One-pot synthesis of 2-isopropyl-3-benzyl-1,3-thiazolidin-4-ones and 2-phenyl-3-isobutyl-1,3-thiazolidin-4-ones from valine, arenealdehydes and mercaptoacetic acid

Article abstract of DOI:10.1016/j.tetlet.2007.06.101

A three-component one-pot synthesis of 2-isopropyl-3-benzyl-1,3-thiazolidin-4-ones and 2-phenyl-3-isobutyl-1,3-thiazolidin-4-ones from valine, arenealdehydes and mercaptoacetic acid with good yields is reported. Characterization of products was generally achieved by NMR techniques and specifically for 2-isopropyl-3-(4-nitrobenzyl)-1,3-thiazolidin-4-one by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2007.06.101

Tetrahedron Letters 48 (2007) 6217–6220
One-pot synthesis of 2-isopropyl-3-benzyl-1,3-thiazolidin-4-ones
and 2-phenyl-3-isobutyl-1,3-thiazolidin-4-ones from valine,
arenealdehydes and mercaptoacetic acid
Wilson Cunico,* Claudia R. B. Gomes, Maria de Lourdes G. Ferreira, Liliane R. Capri,
Marcio Soares and Solange M. S. V. Wardell
FioCruz—Fundac¸a˜o Oswaldo Cruz, Instituto de Tecnologia em Fa´rmacos, FarManguinhos. R. Sizenando Nabuco,
100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil
Received 14 March 2007; revised 15 June 2007; accepted 18 June 2007
Available online 24 June 2007
Abstract—A three-component one-pot synthesis of 2-isopropyl-3-benzyl-1,3-thiazolidin-4-ones and 2-phenyl-3-isobutyl-1,3-thiazol-
idin-4-ones from valine, arenealdehydes and mercaptoacetic acid with good yields is reported. Characterization of products was
generally achieved by NMR techniques and specifically for 2-isopropyl-3-(4-nitrobenzyl)-1,3-thiazolidin-4-one by X-ray
crystallography.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Thiazolidinones and their derivatives are an important
group of heterocyclic compounds, having valuable bio-
logical activities in the areas of medicine and agricul-
ture.1 They have found uses, for example, as
insecticides, tuberculostatic,2 anti-inflammatory3 and
antiviral agents.4 In recent years, 4-thiazolidinones and
4-oxazolidinones are among the most extensively inves-
tigated compounds. While oxazolidinones have emerged
as a new class of antibiotic agents, for example, lizezo-
lid,5,6 1,3-thiazolidin-4-ones have found utility as anti-
HIV agents.4 The biological activity of 1,3-thiazolidin-
4-ones is reported to be associated with their ability to
assume a ‘butterfly-like’ conformation. This provides a
binding mode similar to that provided by other non-
nucleosides reverse transcriptase inhibitors (NNRTIs).7
water. The most common protocol to remove the water
is by azeotropic distillation, but use of chemical dry-
ing agents (scavengers) such as DCC has been
demonstrated.8
The reaction of a (L)-valine ester hydrochloride, an alde-
hyde and mercaptoacetic acid was reported to produce
3-methyl-[2-alkyl(aryl)-4-oxathiazolinin-3-yl]-butanoic
acids, 1 (Fig. 1), in a two-step process, after hydrolysis.9
Such reactions have also been carried out using micro-
wave radiation.10 Recently, we attempted to synthesize
similar heterocycles directly from (L)-valine in a one-step
reaction; however, our products were not the expected
compounds 1, but instead were the non-chiral 2-aryl-3-
benzyl-1,3-thiazolidin-4-ones 2 (Fig. 1).11
The main synthetic routes to 1,3-thiazolidin-4-ones in-
volve three components (an aldehyde, an amine and
mercaptoacetic acid), either in a one- or a two-step pro-
cess.1 The reactions proceed by initial formation of an
imine, which undergoes attack by the sulfur nucleophile,
followed by intramolecular cyclization on elimination of
O
O
O
R
HO
N
S
N
S
2
1
R
R
Keywords: 4-Thiazolidinone; Heterocycles; Valine; One-pot reaction;
Cycloaddition.
*
Figure 1. 3-Methyl-2-(2-aryl-4-oxothiazolinin-3-yl)butanoic acids
and 2-aryl-3-benzyl-1,3-thiazolidin-4-ones 2.
1
Corresponding author. Tel.: +55 2139772463; e-mail: wjcunico@
far.fiocruz.br
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.101

6218
W. Cunico et al. / Tetrahedron Letters 48 (2007) 6217–6220
O
O
O
O
N
S
NH
2
R
i
HO
H
+
N
S
R
+
R
4a-j
3a-j
5a, 5c, 5e-j
HSCH2COOH
Scheme 1. Reagents and conditions: (i) toluene, 110 ꢁC, 16 h, Dean-Stark.
We have subsequently investigated this reaction in more
detail and observed the formation of different and new
1,3-thiazolidinone compounds when the reactions are
carried out in 1:1:3 mole ratio of valine–arenealde-
hyde–mercaptoacetic acid in order to minimize the for-
mation of heterocycle type 2 (Scheme 1).
5j, (40% yield) and only 27% of 2-isopropyl-3-(4-meth-
oxybenzyl)-1,3-thiazolidin-4-one 4j (Table 1, entry 10).
We also identified the presence of 2-(4-methoxyphen-
yl)-1,3-oxathiol-4-one and 2-(4-methoxyphenyl)-3-(4-
methoxybenzyl)-1,3-thiazolidin-4-ones (heterocycle type
2) in small concentrations. Corresponding products
were obtained with other substituted arenealdehydes,
with the 4:5 product ratios dependent on the particular
substituent, see Table 1.
Refluxing a mixture of 4-nitrobenzaldehyde 3d, valine
and mercaptoacetic acid in toluene for 16 h, with azeo-
tropic removal of water, led to the formation of two
new thiazolidinone compounds, 2-isopropyl-3-(4-nitro-
benzyl)-1,3-thiazolidin-4-one 4d (92%) and 2-(4-nitro-
phenyl)-3-isobutyl-1,3-thiazolidin-4-one 5d (3%) (Table
1, entry 4), as well as 2-(4-nitrophenyl)-1,3-oxathiol-4-
one ring (5%), the latter formed from reaction of mer-
captoacetic acid solely with 4-nitrobenzaldehyde.11,12
The same result was found when 2-nitrobenzaldehyde
3b was used as a precursor (entry 2).
Separation of each 4/5 product pair was difficult due to
retention times in chromatography. Thus, only limited
quantities of very pure compounds were obtained. How-
ever, these quantities were sufficient for general charac-
terization by 1D and 2D NMR techniques, and in the
case of compound 4d by single crystal X-ray
crystallography.
The atom arrangements with selected geometric para-
meters are shown in Figure 2.14 The 2-isopropyl-3-(4-
nitrobenzyl)-1,3-thiazolidin-4-one 4d is best described
as having a twisted conformation [on S1–C2] from the
Cremer and Pople puckering analysis.15 The overall
molecule is far from planar with the angle between the
best planes of the thiazolidin-4-one and phenyl rings
being 75.25 (0.05)ꢁ. No classical hydrogen bonds are
found in the structure.
Similar results were obtained using the same ratio of re-
agents in a two-step procedure, in which mercaptoacetic
acid was added to a pre-refluxed (4 h) mixture of 4-
nitrobenzaldehyde 3d and valine in toluene, with further
heating for 12 h. When the reaction was carried out at
low temperature, large quantities of the starting materi-
als were recovered, as well as a low yield of 2-(4-nitro-
phenyl)-1,3-oxathiol-4-one.12
To gain further insight into the reaction, other
substituted arenealdehydes were used. Thus from 4-
methoxybenzaldehyde 3j, the products obtained were
2-(4-methoxyphenyl)-3-isobutyl-1,3-thiazolidin-4-one
A possible mechanism is outlined in Scheme 2. Initial
reaction of valine with arenealdehyde produces imine
I, which at the reflux temperature is decarboxylated to
an equilibriating pair of imines, II and III. When the
Table 1. Yields, melting points and GC-analysis of compounds 4 and 5
Entry
R
Mpa (ꢁC)
Yield (%) mixtureb
GC-analysis13
4
5
4
5
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
H
90–92
Oil
Oil
Oil
Oil
Oil
Oil
Oil
Oil
Oil
Oil
76
83
68
89
74
71
76
64
69
72
35
77
73
92
65
40
34
27
34
27
27
—
12
3
12
25
32
36
28
40
2-NO2
3-NO2
4-NO2
2-F
3-F
4-F
2-OMe
3-OMe
4-OMe
116–118
110–112
119–121
96–97
80–82
90–92
100–101
120–123
115–117
g
h
i
10
j
a Melting points are uncorrected.
b Isolated mixture.

W. Cunico et al. / Tetrahedron Letters 48 (2007) 6217–6220
6219
˚
Figure 2. Molecular structure and selected geometric parameters, (A, ꢁ), for compound 4d. Ellipsoids, for non-hydrogen atoms, are drawn at the 50%
probability level: H atoms are drawn as arbitrary spheres.
O
O
N
H
N
H
N
H
O
O
H
NH2
Ar
-
CO2
HO
-H2O
Ar
H
+
Ar
Ar
H
Imine III
Imine II
Imine I
O
OH
N
H
HS
N
S
O
Ar
Ar
route A
H
Imine II
2-isopropyl-3-benzyl-1,3-thiazolidin-4-one
O
OH
N
H
HS
N
S
O
route B
Ar
Ar
2-phenyl-3-isobutyl-1,3-thiazolidin-4-one
Imine III
Scheme 2. Mechanism of the formation of thiazolidinones 4 and 5.
mercaptoacetic acid reacts with imine II, thiazolidinones
of type 4 are formed (route A), whereas reaction with
imine III produces the type 5 thiazolidinones (route B).
were determined on a Buchi Melting Point B-545 and
are uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker DRX 400 spectrometer (1H at
400.14 MHz and 13C at 100.61 MHz) and on a Bruker
Avance 500 spectrometer (1H at 500.13 MHz and 13C
at 125.75 MHz) in CDCl3 containing TMS as an inter-
nal standard. HPLC analyses were performed on a
LACHROM—Hitachi (injector: L-7250; detector:
L-7455; pump: L-7100). GC/MS analyses were per-
formed on a GC: 6890N Network GC System Agilent;
MS: 5973N Mass detector; Injector: 7683 Series injector.
In conclusion, novel thiazolidinones heterocycles were
formed from valine, arenealdehydes and mercaptoacetic
acid in good yields. The strong withdrawing group,
NO2, present on benzaldehydes, promotes the selective
formation of heterocycle 4 in good yields, whereas the
methoxy and fluoro groups do not show good selectiv-
ity. The study of this reaction with different amino acids
is ongoing.
General procedure: A mixture of valine (5 mmol), arene-
aldehyde (5 mmol) and mercaptoacetic acid (15 mmol)
in toluene (50 ml) was heated at 130 ꢁC with a Dean-
Stark trap until the reaction was complete, as shown
Unless otherwise indicated, all common reagents and
solvents were used as obtained from commercial suppli-
ers without further purification. All melting points

6220
W. Cunico et al. / Tetrahedron Letters 48 (2007) 6217–6220
A.; Chimirri, A.; De Clercq, E.; Monforte, A. M.;
by GC (about 16 h). The organic layer was separated,
washed with saturated NaHCO3 (3 · 100 ml), dried with
MgSO4 and concentrated to give an oil. The oil was
purified by column chromatography on silica gel using
hexane–ethyl acetate as eluent (9:1) to give a mixture
of compounds 4 and 5. The mixture of 4 and 5
(60 mg) was dissolved in 12 ml of water–acetonitrile
(4:6) and injected in 1.0 ml aliquots into the HPLC
preparative column (SHIM-PACK C8 Shimadzu,
250 mm · 20 mm).
`
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Acknowledgements
The authors thank FarManguinhos for the financial
support of the research and thank the EPSRC X-ray
Crystallographic Service, University of Southampton,
England, for the data collections.
9. Homes, C. P.; Chinn, J. P.; Look, C. G.; Gordon, E. M.;
Gallop, M. A. J. Org. Chem. 1995, 60, 7328.
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Wardell, S. M. S. V. Synthesis 2006, 3405.
Supplementary data
12. Satsumabayashi, S.; Irioka, S.; Kudo, H.; Tsujimoto, K.;
Motoki, S. Bull. Chem. Soc. Jpn. 1972, 45, 913.
13. GC-14B Shimadzu, HP-1 (Crosslinked Methyl Siloxane):
Film thickness: 0.25 mm; length: 30 m; phase ratio: 320;
Column ID: 0.32 mm. Program: T0 = 50 ꢁC; t0 = 2.0 min;
rate 16.0 ꢁC/min; Tf = 250 ꢁC; tf = 10.0 min; Inj. =
250 ꢁC; Det. = 270 ꢁC.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
06.101.
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formula C13H16N2O3S; formula weight 280.34;
˚
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˚
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