Synthesis and biological activities of novel 1,4-bridged bis-1,2,4-triazoles, bis-1,3,4-thiadiazoles and bis-1,3,4-oxadiazoles

Article abstract of DOI:10.1080/104265090509199

The terephthalic acid hydrazide (1) reacted with phenyl / benzyl isothiocyanate 2a,b to yield the corresponding bis-thiosemicarbazides 4a,b, via acid hydrolysis of the intermediate 3 whereas cyclization of 4 gave the bis-1,2,4-triazoles 5,6 and bis-1,3,4-

Full text of DOI:10.1080/104265090509199

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Synthesis and Biological
Activities of Novel 1,4-Bridged
Bis-1,2,4-Triazoles, Bis-1,3,4-
Thiadiazoles and Bis-1,3,4-
Oxadiazoles
R. M. Shaker a , A. F. Mahmoud a & F. F. Abdel-Latif a
a Chemistry Department, Faculty of Science, El-
Minia University, El-Minia, A. R.Egypt
Published online: 21 Dec 2010.
To cite this article: R. M. Shaker , A. F. Mahmoud & F. F. Abdel-Latif (2005)
Synthesis and Biological Activities of Novel 1,4-Bridged Bis-1,2,4-Triazoles, Bis-1,3,4-
Thiadiazoles and Bis-1,3,4-Oxadiazoles , Phosphorus, Sulfur, and Silicon and the
Related Elements, 180:2, 397-406, DOI: 10.1080/104265090509199
To link to this article: http://dx.doi.org/10.1080/104265090509199
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Phosphorus, Sulfur, and Silicon, 180:397–406, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090509199
Synthesis and Biological Activities of Novel 1,4-Bridged
Bis-1,2,4-Triazoles, Bis-1,3,4-Thiadiazoles and
Bis-1,3,4-Oxadiazoles
R. M. Shaker
A. F. Mahmoud
F. F. Abdel-Latif
Chemistry Department, Faculty of Science, El-Minia University,
El-Minia, A. R. Egypt
The terephthalic acid hydrazide (1) reacted with phenyl/benzyl isothiocyanate 2a,b
to yield the corresponding bis-thiosemicarbazides 4a,b, via acid hydrolysis of the
intermediate 3 whereas cyclization of 4 gave the bis-1,2,4-triazoles 5,6 and bis-
1,3,4-thiadiazoles 7,8. Similarly, compound 1 reacted with phenyl isocyanate 9 to
give the bis-semicarbazide 10, which was cyclized to the bis-oxadiazole 11 and/or
bis-1,2,4-triazole 12 in POCl and NaOH respectively.
3
Keywords Bis-1,2,4-triazoles; bis-1,3,4-oxadiazoles; bis-1,3,4-thiadiazoles; bis-
thiosemicarbazides; terephthalic acid hydrazide
INTRODUCTION
Certain 1,4-disubstituted thiosemicarbazide, 1,2.4-triazoline-3-thione,
and 1,2,4-triazole-3-thiole derivatives are of interest due to their
bioactivity, including antibacterial,1−3 antifungal,4,5 antitubercular,6
antimycobacterial7 and anticancer8 properties. Moreover, 1,3,4-
oxadiazoles are becoming an important member in the heterocyclic
family not only because of their wide usage as dyes, and photosen-
sitive and electrical materials,9 but also because of their broad spec-
trum in biological activities such as HIV-activity and antibacterial
and antifungal activities.10,11 In recent years, attention has been in-
creasingly paid to the synthesis of bisheterocyclic compounds, which
exhibit various biological activities12−15. Keeping these observations
The authors are thankful to Dr. Ahmed M. A. Hetta, Department of Botany, Faculty of
Science, Minia University for antibacterial and fungicidal screening studies of compounds
reported herein.
Address correspondence to R. M. Shaker, Chemistry Department, Faculty of Science,
El-Minia University, El-Minia 61519, A.R., Egypt. E-mail: rmshaker@yahoo.com
397

398
R. M. Shaker et al.
in mind and in continuation of our work on the synthesis of hetero-
cyclic compounds containing nitrogen and sulphur16,17 and bishetero-
cyclic compounds18−21 with expected biological activity, we report herein
the synthesis of the versatile and hitherto unreported bis thiosemicar-
bazides 4a,b and its utility as a building block in the synthesis of several
new bisheterocyclic compounds.
RESULTS AND DISCUSSION
Thus, the key intermediate in the present study is the terephthalic
acid hydrazide (1) which was prepared according to a previously de-
scribed procedure.22,23 The reaction of 1 with phenyl/benzyl isothio-
cyanate 2a,b in DMF in the presence of sodium hydride gave the non-
isolable intermediate 3 which was converted into the corresponding
thiosemicarbazide 4a,b upon treatment with concentrated hydrochlo-
ric acid (Scheme 1). The structural assignments of compounds 4a,b
SCHEME 1

Triazoles, Thiadiazoles, and Oxadiazoles
399
were established by spectroscopic studies and elemental analysis. In
its 1H NMR spectra signals of the thiosemicarbazide group protons
NHCS (9.30 ppm) and CONH (9.50 ppm) are observed. Also, in the IR
spectra, the absorption of the thiosemicarbazide NH (3160–3285 cm−1
)
and C O (1670–1665 cm−1) due to fragments are observed. The C S
absorption appears at 1345–1350 cm−1 (see Experimental Section).
The bis-thiosemicarbazides 4a,b on treatment with sodium hydrox-
ide underwent cyclization to the bis-1,2,4-triazoles 5a,b (Scheme 1).
The spectral data are in good agreement with the proposed structures.
Thus, the IR spectra of 5 showed N H bands in the region of 3080–3285
cm,−1 C S absorption bands at 1340–1350 cm−1, and the absence of any
absorption about in 2600–2550 cm−1 region cited for S H group con-
firmed that these compounds were in the thionic form in the solid state.
Also, in its 1H NMR spectra the NH group chemical shifts characteris-
tic of 1,2,4-triazole-2-thiones are observed in the down field region at
10.85–11.20 ppm which also supports the proposed thione structure.3,5
Furthermore, the reaction of 4a with ethyl iodide in DMF at room
temperature and in the presence of anhydrous potassium carbonate
gave a solid product of molecular formula C26H24N6S2 (M+ = 484) which
may be formulated as 6a or its isomer 7a (Scheme 1). The structure of
6a was indicated by the 13C NMR spectra of the product which gave
conclusive evidence for the triazole structure. The spectrum reveals low-
field signals at 153.0 ppm (triazole C-3) and 149.0 ppm (triazole C-5). If
this product is the isomeric thiadiazole 7a, the C-2 and C-5 thiadiazole
signals should have appeared at a higher field.24,25 Structural proof was
obtained through another synthetic route by the treatment of 5a with
ethyl iodide (Scheme 1).
In addition, the structure of 6a was confirmed further by an alter-
native synthesis of its isomer bis-thiadiazoles 7a. Thus, compound 4a
reacted with phosphoryl chloride at reflux to give bis-thiadiazoles 8a
which was ethylated with ethyl iodide to yield 7a. Comparison of the
data of 7a with those of 6a showed differences in mp, IR, and 1H NMR
data which indicated the structure of 7a for our product (See Experi-
mental Section). Similarly, compounds 6b, 7b, and 8b were prepared
in a similar way (Scheme 1).
When terephthalic acid hydrazide (1) was refluxed with phenyl iso-
cyanate 9 using the procedure described for the synthesis of com-
pounds 4a,b, the bis-semicarbazide 10 was formed (Scheme 2). The
structure of compounds 10 was confirmed by analytical and spec-
tral data (See Experimental Section). The compound 10 on treatment
with POCl3 and/or NaOH underwent cyclization to the corresponding
5,5ꢀ-(1,4-phenylene)bis(2-phenylamino-1,3,4-oxadiazole) (11) and 5,5ꢀ-
(1,4-phenylene)bis (4-phenyl-3-oxo-1,2,4-triazole) (12) respectively and

400
R. M. Shaker et al.
SCHEME 2
their structures were deduced on the basis of analytical and spectral
data (Scheme 2 and Experimental Section). Alternatively, compound 11
could also be prepared by boiling 4a with iodine and potassium iodide
in the presence of ethanolic sodium hydroxide solution (Scheme 2).
BIOLOGICAL ACTIVITY
Some of the prepared compounds were tested for antibacterial and
fungicidal activity. Gram-negative bacteria (Seratia), gram-positive
bacteria (Bacillus cereus), as well as two different fungi, Fusarium
monoiliforum and Aspergillus flavus, were used for this purpose. The

Triazoles, Thiadiazoles, and Oxadiazoles
401
TABLE I
Fusarium
Bacillus cereus monoiliforum
Aspergillus
flavus
Compound
Seratia
5a
6b
7b
8a
11
12
−
+++
+
−
++
+
−
−
−
−
−
−
++
−
++
−
−
−
−
+
+
−
+
+
Diameter of the zone of inhibition: 1 cm; + = 1 to 1.5 cm; ++ = 1.5
to 2 cm; +++ = 2 cm; The solvent was DMF.
biological assay was determined according to the filter paper disc
method. Assay plates were incubated at 25◦C one day for the bacte-
ria and four days for the fungi used.26 The test results are shown in
Table I.
EXPERIMENTAL
All mps. were recorded on a Gallen Kamp apparatus and are uncor-
rected. IR spectra (cm−1) were recorded (as KBr pellets) on a Shimadzu
480 spectrophotometer. The 1H NMR spectra were measured in DMSO-
d6 with a Bruker AM 400 (400 MHz) spectrometer using TMS as an
internal standard; the 13C NMR spectra were recorded at 100 MHz.
The chemical shifts are expressed as δ values (ppm). Mass spectra were
determined on a Finnigan Mat 8430 mass spectrometer operating at
70 eV. Microanalytical data were obtained from Microanalytical unit at
Cairo University.
General Procedure for the Synthesis of Bis
Thiosemicarbazides 4a,b and Bis Semicarbazide 10
Sodium hydride (25 mmol) [50% pentane washed] was added in portions
to a solution of terephthalic acid dihydrazide1 (12.5 mmol) in absolute
DMF (10 ml) at 0◦C. The aryl isothiocyanate 2a,b and/or phenyl iso-
cyanate 9 (25 mmol) was added dropwise to this stirred mixture while
the temperature of the reaction mixture was maintained at 25◦C. The
whole mixture was stirred at room temperature for 3 h to give 3 which
was poured onto cold water and acidified with conc. HCl to pH 3. The
resulting solid product was collected by filtration, washed with water,
dried, and recrystallized from an appropriate solvent.

402
R. M. Shaker et al.
1,4-Phenylene bis (4-phenylthiosemicarbazido) (4a)
Obtained in 90% yield, m.p. 200–202◦C (from EtOH); (found: C, 56.80;
H, 4.40; N, 18.10; S, 13.90. C22H20N6O2S2 requires C, 56.88; H, 4.34; N,
18.09; S, 13.80%); υmax/cm−1 3165–3285 (NH), 3050 (Ar-CH), 1670 (CO)
and 1345 (C S); δH 7.60–8.20 (m, 14H, Ar-H), 9.30 (s, br, 4H, 4NH), 9.50
(s, br, 2H, 2NH); m/z 464 (M+, 16%).
1,4-Phenylene bis (4-benzylthiosemicarbazido) (4b)
Obtained in 92% yield, m.p. 236–238◦C (from Dioxane); (found: C, 58.30;
H, 4.90; N, 17.10; S, 13.10. C24H24N6O2S2 requires C, 58.52; H, 4.91;
N, 17.06; S, 13.02%); υmax/cm−1 3160–3285 (NH), 3054 (Ar-CH), 2900
(aliph-CH.), 1665 (CO) and 1350 (C S); δH 5.40 (s, 4H, 2CH2), 7.40–
8.20 (m, 14H, Ar-H), 8.34 (s, br, 2H, 2 CSNH-CH2), 9.30 (s, br, 2H, 2
NHNHCS), 9.50 (s, br, 2H, 2 CONHNHCS).
1,4-Phenylene bis (4-phenyl-semicarbazido) (10)
Obtained in 95% yield, m.p. 220–222◦C (from EtOH); (found: C, 61.20;
H, 4.70; N, 19.50. C22H20N6O4 requires C, 61.11; H, 4.66; N, 19.43%);
υmax/cm−1 3350–3160 (NH), 3050 (Ar-CH), 1670 (CO); δH 7.60–8.20 (m,
14H, Ar-H), 9.20–9.50 (m, 6H, NH).
Synthesis of Bis-1,2,4-triazoles 5a,b and 12
To a suspension of 4a,b or 10 (10 mmol) in ethanol (20 ml), aque-
ous NaOH (4 N, 10 ml) was added and the solution was refluxed for
4 hr, cooled, and filtered. The filtrate was neutralized to pH = 6 us-
ing dilute HCl acid and was kept aside for 1 hr. The separated solid
product was filtered, washed with water, dried, and recrystallized from
DMF.
5,5ꢀ-(1,4-Phenylene)bis(4-phenyl-3-mercapto-1,2,4-triazole)
(5a)
Obtained in 65% yield, m.p. >370◦C; (found: C, 61.70; H, 3.80; N, 19.60;
S, 14.90. C22H16N6S2 requires C, 61.66; H, 3.76; N, 19.61; S, 14.96%);
υmax/cm−1 3285–3080 (NH), 3050 (Ar-CH), 1620 (C N), 1350 (C S); δH
7.60–8.20 (m, 14H, Ar-H), 11.20 (s, 2H, 2NH).

Triazoles, Thiadiazoles, and Oxadiazoles
403
5,5ꢀ-(1,4-Phenylene)bis(4-benzyl-3-mercapto-1,2,4-
triazole) (5b)
Obtained in 69% yield, m.p. 360–362◦C; (found: C, 63.10; H, 4.40; N,
18.40; S, 14.10. C24H20N6S2 requires C, 63.13; H, 4.42; N, 18.41; S,
14.04%); υmax/cm−1 3285–3080 (NH), 3050 (Ar-CH), 2900 (aliph-CH.),
1620 (C N), 1340 (C S); δH 5.40 (S, 4H, 2CH2), 7.60–8.20 (m, 14H,
Ar-H), 10.85 (s, 2H, 2NH); m/z 456 (M+, 21%).
5,5ꢀ-(1,4-Phenylene)bis(4-phenyl-3-oxo-1,2,4-triazole) (12)
Obtained in 64% yield, m.p. >370◦C; (found: C, 66.70; H, 4.10; N, 21.10.
C22H16N6O2 requires C, 66.66; H, 4.07; N, 21.20%); υmax/cm−1 3300–
3100 (NH), 3050 (Ar-CH), 1680 (C O), 1620 (C N); δH 7.60-8.20 (m,
14H, Ar-H), 10.90 (s, br, 2H, 2NH).
General Procedure for the Synthesis of Bis-(3-ethylthio-1,2,4-
triazoles) 6a,b
Method A
Ethyl iodide (10 mmol) was added to a mixture of 4a or 4b (5 mmol)
and anhydrous potassium carbonate (10 mmol) in DMF (5 mL). The
reaction mixture was stirred for 1 hr at room temperature and then
poured into cold water. After stirring for 10 min the precipitated product
was collected by filtration, washed with water, dried, and recrystallized
from DMF.
Method B
A solution of 5a or 5b (5 mmol) in 8% aqueous sodium hydroxide was
treated with ethyl iodide (10 mmol) and stirred for 2–3 hr at room tem-
perature. During this period, the precipitate thus obtained was filtered,
washed with water, dried, and recrystallized from DMF.
5,5ꢀ-(1,4-Phenylene)bis(3-ethylthio-4-phenyl-1,2,4-triazole)
(6a)
Obtained in 58% yield, m.p. 310–312◦C; (found: C, 64.40; H, 5.10; N,
17.30; S, 13.20. C26H24N6S2 requires C, 64.44; H, 4.99; N, 17.34; S,
13.23%); υmax/cm−1 3050 (Ar-CH), 2900 (aliph-CH.); 1620 (C N); δH
1.15 (t, 6H, J = 7 Hz, 2CH3), 4.25 (q, 4H, J = 7 Hz, 2CH2), 8.20 (m, 14H,
Ar-H); δC 15.85 (CH3 carbon), 28.0 (CH2 carbon), 127.0–137.0 (Ar-C),
149.0 (C-5), 153.0 (C-3); m/z 484 (M+, 61%).

404
R. M. Shaker et al.
5,5ꢀ-(1,4-Phenylene)bis(3-ethylthio-4-benzyl-1,2,4-triazole) (6b)
Obtained in 62% yield, m.p. 324–326◦C; (found: C, 65.50; H, 5.60; N,
16.40; S, 12.50. C28H28N6S2 requires C, 65.60; H, 5.50; N, 16.39; S,
12.51%); υmax/cm−1 3050 (Ar-CH), 2900 (aliph-CH.); 1620 (C N); δH
1.10 (t, 6H, J = 7Hz, 2CH3), 4.20 (q, 4H, J = 7 Hz, 2CH2), 5.40 (S, 4H,
2CH2), 7.40-8.20 (m, 14H, Ar-H).
General Procedure for the Synthesis of Bis-(2-Arylamino-
1,3,4-thiadiazole) 8a, b and bis-(2-phenylamino-1,3,4-
oxadiazole) 11
A solution of 4a or 4b or 10 (5 mmol) in POCl3 (5 ml) was refluxed
for 2 hr. The excess of POCl3 was removed under reduced pressure
and the residue was poured into cold water. After stirring for 10 min
the precipitated product was collected by filtration, washed with water,
dried, and recrystallized from DMF/EtOH.
5,5ꢀ-(1,4-Phenylene)bis(2-phenylamino-1,3,4-thiadiazole) (8a)
Obtained in 87% yield, m.p. 345–347◦C; (found: C, 61.70; H, 3.80; N,
19.60; S, 14.90. C22H16N6S2 requires C, 61.66; H, 3.76; N, 19.61; S,
14.96%); υmax/cm−1 3200 (NH), 3050 (Ar-CH), 1620 (C N); δH 6.90–7.30
(m, 14H, Ar-H), 11.25 (s, 2H, 2NH); m/z 428 (M+, 69%).
5,5ꢀ-(1,4-Phenylene)bis(2-benzylamino-1,3,4-thiadiazole) (8b)
Obtained in 92% yield, m.p. 276–278◦C; (found: C, 63.20; H, 4.40; N,
18.40; S, 14.00. C24H20N6S2 requires C, 63.13; H, 4.42; N, 18.41; S,
14.04%); υmax/cm−1 3150 (NH), 3050 (Ar-CH), 2900 (aliph-CH.); 1620
(C N); δH 4.5 (s, 4H, 2CH2), 7.00–7.40 (m, 14H, Ar-H), 11.20 (s, 2H,
2NH).
5,5ꢀ-(1,4-Phenylene)bis(2-phenylamino-1,3,4-oxadiazole) (11)
Obtained in 73% yield, m.p. 264–266◦C; (found: C, 66.70; H, 4.00; N,
21.30. C22H16N6O2 requires C, 66.66; H, 4.07; N, 21.20%); υmax/cm−1
3200 (NH), 3050 (Ar-CH), 1620 (C N); δH 7.00–7.40 (m, 14H, Ar-H),
11.30 (s, 2H, 2NH).
Alternative Synthesis of 11
Compound 4a (5 mmol) was suspended in ethanol (20 ml). 5 ml of 4 N
sodium hydroxide and iodine in potassium iodide solution (5 ml, 5%)
were added gradually with stirring and cooling until the color of iodine

Triazoles, Thiadiazoles, and Oxadiazoles
405
persisted. The precipitated product was filtered, dried, and crystallized
from DMF/EtOH to afford 11, m.p. 264–266◦C, mixed m.p. 262–264◦C.
Synthesis of Bis-(2-(N-ethyl)-arylamino-1,3,4-thiadiazole) 7a,b
Ethyl iodide (10 mmol) was added to a solution of 8a,b (5 mmol) in DMF.
The reaction mixture was heated at 60–65◦C for 30 h (monitored by tlc)
Thereafter, the mixture was poured into cold water. After stirring over
night the precipitated product was collected by filtration, washed with
water, dried, and recrystallized from DMF.
5,5ꢀ-(1,4-Phenylene)bis(2-(N-ethyl)-phenylamino-1,3,4-
thiadiazole) (7a)
Obtained in 65% yield, m.p. 356–358◦C; (found: C, 64.40; H, 5.00; N,
17.40; S, 13.20. C26H24N6S2 requires C, 64.44; H,4.99; N, 17.34; S,
13.23%); υmax/cm−1 3050 (Ar-CH), 2900 (aliph-CH.); 1620 (C N); δH
1.40 (t, 6H, J = 7Hz, 2CH3), 4.12 (q, 4H, J = 7 Hz, 2CH2), 7.30–7.80 (m,
14H, Ar-H).
5,5ꢀ-(1,4-Phenylene)bis(2-(N-ethyl)-benzylamino-1,3,4-
thiadiazole) (7b)
Obtained in 69% yield, m.p. >360◦C; (found: C, 65.50; H, 5.60; N, 16.40;
S, 12.50. C28H28N6S2 requires C, 65.60; H, 5.50; N, 16.39; S, 12.51%);
υmax/cm−1 3050 (Ar-CH), 2900 (aliph-CH); δH 1.35 (t, 6H, J = 7 Hz,
2CH3), 4.15 (q, 4H, J = 7 Hz, 2CH2), 4.5 (s, 4H, 2CH2), 7.10–8.00 (m,
14H, Ar-H).
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