New approaches for the synthesis of 1,3,4-thiadiazole and 1,2,4-triazole derivatives with antimicrobial activity

Article abstract of DOI:10.1080/10426500802274534

The thiosemicarbazide derivatives 3a and 3b were cyclized in the presence of concentrated sulfuric acid to give the 5-cyanomethyl-1,3,4-thiadiazole derivatives 4a and 4b, respectively. The latter products were used for many heterocyclic transformations to

Full text of DOI:10.1080/10426500802274534

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New Approaches for the
Synthesis of 1,3,4-Thiadiazole
and 1,2,4-Triazole Derivatives
with Antimicrobial Activity
Wagnat W. Wardakhan a & Nahed N. E. El-Sayed a
a National Organization for Drug Control and
Research (NODCAR) , Cairo, Egypt
Published online: 18 Feb 2009.
To cite this article: Wagnat W. Wardakhan & Nahed N. E. El-Sayed (2009) New
Approaches for the Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives with
Antimicrobial Activity, Phosphorus, Sulfur, and Silicon and the Related Elements,
184:3, 790-804, DOI: 10.1080/10426500802274534
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Phosphorus, Sulfur, and Silicon, 184:790–804, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802274534
New Approaches for the Synthesis of 1,3,4-Thiadiazole
and 1,2,4-Triazole Derivatives with Antimicrobial
Activity
Wagnat W. Wardakhan and Nahed N. E. El-Sayed
National Organization for Drug Control and Research (NODCAR),
Cairo, Egypt
The thiosemicarbazide derivatives 3a and 3b were cyclized in the presence of
concentrated sulfuric acid to give the 5-cyanomethyl-1,3,4-thiadiazole deriva-
tives 4a and 4b, respectively. The latter products were used for many hetero-
cyclic transformations to form coumarin, 1,3,4-thiadiazolo[4,5-a]pyridine, and 5-
thiophenylthiophene. In addition, compound 3b underwent cyclization in NaOH
(2 N) solution to give the 1,2,4-triazole derivative 16. The reactivity of the lat-
ter product towards some chemical reagents was studied. The antimicrobial
activities of the newly synthesized products were measured and showed high
activities.
Keywords Antimicrobial; coumarin; thiadiazole; triazole
INTRODUCTION
The cyclization of suitable linear compounds is one of the most
common and popular methods for preparing heterocyclic com-
pounds. Asymmetrical ureas have been cyclized to produce sev-
eral heterocycles such as 1,3,4-thiadiazoles, 1,2,4-triazoles, and 1,3,5-
triazines. 2,4-Disubstituted semicarbazones have been proposed as
dipeptide isoesters2 and could be a new class of urea peptide
mimetics. The possible biological properties of semi- and thiosemi-
carbazone derivatives make it attractive to study the chemical
reactivity of these compounds. For instance, Kabashima et al. demon-
strated that the reaction of α-halocarbonyl compounds with alkyl-
and arylidenephenylthiosemicarbazones gave 1,2,4-triazoline and
Received 13 May 2008; accepted 16 June 2008.
Address correspondence to Wagnat W. Wardakhan, National Organization for Drug
Control and Research (NODCAR) P.O. Box 29, Cairo, A. R. Egypt. E-mail: wagnatward@
hotmail.com
790

Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives
791
1,2,4-dithiazolidines.3 2,4-Disubstituted thiosemicarbazides were cy-
clized to 1,2,4-triazoline-3-thiones and 1,3,4-thiadiazolines when
treated with acyl isothiocyanates.4 Oxidative cyclization of substi-
tuted aldehyde thiosemicarbazones, induced by different metallic salts,
led to 1,2,4-triazoline derivatives.5−9 Alternatively, the interaction
of thiosemicarbazide and dithiocarbazate derivatives with some π-
acceptors such as propanedinitrile and benzoquinone, as well as
naphthoquinone, afforded thiazines, thiadiazines, thiadiazoles, inda-
zoles, pyridazines, oxathiadiazoles, and various fused heterocyclic com-
pounds possible via a single electron transfer before the ring closure
step.10−14
RESULTS AND DISCUSION
In this work, we use the thiosemicarbazide derivatives 3a and 3b,
which were synthesized according to the literature procedure15,16 in
the synthesis of potentially biologically active 1,3,4-thiadiazole and
1,2,4-triazole derivatives. Therefore, compounds 3a and 3b under-
went cyclization in the presence of concentrated sulfuric acid to give
the 5-cyanomethyl-1,3,4-thiadiazole derivatives 4a and 4b, respec-
tively. The assignment of the structures of compounds 4a,b was based
on analytical and spectroscopic data. Thus, the 1H NMR spectrum
of compound 4a showed the presence of a singlet at δ 4.68 ppm
for the CH2 group, a multiplet at δ 7.26–7.33 ppm corresponding
to the phenyl protons, and a singlet at δ 8.69 ppm for the NH
group.
The reaction of compounds 4a or 4b with benzenediazonium chlo-
ride (5) in ethanol/sodium hydroxide solution at 0–5◦C gave the phenyl
hydrazone derivatives 6a and 6b, respectively. The reaction of com-
pounds 4a and 4b with benzaldehyde (7) gave the benzal derivatives
8a and 8b, respectively. In addition, the reaction of compounds 4a
and 4b with salicylaldehyde (9) gave the coumarin derivatives 10a
and 10b, respectively. Formation of coumarins from the reaction of
cyanomethylene reagents with salicylaldehyde has been reported pre-
viously in the literature.17,18 The analytical and spectroscopic data of
8a,b and 10a,b were in agreement with the proposed structures. Thus
1
the H NMR spectrum 10a a singlet at δ 6.69 ppm corresponding to
coumarin H-4, a multiplet at δ 7.31–7.44 ppm for aromatic protons
and a singlet at δ 8.35 ppm (D2O exchangeable) for an NH group
(Scheme 1).

792
W. W. Wardakhan and N. N. E. El-Sayed
SCHEME 1
The reaction of compounds 4a and 4b with either malononitrile
(11a) or ethyl cyanoacetate (11b) afforded the 1,3,4-thiadiazolo[4,5-
a]pyridine derivatives 12a–d, respectively. The structures of the lat-
ter products were established based on analytical and spectroscopic
data. On the other hand, the reaction of compound 4a and 4b with

Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives
793
the cinnamonitrile derivatives 13a and 13b resulted in the formation
of the 7-phenyl-1,3,4-thiadiazolo[4,5-a]pyridine derivatives 14a–d, re-
spectively. The obtained analytical and spectral data are in agreement
with the proposed structures. Thus, the 1H NMR spectrum of 14a
showed the presence of a singlet at δ 4.68 ppm corresponding to NH2
group, a singlet at δ 5.36 for pyridine H-4, a multiplet at δ 7.29–7.38
ppm for aromatic protons, and a singlet at δ 8.36 (D2O exchangeable)
corresponding to an NH group (Scheme 2).
SCHEME 2

794
W. W. Wardakhan and N. N. E. El-Sayed
The reaction of either compound 4a or 4b with any of the
cyanomethyleno reagents 11a or 11b and elemental sulfur gave the
5-thiophenylthiophene derivatives 15a–d respectively. The reaction
was produced in the same way as the reported in Gewald’s thiophene
synthesis.19,20
Compound 3b underwent ready cyclization in sodium hydroxide (2.0
N) solution to give the 1,2,4-triazole derivative 16. Assignment of the
structure of the latter product was based on analytical and spectro-
1
scopic data. The H NMR spectrum of compound 16 showed the pres-
ence of a singlet at δ 4.82 corresponding to the CH2 group, a broad
singlet at δ 5.26 for the SH group, and a multiplet at δ 7.30–7.37 for the
phenyl protons. Further confirmation for the structure of compound
16 was obtained through studying its reactivity with some chemical
reagents. Thus when compound 16 was allowed to react with hydrazine
hydrate (17a) and phenylhydrazine (17b), the hydrazone derivatives
18a and 18b, respectively, were formed. Moreover, the reaction of com-
pound 16 with benzenediazonium chloride 5 gave the phenylhydra-
zone derivative 19. The analytical and spectroscopic data of compounds
18a,b and 19 were consistent with the proposed structures (see the Ex-
perimental section and Scheme 3).
The reaction of compound 16 with benzaldehyde gave the benzal
derivative 20. Furthermore, the reaction of compound 16 with sali-
cylaldehyde (9) gave the 3-(1,2,4-triazol-3-yl)-coumarin derivative 21
(Scheme 4).
ANTIMICROBIAL ACTIVITY
The in vitro antimicrobial activity of the structurally promising 24 het-
erocyclic derivatives were tested against two strains of Gram-positive
bacteria (Bacillus subtilis CECT 498 and Bacillus cereus CECT 148),
two strains of Gram-negative bacteria (Escherichia coli ECT 101 and
Pseudomonas aeruginosa), andCandida albicans CECT 1394 as a rep-
resentative species of fungi. The newly synthesized products were dis-
solved in aqueous ethanol to give a logarithmic series of concentrations
from 2 to 256 mg/L upon tenfold dilution with the growth medium and
spore suspension of the test fungi. The toxicity of compounds was deter-
mined via pipette additions into the wells of multi-well slides, followed
by with 25 µL of◦the culture medium. The inoculated slides were then
incubated at 25 C until short germ tubes appeared of approximately
50 µm in length (at 0 h).
Five µL volumes of the prepared compound test solutions were added
to the inoculated wells, one control well on each slide being treated

Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives
795
SCHEME 3
with solvent only. The slides were then returned to the incubator until
germ tubes 400 µm ( 50 µm) long were visible in the control wells.
Further growth was arrested by the addition of lactophenol aniline
blue to each of the wells. The minimal inhibitory concentration [(MIC)

796
W. W. Wardakhan and N. N. E. El-Sayed
SCHEME 4
in µg mL−1] was determined using an adaptation of agar streak di-
lution method based on radial diffusion.21,22 Under the same condi-
tions, ampicillin (antibacterial) and cycloheximide (antifungal) were
used as standards. The MIC was considered to be the lowest concen-
tration of the tested compound (in dimethylformamide) that inhibits
growth of bacteria or fungi on the plate (Table I). The diameters of
the inhibition zones corresponding to the MICs are also presented in
Table I.
It is obvious from Table I that compounds 10b (N(5-oxo-2H-
chromen-3-yl)-1,3,4-thiadiazol-2-yl)benzamide), 12d (N-(7-amino-8-
cyano-5-oxo-5H-[1,3,4-]thiadiazolo[3,2-a]pyridine-2-yl)benzamide),
and 15c (N-(5-(3,5-diamino-4-cyanothiophene-2-yl)-1,3,4-thiadiazol-2-
yl)benzamide) are the most active towards E. coli, and their activity
is higher than that of ampicilin. Alternatively, compounds 4a, 4b, 8b,
12b, 12d, and 16 are more active towards B. Cereus than ampicilin.
Compounds 4a, 8b, 12b, 12d, and 15a showed high activity against
B. Subtilis. Moreover, compounds 6a, 6b, 8a, 10a, 10b, 14b, 15a, and
15c showed high activity towards C. Albicans, where compounds 10b
and 15b (both of them with the 2-substituted thiadiazole derivatives)
showed the maximum activities. It is clear that compound 8b (N-(5-
(1-cyano-2-phenylvinyl)-1,3,4-thiadiazol-2-yl)benzamide) showed the
highest activity towards E. Coli, B. Subtilis, and C. Albicans (Tables II
and III).

Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives
797
TABLE I Antimicrobial Activities of the Tested Compounds
MIC (µgmL−1) (zone of inhibition, mm)
Compound No. E. coli ECT B. cereus CECT B. subtilis CECT C. albicans CECT
4a
4b
6a
6b
8a
8b
—
—
—
—
—
22.52 (8)
11.32 (3)
6.05 (15)
12.30 (4)
3.72 (6)
22.38 (8)
20.46 (9)
18.12 (5)
0.40 (10)
18.24 (7)
10.05 (6)
12.25 (2)
4.55 (10)
16.22 (3)
6.22 (6)
0.40 (5)
23.63 (6)
26.12 (3)
18.32 (5)
0.08 (2)
22.33 (5)
6.05 (6)
3.13 (10)
12.50 (10)
0.40 (5)
0.05 (9)
3.13
20.55 (4)
21.01 (8)
16.88 (2)
12.40 (4)
18.22 (8)
24.18 (3)
19.15 (4)
16.45 (6)
18.23 (5)
22.01 (8)
0.61 (6)
22.45 (8)
6.25 (15)
18. 32 (8)
14.40 (4)
12.55 (12)
21.15 (4)
8.22 (2)
10.33 (5)
8.36 (4)
12.22 (8)
4.55 (10)
6.13 (4)
6.13 (4)
8.25 (6)
14.36 (8)
12.50 (10)
—
8.65 (4)
18.73 (8)
22.89 (3)
33.23 (6)
16.58 (12)
22.83 (6)
23.64 (6)
100.00
16.42 (2)
4.13 (10)
30.23 (6)
6.18 (4)
24.44 (2)
10.38 (4)
0.03 (9)
25.36 (8)
50.17
100.00 (5)
23.16 (9)
12.42 (2)
8.66 (6)
12.34 (7)
12.34 (7)
12.50
22.82 (8)
20.11 (4)
—
—
—
10a
10b
12a
12b
12c
12d
14a
14b
14c
14d
15a
15b
15c
15d
16
12.50 (6)
—
—
—
11.34 (4)
—
—
—
—
—
—
14.84
—
—
—
—
—
—
—
6.25
—
18a
18b
19
20
21
Ampicillin
Cycloheximide
—
12.50 (6)
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded (KBr) on
1
a Pye Unicam SP-1000 spectrophotometer. H NMR spectra were ob-
tained on a Varian EM-390 MHz spectrophotometer in DMSO-d6 as the
solvent and TMS as internal reference. Chemical shifts are expressed
in δ or ppm. Antibacterial results were recorded by a research group at
the Botany Department at Cairo University.
5-Cyanomethyl-2-phenylamino-1,3,4-thiadiazole (4a) and
2-Benzoylamino- 5-cyanomethyl-1,3,4-thiadiazole (4b)
A suspension of the corresponding thiosemicarbazide either 3a (2.34
g, 0.01 mol) or 3b (2.62 g, 0.01 mol) in cold concentrated sulfuric acid

798
W. W. Wardakhan and N. N. E. El-Sayed
TABLE II Physical and Analytical Data of the Newly Synthesized
Products
Calcd/Found (%)
Compd
No.
Yield (%)
color
M.p. ◦C Cryst.
solvent
Mol.
Formula (Mr)
C
H
N
S
4a
70 Buff
74 Yellow
173–176
Ethanol
262–264
Ethanol
C10H8N4S
(216.26)
55.54 3.73 25.91 14.83
55.62 4.03 26.24 14.71
54.09 3.30 22.94 13.13
53.96 3.53 23.31 13.04
59.98 3.78 26.23 10.01
60.33 4.01 26.52 9.83
58.61 3.47 24.12 9.20
58.88 3.26 24.31 8.95
67.08 3.97 18.41 10.53
66.89 4.08 18.17 10.33
65.04 3.64 16.86 9.65
64.82 3.91 17.04 9.36
63.54 3.45 13.08 9.98.
63.43 3.66 12.79 10.26
61.88 3.17 12.03 9.18
62.16 3.43 11.89 9.04
55.30 3.57 29.77 11.36
55.09 3.69 29.53 11.08
55.11 3.20 24.72 11.32
54.89 2.93 24.48 11. 17
54.18 3.25 27.08 10.33
53.87 3.38 26.85 10.61
54.01 2.91 22.50 10.30
53.85 3.27 22.83 10.17
64.85 3.81 22.69 8.66
64.47 4.25 23.05 8.89
63.29 4.59 16.78 7.68
63.62 4.31 17.16 7.95
63.30 3.54 21.09 8.05
63.49 3.76 20.86 7.82
62.01 4.30 15.72 7.20
62.17 4.38 15.15 7.27
49.66 3.21 26.73 20.40
49.44 3.50 26.53 20.72
4b
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
11H8N4OS
(244.27)
16H12N6S
(320.37)
17H12N6OS
(348.38)
17H12N4S
(304.37)
18H12N4OS
(332.38)
17H11N3O2S
(321.35)
18H11N3O3S
(349.36)
13H10N6S
(282.32)
13H9N5OS
(283.31)
14H10N6OS
(310.33)
14H9N5O2S
(311.32)
20H14N6S
(370.43)
22H19N5O2S
(417.48)
21H14N6OS
(398.45)
23H19N5O3S
(445.50)
6a
70 Reddish- 194–196
brown
86 Red
Ethanol
252–255
Ethanol
180–183
Ethanol
222–224
Ethanol
>300 Ethanol
6b
8a
62 Yellow
50 Yellow
93 Yellow
69 Yellow
70 Orange
66 Yellow
78 Orange
8b
10a
10b
12a
12b
12c
12d
14a
14b
14c
14d
15a
15b
15c
15d
16
246–248
Ethanol
166–169
1,4–dioxan
132–135
1,4–Dioxan
222–225 DMF
73 Pale
yellow
70 Pale
brown
54 Reddish
brown
60 Reddish
brown
78 Reddish
brown
73 Yellow
189–193
1,4–Dioxan
98–100 Ethanol
230–233
Ethanol
98–102 Ethanol
230–233
Ethanol
258–260
Ethanol
240–245
Ethanol
>300 Ethanol
13H10N6S2
(314.39)
75 Yellow
64 Brown
50 Brown
57 White
65 Yellow
15H15N5O2S2 49.84 4.18 19.39 17.74
(361.44)
14H10N6OS2
(342.41)
16H15N5O3S2 49.34 3.88 17.98 16.47
(389.45)
11H8N4OS
(244.27)
11H10N6O
(241.24)
48.98 4.33 19.27 18.09
49.11 2.94 24.54 18.73
49.04 3.35 24.48 19.16
>300 Ethanol
49.66 3.72 17.81 16.97
54.09 3.30 22.94 13.13
53.85 3.67 23.37 12.84
54.54 4.14 34.69
>300
1,4–Dioxan
282–284
1,4–Dioxan
18a
54.10 4.48 34.83
(Continued on next page)

Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives
799
TABLE II Physical and Analytical Data of the Newly Synthesized
Products (Continued)
Found/Calcd (%)
Compd
No.
Yield (%)
color
M.p. ◦C Cryst.
solvent
Mol.
Formula (Mr)
C
H
N
S
18b
19
50 Yellow
75 Yellow
276–279
1,4–Dioxan
280–282
Ethanol
226–229
Methanol
242–244
Ethanol
C17H14N6O
(318.33)
64.14 4.43 26.40
64.09 4.11 26.32
C
C
C
17H12N6OS
(348.38)
18H12N4OS
(332.38)
18H11N3O3S
(349.36)
58.61 3.47 24.12 9.20
58.89 4.11 24.32 9.33
65.04 3.64 16.86 9.65
65.11 3.88 17.17 9.44
61.88 3.17 12.03 9.18
62.26 3.45 12.48 8.76
20
50 Pale
brown
92 Orange
21
(28 mL) was stirred for 10 min. Then the mixture, in each case, was
allowed to warm to room temperature and stirred for an additional 30
min. The resulting mixture, in each case, was poured onto an ice/water
mixture and made alkaline to pH 8 with aqueous ammonia. The solid
product formed in each case was collected by filtration.
5-(α-Phenylhydrazocyanomethyl-2-phenylamino-1,3,4-
thiadiazole (6a), 2-Benzoylamino-5-(α-
phenylhydrazocyanomethyl-1,3,4-Thiadiazole (6b), and 4-
Benzoyl-(a-phenylhydrazocyanomethyl)-3-thioxo-1,2,4-triazole
(19)
To a cold solution (0–5◦C) of aniline (1.02 g, 1.0 mL, 1.1 equiv.), conc. HCl
(1.09 g, 0.92 mL, 3 equiv.) was added. The temperature was maintained
at 0–5◦C and an aqueous solution of sodium nitrite (0.76 g, 1.1 equiv.)
was added dropwise to the aniline solution. The reaction mixture was
stirred for 15 min. The clear diazonium salt solution 5 was then added
dropwise to a solution of either thiadiazole 4a (2.16 g, 0.01 mol, 1
equiv.) in ethanol (10 mL), thiadiazole 4b (2.44 g, 0.01 mol, 1 equiv.)
in an ethanol/acetic acid mixture (10:2 mL), or triazole 16 (2.44 g,
0.01 mol) in ethanol/DMF (10:2 mL) containing sodium acetate (4.0 g)
at 0–5◦C. After the addition of the diazonium salt was complete, the
reaction mixture was stirred at room temperature for 2 h and left in
the refrigerator overnight. The solid product formed in each case was
collected by filtration.

800
W. W. Wardakhan and N. N. E. El-Sayed
TABLE III Spectral Data of the Newly Synthesized Products
Compd No.
IR (ν/cm-1)
1H NMR (δ ppm) (DMSO-d6)
4a
3465–3341 (NH), 3068 (CH aromatic), 4.68 (s, 2H, CH2), 7.26–7.33 (m,
2989 (CH2), 2227 (CN), 1620 (C C),
1585 (C N)
5H, C6H5), 8.69 (s, 1H, NH)
4b
3455–3337 (NH), 3059 (CH aromatic), 4.70 (s, 2H, CH2), 7.28–7.37 (m,
2981 (CH2), 2224 (CN), 1687 (CO),
1623 (C=C), 1578 (C=N)
5H, C6H5), 8.85 (s, 1H, NH)
6a
3474–3328 (2 NH), 3055 (CH
aromatic), 2224 (CN), 1629 (C=C),
1576 (C=N)
7.31–7.45 (m, 10H, 2 C6H5),
8.64, 8.95 (2s, 2H, 2NH)
6b
3465–3317 (2 NH), 3072 (CH
aromatic), 2220 (CN), 1685 (CO),
1636 (C=C), 1582 (C=N)
7.27–7.40 (m, 10H, 2 C6H5),
8.54, 9.66 (2s, 2H, 2NH)
19
3544–3328 (NH), 3055 (CH aromatic), 5.66 (s, br, 1H, SH), 7.29–7.36
2222 (CN), 1687 (C=O), 1638 (C=C),
(m, 10H, 2 C6H5), 8.61 (s, 1H,
NH)
1577 (C=N)
8a
3489–3331 (NH), 3058 (CH aromatic), 6.91 (s, 1H, CH=C), 7.30–7.38
2225 (CN), 1643 (C=C), 1582 (C=N)
(m, 10 H, 2 C6H5), 8.73 (s, 1H,
NH).
8b
3476–3340 (NH), 3055 (CH aromatic), 5.82 (s, 1H, CH=C), 6.87 (s, 1H,
2223 (CN), 1685 (CO), 1639 (C=C),
1589 (C=N)
NH), 7.27–7.40 (m, 10H, 2
C6H5)
10a
10b
12a
12b
12c
12d
14a
14b
3458–3339 (NH), 3054 (CH aromatic), 6.69 (s, 1H, coumarin H-4),
1687 (CO), 1648 (C=C), 1593 (C=N)
7.31–7.44 (m, 9H, C6H5,
C6H4), 8.35 (s, 1H, NH)
3473–3329 (NH), 3059 (CH aromatic), 6.54 (s, 1H, coumarin H-4),
1693, 1688 (2 CO), 1641 (C=C), 1585
7.28–7.42 (m, 9H, C6H5,
C6H4), 8.32 (s, 1H, NH)
4.66 (s, 2H, NH2), 7.03–7.36 (m,
6H, C6H5, pyridine H-3), 8.68,
9.40 (2s, 2H, NH)
4.68 (s, 2H, NH2), 7.19–7.38 (m,
6H, C6H5, pyridine H-3), 8.66
(s, 1H, NH)
4.71 (s, 2H, NH2), 7.21–7.44 (m,
6H, C6H5, pyridine H-3), 8.68,
9.39 (2s, 2H, 2NH)
(C=N)
3450–3328 (NH2, 2NH), 3046 (CH
aromatic), 2220 (CN), 1641 (C=C),
1586 (C=N)
3466–3332 (NH2, NH), 3048 (CH
aromatic), 2221 (CN), 1687 (CO),
1640 (C=C), 1593 (C=N)
3469–3330 (NH2, 2NH), 3055 (CH
aromatic), 2226 (CN), 1689 (CO),
1644(C=C), 1590 (C=N)
3485–3341 (NH2, NH), 3059 (CH
aromatic), 2224 (CN), 1692, 1688
(2CO), 1640(C=C), 1588 (C=N)
3477–3332 (NH2, NH), 3054 (CH
aromatic), 2228, 2223 (2 CN), 1656
(C=C), 1588 (C=N)
4.67 (s, 2H, NH2), 7.23–7.46 (m,
6H, C6H5, pyridine H-3), 8.65
(s, 1H, NH)
4.68 (s, 2H, NH2), 5.36 (s, 1H,
pyridine H-4), 7.29–7.38 (m,
10H, 2C6H5), 8.36 (s, 1H, NH)
1.36 (t, 3H, J = 7.09 Hz, CH3),
4.23 (q, 2H, J = 9.07 Hz, CH2),
4.67 (s, 2H, NH2), 5.63 (s, 1H,
pyridine H-4), 7.25–7.37 (m,
10H, 2C6H5), 8.59 (s, 1H, NH)
(Continued on next page)
3469–3343 (NH2, NH), 3053 (CH
aromatic), 2987, 2879 (CH3, CH2),
2220 (CN), 1689 (CO), 1654 (C=C),
1587 (C=N)

Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives
801
TABLE III Spectral Data of the Newly Synthesized Products
(Continued)
Compd No.
IR (ν/cm-1)
1H NMR (δ ppm) (DMSO-d6)
14c
3479–3338 (NH2, NH), 3057 (CH
aromatic), 2225, 2222 (2CN), 1705
(CO), 1659 (C=C), 1584 (C=N)
3459–3329 (NH2, NH), 3059 (CH
aromatic), 2229 (CN), 1689, 1684 (2
CO), 1648 (C=C), 1568 (C=N)
4.64 (s, 2H, NH2), 5.72 (s, 1H,
pyridine H-4), 7.28–7.39 (m, 10H,
2C6H5), 8.63 (s, 1H, NH)
1.35 (t, 3H, J = 6.77, CH3), 4.26 (q,
2H, J = 6.77 Hz, CH2), 4.57 (s,
2H, NH2), 5.68 (s, 1H, pyridine
H-4), 7.33–7.47 (m, 10H, 2C6H5),
8.60 (s, 1H, NH)
14d
15a
15b
3475–3331 (2NH2, NH), 3053 (CH
aromatic), 2219 (CN), 1645 (C=C),
1587 (C=N)
4.47, 5.60 (2s, 4H, 2NH2), 7.27–7.39
(m, 5H, C6H5), 8.31 (s, 1H, NH)
3468–3319 (2NH2, NH), 3059 (CH
aromatic), 2987, 2855 (CH3, CH2),
1680 (CO), 1645 (C=C), 1587 (C=N)
1.14 (t, 3H, J = 7.66 Hz, CH3), 4.23
(q, 2H, J = 7.66 Hz, CH2), 4.45,
5.68 (2s, 4H, 2NH2), 7.28–7.37
(m, 5H, C6H5), 8.44 (s, 1H, NH)
4.67, 5.37 (2s, 4H, 2NH2), 7.32–7.38
(m, 5H, C6H5), 8.48 (s, 1H, NH)
15c
15d
3488–3328 (2NH2, NH), 3066 (CH
aromatic), 2221 (CN), 1689 (CO),
1645 (C=C), 1587 (C=N)
3473–3321 (2NH2, NH), 3056 (CH
aromatic), 2980 (CH3), 2877 (CH2),
1689, 1686 (2 CO), 1642 (C=C), 1581
(C=N)
1.42 (t, 3H, J= 6.62 Hz, CH3), 4.21
(q, 2H, J = 6.62 Hz, CH2), 4.60,
5.41 (2s, 4H, 2NH2), 7.34–7.48
(m, 5H, C6H5), 8.52 (s, 1H, NH)
4.82 (s, 2H, CH2), 5.26 (s, br, 1H,
SH). 7.30–7.37 (m, 5H, C6H5)
16
3310 (SH), 3058 (CH aromatic), 1715
(CO), 2897 (CH2), 1652 (C=C), 1580
(C=N)
18a
18b
20
3483–3322 (NH2, NH), 3058 (CH
aromatic), 2227 (CN), 1710 (CO),
1651 (C=C), 1590 (C=N)
4.73 (s, 2H, NH2), 4.85 (s, 2H,
CH2), 7.27–7.40 (m, 5H, C6H5),
8.42 (s, 1H, NH)
4.84 (s, 2H, CH2), 7.29–7.38 (m,
10H, 2C6H5), 8.39, 8.68 (2s, 2H,
2NH)
5.83 (s, br, 1H, SH), 6.79 (s, 1H,
CH=C), 7.27–7.40 (m, 10H, 2
C6H5)
3483–3322 (2 NH), 3061 (CH
aromatic), 2224 (CN), 1713 (CO),
1657 (C=C), 1588 (C=N)
3055 (CH aromatic), 2223 (CN), 1688
(CO), 1639 (C=C), 1589 (C=N)
21
3058 (CH aromatic), 1693, 1682 (2
CO), 1652 (C=C), 1578 (C=N)
6.34 (s, 1H, coumarin H-4), 6.61 (s,
br, 1H, SH), 7.35–7.41 (m, 9H,
C6H5, C6H4)
3-Phenyl-2-(5-(phenylamino)-1,3,4-thiadiazol-2-yl)acrylonitrile
(8a), N-(5-(1-Cyano-2-phenylvinyl)-1,3,4-thiadiazol-2-yl)
benzamide (8b), and 2-(4,5-Dihydro-5-thioxo-3H-1,2,4-
triazol-3-yl-3-phenylacrylonitrile (20)
To a solution of either 4a (1.08 g, 0.005 mol), 4b (1.22 g, 0.005 mol), or
16 (1.22 g, 0.005 mol) in DMF (25 mL) containing piperidine (0.5 mL),

802
W. W. Wardakhan and N. N. E. El-Sayed
benzaldehyde (0.53 g, 0.51 mL, 0.005 mol) was added. The reaction
mixture, in each case, was heated under refluxed for 4 h, and then
cooled and poured onto an ice/water mixture. The pH was made acidic
using hydrochloric acid. The solid product formed, in each case, was
collected by filtration.
7-Amino-5-imino-2-(phenylamino)-5H-[1,3,4]thiadiazolo[3,2-
a]pyridine-8-carbonitrile (12a), 7-Amino-5-oxo-2-
(phenylamino)-5H-[1,3,4]thiadiazolo[3,2-a]pyridine-8-
carbonitrile (12b), N-(7-Amino-8-cyano-5-imino-5H-
[1,3,4-]thiadiazolo[3,2-a]pyridine-2-yl)benzamide (12c), and
N-(7-Amino-8-cyano-5-oxo-5H-[1,3,4-]thiadiazolo
[3,2-a]pyridine-2-yl)benzamide (12d)
To a solution of either thiadiazole 4a (2.16 g, 0.01 mol) or thiadiazole
4b (2.44 g, 0.01 mol) in 1,4-dioxane (50 mL) containing triethylamine
(1.01 g, 1.4 mL, 1.0 equiv.), either malononitrile (0.66 g, 0.01 mol) or
ethyl cyanoacetate (1.07 g, 0.01 mol) was added. The reaction mixture
in each case was heated under reflux for 3 h then poured onto ice water
containing a few drops of hydrochloric acid. The formed solid product,
in each case was collected by filtration.
2,4-Diamino-5-(5-phenylamino)-1,3,4-thiadiazol-2-
yl)thiophene-3-carbonitrile (15a), Ethyl 2,4-diamino-5-(5-
(phenylamino)-1,3,4-thiadiazol-2-yl)thiophene-3-carboxylate
(15b), N-(5-(3,5-Diamino-4-cyanothiophene-2-yl)-1,3,4-
thiadiazol-2-yl)benzamide (15c), and Ethyl 2,4-Diamino-5-
(5-benzamido)-1,3,4-thiazol-2-yl)thiophene-3-carboxylate
(15d)
To a solution of either thiadiazole 4a (2.16 g, 0.01 mol) or thiadiazole
4b (2.44 g, 0.01 mol) in 1,4-dioxane (50 mL) containing triethylamine
(1.01 g, 1.4 ml, 1.0 equiv.) and elemental sulfur (0.32 g, 0.01 mol), ei-
ther malononitrile 11a (0.66 g, 0.01 mol) or ethyl cyanoacetate 11b
(1.13 g, 1.1 ml, 0.01 mol) was added separately. The resulting reaction
mixture in each case was heated under reflux for 4 h then poured
onto an ice/water mixture, and the pH was made acidic using hy-
drochloric acid. The formed solid product, in each case, was collected by
filtration.

Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives
803
3-(5-Phenylamino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one
(10a), N(5-Oxo-2H-chromen-3-yl)-1,3,4-thiadiazol-2-yl)
benzamide (10b), and 3-(4,5-Dihydro-5-thioxo-3H-1,2,
4-triazol-3-yl)-2H-chromen-2-one (21)
To a solution of either thiadiazole 4a (1.08 g, 0.005 mol), thiadiazole
4b, (1.22 g, 0.005 mol), or triazole 16 (1.22 g, 0.005 mol) in 1,4-dioxane
(25 mL) containing a few drops of piperidine, salicylaldehyde (0.67 g,
0.58 mL, 0.005 mol, 1.1 equiv.) was added. The reaction mixture, in each
case, was heated under reflux for 4 h, and then cooled and poured onto
an ice/water mixture. Then the pH was made acidic using hydrochloric
acid. The solid product formed, in each case, was collected by filtration.
2-(1-Benzoyl-4,5-dihydro-5-thioxo-3H-1,2,
4-triazol-3-yl)acetonitrile (16)
A solution of thiosemicarbazide 3b (2.62 g, 0.01 mol) in sodium hydrox-
ide (2 N, 28 mL) was refluxed for 3 h. The resulting solution was cooled
to room temperature and acidified to pH 3–4 with 37% hydrochloric
acid. The solid product formed was collected by filtration.
2(1-Benzoyl-5-hydrazino-1,2,4-Triazol-3-yl)axetonitrile (18a)
and 2(1-Benzoyl-5-phenylhydrazino-1,2,4-triazol-3-yl)
axetonitrile (18b)
To a solution of triazole 16 (1.22 g, 0.005 mol) in ethanol (25 mL), either
hydrazine hydrate (0.25 g, 0.005 mol) or phenylhydrazine (0.54 g, 0.49
mL, 0.005 mol) was added. The reaction mixture, in each case, was
heated under reflux for 4 h, and then poured onto an ice/water mixture
containing few drops of hydrochloric acid. The solid product formed in
each case was collected by filtration.
5-Amino-7-phenyl-2-(phenylamino)-7H-[1,3,4]thiadiazolo[3,2-
a]pyridine-6,8-dicarbonitrile (14a), Ethyl 5-Amino-8-cyano-
7-phenyl-2-(phenylamino)-7H-[1,3,4]thiadiazolo[3,2-a]pyridine-
6-carboxylate (14b), N-(5-Amino-6,8-dicyano-7-phenyl-7H-
[1,3,4]thiadiazolo[3,2-a]pyridine-2-yl0benzamide (14c), and
Ethyl 5-Amino-2-(benzamido)-8-cyano-7-phenyl-7H-[1,3,4]
thiadiazolo[3,2-a]pyridine-6-carboxylate (14d)
To a solution of either the thiadiazol4a (1.2 g, 0.005 mol) or 4b
(1.08, 0.005 mol) in DMF (30 mL) containing triethylamine (0.5 g, 0.7
ml, 1.0 equiv.), either benzalmalononitrile 13a (0.77 g, 0.005 mol) or

804
W. W. Wardakhan and N. N. E. El-Sayed
benzalethyl cyanoacetate 13b (1.0 g, 0.005 mol) was added separately.
The resulting reaction mixture in each case was heated under reflux
for 4 h then poured onto an ice/water mixture and the pH was made
acidic using hydrochloric acid. The formed solid product, in each case,
was collected by filtration.
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