Pd nanoparticles: an efficient catalyst for the solvent-free synthesis of 2,3-disubstituted-4-thiazolidinones

Article abstract of DOI:10.1007/s11164-016-2490-2

Abstract: Palladium nanoparticles (Pd NPs: ~5-nm diameter) catalysed an efficient, solvent-free protocol for the cyclocondensation reaction of the aldehydes, anilines and mercaptoacetic acid has been developed. This method offers a rapid, relatively economical and ecofriendly protocol for the synthesis of 2,3-disubstituted-4-thiazolidinones for the first time. Moreover, the catalyst can also be easily recovered and recycled with no loss of catalytic activity. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2490-2

Res Chem Intermed
DOI 10.1007/s11164-016-2490-2
Pd nanoparticles: an efficient catalyst for the solvent-
free synthesis of 2,3-disubstituted-4-thiazolidinones
Rajkumar R. Harale1 Praveen V. Shitre1
•
•
Bhaskar R. Sathe1 Murlidhar S. Shingare1
•
Received: 12 December 2015 / Accepted: 21 February 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Palladium nanoparticles (Pd NPs: *5-nm diameter) catalysed an efficient, sol-
vent-free protocol for the cyclocondensation reaction of the aldehydes, anilines and mercap-
toacetic acid has been developed. This method offers a rapid, relatively economical and
ecofriendly protocol for the synthesis of 2,3-disubstituted-4-thiazolidinones for the first time.
Moreover, the catalystcan alsobe easily recovered and recycled with no lossof catalyticactivity.
Graphical Abstract
H
O
Ph
NH
O
S
N
2 -R
1
R1
Ph
Ph
R1
N
H2O
HS
O
OH
Pd(OAc)2
aq.NaBH4
RT
9-Decen-1-ol
H
S
O
Pd Nanoparticle
synthesis
N
Ph
OH
R1
O
OH
S
N
H
R1
Ph
&
Murlidhar S. Shingare
prof_msshingare@rediffmail.com
1
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431004, India
123

R. R. Harale et al.
Keywords 4-Thiazolidinones Á Cyclocondensation reaction Á Palladium
nanoparticles
Introduction
4-Thiazolidinone derivatives are of considerable and remarkable interest in the field
of medicinal chemistry. The 4-thiazolidinone heterocycles exhibit a wide range of
biological activities such as anti-cancer [1], anti-malarial [2], anti-bacterial [3], anti-
HIV [4] and nematicidal [5] activities, etc. Moreover, their end derivatives are also
important precursors for the synthesis of useful pharmaceutical compounds, such as
pyrazolothiazole derivatives [6], monofluoro b-lactam [7] and also for the synthesis
of polymethine cyanine dyes [8]. Due to this diversity of the motif in the biological
profile, 4-thiazolidinones have attracted much attention of the research community
to explore the catalytic pathways for its synthesis.
The most recently used methods for the synthesis of thiazolidinone include
condensation of aldehydes, anilines and mercaptoacetic acid using catalyst such as
DCC [9], Saccharomyces cerevisiae [10], HBTU [11], [bmim][PF6] [12],
Bi(SCH2COOH)3 [13], silica chloride [14], silica gel [15], etc. Attempts have also
been made to accelerate the cyclocondensation by simultaneous removal of reaction
water azeotropically or by using dehydrating agents such as molecular sieves [16],
trimethyl orthoformate [17], sodium sulphate [18], and ZnCl2 [19]. Although most
of the processes offer distinct advantages, moreover, they also suffer from certain
drawbacks such as longer reaction times, unsatisfactory yields, harsh reaction
conditions, stoichiometric amounts of catalysts and also environmentally toxic
catalysts. To circumvent these difficulties and to speed up the synthesis, we focused
on developing an alternate and novel route for the solvent-free synthesis of
4-thiazolidinones.
Most organic solvents are well-known for their unrecoverability and unavoidable
polluting characteristics which results from their use in many industrial organic
processes [20]. Hence, there is an urgent need to develop efficient and cost-effective
synthetic methodologies that avoid using organic solvents (i.e. solvent-free
conditions). As a result, the development of such methodologies has become a
vital challenge for synthetic chemists. In addition to reducing pollution, solvent-free
reactions also reduce overall costs and enhance the simplicity of processing and
handling the resulting compounds.
Moreover, the properties of the nano-sized metals may differ from those of the
bulk metals [21]; for example, the catalytic properties of metal nanoparticles (NPs)
are as a function of their size, shape and dispersity. Among the other metal NPs, it
has been proved that palladium (Pd) NPs acts as efficient catalysts due to their large
surface to volume ratio at their tiny dimensions [22], chemo-selectivity, environ-
mental compatibility and end recoverability. Recently, Pd NPs were found to be
proficient catalysts for organic reactions [23–25] such as Heck, Sonogashira and
Hiyama cross-couplings [26]. Herein, we report first time use of Pd NPs along with
solvent-free reaction conditions for the synthesis of 4-thiazolidinones.
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Pd nanoparticles: an efficient catalyst for the solvent…
Preparation of Pd bulk catalyst
In brief, the preparation of Pd bulk catalyst involves, initially, aqueous Pd(OAc)2
(1 mmol) stirred at room temperature (RT) for 30 min with Pd2? ions subsequently
being reduced via drop-wise addition of 20 mL of 0.1-M aq. NaBH4 solution. Upon
the slow addition of NaBH4, the pale yellow color of Pd2? turned reddish violet
indicating the formation of Pd bulk catalyst.
Preparation of Pd NPs
Pd NPs were prepared by a modified Brust synthesis route using 9-decen-1-ol (DOL)
as the capping agent. In brief, NPs were synthesized in a biphasic mixture of water
and toluene (v:v; 1:1) using a 1:3 mol ratio of Pd acetate to DOL. The biphasic
mixture was stirred at RT for 30 min and Pd2? ions were subsequently reduced using
drop-wise addition of 20 mL of 0.1-M aq. NaBH4 solution. Upon the slow addition
of NaBH4, the pale yellow color of Pd2? turned reddish violet, indicating the
formation of Pd NPs. Furthermore, after rigorous stirring for 3 h, Pd NPs were found
to be shifted to the organic phase, turning the upper layer blackish. Subsequently, the
particles were precipitated repeatedly using acetone to remove excess/unbound
capping agent and other by-products. Furthermore, the formation of Pd NPs along
with their morphology and grain size has been proved by the transmission electron
microscopy (TEM) images at different magnifications. Accordingly, Fig. 1a shows a
low-magnification TEM image of as-synthesised Pd NPs, and it confirms particles
Fig. 1 Transmission electron microscopy (TEM) images of mono-dispersed Pd NPs at different a low
and b high magnification having an average particle diameter of 5 0.4 nm. c TEM analysis after four
˚
cycles, d along with the X-ray diffraction (XRD) pattern of Pd NPs using CuKa (1.54 A) radiation; the
patterns (111), (200) and (220) reveal the FCC structures
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R. R. Harale et al.
were well- and mono-dispersed with an interconnected network between them due to
the bifunctional nature of the capping agent (DOL). Figure 1b shows high
magnification of Pd–DOL NPs having a size of 5 0.4 nm. X-ray diffraction
(XRD) analysis was further carried out to investigate the crystallinity of these as-
synthesised Pd–DOL NPs and also to evaluate their size distribution. Figure 1c
shows the XRD patterns corresponding to Pd NPs having a face-centered cubic
(FCC) crystal structure as in agreement with the previous reports [23], although there
are slight differences in the orientation. Moreover, the particle size was calculated
from the full width at the half maxima (FWHM) of the strongest peak; (111) for Pd–
DOL NPs using the Scherrer formula. The calculated crystallite size is comparable
with the corresponding size from TEM analysis shown in Fig. 1a–c.
General procedure for synthesis of 2,3-diaryl-4-thiazolidinones (4a–q)
A mixture of aromatic aldehydes (1a–h; 0.002 mol), aromatic amines (2a–c;
0.002 mol) and mercaptoacetic acid (3; 0.004 mol) with a catalytic amount of Pd
NPs (10 mol%) were mixed followed by stirring at 100 °C. The reaction progress
was monitored by thin-layer chromatography (TLC) using ethyl acetate: n-hexane
(3:7) composition. After completion of the reaction, the reaction mass was poured
on cold water and washed with NaHCO3, and the obtained crude products were
filtered and recrystallised from ethanol.
Spectral data for the representative compounds
2-(4-Chlorophenyl)-3-phenylthiazolidin-4-one (4c): Proton nuclear magnetic reso-
nance (1H NMR; 300 MHz, acetone-d6) d ppm: 7.49 (d, 2H, ArH), 7.35 (d, 2H,
ArH), 7.30 (d, 2H, ArH), 7.26 (d, 2H, ArH), 7.15 (m, 1H, ArH), 6.47 (s, 1H,
methine), 4.00 (d, J = 15.6 Hz, CH2), 3.87 (d, J = 15.6 Hz, CH2); Carbon-13
NMR (13C NMR; 75 MHz, acetone-d6): d 171.22, 140.34, 139.04, 134.66, 130.53,
129.94, 129.67, 129.64, 129.31, 127.36, 126.54, 126.11, 64.51, 33.57; MS (ESI) m/z
290.1 [M ? H]?; Anal. calcd. for C15H12ClNOS: C 62.17, H 4.17, N 4.83, S
11.07 %; found C 61.96, H 4.24, N 4.75, S 11.11 %.
Results and discussion
In the search for better catalytic systems for this 4-thiazolidinone derivative,
optimization of the reaction conditions was carried out by taking benzaldehyde 1a
(0.002 mol), aniline 2a (0.002 mol) and mercaptoacetic acid 3 (0.004 mol) as
model substrates (Scheme 1).
To initiate our study, the model reaction was carried out at 100 °C by constant
stirring in the absence of catalyst for 60 min under solvent-free conditions, but the
desired product was not formed (Table 1, entry 1) Moreover, we studied the same
reaction with different catalyst amounts having 5 and 10 mol% loading of Pd NPs
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Pd nanoparticles: an efficient catalyst for the solvent…
Scheme 1 Standard model reaction for the synthesis of 4-thiazolidinones
Table 1 Screening of the
catalyst with concentration
Entry
Catalyst
Pd-based catalysts
(mol%)
Yielda (%)
1
2
No catalyst
Pd NPs
–
No condensation
5
80
89
88
62
70
70
45
56
42
45
10
15
5
3
Pd bulk
10
15
5
4
5
Pd (OAC)2
Pd Cl2
Reaction conditions: 1a
(0.002 mol), 2a (0.002 mol), 3
(0.004), stirred at 100 °C
(solvent-free), 60 min
10
5
10
a
Isolated yield
under the same reaction conditions and we observed 80 and 89 % of the product,
respectively (Table 1, entry 2).
We also carried out the same reaction using higher catalyst loading (15 mol%) to
generalize our findings (Table 1, entry 2). In conclusion, the best result was
obtained with 10 mol% of Pd NPs while stirring at 100 °C under solvent-free
conditions. A higher Pd NP loading did not have much effect on conversion
efficiency (decreasing the reaction time and increasing product formation).
Furthermore, to evaluate the uniqueness of Pd NPs, we also screened the activities
of other Pd-based catalysts such as Pd(OAc)2 and PdCl2 with 5 and 10 mol%
loading for the above-said reaction, respectively; the screenings, however, resulted
in moderate yields summarised in Table 1, entries 3–4.
We screened various solvents including tetrahydrofuran (THF), 1,4-dioxane,
acetonitrile, dimethylformamide (DMF), water and ethanol, and the results are
shown in Table 2, entries 1–6. Interestingly, the results shows that there was no
condensation under the same reaction conditions, possibly be due to thermody-
namical control.
One of the advantages of using a heterogenous catalyst is the possibility to
recycle the catalyst, thus reducing the cost and environmental impact of the process.
Moreover, the reusability of the Pd NP catalyst was examined. It was found that
the catalyst can be reused for another four consecutive runs under similar reaction
123

R. R. Harale et al.
Yielda (%)
Table 2 Screening of solvents
Entry
Solvent
Temp.
Time (min)
1
2
3
4
5
6
7
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100 °C
60
60
60
60
60
60
60
No condensation
No condensation
No condensation
No condensation
No condensation
No condensation
89
1,4-Dioxane
Acetonitrile
DMF
Reaction conditions: 1a
(0.002 mol), 2a (0.002 mol), 3
(0.004) Pd NPs catalyst (10 mol
%) in solvent (5 mL)
Water
Ethanol
Solvent-free
a
Isolated yield
Table 3 Recovery and
recycling of Pd NPs
Entry
Run
Yielda (%)
1
2
3
4
I
89
87
85
80
Reaction conditions: 1a
(0.002 mol), 2a (0.002 mol), 3
(0.004), Pd NP catalyst
II
III
IV
(10 mol%), stirred at 100 °C
(solvent-free) for 60 min
conditions. After each run, the reaction mixture was centrifuged at 4000 rpm at RT
for 5–7 min and filtered. Then, the residue was washed with water and reused.
To investigate this key feature, four successive condensations of 1a were
performed with Pd NPs which were recovered by centrifugation after each cycle and
reused in the next reaction. It was observed that the recovered Pd NPs worked with
good efficiency up to 2nd run (Table 3, entries 1–2), while in the 3rd and 4th runs
(Table 3, entries 3 and 4), the yield of the product was decreased slightly.
Catalyst behavior
We report one-pot, three-component synthesis of 4-thiazolidinone derivatives
catalyzed by Pd NPs as the heterogenous catalyst under solvent-free conditions.
While performing the whole experiment, it was observed that the catalyst was
recovered and reused four times for the model reaction with no significant loss of
activity and mass loss (Table 3). Moreover, Pd NPs were free from leaching and
nanosalts with a –SH substrate group. It is clear from TEM analysis that the Pd NP
catalyst recovered after four cycles showed no major changes in its morphology
(Fig. 1c).
Having been inspired by these observations and to generalize the synthetic
procedure, a variety of electronically divergent aromatic aldehydes and aromatic
amines were treated with mercaptoacetic acid at 100 °C in the presence of Pd NPs.
Aromatic aldehydes with several functionalities such as –Cl, –OH, –CH3, –OCH3
and –NO2 were found to be compatible under the optimized reaction conditions. Our
conclusive findings say that aldehydes having no substituent on the phenyl ring
reacted smoothly and products were obtained in excellent yields, ranging from 89 to
90 % (Table 4, entries 1–2). Electron-donating groups such as –OCH3, –CH3and –
123

Pd nanoparticles: an efficient catalyst for the solvent…
Table 4 Synthesis of
4-thiazolidinone derivatives
Entries Compounds
R
R1
Yielda (%) M.P.b (°C)
1
4a
4b
4c
4d
4e
4f
H
H
89
90
84
75
81
73
65
88
71
83
105–107
111–113
130–132
124–126
158–160
115–117
155–157
182–184
110–111
158–160
148–150
112–114
210–211
105–107
139–141
132–134
118–120
2
H
Cl
H
3
Cl
4
Cl
Cl
Cl
H
5
OH
CH3
CH3
OH
OCH3
6
7
4g
4h
4i
Cl
H
8
9
H
10
11
12
13
14
15
16
17
4j
OCH3 Cl
4k
4l
OCH3 CH3 85
Reaction conditions: aldehydes
(0.002 mol), 2a (0.002 mol), 3
(0.004 mol), Pd NP catalyst
(10 mol%), stirred at 100 °C for
60 min
H
CH3 78
CH3 75
4m
4n
4o
4p
4q
OH
NO2
NO2
F
H
73
80
86
82
Cl
Cl
Cl
a
Isolated yields
b
Melting points were in good
agreement with literature values
Br
OH present in the parent aldehydes afforded moderate yields in the products
(Table 4, entries 6–11). The presence of the –NO2 group in the aldehydes (Table 4,
entries 14–15) showed enhancement in the product yield. Furthermore, the
4-thiazolidinone products were isolated and characterized, and their melting points
were found to be in good agreement with those reported in the literature [27, 28]. To
show the merits of this work over the methods reported in the literature, comparison
of results obtain by use of Pd NPs with different catalysts like, [bmim][PF6], PEG-
400, Bi(SCH2COOH)3, HClO4–SiO2, Silica gel, Saccharomyces cerevisiae shown
in Table 5.
In a plausible mechanism, the electrophilic characteristics of the carbonyl carbon
of aldehydes and mercaptoacetic acid have been enhanced due to non-covalent
interaction with Pd NPs [23]. The nucleophilic addition of a mercapto group of
mercapto acetic acid on the imino intermediate (generated in situ) resulted in
intermediate (A). The intermediate (B) plays an important role in the rate of
reaction, because the rate of the reaction depends upon the rate of dehydration from
this intermediate. Especially (1) the non-covalent interaction of Pd NPs and (2)
solvent-free stirring at 100 °C, these two conditions might be responsible for
accelerating the rate of reaction by rapid removal of water molecules (dehydration
step) (Scheme 2).
123

R. R. Harale et al.
Table 5 Comparative study of Pd NPs (our studies) and other catalysts reported for synthesis of
4-thiazolidinone derivatives
Entry
Catalyst/solvent
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
[bmim][PF6]
80
5–9
2
47–92
58–92
75–90
70–87
77–96
71–72
65–90
PEG-400
50
Bi(SCH2COOH)3, solvent-free
HClO4–SiO2, toluene
Silica gel, DCM
70
2
100
RT
RT
100
3–6
3–7
40
1
Saccharomyces cerevisiae, THF
Pd NPs, solvent-free
R1
N
2
H
Ph
R1
N
H
HS
O
Ph
O
OH
O
N
R1
S
Ph
(B)
H
O
OH
(A)
O
N
H
R1
S
S
OH
N
Ph
Ph
R1
Scheme 2 Plausible mechanism for 4-thiazolidinones
Conclusion
In conclusion, a novel and efficient synthetic method has been developed for the
preparation of 2,3-disubstituted-4-thiazolidinone derivatives by using as-synthesised
Pd NPs as a recyclable catalyst. The key features of this protocol are its simple
reaction conditions, excellent product yields, applicability to a wide range of
substrates and its benign nature by avoiding the use of volatile and poisonous
conventional organic solvents; these features make this present protocol more
innovative than existing ones.
Acknowledgments An Emeritus Scientist Fellowship awarded to M.S.S. by the Council of Scientific
and Industrial Research, New Delhi (project vide no. 21(0919)/12/EMR-II dated 25-04-2013) is gratefully
acknowledged. The authors are grateful to the Department of Chemistry, Dr. B. A. M. University,
Aurangabad, for providing the laboratory facilities. We also thank SAIF Division, CDRI, Lucknow, for
providing analytical data.
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Pd nanoparticles: an efficient catalyst for the solvent…
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