Efficient microwave enhanced synthesis of 4-thiazolidinones

Article abstract of DOI:10.1055/s-2004-832811

A microwave-enhanced, rapid, three-component one-pot condensation method has been developed for the synthesis of 4-thiazolidinones using environmentally benign solvent ethanol in open vessels at atmospheric pressure. Applying this methodology ten differen

Full text of DOI:10.1055/s-2004-832811

LETTER
2357
Efficient Microwave Enhanced Synthesis of 4-Thiazolidinones
S
ynthesis of 4-Thi
e
azolidinone
e
s
resa Gududuru,a Viet Nguyen,a James T. Dalton,b Duane D. Miller*a
a
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163, USA
Fax +1(901)4483446; E-mail: dmiller@utmem.edu
b
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
Received 14 May 2004
speed up the synthesis we focused on developing an alter-
nate method for the synthesis of 4-thiazolidinones.
Abstract: A microwave-enhanced, rapid, three-component one-pot
condensation method has been developed for the synthesis of
4-thiazolidinones using environmentally benign solvent ethanol in
open vessels at atmospheric pressure. Applying this methodology
ten different 4-thiazolidinones were synthesized in good yields.
Initially introduced in 1986,6 the chemical application of
microwaves has now become an area of interest for the
synthesis of a wide variety of compounds. The advantages
of microwave-expedited chemical synthesis are cleaner
reactions, shorter reaction times and the ease of manipula-
tion. Parekh7 has described microwave-mediated synthe-
sis of 4-thiazolidinones. However, this method7 involves
separate preparation of a hydrazone from the correspond-
ing aldehyde and hydrazine, which was then mixed with
thioglycolic acid and exposed to high power microwave
irradiation.
Key words: microwave, heterocycles, condensation, 4-thiazolidi-
nones, synthesis
Experience has shown that compounds with biological
activity are often derived from heterocyclic structures. In-
deed, one of the richest sources of diversity for the medic-
inal chemist is small heterocyclic rings, which in addition
to often exhibiting biological activity, may serve as rigid
scaffolds for further display of functionalities. Thiazolid-
inones are one such class of heterocycles, which attracted
much attention as they have been reported to possess a
wide range of biological activities including antifungal,
antibacterial, antihistaminic, antimicrobial and anti-in-
flammatory activities.1
In this communication we report microwave enhanced
three-component one-pot condensation of a primary
amine, an aldehyde and mercaptoacetic acid for the syn-
thesis of a diverse set of 4-thiazolidinones (Scheme 1).
O
OH
MW
HS
+
+
R1 NH2·HCl R2 CHO
S
N
As part of our endeavor to discover new anticancer agents
we designed and synthesized highly cytotoxic thiazolidi-
none scaffold containing compounds for prostate cancer
(undisclosed results). During this process we were seek-
ing a rapid and efficient method for the synthesis of 4-thi-
azolidinones. Literature survey shows that many different
protocols have been developed for the synthesis of 4-thia-
zolidinones. Most commonly employed methods2 involve
a one-pot three-component condensation of a primary
amine, an aldehyde and mercaptoacetic acid with simulta-
neous azeotropic distillation of water formed in the
reaction. Alternatively, a recent report3 describes carbodi-
imide (DCC) mediated three-component reaction for the
synthesis of 4-thiazolidinones. In either case the reaction
is believed to proceed via imine formation followed by at-
tack of sulfur on the imine carbon and final intramolecular
cyclization with the elimination of water. However, the
general applicability of the above-mentioned methods are
limited, as the reactions require prolonged heating with
continuous removal of water, and in some cases the reac-
tion is performed in sealed vessels in the presence of a
R1
O
EtOH
2a–f
1a–e
R2
3
4a–j
Scheme 1
A range of primary amines and aldehydes were condensed
with mercaptoacetic acid in the presence of Hünig’s base
and molecular sieves under microwave irradiation
(Figure 1). To optimize the method, initially we examined
the condensation in toluene and observed that desired
product was formed in low yield. Furthermore, all our
attempts to improve the yield at elevated temperature, mi-
crowave power and longer reaction times were met with
unsuccessful results. This may be due to poor microwave
absorbing nature of toluene. In microwave mediated or-
ganic synthesis one of the most important characteristics
of a solvent is its polarity. The more polar a solvent, the
greater its ability to couple with the microwave energy,
the faster the temperature of the reaction mixture increas-
es that leads to faster reaction rates. To increase the effi-
ciency we decided to perform the condensation in a more
polar and high microwave absorbing solvent like ethanol.
However, most of the reported methods2 involve use of ei-
ther high boiling hydrocarbons like toluene or benzene, or
aprotic solvent tetrahydrofuran for this type of condensa-
tions. To check the feasibility of condensation in a protic
solvent, a pilot experiment was carried out using glycine,
4
desiccant like anhydrous ZnCl2 or sodium sulfate5 or mo-
lecular sieves, and the use of stoichiometric amounts of
DCC. In order to circumvent these difficulties and to
SYNLETT 2004, No. 13, pp 2357–2358
0
3
.1
1
.2
0
0
4
Advanced online publication: 08.09.2004
DOI: 10.1055/s-2004-832811; Art ID: S04604ST
© Georg Thieme Verlag Stuttgart · New York

2358
V. Gududuru et al.
LETTER
NH2
CO2Me
NH2
CO2Et
NH2
CO2Me
OH
Ph
H2N
CO2Me
H2N
1e
1a
1b
1d
1c
CHO
Cl
CHO
CHO
CHO
CHO
Ph
CHO
N
MeO
Cl
2b
2c
2d
2a
2f
N
2e
Figure 1 Various amines and aldehydes used for the condensation
benzaldehyde and mercaptoacetic acid (Table 1, entry 1) In conclusion, we have developed a convenient three-
in ethanol and observed that the reaction proceeded component one-pot microwave rate enhanced efficient
uneventfully forming the desired product in good yield. method for the synthesis of 4-thiazolidinones. It is note-
Interestingly, no product was formed when the reaction worthy to mention that all reactions were carried out at at-
was carried out in ethanol in the absence of microwaves.
mospheric pressure in open vessels using environmentally
benign solvent ethanol. The simplicity of this short proce-
dure and generally satisfactory yields render this method
particularly attractive for the rapid synthesis of 4-thiazol-
idinones.
Encouraged by this result and to understand the general
applicability of this protocol, we have synthesized a vari-
ety of 4-thiazolidinones. For this purpose five different
amines and five different aldehydes were selected and
condensed with mercaptoacetic acid (Table 1). With a
chiral center in the amine component (Table 1, entries 8–
10) as one might expect, formation of diastereomeric
products was observed. The diastereomeric ratio was de-
termined by NMR and LC-MS analysis [4h (1:1.8), 4i
(1:1), 4j (1:1.7)]. It was observed that the ratios of reac-
tants at 1:2:3 for amine, aldehyde and mercaptoacetic ac-
id, respectively, gave best yields. This is in agreement
with the earlier observation by Holmes et al.2 According-
ly, the optimized procedure8 involves microwave irradia-
tion (power: 100 W) of a mixture of amine, aldehyde and
mercaptoacetic acid (1:2:3) in presence of 1.25 equiva-
lents of Hünig’s base in ethanol at 120 °C for 30 minutes
at atmospheric pressure and after standard workup gave
the desired 4-thiazolidinones in good to high yields
(Table 1).
Acknowledgment
This research was supported by a grant from the Department of De-
fense (DAMD17-01-1-083)
References
(1) (a) Newkome, G. R.; Nayak, A. Advances in Heterocyclic
Chemistry, Vol. 25; Academic Press: New York, 1979, 83.
(b) Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I.
Chem. Rev. 1981, 81, 175.
(2) Homes, C. P.; Chinn, J. P.; Look, C. G.; Gordon, E. M.;
Gallop, M. A. J. Org. Chem. 1995, 60, 7328.
(3) Srivatsava, T.; Haq, W.; Katti, S. B. Tetrahedron 2002, 58,
7619.
(4) Srivatsava, S. K.; Srivatsava, S. L.; Srivatsava, S. D. J.
Indian Chem. Soc. 2000, 77, 104.
(5) Sharma, R. C.; Kumar, D. J. Indian Chem. Soc. 2000, 77,
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(6) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.;
Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279.
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Parekh, H. H. Indian J. Heterocycl. Chem. 2002, 12, 175.
(8) Typical Procedure for the Synthesis of 4-
Table 1 Isolated Yields of 4-Thiazolidinones
Entry Amine· Aldehyde Mercapto 4-Thiazolidinone Yield
HCl
1a
1a
1a
1a
1a
1a
1b
1c
acid
(%)
80
83
90
65
80
91
76
55
68
63
1
2
2a
2b
2c
2d
2e
2f
3
4a
4b
4c
4d
4e
4f
Thiazolidinones: A mixture of glycine methyl ester
hydrochloride (1a, 0.50 g, 4.00 mmol), aldehyde (2e, 1.66 g,
8.30 mmol), mercaptoacetic acid (0.83 mL, 12.00 mmol),
diisopropylethylamine (0.85 mL, 4.83 mmol), and molecular
sieves (4 Å, 0.10 g) in EtOH (10 mL) was irradiated with
microwaves (power: 100 W) at 120 °C for 30 min, following
which the sample was cooled using compressed air. The
reaction mixture was diluted with CHCl3 (75 mL),
sequentially washed with sat. NaHCO3, H2O, brine, dried
(Na2SO4) and solvent was removed in vacuo to get crude
product that was purified by column chromatography (silica
gel, hexanes–EtOAc) to afford 4e (1.00 g, 80%). 1H NMR
(300 MHz, CDCl3): d = 2.85–2.86 (m, 1 H), 2.92 (s, 6 H),
3.50–3.63 (s, 3 H), 3.83 (br s, 2 H), 4.64 (d, J = 17.1 Hz, 1
H), 6.67 (br s, 0.6 H), 7.07 (br s, 0.7 H), 7.34 (d, J = 9.0 Hz,
1 H), 7.55 (d, J = 3.3 Hz, 2 H), 7.90 (br s, 1 H), 8.31 (m, 1
H). 13C NMR (300 MHz, CDCl3): d = 31.94, 43.75, 44.53,
51.76, 58.47, 76.72, 112.97, 121.63, 122.69, 124.83, 124.94,
126.18, 131.33, 168.09. MS (ESI): m/z = 345 [M + H].
3
3
3
4
3
5
3
6
3
7
2a
2a
2a
2a
3
4g
4h
4i
8
3
9
1d
1e
3
10
3
4j
Synlett 2004, No. 13, 2357–2358 © Thieme Stuttgart · New York