Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2014.06.082

We describe a simple and efficient one-pot method for condensing bisulfite adducts of aromatic aldehydes directly with 2,4-thiazolidinedione catalyzed by acetic anhydride. The two main highlights of this study are the one-pot condensation of bisulfite adducts with 2,4-thiazolidinedione in non-aqueous media and the use of Design of Experiment to understand and optimize the reaction conditions. This methodology was then generalized using other active methylene compounds, such as malononitrile.

Full text of DOI:10.1016/j.tetlet.2014.06.082

Accepted Manuscript
Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with
bisulfite adducts of aldehydes
Sandeep Mohanty, Amrendra Kumar Roy, Vinay K.P. Kumar, Sandeep G.
Reddy, Arun Chandra Karmakar
PII:
S0040-4039(14)01084-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.06.082
TETL 44806
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 April 2014
19 June 2014
20 June 2014
Please cite this article as: Mohanty, S., Roy, A.K., Kumar, V.K.P., Reddy, S.G., Karmakar, A.C., Acetic anhydride-
promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes, Tetrahedron Letters
(
2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.082
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Graphical Abstract
Acetic anhydride-promoted one-pot
condensation of 2,4-thiazolidinedione with
bisulfite adducts of aldehydes
Leave this area blank for abstract info.
Sandeep Mohanty, Amrendra Kumar Roy, Vinay K. P. Kumar, Sandeep G. Reddy and Arun Chandra Karmakar

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with
bisulfite adducts of aldehydes
a,*
a
a
a
Sandeep Mohanty , Amrendra Kumar Roy , Vinay K. P. Kumar , Sandeep G. Reddy and Arun Chandra
Karmakar
b
a
Dr. Reddy’s Laboratories Limited, Process Research and Development, API Plant, Bollaram-III, Plot No’s 116, 126C, Survey No.157, S.V. Co-operative
Industrial Estate, IDA Bollaram, Jinnaram Mandal, Medak District, Hyderabad 502325, Andra Pradesh, India
b
Shasun Pharmaceuticals Limited, Shasun Road, Periakalapet, Pondicherry 605014, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We describe a simple and efficient one-pot method for condensing bisulfite adducts of aromatic
aldehydes directly with 2,4-thiazolidinedione catalyzed by acetic anhydride. The two main
highlights of this study are the one-pot condensation of bisulfite adducts with 2,4-
thiazolidinedione in non-aqueous media and the use of Design of Experiment to understand and
optimize the reaction conditions. This methodology was then generalized using other active
methylene compounds, such as malononitrile.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Acetic anhydride
Aromatic bisulfite adducts
Analysis of variance (ANOVA)
Regression analysis
Substituted olefins obtained from the classical Knoevenagel
condensation, form the basic building blocks of many
pharmacologically important molecules. Examples of aldehydes
deprotection unit operation in the plant in a biphasic media.
Moreover, we proposed deprotecting the bisulfite adduct to form
the aldehyde in situ and performing the subsequent reaction in
the same pot. This method would not only save time, but would
1
used in the production of s2uch olefins include 4-
3
21
®
fluorobenzaldehyde in atorvastatin and in rosiglitazone , 4-
also reduce effluent load. A Scifinder search showed only a
4
hydroxybenzaldehyde in pioglitazone, 4-chlorobenzaldehyde in
few cases in which bisulfite adducts were used directly in organic
5
22-23
lumefantrine,
and 3,4-dihydroxy-5-nitrobenzaldehyde in
synthesis.
One such study was carried out by Kjell et al., in
6
entacapone . Another very important class of Knoevenagel
products is 5-benzylidenethiazolidine-2,4-diones obtained from
the condensation of aldehydes with 2,4-thiazolidinediones. These
compounds form an integral part of many biologically active
compounds such as antidiabetic, anticancer, anti-HIV,
antihistamine, anti-ischemic, anticonvulsant, antihistaminic,
antimicrobial, and anti-inflammatory agents, as well as aldose
which the aldehydes were regenerated from the bisulfite adducts
24
in a non-aqueous medium (Scheme 1).
7-16
reductase inhibitors, inhibitors of MurD ligase, etc. The major
hurdle faced by the pharmaceutical industry in performing large-
scale Knoevenagel condensations is the instability of aldehydes
Scheme 1. Balanced chemical equation proposed by Kjell et
1
7-19
during storage and transportation.
To overcome this
24
al. for the regeneration of aldehydes from bisulfite adducts
instability, two major approaches have been employed: (a)
distillation of aldehydes prior to use, and (b) conversion of
aldehydes into bisulfite adducts. The use of bisulfite adducts is
preferred commercially because these adducts are usually stable
crystalline solids, which makes handling and storage more
convenient, and these adducts can easily be hydrolysed back to
using trimethylsilyl chloride (TMS-Cl)
The key advantage of the above reported procedure is the
deprotection of the bisulfite adducts in an organic solvent instead
of in a biphasic system, which is commonly employed in
industry. The organic solvent contains the free aldehyde after
2
0
the pure aldehyde whenever required.
24
deprotection (as described by Kjell et al. ) and could be used in
situ for a subsequent Knoevenagel condensation if the reaction
by-products are altered appropriately. Herein, we report the
Our idea was to use these stable bisulfite adducts directly in
the condensation reactions, eliminating the need for a separate
*
—
——
Corresponding author: Tel.: +91 08458 279485; Fax: +91 08458 279619; Hand phone: +91 9989997191; E-mail: sandeepmohonty@drreddys.com,
sandeepmohanty@yahoo.com; Dr. Reddy’s Laboratories Limited communication number: IPDO IPM-00403

2
Tetrahedron Letters
optimized conditions for the acetic anhydride-promoted
condensation of a bisulfite adduct with 2,4-thiazolidinedione to
give substituted 5-benzylidenethiazolidine-2,4-diones in a single
pot, utilizing a single solvent. This method provides a promising
solution to the challenges faced by industry on the commercial
scale.
common industrial solvent that can be recovered and recycled
easily.
Table 1. Screening of solvents for the preparation of 5-(4-
ethoxybenzylidene)thiazolidine-2,4-dione (6)
Entry
Solvent
% conversion (6)
2
4
The utility of the methodology described by Kjell et al.
Scheme 1) can be extended by optimizing the reaction
1
2
3
4
5
6
7
8
Acetonitrile
Propionitrile
Tetrahydrofuran
Dichloromethane
Chloroform
Toluene
53.7
73.4
65.8
9.3
(
conditions so that subsequent reactions can be carried out in the
same pot. We focused on altering the in situ generated by-
products (NaCl and HCl) of the aldehyde regeneration reaction
appropriately so that they could facilitate the subsequent
condensation reaction. We focused on NaCl particularly, which
being a neutral salt could not act as a base for the condensation
reaction. If the chloride ion is replaced with an acetate ion then
the resulting sodium acetate could act as a base for the
condensation reaction. However, for the condensation reaction to
proceed with sodium acetate, a weaker acid than HCl needs to be
generated as a by-product, in order to arrest the back conversion
55.6
77.4
76.2
71.4
Chlorobenzene
o-Xylene
It is envisaged that this condensation goes through an in situ
generated aldehyde (1). If this is the case then this is the first
report of acetic anhydride-mediated deprotection of bisulfite
adducts and subsequent condensation with active methylene
compounds in non-aqueous media.
3 3
of CH COONa into CH COOH. The most suitable alternative
reagent to trimethylsilyl chloride (TMS-Cl) is acetic anhydride.
The use of this reagent would generate acetic acid in the system,
along with the desired sodium acetate, which in turn could
facilitate the condensation of the aldehyde with 2,4-
thiazolidinedione as shown in Scheme 2.
In order to understand the reaction and identify any reaction
intermediates, the bisulfite adduct (Table 1, entry 6) was
monitored by proton nuclear magnetic resonance (1H NMR)
spectroscopy at different temperatures during the heating of the
1
reaction. The stacked plot of the H NMR study (Figure 1) shows
that bisulfite adduct 2 was consumed immediately at 65 ºC
(
disappearance of Ar-H proton at ~7.33 and ~6.78 ppm of 2a),
with simultaneous formation of aldehyde 1 (appearance of
aldehydic proton at ~9.9 ppm and Ar-H proton at ~7.87 and
~
~
7.12 ppm of 1) and product 6 (appearance of =CH- proton at
7.25 ppm). Hence, the reaction is considered to proceed via the
Scheme 2. Envisaged one-pot condensation of bisulfite
adducts with 2,4-thiazolidinedione in the presence of Ac O
2
aldehyde intermediate.
2
4
The balanced equation proposed by Kjell et al. (Scheme 1)
using TMS-Cl was the basis for the conversion of the bisulfite
adduct (2) to 5-(4-ethoxybenzylidene)thiazolidine-2,4-dione (6)
in the presence of two equivalents of acetic anhydride as shown
in Scheme 2. All bisulfite adducts (2) were prepared as per the
2
5
reported procedure. However, the adducts were found to be
contaminated with traces of the parent aldehyde (1) as shown by
infrared (IR) analysis. With a little optimization (the precipitated
adduct 2a was washed with n-hexane after isolation), adduct 2
was synthesized without any traces of 1 with our reported
2
6
procedure. This purified material was required to establish
whether the reaction went through an aldehyde intermediate.
A proof of concept, reaction was planned as per Scheme 2
involving bisulfite adduct 2, 2,4-thiazolidinedione (3) and two
equivalents of acetic anhydride in acetonitrile. No reaction
occurred at room temperature, but as the reaction temperature
reached ~85 °C, a new spot was observed by thin layer
chromatography (TLC ). This new spot was consistent with the
reference product (6), but the reaction was slow and showed only
a moderate conversion of 53.7% after 12 h. The success of the
reaction prompted us to screen for a suitable solvent for optimal
yield. Various solvents that were screened are summarized in
Table 1. Interestingly, the conversions obtained in high boiling
non-polar solvents (Table 1; entry 6, 7, and 8) were promising.
From these solvents, toluene was selected (Table 1; entry 6) for
further optimization as conversion was good and it is also a
1
Figure 1. Characteristic H NMR signals of aldehyde 1, adduct 2,
and product 6 at various time intervals during the reaction
2
7
The above experiment was conducted based on the work of
2
4
Kjell et al. and accordingly, two equivalents of acetic anhydride
were used for the initial screening reaction. The first equivalent
of acetic anhydride was thought to regenerate the aldehyde, and
the second equivalent to consume the water formed during the
condensation reaction. In order to optimize and understand the
effect of the various reaction parameters, this reaction was
studied using Design of Experiments (DoE), utilizing a full
factorial design of 2 , i.e., eight experiments. Table 2 shows the
three factors that were considered for optimization and Table 3
2
8
3

3
3
shows the results of the corresponding 2 full factorial
experiments. The analysis of variance (ANOVA, Table 4)
showed that the conversion was affected only by the reaction
time and the equivalents of 2,4-thiazolidinedione, but
surprisingly the equivalents of acetic anhydride (2–4) did not
2
9
affect the conversion.
Table 2. Reaction variables (factors) considered for
optimization
Factor Name Units
Minimum (−1) Maximum (+1)
Figure 2. Contour plot of % conversion with 1.0 equivalent of 2,4-
A
B
C
Time
Ac
(3)
Time (h)
6
2
1
12
4
1
2
thiazolidinedione. Please use R , R … below
2
O
Equivalents
Equivalents
2
3
Table 3. 2 full factorial design (8 experiments) and
corresponding % product formation
2
,4-
Thiazolidinedione
3) equivalents
Experiment
Number
Reaction Ac
2
O
Product
(6) (%)
time (h)
equivalents
(
1
2
3
4
5
6
7
8
6
1
1
2
2
1
1
2
2
1
1
1
1
2
2
2
2
72.15
85.04
58.86
73.89
36.6
12
6
12
6
12
6
50.37
31.58
58.6
12
The relationship between the conversion and the two
significant reaction variables is given by the regression equation
(
1) and the relationship has been depicted by a 3D contour plot in
Figure 2.
%
-
Conversion = 74.91 + 2.86×ReactionTime
28.19×2,4-thiazolidinedione
Figure 3: Proposed reaction mechanism for the one-pot
condensation of bisulfite adducts with 2,4-thiazolidinedione in the
presence of Ac O.
2
(1)
In order to check the validity of ANOVA and the regression
analysis, and to ascertain whether acetic anhydride is acting as a
catalyst, three reactions were planned with various equivalents of
acetic anhydride and the results are shown in Table 5.
Interestingly, even with 0.5 equivalents of acetic anhydride the
same conversion to product was observed for the condensation
reactions.
Table 4. ANOVA Table
a
p-value
Sum of
Mean
Df square
F
(Prob >
F)
Source
Model
A-Time
squares
2180.33
590.13
Values
2
1090.16
25.04
0.0025
1
590.13
13.55
0.0143
C- 2,4-
Thiazolidinedione
Hence, we were successful in demonstrating the direct
condensation reaction of bisulfite adduct 2 with 3, through in situ
generation of aldehyde 1, in a single pot catalyzed by acetic
anhydride. This procedure worked for bisulfite adducts of
aromatic or aliphatic aldehydes, but only moderate yields were
obtained with the aliphatic aldehydes (Table 6). In addition, the
isolation process is quite simple with excellent purity and good
yields.
1590.19
217.64
1
5
7
1590.19
36.53
0.0018
Residual
43.52
Cor Total
2397.97
a
p-value less than 0.05 indicates the variable is significant
The negative relationship between 2,4-thiazolidinedione
equivalents and conversion could be explained by the increased
formation of impurities when more 2,4-thiazolidinedione is
available. Surprisingly, ANOVA and the regression analysis did
Table 5. The effect of acetic anhydride equivalents on the
yield of 6
2
9
Entry Time (h)
T (ºC)
Ac
2
O equivalents
% conversion (6)
not contain acetic anhydride. This could only be explained if <2
equivalents of acetic anhydride are required, as this was the lower
limit taken for the study (Table 2). This means that acetic
anhydride may act as a catalyst as shown in the reaction scheme
proposed in Figure 3.
1
2
3
15
15
15
110
1.5
1.0
0.5
83
110
82.3
83.8
110
In principle, two geometrical isomers, namely E and Z, are
possible for all the products isolated according to Scheme 2; it is
1
well known that E and Z isomers can be distinguished by the H

4
Tetrahedron Letters
3
0
NMR spectral characteristics. The methine proton for the
benzylidene compounds (6a–h) appears between 7.74 and 8.2
ppm and for the alkylidene compounds (6i–j) appears between
acetic anhydride that make the process not only environmental
friendly, but also eliminates the need for either aldehyde
distillation or a biphasic system for the deprotection of bisulfite
adducts on an industrial scale.
6
.92 and 6.91 ppm (Table 6). This indicates that the methine
proton in compounds 6a–j is on the same side as that of the
carbonyl group (4-position) of the 2,4-thiazolidinedione ring and,
hence the products obtained are Z isomers.
2
Interestingly, the synthetic route using 0.5 equivalents of Ac O
produced an array of benzylidene and, alkylidene compounds
with low-levels of impurities. Although not all impurities were
identified, as an exemplar of the generalized one-pot
condensation of aromatic bisulfite adduct 2a with 2,4-
thiazolidinedione 3 using catalytic amounts of acetic anhydride in
the nonpolar solvent system, the improved purity (Table 6, HPLC
purity of 98.6%) and improved colour of the product 6a with this
optimized process is shown in Figure 4 (HPLC purity of 96.7%
with 2.0 equivalent acetic anhydride).
Encouraged by the above results, this methodology was
extended to other active methylene compounds, such as
malononitrile (see Scheme 3 and the experimental section). This
reaction proceeded with moderate yield and 2-(4-
ethoxybenzylidene)malononitrile 7 was isolated as the product
after column chromatography.
Scheme 3. Synthesis of 2-(4-ethoxybenzylidene)malononitrile
(
7).
Figure 4. Physical appearance of product 6a isolated with 2.0 and
In summary, we have developed a generalized one-pot
0
.5 equivalents of acetic anhydride.
condensation of aromatic or aliphatic bisulfite adducts with 2,4-
thiazolidinedione using catalytic amounts of acetic anhydride in a
nonpolar solvent system, such as toluene. This methodology was
also extended to the condensation of other active methylene
compounds, such as malononitrile. The highlight of this
methodology is the use of a single solvent and 0.5 equivalents of
Table 6. Representative examples of products prepared by the current methodology
Yield, Physical
appearance, HPLC purity
Compound
Structure
Spectral data
1
H NMR (400 MHz, CDCl
3
): δ 12.50 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.8
80%, Yellow solid,
98.6%
Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.10 (q, J = 6.8 Hz, 2H), 1.3–1.36 (t, J =
1
3
6
1
1
3
.8 Hz, 3H) ppm; C NMR (100 MHz, CDCl ): 167.9, 167.3, 160.0, 132.1,
6
a
31.8, 125.2, 120.0, 129.5, 115.2, 63.4, 14.4 ppm; ESI-MS: m/z 248.3 (M-
).
1
3
H NMR (400 MHz, CDCl ): δ 12.50 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 8.8
13
Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H) ppm; C NMR (100 MHz,
CDCl ): 167.9, 167.4, 160.9, 132.0, 131.8, 131.7, 125.5, 120.3, 114.8, 55.5
77%, Yellow solid,
99.03%
6
6
b
c
3
ppm; ESI-MS: m/z 234.0 (M-1).
1
H NMR (400 MHz, DMSO-d
H) ppm; C NMR (400 MHz, DMSO-d
6
): δ 12.66 (s, 1H), 7.78 (s, 1H), 7.63–7.58 (m, 80.8%, Light brown
1
3
4
1
1
6
): 172.11, 170.10, 134.11, 132.8,
solid, 99.26%
31.27 (2C), 129.17, 128.27, 127.52, 127.46 ppm; ESI-MS: m/z 238.4 (M-
).
1
O
H NMR (400 MHz, CDCl
3
): δ 12.70 (brs, 1H), 7.90 (s, 1H), 7.45 (m, 4H)
): 173.8, 166.9, 134.4, 131.8, 131.0,
78.6%, Pale yellow solid,
99.85%
(Z)
13
ppm; C NMR (100 MHz, CDCl
130.3, 128.8, 127.2 ppm; ESI-MS: m/z 237.7 (M-1).
3
6
6
6
6
d
e
f
NH
S
Cl
O
1
H NMR (400 MHz, CDCl
.6 Hz, 2H), 7.60–7.80 (d, J = 8.6 Hz, 2H) ppm; C NMR (100 MHz,
CDCl ): 167.3, 167.0, 147.4, 139.3, 130.9, 129.1, 124.2, 116.2 ppm; ESI-
3
): δ 12.82 (s, 1H), 7.86 (s, 1H), 8.30–8.40 (d, J =
81.7%, Yellow solid,
97.15%
1
3
8
3
MS: m/z 249.0 (M-1).
1
H NMR (400 MHz, CDCl
H) ppm; C NMR (100 MHz, CDCl ): δ 167.8, 167.2, 133.0, 131.7, 130.3,
3
): δ 12.65 (brs, 1H), 7.78 (s, 1H), 7.60–7.45 (m,
64%, Off-white solid,
99.50%
1
3
5
3
129.9, 129.2, 123.5 ppm; ESI-MS: m/z 204.1 (M-1).
1
H NMR (400 MHz, CDCl
H), 7.74–7.56 (m, 3H) ppm; C NMR (100 MHz, CDCl ): δ 167.9, 167.3,
3
3
): δ 12.65 (s, 1H), 8.20 (s, 1H), 8.08–7.94 (m,
82.8%, Yellow solid,
91.26%
1
3
4
1
1
33.2, 132.7, 131.7, 130.8, 130.6, 128.9, 128.6, 127.9, 127.6, 127.1, 125.9,
23.7 ppm; ESI-MS: m/z 254.4 (M-1).
h

5
1
H NMR (400 MHz, DMSO-d
.09–2.03 (m, 2H), 1.94–1.82 (m, 1H), 0.91–0.90 (d, J = 6.4, 6H) ppm; C
6
): δ 12.37 (s, 1H), 6.92–6.88 (t, J = 7.3, 1H),
50.0%, Pale yellow
liquid, 94.32%
1
3
2
3
1
NMR (400 MHz, DMSO-d ): 167.63, 165.92, 136.06, 126.04, 70.89, 40.24,
6
6
i
2
7.55, 25.50 (2C) ppm; ESI-MS: m/z 186.05 (M+1).
1
H NMR (400 MHz, DMSO-d ): δ 12.36 (s, 1H), 6.91–6.87 (t, J = 7.3, 1H),
6
3
1
2.10 (m, 2H), 1.22–1.40 (m, 2H), 1.12–1.20 (m, 2H), 0.90 (t, J = 7.4, 3H)
50.0%, Yellow liquid,
90.53%
6
7
j
13
ppm; C NMR (400 MHz, DMSO-d
6
): 167.59, 165.97, 137.3, 127.79, 40.0,
3
0.90, 21.74, 13.59 ppm; ESI-MS: m/z 186.99 (M+1).
1
H NMR (400 MHz, DMSO-d
6
): δ 8.39 (s, 1H), 7.98–7.96 (d, J = 8.8, 2H),
57.7%, Off-white solid,
97.61%
7
.18–7.16 (d, J = 8.8, 2H), 4.18–4.16 (m, 2H), 1.37–1.34 (t, J = 7.4, 3H)
13
ppm; C NMR (400 MHz, DMSO-d
6
): 163.68, 160.43, 133 (2C), 123.95,
1
15.5, 76.63, 64.04, 14.34 ppm; ESI-MS: m/z 217 (M+19).
2
2
2. Ragan, J. A.; am Ende, D. J.; Brenek, S. J.; Eisenbeis, S. A.;
Singer, R. A.; Tickner, D. L.; Teixeira, J. T., Jr.; Vanderplas, B.
C.; Weston, N. Org. Process Res. Dev. 2003, 7, 155−160.
3. A Scifinder® search from 1886 to present-day showed 114 articles
on the various roles of the bisulfite adduct of benzaldehyde; only
two of those articles were on carbon-carbon bond formation.
Acknowledgements
We are thankful to the management of Dr. Reddy’s
Laboratories Ltd., for giving support to carry out our work. We
are also thankful to our colleagues in analytical and process
research for their collaboration.
24. Kjell, D. P.; Slattery, B. J.; Semo, M. J. J. Org. Chem. 1999, 64,
5
722-5724.
2
2
5. Cong, C.; Wang, H.; Hu, Y.; Liu, C.; Ma, S.; Li, X.; Ma, S. Eur. J.
Med. Chem. 2011, 46, 3105-3111.
6. Mohanty, S.; Reddy, S. G.; Karmakar, A. C. Lett. Org. Chem.
2014, 11, 197–202.
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th
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31. General procedure for the condensation of the aliphatic bisulfite
adduct of aldehydes with 2,4-thiazolidinedione. The bisulfite
adduct of aliphatic aldehydes such as sodium 1-hydroxy-4-
methylpentane-1-sulfonate/sodium 1-hydroxypentane-1-sulfonate
was taken with active methylene compounds such as 2,4-
thiazolidinedione/malononitrile as described in the experimental
section to afford compounds 6i–j and 7. Purified through column
by using silica gel (Mesh 100–200, eluting with 5%, 10%, and
15% ethyl acetate in hexane) to obtain title compounds.
5
6
7
.
.
.
2
007/0004, 935, 2007.
(a) Jain, V. S.; Vora, D. K.; Ramaa, C. S. Bioorg. Med.
Chem. 2013, 21, 1599-1620. (b) Chen, H.; Fan, Y.-H.; Natarajan,
A.; Guo, Y.; Iyasere, J.; Harbinski, F.; Luus, L.; Christ, W.; Aktas,
H.; Halperin, J. A. Bioorg. Med. Chem. Lett. 2004, 14, 5401-5405.
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Liang, X.; Peng, A.; Yang, S.; Wei, Y.; Chen, L. J. Med. Chem.
8
9
.
.
32. General procedure for the condensation of the bisulfite adduct of
aldehydes with 2,4-thiazolidinedione. The bisulfite adduct of
3
3
2
011, 54, 2060–2068.
aromatic aldehydes (2a–h, 39.40 mmol) was taken with 2,4-
thiazolidinedione (3, 39.30 mmol) in toluene (50 mL) in a 100 mL
1
1
0. Wu, Y.; Karna, S.; Choi, C. H.; Tong, M.; Tai, H.-H.; Na, D. H.;
Jang, C. H.; Cho, H. J. Med. Chem. 2011, 54, 5260–5264.
1. Hulin, B.; Clark, D. A.; Goldstein, S. W.; McDermott, R. E.;
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Zega, A.; Gobec, S.; Mašič, P.; Kikelj, D. J. Med. Chem. 2010, 53,
round bottom flask. Ac O (2.0 g, 0.5 equiv.) was then added in
2
one portion at 55 ºC. The reaction temperature was gradually
raised to 110 ºC and was maintained for 12 h. After the
completion of the reaction, it was slowly quenched into ice water.
The biphasic slurry was allowed to stir below 20 ºC for 10 min
and the precipitated product was filtered using a Buchner funnel.
The wet cake was washed with 2 × 10 mL toluene at 25 ºC and
dried under vacuum at 50 ºC to afford the desired benzylidene-2,4-
thiazolidinedione (6) in good yields.
1
6
584–6594.
1
1
1
3. Rawal, R. K.; Prabhakar, Y. S.; Katti, S. B.; De Clercq, E. Bioorg.
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33. R CHO, 2a–h (R = 4-EtO-C H , 4-MeO-C H , 4-Cl-C H , 2-Cl-
2
2
6
5
6
5
6
5
4. Suster, D. C.; Feyns, L. V.; Ciustea, G.; Botez, G.; Dobre, V.;
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Krapcho, J.; White, R. E.; Ridgewell, R. E.; Obermeier, M. T. J.
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6 5 2 6 5 6 5
C H , 4-NO -C H , C H , naphthyl)
1
1
6. Somu, R. V.; Boshoff, H.; Qiao, C.; Bennett, E. M.; Barry, C. E.,
III; Aldrich C. C. J. Med. Chem. 2006, 49, 31–34.
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b) van der Beek P. A. A. Recl. Trav. Chim. Pays-Bas 1928,
4
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1
1
2
2
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1. Spent aqueous acid or base used for deprotection would go to an
effluent treatment plant before being discharged.