Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5, 4-d]pyrimidine-2,5-diones

Article abstract of DOI:10.1016/j.crci.2012.04.002

A simple, green and catalyst free one pot synthesis of 7-phenyl-1,4,6,7- tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones via a multicomponent reaction between thiazolidine-2, 4-dione (TZD), aromatic aldehyde and urea analogues is described. The ionic liquid has been used as a solvent as well as catalyst for this reaction. This reaction proceeded smoothly in good to excellent yields and offered several other advantages including short reaction time, simple experimental workup procedure and no by-products.

Full text of DOI:10.1016/j.crci.2012.04.002

C. R. Chimie 15 (2012) 504–510
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Preliminary communication/Communication
Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo
[5,4-d]pyrimidine-2,5-diones
c
c
b
Prashant Singh a,b, , Kamlesh Kumari , Monica Dubey , Vijay K. Vishvakarma ,
*
Gopal K. Mehrotra c, Narender D. Pandey c, Ramesh Chandra d
a A.R.S.D. College, University of Delhi, New Delhi 110021, India
b Department of Applied Chemistry, BBA University, Lucknow, UP, India
c Department of Chemistry, MNNIT Allahabad, UP, India
d ACBR, University of Delhi, New Delhi 110007, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple, green and catalyst free one pot synthesis of 7-phenyl-1,4,6,7-tetrahydro-
thiazolo[5,4-d]pyrimidine-2,5-diones via a multicomponent reaction between thiazoli-
dine-2, 4-dione (TZD), aromatic aldehyde and urea analogues is described. The ionic liquid
has been used as a solvent as well as catalyst for this reaction. This reaction proceeded
smoothly in good to excellent yields and offered several other advantages including short
reaction time, simple experimental workup procedure and no by-products.
Received 21 January 2012
Accepted after revision 6 April 2012
Available online 23 May 2012
Keywords:
Tetrahydro-thiazolo[5,4-d]pyrimidine-
2,5-diones
ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
One pot synthesis
Catalyst free
Ionic liquid
1. Introduction
as useful tools for synthesizing small drug-like mole-
cules with several degrees of structural diversity [5–10].
Heterocyclic compounds bearing nitrogen and sul-
phur have long been the prime focus of synthetic
chemistry research due to their broad spectrum of
applications in biological, pharmaceutical, and material
areas [1,2]. Mainly, thiazolidines containing ketonic
group have attracted much attention due to their
interesting and unique properties such as protein-
nucleic acid interactions, antiviral activity and antidia-
Pioneering work by several research groups in this area
has already established the versatility and uniqueness of
one pot multicomponent coupling protocols as
a
powerful methodology for the synthesis of diverse
structure scaffolds required in the search of novel
therapeutic molecules [11–14].
Thiazolidinone derivatives have been extensively used
in drug discovery. They are reported to have anticonvul-
sant, antibacterial, antiviral and antidiabetic properties.
For example, pioglitazone and rosiglitazone were launched
recently for type-II diabetes mellitus [15–19]. Presence of
these moieties in organic molecules imparts them with the
extensive range of biological and pharmacological proper-
ties, such as antidiabetic, anticancerous and antimicrobial
activities. Moreover, these compounds are also useful as
conducting materials. Many of the methods reported for
the synthesis of organic compounds are associated with
the use of hazardous organic solvents, long reaction time,
betic activity. However, to our knowledge,
a few
methods were developed to construct polysubstituted
thiazolones. Here over, some of these protocols have not
been entirely satisfactory because of drawbacks such as
low yields, long reaction time and cumbersome experi-
mental processes [3,4]. One pot syntheses are emerging
* Corresponding author.
E-mail address: arsdchemistry@yahoo.in (P. Singh).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.04.002

P. Singh et al. / C. R. Chimie 15 (2012) 504–510
505
Scheme 1. Mechanism for the synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones.
and lack of general applicability. Thus, we developed a
2. Experimental
simple one pot synthesis of novel 7-phenyl-1,4,6,7-
tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones under
catalyst free conditions.
In
a
typical experiment, thiazolidine-2, 4-dione
(10 mmol), aromatic aldehydes (10 mmol) and thiourea
Table 1
Optimization of reaction conditions (solvent, mole ratio and temperature of the reactants) for the catalyst free multicomponent reactionsa.
O
CHO
O
S
S
NH
Ionic liquid, 80 °C
HN
}
S
H2N
NH2
+
+
HN
O
NH
4a
S
1
2a
3a
S. no.
Solvent
Mole ratio (1:2a:3a)
t (h)
Temp (8C)
Yield (%)
1
Dioxane
CH3CN
DMF
1:1:1
6
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
45
60
80
65
2
1:1:1
7
64
3
1:1:1
14
8
65
4
Toluene
None
1:1:1
50
5
1:1:1
18
16
8
Complex
55
6
DMSO
THF
1:1:1
7
1:1:1
70
8
[NEt3][Ac]
1:1:1
4
80
9
[bmim][Cl]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
1:1:1
4
78
10
11
12
13
14
15
16
17
18
1:1:1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
80
1:1:1.1
1:1:1.2
1:1:1.3
1:1:0.9
1:1:0.8
1:1:1.1
1:1:1.1
1:1:1.1
84
80
75
72
62
85
90
94
aThe reactions were carried out amongst thiazolidine-2,4-dione (1), benzaldehyde (2a) and thiourea (3a) in a solvent (15 mL).

506
P. Singh et al. / C. R. Chimie 15 (2012) 504–510
Table 2
Catalyst free one pot synthesis of 9-phenyl-3,9-dihydro-chromeno [2,3-d] thiazol-2-one via MCRs between thiazolidine-2,4-dione, aromatic aldehyde, urea
derivative.
O
CHO
R
O
Ionic liquid, 80 0C
X
S
NH
HN
S
H2N
NH2
+
+
HN
}
O
R
NH
X
1
2
3
4
1
:
1
:
1.1
Equivalents
S. no.
1
Reactant2
Reactant3
Product
Compound number
4a
t (h)
2.5
Yield (%)
94
NH2
O
CHO
H2N
H2N
S
NH
NH
S
HN
NH
NH2
O
S
2
3
4
5
6
7
4b
4c
4d
4e
4f
3.0
2.0
2.0
3.0
3.5
4.5
90
92
92
95
93
88
O
O
O
O
CHO
CHO
S
HN
O
NH
NH2
S
H2N
H2N
S
NH
HN
S
NO2
NO2
O
NO2
NH
NH2
O
CHO
S
NH
HN
O
NO2
NH
CHO
NH2
S
S
NH
H2N
O
HN
S
NH
CHO
NH2
O
O
H2N
H2N
S
NH
O
HN
O
O
NH
NH2
S
4g
CHO
O
S
NH
HN
Cl
Cl
NH
S

P. Singh et al. / C. R. Chimie 15 (2012) 504–510
507
Table 2 (Continued )
O
CHO
R
O
Ionic liquid, 80 0C
X
S
NH
HN
S
H2N
NH2
+
+
HN
}
O
R
NH
X
1
2
3
4
1
:
1
:
1.1
Equivalents
S. no.
8
Reactant2
Reactant3
Product
Compound number
4h
t (h)
5.0
Yield (%)
NH2
84
86
82
94
92
90
90
H2N
CHO
O
O
S
NH
NH
HN
Cl
Cl
NH
NH2
S
O
9
4i
6.0
7.5
6.0
6.0
6.0
6.0
H2N
O
O
O
O
O
CHO
Cl
Cl
Cl
S
HN
S
NH
10
11
12
13
14
4j
NH2
O
CHO
CHO
CHO
CHO
H2N
Cl
S
NH
HN
O
NH
4k
NH2
S
H2N
S
NH
NO2
NO2
HN
S
NH
4l
NH2
O
H2N
H2N
S
NH
NO2
NO2
HN
O
NH
NH2
S
4m
S
NH
HN
S
F
F
F
NH
4n
NH2
O
O
CHO
H2N
S
NH
HN
O
F
NH

508
P. Singh et al. / C. R. Chimie 15 (2012) 504–510
Table 2 (Continued )
O
CHO
R
O
Ionic liquid, 80 0C
X
S
NH
HN
S
H2N
NH2
+
+
HN
}
O
R
NH
X
1
2
3
4
1
:
1
:
1.1
Equivalents
S. no.
15
Reactant2
Reactant3
Product
Compound number
4o
t (h)
6.5
Yield (%)
88
NH2
O
CHO
H2N
S
NH
NH
S
HN
Br
Br
Br
NH
S
16
4p
6.5
84
NH2
O
O
CHO
H2N
S
HN
O
Br
NH
(11 mmol) in ionic liquid {[bmim]Br} (15 mL) was stirred at
room temperature (80 8C) for the appropriate time. The
completion of the reaction was monitored by thin layer
chromatography (ethyl acetate: n-hexane: 20: 80). After the
completion of reactions, the compound was isolated from
the reaction mixture by the addition of ethyl ether (three
times  30 mL) and further washed with brine solution
(three times  30 mL). Then ethyl ether was evaporated
under reduced pressure to afford the corresponding
product. Structural assignments of the products are based
on their 1H NMR, 13C NMR, FT-IR and mass analysis. The
analysis of complete spectral and compositional data
revealed the formation of corresponding derivatives in
85–95% yield. The ionic liquid used for the transformation
was recovered and used for the further reactions.
liquid {[bmim]Br} proved to be the best among them
(Table 1, entry 10), while under solvent free conditions, a
complex result was obtained (Table 1, entry 5). To
modulate the ratio of reactants and improve the yield,
we examined various ratios of thiazolidine-2, 4-dione (1),
benzaldehyde (2a) and thiourea (3a) by using ionic liquid
{[bmim]Br} as a solvent (Table 1, entries 10–15). The best
result obtained when the ratio of thiazolidine-2, 4-diones
(1), benzaldehyde (2a) and phenol (3a) is 1:1:1.1 to afford
the product 4a i.e. entry 12. Further, optimization of
temperature was done (Table 1, entries 16–18) and we
found the best yield was obtained at 80 8C (entry 17).
With the optimized condition in hand, we examine the
scope of the multicomponent reaction (Table 2, entries 1–
16). We are pleased to find that the reaction proceeded
smoothly, and the desired products were afforded in
excellent yields. Meaningfully, the substituted group on
the thiazolidine ring could not be selectively induced by
changing the addition order of the aromatic aldehyde and
urea/thiourea under the same employed conditions. The
ionic liquid used for the transformation was recovered and
used for further reactions and gave good yield for further
3. Result and discussion
Thiazolidine-2,4-dione (1) reacts with benzaldehyde
(2a) and thiourea (3a) to afford the product 7-Phenyl-
1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-dione
(4a) in excellent yield (Scheme 1, 94%). The reaction of
thiazolidine-2,4-dione (1) with benzaldehyde (2a) and
thiourea could rapidly form (A) after dehydration. Further
dehydration of A will occur and coupling processes to
afford the target compound (4a). Screening of the reaction
conditions was established suitable solvents, the mole
ratio of reactants as well as temperature for the desired
MCRs (Table 1). It was exciting that the chosen solvents
such as dioxane, N,N–dimethylformamide (DMF), acetoni-
trile (CH3CN), dimethylsulfoxide (DMSO), toluene, etc.
were suitable for the MCRs (Table 1, entries 1–10). Ionic
Table 3
Optimization of the activity of ionic liquid for the synthesis of 4a after
reuse.
S. no.
No. of cycle
Yield (%)
1
2
3
4
5
I
95
94
94
92
92
II
III
IV
V

P. Singh et al. / C. R. Chimie 15 (2012) 504–510
509
Table 4
Optimization and various parameters of the synthesized compounds.
Thermodynamic properties
Compound
Single point
Optimization
Total E
Entropy
Total Free
H (Kcal/mol/deg)
energy (kcal/mol)
energy (kcal/mol)
(Kcal/mol)
(Kcal/mol/deg)
E (Kcal/mol)
1
2
3
4
6604.986
6681.347
12.668
17.283
36.564
21.288
44.367
50.640
0.0716
0.069
0.095
0.099
22.879
29.936
101.392
83.722
0.0137
0.0120
0.0326
0.0338
18193.481
16901.238
129.907
113.479
reactions as shown in Table 3. The mechanism has been
justifiesd through a semi-empirical calculation on the basis
of their energy and the same have incorporated in the
manuscript as Table 4.
thiourea, and thiazolidine-2,4-dione in excellent yields
within a short reaction time. The advantages offered by
ionic liquid as a solvent versus known organic solvent are:
ꢀ
ꢀ
ꢀ
ꢀ
the ionic liquid has high vapor pressure;
highly stable;
reusable;
4. Conclusion
environmentally benign.
In conclusion, a series of biologically and pharmacolog-
ically 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimi-
dine-2,5-diones have been synthesized via one pot three
component condensation of aromatic aldehyde, urea/
The exploration of ionic liquid for other multicompo-
nent reactions leading to biologically active compounds is
underway.
Analytical data of the few selected compounds.
C. no.
4a
Data
IR (
n
in cmÀ1) 3154.21, 2946.72, 2864.15, 1742.20, 1695.46, 1461.08, 1356.26, 1245.70, 1179.92, 807.37, 652.48; 1H NMR
(300 MHz, d-DMSO)
1.98 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO)
(129.3, 125.7, 120.1), for alkenic carbon (113.0, 110.5), benzylic carbon (65.8), HRMS (M+ ion peak) 263.0154.
d
8.45 (s, 1H of NH), 7.00–7.19 (m, 5H),
d 4.58 (s, 1H of benzylic proton), 2.54 (s, 1H of NH),
d
for thiourea carbon (184.6), carbonyl carbon (165.1), aromatic carbon
d
4b
4c
4d
4e
IR (
n
in cmÀ1) 3165.43, 2932.45, 2874.32, 1741.05, 1699.46, 1459.52, 1368.06, 1246.98, 1162.01, 816.09, 665.97; 1H NMR
(300 MHz, d-DMSO) 8.14 (s, 1H of NH), 6.98–7.20 (m, 5H), 4.46 (s, 1H of benzylic proton), 2.79 (s, 1H of NH), 1.95 (s, 1H of NH);
13C NMR (75 MHz, d-DMSO)
for thiourea carbon (182.0), carbonyl carbon (163.4), aromatic carbon (130.1, 123.0, 119.1),
for alkenic carbon (113.9, 111.6), benzylic carbon (66.0), HRMS (M+ ion peak) 247.3248.
d
d
d
d
IR (
n
in cmÀ1) 3165.48, 2932.45, 2872.45, 1746.89, 1699.05, 1469.15, 1378.65, 1260.65, 1170.05, 812.65, 666.01; 1H NMR
(300 MHz, d-DMSO) 8.65 (s, 1H of NH), 7.01-7.29 (m, 4H), 4.65 (s, 1H of benzylic proton), 2.36 (s, 1H of NH), 2.09 (s, 1H of NH);
13C NMR (75 MHz, d-DMSO)
for thiourea carbon (179.3), carbonyl carbon (162.3), aromatic carbon (131.4, 126.8, 121.7), for
alkenic carbon (116.5, 111.0), benzylic carbon (62.2), HRMS (M+ ion peak) 308.4565.
d
d
d
d
IR (
n
in cmÀ1) 3189.13, 2945.65, 2879.03, 1726.78, 1679.09, 1446.46, 1362.19, 1239.62, 1180.49, 812.36, 666.03; 1H NMR
(300 MHz, d-DMSO) 8.49 (s, 1H of NH), 7.05–7.35 (m, 4H), 4.62 (s, 1H of benzylic proton), 2.63 (s, 1H of NH), 2.00 (s, 1H of NH);
13C NMR (75 MHz, d-DMSO)
for thiourea carbon (180.4), carbonyl carbon (161.0), aromatic carbon (131.0, 124.9, 121.8), for
alkenic carbon (114.7, 111.7), benzylic carbon (66.9), HRMS (M+ ion peak) 292.8706.
d
d
d
d
IR (
n
in cmÀ1) 3123.35, 2922.33, 2846.72, 1716.29, 1666.13, 1476.43, 1365.08, 1246.35, 1182.69, 832.35; 1H NMR
(300 MHz, d-DMSO) 8.26 (s, 1H of NH), 6.79–7.33 (m, 4H), 4.46 (s, 1H of benzylic proton), 2.60 (s, 1H of NH),
2.32 (s, 3H of methyl), 1.89 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO)
for thiourea carbon (185.6),
for alkenic carbon (112.6, 111.7), benzylic carbon (63.1),
d
d
d
carbonyl carbon (167.0), aromatic carbon (130.0, 125.0, 121.7),
HRMS (M+ ion peak) 239.5987.
d
4f
IR (
(300 MHz, d-DMSO)
2.12 (s, 3H of methyl), 1.86 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO)
n
in cmÀ1) 3102.32, 2978.29, 2878.45, 1732.49, 1702.23, 1465.78, 1321.22, 1246.08, 1145.65, 845.38, 615.95; 1H NMR
8.11 (s, 1H of NH), 6.83–7.29 (m, 4H), 4.62 (s, 1H of benzylic proton), 2.46 (s, 1H of NH),
for thiourea carbon (188.0), carbonyl carbon
for alkenic carbon (115.7, 113.9), benzylic carbon (60.6),
d
d
d
(164.9), aromatic carbon (131.0, 126.4, 124.4),
HRMS (M+ ion peak) 277.6598.
d
4g
4h
IR (
(300 MHz, d-DMSO)
n
in cmÀ1) 3202.15, 2938.46, 2873.09, 1739.15, 1738.45, 1489.15, 1375.17, 1260.19, 1154.28, 836.97, 666.67; 1H NMR
d
8.23 (s, 1H of NH), 6.88–7.10 (m, 4H),
d
4.32 (s, 1H of benzylic proton), 2.35 (s, 1H of NH), 1.89 (s, 1H of NH);
13C NMR (75 MHz, d-DMSO)
d for thiourea carbon (181.6), carbonyl carbon (166.5), aromatic carbon (128.4, 126.3, 122.7), d for
alkenic carbon (115.1, 111.2), benzylic carbon (61.0), HRMS (M+ ion peak) 297.8977.
IR (
n
in cmÀ1) 3208.65, 2945.68, 2879.46, 1719.18, 1689.39, 1461.08, 1354.72, 1298.15, 1183.36, 835.79, 679.15; 1H NMR
(300 MHz, d-DMSO) 8.32 (s, 1H of NH), 7.00–7.19 (m, 4H), 4.18 (s, 1H of benzylic proton), 2.24 (s, 1H of NH), 1.84 (s, 1H of NH);
13C NMR (75 MHz, d-DMSO)
for thiourea carbon (186.0), carbonyl carbon (160.9), aromatic carbon (124.7, 122.0, 119.3), for
alkenic carbon (111.7, 108.7), benzylic carbon (61.1), HRMS (M+ ion peak) 281.0350.
d
d
d
d

510
P. Singh et al. / C. R. Chimie 15 (2012) 504–510
[7] Z. Jian, Z. Yongmin, Z. Xia, Z. Jing, Z.Li. He, Y. Xin-Shan, Z. Xiao-Lian,
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