Synthesis and antibacterial activity of some new S-triazole derivatives

Article abstract of DOI:10.1080/10426507.2012.690118

Alkylation of 4-anilino-5-phenyl-4H-1,2,4-triazole-3-thiol (1) with some halo compounds yielded the corresponding sulfides 2a-f. Some sulfides 2e,f were cyclized to give triazolothiadiazines 3 and 4. Triazolothiadiazoles 5 and 6 were prepared through the reaction of compound 1 with carbon disulfide or ethyl orthoformate, respectively. Treatment of compound 1 with ethyl chloroformate or phenyl isothiocyanate yielded triazolo-thiadiazole and triazole 9 and 10, respectively. Reaction of compound 1 with Lawesson's reagent gave triazolothiadiazaphosphole derivative 11. Also, compound 1 underwent cyclocondensation reactions with some bidentate reagents to give triazolothiazines 4, 12, and 13. Triazolo-thiazepines and triaziepine 14-16 were synthesized via the reaction of compound 1 with -ketoesters or ethyl cyanoacetate. Tricyclic systems 19 and 20 were prepared through the reaction of compound 4 with the appropriate reagent. Some synthesized compounds were tested for antibacterial activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426507.2012.690118

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Synthesis and Antibacterial Activity of
Some New S-Triazole Derivatives
Abd El-Badih A. G. Ghattas a , Hassan M. Moustafa a , Elsayed A. A.
Hassanein a & Bahgat R. M. Hussein a
a Chemistry Department, Faculty of Science, Sohag University,
Sohag, Egypt
Accepted author version posted online: 09 May 2012.Version of
record first published: 10 Sep 2012.
To cite this article: Abd El-Badih A. G. Ghattas, Hassan M. Moustafa, Elsayed A. A. Hassanein &
Bahgat R. M. Hussein (2012): Synthesis and Antibacterial Activity of Some New S-Triazole Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 187:12, 1469-1481
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Phosphorus, Sulfur, and Silicon, 187:1469–1481, 2012
Copyright ꢀC Sohag University
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.690118
SYNTHESIS AND ANTIBACTERIAL ACTIVITY
OF SOME NEW S-TRIAZOLE DERIVATIVES
Abd El-Badih A. G. Ghattas, Hassan M. Moustafa,
Elsayed A. A. Hassanein, and Bahgat R. M. Hussein
Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
GRAPHICAL ABSTRACT
Abstract Alkylation of 4-anilino-5-phenyl-4H-1,2,4-triazole-3-thiol (1) with some halo com-
pounds yielded the corresponding sulfides 2a–f. Some sulfides 2e,f were cyclized to give tria-
zolothiadiazines 3 and 4. Triazolothiadiazoles 5 and 6 were prepared through the reaction of
compound 1 with carbon disulfide or ethyl orthoformate, respectively. Treatment of compound
1 with ethyl chloroformate or phenyl isothiocyanate yielded triazolo-thiadiazole and triazole 9
and 10, respectively. Reaction of compound 1 with Lawesson’s reagent gave triazolothiadiaza-
phosphole derivative 11. Also, compound 1 underwent cyclocondensation reactions with some
bidentate reagents to give triazolothiazines 4, 12, and 13. Triazolo-thiazepines and triaziepine
14–16 were synthesized via the reaction of compound 1 with β-ketoesters or ethyl cyanoac-
etate. Tricyclic systems 19 and 20 were prepared through the reaction of compound 4 with the
appropriate reagent. Some synthesized compounds were tested for antibacterial activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Lawesson’s reagent; s-triazole; triazolothiadiazine; triazolothiadiazepines
INTRODUCTION
Heterocycles bearing a symmetrical triazole ring are reported to show a broad spec-
trum of biological activities such as antifungal,1–3 antibacterial,4,5 anti-inflammatory,6,7
Received 13 March 2012; accepted 28 April 2012.
The authors are grateful to the Chemistry Department, Faculty of Science, Sohag University, Egypt for both
supporting and facilitating this study. Also, we extend our thanks to Dr. Rehab Moustafa Mohamed and Ms. Dalia
Ahmed Abd El Raheem from the Botany Department, Faculty of Science, Sohag University, Egypt for evaluation
of bacterial inhibiting effects.
Address correspondence to Bahgat R. M. Hussein, Chemistry Department, Faculty of Science, Sohag
University, Sohag 82524, Egypt. E-mail: bahgat.ramadan@yahoo.com
1469

1470
A. E.-B. A. G. GHATTAS ET AL.
antimicrobial,8 and antituberculosis activity.9 Among the 1,2,4-triazole derivatives, the
mercapto- and the thiono-1,2,4-triazole ring systems have been studied and so far a variety
of antitumor properties have been reported for a large number of these compounds.10,11
s-Triazoles are also applied in medicine as follows: alprazolam (tranquilizer), estazolam
(hypnotic, sedative, tranquilizer, etc.), rilmazafon (hypnotic, anxiolytic, used in the case
of neurotic insomnia, etc.), benatradin (diuretic), trapidil (hypotensive), trazodon (antide-
pressant, anxiolytic, etc.), etoperidone (antidepressant), nefazodone (antidepressant, 5-HT2
A-antagonist, etc.), anastrozole, letrozole, vorozole (antineoplastics, nonsteroidal compet-
itive aromatase inhibitors, etc.), ribavirin (the potent antiviral N-nucleoside), fluconazole,
itraconazole, and terconazole (the powerful azole antifungal agents).3,12–15 In view of these
findings and in continuation of our work in the same field,16–22 we report herein the synthesis
of some new s-triazole derivatives and evaluate them for antibacterial activity.
RESULTS AND DISCUSSION
4-Anilino-5-phenyl-4H-1,2,4-triazole-3-thiol (1)23 reacted with halo compounds,
namely chloroacetonitrile, phenacyl bromide, chloroacetamide, N-phenyl chloroacetamide,
bromomalononitrile, and ethyl chloroacetate, to give the corresponding sulfides, namely
4-anilino-5-phenyl-4H-1,2,4-triazol-3-yl-thioacetonitrile (2a), 2-(4-anilino-5-phenyl-4H-
1,2,4-triazol-3-yl)thio-1-phenylethanone (2b), 2-(4-anilino-5-phenyl-4H-1,2,4-triazol-
3-yl)thioacetamide (2c), 2-(4-anilino-5-phenyl-4H-1,2,4-triazol-3-yl)thio-N-phenylacet-
amide (2d), 4-anilino-5-phenyl-4H-1,2,4-triazol-3-yl-thiomalononitrile (2e), and ethyl
(4-anilino-5-phenyl-4H-1,2,4-triazol-3-yl)thioacetate (2f), respectively (cf. Scheme 1). The
structure of these compounds was characterized on the basis of their elemental and spectro-
scopic analyses (cf. Experimental section). The IR spectra of compounds 2a–f showed the
absence of an absorption band corresponding to (NH) in triazole ring, while exhibiting char-
acteristic absorption bands corresponding to (CH) aliphatic groups at 2936–2923, (C N)
2249 (2a); (C O) 1673 (2b); (NH2) 3333 and 3180, (C O) 1687 (2c), (C O) 1672 (2d);
(C N) 2210 (2e), and (C O) 1720 (2f), respectively. The 1H NMR spectrum of compound
2f showed multiplet signals at 7.97–7.55 ppm for aromatic protons + (NH) proton, singlet
signal at 4.29 ppm for S-CH2 protons, quartet signals at 4.18–4.11 ppm for CH2 protons,
and triplet signals at 1.20–1.16 ppm for CH3 protons. Cyclization reaction of compounds
2e and 2f yielded 6-amino-3,5-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-7-
carbonitrile (3) and 3,5-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazin-6(7H)-one (4),
respectively. The IR spectra of compounds 3 and 4 showed the absence of absorption
bands corresponding to (NH) in triazole ring and (NH) anilino group, while exhibiting
characteristic absorption bands corresponding to (NH2) at 3331 and 3202, (C N) 2199
(3), and (C O) 1742 (4). The mass spectra (MS) of compounds 3 and 4 showed the
molecular ion peaks at m/z 330 (M+ − 2, 29.4%) and 308.25 (M+, 0.58%), respectively.
3,5-Diphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole-6(5H)-thione (5) and 6-ethoxy-3,5-
diphenyl-5,6-dihydro-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (6) were prepared via the
reaction of compound 1 with carbon disulfide and/or ethyl orthoformate, respectively
(cf. Scheme 1). The structure of these compounds was characterized on the basis of their
elemental and spectroscopic analyses (cf. Experimental section). MS of compound 5
showed the molecular ion peak at m/z 310 (M+, 8.86%), 1H NMR spectrum of compound
6 showed multiplet signals at 7.98–7.55 ppm for aromatic protons, quartet signals at
3.33–3.29 ppm for CH2 protons, and triplet signals at 1.44–1.39 ppm for CH3 protons.

NEW S-TRIAZOLE DERIVATIVES
1471
N
N
RCH2X
Comp. 1a&2a 1b&2b 1c&2c 1d&2d
1a-d
X
R
Cl
Br
Cl
Cl
Ph
Ph
SCH2R
2 a-d
N
N
CN
COPh CONH2 CONHPh
EtOH / TEA
H
Ph
Ph
N
N
N
N
BrCH(CN)2
EtOH / TEA
EtONa
Ph
S
N
N
SCH(CN)2
2e
N
N
CN
H
Ph
NH2
N
3
N
N
N
ClCH2COOEt
Ac2O
SCH2COOEt
2f
Ph
Ph
Ph
N
N
S
N
Acetone / K2CO3
H
N
Ph
Ph
4
N
N
O
CS2 / KOH
EtOH
N
S
N
N
N
S
H
Ph
5
N
Ph
S
N
N
N
H
Ph
HC(OEt)3
AC2O
1
Ph
Ph
N
S
N
Ph
OEt
6
N
N
N
N
N
H
Ac2O
LR
ClCOOEt
Ph
Ph
5
S
N
N
S
xylene
Acetone / K2CO3
N
N
COOEt
Ph
9
7
Ph
O
N
N
N
H
PhNCS
pyridine
Ph
S
N
Ph
N
N
EtOH / piperidine
N
N
CSNHPh
Ph
10
Ph
8
S
N
N
LR
Ph
N
S
dry CH3CN
N
P
Ph
OCH3
S
11
-
S
S
+
S
S
H CO
P
P
OCH
H CO
P
3
3
3
S
S
Lawessons reagent (LR)
Scheme 1

1472
A. E.-B. A. G. GHATTAS ET AL.
Treatment of compound 1 with ethyl chloroformate in acetone containing anhydrous potas-
sium carbonate or phenyl isothiocyanate in ethanol containing few drops of piperidine, gave
ethyl(3-mercapto-5-phenyl-4H-1,2,4-triazol-4-yl)phenylcarbamate (7) and 1-(3-mercapto-
5-phenyl-4H-1,2,4-triazol-4-yl)-1,3-diphenylthiourea (8), respectively. Compounds 7
and 8 were cyclized to give 3,5-diphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-6(5H)-
one (9) and 3,5,7-triphenyl-5H-1,2,4-triazolo[4,3-b]-1,2,4-triazole-6(7H)-thione (10),
respectively. Thiation of compound 9 by using Lawesson’s reagent in xylene yielded the
corresponding triazolo[3,4-b]thiadiazole derivative 5, (cf. Scheme 1). The structure of
these compounds was characterized on the basis of their elemental and spectroscopic
analyses (cf. Experimental), MS of compounds 8–10 showed the molecular ion peaks at
m/z 403.45(M+, 0.32%), 294.4 (M+, 0.03%), and 369.5 (M+, 0.45%), respectively. The
IR spectra of compounds 7 and 9 showed the absence of absorption bands corresponding
to (NH) anilino group, while exhibiting characteristic absorption bands corresponding
1
to (C Oester) group at 1762 (7) and (C Oamidic) at 1747 (9). H NMR spectrum of
compound 7 showed multiplet signals at 7.93–7.59 for aromatic protons, quartet signals
at 4.49–4.42 ppm for CH2 protons, and triplet signals at 1.38–1.33 ppm for CH3 protons
(ethyl group). Treatment of compound 1 with Lawesson’s reagent in dry acetonitrile
yielded
2-(4-methoxyphenyl)-1,6-diphenyl-1,2-dihydro-1,2,4-triazolo[4,3-d]-1,3,4,2-
thiadiazaphosphole-2-sulfide (11) (cf. Scheme 1). The structure of this compound was
characterized on the basis of its elemental and spectroscopic analyses (cf. Experimental).
1H NMR spectrum of compound 11 showed multiplet signals at 7.62–6.99 ppm for
aromatic protons and singlet signal at 3.80 ppm for CH3 protons. MS of compound 11
showed the molecular ion peak at m/z 436 (M+, 15.37%).
Cyclization of compound 1 with chloroacetyl chloride, 1,2-dibromoethane, and
diethyl oxalate yielded 3,5-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazin-6(7H)-
one (4), 3,5-diphenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (12), and
3,5-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-6,7-dione (13), respectively
(cf. Scheme 2). The structure of these compounds was determined on the basis of their
elemental and spectroscopic analyses (cf. Experimental). 1H NMR spectrum of compound
ClCH2COCl
4
pyridine / TEA
N
N
N
N
N
Br(CH2)2Br
EtOH / TEA
Ph
Ph
SH
N
N
N
S
H
N
Ph
Ph
1
12
O
O
N
EtO
OEt
Ph
N
N
S
Fusion
Ph
O
13
O
Scheme 2

NEW S-TRIAZOLE DERIVATIVES
1473
12 showed multiplet signals at 7.97–7.55 ppm for aromatic protons, triplet signals at
3.81–3.76 ppm for N-CH2 protons, and triplet signals at 2.53–2.89 ppm for S-CH2 protons.
The IR spectrum of compound 13 showed the absence of absorption band corresponding to
(NH) in triazole ring and (NH) anilino group, while exhibiting a characteristic absorption
broad band corresponding to (C O) groups at 1688 (13). MS of compound 13 showed the
molecular ion peak at m/z 322 (M+, 1.42%).
8-Methyl-3,5-diphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepin-6(5H)-one (14), 3,5,
8-triphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepin-6(5H)-one (15), and 3,5-diphenyl-8-
thioxo-8,9-dihydro-5H-1,2,4-triazolo[4,3-b]-1,2,4-triazepin-6(7H)-one (16) were synthe-
sized by reaction of compound 1 with ethyl acetoacetate, ethyl benzoylacetate, and ethyl
cyanoacetate, respectively (cf. Scheme 3). The structure of these compounds was character-
ized on the basis of their elemental and spectroscopic analyses (cf. Experimental section).
The IR spectra of compounds 14–16 showed the absence of absorption bands corresponding
to (NH) in triazole ring and (NH) anilino group, while exhibiting characteristic absorption
bands corresponding to (C O) at 1735 (14), (C O) 1754 (15), (NH) 3135, (C O) at 1697,
and (C S) at 1176 (16). 1H NMR spectrum of compound 14 showed multiplet signals at
7.78–7.39 ppm for aromatic protons, singlet signal at 5.92 ppm for CH proton, and singlet
1
signal at 2.42 ppm for CH3 proton; H NMR spectrum of compound 15 showed multi-
1
plet signals at 7.92–7.54 ppm for aromatic protons + CH proton; H NMR spectrum of
compound 16 showed broad singlet signal at 14.71 ppm NH proton, multiplet signals at
7.90–7.55 ppm for aromatic protons, and singlet signal at 3.42 ppm for CH2 protons.
Compound 4 coupled with p-toluenediazonium chloride to give 3,5-diphenyl-
5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-6,7-dione-7-(p-tolyl)hydrazone (17). Thiation
of compound 4 with LR gave 3,5-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-
6(7H)-thione (18). Polyfused heterocyclic compounds: 7-amino-3,5-diphenyl-5H-
thieno[3,2-e]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-6-carbonitrile (19) and 7-amino-3,
5-diphenyl-9-thioxo-5,9-dihydrothio-pyrano[4,3-e]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-
6-carbonitrile (20) were synthesized by reaction of compound 4 with a mixture of
elemental sulfur and malononitrile or carbon disulfide and malononitrile, respectively
N
N
CH3COCH2COOEt
Fusion
Ph
Ph
Ph
S
N
CH3
N
Ph
14
O
N
N
N
N
PhCOCH2COOEt
Fusion
Ph
SH
N
S
N
NH
Ph
N
Ph
Ph
1
15
O
N
N
CNCH2COOEt
Pyridine
NH
N
S
N
Ph
16
O
Scheme 3

1474
A. E.-B. A. G. GHATTAS ET AL.
N
N
_ toluidine
Ph
P
N
S
NaNO2 / HCl
at -5 °C
N
NH
Ph
N
O
CH3
17
N
N
LR
Ph
N
S
Xylene
N
N
N
Ph
Ph
S
18
N
S
N
N
N
Ph
Ph
S / CH2(CN)2
dioxane / TEA
O
N
S
4
N
Ph
S
NC
N
N
H2
N
19
CS2 / CH2(CN)2 / TEA
Ph
N
N
S
DMF / EtOH
stirring
S
Ph
S
NC
20
N
H2
Scheme 4
(cf. Scheme 4). The structure of these compounds was determined on the basis of their
elemental and spectroscopic analyses (cf. Experimental). The IR spectrum of compound
17 showed absorption bands corresponding to (NH) at 3140 and (C O) at 1750, while
IR spectra of compounds 18–20 showed the absence of absorption band corresponding
to (C O), while exhibiting characteristic absorption bands corresponding to (C S) at
1147 (18), (NH2) at 3328 and 3208, and (C N) at 2202 (19), (NH2) at 3316 and 3186,
and (C N) at 2204.9 (20). MS of compounds 17–20 showed molecular ion peaks at m/z
426.1 (M+, 0.86%), 324.3 (M+, 0.02%), 388.7 (M+, 1.35%), and 432.55 (M+, 0.67%),
respectively.
Antibacterial Activity
The compounds were dissolved in dimethyl sulfoxide (DMSO). In order to ensure
that the solvent had no effect on bacterial growth or enzymatic activity, negative control
tests were performed using DMSO at the same concentrations. The inhibitory effect of com-
pounds 1, 2a, 2c–f, 3, 4, 6–8, 10, 11, 14–17, and 20 in in vitro growth of broad spectrum of
bacteria representing one species of Gram positive bacteria, namely Bacillus cereus and two
species of Gram negative bacteria, namely Pseudomonas aeruginosa and Escherichia coli

NEW S-TRIAZOLE DERIVATIVES
1475
was evaluated using the agar diffusion method (cup and plate method)24 by measuring the
zone of inhibition on agar plates at three different concentrations 10,000 ppm, 30,000 ppm,
and 50,000 ppm. DMSO was used as solvent control. The results are summarized in Table
S1. (Table S1 is available online in Supplemental Materials.)
EXPERIMENTAL
Melting points (mp) were uncorrected and were determined by Kofeler melting point
apparatus. The infrared (IR) (cm−1) spectra were recorded (KBr disc) on a Nicolet 710
Fourier transform infrared (FT-IR) spectrophotometer. 1H NMR (DMSO-d6) spectra were
recorded at 300 MHz on a Varian Gemini NMR spectrometer at Cairo University, and the
chemical shift was expressed in δ-value (ppm) using tetramethylsilane (TMS) as an internal
reference. Elemental analyses were carried out in an elemental analyzer at 240 ◦C. The MS
were performed on Micromass 7070 E spectrometer operating at 70 eV, using direct inlet.
1
Selected H NMR spectra are presented in Figures S1–S5. (Figures S1–S5. are available
online in Supplemental Materials.)
General Procedure for Synthesis of Sulfides 2a–e
To a solution of compound 1 (0.5 g, 1.86 mmol) in ethanol (30 mL) and triethylamine
(1.86 mmol), chloroacetonitrile, phenacyl bromide, chloroacetamide N-phenyl chloroac-
etamide, and/or bromomalononitrile (1.86 mmol) was added. The reaction mixture was
refluxed for 3 h, and the solvent was evaporated under reduced pressure. The formed
precipitate was collected and recrystallized from ethanol.
4-Anilino-5◦-phenyl-4H-1,2,4-triazol-3-yl-thioacetonitrile (2a). Yield 0.46 g
(80%); mp 89–92 C; IR (νmax, cm−1): 3423 (NH), 3055 (CHarom), 2939 (CHaliph), 2249
(C N), 1604 (C N); 1H NMR (δ): 10.39 (s, 1H, NH), 8.01–7.58 (m, 10H, Harom), 4.53 (s,
1H, CH2). Anal. calcd. for C16H13N5S (307.37): C, 62.52; H, 4.26; N, 22.78; S, 10.43%.
Found: C, 62.55; H, 4.33; N, 22.67; S, 10.31%.
2-(4-Anilino-5-phenyl-4H◦-1,2,4-triazol-3-yl)thiophenylethanone
(2b).
Yield 0.45 g (72%); mp 147–149 C; IR (νmax, cm−1): 3440 (NH), 3070 (CHarom), 2923
1
(CHaliph), 1673 (C O), 1594 (C N); H NMR (δ): 8.09–7.55 (m, 15H, Harom), 5.17 (s,
1H, NH), 5.15 (s, 2H, CH2). Anal. calcd. for C22H18N4OS (386.46): C, 68.37; H, 4.49; N,
14.5; S, 8.3%. Found: C, 68.22; H, 4.35; N, 14.66; S, 8.38%.
2-(4-Anilino-5-phenyl-4H-1,2,4-triazol-3-yl)thioacetamide
(2c). Yield
◦
0.73 g (97%); mp 178–180 C; IR (νmax, cm−1): 3439.5 (NH), 3333 and 3180 (NH2),
2999 (CHarom), 2933 (CHAliph), 1687 (C O); 1H NMR (δ): 7.98–7.95 and 7.63–7.57 (m,
10H, Harom), 7.79 (brs, 1H, NH), 7.39 (brs, 2H, NH2), 4.106 (s, 2H, CH2). Anal. calcd. for
C16H15N5OS (325.38): C, 59.06; H, 4.65; N, 21.52; S, 9.85%. Found: C, 59.26; H, 4.75;
N, 21.68; S, 9.73%.
2-(4-Anilino-5-phenyl-4H-1,2,4-triazol-3-yl)thio-N-phenylacetamide (2d).
Yield 0.53 g (88%); mp 148–150 ◦C; IR (νmax, cm−1): 3420 (2NH), 3058 (CHarom), 2932
1
(CHaliph), 1672 (C O), 1609 (C N); H NMR (δ): 10.45 (s, 1H, NH), 7.96–7.55 (m,
15H, Harom + NH), 4.34 (s, 2H, CH2); MS (m/z, I%): M+ 401.3 (0.02%). Anal. calcd. for
C22H16N5OS (401.48): C, 65.81; H, 4.77; N, 17.44; S, 7.99%. Found: C, 65.75; H, 4.82;
N, 17.61; S, 7.87%.

1476
A. E.-B. A. G. GHATTAS ET AL.
4-Anilino-5-phenyl-4H-1,2,4-triazol-3-yl-thiomalononitrile
(2e). Yield
0.94 g (76%); mp 188–190 ◦C; IR (νmax, cm−1): 3419 (NH), 3050 (CHarom), 2931 (CHaliph),
2210 (C N), 1618 (C N); 1H NMR (δ): 14.72 (brs, 1H, NH), 7.90–7.50 (m, 10H, Harom
+ 1H, CH). Anal. calcd. for C17H12N6S (332.38): C, 61.43; H, 3.64; N, 25.28; S, 9.65%.
Found: C, 61.35; H, 3.44; N, 25.39; S, 9.41%.
Synthesis of Ethyl(4-anilino-5-phenyl-4H-1,2,4-triazol-3-yl)
thioacetate (2f)
A mixture of compound 1 (2 g, 7.46 mmol), ethyl chloroacetate (0.79 mL, 7.46 mmol),
and anhydrous potassium carbonate (2.04 g, 14.92 mmol) in dry acetone (40 mL) was re-
fluxed for 8 h on a water bath. The solvent was evaporated and the solid formed was
◦
washed with water and crystallized from benzene, yield 1.92 g (72%); mp 71–73 C; IR
(νmax, cm−1): 3303 (NH), 3019 (CHarom), 2927 (CHAliph), 1744 (C O), 1605 (C N);
1H NMR (δ): 7.97–7.55 (m, 11H, Harom + NH), 4.29 (s, 2H, CH2), 4.18–4.11 (q, J
= 7 Hz, 2H, CH2), 1.20–1.16 (t, J = 7 Hz, 3H, CH3). Anal. calcd. for C18H18N4O2S
(354.4): C, 61.00; H, 5.12; N, 15.81; S, 9.05%. Found: C, 61.11; H, 5.34; N, 15.64;
S, 9.22%.
Synthesis of 6-Amino-3,5-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazine-7-carbonitrile (3)
A suspension of compound 2e (0.322 g, 1 mmol) in sodium ethoxide solution (0.2 g
Na in 30 mL absolute ethanol) was refluxed for 3 h and allowed to cool. The precipitate
was collected, washed with water, and recrystallized from ethanol, yield 0.3 g (90%); mp
190 ◦C; IR (νmax, cm−1): 3331 and 3202 (NH2), 2199 (C N), 1631 (C N); 1H NMR (δ):
8.96 (s, 2H, NH2), 8.10–7.05 (m, 10H, Harom); MS (m/z, I%): M+ − 2, 330 (29.4%). Anal.
calcd. for C17H12N6S (332.38): C, 61.43; H, 3.64; N, 25.28; S, 9.65%. Found: C, 61.45; H,
3.72; N, 25.15; S, 9.52%.
Synthesis of 3,5-Diphenyl-5H-1,2,4triazolo[3,4-b]-1,3,4-thiadiazin-6(7H)-
one (4)
Method A. To a solution of compound 1 (0.7 g, 2.6 mmol) in pyridine (40 mL),
chloroacetyl chloride (0.45 mL, 4 mmol) was added. The reaction mixture was refluxed for
3 h and then poured into ice-cold water. The formed precipitate was collected, filtered, and
recrystallized from ethanol, yield 0.53 g (66%).
Method B. A solution of compound 2f (1 g, 2.82 mmol) in acetic anhydride (25 mL)
was refluxed for 4 h and then poured into ice-cold water. The formed precipitate was
◦
collected, filtered, and recrystallized from ethanol, yield 0.74 g (85%); mp 79–82 C; IR
(νmax, cm−1): 3055.6 (CHarom), 2984–2930 (CHaliph), 1742 (C O), 1608 (C N); 1H NMR
(δ): 7.86–7.22 (m, 10H, Harom), 4.42 (s, 2H, CH2); MS (m/z, I%): M+ 308.25 (0.58%).
Anal. calcd. for C16H12N4OS (308.35): C, 62.32; H, 3.92; N, 18.17; S, 10.40%. Found: C,
62.11; H, 3.76; N, 18.34; S, 10.27%.

NEW S-TRIAZOLE DERIVATIVES
1477
Synthesis of 3,5-Diphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole-6(5H)-
thione (5)
Method A. A mixture of compound 1 (0.5 g, 1.86 mmol) and potassium hydroxide
(0.11 g, 2 mmol) in ethanol (30 mL) was stirred for 0.5 h, then carbon disulfide (22 mL,
3 mmol) was added slowly. The reaction mixture was refluxed until H2S evolution ceased
(12 h), then concentrated and poured into ice-cold water. The precipitate was washed with
water, filtered, and recrystallized from ethanol, yield 0.53 g (91%).
Method B. A mixture of compound 9 (0.5 g, 1.69 mmol) and Lawesson’s reagent
(0.34 g, 1.69 mmol) in xylene (30 mL) was refluxed until H2S ceased (3 h), and the
solvent was then evaporated under reduced pressure. The formed precipitate was collected
◦
and recrystallized from ethanol, yield 0.34 g (65%); mp 320 C; IR (νmax, cm−1): 3055
(CHarom), 1616 (C N), 1107 (C S); 1H NMR (δ): 8.31–7.19 (m, 10H, Harom); MS (m/z,
I%): M+ 310 (8.86%). Anal. calcd. for C15H10N4S2 (310.39): C, 58.04; H, 3.25; N, 18.05;
S, 20.66%. Found: C, 58.25; H, 3.42; N, 18.12; S, 20.44%.
Synthesis of 6-Ethoxy-3,5-diphenyl-5,6-dihydro-1,2,4-triazolo[3,4-b]-
1,3,4-thiadi-azole (6)
To a solution of compound 1 (0.53 g, 2 mmol) in acetic anhydride (20 mL), ethyl
orthoformate (0.6 mL, 4 mmol) was added. The reaction mixture was refluxed for 4 h, and
the solvent was evaporated under reduced pressure. The precipitate formed was collected
and recrystallized from ethanol, yield 0.62 g (96%); mp 215–217 ◦C; IR (νmax, cm−1): 3049
1
(CHarom), 2936 (CHaliph), 1622 (C N); H NMR (δ): 7.98–7.55 (m, 11H, Harom + CH),
3.37–3.29 (q, J = 7.4 Hz, 2H, CH2), 1.44–1.39 (t, J = 7.38 Hz, 3H, CH3). Anal. calcd. for
C17H16N4OS (324.4): C, 62.94; H, 4.97; N, 17.27; S, 9. 88%. Found: C, 62.73; H, 4.69; N,
17.06; S, 9.95%.
Synthesis of Ethyl(3-mercapto-5-phenyl-4H-1,2,4-triazol-4-yl)
phenylcarbamate (7)
A mixture of compound 1 (0.8 g, 2.98 mmol), ethyl choloroformate (0.32 mL,
2.98 mmol), and anhydrous potassium carbonate (1.1 g, 8 mmol) in dry acetone (30 mL)
was stirred at room temperature for 1 h. The solvent was removed under reduced pressure,
the residual solid was washed with water, filtered, and recrystallized from ethanol, yield
◦
0.95 g (93.5%); mp 126–128 C; IR (νmax, cm−1): 3151 (NH), 2986 (CHarom), 2936,
1
(CHAliph), 1762 (C O), 1622 (C N), 1198 (C S); H NMR (δ): 7.93–7.59 (m, 11H,
Harom + NH), 4.49–4.42 (q, J = 7.2 Hz, 2H, CH2), 1.38–1.33 (t, J = 7.2 Hz, 3H, CH3).
Anal. calcd. for C17H16N4O2S (340.39): C, 59.98; H, 4.47; N, 16.46; S, 9.42%. Found: C,
59.88; H, 4.35; N, 16.62; S, 9.58%.
Synthesis of 1-(3-Mercapto-5-phenyl-4H-1,2,4-triazol-4-yl)-1,3-
diphenylthiourea (8)
A mixture of compound 1 (0.5 g, 1.86 mmol), phenyl isothiocyanate (0.22 mL,
1.86 mmol), and few drops of piperidine in ethanol (30 mL) was refluxed for 3 h. The
solvent was evaporated under reduced pressure. The formed precipitate was collected and

1478
A. E.-B. A. G. GHATTAS ET AL.
◦
recrystallized from ethanol, yield 0.69 g (91.6%); mp 98–101 C; IR (νmax, cm−1): 3421
(NHanilino), 3258 (NH), 3044 (CHarom); 1H NMR (δ): 7.87–7.26 (m, 17H, Harom + 2NH);
MS (m/z, I%): M+ 403.45 (0.32%). Anal. calcd. for C21H17N5S2 (403.52): C, 62.51;
H, 4.25; N, 17.36; S, 15.89%. Found: C, 62.41; H, 4.32; N, 17.56; S, 15.58%.
Synthesis of 3,5-Diphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-6(5H)-
one (9)
A solution of compound 7 (0.6 g, 1.76 mmol) in acetic anhydride (20 mL) was
refluxed for 6 h; the solvent was evaporated under reduced pressure, the formed precipitate
◦
was collected and recrystallized from ethanol, yield 0.47 g (90%); mp 142–145 C; IR
(νmax, cm−1): 3077 (CHarom), 1747 (C O), 1619 (C N); 1H NMR (δ): 7.98–7.43 (m, 10H,
Harom); MS (m/z, I%): M+ 294.4 (0.03%). Anal. calcd. for C15H10N4OS (294.33): C, 61.21;
H, 3.42; N, 19.04; S, 10.98%. Found: C, 61.35; H, 3.66; N, 19.24; S, 10.78%.
Synthesis of 3,5,7-Triphenyl-5H-1,2,4-triazolo[4,3-b]-1,2,4-triazole-
6(7H)-thione (10)
A solution of compound 8 (0.5 g, 1.23 mmol) in pyridine (25 mL) was refluxed until
H2S ceased (12 h). The solvent was evaporated under reduced pressure, the formed precip-
◦
itate was collected and recrystallized from ethanol, yield 0.37 g (82%); mp 193–195 C;
IR (νmax, cm−1): 1176 (C S); H NMR (δ): 7.69–7.18 (m, 15H, Harom); MS (m/z, I%):
1
M+ 369.5 (0.45%). Anal. calcd. for C21H15N5S (369.44): C, 68.27; H, 4.09; N, 18.96;
S, 8.68%. Found: C, 68.34; H, 4.22; N, 18.75; S, 8.53%.
Synthesis of 2-(4-Methoxyphenyl)-1,6-diphenyl-1,2-dihydro-1,2,4-
triazolo[4,3-d]-1,3,4,2-thiadiazaphosphole 2-sulfide (11)
A mixture of compound 1 (1 g, 3.73 mmol) and Lawesson’s reagent (0.75 g,
3.73 mmol) in acetonitrile (30 mL) was refluxed until H2S ceased (3 h), and the sol-
vent was then evaporated under reduced pressure. The formed precipitate was collected
◦
and recrystallized from ethanol, yield 1.43 g (88%); mp 224–226 C; IR (νmax, cm−1):
3095 (CHarom), 2921 (CHaliph), 1630 (C N), 690 (P S); 1H NMR (δ): 7.62–7.99 (m, 14H,
Harom), 3.80 (s, 3H, CH3); MS (m/z, I%): M+ 436 (15.37%). Anal. calcd. for C21H17N4OPS2
(436.48): C, 57.78; H, 3.93; N, 12.84; S, 14.69%. Found: C, 57.66; H, 3.82; N, 12.98;
S, 14.41%.
Synthesis of 3,5-Diphenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazine (12)
To a solution of compound 1 (0.5 g 1.86 mmol) in ethanol (30 mL) and drops of
triethylamine, 1,2-dibromoethane (0.14 mL, 1.86 mmol) was added. The reaction mixture
was refluxed for 3 h; the solvent was evaporated under reduced pressure. The formed pre-
cipitate was collected and recrystallized from ethanol, yield 0.37 g (68%); mp 109–111 ◦C;
IR (νmax, cm−1): 3075 (CHarom), 2927 (CHaliph), 1635 (C N); 1H NMR (δ): 7.97–7.55 (m,
10H, Harom), 3.82–3.78 (t, J = 6 Hz, 2H, N-CH2), 2.53–2.49 (t, J = 6 Hz, 2H, S-CH2).

NEW S-TRIAZOLE DERIVATIVES
1479
Anal. calcd. for C16H14N4S (294.37): C, 65.28; H, 4.79; N, 19.03; S, 10.89%. Found: C,
65.15; H, 4.58; N, 19.28; S, 10.76%.
Synthesis of 3,5-Diphenyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-
6,7-dione (13)
A mixture of compound 1 (0.5 g, 1.86 mmol) and diethyl oxalate (0.25 mL,
1.86 mmol) was heated for 1.5 h. The reaction mixture was treated with ethanol. The pre-
cipitate was collected and recrystallized from ethanol, yield 0.45 g (75%); mp 120–122 ◦C;
IR (νmax, cm−1): 3025 (CHarom), 1688 (2C O); 1H NMR (δ): 7.89–7.52 (m, 10H, Harom);
MS (m/z, I%): M+ 322 (1.42%). Anal. calcd. for C16H10N4O2S (322.34): C, 59.62; H, 3.13;
N, 17.38; S, 9.95%. Found: C, 59.51; H, 3.37; N, 17.22; S, 9.84%.
General Procedure for Synthesis of Compounds 14 and 15
To a solution of compound 1 (0.5 g, 1.86 mmol), the appropriated ketoester, namely
ethyl acetoacetate and/or ethyl benzoylacetate (1.86 mmol) was added. The reaction mix-
ture was heated for 1 h, then treated with methanol. The precipitate was collected and
recrystallized from methanol.
8-Methyl-3,5-diphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepin-6(5H)-one
(14). Yield 0.56 g (90%); mp 136–138 ◦C; IR (νmax, cm−1): 3071 (CHarom), 2924 (CHaliph),
1
1754 (C O), 1612 (C N); H NMR (δ): 7.78–7.39 (m, 10H, Harom), 5.92 (s, 1H, CH),
2.42 (s, 3H, CH3). Anal. calcd. for C18H14N4OS (334.39): C, 64.65; H, 4.22; N, 16.75; S,
9.59%. Found: C, 64.43; H, 4.35; N, 16.66; S, 9.71%.
3,5,8-Triphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepin-6(5H)-one
(15).
Yield 0.64 g (86%); mp 214–217 ◦C; IR (νmax, cm−1): 3095 (CHarom), 1735 (C O), 1616
1
(C N); H NMR (δ): 7.92–7.54 (m, 16H, Harom + CH). Anal. calcd. for C23H16N4OS
(396.46): C, 69.68; H, 4.07; N, 14.13; S, 8.09%. Found: C, 69.56; H, 4.19; N, 14.33; S,
8.12%.
Synthesis of 3,5-Diphenyl-8-thioxo-8,9-dihydro-5H-1,2,4-triazolo[4,3-b]-
1,2,4-triazepin-6(7H)-one (16)
A mixture of compound 1 (0.55 g, 2.05 mmol) and ethyl cyanoacetate (0.23 mL,
2.05 mmol) in dry pyridine (30 mL) was refluxed for 6 h, cooled and then poured into
ice-cold water. The formed precipitate was collected, filtered, and recrystallized, yield
0.47 g (69%); mp 217–219 ◦C (ethanol); IR (νmax, cm−1): 3146 (NH), 3010 (CHarom), 2947
1
(CHaliph), 1697 (C O), 1176 (C S), 1610 (C N); H NMR (δ): 14.71 (brs, 1H, NH),
7.90–7.55 (m, 10H, Harom), 3.45 (s, 2H, CH2). Anal. calcd. for C17H13N5OS (335.38): C,
60.88; H, 3.91; N, 20.88; S, 9.56%. Found: C, 60.65; H, 3.82; N, 20.63; S, 9.71%.
Synthesis of 3,5-Diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-6,7-
dione-7-(p-tolyl)hydrazone (17)
The freshly prepared p-toluenediazonium chloride [from p-toluidine (0.54 g, 5 mmol)
in conc. HCl (5 mL) and sodium nitrite (0.48 g, 5mmol)] was added slowly over 30 min
with stirring to an equivalent solution of compound 4 (1.54 g, 5 mmol) in a solution of
20% NaOH (2 mL) at 0–5 ◦C. The mixture was kept in an ice bath for 30 min [during this

1480
A. E.-B. A. G. GHATTAS ET AL.
period the pH was maintained at 8–9], and then neutralized by the addition of acetic acid.
The precipitate formed was filtered off and washed with water, recrystallized from ethanol,
◦
yield 0.47 g (69%); mp 218–220 C; IR (νmax, cm−1): 3140 (NH), 3020 (CHarom), 1750
(C O), 1612 (C N); MS (m/z, I%): M+, 426.1 (0.86%). Anal. calcd. for C23H18N6OS
(426.49): C, 64.77; H, 4.25; N, 19.70; S, 7.52%. Found: C, 64.52; H, 4.41; N, 19.87; S,
7.36%.
Synthesis of 3,5-Diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-6
(7H)-thione (18)
A mixture of compound 4 (0.31 g, 1 mmol) and Lawesson’s reagent (0.20 g, 1 mmol)
in xylene (30 mL) was refluxed for 4 h (until all the H2S gas was evolved); the solvent was
evaporated under reduced pressure, the precipitate formed was collected and recrystallized
from ethanol, yield 0.24 g (65%); mp 125–128 ◦C; IR (νmax, cm−1): 3050 (CHarom), 2930
(CHaliph), 1600 (C N), 1147 (C S); MS (m/z, I%): M+ 324.3 (0.02%). Anal. calcd. for
C16H12N4S2 (324.42): C, 59.23; H, 3.73; N, 17.27; S, 19.77%. Found: C, 59.35; H, 3.68;
N, 17.41; S, 19.92%.
Synthesis of 7-Amino-3,5-diphenyl-5H-thieno[3,2-e][1,2,4]triazolo
[3,4-b][1,3,4]thia-diazine-6-carbonitrile (19)
To a stirred solution of compound 4 (1.1 g, 3.57 mmol) in dry dioxane (20 mL),
sulfur (0.11 g, 3.57 mmol) and drops of triethylamine were added. The reaction mixture
was refluxed for 1 h and then malononitrile (0.23 mL, 3.57 mmol) was added. The reaction
mixture was refluxed for 4 h, and after cooling, the solid precipitate was filtered off, washed
with water, and recrystallized from benzene, yield 1.24 g (90%); mp 91–93 ◦C; IR (νmax
,
cm−1): 3328 and 3208 (NH2), 2984 (CHarom), 2202 (C N), 1627 (C N); MS (m/z, I%):
M+ 388.7 (1.35%). Anal. calcd. for C19H12N6S2 (388.4): C, 58.74; H, 3.11; N, 21.63; S,
16.51%. Found: C, 58.51; H, 3.32; N, 21.53; S, 16.46%.
Synthesis of 7-Amino-3,5-diphenyl-9-thioxo-5,9-dihydrothiopyrano[4,3-
e]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine-6-carbonitrile (20)
To a solution of compound 4 (0.308 g, 1 mmol) in ethanol (20 mL), carbon disulfide
(0.38 mL, 5 mmol) and triethylamine (0.5 mL) were added. The reaction mixture was stirred
at room temperature for 2 h, and malononitrile (0.066 g, 1 mmol) and dimethylformamide
(1 mL) were added. The reaction mixture was refluxed for 4 h. After cooling, the reaction
mixture was poured into water and HCl (100:5 v/v), and the solid product was filtered off,
washed with water, and recrystallized from chloroform, yield 1.24 g (90%); mp 90–93 ◦C;
IR (νmax, cm−1): 3316 and 3186 (NH2), 2204 (C N), 1632 (C N); MS (m/z, I%): M+
432.55 (0.67%). Anal. calcd. for C20H12N6S3 (432.54): C, 55.54; H, 2.80; N, 19.43; S,
22.24%. Found: C, 55.38; H, 2.95; N, 19.61; S, 22.13%.
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