Synthesis of 3-[4-(1-benzofuran-2-yl)-1,3-thiazol-2-yl]-2-(4-aryl)-1,3- thiazolidin-4-one derivatives as biological agents

Article abstract of DOI:10.1080/10426500903376154

A protocol for the synthesis of 3-[4-(1-benzofuran-2-yl)-1,3-thiazol-2-yl]- 2-(4-aryl)-1,3-thiazolidin-4-one derivatives (5a-e) has been developed from 1-(1-benzofuran-2-yl)-2-bromoethanone (2),which served as a key intermediate for the synthesis of the title compounds. The reaction of compound 2 with thiourea furnished 4-(1-benzofuran-2-yl)-1,3-thiazol-2-amine 3, which upon further reaction with various aromatic aldehydes, gave Schiff bases 4a-e. These Schiff bases, when treated with thioacetic acid in the presence of catalytic amount of anhydrous ZnCl₂, yielded thiazolidinone derivatives 5a-e. All the newly synthesized compounds have been characterized by analytical and spectral data and screened for their antimicrobial and analgesic activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright

Full text of DOI:10.1080/10426500903376154

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Synthesis of 3-[4-(1-Benzofuran-2-
yl)-1,3-thiazol-2-yl]-2-(4-aryl)-1,3-
thiazolidin-4-one Derivatives as
Biological Agents
Bhovi K. Venkatesh a , Yadav D. Bodke a & S. A. Biradar a
a Department of Post Graduate Studies and Research in Industrial
Chemistry, Jnana Sahyadri , Kuvempu University , Shankaraghatta,
Karnataka, India
Published online: 25 Aug 2010.
To cite this article: Bhovi K. Venkatesh , Yadav D. Bodke & S. A. Biradar (2010) Synthesis of 3-
[4-(1-Benzofuran-2-yl)-1,3-thiazol-2-yl]-2-(4-aryl)-1,3-thiazolidin-4-one Derivatives as Biological
Agents, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:9, 1926-1931, DOI:
10.1080/10426500903376154
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Phosphorus, Sulfur, and Silicon, 185:1926–1931, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903376154
SYNTHESIS OF 3-[4-(1-BENZOFURAN-2-YL)-1,3-THIAZOL-
2-YL]-2-(4-ARYL)-1,3-THIAZOLIDIN-4-ONE DERIVATIVES
AS BIOLOGICAL AGENTS
Bhovi K. Venkatesh, Yadav D. Bodke,
and S. A. Biradar
Department of Post Graduate Studies and Research in Industrial Chemistry, Jnana
Sahyadri, Kuvempu University, Shankaraghatta, Karnataka, India
A protocol for the synthesis of 3-[4-(1-benzofuran-2-yl)-1,3-thiazol-2-yl]-2-(4-aryl)-1,3-
thiazolidin-4-one derivatives (5a–e) has been developed from 1-(1-benzofuran-2-yl)-2-
bromoethanone (2),which served as a key intermediate for the synthesis of the title com-
pounds. The reaction of compound 2 with thiourea furnished 4-(1-benzofuran-2-yl)-1,3-
thiazol-2-amine 3, which upon further reaction with various aromatic aldehydes, gave Schiff
bases 4a–e. These Schiff bases, when treated with thioacetic acid in the presence of catalytic
amount of anhydrous ZnCl2, yielded thiazolidinone derivatives 5a–e. All the newly synthe-
sized compounds have been characterized by analytical and spectral data and screened for
their antimicrobial and analgesic activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Analgesic and antimicrobial activity; anhydrous ZnCl2; 1-(1-benzofuran-2-yl)-2-
bromoethanone; Schiff base; thiazolidinone ring; thioacetic acid.
INTRODUCTION
The structural and therapeutic diversity coupled with commercial viability of small
heterocyclic molecules has fascinated organic and medicinal chemists. Benzo[b]furan
derivatives are an important class of organic compounds, which are known to be present in
many natural products1 and possess physiological activity. They have found applications in
agrochemicals,2,3 pharmaceuticals,4–10 and cosmetics.11 Benzo[b]furans are building blocks
of optical brighteners.12 Many natural benzo[b]furans have physiological, pharmacologi-
cal, and toxic properties, and as a result, there is continuing interest in their chemical
synthesis. Cyclization reactions of various types have been used to produce substituted
benzo[b]furans.13,15 In recent years, 4-thiazolidinones and oxazolidinones are the most
Received 30 July 2009; accepted 25 September 2009.
The authors thank the Indian Institute of Science, Bangalore, India, and Karnataka University, Dharwad,
India, for providing spectral data. One of the authors (B.K.V.) thanks Kuvempu University for awarding a Research
Fellowship.
Address correspondence to Yadav D. Bodke, Department of Post Graduate Studies and Research in Industrial
Chemistry, Jnana Sahyadri, Kuvempu University, Shankaraghatta 577 451, Shivmoga District, Karnataka, India.
E-mail: ydbodke@gmail.com
1926

SYNTHESIS OF BENZO[b]FURAN DERIVATIVES
1927
extensive investigated class of compounds, which have many interesting activity profiles,
namely antibiotics represented by linezolod, COX-1 inhibitors, inhibitors of the bacterial
enzyme Mur B, non-nucleoside inhibitors of HIV-RT, and antihistaminic agents.16–21 Con-
sequently, many different protocols have been developed that allow for the synthesis of
4-thiazolidinone skeletons. Along with this, a vast amount of literature is available describ-
ing a wide range of biological activity of thiazolidinone derivatives.22–24 Thus with an effort
to capitalize the pharmacological potential of the 4-thiazolidinone nucleus and to improve
the efficiency, output, and quality of the process, the present investigation deals with the
synthesis, characterization, and biological studies of some new 3-[4-(1-benzofuran-2-yl)-
1,3-thiazol-2-yl]-2-(4-aryl)-1,3-thiazolidin-4-one derivatives.
RESULTS AND DISCUSSION
The experiments were directed towards the coupling-cyclization of 1-(1-benzofuran-
2-yl)-2-bromoethanone25 with thiourea in absolute ethanol to form 4-(1-benzofuran-2-yl)-
1,3-thiazol-2-amine.26 The synthesis of 4-(1-benzofuran-2-yl)-1,3-thiazol-2-amine 3 by the
conventional method is preferred over the microwave-assisted method26 when compared to
the yield obtained. The condensation of 4-(1-benzofuran-2-yl)-1,3-thiazol-2-amine 3 with
different aromatic aldehydes furnished the Schiff bases (4a–e), which upon further reaction
with thioacetic acid in a catalytic amount of anhydrous ZnCl2, gave 1,3-thiazolidin-4-one
derivatives (5a–e) with excellent yield. The formation of Schiff bases (4a–e) were confirmed
from IR, NMR, and mass spectral data. In the IR spectrum, the absence of an absorption
band due to NH2 group around 3342 cm−1 and the presence of an absorption band at 1620
cm−1 due to C N group confirmed the formation of Schiff bases. The 1H NMR spectrum
of compound 4a displayed a singlet at δ 2.53 due to HC N proton, another singlet at δ
6.89 due to CH proton of thiazole ring, and a multiplet between δ 7.36–8.07due to the 10
aromatic protons. The absence of a singlet around δ 4.35 ppm due to NH2 confirmed the
formation of Schiff base 4a. The IR spectrum of compound 5a showed absorption band at
1
1678 cm−1 due to C O. H NMR spectrum of compound 5a showed a singlet at δ 3.85
due to methylene protons of the thiazolidinone ring and another singlet at δ 7.28 due to
the methine proton of the thiazole ring. It also displayed a singlet at δ 4.18 due to the
methine proton of the thiazolidinone ring and a multiplet between δ 7.21–7.98 due to 10
aromatic protons. The spectral data revealed the formation of the 1,3-thiazolidin-4-one ring
(Scheme 1).
BIOLOGICAL STUDIES
Antimicrobial Activity
The newly synthesized compounds were screened for antimicrobial activity by the
cup plate method.27 The in vitro antimicrobial activity was carried out using four bacteria
and four fungal organisms. (See the Supplemental Materials, available online, for complete
details.)
Analgesic Activity
Analgesic activity to newly synthesized compounds was carried out using adult
Swiss albino mice (six animals per group) by abdominal constriction method.28 (See the
Supplemental Materials.)

1928
B. K. VENKATESH ET AL.
O
O
O
O
S
H
Br /Acetic acid
2
Cl
OH
O
1
O
2
K CO /Acetone
Br
2
3
H N
NH
2
2
Ethanol
S
R
S
Ethanol
O
O
N
N
Refluxed for 5hr
O
N
NH
2
3
R
4a-e
SH-CH -COOH
2
ZnCl /DMF
2
R
S
O
N
N
S
O
5a-e
a
b
c
d
e
R = H, CH , OCH , Cl, F
3
3
Scheme 1 Synthesis of thiazolidinone derivatives from different Schiff bases.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected. The IR
spectra were recorded on Nicolet Impact 410 FT IR spectrophotometer using KBr pellets
or Nujol. 1H NMR and 13C NMR spectra were recorded on a Bruker 300-MHz FT NMR
spectrometer in CDCl3 and DMSO-d6 with TMS as internal standard. Chemical shifts are
reported in parts per million (δ) and peak multiplicities are designated as follows: s, singlet;
d, doublet; dd, doublet of doublets; t, triplet; br, broad signal; and m, multiplet. Mass spectra
were recorded on a Thermo-Finnigan-MATT, Bremen (Model MAT8200) spectrometer.
Electrospray ionization mass spectrum (ESIMS) was recorded on a Quattro LCZ (Walters-
Micromass, Manchester, UK) and elemental analyses were carried out using a Heraus CHN
rapid analyzer. Thin layer chromatography (TLC) was performed on precoated sheets of
silica gel 60 F254
.

SYNTHESIS OF BENZO[b]FURAN DERIVATIVES
1929
General Procedure for the Synthesis of 4-(1-Benzofuran-2-yl)-
N-[(4-arylphenyl)methylidene]-1,3-thiazol-2-amine(4a–e)
An equimolar mixture of substituted arylaldehyde (0.001 mol) and 4-(1-benzofuran-
2-yl)-1,3-thiazol-2-amine 3 (0.001mol) was taken in dry ethanol (5 mL) and refluxed for
5–6 h. The reaction mixture was cooled at room temperature and poured into ice water,
filtered, and dried. The dried compounds (5a–e) were recrystallized in ethanol.
4-(1-Benzofuran-2-yl)-N-[phenylmethylidene]-1,3-thiazol-2-amine (4a).
Colorless (ethanol), yield 82%, mp 176–178◦C: IR (KBr) ν(cm−1): 3050, 1562, 1442
(C C, C N).1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.53 (s, 1H, CH) 6.89 (s, 1H, CH,
thiazole), 7.36–8.07 (m, 10H, Ar-H), MS: m/z 304, Anal. C18H12 N2OS calcd. for: C,
71.03; H, 3.97; N, 9.20. Found: C, 71.05; H, 3.97; N, 9.22%.
4-(1-Benzofuran-2-yl)-N -[(4-methylphenyl)methylidene]-1,3-thiazol-2-
amine (4b). Brown (ethanol), yield 76%, mp 190–192◦C: IR (KBr) ν(cm−1): 3061,
1538, 1464 (C C, C N).1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.25 (s, 3H),
2.58 (s, 1H, CH), 7.08 (s, 1H, CH, thiazole), 7.21–8.11(m, 9H, Ar-H), MS: m/z 318,
Anal. C19H14 N2OS calcd. for: C, 71.67; H, 4.43; N, 8.80. Found: C, 71.69; H, 4.44;
N, 8.83%.
4-(1-Benzofuran-2-yl)-N-[(4-methoxyphenyl)methylidene]-1,3-thiazol-2-
amine (4c). Colorless (ethanol), yield 61%, mp 188–190◦C: IR (KBr) ν(cm−1): 3045,
1556, 1460 (C C, C N).1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.53 (s, 1H, CH),
3.62(s, 3H, OCH3), 7.11 (s, 1H, CH, thiazole), 7.18–8.05(m, 9H, Ar-H), MS: m/z 334,
Anal.C19H14 N2O2S calcd. for: C, 68.24; H, 4.22; N, 8.38. Found: C, 68.26; H, 4.24; N,
8.41%.
4-(1-Benzofuran-2-yl)-N -[(4-chlorophenyl)methylidene]-1,3-thiazol-2-
amine (4d). Pale yellow (ethanol), yield 65%, mp 201–203◦C: IR (KBr) ν(cm−1): 3055,
1550, 1463 (C C, C N).1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.48 (s, 1H, CH), 7.12
(s, 1H, CH, thiazole), 7.18–8.05 (m, 9H, Ar-H), MS: m/z 338, 339, Anal. C18H11 N2OSCl
calcd. for: C, 68.81; H, 3.27; N, 8.27. Found: C, 68.83; H, 3.30; N, 8.29%.
4-(1-Benzofuran-2-yl)-N -[(4-fluorophenyl)methylidene]-1,3-thiazol-2-
amine (4e). Pale yellow (ethanol), yield 68%, mp 186–188◦C: IR (KBr) ν(cm−1): 3064,
1548, 1436 (C C, C N).1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.50 (s, 1H, CH), 7.05
(s, 1H, CH, thiazole), 7.26–8.17 (m, 9H, Ar-H), MS: m/z 322, Anal. C18H11 N2OSF calcd.
for: C, 67.07; H, 3.44; N, 8.69. Found: C, 67.09; H, 3.45; N, 8.72%.
General Procedure for the Synthesis of 3-[4-(1-Benzofuran-2-yl)-1,3-
thiazol-2-yl]-2-(4-aryl)-1,3-thiazolidin-4-one Derivatives (5a–e)
An equimolar mixture of (0.001 mol) Schiff bases (4a–e) and thioacetic acid (0.07 g,
0.001 mol) in catalytic amount of anhydrous ZnCl2 were taken in DMF (5 mL) and refluxed
for 6–8 h. Excess of DMF was distilled off, and the reaction mixture was poured into ice
cold water, filtered, and dried to furnished 1,3-thiazolidin-4-one derivatives.
3-[4-(1-Benzofuran-2-yl)-1,3-thiazol-2-yl]-2-phenyl-1,3-thiazolidin-4-one
(5a). Brown (ethanol), yield 56%, mp 184–186◦C: IR (KBr) ν(cm−1): 3078, 2921–2856
(aromatic,Ar-H), 1669 (C O), 1548, 1438 (C C, C N). 1H NMR (300 MHz, DMSO-d6)
δ (ppm): 3.85 (s, 2H, methylene), 4.18 (s, 1H, methine), 7.21 (d, 1H, J = 9.06 Hz, 3-CH),
7.28 (s, 1H, CH, thiazole), 7.32 (dd, J = 8.40 Hz, 1H, 6-CH), 7.39 (dd, J = 6.36 Hz, 1H,
7-CH), 7.35 (d, J = 3.65 Hz, 2H, C2, C6H-Ph), 7.26 (d, J = 3.42 Hz, 2H,C3, C5H-Ph),
7.98 (d, 1H, J = 8.16 Hz, 8-CH), 13C NMR (300 MHz, DMSO-d6) δC (ppm): 33.5, 72.5,

1930
B. K. VENKATESH ET AL.
104.8, 120.3, 124.7, 126.3, 128.4, 129.8, 132.4, 134.6, 136.8, 140.5, 142.5, 149.8, 158.2,
171.2. MS: m/z 378, Anal. C20H14 N2O2S2 calcd. for: C,63.47; H,3.73; N, 7.40. Found: C,
63.45; H, 3.73; N, 7.42%.
3-[4-(1-Benzofuran-2-yl)-1,3-oxazol-2-yl]-2-(4-methylphenyl)-1,3-thiazo-
lidin-4-one (5b). Yellow (ethanol), yield 65%, mp 159–162◦C: IR (KBr) ν(cm−1): 3090,
1
2953–2824, 1674 (C O), 1565, 1462 (C C, C N). H NMR (300 MHz, DMSO-d6) δ
(ppm): 1.80 (s, 3H, CH3), 3.65 (s, 2H, methylene), 6.48 (s, 1H, methine), 7.32 (s, 1H,
CH, thiazole), 7.26 (d, J = 1.83 Hz, 1H, 3-CH), 7.30 (dd, J = 4.82 Hz, 1H, 6-CH), 7.36
(d, J = 4.41 Hz, 2H,C3, C5H-Ph), 7.45 (dd, J = 8.25 Hz, 1H, 7-CH), 7.84 (d, J = 5.61
Hz, 1H, 8-CH), 7.98 (d, J = 7.61 Hz, 2H, C2, C6H-Ph), 13C NMR (300 MHz, DMSO-d6)
δC (ppm): 21.6, 33.8, 71.9, 112.8, 122.9, 123.1, 126.3, 128.4, 130.4, 130.6, 133.5, 135.7,
140.0, 143.1, 149.2, 158.2,169.8, MS: m/z 392, Anal. C21H16 N2O2S2 calcd. for: C, 64.26;
H, 4.11; N, 7.14. Found: C, 64.29; H, 4.12; N, 7.16%.
3-[4-(1-Benzofuran-2-yl)-1,3-oxazol-2-yl]-2-(4-chlorophenyl)-1,3-thiazoli-
din-4-one (5c). Colorless (ethanol), yield 82%, mp 241–243◦C: IR (KBr) ν(cm−1): 3058,
1
2984–2852, 1672 (C O), 1559, 1458 (C C, C N). H NMR (300 MHz, DMSO-d6) δ
(ppm): 3.63 (s, 2H, methylene), 6.45 (s, 1H, methine), 7.18 (d, J = 1.6 Hz, 1H, 3-CH),
7.34 (s, 1H, CH, thiazole), 7.35 (dd, J = 9.21 Hz, 1H, 6-CH), 7.31 (d, J = 7.77 Hz, 2H,C3,
C5H-Ph), 7.44 (dd, J = 8.37 Hz, 1H, 7-CH), 7.62 (d, J = 7.52 Hz, 1H, 8-CH), 7.96 (d, J =
7.20 Hz, 2H, C2, C6H-Ph), 13C NMR (300 MHz, DMSO-d6) δC (ppm): 33.2, 72.3, 115.8,
121.9, 123.4, 126.7, 128.5, 130.6, 132.4, 134.6, 135.4, 141.5, 143.3, 150.2, 154.6, 166.8.
MS: m/z 412, Anal. C20H13Cl N2O2S2 calcd. for: C, 58.18; H, 3.17; N, 6.78. Found: C,
58.20; H, 3.16; N, 6.75%.
3-[4-(1-Benzofuran-2-yl)-1,3-oxazol-2-yl]-2-(4-methoxyphenyl)-1,3-thia-
zolidin-4-one (5d). Yellow (ethanol), yield 68%, mp 211–213◦C: IR (KBr) ν(cm−1):
3078, 2950–2838, 1672 (C O), 1566, 1469 (C C, C N). 1H NMR (300 MHz, DMSO-d6)
δ (ppm): 4.2 (s, 3H, OCH3), 3.53 (s, 2H, methylene), 6.44 (s, 1H, methine), 7.28 (s, 1H,
CH, thiazole), 7.18 (d, J = 13.40 Hz, 1H, 3-CH), 7.35 (dd, J = 8.42 Hz, 1H, 6-CH), 7.38
(dd, J = 8.37 Hz, 1H, 7-CH), 7.48 (d, J = 8.57 Hz, 2H, C3, C5H-Ph), 7.63 (d, J = 7.76
Hz, 1H, 8-CH), 7.68 (d, J = 7.45 Hz, 2H,C2, C6H-Ph), 13C NMR (300 MHz, DMSO-d6)
δC (ppm): 65.0, 32.5, 70.7, 110.8, 123.8, 124.6, 125.2, 127.4, 130.6, 132.7, 134.1, 134.8,
141.3, 142.7, 149.8, 155.2, 171.8, MS: m/z 408, Anal. C21H16 N2O3S2 calcd. for: C, 61.75;
H, 3.95; N, 6.86. Found: C, 61.78; H, 3.98; N, 6.83%.
3-[4-(1-Benzofuran-2-yl)-1,3-oxazol-2-yl]-2-(4-fluorophenyl)-1,3-thiazoli-
din-4-one (5e). Yellow (ethanol), yield 65%, mp 204–206◦C: IR (KBr) ν(cm−1): 3051,
1
2946–2867, 1668 (C O), 1559, 1463 (C C, C N). H NMR (300 MHz, DMSO-d6) δ
(ppm): 3.64 (s, 2H, methylene), 6.62 (s, 1H, methine), 7.10 (d, J = 7.62 Hz, 1H, 3-CH),
7.36 (dd, J = 8.10 Hz, 1H, 6-CH), 7.37 (s, 1H, CH, thiazole), 7.49 (dd, J = 7.64 Hz, 1H,
7-CH), 7.31 (d, J = 7.35 Hz, 2H, C2, C6H-Ph), 7.73 (d, J = 8.46 Hz, 1H, 8-CH), 7.84 (d,
J = 7.78 Hz, 2H, C3, C5H-Ph), 13C NMR (300 MHz, DMSO-d6) δC (ppm): 33.0, 72.5,
112.3, 120.6, 122.7, 125.8, 128.8, 131.0, 134.1, 135.9, 135.5, 140.8, 144.5, 148.8, 154.2,
170.8. MS: m/z 396, Anal. C20H13 N2O2S2 calcd. for: C, 60.59; H, 3.31; N, 7.07. Found:
C, 60.55; H, 3.34; N, 7.08%.
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