Utility of 3-chlorobenzothiophene-2-carbonylisothiocyanate for the synthesis of some novel biheterocycles of expected biological activity

Article abstract of DOI:10.1080/10426500903055196

The behavior of 3-chlorobenzothiophene-2-carbonylisothiocyanate 2 towards nitrogen nucleophiles such as primary amines, substituted hydrazines, aryl hydrazines, glycine, anthranilic acid; sulfur nucleophiles such as thioglycolic acid; and oxygen nucleophiles such as substituted phenols has been investigated and found that it proceeds via isothiocyanate heterocyclization to furnish noncondensed heterocyclic compounds containing thiourea, triazole, oxazole, thiazole, and benzoxazole nuclei besides the benzo[b]thiophene nucleus. The structures of the newly synthesized compounds were elucidated on the basis of IR, 1H NMR, and mass spectral data of the compounds, and they have been screened for antimicrobial, analgesic, and anti-inflammatory activities. 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. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500903055196

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Utility of 3-Chlorobenzothiophene-2-
Carbonylisothiocyanate for the Synthesis
of Some Novel Biheterocycles of
Expected Biological Activity
Gadada Naganagowda a & Basavaraj Padmashali a
a Department of Chemistry, Sahyadri Science College (Autonomous),
Kuvempu University, Shimoga, Karnataka, India
Published online: 02 Jul 2010.
To cite this article: Gadada Naganagowda & Basavaraj Padmashali (2010): Utility of 3-
Chlorobenzothiophene-2-Carbonylisothiocyanate for the Synthesis of Some Novel Biheterocycles
of Expected Biological Activity, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:7,
1369-1380
To link to this article: http://dx.doi.org/10.1080/10426500903055196
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Phosphorus, Sulfur, and Silicon, 185:1369–1380, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903055196
UTILITY OF 3-CHLOROBENZOTHIOPHENE-2-
CARBONYLISOTHIOCYANATE FOR THE SYNTHESIS
OF SOME NOVEL BIHETEROCYCLES OF EXPECTED
BIOLOGICAL ACTIVITY
Gadada Naganagowda and Basavaraj Padmashali
Department of Chemistry, Sahyadri Science College (Autonomous), Kuvempu
University, Shimoga, Karnataka, India
The behavior of 3-chlorobenzothiophene-2-carbonylisothiocyanate 2 towards nitrogen nu-
cleophiles such as primary amines, substituted hydrazines, aryl hydrazines, glycine, an-
thranilic acid; sulfur nucleophiles such as thioglycolic acid; and oxygen nucleophiles such
as substituted phenols has been investigated and found that it proceeds via isothiocyanate
heterocyclization to furnish noncondensed heterocyclic compounds containing thiourea, tri-
azole, oxazole, thiazole, and benzoxazole nuclei besides the benzo[b]thiophene nucleus. The
structures of the newly synthesized compounds were elucidated on the basis of IR, 1H NMR,
and mass spectral data of the compounds, and they have been screened for antimicrobial,
analgesic, and anti-inflammatory activities.
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
Analgesic activity; anti-inflammatory activity; antimicrobial activity; 3-
chlorobenzothiophene-2-carbonylisothiocyanate
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 towards thioindigo dyes. The scenario, however, changed with the
advent of bioisosterism, when organic chemists started showing interest in benzothiophene
since it is a bioisoster of indole. The synthesis of several sulfur analogues of bioactive
furanochromones and furanocoumarins are also reported in the literature. These analogues,
consisting of a benzothiophene core, are usually obtained from the latter through suitable
annulation reactions.1–2
Received 12 February 2009; accepted 20 May 2009.
The authors are thankful to the 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, India, for providing spectral data.
Address correspondence to Basavaraj Padmashali, Department of Chemistry, Sahyadri Science College (Au-
tonomous), Kuvempu University, Shimoga– 577 203, Karnataka, India. E-mail: basavarajpadmashali@yahoo.com
1369

1370
G. NAGANAGOWDA AND B. PADMASHALI
CH3
N
O
S
COOMe
F
HN
NH
R
R
S
HN
N
N
N
S
NH
NH
N
NH
N
H
S
Quinazoline thiourea
Thiazole thiourea
PETT1
Figure 1 Potent NNRTIs.
Multiple antiretroviral agents have been produced to block replication of the HIV-1
virus by blocking HIV reverse transcriptase3–4 or by blocking HIV protease.5 Among
the most important antiretroviral agents recently introduced are the non-nucleoside re-
verse transcriptase inhibitors (NNRTI), such as nevirapine6 and delavirdine,7 which are
able to reduce reverse transcriptase inhibition to subnanomolar concentrations. Several
heterocyclic thioureas8–11 have been reported as a new class of potent NNRTIs such as
phenethylthiazolyl-thiourea (PETT1) derivatives (Figure 1).
Uckun and Venkatachalam12 have described the synthesis of a series of thiazolth-
ioureas with alkyl, aryl, and heteroaryl substituents as newly identified NNRTIs of HIV,
including mutant strains of HIV, that are effective in the treatment of multidrug-resistant
HIV infection. Fathala and Pazdera have recently reported a new and efficient synthesis of
novel quinazoline thioureas based on the Domino reaction.13 On the other hand, benzoth-
iophenes are of current interest due to their wide spectrum of pharmacological properties
such as antiallergic, anti-inflammatory, analgesic, antitubercular, antimicrobial, ocular hy-
potensive, and serotonine N-acetyltransferase inhibitors activities.14–19 A drug based on the
benzothiophene ring is raloxifene, approved by the U.S. Food and Drug Administration for
the prevention and treatment of osteoporosis associated with postmenopausal women.20 In
view of these factors, it was thought important to synthesize a benzothiophene-incorporated
biheterocyclic to explore its biological efficacy.
RESULTS AND DISCUSSION
The starting material for the synthesis of the target compounds was 3-chloro
benzothiophene-2-carbonyl chloride 1, which was prepared by the reaction of cinnamic acid
and thionyl chloride in the presence of pyridine in DMF.21 Compound 1, upon treatment
with ammonium thiocyanate in dry acetone, produced 3-chlorobenzothiophene-2-carbonyl
isothiocyanate 2, which was used for further reactions in situ to prevent its decomposi-
tion. Isothiocyanate 2 was reacted with substituted anilines in dry acetone to obtain the
corresponding thioureas 3a–g. Compound 3a has peaks in its IR spectrum at 3280, 1650,
1570, 1220, 1070, and 681cm−1 corresponding to N H, C O, C C, C S, C Cl, and
C S C groups, respectively; the 1H NMR spectrum of 3a exhibited singlets integrating
for one proton each at 11.08 and 12.19 δ ppm due to CONH and CSNH protons, re-
spectively, and a multiplet in between 7.29 and 8.03 δ ppm due to seven aromatic protons.
Furthermore, the structure of 3a was confirmed from its mass spectrum, which exhibited
a molecular ion peak at m/z 399 corresponding to its molecular weight. When glycine
was reacted with 3-chlorobenzothiophene-2-carbonylisothiocyanate 2 in the presence of

SYNTHESIS OF SOME NOVEL BIHETEROCYCLES
1371
pyridine, the thiourea derivative produced was cyclized to 3-chloro-N-(5-oxo-2-sulfanyl-
1,3-oxazolidin-2-yl)-1-benzothiophene-2-carboxamide 4. The IR spectrum of compound 4
exhibited peaks at 3280, 2320, and 1670 cm−1 due to N H, S H, and C O stretching
absorptions. The singlets integrating for one proton at 12.11, 10.23, and 3.50 δ ppm in
1
the H NMR spectra correspond to NH, CONH, and SH protons. A singlet at 2.40
δ is due to –CH2 protons, and a multiplet in between 6.80 and 7.70 δ ppm is due to four
aromatic protons. A molecular ion peak at m/z 328 in its mass spectrum is additional proof
for its formation. Isothiocyanate 2 reacted with thioglycolic acid in which the adduct 5
was produced, which underwent cyclization in the presence of acetic anhydride to 3-[(3-
chloro-1-benzothiophen-2-yl)carbonyl]-2-thioxo-1,3-thiazolidin-4-one 6. The IR spectrum
of compound 6 exhibited peaks at 3280, 1670, and 1230 cm−1 corresponding to N H,
1
C O, and C S stretching absorption frequencies, respectively. The H NMR spectrum
of compound 6 exhibited a multiplet in the region 7.70–8.35 δ ppm due to four aromatic
protons and a singlet at 2.40 δ ppm, which corresponds to two protons of –CH2 groups.
The mass spectrum of compound 6 exhibited a molecular ion peak at m/z 327, which is in
accordance with the structure. 2-Aminophenol was treated with 2 to yield thiocarbamate
7, the IR spectrum of which exhibited peaks at 3285, 1665, and 1225 cm−1 due to N H,
1
C O, and C S stretching absorption frequencies, respectively. The H NMR spectrum
of 7 showed two singlets, one at 10.29 δ ppm and at other 9.86 δ ppm, due to NH2
and CONH protons, respectively. Compound 7 exhibited a molecular ion peak at m/z
362 in its mass spectrum, which confirmed its formation. Fusion of compound 7 also was
associated with the evolution of H2S gas and led to the formation of N-(1,3-benzoxazol-
2-yl)-3-chloro-1-benzothiophene-2-carboxamide 8. Compound 8 showed a peak at 1230
cm−1 due to C S stretching absorption in its IR spectrum and the absence of a peak at
10.23 δ ppm in its 1H NMR spectrum due to a CONH proton, which indicated the formation
of compound 8. Addition of anthranilic acid to isothiocyanate leads to the formation of
thiourea 9, which showed a peaks at 3295 cm−1 in its IR spectrum due to NH stretching;
1
singlets at 13.16 and 10.70 δ ppm in its H NMR spectrum correspond to CSNH and
CONH protons, respectively. As an additional proof, the mass spectrum of 9 exhibited a
molecular ion peak at m/z 390, which confirmed its formation. Compound 10 was prepared
by reacting 9 with acetic anhydride. Compound 10 showed a singlet at 14.26 δ ppm due to
NH proton in its 1H NMR spectrum. The mass spectrum of 10 showed a molecular ion
peak at m/z 372 corresponding to its molecular weight. The reaction of isothiocyanate 2
with substituted hydrazines afforded 5-(3-chloro-1-benzothiophen-2-yl)-1-substitued-1,2-
dihydro-3H-1,2,4-triazole-3-thiones 11a–c. Compound 11a exhibited peaks at 3281, 1655,
and 1230 cm−1 due to N H, C O, and C S stretching absorption frequencies, respec-
tively, in its IR spectrum. The 1H NMR spectrum of 11a showed a singlet at 10.50 δ ppm
due to NH proton and a multiplet in the region 7.27 to 8.05 δ ppm due to nine aromatic
protons, and its mass spectrum showed a molecular ion peak at m/z 343. Compound 2 was
treated with various phenols to obtain the series of substituted [(3-chloro-1-benzothiophen-
2-yl)carbonyl]carbamothioates 12a–d (Scheme 1). Compound 12a exhibited peaks at 3285,
1665, and 1230 cm−1 stretching absorption frequencies in its IR spectrum corresponds to
N H, C O, and C S groups, respectively. The 1H NMR spectrum of 12a showed a singlet
at 11.22 δ ppm due to a CONH proton and a multiplet in between 7.52 and 7.90 δ ppm due
to nine aromatic protons. Furthermore, 12a was confirmed from its mass spectrum, which
exhibited a molecular ion peak at m/z 347 corresponding to its molecular weight. Finally,
3-chlorobenzothiophene-2-carbonylisothiocyanate 2 reacted with 2-aminopyridine and [1-
(aminomethyl)cyclohexyl]acetic acid in the presence of acetone to produce separately

1372
G. NAGANAGOWDA AND B. PADMASHALI
Cl
O
Cl
Cl
O
S
Cl
1
NH
O
OH
NH
NH
S
S
R
R
3
1
NH
O
S
2
S
R
NH SCN
4
3
12a-d
3a-g
R
1
H
N
NH
2
Cl
Cl
S
Cl
R
HS
NH
2
NH
S
glycine
N=C=S
O
N
O
O
NH
R
S
O
S
N
COOH
4
2
O
11a-c
NH
2
OH
NH
HS
OH
2
Cl
Cl
O
2
COOH
H
N
2
NH
S
COOH
NH
S
NH
S
S
Cl
O
5
S
O
9
NH
S
S
O
Ac2O
Ac2O
7
FUSION
H
N
Cl
Cl
S
Cl
O
O
NH
O
N
S
N
S
S
O
N
S
O
S
6
O
8
10
Compound
R1
3-Cl-4-F
4-F
4-COCH3
4-COOH
4-CH3
Compound
12a
R3
H
4-CH3
4-NO2
2-NO2
Compound
R2
H
4-F
4-NO2
3a
3b
3c
11a
11b
11c
12b
12c
12d
3d
3e
3f
4-NO2
2-OH
3g
Scheme 1 General synthetic procedure for 3-chlorobenzothiophene substituted thioureas 3a–g, oxazole 4, thia-
zolidinone 6, benzoxazole 8, quinazoline 10, triazoles 11a–d, and carbamothioates 12a–d.
compounds 13 and 14 (Scheme 2). Compound 13 exhibited peaks at 3285, 1650, and
1227 cm−1 due to N H, C O, and C S groups stretching absorption frequencies. The 1H
NMR spectrum of 13 showed two singlets integrating for one proton each, one at 10.15 δ
ppm and another at 12.85 δ ppm, due to CONH and CSNH protons, respectively.
Compound 13 exhibited a molecular ion peak at m/z 347 in its mass spectrum, which
confirmed its formation. Compound 14 exhibited peaks at 3285, 1650, and 1227 cm−1
due to N H, C O, and C S stretching absorption frequencies in its IR spectrum. The
1H NMR spectrum of 14 showed a singlet at 10.90 δ ppm due to CSNH proton and a
multiplet in the region 7.26 to 7.86 δ ppm due to four aromatic protons and in its mass
spectrum, which showed a molecular ion peak at m/z 424. All the synthesized compounds
were characterized by elemental analysis and spectral data, and have been screened for
their antimicrobial, analgesic, and anti-inflammatory activities. The characterization of the
synthesized compounds is presented in Table I.

SYNTHESIS OF SOME NOVEL BIHETEROCYCLES
1373
Cl
NH
S
N
NH2
NH
O
N
S
13
2
H2N
Cl
S
O
HOOC
NH
HOOC
NH
S
14
Scheme 2 General synthetic procedure for 3-chlorobenzothiophene substituted thioureas 13 and 14.
ANTIBACTERIAL ACTIVITY
Cup plate method using Hi-Media agar medium was employed to study the an-
tibacterial activity of the selected 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 is done as per the standard procedure.22 (See the Supplemental
Materials available online, Table S1.)
Table I Characterization data of the compounds
Sl. No.
Compound
R1
R2
R3
Yield (%)
Mp (◦C)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
4
5
6
7
8
9
10
11a
11b
11c
12a
12b
12c
12d
13
14
3-Cl-4-F
4-F
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
90
89
90
77
87
78
88
45
88
67
76
66
88
77
76
78
66
65
67
65
61
66
81
209–211
202–204
231–233
203–205
213–215
210–212
216–218
230–232
221–223
210–212
240–242
231–233
240–242
231–233
210–212
241–243
231–233
218–220
231–233
260–262
238–240
241–243
221–223
4-COCH3
4-COOH
4-CH3
4-NO2
2-OH
—
—
—
—
—
—
—
—
—
—
9
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
4-F
4-NO2
—
—
—
—
—
—
H
4-CH3
4-NO2
2-NO2
—
—

1374
G. NAGANAGOWDA AND B. PADMASHALI
ANTIFUNGAL ACTIVITY
The antifungal activity of the synthesized compounds was tested against four different
fungi, C. albicans, C. pannical, A. niger, and R. oryzae, by the filter paper disc technique.23
(See the Supplemental Materials, Table S2.)
ANALGESIC ACTIVITY
Albino mice of either sex (20–30 g) were used to evaluate the acetic acid–induced
writhing analgesic activity.24 (See the Supplemental Materials, Table S3.)
ANTI-INFLAMMATORY ACTIVITY
The anti-inflammatory activity of all the newly synthesized compounds was evalu-
ated using the carrageenan-induced rat hind paw edema method.25 (See the Supplemental
Materials, Table S4.)
EXPERIMENTAL
Melting points were determined in open capillary and are uncorrected. IR spectra
(KBr disks) were recorded using a Perkin-Elmer 237 spectrophotometer. 1H NMR spectra
were recorded on a Bruker Aveance II spectrometer (at 400 MHz) using tetramethylsilane
(TMS) as an internal standard and DMSO as a solvent. Chemical shifts were given in
parts per million (ppm). Splitting patterns were designated as follows: s–singlet, d–doublet,
t–triplet, q–quartet, and m–multiplet. Mass spectra (MS) were 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 the compounds were further purified through column
chromatography.
Preparation of 3-Chlorobenzothiophene-2-carbonyl chloride (1)
Compound 1 was prepared according to the procedure in the literature,21 mp
112–114◦C (Literature mp 110–112◦C).
Preparation of 3-Chlorobenzothiophene-2-carbonyl isothiocyanate (2)
Ammonium thiocyanate (0.076 g, 1.0 mmol) was added dropwise to a stirred solution
of 3-chlorobenzothiophene-2-carbonylchloride 1 (0.231 g, 1.0 mmol) in dry acetone (50
mL) at 0◦C. Stirring was continued for 1 h at room temperature. Ammonium chloride was
precipitated during the progress of the reaction; it was filtered, and a pale yellow solution
of 3-chlorobenzothiophene-2-carbonylisothiocyanate 2 was obtained.
Preparation of 3-Chloro-N-[(3-chloro-4-fluorophenyl)carbamothioyl]-
1-benzothiophene-2-carboxamide (3a)
To a solution isothiocyanate 2 (0.253 g, 1.0 mmol) in dry acetone (10 mL), 3-chloro-
4-fluoroaniline (0.146 g, 1.0 mmol) in dry acetone (10 mL) was added with continuous
stirring; thereafter two-thirds of the solvent was distilled under vacuum. The concentrate
was left overnight in refrigerator. The solid product obtained was filtered, washed with
water, and recrystallized from ethanol. Similarly, the compounds 3b–g were prepared.

SYNTHESIS OF SOME NOVEL BIHETEROCYCLES
1375
3-Chloro-N-[(3-chloro-4-fluorophenyl)carbamothioyl]benzothiophene-2-
carboxamide (3a). IR (KBr) ν (cm−1): 3280 (N H), 1650 (C O), 1570 (C C), 1220
1
(C S), 1070 (C Cl), 681 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 7.29–8.03
(7H, m, Ar H), 11.08 (1H, s, CONH), 12.19 (1H, s, CSNH); MS (M+): 399 (12%), 302
(22%). Calcd. (%) for C16H9Cl2FN2OS2: C, 68.13; H, 2.27; N, 7.02; S, 16.06. Found: C,
48.08; H, 2.20; N, 7.00; S, 16.00.
3-Chloro-N-[(4-fluorophenyl)carbamothioyl]benzothiophene-2-carboxa
mide (3b). IR (KBr) ν (cm−1): 3275 (N H), 1654 (C O), 1565 (C C), 1343(C-F),
1215 (C S),1077 (C Cl), 685 (C S C); 1H NMR (400 MHz, DMSO) δ (ppm):
7.10–7.99 (8H, m, ArH), 10.62 (1H, s, CONH), 12.21 (1H, s, CSNH); MS (M+): 364
(18%), 312 (34%). Calcd. (%) for C16H10ClFN2OS2: C, 57.67; H, 2.76; N, 7.68; S, 17.58.
Found: C, 57.63; H, 2.70; N, 7.66; S, 17.55.
4-(Acetylphenyl)carbamothioyl]-3-chlorobenzothiophene-2g-carbox-
amide (3c). IR (KBr) ν (cm−1): 3285 (N H), 1639 (C O), 1565 (C C), 1220 (C S),
1
1072 (C Cl), 688 (C S C), H NMR (400 MHz, DMSO) δ (ppm): 2.61(3H, s, CH3),
7.57–8.02 (8H, m, ArH), 10.57 (1H, s, CONH), 12.59 (1H, s, CSNH); MS (M+): 388
(10%), 322 (28%). Calcd. (%) for C18H13ClN2O2S2: C, 55.59; H, 3.37; N, 7.20; S, 16.49.
Found: C, 55.50; H, 3.35; N, 7.16; S, 16.45.
3-(Chlorobenzothiophen-2-yl)carbonylcarbamothioylaminobenzoic acid
(3d). IR (KBr) ν (cm−1): 3280 (N H), 1650 (C O), 1570 (C C), 1224 (C S), 1077
1
(C Cl), 682 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 1.25 (1H, s, COOH),
7.49–8.10 (8H, m, ArH), 10.38 (1H, s, CONH), 12.57 (1H, s, CSNH); MS (M+): 390
(24%), 352 (44%). Calcd. (%) for C17H11ClN2O3S2: C, 52.24; H, 2.84; N, 7.17; S, 16.41.
Found: C, 52.18; H, 2.80; N, 7.15; S, 16.37.
3-Chloro-N-[(4-methylphenyl)carbamothioyl]benzothiophene-2-car-
boxamide (3e). IR (KBr) ν (cm−1): 3288 (N H), 1663 (C O), 1565 (C C), 1222
(C S), 1073 (C Cl), 690 (C S C); 1H NMR (400 MHz, DMSO) δ (ppm): 2.37 (3H, s,
CH3), 7.22–8.00 (8H, m, ArH), 10.45 (1H, s, CONH), 12.22 (1H, s, CSNH); MS (M+):
360 (16%), 325 (36%). Calcd. (%) for C17H13ClN2OS2: C, 56.58; H, 3.63; N, 7.76; S,
17.77. Found: C, 56.55; H, 3.60; N, 7.70; S, 17.75.
3-Chloro-N-[(4-nitrophenyl)carbamothioyl]benzothiophene-2-carbox-
amide (3f). IR (KBr) ν (cm−1): 3281 (N H), 1664 (C O), 1565 (C C), 1490 (NO2),
1
1230 (C S), 1065 (C Cl), 688 (C S C); H NMR (400 MHz, DMSO) δ (ppm):
7.61–8.29 (8H, m, Ar H), 11.27 (1H, s, CONH), 12.59 (1H, s, CSNH); MS (M+): 391
(12%), 351 (23%). Calcd. (%) for C16H10ClN3O3S2: C, 49.04; H, 2.57; N, 10.72; S, 16.37.
Found: C, 49.00; H, 2.55; N, 10.69; S, 16.30.
3-Chloro-N-[(4-hydroxyphenyl)carbamothioyl]benzothiophene-2-car-
boxamide (3g). IR (KBr) ν (cm−1): 3533–3324 (O H), 3270 (N H), 1665 (C O),
1572 (C C), 1210 (C S), 1073 (C Cl), 688 (C S C); 1H NMR (400 MHz, DMSO) δ
(ppm): 6.85–8.64 (8H, m, Ar H), 9.86 (1H, s, CONH), 10.29 (1H, s, CSNH), 12.55 (1H,
s, OH); MS (M+): 362 (18%), 312 (42%). Calcd. (%) for C16H11ClN2O2S2: C, 52.96; H,
3.06; N, 7.72; S, 17.67. Found: C, 52.90; H, 3.00; N, 7.7; S, 17.60.
Preparation 3-Chloro-N-(5-oxo-2-sulfanyl-1,3-oxazolidin-2-yl)
benzothiophene-2-carboxamide (4)
To a solution of isothiocyanate 2 (0.253 g, 1.0 mmol) in dry acetone (50 mL), glycine
(0.075 g, 1.0 mmol) and a few drops of pyridine were added, and then the reaction mixture

1376
G. NAGANAGOWDA AND B. PADMASHALI
was refluxed for 3 h. After cooling the reaction mixture, a solid product was obtained,
filtered, washed with water, and recrystallized from a 1,4-diaxone. It was further purified
from column chromatography (silica gel, 60–120 mesh) by using petroleum ether and ethyl
acetate (0.5:9.5) as an eluent to yield compound 4.
IR (KBr) ν (cm−1): 3280 (N H), 2320 (SH), 1670 (C O), 1565 (C C), 1074
1
(C Cl), 688 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 2.40 (2H, s, CH2), 3.50
(1H, s, SH), 6.80–7.70 (4H, m, Ar H), 10.23 (1H, s, CONH), 12.11 (1H, s, NH); MS (M+):
328 (22%), 302 (36%). Calcd. (%) for C12H9ClN2O3S2: C, 43.84; H, 2.76; N, 8.52; S,
19.50. Found: C, 43.79; H, 2.70; N, 8.49; S, 19.46.
Preparation of Adduct: 3-Chlorobenzothiophen-2-yl-carbonyl-
carbamothioyl-sulfanyl Acetic Acid (5)
A solution of isothiocyanate 2 (0.253 g, 1.0 mmol) in dry acetone and thioglycolic
acid (0.092 g, 0.075 mL, 1.0 mmol) was refluxed for 2 h. The solid that formed after cooling
was recrystallized from methanol.
Preparation of 3-[(3-Chlorobenzothiophen-2-yl)carbonyl]-2-thioxo-
1,3-thiazolidin-4-one (6)
A solution of adduct 5 (0.345 g, 1.0 mmol) in acetic anhydride (30 mL) was refluxed
for 3 h. Solid product was obtained after cooling, and it was recrystallized from methanol
to obtain product 6.
IR (KBr) ν (cm−1): 3280 (N H), 1670 (C O), 1575 (C C), 1230 (C S), 1072
(C Cl), 684 (C S C); 1H NMR (400 MHz, DMSO) δ (ppm): 2.40 (2H, s, CH2), 7.70–8.35
(4H, m, Ar H); MS (M+): 327 (10%), 312 (28%). Calcd. (%) for C12H6ClNO2S3: C, 43.96;
H, 1.84; N, 4.27; S, 29.34. Found: C, 43.90; H, 1.79; N, 4.20; S, 29.30.
Preparation of o-(2-Aminophenyl)-[(3-chlorobenzothiophen-2-yl)
carbonyl]carbamothioate (7)
To a solution of isothiocyanate 2 (0.253 g, 1.0 mmol) in dry acetone (15 mL), o-
aminophenol (0.109 g, 1.0 mmol) in dry acetone (10 mL) was added. The reaction mixture
was refluxed for 3 h. The solid product that was obtained after cooling was filtered and
recrystallized from methanol to yield solid crystals of the product 7.
IR (KBr) ν (cm−1): 3285 (N H), 1665 (C O), 1570 (C C), 1225 (C S), 1075
(C Cl), 685 (C S C); 1H NMR (400 MHz, DMSO) δ (ppm): 6.80–7.70 (8H, m, Ar H),
9.86 (1H, s, CONH), 10.29 (2H, s, NH2); MS (M+): 362 (12%), 342 (32%). Calcd. (%) for
C16H11ClN2O2S2: C, 52.96; H, 3.06; N, 7.72; S, 17.67. Found: C, 52.90; H, 3.00; N, 7.68;
S, 17.65.
Preparation of N-(1,3-Benzoxazol-2-yl)-3-chlorobenzothiophene-
2-carboxamide (8)
Thiocarbamate derivative 7 was fused for 2 h in an oil bath, which was associated
with the evolution of H2S gas. The reaction mixture was left to cool. The solid product that
was obtained was recrystallized from a methanol to get compound 8 in pure form.
IR (KBr) ν (cm−1): 3280 (N H), 1663 (C O), 1575 (C C), 1230 (C S), 1075
(C Cl), 682 (C S C); 1H NMR (400 MHz, DMSO) δ (ppm): 7.70–8.45 (8H, m, Ar H),

SYNTHESIS OF SOME NOVEL BIHETEROCYCLES
1377
10.23 (1H, s, CONH); MS (M+): 328 (14%), 302 (22%). Calcd. (%) for C16H9ClN2O2S:
C, 58.45; H, 2.76; N, 8.52; S, 9.75. Found: C, 58.41; H, 2.70; N, 8.48; S, 9.70.
Preparation of 3-Chloro(benzothiophen-2-yl)carbonyl
Carbamothioylaminobenzoic Acid (9)
To a solution of isothiocyanate 2 (0.253 g, 1.0 mmol), anthranilic acid (0.137 g, 1.0
mmol) was added dropwise with constant stirring for about 20 min and then refluxed for
2 h. After cooling, a solid product was obtained. It was filtered and recrystallized from
methanol and further purified from column chromatography (silica gel, 60–120 mesh) by
using petroleum ether and ethyl acetate (1:9) as an eluent to get compound 9.
IR (KBr) ν (cm−1): 3295 (N H), 1650 (C O), 1580 (C C), 1225 (C S), 1077
1
(C Cl), 685 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 3.80 (1H, s, COOH),
7.31–8.48 (8H, m, Ar H), 10.70 (1H, s, CONH), 13.16 (1H, s, CSNH); MS (M+): 390
(18%), 355 (45%). Calcd. (%) for C17H11ClN2O3S2: C, 52.24; H, 2.84; N, 7.17; S, 16.41.
Found: C, 52.18; H, 2.80; N, 7.15; S, 16.37.
Preparation of 3-[(3-Chlorobenzothiophen-2-yl)carbonyl]-2-thioxo-2,3-
dihydroquinazolin-4(1H)-one (10)
Thiourea 9 (0.390 g, 1.0 mmol) was heated on a water bath with acetic anhydride (50
mL) for 3 h. A solid product was formed during heating. At the end of the reaction period,
the solid product was filtered off while hot and crystallized from methanol and further
purified from column chromatography (silica gel, 60–120 mesh) by using petroleum ether
and ethyl acetate (1.5:8.5) as an eluent to get pure 10.
IR (KBr) ν (cm−1): 3285 (N H), 1666 (C O), 1570 (C C), 1220 (C S), 1078
(C Cl), 689 (C S C); 1H NMR (400 MHz, DMSO) δ (ppm): 7.41–8.02 (8H, m, Ar H),
14.26 (1H, s, NH); MS (M+): 372 (14%), 341 (31%). Calcd. (%) for C17H9ClN2O2S2: C,
54.76; H, 2.43; N, 7.51; S, 17.20. Found: C, 54.70; H, 2.39; N, 7.48; S, 17.16.
Preparation of 5-(3-Chlorobenzothiophen-2-yl)-1-phenyl-1,2-dihydro-
3H-1,2,4-triazole-3-thione (11a)
A solution of isothiocyanate 2 (0.253 g, 1.0 mmol) and phenyl hydrazine (0.108 g,
0.095 mL, 1.0 mmol) in dry acetone (30 mL) was heated under reflux for 1 h, concentrated,
and treated with methanol to give a solid. Then it was recrystallized from methanol to
obtain pure 11a. Compounds 11b–c were prepared using a similar methodology.
5-(3-Chlorobenzothiophen-2-yl)-1-phenyl-1,2-dihydro-3H-1,2,4-triazole-
3-thione (11a). IR (KBr) ν (cm−1): 3281 (N H), 1655 (C O), 1570 (C C), 1230
1
(C S), 1070 (C Cl), 692 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 7.27–8.05
(9H, m, Ar H), 10.50 (1H, s, NH); MS (M+): 343 (14%). Calcd. (%) for C16H10ClN3S2:
C, 55.89; H, 2.93; N, 12.22; S, 18.65. Found: C, 55.80; H, 2.90; N, 12.16; S, 18.60.
5-(3-Chlorobenzothiophen-2-yl)-1-(4-fluorophenyl)-1,2-dihydro-3H-1,2,
4-triazole-3-thione (11b). IR (KBr) ν (cm−1): 3285 (N H), 1650 (C O), 1575
1
(C C), 1342 (C F), 1220 (C S), 1070 (C Cl), 686 (C S C); H NMR (400 MHz,
DMSO) δ (ppm): 7.54–8.16 (8H, m, Ar H), 10.53 (1H, s, NH); MS (M+): 361 (13%).
Calcd. (%) for C16H9ClFN3S2: C, 53.11; H, 2.51; N, 11.61; S, 17.72. Found: C, 53.00; H,
2.47; N, 11.58; S, 17.70.

1378
G. NAGANAGOWDA AND B. PADMASHALI
5-(3-Chlorobenzothiophen-2-yl)-1-(4-nitrophenyl)-1,2-dihydro-3H-1,2,4-
triazole-3-thione (11c). IR (KBr) ν (cm−1): 3280 (N H), 1650 (C O), 1570 (C C),
1342 (NO2), 1220 (C S), 1070 (C Cl), 681 (C S C); 1H NMR (400 MHz, DMSO) δ
(ppm): 7.50–7.95 (8H, m, Ar H), 10.53 (1H, s, NH); MS (M+): 388 (12%). Calcd. (%)
for C16H9ClN4O2S2: C, 49.42; H, 2.33; N, 14.41; S, 16.49. Found: C, 49.37; H, 2.28; N,
14.37; S, 16.45.
Preparation of o-phenyl [(3-chlorobenzothiophen-2-yl)carbonyl]
carbamothioate (12a)
Ammonium thiocyanate (0.076 g, 1.0 mmol) in dry acetone (10 mL) was slowly
added dropwise at 0◦C to an 3-chloro-1-benzothiophene-2-carbonyl chloride 1 (0.231 g,
1.0 mmol) in dry acetone (10 mL) with continuous stirring and then filtered. The filtrate
was slowly added at room temperature to a phenol (0.094 g, 0.075 mL, 1.0 mmol) in
acetone (10 mL) with continuous stirring. Thereafter, two-thirds of the solvent was distilled
under vacuum. The concentrate was left overnight in a refrigerator. The solid product
was filtered off, washed with water, and recrystallized from methanol and purified from
column chromatography (silica gel, 60–120 mesh) by using petroleum ether and ethyl
acetate (0.5:9.5) as an eluent to get pure 12a. Compounds 12b–d were prepared in a similar
manner.
Phenyl[(3-chlorobenzothiophen-2-yl)carbonyl]carbamothioate (12a). IR
(KBr) ν (cm−1): 3285 (N H), 1665 (C O), 1570 (C C), 1230 (C S), 1075 (C Cl), 683
1
(C S C); H NMR (400 MHz, DMSO) δ (ppm): 7.52–7.90 (9H, m, Ar H), 11.22 (1H,
s, CONH); MS (M+): 347 (18%). Calcd. (%) for C16H10ClNO2S2: C, 55.25; H, 2.90; N,
4.03; S, 18.44. Found: C, 55.19; H, 2.87; N, 4.00; S, 18.38.
[(4-Methylphenyl)-(3-chlorobenzothiophen-2-yl)carbonyl]carbamothio-
ate (12b). IR (KBr) ν (cm−1): 3276 (N H), 1670 (C O), 1575 (C C), 1230 (C S),
1
1075 (C Cl), 686 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 2.16 (3H, s, CH3),
7.42–8.02 (8H, m, Ar H), 10.19 (1H, s, CONH); MS (M+): 361 (15%). Calcd. (%) for
C17H12ClNO2S2: C, 56.42; H, 3.34; N, 3.87; S, 17.72. Found: C, 56.38; H, 3.30; N, 3.85;
S, 17.69.
[(4-Nitrophenyl)-[(3-chlorobenzothiophen-2-yl)carbonyl]carbamothioate
(12c). IR (KBr) ν (cm−1): 3275 (N H), 1660 (C O), 1565 (C C), 1452 (NO2),
1
1230 (C S), 1065 (C Cl), 684 (C S C); H NMR (400 MHz, DMSO) δ (ppm):
7.42–8.06 (8H, m, Ar H), 11.19 (1H, s, CONH); MS (M+): 392.05 (18%). Calcd. (%) for
C16H9ClN2O4S2: C, 48.42; H, 2.31; N, 7.13; S, 16.32. Found: C, 48.38; H, 2.28; N, 7.09;
S, 16.21.
[(2-Nitrophenyl)-[(3-chlorobenzothiophen-2-yl)carbonyl]carbamothioate
(12d). IR (KBr) ν (cm−1): 3315 (N H), 1673 (C O), 1570 (C C), 1442 (NO2), 1220
1
(C S), 1067 (C Cl), 684 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 6.80–7.70
(8H, m, ArH), 7.40 (1H, s, CONH); MS (M+): 392 (14%). Calcd. (%) for C16H9ClN2O4S2:
C, 48.42; H, 2.31; N, 7.13; S, 16.32. Found: C, 48.38; H, 2.28; N, 7.09; S, 16.23.
Preparation of 3-Chloro-N-(pyridin-3-ylcarbamothioyl)benzothiophene-
2-carboxamide 13 and {1-[(2-{[(3-Chlorobenzothiophen-2-yl)carbonyl]
carbamothioyl}hydrazinyl)methyl]cyclohexyl}acetic Acid 14
These compounds were prepared following the same procedure used in preparation
of compounds 3a–g.

SYNTHESIS OF SOME NOVEL BIHETEROCYCLES
1379
3-Chloro-N-(pyridin-3-ylcarbamothioyl)benzothiophene-2-carboxamide
(13). IR (KBr) ν (cm−1): 3285 (N H), 1650 (C O), 1570 (C C), 1227 (C S), 1074
1
(C Cl), 688 (C S C); H NMR (400 MHz, DMSO) δ (ppm): 7.16–8.85 (8H, m, Ar
H), 10.15 (1H, s, CONH), 12.85 (1H, s, CSNH); MS (M+): 347 (10%). Calcd. (%) for
C15H10ClN3OS2: C, 51.79; H, 2.90; N, 12.08; S, 18.44. Found: C, 51.73; H, 2.87; N,
12.00; S, 18.39.
3-Chloro-(benzothiophen-2-carbonyl)carbamothioylaminomethylcyclo-
hexylacetic acid (14). IR (KBr) ν (cm−1): 3285 (N H), 1650 (C O), 1570 (C C),
1
1227 (C S), 1075 (C Cl), 681 (C S C); H NMR (400 MHz, DMSO) δ (ppm):
1.48–1.56 (12H, s, (CH2)6), 2.58 (1H, s, COOH), 7.26–7.86 (4H, m, Ar H), 9.99 (1H, s,
CONH), 10.90 (1H, s, CSNH); MS (M+): 424 (14%). Calcd. (%) for C19H21ClN2O3S2: C,
57.70; H, 4.98; N, 6.59; S, 15.09. Found: C, 57.68; H, 4.87; N, 6.54; S, 15.04.
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