Three-component domino reaction in PPG: An easy access to 4-thiazolidinone derivatives

Article abstract of DOI:10.1002/jhet.838

A simple, economical, and convenient synthesis of a new series of 4-thiazolidinone derivatives using one-pot three-component condensation of aromatic amines, thioglycolic acid and aromatic aldehydes or cyclohexanone in polypropylene glycol (PPG), a recyclable and inexpensive solvent medium is reported. All the reactions are carried out at 110°C without using catalyst or additives. The products are obtained in good to excellent yields (60-97%) after easy workup and purification.

Full text of DOI:10.1002/jhet.838

628
Three-Component Domino Reaction in PPG: An Easy Access to
4-Thiazolidinone Derivatives
Vol 49
*
Davinder Prasad and Mahendra Nath
Department of Chemistry, University of Delhi, Delhi 110007, India
*
E-mail: mnath@chemistry.du.ac.in
Received September 24, 2010
DOI 10.1002/jhet.838
View this article online at wileyonlinelibrary.com.
A simple, economical, and convenient synthesis of a new series of 4-thiazolidinone derivatives using
one-pot three-component condensation of aromatic amines, thioglycolic acid and aromatic aldehydes or
cyclohexanone in polypropylene glycol (PPG), a recyclable and inexpensive solvent medium is reported.
All the reactions are carried out at 110ꢀC without using catalyst or additives. The products are obtained in
good to excellent yields (60–97%) after easy workup and purification.
J. Heterocyclic Chem., 49, 628 (2012).
INTRODUCTION
rate determining and seems to be critical for obtaining
4-thiazolidinones in better yields. The most common
approach to remove water from the reaction medium is
by azeotropic distillation using Dean Stark trap [10].
Besides this, various dehydrating agents such as Na2SO4
[11], molecular sieves [10(a)], DCC [12], HBTU [13],
and Lewis acid catalysts such as anhydrous ZnCl2 [14]
and SnCl2 [15] have also been used to improve the yield
of the desired product.
The use of multi-component domino reactions for
the construction of complex organic structures from
simple and easily available precursors has received con-
siderable attention in recent years [1]. In comparison to
conventional chemical reactions, these processes avoid
multi-step synthetic protocols and offer an easy access
to a variety of pharmaceutically useful heterocyclic mole-
cules [2].
4-Thiazolidinones are an important class of five mem-
bered heterocycles and occupy a unique place in therapeu-
tic and medicinal fields because of their pharmacological
profiles as anticonvulsant [3], anti-HIV [4], antifungal
[5], antibacterial [6], COX-1 inhibitors [7], and nematicidal
agents [8]. Although a number of methods are reported in
the literature employing either a two step or an one step
procedure to afford 4-thiazolidinones by a condensation
cyclization reaction between amine, carbonyl compound
(ketone or an aldehyde) and thioglycolic acid but the
design of simple, economical, and efficient synthetic routes
for the synthesis of these biologically active molecules is
highly desired.
Thorough literature search revealed that the reaction pro-
ceeds via initial formation of a Schiff base intermediate,
which undergoes attack by sulfur nucleophile followed
by intramolecular cyclization with the expulsion of water
to form the cyclized product [9]. It is generally believed
that the last step, that is, removal of water molecule is the
In view of enormous pharmacological potential of 4-
thiazolidinone class of compounds, we hereby report a
simple, economical, and robust one-pot three-component
synthesis of these heterocycles in good to excellent yields
using polypropylene glycol (PPG) as a solvent medium
(Scheme 1).
To the best of our knowledge, PPG has not been used
previously as a solvent medium for the construction of
4-thiazolidinone derivatives. We have chosen PPG as a
solvent because it is immiscible with water and hence can
easily facilitate the reaction rate by eliminating water mole-
cules from the reaction medium. Furthermore, PPG is an
environmentally benign solvent and also offers many
advantages like low cost, less toxicity, recyclability, easy
work-up, and miscibility with a wide range of organic
solvents. In comparison to reported one-pot methods [10
(a),12,13,16], our synthetic protocol does not require any
catalyst or additives and products were obtained in good
to excellent yields at 110ꢀC in 4–11 h.
© 2012 HeteroCorporation

May 2012
Three-Component Domino Reaction in PPG: An Easy Access to
4-Thiazolidinone Derivatives
629
Table 1
Scheme 1
One-pot three-component synthesis of 4-thiazolidinones (4a-m)
in PPG.
Time Yield
Entry
R
R1 R2 R3
(h)
(%) Product
1
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
CF3
CH3
Cl
7
81
97
80
79
78
76
84
4a
4b
4c
4d
4e
4f
2
3
4
5
6
7
4
11
7
RESULTS AND DISCUSSION
For the synthesis of a novel series of 4-thiazolidinones
(4a-m and 6a-d), various aromatic amines (1) were pre-
pared according to the literature procedure [17]. The
synthesis of 3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-
2-phenylthiazolidin-4-one (4a) was attempted by reacting
4-((1H-1,2,4-triazol-1-yl)methyl)aniline with benzalde-
hyde and thioglycolic acid in PPG at 110ꢀC for 7 h. After
completion of the reaction, as indicated by TLC, the mix-
ture was allowed to cool at 25ꢀC and diluted with hexane.
The precipitated crude product was filtered, washed well
with hexane, and chromatographed over silica gel to afford
pure compound in 81% yield. The filtrate (hexane layer)
was evaporated under reduced pressure to recover PPG
which can be reused. To optimize the reaction conditions,
a number of reactions were carried out with varying
amounts of the reactants and it was noticed that the reac-
tion proceeds quantitatively by using amine, aldehyde,
and thioglycolic acid in 1:2:3 ratio, respectively. Encour-
aged by this result and to gain insight into the reaction, a
library of novel 4-thiazolidinones (4b-m) has been synthe-
sized by condensing the corresponding aromatic amines
with different aromatic aldehydes and thioglycolic acid in
PPG at 110ꢀC for 4–11 h. In general, the reaction proceeds
well with aromatic aldehydes having electron withdrawing
substituents such as CF3 (Table 1, Entries 2, 8, and 13)
while aldehydes having electron donating substituents such
as CH3 on the aromatic ring (Table 1, Entry 3) retards the
rate of reaction. In addition, the position of substituents
viz. o-, m-, or p- (Table 1, Entries 4, 5, and 6) with respect
to carbonyl group does not have any influence on the reac-
tion rate. Similarly, the reaction is merely affected by the
nature of “R” group of aromatic amines as evident from
Table 1.
H
7
H
7
Br
6
4g
8
CF3
H
H
H
H
H
H
H
H
H
Br
H
F
4
7
6
7
4
4
91
80
86
86
88
92
4h
4i
9
10
11
12
13
H
4j
H
4k
4l
All the synthesized compounds (4a-m) have been char-
acterized by IR, mass, NMR, and elemental analysis. The
infrared absorption spectrum of novel 3-(4-((1H-1,2,
4-triazol-1-yl)methyl)phenyl)-2-phenylthiazolidin-4-one (4a)
exhibited characteristic strong absorption band at 1662
cmÀ1 due to stretching of C=O bond. The presence of
thiazolidinone moiety in the molecule was confirmed by
H
CF3
H
4m
1
NMR spectroscopy. H NMR spectrum of 4a in CDCl3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

630
D. Prasad and M. Nath
Vol 49
Table 3
PPG recycle for the one-pot condensation reaction of 4-
Scheme 2
morpholinoaniline, thioglycolic acid, and 4-fluorobenzaldehyde
at 110ꢀC.
Entry
Run
Time (h)
Yield (%)a
1
2
3
4
1
2
3
4
4
4
4
4
90
89
89
89
aIsolated yields for product (4l) after each cycle.
showed a characteristic singlet at 6.08 ppm for one proton
corresponds to N—CH—S with additional doublets at
3.85 and 3.98 ppm due to coupling between two geminal
protons of SCH2CO group of the thiazolidinone ring.
To test the versatility of this procedure, synthesis of
novel spiro-thiazolidinones (6a-d) has also been carried
out under standardized reaction conditions through one-
pot condensation of corresponding aromatic amine with
cyclohexanone and thioglycolic acid in PPG at 110ꢀC for
11 h (Scheme 2).
Over all, the reaction of amine (1) with cyclohexanone
and thioglycolic acid was found to be sluggish and
produced desired products (6a-d) in moderate yields.
Surprisingly, the substituent “R” of aromatic amine does
not have any significant influence on the reaction rate within
the series (Table 2). The spectral and analytical data of these
compounds were found in full agreement with the proposed
structures and are presented in the experimental section.
Additionally, we have investigated the recyclability
of PPG for the synthesis of 2-(4-fluorophenyl)-3-(4-
morpholinophenyl)thiazolidin-4-one (4l). After each run,
the PPG was extracted with hexane and reused after the
removal of solvent by vacuum. The good yields were
obtained in all four runs (Table 3).
EXPERIMENTAL
All the chemicals were purchased from Aldrich and used
without further purification. Thin layer chromatography (TLC)
was performed using silica gel 60 F254 (pre-coated aluminium
sheets) from Merck. Reactions were monitored by TLC and
products were purified by column chromatography using silica
gel (60–120 mesh size). 1H NMR spectra were obtained in
CDCl3, using a Bruker 300 MHz and Jeol ECX 400 MHz
NMR spectrometer. Chemical shifts are expressed in parts per
million (ppm) relative to tetramethylsilane (TMS; 0 ppm) as an
internal standard. Coupling constants (J) are reported in hertz
(Hz). Infrared spectra were recorded on Perkin Elmer IR
spectrometer and absorption maxima (υmax) are given in cmÀ1
Mass spectra were recorded on ESI-MS (micromass LCT,
waters) mass spectrometer.
.
General procedure for the synthesis of 4-thiazolidinones
(4a-m and 6a-d).
To a mixture of aromatic amine (1.0
mmol) and aromatic aldehyde or cyclohexanone (2.0 mmol) in
PPG-2000 (3.0 mL), thioglycolic acid (3.0 mmol) was added.
The reaction mixture was heated at 110ꢀC for 4–11 h. Then, the
mixture was cooled to room temperature and PPG was extracted
with hexane (10 mL Â 3 times). After complete removal of
PPG, the residue was dissolved in ethyl acetate (25 mL) and
washed with saturated NaHCO3 solution (15 mL Â 3 times)
followed by water (15 mL Â 3 times). The ethyl acetate layer
was dried over anhydrous Na2SO4 and evaporated under vacuum.
The crude product was purified by column chromatography over
silica gel (60 mesh size) using 2–4% MeOH in benzene as
eluent. PPG was recovered quantitatively after the evaporation of
hexane under vacuum and can be recycled.
Table 2
One-pot three-component synthesis of spiro-thiazolidinones
(6a-d) in PPG.
Entry
R
Time (h)
11
Yield (%)
60
Product
1
6a
2
11
62
6b
3-(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)-2-phenylthia-
zolidin-4-one (4a). Yellow solid; m.p. 126ꢀC. IR (Nujol): υ =
1662, 1508, 1457, 1390, 1344, 1267, 1139, 1018, 956, 801, 767,
1
721, 693 cm–1; H NMR (300 MHz, CDCl3): d = 7.98 (s, 1 H,
ArH), 7.94 (s, 1H, ArH), 7.36–7.14 (m, 9H, ArH), 6.08 (s, 1H,
CH), 5.25 (s, 2H, CH2), 3.98 (d, J = 16.2 Hz, 1H, CH2), 3.85
(d, J = 15.9 Hz, 1H, CH2) ppm; 13C NMR (75 MHz, CDCl3):
d = 170.12, 151.19, 142.08, 138.23, 136.86, 132.15, 128.00,
127.53, 125.72, 124.77, 122.68, 64.30, 51.82, 32.38 ppm; MS
(ESI): m/z 337 [M+H]+.
3
4
11
11
61
62
6c
6d
3-(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)-2-(4-(trifluor-
omethyl)phenyl)thiazolidin-4-one (4b). Light yellow solid;
m.p. 174ꢀC. IR (Nujol): υ = 1687, 1514, 1458, 1373, 1319,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Three-Component Domino Reaction in PPG: An Easy Access to
4-Thiazolidinone Derivatives
631
1111, 1063, 1012, 855, 754, 721 cmÀ1
;
1H NMR (300 MHz,
= 8.48 (s, 1H, ArH), 8.07 (s, 1H, ArH), 7.62 (dd, J1 = 6.88 Hz,
J2 = 2.28 Hz, 2H, ArH), 7.44 (dd, J1 = 6.64 Hz, J2 = 2.08 Hz,
2H, ArH), 7.33 (dd, J1 = 6.88 Hz, J2 = 2.08 Hz, 2H, ArH), 7.19
(dd, J1 = 6.63 Hz, J2 = 1.84 Hz, 2H, ArH), 6.12 (s, 1H, CH),
3.98 (dd, J1 = 15.9 Hz, J2 = 1.6 Hz, 1H, CH2), 3.90 (dd, J1 =
15.8 Hz, J2 = 0.68 Hz, 1H, CH2) ppm; 13C NMR (100 MHz,
CDCl3): d = 171.03, 152.72, 140.99, 137.97, 136.97, 135.24,
132.31, 128.77, 126.63, 123.25, 120.60, 64.65, 35.51 ppm; MS
(ESI): m/z 401 [M]+; Anal. calcd for C17H13BrN4OS.0.51H2O:
C, 49.74; H, 3.44; N, 13.65; S, 7.81. Found: C, 50.11; H, 3.66;
N, 13.25; S, 7.63.
CDCl3): d = 8.04 (s, 1 H, ArH), 7.95 (s, 1H, ArH), 7.57 (d,
J = 8.4 Hz, 2H, ArH), 7.40 (d, J = 8.1 Hz, 2H, ArH),
7.26–7.16 (m, 4H, ArH), 6.14 (s, 1H, CH), 5.27 (s, 2H, CH2),
3.98 (dd, J1 = 16.0 Hz, J2 = 0.9 Hz, 1H, CH2), 3.87 (d, J =
15.9 Hz, 1H, CH2) ppm; 13C NMR (100 MHz, CDCl3): d =
170.85, 152.04, 143.29, 143.08, 137.32, 133.48, 128.52,
126.93, 125.98, 125.95, 125.38, 124.88, 64.27, 52.55, 33.13
ppm; MS(ESI): m/z 405 [M+H]+; Anal. calcd for
C19H15F3N4OS.H2O.0.4C6H6: C, 56.66; H, 4.31; N, 12.35; S,
7.07. Found: C, 56.43; H, 4.39; N, 12.35; S, 7.43.
3-(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)-2-p-tolylthia-
zolidin-4-one (4c).
(Nujol): υ = 1686, 1610, 1560, 1513, 1426, 1414, 1376, 1336,
3-(4-((1H-Imidazol-1-yl)methyl)phenyl)-2-(2-(trifluorome-
thyl)phenyl)thiazolidin-4-one (4h). Gummy yellow solid; IR
(CHCl3): υ = 1693, 1608, 1515, 1455, 1392, 1313, 1271, 1232,
Light yellow solid; m.p. 138ꢀC. IR
1165, 1118, 1059, 1038, 906, 816, 761, 724, 662, 612 cmÀ1
;
1301, 1272, 1214, 1180, 1137, 1017, 957, 900, 829, 752, 679
cmÀ1 1H NMR (300 MHz, CDCl3): d = 8.06 (s, 1 H, ArH),
;
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J = 8.04 Hz, 1H,
ArH), 7.56–7.54 (m, 2H, ArH), 7.47 (s, 1H, ArH), 7.38–7.37
(m, 1H, ArH), 7.27–7.25 (m, 2H, ArH), 7.06–7.04 (m, 3H,
ArH), 6.83 (s, 1H, ArH), 6.55 (s, 1H, CH), 5.03 (s, 2H, CH2),
3.99 (dd, J1 = 16.1 Hz, J2 = 1.32 Hz, 1H, CH2), 3.86 (d, J =
16.1 Hz, 1H, CH2) ppm; MS (ESI): m/z 404 [M+H]+.
7.93 (s, 1H, ArH), 7.18–7.09 (m, 8H, ArH), 6.06 (s, 1H, CH),
5.23 (s, 2H, CH2), 3.95 (d, J = 15.9 Hz, 1H, CH2), 3.82 (d,
J = 15.3 Hz, 1H, CH2), 2.36 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 171.03, 151.91, 143.02, 138.82,
137.66, 135.97, 133.00, 129.50, 128.32, 126.52, 125.66,
64.99, 52.60, 33.27, 21.02 ppm; MS (ESI): m/z 351 [M+H]+.
3-(4-(1H-Imidazol-1-yl)phenyl)-2-phenylthiazolidin-4-one
(4i). Yellow solid; m.p. 136ꢀC. IR (CHCl3): υ = 1688, 1682,
1607, 1520, 1490, 1456, 1431, 1382, 1344, 1303, 1265, 1247,
1219, 1178, 1131, 1111, 1074, 1056, 1029, 964, 904, 838, 816,
3-(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)-2-(4-chlorophe-
nyl)thiazolidin-4-one (4d).
(Nujol): υ = 1686, 1514, 1491, 1376, 1272, 1216, 1137, 1089,
1015, 957, 844, 798, 752, 679 cmÀ1 1H NMR (300 MHz,
Yellow solid; m.p. 164ꢀC. IR
1
743, 700, 659 cmÀ1; H NMR (400 MHz, CDCl3): d = 7.75 (s,
;
CDCl3): d = 8.03 (s, 1 H, ArH), 7.94 (s, 1H, ArH), 7.25–7.17
(m, 8H, ArH), 6.07 (s, 1H, CH), 5.27 (s, 2H, CH2), 3.96 (d, J =
15.9 Hz, 1H, CH2), 3.85 (d, J = 15.6 Hz, 1H, CH2) ppm; MS
(ESI): m/z 371 [M+H]+.
1H, ArH), 7.32–7.30 (m, 9H, ArH), 7.17 (d, J = 8.24 Hz, 2H,
ArH), 6.12 (s, 1H, CH), 4.00 (dd, J1 = 15.91 Hz, J2 = 1.37 Hz,
1H, CH2), 3.89 (dd, J1 = 15.9 Hz, J2 = 0.69 Hz, 1H, CH2) ppm;
13C NMR (100 MHz, CDCl3): d = 170.69, 138.61, 136.08,
134.93, 130.01, 128.68, 128.60, 126.50, 126.30, 121.25,
117.55, 64.73, 32.98 ppm; MS (ESI): m/z 322 [M+H]+; Anal
calcd for C18H15N3OS.0.25H2O: C, 66.34; H, 4.79; N, 12.89; S,
9.84. Found: C, 66.55; H, 4.75; N, 12.73; S, 10.13.
3-(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)-2-(3-chlorophe-
nyl)thiazolidin-4-one (4e).
White solid; m.p. 148ꢀC. IR
(Nujol): υ = 1690, 1513, 1477, 1432, 1375, 1328, 1273, 1244,
1199, 1137, 1078, 1017, 999, 957, 883, 855, 798, 750, 700, 680,
1
665, 634 cmÀ1; H NMR (400 MHz, CDCl3): d = 8.01 (s, 1 H,
3-(4-(1H-Imidazol-1-yl)phenyl)-2-(4-bromophenyl)thiazoli-
din-4-one (4j). Light yellow solid; m.p. 126ꢀC. IR (CHCl3): υ
= 1688, 1520, 1488, 1409, 1379, 1303, 1263, 1247, 1218, 1111,
ArH), 7.95 (s, 1H, ArH), 7.27–7.13 (m, 8H, ArH), 6.04 (s, 1H,
CH), 5.27 (s, 2H, CH2), 3.98 (dd, J1 = 16.0 Hz, J2 = 1.37 Hz,
1H, CH2), 3.85 (d, J = 16.0 Hz, 1H, CH2) ppm; 13C NMR (100
MHz, CDCl3): d = 171.02, 152.26, 143.32, 141.57, 137.54,
134.89, 133.66, 130.41, 129.29, 128.69, 126.95, 125.76, 124.99,
64.56, 52.73, 33.35 ppm; MS (ESI): m/z 371 [M+H]+; Anal.
calcd for C18H15ClN4OS.0.25H2O: C, 57.60; H, 4.16; N, 14.93;
S, 8.54. Found: C, 57.68; H, 4.10; N, 14.79; S, 8.74.
1
1071, 1056, 1010, 964, 904, 834, 799, 756, 681, 658 cmÀ1; H
NMR (400 MHz, CDCl3): d = 7.78 (s, 1H, ArH), 7.45 (dd, J1 =
6.53 Hz, J2 = 1.83 Hz, 2H, ArH), 7.33–7.28 (m, 4H, ArH),
7.21–7.17 (m, 4H, ArH), 6.10 (s, 1H, CH), 3.98 (dd, J1 = 15.9
Hz, J2 = 1.37 Hz, 1H, CH2), 3.89 (dd, J1 = 16.0 Hz, J2 = 0.69
Hz, 1H, CH2) ppm; 13C NMR (100 MHz, CDCl3): d = 170.87,
137.86, 136.18, 135.56, 135.27, 132.11, 130.37, 128.52,
126.65, 123.02, 121.89, 117.92, 64.50, 33.24 ppm; MS (ESI):
m/z 400 [M]+; Anal calcd for C18H14BrN3OS.0.4H2O: C, 53.05;
H, 3.66; N, 10.31; S, 7.87. Found: C, 53.10; H, 3.68; N, 9.98;
S, 7.89.
3-(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)-2-(2-chlorophe-
nyl)thiazolidin-4-one (4f).
White solid; m.p. 142ꢀC. IR
(Nujol): υ = 1693, 1514, 1473, 1445, 1376, 1339, 1304, 1272,
1218, 1138, 1047, 1017, 957, 852, 800, 749, 698, 679, 610
cmÀ1 1H NMR (400 MHz, CDCl3): d = 8.00 (s, 1 H, ArH),
;
7.94 (s, 1H, ArH), 7.38–7.18 (m, 8H, ArH), 6.53 (s, 1H, CH),
5.27 (s, 2H, CH2), 3.92 (dd, J1 = 16.0 Hz, J2 = 1.37 Hz, 1H,
CH2), 3.79 (d, J = 16.0 Hz, 1H, CH2) ppm; 13C NMR (100
MHz, CDCl3): d = 171.42, 152.24, 143.19, 137.88, 136.79,
132.91, 132.41, 130.38, 129.89, 128.68, 127.62, 126.91, 124.29,
61.61, 52.82, 32.98 ppm; MS (ESI): m/z 371 [M+H]+; Anal.
calcd for C18H15ClN4OS.0.2H2O: C, 57.73; H, 4.15; N, 14.96;
S, 8.56. Found: C, 57.92; H, 4.43; N, 14.61, S, 8.54.
3-(4-Morpholinophenyl)-2-phenylthiazolidin-4-one (4k).
Pale yellow solid; m. p. 186ꢀC. IR (CHCl3): υ = 1682, 1608,
1516, 1450, 1379, 1341, 1303, 1263, 1234, 1176, 1121, 1072,
1051, 1029, 930, 826, 805, 786, 752, 705, 697, 657, 608
cmÀ1 1H NMR (400 MHz, CDCl3): d = 7.30–7.24 (m, 5H,
;
ArH), 7.01 (dd, J1 = 6.88 Hz, J2 = 1.84 Hz, 2H, ArH), 6.77
(dd, J1 = 7.09 Hz, J2 = 1.84 Hz, 2H, ArH), 5.98 (d, J = 1.84
Hz, 1H, CH), 3.99 (dd, J1 = 16.0 Hz, J2 = 1.84 Hz, 1H, CH2),
3.86(d, J = 16.0 Hz, 1H, CH2), 3.79 (t, J = 5.0 Hz, 4H,
morpholine), 3.08 (t, J = 5.0 Hz, 4H, morpholine) ppm; 13C
NMR (100 MHz, CDCl3): d = 171.19, 150.09, 129.26, 128.97,
127.08, 126.96, 115.79, 66.83, 65.99, 65.83, 48.90, 33.44
3-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-2-(4-bromophenyl)thia-
zolidin-4-one (4g). Yellow solid; m. p. 128ꢀC. IR (CHCl3): υ
= 1686, 1521, 1489, 1375, 1278, 1144, 1071, 1051, 1009, 982,
1
954, 835, 771, 673, 567 cmÀ1; H NMR (400 MHz, CDCl3): d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

632
D. Prasad and M. Nath
Vol 49
ppm; MS (ESI): m/z 341 [M+H]+; Anal. calcd for
C19H20N2O2S.0.15H2O: C, 66.50; H, 5.96; N, 8.16; S, 9.34.
Found: C, 66.26; H, 5.75; N, 7.96; S, 9.83.
1H, ArH), 3.70 (s, 2H, CH2), 2.03–2.01 (m, 2H, cyclohexane),
1.78–1.60 (m, 8H, cyclohexane) ppm; MS (ESI): m/z 313 [M]+.
4-(4-Morpholinophenyl)-1-thia-4-azaspiro[4.5]-decan-3-
one (6d). White solid; m. p. 190ꢀC. IR (CHCl3): υ = 1682,
1607, 1515, 1449, 1377, 1334, 1303, 1261, 1230, 1122, 1069,
2-(4-Fluorophenyl)-3-(4-morpholinophenyl)thiazolidin-4-
one (4l). Yellow solid; m.p. 132ꢀC. IR (CHCl3): υ = 1684,
1605, 1515, 1450, 1428, 1378, 1334, 1304, 1263, 1234, 1176,
1157, 1121, 1095, 1070, 1051, 1030, 1013, 930, 846, 826,
1052, 930, 904, 822, 753, 662 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d = 7.03 (d, J = 9.08 Hz, 2H, ArH), 6.93 (d, J = 9.08
Hz, 2H, ArH), 3.85 (t, J = 4.7 Hz, 4H, morpholine), 3.66
(s, 2H, CH2), 3.20 (t, J = 5.0 Hz, 4H, morpholine), 1.96–1.93
(m, 2H, cyclohexane), 1.74–1.58 (m, 8H, cyclohexane) ppm;
13C NMR (100 MHz, CDCl3): d = 172.11, 151.21, 131.02,
127.64, 115.75, 74.20, 66.87, 48.76, 39.15, 31.60, 24.37,
23.53 ppm; MS (ESI) m/z 333 [M+H]+; Anal calcd for
C18H24N2O2S.0.1H2O: C, 64.68; H, 7.30; N, 8.38; S, 9.59.
Found: C, 64.37; H, 6.94; N, 8.22; S, 9.96.
790, 754, 695, 656 cmÀ1 1H NMR (400 MHz, CDCl3): d =
;
7.29–7.26 (m, 2H, ArH), 6.99–6.94 (m, 4H, ArH), 6.77 (dd,
J1 = 6.87 Hz, J2 = 2.29 Hz, 2H, ArH), 5.97 (d, J = 1.37 Hz,
1H, CH), 3.96 (dd, J1 = 15.8 Hz, J2 = 1.83 Hz, 1H, CH2),
3.87 (d, J = 15.8 Hz, 1H, CH2), 3.80 (t, J = 4.58 Hz, 4H,
morpholine), 3.09 (t, J = 4.81 Hz, 4H, morpholine) ppm; 13C
NMR (100 MHz, CDCl3): d = 170.82, 149.99, 129.11,
129.03, 128.66, 126.97, 115.77, 115.6, 115.55, 65.59, 65.06,
48.60, 33.24 ppm; MS (ESI): m/z 359 [M+H]+; Anal. calcd
for C19H19FN2O2S: C, 63.66; H, 5.31; N, 7.62; S, 8.68.
Found: C, 63.67; H, 5.34; N, 7.82; S, 8.95.
CONCLUSION
3-(4-Morpholinophenyl)-2-(2-(trifluoromethyl)phenyl)thia-
zolidin-4-one (4m). White solid; m.p. 206ꢀC. IR (CHCl3): υ =
1690, 1608, 1516, 1451, 1382, 1337, 1313, 1264, 1234, 1165,
In conclusion, we have developed a simple, convenient,
and inexpensive procedure for the synthesis of novel 4-
thiazolidinones in good to excellent yields via three-com-
ponent domino reaction using PPG as a solvent medium.
It is important to mention that this methodology does not
require any catalyst and other additives.
1
1118, 1059, 1038, 931, 826, 805, 790, 765, 654, 613 cmÀ1; H
NMR (400 MHz, CDCl3): d = 7.64 (d, J = 7.72 Hz, 1H, ArH),
7.57 (d, J = 7.72 Hz, 2H, ArH), 7.37–7.33 (m, 1H, ArH), 7.12
(dd, J1 = 6.72 Hz, J2 = 2.01 Hz, 2H, ArH), 6.78 (dd, J1 = 6.72
Hz, J2 = 2.01 Hz, 2H, ArH), 6.49 (s, 1H, CH), 3.99 (dd, J1 =
15.7 Hz, J2 = 1.68 Hz, 1H, CH2), 3.86 (d, J = 15.7 Hz, 1H,
CH2), 3.79 (t, J = 4.70 Hz, 4H, morpholine), 3.08 (t, J = 4.70
Hz, 4H, morpholine) ppm; 13C NMR (100 MHz, CDCl3): d =
171.16, 149.86, 139.38, 132.75, 128.75, 128.47, 127.60,
127.26, 126.97, 126.26, 125.94, 115.62, 66.70, 60.20, 48.68,
32.97 ppm; MS (ESI): m/z 409 [M+H]+; Anal. calcd for
C20H19F3N2O2S. 0.3H2O: C, 58.04; H, 4.77; N, 6.77; S, 7.75.
Found: C, 57.94; H, 4.48; N, 6.54; S, 7.69.
Acknowledgments. This work is supported by University of
Delhi, India, under the scheme to strengthen R&D Doctoral
Research Program. The authors are thankful to University
Science Instrumentation Centre, University of Delhi, for
providing NMR data and CHN analysis. Davinder Prasad is
grateful to CSIR, New Delhi, India, for Junior Research
Fellowship.
4-(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)-1-thia-4-azaspiro
[4.5]decan-3-one (6a). Gummy brown matter; IR (CHCl3): υ =
1679, 1609, 1512, 1447, 1418, 1377, 1338, 1270, 1224, 1136,
1016, 956, 906, 854, 746, 698, 677, 660 cmÀ1 1H NMR (400
;
MHz, CDCl3): d = 8.14 (s, 1H, ArH), 8.00 (s, 1H, ArH), 7.32
(dd, J1 = 6.41 Hz, J2 = 2.06 Hz, 2H, ArH), 7.16 (dd, J1 = 6.41
Hz, J2 = 2.06 Hz, 2H, ArH), 5.39 (s, 2H, CH2-Ph), 3.67 (s, 2H,
CH2), 1.98–1.95 (m, 2H, cyclohexane), 1.73–1.56 (m, 8H,
cyclohexane) ppm; 13C NMR (100 MHz, CDCl3): d = 171.92,
152.13, 143.27, 136.52, 135.42, 130.86, 128.61, 74.08, 52.63,
38.92, 31.43, 23.98, 23.25 ppm; MS (ESI): m/z 328 [M]+.
REFERENCES AND NOTES
[1] (a) Tietze, L. F. Chem Rev 1996, 96, 115; (b) Ivanov, A. S.
Chem Soc Rev 2008, 37, 789; (c) Padwa, A. Chem Soc Rev 2009, 38,
3072.
[2] (a) Jiang, B.; Li, C.; Shi, F.; Tu, S. J.; Kaur, P.; Wever, W.; Li,
G. J Org Chem 2010, 75, 2962; (b) Jiang, B.; Hao, W. J.; Zhang, J. P.; Tu,
S. J.; Shi, F. Org Biomol Chem 2009, 7, 1171; (c) Jiang, B.; Tu, S. J.;
Kaur, P.; Wever, W.; Li, G. J Am Chem Soc 2009, 131, 11660; (d) Jiang,
B.; Wang, X.; Shi, F.; Tu, S. J.; Ai, T.; Ballew, A.; Li, G. J Org Chem
2009, 74, 9486; (e) Tu, S. J.; Jiang, B.; Jia, R. H.; Zhang, J. Y.; Zhang,
Y.; Yao, C. S.; Shi, F. Org Biomol Chem 2006, 4, 3664.
[3] (a) Dwivedi, C.; Gupta, T. K.; Parmar, S. S. J Med Chem
1972, 15, 553; (b) Parmar, S. S.; Dwivedi, C.; Chaudhari, A.; Gupta, T.
K. J Med Chem 1972, 15, 99.
[4] (a) Rawal, R. K.; Tripathi, R.; Katti, S. B.; Pannecouque, C.;
De Clercq, E. Bioorg Med Chem 2007, 15, 3134; (b) Rawal, R. K.;
Tripathi, R.; Katti, S. B.; Pannecouque, C.; De Clercq, E. Eur J Med Chem
2008, 43, 2800.
[5] Omar, K.; Geronikaki, A.; Zoumpoulakis, P.; Camoutsis, C.;
Sokovic, M.; Ciric, A.; Glamoclija, J. Bioorg Med Chem 2010, 18, 426.
[6] Vicini, P.; Geronikaki, A.; Anastasia, K.; Incerti, M.; Zani, F.
Bioorg Med Chem 2006, 14, 3859.
4-(4(1H-1,2,4-Triazol-1-yl)phenyl)-1-thia-4-azaspiro[4.5]-
decan-3-one (6b). Light brown solid; m.p. 132ꢀC. IR (CHCl3):
υ = 1681, 1607, 1521, 1450, 1380, 1335, 1278, 1216, 1145, 1050,
1
1011, 982, 954, 843, 794, 754, 674 cmÀ1; H NMR (400 MHz,
CDCl3): d = 8.58 (s, 1H, ArH), 8.13 (s, 1H, ArH), 7.78 (dd, J1 =
6.64 Hz, J2 = 2.06 Hz, 2H, ArH), 7.32 (dd, J1 = 6.64 Hz, J2 =
2.06 Hz, 2H, ArH), 3.70 (s, 2H, CH2), 2.03–2.01 (m, 2H,
cyclohexane), 1.77–1.59 (m, 8H, cyclohexane) ppm; MS (ESI):
m/z 315 [M+H]+.
4-(4-(1H-Imidazol-1-yl)phenyl)-1-thia-4-azaspiro[4.5]decan-
3-one (6c). Gummy brown matter; IR (CHCl3): υ = 1677, 1605,
1542, 1521, 1449, 1382, 1335, 1305, 1247, 1128, 1057, 1011,
963, 904, 842, 752, 659, 622 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d = 7.87 (d, J = 0.69 Hz, 1H, ArH), 7.49 (s, 1H, ArH),
7.47 (s, 1H, ArH), 7.30–7.28 (m, 3H, ArH), 7.23 (d, J = 0.92,
[7] (a) Vigorita, M. G.; Ottana, R.; Monforte, F.; Maccari, R.;
Monforte, M. T.; Trovato, A.; Taviano, M. F.; Miceli, N.; De Luca, G.;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Three-Component Domino Reaction in PPG: An Easy Access to
4-Thiazolidinone Derivatives
633
Alcaro, S.; Ortuso, F. Bioorg Med Chem 2003, 11, 999; (b) Previtera, T.;
Vigorita, M. G.; Basile, M.; Fenech, G.; Trovato, A.; Occhiuto, F.;
Monforte, M. T.; Barbera, R. Eur J Med Chem 1990, 25,569.
[8] Srinivas, A.; Nagaraj, A.; Reddy, C. S. Eur J Med Chem 2010,
45, 2353.
[9] Bolognese, A.; Correale, G.; Manfra, M.; Lavecchia, A.;
Novellino, E.; Barone, V. Org Biomol Chem 2004, 2, 2809.
[10] (a) Holmes, C. P.; Chinn, J. P.; Look, G. C.; Gordon, E. M.;
Gallop, M. A. J Org Chem 1995, 60, 7328; (b) Tierney, J. J Heterocycl
Chem 1989, 26, 997; (c) Surrey, A. R. J Am Chem Soc 1947, 69, 2911;
(d) Fadda, A. A. Ind J Chem 1991, 30B, 834; (e) Ma, H.; Hou, Y.; Bai,
Y.; Lu, J.; Yang, B. J Organomet Chem 2001, 637, 742.
[12] Srivastava, T.; Haq, W.; Katti, S. B. Tetrahedron 2002, 58,
7619.
[13] Rawal, R. K.; Srivastava, T.; Haq, W.; Katti, S. B. J Chem Res
2004, 5, 368.
[14] Srivastava, S. K.; Srivastava, S. L.; Srivastava, S. D. J Ind
Chem Soc 2000, 77, 104.
[15] Nagarajan, A. S.; Kamalraj, S.; Muthumary, J.; Reddy, B. S. R.
Ind J Chem 2009, 48B, 1577.
[16] Lingampalle, D.; Jawale, D.; Waghware, R.; Mane, R. Synth
Commun 2010, 40, 2397.
[17] Tsou, H. R.; Otteng, M.; Tran, T.; Junior, M. B. F.; Reich, M.;
Birnberg, G.; Kutterer, K.; Ayral-Kaloustian, S.; Ravi, M.; Nilakantan, R.;
Grillo, M.; McGinnis, J. P.; Rabindran, S. K. J Med Chem 2008, 51, 3507.
[11] Sharma, R. C.; Kumar, D. J Ind Chem Soc 2000, 77, 492.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet