New Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Benzotriazolium-Based Ionic Liquids under Solvent-Free Conditions

Article abstract of DOI:10.3390/molecules21040462

An efficient synthesis of novel 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives, using Br?nsted acidic ionic liquid [C2 O2 BBTA][TFA] as a catalyst, from the condensation of aryl aldehyde, β-ketoester and urea was described. Reactions procee

Full text of DOI:10.3390/molecules21040462

molecules
Article
New Efficient Synthesis of 3,4-Dihydropyrimidin-
2(1H)-ones Catalyzed by Benzotriazolium-Based
Ionic Liquids under Solvent-Free Conditions
Zhiqing Liu 1,†, Rong Ma 1,†, Dawei Cao 1 and Chenjiang Liu 1,2,
*
1
Key Laboratory of Oil and Gas Fine Chemicals of Ministry of Education, School of Chemistry and Chemical
Engineering, Xinjiang University, Urumqi 830046, China; 15293606480@163.com (Z.L.);
marong19851208@126.com (R.M.); lzxlxx123@126.com (D.C.)
Physics and Chemistry Detecting Center, Xinjiang University, Urumqi 830046, China; pxylcj@126.com
Correspondence: pxylcj@126.com; Tel.: +86-991-858-2901
2
*
†
The two authors contributed equally to this paper.
Academic Editors: Joaquín García Álvarez and Jonathan Sperry
Received: 13 March 2016; Accepted: 5 April 2016; Published: 7 April 2016
Abstract: An efficient synthesis of novel 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their
derivatives, using Brønsted acidic ionic liquid [C2O2BBTA][TFA] as a catalyst, from the condensation
of aryl aldehyde, β-ketoester and urea was described. Reactions proceeded smoothly for 40 min
under solvent-free conditions and gave the desirable products with good to excellent yields (up to
99%). The catalyst could be easily recycled and reused with similar efficacies for at least six cycles.
Keywords: Benzotriazolium-based ionic liquids; Biginelli reaction; synthesis; catalysis
1. Introduction
In recent years, 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives have received
much attention because they are important substructures in both biologically active compounds
and several marine alkaloids involving the DHPM core units [
for their synthesis involves the conjugate addition of aryl aldehyde,
presence of either protic or Lewis acids. In recent years, several improved methods have been
1
]. A simple and direct approach
β-ketoester and urea in the
reported for the preparation of these compounds using various catalysts such as p-TsOH
H3BO3 [ ], [Al(H2O)6](BF4)3 [ ], thiamine hydrochloride [ ], L-(+)-tartaric acid-dimethylurea [
imidazole-1–yl-acetic acid [ ], HClO4-SiO2 ], polyvinylsulfonic acid [ ], SnCl2
NaCl [11], SrCl2 6H2O [12], Al-planted MCM-41 [13], (NH4)2CO3 [14], CeCl3 7H2O [15], CaCl2 [16],
Ce(NH4)2(NO3)6 [17] and Fe(OTs)3 6H2O [18]. However, several of these reported procedures suffer
¨
H2O [
2
],
],
3
4
5
6
7
[8
9
¨
2H2O [10],
¨
¨
¨
from some drawbacks such as strong acidic conditions, long reaction times, use of expensive or
hazardous reagents, complex handling and low yields of products. Moreover, most of these methods
employ organic solvents as the reaction medium. Hence, new, efficient and environmentally friendly
procedures are still strongly demanded in organic transformations such as condensation reactions.
Currently, ionic liquids (ILs) have been widely used as environmentally benign reaction media
and catalysts in organic synthesis owing to their unique properties of non-volatility, excellent solubility,
high thermal stability and recyclability [19,20]. In particular, the synthesis of task-specific ILs (TSIL)
with special functions according to the requirement of a specific reaction has become an attractive field.
Extensive effort has been focused on the elucidation of the mechanism of Lewis acid–catalyzed Biginelli
reactions in ionic liquids [21]. Sharma et al. [22] reported highly recyclable amino acid ionic liquids as
a catalyst, particularly glycine nitrate, for the one-pot, three-component Biginelli condensation under
microwave irradiation (MW). Recently, Kandasamy and co-workers realized the synthesis of 1-alkyl
Molecules 2016, 21, 462; doi:10.3390/molecules21040462
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Molecules 2016, 21, 462
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triazolium triflate room temperature ionic liquids and their catalytic studies in a multi-component
Biginelli reaction [23]. In continuation of our interest in the Biginelli reaction [24 26], herein we employ
–
Brønsted acid ionic liquid 1-butyl-3-carboxymethyl-benzotriazolium trifluoroacetate [C2O2BBTA][TFA]
as a catalyst to study the possibility of synthesizing DHPMs under solvent-free conditions (Scheme 1).
Scheme 1. Condensation of aryl aldehyde, β-ketoester and urea in the presence of [C2O2BBTA][TFA].
2. Results and Discussion
The catalytic activity of [C2O2BBTA][TFA] was investigated in a one-pot Biginelli condensation
of aryl aldehyde, -ketoester and urea. The results are presented in Table 1. The best result was
achieved by carrying out the reaction at 90 ˝C for 40 min in the presence of 10% catalytic amount of
[C2O2BBTA][TFA] without any solvent (Table 1, entry ). Inspired by Clark’s work [27], we explored
the relationship between the catalyst and solvents (Table 1, entries ). When molecular solvents, such
β
8
1–8
as H2O, MeOH, CH3CN or toluene, were employed, the reaction afforded a mixture of benzaldehyde,
ethyl acetoacetate and urea under similar conditions, and DHPMs were obtained only in a very low
yield (<19%). When no catalyst was used in this reaction system, the reaction did not give the desired
product. This showed that ionic liquid plays a very important role in the reaction system (Table 1,
entry
entries
not change significantly (Table 1, entry
9
). The influence of the reaction time on the yield was also investigated as shown in Table 1,
, 15–19. It turned out that although the reaction time was increased to 40 min, the yield did
). For the purpose of saving energy, we chose 40 min as the
8
8
reaction time. Hence, the best conditions employed a 0.1:2:2:3 mole ratio of [C2O2BBTA][TFA], aryl
˝
aldehyde, β-ketoester, and urea at 90 C for 40 min under solvent-free conditions.
Table 1. Effect of catalyst [C2O2BBTA][TFA] under different conditions for the reaction of aryl aldehyde,
β-ketoester and urea a.
Yield (%) b
Entry
Solvent
IL (mol %)
Time (min)
1
2
3
4
5
H2O
MeOH
EtOH
CH2Cl2
CH3CN
DMF
Toluene
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
10
10
10
10
10
10
10
10
None
1
40
40
40
40
40
40
40
40
40
40
40
40
40
40
10
20
30
50
60
5
3
10
16
19
NR
5
6
7
8 c
9
96, 95, 95, 94, 93, 92
NR
81
84
85
95
93
75
91
94
91
93
10
11
12
13
14
15
16
17
18
19
2.5
5
15
20
10
10
10
10
10
a
Reaction conditions: benzaldehyde (2 mmol), ethyl acetoacetate (2 mmol), urea (3 mmol) and catalyst in
solvent (5 mL) or solvent-free, 90 ˝C; b Isolated yield; c catalyst was recycled six times.

Molecules 2016, 21, 462
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The recycling performance of TSIL [C2O2BBTA][TFA] was one of its most important benefits,
which was also investigated in the reaction of aryl aldehyde, -ketoester and urea. After separation of
β
the product, the filtrate containing catalyst was vacuumed to remove water and the resulting catalyst
was reused directly for the next run. As shown in Table 1, Brønsted acidic ionic liquid [C2O2BBTA][TFA]
can be recycled at least six times without showing a significant decrease in catalytic activity, and the
yields ranged from 96% to 92% (Table 1, entry 8). This indicated that ionic liquid [C2O2BBTA][TFA] was
an efficient and recyclable catalyst for the preparation of 3,4-dihydropyrimidin-2(1H)-ones derivatives.
In order to explore the scope and limitations of this reaction, we extended the procedure to
various aryl-substituted aldehydes carrying either electron-donating or -withdrawing groups in the
ortho, meta, and para positions. In general, the reaction proceeded easily under the best conditions and
the adducts were isolated in excellent yields and high purity. In addition, compared to the reported
synthetic method of 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Table 2,
entry 3a) by using HCl as a catalyst and ethonal as a solvent [28], our strategy has the advantages of
higher yield (96% vs. 78%) and shorter reaction time (40 min vs. 3 h). The obtained results indicated
that the electron-donating or -withdrawing groups at the aryl ring did not seem to affect the reaction
significantly in terms of yield (Table 2, entries 3a
to provide the corresponding S-dihydropyrimidinones analogues, which are also of interest due to
their biological activities (Table 2, entries 3p 3t). The use of different substituted -ketoester as a
–3o). Thiourea has been used with similar success
–
β
1,3-dicarbonyl moiety in place of ethyl acetoacetate also gave similar results, as shown in Table 2
(entries 3u–3ab).
Table 2. The [C2O2BBTA][TFA]-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones a.
Mp (˝C) c
Yields b (%)
Entry
R1
R2
X
Found
Reported (lit.)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
C6H5
2-F-C6H4
3-F-C6H4
4-F-C6H4
2-Cl-C6H4
2-Br-C6H4
3-Br-C6H4
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
O
O
O
O
O
O
O
O
96
96
97
98
93
93
94
92
97
98
93
88
85
89
89
83
86
86
90
93
98
96
92
99
94
98
99
95
201–202
236–237
209–211
175–176
211–213
204–205
190–191
228–230
209–211
171–172
219–221
195–197
193–195
232–234
249–251
202–204
192–193
193–195
184–186
140–142
188–189
202–203
206–208
231–233
196–198
192–194
147–149
212–214
200–202 [29]
235–237 [30]
209–211 [31]
175–177 [32]
211–213 [33]
205–207 [30]
190–192 [26]
228–230 [34]
209–212 [35]
172–174 [36]
219–220 [37]
3-Me-C6H4
4-Me-C6H4
3,4-(MeO)2-C6H3
3-MeO-C6H4
2-Cl-4-F-C6H3
3-Br-4-F-C6H3
3,4-(HO)2-C6H3
4-N(CH3)2-C6H4
C6H5
233–235 [37]
249–250 [38]
202–204 [39]
191–192 [40]
194–195 [41]
185–186 [42]
141–143 [37]
188–190 [43]
202–204 [44]
204–206 [29]
231–233 [45]
4-F-C6H4
3-Me-C6H4
4-Me-C6H4
3-MeO-C6H4
4-F-C6H4
4-Me-C6H4
3-MeO-C6H4
4-OH-C6H4
3-MeO-C6H4
4-OH-C6H4
4-F-C6H4
EtO
EtO
EtO
3s
3t
3u
3v
3w
3x
3y
3z
3aa
3ab
MeO
MeO
MeO
MeO
i-PrO
i-PrO
t-BuO
t-BuO
3-MeO-C6H4
a
Reaction conditions: benzaldehyde (2 mmol), ethyl acetoacetate (2 mmol), urea (3 mmol) and catalyst in
solvent-free, 90 ˝C; b Isolated yield; c Melting points are uncorrected.
3. Experimental Section
All melting points were determined using a Büchi B-540 instrument. All melting points are
uncorrected. All new compounds were characterized by IR, 1H- and 13C-NMR spectra. The IR spectra

Molecules 2016, 21, 462
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were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, Hercules, CA,
USA). The 1H-NMR spectra were measured on a Varian Inova-400 spectrometer (at 400 and 100 MHz,
respectively) using TMS as an internal standard in CDCl3 or DMSO-d6.
3.1. General Procedure for the Synthesis of 1-Butyl-3-carboxymethyl-benzotriazolium Trifluoroacetate
[C2O2BBTA][TFA]: benzotriazole (0.2 mol) and chlorobutane (0.24 mol) were dissolved in 30%
aqueous solution of sodium hydroxide (100 mL). Tetrabutylammonium bromide (1 g) was added and
˝
the solution was stirred 24 h at 80 C until two phases formed. The top organic phase and bottom water
phase were separated with separating funnel. Any remaining water in the organic phase was removed
by decompressing Ratovapor at 70 ˝C [46]. The 1-butylbenzotriazole (0.1 mol) and chloroacetic acid
(0.1 mol) were added to a 50 mL round bottom flask fitted with a reflux condenser. The solution
was stirred for 36 h at 90 ˝C. Then the mixture was washed at least three times with diethyl ether
and acetone. The product ([C2O2BBTA][Cl]) precipitated as a white solid and then was collected by
filtration and dried in vacuo for 24 h. The [C2O2BBTA][Cl] (0.05 mol) was transferred to a 25 mL round
bottom flask and trifluoroacetic acid (TFA, 0.06 mol) was added dropwise, then stirred 24 h at 80 ˝C.
Finally, any remaining TFA was removed by decompressing Ratovapor at 90 ˝C for 1 h and dried
in vacuo for 24 h (Scheme 2).
Scheme 2. Synthesis of [C2O2BBTA][TFA].
3.2. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-(thio)ones
A mixture of aryl aldehyde (2 mmol), β-ketoester (2 mmol), urea (2 mmol) and [C2O2BBTA][TFA]
(0.2 mmol) were heated at 90 ˝C under solvent-free conditions for 40 min with stirring (Scheme 1).
After cooling, the reaction mixture was poured onto crushed ice (30 g) and stirred for 10 min.
The separated solid was filtered under suction, washed with cold water (30 mL) and then recrystallized
from ethanol to afford the pure product. The resulting precipitate was filtered under suction.
The results are summarized in Table 2. All products (except 3l–3m, 3y–3ab) are known compounds,
which were characterized by IR, 1H and 13C-NMR spectra.
1-Butyl-3-carboxymethyl-benzotriazolium Trifluoroacetate [C2O2BBTA][TFA]: brown liquid; 1H-NMR
(DMSO-d6, 400 MHz, TMS): 0.93 (t, 3H, CH3), 1.31–1.41 (m, 2H, CH2), 2.00–2.07 (m, 2H, CH2),
5.11 (t, 2H, CH2), 6.13 (s, 2H, CH2), 8.00–8.53 (m, 4H, Ar-H); 13C-NMR (DMSO-d6, 100 MHz, ppm):
166.4, 158.3 (q, COCF3), 135.0, 134.3, 131.4, 130.9, 115.6 (q, CF3), 114.1, 114.0, 51.9, 51.2, 30.2, 18.7,
δ
δ
13.0 ppm; IR (KBr, ν
/cm´1): 3106, 2967, 2940, 2879, 2511, 1738, 1505, 1471, 1364, 1190, 1141, 1029, 754,
´
718, 643, 599; ESI-MS: m/z (%) = 234.1 (100) [M]+, 113.0 (100) [M] .
5-Ethoxycarbonyl-6-methyl-4-(2-chloro-4-fluorophenyl)-3,4-dihydropyrimidin-2(1H)-thione (3l): white solid;
1H-NMR (400 MHz, DMSO-d6),
(s, 1H, CH), 7.20 (t, 1H, Ar-H), 7.32–7.39 (dd, 2H, Ar-H), 7.73 (s, 1H, NH), 9.30 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6), : 13.80, 17.56, 39.07, 39.59, 50.90, 58.98, 97.61, 115.53, 131,26, 138.24, 138.27,
δ: 1.00 (t, 3H, OCH2CH3), 2.29 (s, 3H, CH3 ), 3.89 (q, 2H, OCH2), 5.59
δ
149.28, 151.08, 159,52, 162.98, 164.74; IR (KBr,
903, 805.
ν
/cm´1): 3346, 3225, 3112, 2976, 1697, 1644, 1223, 1093,
5-Ethoxycarbonyl-6-methyl-4-(3-bromo-4-fluorophenyl)-3,4-dihydropyrimidin-2(1H)-thione (3y): white solid;
1H-NMR (400 MHz, DMSO-d6), : 1.09 (t, 3H, OCH2CH3), 2.25 (s, 3H, CH3 ), 3.99 (q, 2H, OCH2), 5.15
(s, 1H, CH), 7.24–7.27 (m, 1H, Ar-H), 7.33–7.37 (t, 1H, Ar-H), 7.48–7.50 (dd, 1H, Ar-H), 7.79 (s, 1H, NH),
9.29 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6),
: 13.92, 17.72, 52.97, 59.20, 98.41, 112.13, 127.44,
δ
δ

Molecules 2016, 21, 462
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131.19,142.88, 148.95, 151.66, 156.05, 158.49, 164.99; IR (KBr,
1232, 1099, 895, 804.
ν
/cm´1): 3342, 3203, 3100, 2984, 1702, 1658,
5-Isopropoxycarbonyl-6-methyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione (3z): white solid;
1H-NMR (400 MHz, DMSO-d6), : 1.01 (d, 3H, CH3), 1.16 (d, 3H, CH3CH), 2.23 (s, 3H, CH3C), 3.72 (s,
3H, MeO), 4.82 (m, 1H, CHCH3), 5.10 (s, 1H, CH), 6.76–6.83 (m, 3H, Ar-H), 7.24 (t, H, Ar-H), 7.70 (s,
1H, NH), 9.15 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6),
: 17.60, 21.54, 53.73, 54.86, 66.24, 99.34,
/cm´1): 3234, 3106, 2981, 2948,
δ
δ
112.16, 118.19, 129.37, 146.34, 148.05, 152.07, 159.07, 164.73; IR (KBr,
1721, 1652, 1599, 1463, 1431, 1374, 1282, 1232, 1092, 1073, 788.
ν
5-Isopropoxycarbonyl-6-methyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione (3z): orange solid;
1H-NMR (400 MHz, DMSO-d6), : 1.00 (d, 3H, CH3), 1.15 (d, 3H, CH3CH), 2.22 (s, 3H, CH3C), 4.80 (m,
1H, CHCH3), 5.02 (s, 1H, CH), 6.68 (d, 2H, Ar-H), 7.02 (d, 2H, Ar-H), 9.07 (s, 1H, NH), 9.31 (s, 1H, OH);
13C-NMR (100 MHz, DMSO-d6),
: 17.56, 21.39, 21.69, 53.44, 66.09, 99.91, 114.79, 114.79, 127.35, 127.35,
135.46, 147.35, 152.02, 156.39, 164.79; IR (KBr,
/cm´1): 3289, 3227, 3109, 2979, 2808, 1706, 1686, 1651,
1511, 1448, 1371, 1282, 1226, 1173, 1086, 783, 680.
δ
δ
ν
5-Tert-Butoxycarbonyl-6-methyl-4-(4-fluorophenyl)-3,4-dihydropyrimidin-2(1H)-thione (3aa): faint yellow
solid; 1H-NMR (400 MHz, DMSO-d6), : 1.28 (s, 9H, (CH3)3C), 2.21 (s, 3H, CH3C), 5.07 (s, 1H, CH),
7.13–7.18 (m, 2H, Ar-H), 7.22–7.26 (m, 2H, Ar-H), 7.66 (s, 1H, NH), 9.09 (s, 1H, NH); 13C-NMR (100 MHz,
DMSO-d6), : 17.56, 27.72, 27.72, 53.60, 79.09, 100.25, 114.92, 128.12, 128.20, 141.12, 141.15, 147.43, 151.81,
159.96, 162.38, 164.61; IR (KBr,
/cm´1): 3230, 3107, 2975, 2930, 1697, 1644, 1507, 1452, 1366, 1292, 1230,
δ
δ
ν
1164, 1090, 1035, 837, 798, 759, 658.
5-Tert-Butoxycarbonyl-6-methyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione (3ab): faint yellow
solid; 1H-NMR (400 MHz, DMSO-d6),
5.07 (s, 1H, CH), 7.01–7.06 (m, 3H, Ar-H), 7.18–7.22 (t, 1H, Ar-H), 7.63 (s, 1H, NH), 9.05 (s, 1H, NH);
13C-NMR (100 MHz, DMSO-d6),
: 17.56, 21.01, 27.72, 27.72, 27.72, 54.20, 78.99, 100.50, 123.22, 126.79,
127.67, 128.12, 137.07, 144.89, 147.04, 152.05, 164.73; IR (KBr,
/cm´1): 3226, 3099, 2977, 2935, 1699,
δ: 1.29 (s, 9H, (CH3)3C), 2.21 (s, 3H, CH3C), 2.27 (s, 3H, CH3C),
δ
ν
1647, 1489, 1438, 1366, 1294, 1232, 1165, 1087, 859, 813, 774, 745, 697, 670, 599.
4. Conclusions
In summary, we have reported an efficient and convenient method for the synthesis of a series
of novel dihydropyrimidin-2(1H)-ones using aryl aldehyde, β-ketoester and urea as substrates and
employing Brønsted acidic ionic liquid [C2O2BBTA][TFA] as a catalyst. This method offers several
advantages including high yields, short reaction times, and a simple work-up procedure. It also has
the ability to tolerate a wide variety of substituted groups in all three components, which is lacking in
existing procedures.
Acknowledgments: The authors are grateful to Key Laboratory of Xinjiang Uyghur Autonomous Region
(2015KL014), NSFC (21572195, 21262035, and 21162025), the Program for Outstanding Youth Science and
Technology Innovation Talents Training in Xinjiang Uygur Autonomous Region (2014721004), and Natural
Science Foundation of Xinjiang University (BS110133 and BS150230) for financial support of this research.
Author Contributions: Zhiqing Liu and Rong Ma contributed equally to this paper. Chenjiang Liu conceived the
idea of this piece of research; Zhiqing Liu, Rong Ma and Chenjiang Liu designed the experiments; Zhiqing Liu,
Rong Ma, and Dawei Cao performed the chemical experiments; Zhiqing Liu and Rong Ma performed the
performed the spectra analyses; Zhiqing Liu, Rong Ma and Chenjiang Liu wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: All samples are available from the authors.
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