Synthesis of 3-[4-({Methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}amino)- 1,3-thiazol-2-yl]-2-aryl-1,3-thiazolan-4-ones as potential biodynamic agents

Article abstract of DOI:10.1080/10426500802273999

A series of isoxazolyl thiazolyl thiazolidinones (4a-h) were synthesized starting from isoxazolyl chloroacetamide 1. Compound 1 upon heating with thiourea in ethanol furnished N4-{3-methyl-5-[(E)-2-phenyl-1-ethenyl]-4- isoxazolyl]-1,3-thiazole-2,4-diamine

Full text of DOI:10.1080/10426500802273999

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Phosphorus, Sulfur, and Silicon
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Synthesis of 3-[4-({Methyl-5-
[(E)-2-phenyl-1-ethenyl]-4-
isoxazolyl}amino)-1,3-
thiazol-2-yl]-2-aryl-1,3-
thiazolan-4-ones as Potential
Biodynamic Agents
E. Rajanarendar a , P. Ramesh a , M. Srinivas a &
Firoz Pasha Shaik a
a Department of Chemistry , Kakatiya University ,
Warangal, India
Published online: 19 Feb 2009.
To cite this article: E. Rajanarendar , P. Ramesh , M. Srinivas & Firoz Pasha Shaik
(2009) Synthesis of 3-[4-({Methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}amino)-1,3-
thiazol-2-yl]-2-aryl-1,3-thiazolan-4-ones as Potential Biodynamic Agents,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:3, 733-742, DOI:
10.1080/10426500802273999
To link to this article: http://dx.doi.org/10.1080/10426500802273999
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Phosphorus, Sulfur, and Silicon, 184:733–742, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802273999
Synthesis of 3-[4-({Methyl-5-[(E)-2-phenyl-1-ethenyl]-4-
isoxazolyl}amino)-1,3-thiazol-2-yl]-2-aryl-1,3-thiazolan-4-
ones as Potential Biodynamic Agents
E. Rajanarendar, P. Ramesh, M. Srinivas,
and Firoz Pasha Shaik
Department of Chemistry, Kakatiya University, Warangal, India
A series of isoxazolyl thiazolyl thiazolidinones (4a–h) were synthesized start-
ing from isoxazolyl chloroacetamide 1. Compound 1 upon heating with thiourea
in ethanol furnished N4-{3-methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl]-1,3-
thiazole-2,4-diamine 2. Condensation of 2 with aromatic aldehydes afforded corre-
sponding Schiff bases (3a–h), which undergo cyclocondensation on treatment with
mercaptoacetic acid to give 3-[4-({methyl-5-(E)-2-phenyl-1-ethenyl]-4-isoxazolyl]
amino)-1,3-thiazol-2-yl]-2-aryl-1, 3-thiazolyl –4-ones (4a–h) in excellent yields.
Structures of all the synthesized compounds have been established by elemental
analyses, IR, 1H NMR, and mass spectral data.
Keywords Isoxazolyl thiazoles; isoxazolyl thiazolyl Schiff bases; isoxazolyl thiazolyl
thiazolidinones
INTRODUCTION
The importance of heterocyclic compounds has long been recognized
in the field of synthetic organic chemistry. It is well-known that
a number of heterocyclic compounds containing nitrogen and sul-
fur exhibit a variety of biological activities.1−4 Heterocycles bear-
ing isoxazole, thiazole, and thiazolidinones have been found to be
associated with diverse pharmacological activities. The chemistry
of isoxazole derivatives continues to draw the attention of syn-
thetic organic chemists due to their varied biological activities.5
Several of these derivatives are potent antitumor,6 CNS-active,7
analgesic,8 antimicrobial,9 and chemotherapeutic agents.10 Thiazole
derivatives have been employed as antipsychotics,11 antimalarials,12
antibacterials,13 and antiparasitics.14 Thiazolidinones have occupied a
Received 12 March 2008; accepted 16 June 2008.
Address correspondence to E. Rajanarendar, Department of Chemistry, Kakatiya Uni-
versity, Warangal 506 009, India. E-mail: eligeti rajan@yahoo.co.in
733

734
E. Rajanarendar et al.
unique place, and they have been found to be associated with diverse
pharmacological activities, such as antimicrobial,15 antihistamic,16
anti-inflammatory, analgesic, and anticonvulsants.17 In addition, thia-
zolidinones have been proven as calcium antagonists with both calcium
overload inhibition and antioxidant activity.18
A survey of the literature reveals that when one biodynamic het-
erocyclic system was coupled with another, a molecule with en-
hanced biological activity19,20 was produced. The chemistry of these
linked heterocycles has been a fascinating field of investigation
in medicinal chemistry, as they have been found to exhibit en-
hanced biological profiles.21 In continuation of our interest in de-
signing the synthesis of biologically active heterocycles containing
an isoxazole unit,22−27 the synthesis of some new biologically ac-
tive 3-[4-({methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl} amino)-1,3-
thiazol-2-yl]-2-aryl-1,3-thiazolan-4-ones has been undertaken.
RESULTS AND DISCUSSION
The synthetic scheme of compounds 4a–h is shown in Scheme 1.
The starting material used in this synthesis, N1-{3-methyl-5-[(E)-
2-phenyl-1-ethenyl]-4-isoxazolyl]-2-chloroacetamide (1),28 has been
prepared by the interaction of 4-amino-3-methyl 5-styrylisoxazole
with chloroacetyl chloride in the presence of E3N in dry benzene. The
isoxazolyl chloroacetamide (1), on heating with thiourea in ethanol,
furnished N4-{3-methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl]-1,3-
thiazole-2,4-diamine (2). Condensation of (2) with aromatic aldehydes
in the presence of glacial acetic acid in ethanol afforded the corre-
sponding Schiff bases, viz., N4-{3-methyl-5-[(E)-2-phenyl-1-ethenyl]-
4-isoxazolyl}-N2-[(E)-1-arylmethylidene]-1,3-thiazole-2,4-diamines
(3a–h). The Schiff bases (3) upon cyclocondensation with mercap-
toacetic acid in refluxing dioxane in the presence of anhydrous ZnCl2
led to the formation of 3-[4-(methyl-5-(E)-2-phenyl-1-ethenyl]-4-
isoxazolyl] amino)-1,3-thiazol-2-yl]-2-aryl-1,3-thiazolan-4-ones (4a–h)
in excellent yields (Scheme 1).
Structures of new compounds (2), (3), and (4) were confirmed by
their spectral and micro-analytical data. Disappearance of the carbonyl
group absorption at 1675 cm−1 in the IR spectrum of (2) and the pres-
ence of two new bands at 3420 and 3340 cm−1 due to NH2 and NH
1
functional groups confirm the structure of (2). The H NMR spectrum
of 2 displayed two broad singlets at δ 4.0 and 7.8 due to NH2 and
NH protons, which are D2O exchangeable, confirming the formation of
isoxazolyl amino thiazole (2). One of the styryl protons appeared as a

Synthesis of Isoxazolyl Thiazolyl Thiazolidinones
735
SCHEME 1
doublet at δ 6.8 (J = 12 Hz), whereas another styryl proton signal, when
clubbed with aromatic proton signals and a thiazole ring proton sig-
nal, appeared as a complex multiplet between δ 7.2–7.6. The isoxazole
methyl proton exhibited a sharp singlet at δ 2.2. The Schiff bases (3a–h)
exhibited characteristic stretching vibrations between 1620–1660 cm−1
1
due to the C N functional group, and the H NMR spectrum of 3 dis-
played the newly formed azomethine proton signal at δ 7.8 as a singlet.
The compounds (4a–h) exhibited prominent absorption bands between
1675–1695 and 1210–1240 cm−1 due to C O and C S functionalities,
respectively, in their IR spectra, and showed two distinct singlets at δ
4.2 and 6.4 due to the newly formed 1,3-thiazolan-4-ones ring (CH2 and
CH) protons respectively, in their 1H NMR spectra. Mass spectral data

736
E. Rajanarendar et al.
and elemental analyses further confirm the structures of compounds
(2), (3), and (4).
EXPERIMENTAL
Melting points were recorded on an Electrothermal type 9100 melting
point apparatus and are uncorrected. The IR spectra were recorded
1
on Nicolet Impact 410 FTIR spectrophotometer using KBr pellets. H
NMR spectra were recorded on Bruker AC 300 spectrometer in CDCl3
and with TMS as internal standard. The mass spectra were obtained
on a Varian MATCH-7 instrument at 70 eV. Elemental analyses were
carried out using Perkin-Elmer 240C CHN- analyzer.
N4-{3-Methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}-1,3-
thiazole-2,4-diamine (2)
To a solution of N1-{3-methyl-5-[(E)-2-phenyl-1-3ethenyl]-4-isoxazolyl-
2-chloroacetamide (l) (0.01 mol) in ethanol (20 mL), thiourea (0.015
mol) was added, and the reaction mixture was refluxed for 5–8 h.
After completion of the reaction, the reaction mixture was allowed
to cool down and was later poured into ice-cold water. The isolated
solid was filtered and washed with 2% NaHCO3 solution (15 mL)
and 12% brine solution (10 mL), and then dried over MgSO4. Evap-
oration of the solvent furnished the crude product, which was fur-
ther purified by recrystallization from absolute ethanol. Colorless solid
(absolute ethanol), yield 73%, mp 105–107◦C, IR (KBr); 3420, 3340
cm−1 1HNMR (300 MHz, CDCl3) δ; 2.2 (s, 3H, CH3), 4.0 (bs, 2H,
,
NH2, D2O exchangeable), 6.8 (d, 1H, CH=CH, J = 12Hz), 7.2-7.6 (m,
5H, Ar-H & 1H, CH=CH, & 1H, thiazole-H), 7.8 (bs, 1H, NH, D2O
exchangeable), MS: m/z 299 (M+). Anal. Calcd. for C15H14N4OS; C,
60.40; H, 4.69; N, 18.79; S, 10.73 Found: C, 60.42; H, 4.60; N, 18.72; S,
10.78%.
N4–{3-Methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}-N2-[(E)-
1-arylmethylidene]-1,3-thiazole-2,4-diamines (3a–h)
A mixture of isoxazolylthiazole (2) (0.01 mol) and aromatic aldehyde
(0.01 mol) was taken in ethanol, 4–5 drops of glacial acetic acid was
added to it, and the contents were refluxed on a steam bath for 3–5 h.
After the completion of the reaction (monitored by TLC), the solvent was
removed under reduced pressure. The residue was dissolved in ethy-
lacetate (15 mL) and washed with 10% NaHCO3 solution (2 × 20 mL),

737

738

Synthesis of Isoxazolyl Thiazolyl Thiazolidinones
739
TABLE III Spectral Data of Compounds 3 and 4
Compd.
IR (ν
cm−1
)
1H NMR (δ ppm)
Mass spectra m/z M+
386
max
3a
3490, 1650
3370, 1635
3390, 1645
3365, 1629
3352, 1621
3395, 1642
3410, 1662
3405, 1639
2.20 (s, 3H, CH3), 6.62 (d 1H,
CH=CH, J = 12 Hz), 7.20–7.65
(m, 10H, Ar-H & 1H, thiazole-H &
1H, NH & 1H, CH=CH), 8.53 (s,
1H, CH=N)
3b
3c
3d
3e
3f
2.15 (s, 3H, CH3), 2.40 (s, 3H,
CH3), 6.76 (d, 1H, CH=CH, J =
12 Hz), 7.12–7.78 (m, 9H, Ar –H
& 1H, thiazole-H & 1H, NH &
1H, CH=CH), 8.33 (s, 1H, CH=N)
2.30 (s, 3H, CH3), 3.72(s, 3H,
OCH3), 6.80(d, 1H, CH=CH, J =
12 Hz), 7.21–7.85(m, 9H, Ar –H &
1H, thiazole-H & 1H, NH & 1H,
CH=CH), 8.65(s, 1H, CH=N)
2.20 (s, 3H, CH3), 6.73 (d, 1H,
CH=CH, J = 12 Hz), 7.12–7.65
(m, 9H, Ar–H & 1H, thiazole-H &
1H, NH & 1H, CH=CH), 8.60 (s,
1H, CH=N)
400
416
420
420
454
454
431
460
2.35 (s, 3H, CH3), 6.80 (d, 1H,
CH=CH, J = 12 Hz), 7.05–7.65
(m, 9H, Ar–H & 1H, thiazole-H &
1H, NH & 1H, CH=CH), 8.65 (s,
1H, CH=N)
2.18 (s, 3H, CH3), 6.65 (d, 1H,
CH=CH, J = 12 Hz), 7.08–7.69
(m, 8H, Ar–H & 1H, thiazole-H &
1H, NH & 1H, CH=CH), 8.55 (s,
1H, CH=N)
3g
3h
4a
2.05 (s, 3H, CH3), 6.74 (d, 1H,
CH=CH, J = 12 Hz), 7.12–7.64
(m, 8H, Ar–H & 1H, thiazole-H &
1H, NH & 1H, CH=CH), 8.80 (s,
1H, CH=N)
2.25 (s, 3H, CH3), 6.71 (d, 1H,
CH=CH, J = 12 Hz), 7.13–7.82
(m, 9H, Ar–H & 1H, thiazole-H &
1H, NH & 1H, CH=CH), 8.86 (s,
1H, CH=N)
3275, 1675, 1215 2.25 (s, 3H, CH3), 4.25 (s, 2H,
CH2), 6.4 (s, 1H, CH), 7.25–8.26
(m, 10H, Ar –H & 2H, CH=CH, &
1H, thiazole – H), 8.62 (bs, 1H,
NH, D2O exchangeable)
(Continued on next page)

740
E. Rajanarendar et al.
TABLE III Spectral Data of Compounds 3 and 4 (Continued)
Compd.
IR (ν
cm−1
)
1H NMR (δ ppm)
Mass spectra m/z M+
474
max
4b
3320, 1692, 1224 2.16 (s, 3H, CH3), 2.45 (s, 3H,
CH3), 4.12 (s, 2H, CH2), 6.33 (s,
1H, CH), 7.05–8.15 (m, 9H, Ar –H
& 2H, CH=CH & 1H, thiazole –
H), 8.90 (bs, 1H, NH, D2O
exchangeable)
4c
3359, 1685, 1232 2.21 (s, 3H, CH3), 3.82 (S, 3H,
OCH3), 4.22 (s, 2H, CH2), 6.45 (s,
1H, CH), 7.10–7.93 (m, 9H, Ar –H
& 2H, CH=CH & 1H, thiazole –
H), 8.92 (bs, 1H, NH, D2O
490
exchangeable)
4d
4e
4f
3371, 1679, 1245 2.25 (s, 3H, CH3), 4.42 (s, 2H,
CH2), 6.15 (s, 1H, CH), 7.05–7.95
(m, 9H, Ar –H & 2H, CH=CH &
1H, thiazole – H), 8.80 (bs, 1H,
NH, D2O exchangeable)
3354, 1686, 1235 2.30 (s, 3H, CH3), 4.32 (s, 2H,
CH2), 6.22 (s, 1H, CH), 6.92–8.05
(m, 9H, Ar –H & 2H, CH=CH &
1H, thiazole – H), 8.90 (bs, 1H,
NH, D2O exchangeable)
3320, 1690, 1210 2.25 (s, 3H, CH3), 4.22 (s, 2H,
CH2), 6.45 (s, 1H, CH), 7.05–8.15
(m, 8H, Ar –H & 2H, CH=CH &
1H, thiazole – H), 8.80 (bs, 1H,
NH, D2O exchangeable)
3398, 1699, 1210 2.13 (s, 3H, CH3), 4.12 (s, 2H,
CH2), 6.35 (s, 1H, CH), 7.12–8.26
(m, 8H, Ar –H & 2H, CH=CH &
1H, thiazole – H), 8.85 (bs, 1H,
NH, D2O exchangeable)
494
494
528
528
505
4g
4h
3325, 1682, 1227 2.05 (s, 3H, CH3), 4.12 (s, 2H,
CH2), 6.35 (s, 1H, CH), 7.13–8.05
(m, 9H, Ar –H & 2H, CH=CH &
1H, thiazole – H), 8.65 (bs, 1H,
NH, D2O exchangeable)
water (1 × 20 mL), and brine solution (1 × 20mL). The organic layer
was dried over anhydrous Na2SO4. The crude compound was purified
by column chromatography by elution with ethylacetate:n-hexane (1:9
ratio) (Table I).

Synthesis of Isoxazolyl Thiazolyl Thiazolidinones
741
3[4-({Methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}amino)-
1,3-thiazol-2-yl]-2-aryl-1,3-thiazolan-4-ones (4a–h)
A mixture of compound (3) (0.01 mol) and mercaptoacetic acid (0.01 mol)
was dissolved in 1,4-dioxane (15 mL), 0.2 g of anhydrous zinc chloride
was added, and the contents were refluxed for 5–8 h. After completion
of the reaction (monitored by TLC), the reaction mixture was allowed
to cool down and was poured over crushed ice. The organic layer was
extracted with ethyl acetate (20 mL); washed with 10% sodium bicar-
bonate solution (1 × 20 mL), water (2 × 20 mL), and 12% brine solution
(1 × 20 mL); and dried over anhydrous sodium sulfate. The solvent
was removed under vacuum, and the residue was recrystallized from
benzene:hexane to give 4a–h (Tables II and III).
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