Solvent free microwave accelerated synthesis of heterocyclic thiazolidin-4-ones as antimicrobial and antifungal agents

Article abstract of DOI:10.5012/bkcs.2010.31.5.1219

A simple and efficient method has been developed for conversion of arenecarbaldehyde-3-methylquinoxalin-2-ylhydrazones to 3-(2-methylquinoxalin-3- yl)-2-(substitutedphenyl)thiazolidin-4-ones in good yields using microwave irradiation technique on silica a

Full text of DOI:10.5012/bkcs.2010.31.5.1219

Solvent Free Microwave Accelerated Synthesis
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 5 1219
DOI 10.5012/bkcs.2010.31.5.1219
Solvent Free Microwave Accelerated Synthesis
of Heterocyclic Thiazolidin-4-ones as Antimicrobial and Antifungal Agents
Kondapalli Venkata Gowri Chandra Sekhar,†,* Vajja Sambasiva Rao, Aravalli Satish Reddy, Ravada Sunandini,
†
and V S A Kumar Satuluri
Chemistry Group, BITS, Pilani-333 031, Rajasthan, India
†
Chemistry Group, BITS, Pilani-Hyderabad Campus, Jawahar Nagar, Shamirpet Mandal, Ranga Reddy District,
*
Hyderabad-500 078, Andhra Pradesh, India. E-mail: kvgc@bits-hyderabad.ac.in
Received January 4, 2010, Accepted March 3, 2010
A simple and efficient method has been developed for conversion of arenecarbaldehyde-3-methylquinoxalin-2-yl-
hydrazones to 3-(2-methylquinoxalin-3-yl)-2-(substitutedphenyl)thiazolidin-4-ones in good yields using microwave
irradiation technique on silica as solid support under solvent free conditions. The synthesized compounds were cha-
1
racterized by elemental microanalysis, infrared spectroscopy, H NMR, and mass spectroscopy. All the synthesized
thiazolidinones were investigated for their antimicrobial and antifungal activities. The results of the biological activities
revealed that the compounds 3b, 3d, 3f and 3hexhibited excellent antibacterial activities while 3dand 3h exhibited
good antifungal activity.
Key Words: Quinoxalines, Silica, Microwave irradiation, Antibacterial, Antifungal
Introduction
microwave irradiation technique has several advantages. When
reactants are adsorbed onto solid supports, good dispersion of
active (reagent) site leads to significant improvement of reacti-
vity due to availability of large surface area and the constraints
of the (molecular dimensions) pores and the characteristics of
the surface adsorption will also lead to useful improvement in
Quinoxaline derivatives have been found to be biologically
active compounds having antibacterial, antifungal, antiinfla-
mmatory, antidepressant, anthelmintic and herbicidal proper-
1-3
4
5
ties. They also have antimicrobial, antimycobacterial, anti-
6
7
12
cancer and antiallergic properties. In view of the above interest
in these compounds and in continuation of our studies on the
reaction selectivity. Mineral supports behave as efficient ab-
sorbers of microwave energy with consequently attaining more
homogeneity in temperature when compared to carrying out
reactions in solution phase. There are distinct advantages of
these solvent-free protocols since they provide reduction or
elimination of solvents thereby preventing pollution in organic
8-10
cyclization of heterocyclic compounds we have investigat-
ed arenecarbaldehyde 3-methylquinoxalin-2-yl-hydrazones in
ring-closure reactions with thioglycolic acid under microwave
irradiation technique under solvent free conditions on silica
support. Microwave-induced Organic Reaction Enhancement
12
synthesis ‘at source’. Thiazolidinones, synthesized via variety
1
1
[
MORE] chemistry has received considerable attention in the
of routes such as reaction between benzylidene-amines and
13
recent years due to several advantages like short reaction time,
ease of work-up, excellent yields and due to its cost effective-
ness (only simple glassware needed). Moreover, it is an envi-
ronmentally friendly technique and is understood to be a step
mercaptoacetic acid or by condensation of either aliphatic or
aromatic moieties containing a formyl group with different
14
aminothiols or by refluxing a solution of arylhydrazones and
1
5
thioglycolic acid in DMF in the presence of anhydrous ZnCl
2
12
16-17
towards green chemistry. Most of the reactions in microwave
oven are carried out in solution phase. However, in these solu-
tion-phase reactions, the development of high pressure, which
leads to explosion, and the use of sealed containers are some of
the limitations. During recent years, a novel practical dimen-
sion to the microwave heating protocols has been added by
accomplishing reactions on solid supports under solvent-free
conditions. A reaction can be carried out by adsorbing the re-
actants on an inorganic solid support viz., alumina, silica, clay
and zeolite in a sealed or open vessel under microwave environ-
ment. Though reactants are adsorbed onto the solid support and
exposed to microwaves only the reactants absorb the radiations.
The solid support does not absorb or restrict their transmission.
These solvent-free microwave assisted reactions provide an
opportunity to work with open vessels thus avoiding the risk of
high-pressure development and increasing the potential of such
etc.,
are known to have antibacterial, antifungal, anticonvul-
sant, anti-inflammatory, anti-diarrhoeal, anti-HIV, anticancer,
18-24
antimicrobial properties
and are also found to be new thera-
25
peutic agents for Type-2 Diabetes. Keeping in view the im-
portance of microwave assisted organic synthesis under solvent
free conditions and biological activity of thiazolidinones, we
here in report, rapid and efficient conversion of arenecarbalde-
hyde-3-methylquinoxalin-2-yl-hydrazones (2) to the corres-
ponding heterocyclic thiazolidin-4-ones (3) (Scheme 1) using
microwave assisted synthesis on silica support under solvent
free conditions. The synthesized compounds were screened for
antibacterial and antifungal activity.
Experimental
Melting points were determined in open capillaries using
Buchi 530 apparatus and are uncorrected. The purity of the com-
1
2
reactions to upscale. Usage of solid mineral supports during

1
220 Bull. Korean Chem. Soc. 2010, Vol. 31, No. 5
Kondapalli Venkata Gowri Chandra Sekhar et al.
Scheme 1. Design of target compounds (3a-h)
a
Table 1. Physical constants of compounds 3a-h
o
Entry
Ar
Reaction Period (mins)
Yield (%)
M.P. ( C)
Mol. formula (Mol. Wt.)
3
a
C
6
H
5
4.0
3.5
3.0
5.0
4.5
4.5
4.0
5.0
75
79
81
88
83
75
71
70
130 - 131
153 - 155
194 - 196
174 - 176
173 - 175
145 - 146
128 - 130
210 - 211
C
18
H
16
N
4
OS (336)
3
b
m-NO
2
-C
-C
-C
-C
6
H
4
C
C
18
H
H
15
N
N
5
O
O
3
S (381)
S (381)
3
c
p-NO
2
6
H
4
18
15
5
3
3
d
p-CH
3
6
H
6
4
C
19
H
18
N
4
OS (350)
3
e
p-OCH
3
H
4
C
C
19
H
H
18
N
N
4
O
O
2
S (366)
S (352)
3
f
o-OH-C
6
H
4
18
16
4
2
3
g
p-Cl-C
6
H
4
C
18
H
15ClN
4
OS (370.5)
3h
p-OH-m-OCH
3
-C
6
H
3
C
19
H
18
N
4
O S (382)
3
a
All new compounds showed C, H, N analysis within ± 0.4%.
pounds was checked by ascending TLC on Merck’s precoated
silica-gel plates (0.25 mm). Microwave irradiations were carried
out in microwave oven specially designed for organic synthesis
3-(2-Methylquinoxalin-3-yl)-2-(3-nitrophenyl)thiazolidin-
4-one (3b): Light-yellow solid; IR (KBr) νmax 3050, 3025,
2975, 2945, 2907, 1712, 1612, 1510, 1557, 1364, 1200, 1170.
1
(LG Electronics, model MG-605AP, 2450 MHZ, 1000 W). Infra
H NMR δ 8.11-8.16 (d, 2H, H
2
’ & H ’Ph); 8.03-8.05 (d, 2H,
4
red (IR) spectra were recorded in KBr pellets on Schimadzu
J = 8.3 Hz); 7.66-7.73 (d, 2H, J = 8.3 Hz); 7.34-7.43 (d, 2H,
’ & H ’Ph); 5.92 (s, 1H, CH); 3.29-3.36 (s, 2H, CH ); 2.36
(s, 3H, CH ). HRMS (FAB) Calcd. for C18 S 381.0948,
Found 381.0946.
‒1
1
IR Prestige-21 FT-IR spectrophotometer (νmax in cm ); H NMR
H
5
6
2
spectra on Bruker DRX300 spectrometer using TMS as internal
3
H N O
15 5 3
standard (chemical shifts in δ, ppm) in DMSO-d ; elemental
6
analysis on a Carla Erba 1108 elemental analyzer and mass
spectra on a VG-70-S mass spectrometer. 2-Hydrazino-3-me-
thylquinoxaline (1) was prepared by reaction of 2-chloro-3-
methyl quinoxaline with hydrazine hydrate as per the literature
3-(2-Methylquinoxalin-3-yl)-2-(4-nitrophenyl)thiazolidin-
4-one (3c): Light-yellow solid; IR (KBr) νmax 3030, 3015,
2960, 2945, 2900, 1705, 1605, 1500, 1562, 1362, 1203, 1169.
1
H NMR δ 8.06-8.12 (d, 2H, H
3
’ & H ’Ph); 7.97-8.03 (d, 2H,
5
2
6
protocol. Arene carbaldehyde-3-methylquinoxalin-2-yl hy-
J = 8.1 Hz); 7.28-7.74 (m, 4H, J = 8.1 Hz); 7.27-7.39 (d, 2H,
’ & H ’Ph); 5.94 (s, 1H, CH); 3.28-3.38 (s, 2H, CH ); 2.35
(s, 3H, CH ). HRMS (FAB) Calcd. for C18 S 381.0956,
Found: 381.0954.
drazones (2a-h) were prepared according to the general pro-
H
2
6
2
9,27
cedure.
3
H N O
15 5 3
General procedure. A mixture of appropriate heterocyclic
hydrazone 2 (2 mM) and thioglycolic acid (2 mM) was mixed
in pestle and mortar homogeneously along with 1 g of silica
gel (60 - 120 mesh size) for about a period of three minutes.
This mixture is subjected to microwave irradiation at 60%
power output (540 watt) for the period indicated in Table 1.
After completion of the reaction (monitored by TLC), the re-
action mixture was cooled to room temperature and triturated
with water and extracted using 3 × 20 mL portions of ethyl
acetate, dried over anhydrous sodium sulpahte and concentrated
in vacuo to afford 3. All the synthesized compounds were re-
crystallized from ethanol. The yields obtained along with the
melting points of final compounds are tabulated in Table 1.
3-(2-Methylquinoxalin-3-yl)-2-(4-methylphenyl)thiazolidin-
4-one (3d): Yellow solid; IR (KBr) νmax 3035, 3020, 2975,
1
2940, 2890, 1704, 1606, 1514, 1204, 1170. H NMR δ 7.99-
8.13 (d, 2H, J = 8.1 Hz); 7.54-7.69 (d, 2H, J = 8.1 Hz); 6.78-
6.94 (m, 4H); 5.92 (s, 1H, CH); 3.29-3.36 (s, 2H, CH ); 2.62
2
(s, 3H, 4’ CH
3
); 2.32 (s, 3H, CH ). HRMS (FAB) Calcd. for
3
C
H N
19 18 4
OS 350.4465, Found 350.4464.
2-(4-Methoxyphenyl)-3-(2-methylquinoxalin-3-yl)-thiazoli-
din-4-one (3e): Light-yellow solid; IR (KBr) νmax 3045, 3016,
1
2977, 2945, 2921, 1700, 1602, 1512, 1200, 1165. H NMR δ
7.92-8.12 (d, 2H, J = 8.1 Hz); 7.60-7.81 (d, 2H, J = 8.1 Hz);
6.40-7.01 (m, 4H); 5.90 (s, 1H, CH); 3.74 (s, 3H, OCH ); 3.29-
3
3
-(2-Methylquinoxalin-3-yl)-2-phenylthiazolidin-4-one (3a):
3.34 (s, 2H, CH
2
); 2.38 (s, 3H, CH ). HRMS (FAB) Calcd. for
3
Light-yellow solid; IR (KBr) νmax 3037, 3019, 2979, 2943,
C
19
H
18
N
4
O
2
S 366.4462, Found 366.4460.
1
2
8
7
901, 1708, 1596, 1504, 1205, 1167. H NMR (CDCl
.12 (d, 2H, J = 8.1 Hz); 7.67-7.75 (d, 2H, J = 8.1 Hz); 7.06-
.14 (m, 5H); 5.92 (s, 1H, CH); 3.27-3.38 (s, 2H, CH ); 2.32
). HRMS (FAB) Calcd. for C18 OS 336.4167,
3
) δ 8.01-
2-(2-Hydroxyphenyl)-3-(2-methylquinoxalin-3-yl)-thiazoli-
din-4-one (3f): Light-yellow solid; IR (KBr) νmax 3420-3550,
2
3034, 3012, 2965, 2943, 2900, 1704, 1602, 1512, 1205, 1165.
1
(
s, 3H, CH
3
H N
16 4
H NMR δ 8.04-8.10 (d, 2H, J = 7.9 Hz); 7.66-7.91 (d, 2H, J =
Found 336.4163.
7.9 Hz); 6.61-6.91 (m, 4H, Ph); 5.92 (s, 1H, CH); 5.36 (s, 1H,

Solvent Free Microwave Accelerated Synthesis
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 5 1221
‒
1
OH, D
CH ). HRMS (FAB) Calcd. for C18
52.4163.
-(4-Chlorophenyl)-3-(2-methylquinoxalin-3-yl)-thiazoli-
din-4-one (3g): Light-yellow solid; IR (KBr) νmax 3032, 3017,
2
O exchangeable); 3.29-3.36 (s, 2H, CH
2
); 2.33 (s, 3H,
amino group at 3350 cm in IR spectra. An important charac-
1
3
H N
16 4
O
2
S 352.4167, Found
teristic feature in the H NMR spectra of 3 was the disappear-
3
ance of the signals at δ 8.5 and 9.3 for aldehydic H and for NH,
respectively, which were present in the spectra of the inter-
mediate hydrazones (2a-h). IR spectral analysis of the final com-
2
1
‒1
‒1
2
976, 2940, 2895, 1702, 1599, 1505, 1202, 1169, 720. H NMR
pounds (3a-h) show absorption band at ~1700 cm , ~1200 cm
‒
1
δ 8.02-8.11 (d, 2H, J = 8.1 Hz); 7.67-7.81 (d, 2H, J = 8.1 Hz);
and ~1170 cm due to C=O, C-S and C-N functions of thia-
1
7
2
3
.01-7.24 (m, 4H); 5.91 (s, 1H, CH); 3.29-3.36 (s, 2H, CH
.34 (s, 3H, CH ). HRMS (FAB) Calcd. for C18 OS
70.8658, Found 370.8655.
2
);
zolidinone moiety respectively. In H NMR spectra, peak at δ
3
H15ClN
4
7.66-8.33 and δ 6.35-8.07 indicates the presence of quinoxaline
ring and phenyl ring respectively. Elemental (CHN) analysis
indicated that calculated and observed values were within the
acceptable limits (± 0.4%).
2
-(4-Hydrox-3-methoxyyphenyl)-3-(2-methylquinoxalin-
3
-yl)-thiazolidin-4-one (3h): Yellow solid; IR (KBr) νmax 3440-
3
525, 3037, 3019, 2979, 2943, 2901, 1706, 1592, 1504, 1204,
Antibacterial activity. All the compounds were active against
Escherichia coli and Staphylococcus aureus. Compounds 3b,
3e, 3f and 3hwere active against Bacillus subtilis while 3a, 3c,
3d, 3f and 3h showed good activity against Pseudomonas aero-
genosa. Compounds 3b, 3dand 3g were active against Klebsilla
aerogenes. The other compounds showed either moderate or
less activity against these organisms.
1
1
170. H NMR δ 8.06-8.22 (d, 2H, J = 8.2 Hz); 7.63-7.71 (d,
2
H, J = 8.2 Hz); 6.38-6.54 (m, 3H, Ph); 5.92 (s, 1H, CH); 5.12
s, 1H, OH, D O exchangeable); 3.73 (s, 3H, OCH ); 3.27-3.33
); 2.29 (s, 3H, CH ). HRMS (FAB) Calcd. for C19
S 382.4459, Found 382.4452.
(
(
2
3
s, 2H, CH
2
3
H
18 4
N O
3
Antimicrobial activity. The test microorganisms were ob-
tained from Department of Microbiology, Madurai Medical
College and Research Institute, Madurai, India. Muller Hinton
Antifungal activity. Most of the synthesized compounds were
found to possess moderate activity against tested fungi. Com-
pounds 3dand 3hwere found to be most active against Asper-
gillus flavus and Candida albican respectively. The antifungal
activities of test compounds were compared with standard
Salicylic acid (20 - 30 mm) and Clotrimazole (25 - 30 mm).
The results of antibacterial and antifungal activity tests are
summarized in Tables 2 and 3.
o
agar plates (37 C, 24 h) and Sabouraud’s dextrose agar plates
o
(
26 C, 48 - 72 h) were used for the cultivation of bacteria and
fungi, respectively. The zone of inhibition was measured in mm.
All synthesized compounds were screened for antibacterial
28
activity by cup-plate agar diffusion method against gram-posi-
tive species Staphylococcus aureu, and Bacillus subtilis and
gram-negative species Escherichia coli, Pseudomonas aero-
genosa and Klebsilla aerogenes in the concentration of 25 µg/
mL. These compounds were also screened for antifungal activity
against fungi Aspergillus niger, Aspergillus flavus and Candida
Conclusions
In conclusion, a microwave-assisted rapid synthesis of thia-
zolidinones has been achieved under solvent free conditions.
While this environmentally friendly method does not differ
significantly from the conventional method in terms of product
2
9
albican by the paper disc diffusion method in the same con-
centration. The activities were compared with standard drugs
Ciprofloxacin, Norfloxacin, Salicylic acid and Clotrimazole.
All the synthesized compounds were dissolved in DMF, which
was used as a control.
30
nature and yield, it however provides advantages, such as
shorter reaction time, solvent-free conditions and minimal puri-
fication of the products. All the synthesized compounds were
screened for antibacterial activity against Escherichia coli,
Bacillus subtilis, Pseudomonas aerogenosa, Klebsilla aero-
genes and Staphylococcus aureus and compound 3b was found
Results and Discussion
Chemical synthesis. We report herein synthesis of quinoxali-
nyl thiazolidinones using microwave irradiation technique on
silica support under solvent free conditions. Substituted hydra-
zones and thioglycolic acid were adsorbed onto silica gel and
irradiated in a microwave oven under solvent free conditions
for about 3 - 5 minutes at 540 watt power output to afford thia-
zolidinones. When the reaction mixture was subjected to micro-
wave irradiation at either < 540 watts or > 540 watts, yields
obtained were very poor. Probably at higher power output thio-
a
Table 2. Antibacterial activity of thiazolidinone derivatives
Entry
EC
SA
BS
PA
KA
3
a
++
+
+++
++
‐
+++
‐
++++
+
‐
3
b
c
++++
‐
++++
‐
‐
+++
‐
++++
++++
3
3d
++
+++
+
+++
++
o
+++
++
‐
glycolic acid is evaporating (boiling point: 101.5 C) and thereby
3
e
++
+++
++++
‐
++
++++
++++
‐
the reaction progress is hampered giving poor yields. All the
microwave conversions were carried out in triplicates to exa-
mine the reproducibility. The starting material, 2-hydrazino-
3
f
+
+++
++
+++
‐
+++
++++
++++
3
g
++++
++
3
h
++
3
-methylquinoxaline (1), was prepared as per the literature
Norfloxacin
Ciprofloxacin ++++
++++
++++
+++
26
protocol.
All the synthesized compounds (3a-h) were characterized by
a
1
Data are zones of inhibition (mm). EC is Escherichia coli; SAis Staphy-
elemental analysis (CHN) and spectral (IR, H NMR and MS)
lococcus aureus; BS is Bacillus subtilis; PA is Pseudomonas aerogenosa
and KA is Klebsilla aerogenes. ‐ = < 10 mm; + = 10 - 15 mm; ++ = 15 -
20 mm; +++ = 20 - 25 mm; ++++ = 25 - 30.
data. Formation of hydrazones (2a-h) was confirmed by pre-
9
viously reported melting points and the absence of primary

1
222 Bull. Korean Chem. Soc. 2010, Vol. 31, No. 5
Kondapalli Venkata Gowri Chandra Sekhar et al.
a
Table 3. Antifungal activity of thiazolidinone derivatives
7. Love, B.; Musser, J. H.; Brown, R. E.; Jones, H.; Kahen, R.; Huang,
F. C.; Khandwala, A.; Sonnino, G. P.; Leibowitz, M. J. Med. Chem.
1985, 28, 363.
Inhibition of
Inhibition of
Inhibition of
Entry
A. niger
A. flavus
C. albican
8. Rao, V. S.; Chandra Sekhar, K. V. G. Synth. Comm. 2004, 34, 2153.
9
. Kumar, D.; Chandra Sekhar, K. V. G.; Dhillon, H.; Rao, V. S.;
3
a
+
++
++
‐
++
+
‐
++
+
+
Varma, R. S. Green Chem. 2004, 6, 156.
3
b
+
10. Chandra Sekhar, K. V. G.; Rao, V. S.; Murali Krishna Kumar, M.
3
c
‐
++
J. Enzym. Inhib. Med. Ch. 2009, 24, 871.
3
d
++++
‐
11. Banik, B. K.; Manhas, M. S.; Newas, S. N. ; Bose, A. K. Bioorg.
3
e
‐
+
Med. Chem. Lett. 1993, 33, 2363.
3
f
‐
12. Varma, R. S. Green Chem. 1999, 1, 43.
3
3
g
h
++
+++
++++
++++
‐
++
++
+++
++++
‐
++
13. Bolognese, A.; Correale, G.; Manfra, M.; Lavecchia, A.; Novel-
lino, E.; Barone, V. Org. Biomol. Chem. 2004, 2, 2809.
++++
++++
++++
‐
14. Sattigeri, V. J.; Soni, A.; Singhal, S.; Khan, S.; Pandya, M.; Bhateja,
Salicylic acid
Clotrimazole
DMF
P.; Mathur, T.; Rattan, A.; Khanna, J.; Mehta, A. Arkovic 2005,
ii, 46.
15. Cacic, M.; Molnar, M.; Balic, T.; Rajkovic, V. Molecules 2009,
a
Data are zones of inhibition (mm). ‐ = < 10 mm; + = 10 - 15 mm; ++ =
5 - 20 mm; +++ = 20- = 20 - 25 mm; ++++ = 25 - 30 mm.
14, 2501.
1
16. Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I. Chem. Rev.
1981, 81, 175.
17. Hamama, W. S.; Ismail, M. A.; Shaaban, S.; Zoorob, H. H. J.
to be the most active compound. Thiazolidinones were also
screened for antifungal activity against Aspergillus niger, Asper-
gillus flavus and Candida albican and 3d and 3h were the
most active compounds.
Heterocyclic Chem. 2008, 45, 939.
1
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Acknowledgments. We thank UGC, India for financial su-
pport and the SAIF, CDRI, Lucknow, India and the SAIF,
Panjab University, Chandigarh, India for analytical and spec-
tral data.
1
2
2
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