The first solvent-free, microwave-accelerated, three-component synthesis of thiazolidin-4-ones via one-pot tandem Staudinger/aza-wittig reaction

Article abstract of DOI:10.1002/jhet.1705

An efficient and rapid, solvent-free, microwave-accelerated, one-pot, three-component protocol for thiazolidin-4-ones synthesis from organic azides has been reported for the first time via Staudinger/aza-Wittig reaction. The microwave-accelerated, solvent-free approach overcomes the limitations associated with the prevailing solution phase methodologies. In particular, its novelty is that it eradicates the vital limitation, that is, accumulation of water (byproduct) that is known to affect the yield and rate of the reaction. Thus, a library of thiazolidin-4-ones has been synthesized in short time in excellent yields (92-96%).

Full text of DOI:10.1002/jhet.1705

1004
The First Solvent-Free, Microwave-Accelerated, Three-Component Synthesis
of Thiazolidin-4-ones via One-Pot Tandem Staudinger/aza-Wittig Reaction
Vol 51
Poovan Shanmugavelan, Murugan Sathishkumar, Sangaraiah Nagarajan, Raja Ranganathan, and
*
Alagusundaram Ponnuswamy
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamilnadu, India
*
E-mail: ramradkrish@yahoo.co.in
Received November 21, 2011
DOI 10.1002/jhet.1705
Published online 16 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
CHO
solvent-free
MW-Irradiation
130-1500C
10-15 min
O
O
3
S
R
N3
PPh3
HS
Ph3PO
N
4
OH
R
R1
1
R1
N3
2
O
O
N3
N3
R = A)
B)
N3
C)
N3
E)
D)
O
O
H3C
An efficient and rapid, solvent-free, microwave-accelerated, one-pot, three-component protocol for
thiazolidin-4-ones synthesis from organic azides has been reported for the first time via Staudinger/aza-
Wittig reaction. The microwave-accelerated, solvent-free approach overcomes the limitations associated with
the prevailing solution phase methodologies. In particular, its novelty is that it eradicates the vital limitation,
that is, accumulation of water (byproduct) that is known to affect the yield and rate of the reaction. Thus, a
library of thiazolidin-4-ones has been synthesized in short time in excellent yields (92–96%).
J. Heterocyclic Chem., 51, 1004 (2014).
INTRODUCTION
N-dicyclohexyl carbodiimide (DCC) [15], or 2-(1H-benzo-
triazo-1-yl)-1,1,3,3-tetramethyl uraniumhexafluorophospate
(HBTU) [16] have been used as the dehydrating agents to
accelerate the intramolecular cyclization resulting in shorten-
ing the reaction time and improved yields. On the other hand,
usage of condensation agents [15–17], microwaves [18a],
Lewis acids or bases [18b], and ionic liquids [18b] had
resulted in improved yields of thiazolidin-4-ones. Thus, the
main drawback in the existing solution phase protocols is
the accumulation of water eliminated during the course of
the reaction that either forms an azeotrope with the solvent
or becomes collected in the reaction mixture.
Thiazolidin-4-ones are important group of heterocycles
found in numerous natural products and pharmaceuticals
[1]. They exhibit diversified pharmacological activities such
as platelet activating factor (PAF) antagonist [2], antifungal
activity [3], cardioprotective [4], antihistaminic [5],
anti-HIV [6], analgesic [7], cytotoxic [8], COX-1 inhibitors
[9], and nonnucleoside inhibitors of HIV-RT [10].
Therefore, the synthesis of thiazolidin-4-ones is of consider-
able interest. Consequently, focus is directed more towards
the development of elegant and eco-friendly protocols for
their synthesis.
Alternatively, Staudinger/aza-Wittig reactions are a
powerful tool in organic synthetic strategies towards
constructing nitrogen containing heterocycles [19], that is,
azides are employed as an alternative to amines. With regard
to thiazolidin-4-one synthesis, to the best of our knowledge,
there is only a couple of recent reports [20,21] that utilizes
Staudinger/aza-Wittig reactions to afford imine intermediate
that with mercaptoacetic acid affords the product (Scheme 1,
route B). However, these are also solution phase protocols.
The advantage of these protocols using azides in the place
of amines is that they involve elimination of nitrogen instead
of water in step 1 (Scheme 1, route B). However, water
elimination in step 3 and its azeotrope formation is unavoid-
able that affects the reaction rate and/or yield of thiazolidin-
4-ones [20,21]. Thus, from the discussion vide supra, it is
understood that solution phase methodologies for thiazolidin-
4-one synthesis is unhealthy as they are associated with
RESULTS AND DISCUSSION
Of the most frequently used methodologies for thiazolidin-
4-ones, the three-component reactions involving an amine, a
carbonyl compound, and mercaptoacetic acid have been well
documented [11,12], wherein condensation of amines with
aldehydes afford the imines that react with mercaptoacetic
acid to afford thiazolidin-4-ones. The vital limitation of this
method is the accumulation of water that is eliminated in
steps 1 and 3 (Scheme 1, route A) that decreases both the rate
of the reaction and yield of the product.
Thus, the azeotropic removal of water has been reported
to be crucial for obtaining high yields of thiazolidin-4-ones
in short time. Alternatively, desiccants such as molecular
sieves, anhydrous ZnCl2 [13], sodium sulfate [14], N,
© 2013 HeteroCorporation

July 2014
Synthesis of Thiazolidin-4-ones via One-Pot Tandem Staudinger/aza-Wittig Reaction
1005
Scheme 1. Mechanistic pathway in thiazolidin-4-ones synthesis starting from amines and azides.
route B
step 1
O
route A
step 1
O
Staudinger
-N2
R2
R3
R2
R3
R1 N3
PPh3
R1
N PPh3
R1-NH2
R1
N
C
R2
R3
Aza-Wittig
-Ph3PO
-H2O
O
SH
HO
R4
step 2
R5
O
R3
R2
C
R1
R2
step 3
-H2O
R5
R4
H
R1
N
N
S
S
HO
R5
R4
R3
O
Scheme 2. Tandem one-pot synthesis of thiazolidin-4-one (4a) in solvent.
O
S
CHO
O
N
solvent
reflux
N3
Ph3PO
HS
PPh3
OH
4a
1A
3
2a
many limitations such as toxicity of the solvents, usage
of condensation agents, and desiccants, the vital being
accumulation of water that would restrict their broad
scope and question their eco-friendliness. Thus, search
for newer protocols overcoming the limitations is worth
the attempt.
time affording excellent yield, the details of which are
discussed vide infra.
At the outset, for the purpose of optimization, the one-
pot, three-component synthesis of thiazolidin-4-one was
attempted (Scheme 2) in various solvents and solvent-free
conditions. That is, a mixture of benzyl azide (1A, 1 eq),
triphenylphosphine (1.1 eq), benzaldehyde (2a, 1 eq), and
mercaptoacetic acid (3, 1.1 eq) was refluxed in various
solvents that took around 2–6 h (Table 1, entry 1–5) for
completion affording 75–82% of thiazolidin-4-one (4a).
From the aforementioned solvent screening, it could be
inferred that the rate of the reaction is temperature depen-
dent. That is, in high boiling solvents with relatively lower
polarity, viz. toluene and xylene (Table 1, entry 4 and 5),
the reaction is fast and completed within 2–2.5 h. On the
In this regard, we have recently reported for the first time
the advantages of switching over from a solution phase to a
solvent-free methodology by achieving the efficient and
rapid syntheses of amides [22], thioamides [23], and cyclic
imides [24], under solvent-free condition overcoming the
limitations associated with the solution phase protocols.
In continuation of this, we were tempted to attend the
three-component synthesis of thiazolidin-4ones via
microwave-accelerated, solvent-free condition with added
advantage, that is, the change from the solution phase
protocol to microwave-accelerated, solvent-free condition
would decrease the accumulation of water (eliminated
during the course of the reaction) in two ways, viz. (1) no
azeotrope formation and (2) the microwave-accelerated
rate of heating leading to spontaneous vaporization of
water. With this objective, it was envisaged that an envi-
ronmentally benign synthesis of thiazolidin-4ones could
be accomplished. Thus, we herein submit the first report
on solvent-free, microwave-accelerated, one-pot, three-
component synthesis of thiazoldin-4-ones by tandem
Staudinger/aza-Wittig coupling/cyclization. Interestingly,
the present study is characterized by very short reaction
Table 1
Optimization for the synthesis of the thiazolidin-4-one (4a).
Entry
Reaction condition
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
THF
6
5
5
77
75
76
82
80
94
Acetonitrile
Benzene
Toluene
Xylene
2.5
2.0
10 minb
Solvent-free
aIsolated yield.
bMicrowave-irradiation (temperature 150ꢀC, power 80 W).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1006
P. Shanmugavelan, M. Sathishkumar, S. Nagarajan, R. Ranganathan, and A. Ponnuswamy
Vol 51
basis of this, it was envisaged that higher reaction tempera-
tures could be obtained in absence of solvent and the rate of
heating may be further accelerated using microwave
irradiation. To our delight, as expected, under microwave
assisted (CEM DISCOVER, Benchmate model, single-mode
design with inbuilt IR sensor) solvent-free condition, accumu-
lation of water is avoided thus resulting in a prominent in-
crease in the rate of the reaction affording excellent yield
(94%) of the product (4a) in just 10 min (Table 1, entry 6).
Having optimized the reaction conditions, the broad scope
of the eco-friendly protocol has been established by the conve-
nient synthesis of a library of compounds (20 examples). This
resulted in the rapid synthesis of thiazolidin-4-ones in just
10–15 min by microwave-accelerated one-pot, solvent-free
three-component methodology. That is, in situ formation of
imines by aza-Wittig reaction of nascent phosphazenes (gener-
ated from azides and triphenylphosphine) with aldehydes fol-
lowed by the instantaneous reaction of the imine with
mercaptoacetic acid at 130–150ꢀC (Scheme 3) to afford thia-
zolidin-4-ones (4a–t) in excellent yields (92–96%, Table 2).
Subsequently, the reason for the high rate of thiazolidin-4-
one formation under solvent-free condition was sought for. In
this regard, it was envisaged that the conversion of azide to
phosphazene in the first step of the reaction (Scheme 1, route
B) might have been enhanced. As an attempt to understand
this prediction, the consumption of the azide in the reaction
of benzyl azide with triphenylphosphine at room temperature
under solvent-free condition was monitored by FTIR (FTIR
monitoring of the consumption of azide in the reaction under
microwave irradiation involving higher temperature was not
attempted based on the safety ground). That is, the intensity
of the band because of the azido group around 2100 cmÀ1
was examined at varying time intervals (Fig. 1). It was
observed that the intensity of the band decreased (Fig. 1a–f)
as the time progressed and disappeared in 2.5 h (Fig. 1f). This
clearly indicates that the conversion of the azide to the
phosphazene is accelerated as envisaged.
solvent-free condition. Further, the rate enhancement may
also be due to the high collision between the polar compo-
nents in the intimacy generated in the fused molten phase
at higher temperature under solvent-free condition.
All the synthesized compounds were completely charac-
terized by NMR (1D and 2D), IR, and mass spectral techni-
ques. Recently, we have published the X-ray crystal structure
of 4a [25], which prove its structure unequivocally.
CONCLUSION
In conclusion, we have described a rapid and environ-
mentally benign synthesis of the thiazolidin-4-ones in
excellent yields from organic azides, triphenylphosphine,
aldehydes with mercaptoacetic acid by a tandem one-pot,
solvent-free, microwave-accelerated, three-component
protocol. The tandem reaction is initiated by the in situ
generation of nascent phosphazenes that with aldehydes
afford the imines that is trapped by intermolecular nucleo-
philic attack of mercaptoacetic acid followed by intramo-
lecular cyclization to afford the thiazolidin-4-ones. This
solvent-free protocol overcomes most of the limitations
associated with the solution phase methods, the vital
limitation being the water accumulation in the course of
the reaction resulting in an efficient and rapid synthesis.
This is the first report on the solvent-free synthesis of
thiazolidin-4-ones by microwave-accelerated, one-pot,
three-component strategy.
EXPERIMENTAL
General.
All chemicals, reagents, and solvents were of
commercially high purity grade purchased from Avra Synthesis
Pvt. Ltd. and Merck Ltd. India. Silica gel (60–120 mesh) was
used for column chromatographic isolation and purification of
the compounds synthesized. Organic azides used in the
investigation were prepared according to the literature
procedures. Melting points were obtained on electro-thermal
apparatus and are uncorrected. 1H NMR (300 MHz) and 13C
NMR (75 MHz) spectra were recorded in CDCl3 on Bruker
Avance 300 MHz spectrometer and the chemical shifts are reported
as d values in parts per million (ppm) relative to tetramethylsilane,
with coupling constant (J) values in Hertz (Hz). The splitting
This is also supported by a recent report [21] that
discloses that phosphazene formation in THF occurs just
in 5 min under microwave irradiation. On a similar ground,
in the present study, it is understood that phosphazene
formation is accelerated by microwave irradiation under
Scheme 3. Tandem one-pot solvent-free, microwave-accelerated synthesis of thiazolidin-4-ones (4).
CHO
solvent-free
MW-Irradiation
130-1500C
10-15 min
O
O
S
R
N3
PPh3
HS
Ph3PO
N
4
OH
R
R1
3
1
R1
N3
2
O
O
N3
N3
R = A)
B)
N3
C)
N3
E)
D)
O
O
H3C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis of Thiazolidin-4-ones via One-Pot Tandem Staudinger/aza-Wittig Reaction
1007
Table 2
Solvent-free, microwave-accelerated, one-pot synthesis of the thiazolidin-4-ones (4a–t).
Entry
Azides
Aldehydes
Thiazolidin-4-ones
MW-irradiation
1
2
R1=
4a–t
R=
Temp.
(ꢀC)
Time
(min)
Yielda
(%)
1
2
A
A
150
10
94
a
150
10
96
b
3
4
A
A
150
150
10
10
94
93
c
d
5
6
7
A
A
A
150
150
150
10
10
10
92
94
94
e
f
g
8
9
A
B
150
150
10
15
95
94
h
i
(Continued)
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DOI 10.1002/jhet

1008
P. Shanmugavelan, M. Sathishkumar, S. Nagarajan, R. Ranganathan, and A. Ponnuswamy
Vol 51
Table 2
(Continued)
Entry
Azides
Aldehydes
Thiazolidin-4-ones
MW-irradiation
1
2
R1=
4a–t
R=
Temp.
(ꢀC)
Time
(min)
Yielda
(%)
10
B
150
15
96
j
11
12
C
C
140
140
15
15
95
96
k
l
13
14
C
C
140
140
15
15
93
94
m
n
o
15
16
D
D
130
130
10
10
94
94
p
q
17
D
130
10
93
(Continued)
Journal of Heterocyclic Chemistry
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Synthesis of Thiazolidin-4-ones via One-Pot Tandem Staudinger/aza-Wittig Reaction
1009
Table 2
(Continued)
Entry
Azides
Aldehydes
Thiazolidin-4-ones
MW-irradiation
1
2
R1=
4a–t
R=
Temp.
(ꢀC)
Time
(min)
Yielda
(%)
18
D
130
10
93
r
19
20
E
E
130
130
10
10
95
94
s
t
aIsolated yield.
patterns in 1H NMR spectra are reported as follows: m, multiplet; s,
singlet; d, doublet; and t, triplet. 13C NMR data are reported with the
solvent peak (CDCl3 = 77.00) as the internal standard. Elemental
analyses were performed and were found to be in agreement, that
is, within Æ0.4% of the calculated values. Compounds 4a [15],
(4b, 4c, 4d) [26], 4e [27], (4k, 4l) [12a], (4o, 4p, 4q) [28], and (4r,
4s, 4t) [29] are known, and their 1H and 13C NMR spectra are
identical to the reported values.
General procedure for the synthesis of thiazoldin-4-ones
(4a–t).
To a well ground intimate mixture of triphenyl
phosphine (1.1 eq) and aldehyde, 2 (1.0eq) in a microwave vial
(10 mL) equipped with a magnetic stirring bar, the organic azide,
1 (0.2 g, 1.0 eq) was added in drops while stirring. Stirring was
continued until liberation of nitrogen ceased, and the
mercaptoacetic acid 3 (1.1eq) was added to the aforementioned
mixture, and the reaction vessel was sealed with a septum. It was
then placed into the cavity of a focused monomode microwave
reactor (CEM Discover, Benchmate) and operated at 130–150ꢀC
(temperature monitored by a built-in IR sensor), power 80W for
10–15min. The reaction temperature was maintained by
modulating the power level of the reactor. The reaction mixture
was allowed to stand at room temperature. Then, the residue was
purified by column chromatography on silica (petroleum ether-
ethyl acetate, 94:6) to afford the thiazolidin-4-ones (4a–t) in
92–96% yield. The obtained results are summarized in Table 2.
3-Benzyl-2-(furan-2-yl)thiazolidin-4-one (4f).
Gummy
matter. Yield: 94%. 1H NMR (300 MHz, CDCl3): d 7.17–7.43 (m,
6H, ArH). 6.30 (d, 1H, J = 3.0 Hz, ArH), 6.35 (m, 1H, ArH), 5.43
(s, 1H, NCHS), 5.12 (d, 1H, J = 15.0Hz, NCH2), 3.93 (d, 1H,
J = 15.3Hz, NCH2). 3.69 (d, 1H, J = 6.3 Hz, SCH2), 3.64 (d, 1H,
J = 6.0 Hz, SCH2); 13C NMR (75MHz, CDCl3): d 170.82,
150.84, 143.64, 135.64, 128.76, 128.21, 127.89, 110.49, 109.25,
55.63, 46.48, 32.57; Anal. Calcd for C14H13NO2S: C, 64.84; H,
5.05; N, 5.40; S, 12.36. Found: C, 64.86; H, 5.06; N, 5.41; S, 12.37.
3-Benzyl-2-(thiophen-3-yl)thiazolidin-4-one (4g).
Gummy
1
matter. Yield: 94%; H NMR (300MHz, CDCl3): d 7.03 (d, 1H,
J = 5.7Hz, ArH), 7.14 (m, 3H, ArH), 7.26–7.38 (m, 5H, ArH),
5.53 (s, 1H, NCHS), 5.12 (d, 1H, J = 14.7Hz, NCH2), 3.87
Figure 1. Phosphazene (C6H5CH2N═PPh3) formation under solvent-free
condition from benzyl azide and triphenyl phosphine at room temperature:
(a) 0 min, (b) 30 min, (c) 1 h, (d) 1.5 h, (e) 2 h, and (f) 2.5 h.
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DOI 10.1002/jhet

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P. Shanmugavelan, M. Sathishkumar, S. Nagarajan, R. Ranganathan, and A. Ponnuswamy
Vol 51
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(d, 1H, J = 15.6Hz, SCH2), 3.74 (d, 1H, J = 15.6Hz, SCH2), 3.61
(d, 1H, J = 15.0Hz, NCH2); 13C NMR (75 MHz, CDCl3): d
170.76, 140.30, 128.71, 128.26, 127.84, 127.66, 125.79, 124.00,
57.97, 46.19, 32.85; Anal. Calcd for C14H13NOS2: C, 61.06; H,
4.76; N, 5.09; S, 23.29. Found: C, 61.07; H, 4.75; N, 5.08; S, 23.28.
3-Benzyl-2-(pyridine-2-yl)thiazolidin-4-one (4h).
Gummy
matter. Yield: 95%. 1H NMR (300 MHz, CDCl3): d 7.09 (m, 2H,
ArH), 7.21–7.38 (m, 7H, ArH), 5.38 (s, 1H, NCHS), 5.16 (d, 1H,
J = 14.7Hz, NCH2), 3.90 (d, 1H, J = 15.3 Hz, SCH2), 3.76 (d, 1H,
J = 15.6Hz, SCH2), 3.52 (d, 1H, J = 14.7Hz, NCH2); 13C NMR
(75 MHz, CDCl3): d 171.18, 139.10, 135.24, 131.04, 129.15,
129.07, 128.71, 128.36, 127.87, 127.10, 62.69, 47.16, 32.96;
Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36; S,
11.86. Found: C, 66.63; H, 5.21; N, 10.35; S, 11.85.
Ethyl 2-(4-oxo-2-phenylthiazolidin-3-yl)acetate (4i).
Gummy matter. Yield: 94%. 1H NMR (300 MHz, CDCl3): d
7.32–7.40 (m, 5H, ArH), 5.84 (s, 1H, NCHS), 4.43 (d, 1H,
J = 17.7 Hz, NCH2), 4.15 (m, 2H, OCH2CH3), 3.80 (s, 2H,
SCH2), 3.30 (d, 1H, J = 17.4 Hz, NCH2), 1.23 (t, 3H, J = 6.9 Hz
OCH3CH2); 13C NMR (75 MHz, CDCl3): d 171.93, 167.87,
137.77, 129.51, 129.08, 127.60, 63.65, 61.45, 43.81, 32.69,
29.61, 14.00; Anal. Calcd for C13H15NO3S: C, 58.85; H, 5.70;
N, 5.28; S, 12.09. Found: C, 58.83; H, 5.71; N, 5.28; S, 12.08.
Ethyl 2-(2-(4-methoxyphenyl)4-oxothiazolidin-3-yl)acetate
(4j).
Gummy matter. Yield: 96%. 1H NMR (300 MHz,
CDCl3): d 7.28 (d, 2H, J = 9.6 Hz, ArH), 6.89 (d, 2H, J = 9.6 Hz,
ArH), 5.81 (s, 1H, NCHS), 4.39 (d, 1H, J = 17.7 Hz, NCH2),
4.14 (m, 2H, OCH2CH3), 3.79 (s, 3H, OCH3), 3.78 (s, 2H,
SCH2), 3.29 (d, 1H, J = 17.7 Hz, NCH2), 1.24 (t, 3H, J = 7.2 Hz,
OCH2CH3); 13C NMR (75 MHz, CDCl3): d 171.80, 167.97,
160.50, 129.19, 114.42, 63.41, 61.43, 55.32, 43.69, 32.83,
29.63, 14.03; Anal. Calcd for C14H17NO4S: C, 56.93; H, 5.80;
N, 4.74; S, 10.86. Found: C, 56.93; H, 5.81; N, 4.75; S, 10.85.
Methyl 2-(2-(2-chlorophenyl)-4-oxothiazolidin-3-yl)acetate
(4m).
Gummy matter. Yield 93%. 1H NMR (300 MHz,
CDCl3): d 7.28–7.45 (m, 4H, ArH), 6.28 (s, 1H, NCHS), 4.54
(d, 1H, J = 17.7 Hz, NCH2), 3.79 (s, 2H, SCH2), 3.72 (s, 3H,
OCH3), 3.39 (d, 1H, J = 17.7 Hz, NCH2); 13C NMR (75 MHz,
CDCl3): d 172.44, 168.09, 135.66, 132.04, 131.18, 130.19,
127.72, 126.55, 59.92, 52.45, 44.01, 32.03; Anal. Calcd for
C12H12ClNO3S: C, 50.44; H, 4.23; N, 4.90; S, 11.22. Found: C,
50.46; H, 4.23; N, 4.90; S, 11.21.
Methyl 2-(2-(furan-2-yl)4-oxothiazolidin-3-yl)acetate (4n).
Gummy matter. Yield: 94%. 1H NMR (300 MHz, CDCl3): d 7.45
(s, 1H, ArH), 6.44 (s, 1H, ArH), 6.36 (s, 1H, ArH), 5.88 (s, 1H,
NCHS), 4.45 (d, 1H, J = 17.7 Hz, NCH2), 3.81 (d, 1H,
J = 15.6 Hz, SCH2), 3.70 (s, 3H, OCH3), 3.65 (d, 1H, merged
with OCH3, SCH2), 3.47 (d, 1H, J = 17.7 Hz, NCH2); 13C NMR
(75 MHz, CDCl3): d 170.54, 167.89, 149.55, 143.54, 110.18,
109.73, 55.70, 51.85, 43.26, 31.51; Anal. Calcd for
C10H11NO4S: C, 49.78; H, 4.60; N, 5.81; S, 13.29. Found: C,
49.77; H, 4.60; N, 5.80; S, 13.30.
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Acknowledgments. The authors thank IRHPA, DST for providing
300 MHz NMR instrument for recording the NMR spectra for the
compounds synthesized and UGC for giving financial support.
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