One-pot synthesis of 3,4-dihydro-2(H)-pyrimidinones catalyzed by reusable acidic choline-based ionic liquids

Article abstract of DOI:10.1007/s10562-013-0978-6

A series of choline-based ionic liquids (CIL) have been synthesized in this work. The results suggested that both the cations and the anions have significant influences on their properties such as thermostabilities, acidities and their performances for the synthesis of 3,4-dihydro-2(H)-pyrimidinones. The optimized catalytic system based on the CIL [DMEA][HSO₄] for the Biginelli reactions benefits from the wide substrates tolerance, benign reaction conditions, easy work-up procedures, and the feasible reusability of the ionic liquid. Graphical Abstract: The thermostabilities, acidities, and the catalytic activities for the Biginelli reactions are all follows the sequence of [DMEA][HSO₄] > [Choline] [HSO₄] > [DMEA][H ₂PO₄] > [Choline] [H₂PO₄][Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-013-0978-6

Catal Lett (2013) 143:463–468
DOI 10.1007/s10562-013-0978-6
One-Pot Synthesis of 3,4-Dihydro-2(H)-Pyrimidinones Catalyzed
by Reusable Acidic Choline-Based Ionic Liquids
•
•
•
Anlian Zhu Qianqian Li Lingjun Li
Jianji Wang
Received: 22 January 2013 / Accepted: 14 February 2013 / Published online: 26 February 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of choline-based ionic liquids (CIL)
have been synthesized in this work. The results suggested
that both the cations and the anions have significant
influences on their properties such as thermostabilities,
acidities and their performances for the synthesis of 3,
4-dihydro-2(H)-pyrimidinones. The optimized catalytic
system based on the CIL [DMEA][HSO4] for the Biginelli
reactions benefits from the wide substrates tolerance,
benign reaction conditions, easy work-up procedures, and
the feasible reusability of the ionic liquid.
Knoevenagel reactions [9]. Lewis acidic CILs have excellent
performance in selective esterification of cellulose and direct
nucleophilic substitution of alcohols [4, 10, 11]. However,
non-metallic bronsted acidic CILs have not been reported as
catalysts up to now. Here, a new type of bronsted acidic CILs
was synthesized and their acidities were characterized using
Hammett acidity functions. It was found that this type of
acidic CILs have high thermal stability, which made them
applicable in a wide range of temperature.
It has been acknowledged that the Biginelli reaction is
powerful for the synthesis of 3,4-dihydro-2(H)-pyrimidinones
(DHPMs) which have shown significant pharmaceutical and
therapeutic properties, such as antiviral, antitumor and anti-
bacterial activities [12, 13], and have been suggested to be
useful building blocks for the synthesis of versatile heterocyclic
derivatives [14–16]. Numerous catalytic methods have been
developed for the synthesis of DHPMs including those using
acidic imidazolium ILs as catalysts [17–26]. However, the
present methods are often suffered from low reaction activity,
tedious products isolation and the difficulty to reuse the cata-
lyst. Therefore, it is still necessary to develop recyclable cata-
lytic systems with wide substrate tolerance. In this work, the
synthesized bronsted acidic CILs have been found to have
significant performance in the one-pot synthesis of DHPMs by
the Biginelli reactions, and the catalytic systems are also benefit
from the easy work-up procedures and the convenient reus-
ability of the CILs in addition to the merit of the CILs them-
selves such as much more biocompatible and affordable.
Keywords Choline-based ionic liquids ꢀ
Thermostabilities ꢀ Acidities ꢀ Biginelli reactions ꢀ
3,4-Dihydro-2(H)-pyrimidinones
1 Introduction
Choline-based ionic liquids (CILs) are promising in catalytic
processes due to their superiority in the ecological effect and
economic reasons [1, 2]. Literature survey reveals that the
eutectic mixtures based on choline chloride have shown
many intriguing applications in electrochemistry [3, 4],
metal processing [5, 6], and ionothermal synthesis [7, 8].
Bronsted basic CILs also have good catalytic activity on the
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-013-0978-6) contains supplementary
material, which is available to authorized users.
2 Experimental Section
A. Zhu ꢀ Q. Li ꢀ L. Li ꢀ J. Wang (&)
School of Chemistry and Chemical Engineering, Key Laboratory
of Green Chemical Media and Reactions, Ministry of Education,
Henan Normal University, Xinxiang 453007, Henan,
People’s Republic of China
2.1 Materials and Instruments
N,N0-Dimethylaminoethanol (DMEA) of AR grade was
obtained from Beijing Chem. Reagent Co. and distilled at
e-mail: jwang@henannu.edu.cn
123

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A. Zhu et al.
reduced pressure before use. Choline chloride of AR grade
was also obtained from Beijing Chem. Reagent Co. Sul-
furic acid (H2SO4) and phosphoric acid (H3PO4) of AR
grade were purchased from Shanghai Reagent Co. Strong
basic ion exchange resin (Ambersep 900 OH) and
4-nitroaniline were purchased from Alfa Aesar. Benzal-
dehyde, substituted benzaldehydes, ethyl acetoacetate and
acetylacetone were all AR grade purchased from Aladdin
Reagent Co. Urea and thiourea of AR grade were obtained
from Shanghai Regent Co. and recrystallized with alcohol
before use. All of the commercially available reagents were
used as received unless indicated otherwise.
1H-NMR spectra were recorded on a BRUKER AV-400
instrument at room temperature by using TMS as internal
standard. Thermal stability measurements were conducted
using a NETZSCH STA 449C system. Melting points were
taken from a XRC-1Microscopic melting point measurer
(Sichuan University Instrument Factory) without correc-
tion. UV–Vis spectra were determined by a TU-1810
spectrometer (Beijing Persee Instrument Company) with a
standard 2 mm cell, and the temperature was controlled to
25.0 0.1 °C with a DC-2006 low temperature thermostat
(Shanghai Hengping Instrument & Meter Factory).
then the water was removed under reduced pressure to give
the protic CILs.
The aprotic CILs [Choline][HSO4] and [Choline][H2PO4]
were synthesized through a two-step method. Commercially
available [Choline][Cl] was ion-exchanged into [Choline][OH]
from the strong basic ionic exchange resin, and then [Cho-
line][OH] was neutralized with sulfuric acid or phosphate acid
to get the bronsted acidic CILs.
2.3 Thermal Stability of the Acidic CILs
A NETZSCH STA 449C system was used to collect TG
scans. The instrument was calibrated in the temperature
range of 25–500 °C. The ILs were dried under vacuum at
55 °C for 24 h to remove water. Experiments were carried
out in alumina crucibles at the temperature range from 25
to 500 °C with heating rate of 10 °C/min under a nitrogen
atmosphere (50 ml/min).
2.4 Measurements of Acidity of the CILs
Hammett acidic functions were measured for different ILs
on an UV–Vis spectroscopy using 4-nitroaniline as the
basic indicator by following the procedure described in
literatures [27–29]. In this experiment, water was chosen as
the solvent because it is the by-product of the Biginelli
reactions and can dissolve all the tested ionic liquids with
high solubility. The maximal absorbance of the un-pro-
tonated form of 4-nitroaniline was observed at 380 nm in
water. As the concentration of the acidic CIL increases, the
maximal absorbance of the un-protonated form of the
indicator molecules decreases (Fig. 1). Therefore, absor-
bance strength of the indicator in pure water, where no
acidic CILs was added, can be taken as the initial reference
for the total unprotonated form of the indicator to
2.2 Synthesis of the CILs
The protic CILs [DMEA][HSO4] and [DMEA][H2PO4]
were synthesized by simple neutralization of N,N0-dimeth-
ylaminoethanol with corresponding acids such as sulfuric
acid or phosphate acid in an equal molar ratio [Scheme 1,
path (a)]. In a typical reaction, 0.1 mol N,N0-dimethyl-
aminoethanol dissolved in 10 ml water was put into a
100 ml flask, and equal molar acid diluted with water was
slowly added under stirring. The solution was stirred at
room temperature for 24 h to complete the reaction, and
Scheme 1 Procedures for the
preparation of the acidic
choline-based ILs
(a)
(b)
123

One-Pot Synthesis of DHPMs
465
determine the values of [I]/[IH?] ratio from the measured
absorbance for solutions with the addition of different
acidic CILs. Then the Hammett acidity function (H0) can
be calculated by the equation
thermal stability than those of [H2PO4] anion, and the protic
CIL [DMEA][HSO4] exhibits distinguished one-step mass
loss above 270 °C. Seth et al. [30] have suggested that there
exists hydrogen bond between the hydrogen atom attached
to the nitrogen atom of the cation and the oxygen atom of
the anion of the protic ionic liquid DMEA formate. The
substitute of the formate anion with [HSO4] should keep
the existence of the hydrogen bond, and the existence of the
hydrogen bond interaction between the cation and the anion
perhaps is the main reason for its high thermal stability. The
high thermal stability of [DMEA][HSO4] suggests that such
an IL can be used in a wide temperature range.
À
Á
H0 ¼ pKðIÞaqþ log ½Iꢁs=½IHþꢁs
ð1Þ
where ‘‘I’’ stands for indicator pK(I)aq = pKa = 0.99,
[IH?]s and [I]s are respectively molarities of the protonated
and unprotonated forms of the indicator. Herein, the ILs
and indicator were dissolved in water with the concentra-
tions of 20 and 7.24 9 10-1 mmol/l, respectively.
2.5 Typical Procedures for the Synthesis of 3,4-
Dihydro-2(H)-Pyrimidinones by Biginelli
Reactions Using CILs as Catalysts
3.2 Acidities of the Different CILs
Acidities of the different CILs have been examined using
Hammett acidity method. Figure 3 shows the absorbance
spectra of 4-nitroaniline in the presence of different CILs in
water at the concentration of 20.0 mmol/l and 20 °C, and the
H0 values calculated for different acidic ILs are collected in
Table 1. It is clearly indicated that acidities of the CILs
decrease in the sequence: [DMEA][HSO4] [ [Cho-
line][HSO4] [ [DMEA][H2PO4] [ [Choline][H2PO4]. It is
interesting to note that the CIL [DMEA][HSO4] has the
highest acidity as well as the thermal stability. As it has been
discussed above, there exists hydrogen bond between the
cation and the anion of [DMEA][HSO4], and the accepted
hydrogen will increased the acidity of the anion, which then
makes the protic [HSO4] IL has the highest acidity.
A mixture of benzaldehyde (2 mmol), ethyl acetoacetate
(2 mmol), urea/thiourea (3 mmol) and IL (0.4 mmol) were
added into a 10 ml round bottom flask, and the mixture was
stirred at 90 °C for the desired time and monitored by TLC
method. After completion of the reaction, the reaction
mixtures were cooled to room temperature and then
washed with the mixture of ice-cold water and ethanol
(60–80 % volume of ethanol) several times. The crude
products can be filtered off from the water and ethanol
solution of IL. All of the products were identified by
melting point and 1H NMR. The ILs could be easily reused
from the filtrate by the removal of the solvent.
3 Results and Discussion
3.3 Catalytic Activity of the CILs on the Biginelli
Reactions
3.1 Thermal Stabilities of the Acidic CILs
Catalytic activity of the CILs on the Biginelli reactions
was investigated by using the model reaction among
Figure 2 shows the TGA scans of different ILs. It can be
seen that the CILs with the [HSO4] anion have higher
1.6
(a)blank
a
[DMEA][HSO4]
[Choline][HSO4]
[DMEA][H2PO4]
[Choline][H2PO4]
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
(b)c=20mmol/L
(c)c=10mmol/L
(d)c=5mmol/L
100
80
60
40
20
d
c
b
300
400
500
150
200
250
300
350
400
450
500
nm
Temperature
Fig. 1 Influence of the IL concentrations on the absorbance of the
indicator in water
Fig. 2 The TGA scans for the acidic CILs
123

466
A. Zhu et al.
benzaldehyde, ethyl acetoacetate and urea, and the results
were collected in Table 2. It was found that catalytic
activity of different ILs follows the same sequence with the
acidity strength, suggesting that the increase in acidity of
the ILs enhanced the catalytic activity of the CILs on the
Biginelli reactions. Thereafter, we optimized the reac-
tion conditions using the same model reaction with
[DMEA][HSO4] as the catalyst which has the highest
acidity and the highest catalytic activity, and the results are
collected in Table 3.
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
a: blank
b: [DMEA][HSO4]
a
c: [Choline] [HSO4]
d: [DMEA][H2PO4]
e: [Choline] [H2PO4]
e
d
c
b
3.4 Synthesis of 3,4-Dihydropyrimidinones Catalyzed
by [DMEA][HSO4] Under Solvent-Free Conditions
300
400
500
nm
Under the optimized reaction conditions, the reactions of
various aromatic aldehydes with ethyl acetoacetate and
urea were investigated and the results were given in
Table 4 (entry 1–10). It was found that both of the alde-
hydes with electron donating and electron withdrawing
group could afford to the desired 3,4-dihydropyrimidinones
with good to excellent isolated yields in a reasonable
reaction time. The acetylacetone was also employed in the
Biginelli reactions (Table 4, entry 11, 12) and the corre-
sponding dihydropyrimidones were obtained smoothly
with excellent isolated yields. Furthermore, the thiourea
instead of urea (Table 4, entry 13, 14) could also produce
Fig. 3 UV-vis absorbance spectra of 4-nitroaniline in the presence of
different CILs in water at the concentration of 20.0 mmol/l and 20 °C
Table 1 Hammett acidity functions of different CILs (20.0 mmol/l)
in water at 20 °C
Entry
IL (mmol)
Amax
[I] (%)
[IH] (%)
H0
1
2
3
4
5
–
1.46
0.43
1.20
1.19
1.27
100
0
–
[DMEA][HSO4]
[DMEA][H2PO4]
[Choline][HSO4]
[Choline][H2PO4]
29.5
82.2
81.5
86.9
70.5
17.8
18.5
13.1
0.61
1.65
1.63
1.81
Table 2 Catalytic performance of different CILs on the Biginelli reactions
O
Ph
H
EtO2C
Me
O
O
O
IL
NH
+
+
90oC
solvent free
H2N
NH2
Ph
H
H3C
OEt
N
H
O
Entry
IL
Reaction time (h)
Isolated yield (%)
1
2
3
4
[DMEA][HSO4]
[DMEA][H2PO4]
[Choline][HSO4]
[Choline][H2PO4]
2
2
2
2
89
62
66
52
The reaction was proceed at 90 °C with the molar ratio of benzaldehyde:ethyl acetoacetate:urea:IL = 1:1:1.5:0.2
Table 3 Optimization of the reaction conditions using [DMEA][HSO4] as the catalyst for the Biginelli reactions
Entry
Urea (mmol)
IL (mmol)
Reaction time (h)
Reaction temperature (oC)
Isolated yield (%)
1
2
3
4
5
6
7
1.5
1.5
1.5
1.5
1.2
1.5
1.5
0.02
0.1
0.2
0.5
0.2
0.2
0.2
2
2
2
2
2
3
2
90
90
90
90
90
90
70
64
81
89
89
75
93
78
In the model reaction among benzaldehyde, ethyl acetoacetate and urea catalyzed by [DMEA][HSO4], 1 mmol of benzaldehyde and 1 mmol of
ethyl acetoacetate were used
123

One-Pot Synthesis of DHPMs
467
Table 4 Synthesis of 3,4-dihydropyrimidinones catalyzed by [DMEA][HSO4] under solvent-free conditions
Ar
H
EtO2C
X
O
O
O
[DMEA][HSO4]
NH
+
+
90oC
solvent free
H2N
R1
NH2
Ar
H
H3C
Me
N
H
X
Entry
Ar
R1
X
Yield (%)
Mp (°C)
Found
Reported
1
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
94
81
79
78
87
93
93
89
90
77
98
99
51
208–212
212–214
172–174
206–209
214–216
226–230
195–198
232–234
236–239
233–235
227–230
218–220
–
205–207 [31]
209–211 [13]
175–177 [22]
199–201 [17]
207–210 [17]
232–234 [22]
201–203 [29]
231–233 [22]
233–235 [32]
232–235 [17]
232–235 [13]
–
2
4-Cl–C6H4
4-F–C6H4
3
4
4-OCH3–C6H4
4-NO3–C6H4
3-NO3–C6H4
2-OH–C6H4
4-OH–C6H4
5
6
7
8
9
4-(OH)-3-(OCH3)–C6H3
C6H5CH=CH
10
11
12
13
C6H5
4-(OH)-3-(OCH3)–C6H3
Me
OEt
–
O
14
15
C6H5
OEt
OEt
S
S
87
96
208–210
209–211
209–211 [31]
–
4-(OH)-3-(OCH3)–C6H3
100
3.5 The Reusability of [DMEA][HSO4] in Biginelli
Reactions
80
60
40
20
0
[DMEA][HSO4] was used as a model IL to study the
reusability of [DMEA][HSO4] in Biginelli reactions. For
this purpose, the IL was recovered by evaporation of the
water in the filtrate, and then directly used for the next run.
It was found from Fig. 4 that there was no significant
activity decrease after six runs using of the IL.
4 Conclusions
1
2
3
4
5
6
In summary, a type of feasible choline-based bronsted acidic
ionic liquids have been synthesized, and their thermal sta-
bility and acidity have been detected using TGA scan and
Hammett acidity method. It was shown that the cation as well
as the anion has significant influence on the thermal stability
and the acidity of the ILs. When this type of CILs was used as
catalysts for the synthesis of 3,4-dihydro-2(H)-pyrimidi-
nones by Biginelli reactions, it was found that [DMEA]
[HSO4] which has the highest acidity as well as the thermal
stability showed the highest catalytic activity. The further
Run number
Fig. 4 The recycle of [DMEA][HSO4] ionic liquid catalyst
the corresponding 3,4-dihydropyrimidin-2-(1H)-thiones in
good yields. From the comparison of the reaction of
ortho-substituted 2-hydroxylbenzaldehyde (Table 4, entry
7) with that of the para-substituted 4-hydroxylbenzalde-
hyde (Table 4, entry 8), it is clear that no significant steric
effect has been observed for the reaction efficiency.
123

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A. Zhu et al.
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Lett 48:6962
researches showed that under the catalysis of [DMEA]
[HSO4], various aromatic aldehydes with electron donating
or electron withdrawing groups can all be fluently reacted
with ethyl acetoacetate or acetylacetone and urea or thiourea
with good to excellent isolated yields. In addition, this cat-
alytic system also benefit from benign reaction conditions,
easy work-up procedures, and the feasible reusability of the
ionic liquid.
11. Zhu AL, Li LJ, Wang JJ, Zhuo KL (2011) Green Chem 13:1244
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Acknowledgments This study was supported by the National Nat-
ural Science Foundation of China (Grant 20903037, 21172058), and
the Research Fund for the Doctoral Program of Higher Education of
China (20094104120003).
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