Synthesis, antimicrobial, and anthelmintic activities of some new 3-chlorobenzothiophene-2-carbonylchloride derivatives

Article abstract of DOI:10.1080/10426500903241713

3-Chlorobenzothiophene-2-carbonylchloride 1 was prepared from cinnamic acid and then converted into the acid hydrazide 2. Reaction of 3-chloro-1- benzothiophene-2-carbohydrazide 2 with the appropriate isothiocyanate yielded the substituted thiosemicarbazi

Full text of DOI:10.1080/10426500903241713

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis, Antimicrobial, and
Anthelmintic Activities of Some
New 3-Chlorobenzothiophene-2-
Carbonylchloride Derivatives
Gadada Naganagowda a & Basavaraj Padmashali a
a Department of Chemistry , Sahyadri Science College (Autonomous),
Kuvempu University , Shimoga, Karnataka, India
Published online: 02 Aug 2010.
To cite this article: Gadada Naganagowda & Basavaraj Padmashali (2010) Synthesis, Antimicrobial,
and Anthelmintic Activities of Some New 3-Chlorobenzothiophene-2-Carbonylchloride
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:8, 1691-1700, DOI:
10.1080/10426500903241713
To link to this article: http://dx.doi.org/10.1080/10426500903241713
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Phosphorus, Sulfur, and Silicon, 185:1691–1700, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903241713
SYNTHESIS, ANTIMICROBIAL, AND ANTHELMINTIC
ACTIVITIES OF SOME NEW
3-CHLOROBENZOTHIOPHENE-2-CARBONYLCHLORIDE
DERIVATIVES
Gadada Naganagowda and Basavaraj Padmashali
Department of Chemistry, Sahyadri Science College (Autonomous), Kuvempu
University, Shimoga, Karnataka, India
3-Chlorobenzothiophene-2-carbonylchloride 1 was prepared from cinnamic acid and
then converted into the acid hydrazide 2. Reaction of 3-chloro-1-benzothiophene-2-
carbohydrazide 2 with the appropriate isothiocyanate yielded the substituted thiosemicar-
bazides 3a–b, which are cyclized into thioxotetrahydropyrimidine 4a–b, 1,3,4-thiadiazoles
5a–b, thiazolidine 6a–b, 1,3,4-oxadiazole 7a–b, triazoles 8a–b, 1,2,4-triazole substitut-
edthioate 9a–f, and 1,3-thiazolylidenes 10a–b, respectively. The structures of the newly
synthesized compounds were elucidated on the basis of elemental analyses, IR, 1H NMR,
and mass spectral data and have been screened for antimicrobial and anthelmintic activities.
Keywords Benzothiophene; biological activity; 1,3,4-oxadiazoles; 1,3,4-thiadiazoles; 1,3-
thiazolylidenes; triazoles
INTRODUCTION
The synthesis of biheterocycles has recently been of great interest because they
possess a high biological profile. They are grabbing the attention of medicinal chemists
for molecular manipulation and of biologists for further pharmacological evaluation. It has
been reported that the presence of two or more pharmacophores in a drug molecule would
enhance the biological profile many times over. In view of this observation, in this article
we report the synthesis of benzothiophene linked to pyrimidine, thiadiazole, oxadiazole,
triazole, and thiazole moieties.
Benzothiophene, second in importance to thiophene among sulfur heterocycles, has
attracted scant attention of organic chemists since it is a bioisoster of indole. The chem-
istry of benzothiophene, in the 1960s and 1970s, was centered around the synthesis of
its derivatives, which are analogues of bioactive indole derivatives, and the literature on
benzothiophene up to 1980 has been reviewed.1–3 The interest in this class of compounds
Received 6 March 2009; accepted 4 August 2009.
The authors are thankful to Principal, Sahyadri Science College (Autonomous), for providing laboratory
facilities to carry out the synthesis and pharmacological activity of the compounds. The authors are also thankful
to Sophisticated Instrumentation Facility, Indian Institute of Science, Bangalore, for providing spectral data.
Address correspondence to Gadada Naganagowda, Department of Chemistry, Sahyadri Science College
(Autonomous), Kuvempu University, Shimoga-577 203, Karnataka, India. E-mail: ratna-gowda@yahoo.co.in
1691

1692
G. NAGANAGOWDA AND B. PADMASHALI
is principally due to their usefulness in the synthesis of sulfur analogues of several impor-
tant bioactive indole derivatives, viz. serotonin, and annulation of oxygenated rings onto
the benzothiophene core. The benzothiophene nucleus is associated with diverse pharma-
cological activities such as nervous system depressing,4 analgesic,5 herbicidal,6 muscle
relaxant,7 and tranquilizing8 activities. The synthesis of compounds incorporating pyrimi-
dine, thiadiazole, oxadiazole, triazole, and thiazole moieties has been attracting widespread
attention due to their diverse pharmacological properties such as antimicrobial, antiinflam-
matory, analgesic, and antitumor activities.9–13 Because the substituted thiosemicarbazides
are valuable building blocks for the synthesis of five-memberd heterocyclics,14 we thought
to synthesize benzothiophene linked to pyrimidine, thiadiazole, oxadiazole, triazole, and
thiazole moieties via semicarbazides intermediate, with the purpose of investigating in the
future their possible antibacterial, antifungal, and anthelmintic activities.
RESULTS AND DISCUSSION
In this article, we report the synthesis and biological properties of some new thiox-
otetrahydropyrimidines, 1,3,4-thiadiazoles, thiazolidines, 1,3,4-oxadiazoles, thiotriazoles,
and 1,3-thiazolylidenes derivative incorporated with the benzothiophene ring, following the
sequence of reactions as depicted in Scheme 1. The starting material for the synthesis of the
Cl
Cl
S
O
S
NH N
O
1
N
Cl
NH NH .2H
2
O
2
R
1
Cl
S
NHNH
O
2
S
10a-b
2
N=C=S
PhCOCH Br
2
R
1
Cl
Cl
R
1
S
COOH
N
N
N
NH
O
R
COOH
Cl
N
N
1
Cl
O
S
S
NaOH
SH
HN
O
O
NH
H
C
8a -b
3
4a-b
S
NH
S
R
O
1
3a-b
I
+KI
2
Con H SO
2
4
R
-Cl
2
Cl CH COOH
2
+
CH COONa
3
Cl
Cl
N
S
N
Cl
N
N
R
Cl
2
N
O
S
N
O
S
NH
N
S
S
NH
N
O
S
S
N
5a-b
NH
R
1
O
R
7a-b
1
6a-b
R
9a-f
1
R
1
Compound
R1
R2
COCH3
9a
9b
9c
9d
9e
9f
H
H
C6H5CO
CH3
Compound
R1
3a
3b
H
4-Cl
H
4-Cl
4-Cl
4-Cl
COCH3
C6H5CO
CH3
Scheme 1 General synthetic procedure for 3-chlorobenzothiophene-2-carbonyl chloride substituted thiosemicar-
bazides 3a–b, thioxotetrahydropyrimidines 4a–b, 1,3,4-thiadiazoles 5a–b, thiazolidines 6a–b, 1,3,4-oxadiazoles
7a–b, triazoles 8a–b, 1,2,4-triazole substitutedthioates 9a–f, and 1,3-thiazolylidenes 10a–b.

3-CHLOROBENZOTHIOPHENE-2-CARBONYLCHLORIDE DERIVATIVES
1693
target compounds is 3-chlorobenzothiophene-2-carbonylchloride 1, which was prepared by
the reaction of cinnamic acid, thionyl chloride in the presence of pyridine in DMF.15 The
compound 1 was treated with hydrazine hydrate to obtain 3-chloro-1-benzothiophene-2-
carbohydrazide 2 in good yield. The IR spectrum of compound 2 was found to exhibit peaks
at 3020 and 1605 cm−1 due to N H and C O groups stretching absorption frequencies,
1
respectively. The H NMR spectrum of the same compound was found to show a singlet
corresponding to one proton at 8.20 δ ppm due to CONH proton, a multiplet in the region
7.92–7.41 δ ppm corresponding to four aromatic protons and a broad peak at 4.21 δ ppm
(D2O exchangeable) corresponding to two NH2 protons. The 13C NMR spectrum of the
compound 2 exhibited a peak at 185 δ ppm due to CONH carbon, the peaks at 138, 131,
129, 128, 125, 123, and 122.98 correspond to eight aromatic carbons. The formation of the
compound 2 was also confirmed by its mass spectrum, which exhibited a molecular ion
peak at m/z 226.68.
Condensation of carbohydrazide 2 with aryl isothiocyanates separately afforded
thiosemicarbazides 3a–b in good yields. In confirmation, compound 3a exhibited peaks
at 3170, 1660, and 1220 cm−1 stretching absorption frequencies in its IR spectrum corre-
1
sponding to N H, C O, and C S groups. H NMR spectrum of compound 3a showed
three singlets in the region 10.41–9.72 δ ppm due to three NH protons separately and a
multiplet in between 8.15 and 7.15 δ ppm due to eight aromatic protons. This was further
confirmed by its mass spectrum that showed a molecular ion peak at m/z 360.10, which
agrees with the molecular weight of the compound.
Thiosemicarbazides 3a–b upon reaction with malonic acid in the presence of
acetyl chloride underwent intermolecular cyclization to afford 3-chloro-N-(4,6-dioxo-
3-aryl-2-thioxotetrahydropyrimidin-1(2H)-yl)-1-benzothiophene-2-carboxamides 4a–b.
Compound 4a exhibited peaks at 3140, 1635, and 1220 cm−1 due to N H, C O, and C S
stretching absorption frequencies in its IR spectrum. 1H NMR spectrum of compound 4a
showed two singlets at 2.25 and 10.58 δ ppm due to CH2 and NH protons and a multiplet in
the region 8.00–7.20 δ ppm due to nine aromatic protons. This was further confirmed by its
mass spectrum, which showed a molecular ion peak at m/z 428.90. Cyclodehydration of the
thiosemicarbazides 3a–b with cold concentrated sulfuric acid produced 1,3,4-thiadiazoles
5a–b. The IR spectrum of the compound 5a showed peaks at 3130 and 1643 cm−1 due to
1
N H and C O stretching absorption frequencies. The H NMR spectrum of compound
5a exhibited a broad singlet at 10.90 δ ppm corresponding to one proton of NH group and
a multiplet in the region 8.16–7.03 δ ppm due to nine aromatic protons. As an additional
proof, the mass spectrum of compound 5a exhibited a molecular ion peak at m/z 343.80.
The compound 3-chloro-N-[4-oxo-2-(arylimino)-5-thioxo-1,3-thiazolidin-3-yl]-1-
benzothiophene-2-carboxamides 6a–b were obtained by cyclizing thiosemicarbazides
3a–b with chloroacetic acid in the presence of sodium acetate in acetic acid. In confirma-
tion, compound 6a showed peaks at 3155 and 1645 cm−1 in its IR spectrum due to N H and
C N stretching frequencies. Two singlets at 11.05 and 2.85 δ ppm due to CONH and CH2
protons, and a multiplet in the region 8.00–7.20 δ ppm due to nine aromatic protons in its
1H NMR spectrum also indicated its formation. As an additional proof, the mass spectrum
of compound 6a exhibited a molecular ion peak at m/z 401.88. Thiosemicarbazides 3a–b
were subjected to oxidative cyclization to 2-arylamino-5-substituted-1,3,4-oxadiazoles
7a–b by treatment with iodine and potassium iodide in ethanolic sodium hydroxide.
The compound 7a exhibited peaks at 3320, 1635, and 690 cm−1 due to N H, C N,
1
and C S C stretching absorption frequencies in its IR spectrum. H NMR spectrum of
compound 7a showed a singlet at 10.92 δ ppm due to NH proton and a multiplet in the

1694
G. NAGANAGOWDA AND B. PADMASHALI
Table I Characterization data of the compounds
Compound
R1
R2
Yield (%)
Mp (◦C)
2
—
H
4-Cl
H
4-Cl
H
4-Cl
H
4-Cl
H
4-Cl
H
4-Cl
H
H
H
4-Cl
4-Cl
4-Cl
H
—
—
—
—
—
—
—
—
—
—
—
—
—
97
75
55
45
44
44
65
65
55
72
66
44
45
55
56
45
75
71
72
56
54
183–185
245–247
231–233
243–245
254–256
260–262
241–243
249–251
254–256
270–272
278–280
263–265
245–247
234–236
225–227
230–232
234–236
243–245
241–243
270–272
275–277
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
9c
9d
9e
9f
COCH3
C6H5CO
CH3
COCH3
C6H5CO
CH3
—
10a
10b
4-Cl
—
region 8.16–7.03 δ ppm due to nine aromatic protons. The mass spectrum molecular ion
peak at m/z 326.18 corresponds to its molecular weight.
The compounds 3a–b upon heating with 4N NaOH in ethanol underwent smooth cy-
clization through dehydration to form 5-substituted-4-aryl-3-mercapto-4H-1,2,4-triazoles
8a–b. Condensation of acid chlorides or alkyl halides with compounds 8a–b afforded the
acylated and alkylated derivatives 9a–f. Compound 9a exhibited peaks at 1650 and 1615
cm−1 due to C O and C N stretching absorption frequencies in its IR spectrum. 1H NMR
spectrum of compound 9a showed a multiplet in the region 8.92–8.41 δ ppm due to nine
aromatic protons and a singlet at 3.55 δ ppm due to CH3 proton. Finally, the thiosemicar-
bazides 3a–b were refluxed with phenacylbromide to give 1,3-thiazolylidenes derivative
10a–b. The purity of the newly synthesized compounds was monitored by TLC. The struc-
tures of newly synthesized compounds were elucidated on the basis of elemental analyses
and spectral data, and have been screened for antimicrobial and anthelmintic activities. The
physical constants and yields of the obtained compounds are presented in Table I.
Antibacterial Activity
Cup plate method using Hi-Media agar medium was employed to study the an-
tibacterial activity of the newly synthesized compounds against S. aureus, B. subtilis, P.
aeruginosa, and E. coli. Preparation of nutrient broth, subculture, base layer medium, agar
medium, and peptone water was done as per the standard procedure.16 The compounds
were tested at the dose of 1000 µg/mL concentration. Amoxycillin and erythromycin were
used as standard drugs and dimethyl formamide was used as a control. The zone of inhi-
bition produced by each compound was measured in mm. The tested compounds showed
moderate antibacterial activity compared to the standard drugs against all microorganisms.

3-CHLOROBENZOTHIOPHENE-2-CARBONYLCHLORIDE DERIVATIVES
1695
Table II Anthelmintic activity of the selected compounds
Number of earth
worms tested
Concentration
(wt/vol) (mg)
Mean paralysis
time SE(min)
Mean death
time SE(min)
Compound
3a
3b
4a
5a
5b
6a
7a
7b
8a
9a
9c
10b
6
6
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
100
100
64.20 2.46
88.40 1.40
28.32 2.14
34.12 2.46
44.20 1.36
28.12 2.42
30.42 3.04
25.10 1.36
40.24 1.22
32.16 2.42
34.12 2.46
71.48 2.16
22.48 2.30
18.24 2.16
NE
83.42 0.36
126.14 3.16
32.00 2.12
48.16 3.02
68.12 1.46
34.36 1.42
38.26 3.16
30.18 3.10
62.18 2.18
40.10 1.30
48.16 3.02
83.32 3.16
46.28 2.42
55.32 3.42
NE
Piperazine citrate
Mependazole
Control
Earthworm: Sp. portoscoplex corethrusus; amount of sample: 100 mg; standard drugs: piperazine citrate and
mependazole; control: distilled water +0.5% Tween-80; NE: no effect; SE: standard error.
Antifungal Activity
The antifungal activity of the synthesized compounds was tested against four dif-
ferent fungi such as C. albicans, C. pannical, A. niger, and R. oryzae by filter paper disc
technique.17 The concentration of test compounds was 1000 µg/mL. After 48 h treatment,
the zone of inhibition produced by each compound was measured in mm. Griseofulvin was
used as the standard antifungal agent, and dimethyl formamide was used as a control. All
the tested compounds showed slight to moderate antifungal activity.
Anthelmintic Activity
The anthelmintic activity studies were carried out against earthworms (pontoscolex
corethrusus) according to the method of Grag and Atal.18 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 comprising six worms in the distilled
water and tween-80 (0.5%) was kept. The drug concentrations were 0.1% (wt/ vol) for
the standard and the test sample. The times required for paralysis (movement stopped)
and death of the worms were noted using a stopwatch. The compound 4b and 7a showed
significant anthelmintic activity.
EXPERIMENTAL
Melting points were determined in open capillary tubes and are uncorrected. IR
spectra (KBr disks) were recorded using a Perkin-Elmer 237 spectrophotometer. 1H NMR
spectra were recorded on a Bruker Supercon FT NMR spectrometer (at 400 MHz) using
tetramethylsilane (TMS) as an internal standard and DMSO-d6 as a solvent. Chemical
shifts were given in parts per million (ppm). Splitting patterns were designated as fol-
lows s–singlet, d–doublet, t–triplet, q–quartet, and m–multiplet. Mass spectra (MS) were

1696
G. NAGANAGOWDA AND B. PADMASHALI
recorded on a Shimadzu 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 silica gel and were further purified through
column chromatography (silica gel, 60–120 mesh).
Preparation of 3-Chloro-1-benzothiophene-2-carbonyl chloride (1)
The compound 1 was prepared according to the literature procedure,29 m.p 112–114◦C
(literature mp 110–112◦C).
Preparation of 3-Chloro-1-benzothiophene-2-carbohydrazide (2)
Compound 1 (2.31 g, 10.0 mmol) was added to hydrazine hydrate (0.54 g, 0.53 mL,
10.0 mmol) directly and slowly with constant stirring, then the reaction mixture was stirred
vigorously for 7 h on a magnetic stirrer. The reaction mixture was cooled to room temputure
and was decomposed in crushed ice slowly. The solid that separated was filtered, washed
with water, and recrystallized from ethanol to furnish a light yellowish solid 2.
IR (KBr) ν (cm−1): 3020 (N H), 1605 (C O), 1570 (C C), 1070 ( C Cl), 680
(C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.20 (1H, s, CONH), 7.92–7.41 (4H,
m, Ar-H), 4.21 (2H, NH2); 13C NMR δ:185 (C O), 138, 131, 129, 128, 125, 123, 122
(aromatic carbon); MS (M+): 226.68, 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 2-[(3-Chloro-1-benzothiophen-2-yl)carbonyl]-N-phenyl
hydrazinecarbothioamide (3a–b)
A mixture of carbohydrazide 2 (2.26 g, 10.0 mmol) and phenyl isothiocyanate (1.35
g, 1.27 mL, 10.0 mmol) 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 solid that
precipitated was filtered, washed with ethanol, dried, and recrystallized from ethanol to get
a pure compound 3a. The compound 3b was prepared in a similar manner.
2-[(3-Chloro-1-benzothiophen-2-yl)carbonyl]-N-phenylhydrazinecarbo
thioamide (3a). IR (KBr) ν (cm−1): 3170 (N H), 1660 (C O), 1570 (C C), 1220
(C S), 1070 ( C Cl), 690 (C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm):
10.41–9.72 (3H, s, NH), 8.15–7.15 (9H, m, Ar-H); MS (M+): 360.10, Calcd. (%) for
C16H12ClN3OS2:C, 53.11; H, 3.34; N, 11.61; S, 17.72. Found: C, 53.01; H, 3.30; N, 11.56;
S, 17.68.
2-[(3-Chloro-1-benzothiophen-2-yl)carbonyl]-N-(4-chlorophenyl)hydra
zinecarbothioamide (3b). IR (KBr) ν (cm−1): 3165 (N H), 1657 (C O), 1225
(C S), 758 (C Cl), 690 (C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm):
11.00–9.52 (3H, s, NH), 8.00–7.20 (8H, m, Ar-H); MS (M+): 396.10, Calcd. (%) for
C16H11Cl2N3OS2:C, 48.49; H, 2.80; N, 10.60; S, 16.18. Found: C, 48.41; H, 2.75; N,
10.57; S, 16.12.

3-CHLOROBENZOTHIOPHENE-2-CARBONYLCHLORIDE DERIVATIVES
1697
Preparation of 3-Chloro-N-(4,6-dioxo-3-phenyl-2-
thioxotetrahydropyrimidin-1(2H)-yl)-1-benzothiophene-2-
carboxamide (4a–b)
To compound 3a (1.80 g, 5.0 mmol) in acetyl chloride (10 mL), malonic acid (2.08 g,
10.0 mmol) was added, and the mixture was heated for 6 h at 40◦C. It was then cooled and
poured into crushed ice, and the resulting solid was recrystallized from ethanol and then
purified from column chromatography (silica gel, 60–120 mesh) by using petroleum ether
and ethyl acetate (5:95) as an elutent to get pure 4a. Compound 4b was similarly prepared.
3-Chloro-N-(4,6-dioxo-3-phenyl-2-thioxotetrahydropyrimidin-1(2H)-yl)-
1-benzothiophene-2-carboxamide (4a). IR (KBr) ν (cm−1): 3140 (N H), 1635
(C O), 1570 (C C), 1220 (C S), 1065 ( C Cl), 688 (C S C); 1H NMR (400 MHz,
DMSO-d6) δ (ppm): 10.58 (1H, s, CONH), 8.00–7.20 (9H, m, Ar-H), 2.25 (2H, s, CH2);
MS (M+): 428.90, Calcd. (%) for C19H12ClN3O3S2:C, 53.08; H, 2.81; N, 9.77; S, 14.92.
Found: C, 53.00; H, 2.76; N, 9.71; S, 14.88.
3-Chloro-N-[3-(4-chlorophenyl)-4,6-dioxo-2-thioxotetrahydropyrimidin-1
(2H)-yl]-1-benzothiophene-2-carboxamide (4b). IR (KBr) ν (cm−1): 3135 (N H),
1
1620 (C O), 1570 (C C), 1225 (C S), 755 (C Cl), 690 (C S C); H NMR (400
MHz, DMSO-d6) δ (ppm): 11.05 (1H, s, CONH), 8.07–7.09 (8H, m, Ar-H), 2.30 (2H, s,
CH2); MS (M+): 464.13, Calcd. (%) for C19H11Cl2N3O3S2:C, 49.15; H, 2.39; N, 9.05; S,
13.81. Found: C, 49.02; H, 2.30; N, 9.00; S, 13.75.
Preparation of 5-(3-Chloro-1-benzothiophen-2-yl)-N-phenyl-1,3,4-
thiadiazol-2-amine (5a–b)
Thiosemicarbazide 3a (1.80 g, 5.0 mmol) was added gradually with stirring to cold
concentrated sulfuric acid (10 mL) at 70◦C during the course of 20 min. The reaction mixture
was heated with stirring at 70◦C for another 1 h, then it was poured over crushed ice under
stirring. The solid precipitated was filtered, washed with water, dried, and recrystallized
from methanol to get 5a. Compound 5b was similarly prepared.
5-(3-Chloro-1-benzothiophen-2-yl)-N-phenyl-1,3,4-thiadiazol-2-amine
1
(5a). IR (KBr) ν (cm−1): 3130 (N H), 1643 (C O), 1220 (C S), 690 (C S C); H
NMR (400 MHz, DMSO-d6) δ (ppm): 10.90 (1H, s, NH), 8.16–7.03 (9H, m, Ar-H); MS
(M+): 343.80, Calcd. (%) for C16H10ClN3S2:C, 55.89; H, 2.93; N, 12.22; S, 18.65. Found:
C, 55.80; H, 2.89; N, 12.13; S, 18.61.
5-(3-Chloro-1-benzothiophen-2-yl)-N-(4-chlorophenyl)-1,3,4-thiadiazol-
2-amine (5b). IR (KBr) ν (cm−1): 3142 (N H), 1635 (C O), 1220 (C S), 760 (C Cl),
1
690 (C S C); H NMR (400 MHz, DMSO-d6) δ (ppm): 10.51 (1H, s, NH), 8.20–7.05
(8H, m, Ar-H); MS (M+): 373.01, Calcd. (%) for C16H9Cl2N3S2:C, 50.80; H, 2.40; N,
11.11; S, 16.95. Found: C, 50.75; H, 2.35; N, 11.05; S, 16.89.
Preparation of 3-Chloro-N-[(2Z)-4-oxo-2-(phenylimino)-1,3-thiazolidin-
3-yl]-1-benzothiophene-2-carboxamide (6a–b)
Compound 3a (1.80 g, 5.0 mmol) was treated with chloroacetic acid (0.47 g, 5.0
mmol) in the presence of sodium acetate (0.41 g, 5.0 mmol) in glacial acetic acid (20 mL),
and the mixture was refluxed for 10 h at 110◦C. The reaction mixture was monitored by
TLC. After completion, the reaction mixture was cooled and poured into crushed ice, the

1698
G. NAGANAGOWDA AND B. PADMASHALI
separated solid was filtered, dried, and recrystallized from 1.4-diaxone to obtain pure 6a.
The compound 6b was prepared in a similar manner.
3-Chloro-N-[(2Z)-4-oxo-2-(phenylimino)-1,3-thiazolidin-3-yl]-1-benzothio
phene-2-carboxamide (6a). IR (KBr) ν (cm−1): 3155 (N H), 1645 (C N), 1615
1
(C O), 1575 (C C), 1070 ( C Cl) 688 (C S C); H NMR (400 MHz, DMSO-d6)
δ (ppm): 11.05 (1H, s, CONH), 8.00–7.20 (9H, m, Ar-H), 2.85 (2H, s, CH2); MS (M+):
401.88, Calcd. (%) for C18H12ClN3O2S2:C, 53.79; H, 3.01; N, 10.46; S, 15.96. Found: C,
53.75; H, 3.00; N, 10.43; S, 15.94.
3-Chloro-N-{(2Z)-2-[(4-chlorophenyl)imino]-4-oxo-1,3-thiazolidin-3-yl}-1-
benzothiophene-2-carboxamide (6b). IR (KBr) ν (cm−1): 3155 (N H), 1620
1
(C O), 1575 (C C), 763 (C Cl), 685 (C S C); H NMR (400 MHz, DMSO-d6) δ
(ppm): 10.06 (1H, s, CONH), 8.04–7.08 (8H, m, Ar-H), 2.92 (2H, s, CH2); MS (M+):
436.33, Calcd. (%) for C18H11Cl2N3O2S2:C, 49.55; H, 2.54; N, 9.63; S, 14.70. Found: C,
49.52; H, 2.53; N, 9.61; S, 14.69.
Preparation of 5-(3-Chloro-1-benzothiophen-2-yl)-N-phenyl-1,3,4-
oxadiazol-2-amine (7a–b)
Compound 3a (1.90 g, 4.0 mmol) in ethanol (10 mL) was dissolved in aqueous
sodium hydroxide (10%, 5 mL) under cooling and stirring, resulting in a clear solution. To
this, iodine in potassium iodide solution (5%) was added gradually under stirring until the
iodine color persisted at room temperature. The reaction mixture was then refluxed for 6 h
in a water bath. It was then cooled and poured over crushed ice. The solid mass that was
precipitated was filtered, dried, and recrystallized from ethanol and further purified through
column chromatography (silica gel, 60–120 mesh) by using ethyl acetate and petroleum
ether (20:80) as an elutent to get pure compound 7a. Similarly, the compound 7b was
prepared.
5-(3-Chloro-1-benzothiophen-2-yl)-N-phenyl-1,3,4-oxadiazol-2-amine (7a).
IR (KBr) ν (cm−1): 3220 (N H), 1635 (C N), 1070 ( C Cl), 690 (C S C); 1H NMR
(400 MHz, DMSO-d6) δ (ppm): 10.92 (1H, s, NH), 8.16–7.03 (9H, m, Ar-H); MS (M+):
326.18, Calcd. (%) for C16H10ClN3OS:C, 58.63; H, 3.07; N, 12.82; S, 9.78. Found: C,
58.55; H, 3.00; N, 12.76; S, 9.72.
5-(3-Chloro-1-benzothiophen-2-yl)- N-(4-chlorophenyl)-1,3,4-oxadiazol-
2-amine (7b). IR (KBr) ν (cm−1): 3215 (N H), 762 (C Cl), 690 (C S C); 1H NMR
(400 MHz, DMSO-d6) δ (ppm): 10.82 (1H, s, NH), 8.10–7.06 (8H, m, Ar-H); MS (M+):
362.01, Calcd. (%) for C16H9Cl2N3OS:C, 53.05; H, 2.50; N, 11.60; S, 8.85. Found: C,
53.00; H, 2.45; N, 11.52; S, 8.80.
Preparation of 5-(3-chloro-1-benzothiophen-2-yl)-4-phenyl-4H-1,2,4-
triazole-3-thiol (8a–b)
The compound 3a (1.80 g, 5.0 mmol) in ethanol (10 mL) was dissolved in aqueous
sodium hydroxide (4%, 8 mL), and the mixture was refluxed gently for 2 h. The resulting
solution was treated with decoloring charcoal, cooled, and filtered. The filtrate was adjusted
to pH 6 with dilute acetic acid (10%), and the separated solid was filtered, dried, and the
residue purified by recrystallization from ethanol to give pure compound of 8a. Compound
8b was similarly prepared.

3-CHLOROBENZOTHIOPHENE-2-CARBONYLCHLORIDE DERIVATIVES
1699
5-(3-Chloro-1-benzothiophen-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (8a).
IR (KBr) ν (cm−1): 3320 (N H), 1630 (C N), 1310 (C S thione), 1065 ( C Cl), 686
(C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.92–8.22 (9H, m, Ar-H), 3.82 (1H,
s, NH); MS (M+): 343.80, Calcd. (%) for C16H10ClN3S2: C, 55.89; H, 2.93; N, 12.22; S,
18.65. Found: C, 55.80; H, 2.90; N, 12.17; S, 18.60.
5-(3-Chloro-1-benzothiophen-2-yl)-4-(4-chlorophenyl)-4H-1,2,4-triazole-
3-thiol (8b). IR (KBr) ν (cm−1): 3310 (N H), 1630 (C N), 1310 (C S thione), 756
1
(C Cl), 688 (C S C); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.20–8.51 (8H, m,
Ar-H), 3.72 (1H, s, NH); MS (M+): 378.02, Calcd. (%) for C16H9Cl2N3S2: C, 50.80; H,
2.40; N, 11.11; S, 16.95. Found: C, 50.77; H, 2.37; N, 11.06; S, 16.90.
Preparation of S-[5-(3-Chloro-1-benzothiophen-2-yl)-4-phenyl-4H-
1,2,4-triazol-3-yl]ethanethioate (9a–f)
A mixture of 8a (1.71 g, 5.0 mmol), acid chlorides/alkyl halides (6.0 mmol) in ethanol
(20 mL), and 10% NaOH (5 mL) were created and then refluxed in a water bath for 2 h. The
reaction mixture was cooled and filtered, and the filtrate was acidified with dil HCl to get
the precipitate, which was collected by filtration and recrystallized from ethanol to get 9a.
Similarly, compounds 9b–f were prepared with some change in reflux time and reaction
workup. Their characteristic spectral and analytical data are given below.
S-[5-(3-Chloro-1-benzothiophen-2-yl)-4-phenyl-4H-1,2,4-triazol-3-yl]etha
nethioate (9a). IR (KBr) ν (cm−1): 1650 (C O), 1615 (C N), 1070 ( C Cl), 685
(C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.92–8.41 (9H, m, Ar-H), 3.55 (3H,
s, CH3); MS (M+): 385.80, Calcd. (%) for C18H12ClN3OS2: C, 56.02; H, 3.13; N, 10.89;
S, 16.62. Found: C, 56.00; H, 3.09; N, 10.85; S, 16.58.
S-[5-(3-Chloro-1-benzothiophen-2-yl)-4-phenyl-4H-1,2,4-triazol-3-yl]ben
zenecarbothioate (9b). IR (KBr) ν (cm−1): 1650 (C O), 1620 (C N), 1070 ( C Cl),
689 (C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.50–8.13 (14H, m, Ar-H); MS
(M+): 443.90, Calcd. (%) for C23H14ClN3OS2:C, 61.67; H, 3.15; N, 9.38; S, 14.32. Found:
C, 61.65; H, 3.09; N, 9.35; S, 14.23.
3-(3-Chloro-1-benzothiophen-2-yl)-5-(methylsulfanyl)-4-phenyl-4H-1,2,4-
triazole (9c). IR (KBr) ν (cm−1): 1620 (C N), 1570 (C C), 1070 ( C Cl); 1H NMR
(400 MHz, DMSO-d6) δ (ppm): 8.90–8.04 (9H, m, Ar-H), 3.85 (3H, s, CH3); MS (M+):
357.01, Calcd. (%) for C17H12ClN2S2:C, 57.05; H, 3.38; N, 11.74; S, 17.92. Found: C,
57.00; H, 3.28; N, 11.65; S, 17.87.
S-[5-(3-Chloro-1-benzothiophen-2-yl)-4-(4-chlorophenyl)-4H-1,2,4-triazol-
3-yl] ethanethioate (9d). IR (KBr) ν (cm−1): 1655 (C O), 1615 (C N), 1570 (C C),
760 (C Cl), 690 (C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.75–8.00 (8H, m,
Ar-H), 3.45 (3H, s, CH3); MS (M+): 420.23, 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, 15.20.
S-[5-(3-Chloro-1-benzothiophen-2-yl)-4-(4-chlorophenyl)-4H-1,2,4-triazol-
3-yl] benzenecarbothioate (9e). IR (KBr) ν (cm−1): 1650 (C O), 1625 (C N), 762
1
(C Cl), 688 (C S C); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.00–7.20 (13H, m,
Ar-H); MS (M+): 482.13, Calcd. (%) for C23H13Cl2N3OS2:C, 57.26; H, 2.72; N, 8.71; S,
13.29. Found: C, 57.20; H, 2.67; N, 8.68; S, 13.20.
3-(3-Chloro-1-benzothiophen-2-yl)-4-(4-chlorophenyl)-5-(methylsulfanyl)-
4H-1,2,4-triazole (9f). IR (KBr) ν (cm−1): 1613 (C N), 1575 (C C), 760 (C Cl), 690
(C S C); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90–8.02 (8H, m, Ar-H), 3.23 (3H,

1700
G. NAGANAGOWDA AND B. PADMASHALI
s, CH3); MS (M+): 391.31, Calcd. (%) for C17H11Cl2N3S2:C, 52.04; H, 2.83; N, 10.71; S,
16.35. Found: C, 52.00; H, 2.79; N, 10.65; S, 16.30.
Preparation of 3-Chloro-Nꢀ-[(2Z)-3,4-diphenyl-1,3-thiazol-2(3H)-
ylidene]-1-benzothiophene-2-carbohydrazide (10a–b)
A mixture of compound 3a (1.80 g, 5.0 mmol) and phenacyl bromide (0.98 g, 5.0
mmol) in distilled ethanol (15 mL) was refluxed for 6 h in a water bath and then cooled and
neutralized with ammonium hydroxide solution. The precipitate was filtered off, washed
with water, dried, and recrystallized from ethanol to give 10a as a white solid. Compound
10b was similarly prepared.
3-Chloro-Nꢀ-[(2Z)-3,4-diphenyl-1,3-thiazol-2(3H)-ylidene]-1-benzothioph
1
ene-2-carbohydrazide (10a). IR (KBr) ν (cm−1): 3189 (N H), 1635 (C O); H
NMR (400 MHz, DMSO-d6) δ (ppm): 11.05 (1H, s, CONH), 8.00–7.20 (14H, m, Ar-H);
MS (M+): 461.98, Calcd. (%) for C24H16ClN3OS2:C, 62.40; H, 3.49; N, 9.10; S, 13.88.
Found: C, 62.38; H, 3.43; N, 9.04; S, 13.85.
3-Chloro-Nꢀ-[(2Z)-3-(4-chlorophenyl)-4-phenyl-1,3-thiazol-2(3H)-ylidene]-
1-benzothiophene-2-carbohydrazide (10b). IR (KBr) ν (cm−1): 3189 (N H), 1635
1
(C O), 765 (C Cl); H NMR (400 MHz, DMSO-d6) δ (ppm): 10.34 (1H, s, CONH),
8.00–7.25 (13H, m, Ar-H); MS (M+): 496.43, Calcd. (%) for C24H15Cl2N3OS2:C, 58.07;
H, 3.05; N, 8.46; S, 12.92. Found: C, 58.02; H, 3.00; N, 8.42; S, 12.89.
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