 7.25–7.28 (m, 2H, Ar-H), 7.33–7.39
(m, 3H, Ar), 7.45–7.53 (m, 3H, Ar-H); Anal. Calcd for C28H30N4O8S (582.63):
C, 57.72; H, 5.19; N, 9.62. Found: C, 57.31; H, 5.02; N, 9.43.
0
0
0
5-(2-Hydroxyphenyl)-4-phenyl-3-(20-acetamido-20-deoxy-30,40,60-tri-O-
acetyl-b-D-glucopyranosylthio)-4H-1,2,4-triazole (15). Colorless crystals;
mp: 162–1648C; TLC, Rf 0.67 (1:1 Hexane/EtOAc); 1H NMR (500 MHz, CDCl3)
0
00
d ¼ 1.95, 1.97, 2.01, 2.02 (4s, 12H, 3 OAc, NAc), 3.80 (dddd, 1H, J5 ,6 ¼ 2.3,
J5 ,6 ¼ 5.3, J5 ,4 ¼ 9.9 Hz, H-50), 4.08 (dd, 1H, J6 ,5 ¼ 2.3, J6 ,6 ¼ 12.2 Hz,
0
0
0
0
00
0
00
0
H-60), 4.27 (dddd, 2H, J6 ,5 ¼ 5.3, J6 ,6 ¼ 12.2, J2 ,1 ¼ 10.7, J2 ,3 ¼ 9.9,
0
0
0
00
0
0
0
0
J2 ,NH ¼ 8.4 Hz, H-600, H-20), 5.07 (t, 1H, J4 ,3 ¼ J4 ,5 ¼ 9.9 Hz, H-40), 5.31
0
0
0
0
0
(t, 1H, J3 ,2 ¼ J3 ,4 ¼ 9.9 Hz, H-30), 5.62 (d, 1H, J1 ,2 ¼ 10.7 Hz, H-10),
0
0
0
0
0
0
0
6.45–6.57 (m, 3H, Ar-H), 6.98 (d, 1H, D2O exchangeable, JNH,2 ¼ 8.4 Hz,
NHAc), 7.14–7.17 (m, 1H, Ar-H), 7.33 (d, 2H, J ¼ 7.7, Ar-H), 7.55–7.63
(m, 3H, Ar-H), 11.43 (s, 1H, D2O exchangeable OH); 13C NMR (125.7 MHz,
CDCl3) d ¼ 20.7, 20.8, 23.2 (CH3CO, NAc), 53.2 (C-20), 61.8 (C-60), 68.1 (C-40),
73.6 (C-30), 76.3 (C-50), 85.4 (C-10), 109.9, 117.9, 118.8, 125.8, 127.9, 130.5,
131.8, 133.9 (Ar-C), 169.4, 170.7, 171.1 (CH3CO); Anal. Calcd for C28H30N4O9S
(598.63): C, 56.18; H, 5.05; N, 9.36. Found: C, 56.27; H, 5.35; N, 9.12.
4,5-Diphenyl-3-(20,30,40,60-tetra-O-acetyl-b-D-galactopyranosylthio)-4H-
1,2,4-triazole (16). Colorless plates; mp 130–1318C; TLC, Rf 0.21 (2:1
Hexane/EtOAc); 1H NMR (500 MHz, CDCl3) d ¼ 1.97, 1.99, 2.04, 2.12 (4s,
12H, 4 CH3CO), 3.94–3.96 (m, 1H, H-50), 4.08 (dd, 1H, J6 ,5 ¼ 4.6,
0
0
J6 ,6 ¼ 12.2 Hz, H-60), 4.25 (dd, 1H, J6 ,5 ¼ 7.6, J6 ,6 ¼ 12.2 Hz, H-600), 5.11
0
00
0
0
0
00
(dd, 1H, J3 ,2 ¼ 9.9, J3 ,4 ¼ 3.5 Hz, H-30), 5.64 (d, 1H, J1 ,2 ¼ 9.9 Hz, H-10),
0
0
0
0
0
0
5.28 (t, 1H, J2 ,1 ¼ J2 ,3 ¼ 9.9 Hz, H-20), 5.45 (d, 1H, J4 ,3 ¼ 3.5 Hz, H-40),
7.03 (d, 2H, J ¼ 6.9 Hz, Ar-H), 7.24–7.26 (m, 2H, Ar-H), 7.36–7.40 (m, 3H,
Ar-H), 7.45–7.52 (m, 3H, Ar-H); Anal. Calcd for C28H29N3O9S (583.61): C,
57.62; H, 5.01; N, 7.20. Found: C, 56.92; H, 4.63; N, 6.82.
0
0
0
0
0
0
5-(o-Hydroxyphenyl)-4-phenyl-3-(20,30,40,60-tetra-O-acetyl-b-D-galactopyr-
anosyl-thio)-4H-1,2,4-triazole (17). Colorless crystals; mp 118–1198C, TLC,
1
Rf 0.21 (2:1 Hexane/EtOAc); H NMR (500 MHz, CDCl3) d ¼ 1.76, 1.95, 1.96,
2.12 (4s, 12H, 4 OAc), 3.94–3.96 (m, 1H, H-50), 4.08 (dd, 1H, J6 ,5 ¼ 4.6,
0
0

Synthesis of 5-Aryl-3-glycosylthio-4-phenyl-4h-1,2,4-triazoles
81
J6 ,6 ¼ 12.2 Hz, H-60), 4.25 (dd, 1H, J6 ,5 ¼ 7.7, J6 ,6 ¼ 12.2 Hz, H-600), 4.82
0
00
00
0
00
0
(d, 1H, J1 ,2 ¼ 9.9 Hz, H-10), 5.05 (dd, 1H, J3 ,4 ¼ 3.1, J3 ,2 ¼ 9.9 Hz, H-30), 5.26
0
0
0
0
0
0
(t, 1H, J2 ,1 ¼ J2 ,3 ¼ 9.9 Hz, H-20), 5.41 (d, 1H, J4 ,3 ¼ 3.1 Hz, H-40), 7.23–7.37
(m, 5 H, Ar-H), 7.46 (d, 2H, J ¼ 7.7 Hz, Ar-H), 7.58 (d, 2H, J ¼ 7.7 Hz, Ar-H),
10.12 (s, 1H, D2O exchangeable, OH); Anal. Calcd for C28H29N3O10S (599.61):
C, 56.09; H, 4.87; N, 7.01. Found: C, 56.46; H, 5.09; N, 7.08.
0
0
0
0
0
0
Preparation of Alkylated Analogs 21–26; General
Procedure
Conventional Method (CM)
To a solution of compounds 7 or 8 (1 mmol) in an ethanolic solution of
sodium ethoxide prepared from sodium metal (0.0023 g) in ethanol (15 mL)
was added hydroxyl alkylating agents 18–20. The reaction mixture was
heated for 2 to 4 h, concentrated, cooled, diluted with water, and left overnight.
The precipitate was washed with water and recrystallized from ethanol.
Microwave Method (MW)
To a solution of compounds 7 or8 (0.33 mmol) in an ethanolic solution of
sodium ethoxide prepared from sodium metal (0.76 mg) in ethanol (5 mL) in a
closed Teflon vessel was irradiated by MW for 2 to 4 min. The reaction mixture
was cooled and processed as described above to give the same products (Table 1).
4,5-Diphenyl-3-[(2-hydroxyeth-1-yl)thio]-4H-1,2,4-triazole (21). Color-
less crystals; mp 152–1538C; 1H NMR (DMSO-d6) d ¼ 3.15 (t, 2H,
J ¼ 6.9 Hz, SCH2), 3.66 (m, 2H, CH2O), 5.19 (bt, 1H, D2O exchangeable,
OH), 7.16–7.18 (m, 1H, Ar-H), 7.23–7.28 (m, 3H, Ar-H), 7.30–7.34 (m, 4 H,
Ar-H), 7.40–7.42 (m, 2H, Ar-H); Anal. Calcd for C16H15N3OS (297.38): C,
64.62; H, 5.08; N, 14.13. Found: C, 64.90; H, 5.23; N, 14.39.
3-[(2-Hydroxyeth-1-yl)thio]-5-(o-hydroxyphenyl)-4-phenyl-4H-1,2,4-
triazole (22). Colorless crystals; mp 160–1618C; 1H NMR (DMSO-d6)
d ¼ 3.25 (t, 2H, J ¼ 6.9 Hz, SCH2), 3.67 (q, 2H, J ¼ 4.5, J ¼ 6.9 Hz, CH2O),
5.06 (t, 1H, J ¼ 6.1, D2O exchangeable, OH), 6.71–6.76 (m, 2H, Ar-H),
7.12 (d, 1H, J ¼ 9.2, Ar-H), 7.17–7.21 (m, 1H, Ar-H), 7.26–7.28 (m, 2H,
Ar-H), 7.42–7.43 (m, 3H, Ar-H), 10.19 (s, 1H, D2O exchangeable, OH);
Anal. Calcd for C16H15N3O2S (313.38): C, 61.32; H, 4.82; N, 13.41. Found:
C, 61.28; H, 4.63; N, 13.18.
3-[(3-Hydroxyprop-1-yl)thio]-4,5-diphenyl-4H-1,2,4-triazole (23). Colorless
1
crystals; mp 1488C; H NMR (DMSO-d6) d ¼ 1.75–1.79 (pentet, 2H, J ¼ 6.9 Hz,
CH2CH2CH2), 3.16 (t, 2H, J ¼ 6.9 Hz, SCH2), 3.44 (q, 2H, J ¼ 5.4, J ¼ 10.7 Hz,

El S. H. El-Ashry et al.
82
CH2O), 4.57 (t, 1H, J ¼ 5.4 Hz, D2O exchangeable, OH), 7.28–7.31 (m, 3H, Ar-H),
7.35–7.37 (m, 3H, Ar-H), 7.50–7.51 (m, 4 H, Ar-H); Anal. Calcd for C17H17N3OS
(311.40): C, 65.57; H, 5.50; N, 13.49. Found: C, 65.18; H, 5.23; N, 13.16.
3-[(3-Hydroxyprop-1-yl)thio]-5-(o-hydroxyphenyl)-4-phenyl-4H-1,2,4-
triazole (24). Colorless crystals; mp 140–1428C; 1H NMR (DMSO-d6) d ¼ 1.78–
1.82 (pentet, 2H, CH2CH2CH2), 3.16 (t, 2H, J ¼ 6.9 Hz, SCH2), 3.40–3.41
(m, under solvent peak 2H, CH2O), 4.61 (t, 1H, J ¼ 4.6 Hz, D2O exchangeable,
OH), 6.71–6.77 (m, 2H, Ar-H), 7.11 (d, 1H, J ¼ 7.7, Ar-H), 7.17–7.20 (m, 1H,
Ar-H), 7.26–7.28 (m, 2H, Ar-H), 7.42–7.43 (m, 3H, Ar-H), 10.21 (s, 1H, D2O
exchangeable, OH); Anal. Calcd for C17H17N3O2S (327.40): C, 62.36; H, 5.23; N,
12.83. Found: C, 62.51; H, 5.47; N, 13.09.
3-[(2,3-Dihydroxyprop-1-yl)thio]-4,5-diphenyl-4H-1,2,4-triazole (25). Col-
orless crystals; mp 138–1408C; 1H NMR (DMSO-d6) d ¼ 3.15 (dd, 1H, J ¼ 5.4,
J ¼ 6.9, J ¼ 10.7 Hz, SCH2), 3.31 (dd, 1H, J ¼ 5.4, J ¼ 10.7 Hz, SCH2),
3.32–3.41 (m, 2H, CH2O), 3.68–3.73 (m, 1H, CHO), 4.75 (t, 1H, J ¼ 6.2 Hz,
D2O exchangeable, OH), 5.11 (d, 1H, J ¼ 5.4 Hz, D2O exchangeable, OH),
7.28–7.38 (m, 7 H, Ar-H), 7.50–7.52 (m, 3H, Ar-H); Anal. Calcd for
C17H17N3O2S (327.40): C, 62.36; H, 5.23; N, 12.83. Found: C, 62.09; H, 5.49;
N, 13.01.
3-[(2,3-Dihydroxyprop-1-yl)thio]-5-(o-hydroxyphenyl)-4-phenyl-4H-
1,2,4-triazole (26). Colorless crystals; mp 122–1238C; 1H NMR (DMSO-d6)
d ¼ 3.17 (dd, 1H, J ¼ 6.9, J ¼ 7.7, J ¼ 10.7 Hz, SCH2), 3.32 (dd, 1H, J ¼ 5.4,
J ¼ 10.7 Hz, SCH2), 3.35–3.39 (m, 2H, CH2O), 3.75 (ddd, 1H, J ¼ 5.4,
J ¼ 6.1, J ¼ 10.7 Hz, CHO), 4.75 (d, 1H, J ¼ 5.4 Hz, D2O exchangeable,
OH), 5.12 (d, 1H, J ¼ 5.4 Hz, D2O exchangeable, OH), 6.71–6.77 (m, 2H,
Ar-H), 7.11 (d, 1H, J ¼ 7.7, Ar-H), 7.17–7.20 (m, 1H, Ar-H), 7.28–7.30
(m, 2H, Ar-H), 7.43–7.44 (m, 3H, Ar-H), 10.20 (s, 1H, D2O exchangeable,
OH); Anal. Calcd for C17H17N3O3S (343.40): C, 59.46; H, 4.99; N, 12.24.
Found: C, 59.73H, 5.13; N, 12.13.
Action of tosyl chloride in pyridine on 3-[(2,3-Dihydroxyprop-1-
yl)thio]-5-(o-hydroxyphenyl)-4-phenyl-4H-1,2,4-triazole (26). A cold
solution of 26 (1 mmol) in pyridine (5 mL) was treated with p-toluenesulfonyl
chloride (1.1 mmol) during 1 h at 08C. The reaction mixture was then heated
under reflux for 6 h. After cooling, the reaction mixture was poured onto ice-
cold water (15 mL). The resulting solution was extracted with methylene
chloride (3 ꢁ 20 mL), washed with water, and dried over anhydrous
Na2SO4. It was evaporated under reduced pressure and then the resulting
solid was recrystallized with ethanol to give 5-(o-hydroxyphenyl)-4-phenyl-
1
1,2,4-triazol-3-one(29); mp 251–2528C. H NMR (DMSO-d6) d ¼ 6.56–6.64

Synthesis of 5-Aryl-3-glycosylthio-4-phenyl-4h-1,2,4-triazoles
83
(m, 2H, Ar-H), 7.02–7.04 (m, 1H, Ar-H), 7.21–7.26 (m, 2H, Ar-H), 7.34–7.37
(m, 2H, Ar-H), 7.55–7.56 (m, 2H, Ar-H), 9.93 (s, 1H, D2O exchangeable NH),
11.21 (s, 1H, D2O exchangeable OH); Anal. Calcd for C14H11N3O2 (253.26): C,
66.40; H, 4.38; N, 16.59. Found: C, 66.11; H, 4.23; N, 16.45.
Oxidation of 2-[(2,3-dihydroxyprop-1-yl)thio]-5-(o-hydroxyphenyl)-4-
phenyl-4H-1,2,4-triazole with sodium metaperiodate. To a solution of
26 (1 mmol) in distilled water (5 mL), a solution of sodium metaperiodate
(1.5 mmol) in distilled water (5 mL) was added. The reaction mixture was
stirred for 3 h, and then left for overnight. The product was recrystallized
from ethanol to give 8; mp: 2718C; (Lit[27] mp 2738C).
ACKNOWLEDGMENTS
The help from AvH and HEC are highly appreciated.
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