Synthesis and characterization of mono- and bicyclic heterocyclic derivatives containing 1,2,4-triazole, 1,3,4-thia-, and -oxadiazole rings

Article abstract of DOI:10.1007/s00706-008-0881-9

A series of new N- and S-substituted 1,3,4-oxadiazole derivatives were synthesized. 5-Pyridin-3-yl-3-[2-(5-thioxo-4,5-dihydro-l,3,4-thiadiazol-2-yl) ethyl]-1,3,4-oxadiazole-2(3H)-thione and 5-[(5-(pyridin-3-yl)-1,3,4-oxadiazol-2- ylthio)methyl]-N-phenyl-1

Full text of DOI:10.1007/s00706-008-0881-9

Monatsh Chem 139, 1055–1060 (2008)
DOI 10.1007/s00706-008-0881-9
Printed in The Netherlands
Synthesis and characterization of mono- and bicyclic heterocyclic
derivatives containing 1,2,4-triazole, 1,3,4-thia-, and -oxadiazole rings
Wael A. El-Sayed1, Mohamed I. Hegab1, Hala E. M. Tolan2, Adel A.-H. Abdel-Rahman2
1
National Research Centre, Department of Photochemistry, Cairo, Egypt
2
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
Received 6 December 2007; Accepted 20 December 2007; Published online 1 February 2008
# Springer-Verlag 2008
Abstract A series of new N- and S-substituted
1,3,4-oxadiazole derivatives were synthesized. 5-Pyri-
din-3-yl-3-[2-(5-thioxo-4,5-dihydro-l,3,4-thiadiazol-
2-yl)ethyl]-1,3,4-oxadiazole-2(3H)-thione and 5-[(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)methyl]-N-
phenyl-1,3,4-thiadiazol-2-amine were formed by
cyclization of 3-(5-pyridin-3-yl-2-thioxo-1,3,4-oxadi-
azol-3(2H)-ylpropanimidohydrazide and 2-[(5-pyri-
din-3-yl-1,3,4-oxadiazol-2-yl)thio]thiosemicarbazide
with CS2 and H2SO4. On the other hand, a number
of new bicyclic 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole
derivatives were synthesized. 6-Pyridin-3-ylbis[1,2,4]-
triazolo[3,4-b:40,30-d][1,3,4]thiadiazole-3(2H)-thione
was synthesized by reaction of 6-(hydrazino)-3-pyri-
dine-3-yl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole with
CS2=KOH=EtOH. The structures of the newly synthe-
sized compounds were elucidated by the spectral and
fields showing antibacterial [1], antimicrobial [2],
insecticidal [3], herbicidal=fungicidal [4], antiin-
flammatory [5], hypoglycaemic [6], hypotension
[7], and antitumor activity [8]. In the field of me-
dicinal chemistry, oxadiazoles are utilized as ester or
amide surrogates. A number of biologically relevant
entities containing the 1,3,4-oxadiazole motif are
used as HIV integrase inhibitor and angiogenesis
inhibitor [9, 10]. In addition, compounds incorporat-
ing both 1,2,4-triazole and 1,3,4-thiadiazole rings
have been attracting widespread attention due to
their diverse pharmacological prosperities such as
antimicrobial, antiinflammatory, analgesic, and an-
titumoral activities [11–20]. Acylhydrazides and
their derivatives have been, in general, used as the
starting materials for the synthesis of 1,3,4-oxadia-
zoles, 1,3,4-thiadiazoles, and 1,2,4-triazoles [21, 22].
Furthermore, heterocyclic hydrazines are generally
utilized as intermediates for the synthesis of several
condensed systems containing triazoles and other
ring systems [23, 24]. Consequently, in view of the
above facts and as a part of an ongoing investigation
into biologically more active and less toxic sub-
stances, our current interest is focused on the synthesis
of a series of new 1,3,4-oxadiazoles and condensed
1,2,4-triazolothiadiazole derivatives.
1
analytical data IR, Mass, and H NMR spectra.
Introduction
During recent years there has been intense investiga-
tion of different classes of 1,3,4-oxadiazoles and
the related thiadiazole derivatives, many of which
have demonstrated a broad spectrum of biological
activity in both agrochemical and pharmaceutical
Results and discussion
Correspondence: Adel A.-H. Abdel-Rahman, Department of
Chemistry, Faculty of Science, Menoufia University, Shebin
El-Koam, Egypt. E-mail: adelnassar63@hotmail.com; Wael
A. El-Sayed, National Research Centre, Department of Photo-
chemistry, Cairo, Egypt. E-mail: Waelshendy@gmail.com
The starting material 5-pyridin-3-yl-1,3,4-oxadia-
zole-2-thiol (1) [23] was synthesized by reflux-
ing nicotinic acid hydrazide and CS2=KOH=EtOH.

1056
W. A. El-Sayed et al.
Reaction of the thiol 2 with acrylonitrile in ethanol
afforded 3-(5-pyridin-3-yl-2-thioxo-1,3,4-oxadiazole-
3(2H)-yl)propanenitrile (2) in 75% yield.
thiadiazol-2-yl)ethyl]-1,3,4-oxadiazole-2(3H)-thione
(4) was obtained. Its IR spectrum showed character-
istic absorption bands at ꢀꢀ¼ 3419 and 1652 cmꢀ1
corresponding to the NH and C¼N groups and its
1H NMR agrees with the assigned structure. Reac-
tion of 1 with ethyl chloroacetate and NaOH=EtOH
gave ethyl[(5-pyridin-3-yl-l,3,4-oxadiazol-2-yl)thio]-
acetate (5) in 70% yield. Its IR spectrum showed a
characteristic adsorption band in the carbonyl fre-
quency region at ꢀꢀ¼ 1739 cmꢀ1 corresponding to the
ester group. The 1H NMR spectrum showed the sig-
nals as triplet at ꢁ ¼ 1.18 ppm for the CH3 group,
quartet at ꢁ ¼ 4.14 ppm for the CH2 group, and
SCH2 as singlet at ꢁ ¼ 4.30 ppm in addition to the
protons of the pyridyl ring. Treatment of 5 with hy-
The IR spectrum showed a characteristic absorp-
tion band at ꢀꢀ¼ 2248 cmꢀ1 corresponding to the CN
1
group. The H NMR spectrum showed the two CH2
groups as triplets in addition to the protons of the
pyridyl ring. Treatment of 2 with hydrazine hydrate
in ethanol at reflux temperature afforded 3-(5-pyri-
din-3-yl-2-thioxo-1,3,4-oxadiazole-3(2H)-yl)propan-
imidohydrazide (3) in 90% yield. Its 1H NMR
spectrum showed the two CH2 groups as triplets,
the NH2 as singlet in addition to the protons of the
pyridyl ring. When 3 was refluxed with CS2 in buta-
nol, 5-pyridin-3-yl-3-[2-(5-thioxo-4,5-dihydro-1,3,4-
Scheme 1

Heterocyclic derivatives containing 1,2,4-triazole, 1,3,4-thia-, and -oxadiazole
1057
drazine hydrate in ethanol at reflux temperature gave
2-[(5-pyridin-3-yl-1,3,4-oxadiazol-2-yl)thio]aceto-
hydrazide (6). The IR spectrum of this compound
showed a characteristic carbonyl frequency at
ꢀꢀ¼ 1684 cmꢀ1 in addition to the C¼N group at
3-yl-1,3,4-oxadiazol-2-yl)thio]methyl-1,3,4-thiadia-
zol-2-amine (8). Its IR spectrum showed the two
peak frequencies at ꢀꢀ¼ 3418 and 1663 cmꢀ1 corre-
sponding to NH and C¼N and its 1H NMR spectrum
agrees with the assigned structure (Scheme 1).
Because one of the most important methods for
the synthesis of bicyclic triazole systems is the cycli-
zation of 1-amino-2-thio- or 2-hydrazino-derivatives
to give the bicyclic ring systems, 4-amino-5-pyridin-
3-yl-4H-1,2,4-triazole-3-thiol (9) [24], formally
synthesized from potassium 2-(pyridin-3-ylcarbon-
yl)hydrazinecarbodithioate, was used as a starting
material for the synthesis of a series of condensed
heterocyclic compounds. Thus, reaction of the 1-
amino-1,2,4-triazole derivative 9 with benzoic acid
or chlorobenzoic acid afforded 6-phenyl-3-pyri-
din-3-yl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (14)
1
ꢀꢀ¼ 1652 cmꢀ1. Its H NMR spectrum agrees with
the assigned structure. Reaction of the hydrazide 6
with phenyl isothiocyanate afforded the correspond-
ing thiosemicarbazide derivative 7 in a good yield
(84%) [25]. The IR spectrum of 7 showed a charac-
teristic absorption band at 1596 cmꢀ1 corresponding
to the C¼N group in addition to the amino frequen-
cies at ꢀꢀ¼ 3117–3216 cmꢀ1 and at ꢀꢀ¼ 3444 cmꢀ1.
The 1H NMR spectrum showed the SCH2 and NH as
singlets in addition to the protons of the pyridyl ring.
The thiosemicarbazide 7 was treated with H2SO4
at room temperature to form N-phenyl-5-[(5-pyridin-
Scheme 2

1058
W. A. El-Sayed et al.
1
(CꢃN), 1614 (C¼N) cmꢀ1; H NMR (DMSO-d6, 300 MHz):
ꢁ ¼ 3.11 (t, J ¼ 6.4 Hz, CH2CH2CN), 4.40 (t, J ¼ 6.4 Hz,
CH2CH2CN), 7.62–7.71 (m, pyridyl-H), 8.27 (d, J ¼ 7.9 Hz,
pyridyl-H), 8.81 (d, J ¼ 6.6 Hz, pyridyl-H), 9.05 (s, pyridyl-H)
ppm; MS: m=z (%) ¼ 255 (Mþ þ Na, 25).
or 6-(4-chlorophenyl)-3-pyridin-3-yl[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazole (15). When 9 was treated
with CS2 and ethanolic KOH it gave 3-pyridin-3-
yl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-6-thiol (10).
1
The H NMR spectrum showed the NH group as
a singlet at ꢁ ¼ 14.0 ppm in addition to the protons
of the pyridyl ring in the range ꢁ ¼ 56–8.76 ppm.
Treatment of 10 with ethyl iodide in aqueous solu-
tion of KOH gave 11, which was allowed to react
3-(5-Pyridin-3-yl-2-thioxo-1,3,4-oxadiazol-3(2H))-ylpro-
panimidohydrazide (3, C10H12N6OS)
A mixture of 10.7 g 2 (46.3 mmol), 8.5 cm3 EtOH, and 6.9 g
N2H4 ꢁ H2O (138mmol) was refluxed for 1 h and the solvent
was removed under reduced pressure. The remaining precipi-
tate was collected, dried, and recrystallized from EtOH to
afford 9.6 g 3 in 90% yield as yellow solids. Rf ¼ 0.25 (ethyl
acetate=chloroform, 1=1). Mp 195–197ꢂC; IR (KBr): ꢀꢀ¼
1
with N2H4 ꢁ H2O=EtOH to give 12. The H NMR
spectrum of 11 showed the CH3 group as a triplet
at ꢁ ¼ 1.45 ppm and the CH2 group as a quartet at
ꢁ ¼ 3.40 ppm in addition to the protons of the pyridyl
ring at ꢁ ¼ 7.62–9.99 ppm. 6-Hydrazino-3-pyridine-
3-yl[l,2,4]triazolo[3,4-b][1,3,4]thiadiazole (12) was
treated with CS2=KOH=EtOH to give 6-pyridin-3-
ylbis[1,2,4]triazolo[3,4-b:40,30-d][1,3,4]thiadiazole-
3(2H)-thione (13). Its IR spectrum showed an
absorption band at ꢀꢀ¼ 1614 cmꢀ1 corresponding to
the C¼N group. The 1H NMR showed the NH group
at ꢁ ¼ 12.86 ppm and the protons of the pyridyl ring at
ꢁ ¼ 7.05–8.56 ppm. Acetylation of 9 with acetic anhy-
dride gave N-(3-mercapto-5-pyridin-3-yl-(4H)-1,2,4-
triazol-4-yl)acetamide (16). Its IR spectrum showed
a characteristic absorption band in the carbonyl fre-
quency region for the NH–CO group (Scheme 2).
1
3439 (NH), 3278–3163 (NH2) cmꢀ1; H NMR (DMSO-d6,
300 MHz): ꢁ ¼ 3.80 (br, s, NH2), 4.56 (t, J ¼ 7.1 Hz, CH2),
5.88 (t, J ¼ 7.1 Hz, CH2), 7.58–7.61 (m, pyridyl-H), 8.34 (d,
J ¼ 7.4Hz, pyridyl-H), 8.72 (d, J ¼ 5.9Hz, pyridyl-H), 9.03 (s,
pyridyl-H), 9.12 (br, s, NH) ppm.
5-Pyridin-3-yl-3-[2-(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-
2-yl)ethyl]-1,3,4-oxadiazole-2(3H)-thione (4, C11H9N5OS3)
Carbon disulfide (5cm3, 16mmol) was added to a solution of
2.1 g 3 (8mmol) in 30cm3 BuOH. The mixture was refluxed
for 5 h and the solvent was removed under reduced pressure.
The formed precipitate was recrystallized from BuOH to give
0.7 g 4 in 35% yield as pink crystals. Rf ¼ 0.65 (chloroform=
methanol, 2=1). Mp 235–237ꢂC; IR (KBr): ꢀꢀ¼ 1652 (C¼N),
l
3419 (NH) cmꢀ1; H NMR (DMSO-d6, 300 MHz): ꢁ ¼ 4.45
(t, J ¼ 6.7 Hz, CH2), 5.88 (t, J ¼ 6.8 Hz, CH2), 7.22–7.32
(m, pyridyl-H), 8.17 (d, J ¼ 7.2Hz, pyridyl-H), 8.33 (d, J ¼
7.1 Hz, pyridyl-H), 9.02 (s, pyridyl-H), 12.10 (br, s, NH) ppm;
MS: m=z (%) ¼ 323 (Mþ, 44).
Experimental
Ethyl [(5-pyridin-3-yl-1,3,4-oxadiazol-2-yl)thio]acetate
(5, C11H11N3O3S)
Melting Points were taken on a digital melting point appara-
tus. Infrared spectra were measured on KBr using a Bruker-
Vector 22. Mass spectra were measured on a Hewlett-Packard
5988 A (1000 Hz) instrument. 1H NMR spectra were obtained
using a Varian Gemini (300 MHz) spectrometer (DMSO-d6)
with TMS as internal standard. All reactions were monitored
by TLC. The microanalyses were performed at the microana-
lytical unit, Cairo University, Egypt and were found to agree
favourably with the calculated values. 5-Pyridin-3-yl-1,3,4-
oxadiazole-2-thiol (1) was obtained as reported [23], by
refluxing nicotinic acid hydrazide with CS2=KOH=EtOH.
4-Amino-5-pyridin-3-yl-(4H)-1,2,4-triazole-3-thiol (9) was ob-
tained by refluxing potassium salt of nicotinic acid hydrazide
with N2H4 ꢁ H2O [24].
A solution of compound 1.79g 1 (10 mmol), 0.4 g NaOH
(10 mmol), and 30cm3 EtOH was heated under reflux for
45min followed by addition of 1.22 g ethyl chloroacetate
(10 mmol). The resulting mixture was heated for 6 h, filtered,
cooled and poured on crushed ice. The precipitate was filtered
off and recrystallized from EtOH to afford 1.2 g 5 in 70%
yield as pink crystals. Rf ¼ 0.65 (chloroform=methanol, 2=1).
Mp 175–177ꢂC; IR (KBr): ꢀꢀ¼ 1739 (C¼O), 1605 (C¼N)
cmꢀ1; lH NMR (DMSO-d6, 300MHz): ꢁ ¼ 1.18 (t, J ¼ 7.1 Hz,
CH2CH3), 4.15 (q, J ¼ 7.1 Hz, CH2CH3), 4.30 (s, SCH2), 7.62–
7.72 (m, pyridyl-H), 8.32 (d, J ¼ 7.8 Hz, pyridyl-H), 8.77
(d, J ¼ 6.4 Hz, pyridyl-H), 9.24 (s, pyridyl-H) ppm; MS: m=z
(%) ¼ 304 (Mþ þ K, 45).
3-(5-Pyridin-3-yl-2-thioxo-1,3,4-oxadiazol-3(2H)-yl)pro-
panenitrile (2, C10H8N4OS)
2-[(5-Pyridin-3-yl-1,3,4-oxadiazol-2-yl)thio]acetohydrazide
(6,C9H9N5O2S)
A mixture of 10.1g 1 [23] (56.5 mmol), 2.9g acrylonitrile
(56.5mmol), and 1.8 g Et3N (20 mmol) was dissolved in
30cm3 absolute EtOH. The reaction mixture was heated under
reflux for 3 h and then cooled to room temperature. The ob-
tained precipitate was filtered off, dried, and recrystallized
from EtOH to give 7.5g 2 as white crystals in 75% yield.
Rf¼ 0.65 (chloroform). Mp 233–235ꢂC; IR (KBr): ꢀꢀ¼ 2248
A mixture of 2.65 g 2 (10 mmol), 4 cm3 EtOH, and 1.5 g
N2H4 ꢁ H2O (30 mmol) was refluxed for 4 h and the solvent
was removedunder reduced pressure. The remaining precipitate
was collected, dried, and recrystallized from EtOH to afford
1.6 g 6 in 63% yield as yellow crystals. Rf ¼ 0.65 (chloroform=
methanol, 2=1). Mp 140–142ꢂC; IR (KBr): ꢀꢀ¼ 3321 (NH),

Heterocyclic derivatives containing 1,2,4-triazole, 1,3,4-thia-, and -oxadiazole
1059
3207–3143 (NH2), 1616 (C¼N), 1684 (C¼O) cmꢀ1; lH NMR
(DMSO-d6, 300 MHz): ꢁ ¼ 3.91 (s, NH2), 4.64 (s, SCH2), 7.33–
7.91 (m, pyridyl-H), 8.01 (s, pyridyl-H), 8.76 (br, s, NH) ppm.
yield as white crystals. Rf ¼ 0.56 (chloroform=methanol, 2=1).
l
Mp 168–170ꢂC; IR (KBr): ꢀꢀ¼ 1614 (C¼N) cmꢀ1; H NMR
(DMSO-d6, 300 MHz): ꢁ ¼ 1.45 (t, J ¼ 7.2 Hz, CH2CH3), 3.40
(q, J ¼ 7.2 Hz, CH2CH3), 7.62–7.72 (m, pyridyl-H), 8.48 (d,
J ¼ 5.8Hz, pyridyl-H), 8.72 (d, J ¼ 6.2Hz, pyridyl-H), 9.33 (s,
pyridyl-H) ppm; MS: m=z (%) ¼ 263 (Mþ, 35).
2-[(5-Pyridin-3-yl-1,3,4-oxadiazol-2-yl)thio]thiosemicar-
bazide (7,C16H14N6O2S2)
Phenyl isothiocyanate (2.7g, 20mmol) was added to a solu-
tion of 7.7 g 6 (20 mmol) in 100 cm3 EtOH. The reaction mix-
ture was heated under reflux for 12 h. The solid product which
separated on cooling was filtered off, washed with EtOH,
dried, and recrystallized from EtOH to give 6.5 g 7 in 86%
yield as brown crystals. Rf ¼ 0.53 (chloroform). Mp 233–
235ꢂC; IR (KBr): ꢀꢀ¼ 3446 (NH), 3216–3117 (NH2), 1596
6-(Hydrazino)-3-pyridine-3-yl[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazole (12, C8H7N7S)
A solution of 1.3 g 11 (5mmol) in 10cm3 EtOH and 0.75 g
N2H4 ꢁ H2O (15 mmol) was heated under reflux for 3 h. The
solvent was removed under reduced pressure and the precipi-
tated solid was filtered off, washed with EtOH, and recrystal-
lized from EtOH to afford 1.0g 12 in 79% yield as grey
crystals. Rf ¼ 0.65 (chloroform=methanol, 2=1). Mp 244–
1
(C¼O) cmꢀ1; H NMR (DMSO-d6, 300 MHz): ꢁ ¼ 3.44 (s,
CH2), 4.49 (br, s, NH), 7.12–7.38 (m, Ar–H), 7.42–7.51 (m,
pyridyl-H), 7.95 (s, pyridyl-H), 9.88 (s, NH), 11.01 (br, s, NH)
ppm; MS: m=z (%) ¼ 287 (Mþ, 45).
246ꢂC; IR (KBr): ꢀꢀ¼ 3444 (NH), 3329–3207 (NH2) cmꢀ1
.
6-Pyridin-3-ylbis[1,2,4]triazolo[3,4-b:40,30-d][1,3,4]-
5-[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio]methyl-N-
phenyl-1,3,4-thiadiazol-2-amine (8, C16H12N6OS2)
A suspension of 0.38 g 7 (1mmol) in 15 cm3 cold cone. H2SO4
was stirred until dissolution and then left at room temperature
for 6 h. The reaction mixture was poured onto crushed ice and
the precipitated product was filtered off, washed with water,
and recrystallized from EtOH to afford 0.2 g 8 in 63% yield as
a white powder. Rf ¼ 0.36 (ethyl acetate=chloroform, 1=1). Mp
193–195ꢂC; IR (KBr): ꢀꢀ¼ 3418 (NH), 1663 (C¼N) cmꢀ1; lH
NMR (DMSO-d6, 300 MHz): ꢁ ¼ 3.87 (s, SCH2), 4.49 (br, s,
NH), 7.12–7.21 (m, Ar–H), 7.38 (m, Ar–H) 7.42–7.51 (m,
pyridyl-H), 7.62 (s, pyridyl-H) ppm; MS: m=z (%) ¼ 408
(Mþ þ K þ 1, 22).
thiadiazole-3(2H)-thione (13, C9H5N7S2)
A mixture of an alcoholic KOH solution (0.28 g, 5 mmol in
7 cm3 EtOH) and 3 cm3 H2O was added to a solution of 1.16 g
12 (5 mmol) in 25 cm3 EtOH with stirring. CS2 (0.38g, 5 mmol)
was added dropwise with continuous stirring and the reaction
mixture was refluxed until the H2S ceased (20 h). The reaction
mixture was concentrated, cooled to room temperature and
poured into 100 cm3 of an ice-water mixture, then acidified
with conc. HCl. The precipitate was filtered off and recrystal-
lized from dioxane to give 0.98g 13 in 85% yield as brown
solids. Rf ¼ 0.45 (chloroform=methanol, 2=1). Mp 254–256ꢂC;
IR (KBr): ꢀꢀ¼ 1614 (C¼N) cmꢀ1
;
lH NMR (DMSO-d6,
300 MHz): ꢁ ¼ 4.62 (s, SH), 7.05–8.05 (m, pyridyl-H), 8.56 (s,
pyridyl-H), 12.68 (s, NH) ppm; MS: m=z (%) ¼ 275 (Mþ, 20).
3-Pyridin-3-yl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-6-
thiol (10,C8H5N5S2)
6-Phenyl-3-pyridin-3-yl[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazole (14, C14H9N5S) and 6-(4-chlorophenyl)-3-
pyridin-3-yl[1 ,2,4]triazolo[3,4-b][1,3,4]thiadi-azole
(15, C14H8ClN5S)
Carbon disulfide (3.3cm3, 10mmol) was added to a mixture
of 1.9 g 9 (10 mmol) in ethanolic KOH solution (0.56 g,
10mmol of KOH in 30cm3 EtOH). The reaction mixture
was heated under reflux for 6 h, most of the solvent was then
distilled off under reduced pressure, and the residue was dis-
solved after being cooled in 10% KOH solution and filtered,
the cold filtrate was acidified with conc. HCl and the separated
solid was filtered off, washed with water and recrystallized
from aqueous EtOH to give 1.0 g 10 in 53% yield as a
white powder. Rf ¼ 0.56 (chloroform=methanol, 2=1). Mp 276–
278ꢂC; IR (KBr): ꢀꢀ¼ 1602 (C¼N), 3110 (SH) cmꢀ1; 1H NMR
(DMSO-d6, 300 MHz): ꢁ ¼ 7.56–7.61 (m, pyridyl-H), 8.36 (d,
J ¼ 5.8 Hz, pyridyl-H), 8.71 (d, J ¼ 6.2 Hz, pyridyl-H), 9.13 (s,
pyridyl-H), 14.0 (s, NH) ppm; MS: m=z (%) ¼ 235 (Mþ, 7).
A mixture of 0.96 g 9 (5mmol), benzoic acid or 4-chloroben-
zoic acid (5mmol), and 25cm3 POCl3 was refluxed for 5–6 h.
The excess of POCl3 was removed under reduced pressure and
the residue was poured onto crushed ice to give a solid product
which was washed with 20cm3 aqueous solution of NaHCO3
(20%) and 20cm3 H2O. The collected solid was filtered off,
dried, and recrystallized from EtOH to give 14 and 15 in 50–
64% yields as white crystals.
Compound 14: 1.0 g (64%). Rf ¼ 0.45 (chloroform=metha-
nol, 2=1). Mp 203–205ꢂC; IR (KBr): ꢀꢀ¼ 1578 (C¼N) cmꢀ1
;
1H NMR (DMSO-d6, 300 MHz): ꢁ ¼ 7.46 (m, Ar–H), 7.63 (m,
Ar–H), 7.82 (m, pyridyl-H), 7.93 (s, pyridyl-H) ppm; MS m=z
(%) ¼ 279 (Mþ, 34).
6-(Ethylthio)-3-pyridin-3-yl[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazole (11, C10H9N5S2)
Compound 15: 0.88 g (50%). Rf ¼ 0.43 (chloroform=metha-
nol, 2=1). Mp 215–217ꢂC; IR (KBr): ꢀꢀ¼ 1614 (C¼N) cmꢀ1
MS: m=z (%) ¼ 313 (Mþ, 22).
;
The thiol derivative 10 (0.71 g, 3 mmol) was dissolved in an
aqueous solution of KOH (0.16 g, 3 mmol in 20 cm3 H2O).
Ethyl iodide (0.47 g, 3 mmol) was added with continuous
shaking for a few minutes until the product separated. The
excess of ethyl iodide was removed by heating on a water bath
and the crude ethyl thioether was separated by filtration and
recrystallized from aqueous EtOH to give 0.5g 11 in 80%
N-(3-Mercapto-5-pyridin-3-yl-4H-1,2,4-triazol-4-yl)-
acetamide (16, C9H9N5OS)
A mixture of 0.96g 9 (5mmol) and 5 cm3 AcOH in 25cm3 dry
pyridine was refluxed for 8 h. The reaction mixture poured

1060
W. A. El-Sayed et al.
into 100 cm3 H2O. The solid product which formed was fil-
tered off, dried, and recrystallized from AcOH to afford 0.33g
16 in 35% yield as brownish crystals. Rf ¼ 0.53 (chloroform).
Mp 182–184ꢂC; IR (KBr): ꢀꢀ¼ 3421 (NH), 1702 (C¼O), 1558
(C¼N) cmꢀ1; MS: m=z (%) ¼ 236 (Mþ þ 1, 17).
7. (a) Tyagi M, Kumar A (2002) Oriental J Chem 18:25; (b)
Vio L, Mamalo MG, Laneve A (1989) Farmaco 44:165
8. Lokanatha Rai KM, Linganna N (2000) Farmaco 55:
389
9. Awad LF, El Ashry ESH (1998) Carbohydrate Res
312:9
10. Amir M, Shikha K (2004) Eur J Med Chem 39:535
11. Palaska E, Sahin G, Kelicen P, Durlu NT, Altinok G
(2002) Farmaco 57:101
12. Holla BS, Poorjary KN, Rao BS, Shivananda MK (2002)
Eur J Med Chem 37:511
13. Henichart JP, Houssin R, Berier JL (1986) J Het Chem
23:1531
14. Varvarasou A, Siatra-Papastaikoudi T, Tsantili-Kakoulidou
A, Vamvakides A (1998) Farmaco 53:320
15. Mishrah L, Said MK, Itokawa H, Takeya K (1995) Bioorg
Med Chem 3:1241
References
1. Ates O, Kocabalkanli A, Sanis GO, Ekinci A, Vidin A
(1997) Drug Res 47:1134
2. (a) Cesur N, Birteksoz S, Otuk G (2002) Pharm Turcica
44:23; (b) Nofal ZM, Fahmy HH, Mohamed HS (2002)
Arch Pharm Res 25:28; (c) Laddi, UV, Desai SR, Bennur
RS, Bennur SC (2002) Ind J Het Chem 11:319; (d) Khan
MSY, Khan RM, Drabu S (2001) Ind J Het Chem 11:119;
(e) Holla B, Gonsalves R, Shenoy S (2000) Eur J Med
Chem 35:267; (f) Kagthara PR, Shah NS, Doshi RK,
Parekh HH (1999) Ind J Chem Sec B Org Chem Inc Med
Chem 38:572; (g) Rollas S, Karakus S, Durgun BB (1996)
Farmaco51:811; (h) Habib NS, KhalilMA(1987) Farmaco
42:973
16. Szarvasi E, Fontaine L, Betbeder-Matibet A (1973) J Med
Chem 16:281
17. Patel JM, Dave MP, Langalia NA, Thaker KA (1984)
J Indian Chem Soc 61:718
3. Li XZZ, Wang Y, Chen W, Huang Q, Liu C, Song G
(2003) J Fluorine Chem 123:163
18. Girges M.M, Arzneim F (1994) Drug Res 44:490
19. Canstz A, Koparir M, Demirdag A (2004) Molecules
9:204
20. Rostom SAF, Shalaby MA, El-Demellawy MA (2003)
J Med Chem 38:959
21. Johi RC, Chand P (1983) J Het Chem 17:1980
22. Monge Vega A, Aldama I, Rabbani MM, Fernandez AE
(1980) J Heterocycl Chem 17:77
23. Amir M, Shikha K (2004) Eur J Med Chem 39:535
24. Abdel-Samie ZK, Al-Ashmawi MI, Abdel-Fattah (1987)
Egypt J Pharm Sci 28:395
4. (a) Zo X, Zhang Z, Jin GJ (2003) J Chem Res 228; (b) Zou
XJ, Lai LH, Jin GY, Zhang ZX (2002) JAgric Food Chem
50:3757; (c) Singh H, Srivastava MK, Singh BK, Singh
SK, Dubey C (2001) Ind J Chem Sec B Org Chem Med
Chem 40:159; (d) Mazzone G, Bonina F, Puglisi G,
Arrigo-Reina R, Cosentino C, Blandino G (1982) Farmaco
37:685
5. (a) Palaska E, Sahin G, Kelicen P, Durlu NT (2002)
Farmaco 57:101; (b) Misra U, Hitkari A, Axena AK,
Gurtu S, Hanker K (1996) Euro J Med Chem 31:629
6. Mhasalkar MY, Shah MH, Pilankar PD, Nikan ST,
Nantanarayan KG, Deliwala CV (1971) J Med Chem
4:1000
25. (a) Abdel-Aal MT, El-Sayed WA, Abdel-Aleem AH, El
Ashry ESH (2003) Pharmazie 58:788; (b) El-Essawy FA,
Khattab AF, Abdel- Rahman AA-H (2007) Monatsh Chem
138:777