Synthesis of 5-arylidene-2,4-thiazolidinediones by Knoevenagel condensation catalyzed by baker's yeast

Article abstract of DOI:10.1039/c0nj00691b

An ecofriendly baker's yeast catalyzed Knoevenagel condensation of aromatic aldehydes and active methylene compounds has been performed. The developed protocol has been found to be applicable for obtaining 5-arylidene-2,4- thiazolidinediones, the precursors of hypoglycemic agents. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011.

Full text of DOI:10.1039/c0nj00691b

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
NJC
Cite this: New J. Chem., 2011, 35, 49–51
www.rsc.org/njc
LETTER
Synthesis of 5-arylidene-2,4-thiazolidinediones by Knoevenagel
condensation catalyzed by baker’s yeast
Umesh R. Pratap, Dhanaji V. Jawale, Rahul A. Waghmare, Dinesh L. Lingampalle
and Ramrao A. Mane*
Received (in Gainesville, FL, USA) 7th September 2010, Accepted 19th October 2010
DOI: 10.1039/c0nj00691b
1
3
An ecofriendly baker’s yeast catalyzed Knoevenagel condensation
of aromatic aldehydes and active methylene compounds has been
performed. The developed protocol has been found to be applic-
able for obtaining 5-arylidene-2,4-thiazolidinediones, the pre-
cursors of hypoglycemic agents.
chemical catalysis. Aldolases, transketolase, and hydroxynitrile
14
lyases catalyze the C–C bond forming reactions.
There is scanty information on the use of enzymes for the
acceleration of Knoevenagel condensation. Isolated lipases
1
5,16
have been found to catalyze this condensation.
The use
of isolated pure enzymes to accelerate organic transformations
has several drawbacks such as high cost, narrow substrate
specificities and in some cases low performance under
nonnatural conditions.
Knoevenagel condensation is one of the classical organic
reactions of immense importance in the formation of C–C
1
bonds. A wide range of useful products have been synthesized
2
using the condensation. It has been used to obtain a range of
Here, we have attempted the Knoevenagel condensation
using a cheaper whole cell biocatalyst, active dry baker’s yeast
(Saccharomyces cerevisiae). The cell of baker’s yeast acts as a
mini reactor and produces a variety of enzymes and is known
to provide specific enzyme for specific reaction. Baker’s yeast
substituted alkenes, a,b-unsaturated nitriles, esters, acids,
drugs, dyes and polymers.
3
,4
The condensation of 2,4-thiazolidinediones with aldehydes
has been a subject of considerable interest. The products
1
7
5
-arylidene-2,4-thiazolidinediones are important structural
has the ability to catalyze various organic transformations. It
elements in medicinal chemistry and are found to possess
is also used in the formation of CQC double bonds via acyloin
5
6
significant hypoglycemic, anti-inflammatory, aldose reductase
1
8,19
20
condensation,
and Michael addition reaction.
Due
7
inhibitor, tyrosine phosphate inhibitor, antihypertensive
8
9
to this important aspect, baker’s yeast is gaining much
21
importance in organic synthesis.
1
0
and anticancer activities.
Knoevenagel condensation of 2,4-thiazolidinediones with
aldehydes is a key step in the synthesis of some clinically used
antidiabetic agents like rosiglitazone, englitazone and
The active methylene compounds used in the work are
malononitrile, ethyl cyanoacetate and 2,4-thiazolidinedione.
The condensations were performed by stirring in ethanol at
room temperature (rt) giving moderate to excellent yields of
the arylidenyl derivatives.
3
netoglitazone.
In view of the significance of 5-arylidene-2,4-thiazolidine-
diones, synthetic chemists are taking keen interest in the
development of green, rapid and economic protocols for their
Initially to optimize the reaction conditions, the condensation
of benzaldehyde (1a) and the active methylene compound
malononitrile (2a) was carried out using baker’s yeast
1
1
synthesis. Catalysts used for Knoevenagel condensations are
1
amines or buffer systems containing an amine and acid.
2
(
S. cerevisiae) in water with stirring at room temperature.
These protocols provide the access to 5-arylidene-2,4-
thiazolidinediones but suffer from harsh reaction conditions,
use of toxic and volatile solvents and corrosive/toxic bases.
Therefore, there is an urgent need to provide a more
effective and environmental benign procedure for obtaining
The product (3a) formation was recorded. However, for its
isolation critical extraction with ethyl acetate was needed.
To avoid the tedious extraction procedure and to accelerate
the rate, the reaction was carried out in ethanol. Excellent
yield of the product 3a was obtained after 3 h of stirring at rt.
5
-arylidene-2,4-thiazolidinediones.
(
Table 1). This protocol did not need extraction and the
Biocatalysis is one of the green methods in organic synthesis
product isolation was easier. After 3 h of stirring the reaction
mass was filtered to remove yeast as a residue. The product
was obtained on removal of ethanol from filtrate by vacuum
distillation.
which is used to synthesize a wide variety of organic compounds.
The method has become a preferable alternative for traditional
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad-431004, India.
E-mail: manera2011@gmail.com; Fax: +91 0240-02403113;
Tel: +91 0240-02403311
Then the variety of aryl aldehydes were separately
condensed with malononitrile (Scheme 1) under optimized
reaction conditions and the products were obtained with
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011
New J. Chem., 2011, 35, 49–51 49

View Article Online
Table 1 Baker’s yeast catalyzed condensation of aryl aldehydes with
active methylene compounds
Table
thiazolidinediones in ethanol
2
Baker’s yeast catalyzed synthesis of 5-arylidiene-2,4-
a
a
b
Yield (%)
b
Yields (%)
Entry
R
X
Product
Time/h
Entry
R
Product
1
2
3
4
5
6
7
8
9
H
CN
CN
CN
CN
CN
CN
COOEt
COOEt
COOEt
3a
3b
3c
3d
3e
3f
3g
3h
3i
3
3
3
3
3
3
5
5
5
92
86
85
88
94
95
75
70
67
1
2
3
4
5
6
7
8
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
45
50
49
40
42
55
38
62
59
80
74
72
3-Cl
4-Cl
4-Br
2-OH
4-OCH
4-Cl
H
4-OCH
3
4-CH
3
2-OH
4-OH
3 2
4-N(CH )
3,4-di OCH
4-Cl
2-Cl
4-Br
4-F
2,4-di Cl
3
3
4-OCH
3
9
10
1
a
6j
6k
6l
Reaction conditions: malononitrile or ethyl cyanoacetate (8 mmol), aryl
aldehyde (8 mmol) and baker’s yeast (2 g) in ethanol (30 mL) stir, rt.
1
2
1
b
Isolated yields.
a
Reaction conditions: 2,4-thiazolidinedione (8 mmol), aryl aldehyde
8 mmol) and baker’s yeast (2 g) in ethanol (30 mL) stir, rt for 40 h.
(
b
Isolated yields.
To examine the catalytical efficiency of baker’s yeast,
reaction of benzaldehyde and 2,4-thiazolidinedione was
performed in the absence of yeast as the control experiment
where we found that there was no formation of the product.
The result indicates that the baker’s yeast is necessary to
catalyze the reaction.
Scheme
1 Knoevenagel condensation of aryl aldehydes with
Next, we tried to condense 2,4-thiazolidinedione with
heteroaryl aldehydes viz. 2-chloro 3-formyl quinoline,
malononitrile and ethyl cyanoacetate.
3
-formyl indole and pyridine 3-carboxaldehyde. We observed
excellent yields (Table 1, products 3a–f). In the next attempt
we carried out the Knoevenagel condensation of aryl
aldehydes and ethyl cyanoacetate (Scheme 1) using baker’s
yeast in ethanol and obtained the good yields of the products.
The time required for the completion of reaction was found to
be longer than the condensation with malononitrile (Table 1,
products 3g–i). The Knoevenagel condensation of acetyl
acetone and ethyl acetoacetate with benzaldehyde was
separately performed but we did not observe the desired
products even after 2 days of stirring.
no condensations in these experiments.
Recently, Sonawane et al. have reported the lipase catalyzed
Knoevenagel condensation and also proposed the catalytical
16
role of lipase in the condensation. Literature reveals that
25
baker’s yeast does produce lipolytic enzyme e.g. lipase. Such
an enzyme could be responsible for the acceleration of
Knoevenagel condensation. A yeast lipase might be abstracting
a proton from the active methylene to form the nucleophile.
Thus the generated nucleophile would attack the electrophilic
carbon of the aldehyde resulting in the aldol adduct which on
sequential dehydration leads to Knoevenagel products.
In summary, we have described a novel biocatalytical
method for the Knoevenagel condensation of aryl aldehydes
and various active methylene compounds at mild reaction
conditions in ethanol using baker’s yeast as the whole cell
biocatalyst. The newly developed protocol is eco-friendly and
might be useful in the synthesis of precursors of antidiabetic
drugs, 5-arylidene-2,4-thiazolidinediones.
After having these results then we attempted the synthesis of
a series of 5-arylidene-2,4-thiazolidinediones by condensing
aryl aldehydes with 2,4-thiazolidinedione (Scheme 2) in the
presence of baker’s yeast (Table 2, products 4a–l) in ethanol at
room temperature.
The geometry of 5-arylidene-2,4-thiazolidinediones may be
E or Z. It is well known that the E and Z isomers can be
1
distinguished by the H NMR spectral characteristics. Benzylidine
proton appears below 7.42 d ppm in E isomer and above
22–24
1
From the spectral data ( H NMR)
7.90 d ppm in Z isomer.
it was confirmed that all the products obtained are Z isomers.
Experimental section
General remarks
All chemicals used were obtained from commercial suppliers
and used without further purification. Progress of the reaction
was monitored by thin layer chromatography on MERKs
1
silica plates. H-NMR spectra were recorded on Bruker
DRX FT NMR at 300 and 200 MHz using TMS as internal
standard. Mass spectral data were obtained by JEOL
AccuTOF DART mass spectrometer. Dry baker’s yeast
(S. cerevisiae) was procured from Kothari Fermentations
and Biochem Ltd, India.
Scheme 2 Knoevenagel condensation of 2,4-thiazolidinedione and
aryl aldehydes.
5
0
New J. Chem., 2011, 35, 49–51
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011

View Article Online
General experimental procedure
(c) D. Lednicer, Strategies for Organic Drug Synthesis and Design,
2
nd edn, John Wiley & Sons Inc., 2008.
4 (a) T. Inokuchi and H. Kawafuchi, J. Org. Chem., 2006, 71, 947;
b) R. Chen, X. Yang, H. Tian, X. Wang, A. Hagfeldt and L. Sun,
Chem. Mater., 2007, 19, 4007; (c) H. Salim and O. Piva, J. Org.
Chem., 2009, 74, 2257; (d) V. Boucard, Macromolecules, 2001, 34,
A mixture of active methylene compound (8 mmol), aryl
aldehyde (8 mmol) and dry baker’s yeast (2 g) in ethanol
(
(
30 mL) was stirred at room temperature for the specified time.
The progress of the reaction was monitored by thin layer
chromatography using ethyl acetate : pet ether (4 : 6) as an
eluent. After the specified reaction time the reaction content
was filtered through the bed of Celite to remove the yeast.
Ethanol was removed from the filtrate by vacuum distillation
and crude residues were then purified by crystallization from
ethanol (3a–i) and ethanol : DMF (6a–l).
4
E. Cano and E. Sotelo, J. Med. Chem., 2007, 50, 6476.
L. Fernanda, C. C. Leite, R. H. V. Mourao, M. C. A. Lima,
S. L. Galdino, M. Z. Hernandes, F. A. R. Neves, S. Vidal, J. Barbe
and I. R. Pitta, Eur. J. Med. Chem., 2007, 42, 1239.
R. Ottana, R. Maccari, M. L. Barreca, G. Bruno, A. Rotondo,
A. Rossi, G. Chiricosta, R. D. Paola, L. Sautebin, S. Cuzzocrea
and M. G. Vigorita, Bioorg. Med. Chem., 2005, 13, 4243.
R. Maccari, R. Ottana, R. Ciurleo, M. G. Vigorita, D. Rakowitz,
T. Steindl and T. Langer, Bioorg. Med. Chem. Lett., 2007, 17, 3886.
8 R. Maccari, P. Paoli, R. Ottana, M. Jacomelli, R. Ciurleo,
G. Manao, T. Steindl, T. Langer, M. G. Vigorita and G. Camici,
Bioorg. Med. Chem. Lett., 2007, 15, 5137.
308; (e) A. Coelho, E. Ravina, N. Fraiz, M. Yanez, R. Laguna,
5
6
7
All the products are well characterized by the comparison of
1
their spectral ( H-NMR, Mass) and physical data (mp) with
2
3,26
those reported in literature.
1
9
S. V. Bhandari, K. G. Bothara, A. A. Patil, T. S. Chitre,
A. P. Sarkate, S. T. Gore, S. C. Dangre and C. V. Khachane,
Bioorg. Med. Chem. Lett., 2009, 17, 390.
(Z)-5-Benzylidene-2,4-thiazolidinedione (6a).
H-NMR
(
(
300 MHz, DMSO-d ): d 7.48 (m, 5H), 7.79 (s, 1H), 12.64
6
+ +
s, 1H). DART-MS (ESI , m/z): 206 (M ).
1
1
0 D. Kaminsky, B. Zimenkovsky and R. Lesyk, Eur. J. Med. Chem.,
009, 44, 3627.
2
(
Z)-5-(4-Methoxybenzylidene)-2,4-thiazolidinedione
(6b).
1 (a) O. Yoshitata, M. Teruo, N. Mishiko, J. Motoyuki and
K. Norio, Chem. Pharm. Bull., 1992, 40, 907; (b) I. Hitoshi,
K. Hirogas, K. Keiko and K. Hirohiko, US Pat. 489706,
RZhChim., 1991, 10070; (c) W. Hanefeld and M. J. Schlietzer,
J. Heterocycl. Chem., 1995, 32, 1019; (d) Y. Sluka, S. Kadl and
M. Sova, CSFR Pat. 275290, RZhChim., 1994, 2072;
1
H-NMR (200 MHz, CDCl
3
): d 3.89 (s, 3H), 6.98 (d, J = 8
Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 8.81 (s, 1H), 11.05 (s, 1H).
+ +
DART-MS (ESI , m/z): 236 (M ).
(
Z)-5-(4-Methylbenzylidene)-2,4-thiazolidinedione
(6c).
(e) W. Hanefeld, V. Helfrich, M. Jalili and M. Schlitzer, Arch.
Pharm., 1993, 326, 359.
1
H-NMR (200 MHz, CDCl ): d 2.43 (s, 3H), 7.27 (d,
3
J = 8 Hz, 2H), 7.39 (d, J = 8 Hz, 2H), 8.81 (s, 1H), 10.98
+ +
s, 1H). DART-MS (ESI , m/z): 220 (M ).
12 (a) M. Tuncbine, O. B. Dundar, G. Ayhan-Kilcigil, M. Ceylan,
A. Waheed, E. J. Verspohl and R. Ertan, Il Farmaco, 2003, 58, 79;
(
(
b) D. A. Clark, S. W. Goldstein, R. A. Volkmann, J. F. Eggler,
G. F. Holland, B. Hulin, R. W. Stevenson, E. M. Kreutzer,
E. M. Gibbs, M. N. Krupp, C. H. Lamphere, F. J. Rajeskas,
W. H. Kappeler, W. H. McDermott, N. J. Hutson and
M. R. Johnson, J. Med. Chem., 1991, 34, 319; (c) N. B. Levshyn,
N. B. Curkan, K. A. V’yunov and A. I. Ginak, Zh. Prikl. Khim.,
(
Z)-5-(2-Hydroxybenzylidene)-2,4-thiazolidinedione
(6d).
1
H-NMR (300 MHz, DMSO-d
6
): d 6.94 (q, J = 8.1 Hz,
2
1
H), 7.31 (t, J = 8.7 Hz, 2H), 8.01 (s, 1H), 10.53 (s, 1H),
+ +
2.51 (s, 1H). DART-MS (ESI , m/z): 222 (M ).
1983, 56, 1453; (d) K. Popov-Pergal, Z. Chekovich and M. Pergal,
Zh. Obshch. Khim., 1994, 61, 2112.
(Z)-5-(4-Fluorobenzylidene)-2,4-thiazolidinedione
(6k).
1
13 K. M. Koeller and C. H. Wong, Nature, 2001, 409, 232.
14 B. G. Davis and V. Boyer, Nat. Prod. Rep., 2001, 18, 618.
15 X. W. Feng, C. Li, N. Wang, K. Li, W. Zhang, Z. Wang and
X. Yu, Green Chem., 2009, 11, 1933.
6 Y. A. Sonawane, S. B. Phadtare, B. N. Borse, A. R. Jagtap and
H-NMR (200 MHz, CDCl
3
): d 7. 14 (d, J = 10 Hz, 1H),
7
.47 (d, J = 6 Hz, 2H), 7.81 (s, 1H), 11.28 (s, 1H). DART-MS
+ +
ESI , m/z): 224 (M ).
(
1
G. S. Shankarling, Org. Lett., 2010, 12, 1456.
17 R. Csuk and B. I. Glanzer, Chem. Rev., 1991, 91, 49.
Acknowledgements
1
1
2
8 G. Fronza, C. Fugatti, L. Majori, G. Pedrocchi-Fantoni and
F. Spreafico, J. Org. Chem., 1982, 47, 3289.
9 G. Fronza, C. Fugatti, P. Grasseli, G. Poli and S. Servi,
Biocatalysis, 1990, 3, 51.
0 T. Kitazume and N. Ishikawa, Chem. Lett., 1984, 1815.
Authors are thankful to Professor D. B. Ingle for his valuable
suggestions and discussions. One of the authors URP is
grateful to University Grants Commission, New Delhi for
the award of research fellowship.
21 B. Pscheidt and A. Glieder, Microb. Cell Fact., 2008, 7, 25.
2
2 Y. Momose, K. Meguro, H. Ikeda, C. Hatanaka, S. Oi and
T. Sodha, Chem. Pharm. Bull., 1991, 39, 1440.
Notes and references
2
3 Y. Luo, L. Ma, H. Zheng, L. Chen, R. Li, C. He, S. Yang, X. Ye,
Z. Chen, Z. Li, Y. Gao, J. Han, G. He, L. Yang and Y. Wei,
J. Med. Chem., 2010, 53, 273.
1
(a) Comprehensive Organic Synthesis, ed. B. M. Trost, Pergamon
press, Oxford, 1991, vol. 2, p.133; (b) G. Jones, Org. React., 1967,
2
4 Z. Xia, C. Knaak, J. Ma, Z. M. Beharry, C. McInnes, W. Wang,
A. S. Kraft and C. D. Smith, J. Med. Chem., 2009, 52, 74.
15, 204.
2
(a) J. Wang, R. P. Discordia, G. A. Crispino, J. Li, J. A. Grosso,
R. Polniaszek and V. C. Truc, Tetrahedron Lett., 2003, 44, 4271;
25 (a) K. Athenstaedt and G. Daum, J. Biol. Chem., 2003, 278, 23317;
(b) SGD pages: Database Copyright 1997–2008, YeastCyc:
Saccharomyces cerevisiae Biochemical Pathway Overview, 2008.
26 (a) B. M. Reddy, M. K. Patil, K. N. Rao and G. K. Reddy, J. Mol.
Catal. A: Chem., 2006, 258, 302; (b) M. Gupta, R. Gupta and
M. Anand, Beilstein J. Org. Chem., 2009, 5, 68; (c) K. F. Shelke,
S. B. Sapkal, G. K. Kakade, S. A. Sadaphal, B. B. Shingate and
M. S. Shingare, Green Chem. Lett. Rev., 2010, 3, 17;
(d) D. H. Yangt, B. Y. Yangt, B. C. Chentt and S. Y. Chentf,
Org. Prep. Proced. Int., 2006, 38, 81.
(
(
b) J. K. Gallos and A. E. Koumbis, ARKIVOC, 2003, vi, 135;
c) G. Sabitha, G. S. K. K. Reddy, M. Rajkumar, J. S. Yadav, K.
V. S. Ramakrishna and A. C. Kunwar, Tetrahedron Lett., 2003, 44,
455; (d) S. Marcaccini, R. Pepino, M. C. Pozo, S. Basurto,
M. G. Valverda and T. Torroba, Tetrahedron Lett., 2004, 45,
999; (e) C. Xing and S. Zhu, J. Org. Chem., 2004, 69, 6486.
7
3
3
(a) J. Cossy, C. Menciu, H. Rakotoarisoa, P. H. Kahn and
J. R. Desmurs, Bioorg. Med. Chem. Lett., 1999, 9, 3439;
(b) S. L. Gaonkar and H. Shimizu, Tetrahedron, 2010, 66, 3314;
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011
New J. Chem., 2011, 35, 49–51 51