Synthesis and antimicrobial activity of novel 2-(aryl)-3-[5-(2-oxo-2H-3- chromenyl)-1,3-oxazol-2-yl]-1,3-thiazolan-4-ones

Article abstract of DOI:10.1002/jhet.505

A series of novel 2-(aryl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-2-yl]-1, 3-thiazolan-4-ones 4a-j have been synthesized and assayed for their antibacterial activity against Gram-positive bacteria viz. Bacillus subtilis (ATCC 6633), Staphylococcus aureus

Full text of DOI:10.1002/jhet.505

176
Synthesis and Antimicrobial Activity of Novel 2-(aryl)-3-[5-(2-
oxo-2H-3-chromenyl)-1,3-oxazol-2-yl]-1,3-thiazolan-4-ones
Vol 48
Ch. Sanjeeva Reddy,a* M. Vani Devi,a G. Rajesh Kumar,a
L. Sanjeeva Rao,a and A. Nagarajb
aDepartment of Chemistry, Kakatiya University, Warangal 506009, India
bDepartment of Pharmaceutical Chemistry, Telangana University, Nizamabad 503 175, India
*E-mail: chsrkuc@yahoo.co.in
Received January 3, 2010
DOI 10.1002/jhet.505
Published online 7 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 2-(aryl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-2-yl]-1,3-thiazolan-4-ones 4a–j
have been synthesized and assayed for their antibacterial activity against Gram-positive bacteria viz. Ba-
cillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 6538p), Micrococcus luteus (IFC 12708),
and Gram-negative bacteria viz. Proteus vulgaris (ATCC 3851), Salmonella typhimurium (ATCC
14028), Escherichia coli (ATCC 25922), and also antifungal activity against Candida albicans (ATCC
10231), Aspergillus fumigatus (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichophyton menta-
grophytes (IFO 40996). Among the screened compounds, 4d, 4e, 4f, 4g, and 4j exhibited potent inhibi-
tory activity compared with the standard drug at the tested concentrations. The results reveal that, the
presence of difluorophenyl in 4f and pipernyl ring in 4j at 2-position of thiazolidine-4-one ring show
significant inhibitory activity. The other compounds also showed appreciable activity against the test
bacteria and fungi and emerged as potential molecules for further development.
J. Heterocyclic Chem., 48, 176 (2011).
INTRODUCTION
rants for further investigation in drug discovery. In view
of the biological significance of thiazolidine-4-one, pyr-
azole and in continuation of our work on the synthesis
of biologically active heterocyclics [33–35], we herein,
report the synthesis of a series of thiazolidine-4-one 4a–
j, with different pharmacologically active groups, in
one-pot three-component system using 3-(2-amino-1,3-
oxazol-5-yl)-2H-2-chromenone 3, different aromatic
aldehydes and thioglycolic acid in the presence of dicy-
clohexylcarbodiimide as the cyclizing agent. Furthur, all
the newly synthesized compounds were evaluated for
their in vitro antimicrobial activity by the disk diffusion
and micro dilution methods against pathogenic strains.
The structural and therapeutic diversity coupled with
commercial viability of small molecules have fascinated
the organic and medicinal chemists. Coumarins are a
class of compounds with biological activity, such as
analgesics [1,2], anticoagulant [3], specific inhibitors of
a-chymotripsin [4], human leukocyte elastase [5], diu-
retics [6], platelet aggregation [7], anticancer [8], inhibi-
tor of HIV-1 protease [9], and antibacterial [10,11]. Fur-
ther, there is a considerable interest in the chemistry of
thiazolidine-4-one ring system, which is a core structure
in various synthetic pharmaceuticals displaying a broad
spectrum of biological activities [12–14], such as anti-
convulsant [15], antidiarrheal [16], antiplatelet activating
factor [17–19], antihistaminic [20,21], antimicrobial
[22,23], antidiabetic, [24] cyclooxygenase (COX) inhibi-
tory [25], Ca2þ-channel blocker [26], platelet activating
factor (PAF) antagonist [27], cardioprotective [28], anti-
ischemic [29], anticancer [30], tumor necrosis factor-a
antagonist [31], and nematicidal [32]. Therefore, the
simple and efficient method for rapid synthesis of thia-
zolidine-4-ones would be greatly advantageous and war-
RESULTS AND DISCUSSION
The compound 2 required for the synthesis of the title
compounds was prepared by cyclocondensation of sali-
cylaldehyde 1 with ethylacetoacetate in the presence of
piperidine in methanol [36]. The compound 2 on cyclo-
condensation with urea in the presence of iodine in
methanol at reflux for 8 h, results 3-(2-amino-1,3-
C
V
2010 HeteroCorporation

January 2011
Synthesis and Antimicrobial Activity of Novel 2-(aryl)-3-[5-(2-oxo-2H-
3-chromenyl)-1,3-oxazol-2-yl]-1,3-thiazolan-4-ones
177
Scheme 1
oxazol-5-yl)-2H-2-chromenone 3. The one-pot, three-
component condensation of 3 with different aromatic
aldehydes and thioglycolic acid in the presence of dicy-
clohexylcarbodiimide as cyclizing agent in tetrahydrofu-
ran solvent at room temperature, resulted the new series
of 2-(aryl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-2-
yl]-1,3-thiazolan-4-ones 4a–j in high-yields. The hetero-
cyclic aldehyde, such as 2-furfuraldehyde, was also used
to construct the new thiazolidine-4-one (Scheme 1).
However, the two step reaction as reported [35], involv-
ing condensation of amino compounds with aromatic
aldehydes in acetic acid resulted the Schiff’s base,
which on cyclocondensation with thioglycolic acid in
presence of ZnCl2 in toluene, at high-temperature,
resulted thiazolidine-4-one derivatives in lower yields.
The structures of the compounds 4a–j were deduced
from their IR, NMR, and MS spectra. In the IR spectra
of compounds 4a–j, the disappearance of the absorption
band at 3420 cmꢀ1 corresponding to ANH2 group,
which was present in compound 3, indicates the cycliza-
tion has occurred involving the ANH2 group. The pres-
ence of vibrational frequency of C¼¼O in the range of
1690 – 1700 cmꢀ1 clearly demonstrate the formation of
thiazolidine-4-one ring. In the 1H NMR spectra, the
CH2ACO protons, NACHAS proton of thiazolidine-4-
one ring, appeared as singlet at 3.66 and 5.82–6.00 ppm,
respectively. These signals clearly demonstrate the for-
mation of thiazolidine-4-one ring. The proton of
NACHAS moiety appeared at a higher field owing to
the shielding effect of the nearly coplanar sulfur orbital.
Further support was obtained from 13C NMR spectra.
For all the compounds the signals corresponding to the
carbons of thiazolidine-4-one appeared at ꢁ172.4,
ꢁ72.0, 33.7 ppm. The other signals were observed at
the expected chemical shifts and integral values. In
addition, elemental analyses are consistent with the
structures proposed for the compounds 4a–j.
Antibacterial assay. All the compounds 4a–j were
assayed for their antibacterial activity against Gram-pos-
itive bacteria viz. Bacillus Subtilis (MTCC 441), Bacil-
lus Sphaericus (MTCC 11), Staphylococcus Aureus
(MTCC 96), and Gram-negative bacteria viz. Pseudomo-
nas Aeruginosa (MTCC 741), Klobsinella Aerogenes
(MTCC 39), Chromobacterium Violaceum (MTCC
2656) by disc diffusion, microdilution/ turbidometric
methods [37]. For the antibacterial assay standard inocu-
lums (1–2 ꢂ 107 c.f.u/mL 0.5 Mc Farland standards)
were introduced on to the surface of sterile agar plates,
and a sterile glass spreader was used for even distribu-
tion of the inoculums. The discs measuring 6.26 mm in
diameter were prepared from Whatman no.1 filter paper
and sterilized by dry heat at 140ꢃC for 1 h. The sterile
discs previously soaked in a known concentration of the
test compounds were placed in nutrient agar medium.
The plates were inverted and incubated for 24 h at
37ꢃC. The inhibition zones were measured and com-
pared with the standard. For the determination of MIC,
bacteria were grown over night in Luria Bertani (LB)
broth at 37ꢃC harvested by centrifugation, and then
washed twice with sterile distilled water. Stock solutions
of the series of compounds were prepared in DMSO.
Each stock solution was diluted with standard method
broth (Difco) to prepare serial two-fold dilutions in the
range of 50–0.8 lg/mL. 10 mL of the broth containing
about 105 c.f.u/mL of test bacteria was added to each
well of 96-well microtiter plate. Culture plates were
incubated for 24 h at 37ꢃC, and the growth was moni-
tored visually and spectrometrically. The lowest concen-
tration required to arrest the growth of bacteria was
regarded as minimum inhibitory concentration (MIC,
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Ch. S. Reddy, M. V. Devi, G. R. Kumar, L. S. Rao, and A. Nagaraj
Vol 48
Table 1
Antibacterial activity of compounds 4a–j.
Minimal inhibitory concentration (MIC) (lg/mL)a
Compound
B. subtilis
B. sphaericus
S. aureus
P. aeruginosa
K. aerogenes
C. violaceum
4a
4b
4c
4d
4e
4f
4g
25 6 1.1
32 6 1.2
28 6 1.1
13 6 0.5
18 6 0.8
8 6 0.3
10 6 0.4
28 6 1.0
30 6 0.9
10 6 0.4
15 6 0.5
23 6 0.8
30 6 1.0
25 6 1.1
15 6 0.6
20 6 1.0
10 6 0.4
13 6 0.5
25 6 1.0
26 6 1.1
10 6 0.4
19 6 0.8
22 6 0.8
26 6 1.1
25 6 1.0
12 6 0.5
18 6 0.8
10 6 0.4
10 6 0.5
25 6 0.8
25 6 1.0
10 6 0.4
18 6 0.8
14 6 0.5
20 6 0.7
17 6 0.4
12 6 0.5
15 6 0.5
10 6 0.4
10 6 0.3
22 6 0.8
25 6 1.0
10 6 0.4
20 6 0.5
22 6 1.1
26 6 1.2
25 6 0.5
13 6 0.8
16 6 1.0
10 6 0.5
10 6 1.0
26 6 1.1
24 6 0.6
10 6 0.8
20 6 1.0
20 6 1.0
12 6 0.4
10 6 0.8
18 6 0.7
22 6 0.4
15 6 0.34
30 6 1.1
10 6 1.2
17 6 1.0
22 6 0.9
18 6 0.5
4h
4i
4j
Streptomycin
a Values are means of three determinations, the ranges of which are less than 5% of the mean in all cases.
lg/mL), and mean inhibition zone were also determined
and compared with the standard drug streptomycin. The
MIC and MZI data are presented in Table 1 and Table
2.
ence of dimethylaminophenyl group showed consider-
able inhibitory activity.
Antifungal assay. The compounds 4a–j were also
screened for their antifungal activity against Candida
Albicans (ATCC 10231), Aspergillus Fumigatus (HIC
6094), Trichophyton rubrum (IFO 9185), and Trichophy-
ton Mentagrophytes (IFO 40996) in DMSO by agar dif-
fusion and broth dilution methods [37]. For the antifun-
gal assay, Sabourands agar media was prepared by dis-
solving peptone (1 g), D-glucose (4 g), and agar (2 g) in
distilled water (100 mL) and adjusting the pH to 5.7.
Normal saline was used to make a suspension of spore
of fungal strain for lawning. A loopful of particular fun-
gal strain was transferred to 3 mL saline to get a sus-
pension of corresponding species. 20 mL of agar media
was poured into each petri-dish, excess of suspension
was decanted, and the plates were dried by placing in
an incubator at 37ꢃC for 1 h. Using an agar punch wells
The investigation of antibacterial screening data
reveal that, almost all the compounds 4a-j are active
and showing moderate to good antibacterial activity.
Compounds 4d, 4e, 4f, 4g, and 4j exhibited potent in-
hibitory activity compared to the standard drug at the
tested concentrations. The obtained results reveal that
the presence of difluorophenyl in 4f and pipernyl ring in
4j at 2-position of thiazolidine-4-one ring, might be the
reason for the significant inhibitory activity. Also, the
presence of hydroxyphenyl in the molecules would
enhance the inhibitory activity stoichiometrically as
shown by 4e. Presence of chlophenyl in 4b and nitro-
phenyl in 4c did not show significant inhibition. But in
4a, presence of the methylphenyl group and in 4g pres-
Table 2
Antibacterial activity of compounds 4a–j.
Mean zone inhibition (MZI) (mm)a
Compound
B. subtilis
B. sphaericus
S. aureus
P. aeruginosa
K. aerogenes
C. violaceum
4a
4b
4c
4d
4e
4f
4g
13 6 0.4
8 6 0.2
12 6 0.5
8 6 0.3
8 6 0.3
14 6 0.5
9 6 1.1
10 6 0.5
8 6 0.4
5 6 0.5
19 6 0.8
18 6 0.5
20 6 1.2
22 6 1.0
8 6 0.3
6 6 0.4
22 6 1.1
18 6 0.6
12 6 0.4
5 6 0.2
6 6 0.3
14 6 0.2
23 6 1.0
5 6 1.2
10 6 0.3
22 6 0.8
18 6 0.5
25 6 1.0
21 6 1.0
10 6 0.4
4 6 0.2
10 6 0.7
21 6 1.1
20 6 1.0
26 6 0.4
24 6 0.5
10 6 1.2
8 6 0.3
20 6 1.0
16 6 0.7
22 6 1.1
23 6 1.1
8 6 0.3
10 6 0.2
20 6 1.0
17 6 0.5
22 6 1.1
20 6 0.8
26 6 1.0
20 6 0.3
7 6 1.2
10 6 0.3
20 6 1.2
16 6 0.8
18 6 0.6
14 6 1.0
25 6 0.3
10 6 0.4
12 6 1.2
24 6 0.7
18 6 0.2
20 6 0.5
4h
4i
4j
Streptomycin
20 6 1.0
15 6 0.5
23 6 1.0
20 6 1.0
Streptomycin (25 lg/disc) and compounds 4a-j (50 lg/disc) were used for the assay.
a Values are means of three determinations, the ranges of which are less than 5% of the mean in all cases.
Journal of Heterocyclic Chemistry
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January 2011
Synthesis and Antimicrobial Activity of Novel 2-(aryl)-3-[5-(2-oxo-2H-
3-chromenyl)-1,3-oxazol-2-yl]-1,3-thiazolan-4-ones
179
Table 3
Antifungal activity of compounds 4a–j.
Minimal inhibitory concentration (MIC) (lg/mL)a
Compound
C. albicans
A. fumigatus
T. rubrum
T. mentagrophytes
4a
4b
4c
4d
4e
4f
4g
25 6 1.2
36 6 1.1
16 6 0.6
20 6 1.0
21 6 0.8
30 6 1.2
20 6 0.8
28 6 1.0
32 6 1.6
18 6 0.8
15 6 1.1
30 6 1.4
36 6 1.2
18 6 0.6
20 6 0.7
20 6 1.0
32 6 1.2
20 6 0.6
30 6 1.2
25 6 1.6
20 6 0.8
20 6 1.0
35 6 1.6
45 6 1.4
18 6 0.6
26 6 1.0
36 6 1.2
21 6 1.6
32 6 1.0
50 6 1.4
20 6 1.5
36 6 0.9
22 6 1.3
28 6 1.2
52 6 2.0
14 6 0.6
26 6 0.9
24 6 0.7
30 6 1.2
16 6 0.8
30 6 1.6
42 6 0.8
18 6 1.0
18 6 0.8
4h
4i
4j
Amphotericin B
a Values are means of three determinations, the ranges of which are less than 5% of the mean in all cases.
were made and each well was labeled. A control was
also prepared in triplicate and maintained at 37ꢃC for 3–
4 days. The C. albicans was grown for 48 h at 28ꢃC in
YPD broth (1% yeast extract, 2% peptone, and 2%
dextrose), harvested by centrifugation and then
washed twice with sterile distilled water. A. fumigatus,
T. rubrum, and T. mentagrophytes were plated in potato
dextrose agar (PDA) (Difco) and incubated at 28ꢃC for
2 weeks. Spores were washed three times with sterile
distilled water and resuspended in distilled water to
obtain an initial inoculums size of 105 spores/mL. Each
test compound was dissolved in DMSO and diluted with
potato dextrose broth (Difco) to prepare serial two-fold
dilutions in the range 100–0.8 lg/mL. 10 mL of the
broth containing about 103 (for yeast) and 104 (for fila-
mentous fungi) cells/mL of test fungi was added to each
well of a 96-well microtiter plate. Culture plates were
incubated for about 48–72 h at 28ꢃC. The lowest con-
centration required to arrest the growth of fungi was
regarded as minimum inhibitory concentration (MIC,
lg/mL), and mean inhibition zone were also determined
and compared with the standards drug Amphotericin B.
The MIC and MZI data are presented in Table 3 and
Table 4.
The antifungal screening data reveal that, most of the
new compounds are active and show moderate to good
antifungal activity. Among the screened compounds, the
compounds 4c and 4d with nitrophenyl group at 2-posi-
tion of thiazolidine-4-one ring showed highest activity
against all the microorganisms employed. The activity
of these compounds is almost equal to the standard.
Compounds 4g and 4j also showed good inhibition to-
ward A. fumigatus and T. mentagrophytes.
In conclusion, a series of novel 2-(aryl)-3-[5-(2-oxo-2
H-3-chromenyl)-1,3-oxazol-2-yl]-1,3-thiazolan-4-ones 4a–j
have been synthesized and evaluated for their antibacterial
Table 4
Antifungal activity of compounds 4a–j.
Mean zone inhibition (MZI) (mm)a
Compound
C. albicans
A. fumigatus
T. rubrum
T. mentagrophytes
4a
4b
10 6 0.6
6 6 0.4
14 6 1.4
8 6 1.2
17 6 1.0
6 6 1.1
16 6 0.8
8 6 1.2
4c
4d
4e
4f
4g
4h
4i
18 6 1.0
20 6 0.6
14 6 0.7
10 6 0.6
16 6 0.8
14 6 0.5
8 6 0.3
20 6 0.6
16 6 0.7
18 6 1.0
12 6 1.2
18 6 0.6
10 6 1.2
8 6 1.6
25 6 0.5
20 6 1.1
14 6 1.0
14 6 0.6
12 6 1.0
6 6 1.2
14 6 0.9
8 6 0.7
18 6 1.1
26 6 0.4
18 6 0.7
18 6 0.5
12 6 1.0
26 6 0.7
19 6 0.5
10 6 0.6
20 6 1.0
22 6 0.6
4j
Amphotericin B
16 6 0.9
20 6 1.0
18 6 0.8
19 6 1.0
Amphotericin B (50 lg/disc) and compounds 4a–j (100 lg/disc) were used for assay.
a Values are means of three determinations, the ranges of which are less than 5% of the mean in all cases.
Journal of Heterocyclic Chemistry
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Ch. S. Reddy, M. V. Devi, G. R. Kumar, L. S. Rao, and A. Nagaraj
Vol 48
2-(4-methylphenyl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxaz-
ol-2-yl]-1,3-thiazolan-4-one (4a). This was obtained as yellow
solid; Yield 71%; mp 130–32ꢃC; IR (KBr): m 3065, 1705,
(MIC/MZI) activity and antifungal (MIC/ MZI) activity
against various bacteria and fungi. Many of the synthe-
sized compounds showed good activity against the test
bacteria and fungi
1695, 1560, 1180, 718 cmꢀ1 1H NMR (DMSO-d6): d 7.50–
;
7.40 (m, 2H, ArH), 7.30–7.15 (m, 7H, ArH), 6.84 (s, 1H,
ArH), 5.82 (s, 1H, NACHAS), 3.66 (s, 2H, CH2CO), 2.30 (s,
3H, CH3); 13C NMR (DMSO-d6): d 171.5, 158.6, 155.4,
153.5, 136.9, 134.6, 129.6, 128.0, 127.9, 127.5, 127.0, 125.4,
123.1, 114.5, 113.2, 112.2, 105.4, 70.6, 33.7, 22.0; MS: m/z
404 (Mþ). Anal. Calcd for C22H16N2O4S: C, 65.34; H, 3.99;
N, 6.93. Found: C, 65.39; H, 3.93; N, 6.85.
EXPERIMENTAL
Reagents were commercial grade and were used as supplied.
Reactions were monitored by thin-layer chromatography (TLC)
on precoated silica gel F254 plates from Merck and compounds
visualized either by exposure to UV light or dipping in 1% aque-
ous potassium permanganate solution. Chromatographic col-
umns 70–230 mesh silica gel for separations were used. Melting
points were determined through a Fisher–Johns apparatus and
are uncorrected. IR spectra were recorded using KBr disk on a
Perkin–Elmer FTIR spectrometer. The 1H NMR (300 MHz) and
13C NMR (75 MHz) spectra were recorded on a Varian Gemini
spectrometer. Chemical shifts are reported in d ppm units with
respect to TMS as internal standard and coupling constants (J)
are reported in Hz units. Mass spectra were recorded on a VG
micro mass 7070H spectrometer. Elemental analyses (C, H, N)
determined by means of a Perkin–Elmer 240 CHN elemental an-
alyzer, were within 6 0.4% of theory.
2-(4-chlorophenyl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxaz-
ol-2-yl]-1,3-thiazolan-4-one (4b). This was obtained as yellow
solid; Yield 66%; mp 138–40ꢃC; IR (KBr): m 3065, 1700,
1695, 1560, 1180, 718, 685 cmꢀ1 1H NMR (DMSO-d6): d
;
7.50–7.40 (m, 2H, ArH), 7.30–7.20 (m, 7H, ArH), 6.86 (s, 1H,
ArH), 5.82 (s, 1H, NACHAS), 3.66 (s, 2H, CH2CO); 13C
NMR (DMSO-d6): d 171.5, 158.6, 155.3, 153.7, 137.6, 134.1,
129.6, 129.0, 128.5, 128.0, 127.8, 127.0, 123.1, 114.5, 113.2,
112.2, 105.4, 70.6, 33.7; MS: m/z 424 (Mþ). Anal. Calcd for
C22H13ClN2O4S: C, 59.37; H, 3.08; N, 6.59. Found: C, 59.31;
H, 3.00; N, 6.55.
2-(4-nitrophenyl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-
2-yl]-1,3-thiazolan-4-one (4c). This was obtained as brown
solid; Yield 72%; mp 124–26ꢃC; IR (KBr): m 3066, 1702,
1695, 1560, 1370, 1180, 712 cmꢀ1 1H NMR (DMSO-d6): d
;
3-(2-amino-1,3-oxazol-5-yl)-2H-2-chromenone (3). A mix-
ture of urea (0.02 mol) and Iodine (0.01 mol) were triturated
and mixed with a solution of 3-acetyl-2H-2-chromenone 2
(0.01 mol) in methanol (20 mL). The mixture was heated on a
water bath with occasional stirring for 8 h. The obtained solid
was triturated with diethyl ether to remove unreacted com-
pound 2, washed the residue with aqueous sodium thiosulfate
and then water to remove excess iodine. The crude product
was dissolved in hot water, filtered to remove the sulphone,
and the product was precipitated by addition of NH3. The
crude solid obtained on evaporation of the solvent under
reduced pressure was recrystallized from methanol to furnish
the pure compound 3 as yellow crystals; Yield 65%, mp 144–
46ꢃC; IR (KBr): m 3420, 3240, 3072, 1698, 1560, 1070, 770
7.62 (d, J ¼ 8.2 Hz, 2H, ArH), 7.50–7.40 (m, 4H, ArH), 7.30–
7.20 (m, 3H, ArH), 6.82 (s, 1H, ArH), 5.82 (s, 1H,
NACHAS), 3.66 (s, 2H, CH2CO); 13C NMR (DMSO-d6): d
171.4, 158.5, 155.4, 153.5, 148.7, 144.8, 129.6, 128.0, 127.8,
127.0, 126.8, 124.1, 123.2, 114.5, 113.2, 112.2, 105.4, 70.5,
33.6; MS: m/z 435 (Mþ). Anal. Calcd for C21H13N3O6S: C,
57.93; H, 3.01; N, 9.65. Found: C, 57.90; H, 3.10; N, 9.60.
2-(3-nitrophenyl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-
2-yl]-1,3-thiazolan-4-one (4d). This was obtained as pink
solid; Yield 66%; mp 130–32ꢃC; IR (KBr): m 3062, 1700,
1697, 1565, 1370, 1180, 715 cmꢀ1 1H NMR (DMSO-d6): d
;
8.20 (s, 1H, ArH), 8.05 (s, 1H, ArH), 7.60–7.50 (m, 4H, ArH),
7.37 (s, 1H, CH¼¼C), 7.20–7.15 (m, 2H, ArH), 6.84 (s, 1H,
ArH), 5.99 (s, 1H, NACHAS), 3.66 (s, 2H, CH2CO); 13C
NMR (DMSO-d6): d 171.5, 158.4, 155.3, 153.6, 148.4, 140.4,
131.4, 133.4, 129.6, 128.0, 127.0, 126.7, 123.9, 123.1, 121.0,
114.5, 113.1, 112.2, 105.5, 71.1, 33.6; MS: m/z 435 (Mþ).
Anal. Calcd for C21H13N3O6S: C, 57.93; H, 3.01; N, 9.65.
Found: C, 57.95; H, 3.00; N, 9.62.
cmꢀ1 1H NMR (DMSO-d6): d 7.67 (s, 1H, ArH), 7.50–7.45
;
(m, 2H, ArH), 7.30–7.20 (m, 3H, ArH), 4.24 (bs, 2H, NH2);
13C NMR (DMSO-d6): d 163.2, 158.6, 155.2, 143.1, 128.6,
127.6, 125.7, 123.4, 120.8, 114.8, 111.8; MS: m/z 228 (Mþ).
Anal. Calcd for C12H8N2O3: C, 63.16; H, 3.53; N, 12.28.
Found: C, 63.11; H, 3.60; N, 12.23.
2-(4-hydroxyphenyl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxa-
zol-2-yl]-1,3-thiazolan-4-one (4e). This was obtained as pale
yellow solid; Yield 67%; mp 122–24ꢃC; IR (KBr): m 3339, 3060,
1704, 1696, 1565, 1180, 715 cmꢀ1; 1H NMR (DMSO-d6): d 7.50–
7.40 (m, 3H, ArH), 7.20–7.15 (m, 4H, ArH), 6.91 (d, J ¼ 8.1 Hz,
2H, ArH), 6.84 (s, 1H, ArH), 5.82 (s, 1H, NACHAS), 5.05 (s, 1H,
OH), 3.66 (s, 2H, CH2CO); 13C NMR (DMSO-d6): d 171.9,
160.1, 158.3, 155.4, 153.7, 134.0, 129.6, 128.1, 127.6, 127.0,
126.7, 123.2, 115.9, 114.5, 113.7, 112.2, 105.4, 70.6, 33.5; MS: m/
z 406 (Mþ). Anal. Calcd for C21H14N2O5S: C, 62.06; H, 3.47; N,
6.89. Found: C, 62.00; H, 3.50; N, 6.83.
2-(aryl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-2-yl]-1,3-
thiazolan-4-one (4a–j). A mixture of 3-(2-amino-1,3-oxazol-5-
yl)-2H-2-chromenone 3 (0.01 mol) and corresponding arylde-
hyde (0.012 mol) in dry tetrahydrofuran was stirred with ice
cooling for 10 min, followed by the addition of thioglycolic acid
(0.015 mol). After 10 min, dicyclohexylcarbodiimide (0.015
mol) was added to the reaction mixture at 0ꢃC and the reaction
mixture was stirred for about 5–6 h at room temperature to com-
plete the reaction. The precipitated dicyclohexylurea was filtered
off; the filtrate was concentrated to dryness under reduced pres-
sure. Deionized water was added to the residue and extracted
with dichloromethane. The organic layer was washed with 5%
NaHCO3 solution/citric acid solution and dried over anhydrous
Na2SO4. The crude solid obtained on evaporation of the solvent
under reduced pressure was recrystallized from methanol to fur-
nish the pure compound.
2-(2,6-difluorophenyl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-ox-
zol-2-yl]-1,3-thiazolan-4-one (4f). This was obtained as yellow
solid; Yield 69%; mp 167–69ꢃC; IR (KBr): m 3065, 1705,
1692, 1562, 1180, 811, 715 cmꢀ1 1H NMR (DMSO-d6): d
;
7.50–7.40 (m, 3H, ArH), 7.30–7.25 (m, 3H, ArH), 6.86 (s, 1H,
ArH), 6.67 (d, J ¼ 7.9 Hz, 2H, ArH), 6.41 (s, 1H, NACHAS),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis and Antimicrobial Activity of Novel 2-(aryl)-3-[5-(2-oxo-2H-
3-chromenyl)-1,3-oxazol-2-yl]-1,3-thiazolan-4-ones
181
3.66 (s, 2H, CH2CO); 13C NMR (DMSO-d6): d 171.0, 158.4,
155.4, 154.7, 153.6, 129.8, 129.0, 128.0, 127.0, 126.7, 123.1,
116.5, 114.5, 113.9, 113.7, 112.2, 105.9, 71.0, 33.4; MS: m/z
426 (Mþ). Anal. Calcd for C21H12F2N2O4S: C, 59.15; H, 2.84;
N, 6.57. Found: C, 59.19; H, 2.80; N, 6.60.
REFERENCES AND NOTES
[1] Billeret, D.; Blondeau, D.; Sliwa, H. J Heterocycl Chem
1993, 30, 671.
[2] Vallet, F. M. J Ger Offen 1978, 2, 751.
[3] Suzmann, M. M. In Abstr. IV World Congress of Cardiol-
ogy, Mexico City, 1962, p 344.
2-[4-(dimethylamino)phenyl]-3-[5-(2-oxo-2H-3-chromenyl)-
1,3-oxazol-2-yl]-1,3-thiazolan-4-one (4g). This was obtained
as red solid; Yield 70%; mp 144–46ꢃC; IR (KBr): m 3062,
[4] Doucet, C.; Pochet, L.; Thierry, N.; Pirotte, B.; Delarge, J.;
Reboud-Ravaux, M. J Med Chem 1999, 42, 4161.
[5] Pochet, L.; Doucet, C.; Schynts, M.; Therry, N.; Boggetto,
N.; Pirotte, B.; Jiang, K. Y.; Masereel. B.; de Tullio, P.; Delarge, J.;
Reboud-Ravaux, M. J Med Chem 1996, 39, 2579.
[6] Spiro, V.; Madonia, P. Atti Acad Sci Lett Antipalermo
1959,A95920187.
1705, 1695, 1561, 1407, 1185, 715 cmꢀ1 1H NMR (DMSO-
;
d6): d 7.50–7.45 (m, 2H, ArH), 7.32 (s, 1H, CH¼¼C), 7.20–
7.15 (m, 4H, ArH), 6.84 (s, 1H, ArH), 6.40 (d, J ¼ 8.1 Hz,
2H, ArH), 5.82 (s, 1H, NACHAS), 3.66 (s, 2H, CH2CO), 2.89
(s, 6H, CH3); 13C NMR (DMSO-d6): d 171.2, 158.4, 155.4,
153.5, 144.0, 135.6, 129.6, 128.9, 128.0, 127.0, 126.7, 123.1,
114.5, 113.9, 113.2, 112.2, 105.9, 70.6, 46.1, 33.4; MS: m/z
433 (Mþ). Anal. Calcd for C23H19N3O4S: C, 63.73; H, 4.42;
N, 9.69. Found: C, 63.75; H, 4.36; N, 9.62.
[7] (a) Mitra, A. K.; De, A.; Karchaudhuri, N.; Misra, S. K.;
Mukhopadhyay, A. K. J Indian Chem Soc 1998, 75, 666; (b) Cra-
votto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S. Tetrahedron:
Asymmetry 2001, 12, 707.
2-(4-hydroxy-3-methoxyphenyl)-3-[5-(2-oxo-2H-3-chromen-yl)-
1,3-oxazol-2-yl]-1,3-thiazolan-4-one (4h). This was obtained as
orange solid; Yield 67%; mp 163–65ꢃC; IR (KBr): m 3334,
[8] Wang, C. J.; Hsieh, Y. J.; Chu, C. Y.; Lin, Y. L.; Tseng, T.
H. Cancer Lett 2002, 183, 163.
[9] Kirkiacharian, S.; Thuy, D. T.; Sicsis, S.; Bakhchinian, R.;
Kurkjian, R.; Tonnaire, T. Il Farmaco 2002, 57, 703.
[10] Kayser, O.; Kolodziej, H. Planta Med 1997, 63, 508.
[11] Olayinka, O. A.; Obinna, C. N. J Heterocycl Chem 2010,
47, 179.
3066, 1700, 1695, 1561, 1185, 1070, 711 cmꢀ1 1H NMR
;
(DMSO-d6): d 7.50–7.40 (m, 2H, ArH), 7.30–7.20 (m, 3H,
ArH), 7.10–7.05 (m, 2H, ArH), 6.91 (s, 1H, ArH), 6.86 (s, 1H,
ArH), 5.82 (s, 1H, NACHAS), 4.85 (s, 1H, OH), 3.81 (s, 3H,
OCH3), 3.66 (s, 2H, CH2CO); 13C NMR (DMSO-d6): d 171.4,
158.5, 155.4, 153.7, 151.7, 149.6, 135.4, 129.6, 128.0, 127.0,
126.6, 123.1, 120.4, 119.1, 114.4, 113.2, 112.2, 108.4, 105.6,
73.1, 57.1, 33.5; MS: m/z 436 (Mþ). Anal. Calcd for
C22H16N2O6S: C, 60.55; H, 3.70; N, 6.42. Found: C, 60.51; H,
3.76; N, 6.40.
[12] Vigorita, M. G.; Ottana, R.; Monforte, F.; Maccari, R.; Tro-
vato, A.; Monforte, M. T.; Taviano, M. F. Bioorg Med Chem Lett
2001, 11, 2791.
[13] Chande, M. S.; Suryanarayan, V.
345.
[14] Kavitha, C. V.; Basappa, S.; Swamy, N.; Mantelingu, K.;
J Chem Res 2005,
Doreswamy, S.; Sridhar, M. A.; Prasad, S.; Rangappa, K. S. Bioorg
Med Chem 2006, 14, 2290.
2-(2-furyl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-2-yl]-
1, 3-thiazolan-4-one (4i). This was obtained as black solid;
Yield 69%; mp 142–44ꢃC; IR (KBr): m 3064, 1700, 1696,
[15] Ergene, N.; Capan, G. Il Farmaco 1994, 49, 449.
[16] Diurno, M. V.; Mazzoni, O.; Izzo, A. A.; Bolognese, A. Il
Farmaco 1997, 52, 237.
1560, 1410, 1182, 1070, 715 cmꢀ1 1H NMR (DMSO-d6): d
;
7.55–7.45 (m, 3H, ArH), 7.30–7.20 (m, 3H, ArH), 6.88 (s, 1H,
ArH), 6.42 (d, J ¼ 7.7 Hz, 1H, ArH), 6.11 (d, J ¼ 7.7 Hz,
1H, ArH), 6.07 (s, 1H, NACHAS), 3.66 (s, 2H, CH2CO); 13C
NMR (DMSO-d6): d 171.2, 158.4, 155.4, 153.6, 149.3, 146.4,
129.6, 128.0, 127.0, 126.5, 123.8, 123.1, 114.4, 113.1, 112.2,
109.2, 105.4, 57.9, 33.6; MS: m/z 380 (Mþ). Anal. Calcd for
C19H12N2O5S: C, 60.00; H, 3.18; N, 7.36. Found: C, 59.95; H,
3.20; N, 7.40.
[17] Tanabe, Y.; Komuro, Y.; Imanishi, N.; Morooka, S.; Eno-
moto, M.; Kojima, A.; Sanemitsu, Y.; Mizutani, M. Tetrahedron Lett
1991, 32, 379.
[18] Koike, H.; Imanashi, N.; Natsume, Y.; Morooka, S. Eur J
Pharmacol 1994, 269, 299.
[19] Tanabe, Y.; Yamamoto, H.; Murakami, M.; Yanagi, K.;
Kubota, Y.; Okumura, H.; Sanemitsu, Y.; Suzukamo, G. J Chem Soc
Perkin Trans I 1995, 7, 935.
2-(1,3-benzodioxol-5-yl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-
oxazol-2-yl]-1,3-thiazolan-4-one (4j). This was obtained as
black solid; Yield 71%; mp 133–35ꢃC; IR (KBr): m 3064,
[20] Diurno, M. V.; Mazzoni, O.; Correale, G.; Monterry, I. G.
Il Farmaco 1999, 54, 579.
[21] Previtera, T.; Vigorita, M. G.; Bisila, M.; Orshini, F.; Bene-
tolla, F.; Bombieri, G. Eur J Med Chem 1994, 29, 317.
[22] Sharma, R. C.; Kumar, D. J Indian Chem Soc 2000, 77,
492.
1700, 1694, 1560, 1182, 715 cmꢀ1 1H NMR (DMSO-d6): d
;
7.50–7.40 (m, 3H, ArH), 7.30–7.20 (m, 3H, ArH), 7.10 (d, J
¼ 8.2 Hz, 1H, ArH), 6.90–6.85 (m, 2H, ArH), 6.81 (s, 1H,
ArH), 5.80 (s, 1H, NACHAS), 5.49 (s, 2H, OACH2AO),
3.66 (s, 2H, CH2CO); 13C NMR (DMSO-d6): d 171.4, 158.3,
155.4, 153.7, 149.1, 148.5, 136.0, 129.6, 128.0, 127.0, 126.9,
123.1, 120.6, 114.6, 113.2, 112.2, 111.2, 107.1, 105.5, 101.2,
74.1, 33.4; MS: m/z 434 (Mþ). Anal. Calcd for
C22H14N2O6S: C, 60.83; H, 3.25; N, 6.45. Found: C, 60.86;
H, 3.29; N, 6.50.
[23] Piscapo, E.; Diurno, M. V.; Gagliardi, R.; Mazzoni, O. Boll
Soc Ital Biol Sper 1989, 65, 853.
[24] Ueno, H.; Oe, T.; Snehiro, I.; Nakamura, S. US Pat.
5,594,116 (1997); Chem Abstr 1977, 126, 157507.
[25] Ottana, R.; Mazzon, E.; Dugo, L.; Monforte, F.; Maccari,
R.; Sautebin, L.; De Luca, G.; Vigorita, M. G.; Alcaro, S.; Ortuso, F.
Eur J Pharmacol 2002, 448, 71.
[26] Kato, T.; Ozaki, T.; Tamura, K. J Med Chem 1999, 42,
3134.
Acknowledgment. The authors are grateful to the Director, In-
dian Institute of Chemical Technology, Hyderabad, India, for
providing NMR and Mass spectral data. Financial assistance
from the UGC SAP (Phase-I)-DRS Programme, New Delhi,
India, is greatly acknowledged.
[27] Tanabe, Y.; Suzukamo, G.; Komuro, Y.; Imanishi, N.;
Morooka, S.; Enomoto, M.; Kojima, A.; Sanemitsu, Y.; Mizutani, M.
Tetrahedron Lett 1991, 32, 379.
[28] Kato, T.; Ozaki, T.; Ohi, N. Tetrahedron: Asymmetry 1999,
10, 3963.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

182
Ch. S. Reddy, M. V. Devi, G. R. Kumar, L. S. Rao, and A. Nagaraj
Vol 48
[29] Adachi, Y.; Suzuki, Y.; Homma, N.; Fukazawa, M.;
[33] Sanjeeva Reddy, Ch.; Nagaraj, A.; Srinivas, A. Chem
Pharm Bull 2009, 57, 685.
Tamura, K.; Nishie, I.; Kuromaru, O. Eur J Pharmacol 1999, 367,
267.
[34] Sanjeeva Reddy, Ch.; Raghu, M.; Nagaraj, A. J Heterocycl
Chem 2009, 46, 261.
[30] Ebeid, M. Y.; Fathallah, O. A.; El-Zaber, M. I.; Kamel, M.
M.; Abdon, W. A.; Anwar, M. M. Bull Fac Pharmacol 1996, 34,
125.
[35] Sanjeeva Reddy, Ch.; Raghu, M.; Nagaraj, A. J Heterocycl
Chem 2008, 45, 1121.
[31] Voss, M. E.; Carter, P. H.; Tebben, A. J.; Scherle, P. A.;
Brown, G. D.; Thompson, L. A.; Xu, M.; Lo, Y. C.; Yang Liu, R. R.-
Q. Bioorg Med Chem Lett 2006, 16, 1907.
[36] Sahu, S. K.; Mishra, A.; Behera, R. K. Indian J Heterocycl
Chem 1996, 6, 91.
[37] National Committee for Clinical Laboratory Standards (NCCLS).
Standard methods for dilution antimicrobial susceptibility tests for bacteria,
which grows aerobically. Nat Comm Lab Stands Villanova, 1982, p 242.
[32] Manrao, M. R.; Monika, J.; Kaul, V. K. Pl Dis Res 1997,
12, 70.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet