Carbodiimide mediated synthesis of 4-thiazolidinones by one-pot three-component condensation

Article abstract of DOI:10.1016/S0040-4020(02)00866-9

In the present study, 4-thiazolidinones have been assembled by DCC mediated three-component reaction of amine, aldehyde and mercaptoacetic acid. The final compounds are obtained in quantitative yields within one hour.

Full text of DOI:10.1016/S0040-4020(02)00866-9

Tetrahedron 58 (2002) 7619–7624
Carbodiimide mediated synthesis of 4-thiazolidinones by one-pot
three-component condensation
*
Tumul Srivastava, W. Haq and S. B. Katti
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 22 April 2002; revised 24 June 2002; accepted 18 July 2002
Abstract—In the present study, 4-thiazolidinones have been assembled by DCC mediated three-component reaction of amine, aldehyde and
mercaptoacetic acid. The final compounds are obtained in quantitative yields within one hour. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
difficulties we have chosen a radically different approach to
generate 4-thiazolodinone scaffolds by simpler methods in
quantitative yields. The protocol is ideally suited for the
synthesis of a thiazolidinone library.
The structural and therapeutic diversity coupled with
commercial viability of small heterocyclic molecules has
fascinated organic and medicinal chemists. In recent years,
4-thiazolidinones and oxazolidinones are the most exten-
sively investigated class of compounds. While oxazolidi-
nones are emerging as new class of antibiotics represented
by Linezolid,1 4-thiazolidinones have many interesting
activity profiles namely COX-1 inhibitors,2 inhibitors of
the bacterial enzyme MurB,3 non-nucleoside inhibitors of
HIV-RT4 and anti-histaminic agents.5 Consequently, many
different protocols have been developed that allow the
synthesis of 4-thiazolidinone skeletons. These methods
employ a one-pot three-component condensation or a two
step synthesis.6 The reaction is believed to proceed via
imine formation in the first step followed by attack of sulfur
nucleophile on the imine carbon and finally intramolecular
cyclization with the elimination of water. The latter step
seems to be critical for obtaining high yields of 4-thiazo-
lidinones. Therefore, variations have been made in the
removal of water during the cyclization. Most commonly
followed protocols7 use either azeotropic distillation or
molecular sieves. In addition, there are scattered reports of
A variety of desiccants namely, trimethylorthoformate,
molecular sieves, sodium sulphate and azeotropic distil-
lation have been reported in the literature for the preparation
of thiazolidinones. It is generally believed that the first
step in the annulation is addition of sulfur nucleophile to
the imine centre followed by attack of the nitrogen on the
carboxylic moiety with the expulsion of water giving
the cyclized product. The rate-limiting step appears to be
the attack of the amine nitrogen at the carbonyl carbon.
If this could be enhanced, one could rapidly obtain the
thiazolidinones in high yields. Bearing this in mind we
surmised that carbodiimides, which are extensively used in
peptide synthesis for dehydration leading to peptide bond
formation,10 could be an ideal candidate to activate the
carboxyl group of the adduct obtained by the sulfur addition
to the imine thereby facilitating cyclization.
2. Result and discussion
using anhydrous ZnCl2 or sodium sulphate9 as desiccant.
8
In all the above-mentioned methods, the reaction requires
prolonged heating at high temperatures (70–808C) for
nearly 17–20 h. Alternatively, reaction is performed in
sealed vessels at 708C using molecular sieves.7 These
protocols tend to be limited by yields ranging from
moderate to very good depending on the reactants.
Secondly, it is desirable to avoid the use of another solid
component like molecular sieves and/or ZnCl2 particularly
in solid phase synthesis. In order to circumvent these
A pilot experiment using benzylamine, benzaldehyde and
mercaptoacetic acid proceeded uneventfully and the product
was isolated in quantitative yield after work up. To optimize
the ratios of reactants, experiments were carried out using
different proportions of the reactants. It was observed that
the ratios of reactants at 1:2:3 for amine, aldehyde and
mercapto acetic acid, respectively gave almost quantitative
yields. This is in agreement with the earlier observation by
the Holmes et al.7 In a typical experiment, amine and
aldehyde are stirred in THF under ice cooling for 5 min,
followed by addition of mercaptoacetic acid and DCC and
the reaction mixture is stirred for an additional 55 min. The
DCU, which was precipitated, was removed by filtration and
Keywords: thiazolidinones; metathiazanones; carbodiimide.
*
Corresponding author. Fax: þ91-522-223405;
e-mail: setu_katti@yahoo.com
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00866-9

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T. Srivastava et al. / Tetrahedron 58 (2002) 7619–7624
Scheme 1. Synthesis of 4-thiazolidinone and 4-metathiazanone derivatives.
the usual work-up gave the desired products in almost
quantitative yields. We have observed that addition of DCC
in ice cold conditions gives better yields as compared with
the reaction carried out at ambient temperature.
presented in Table 1 underscores the efficiency of the
present method and the yields of the thiazolidinones are
independent of the nature of the amine and aldehyde
component. As an obvious extension of this protocol, we
performed the reaction using a ketone (2f) instead of an
aldehyde. We obtained the corresponding thiazolidinone in
nearly quantitative yield (entries 5a,b, Table 1). This is a
significant development considering the fact that there are
few reports in the literature for making thiazolidinones
using ketones. Generally low yields of thiazolidinones are
reported in the literature when amino acids are used as a
source of amine,7 however it may be appropriate to mention
here that with present protocol moderate yields were
obtained. Bearing in mind the versatility of the protocol
and to further enhance the scope of this reaction we
concentrated our efforts on adaptation to synthesis of
metathiazanones, another biologically active chromophore.
Until recently one of the compounds in this series, namely
Chlormezanone,11 was used as skeletal muscle relaxant. The
yields are better (entries 6a–d, Table 1) than the reported
Encouraged by this result and to gain more insight into the
reaction we have synthesized a variety of 4-thiazolidinones
with different amines and aldehydes (Scheme 1). It has been
observed that sterically hindered and aromatic amines react
sluggishly during cyclization, leading to poor yields. In
order to avert these shortcomings, sterically hindered
amines including amino acids were examined (Table 1).
The results obtained were excellent (entries 4f,g,q–v, 6c,d,
Table 1). We next turned our attention to address the scope
and limitation of the present protocol. We concentrated on
aldehydes having electron donating (2c) and electron
withdrawing (2b, 2e) substituents. It is evident from the
yields reported in Table 1 (entries 4b,c,e,m,n) that the
present method obviates the limitations of the earlier
methods and is more versatile. Furthermore, the data
Table 1. Isolated yields and FAB-MS data of 4-thiazolidinones and 4-Metathiazanones
Product
1
2
3
% Yield
FABMS [MþH]þ
Product
1
2
3
% Yield
FABMS [MþH]þ
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1c
1d
1d
1e
2a
2b
2c
2d
2e
2a
2b
2a
2b
2c
2d
2a
2b
2c
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
78
86
88
86
95
91
94
60
95
63
54
95
90
94
270
304
300
320
295
256
290
262
296
292
312
236
270
322
4o
4p
4q
4r
4s
1e
1e
1f
1f
1f
2d
2e
2a
2b
2c
2d
2a
2b
2f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
85
82
65
84
59
66
67
65
95
87
92
90
51
52
342
317
222
256
252
272
342
376
262
284
284
334
356
386
4t
1f
4u
4v
5a
5b
6a
6b
6c
6d
1g
1g
1a
1e
1a
1a
1g
1g
2f
2a
2d
2a
2c

T. Srivastava et al. / Tetrahedron 58 (2002) 7619–7624
7621
procedures.7,11 It is apparent from the variety of reactants
mentioned in the table that the present method has the
potential to generate a battery of thiazolidinones and
metathiazanones by solution as well as solid phase
combinatorial synthesis.
(2C), 129.51 (2C), 129.16 (2C), 128.81 (2C), 127.57 (2C),
63.17, 46.66, 33.37; FAB-MS m/z 270 [MþH]þ.
3.1.2. 3-Benzyl-2-(4-chlorophenyl)-1,3-thiazolidin-4-one
(4b). This compound was obtained as gummy matter in 86%
yield; Anal. Calcd for C16H14ClNOS: C, 63.25; H, 4.64; N,
4.61. Found: C, 63.65; H, 4.87; N, 4.71; Rf 0.57; IR (neat)
In summary, the straightforward protocol described here has
many unique features and should be of general interest for
the following reasons. Reaction conditions are extremely
simple. The products are obtained in quantitative yields and
amenable to scale-up operations. The yields of the
thiazolidinones are independent of the nature of the
reactants.
1
nmax CvO 1677 cm21; H NMR (CDCl3) d 3.53 (d, J¼
14.7 Hz, 1H, CH2Ph), 3.76 (d, J¼15.6 Hz, 1H, CH2), 3.91
(d, J¼15.6 Hz, 1H, CH2), 5.15 (d, J¼14.7 Hz, 1H, CH2Ph),
5.36 (s, 1H, CH ), 7.05–8.04 (m, 9H, Ar); 13C NMR
(50 MHz, CDCl3) d 171.51, 138.14, 135.52, 135.45, 129.72
(2C), 129.22 (2C), 129.01 (2C), 128.76 (2C), 128.41, 62.52,
46.73, 33.33; FAB-MS m/z 304 [MþH]þ.
3.1.3. 3-Benzyl-2-(2-methoxyphenyl)-1,3-thiazolidin-4-
one (4c). This compound was obtained as gummy matter
in 88% yield; Anal. Calcd for C17H17NO2S: C, 68.20; H,
5.72; N, 4.68. Found: C, 68.48; H, 5.84; N, 4.38; Rf 0.41; IR
(neat) nmax CvO 1672 cm21; 1H NMR (CDCl3) d 3.63 (d,
J¼14.8 Hz, 1H, CH2Ph), 3.75 (d, J¼15.7 Hz, 1H, CH2),
3.79 (s, 3H, OCH3), 3.83 (d, J¼15.7 Hz, 1H, CH2), 5.15 (d,
J¼14.8 Hz, 1H, CH2Ph), 5.75 (s, 1H, CH ), 6.88–7.32 (m,
9H, Ar); 13C NMR (50 MHz, CDCl3) d 171.98, 157.11,
135.65, 129.94, 128.62 (2C), 128.25 (2C), 127.72, 127.38,
126.96, 120.87, 111.20, 57.85, 55.54, 46.54, 32.79;
FAB-MS m/z 300 [MþH]þ.
3. Experimental
Melting points (mp) were determined on a Complab melting
point apparatus and are uncorrected. The C, H, N analyses
were carried out on CARLO-ERBA EA1108 elemental
analyser. Thin-layer chromatography (tlc) was performed
on readymade silica gel plates (Merck) using ethyl acetate–
hexane (4:6) as solvent system. Iodine was used as
developing reagent. Infrared (IR) spectra were recorded
1
on an FT-IR Perkin–Elmer spectrometer. The H spectra
were recorded on a DPX-200 Bruker FT-NMR spectro-
meter. The chemical shifts were reported as parts per
million (d ppm) from (CH3)4Si (TMS) as an internal
standard. The 13C NMR spectra were recorded on a
DPX-200 Bruker FT-NMR (50 MHz) spectrometer. Mass
spectra were obtained on a JEOL-SX-102 instrument using
fast atom bombardment (FAB positive). Column chroma-
tography separations were obtained on silica gel (230–400
mesh).
3.1.4. 3-Benzyl-2-(1-naphthyl)-1,3-thiazolidin-4-one
(4d). This compound was obtained as gummy matter in
86% yield; Anal. Calcd for C20H17NOS: C, 75.20; H, 5.36;
N, 4.39. Found: C, 74.94; H, 5.41; N, 4.28; Rf 0.20; IR (neat)
1
nmax CvO 1674 cm21; H NMR (CDCl3) d 3.63 (d, J¼
15.2 Hz, 1H, CH2Ph), 3.77 (d, J¼15.9 Hz, 1H, CH2), 3.89
(d, J¼15.9 Hz, 1H, CH2), 5.33 (d, J¼15.2 Hz, 1H, CH2Ph),
6.15 (s, 1H, CH ), 7.10–7.94 (m, 12H, Ar); 13C NMR
(50 MHz, CDCl3) d 172.36, 135.78, 134.68, 130.0, 129.65,
129.21 (2C), 128.75 (2C), 128.38, 127.23, 127.02, 126.63,
125.82, 124.39 (2C), 122.44, 63.44, 47.27, 33.18; FAB-MS
m/z 320 [MþH]þ.
3.1. Reaction of primary amines (or amino acid esters)
and aldehydes with mercaptoacetic acid
The appropriate amine or amino acid ester (1.0 mmol) and
aldehyde (2.0 mmol) were stirred in THF under ice cold
conditions for 5 min, followed by addition of mercapto-
acetic acid (3.0 mmol). After 5 min DCC (1.2 mmol) was
added to the reaction mixture at 08C and the reaction
mixture stirred for an additional 50 min at room temp. DCU
was removed by filtration and the filtrate was concentrated
to dryness under reduced pressure and the residue was taken
up in ethyl acetate. The organic layer was successively
washed with 5% aq. citric acid, water, 5% aq. sodium
hydrogen carbonate and then finally with brine. The organic
layer was dried over sodium sulphate and solvent was
removed under reduced pressure to get a crude product that
was purified by column chromatography on silica gel using
hexane–ethyl acetate as eluent.
3.1.5. 4-[(3-Benzyl)-4-oxo-1,3-thiazolidin-2-yl] benzo-
nitrile (4e). This compound was obtained as gummy matter
in 95% yield; Anal. Calcd for C17H14N2OS: C, 69.36; H,
4.79; N, 9.52. Found: C, 69.28; H, 5.04; N, 9.38; Rf 0.46; IR
(neat) nmax CvO 1680 cm21; 1H NMR (CDCl3) d 3.57 (d,
J¼14.8 Hz, 1H, CH2Ph), 3.77 (d, J¼15.7 Hz, 1H, CH2),
3.92 (d, J¼15.7 Hz, 1H, CH2), 5.15 (d, J¼14.8 Hz, 1H,
CH2Ph), 5.40 (s, 1H, CH ), 7.06–8.01 (m, 9H, Ar); FAB-MS
m/z 295 [MþH]þ.
3.1.6. 2,3-Diphenyl-1,3-thiazolidin-4-one (4f). This com-
pound was obtained as gummy matter in 91% yield; Anal.
Calcd for C15H13NOS: C, 70.56; H, 5.13; N, 5.49. Found: C,
70.87; H, 5.31; N, 5.38; Rf 0.63; IR (neat) nmax CvO
3.1.1. 3-Benzyl-2-phenyl-1,3-thiazolidin-4-one (4a). This
compound was obtained as white solid in 78% yield. mp
152–1558C; Anal. Calcd for C16H15NOS: C, 71.34; H, 5.61;
N, 5.20 Found: C, 71.80; H, 5.38; N, 4.91; Rf 0.57; IR (KBr)
1
1672 cm21; H NMR (CDCl3) d 3.86 (d, J¼15.7 Hz, 1H,
CH2), 4.0 (d, J¼15.7 Hz, 1H, CH2), 6.09 (s, 1H, CH), 7.14–
7.38 (m, 10H, Ar); 13C NMR (50 MHz, CDCl3) d 171.42,
140.01, 138.01, 129.46 (2C), 129.27 (4C), 127.34 (2C),
126.0 (2C), 66.03, 33.85; FAB-MS m/z 256 [MþH]þ.
n
max CvO 1672 cm21; 1H NMR (200 MHz, CDCl3) d 3.54
(d, J¼14.7 Hz, 1H, CH2Ph), 3.75 (d, J¼15.6 Hz, 1H, CH2),
3.91 (d, J¼15.6 Hz, 1H, CH2), 5.16 (d, J¼14.7 Hz, 1H,
CH2Ph), 5.39 (s, 1H, CH ), 7.08–7.42 (m, 10H, Ar); 13C
NMR (50 MHz, CDCl3) d 171.61, 139.61, 135.76, 129.59
3.1.7. 2-(4-Chlorophenyl)-3-phenyl-1,3-thiazolidin-4-one
(4g). This compound was obtained as white solid in 94%

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T. Srivastava et al. / Tetrahedron 58 (2002) 7619–7624
yield; mp 124–1278C; Anal. Calcd for C15H12ClNOS: C,
62.17; H, 4.17; N, 4.83. Found: C, 61.98; H, 4.33; N, 4.90;
Rf 0.48; IR (KBr) nmax CvO 1678 cm21; 1H NMR (CDCl3)
d 3.87 (d, J¼15.7 Hz, 1H, CH2), 3.98 (d, J¼15.7 Hz, 1H,
CH2), 6.07 (s, 1H, CH ), 7.12–7.34 (m, 9H, Ar); 13C NMR
(50 MHz, CDCl3) d 171.20, 138.47, 137.73, 135.12, 129.59
(2C), 129.50 (2C), 128.81 (2C), 127.61, 126.0 (2C), 65.29,
33.79; FAB-MS m/z 290 [MþH]þ.
Found: C, 66.45; H, 7.39; N, 5.87; Rf 0.65; IR (neat) nmax
1
CvO 1667 cm21; H NMR (CDCl3) d 0.85 (t, J¼7.1 Hz,
3H, CH3C3H6), 1.18–1.46 (m, 4H, CH3(CH2)2CH2), 2.63–
2.68 (m, 2H, C3H7CH2), 3.67 (d, J¼15.5 Hz, 1H, CH2), 3.76
(d, J¼15.5 Hz, 1H, CH2), 5.63 (s, 1H, CH ), 7.26–7.43 (m,
5H, Ar); 13C NMR (50 MHz, CDCl3) d 171.06, 139.60,
130.42, 129.51, 129.44, 128.74, 127.32, 63.51, 42.62, 32.88,
28.74, 19.86, 13.53; FAB-MS m/z 236 [MþH]þ.
3.1.8. 3-Cyclohexyl-2-phenyl-1,3-thiazolidin-4-one (4h).
This compound was obtained as white solid in 60% yield;
mp 118–1218C; Anal. Calcd for C15H19NOS: C, 68.93; H,
7.33; N, 5.36. Found: C, 68.88; H, 7.66; N, 5.49; Rf 0.61;
IR (KBr) nmax CvO 1663 cm21; 1H NMR (CDCl3) d 0.94–
1.27 (m, 6H, cyclohexyl), 1.50–1.76 (m, 4H, cyclohexyl),
3.59 (d, J¼15.5 Hz, 1H, CH2), 3.80–3.87 (m, 1H, cyclo-
hexyl), 3.91 (d, J¼15.5 Hz, 1H, CH2), 5.64 (s, 1H, CH ),
7.21–7.43 (m, 5H, Ar); 13C NMR (50 MHz, CDCl3) d 171.94,
143.20, 129.27 (2C), 129.07, 126.55 (2C), 62.98, 56.43, 33.46,
31.25, 30.34, 26.29 (2C), 25.62; FAB-MS m/z 262 [MþH]þ.
3.1.13. 3-Butyl-2-(4-chlorophenyl)-1,3-thiazolidin-4-one
(4m). This compound was obtained as gummy matter in
90% yield; Anal. Calcd for C13H16ClNOS: C, 57.87; H,
5.98; N, 5.19. Found: C, 57.53; H, 6.06; N, 4.81; Rf 0.23;
IR (neat) nmax CvO 1674 cm21 1H NMR (CDCl3) d
;
0.86 (t, J¼7.1 Hz, 3H, CH3C3H6), 1.19–1.45 (m, 4H,
CH3(CH2)2CH2), 2.62–2.66 (m, 2H, C3H7CH2), 3.68 (d,
J¼15.5 Hz, 1H, CH2), 3.83 (d, J¼15.5 Hz, 1H, CH2), 5.60
(s, 1H, CH), 7.22–7.85 (m, 4H, Ar); 13C NMR (50 MHz,
CDCl3) d 171.36, 138.67, 135.34, 129.69 (2C), 128.72 (2C),
63.26, 43.08, 33.28, 29.20, 20.33, 14.01; FAB-MS m/z 270
[MþH]þ.
3.1.9. 2-(4-Chlorophenyl)-3-cyclohexyl-1,3-thiazolidin-4-
one (4i). This compound was obtained as crystalline solid in
95% yield; mp 111–1138C; Anal. Calcd for C15H18ClNOS:
C, 60.90; H, 6.13; N, 4.73. Found: C, 60.74; H, 6.05; N,
3.1.14. 2-(2-Methoxyphenyl)-3-octyl-1,3-thiazolidin-4-
one (4n). This compound was obtained as gummy matter
in 94% yield; Anal. Calcd for C18H27NO2S: C, 67.25; H,
8.47; N, 4.36. Found: C, 67.29; H, 8.71; N, 4.37; Rf 0.56;
1
4.83; Rf 0.74; IR (KBr) nmax CvO 1667 cm21; H NMR
(CDCl3) d 0.96–1.28 (m, 6H, cyclohexyl), 1.51–1.79 (m,
4H, cyclohexyl), 3.59 (d, J¼15.5 Hz, 1H, CH2), 3.63–3.84
(m, 1H, cyclohexyl), 3.88 (d, J¼15.5 Hz, 1H, CH2), 5.61 (s,
1H, CH), 7.22–7.40 (m, 4H, Ar); 13C NMR (50 MHz,
CDCl3) d 172.05, 142.10, 135.01, 129.51 (2C), 127.91 (2C),
62.23, 56.44, 33.34, 31.40, 30.37, 26.24 (2C), 25.58; FAB-
MS m/z 296 [MþH]þ.
IR (neat) nmax CvO 1679 cm21 1H NMR (CDCl3) d
;
0.86 (t, J¼6.8 Hz, 3H, CH3C7H14), 1.23–1.47 (m, 12H,
CH3(CH2)6CH2), 2.62–2.67 (m, 2H, C7H15CH2), 3.60 (d,
J¼15.3 Hz, 1H, CH2), 3.75 (d, J¼15.3 Hz, 1H, CH2), 3.87
(s, 3H, OCH3), 5.99 (s, 1H, CH ), 6.89–7.30 (m, 4H, Ar);
13C NMR (50 MHz, CDCl3) d 172.18, 157.30, 130.14,
128.36, 126.89, 121.28, 111.44, 58.19, 55.98, 43.55, 33.08,
32.12, 29.54, 29.47, 27.30, 27.14, 22.97, 14.41; FAB-MS
m/z 322 [MþH]þ.
3.1.10. 3-Cyclohexyl-2-(2-methoxyphenyl)-1,3-thiazoli-
din-4-one (4j). This compound was obtained as gummy
matter in 63% yield; Anal. Calcd for C16H21NO2S: C,
65.95; H, 7.26; N, 4.81. Found: C, 65.58; H, 7.46; N, 4.87;
Rf 0.55, IR (neat) nmax CvO 1670 cm21; 1H NMR (CDCl3)
d 0.90–1.32 (m, 6H, cyclohexyl), 1.57–1.79 (m, 4H,
cyclohexyl), 3.51 (d, J¼15.2 Hz, 1H, CH2), 3.85–3.95 (m,
1H, cyclohexyl), 3.82 (d, J¼15.2 Hz, 1H, CH2), 3.91 (s, 3H,
OCH3), 5.97 (s, 1H, CH ), 6.88–7.28 (m, 4H, Ar); 13C NMR
(50 MHz, CDCl3) d 172.78, 156.94, 131.31, 129.80, 126.73,
121.30, 111.39, 55.85, 33.53, 31.03, 30.56, 30.45, 26.23,
25.78, 25.69, 25.58; FAB-MS m/z 292 [MþH]þ.
3.1.15. 2-Naphthyl-3-octyl-1,3-thiazolidin-4-one (4o).
This compound was obtained as gummy matter in 85%
yield; Anal. Calcd for C21H27NOS: C, 73.86; H, 7.97; N,
4.10. Found: C, 74.01; H, 8.07; N, 3.95; Rf 0.63;
IR (neat) nmax CvO 1680 cm21 1H NMR (CDCl3) d
;
0.85 (t, J¼6.8 Hz, 3H, CH3C7H14), 1.11–1.70 (m, 12H,
CH3(CH2)6CH2), 2.65–2.74 (m, 2H, C7H15CH2), 3.75
(d, J¼15.2 Hz, 1H, CH2), 3.87 (d, J¼15.2 Hz, 1H, CH2),
6.40 (s, 1H, CH ), 7.26–7.94 (m, 7H, Ar); 13C NMR
(50 MHz, CDCl3) d 172.22, 134.66, 130.63, 130.36, 129.69,
127.25, 126.58, 125.75, 123.25, 122.81, 122.46, 44.05,
33.20, 32.81, 32.09, 29.51, 29.45, 27.48, 27.17, 22.96,
14.41; FAB-MS m/z 342 [MþH]þ.
3.1.11. 3-Cyclohexyl-2-(1-naphthyl)-1,3-thiazolidin-4-
one (4k). This compound was obtained as gummy matter
in 54% yield; Anal. Calcd for C19H21NOS: C, 73.27; H,
6.80; N, 4.50. Found: C, 73.74; H, 6.93; N, 4.48; Rf 0.26; IR
3.1.16. 4-(3-Octyl-4-oxo-1,3-thiazolidin-2-yl) benzo-
nitrile (4p). This compound was obtained as gummy matter
in 82% yield; Anal. Calcd for C18H24N2OS: C, 68.32; H,
7.64; N, 8.85. Found: C, 68.44; H, 7.82; N, 8.76; Rf 0.61;
1
(neat) nmax CvO 1670 cm21; H NMR (CDCl3) d 0.90–
1.33 (m, 6H, cyclohexyl), 1.54–2.07 (m, 4H, cyclohexyl),
3.60–3.86 (m, 1H, cyclohexyl), 3.82 (d, J¼15.4 Hz, 1H,
CH2), 3.96 (d, J¼15.4 Hz, 1H, CH2), 6.42 (s, 1H, CH ),
7.25–7.93 (m, 7H, Ar); 13C NMR (50 MHz, CDCl3) d
172.19, 134.57, 129.70 (2C), 129.21, 128.39, 127.20,
126.52, 125.53 (2C), 122.13, 56.23, 33.54, 31.30, 30.66,
26.18 (2C), 25.55 (2C); FAB-MS m/z 312 [MþH]þ.
IR (neat) nmax CvO 1679 cm21 1H NMR (CDCl3) d
;
0.87 (t, J¼6.7 Hz, 3H, CH3C7H14), 1.22–1.68 (m, 12H,
CH3(CH2)6CH2), 2.57–2.64 (m, 2H, C7H15CH2), 3.65 (d,
J¼15.3 Hz, 1H, CH2), 3.80 (d, J¼15.3 Hz, 1H, CH2), 5.64,
(s, 1H, CH), 7.40 (d, J¼8.2 Hz, 2H, Ar), 7.70 (d, J¼8.2 Hz,
2H, Ar); FAB-MS m/z 317 [MþH]þ.
3.1.12. 3-Butyl-2-phenyl-1,3-thiazolidin-4-one (4l). This
compound was obtained as gummy matter in 95% yield;
Anal. Calcd for C13H17NOS: C, 66.34; H, 7.28; N, 5.95.
3.1.17. 3-(Isopropyl)-2-phenyl1,3-thiazolidin-4-one (4q).
This compound was obtained as white solid in 65% yield;

T. Srivastava et al. / Tetrahedron 58 (2002) 7619–7624
7623
mp 99–1028C; Anal. Calcd for C12H15NOS: C, 65.12; H,
6.83; N, 6.33. Found: C, 64.94; H, 6.93; N, 6.49; Rf 0.63; IR
(KBr) nmax CvO 1669 cm21; 1H NMR (CDCl3) d 0.94 (d,
J¼6.9 Hz, 3H, CH3CHCH3), 1.26 (d, J¼6.9 Hz, 3H,
CH3CHCH3), 3.61 (d, J¼15.4 Hz, 1H, CH2), 3.89 (d, J¼
15.4 Hz, 1H, CH2), 4.02–4.16 (m, 1H, CH3CHCH3), 5.63
(s, 1H, CH ), 7.24–7.44 (m, 5H, Ar); 13C NMR (50 MHz,
CDCl3) d 169.67, 140.59, 127.15 (2C), 127.07, 124.72 (2C),
60.93, 46.10, 31.45, 18.59, 17.78; FAB-MS m/z 222 [MþH]þ.
COOCH3), 4.36 (bs, 1H, a-H, Phe), 5.58 (s, 1H, CH ),
6.87–7.38 (m, 9H, Ar); FAB-MS m/z 376 [MþH]þ.
3.2. Reaction of primary amines and cyclohexanone with
mercaptoacetic acid
The appropriate amine (1.0 mmol) and cyclohexanone
(2.0 mmol) were stirred in THF under ice cold conditions
for 5 min, followed by addition of mercaptoacetic acid
(3.0 mmol). After 5 min DCC (1.2 mmol) was added to the
reaction mixture at 08C and the reaction mixture is stirred
for an additional 50 min at room temperature. DCU was
removed by filtration and the filtrate was concentrated to
dryness under reduced pressure and the residue was taken up
in ethyl acetate. The organic layer was successively washed
with 5% aq. citric acid, water, 5% aq. sodium hydrogen
carbonate and then finally with brine. The organic layer was
dried over sodium sulphate and solvent was removed under
reduced pressure to get a crude product that was purified by
column chromatography on silica gel using hexane–ethyl
acetate as eluent.
3.1.18. 2-(4-Chlorophenyl)-3-isopropyl-1,3-thiazolidin-
4-one (4r). This compound was obtained as gummy matter
in 84% yield; Anal. Calcd for C12H14ClNOS: C, 56.35; H,
5.52; N, 5.48. Found: C, 56.57; H, 5.60; N, 5.61; Rf 0.63, IR
(neat) nmax CvO 1673 cm21; 1H NMR (CDCl3) d 0.95 (d,
J¼6.9 Hz, 3H, CH3CHCH3), 1.25 (d, J¼6.9 Hz, 3H,
CH3CHCH3), 3.61 (d, J¼15.5 Hz, 1H, CH2), 3.87 (d, J¼
15.5 Hz, 1H, CH2), 4.02–4.16 (m, 1H, CH3CHCH3), 5.61
(s, 1H, CH ), 7.24–7.43 (m, 4H, Ar); FAB-MS m/z 256
[MþH]þ.
3.1.19. 3-Isopropyl-2-(2-methoxyphenyl)-1,3-thiazolidin-
4-one (4s). This compound was obtained as gummy matter
in 59% yield; Anal. Calcd for C13H17NO2S: C, 62.12; H,
6.82; N, 5.57. Found: C, 62.06; H, 6.85; N, 5.52; Rf 0.55;
3.2.1. 4-Benzyl-1-oxa-4-azaspiro[4.5]decan-3-one (5a).
This compound was obtained as gummy matter in 95%
yield; Anal. Calcd for C15H19NOS: C, 68.93; H, 7.33; N,
5.36. Found: C, 68.63; H, 7.64; N, 5.42; Rf 0.66; IR (neat)
1
IR (neat) nmax CvO 1668 cm21; H NMR (CDCl3) d 0.91
n
max CvO 1673 cm21; 1H NMR (CDCl3) d 1.53–1.72 (m,
(d, J¼6.9 Hz, 3H, CH3CHCH3), 1.26 (d, J¼6.9 Hz, 3H,
CH3CHCH3), 3.52 (d, J¼15.2 Hz, 1H, CH2), 3.84 (d, J¼
15.2 Hz, 1H, CH2), 3.88 (s, 3H, OCH3), 4.17–4.24 (m, 1H,
CH3CHCH3), 5.97 (s, 1H, CH ), 6.87–7.29 (m, 4H, Ar);
FAB-MS m/z 252 [MþH]þ.
10H, cyclohexyl), 3.61 (s, 2H, CH2), 4.57 (s, 2H, CH2Ph),
7.22–7.27 (m, 5H, Ar); 13C NMR (50 MHz, CDCl3) d
172.15, 138.47, 128.91 (2C), 127.60, 127.52 (2C), 74.75,
45.62, 38.77 (2C), 31.75, 24.95, 23.88 (2C); FAB-MS m/z
262 [MþH]þ.
3.1.20. 3-Isopropyl-2-(1-naphthyl)-1,3-thiazolidin-4-one
(4t). This compound was obtained as gummy matter in 66%
yield; Anal. Calcd for C16H17NOS: C, 70.81; H, 6.31; N,
5.16. Found: C, 70.95; H, 6.37; N, 4.92; Rf 0.68; IR (neat)
3.2.2. 4-Octyl-1-oxa-4-azaspiro[4.5]decan-3-one (5b).
This compound was obtained as gummy matter in 87%
yield; Anal. Calcd for C16H29NOS: C, 67.79; H, 10.31;
N, 4.94. Found: C, 67.73; H, 10.55; N, 5.03; Rf 0.66;
1
nmax CvO 1672 cm21; H NMR (CDCl3) d 0.96 (d, J¼
7.2 Hz, 3H, CH3CHCH3), 1.32 (d, J¼7.2 Hz, 3H,
CH3CHCH3), 3.63 (d, J¼15.3 Hz, 1H, CH2), 3.88 (d, J¼
15.3 Hz, 1H, CH2), 4.13–4.24 (m, 1H, CH3CHCH3), 6.41
(s, 1H, CH ), 7.25–7.93 (m, 7H, Ar); FAB-MS m/z 272
[MþH]þ.
IR (neat) nmax CvO 1670 cm21 1H NMR (CDCl3) d
;
0.81 (t, J¼6.6 Hz, 3H, CH3C7H14), 0.99–1.21 (m, 12H,
CH3(CH2)6CH2), 1.50–1.73 (m, 10H, cyclohexyl), 3.08–
3.16 (m, 2H, C7H15CH2), 3.41 (s, 2H, CH2); 13C NMR
(50 MHz, CDCl3) d 171.35, 74.32, 42.92, 38.85, 32.15,
31.78, 29.95, 29.63, 27.64, 26.31, 25.90, 24.96, 23.83,
22.97, 21.80, 14.40; FAB-MS m/z 284 [MþH]þ.
3.1.21. Methyl-2-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)-3-
phenylpropanoate (4u). This compound was obtained as
gummy matter in 67% yield; Anal. Calcd for C19H19NO3S:
C, 66.84; H, 5.61; N, 4.10. Found: C, 66.53; H, 5.50; N,
4.14; Rf 0.54; IR (neat) nmax CvO 1683 and CvO
3.3. Reaction of primary amines (or amino acid esters)
and aldehydes with mercaptopropionic acid
1
1743 cm21; H NMR (CDCl3) d 3.25–3.36 (m, 2H, CH2),
The appropriate amine or amino acid ester (1.0 mmol) and
aldehyde (2.0 mmol) were stirred in THF under ice cold
conditions for 5 min, followed by addition of mercapto-
propionic acid (3.0 mmol). After 5 min DCC (1.2 mmol)
was added to the reaction mixture at 08C and the reaction
mixture is stirred for an additional 50 min at room temp.
DCU was removed by filtration and the filtrate was
concentrated to dryness under reduced pressure and the
residue was taken up in ethyl acetate. The organic layer was
successively washed with 5% aq. citric acid, water, 5% aq.
sodium hydrogen carbonate and then finally with brine. The
organic layer was dried over sodium sulphate and solvent
was removed under reduced pressure to get a crude product
that was purified by column chromatography on silica gel
using hexane–ethyl acetate as eluent.
3.58–3.75 (m, 2H, CH2Ph), 3.73 (s, 3H, COOCH3), 4.42
(bs, 1H, a-H, Phe), 5.63 (s, 1H, CH ), 7.09–7.40 (m, 10H,
Ar); 13C NMR (50 MHz, CDCl3) d 172.85, 169.19, 137.85,
137.18, 129.89, 129.64, 129.33, 129.15, 129.08, 128.91,
128.81, 128.70, 127.61, 127.07, 65.37, 59.14, 52.88, 34.63,
32.91; FAB-MS m/z 342 [MþH]þ.
3.1.22. Methyl-2-[2-(4-chlorophenyl)-4-oxo-1,3-thiazo-
lidin-3-yl]-3-phenylpropanoate (4v). This compound was
obtained as gummy matter in 65% yield; Anal. Calcd for
C19H18ClNO3S: C, 60.71; H, 4.83; N, 3.73. Found: C,
60.49; H, 4.96; N, 3.44; Rf 0.56; IR (neat) nmax CvO 1685
1
and CvO 1744 cm21; H NMR (CDCl3) d 3.26–3.36 (m,
2H, CH2), 3.64–3.70 (m, 2H, CH2Ph), 3.74 (s, 3H,

7624
T. Srivastava et al. / Tetrahedron 58 (2002) 7619–7624
3.3.1. 3-Benzyl-2-phenyl-1,3-thiazinan-4-one (6a). This
compound was obtained as gummy matter in 92% yield;
Anal. Calcd for C17H17NOS: C, 72.05; H, 6.05; N, 4.94.
Found: C, 71.92; H, 6.25; N, 5.07; Rf 0.50; IR (neat) nmax
Acknowledgments
The authors thank the RSIC staff for providing the spectral
data. One of us, T. S. thanks the Department of Bio-
technology, New Delhi for financial assistance in the form
of fellowship. CDRI Communication No. 6261.
1
CvO 1638 cm21; H NMR (CDCl3) d 2.78–2.99 (m, 4H,
CH2CH2), 3.54 (d, J¼15.2 Hz, 1H, CH2Ph), 5.40 (s, 1H,
CH ), 5.76 (d, J¼15.2 Hz, 1H, CH2Ph), 7.20–7.43 (m, 10H,
Ar); 13C NMR (50 MHz, CDCl3) d 169.83, 139.49, 136.70,
129.12 (2C), 128.55 (2C), 128.32 (2C), 127.97 (2C), 126.91
(2C), 61.24, 49.94, 34.96, 22.14; FAB-MS m/z 284
[MþH]þ.
References
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Manninen, M. N.; P, R.; Ulanowicz, D. A.; Garmon, S. A.;
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3.3.2. 3-Benzyl-2-(1-naphthyl)-1,3-thiazinan-4-one (6b).
This compound was obtained as gummy matter in 90%
yield; Anal. Calcd for C21H19NOS: C, 75.64; H, 5.74; N,
4.20. Found: C, 75.48; H, 5.84; N, 4.31; Rf 0.47; IR (neat)
n
max CvO 1633 cm21; 1H NMR (CDCl3) d 2.82–3.05 (m,
4H, CH2CH2), 3.48 (d, J¼15.2 Hz, 1H, CH2Ph), 5.80 (d,
J¼15.2 Hz, 1H, CH2Ph), 6.12 (s, 1H, CH ), 7.18–7.93 (m,
12H, Ar); FAB-MS m/z 334 [MþH]þ.
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3.3.3. Methyl-2-(4-oxo-2-phenyl-1,3-thiazinan-3-yl)-3-
phenylpropanoate (6c). This compound was obtained as
gummy matter in 51% yield; Anal. Calcd for C20H21NO3S:
C, 67.58; H, 5.95; N, 3.94. Found: C, 67.48; H, 5.84; N, 4.18;
4. Barreca, M. L.; Chimirri, A.; Luca, L. D.; Monforte, A.;
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Rf 0.34; IR (neat) nmax CvO 1641 and CvO 1739 cm21
;
1H NMR (CDCl3) d 2.71–2.91 (m, 4H, CH2CH2), 3.12–
3.39 (m, 2H, CH2Ph), 3.30 (s, 3H, COOCH3), 4.71
(t, J¼6.7 Hz, 1H, a-H, Phe), 5.79 (s, 1H, CH ), 7.01–7.37
(m, 10H, Ar); FABMS m/z 356 [MþH]þ.
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Bolognese, A. J. Med. Chem. 1992, 35, 2910–2912.
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3.3.4. Methyl-2-[2-(2-methoxyphenyl)-4-oxo-1,3-thiazi-
nan-3-yl]-3-phenylpropanoate (6d). This compound was
obtained as gummy matter in 52% yield; Anal. Calcd for
C21H23NO4S: C, 65.43; H, 6.01; N, 3.63. Found: C, 65.37;
H, 6.15; N, 3.83; Rf 0.28; IR (neat) nmax CvO 1641.0 and
7. Homes, C. P.; Chinn, J. P.; Look, C. G.; Gordon, E. M.;
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1
CvO 1741 cm21; H NMR (CDCl3) d 2.67–2.87 (m, 4H,
9. Sharma, R. C.; Kumar, D. J. Indian Chem. Soc. 2000, 77,
492–493.
CH2CH2), 3.05–3.38 (m, 2H, CH2Ph), 3.23 (s, 3H,
COOCH3), 3.90 (s, 3H, OCH3), 4.95 (t, J¼6.7 Hz, 1H,
a-H, PheOMe), 6.12 (s, 1H, CH ), 6.87–7.28 (m, 9H, Ar);
FAB-MS m/z 386 [MþH]þ.
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