Synthesis and biological activity of some more heterocyclic compounds containing benzothiophene moiety

Article abstract of DOI:10.1080/17415993.2011.583394

3-Chloro-1-benzothiophene-2-carbonylchloride 1 was allowed to react with hydrazine hydrate to give carbohydrazide 2. The reaction of 3-chloro-1- benzothiophene-2-carbohydrazide 2 with potassium thiocyanate gave compound 3, which was cyclized to form thioxotetrahydropyrimidine 4, thiazoles 5a-e, triazoles 7a-e and oxadiazoles 10a-h. The structures of all the synthesized compounds were confirmed by spectral data and have been screened for antimicrobial, analgesic and anthelmintic activities.

Full text of DOI:10.1080/17415993.2011.583394

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Synthesis and biological activity of
some more heterocyclic compounds
containing benzothiophene moiety
Gadada Naganagowda a , Patchanita Thamyongkit a , Runchana
Klai-U-dom a , Waraporn Ariyakriangkrai a , Arithat Luechai a &
Amorn Petsom a
a Research Center for Bioorganic Chemistry, Department of
Chemistry, Faculty of Science, Chulalongkorn University, Bangkok,
10330, Thailand
Published online: 19 May 2011.
To cite this article: Gadada Naganagowda , Patchanita Thamyongkit , Runchana Klai-U-dom ,
Waraporn Ariyakriangkrai , Arithat Luechai & Amorn Petsom (2011) Synthesis and biological activity
of some more heterocyclic compounds containing benzothiophene moiety, Journal of Sulfur
Chemistry, 32:3, 235-247, DOI: 10.1080/17415993.2011.583394
To link to this article: http://dx.doi.org/10.1080/17415993.2011.583394
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Journal of Sulfur Chemistry
Vol. 32, No. 3, June 2011, 235–247
Synthesis and biological activity of some more heterocyclic
compounds containing benzothiophene moiety
Gadada Naganagowda*, Patchanita Thamyongkit, Runchana Klai-U-dom,
Waraporn Ariyakriangkrai, Arithat Luechai and Amorn Petsom
Research Center for Bioorganic Chemistry, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Bangkok 10330, Thailand
(Received 7 February 2011; final version received 16 April 2011)
3-Chloro-1-benzothiophene-2-carbonylchloride 1 was allowed to react with hydrazine hydrate to give car-
bohydrazide 2. The reaction of 3-chloro-1-benzothiophene-2-carbohydrazide 2 with potassium thiocyanate
gave compound 3, which was cyclized to form thioxotetrahydropyrimidine 4, thiazoles 5a–e, triazoles 7a–e
and oxadiazoles 10a–h. The structures of all the synthesized compounds were confirmed by spectral data
and have been screened for antimicrobial, analgesic and anthelmintic activities.
O
Br
Cl
O
Cl
O
NH
N
NH
R
R
S
NH NH
H2N
S
S
C2H5OH
S
3
5a-e
Reflux, 10h
Compound
R
-H
-F
-NO2
5a
5b
5c
5d
5e
-Br
-Cl
Keywords: benzothiophene; thiazole; triazole; oxadiazole; biological activity
1. Introduction
Benzothiophene, second in importance to thiophene among sulfur heterocycles and discovered
soon after the latter’s discovery, attracted scant attention at that time, apart from some interest
shown toward thioindigo dyes. The scenario, however, changed with the advent of bioisosterism,
*Corresponding author. Email: ratna_gowda@yahoo.co.in
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
DOI: 10.1080/17415993.2011.583394
http://www.informaworld.com

236 G. Naganagowda et al.
when organic chemists started showing interest in benzothiophene since it is a bioisoster of indole.
The synthesis of several sulfur analogs of bioactive furanochromones and furanocoumarins are
also reported in the literature (1, 2). These analogs consisting of a benzothiophene core are
usuallyobtainedfromthelatterthroughsuitableannulationreactions.Thebenzothiophenenucleus
is associated with diverse pharmacological activities such as nervous system depression (3),
analgesic (4), herbicidal (5), muscle relaxant (6) and tranquilizing (7) activities. The generation
of compounds incorporating thiazole, triazole and oxadiazole moieties have attracted widespread
attention due to their diverse pharmacological properties such as antimicrobial, anti-inflammatory,
analgesic and anti-tumor activities (8–12). We report here the synthesis of compounds derived
from benzothiophene containing thioxotetrahydropyrimidine, thiazoles, triazoles and oxadiazoles
moieties via carbothioamide intermediate. We also report the results of biological screening for
possible antibacterial, antifungal, analgesic and anthelmintic activity of the resulting derivatives.
Cl
Cl
Cl
O
NH NH2
O
NH2NH2.2H2O
Stirred, 7h, rt
S
S
1
2
C2H5OH
KSCN / HCl
Reflux, 10h
Cl
Cl
O
O
NH
S
CH2(COOC2H5)2
S
N
C2H5OH
S
NH NH
H2N
O
N
H
O
Reflux, 5h
3
S
4
Scheme 1. Synthesis of thioxotetrahydropyrimidine 4.
2. Results and discussion
3-Chloro-1-benzothiophene-2-carbonylchloride 1 was prepared by the reaction of cinnamic acid
with thionyl chloride in dimethyl formamide (DMF) and dry pyridine according to the reported
method (13). Compound 1 was then treated with hydrazine hydrate to obtain benzothiophene-
2-carbohydrazide 2. As anticipated, the IR spectrum of compound 2 exhibited peaks at 3020
and 1605 cm−1 corresponding to NH and C O stretching absorption frequencies, respectively.
The H-nuclear magnetic resonance (NMR) spectrum of compound 2 exhibited a multiplet in
=
1
the region between 7.92 and 7.41 ppm (parts per million) due to four aromatic protons and a
singlet at 8.22 ppm which corresponds to the one proton of the CONH group and a broad peak at
4.22 ppm (D2O exchangeable) corresponding to the two protons of the NH2 group. Finally, com-
pound 2 produced a molecular ion peak at m/z 226.68 which is in accordance with the structure.
Condensation of compound 2 with potassium thiocyanate gave carbothioamide 3. Compound 3
was reacted with diethyl malonate, resulting in compound 4 which showed a characteristic sin-
glet at 3.25 ppm due to the CH2 proton. Compound 3 also reacts with phenacyl bromide which
underwent cyclization to give 5a–e. The IR spectrum of compound 5a exhibited peaks at 3212
and 1695 cm−1 corresponding to NH and C O stretching absorption frequencies, respectively.
=

Journal of Sulfur Chemistry 237
1
The H-NMR spectrum of compound 5a exhibited a multiplet in the region between 8.23 and
8.11 ppm due to ten aromatic protons and two singlets at 9.94 and 4.12 ppm which corresponds to
the two protons of the CONH and NH groups. Finally, 5a produced a molecular ion peak at m/z
385.89 which is in accordance with the structure. Compound 3 upon heating with 4% NaOH in
ethanol underwent cyclization with loss of water to form 1,2,4-triazole-3-thiol 6. Condensation of
phenacyl bromide with compound 6 gave compound 7a. This was confirmed by its mass spectrum
(MS) that showed a molecular ion peak at m/z 385.89, which agrees with the molecular weight of
the compound. Compound 2 was also treated with chloroacetyl chloride, resulting in compound
8 which showed a characteristic singlet at 3.48 ppm due to the CH2 proton. Compound 8 when
treated with POCl3 gave 2-(3-chloro-1-benzothiophen-2-yl)-5-(chloromethyl)-1,3,4-oxadiazole
9. Compound 9 served as the precursor of compounds 10a–h by nucleophilic displacement of the
1
chloride with a series of aromatic amines. Two singlets in the H-NMR spectrum at 10.02 and
3.38 ppm corresponding to the NH and CH2 groups in 10a, provided confirmation of its structure.
The 1H and 13C, IR, MS and combustion analyses of 10a–h, which are given in the experimental
section, provide compelling evidence for the structures of these new benzothiophene derivatives.
3. Biological evaluation
3.1. Antibacterial activity
The cup plate method using Hi-Media agar medium was employed to study the antibacterial
activity of the synthesized compounds against two Gram-positive bacteria, Staphylococcus
aureus-ATCC 25923, Bacillus subtilis-ATCC 6633 and Gram-negative bacteria, Pseudomonas
aeruginosa-ATCC 10145, Escherichia coli-ATCC 35218. Preparation of nutrient broth, subcul-
ture, base layer medium, agar medium and peptone water was carried out according to a standard
procedure (14). Each test compound (50 mg) was dissolved in DMF (50 ml, 1000 μg/ml) to obtain
a sample solution. The sample volume for all the compounds was fixed at 0.1 ml. The cups were
made by scooping out agar medium with sterilized cork borer in a Petri dish, which was previously
inoculated with the microorganisms. The solution of each test compound (0.1 ml) was added in
the cups and Petri dishes were subsequently incubated at 37 ◦C for 48 h. Ampicillin and strepto-
mycin were used as reference drugs and DMF as a control. The zone of inhibition produced by
each compound was measured in millimeters. As shown in Table 1, the tested compounds showed
moderate antibacterial activity compared with standard drugs against each microorganism.
3.2. 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 the
filter paper disc technique (15). The concentration of test compounds was 1000 μg/ml. After
48 h treatment, the zone of inhibition produced by each compound was measured in millimeters.
Griseofulvin was used as the standard antifungal agent and DMF as a control. The results of
the antifungal activity are depicted in Table 2. Tested compounds showed slight to moderate
antifungal activity.
3.3. Analgesic activity
Albino mice of either sex (20–30 g) were used to evaluate acetic acid induced writhing anal-
gesic activity (16). Acetic acid (0.6%, 10 ml/kg) was used to induce writhing in mice. The

238 G. Naganagowda et al.
O
Cl
NH
NH
N
R
Compound
5a
R
–H
S
S
5b
5c
–F
–NO2
5a–e
5d
5e
–Br
–Cl
O
Br
C2H2OH
Reflux, 10h
O
Cl
R
O
Cl
Cl
Cl
Cl
N
N
O
NH NH
NH NH
O
Cl
NaOH
S
N
H
Reflux, 3 h
Reflux, 2 h
S
S
S
SH
8
6
3
O
H2N
Br
R1
Reflux, 12 h
POCl3
Cl
N
N
R2
Cl
S
O
Cl
9
N
NH2
N
R1
R2
S
N
H
O
1,4-dioxane
Reflux, 4 h
S
7a–e
R1
R3
Cl
Compound R1 R2
N
7a
7b
7c
–H –H
–F
–H –NO2
–H –Br
–Cl –H
R2
N
R1
–H
NH
S
O
R2
7d
7e
10a–h
R2
Compound R1
R2
R3
10a
10b
10c
–H
–H
–H
–Cl
–H
–F
–F
–NO2
–H
-Cl
–H
–H
–H
–H
10d
10e
10f
–H
–H
–H
–H
–H
–H
–Cl
–Br
10g
10h
–CH3
–CF3
Scheme 2. Synthesis of thiazoles 5a–e, triazoles 7a–e and oxadiazoles 10a–h.
mice were divided into five groups, each consisting of six animals. The analgesic response
was assessed by counting the number of abdominal constrictions for 20 min starting 3 min after
the injection of acetic acid solution. Groups 1–4 received the suspension of test compounds
at the dose of 100 mg/kg, respectively, and Group 5 received the standard drug suspension
(Ibuprofen) at the dose of 100 mg/kg.After 1 h, an acetic acid solution was administered intraperi-
toneally and the number of abdominal constrictions was recorded for 20 min starting from 3 min,
after the injection of acetic acid solution. All tested compounds showed varying degree of

Journal of Sulfur Chemistry 239
Table 1. Antibacterial activity of the tested compounds.
Zone of inhibition (mm)
Gram-positive bacteria Gram-negative bacteria
Compound
S. aureus
B. subtilis
P. aeruginosa
E. coli
4
5a
5b
6
7a
7b
9
10a
14
15
13
15
14
16
14
14
13
14
00
22
23
14
14
13
14
14
15
14
15
14
15
00
25
20
13
12
10
13
14
15
12
13
10
12
00
20
18
15
13
13
12
12
12
14
12
13
10
00
22
20
10b
10c
Control (DMF)
Ampicillin
Streptomycin
Table 2. Antifungal activity of the tested compounds.
Zone of inhibition (mm)
Compound
C. albicans
C. pannical
A. niger
R. oryzae
4
5a
5b
6
7a
7b
9
10a
12
15
14
14
16
12
12
13
12
15
00
24
17
15
11
13
12
11
15
10
17
12
00
25
15
11
11
14
11
12
14
13
15
12
00
23
15
12
11
14
13
14
11
13
15
15
00
22
10b
10c
Control (DMF)
Griseofulvin
analgesic activity with respect to ibuprofen taken as the standard drug. The analgesic activity
was calculated as the percentage maximum possible effect (% MPE) and the results are given
in Table 3.
3.4. Anthelmintic activity
The anthelmintic activity studies were carried out against earthworms (pontoscolex corethrusus)
according to a reported method (17). Six earthworms of approximately the same size were placed
in each Petri dish containing a 50 ml suspension of the specific concentration at 28
1 ◦C.
Simultaneously, a control study comprising six worms in distilled water and Tween-80 (0.5%)
was run. The drug concentrations were 0.1% (wt/vol.) for the standard and the test sample. The
times required for paralysis (movement stopped) and deaths of the worms were noted using a
stopwatch and the results are given in Table 4.

240 G. Naganagowda et al.
Table 3. Analgesic activity of the tested compounds.
Mean number of abdominal constrictions
that occurred between 3 and 20 min
Compound
Dose (mg/kg)
Before drug
After drug
% MPE
4
5a
5b
6
7a
7b
9
10a
100
100
100
100
100
100
100
100
100
100
100
40.1 2.00
24.8 1.21
40.1 2.00
28.6 1.73
40.6 2.12
52.4 2.51
23.1 1.51
26.4 1.63
23.8 1.02
40.1 2.00
47.1 2.50
15.2 1.40
08.4 0.92
15.2 1.40
12.2 1.21
13.8 0.43
17.2 2.61
08.9 0.82
10.4 1.33
08.3 1.22
15.2 1.40
11.8 1.27
60.1∗
66.1∗
60.1∗
64.1∗
61.3∗
60.3∗
66.4∗
62.2∗
61.7∗
60.1∗
75.1∗
10b
10c
Ibuprofen
Notes: Analgesic activity, Student’s t-test, n = 6.
∗P < 0.001 vs. control.
Table 4. Anthelmintic activity of the tested compounds.
Number of earth
worms tested
Concentration
(wt/vol.) (mg)
Mean paralysis
time SE (min)
Mean death
time SE (min)
Compound
4
5a
5b
6
7a
7b
9
10a
6
6
6
6
6
6
6
6
6
6
6
6
6
100
100
100
100
100
100
100
100
100
100
100
100
100
88.40 1.40
28.32 2.14
20.14 0.40
72.48 2.16
30.42 3.04
25.10 1.36
34.12 2.46
25.44 2.42
71.48 2.16
20.12 0.41
22.48 2.30
18.24 2.16
NE
126.14 3.16
32.00 2.12
25.12 0.68
84.32 3.16
38.26 3.16
30.18 3.10
48.16 3.02
34.28 2.48
83.32 3.16
25.16 0.65
46.28 2.42
55.32 3.42
NE
10b
10c
Piperazine citrate
Mependazole
Control
4. Conclusion
In conclusion, a new series of benzothiophene containing thioxotetrahydropyrimidine, thiazoles,
triazoles and oxadiazoles derivatives were synthesized and evaluated for their antibacterial, anti-
fungal, analgesic and anthelmintic activities. The newly synthesized heterocyclics exhibited
moderate antibacterial activity against S. aureus, B. subtilis, P. aeruginosa and E. coli and signifi-
cant antifungal activity against C. albicans, C. pannical, A. niger and R. oryzae and also moderate
analgesic and anthelmintic activities. It can be concluded that these classes of compounds certainly
hold great promise toward good active leads in medicinal chemistry.
5. Experimental
All chemicals were of 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 spectrum (KBr discs) were recorded using a

Journal of Sulfur Chemistry 241
Perkin-Elmer 237 spectrophotometer. 1H-NMR spectra were recorded on a Bruker Supercon FT-
NMR spectrometer (at 500 MHz) using DMSO-d6 as a solvent. 13C-NMR spectrum at 100 MHz
was recorded on a Bruker model ACF200 spectrophotometer. All chemical shifts were reported
in ppm using residual proton or carbon signals in deuterated solvents as internal references. MS
is recorded on Schimadzu GC-MS. Elemental analysis (C, H, N and S) was performed on a
Perkin Elmer 240 analyzer and all products were purified by recrystallization. The purity of the
compounds was checked by TLC on a silica gel and further purification was performed through
column chromatography (silica gel, 60–120 mesh).
5.1. Preparation of 3-chloro-1-benzothiophene-2-carbonyl chloride (1)
Compound 1 was prepared according to the literature procedure (13), mp 112–114 ◦C (Lit. mp
110–112 ◦C).
5.2. Preparation of 3-chloro-1-benzo[b]thiophene-2-carboxylicacidhydrazide (2)
Compound 1 (2.0 g, 0.0086 mol) was added directly to hydrazine hydrate (5.54 g, 5.33 ml and
0.17 mol) slowly with stirring, then the reaction mixture was stirred vigorously for about 7 h on a
magnetic stirrer. The reaction mixture was cooled down to room temperature and slowly decom-
posed in crushed ice. The solid that separated was filtered, washed with water and recrystallized
from ethanol to afford 2.
Yield 85%; mp 183–185 ◦C; IR ν (cm−1): 3020 (N H), 1605 (C O), 1570 (C C), 1070
−
=
=
1
= −
− −
−
( C Cl), 680 (C S C); H-NMR δ (ppm): 8.22 (s, 1H, CONH), 7.92–7.41 (m, 4H, Ar CH),
4.22 (2H, NH2); 13C-NMR δ (ppm): 169.2, 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%.
5.3. Preparation of 2-[(3-chloro-1-benzo[b]thiophen-2-yl)carbonyl]hydrazinecarbothio
amide (3)
A mixture of carbohydrazide 2 (2.26 g, 0.01 mol) and potassium thiocyanate (0.97 g, 0.01 mol) in
the presence of hydrochloric acid (5 ml) in distilled ethanol (50 ml) was refluxed on a steam bath
for 10 h. It was then concentrated, cooled and kept overnight in a refrigerator. The precipitate was
filtered, washed with ethanol, dried and recrystallized from methanol to get a pure compound 3.
1
Yield 66%; mp 194–196 ◦C; IR ν (cm−1): 3165 (N H), 1712 (C O), 1225 (C S); H-NMR
−
=
=
−
δ (ppm): 10.75 (s, 1H, CONH), 9.53 (s, NH2), 7.43–7.91 (m, 4H, Ar CH), 2.13 (s, 1H, NH);
13C-NMR δ (ppm): 160.6, 182.5, 141.6, 135.9, 133.4, 129.9, 126.7, 124.4, 124.3, 122.8; MS,
m/z: 285.77 (M+). Anal. calcd. for C10H5ClN2OS2: C, 42.03; H, 2.82; N, 14.70; S, 22.44; found:
C, 42.01; H, 2.79; N, 14.68; S, 22.40%.
5.4. Preparation of 3-chloro-N-(4,6-dioxo-2-thioxotetrahydropyrimidin-1(2H)-yl)-1-
benzothiophene-2-carboxamide (4)
A mixture of 3 (2.85 g, 0.01 mol) and diethyl malonate (1.60 g, 1.45 ml and 0.01 mol) in ethanol
(20 ml) and few drops of piperidine in glacial acetic acid was refluxed for 5 h.After the completion
of the reaction (TLC monitoring), the reaction mixture was cooled down to room temperature
and then poured into cold dilute HCl (10%). The precipitate was filtered, dried and recrystallized
from methanol to give pure product 4 as yellow solid.

242 G. Naganagowda et al.
1
Yield 58%; mp 203–205 ◦C; IR ν (cm−1): 3151 (N H), 1702 (C O), 1214 (C S); H-NMR
−
=
=
−
δ (ppm): 10.04 (s, 1H, CONH), 8.13 (s, 1H, NH), 7.43–7.91 (m, 4H, Ar CH), 3.25 (s, 2H, CH2);
13C-NMR δ (ppm): 183.0, 170.2, 166.3, 160.1, 141.4, 135.5, 133.3, 129.2, 126.7, 124.4, 124.1,
122.8, 42.1; MS, m/z: 353.80 (M+). Anal. calcd. for C13H8ClN3O4S2: C, 44.13; H, 2.28; N,
11.88; S, 18.13; found: C, 44.10; H, 2.25; N, 11.84; S, 18.10%.
5.5. The general procedure for the synthesis of compounds 5a–e.
5.5.1. Exemplary details for 3-chloro-Nꢀ-(4-phenyl-1,3-thiazol-2-yl)-1-benzo[b]thiophene-
2-carbohydrazide (5a)
A mixture of 3 (2.85 g, 0.01 mol) and phenacyl bromide (1.99 g, 0.01 mol) in absolute ethanol
(50 ml) was refluxed for 10 h. The completion of the reaction was monitored through TLC. After
completion of the reaction, the reaction mixture was cooled down to room temperature and poured
into crushed ice with vigorous stirring. The precipitate was filtered, washed with water, dried and
purified through column chromatography by using n-hexane and ethyl acetate (70:30) as an elutent
to get pure compound 5a. Compounds 5b–e were prepared in a similar manner.
Yield 65%; mp 210–212 ◦C; IR ν (cm−1): 3212 (N H), 1695 (C O); H-NMR δ (ppm): 9.94
1
−
=
(s, 1H, CONH), 8.23–8.11 (m, 10H, Ar CH and thiazole ring), 4.12 (s, 1H, NH); 13C-NMR δ
(ppm): 173.1, 160.4, 150.5, 141.6, 135.7, 133.4, 133.1, 129.9, 129.2, 129.2, 128.7, 127.5, 127.5,
126.7, 124.4, 124.3, 122.7, 105.0; MS, m/z: 385.89 (M+). Anal. calcd. for C18H12ClN3OS2: C,
56.02; H, 3.13; N, 10.89; S, 16.62; found: C, 56.00; H, 3.09; N, 10.87; S, 16.60%.
−
5.5.2. 3-Chloro-Nꢀ-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-1-benzo[b]thiophene-2-
carbohydrazide (5b)
Yield 66%; mp 234–236 ◦C; IR ν (cm−1): 3220 (N H), 1703 (C O), 1209 (C F); H-NMR
1
−
=
−
−
δ (ppm): 9.23 (s, 1H, CONH), 8.43–8.01 (m, 9H, Ar CH and thiazole ring), 4.10 (s, 1H,
NH); 13C-NMR δ (ppm): 173.1, 162.4, 160.3, 150.1, 141.2, 135.4, 133.3, 130.6, 130.6, 129.9,
128.6, 126.7, 124.4, 124.3, 122.8, 116.0, 116.0, 106.1; MS, m/z: 403.88 (M+). Anal. calcd. for
C18H11ClFN3OS2: C, 53.53; H, 2.75; N, 10.40; S, 15.88; found: C, 53.50; H, 2.70; N, 10.37;
S, 15.85%.
5.5.3. 3-Chloro-Nꢀ-[4-(4-nitrophenyl)-1,3-thiazol-2-yl]-1-benzo[b]thiophene-2-
carbohydrazide (5c)
1
Yield 62%; mp 240–242 ◦C; IR ν (cm−1): 3214 (N H), 1710 (C O), 1488 (Ar NO2); H-
−
=
−
−
NMR δ (ppm): 9.22 (s, 1H, CONH), 8.51–8.15 (m, 9H, Ar CH and thiazole ring), 4.19 (s, 1H,
NH); 13C-NMR δ (ppm): 173.5, 160.3, 150.2, 147.4, 141.3, 139.1, 135.9, 133.4, 129.2, 126.1,
126.2, 126.2, 124.5, 124.5, 124.3, 124.3, 122.5, 106.1; MS, m/z: 430.88 (M+); Anal. calcd. for
C18H11ClN4O3S2: C, 50.17; H, 2.57; N, 13.00; S, 14.88; found: C, 50.15; H, 2.54; N, 12.97; S,
14.84%.
5.5.4. 3-Chloro-Nꢀ-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-1-benzo[b]thiophene-2-
carbohydrazide (5d)
1
Yield 63%; mp 250–252 ◦C; IR ν (cm−1): 3204 (N H), 1714 (C O), 576 (C Br); H-NMR δ
−
=
−
(ppm): 9.09 (s, 1H, CONH), 8.91–8.05 (m, 9H, Ar CH and thiazole ring), 4.22 (s, 1H, NH); 13C-
NMR δ (ppm): 173.7, 160.2, 150.2, 141.1, 135.9, 133.4, 132.3, 132.3, 132.0, 129.4, 128.2, 128.3,
−

Journal of Sulfur Chemistry 243
126.7, 124.4, 124.3, 122.8, 105.0; MS, m/z: 464.78 (M+). Anal. calcd. for C18H11ClBrN3OS2:
C, 46.51; H, 2.39; N, 9.04; S, 13.80; found: C, 46.48; H, 2.35; N, 9.01; S, 13.78%.
5.5.5. 3-Chloro-Nꢀ-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-1-benzo[b]thiophene-2-
carbohydrazide (5e)
1
Yield 66%; mp 239–241 ◦C; IR ν (cm−1): 3203 (N H), 1711 (C O); H-NMR δ (ppm): 9.07 (s,
−
=
1H, CONH), 8.66–8.14 (m, 9H, Ar CH and thiazole ring), 4.16 (s, 1H, NH); 13C-NMR δ (ppm):
173.9, 160.1, 150.2, 141.6, 135.9, 134.3, 133.4, 131.2, 129.5, 129.4, 129.4, 128.5, 128.9, 126.7,
124.4, 124.1, 122.5, 105.0; MS, m/z: 420.33 (M+). Anal. calcd. for C18H11Cl2N3OS2: C, 51.43;
H, 2.64; N, 10.00; S, 15.26; found: C, 51.40; H, 2.61; N, 9.97; S, 15.22%.
−
5.6. Preparation of 5-(3-chloro-1-benzo[b]thiophen-2-yl)-4H-1,2,4-triazole-3-thiol (6)
A mixture of compound 3 (2 g) and sodium hydroxide (4%, 10 ml) was refluxed for 3 h. After
completion of reaction, the reaction mixture was acidified with dilute. HCl, the precipitate was
collected, dried and recrystallized from ethanol. Purification by column chromatography [silica
gel, petroleum ether/ethyl acetate (5:95)] yielded pure 6.
Yield 70%; mp 200–202 ◦C; IR ν (cm−1): 3310 (N H), 1630 (C N), 1310 (C S thione);
−
=
=
1
H-NMR δ (ppm): 9.17 (s, 1H, NH), 8.32–8.11 (m, 4H, Ar CH), 3.52 (s, 1H, SH); 13C-NMR
−
δ (ppm): 141.5, 138.7, 136.9, 124.4, 124.3, 123.2, 122.8, 118.4; MS, m/z: 267.75 (M+). Anal.
calcd. for C10H6ClN3S2: C, 44.86; H, 2.26; N, 15.69; S, 23.95; found: C, 44.84; H, 2.23; N, 15.65;
S, 23.91%.
5.7. General procedure for synthesis of compounds 7a–e
5.7.1. Exemplary detail for the preparation of 2-{[5-(3-chloro-1-benzo[b]thiophen-2-yl)-4H-
1,2,4-triazol-3-yl]sulfanyl}-1-phenylethanone (7a)
To a stirred solution of compound 6 (2.67 g, 0.01 mol) and sodium acetate (0.02 mol) in ethanol
(20 ml), phenacyl bromide (1.99 g, 0.01 mol) was added. The mixture was refluxed for 4 h. After
the completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled down to
room temperature and then added to crushed ice. The precipitate was filtered, washed with water,
dried and purified through column chromatography by using petroleum ether and ethyl acetate
(60:40) as an eluent to afford pure 7a. Compounds 7b–e was prepared in similar methodology.
Yield 62%; mp 231–233 ◦C; IR ν (cm−1): 3305 (N H), 1712 (C O), 1635 (C N); H-NMR
1
−
=
=
δ (ppm): 9.45 (s, 1H, NH), 8.32–7.89 (m, 9H, Ar CH), 3.40 (s, 2H, CH2); 13C-NMR δ (ppm):
194.6, 158.3, 141.2, 138.1, 136.4, 135.4, 133.2, 128.1, 128.1, 128.4, 128.4, 124.4, 124.3, 123.2,
122.8, 118.4, 38.5; MS, m/z: 385.89 (M+). Anal. calcd. for C18H12ClN2OS2: C, 56.02; H, 3.13;
N, 15.60; S, 23.95; found: C, 56.00; H, 3.10; N, 15.63; S, 23.92%.
−
5.7.2. 2-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-1-(4-
fluorophenyl)ethanone (7b)
1
Yield 61%; mp 241–243 ◦C; IR ν (cm−1): 3321 (N H), 1702 (C O), 1630 (C N); H-NMR
−
=
=
δ (ppm): 9.52 (s, 1H, NH), 8.12–7.99 (m, 8H, Ar CH), 3.35 (s, 2H, CH2); 13C-NMR δ (ppm):
194.5, 167.3, 158.2, 141.1, 138.4, 136.5, 131.6, 130.4, 124.4, 124.3, 123.2, 122.8, 118.4, 115.4,
115.4, 38.2; MS, m/z: 403.88 (M+). Anal. calcd. for C18H11ClFN3OS2: C, 53.53; H, 2.75; N,
10.40; S, 15.88; found: C, 53.50; H, 2.70; N, 10.38; S, 15.86%.
−

244 G. Naganagowda et al.
5.7.3. 2-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-1-(4-
nitrophenyl)ethanone (7c)
Yield 62%; mp 222–224 ◦C; IR ν (cm−1): 3301 (N H), 1704 (C O), 1629 (C N), 1491
−
=
=
1
−
−
(Ar NO2); H-NMR δ (ppm): 9.11 (s, 1H, NH), 8.76–8.11 (m, 8H, Ar CH), 3.43 (s, 2H, CH2);
13C-NMR δ (ppm): 194.1, 158.6, 152.1, 141.4, 141.4, 138.5, 136.9, 129.4, 129.4, 124.4, 124.3,
123.8, 123.8, 123.2, 122.8, 118.5, 38.7; MS, m/z: 430.88 (M+).Anal. calcd. for C18H11ClN4O3S2:
C, 50.17; H, 2.57; N, 13.00; S, 14.88; found: C, 50.16; H, 2.56; N, 12.98; S, 14.86%.
5.7.4. 2-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-1-(4-
bromophenyl)ethanone (7d)
Yield 60%; mp 250–252 ◦C; IR ν (cm−1): 3307 (N H), 1708 (C O), 1625 (C N), 569 (C Br);
−
=
=
−
1
H-NMR δ (ppm): 9.80 (s, 1H, NH), 8.88–8.14 (m, 8H, Ar CH), 3.49 (s, 2H, CH2); 13C-NMR δ
−
(ppm): 194.7, 158.4, 141.2, 138.5, 136.9, 134.2, 131.1, 131.5, 129.8, 129.8, 127.5, 124.4, 124.1,
123.1, 122.2, 118.4, 38.2; MS, m/z: 464.78 (M+). Anal. calcd. for C18H11BrClN3OS2: C, 46.51;
H, 2.39; N, 9.04; S, 13.80; found: C, 46.49; H, 2.35; N, 9.01; S, 13.76%.
5.7.5. 2-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-1-(2-
chlorophenyl)ethanone (7e)
1
Yield 62%; mp 260–262 ◦C; IR ν (cm−1): 3300 (N H), 1705 (C O), 1633 (C N); H-NMR δ
−
=
=
(ppm): 10.01 (s, 1H, NH), 8.06–7.77 (m, 8H, Ar CH), 3.48 (s, 2H, CH2); 13C-NMR δ (ppm):
194.8, 158.4, 141.3, 138.2, 138.7, 136.9, 133.4, 130.1, 130.2, 128.7, 128.7, 124.4, 124.3, 123.2,
122.1, 118.2, 38.4; MS, m/z: 420.33 (M+). Anal. calcd. for C18H11Cl2N3OS2: C, 51.43; H, 2.64;
N, 10.00; S, 15.26; found: C, 51.40; H, 2.60; N, 9.98; S, 15.23%.
−
5.8. Preparation of 3-chloro-Nꢀ-(chloroacetyl)-1-benzo[b]thiophene-2-carbohydrazide (8)
Carbohydrazide 2 (2.26 g, 0.01 mol) was added to chloroacetyl chloride (1.12 g, 0.81 ml and
0.01 mol) in pyridine (10 ml) and refluxed for 2 h. The reaction mixture was then poured over an
ice/HCl mixture. The resulting precipitate was filtered and recrystallized from toluene to afford 8.
1
Yield 85%; mp 245–247 ◦C; IR ν (cm−1): 3291 (N H), 1691 (C O); H-NMR δ (ppm): 10.71
−
=
(s, 1H, NH), 10.07 (s, 1H, CONH), 8.56–8.10 (m, 4H, Ar CH), 3.41 (s, 2H, CH2); 13C-NMR
δ (ppm): 166.3, 160.6, 141.6, 135.5, 133.4, 129.9, 126.7, 124.7, 124.3, 122.8, 41.5; MS, m/z:
303.16 (M+). Anal. calcd. for C11H8Cl2N2O2S: C, 43.58; H, 2.66; N, 9.24; S, 10.58; found: C,
43.56; H, 2.62; N, 9.20; S, 10.54%.
−
5.9. Preparation of 2-(3-chloro-1-benzo[b]thiophen-2-yl)-5-(chloromethyl)-1,3,4-
oxadiazole (9)
3-Chloro-Nꢀ-(chloroacetyl)-1-benzo[b]thiophene-2-carbohydrazide 8 (3.03 g and 0.01 mol) in
POCl3 (50 ml) was refluxed for 12 h. The completion of the reaction was monitored through
TLC. Upon completion of the reaction, the reaction mixture was cooled down to room tem-
perature and poured into crushed ice with vigorous stirring and neutralized with saturated
sodium bicarbonate solution. The precipitate was filtered, washed with water, dried and puri-
fied through column chromatography by using n-hexane and ethyl acetate (90:10) as an elutent to
afford 9.

Journal of Sulfur Chemistry 245
1
Yield 70%; mp 256–258 ◦C; IR ν (cm−1): 1635 (C N); H-NMR δ (ppm): 8.76–8.12 (m, 4H,
−
=
Ar CH), 3.46 (s, 2H, CH2); 13C-NMR δ (ppm): 161.1, 141.4, 138.5, 124.3, 124.3, 123.2, 122.5,
118.4, 47.5, 36.5; MS, m/z: 285.14 (M+). Anal. calcd. for C11H6Cl2N2OS: C, 46.33; H, 2.12; N,
9.82; S, 11.24; found: C, 46.30; H, 2.09; N, 9.79; S, 11.20%.
5.10. General procedure for synthesis of compounds 10a–h
5.10.1. Exemplary detail for N-{[5-(3-chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-
yl]methyl}-4-fluoroaniline (10a)
A mixture of 9 (2.85 g and 0.01 mol) and 4-fluoroaniline (1.11 g, 0.98 ml and 0.01 mol) in 1,4-
dioxane (20 ml) was refluxed for 4 h. After completion of the reaction, the reaction mixture was
cooleddowntoroomtemperatureandpouredintoicecooledwaterwithstirring, theprecipitatewas
filtered, washed with water, dried and recrystallized from 1,4-dioxane. Purification by column
chromatography [silica, petroleum ether/ethyl acetate (50:50)] afforded pure white crystals of
10a. Similarly, compounds 10b–h were prepared with little change in refluxed time and reaction
work-up.
1
Yield 60%; mp 249–251 ◦C; IR ν (cm−1): 3303 (N H), 1623 (C N); H-NMR δ (ppm): 10.02
−
=
(s, 1H, NH), 8.74–8.21 (m, 8H, Ar CH), 3.38 (s, 2H, CH2); 13C-NMR δ (ppm): 163.6, 161.2,
147.3, 141.5, 138.7, 136.9, 131.2, 124.4, 124.3, 123.2, 122.8, 118.4, 110.5, 109.1, 103.4, 51.6;
MS, m/z: 259.80 (M+). Anal. calcd. for C17H11ClFN3OS: C, 56.75; H, 3.08; N, 11.68; S, 8.91;
found: C, 56.74; H, 3.06; N, 11.65; S, 8.89%.
−
5.10.2. 3-Chloro-N-{[5-(3-chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-4-
fluoroaniline (10b)
1
Yield 61%; mp 260–262 ◦C; IR ν (cm−1): 3310 (N H), 1629 (C N); H-NMR δ (ppm): 10.11
−
=
(s, 1H, NH), 8.54–8.31 (m, 8H, Ar CH), 3.32 (s, 2H, CH2); 13C-NMR δ (ppm): 163.7, 161.3,
147.1, 141.5, 138.1, 136.1, 131.2, 124.4, 124.3, 123.2, 122.8, 118.4, 110.5, 109.1, 103.4, 51.3;
MS, m/z: 394.25 (M+). Anal. calcd. for C17H10Cl2N3OS: C, 51.79; H, 2.56; N, 10.66; S, 8.13;
found: C, 51.74; H, 2.53; N, 10.63; S, 8.09%.
−
5.10.3. N-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-4-
nitroaniline (10c)
Yield 66%; mp 278–280 ◦C; IR ν (cm−1): 3298 (N H), 1620 (C N), 1485 (Ar NO2); H-NMR
1
−
=
−
δ (ppm): 9.89 (s, 1H, NH), 8.91–8.09 (m, 8H, Ar CH), 3.46 (s, 2H, CH2); 13C-NMR δ (ppm):
161.2, 155.3, 141.1, 138.6, 136.7, 136.1, 127.3, 127.3, 124.2, 124.1, 123.2, 122.8, 118.4, 114.4,
114.4, 51.1; MS, m/z: 386.80 (M+). Anal. calcd. for C17H11ClN4O3S: C, 52.79; H, 2.87; N,
14.48; S, 8.29; found: C, 52.74; H, 2.85; N, 14.44; S, 8.25%.
−
5.10.4. N-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-
chloroaniline (10d)
1
Yield 60%; mp 245–247 ◦C; IR ν (cm−1): 3312 (N H), 1631 (C N); H-NMR δ (ppm): 10.11
−
=
(s, 1H, NH), 8.99–8.41 (m, 8H, Ar CH), 3.44 (s, 2H, CH2); 13C-NMR δ (ppm): 161.1, 143.4,
141.3, 138.6, 136.5, 130.3, 127.6, 124.4, 124.3, 123.8, 123.2, 122.8, 122.4, 118.4, 114.9, 51.2;
MS, m/z: 376.25 (M+). Anal. calcd. for C17H11Cl2N3OS: C, 54.27; H, 2.95; N, 11.17; S, 8.52;
found: C, 54.25; H, 2.92; N, 11.15; S, 8.48%.
−

246 G. Naganagowda et al.
5.10.5. N-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-4-
chloroaniline (10e)
1
Yield 62%; mp 230–232 ◦C; IR ν (cm−1): 3308 (N H), 1619 (C N); H-NMR δ (ppm): 9.88
−
=
(s, 1H, NH), 8.66–8.21 (m, 8H, Ar CH), 3.49 (s, 2H, CH2); 13C-NMR δ (ppm): 161.7, 143.3,
141.2, 138.1, 136.4, 130.5, 124.4, 124.3, 123.8, 123.1, 122.1, 122.4, 118.4, 114.9, 53.1; MS, m/z:
376.25 (M+). Anal. calcd. for C17H11Cl2N3OS: C, 54.27; H, 2.95; N, 11.17; S, 8.52; found: C,
54.25; H, 2.90; N, 11.14; S, 8.50%.
−
5.10.6. N-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-4-
bromoaniline (10f)
1
Yield 57%; mp 278–280 ◦C; IR ν (cm−1): 3301 (N H), 1633 (C N), 581 (C Br); H-NMR δ
−
=
−
(ppm): 10.12 (s, 1H, NH), 8.72–8.01 (m, 8H, Ar CH), 3.43 (s, 2H, CH2); 13C-NMR δ (ppm):
161.5, 148.1, 141.4, 138.7, 136.9, 132.4, 132.3, 124.3, 124.2, 123.1, 122.1, 118.4, 115.4, 114.4,
114.5, 51.6; MS, m/z: 420.71 (M+). Anal. calcd. for C17H11ClBrN3OS: C, 48.53; H, 2.64; N,
9.99; S, 7.62; found: C, 48.50; H, 2.60; N, 9.96; S, 7.59%.
−
5.10.7. N-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-4-
methylaniline (10g)
1
Yield 64%; mp 245–247 ◦C; IR ν (cm−1): 3293 (N H), 1631 (C N); H-NMR δ (ppm): 9.85 (s,
−
=
1H, NH), 8.76–8.09 (m, 8H, Ar CH), 3.44 (s, 2H, CH2), 2.89 (s, 3H, CH3); 13C-NMR δ (ppm):
161.1, 146.2, 141.4, 138.7, 136.9, 129.8, 129.8, 129.6, 124.4, 124.1, 123.1, 122.4, 118.3, 113.4,
113.4, 51.3, 21.1; MS, m/z: 355.84 (M+). Anal. calcd. for C18H14ClN3OS: C, 60.76; H, 3.97; N,
11.81; S, 9.01; found: C, 60.74; H, 3.95; N, 11.78; S, 9.00%.
−
5.10.8. N-{[5-(3-Chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-4-
(trifluoromethyl)aniline (10h)
Yield 66%; mp 250–252 ◦C; IR ν (cm−1): 3299 (N H), 1637 (C N); H-NMR δ (ppm): 9.99
1
−
=
(s, 1H, NH), 8.71–8.17 (m, 8H, Ar CH), 3.46 (s, 2H, CH2); 13C-NMR δ (ppm): 161.8, 152.3,
141.2, 138.5, 136.7, 125.7, 125.7, 124.3, 124.4, 124.3, 124.1, 123.2, 122.8, 118.3, 113.4, 113.4,
51.2; MS, m/z: 409.81 (M+). Anal. calcd. for C18H11ClF3N3OS: C, 52.75; H, 2.71; N, 10.25; S,
7.82; found: C, 52.73; H, 2.69; N, 10.23; S, 7.80%.
−
Acknowledgements
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. AM1079). The post doctoral fellowship grant from
the Ratchadapisakesompote Endownment Fund, Chulalongkorn University (to G.N.) was gratefully acknowledged.
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