Ionic liquid mediated and promoted eco-friendly preparation of thiazolidinone and pyrimidine nucleoside-thiazolidinone hybrids and their antiparasitic activities

Article abstract of DOI:10.1016/j.bmcl.2009.09.101

Without any catalyst, 2,3-disubstituted-1,3-thiazolidin-4-one derivatives were synthesized efficiently via the three-component reaction of aldehyde, amine and mercaptoacetic acid in [bmim][PF₆]. The whole procedure is simple and straightforward

Full text of DOI:10.1016/j.bmcl.2009.09.101

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6280–6283
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Ionic liquid mediated and promoted eco-friendly preparation of thiazolidinone
and pyrimidine nucleoside–thiazolidinone hybrids and their
antiparasitic activities
a
b
Xinying Zhang a, Xiaoyan Li a, Dongfang Li a, Guirong Qu a, , Jianji Wang , Philippe M. Loiseau ,
*
Xuesen Fan a,
*
a School of Chemistry and Environmental Sciences, Henan Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan 453007, PR China
b Chimiothérapie Antiparasitaire, UMR-CNRS 8076, Université Paris-Sud, 92290 Chatenay Malabry F-92290, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2009
Revised 9 September 2009
Accepted 25 September 2009
Available online 29 September 2009
Without any catalyst, 2,3-disubstituted-1,3-thiazolidin-4-one derivatives were synthesized efficiently via
the three-component reaction of aldehyde, amine and mercaptoacetic acid in [bmim][PF6]. The whole
procedure is simple and straightforward and no aqueous work-up is needed. By employing this protocol,
a series of novel pyrimidine nucleoside–thiazolidin-4-one hybrids were prepared and their preliminary
antiparasitic activities were also studied and reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Thiazolidinone
Pyrimidine nucleoside–thiazolidinone
Hybrids
Ionic liquid
Eco-friendly synthesis
Multi-component reaction
Antiparasitic activities
It is well known that thiazolidinone and their derivatives are
important heterocyclic compounds due to their broad biological
activities such as anti-inflammatory,1 antiproliferative,2 anti-
cyclooxygenases (COX-1 and COX-2),3 anti-histaminic4 and anti-
bacterial activities.5 More importantly, some of the 2,3-diaryl-
1,3-thiazolidin-4-ones were found to be highly effective against
HIV-1 replication, thereby acting as non-nucleoside HIV-I reverse
transcriptase inhibitors (NNRTIs).6 Recently, they were also found
to be potent as inhibitors for HCV NS5B RNA polymerase.7 As a re-
sult, various protocols have been developed to prepare more struc-
turally diverse thiazolidinones and related compounds for
quantitative structure–activity relationship (QSAR) studies. Gener-
ally, the thiazolidinone ring was constructed by a three-compo-
nent reaction of aldehyde, amine and mercaptoacetic acid via a
sequence of imine formation, sulfur nucleophilic attack on the
imine carbon and intramolecular cyclization. Usually, the above
process is realized in benzene or toluene under reflux with a
Dean–Stark trap or molecular sieves to remove the in situ formed
water and drive the reaction to complete.6b,d,f,8 There are also re-
assist the formation of thiazolidinone derivatives. Katti et al. re-
ported a novel process by employing DCC to promote the reaction
and the product was obtained with high yield.11 Bazureau et al.
also reported an alternative method by using a combination of
task-specific ionic liquid and microwave dielectric heating.12 More
recently, Yan et al. reported a microwave-assisted fluorous synthe-
sis of 2-aryl-substituted thiazolidinone library.13 However, some
of these reported methods still suffered one or more limitations
such as using either poisonous solvent or expensive catalyst,
employing specific apparatus, necessitating long reaction period
and tedious handling processes, resulting in low or moderate
yields. Therefore, it is of interest to develop highly efficient and
more practical method for the preparation of this important het-
erocyclic framework.
The development of environmentally friendly catalysts and sol-
vents for organic chemistry and medicinal chemistry is an area of
considerable importance. From both economical and environmen-
tal points of view, the use of non-volatile solvents and green cata-
lysts is very promising. In the last a few years room temperature
ionic liquids (RTILs) have been recognized as a possible environ-
mentally benign alternative to chemical volatile solvents because,
in contrast with the conventional organic solvents, they are non-
volatile, non-explosive, easy to handle, thermally robust and recy-
9
ports using anhydrous ZnCl2 or sodium sulfate10 as desiccant to
* Corresponding authors. Tel.: +86 373 3329261 (X.F.).
E-mail address: xuesen.fan@yahoo.com (X. Fan).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.101

X. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6280–6283
6281
R
NO2
CHO
NH2
HO
[bmim][PF6]
80 °C
SH
HO
R'
S
N
O
solvent
R-CHO
+
R'-NH2
+
SH
+
O
+
O
1
2
3
H3C
S
N
O
NO2
CH3
4
1a
2a
3
Scheme 2.
4a
Scheme 1.
Table 3
Preparation of compound 4 in [bmim][PF6]a
Table 1
Preparation of 4a under different reaction conditionsa
Entry
R
R0
Product Reaction time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
p-NO2C6H4 p-CH3C6H4 4a
5
5
7
7
6
7
9
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
87
91
76
80
83
81
47
56
75
80
81
48
82
85
80
81
92
76
80
88
90
87
Entry
Solvent
Temperature (°C)
Reaction time (h)
Yield (%)
p-NO2C6H4 p-ClC6H4
4b
4c
4d
1
2
3
4
5
6
7
8
9
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][BF4]
CH2Cl2
EtOH
THF
Toluene
rt
50
70
80
90
80
Reflux
Reflux
Reflux
Reflux
10
8
6
5
5
50
76
82
87
87
74
55
10
30
85
p-ClC6H4
p-CH3C6H4
p-ClC6H4
p-FC6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4 4e
p-CH3C6H4 4f
p-ClC6H4
p-CH3C6H4
p-BrC6H4
p-BrC6H4
p-FC6H4
2-Pyridyl
p-CH3C6H4 4h
p-CH3C6H4 4i
p-ClC6H4
p-ClC6H4
2-Pyridyl
p-BrC6H4
p-BrC6H4
p-BrC6H4
p-BrC6H4
4g
8
24
24
24
8
4j
4k
4l
4m
4n
4o
4p
4q
4r
10
p-FC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
p-CH3C6H4
p-NO2C6H4 p-BrC6H4
a
Reaction conditions: 1 mmol of 1a, 2a and 3, respectively; 1.5 g of [bmim][PF6]
for entries 1–6, or 4 mL of solvent for entries 7–10.
o-ClC6H4
o-BrC6H4
p-ClC6H4
p-BrC6H4
Table 2
4s
Studies on the recovery and reuse of [bmim][PF6]a
o-NO2C6H4 p-CH3C6H4 4t
o-NO2C6H4 p-BrC6H4
o-NO2C6H4 p-ClC6H4
4u
4v
Round
Time (h)
Temperature (°C)
Yield (%)
IL recovered (w/w%)
1
2
3
4
5
5
5
5
5
5
80
80
80
80
80
87
88
85
83
80
98
97
97
95
93
a
Reaction conditions: 1 mmol of 1, 2 and 3, respectively; 1.5 g of [bmim][PF6];
80 °C.
b
Isolated yields.
a
Reaction conditions: 1 mmol of 1a, 2a and 3, respectively; 1.5 g of [bmim][PF6]
was used for the first run.
create a micro-environment to drive the equilibrium by extruding
water out of the ionic liquid phase and thus result in a higher
conversion.
clable.14 Accordingly they are emerging as novel replacements for
volatile organic solvents in organic synthesis.15
The same reaction was also run in several conventional organic
solvents and the results were also included in Table 1. Comparing
with CH2Cl2, EtOH and THF, ionic liquids exhibited enhanced reac-
tivity by reducing reaction time and improving the yields signifi-
cantly. For example, treatment of 1a, 2a and 3 in [bmim][PF6]
afforded 4a in 87% over 5 h at 80 °C whereas the same reaction
in refluxing CH2Cl2 gave 4a in a yield of 55% over 24 h (Table 1, en-
tries 4 and 7). When EtOH or THF was used, the yield of 4a was
even lower (Table 1, entries 8 and 9) with the corresponding imine
as the main product. On the other hand, toluene gave comparable
result in terms of yield (Table 1, entry 10). However, as one of the
environmental priority pollutants, toluene poses a serious threat to
the environment.17 Therefore it is not a solvent of choice for sus-
tainable chemistry. In contrast, [bmim][PF6] is non-volatile and
easy to handle, thus acting as a benign and efficient medium.
The recovery and reuse of [bmim][PF6] were also studied, and
1a, 2a and 3 were used as model substrates. Upon completion of
the condensation process, 4a was obtained by thorough extraction
with diethyl ether and the remaining ionic liquid phase was recy-
cled in subsequent reactions. Further studies showed that the
recovered [bmim][PF6] could be successively recycled for at least
five times without obvious loss in its efficiency (Table 2).
Considering the fact that ILs have been used as useful and effi-
cient media for esterification reactions in despite of the in situ for-
mation of water16 because they can create an opportunity to drive
the equilibrium, we studied the possibility of employing the easily
made 1,3-dialkylimidazolium cation based ionic liquid as green
and efficient solvent for the preparation of thiazolidinone deriva-
tives via the three-component condensation of aldehyde, amine
and mercaptoacetic acid.
Our study was initiated by the reaction of 4-nitrobenzaldehyde
(1a), 4-methylphenylamine (2a) and mercaptoacetic acid (3)
(Scheme 1). The effect of different solvents, various temperature
conditions on the condensation process was studied and the re-
sults were summarized in Table 1.
It turned out that the multi-component reaction of 1a, 2a and 3
went smoothly in an ionic liquid, [bmim][PF6], 1-butyl-3-methyl-
imidazolium hexafluorophosphate, and gave the corresponding
2,3-disubstituted-1,3-thiazolidin-4-one (4a). The yield of 4a in-
creased remarkably with the temperature increasing until 80 °C
(Table 1, entries 1–5). Interestingly, of the two ILs studied, namely
[bmim][PF6] and [bmim][BF4], [bmim][PF6] gave better result (Ta-
ble 1, entries 4 and 6), presumably due to its hydrophobic activa-
tion activity. It is postulated that water formed in situ from the
condensation process is miscible with hydrophilic [bmim][BF4]
and thus detained, which prevents the reaction from going com-
pletely. In contrast, the hydrophobic nature of [bmim][PF6] would
Encouraged by the results obtained above, we extended this
process to various aldehyde and amine substrates to gain more in-
sight into this reaction (Scheme 2). It turned out that in
[bmim][PF6], various aldehyde and amine substrates reacted
smoothly with mercaptoacetic acid and afforded the corresponding

6282
X. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6280–6283
O
O
N
OHC
NH
HN
N
OAc
O
O
O
HO
R' NH2
+
[bmim][PF6]
80 °C
AcO
SH
+
O
OAc
S
R'
N
O
OAc
O
5
2
3
6
Scheme 3.
studies on the applications of ionic liquids in the preparation of
nucleoside derivatives are still limited.20
Table 4
Preparation of compound 6 in [bmim][PF6]a
The preparation was realized from the reaction of 5-formyl-20-
deoxyuridine, acting as an aldehyde, with amines and mercaptoa-
cetic acid by employing [bmim][PF6] as the reaction medium and
promoter. Thus, 30,50-di-O-acetyl-5-formyl-20-deoxyuridine (5),
previously prepared from thymidine, was treated with aromatic
amines (2) and mercaptoacetic acid (3) in [bmim][PF6] (Scheme
3). The results were included in Table 4. It turned out that under
the optimized reaction condition, 5 reacted smoothly with various
amine substrates and mercaptoacetic acid and afforded the desired
hybrids (6) in good to moderate yields.
As nucleosides are known to exhibit antileishmanial and try-
panocidal activities21, the hybrid compounds were evaluated
against trypomastigote forms of Trypanosoma brucei brucei GVR
35 and promastigote forms of Leishmania donovani LV9. The results
are listed in Table 5.
Entry
R0
Product
Reaction time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
6a
6b
6c
6d
6e
6f
6
5
6
6
6
6
8
8
70
75
58
62
65
60
53
50
p-CH3C6H4
p-BrC6H4
p-ClC6H4
p-FC6H4
m-NO2C6H4
2-Pyridyl
6-Br-2-pyridyl
6g
6h
a
Reaction conditions: 1 mmol of 5, 2 and 3, respectively; 1.5 g of [bmim][PF6];
80 °C.
b
Isolated yields.
Table 5
Antiparasitic activities of compounds 6a–ha
As indicated in Table 5, part of the hybrids tested possess mod-
erate activities against trypomastigote forms of T. brucei brucei,
indicating they may be used as lead compounds for further elabo-
ration. On the other hand, they are inactive against promastigote
forms of L. donovani LV9.
Compound L. donovani Promastigote
T. brucei brucei trypomastigote
IC50
(l
M) SD
IC50 (l
M) SDb
6a
6b
6c
6d
6e
6f
>100
>100
NDc
>100
>100
>100
>100
>100
50
100
NDc
25
In summary, a novel and efficient procedure for the preparation
of 2,3-disubstituted-1,3-thiazolinin-4-one derivatives by using io-
nic liquids as recyclable promoter and reaction medium was devel-
oped. The notable advantages of this method include high
efficiency, simple procedure and benign nature by avoiding the
use of volatile and poisonous conventional organic solvents. In
addition, the ionic liquids used were found to be easily recovered
and efficiently reused. With this novel protocol, a series of pyrim-
idine nucleoside–thiazolinin-4-one hybrids were prepared and
part of the hybrids possess moderate activity on trypomastigote
forms of T. brucei brucei. The test of these hybrids as potential
antivirals and the search for the application of the novel process
presented herein in the synthesis of biological interesting com-
pounds are currently underway and the results will be reported
in due course.
50
>100
>100
50
6g
6h
The evaluations were performed as previously described.21
IC50 defined as inhibitory concentration 50%.
ND, not determined.
a
b
c
2,3-disubstituted-1,3-thiazolinin-4-ones (4) in good to excellent
yields (Table 3). It is worth to be noted that the procedure is simple
and convenient, and does not require any aqueous work-up there-
by avoiding the generation of toxic waste.
As a further respect, the ‘privileged’ structure of nucleosides has
led to a variety of efficacious antiviral agents such as AZT, d4T, lam-
ivudine and acyclovir. Many pyrimidine nucleoside analogues with
potent biological properties have arisen by substitution at the 5-
position of the uracil base, particularly in the 20-deoxyuridine ser-
ies.18 In this regard, we have an ongoing program on the design and
preparation of novel 5-substituted pyrimidine nucleoside deriva-
tives with potential biological activities.19 Our approach to new
lead compounds has been guided by the following considerations.
Firstly, the nucleosides scaffold is an excellent point of departure in
the search for new compounds with potential activities; secondly,
other privileged molecular scaffolds, taking thiazolidinone as an
example, has also spawned a significant number of drugs and bio-
logically active agents. With the novel procedure developed in this
paper, we were interested in the preparation of novel hybrids of 5-
substituted pyrimidine nucleoside and thiazolidin-4-ones to get
new entities with synergetic biological activities as potential bio-
logically active agents. To the best of our knowledge, precedent
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (Nos. 20772025 and 20772024) and
Program for Science & Technology Innovation Talents in Universi-
ties of Henan Province (No. 2008HASTIT006). The authors sincerely
thank Professor Dr. Paul F. Torrence, Department of Chemistry,
Northern Arizona University, USA, for his kind help and excellent
instructions.
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