Synthesis and antimicrobial evaluation of some 1,2,4-triazole, 1,3,4-oxa(thia)diazole, and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives

Article abstract of DOI:10.1002/hc.20162

3-Methyl-2-benzofurancarboxylic acid hydrazide (2) reacts with carbon disulfide and potassium hydroxide to give the corresponding potassium carbodithioate salt 3. Treatment of the latter salt with hydrochloric acid, hydrazine hydrate, and with phenacyl br

Full text of DOI:10.1002/hc.20162

Heteroatom Chemistry
Volume 16, Number 7, 2005
Synthesis and Antimicrobial Evaluation of
Some 1,2,4-Triazole, 1,3,4-Oxa(thia)diazole,
and 1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazine
Derivatives
Kamal M. Dawood, Ahmad M. Farag, and Hatem A. Abdel-Aziz
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Received 24 April 2005; revised 9 August 2005
INTRODUCTION
ABSTRACT: 3-Methyl-2-benzofurancarboxylic acid
hydrazide (2) reacts with carbon disulfide and pota-
ssium hydroxide to give the corresponding potassium
carbodithioate salt 3. Treatment of the latter salt with
hydrochloric acid, hydrazine hydrate, and with phen-
acyl bromide afforded the corresponding 1,3,4-oxadia-
zole-5-thione 4, 4-amino-1,2,4-triazole-5-thione 5,
and thiazolidine-2-thione 9 derivatives, respectively.
The reaction of either 1,3,4-oxadiazole-5-thione 4
or 4-amino-1,2,4-triazole-5-thione 5 with phenacyl
bromide resulted in the formation of 1,2,4-triazolo[3,
4-b]-1,3,4-thiadiazine derivative 8. Treatment of com-
pounds 3 or 4 with hydrazonoyl halides 10a–d furn-
ished the same 1,3,4-thiadiazol-2-ylidene derivatives
11a–d. The 7-arylhydrazono-1,2,4-triazolo[3,4-b]-1,
3,4-thiadiazine derivatives 12a–d were obtained either
by treatment of 4-amino-1,2,4-triazole-5-thione 5
with hydrazonoyl halides 10a–d or by cou-
pling of the 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine
Benzofuran moiety is incorporated in various nat-
ural products [1–4] and pharmaceuticals [5–8]. In
addition, the therapeutic effects of 1,2,4-triazole [9–
11] and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine [12–
14] derivatives have been well documented. There
is no single report about 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazine incorporating benzofuran moiety,
although the biologically active 3-methyl-2-benzo-
furancarboxylic acid hydrazide (2) [15] has been
reported once three decades ago. This may be at-
tributed to the difficulties that were faced during
the preparation of the precursor ethyl 3-methyl-
2-benzofurancarboxylate (1) from phenol [16,17].
In continuation to our endeavors on the synthe-
sis of various substituted heterocyclic ring sys-
tems of potentially biological activities [18–24],
we report here a new access to some functional-
ized 1,2,4-triazole, 1,3,4-oxa(thia)diazole, and 1,2,
4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives incor-
porating 3-methylbenzofuran moiety utilizing com-
pound 2 toward biological screening. Some of the
obtained products showed good antibacterial and
antifungal activities.
ꢀ
C
derivative 8 with diazonium salts.
2005 Wiley
Periodicals, Inc. Heteroatom Chem 16:621–627, 2005;
Published online in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/hc.20162
RESULTS AND DISCUSSION
Acid hydrazides can be considered as useful inter-
mediates leading to the formation of several hete-
rocycles such as 1,2,4-triazoles, 1,3,4-oxadiazoles,
Correspondence to: Kamal M. Dawood; e-mail: dr dawood@
yahoo.com.
2005 Wiley Periodicals, Inc.
c
ꢀ
621

622 Dawood, Farag, and Abdel-Aziz
and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines [25].
Therefore, 3-methyl-2-benzofurancarboxylic acid
hydrazide (2) was prepared from the reaction of
ethyl 3-methyl-2-benzofurancarboxylate (1) with hy-
drazine [15]. Treatment of compound 2 with carbon
disulfide in ethanol, in the presence of potassium
hydroxide, resulted in the formation of the potas-
sium salt of hydrazinecarbodithioate 3 which on
treatment with hydrochloric acid afforded a product
identified as 2-(3-methylbenzofuran-2-yl)-1,3,4-
oxadiazole-5-thione (4) (Scheme 1). Its IR spectrum
showed an absorption band at 3164 cm−1 due to NH,
and its mass spectrum showed a peak corresponding
to its molecular ion at m/z 232. The formation of
the oxadiazole 4 can be discussed according to a re-
lated literature [26]. Furthermore, treatment of the
potassium salt 3 with hydrazine hydrate in aqueous
ethanol afforded the corresponding 4-amino-1,2,4-
triazole-5-thione derivative 5 as shown in Scheme
1. The structure of compound 5 was established on
the basis of its elemental analyses and spectral data.
The IR spectrum of compound 5 showed absorption
bands at 3233, 3185, and 3097 cm−1 due to NH2 and
all respects (mp and spectral data) with compound 5
(Scheme 1).
Next, the treatment of 2-(3-methylbenzofuran-
2-yl)-1,3,4-oxadiazole-5-thione (4) with phenacyl
bromide (6) in refluxing acetone, in the presence of
anhydrous potassium carbonate, afforded a single
product that was identified as 2-(3-methylbenzo-
furan-2-yl)-5-(ꢁ-benzoylmethylthio)-1,3,4-oxadiazole
(7) (Scheme 1) on the basis of its spectral data. The
structure of the latter product was confirmed by the
appearance of carbonyl band at 1682 cm−1 in its
IR spectrum, and the presence of a characteristic
signal was due to methylene protons at ꢀ 4.25 in its
1H NMR spectrum.
Treatment of 4-amino-2-(3-methylbenzofuran-
2-yl)-5-mercapto-1,2,4-triazole (5) with phenacyl
bromide (6) in refluxing ethanol, in the pres-
ence of triethylamine, afforded the correspond-
ing 3-(3-methylbenzofuran-2-yl)-6-phenyl-7H-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine (8) as shown in
Scheme 1. The structure of the latter product was
confirmed by the absence of the amino bands in its
IR spectrum and the appearance of a characteristic
singlet signal at ꢀ 4.52 due to methylene protons, ꢁ to
the sulfur atom, in its 1H NMR spectrum. The struc-
ture of compound 8 was further confirmed by its
alternative synthesis from the reaction of the 1,3,4-
oxadiazole derivative 7 with hydrazine hydrate in re-
fluxing ethanol as outlined in Scheme 1.
1
NH functions, and its H NMR spectrum revealed
two signals (D2O exchangeable) at ꢀ 9.75 and 11.13
assigned to NH2 and NH protons, respectively.
1,3,4-Oxadiazoles can be easily converted into the
corresponding 4-amino-1,2,4-triazoles under the
action of hydrazine [25]. Therefore, when the 1,3,4-
oxadiazole derivative 4 was treated with hydrazine
hydrate in ethanol, it afforded a product identical in
Treatment of the potassium salt 3 with phenacyl
bromide (6) furnished a compound identified as the
thiazolidene derivative 9 (Scheme 1) on the basis of
the elemental analyses and spectral data of the reac-
tion product (cf. Experimental part).
Reactions of the potassium salt 3 with hydra-
zonoyl halides 10a–d were also conducted in reflux-
ing ethanol, and in each case resulted in the for-
mation of a single product as examined by TLC.
The structures of obtained products were established
as the N-(3H-1,3,4-thiadiazol-2-ylidene)-3-methy-
lbenzofuran-2-carbohydrazide derivatives 11a–d, on
the basis of the elemental analyses and spec-
tral data of the reaction products. In all cases,
their mass spectra showed, among other fragments,
peaks corresponding to their molecular ions. The
structures of compounds 11a–d were further con-
firmed by their independent synthesis as out-
lined in Scheme 2. Thus, treatment of 2-(3-methy-
lbenzofuran-2-yl)-1,3,4-oxadiazole-5-thione (4) with
hydrazonoyl halides 10a–d in refluxing ethanol, in
the presence of triethylamine, afforded products
identical in all respects with compounds 11a–d that
were obtained from the reaction of the salt 3 with
hydrazonoyl halides 10a–d. A mechanism that can
describe these reactions is postulated in Scheme 2.
SCHEME 1

SynthesisandAntimicrobialEvaluationofSome1,2,4-Triazole, 1,3,4-Oxa(thia)diazole, and1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazineDerivatives 623
SCHEME 3
recorded on Shimadzu FT-IR 8101 PC infrared spec-
trophotometer. The 1H NMR spectra were deter-
mined in CDCl3 or DMSO-d6 at 300 MHz on a
Varian mercury VX 300 NMR spectrometer using
TMS as an internal standard. Mass spectra were
measured on a GCMS-QP1000 EX spectrometer at
70 eV. Elemental analyses were carried out at the Mi-
croanalytical Center of Cairo University. 3-Methyl-
2-benzofurancarbohydrazide (2) [15], phenacylbro-
mide (6) [27], hydrazonoyl bromide 10a [28], and
hydrazonoyl chlorides 10b–d [29] were prepared fol-
lowing the literature procedures.
SCHEME 2
Next, treatment of 4-amino-3-(3-methylbenzofu-
ran-2-yl)-1,2,4-triazole-5-thione (5) with the hydra-
zonoyl halides 10a–d in refluxing ethanol, in the
presence of triethylamine, afforded compounds
identified as 7-arylhydrazono-3-(3-methylbenzofu-
ran-2-yl)-6-(methyl)phenyl-1,2,4-triazolo[3,4-b]-1,3,
4-thiadiazines 12a–d as shown in Scheme 3. The
structures of the latter products were confirmed
from the spectral data of the reaction products.
Interestingly, compound 12a could be alternatively
obtained in a good yield through the coupling of
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivative 8
with benzenediazonium chloride.
Potassium 3-(3-methylbenzofuran-2-yl)
carbonyl-hydrazinecarbodithioate 3
To
a
solution of 3-methyl-2-benzofurancarbo-
hydrazide (2) (1.9 g, 10 mmol) in ethanol (100 mL),
a solution of potassium hydroxide (0.84 g, 15 mmol)
in water (10 mL) and carbon disulfide (5 mL) were
added. The reaction mixture was heated under
reflux for 3 h, then left to cool. The solvent was
evaporated under reduced pressure till dryness, then
the residue was treated with dry benzene (50 mL),
and the precipitate was collected by filtration,
washed with ether, and dried to afford 2.5 g of the
potassium salt 3 which was used directly in the next
reactions without further purification: (82% yield);
mp >300◦C; IR (KBr) ꢂ 3379, 3101 (2 NH), 1651
(C O) cm−1.
4-Amino-3-(3-methylbenzofuran-2-yl)-1,2,4-tri-
azole-5-thione (5) also reacted with different aro-
matic aldehydes in refluxing ethanol and in the
presence of a catalytic amount of piperidine to
afford the corresponding imines 13a–d as outlined
in Scheme 3. The IR spectra of the latter products
showed, in each case, the appearance of NH absorp-
tion band in the region 3121–3090 cm−1 and showed
1
CH N proton signal near ꢀ 9.1 in their H NMR
spectra. Trials to convert compounds 13a–d into the
fused systems 14a–d via boiling 13a–d in pyridine
were unsuccessful.
2- (3-Methylbenzofuran-2-yl)-1,3,4-oxadiazole-
5-thione 4
The potassium salt 3 (3.04 g, 10 mmol) was dissolved
in aqueous potassium hydroxide solution (0.84 g,
15 mmol ) in water (10 mL) and refluxed for 2 h then
cooled. The resulting reaction mixture was treated
EXPERIMENTAL
Melting points were measured with a Gallenkamp
apparatus and are uncorrected. IR spectra were

624 Dawood, Farag, and Abdel-Aziz
with dilute hydrochloric acid till pH ∼ 4. The re-
sulting solid was collected by filtration, washed with
water, and recrystallized from EtOH/DMF to give the
1,3,4-oxadiazole derivative 4 in 76% yield. mp 209–
water, dried and recrystallized from ethanol to afford
compound 7. Yield (64%); mp 164–166◦C; IR (KBr)
1
ν 1682 (C O), 1603 (C N) cm−1; H NMR (DMSO-
d6) δ 2.53 (s, 3H, CH3), 4.25 (s, 2H, CH2), 7.27–7.47
(m, 5H, ArH), 7.50–7.82 (m, 4H, ArH); MS m/z (%)
351 (6.7), 350 (M+, 13.6), 232 (12.6), 159 (49.5), 105
(100), 77 (55.3). For C19H14N2O3S Calcd: C, 65.13; H,
4.03; N, 7.99; S, 9.15%. Found: C, 65.41; H, 4.19; N,
8.23; S, 9.32%.
1
211◦C; IR (KBr) ꢂ3164 (NH), 1620 (C N) cm−1; H
NMR (DMSO-d6) δ 2.51 (s, 3H, CH3), 7.21–7.43 (m,
2H, ArH), 7.48–7.75 (m, 2H, ArH), 9.84 (s, 1H, NH,
D2O-exchangeable); MS m/z (%) 233 (13.4), 232 (M+,
100), 171 (56.4), 131 (23.8), 86 (17.2), 51 (28.8). For
C11H8N2O2S Calcd: C, 56.88; H, 3.47; N, 12.06; S,
13.81%. Found: C, 56.65; H, 3.61 N, 11.85; S, 13.63%
3-(3-Methylbenzofuran-2-yl)-6-phenyl-7H-1,2,4–
triazolo[3,4-b]-1,3,4-thiadiazine 8
4-Amino-3-(3-methylbenzofuran-2-yl)-
Method A. A mixture of 4-amino-3-(3-methy-
lbenzofuran-2-yl)-1,2,4-triazole-5-thione (5) (0.49 g,
2 mmol), phenacyl bromide (6) (0.4 g, 2 mmol),
and triethylamine (0.2 mL, 2 mmol) in ethanol
(30 mL) was heated under reflux for 2 h, then
cooled. The formed precipitate was filtered off,
washed with ethanol, dried and finally recrystal-
lized from DMF/H2O to give the corresponding 1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine derivative 8 in 80%
yield.
1,2,4-triazole-5-thione 5
Method A. To a solution of potassium salt 3
(3.04 g, 10 mmol) in ethanol (20 mL) and water
(20 mL), hydrazine hydrate (1 mL) was added. The
reaction mixture was heated under reflux for 2 h,
then left to cool, then poured into crushed ice. The re-
sulted reaction mixture was acidified with dilute hy-
drochloric acid. The resulting solid was collected by
filtration, washed with water, and crystallized from
EtOH/DMF to give compound 5 in 77% yield.
Method B. To 2-(3-methylbenzofuran-2-yl)-5-
(ꢁ-benzoylmethylthio)-1,3,4-oxadiazole (7) (0.7 g,
2 mmol) in ethanol (20 mL), hydrazine hydrate
(0.1 mL, 2 mmol) was added. The reaction mixture
was heated under reflux for 3 h, then left to cool. The
resulting solid was collected by filtration, washed
with water, and recrystallized from DMF/H2O to give
compound 8 in 83% yield. mp 225–227◦C; IR (KBr)
1609 (C N) cm−1; 1H NMR (DMSO-d6) δ 2.48 (s, 3H,
CH3), 4.52 (s, 2H, CH2), 7.37–8.52 (m, 5H, Ar) 7.55–
7.64 (m, 2H, ArH), 7.75–8.03 (m, 2H, ArH); MS m/z
(%) 347 (9.3), 346 (M+, 37.6), 243 (37), 182 (87.7), 77
(100). For C19H14N4OS Calcd: C, 65.88; H, 4.07; N,
16.17; S, 9.26%. Found: C, 65.55; H, 3.88; N, 16.02;
S, 9.43%.
Method B. A mixture of 2-(3-methylbenzofuran-
2-yl)-1,3,4-oxadiazole-5-thione (4) (2.32 g, 10 mmol)
in ethanol (20 mL) and hydrazine hydrate (1 mL)
was heated under reflux for 2 h, then left to cool and
poured onto crushed ice. The reaction mixture was
acidified with dilute hydrochloric acid till pH ∼ 4.
The resulting solid was collected by filtration,
washed with water, and crystallized from EtOH/DMF
to give compound 5 in 86% yield. Mp 249–251◦C;
IR (KBr) ꢂ 3233, 3185, 3096 (NH2 and NH), 1632
(C N) cm−1; 1H NMR (DMSO-d6) δ 2.52 (s, 3H, CH3),
7.26–7.47 (m, 2H, ArH), 7.50–7.85 (m, 2H, ArH), 9.75
(br s, 2H, NH2, D2O exchangeable), 11.13 (br s, 1H,
NH, D2O exchangeable); MS m/z (%) 247 (16.4), 246
(M+, 100), 182 (33.7), 131 (15.0), 91 (17.3), 52 (6.2).
For C11H10N4OS Calcd: C, 53.64; H, 4.09; N, 22.75; S,
13.02%. Found: C, 53.92; H, 3.88; N, 22.94; S, 13.16%
3-(3-Methylbenzofuran-2-yl)carbamido-4-
phenyl-2,3-dihydrothiazole-2-thione 9
A mixture of potassium salt 3 (0.608 g, 2 mmol)
and phenacyl bromide (6) (0.4 g, 2 mmol) in ethanol
(20 mL) was heated under reflux for 3 h, then left to
cool. The precipitated solid was collected by filtra-
tion, washed with ethanol, dried and recrystallized
from ethanol to afford the corresponding thiazole
derivative 9 in 70% yield. mp 136–138◦C; IR (KBr)
ν3263 (NH), 1659 (C O) cm−1; 1H NMR (DMSO-d6)
δ 2.54 (s, 3H, CH3), 7.26–7.44 (m, 5H, ArH), 7.54–7.92
(m, 4H, ArH), 8.23 (s, 1H, CH), 9.35 (s, 1H, NH, D2O
exchangeable); MS m/z (%) 366 (M+, 100), 232 (64),
175 (21.7), 159 (9.4), 105 (31.5), 77 (6.4), 51 (3.64).
2-(3-Methylbenzofuran-2-yl)-5-(ꢁ-benzoyl-
methylthio)-1,3,4-oxadiazole 7
A
mixture of 2-(3-methylbenzofuran-2-yl)-1,3,4-
oxadiazole-5-thione (4) (0.464 g, 2 mmol), phenacyl
bromide (6) (0.4 g, 2 mmol), and anhydrous potas-
sium carbonate (0.3 g, 2.2 mmol) in of acetone
(30 mL) was refluxed for 6 h. The formed precipi-
tate was filtered off and washed with acetone. The
filtrate was distilled under reduced pressure till dry-
ness then the residue was treated with water. The
solid formed was collected by filtration, washed with

SynthesisandAntimicrobialEvaluationofSome1,2,4-Triazole, 1,3,4-Oxa(thia)diazole, and1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazineDerivatives 625
For C19H14N2O2S2 Calcd: C, 62.27; H, 3.85; N, 7.64; S,
17.50%. Found: C, 62.54; H, 3.63; N, 7.43; S, 17.26%.
(5.1), 131 (100), 77 (16.5). For C21H18N4O3S Calcd:
C, 62.05; H, 4.46; N, 13.78; S, 7.89%. Found: C,
62.33; H, 4.28; N, 13.95; S, 8.02%.
N-(3H-1,3,4-Thiadiazol-2-ylidene)-3-methylben-
zofuran-2-carbohydrazide Derivatives 11a–d
N-[5-Acetyl-3-(4-chlorophenyl)-3H-1,3,4-thiadi-
azol-2-ylidene]-3-methylbenzofuran-2-carbohydrazide
11d. Yield (74%); mp 201–203◦C; IR (KBr) ν 3155
(NH), 1651 (C O), 1597 (C N) cm−1; 1H NMR
(DMSO-d6) δ 2.49 (s, 3H, CH3), 2.55 (s, 3H, CH3),
7.18–7.45 (m, 4H, ArH), 7.49–7.91 (m, 4H, ArH),
11.44 (s, 1H, NH, D2O exchangeable); MS m/z (%)
428 (13.0), 427 (21.6), 426 (M+, 100), 406 (34.7), 281
(66.4), 228 (19.4), 152 (28.3), 126 (19.8), 99 (22.6),
63 (14.7). For C20H15ClN4O3S Calcd: C, 56.27; H,
3.54; N, 13.12; S, 7.51%. Found: C, 56.04; H, 3.70;
N, 13.26; S, 7.64%.
General Procedure
Method A. To a solution of potassium salt 3
(0.608 g, 2 mmol) in ethanol (20 mL), the appropri-
ate hydrazonoyl halide 10a–d (2 mmol) was added.
The reaction mixture was heated under reflux for 3
h, then left to cool. The precipitated product was
collected by filtration, washed with ethanol, dried
and recrystallized from EtOH/DMF to afford the cor-
responding 3H-1,3,4-thiadiazol-2-ylidene derivatives
11a–d.
Method B. A mixture of 2-(3-methylbenzofu-
ran-2-yl)-5-mercapto-1,3,4-oxadiazole (4) (0.464 g,
2 mmol) and the appropriate hydrazonyl halide 10a–
d (2 mmol) in the presence of triethylamine (0.2 mL,
2 mmol) in ethanol (20 mL) was refluxed for 6 h. The
formed precipitate was filtered off, washed with wa-
ter followed by ethanol, and dried. Recrystallization
from EtOH/DMF afforded the corresponding com-
pounds 11a–d.
3-(3-Methylbenzofuran-2-yl)-6-methyl(phenyl)-7-
arylhydrazono-1,2,4-triazolo[3,4-b]-1,3,4-thiadi-
azines 12a–d
General Procedure
Method A. To a mixture of 4-amino-3-(3-methy-
lbenzofuran-2-yl)-1,2,4-triazole-5-thione (5) (0.49 g,
2 mmol) and the appropriate hydrazonoyl halide
10a–d (2 mmol) in ethanol (20 mL), triethylamine
(0.2 mL, 2 mmol) was added portionwise. The reac-
tion mixture was heated under reflux for 3 h, then
left to cool. The precipitated solid was collected by
filtration, washed with ethanol, and dried. Recrys-
tallization of the reaction products from DMF/H2O
afforded the corresponding 7-arylhydrazono-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine derivatives 12a–d in
64–79% yields.
Method B (for Compound 12a). To a cold so-
lution of 3-(3-methylbenzofuran-2-yl)-6-phenyl-5H-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (8) (0.346 g,
1 mmol) in pyridine (20 mL) was added the ben-
zenediazonium chloride solution (1 mmol) portion-
wise over a period of 30 min at 0–5◦C. After com-
plete addition, the reaction mixture was stirred for
further 4 h, then kept in an ice-chest for 12 h, and
finally diluted with water. The precipitated solid was
collected, washed with water and ethanol, dried and
finally recrystallized from DMF/H2O to afford com-
pound 12a in 72% yield.
N-(5-Benzoyl-3-phenyl-3H-1,3,4-thiadiazol-2-yli-
dene)-3-methylbenzofuran-2-carbohydrazide
11a.
Yield (75%); mp 205–207˚C; IR (KBr) 3151 (NH),
1626 (C O), 1600 (C N) cm−1; 1H NMR (DMSO-d6) δ
2.56 (s, 3H, CH3), 7.15–7.36 (m, 8H, ArH), 7.39–7.56
(m, 4H, ArH), 7.64–7.98 (m, 2H, ArH), 11.46 (br s,
1H, NH); MS m/z (%) 455 (22.8), 454 (M+, 100), 371
(53.0), 346 (26.3), 255 (34.9), 157 (18), 131 (36.1), 77
(75.7). For C25H18N4O3S Calcd: C, 66.07; H, 3.99; N,
12.33; S, 7.05%. Found: C, 65.82; H, 3.73; N, 12.52;
S, 7.17%
N-(5-Acetyl-3-phenyl-3H-1,3,4-thiadiazol-2-ylid-
ene)-3-methylbenzofuran-2-carbohydrazide
11b.
Yield (72%); mp 199–201◦C; IR (KBr) 3109 (NH),
1651 (C O), 1597 (C N) cm−1; MS m/z (%) 393
(38.5), 392 (M+, 100), 312 (17.4), 273 (9.6), 228 (46.3),
202 (55), 131 (82.6), 77 (53.3). For C20H16N4O3S
Calcd: C, 61.21; H, 4.11; N, 14.28; S, 8.17%. Found:
C, 61.46; H, 3.97; N, 14.06; S, 8.32%.
N-[5-Acetyl-3-(4-tolyl)-3H-1,3,4-thiadiazol-2-yli-
3-(3-Methylbenzofuran-2-yl)-6-phenyl-7-phenylh-
ydrazono-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine 12a.
Yield (64%); mp 265–267◦C; IR (KBr) ν 3176 (NH),
1602 (C N) cm−1; 1H NMR (DMSO-d6) δ 2.50 (s,
3H, CH3), 7.29–7.46 (m, 8H, ArH), 7.51–7.78 (m,
6H, ArH), 10.83 (s, 1H, NH, D2O exchangeable); MS
m/z (%) 451 (19.8), 450 (M+, 37.3), 346 (23.3), 255
(33.2), 157 (48.7), 77 (100). For C25H18N6OS Calcd:
dene]-3-methylbenzofuran-2-carbohydrazide
11c.
Yield (76%); mp 207–209◦C; IR (KBr) ν 3163 (NH),
1651 (C O), 1605 (C N) cm−1; 1H NMR (DMSO-d6)
δ 2.36 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.55 (s, 3H,
CH3), 7.18–7.52 (m, 4H, ArH), 7.55–7.91 (m, 4H,
ArH), 11.45 (s, 1H, NH, D2O exchangeable); MS m/z
(%) 407 (6.1), 406 (M+, 7.4), 371 (4), 305 (3.3), 246

626 Dawood, Farag, and Abdel-Aziz
C, 66.65; H, 4.03; N, 18.65; S, 7.12%. Found: C,
66.38; H, 4.16; N, 18.44; S, 7.06%.
(m, 3H, ArH), 9.09 (s, 1H, CH), 11.61 (s, 1H, NH,
D2O exchangeable); MS m/z (%) 335 (34.3), 334
(M+, 100), 231 (72.8), 130 (37.9), 77 (52.6). For
C18H14N4OS Calcd: C, 64.65; H, 4.22; N, 16.75; S,
9.59%. Found: C, 64.92; H, 4.06; N, 16.96; S, 9.76%.
3-(3-Methylbenzofuran-2-yl)-6-methyl-7-phenylh-
ydrazono-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine 12b.
Yield (79%); mp 285–287◦C; IR (KBr) ν 3186 (NH),
1605 (C N) cm−1; 1H NMR (DMSO-d6) δ 2.44 (s,
3H, CH3), 2.48 (s, 3H, CH3), 6.98–7.40 (m, 6H, ArH)
7.44–7.78 (m, 3H, ArH), 10.81 (s, 1H, NH, D2O
exchangeable); MS m/z (%) 389 (12.3), 388 (M+,
49), 255 (53.9), 156 (69.2), 77 (100). For C20H16N6OS
Calcd: C, 61.84; H, 4.15; N, 21.63; S, 8.25%. Found:
C, 62.12; H, 4.00; N, 21.93; S, 8.39%.
4-(4-Methoxybenzylideneamino)-5-(3-methylben-
zofuran-2-yl)-4H-1,2,4-triazole-3-thione 13b. Yield
(76%); mp >300◦C; IR (KBr) ν 3090 (NH), 1609
(C N) cm−1; MS m/z (%) 364 (M+, 13.7), 301 (4.7),
276 (3.8), 205 (6), 162 (3.3), 131 (100), 108 (32), 77
(19.3). For C19H16N4O2S Calcd: C, 62.62; H, 4.43; N,
15.37; S, 8.80%. Found: C, 62.34; H, 4.26; N, 15.54;
S, 8.82%.
3-(3-Methylbenzofuran-2-yl)-6-methyl-7-(4-tol-
ylhydrazono)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine
12c. Yield (72%); mp 270–272◦C; IR (KBr) ν 3163
4-(4-Chlorobenzylideneamino)-5-(3-methylbenzo-
furan-2-yl)-4H-1,2,4-triazole-3-thione 13c. Yield
(72%); mp >300◦C; IR (KBr) ν3121 (NH), 1597
(C N) cm−1; 1H NMR (DMSO-d6) δ 2.50 (s, 3H,
CH3), 7.26–7.49 (m, 5H, ArH), 7.53–7.87 (m, 3H,
ArH), 9.21 (s, 1H, CH), 11.60 (s, 1H, NH, D2O
exchangeable); MS m/z (%) 370 (26.4), 369 (32), 368
(M+, 100), 246 (6.6), 183 (4.1), 122 (3.5), 77 (16). For
C18H13ClN4OS Calcd: C, 58.61; H, 3.55; N, 15.19; S,
8.69%. Found: C, 58.33; H, 3.37; N, 15.05; S, 8.85%
1
(NH), 1609 (C N) cm−1; H NMR (DMSO-d6) δ 2.45
(s, 3H, CH3), 2.48 (s, 3H, CH3), 2.56 (s, 3H, CH3),
7.36–7.42 (m, 5H, ArH), 7.46–7.81 (m, 3H, ArH),
10.75 (s, 1H, NH, D2O exchangeable); MS m/z (%)
403 (8.6), 402 (M+, 100), 315 (62), 266 (18.5), 157
(36.3), 77 (54.1). For C21H18N6OS Calcd: C, 62.67; H,
4.51; N, 20.88; S, 7.97%. Found: C, 62.38; H, 4.74;
N, 20.66; S, 8.14%.
3-(3-Methylbenzofuran-2-yl)-6-methyl-7-(4-chlor-
ophenylhydrazono)-1,2,4-triazolo[3,4-b]-1,3,4-thiadi-
azine 12d. Yield (78%); mp 288–290◦C; IR (KBr) ν
4-(2-Hydroxybenzylideneamino)-5-(3-methylben-
zofuran-2-yl)-4H-1,2,4-triazole-3-thione 13d. Yield
(79%); mp >300◦C; IR (KBr) ν 3422 (OH), 3098
1
1
3302 (NH), 1597 (C N) cm−1; H NMR (DMSO-d6)
(NH), 1605 (C N) cm−1; H NMR (DMSO-d6) δ 2.52
δ 2.44 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.36–7.44
(m, 5H, ArH), 7.46–7.81 (m, 3H, ArH), 10.82 (s,
1H, NH, D2O exchangeable); MS m/z (%) 424 (6.4),
423 (13.2), 422 (M+, 30.5), 126 (28.3), 77 (100). For
C20H15ClN6OS Calcd: C, 56.80; H, 3.58; N, 19.87; S,
7.58%. Found: C, 56.77; H, 3.44; N, 20.06; S, 7.74%.
(s, 3H, CH3), 7.26–7.34 (m, 4H, ArH), 7.37–7.55
(m, 2H, ArH), 7.61–7.86 (m, 2H, ArH), 9.13 (s, 1H,
CH), 11.65 (s, 1H, NH, D2O exchangeable), 12.84 (s,
1H, OH, D2O exchangeable); MS m/z (%) 351 (4.9),
350 (M+, 13.9), 231 (100), 158 (21.7), 121 (11), 119
(20.8), 115 (7), 91 (21.9), 77 (7.3). For C18H14N4O2S
Calcd: C, 61.70; H, 4.03; N, 15.99; S, 9.15%. Found:
C, 61.92; H, 3.86; N, 15.87; S, 9.11%.
4-(Arylideneamino)-3-(3-methylbenzofuran-2-yl)-
4H-1,2,4-triazole-5-thiones 13a–d
BIOLOGICAL ACTIVITY
General Procedure. A mixture of the appro-
priate aldehyde (2 mmol), 4-amino-3-(3-methy-
lbenzofuran-2-yl)-1,2,4-triazole-5-thione (5) (0.49 g,
2 mmol) in ethanol (20 mL) in the presence of
pipredine (0.2 mL) was refluxed for 4 h, then left to
cool. The solid product was collected by filtration,
washed with water and dried. Recrystallization
from DMF/H2O afforded the corresponding 4-(benz-
ylideneamino)-1,2,4-triazole derivatives 13a–d.
The antibacterial and antifungal activities were car-
ried out in the Microbiology Division of the Mi-
croanalytical Center of Cairo University, using the
diffusion plate method [30–32]. A bottomless cylin-
der containing a measured quantity (1 mL, mg/mL)
of the sample is placed on a plate (9 cm diame-
ter) containing a solid bacterial medium (nutrient
agar broth) or a fungal medium (Dox’s medium)
which has been heavily seeded with the spore sus-
pension of the test organism. After incubation (24
for bacteria and 5 days for fungi), the diameter of
the clear zone of inhibition surrounding the sam-
ple is taken as a measure of the inhibitory power
of the sample against the particular test organism
4-(Benzylideneamino)-5-(3-methylbenzofuran-2-
yl)-4H-1,2,4-triazole-3-thione 13a. Yield (70%); mp
>300◦C; IR (KBr) ν 3096 (NH), 1607 (C N) cm−1;
1H NMR (DMSO-d6) δ 2.52 (s, 3H, CH3), 7.25–7.38
(m, 4H, ArH), 7.41–7.57 (m, 2H, ArH), 7.65–7.88

SynthesisandAntimicrobialEvaluationofSome1,2,4-Triazole, 1,3,4-Oxa(thia)diazole, and1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazineDerivatives 627
TABLE 1 The Antibacterial and Antifungal Activities of the
[5] Carlsson, B.; Singh, B. N.; Temciuc, M.; Nilsson, S.;
Li, Y.; Mellin, C.; Malm, J. J Med Chem 2002, 45, 623.
[6] Vinh, T. K.; Ahmadi, M.; Delgado, P. O. L.; Prerez, S. F.;
Walters, H. M.; Smith, H. J.; Nicholls, P. J.; Simons,
C. Bioorg Med Chem Lett 1999, 9, 2105.
[7] Tomaszewski, Z.; Johnson, M. P.; Haung, X.; Nichols,
D. E. J Med Chem 1992, 35, 2061.
Synthesized Compounds
Antibacterial
Activityb
Antifungal
Activityc
Compound
Number a
Inhibition (%)d
Inhibition (%)d
4
61.1
30
1.2
–
48
50
–
[8] Ellingboe, J. W.; Alessi, T. R.; Dolak, T. M.; Nguyen,
T. T.; Tomer, J. D.; Guzzo, F.; Bagli, J. F.; McCaleb,
M. L. J Med Chem 1992, 35, 1176.
[9] Tozkoparan, B.; Go¨khan, N.; Aktay, G.; Yes¸ilada, E.;
Ertan, M. Eur J Med Chem 2000, 35, 743.
[10] Demirbas, N.; Ugurluoglu, R.; Demirbas, A. Bioorg
Med Chem 2002, 10, 3717.
[11] Turan-Zitouni, G.; Sıvacı, M.; Kılıc¸, F. S.; Erol, K. Eur
J Med Chem 2001, 36, 685.
[12] Holla, B. S.; Akberali, P. M.; Shivananda, M. K. Far-
maco 2001, 56, 919.
[13] Holla, B. S.; Kalluraya, B.; Sridhar, K. R.; Drake, E.;
Thomas, L. M.; Bhandary, K. K.; Levine, M. J. Eur
J Med Chem 1994, 29, 301.
[14] Prasad, A. R.; Ramalingam, T.; Rao, A. B.; Diwan, P. V.;
Sattur, P. B. Eur J Med Chem 1989, 24, 199.
[15] Ghabgharan, F.; Kooshkabadi, H.; Emami, M.;
Rashidbaigi, A.; Shafiee, A. J Pharm Sci 1976, 65,
1085.
[16] Boehme, W. R. Org Synth 1963, 5, 590.
[17] Dawood, K. M.; Farag, A. M.; Abdel-Aziz, H. A. J Chem
Res 2005, 378.
[18] Dawood, K. M. Tetrahedron 2005, 61,5229.
[19] Dawood, K. M. J Heterocycl Chem 2005, 42, 221.
[20] Dawood, K. M. Heteroatom Chem 2004, 15, 432.
[21] Farag, A. M.; Dawood, K. M.; Elmenoufy, H. A. Het-
eroatom Chem 2004, 15, 508.
5
13d
CHCl3 (solvent)
Reference drugs
Duricef
–
93
35
–
80
35
47.5
Ampicillin
Ultragriseofolvin
aThe biological activity of the other compounds 8, 9, 10b–d, 11b,d
and12b cited in this paper were also examined; however, no inhibition
activities were observed.
bThe tested microorganism was Bacillus cereus.
cThe tested microorganism was Fusarium oxysporium.
d100% Inhibition means no growth of either bacteria or fungi allover
the plate.
(% inhibition = sample inhibition zone (cm)/plate
diameter × 100). All measurements were done in
chloroform as a solvent which has zero inhibition
activity. The obtained results were compared with
some reference antibiotics that were purchased from
Egyptian markets. As shown in Table 1, 5-mercapto-
1,2,4-triazole 5 and 5-mercapto-1,3,4-oxadiazole 4
derivatives were found be active against both Bacil-
lus cereus and Fusarium oxysporium microorgan-
isms with respect to the used reference. The antifun-
gal activity of compounds 4 and 5 were found to be
higher than both of ampicillin and ultragriseofolvin
drugs.
[22] Farag, A. M.; Dawood, K. M.; Abdel-Aziz, H. A. J Chem
Res 2004, 808.
[23] Dawood, K. M.; Ragab E. A.; Farag, A. M. J Chem Res
2003, (S), 685 (M), 1151.
[24] Dawood, K. M.; Raslan, M. A.; Farag, A. M. Synth
Commun 2003, 33, 4095.
[25] Vainilavicius, P.; Smicius, R.; Jakubkiene, V. Monatsh
Chem 2001, 132, 825
[26] Ainsworth, C. J Am Chem Soc 1956, 78, 4475.
[27] Cowper, R. M.; Davidson, L. H. Org Synth 1943, 2,
840.
[28] Farag, A. M. Org Prep Proced 1988, 18, 285.
[29] Dieckmann; Platz, O. Chem Ber 1906, 38, 2989.
[30] Muanz, D. N.; Kim, B. W.; Euler, K. L.; William, L. Int
J Pharmacog 1994, 32, 337.
[31] Grager, R. J.; Harbone, J. B. Phytochemistry 1994, 37,
19.
[32] Irab, O. N.; Young, M. M.; Anderson, W. A. Int J Phar-
macog 1996, 34, 87.
REFERENCES
[1] Apers, S.; Paper, D.; Burgermeister, J.; Baronikova, S.;
Van Dyck, S.; Lemiere, G.; Vlietinck, A.; Pieters, L. J
Nat Prod 2002, 65, 718.
[2] Walker, J. A.; Rossen, K.; Reamer, R. A.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett 1999, 40, 4917.
[3] Ganzalez, A. G.; Barrera, J. B.; Yanes, A. C.; Diaz, J.
G.; Rodriguez, E. M. Phytochemistry 1989, 28, 2520.
[4] Carvalho, C. F.; Sargent, M. V. J Chem Soc, Perkin
Trans I 1984, 1605.