Efficient and Green Microwave-Assisted Multicomponent Biginelli Reaction for the Synthesis of Dihydropyrimidinones Catalyzed by Heteropolyanion-Based Ionic Liquids under Solvent-Free Conditions

Article abstract of DOI:10.1080/00397911.2014.976346

An efficient and green route for the synthesis of dihydropyrimidinones via microwave-assisted Biginelli reaction catalyzed by 3 mol% of heteropolyanion-based ionic liquids under solvent-free conditions has been reported. The practical reaction was found t

Full text of DOI:10.1080/00397911.2014.976346

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Efficient and Green Microwave-Assisted
Multicomponent Biginelli Reaction for the Synthesis of
Dihydropyrimidinones Catalyzed by Heteropolyanion-
Based Ionic Liquids Under Solvent-Free Conditions
a
a
a
a
a
a
Renzhong Fu , Yang Yang , Wenchen Lai , Yongfeng Ma , Zhikai Chen , Jian Zhou , Wen
a
a
a
Chai , Quan Wang & Rongxin Yuan
a
Jiangsu Laboratory of Advanced Functional Material, School of Chemistry and Materials
Engineering, Changshu Institute of Technology, Changshu, Jiangsu, PR China
Accepted author version posted online: 30 Oct 2014.
To cite this article: Renzhong Fu, Yang Yang, Wenchen Lai, Yongfeng Ma, Zhikai Chen, Jian Zhou, Wen Chai, Quan
Wang & Rongxin Yuan (2014): Efficient and Green Microwave-Assisted Multicomponent Biginelli Reaction for the
Synthesis of Dihydropyrimidinones Catalyzed by Heteropolyanion-Based Ionic Liquids Under Solvent-Free Conditions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2014.976346
To link to this article: http://dx.doi.org/10.1080/00397911.2014.976346
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EFFICIENT AND GREEN MICROWAVE-ASSISTED MULTICOMPONENT
BIGINELLI REACTION FOR THE SYNTHESIS OF
DIHYDROPYRIMIDINONES CATALYZED BY HETEROPOLYANION-BASED
IONIC LIQUIDS UNDER SOLVENT-FREE CONDITIONS
1
1
1
1
1
1
Renzhong Fu , Yang Yang , Wenchen Lai , Yongfeng Ma , Zhikai Chen , Jian Zhou ,
1
1
1
Wen Chai , Quan Wang , Rongxin Yuan
1
Jiangsu Laboratory of Advanced Functional Material, School of Chemistry and
Materials Engineering, Changshu Institute of Technology, Changshu, Jiangsu, PR China
Jiangsu Laboratory of Advanced Functional Material, School of Chemistry and Materials
Engineering, Changshu Institute of Technology, Changshu, Jiangsu 215500, PR China
E-mail: yangyangirisjs@126.com (Y. Yang), wangquanlzu@gmail.com (Q. Wang)
Abstract
An efficient and green route for the synthesis of dihydropyrimidinones via
microwave-assisted Biginelli reaction catalyzed by 3 mol % of heteropolyanion-based
ionic liquids under solvent-free conditions has been reported. The practical reaction was
found to be compatible with different structurally diverse substrates. Good to excellent
yields, short reaction times and operational simplicity are the main highlights of this
protocol. Moreover, the heteropolyanion-based ionic liquids were easily reusable for this
Biginelli reaction.
1

KEYWORDS: Biginelli reaction; dihydropyrimidinone; ionic liquid; microwave;
solvent-free condition
INTRODUCTION
Multicomponent reactions (MCRs) promote the formation of several bonds in one single
operation with remarkable advantages, such as simple procedure, multi bond forming
efficiency, time and energy saving, easy extraction and purification processes, and hence
[1]
minimized waste generation. From an environmental and economic perspective, MCRs
have acted as efficient tools for the construction of chemical libraries of drug-like
[
2]
[3]
compounds with structurally complexity and diversity. Biginelli reaction is ranked as
one of the most powerful MCRs for the synthesis of dihydropyrimidinones (DHPMs)
scaffold, which have exhibited a wide range of pharmaceutical and therapeutic properties,
[
4]
such as antiviral, antitumour, antibacterial and anti-inflammatory activities, and have
been suggested to be useful building blocks for the synthesis of versatile heterocyclic
[
5]
derivatives. Classical Biginelli reaction involves one-pot condensation of aldehyde,
β-ketoester, and urea under strongly acidic conditions, which suffers from the drawbacks
[
6]
like harsh conditions, long reaction times, low yields and purities. These disadvantages
have led to the development of a number of improved catalytic systems which involve
2

[
7]
[8]
[9]
[10]
Brønsted acids or bases, metal Lewis acids, organocatalysts and heterogeneous
[
11]
catalysts. However, in spite of their potential utility many of these methods involve
expensive and/or toxic catalysts and reagents, stoichiometric amount of catalyst, strongly
acidic conditions, unsatisfactory yields, purification issues and limited substrate scope,
and thus are not closer to the principles of green chemistry. Hence, the development of
clean, high-yielding and environmentally friendly approaches employing recyclable
catalysts in Biginelli synthesis still remains an active area of research.
Over the past decades, ionic liquids (ILs) have attracted much interest as environmentally
benign solvent and/or catalysts different from classical conventional ones due to their
remarkable properties, such as negligible vapor pressure, low toxicity, low flammability,
high thermal and chemical stability, solvent power, reusability and structural
[
12]
versatility. Moreover, a variety of organic transformations have been successfully
conducted using ILs as environmentally friendly alternative to traditional organic
[
13]
solvents or catalysts. In recent years, a variety of ILs have already been employed with
success as efficient catalysts for the Biginelli reaction, including cations derived from
[
14]
alkylammonium, dialkylimidazolium and pyridinium based ILs. Most recently, a series
of heteropolyanion-based ILs (HPAILs) have been prepared as hybrid materials by
[
15]
combining Keggin heteropolyanions with task-specific ILs (TSILs) cations. In view of
the advantages of heteropolyanions and TSILs, HPAILs attract great research interest due
to their diverse chemical structures and improved catalytic behaviors. HPAILs usually
3

have high melting points and high thermal and chemical stability because of the
heteropolyanion existing in the compounds, that is consistent with the requirements of a
solid acid catalyst. Moreover, HPAILs have turned out to be an environmental-friendly,
[16]
high-efficient and reusable catalyst for acid-catalyzed or oxidative organic
[
17]
transformations due to their advantages, such as operationally simplicity, no toxicity,
low cost, easily isolation, and reusability. To the best of our knowledge, there has been
only one paper on the HPAILs catalyzed Biginelli reaction reported by Neto and
[
14n]
co-workers.
Although excellent yields were obtained, the catalytic system involved
1
-n-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (BMI.NTf ) as
2
o
reaction solvent/medium at 90 C for 4h. Thus, it is recognized that the HPAILs catalyzed
Biginelli reaction was not fully explored especially with regard to solvent-free conditions.
During the last few years, ‘non-classical’ methods have been developed in organic
[18]
synthesis in order to improve yields, selectivity, and experimental conditions.
Amongst them microwave-assisted technology has become an important method due to
their unique advantages, such as the significant rate enhancements, yield and selectivity
improvements, very simplified ease of manipulation and work-up and less environmental
[
19]
polluting processes. Especially the use of microwave-assisted technology in
conjunction with solvent-free conditions allows expeditious and efficient procedures in
[
20]
organic synthesis. With our continuous investigation on the methodology of green
[
21]
synthesis, herein we wish to report an efficient and environmentally benign protocol
4

for Biginelli reaction successfully accomplished by using HPAILs as catalyst under
microwave irradiation (MWI) and solvent-free conditions (Scheme 1).
RESULTS AND DISCUSSION
Amongst the various HPAILs, our study is mainly focused on N-substituted imidazole,
pyrdine and triethylamine based HPAILs, which have already been used as catalysts for
[21]
[16]
many different acid-catalyzed transformations by us and by others. Thus, six
structurally related HPAILs (Figure 1) were prepared according to the procedure
[
16a]
described in the literature.
Initially, the cyclocondensation of benzaldehyde, ethylacetoacetate and urea under MWI
and solvent-free condition was considered as a standard model reaction to determine the
optimum condition (Table 1). Firstly, when the reaction was carried out in the absence of
o
any catalyst under MWI at 100 C for 30 min, only 8% yield of desired
dihydropyrimidinone was obtained (Table 1, entry 1). Whereas the rate and yield of the
reaction both increased dramatically in the presence of 2 mol % amount of
[
MIMPS] PW O (Table 1, entry 2). The results revealed that the catalyst should be
3 12 40
absolutely necessary for the Biginelli reaction. At the same time it was shown that the
o
yield of the reaction increased when heating at 120 C (Table 1, entry 3), but there was
o
not appreciable change at higher temperature (130 C) (Table 1, entry 4). In the screening
5

test of optimum catalyst concentration, it was found that using 3 mol % amount of
MIMPS] PW O (Table 1, entry 5) could give the best result as well as higher amount
[
3
12 40
of the catalyst did not obviously improve the result (Table 1, entry 6). Thus, catalytic
activities of other related catalysts were investigated under the same reaction condition.
From the results, it was noticed that all six HPAILs prepared before could promote the
reaction in different degrees. It was shown that the catalytic activities of
[
[
MIMPS] PW O and [TEAPS] PW O were slightly lower than that of
3 12 40 3 12 40
PyPS] PW O (Table 1, entries 5, 8, 10). In the cases of catalysts combining with
3
12 40
different heteropolyanions, the results demonstrated that PW O was more active than
1
2
40
PMo O HPAILs (Table 1, entries 5, 7–11). Although pure HPA catalyst H PW O
12 40
12
40
3
gave a high yield of 90%, its good solubility throughout organic solvents and water made
its isolation from the reaction mixture difficult (Table 1, entry 12). Finally, optimum
result was obtained when the reaction was performed using 3 mol % of [PyPS] PW O
3
12 40
under MWI (700 W) and solvent-free condition affording dihydropyrimidinone in 95%
o
yield at 120 C for 5 min (Table 1, entry 8).
In order to examine the substrate scope of this catalyzed Biginelli reaction, a variety of
aromatic, heterocyclic and aliphatic aldehydes were subjected to react with
1
,3-dicarbonyl compounds and urea/thiourea under the above optimized reaction
conditions. The results were summarized in Table 2. In all cases, the reaction proceeded
smoothly to afford the corresponding DHPMs and -thiones within short reaction time
6

(5–10 min) in good to high yields (83%–96%). It could be noticed that a wide range of
aromatic aldehydes bearing either electron-donation or electron-withdrawing substituents
at different positions afforded good yields of DHPMs in high purity (Table 2, entries 1–7,
1
1–28). Meanwhile, the HPAILs catalyzed condensation was compatible with a variety
of functional groups including methoxy, methyl, chloro, nitro and hydroxyl. Besides the
β-ketoester, β-diketone (Table 2, entries 23–28) could also be employed with similar
success to provide the corresponding products. In addition, both urea and thiourea were
suitable substrates as demonstrated from the yields of the corresponding Biginelli adducts
(Table 2, entries 11–14, 20–22, 26–28). However, it was observed that the reaction of
aromatic aldehydes with urea is fast as compared to thiourea. Another important feature
of this procedure is that good yields were achieved (83%–88% yield) in the cases of
heterocyclic and aliphatic aldehydes (Table 2, entries 8–10), which normally were less
reactive or completely inert to the Biginelli reaction.
It was realized that the outstanding feature of the HPAILs as catalysts over conventional
ones are their excellent solubility in water or strong polar solvents but nonmiscibility
with apolar esters, that would lie in the feasibility of their recovery. Hence, the recycling
of [PyPS] PW O in the multicomponent Biginelli reaction was investigated (Table 3).
3
12 40
In each case, after completion of the reaction (monitored by TLC), [PyPS] PW O was
3
12 40
removed from the reaction mixture by simple filtration after vigorous stirring with hot
EtOAc. After removal of the solvent, the almost pure product was obtained and
7

recrystallization could be used for further purification. The catalyst could be reused five
times for the synthesis of dihydropyrimidinone with a little loss of activity (Table 3). It
was proved that HPAIL is easily reusable for this multicomponent Biginelli reaction.
[
22]
According to the mechanism suggested by Folkers, Johnson and Kappe, the reaction
may proceed through imine formation from the aldehyde and urea, subsequent addition of
the carbanion derived from 1,3-dicarbonyl compounds to the imine followed by
cyclodehydration to afford DHPMs. In our cases, HPAIL promotes the reactions due to
its inherent Brønsted acidity. Hydrogen bonding is formed between HPAIL and carbonyl
oxygen of aldehyde as well as ethyl acetoacetate during the reaction. The formation of
hydrogen bond between IL and substrate leads them to the activation. The hydrogen ion,
donated by HPAIL, not only helps the dehydration but also benefits the enolization of
1
,3-dicarbonyl compounds to form enolate intermediate. Based on this, the plausible
mechanistic pathway for this reaction is suggested (Figure 2).
In conclusion, we have successfully developed a microwave-assisted HPAILs catalyzed
approach for the synthesis of bioactive dihydropyrimidinones under solvent-free
conditions. The developed method not only preserved the operational simplicity of
Biginelli’s one-pot condensation but also provided compatibility with various functional
groups and good to excellent yields of dihydropyrimidinones within short reaction times.
Moreover, the HPAILs are recyclable and reused for more than five cycles without
8

showing any significant loss in its catalytic activity. This strategy complements the
existing reports on the synthesis of dihydropyrimidinones.
EXPERIMENTAL SECTIONS
Synthetic Procedure For Hpails.
Methylimidazole (0.11 mol) and 1,3-propane sulfone (0.10 mol) were dissolved in
o
toluene (30 mL) and stirred for 24 h at 50 C under a nitrogen atmosphere. A white
precipitate (MIMPS) formed, which was filtered, washed with diethyl ether three times,
then dried in a vacuum. MIMPS (0.09 mol) was added to an aqueous solution of
H PW O (0.03 mol), and then the mixture was stirred at room temperature for 24 h.
3
12 40
Water was removed in vacuum to give the product [MIMPS] PW O as a solid. Thus
3
12 40
[
[
MIMPS] PMo O , [PyPS] PW O , [PyPS] PMo O , [TEAPS] PW O and
3 12 40 3 12 40 3 12 40 3 12 40
TEAPS] PMo O were prepared using according starting materials (Figure 1).
3
12 40
Synthetic Procedure For Dihydropyrimidinones.
To a mixture of aldehyde (3 mmol), 1,3-dicarbonyl compound (3.0 mmol) and urea /
thiourea (4.5 mmol) in a 10 mL round bottomed flask was added [PyPS] PW O (314
3
12 40
o
mg, 0.09 mmol). The reaction mixture was stirred at 120 C under MWI (700 W). The
progress of the reaction was monitored by TLC. On completion, the mixture was diluted
with hot ethyl acetate (20 mL) with stirring for 30 min. The insoluble catalyst was
9

recovered by filtration. The filtrate was evaporated and the residue in almost pure form.
Recrystallization or column chromatography could be used for further purification.
5
-Ethoxycarbonyl-6-Methyl-4-Phenyl-3,4-Dihydropyrimidin-2(1H)-One (Table 2,
Entry 1).
White solid. Mp: 201.1-203.6 °C; IR (KBr): 3244, 3109, 2933, 1710, 1650, 1222, 1089
-1 1
cm ; H NMR (300 MHz, DMSO-d ) δ 9.20 (s, 1H), 7.74 (s, 1H), 7.35-7.30 (m, 2H),
6
7
.25-7.21 (m, 3H), 5.15 (d, J = 3.0 Hz, 1H), 3.98 (q, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.09 (t,
1
3
J = 7.0 Hz, 3H); C NMR (75 MHz, DMSO-d ) δ 165.4, 152.2, 148.4, 144.9, 128.4,
6
+
1
2
27.3, 126.3, 99.3, 59.2, 54.0, 17.8, 14.1; HRMS Calcd for C H N O (M + H ):
1
4
17
2
3
61.1234; Found: 261.1238.
5
-Ethoxycarbonyl-6-Methyl-4-Phenyl-3,4-Dihydropyrimidin-2(1H)-Thione (Table 2,
Entry 11).
Yellow solid. Mp: 200.4-202.5 °C; IR (KBr): 3322, 34663176, 3111, 1670, 1575, 1470,
-
1 1
1
7
277, 1197, 1105, 696 cm ; H NMR (300 MHz, DMSO-d ) δ 10.34 (s, 1H), 9.65 (s, 1H),
6
.37-7.21 (m, 5H), 5.18 (d, J = 3.6 Hz, 1H), 4.01 (q, J = 6.9 Hz, 2H), 2.29 (s, 3H), 1.10 (t,
1
3
J = 6.9 Hz, 3H); C NMR (75 MHz, DMSO-d ) δ 174.2, 165.1, 145.0, 143.5, 128.6,
6
+
1
2
27.7, 126.4, 100.7, 59.6, 54.1, 17.2, 14.0; HRMS Calcd for C H N O S (M + H ):
1
4
17
2
2
77.1005; Found: 277.1006.
10

5
-Methoxycarbonyl-6-Methyl-4-Phenyl-3,4-Dihydropyrimidin-2(1H)-One (Table 2,
Entry 15).
Yellow solid. Mp: 211.3-213.7 °C; IR (KBr): 3238, 3117, 2933, 1719, 1645, 1222, 1092
-1 1
cm ; H NMR (300 MHz, DMSO-d ) δ 9.23 (s, 1H), 7.77 (s, 1H), 7.35-7.30 (m, 2H),
6
1
3
7
.26-7.21 (m, 3H), 5.15 (d, J = 3.3 Hz, 1H), 3.53 (s, 3H), 2.26 (s, 3H); C NMR (75
MHz, DMSO-d ) δ 165.9, 152.2, 148.7, 144.7, 128.5, 127.4, 126.2, 99.1, 53.9, 50.9, 17.9;
6
+
HRMS Calcd for C H N O (M + H ): 247.1077; Found: 247.1079.
1
3
15
2
3
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
Financial Supported National Nature Science Foundation of China (No. 21302013,
5
1203013), Nature Science Foundation of Jiangsu Province (No. BK2012207), Nature
Science Foundation of Jiangsu Educational Department (No. 12KJB150001,
1
1
1
2KJB610001), Foundation of Jiangsu Laboratory of Advanced Functional Material (No.
2KFJJ008), Key University Science Research Project of Jiangsu Province (No.
2KJA150001), Prospective joint research project of Jiangsu Province (No. BY2013041),
China Postdoctoral Science Foundation (No. 20100480990).
11

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17

Table 1. Optimization of the reaction conditions for benzaldehyde, ethylacetoacetate and
a
urea catalyzed by HPAILs.
o
b
Entry Catalyst
No Catalyst
Temp ( C) Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
1
1
100
30
10
5
8
[MIMPS] PW O , 2 mol % 100
83
91
91
93
93
86
95
89
84
78
90
3
12 40
[MIMPS] PW O , 2 mol % 120
3
12 40
[MIMPS] PW O , 2 mol % 130
5
3
12 40
[MIMPS] PW O , 3 mol % 120
5
3
12 40
[MIMPS] PW O , 4 mol % 120
5
3
12 40
[MIMPS] PMo O , 3 mol % 120
5
3
12 40
[PyPS] PW O , 3 mol %
120
120
120
5
3
12 40
[PyPS] PMo O , 3 mol %
5
3
12 40
0
1
2
[TEAPS] PW O , 3 mol %
5
3
12 40
[TEAPS] PMo O , 3 mol % 120
5
3
12 40
1
H PW O , 3 mol %
120
5
3
12 40
a
Reaction conditions: benzaldehyde (3.0 mmol), ethylacetoacetate (3.0 mmol), urea (4.5
mmol), related catalyst, MWI (700 W).
b
Isolated yields.
18

Table 2. Scope of microwave-assisted Biginelli reaction catalyzed by HPAILs under
a
solvent-free conditions.
1
2
b
Entry R
R
X Time(min) Yield(%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
C H
OEt O 5
95
96
95
92
93
91
90
88
85
83
93
91
92
90
94
95
6
5
4-MeO-C H OEt O 5
6
4
4-Me-C H
OEt O 5
OEt O 5
OEt O 5
OEt O 5
OEt O 8
OEt O 8
OEt O 8
OEt O 8
OEt S 10
OEt S 10
OEt S 10
OEt S 10
OMe O 5
6
4
4-Cl-C H
6
4
4-NO -C H
4
2
6
4-OH-C H
6
4
2-OH-C H
6
4
2-Furyl
n-C H
6
13
0
1
2
3
4
5
6
i-Pr
C H
6
5
4-Me-C H
6
4
4-Cl-C H
6
4
4-NO -C H
4
2
6
C H
6
5
4-MeO-C H OMe O 5
6
4
19

1
1
1
2
2
2
2
2
2
2
2
7
8
9
0
1
2
3
4
5
6
7
8
4-Me-C H
OMe O 5
OMe O 5
OMe O 8
OMe S 10
OMe S 10
OMe S 10
93
92
90
94
91
92
94
93
92
92
91
85
6
4
4-Cl-C H
6
4
4-NO -C H
2
6
4
4
4
4
C H
6
5
4-Me-C H
6
4
4-NO -C H
2
6
C H
Me
Me
Me
Me
Me
Me
O 5
O 5
O 5
S 5
S 5
S 5
6
5
4-Me-C H
6
4
4-NO -C H
2
6
C H
6
5
4-Me-C H
6
4
2
4-NO -C H
2 6
a
Reaction conditions: aldehyde (3.0 mmol), 1,3-dicarbonyl compound (3.0 mmol),
o
urea/thiourea (4.5 mmol), [PyPS] PW O (3 mol %), MWI (700 W), 120 C.
3
12 40
b
Isolated yields.
20

a
Table 3. Reusability studies of catalyst for the synthesis of DHPMs.
Number of cycles 1
2
3
4
5
b
Yield (%)
95 93 91 90 90
a
Reaction conditions: benzaldehyde (3.0 mmol), ethylacetoacetate (3.0 mmol), urea (4.5
o
mmol), [PyPS] PW O (3 mol %), MWI (700 W), 120 C.
3
12 40
b
Isolated yields.
21

Scheme 1. Microwave-assisted Biginelli reaction catalyzed by HPAILs under
solvent-free conditions.
22

Figure 1. N-substituted imidazole, pyrdine and triethylamine based HPAILs.
23

Figure 2. Plausible mechanism of HPAIL catalyzed Biginelli reaction.
24