A facile synthesis of bromo-substituted benzofuran containing thiazolidinone nucleus bridged with quinoline derivatives: Potent analgesic and antimicrobial agents

Article abstract of DOI:10.1080/10426500902717317

Treatment of 5-bromo-2-acetyl benzofuran with hydrazine followed by condensation of the resulting hydrazone with different quinoline derivatives gave the corresponding Schiff bases. Reaction of these Schiff bases with thioacetic acid furnished the target thiazolidinone molecule. Some of the newly synthesized compounds show promising analgesic and antimicrobial 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.

Full text of DOI:10.1080/10426500902717317

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A Facile Synthesis of Bromo-Substituted
Benzofuran Containing Thiazolidinone
Nucleus Bridged with Quinoline
Derivatives: Potent Analgesic and
Antimicrobial Agents
Venkatesh K. Bhovi a , Yadav D. Bodke a , S. Biradar b , B. E. Kumara
Swamy a & S. Umesh b
a Department of Studies and Research in Industrial Chemistry, Jnana
Sahyadri, Kuvempu University, Shankaraghatta, Karnataka, India
b Biocon International Ltd., Bangalore, India
Version of record first published: 28 Dec 2009
To cite this article: Venkatesh K. Bhovi, Yadav D. Bodke, S. Biradar, B. E. Kumara Swamy & S. Umesh
(2009): A Facile Synthesis of Bromo-Substituted Benzofuran Containing Thiazolidinone Nucleus Bridged
with Quinoline Derivatives: Potent Analgesic and Antimicrobial Agents, Phosphorus, Sulfur, and Silicon
and the Related Elements, 185:1, 110-116
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Phosphorus, Sulfur, and Silicon, 185:110–116, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902717317
A FACILE SYNTHESIS OF BROMO-SUBSTITUTED
BENZOFURAN CONTAINING THIAZOLIDINONE
NUCLEUS BRIDGED WITH QUINOLINE DERIVATIVES:
POTENT ANALGESIC AND ANTIMICROBIAL AGENTS
Venkatesh K. Bhovi,1 Yadav D. Bodke,1 S. Biradar,2
B. E. Kumara Swamy,1 and S. Umesh2
1Department of Studies and Research in Industrial Chemistry, Jnana Sahyadri,
Kuvempu University, Shankaraghatta, Karnataka, India
2Biocon International Ltd., Bangalore, India
Treatment of 5-bromo-2-acetyl benzofuran with hydrazine followed by condensation of
the resulting hydrazone with different quinoline derivatives gave the corresponding Schiff
bases. Reaction of these Schiff bases with thioacetic acid furnished the target thiazolidi-
none molecule. Some of the newly synthesized compounds show promising analgesic and
antimicrobial 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 Antimicrobial agent; 5-bromo-salicylaldehyde; cyclic voltammetry; quinoline
derivatives; Schiff base; thioacetic acid
INTRODUCTION
Benzo[b]furans are of great synthetic interest because of their wide distribution in
nature and useful biological activities.1 The benzo[b]furan ring is often incorporated in
pharmaceutical agents as a core structural motif, and as a result it continues to attract exten-
sive synthetic efforts.2,3 Many reported synthetic approaches are based on the construction
of furan rings from various arene derivatives.3h Benzofuran and its derivatives exhibit
various biological activities. Such derivatives were investigated as antibacterial4 or anti-
fungal agents.4,5 Moreover, many researchers have synthesized fused or coupled nitrogen-
containing heterocycles,6,7 which have shown very good biological activities. Quinoline is
the important nitrogen-containing heterocyclic compound having biological activity. The
presence of a halogen atom also shows good antimicrobial properties.8 Quinoline and its
derivatives are known for their antimalarial and therapeutic effects.9 A number of quinoline
Received 25 October 2008; accepted 1 January 2009.
The authors thank the Indian Institute of Science Bangalore and Karnataka University Dharwad for providing
spectral data. One of the authors (V.K.B.) thanks Kuvempu University for awarding a research fellowship.
Address correspondence to Yadav D. Bodke, Department of Studies and Research in Industrial Chemistry,
Jnana Sahyadri, Kuvempu University, Shankaraghatta-577 451, Karnataka, India. E-mail: ydbodke@gmail.com
110

5-BROMO-SUBSTITUTED BENZOFURAN
111
derivatives are known to possess antibacterial, antifungal, antihypertensive, analgesic, and
anti-inflammatory activities.10–13 The applications of quinoline derivatives14–17 are impres-
sive, spreading from antimalarial to almost every branch of medicinal chemistry.18,19
In continuation of work on condensed heterocycles20–22 and in view of our growing
interest in the field of bioactive agents, in this article we report an efficient synthesis of
novel compounds 5a–e and 6a for their profile of analgesic and antimicrobial activities.
RESULTS AND DISCUSSION
In continuation of our studies in developing condensed quinoline derivatives due
to their significant biological activities, it appeared expedient to synthesize a series
of systematically condensed and appropriately functionalized 3-{[1-(5-bromo-1H-inden-
2-yl)ethylidene]amino}-2-(2-chloroquinolin-3-yl)-1,3-thiazolidin-4-ones 6a. The starting
material, 5-bromo-2-acetyl benzofuran 2 was prepared by the reaction of 5-bromo-2-
hydroxy benzaldehyde with chloroacetone in anhydrous acetone.23,24 Compound 2 was
reacted with hydrazine hydrate under acidic conditions in ethanol at reflux temperature to
form 1-(5-bromo-1-benzofuran-2-yl)ethanone hydrazone 3 in good yield. The structure of
3 was confirmed by IR and 1H NMR data. The IR spectrum of 3 showed a sharp absorption
band at 3300–3400 cm−1 due to NH2 group. The absence of a carbonyl stretching frequency
at 1665 cm−1 and the appearance of an absorption band at 3300–3400 cm−1 reveals the
formation of hydrazone 3. The 1H NMR spectrum of compound 3 exhibits a broad singlet
at δ 5.63 ppm for –NH2 protons, another singlet at δ 1.63 ppm due to three methyl protons,
and a multiplet between δ 7.22–7.78 ppm for aromatic protons.
The treatment of compound 3 with different substituted 2-chloro-3-formyl quino-
lines25 4a–e in the presence of a catalytic amount of acetic acid in absolute ethanol fur-
nished the Schiff bases 5a–e (Scheme 1. The structures of the newly synthesized Schiff
1
bases were confirmed by IR, H NMR, and mass spectral data. The IR spectrum of 5a
1
exhibits absorption bands at 1615 and 1618 cm−1 due to two C N groups. H NMR
spectrum of 5a displayed a multiplet between δ 7.27–7.86 ppm for nine aromatic pro-
tons and a sharp intensive singlet at δ 1.64 ppm due to –CH3 protons. The absence of a
singlet at δ 5.58 ppm due to –NH2 protons revealed the formation of desired compounds
5a, and it also showed the isotopic peaks at m/z 427 and 429. The structure was further
confirmed from its mass spectrum, which gave the molecular ion peak at m/z 425 (M+)
that corresponds to molecular weight of compound 5a. Similarly, the structures of the com-
pounds 5b–e were assigned on the basis of their spectral data. Cyclization of Schiff base 5a
with thioacetic acid in DMF at reflux temperature using a catalytic amount of anhydrous
ZnCl2 furnished the compound, which was identified as 3-{[1-(5-bromo-1-benzofuran-2-
yl)ethylidene]amino}-2-(2-chloroquinolin-3-yl)-1,3-thiazolidin-4-one (6a) on the basis of

112
V. K. BHOVI ET AL.
Scheme 1
spectral data. The IR spectrum of 6a exhibits absorption bands at 1676 cm−1 due to a
carbonyl stretching and 1620 cm−1 due to a C N. Its mass spectrum showed a molecular
ion peak(M+) at m/z 500 and isotopic peaks at m/z 502 and 504 in the intensity ratio of
3:4:1. The 1H NMR spectrum of compound 6a displayed four signals—a singlet at δ 1.06
ppm due to three methyl protons, another two singlets at δ 3.12 ppm (2H) and δ 4.56 ppm
(1H) due to methylene and methine protons of thiazolidone ring, respectively, and nine
aromatic protons appeared as a multiplet between δ 7.14–8.28 ppm.
BIOLOGICAL STUDIES
Antimicrobial Activity
The newly synthesized compounds were screened for their antimicrobial activity by
the cup plate method.26 The in vitro anitimicrobial activity was carried out against 24 h
old cultures of four bacteria and four fungal organisms. (See the Supplemental Materials
online.)
Cyclic Voltammetric Studies of Compound 5a
Figure 1 shows the cyclic voltammogram of chloroquinoline-3-carbaldehyde[1-(5-
bromo-1-benzofuran-2-yl)ethylidene] hydrazone at a glassy carbon electrode in 20 mM

5-BROMO-SUBSTITUTED BENZOFURAN
113
Figure 1 (a) The cyclic voltammogram of 1 mM comp 5a in 20 mM sulfuric acid media at glassy carbon
electrode. (b) Variation of scan rate from 20 mVs−1 to 140 mVs−1
.
sulfuric acid media at 50 mV s−1. The compound showed a cathodic peak potential at
–618 mV for the reduction of the C N moiety. The irreversibility was confirmed by
the absence of an anodic peak between the potential of +100 mV to –900 mV. The effect
of the scan rate was studied from 20 to 250 mVs−1, and the cathodic peak current was
proportional to the scan rate and the process is diffusion-controlled. The calculated number
of electrons was found to be 1.96, which is close to the two-electron change during the
electrochemical reaction. From the graph, we can see that the C N group in the Schiff
base is easily reduced at the glassy carbon electrode by cyclic voltammetry. From this
evidence, the probable structure for reduced compound may be as shown in Scheme 2.
Scheme 2 The probable structure for reduced compound 5a.
EXPERIMENTAL
The melting points were determined in an open capillary tube and are uncorrected.
The purity of the compounds was checked by TLC on silica gel and was purified by column
1
chromatography. H NMR spectra (300 MHz) were recorded on a Bruker Supercon FT
NMR instrument using TMS as an internal standard, and chemical shifts are expressed in
δ units. IR spectra were recorded on a Perkin Elmer 157 Infrared Spectrophotometer and
mass spectra on a Jeol JMS-D 300 mass spectrometer operating at 70 eV.
General Procedure
Synthesis of aryl hydrazone (3a). The mixture of 1-(5-bromo-1-benzofuran-2-
yl)ethanone (2) (10 mmol, 0.8g) and hydrazine hydrate (98%, 0.01 mol) was refluxed in
ethanol for 6 h. The excess ethanol was distilled out, and the contents were allowed to cool.

114
V. K. BHOVI ET AL.
The crystals formed were filtered and dried. The completion of the reaction was monitored
on TLC by using silica gel-G coated plates by using ethyl acetate and pet ether (1:1) as the
eluent and observed under UV light. IR (KBr) (cm−1): 3300–3400 (NH2), 3056 (aromatic
CH stretching), 1586, 1573 (C C ring stretching), 2970, 2848 (methyl CH stretching),
1284 (N-N C). 1H NMR (300 MHz) (DMSO-d6) (δ) ppm; 1.63 (s, 3H, CH3); 5.63 (s, 2H,
NH2); 7.22–7.78 (4H, aromatic).
Chloroquinoline-3-carbaldehyde-[1-(5-bromo-1-benzofuran-2-yl)ethylid
ene] Hydrazone (5a). A mixture of 1-(5-bromo-1-benzofuran-2-yl) ethanone hydrazone
3 (0.25 g, 0.001mol) and 2-chloroquinoline-3-carbaldehyde 4a (0.19g, 0.01mole) was
taken in ethanol (10 mL) with a catalytic amount of acetic acid and heated at reflux
temperature for 5–6 h. After the completion of the reaction (checked by TLC), the
reaction mixture was poured onto crushed ice. The solid mass thus separated out was
filtered, washed with water, and crystallized from ethanol to give the desired compound
◦
5a in 83% yield, mp 216–218 C; IR (KBr, cm−1) 1618, and 3058(aromatic ring); Calc.:
C20H13BrClN3O: C, 56.30; H, 3.07; N, 9.85; Anal. Found: C, 56.44; H, 3.32; N, 10.15;
MS: m/z 425; 1H NMR: (DMSO-d6): δ 1.64 (s, 3H), δ 7.20 (1H, CH), δ 7.27–7.86 (m, 9H,
Ar H).
3-[[1-(5-Bromo-1-benzofuran-2-yl)ethylidene]hydrazinylidenemethyl-2-
chloro-6-methylquinoline (5b). The same procedure was followed as for 5a. Yellow
◦
solid, crystallized from ethanol, 75% yield, mp 223–226 C; IR (KBr, cm−1), Aromatic
C H stretching 3070, 3030, Methyl (C H)2869, (C N) 1689; Calc.: C21H15BrClN3O:
1
C, 57.23; H, 3.43; N, 9.53; Anal. Found: C, 57.39; H, 3.47; N, 9.91; MS: m/z 439; H
NMR: (DMSO-d6): δ 1.78(s, 3H), δ 2.15(s, 3H), δ 7.18 (1H, CH), δ 7.34–8.86 (m, 8H,
Ar H).
3-[[1-(5-Bromo-1-benzofuran-2-yl)ethylidene]hydrazinylidenemethyl]-2-
chloro-8-methylquinoline (5c). The same procedure was f◦ollowed as for 5a.
Yellow solid, crystallized from ethanol, 60% yield, mp 206–209 C; IR (KBr, cm−1),
Aromatic C H stretching 3070,3030, Methyl (C H) 2893, (C N) 1689; Anal. Calc.:
C21H15BrClN3O: C, 57.23; H, 3.43; N, 9.53; Anal. Found: C, 57.41; H, 3.51; N, 9.58
1
MS: m/z 439; H NMR: (DMSO-d6): δ 1.65 (s, 3H), δ 2.35 (s, 3H), δ 7.18(1H, CH), δ
7.34–8.86 (m, 8H, Ar H).
3-[[1-(5-Bromo-1-benzofuran-2-yl)ethylidene]hydrazinylidenemethyl]-2-
chloro-6-methoxyquinoline (5d). The same procedure was followed as for 5a.
Pale yellow solid, Crystallized from ethanol, 65% yield, mp 236–238 ◦C; IR (KBr,
cm−1), Aromatic C H stretching 3070, 3030, Methyl (C H) 2893, (C N) 1689; Calc.:
C21H15BrClN3O2: C, 55.23; H, 3.31; N, 9.20; Anal. Found: C, 55.39; H, 3.42; N, 9.45;
1
MS: m/z 455; H NMR: (DMSO-d6): δ 1.45 (s, 3H), δ 3.44 (s, 3H), δ 7.20(1H, CH), δ
7.14–8.36 (m, 8H, Ar H).
3-[[1-(5-Bromo-1-benzofuran-2-yl)ethylidene]hydrazinylidenemethyl]-2-
chloro-8-methoxyquinoline (5e). The same procedure was followed as for 5a.
Greenish yellow solid, crystallized from ethanol, 77% yield, mp 209–212 oC; IR (KBr,
cm−1), Aromatic C H stretching 3070,3030, Methyl (C H) 2893, (C N) 1689;
C21H15BrClN3O2: Calc.: C, 55.23; H, 3.31; N, 9.20; Anal. Found: C, 55.41; H, 3.39; N,
9.82; MS: m/z, 455; 1H NMR: (DMSO-d6): δ 1.25 (s,3H), δ 3.94 (s,3H), δ 7.08 (1H,CH),
δ 7.14–7.96 (m, 8H, Ar H).
3-{[1-(5-Bromo-1-benzofuran-2-yl)ethylidene]amino}-2-(2-chloroquinoli
n-3-yl)-1,3-thiazolidin-4-one (6a). 3-[1-(5-Bromo-1-benzofuran-2-yl)ethylidene]hyd-
razinylidene}methyl]-2-chloroquinoline (0.001 mol, 0.426 g) and mercaptoacetic acid

5-BROMO-SUBSTITUTED BENZOFURAN
115
(0.01 mol, 1.84 g) were refluxed in the presence of a catalytic amount of anhydrous ZnCl2
in dry DMF (25 mL) for 6 h. The reaction mixture was then cooled and poured onto
crushed ice. The product that separated out was filtered, dried, and recrystallized from
ethanol as a light brown solid. Yield 86%, mp 239–241◦C; IR (KBr, cm−1), carbonyl
(C O) 1676, Aromatic C H stretching 3070, 3030, Methyl (C H) 2893, (C N) 1620;
Calc.: C22H15BrClN3O2S; C, 52.76; H, 3.02; N, 8.39; Anal. Found: C, 52.93; H, 3.28; N,
1
8.45; MS: m/z 500; H NMR (DMSO-d6): δ 1.06(s,3H), δ 3.12 (m, 2H), δ 4.56 (1H), δ
7.14–8.28 (m, 9H, Ar H).
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