Substituted 4-thiazolidinones under solvent free conditions

Article abstract of DOI:10.1515/HC.2011.027

Condensation of thiosemicarbazones 2 derived from 1-tetralones ( 1 ) with chloroacetic acid in presence of N -methylpyridinium tosylate (an ionic liquid) yields 2-substituted- 4-thiazolidinones 3 . The reaction of 2 with α-halo carbonyl compounds at room

Full text of DOI:10.1515/HC.2011.027

Heterocycl. Commun., Vol. 17(3-4), pp. 147–150, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.027
Efficient synthesis of 2,4-disubstituted thiazoles and
2-substituted 4-thiazolidinones under solvent free conditions
apparatus and molecular sieves are employed for removal
of water from the reaction mixture. In the present paper,
a convenient two component cyclocondensation using an
ionic liquid for obtaining 2-substituted-4-thiazolidinones
with excellent yield is reported. Also in this article we
describe a highly efficient synthesis of 2,4-disubstituted
thiazoles by grinding thiosemicarbazones with α-halo car-
bonyl compounds without any solvent at room temperature
in excellent yields (Scheme 1).
Deepika Gautam, Poonam Gautam and
Ram P. Chaudhary*
Department of Chemistry, Sant Longowal Institute of
Engineering and Technology, Longowal (Sangrur),
Punjab 148106, India
*Corresponding author
e-mail: rpchaudhary65@gmail.com
Abstract
Results and discussion
Condensation of thiosemicarbazones
2 derived from
1-tetralones (1) with chloroacetic acid in presence of
N-methylpyridinium tosylate (an ionic liquid) yields 2-sub-
stituted-4-thiazolidinones 3. The reaction of 2 with α -halo
carbonyl compounds at room temperature under grinding
conditions yields 2,4-disubstituted thiazoles 4 in excellent
yields. The structures of compounds 2–4 have been estab-
lished on the basis of elemental analysis, IR, NMR and mass
spectral data.
Reaction of 1-tetralone with thiosemicarbazide in ethanol
containing a catalytic amount of concentrated HCl gave
hydrazinecarbothioamide 2a. Compound 2a was allowed
to react with chloroacetic acid in the presence of sodium
acetate (conventional method) and in the presence of an
ionic liquid (N-methylpyridinium tosylate) affording thiazo-
lidinone 3a in moderate yield (Table 1). The IR spectrum
of 3a displayed the presence of a carbonyl group peak at
1
1705 cm-1. The H NMR spectrum of 3a exhibited a sharp
Keywords: grinding; ionic liquid; thiazoles; thiosemicarba-
zones; 4-thiazolidinones.
singlet at δ 3.79 for the SCH2 group in the thiazolidinone
unit, suggesting that cyclization had occurred. Two triplets
at δ 2.80 (J=6.2 Hz), δ 2.88 (J=6.6 Hz) and one multiple at
1
δ 1.85–1.91 integrating for two protons each in H NMR
Introduction
spectrum of 3a were assigned to the tetrahydronaphthalene
ring. The mass spectrum of 3a showed the [M+H]+ peak at
m/z 260 (100%). Thiazolidinone 3a was also obtained under
solvent free conditions by heating 2a and chloroacetic acid
in the presence of ionic liquid at 80–90°C for 3 h (Table 1).
Analogues 2b and 3b were similarly obtained by adopting
the same procedure.
Compound 2a was also allowed to react with p-chloro-
phenacyl bromide by stirring in absolute ethanol or by grind-
ing in the absence of solvent at room temperature to give
thiazole 4a'. The IR spectrum of 4a' exhibit absorption at
3204, 1605, 1481 cm-1 attributed to the respective NH, C=N,
C=C functional groups. The 1H NMR spectrum of 4a' exhib-
its a singlet at δ 6.75 for the =CH proton of the thiazole ring.
The analogues 4a", 4b' and 4b" were similarly prepared by
adopting the same procedure and their structures were con-
firmed by elemental analysis and spectral (IR and NMR) data
(Scheme 1). The reaction times and yields for the formation
of compounds 3 and 4 by conventional method as well as by
solvent free method are reported (Table 1). The ionic liquid,
N-methylpyridinium tosylate was synthesized by the literature
method. The recovery of the ionic liquid was also attempted
and we found that it could be re-used for two more cycles.
Thiazoles and 4-thiazolidinones have been exploited in the
past few decades for their wide range of biological activities
such as anti-fungal, anti-convulsant (Gursoy and Terzioglu,
2005), anti-HIV (Rawal et al., 2007), analgesic, diuretic,
anti-viral, anti-protozoal (Tenorio et al., 2005), anti-bacterial
(Bonde and Gaikwad, 2004; Kucukguzel et al., 2006), anti-
cancer (Gududuru et al., 2005), anti-inflammatory (Wilson
et al., 2001; Ottana et al., 2005), cytotoxic (Brantley et al.,
2005), anti-allergic (Hargrave et al., 1983) and anti-tuber-
culotic (Kachhadia et al., 2005) activities. Several methods
for the preparation of 4-thiazolidinones have been reported
in the literature. The commonly employed methods involve
either a one pot, three component cyclocondensation of
amines, carbonyl compounds and mercaptoacetic acid or
two-step synthesis via Schiff base intermediates followed by
their cyclocondensation with mercaptoacetic acid. The two-
step approach involves hazardous solvents and long reac-
tion times with moderate to poor yields. In these reactions
various desiccants such as N,N'-Dicyclohexylcarbodiimide
(DCC) (Srivastava et al., 2002), anhydrous ZnCl2 (Sharma
and Kumar, 2000; Desai and Desai, 2006), Dean-Stark
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148 D. Gautam et al.
Ar
R
R
R
O
S
S
N
ArCOCH2Br
Grind, RT
Ionic liquid
N
N
H
NNHCNH2
N
S
N
NH
ClCH2COOH
3a,b
2a,b
4a', R=H, Ar=p-Cl-C6H4
4a", R=H, Ar=p-O2N-C6H4
S
NH CNH
H2N
O
2
4b', R=OMe, Ar=p-Cl-C6H4
4b", R=OMe, Ar=p-O2N-C6H4
a: R=H
R
b: R=OMe
1a,b
Scheme 1
91%; IR: ν 3410, 3217, 3140 (NH), 1597 (C=N), 1489 (C=C),
1288 cm-1 (C=S); 1H NMR δ 1.95–2.01 (m, 2H, CH2), 2.61 (t, 2H,
CH2, J=6.6 Hz), 2.79 (t, 2H, CH2, J=6.2 Hz), 6.51 (br, 1H, NH ex-
changed with D2O), 7.15–7.32 (m, 3H, C6H5), 7.40 (br, 1H, NH2
exchangeable with D2O), 7.99 (dd, 1H, C6H5), 8.80 (br, 1H, NH2 ex-
changeable with D2O). Analysis: found for C11H13N3S: C, 60.22%;
H, 5.90%; N, 19.22%; S, 14.58. Calculated: C, 60.27; H, 5.98%; N,
19.12%; S, 14.62%.
Conclusion
A convenient and efficient method for the synthesis of 2,4-
disubstituted thiazoles under grinding and synthesis of 4-thia-
zolidinones under solvent free conditions using ionic liquid
is described. The yields of the products under solvent free
conditions are almost quantitative.
(E)-2-(6-Methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)hy-
drazinecarbothioamide (2b): Light brown crystals, m.p. 198–
200°C, yield 86.5%. IR: ν 3433, 3194, 3117 (NH), 1582 (C=N),
1489 (C=C), 1250 cm-1 (C=S); 1H NMR δ 1.87–1.93 (m, 2H, CH2),
2.49 (t, 2H, CH2, J=6.6 Hz), 2.68 (t, 2H, CH2, J=6.2 Hz), 3.75 (s,
3H, OCH3), 6.30 (br, 1H, NH exchangeable with D2O), 6.59 (d, 1H,
C6H5, J=2.6 Hz), 6.70–6.73 (m, 1H, C6H5), 7.28 (br, 1H, NH2 ex-
changeable with D2O), 7.85 (d, 1H, C6H5, J=8.8 Hz), 8.66 (br, 1H,
NH2 exchangeable with D2O). Analysis: found for C12H15N3SO: C,
57.80; H, 5.98; N, 16.82; S, 12.81. Calculated: C, 57.91; H, 6.05;
N, 16.88; S, 12.86%.
Experimental section
The chemicals were obtained from Sigma (Sigma, Bangalore, India)
and used without further purification. Melting points were determined
in open capillaries and are uncorrected. Elemental analysis was done
on a Carlo-Erba 1108 elemental analyzer. Mass spectra were record-
1
ed on a TOF MS ES+2.44e 4 instrument. H NMR (400 MHz) and
13C NMR (100 MHz) were recorded in CDCl3 on a Bruker AVANCE
II 400 NMR spectrometer using tetramethylsilane (TMS) as an inter-
nal standard. IR spectra were recorded on ABB FTIR spectrometer.
Thin layer chromatography (TLC) was performed on silica gel G
coated plates and using iodine vapor as visualizing agent.
Solvent free general procedure for synthesis of 3
Synthesis of ionic liquid
An equimolar mixture of 2 (0.025 mol) and chloroacetic acid (0.23 g,
0.025 mol) in premolten ionic liquid (2.0 g) was stirred at 80–90°C
for 3–4 h. The reaction was monitored by TLC. The mixture was
poured into ice cold water and the resultant solid was filtered, dried
and crystallized from ethanol.
Pyridine (1.1 mol) was added to a methyl-4-toluene sulfonate
(1.0 mol) at 0–10°C.After completion of the addition, the mixture was
stirred at room temperature for 1 h. The solid of N-methylpyridinium
tosylate was filtered. The product was then washed with ethyl ac-
etate and dried. The physical parameters of the ionic liquid are in
good agreement with those reported in the literature (Kroutil and
Budesinsky, 2007).
Table 1 Synthesis of 2,4-disubstituted thiazoles and 4-thiazolidi-
nones by a conventional method and under solvent free conditions.
General procedure for synthesis of 2
Entry
Solvent-free method
Conventional method
A mixture of 1 (0.03 mol), thiosemicarbazide (2.73 g, 0.03 mol) and
concentrated HCl (0.8 ml) in absolute ethanol (40 ml) was stirred
at room temperature for 3 h. The mixture was poured into ice cold
water. The resultant white solid was filtered, dried and crystallized
from ethanol.
Compound Reaction time Yield (%) Reaction time Yield (%)
3a
2.5 h
2.5 h
90
88
95
92
94
93
5 h
63
64
65
64
63
64
3b
5 h
4a'
4a"
4b'
4b"
10 min
12 min
10 min
12 min
15 min
20 min
15 min
20 min
(E)-2(3,4-Dihydronaphthalen-1(2H)-ylidene)hydrazinecarbo-
thioamide (2a): Bright white needles; m.p. 202–206°C; yield
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2,4-Disubstituted thiazoles and 2-substituted 4-thiazolidinones 149
7.14–8.27 (m, 8H, C6H5), 8.80 (br, 1H, NH exchangeable with D2O).
Analysis: found for C19H16N4SO2: C, 62.65; H, 4.36; N, 15.32; S,
Conventional procedure for synthesis of 3
A mixture of 2 (0.005 mol), chloroacetic acid (0.47 g, 0.005 mol), an-
hydrous sodium acetate (0.8 g, 0.01 mol), glacial acetic acid (3.0 ml)
and acetic anhydride (1.0 ml) was heated under reflux for 4 h. The re-
action mixture was cooled to room temperature and then poured into
ice cold water. The resultant solid was filtered, washed with water
and crystallized from ethanol.
8.76. Calculated: C, 62.76; H, 4.44; N, 15.38; S, 8.89%.
(E)-4-(4-Chlorophenyl)-2-(2-(6-methoxy-3,4-dihydronaphthalen-
1(2H)-ylidene)hydrazinyl)thiazole (4b’): White crystals; m.p.
218–220°C; IR: ν 3040 (NH), 1620 (C=N), 1497 (C=C), 748 cm-1
1
(C-Cl); H NMR δ 1.87 (t, 2H, CH2, J=6.2 Hz), 2.50 (t, 2H, CH2,
J=6.0 Hz), 2.66–2.74 (m, 4H, 2CH2), 3.76 (s, 3H, OCH3), 6.63 (d,
1H, C6H5, J=2.0 Hz), 6.73–6.76 (m, 1H, C6H5), 7.12 (s, 1H, CH),
7.35 (d, 1H, C6H5, J=8.4 Hz), 7.62 (d, 1H, C6H5, J=8.0 Hz), 7.71
(d, 2H, C6H5, J=8.5 Hz), 7.98 (br, 1H, NH exchanged with D2O).
Analysis: found for C20H18N3SClO: C, 62.62; H, 4.64; N, 10.92; S,
8.32. Calculated: C, 62.76; H, 4.69; N, 10.98; S, 8.41%.
(Z)-2-((E)-(3,4-Dihydronaphthalen-1(2H)ylidene)hydrazono)-
thiazolidin-4-one (3a): Light yellow crystals; m.p. 206–208°C;
IR: ν 2800 (NH), 1705 (N-C=O), 1605 cm-1 (C=N); 1H NMR δ
1.85–1.91 (m, 2H, CH2), 2.79 (t, 2H, CH2, J=6.2 Hz), 2.86 (t, 2H,
CH2, J=6.6 Hz), 3.79 (s, 2H, SCH2), 7.14 (d, 1H, C6H5, J=7.5 Hz),
7.22–7.32 (m, 2H, C6H5), 8.21–8.24 (m, 1H, C6H5); 13C NMR δ
173.5 (C=O), 162.5 (C=N), 162.1 (C=N), 140.9, 132.3, 130.1, 128.6,
126.3, 125.5 (C6H5), 33.1 (SCH2), 29.9 (CH2), 27.4 (CH2), 22.2
(CH2); EIMS: m/z 260 (M+H+, 100%), 144 (M-C3H3N2SO, 29%).
Analysis: found for C13H13N3SO: C, 60.20; H, 5.04%; N, 16.18; S,
12.32. Calculated: C, 60.32; H, 5.11; N, 16.24; S, 12.38%.
(E)-2-(2-(6-Methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)-
hydrazinyl)-4-(4-nitrophenyl)thiazole (4b’’): Light brown crys-
tals; m.p. 211–212°C; IR: ν 3348 (NH), 1597 (C=N), 1558, 1342
(NO2), 1512 cm-1 (C=C); 1H NMR δ 1.84–1.90 (m, 2H, CH2), 2.50 (t,
2H, CH2, J=6.1 Hz), 2.64–2.72 (m, 4H, 2CH2), 3.75 (s, 3H, OCH3),
6.61 (1H, d, C6H5, J=2.4 Hz), 6.72–6.75 (m, 1H, C6H5), 7.33 (s, 1H,
CH), 7.93 (d, 1H, C6H5, J=8.8 Hz), 8.00 (d, 2H, C6H5, J=2.0 Hz),
8.16 (d, 2H, C6H5, J=2.2 Hz), 10.87 (br, 1H, NH exchanged with
D2O). Analysis: found for C20H18N4O3S: C, 60.89; H, 4.52;
N, 14.18; S, 8.09. Calculated: C, 60.94; H, 4.62; N, 14.12; S,
8.14%.
(Z)-2-[(E)-(6-Methoxy-3,4-dihydronaphthalen-1(2H)-ylidene]hy-
drazono)thiazolidin-4-one (3b): Shining white crystals; m.p. 224–
226°C; IR: ν 3124 (NH), 1697 (N-C=O), 1597 cm-1 (C=N); 1H NMR δ
1.78–1.84 (m, 2H, CH2), 2.72–2.78 (m, 4H, 2CH2), 3.72 (s, 2H, SCH2),
3.76 (s, 3H, OCH3), 6.64 (d, 1H, C6H5, J=2.5 Hz), 6.72–6.75 (m, 1H,
C6H5), 8.01 (d, 1H, C6H5, J=8.6 Hz); 13C NMR δ 173.5 (C=O), 160.3
(C=N), 159.5 (C=N), 142.0, 126.5, 125.0, 128.6 (C6H5), 54.9 (OCH3),
32.7 (SCH2), 29.7 (CH2), 26.8 (CH2), 21.8 (CH2). Analysis: found for
C14H15N3O2S: C, 58.10; H, 5.14; N, 14.56%, S, 11.02. Calculated: C,
58.23; H, 5.22; N, 14.58; S, 11.17%.
Acknowledgements
The facilities provided by the authorities of Sant Longowal
Institute of Engineering and Technology, Longowal are gratefully
acknowledged.
Solvent-free general procedure for synthesis of 4
A mixture of 2 (0.001 mol) and p-substituted phenacyl bromide
(0.001 mol) was grinded in a pestle mortar without a solvent for
15–20 min at room temperature. The progress of the reaction was
monitored by TLC. After completion of the reaction, the product was
extracted with ethyl acetate. The solvent was removed under reduced
pressure to obtain the crude solid that was crystallized from ethanol.
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(E)-4-(4-Chlorophenyl)-2-(2-(3,4-dihydronaphthalen-1(2H)-
ylidene)hydrazinyl)thiazole (4a’): Dark brown needles; m.p. 232–
235°C; IR: ν 3204 (NH), 1605 (C=N), 1481 (C=C), 733 cm-1 (C-Cl);
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Received May 29, 2011; accepted June 30, 2011
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