Synthesis and antimicrobial activity of some new 5-(3-chloro-1- benzothiophen-2-YL)-1,3,4-oxadiazole-2-thiol and their derivatives

Article abstract of DOI:10.1080/10426507.2011.586905

3-Chloro-1-benzothiophene-2-carbonylchloride 1 was made to reacts with hydrazine hydrate afforded 3-chloro-1-benothiophene-2-carbohydrazide 2 in good yield. 5-(3-chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazole-2-thiol 4 was synthesized from 3-chloro- 1-benz

Full text of DOI:10.1080/10426507.2011.586905

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis and Antimicrobial Activity
of Some New 5-(3-Chloro-1-
Benzothiophen-2-YL)-1,3,4-
Oxadiazole-2-Thiol and Their Derivatives
Gadada Naganagowda a & Amorn Petsom a
a Research Center for Bioorganic Chemistry, Department of
Chemistry, Faculty of Science , Chulalongkorn University , Bangkok,
Thailand
Published online: 14 Oct 2011.
To cite this article: Gadada Naganagowda & Amorn Petsom (2011) Synthesis and Antimicrobial
Activity of Some New 5-(3-Chloro-1-Benzothiophen-2-YL)-1,3,4-Oxadiazole-2-Thiol and Their
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:10, 2112-2121, DOI:
10.1080/10426507.2011.586905
To link to this article: http://dx.doi.org/10.1080/10426507.2011.586905
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Phosphorus, Sulfur, and Silicon, 186:2112–2121, 2011
Copyright ꢀC 2011 Chulalongkorn University
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.586905
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME
NEW 5-(3-CHLORO-1-BENZOTHIOPHEN-2-YL)-1,3,4-
OXADIAZOLE-2-THIOL AND THEIR
DERIVATIVES
Gadada Naganagowda and Amorn Petsom
Research Center for Bioorganic Chemistry, Department of Chemistry,
Faculty of Science, Chulalongkorn University, Bangkok, Thailand
GRAPHICAL ABSTRACT
Abstract 3-Chloro-1-benzothiophene-2-carbonylchloride
1 was made to reacts with
hydrazine hydrate afforded 3-chloro-1-benothiophene-2-carbohydrazide 2 in good yield.
5-(3-chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazole-2-thiol 4 was synthesized from 3-chloro-
1-benzothiophene-2-carbohydrazide 2. Mannich bases, alkyl halide, and acid chlorides
derivatives were then prepared. Compound 4 on condensation with chloroacetone in the
presence of NaOH as base and ethanol as solvent gave 1-{[5-(3-chloro-1-benzo[b]thiophen-
2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}propan-2-on 6. Condensation of compound 6 with various
aromatic aldehydes afforded a series of chalcones 7a–h. The structures of all the synthesized
compounds were confirmed by spectral data and have been screened 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 Benzothiophene; oxadiazole-2-thiol; Mannich bases; antibacterial activity
Received 19 January 2011; accepted 22 April 2011.
This work was supported by the Higher Education Research Promotion and National Research University
Project of Thailand, Office of the Higher Education Commission (Project No: AM1079B). The post doctoral
fellowship grant from the Ratchadapisakesompote Endownment Fund, Chulalongkorn University (to G.N.) was
gratefully acknowledged.
Address correspondence to Gadada Naganagowda, Research Center for Bioorganic Chemistry, De-
partment of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand. E-mail:
ratna gowda@yahoo.co.in
2112

NEW BENZOTHIOPHENE-OXADIAZOLE-2(3H)-THIONE DERIVATIVES
2113
INTRODUCTION
The study of nitrogen- and sulfur-containing heterocycles is currently an interesting
topic in pesticide chemistry.1–7 Benzothiophene compounds are of current interest due to
their wide spectrum of pharmacological properties as antiallergic,8 anti-inflammatory,9 anal-
gesic,10 and ocular hypotensive activities.11 The substituted oxadiazoles are heterocyclic
compounds, which serve both as biomimetic and reactive pharmacophores, and many of
them are key elements with potential biological activities12–14 such as pesticidal,15 hypoten-
sive,16 insecticidal,17 bactericidal,18 diuretic,19 herbicidal,20,21 and fungicidal activities.22,23
This study focuses mainly on benzothiophene as our basic structure and investigation of
its combination with oxadiazole heterocyclic, prompted by the biological interest and con-
tinuation of our search for bioactive molecules. We report on the synthesis of compounds
derived from benzothiophene containing oxadiazole moiety; with the purpose of investiga-
tion in the future, all derivatives of their possible antibacterial and antifungal activities of
the resulting derivatives were screened and the relationship of molecular structure and the
bioactivity are discussed.
RESULTS AND DISCUSSION
The starting material for the synthesis of the target compound is 3-chlorobenzo
thiophene-2-carbonylchloride 1 which was prepared by the reaction of cinnamic acid with
thionyl chloride in dimethylformamide and dry pyridine according to the reported method.24
Reaction between compound 1 and hydrazine hydrate afforded the 3-chlorobenzothiophene-
2-carbohydrazide 2 in good yield. In confirmation, the IR spectrum of the compound 2
showed the peaks near 3020 and 1605 cm−1 due to N H and C O stretching absorption
frequencies. Compound 2 was refluxed with carbon disulfide and potassium hydroxide in
distilled ethanol to get compound 3, which on subsequent treatment with dilute hydrochloric
acid to gave 5-(3-chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazole-2-thiol 4, which exists
in tautomeric thiol-thione equilibrium, as indicated by the C S stretching band at 1255
cm−1 in its IR spectrum (Scheme 1). Compound 4 by using alkyl halide and various acid
chlorides afford the compounds 5a–d. The formation of compound 5a was indicated by
the absence of C S stretching band at 760 cm−1 and C N at 1630 cm−1. The compound
4 was also treated with chloroacetone in the presence of a base to obtain compound 6 that
on condensation with various aldehydes in the presence of potassium hydroxide afforded
various chalcones 7a–h. The peaks at 1625 cm−1 indicated at C N the formation of
the compound 7a. Similarly, compound 4 was also subjected to Mannich reaction in the
presence of formaldehyde and various amines to get 8a–c. Compound 8a that exhibited a
stretching absorption peaks at 3320 cm−1 and 1265 cm−1 corresponds to N H and C S
groups indicated its formation (Scheme 2).
BIOLOGICAL EVALUATION
Antibacterial Activity
A cup–plate method using HiMedia agar medium was employed to study the antibac-
terial activity of the synthesized compounds against two Gram-positive bacteria, Staphylo-
coccus aureus-ATCC 25923 and Bacillus subtilis-ATCC 6633, and Gram-negative bacteria,
Pseudomonas aeruginosa-ATCC 10145 and Escherichia coli-ATCC 35218. Preparation of
nutrient broth, subculture, base layer medium, agar medium, and peptone water was carried

2114
G. NAGANAGOWDA AND A. PETSOM
Cl
Cl
S
O
1
stirred
r.t., 7h
NH NH 2H O
2
2
2
Cl
NH
O
NH2
S
2
C2H5OH
CS2 / KOH
Reflux, 12h
Cl
-
S
K+
NH
S
NH
S
3
O
acidified, dil HCl
Cl
Cl
N
N
N
O
NH
S
O
S
SH
S
4
Scheme 1 Synthesis of 5-(3-chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazole-2-thiol 4.
out as per the standard procedure.25 The activities are shown in the supplemental materials
(Table S 1).
Antifungal Activity
The antifungal activity of the synthesized compounds was tested against four different
fungi, i.e., Candida albicans, Crysosporium pannical, Aspergillus niger, and Rhizopus
oryzae, by a filter paper disc technique.26 The activities are shown in the supplemental
materials (Table S 2).

NEW BENZOTHIOPHENE-OXADIAZOLE-2(3H)-THIONE DERIVATIVES
2115
R
1
R
2
NH
2
HN
Cl
Cl
Cl
R
2
N
N
N
N
O
N
R
-
Cl
N
R
1
S
O
NaOH
HCHO
SH
O
S
S
S
SR
C H OH
2
5
4
5a-d
8a-
c
H C
O
3
Compound R1
R2
Compound
5a
R
CH3
NaOH
8a
8b
8c
−Cl
−H
−H
−F
−F
−NO2
Cl
Cl
5b
5c
5d
CH3CO
C6H5CO
ClCH2CO
N
O
N
S
CH
3
S
6
O
O
R
R
KOH
1
R
2
Cl
N
O
N
R
2
S
S
R
1
7a-h
O
R
Compound
R
R1
R2
7a
7b
7c
7d
7e
−H
−H
−H
−H
−H
−OH
−H
−Cl −H
−H
−H
−H
−H
−Cl
−OCH3
7f
−H
−NO2 −H
7g
7h
−H
−H
−H
−Br
−NO2
−H
Scheme 2 Synthesis of 5-(3-chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazole-2-thiol derivatives.
CONCLUSION
In conclusion, a new series of benzothiophene-oxadiazole-2(3H)-thione deriva-
tives were synthesized and evaluated for their antibacterial and antifungal activities. The
newly synthesized heterocyclics exhibited moderate antibacterial activity against S. aureus,

2116
G. NAGANAGOWDA AND A. PETSOM
B. subtilis, P. aeruginosa, and E. coli and significant antifungal activity against C. albicans,
C. pannical, A. niger, and R. oryzae. It can be concluded that these classes of compounds
certainly hold great promise toward good active leads in medicinal chemistry. A further
study to acquire more information concerning pharmacological activity is in progress.
EXPERIMENTAL
All chemicals were analytical grade, purchased from commercial suppliers and used
as received without further purification. Melting points were determined in open capillary
and were uncorrected. Fourier Transformed Infrared (FT-IR) spectra (KBr disks) were
1
recorded using a Perkin-Elmer 237 spectrophotometer. H-NMR and 13C-NMR were ob-
1
tained in DMSO-d6 at 500 MHz for H nuclei and 100 MHz for 13C nuclei (Bruker and
Varian Company, USA). All chemical shifts were reported in parts per million (ppm) using
residual proton or carbon signal in deuterated solvents as internal references. Mass spectra
(MS) are recorded on Schimadzu GC-MS. Elemental analysis (C, H, N and S) was per-
formed on Perkin Elmer 2400 analyzer and all products were purified by recrystallization.
The purity of the compounds was checked by TLC on silica gel and further purification
was performed through column chromatography (silica gel, 60–120 mesh).
Preparation of 3-Chloro-1-benzo[b]thiophene-2-carbonylchloride (1)
Compound 1 was prepared according to the literature procedure,24 melting point (mp)
112–114 ◦C [Literature melting point (Lit. mp) 110–112 ◦C).
Preparation of 3-Chloro-1-benzo[b]thiophene-2-carboxylic Acid
Hydrazide (2)
Compound 1 (2.0 g, 0.0086 mol) was added to hydrazine hydrate (5.54 g, 5.33 mL,
0.17 mol) directly slowly with stirring; then the reaction mixture was stirred vigorously for
about 7 h on a magnetic stirrer. The reaction mixture was cooled to room temperature and
was decomposed in crushed ice slowly. The precipitated solid that separated was filtered,
washed with water, and recrystallized from ethanol to get pure compound 2.
Yield 89%; mp 183–186 ◦C; IR ν (cm−1): 3020 (N H), 1605 (C O), 1570 (C C),
1070 ( C Cl), 680 (C S C); 1H NMR δ (ppm): 8.22 (s, 1H, CONH), 7.92–7.41 (m, 4H,
Ar CH), 4.22 (2H, NH2); 13C NMR δ (ppm): 185, 138, 131, 129, 128, 125, 123, 122; MS,
m/z: 226.68 (M+). Anal. calcd. for C9H7ClN2OS: C, 47.69; H, 3.11; N, 12.36; S, 14.15;
found: C, 47.65; H, 3.09; N, 12.35; S, 14.12%.
Preparation of 5-(3-Chloro-1-benzo[b]thiophen-2-yl)-
1,3,4-oxadiazole-2-thiol (4)
A mixture of compound 2 (2.26 g, 0.01 mol), potassium hydroxide (0.4 g, 0.01 mol),
carbon disulfide (1.52 g, 1.45 mL, 0.02 mol), and absolute ethanol (100 mL) was refluxed for
12 h. The excess of solvent was removed by vacuum, and the residue was dissolved in water
and filtered; the filtrate was acidified with dilute hydrochloric acid (50%); the precipitate
was filtered and washed thoroughly with ice-cold water. The product was recrystallized
from ethanol to give compound 4 as light yellowish solid.

NEW BENZOTHIOPHENE-OXADIAZOLE-2(3H)-THIONE DERIVATIVES
2117
Yield 65%; mp 210–212 ◦C; IR ν (cm−1): 3356 (N H), 1642 (C N), 1255 (C S),
1
1070 ( C Cl), 683 (C S C); H NMR δ (ppm): 8.23–7.65 (m, 4H, Ar CH), 3.40 (s,
1H, SH); 13C NMR δ (ppm): 161.4, 141.3, 138.2, 136.1, 124.4, 124.3, 123.2, 122.4, 118.3;
MS, m/z: 268.70 (M+). Anal. calcd. for C10H5ClN2OS2: C, 44.69; H, 1.88; N, 10.42; S,
23.86; found: C, 44.65; H, 1.81; N, 10.35; S, 23.80%.
General Procedure for Synthesis of Compounds 5a–d. Exemplary
Detail for 2-(3-Chloro-1-benzo[b]thiophen-2-yl)-5-(methylsulfanyl)-
1,3,4-oxadiazole (5a)
A mixture of compound 4 (2.68 g, 0.01 mol), 4-fluoroaniline (1.11 g, 0.98 mL, 0.01
mol) in the presence of 36% formaldehyde (0.02 mol) in absolute ethanol (30 mL) was
refluxed for 10 h. The completion of the reaction was monitored by TLC. The reaction
mixture was allowed to cool down to room temperature, and then poured into crushed ice.
The precipitate was filtered, dried and recrystallized from methanol. The resulting solid was
further purified by column chromatography [silica, petroleum ether/ethyl acetate (70:30)],
leading to pure compound 8a. Similarly, compounds 8b–c were prepared.
Yield 56%; mp 231–232 ◦C; IR ν (cm−1): 1630 (C N), 1070 ( C Cl), 760 (C S),
1
681 (C S C); H NMR δ (ppm): 8.23–7.44 (m, 4H, Ar CH), 2.11 (s, 3H, SCH3); 13C
NMR δ (ppm): 161.3, 141.2, 138.4, 136.3, 124.4, 124.3, 123.2, 122.4, 118.1, 14.2; MS,
m/z: 282.76 (M+). Anal. calcd. for C11H7ClN2OS2: C, 46.72; H, 2.50; N, 9.91; S, 22.68;
found: C, 46.54; H, 2.45; N, 9.76; S, 21.22%.
5-(3-Chloro-1-benzo[b]◦thiophen-2-yl)-1,3,4-oxadiazol-2-yl]ethanethioate
1
(5b). Yield 55%; mp 240–242 C; IR ν (cm−1): 1650 (C O), 1625 (C N); H NMR δ
(ppm): 8.15–7.14 (m, 4H, Ar CH), 2.30 (s, 3H, CH3); 13C NMR δ (ppm): 193.1, 161.8,
141.4, 138.3, 124.4, 124.3, 123.2, 122.4, 118.2, 36.5, 30.4; MS, m/z: 310.77 (M+). Anal.
calcd. for C12H7ClN2O2S2: C, 46.38; H, 2.27; N, 9.01; S, 20.64; found: C, 45.30; H, 2.20;
N, 8.98; S, 20.60%.
5-(3-Chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazol-2-yl]benzenecarboth
◦
1
ioate (5c). Yield 54%; mp 240–241 C; IR ν (cm−1): 1652 (C O), 1630 (C N); H
NMR δ (ppm): 8.46–7.31 (m, 9H, Ar CH); 13C NMR δ (ppm): 187.3, 161.7, 141.4, 138.5,
136.4, 134.7, 134.1, 128.9, 128.9, 128.1, 128.1, 124.4, 124.3, 123.2, 122.8, 118.4; MS,
m/z: 372.84 (M+). Anal. calcd. for C17H9ClN2O2S2: C, 54.76; H, 2.43; N, 7.51; S, 17.20;
found: C, 54.70; H, 2.33; N, 7.47; S, 17.13%.
5-(3-Chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazol-2-yl]chloroethaneth
◦
1
ioate (5d). Yield 58%; mp 212–214 C; IR ν (cm−1): 1645 (C O), 1620 (C N); H
NMR δ (ppm): 8.25–7.74 (m, 4H, Ar CH), 4.40 (s, 2H, CH2); 13C NMR δ (ppm): 188.3,
161.6, 141.4, 138.5, 136.5, 124.4, 124.3, 123.2, 122.4, 118.1, 47.4; MS, m/z: 342.22 (M+).
Anal. calcd. for C12H6Cl2N2O2S2: C, 41.75; H, 1.75; N, 8.11; S, 18.58; found: C, 41.65;
H, 1.71; N, 8.09; S, 18.54%.
Preparation of 5-(3-Chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazol-2-
yl]sulfanyl}propan-2-one (6)
A mixture of thione 4 (1.62 g, 0.005 mol), sodium hydroxide (0.2 g, 0.005 mol),
and chloroacetone (0.56 g, 0.55 mL, 0.006 mol) was stirred in a mixture of ethyl alcohol
(50 mL) and water (5 mL) for about 5 h. The excess of solvent was removed by vacuum

2118
G. NAGANAGOWDA AND A. PETSOM
evaporation, and the separated solid was collected by filtration, washed with cold water,
dried, recrystallized from methanol, and purified through column chromatography by using
n-hexane and ethyl acetate (80:20) as an eluent to give pure compound 6.
◦
1
Yield 58%; mp 222–224 C; IR ν (cm−1): 1650 (C O), 1635 (C N); H NMR δ
(ppm): 8.18–7.32 (m, 4H, Ar CH), 3.65 (s, 2H, SCH2), 2.13 (s, 3H, CH3); 13C NMR δ
(ppm): 200.1, 161.3, 141.2, 138.6, 136.9, 124.4, 124.1, 123.1, 122.5, 118.3, 47.5, 26.3; MS,
m/z: 324.80 (M+). Anal. calcd. for C13H9ClN2O2S2: C, 48.07; H, 2.79; N, 8.62; S, 19.74;
found: C, 48.05; H, 2.75; N, 8.60; S, 19.65%.
General Procedure for Synthesis of Compounds 7a–h. Exemplary
Detail for 5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-
yl]sulfanyl}-4-phenylbut-3-en-2-one (7a)
A mixture of NaOH (2.0 g, 0.05 mol) and alcohol (60 mL) in a 250-mL round-
bottomed flask was cooled (crushed ice) with stirring for about 15 min. Compound 6 (3.24 g,
0.01 mol) was added followed by addition of benzaldehyde (1.06 g, 1.02 mL, 0.01 mol);
the reaction mixture was kept at 25 ◦C with stirring until the stirring was no longer possible
2–3 h. The reaction mixture was left overnight in a refrigerator. The separated precipitate
product was filtered, washed with cold water until the washing was neutral to litmus, then
with chilled alcohol, and recrystallized from 1,4-dioxane to afford pure 7a. Similarly, the
compounds 7b–h were prepared with little change in stirring time and reaction work-up.
◦
1
Yield 45%; mp 276–278 C; IR ν (cm−1): 1645 (C O), 1625 (C N); H NMR δ
(ppm): 8.10–7.26 (m, 9H, Ar CH), 6.74 (d, 1H, Ar CH ), 6.53 (d, 1H, CO CH ),
3.70 (s, 2H, SCH2); 13C NMR δ (ppm): 196.3, 161.1, 142.4, 141.3, 138.4, 136.3, 135.2,
128.6, 128.6, 128.5, 128.5, 127.9, 126.2, 124.4, 124.3, 123.1, 122.5, 118.2, 45.3; MS, m/z:
412.91 (M+). Anal. calcd. for C20H12ClN2O2S2: C, 58.18; H, 3.17; N, 6.78; S, 15.53;
found: C, 58.13; H, 3.12; N, 6.71; S, 15.44%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}-4-(4-
hydroxylphenyl)but-3-en-2-one (7b). Yield 48%; mp 266–268 ◦C; IR ν (cm−1):
3421 (OH), 1640 (C O), 1625 (C N); 1H NMR δ (ppm): 10.12 (s, 1H, OH), 7.97–7.26
(m, 8H, Ar CH), 6.75 (d, 1H, Ar CH ), 6.50 (d, 1H, CO CH ), 3.71 (s, 2H, SCH2);
13C NMR δ (ppm): 196.6, 161.4, 157.6, 142.5, 141.3, 138.2, 136.1, 130.7, 130.6, 130.6,
126.2, 124.4, 124.3, 123.2, 122.8, 118.4, 115.2, 115.2, 45.8; MS, m/z: 428.91 (M+). Anal.
calcd. for C20H13ClN2O2S2: C, 56.01; H, 3.05; N, 6.53; S, 14.95; found: C, 56.05; H, 3.00;
N, 6.50; S, 14.88%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}-4-(2-
◦
chlorophenyl)but-3-en-2-one (7c). Yield 55%; mp 287–289 C; IR ν (cm−1): 1645
(C O), 1620 (C N), 745 (C Cl), 685 (C S C); 1H NMR δ (ppm): 8.12–7.45 (m, 8H,
Ar CH), 6.74 (d, 1H, Ar CH ), 6.55 (d, 1H, CO CH ), 3.72 (s, 2H, SCH2); 13C
NMR δ (ppm): 196.1, 161.1, 142.4, 141.3, 138.2, 136.1, 133.4, 133.3, 129.0, 129.0, 128.7,
128.7, 126.2, 124.4, 124.4, 123.1, 122.3, 118.1, 45.0; MS, m/z: 447.35 (M+). Anal. calcd.
for C20H12Cl2N2O2S2: C, 53.70; H, 2.70; N, 6.26; S, 14.34; found: C, 53.65; H, 2.65; N,
6.22; S, 14.22%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}-4-(4-
chlorophenyl)but-3-en-2-one (7d). Yield 55%; mp 281 282 ◦C; IR ν (cm−1):
1
1642 (C O), 1625 (C N); H NMR δ (ppm): 8.00–7.22 (m, 8H, Ar CH), 6.74 (d,
1H, Ar CH ), 6.50 (d, 1H, CO CH ), 3.70 (s, 2H, SCH2); 13C NMR δ (ppm):
196.9, 161.1, 142.3, 141.2, 138.4, 136.6, 133.3, 133.1, 129.0, 129.0, 128.7, 128.7,

NEW BENZOTHIOPHENE-OXADIAZOLE-2(3H)-THIONE DERIVATIVES
2119
126.2, 124.4, 124.3, 123.1, 122.3, 118.2, 45.1; MS, m/z: 447.01 (M+). Anal. calcd. for
C20H12Cl2N2O2S2: C, 53.70; H, 2.70; N, 6.26; S, 14.34; found: C, 53.65; H, 2.65; N, 6.22;
S, 14.22%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}-4-(4-
◦
methoxyphenyl)but-3-en-2-one (7e). Yield 57%; mp 290–292 C; IR ν (cm−1):
1
1648 (C O), 1630 (C N); H NMR δ (ppm): 8.05–7.32 (m, 4H, Ar CH), 6.74 (d, 1H,
Ar CH ), 6.55 (d, 1H, CO CH ), 3.80 (s, 3H, OCH3), 3.79 (s, 2H, SCH2); 13C NMR
δ (ppm): 196.1, 161.7, 159.3, 142.3, 141.3, 138.3, 136.4, 130.2, 130.2, 130.2, 126.2, 124.4,
124.3, 123.2, 122.8, 118.4, 114.2, 114.2, 55.1, 45.3; MS, m/z: 442.93 (M+). Anal. calcd.
for C21H15ClN2O3S2: C, 53.94; H, 3.41; N, 6.32; S, 14.48; found: C, 53.80; H, 3.39; N,
6.27; S, 14.41%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}-4-(2-
◦
nitrophenyl)but-3-en-2-one (7f). Yield 56%; mp 294–296 C; IR ν (cm−1): 1640
(C O), 1635 (C N), 1350 (NO2); 1H NMR δ (ppm): 7.98–7.32 (m, 8H, Ar CH), 6.75 (d,
1H, Ar CH ), 6.50 (d, 1H, CO CH ), 3.77 (s, 2H, SCH2); 13C NMR δ (ppm): 196.0,
161.0, 147.3, 142.3, 141.2, 138.7, 137.3, 136.4, 134.6, 129.5, 126.2, 124.4, 124.3, 123.2,
123.1, 122.8, 122.7, 118.1, 45.0; MS, m/z: 457.80 (M+). Anal. calcd. for C20H12ClN2O4S2:
C, 52.46; H, 2.64; N, 9.18; S, 14.00; found: C, 52.41; H, 2.61; N, 9.12; S, 13.78%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}-4-(4-
◦
nitrophenyl)but-3-en-2-one (7g). Yield 59%; mp 289–291 C; IR ν (cm−1): 1647
(C O), 1631 (C N), 1353 (NO2); 1H NMR δ (ppm): 7.95–7.30 (m, 8H, Ar CH), 6.79 (d,
1H, Ar CH ), 6.54 (d, 1H, CO CH ), 3.69 (s, 2H, SCH2); 13C NMR δ (ppm): 196.1,
161.0, 147.3, 142.3, 141.2, 138.1, 137.1, 136.1, 134.1, 129.3, 126.2, 124.4, 124.3, 123.2,
123.1, 122.8, 122.5, 118.3, 45.8; MS, m/z: 457.90 (M+). Anal. calcd. for C20H12ClN2O4S2:
C, 52.46; H, 2.64; N, 9.18; S, 14.00; found: C, 52.41; H, 2.61; N, 9.12; S, 13.78%.
4-(3-Bromophenyl)-1-{[5-(3-chloro-1-benzothiophen-2-yl)-1,3,4-oxadiaz
ol-2-yl]sulfanyl}but-3-en-2-one (7h). Yield 47%; mp 276–278 ◦C; IR ν (cm−1):
1635 (C O), 1625 (C N), 610 (C Br); 1H NMR δ (ppm): 7.87–7.04 (m, 8H, Ar CH),
6.70 (d, 1H, Ar CH ), 6.55 (d, 1H, CO CH ), 3.68 (s, 2H, SCH2); 13C NMR δ
(ppm): 196.0, 161.3, 142.4, 141.2, 138.7, 137.4, 136.9, 133.1, 130.8, 129.6, 127.5, 126.2,
124.4, 124.3, 123.3, 123.1, 122.3, 18.1, 45.9; MS, m/z: 491.80 (M+). Anal. calcd. for
C20H12ClBrN2O2S2: C, 48.84; H, 2.46; N, 5.70; S, 13.04; found: C, 48.75; H, 2.41; N,
5.65; S, 13.00%.
General Procedure for Synthesis of Compounds 8a–c. Exemplary
Detail for 5-(3-Chloro-1-benzo[b]thiophen-2-yl)-3-{[(3-chloro-4-
fluorophenyl)amino]methyl}-1,3,4-oxadiazole-2(3H)-thione (8a)
A mixture of compound 4 (2.68 g, 0.01 mol), 4-fluoroaniline (1.11 g, 0.98 mL,
0.01 mol), and 36% formaldehyde (0.02 mol) in ethyl alcohol was refluxed for 10 h.
Mean while a solid that separated was filtered, washed with water, dried, and recrystallized
from methanol which was purified by column chromatography using a gradient mixture
of petroleum ether/ethyl acetate (70:30) as an eluent to get compound 8a. Similarly, com-
pounds 8b–c were prepared.
◦
Yield 56%; mp 245–247 C; IR ν (cm−1): 3320 (N H), 2965 (CH), 1629 (C N),
1
1265 (C S), 1054 (C F); H NMR δ (ppm): 8.45–7.12 (m, 7H, Ar CH), 5.85 (d, 2H,
N CH2 NH), 5.45 (br, 1H, N CH2 NH); 13C NMR δ (ppm): 177.3, 155, 147.1, 144.3,

2120
G. NAGANAGOWDA AND A. PETSOM
131.2, 126.1, 125.9, 124.4, 124.3, 122.8, 122, 121.5, 119.9, 117.0, 115.5, 114.2, 68.1; MS,
m/z: 426.20 (M+). Anal. calcd. for C17H10Cl2FN3OS2: C, 47.89; H, 2.36; N, 9.86; S, 15.04;
found: C, 47.81; H, 2.32; N, 9.81; S, 15.00%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-3-{[(4-fluorophenyl)amino]methyl}-
1,3,4-oxadiazole-2(3H)-thione (8b). Yield 55%; mp 233–235 ◦C; IR ν (cm−1): 3315
(N H), 2970 (CH), 1630 (C N), 1264 (C S), 1070 ( C Cl), 1050 (C F), 740
1
(C Cl), 684 (C S C); H NMR δ (ppm): 8.22–7.16 (m, 8H, Ar CH), 5.85 (d, 2H,
N CH2 NH), 5.40 (br, 1H, N CH2 NH); 13C NMR δ (ppm): 177.1, 155.7, 155, 143.2,
131.3, 126.2, 125.1, 124.2, 124.1, 122.8, 122, 119.9, 118.9, 118.9, 116.3, 116.1, 68.7;
MS, m/z: 391.87 (M+). Anal. calcd. for C17H11ClFN3OS2: C, 52.10; H, 2.83; N, 10.72; S,
16.37; found: C, 52.01; H, 2.72; N, 10.65; S, 16.30%.
5-(3-Chloro-1-benzo[b]thiophen-2-yl)-3-{[(4-nitrophenyl)amino]methyl}-
1,3,4-oxadiazole-2(3H)-thione (8c). Yield 49%; mp 265–267 ◦C; IR ν (cm−1): 3322
(N H), 2972 (CH), 1635 (C N), 1345 (NO2), 1260 (C S); 1H NMR δ (ppm): 8.25–7.23
(m, 8H, Ar CH), 5.90 (d, 2H, N CH2 NH), 5.42 (br, 1H, N CH2 NH); 13C NMR δ
(ppm): 177.7, 155.9, 153.4, 136.2, 131.3, 127.1, 127.5, 126.7, 125.9, 124.4, 124.3, 122.5,
122.1, 119.9, 114.1, 114.2, 68.9; MS, m/z: 418.75 (M+). Anal. calcd. for C17H11ClN4O3S2:
C, 48.74; H, 2.65; N, 13.38; S, 15.31; found: C, 48.70; H, 2.59; N, 13.35; S, 15.23%.
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