Synthesis and biological activities of some novel triazolothiadiazines and Schiff bases derived from 1,2,4-triazole

Article abstract of DOI:10.1080/10426500600976884

3-substituted-4-amino-5-mercapto-1,2,4-triazoles are versatile compounds for constructing various biologically active heterocycles. To find more 1,2,4-triazole derivatives that may possess significant biological activities, we synthesized a number of nove

Full text of DOI:10.1080/10426500600976884

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Synthesis and Biological
Activities of Some Novel
Triazolothiadiazines and Schiff
Bases Derived from 1,2,4-
Triazole
Sannu Zhou a , Lixue Zhang a , Jianyu Jin b , Anjiang
Zhang a , Xinxiang Lei a , Jianshuang Lin a , Jiangwei
He a & Haile Zhang c
a College of Chemistry and Materials Science,
Wenzhou University, Wenzhou, P.R. China
b College of Education, Wenzhou University,
Wenzhou, P.R. China
c Department of Molecular Biology and Chemistry,
Scripps Research Institute, San Diego, California,
USA
Published online: 18 Feb 2007.
To cite this article: Sannu Zhou , Lixue Zhang , Jianyu Jin , Anjiang Zhang , Xinxiang
Lei , Jianshuang Lin , Jiangwei He & Haile Zhang (2007) Synthesis and Biological
Activities of Some Novel Triazolothiadiazines and Schiff Bases Derived from 1,2,4-
Triazole, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:2, 419-432,
DOI: 10.1080/10426500600976884
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Phosphorus, Sulfur, and Silicon, 182:419–432, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600976884
Synthesis and Biological Activities of Some Novel
Triazolothiadiazines and Schiff Bases Derived from
1,2,4-Triazole
Sannu Zhou
Lixue Zhang
College of Chemistry and Materials Science, Wenzhou University,
Wenzhou, P.R. China
Jianyu Jin
College of Education, Wenzhou University, Wenzhou, P.R. China
Anjiang Zhang
Xinxiang Lei
Jianshuang Lin
Jiangwei He
College of Chemistry and Materials Science, Wenzhou University,
Wenzhou, P.R. China
Haile Zhang
Department of Molecular Biology and Chemistry, Scripps Research
Institute, San Diego, California, USA
3-substituted-4-amino-5-mercapto-1,2,4-triazoles are versatile compounds for con-
structing various biologically active heterocycles. To find more 1,2,4-triazole deriva-
tives that may possess significant biological activities, we synthesized a number
of novel 3-(4-ethoxyphenyl)-6-aryl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines and 4-
(arylmethylidene)amino-5-(4-ethoxyphenyl)-3-mercapto-4H-1,2,4-triazoles. All the
title compounds were characterized by elemental analysis and NMR data, and the
compound 5f was investigated with X-ray crystallography (CCDC No. 611639).
The plant-growth regulating effects of those Schiff bases were examined, and they
showed an inhibiting effect on the growth of wheat radicles and radish radicles.
Keywords 1,2,4-triazoles; biological activities; crystal structure; Schiff base; synthesis;
triazolothiadiazines
Received July 7, 2006; accepted August 1, 2006.
We are grateful for financial support from the National Science Foundation of Zhejiang
Province, China (Project No. M203149).
Address correspondence to Lixue Zhang, College of Chemistry and Materials En-
gineering, Wenzhou University, Wenzhou, 325027, P.R. China. E-mail: zhanglixuelz@
sina.com
419

420
S. Zhou et al.
INTRODUCTION
Triazoles and their heterocyclic derivatives represent an interesting
class of compounds possessing a wide spectrum of biological activi-
ties, such as analgesic,1 anthelmintic,2 antitubercular,3 plant-growth
regulating,4 antiviral,5 antifungal6 and anticancer7 activities. In a
previous article, Ye et al. reported the synthesis of some compounds
containing the triazolothiadiazine ring, which possess a moderate pro-
moting effect on the growth of mung bean sprouts.8 In view of these
facts and as a continuation of our research on the synthesis and biolog-
ical properties of triazole derivatives, we have synthesized a series of
4-ethoxyphenyl substituted fused-triazole systems and determined the
plant-growth regulating effects of some title compounds.
RESULTS AND DISCUSSION
In 1H NMR spectra of triazolothiadiazines, the characteristic downfield
signal at δ 13.8 ppm attributed to the N C SH moiety was absent.
A sharp signal at δ 5.8 ppm attributable to the N NH2 group in the
parent triazole was also absent in the cyclized product. In NMR spectra
of the title compounds 5a–5j, the observation of additional resonances
1
assigned to the SCH2 (δ 4.4–4.5 ppm in H NMR spectra and 22.8–
25.8 ppm in 13C NMR spectra) confirmed the ring closure. Concerning
1H NMR and 13C NMR spectra of fluoro-substituted compounds 5e and
5f, it should be noted that the second-order pattern representative of a
substituted phenyl ring was further complicated due to the presence of
couplings with 19F.
In an attempt to prepare ring-closed derivatives 7, we applied a pre-
viously reported procedure9 and treated triazole 4 with the appropri-
ate benzaldehyde, maintaining pH values during the reaction at 5–
6 because the acidity of the reaction medium is crucial, as reported
previously.9 However, with seven differently substituted benzaldehy-
des that we have used to carry out this reaction under the previously
mentioned conditions, we could only obtain open-chain hydrazones 6a–
g. Compounds 6a–g were established unambiguously by 1H NMR and
13C NMR data. In 1H NMR and 13C NMR spectra we observed the peak
of the N CH proton at 9.49–10.15 ppm and the corresponding car-
bon at about 150 ppm, which correspond to the previously mentioned
open-chain structure. A downfield signal appearing at 10.7–11.7 ppm
1
is attributed to the NH C S moiety. A triplet at 1.5 ppm in the H
NMR spectra and the corresponding carbon at about 14 ppm 13C NMR
spectra are attributable to the CH3 group. A quartet at 4.1 ppm in
1
the H NMR spectra and the corresponding carbon at about 63 ppm
13C NMR spectra are attributable to the OCH2 group. The remaining
protons resonated as multiplets in the aromatic region δ 7.0–7.9 ppm.

Some Novel Triazolothiadiazines and Schiff Bases
421
TABLE I Effect of the Title Compounds on Wheat- and
Radish-Radicles Growth
Growth Promotion on
Wheat Radicles (%)
Growth Promotion on
Radish Radicles (%)
Compound
5 ppm
1 ppm
5 ppm
1 ppm
6a
6b
6c
6d
6e
6f
−60.1
−49.8
−100
−90.5
−87.9
−83.2
−82.6
−59.2
−60.2
−80.0
−84.0
−73.9
−79.0
−77.1
−43.1
−12.3
−100
−87.7
−81.5
−74.5
−75.4
−41.0
−38.5
−63.6
−66.7
−50.0
−63.6
−63.6
6g
The effect of the title compounds 6a–g on sprouting wheat and radish
seeds was been investigated. After treating with a culture solution of
5 μg/mL of the title compounds 6a–g for 36 h, the lengths of wheat
radicles (“radicle” refers to the part of a plant embryo that develops
into a root) were measured with reference of distilled water, then the
growth-promoting percentages were calculated. Using same method,
the percentage concentration of 1 μg/mL and corresponding values on
radish radicles were also obtained. The results are shown in Table I.
The results indicate that newly syhthesized compounds 6a–g show an
inhibiting effect on the growth of wheat and radish radicles at a mass
concentration of 5 μg/mL and 1 μg/mL, and therefore the structures
need to be optimized.
EXPERIMENTAL
All melting points were determined on an XT-4A apparatus and are
1
uncorrected. The H NMR and 13C NMR spectra were measured on
a Bruker Advance 300 spectrometer in DMSO-d6 or CDCl3 solutions
using TMS as an internal reference. Elemental analyses were carried
out with an EA 1112 elemental analyzer. The crystal structure was
measured on a Bruker APEX area-detector diffractometer. All reagents
used were analytical reagents.
Ethyl 4-ethoxybenzoate 1 (50 mL) and 85% hydrazine hydrate
(25 mL) were converted first to the corresponding hydrazide 2. Hy-
drazide 2 (0.1 mol) was heated with carbon disulfide (10 mL) in the
presence of absolute ethanol (100 mL) and potassium hydroxide (10 g) to
afford intermediate potassium acylhydrazine dithioformate
3
(Scheme 1). This salt (0.05 mol) underwent ring closure with an
excess of 85% hydrazine hydrate (0.16 mol) to give 4-amino-3-(4-
ethoxyphenyl)-5-mercapto-1,2,4-triazole 4. Heating at reflux triazole

422
S. Zhou et al.
SCHEME 1 (a) NH2NH2H2O 85%; (b) CS2, EtOH, KOH, reflux;
(c) NH2NH2H2O 85%, reflux; (d) R1COCH2X (X Br, Cl), EtOH, reflux;
(e) R2CHO, EtOH, pH = 5–6, reflux.
4 (1 mmol) with absolute ethanol (1 5 mL) and the appropriate
substituted phenacyl bromide (or chloride) (1 mmol) provided the
3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 5a–j.
Purified product 5f was dissolved in 95% ethanol and kept at r.t. for
5 d, and single crystals of 5f were formed. The structure of 5f is shown
in Figure 1. Fractional coordinates and mean temperature factors with
estimated standard deviations for non–hydrogen atoms are listed in
Table II and selected bond angles are given in Table III. Geometric
calculations were performed using the program SHELXL-97.
The reaction of triazole 4 and the appropriate benzaldehyde in abso-
lute ethanol maintaining pH values during the reaction at 5–6 afforded
Schiff bases 6a–g.
5a: 6-(4-Chlorophenyl)-3-(4-ethoxyphenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
To a solution of compound 4 (236 mg, 1 mmol) in absolute C2H5OH
(20 mL) was added 2-bromo-4ꢀ-chloroacetophenone (233 mg, 1 mmol).

Some Novel Triazolothiadiazines and Schiff Bases
423
FIGURE 1 An ORTEP drawing of compound 5f showing the atom numbering
scheme.
The mixture was refluxed for 7 h. The solid obtained on cooling was fil-
tered, washed with cold water, dried, and recrystallized from C2H5OH
1
to give the title compound (yield: 73.0%). M.p. 215–217◦C; H NMR
(300 MHz, DMSO-d6, 25◦C, TMS) δ (ppm) = 7.97 (dd, J= 8.6Hz, 4H,
ArH), 7.38 (dd, J= 8.9Hz, 4H, ArH), 4.41 (s, 2H, SCH2), 4.11 (q,
J= 6.9Hz, 2H, OCH2), 1.36 (t, J= 6.9Hz, 3H, CH3); 13C NMR (DMSO-
d6) δ (ppm) = 160.26, 155.00, 151.76, 142.06, 136.94, 132.61, 129.71,
129.52, 129.41, 118.31, 114.87, 63.54, 22.85, 14.76; elemental anal.
calcd. (%) for C18H15ClN4OS(370.9): C 58.30, H 4.08, N 15.11, S 8.65;
found: C 58.50, H 4.16, N 15.00, S 8.59.
The following compounds were prepared by an analogous procedure.
5b: 3-(4-Ethoxyphenyl)-6-phenyl-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
Yield: 68.3%; m.p. 189–191◦C; 1H NMR (300 MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 8.00 (d, J= 8.6Hz, 2H, ArH), 7.62–7.55 (m, 5H, ArH),
7.14 (q, J= 2.7Hz, 2H, ArH), 4.44 (s, 2H, SCH2), 4.13 (q, J= 6.9Hz,

424
S. Zhou et al.
TABLE II Crystal Data and Summary of Data Collection and
Structure Refinement
Compound
Color
C18H13F2N4O S
Yellow
Formula weight
Crystal system
317.38
Triclinic
25(298K)
Temperature, ◦
Cell constants
C
˚
a (A)
9.243(3)
10.332(3)
10.807(3)
70.109(5)
66.434(4)
69.239(5)
860.5(4)
˚
b (A)
˚
c (A)
˚
α (A)
˚
β (A)
˚
γ (A)
Volume (A )
3
˚
Formula units
Calculated density (g/cm−3
F(000)
2
)
1.433
382
0.223
Absorption coefficient, μm−3
Limiting indices
−10 ≤ h ≤ 10; −12 ≤ k ≤ 12; −12 ≤ l ≤ 12
4544/2997 [R(int) = 0.0114]
Semi-empirical from equivalents
0.9425 and 0.9101
Full-matrix least-squares on F2
2997/0/239
Reflections collected/unique
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness of fit on F2
1.027
Final R indices
Largest diff. peak and hole (e A
R1 = 0.0483, wR2 = 0.1247
−3
˚
)
0.434 and −0.327
2H, OCH2), 1.34 (t, J= 6.9Hz, 3H, CH3); 13C NMR (DMSO-d6) δ
(ppm) = 160.03, 155.94, 134.02, 132.01, 129.59, 129.26, 127.66, 127.54,
118.01, 114.90, 114.81, 63.46, 22.89, 14.72; elemental anal. calcd. (%)
for C18H16N4OS(336.4): C 64.26, H 4.79, N 16.65, S 9.53; found: C 64.06,
H 4.58, N 16.41, S 9.42.
5c: 3-(4-Ethoxyphenyl)-6-(4-methoxyphenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
Yield: 69.1%; m.p. 201–202◦C; 1H NMR (300 MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 8.00–7.95 (m, 4H, ArH), 7.13–7.10 (m, 4H, ArH), 4.39
(s, 2H, SCH2), 4.11 (q, J= 6.9Hz, 2H, OCH2), 3.85 (s, 3H, OCH3), 1.35
(t, J= 6.9Hz, 3H, CH3); 13C NMR (DMSO-d6) = 162.24, 159.94, 155.27,
151.28, 141.91, 129.37, 125.58, 118.36, 114.59, 114.55, 114.13, 63.29,
55.55, 22.48, 14.58; elemental anal. calcd. (%) for C19H18N4O2S (366.4):

Some Novel Triazolothiadiazines and Schiff Bases
425
TABLE III Fractional Coordinates and Mean
Temperature Factors with Estimated Standard
Deviations for Non–hydrogen Atoms
x
y
z
U(eq)
S(1)
F(1)
F(2)
10990(1)
1443(2)
6666(3)
5597(7)
7739(2)
8394(2)
10042(2)
12612(2)
12202(2)
3054(3)
4061(3)
5683(3)
6308(2)
5206(3)
3568(3)
8060(2)
9321(3)
11304(3)
10664(2)
9803(2)
8306(3)
7565(3)
8330(2)
9832(3)
10555(3)
6131(3)
5747(4)
8856(1)
9958(2)
7444(2)
10078(7)
4970(2)
8096(2)
7697(2)
7760(2)
7212(2)
9566(3)
8684(3)
8316(2)
8793(2)
9692(2)
10101(3)
8316(2)
8099(2)
8048(2)
7195(2)
6665(2)
6362(2)
5830(2)
5554(2)
5849(3)
6388(3)
4754(3)
4179(3)
1574(1)
5028(2)
5033(2)
933(6)
64(1)
116(1)
85(1)
85(1)
64(1)
48(1)
47(1)
64(1)
61(1)
76(1)
74(1)
60(1)
50(1)
61(1)
75(1)
47(1)
59(1)
54(1)
48(1)
47(1)
57(1)
58(1)
52(1)
62(1)
60(1)
64(1)
90(1)
F(2ꢀ)
O(1)
N(1)
N(2)
N(3)
N(4)
C(1)
−3153(2)
961(2)
227(2)
−734(2)
−1528(2)
4330(3)
5056(3)
4331(2)
2903(2)
2207(2)
2920(3)
2156(2)
2798(2)
292(2)
−960(2)
−1481(2)
−724(2)
−1252(2)
−2559(2)
−3333(2)
−2804(2)
−2442(3)
−3337(3)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
C 62.28, H 4.95, N 15.29, S 8.75; found: C 62.09, H 4.77, N 15.01,
S 8.69.
5d: 6-(2,4-Dichlorophenyl)-3-(4-ethoxyphenyl)-1,2,4-
triazolo[3,4-b][1,3,4]thiadiazine
Yield: 69.0%; m.p. 187–189◦C; 1H NMR (300 MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 7.98–7.74 (m, 5H, ArH), 7.13 (d, 2H, ArH), 4.30 (s,
2H, SCH2), 4.11 (q, J= 6.9Hz, 2H, OCH2), 1.35 (t, J= 6.9Hz, 3H,
CH3); 13C NMR (DMSO-d6) = 160.73, 159.90, 132.47, 131.66, 130.21,
129.95, 129.62, 129.52, 128.20, 127.73, 114.78, 114.62, 114.51, 63.44,
25.79, 14.68; elemental anal. calcd. (%) for C18H14Cl2N4OS(405.3):

426
S. Zhou et al.
˚
TABLE IV Selected Bond Lengths (A)
S(1)
S(1)
F(1)
F(2)
C(9)
C(8)
C(1)
C(3)
C(5)
C(14)
C(17)
C(7)
N(2)
C(9)
C(10)
C(9)
N(4)
C(10)
C(2)
C(6)
C(3)
C(4)
C(5)
C(7)
C(6)
C(8)
H(8B)
C(11)
C(12)
C(16)
C(13)
C(14)
C(15)
C(16)
C(18)
1.730(2)
1.807(2)
1.354(3)
1.311(3)
1.232(6)
1.360(2)
1.434(3)
1.282(2)
1.389(2)
1.371(3)
1.378(3)
1.295(3)
1.394(3)
1.308(3)
1.345(4)
1.373(4)
1.366(3)
1.390(3)
1.390(3)
1.475(3)
1.378(3)
1.499(3)
0.9700
F(2ꢀ)
O(1)
O(1)
N(1)
N(1)
N(2)
N(2)
N(3)
N(3)
N(4)
C(1)
C(1)
C(2)
C(3)
C(4)
C(4)
C(5)
C(7)
C(8)
C(10)
C(11)
C(11)
C(12)
C(13)
C(14)
C(15)
C(17)
1.459(3)
1.382(3)
1.397(3)
1.374(3)
1.382(3)
1.385(3)
1.367(3)
1.493(3)
C 53.34, H 3.48, N 13.82, S 7.91; found: C 53.21, H 3.29, N 13.94,
S 7.85.
5e: 3-(4-Ethoxyphenyl)-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
Yield: 72.0%; m.p. 215–217◦C; 1H NMR (300 MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 7.98–7.93 (m, 4H, ArH), 7.13–7.04 (m, 4H, ArH), 4.42 (s,
2H, SCH2), 4.10 (q, J= 6.9Hz, 2H, OCH2), 1.36 (t, J= 6.9Hz, 3H, CH3);
13C NMR (DMSO-d6) = 166.73, 159.89, 149.21, 130.37, 130.26, 129.69,

Some Novel Triazolothiadiazines and Schiff Bases
427
TABLE V Selected Bond Angles (◦)
C(9)
C(14)
C(7)
C(9)
C(9)
C(10)
C(9)
C(10)
C(2)
C(2)
F(1)
S(1)
O(1)
N(1)
N(2)
N(2)
N(2)
N(3)
N(4)
C(1)
C(8)
C(17)
N(2)
C(10)
N(1)
N(1)
N(4)
N(3)
F(1)
94.59(10)
118.13(16)
115.91(16)
105.37(16)
127.62(17)
125.05(16)
106.54(17)
108.90(17)
118.2(3)
C(1)
C(1)
C(6)
C(6)
123.8(2)
118.1(3)
C(1)
F(2)
C(2)
C(3)
C(3)
C(2)
117.1(2)
117.3(2)
F(2)
C(3)
C(4)
119.6(2)
C(2)
C(5)
C(5)
C(3)
F(2ꢀ)
F(2ꢀ)
C(6)
C(1)
N(1)
N(1)
C(4)
C(7)
N(3)
N(3)
N(2)
N(4)
N(4)
N(2)
C(12)
C(12)
C(16)
C(13)
C(12)
O(1)
O(1)
C(13)
C(16)
C(15)
O(1)
C(3)
C(4)
C(4)
C(4)
C(5)
C(5)
C(5)
C(6)
C(7)
C(7)
C(7)
C(8)
C(9)
C(9)
C(9)
C(10)
C(10)
C(10)
C(11)
C(11)
C(11)
C(12)
C(13)
C(14)
C(14)
C(14)
C(15)
C(16)
C(17)
C(4)
C(3)
C(7)
C(7)
C(6)
C(4)
C(4)
C(5)
C(4)
C(8)
C(8)
S(1)
N(2)
S(1)
S(1)
N(2)
C(11)
C(11)
C(16)
C(10)
C(10)
C(11)
C(14)
C(13)
C(15)
C(15)
C(14)
C(11)
C(18)
123.0(2)
117.2(2)
121.67(18)
121.08(19)
116.1(4)
122.8(3)
120.8(2)
118.1(2)
115.47(17)
124.01(18)
120.52(17)
111.71(15)
110.76(19)
128.83(16)
120.31(16)
108.40(17)
124.82(18)
126.72(17)
117.37(19)
124.04(17)
118.54(18)
121.72(19)
120.19(19)
124.91(19)
116.16(17)
118.91(19)
120.52(19)
121.27(19)
107.5(2)
129.60, 129.51, 117.83, 116.51, 116.22, 114.80, 114.50, 114.47, 109.46,
63.46, 22.82, 14.65; elemental anal. calcd. (%) for C18H15FN4OS(354.4):
C 61.00, H 4.27, N 15.81, S 9.05; found: C 61.21, H 4.21, N 15.94,
S 8.95.

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S. Zhou et al.
5f: 3-(4-Ethoxyphenyl)-6-(2,4-difluorophenyl)-1,2,4-
triazolo[3,4-b][1,3,4]thiadiazine
Yield: 68.7%; m.p. 190–191◦C; 1H NMR (300MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 7.94–7.86 (m, 3H, ArH), 7.58–7.53 (m, 1H, ArH), 7.30–
7.28 (m, 1H, ArH), 7.09–7.06 (m, 2H, ArH), 4.33 (d, 2H, SCH2), 4.08
(q, J= 6.9Hz, 2H, OCH2), 1.34 (t, J= 6.9Hz, 3H, CH3); 13C NMR
(DMSO-d6) = 165.91, 165.74, 162.57, 162.40, 160.07, 159.19, 159.02,
152.79, 152.76, 151.51, 141.84, 132.16, 132.12, 132.03, 131.98, 129.42,
119.64, 119.59, 119.49, 119.44, 118.00, 114.58, 112.79, 112.75, 112.50,
112.46, 105.68, 105.34, 104.99, 63.29, 24.86, 24.78, 14.55; elemental
anal. calcd. (%) for C18H14F2N4OS(372.4): C 58.06, H 3.79, N 15.05, S
8.61; found: C 58.13, H 3.86, N 15.12, S 8.51.
5g: 6-(4-Bromophenyl)-3-(4-ethoxyphenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
Yield: 72.6%; m.p. 230–232◦C; 1H NMR (300MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 8.03–7.91 (m, 4H, ArH), 7.79 (d, J= 8.6Hz, 2H,
ArH), 7.11 (d, J= 8.8Hz, 2H, ArH), 4.41 (s, 2H, SCH2), 4.12 (q,
J= 6.9Hz, 2H, OCH2), 1.35 (t, J= 6.9Hz, 3H, CH3); 13C NMR (DMSO-
d6) = 160.19, 155.04, 151.67, 141.97, 132.93, 132.28, 129.61, 129.53,
125.81, 118.28, 114.81, 63.46, 22.74, 14.71; elemental anal, calcd. (%)
for C18H15BrN4OS(415.3): C 52.06, H 3.64, N 13.49, S 7.72; found: C
52.19, H 3.52, N 13.56, S 7.65.
5h: 3-(4-Ethoxyphenyl)-6-(4-nitrophenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
Yield: 67.6%; m.p. 239–241◦C; 1H NMR (300MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 8.33 (dd, J= 7.4Hz, 4H, ArH), 7.94 (d, J= 7.0Hz,
2H, ArH), 7.14–7.11 (m, 2H, ArH), 4.50 (s, 2H, SCH2), 4.11 (q, J =
6.9Hz, 2H, OCH2), 1.25 (t, J= 6.9Hz, 3H, CH3); 13C NMR (DMSO-
d6) = 160.29, 154.27, 151.87, 149.28, 141.92, 139.64, 129.72, 129.07,
124.25, 118.10, 114.87, 63.49, 23.00, 14.71; elemental anal. calcd. (%) for
C18H15N5O3S(381.4): C 56.68, H 3.96, N 18.36, S 8.41; found: C 56.59,
H 3.88, N 18.31, S 8.22.
5i: 3-(4-Ethoxyphenyl)-6-(4-methylphenyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
Yield: 66.9%; m.p. 225–226◦C; 1H NMR (300 MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 7.93 (dd, J= 8.8Hz, 4H, ArH), 7.38 (d, J= 8.1Hz,

Some Novel Triazolothiadiazines and Schiff Bases
429
2H, ArH), 7.11 (d, J= 8.8Hz, 2H, ArH), 4.40 (s, 1H, SCH2), 4.12 (q,
J= 6.9Hz, 2H, OCH2), 2.40 (s, 3H, ArCH3), 1.36 (t, J= 6.9Hz, 3H, CH3);
13C NMR (DMSO-d6) δ: 160.14, 155.81, 151.55, 142.28, 142.07, 130.88,
129.83, 129.55, 127.61, 118.44, 114.78, 63.46, 22.77, 21.17, 14.71; ele-
mental anal. calcd. (%) for C19H18N4OS(350.4): C 65.12, H 5.18, N 15.99,
S 9.15; found: C 65.01, H 5.09, N 15.94, S 8.99.
5j: 3-(4-Ethoxyphenyl)-6-(4-biphenylyl)-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine
Yield: 73.9%; m.p. 196–197◦C; 1H NMR (300MHz, DMSO-d6, 25◦C,
TMS) δ (ppm) = 8.09 (d, J= 8.3Hz, 2H, ArH), 7.97 (d, J= 8.8Hz, 2H,
ArH), 7.88 (d, J= 8.3Hz, 4H, ArH), 7.77 (d, J= 8.8Hz, 2H, ArH), 7.51
(t, J= 7.2Hz, 2H, ArH), 7.43 (t, J= 7.2Hz, 1H, ArH), 7.11 (d, J= 8.8Hz,
2H, ArH), 4.46 (s, 1H, SCH2), 4.12 (q, J= 6.9Hz, 2H, OCH2), 1.36 (t,
J= 6.9Hz, 3H, CH3); 13C NMR (DMSO-d6) δ: 160.01, 155.38, 151.48,
143.28, 141.99, 138.77, 132.39, 129.47, 129.10, 128.33, 128.17, 127.23,
126.86, 118.22, 114.63, 63.30, 22.63, 14.59; elemental anal. calcd. (%)
for C24H20N4OS(412.5): C 69.88, H 4.89, N 13.58, S 7.77; found: C 69.76,
H 4.78, N 13.49, S 7.65.
6a: 4-(Benzylidene)amino-5-(4-ethoxyphenyl)-3-mercapto-4H-
1,2,4-triazole
Benzaldehyde (117 mg, 1.1 mmol) was added to a solution of 4-amino-
5-(4-ethoxyphenyl)-3-mercapto-1,2,4-triazole (4, 236 mg, 1 mmol) in
ethanol (10 mL). The pH value then was adjusted to 5–6 with diluted
HCl, and the mixture was heated at 90◦C for 6 h and allowed to stand
overnight. The precipitate was filtered, washed with 5% NaHCO3 so-
lution and water, and air-dried. The crude product then was recrys-
tallized from acetone and distilled water (9:1, volume) to yield pure
1
6a as a light yellow product (yield: 67.6%). M.p. 184–186◦C; H NMR
(300 MHz, CDCl3, 25◦C, TMS) δ (ppm = 1.46 (t, J= 7.0Hz, 3H, CH3),
4.11 (q, J= 7.0Hz, 2H, OCH2), 7.01–7.00 (m, 2H, ArH), 7.58–7.49 (m,
3H, ArH), 7.93–7.90 (m, 4H, ArH), 10.09 (s, 1H, CH N), 11.10 (s, 1H,
NH C S); 13C NMR (CDCl3) δ: 14.40, 63.37, 114.25, 117.16, 128.69,
128.72, 130.01, 132.08, 132.31, 149.81, 160.72, 162.55, 163.66; elemen-
tal anal. calcd. (%) for C17H16N4OS(324.4): C 62.94, H 4.97, N 17.27, S
9.88; found: C 62.86, H 4.81, N 17.13, S 9.78. The following compounds
were prepared by an analogous procedure.

430
S. Zhou et al.
6b: 5-(4-Ethoxyphenyl)-4-(4-methylbenzylidene)amino-3-
mercapto-4H-1,2,4-triazole
1
Yield: 62.1% m.p. 196–198◦C; H NMR (300 MHz, CDCl3, 25◦C, TMS)
δ (ppm) = 1.46 (t, J= 7.0Hz, 3H, CH3), 2.45 (s, 3H, ArCH3), 4.11 (q,
J= 7.0Hz, 2H, OCH2), 6.98 (d, J= 8.9Hz, 2H, ArH), 7.30 (d, J= 7.9Hz,
2H, ArH), 7.80 (d, J= 7.9Hz, 2H, ArH), 7.91 (d, J= 8.9Hz, 2H, ArH),
9.93 (s, 1H, CH N), 11.74 (s, 1H, NH C S); 13C NMR (CDCl3) δ:
14.41, 21.47, 63.35, 114.22, 117.26, 128.74, 129.32, 129.46, 129.97,
143.12, 149.63, 160.64, 162.27, 164.25; elemental anal. calcd (%) for
C18H18N4OS(338.4): C 63.88, H 5.36, N 16.56, S 9.47; found: C 63.79,
H 5.25, N 16.46, S 9.39.
6c: 5-(4-Ethoxyphenyl)-4-(4-methoxybenzylidene)amino-3-
mercapto-4H-1,2,4-triazole
Yield: 69.0%; m.p. 174–176◦C; 1H NMR (300 MHz, CDCl3, 25◦C, TMS)
δ (ppm = 1.48 (t, J= 7.0Hz, 3H, CH3), 3.93 (s, 3H, OCH3), 4.11 (q,
J= 7.0Hz, 2H, OCH2), 6.96–7.04 (m, 4H, ArH), 7.85–8.09 (m, 4H,
ArH), 9.81 (s, 1H, CH N), 11.48 (s, 1H, NH C S); 13C NMR (CDCl3)
δ: 14.39, 55.21, 63.35, 114.02, 114.23, 124.58, 129.45, 129.93, 130.64,
131.69, 149.62, 160.67, 163.09, 164.03; elemental anal. calcd. (%) for
C18H18N4O2S(354.4): C 61.00, H 5.12, N 15.81, S 9.05; found: C 60.95,
H 5.01, N 15.84, S 8.91.
6d: 5-(4-Ethoxyphenyl)-4-(4-N,N-dimethyl)benzylidene)amino-
3-mercapto-4H-1,2,4-triazole
Yield: 70.4%; m.p. 174–176◦C; 1H NMR (300 MHz, CDCl3, 25◦C, TMS)
δ (ppm) = 1.45 (t, J= 6.9Hz, 3H, CH3), 3.09 (d, J= 8.4Hz, 6H, NCH3),
4.11 (q, J= 6.9Hz, 2H, OCH2), 6.83 (d, J= 8.7Hz, 2H, ArH), 6.96 (d,
J= 8.8Hz, 2H, ArH), 7.80 (d, J= 8.8Hz, 2H, ArH), 7.93 (d, J= 8.7Hz,
2H, ArH), 9.49 (s, 1H, CH N), 11.47 (s, 1H, NH C S); 13C NMR
(CDCl3) δ: 14.40, 40.31, 63.31, 112.08, 112.11, 114.18, 117.46, 120.27,
129.86, 130.64, 149.46, 152.48, 160.55, 165.33; elemental anal. calcd.
(%) for C19H21N5OS(367.5): C 62.10, H 5.76, N 19.06, S 8.73; found: C
61.91, H 5.69, N 18.95, S 8.62.
6e: 4-(4-Chlorobenzylidene)amino-5-(4-ethoxyphenyl)-3-
mercapto-4H-1,2,4-triazole
Yield: 68.8%; m.p. 174–176◦C; 1H NMR (300 MHz, CDCl3, 25◦C, TMS) δ
(ppm) = 1.46 (t, J= 7.0Hz, 3H, CH3), 4.11 (q, J= 7.0Hz, 2H, OCH2), 6.94

Some Novel Triazolothiadiazines and Schiff Bases
431
(d, J= 8.7Hz, 2H, ArH), 7.48 (d, J= 8.8Hz, 2H, ArH), 7.79 (d, J= 8.8Hz,
2H, ArH), 7.86 (d, J= 8.7Hz, 2H, ArH), 10.13(s, 1H, CH N), 11.73 (s,
1H, NH C S); 13C NMR (CDCl3) δ: 14.21, 63.20, 114.07, 116.86, 128.92,
129.48, 129.59, 129.83, 130.40, 138.33 149.65, 160.56, 161.73; elemental
anal. calcd. (%) for C17H15ClN4OS(358.9): C 56.90, H 4.21, N 15.61, S
8.94; found: C 56.96, H 4.11, N 15.54, S 8.81.
6f: 5-(4-Ethoxyphenyl)-4-(2-hydroxybenzylidene)amino-
3-mercapto-4H-1,2,4-triazole
Yield: 64.6%; m.p. 174–176◦C; 1H NMR (300 MHz, CDCl3, 25◦C, TMS)
δ (ppm) = 1.46 (t, J= 7.0Hz, 3H, CH3), 4.11 (q, J= 7.0Hz, 2H, OCH2),
7.00–7.06 (m, 4H, ArH), 7.45–7.49 (m, 2H, ArH), 7.49–7.74 (m, 2H,
ArH), 10.13 (s, 1H, OH), 10.15 (s, 1H, CH N), 10.74 (s, 1H, NH C S);
13C NMR (CDCl3) δ: 14.17, 63.24, 114.46, 115.57, 116.14, 117.14, 119.61,
129.53, 133.10, 134.22, 149.61, 159.37, 160.89, 163.10, 166.63; elemen-
tal anal. calcd. (%) for C17H16N4O2S (340.4): C 59.98, H 4.74, N 16.46,
S 9.42; found: C 60.06, H 4.56, N 16.38, S 9.32.
6g: 5-(4-Ethoxyphenyl)-4-(2-furanylidene)amino-3-mercapto-
4H-1,2,4-triazole
Yield: 67.3%; m.p. 194–196◦C; 1H NMR (300 MHz, CDCl3, 25◦C, TMS)
δ (ppm) = 1.46 (t, J= 7.0Hz, 3H, CH3), 4.11 (q, J= 7.0Hz, 2H, OCH2),
6.64–6.66 (m, 1H, furanyl-H), 6.97–7.00 (m, 2H, ArH), 7.12 (d, 1H,
furanyl-H), 7.71 (s, 1H, furanyl-H), 7.92–7.95 (m, 2H, ArH), 10.01 (s,
1H, CH N), 11.29 (s, 1H, NH C S); 13C NMR (CDCl3) δ: 14.20, 63.16,
112.14, 114.09, 116.90, 118.46, 129.82, 146.55, 147.41, 149.53, 151.03,
160.55, 162.19; elemental anal. calcd. (%) for C15H14N4O2S(314.4): C
57.31, H 4.49, N 17.82, S 10.20; found: C 57.42, H 4.56, N 17.69, S 10.11.
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