Saccharomyces cerevisiae catalyzed one-pot three component synthesis of 2,3-diaryl-4-thiazolidinones

Article abstract of DOI:10.1016/j.tetlet.2011.01.143

Saccharomyces cerevisiae (baker's yeast) catalyzed one-pot three component cyclocondensation of aryl aldehydes, amines, and thioglycolic acid in organic medium leading to 2,3-diaryl 4-thiazolidinones has been carried out for the first time.

Full text of DOI:10.1016/j.tetlet.2011.01.143

Tetrahedron Letters 52 (2011) 1689–1691
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Saccharomyces cerevisiae catalyzed one-pot three component synthesis of
2,3-diaryl-4-thiazolidinones
⇑
Umesh R. Pratap, Dhanaji V. Jawale, Manisha R. Bhosle, Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra 431004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Saccharomyces cerevisiae (baker’s yeast) catalyzed one-pot three component cyclocondensation of aryl
aldehydes, amines, and thioglycolic acid in organic medium leading to 2,3-diaryl 4-thiazolidinones has
been carried out for the first time.
Received 2 December 2010
Revised 21 January 2011
Accepted 30 January 2011
Available online 4 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Baker’s yeast
4-Thiazolidinone
Cyclocondensation
Biocatalysis
4-Thiazolidinones are the structural units of biological and
medicinal importance.1 Some of the thiazolidiones are found to
possess interesting biological activities, such as anticancer,2 anti-
HIV,3 antimalarial,4 tuberculostatic,5 antihistaminic,6 anticonvul-
sunt,7 antibacterial8, and antiarrythmic.9 In view of the
biological/pharmacological significance of 4-thiazolidinones con-
siderable synthetic efforts have been made to construct this class
of heterocycles.10
Several synthetic protocols for 4-thiazolidinones are reported in
the literature. One-pot three component cyclocondensation of
carbonyl compounds, amines, and mercaptoacetic acid or its
derivatives has been widely used as a synthetic route for the 4-
thiazolidinones. The above mentioned cyclocondensation can be
either run in one-pot or in two steps with prolonged heating in tol-
uene or benzene.11
While the DCC mediated route has been found to be better the
separation of the byproduct, N,N0-dicyclohexyl urea is tedious.
Therefore, the design of a new method which circumvents these
difficulties is needed.
Whole cell biocatalysis with baker’s yeast (Saccharomyces cere-
visae) is gaining prime importance in synthetic organic chemis-
try22,23 as yeast catalyzes variety of organic transformations.
Baker’s yeast is easily available, cheap and has the ability to accel-
erate the transformations under mild reaction conditions.24,25
Cyclocondensation using biocatalysts has not been explored. Li-
pases and baker’s yeast have the ability to catalyze the cyclocon-
densations leading to bioactive heterocycles, such as
benzimidazoles,26
dihydropyridines,27
dihydropyrimidines,28
polyhydroquinolines,29 benzothiazoles,30 benzotriazoles,31 and
quinoxaline.32 but the role of biocatalysts in the formation of
4-thiazolidinones has not been investigated.
There are reports for accelerating the above cyclocondensation
using catalysts like N,N0-dicyclohexylcarbodiimide (DCC),12 O-
(benzotriazol-yl)-N,N,N0,N0-tetramethyluronium hexafluoro phos-
In view of the useful applications of 4-thiazolidinones and in
continuation of our earlier interest in biocatalysis33 leading to bio-
dynamic heterocycles and 4-thiazolidinones,34,35 we thought it is
worthwhile to use biocatalyst, baker’s yeast in the cyclocondensa-
tion to accelerate the one-pot three component synthesis of 4-
thiazolidinones.
In this Letter we wish to report a three-component one-pot
cyclocondensation of aryl aldehydes, amines, and thioglycolic acid
leading to 4-thiazolidinones employing baker’s yeast as a whole
cell biocatalyst at an ambient temperature in an organic medium.
To optimize the reaction conditions, the condensation of anisal-
dehyde, aniline, and thioglycolic acid was considered as the model
reaction.
phate (HBTU),13 ferrite,14 ZnCl2,15 sodium sulfate,16 [bmim][PF6]17
,
and activated fly ash.18 The use of microwave heating,19 solid
phase,20 and polymer supported21 systems to run the cycloconden-
sation leading to 2,3-disubstitiuted 4-thiazolidinones have also
been reported. However, the use of above mentioned protocols
has certain limitations, such as harsh reaction conditions, pro-
longed heating, simultaneous removal of water by Dean and Stark
distillation system or by incorporating desiccant, and need of inert
and dry atmosphere to accelerate the cyclocondensation.
⇑
Corresponding author. Tel.: +91 0240 02403311; fax: +91 0240 02403113.
E-mail addresses: manera2011@gmail.com, manera@indiatimes.com (R.A.
Baker’s yeast displays better catalytic behavior in aqueous
medium.22,23 However organic substrates are not soluble/compat-
Mane).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.143

1690
U. R. Pratap et al. / Tetrahedron Letters 52 (2011) 1689–1691
Table 1
ible with water. Therefore, the cyclocondensation has been carried
out in organic medium using baker’s yeast.
Baker’s yeast catalyzed synthesis of 4-thiazolidinones in tetrahydrofuran.a
Entry
R
R0
Product
Yieldb (%)
Initially when the model reaction was run in ethanol the de-
sired product was not formed, however the intermediate, imine
(Schiff base) was isolated. This indicates that the ethanol does
not favor further cyclization of the Schiff base to 4-thiazolidinone
(4b).
When the model reaction was allowed to run in tetrahydrofu-
ran (THF) it was found that the cyclocondensation has taken place
leading to 4-thiazolidinone in 40 h at room temperature. The
cyclocondensations catalyzed by DCC13 in THF leading to high
yields thiazolidinones have been reported.
After having these results an effort was made to carry out the
reaction in two steps. In the first step the condensation of anisalde-
hyde and aniline was carried using baker’s yeast in THF to obtain
better yield of the imines. Then in the second step the isolated
imine was condensed with thioglycolic acid using baker’s yeast
in THF to form, 4-thiazolidinone. From this result it is clear that
the baker’s yeast is able to catalyze the formation of the interme-
diate, imine as well as the subsequent cyclization of imine and
thioglycolic acid in THF without a loss in activity leading to 4-
thiazolidinone.
The model reaction was performed by varying the amount of
baker’s yeast from 1 to 3 g per 10 mmol of the reactants. It was ob-
served that when 2 g of baker’s yeast was used, the condensation
was found to be complete within 40 h yielding 62% of 4-
thiazolidinone.
1
2
3
4
5
6
7
8
9
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
60
62
69
65
53
71
66
58
55
51
72
68
4-OCH3
4-Cl
H
3-Cl
4-Cl
3-NO2
H
4-OCH3
4-OH
4-Cl
4-OH
4-CH3
4-CH3
4-CH3
4-CH3
4-Cl
4-Cl
4-Cl
4-Cl
4-CH3
10
11
12
4j
4k
4l
a
Reaction conditions: aryl aldehyde (10 mmol), aryl amine (10 mmol), thiogly-
colic acid (10 mmol), and baker’s yeast (2 g) in THF (40 mL) stir, 40 h r.t.
b
Isolated yields.
Histidine
Histidine
N
. .
N
H
H2N
Ar'
Ar
C
N
HO
NH Ar'
N
H
O
C
H
Ar
H
With these optimized reaction conditions diverse set of alde-
hydes and amines were cyclocondensed with thioglycolic acid to
afford a variety of 2,3-disubstituted-4-thiazolidinones (Scheme 1,
Table 1).36,37 Aryl aldehydes bearing electron withdrawing and
donating functionalities smoothly undergo cyclocondensation to
respective 4-thiazolidinones with good to moderate yields.
To assess the catalytic efficiency of baker’s yeast, one-pot three
component condensation of 4-anisaldehyde, aniline, and thiogly-
colic acid was performed in tetrahydrofuran without baker’s yeast
as a blank reaction at room temperature. It was noticed that there
was neither formation of imines nor 4-thiazolidinone. A model
reaction was also performed using inactivated (heat treated) ba-
ker’s yeast as a catalyst where we found that there was no forma-
tion of the product. It reveals that the role of baker’s yeast is crucial
for the cyclocondensation.
-H2O
H
C
H
Ar
N-
Ar'
Ar
H
C
N
Ar'
OH
Aspartic anion
S
OH
OH
O
S
O
C
O-
H
O
C
O
Aspartic acid
Aspartic anion
C
O-
O
We believe that the enzyme lipase available in baker’s yeast
might be responsible for accelerating the formation of imines as
well as cyclondensed products, 4-thiazolidinones. Therefore, we
have carried a model reaction employing isolated lipase, Candida
antarctica lipase B in THF. The formation of imine took place but
the cyclocondensation of imine with thioglycolic acid was found
to be slower and the final product was obtained in 10% yield. This
indicates that lipase catalyzes both steps but the rate of cyclocon-
Ar'
Ar'
Ar
Ar
N
N
-H2O
OH
OH
S
S
O
Scheme 2. Plausible mechanism for the formation of 4-thiazolidinone.
densation is slower. In our case yeast lipase accelerated the rate of
imine formation and cyclocondensation.
CHO
NH2
It is known that lipases are functional proteins having amino
acid residues with varied functionalities at particular locations.
The amino acid residues like histidine, serine, and aspartic acid
might be participating in this condensation. Amino hydrogen of
histidine may be responsible for enhancing electrophilic character
of aldehydic carbon forming hydrogen bonding with carbonyl oxy-
gen, thereby accelerating the rate of addition of amines to alde-
hydes. Another amino acid residue, aspartic anion may be
responsible for enhancing nucleophilicity of mercapto group of
thioglycolic acid causing its facile addition on the imino intermedi-
ate generated in situ. These factors are probably responsible for the
cyclocondensation at room temperature in successive steps form-
ing the desired 4-thiazolidinones (Scheme 2).
R
R'
R'
2a-c
R
Saccharomyces
cerevisiae
N
1a-f
THF, r.t.
S
O
HS
COOH
4a-l
3
R= H, 4-OCH3, 3-Cl, 3-NO2, 4-OH and 4-Cl
R' = H, 4-CH3 and 4-Cl
Scheme 1. Baker’s yeast catalyzed one-pot three component synthesis of 4-
thiazolidinones.

U. R. Pratap et al. / Tetrahedron Letters 52 (2011) 1689–1691
1691
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7.30 (m, 5H). DART MS (ES+) m/z: 286 (M+). (4c):1H NMR (CDCl3, 300 MHz): d
3.83–4.06 (dd, 2H), 6.06 (s, 1H), 7.10–7.49 (m, 9H). DART MS (ES+) m/z: 290
(M+), 292 (M++2). (4e): 1H NMR (CDCl3, 300 MHz): d 2.26 (s, 3H), 3.83–4.02 (dd,
2H), 5.99 (s, 1H), 7.01–7.29 (m, 8H). DART MS (ES+) m/z: 304 (M+), 306 (M++2).
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