Synthesis and antibacterial activity of bisthioether derivatives containing a 1,3,4-thiadiazoles moiety

Article abstract of DOI:10.1080/10426507.2013.798789

A series of bisthioether derivatives containing 1,3,4-thiadiazole moieties were designed and synthesized. All of the synthesized compounds were confirmed by ¹H-NMR, ¹³C-NMR, IR, and elemental analysis. The antibacterial activities of bisthioether derivatives against Ralstonia solanacearum were evaluated in vivo; the results indicated that the synthesized compounds showed good antibacterial activity against R. solanacearum at 200 mg/L. In particular, the activity of compound 3m was up to 73% at 100 mg/L. 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:10.1080/10426507.2013.798789

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Synthesis and Antibacterial Activity of
Bisthioether Derivatives Containing a
1,3,4-Thiadiazoles Moiety
Xuehai Chen a , Juan Yin a , Pei Li a , Ming He a , Linhong Jin a , Jian
Wu a , Song Yang a & Deyu Hu a
a State Key Laboratory Breeding Base of Green Pesticide and
Agricultural Bioengineering/Key Laboratory of Green Pesticide
and Agricultural Bioengineering, Ministry of Education , Guizhou
University , Guiyang , P.R. China
Accepted author version posted online: 26 Jul 2013.Published
online: 03 Dec 2013.
To cite this article: Xuehai Chen , Juan Yin , Pei Li , Ming He , Linhong Jin , Jian Wu , Song Yang &
Deyu Hu (2014) Synthesis and Antibacterial Activity of Bisthioether Derivatives Containing a 1,3,4-
Thiadiazoles Moiety, Phosphorus, Sulfur, and Silicon and the Related Elements, 189:1, 134-142, DOI:
10.1080/10426507.2013.798789
To link to this article: http://dx.doi.org/10.1080/10426507.2013.798789
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Phosphorus, Sulfur, and Silicon, 189:134–142, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.798789
SYNTHESIS AND ANTIBACTERIAL ACTIVITY
OF BISTHIOETHER DERIVATIVES CONTAINING
A 1,3,4-THIADIAZOLES MOIETY
Xuehai Chen, Juan Yin, Pei Li, Ming He, Linhong Jin,
Jian Wu, Song Yang, and Deyu Hu
State Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering/Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Guiyang, P.R. China
GRAPHICAL ABSTRACT
Abstract A series of bisthioether derivatives containing 1,3,4-thiadiazole moieties were
designed and synthesized. All of the synthesized compounds were confirmed by 1H-NMR,
13C-NMR, IR, and elemental analysis. The antibacterial activities of bisthioether derivatives
against Ralstonia solanacearum were evaluated in vivo; the results indicated that the synthe-
sized compounds showed good antibacterial activity against R. solanacearum at 200 mg/L. In
particular, the activity of compound 3m was up to 73% at 100 mg/L.
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 Bisthioether compounds; 1,3,4-thiadiazoles moiety; synthesis; tobacco bacterial
wilt; antibacterial activity
INTRODUCTION
Tobacco bacterial wilt, one of the primary diseases affecting tobacco production, is
caused by Ralstonia solanacearum and is mainly spread through soil. Biological control of
tobacco bacterial wilt is a promising approach. The result of numerous experiments showed
that the biological control of tobacco disease can be greatly achieved in the laboratory;
however, due to environment factors, biological control of the disease in the field is not
Received 17 February 2013; accepted 20 April 2013.
This work was supported by the National Key Project for Basic Research (Grant No. 2010CB126105), the
National Key Technologies R&D Program of China (Grant No. 2011BAE06B05-6), and the Special Fund for
Agro-Scientific Research in the Public Interest (Grant No. 201203022).
Address correspondence to Professor Deyu Hu, State Key Laboratory Breeding Base of Green Pesticide
and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry
of Education, Guizhou University, Huaxi street, Guiyang 550025, P.R. China. E-mail: fcc.dyhu@gzu.edu.cn
134

BISTHIOETHER DERIVATIVES
135
as comparable. Controlling the disease requires continued pesticide use, but those utilized
are mainly based on traditional organic pesticides, antibiotics, and copper compounds. The
application of traditional organic pesticides is moderately effective, but high residue level
and, consequently, negative environmental impact occur. Although antibiotics are highly
efficient in tobacco bacterial wilt control, the emergence of resistant strains and the ban
of using antibiotics in China and other countries complicate the management of the plant
disease. Copper formulation, a commercial bactericide, is a type of inorganic pesticide that
can enhance resistance of the host tobacco plant. Despite being useful in the treatment of
plants affected by tobacco bacterial wilt, the use of copper formulation for field trials is
largely limited by its phytotoxicity, strong alkalinity, and low mobility. Extensive research
has been conducted to combat tobacco bacterial wilt, the most common methods being
biological and chemical control. The chemical control method plays an important role in
disease prevention because of its simple operation and economic advantages. Thus, the
development of efficient, environmentally friendly antibacterial agents through chemical
synthesis has become the core area of research for the eradication and/or prevention of
tobacco bacterial wilt.1
1,3,4-Thiadiazoles derivatives have a wide range of biological activity in pesti-
cides, including antibacterial,2 antituberculosis,3 antiviral,4 antifungal,5 anticancer,6 anti-
inflammatory,7 and antiulcer properties.8 One example of these derivatives is the 3-(5-
nitrofuran-2-yl)-N-phenyl1,2,4 triazolo[3,4-b][1, 3, 4]thiadiazol-6-amine prepared by Badr
and Barwa .9 This compound exhibits good antibacterial activity against Staphylococcus au-
reus, with the minimum inhibitory concentration of 25 μg/mL. Moreover, the N2,N4- bis(4-
chlorophenyl)-6-((5-((3,5-dimethyl-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)amino)-1, 3, 4-
thiadiazol-2-yl)thio)-1, 3, 5-triazine-2, 4-diamine reported by Dubey et al.10 exhibits strong
activity against Pseudomonas aeruginosa and Bacillus cereus, with the minimum inhibitory
concentrations of 6.25 and 12.5 μg/mL, respectively. In the past decades, a large number
of pesticides with potent bioactivities and containing 1,3,4-thiadiazoles such as fluthi-
amide,11 fluthiacet-methyl12 (Figure 1), bismerthiazol,13 and thiodiazole-copper14 have be-
come commercial agents and have been widely used to control plant disease (Figure 1).
Figure 1 The commercialized pesticides of 1,3,4-thidiazole and thioether derivatives.

136
X. CHEN ET AL.
With the increasing applications mentioned above, research on the synthesis and bioac-
tivity of 1,3,4-thiadiazoles derivatives has attracted growing attention from chemists and
biologists in recent years.
Certain thioethers prepared by different groups have often displayed other inter-
esting bioactivities, e.g., antibacterial,15 antifungal,16 antiviral,17 and antitumor18,19 prop-
erties. Some representative examples of these derivatives are commercialized as pesti-
cides. Allicin, Diphenprophos, and DPX-PE350 are known for their ability to protect
certain plants from severe diseases and pests (Figure 1). In our previous work,20 a series
of 2-substituted methylthio-5(2,4-dichlorophenyl)-1,3,4-thiadiazole were synthesized and
evaluated for their antifungal activities, the results showed that these compounds exhibit
moderate to good antifungal activity against Rhizoctonia solani.
To create efficient, environment friendly agents, we synthesized a series of bist-
hioether derivatives containing a 1,3,4-thidiazole moiety and evaluated them for antibacte-
rial activity against R. solanacearum. Using the turbidity method and with R. solanacearum
and P. solanacearum (Pseuclomonas solanacearum) as the test object, we conducted pre-
liminary antibacterial activity testing on the synthesized compounds. The results showed
that some compounds exhibited in vitro antibacterial activity against R. solanacearum
at 200 mg/L. Among these compounds, 3e, 3h, 3i, 3j, 3k, and 3m showed better activ-
ity than the rest, especially 3k and 3m, with antibacterial activities of 81% and 88% at
200 mg/L, respectively. In addition, 3j and 3m displayed antibacterial activities of 52% and
73% at 100 mg/L, respectively. However, the synthesized compounds exhibited weak ac-
tivity against P. solanacearum. The present work demonstrates that bisthioether derivatives
containing a 1,3,4-thidiazole moiety can be used to develop potential agrochemicals. To
the best of our knowledge, this is the first report on the antibacterial activity of bisthioether
derivatives containing a 1,3,4-thidiazole moiety.
RESULTS AND DISCUSSION
Chemistry
The synthetic route of the title compounds is demonstrated in Figure 2. The inter-
mediates 1 (5-amino-1,3,4-thiadiazole-2-thiol) was prepared by treating thiosemicarbazide
and carbon disulfide using readily available starting materials and a procedure described
in literature.17 Th◦e subsequent reaction of intermediates 1 with 30% formaldehyde readily
proceeded at 50 C, resulting in the synthesis of intermediates 2. Subsequent treatment
of intermediates 2 dissolved in KOH solution and then with different substituted benzyl
chloride reactions at room temperature obtained the final compounds (3a–3o).
Figure 2 Schematic diagram for synthesis of final compounds (3a–3o).

BISTHIOETHER DERIVATIVES
137
Table 1 Yields of 3a at different reaction conditionsa
Entry
Base
Time (h)
Temperature (◦C)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
K2CO3
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
5
5
5
2.5
5
10
5
5
5
5
5
25
25
25
25
25
25
12.5
25
50
25
25
25
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
22
30
60
28
61
60
30
59
45
62
34
23
10
11
12
H2O
C2H5OH
CH3CN
5
aGeneral reaction conditions: n (intermediates 2): n (KOH): n (benzyl bromide) = 1:2:2, n = 1 mmol; H2O =
20 mL, 25 ◦C, 5 h.
To optimize the reaction conditions for the preparation of the title compounds, the
compound 3a was carried out under different conditions. The effects of different types of
base, reaction time, reaction temperature, and solvents are summarized in Table 1. First,
the effect of different types of base was investigated. Table 1 indicates that the reaction
can yield 60% of the product when using KOH base (entry 3), whereas in the other base,
the 3a yield was significantly lower (entries 1 and 2). The reaction was carried out using
various solvents in the presence of KOH at room temperature for 5 h. In H2O, 3a was ob-
tained as a 62% yield (entry 10). Other solvents such as CH3CN, and C2H5OH were used,
with the 3a yields being 23% and 34% respectively (entries 11 and 12). Furthermore, we
examined the effect of reaction time on the thioetherification reaction of thiol to thioether.
When the reaction time was prolonged from 2.5 to 5 h, 3a yield increased from 28% to
61%. However, when the reaction time was further increased to 10 h, no improvement
was observed (60%, entry 6). We also examined the effects of reaction temperature. When
the reaction temperature was increased from 12.5◦C to 25◦C and then to 50◦C, the yields
obtained were 30%, 59%, and 45%, respectively (entries 7, 8, and 9). Based on these
results, the optimal conditions for synthesis were selected in H2O solvent with KOH base
at a reaction temperature of 25◦C and a reaction time of 5 h. However, the yields were
moderate (52%–70%), may be due to the poor solubility of benzyl chloride in water, and
part of benzyl chloride was turned into benzyl alcohol in percentage of KOH in H2O.
Therefore, 5,5ꢁ-(methylenebis(azanediyl))bis(1,3,4-thiadiazole-2-thiol) seemed excessive,
and the excessive 5,5ꢁ-(methylenebis(azanediyl))bis(1,3,4-thiadiazole-2-thiol) become the
corresponding potassium salt and dissolved in water, which then lost during the postpro-
cessing.
All of the synthesized compounds (3a–3o) were confirmed by 1H-NMR, 13C-NMR,
IR, and elemental analysis (Table 2). From the spectral data of compounds 3a to 3o, the
IR spectrum of all the synthesized compounds showed broad absorption bands of around
3360 to 3220 cm−1 for NH, 3100 to 3020 cm−1 for Ar H, and 2964 to 2914 cm−1 for CH2,
with the distinguishing benzene ring broad absorption peaks observed in the range of 1650
to 1612 cm−1 and C N for amide in the range of 1575 to 1525 cm−1. 1H NMR spectrum
showed the characteristic three peaks near δ 8.61 to 8.58 ppm for –NH- proton and near δ

138
X. CHEN ET AL.
Table 2 Physical and analytical data of the newly synthesized compounds 3a–3o
Elemental analysis
Found (%)
H
Calculated (%)
Entry
Mol. Formula
Yield (%)
MW
MP (◦C)
C
N
C
H
N
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
C19H18N6S4
C19H16F2N6S4
60
61
64
70
62
62
64
55
66
58
52
58
68
60
64
458.65 200–201 49.43 4.19 18.40 49.76 3.96
494.63 147–148 46.44 3.67 16.93 46.14 3.26
494.63 165–166 46.45 3.56 16.52 46.14 3.26
494.63 153–154 46.49 3.47 16.75 46.14 3.26
486.70 148–149 51.56 4.82 17.10 51.82 4.56
486.70 145–147 52.05 5.01 17.21 51.82 4.56
486.70 137–138 51.94 4.86 17.53 51.82 4.56
527.54 149–151 43.62 3.24 15.44 43.26 3.06
527.54 152–154 43.34 3.36 15.58 43.26 3.06
527.54 148–150 43.15 3.27 15.67 43.26 3.06
596.43 142–143 38.47 2.35 14.15 38.26 2.37
596.43 145–147 38.44 2.53 14.14 38.26 2.37
518.70 145–147 48.86 4.33 16.62 48.63 4.28
548.64 142–143 41.45 3.05 20.06 41.59 2.94
548.64 146–148 41.88 2.83 19.96 41.59 2.94
18.32
16.99
16.99
16.99
17.27
17.27
17.27
15.93
15.93
15.93
14.09
14.09
16.20
20.42
20.42
C
C
19H16F2N6S4
19H16F2N6S4
C
21H22N6S4
21H22N6S4
C21H22N6S4
C
C
C
C
C
C
19H16Cl2N6S4
19H16Cl2N6S4
19H16Cl2N6S4
19H14Cl4N6S4
19H14Cl4N6S4
C
C
C
21H22N6O2S4
19H16N8O4S4
19H16N8O4S4
4.73 to 4.71 ppm for NHCH2NH- proton, with the characteristic singlet near δ 4.28 ppm
for –SCH2Ar proton, appearing as a broad multiplet at δ 7.21 to 7.28 ppm for -ArH proton,
with the methyl (Ar-CH3) proton signals observed as a singlet near δ 2.24 to 2.20 ppm.
Antibacterial Activity
The herbicidal activities of title compounds against R. solanacearum and P.
solanacearum were evaluated using the turbidimeter test ;21 the results indicated that the
synthesized compounds showed good antibacterial activities. In particular, the activity of
compound 3m R. solanacearum was up to 73% at 100 mg/L. The experimental details,
table of activities (Table S 1), and the structure–activity relationship are presented in the
online Supplemental Materials.
CONCLUSION
A new type of (bis)sulfide derivatives containing the 1,3,4-thiadiazoles moiety was
designed and synthesized, and the antibacterial activities for compounds 3a to 3o against
R. solanacearum and P. solanacearum were evaluated in vitro. Preliminary biological test
results show that the synthesized compounds have weak to good antibacterial activity. In
particular, the compound 3m can inhibit R. solanacearum from reaching 73% at 100 mg/L.
When the phenyl ring group had a 3-methoxyl substituent, the compound has significantly
higher activity than the rest. To the best of our knowledge, this is the first report of synthesis
and antibacterial activity of (bis)sulfide derivatives containing the 1,3,4-thiadiazoles moiety.

BISTHIOETHER DERIVATIVES
139
EXPERIMENTAL
Chemistry
Materials and Instrumentation. Substituted benzyl chloride was purchased
from Aladdin and the Adamas. Unless otherwise stated, all the reagents and reactants
were purchased from commercial suppliers, and melting points were uncorrected and de-
termined on an XT-4 binocular microscope (Beijing Tech Instrument Co., China). The 1H
NMR and 13C NMR spectra were recorded at room temperature on a JEOL ECX 500
1
NMR spectrometer operating at 500 MHz for H NMR and 125 MHz for 13C NMR by
using dimethyl sulfoxide (DMSO) as solvents and tetramethylsilane (TMS) as an internal
standard. Infrared spectra were recorded in KBr on a Bruker VECTOR 22 spectrometer,
and elemental analysis was performed on an Elemental Vario-III CHN analyzer. The course
of the reactions was monitored by thin layer chromatography (TLC); analytical TLC was
performed on silica gel GF 254. Intermediates 1 and 2 were prepared according to the
1
reported methods17,22 and used without further purifications. Sample H and 13C NMR
spectra for 3a and 3f are presented in the online Supplemental Materials (Figures S 1–S 4).
Experimental Procedure for the Synthesis of Compounds
To a stirred solution of intermediate 2 (0.28 g, 1 mmol) in 20 mL 0.1 mol/L potassium
hydroxide solution, substituted benzyl chloride (2 mmol) in ethanol (2 mL) was slowly
◦
added at room temperature. The mixture was stirred and heated at 50 C for 8 h. The
solvent was removed and the residue was purified by chromatography on silica gel (ethyl
acetate/petroleum ether = v/v 1:1) to give the desired compound 3a to 3o.
Characterization of Final Compounds (3a–3o)
N,N’-Bis(5-(benzylthio)-1,3,4-thiadiazol-2-yl)methanediamine (3a). IR
(KBr, cm−1): v 3360 ( NH str.), 3028 (ArH str.), 1525 (Ar-H str.), 1203 (C N str.), 700
1
(S C str.); H NMR (DMSO-d6, ppm): δ 8.64 (t, J = 5.7 Hz, 2H, NH), 7.37–7.21 (m,
10H, Ar-H), 4.77 (t, J = 5.75 Hz, 2H, CH2), 4.28 (s, 4H, ArCH2); 13C NMR (DMSO-d6,
δppm): 169.0 (C N), 151.5(C N), 137.5 (Ar C), 129.5 (Ar C), 129.0 (Ar C), 128.0
(Ar C), 52.8 (C N), 39.8 (Ar CH2).
N,N’-Bis(5-((2-fluorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methane Diamine
(3b). IR (KBr, cm−1): v 3259 ( NH str.), 3062 (ArH str.), 1489 (Ar H str.), 1230 (C N
str.), 758 (S C str.); 1H NMR (DMSO-d6, ppm): δ 8.70 (t, J = 5.75 Hz, 2H, NH), 7.40–7.31
(m, 4H, ArH), 7.21–7,13 (m, 4H, Ar H), 4.78 (t, J = 5.75 Hz, 2H, CH2), 4.28 (s, 4H,
ArCH2); 13C NMR (DMSO-d6, ppm): δ 169.3 (C N), 161.8 (C N), 159.8 (C N), 150.7
(C N), 131.9 (Ar C), 130.4 (Ar C), 125.0 (Ar C), 124.5 (Ar C), 124.7 (Ar C), 116.0
(Ar C), 115.9 (Ar C), 53.0 (C N), 34.3 (Ar CH2) .
N,N’-Bis(5-((3-fluorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanediamine
(3c). IR (KBr, cm−1): v 3298.2 ( NH str.), 3084 (ArH str.), 1510 (Ar-H str.), 1259 (C N
1
str.), 723 (S C str.); H NMR (500 MHz, DMSO-d6, ppm): δ 8.70 (t, J = 4.6 Hz, 2H,
NH), 7.41–7.33 (m, 4H, Ar H), 7.21–7.13 (m, 4H, Ar H), 4.78 (t, J = 6.0 Hz, 2H,
CH2), 4.33 (s, 4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, ppm): δ 169.3 (C N), 159.7
(C N), 150.8 (C N), 131.8 (Ar C), 130.4 (Ar C), 125.0 (Ar C), 124.7 (Ar C), 116.0
(Ar C), 53.0 (C N), 32.8 (Ar CH2).

140
X. CHEN ET AL.
N,N’-Bis(5-((4-fluorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanediamine
(3d). IR (KBr, cm−1): v 3273 ( NH str.), 3076 (ArH str.), 1598 (Ar H str.), 1217 (C N
1
str.), 723 (S C str.); H NMR (500 MHz, DMSO-d6, ppm): δ 8.66 (t, J = 6.3 Hz, 2H,
NH), 7.44–7.39 (m, 4H, Ar H), 7.29–7.23 (m, 4H, Ar H), 4.75 (t, J = 5.7 Hz, 2H,
CH2), 4.38 (s, 4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, ppm): δ 169.0 (C N), 162.9
(C N), 161.0 (C N), 151.4 (C N), 133.9 (Ar C), 131.5 (Ar C), 125.4 (Ar C), 115.9
(Ar C), 53.0 (C N), 37.8 (Ar CH2).
N,N’-Bis(5-((2-methylbenzyl)thio)-1,3,4-thiadiazol-2-yl)methanedia-
mine (3e). IR (KBr, cm−1): v 3259 ( NH str.), 3061 (ArH str.), 1639 (Ar H str.), 1230
1
(C N str.), 758 (S-C str.); H NMR (500 MHz, DMSO-d6, ppm): δ 8.63 (t, J = 5.7 Hz,
2H, NH), 7.21–7.12 (m, 6H, Ar H), 7.08–7.06 (m, 2H, Ar H), 4.77 (t, J = 5.75 Hz,
2H, CH2), 4.28 (s, 4H, ArCH2), 2.26 (s, 6H, ArCH3); 13C NMR (125 MHz, DMSO-d6): δ
168.9 (C N), 151.6 (C N), 138.1 (Ar C), 137.3 (Ar C), 130.0 (Ar C), 128.9 (Ar C),
128.6 (Ar C), 126.5 (Ar C), 53.1 (C-N), 39.8 (Ar CH2), 21.4 (Ar CH3).
N,N’-Bis(5-((3-methylbenzyl)thio)-1,3,4-thiadiazol-2-yl)methanedia-
mine (3f). IR (KBr, cm−1): v 3319 ( NH str.), 3101 (ArH str.), 1631 (Ar H str.), 1217
(C N str.), 723 (S-C str.); 1H NMR (500 MHz, DMSO-d6, ppm): δ 8.59 (t, J = 5.95 Hz,
2H, NH), 7.20–7.18 (m, 4H, Ar H), 7.08–7.07(m, 4H, Ar H), 4.73 (t, J = 5.7 Hz, 2H,
CH2), 4.24 (s, 4H, ArCH2) , 2.22 (s, 6H, ArCH3);13C-NMR (125 MHz, DMSO-d6, ppm): δ
168.9 (C N), 151.6 (C N), 138.1 (Ar C), 137.3 (Ar C), 130.0 (Ar C), 128.9 (Ar C),
128.6 (Ar C), 126.5 (Ar C), 53.0 (C-N), 32.1 (Ar CH2), 21.4 (Ar CH3).
N,N’-Bis(5-((4-methylbenzyl)thio)-1,3,4-thiadiazol-2-yl)methanedia-
mine (3g). IR (KBr, cm−1): v 3257 ( NH str.), 3061 (ArH str.), 1639 (Ar H str.), 1230
1
(C N str.), 759 (S-C str.); H NMR (500 MHz, DMSO-d6, ppm): δ 8.65 (t, J = 5.7 Hz,
2H, NH), 7.21–7.13 (m, 6H, Ar H), 7.08–7.06 (m, 2H, Ar H), 4.77 (t, J = 5.15 Hz,
2H, CH2), 4.28 (s, 4H, ArCH2) , 2.26 (s, 6H, ArCH3); 13C NMR (125 MHz, DMSO-d6,
ppm): δ 168.9 (C N), 151.6 (C N), 138.1 (Ar C), 137.3 (Ar C), 130.0 (Ar C), 128.9
(Ar C), 128.6 (Ar C), 126.5 (Ar C), 53.0 (C-N), 38.9 (Ar CH2), 21.4 (Ar CH3).
N,N’-Bis(5-((2-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanediamine
(3h). IR (KBr, cm−1): v 3240 ( NH str.), 2976 (ArH str.), 1597 (Ar H str.), 1210 (C N
1
str.), 775 (S-C str.); H NMR (500 MHz, DMSO-d6, ppm): δ 8.71 (t, J = 5.75 Hz, 2H,
NH), 7.48–7.43 (m, 4H, Ar H), 7.34–7.27 (m, 4H, Ar H), 4.79 (t, J = 5.75 Hz, 2H,
CH2), 4.40 (s, 4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, ppm): δ 169.3 (C N), 150.7
(C N), 134.9 (Ar C), 133.7 (Ar C), 131.9 (Ar C), 130.1 (Ar C), 127.8 (Ar C), 53.0
(C-N), 32.1 (Ar CH2).
N,N’-Bis(5-((3-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanediamine
(3i). IR (KBr, cm−1): v 3204 ( NH str.), 2976 (ArH str.), 1597 (Ar H str.), 1201 (C N
str.), 719 (S-C str.); 1H NMR (500 MHz, DMSO-d6, ppm): δ 8.67 (t, J = 5.75 Hz, 2H, NH),
7.44 (s, 2H, Ar H), 7.36–7.33 (m, 6H, Ar H), 4.76 (t, J = 5.15 Hz, 2H, CH2), 4.33 (s,
4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, ppm): δ 169.3 (C N), 150.7 (C N), 134.9
(Ar C), 133.7 (Ar C), 131.9 (Ar C), 130.1 (Ar C), 127.8 (Ar C), 107.4 (Ar C),
53.1 (C-N), 36.9 (Ar CH2).
N,N’-Bis(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanediamine
(3j). IR (KBr, cm−1): v 3319 ( NH str.), 3086 (ArH str.), 1633 (Ar H str.), 1132 (C N
str.), 839 (S-C str.); 1H NMR (500 MHz, DMSO-d6, ppm): δ 8.66 (t, J = 5.7 Hz, 2H, NH),
7.38–7.33 (m, 8H, Ar H), 4.77 (t, J = 5.75 Hz, 2H, CH2), 4.31 (s, 4H, ArCH2); 13C NMR
(125 MHz, DMSO-d6, ppm): δ 169.1 (C N), 151.1 (C N), 150.5 (C N), 136.9 (Ar C),
132.5 (Ar C), 131.3 (Ar C), 128.9 (Ar C), 52.9 (C-N), 37.9 (Ar CH2).

BISTHIOETHER DERIVATIVES
141
N,N’-Bis(5-((3,4-dichlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanedia-
mine (3k). IR (KBr, cm−1): v 3304 ( NH str.), 2987 (ArH str.), 1558 (Ar H str.), 1124
1
(C N str.), 819 (S-C str.); H NMR (500 MHz, DMSO-d6, ppm): δ 8.66 (t, J = 5.7 Hz,
2H, NH), 7.62–7.56(s, 4H, Ar H), 7.34–7.33 (m, 2H, Ar H), 4.76 (t, J = 6.3 Hz, 2H,
CH2), 4.32 (s, 4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, ppm): δ 170.2 (C N) 169.1
(C N), 150.8 (C N), 139.7 (Ar C), 139.2 (Ar C), 131.4 (Ar C), 131.1 (Ar C), 130.5
(Ar C), 129.9 (Ar C), 53.0 (C-N), 37.3 (Ar CH2).
N,N’-Bis(5-((2,6-dichlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanea-
mine (3l). IR (KBr, cm−1): v 3280 ( NH str.), 3091 (ArH str.), 1558 (Ar H str.), 1215
(C N str.), 781 (S-C str.); 1H NMR (500 MHz, DMSO-d6, ppm): δ 8.78 (t, J = 5.75 Hz,
2H, NH), 7.49–7.48 (s, 4H, Ar H), 7.37–7.34 (m, 2H, Ar H), 4.82 (t, J = 5.7 Hz, 2H,
CH2), 4.48 (s, 4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, ppm): δ 168.9 (C N), 151.6
(C N), 138.1 (Ar C), 137.3 (Ar C), 130.0 (Ar C), 128.9 (Ar C), 128.6 (Ar C),
126.5 (Ar C), 53.1 (C-N), 38.8 (Ar CH2).
N,N’-Bis(5-((3-methoxybenzyl)thio)-1,3,4-thiadiazol-2-yl)methanedia-
mine (3m). IR (KBr, cm−1): v 3242 ( NH str.), 2933 (ArH str.), 1602 (Ar H str.),
1
1261 (C N str.), 704 (S-C str.); H NMR (500 MHz, DMSO-d6, ppm): δ 8.66 (t, J =
6.3 Hz, 2H, NH), 7.24–7.21 (s, 2H, Ar H), 6.91–6.90 (m, 4H, Ar H), 6.84–6.80 (m,
2H, Ar H), 4.77 (t, J = 6.0 Hz, 2H, CH2), 4.31 (s, 4H, ArCH2), 3.71 (s, 6H, OCH3); 13
C
NMR (125 MHz, DMSO-d6, ppm): δ 169.0 (C N), 159.7 (C N), 151.5 (C N), 139.0
(Ar C), 130.1 (Ar C), 121.6 (Ar C), 115.0 (Ar C), 113.4 (Ar C), 55.5 (OCH3), 52.9
(C-N), 38.9 (Ar CH2).
N,N’-Bis(5-((3-nitrobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanediamine
(3n). IR (KBr, cm−1): v 3317 ( NH str.), 3122 (ArH str.), 1625 (Ar H str.), 1236 (C N
str.), 692 (S-C str.); 1H NMR (500 MHz, DMSO-d6, ppm): δ 8.70 (t, J = 5.7 Hz, 2H, NH),
7.41–7.38 (m, 2H, Ar H), 7.34–7.31 (m, 2H, Ar H) 7.21–7.13 (m, 4H, Ar H), 4.78 (t,
J = 5.75 Hz, 2H, CH2), 4.28 (s, 4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, δppm):
169.7 (C N), 150.3 (C N), 148.1 (C N), 140.5 (C N), 136.2 (Ar C), 130.4 (Ar C),
124.1 (Ar C), 122.8 (Ar C), 107.5 (Ar C), 86.2 (Ar C), 67.1 (C-N), 37.6 (Ar CH2).
N,N’-Bis(5-((4-nitrobenzyl)thio)-1,3,4-thiadiazol-2-yl)methanediamine
(3o). IR (KBr, cm−1): v 3298 ( NH str.), 3122 (ArH str.), 1624 (Ar H str.), 1298 (C N
str.), 692 (S-C str.); 1H NMR (500 MHz, DMSO-d6, ppm): δ 8.70 (t, J = 6.3 Hz, 2H, NH),
7.44–7.39 (m, 4H, Ar H), 7.29–7.23 (m, 4H, Ar H), 4.78 (t, J = 5.7 Hz, 2H, CH2), 4.33
(s, 4H, ArCH2); 13C NMR (125 MHz, DMSO-d6, ppm): δ 169.7 (C N), 150.2 (C N),
147.1 (C N), 146.1 (C N), 130.7 (Ar C), 124.1 (Ar C), 103.5 (Ar C), 66.5 (C N),
37.7 (Ar CH2).
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