One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by acidic ionic liquids under solvent-free conditions

Article abstract of DOI:10.1080/00397910902774042

The acidic ionic liquids were new catalysts for the one-pot Biginelli reaction coupling of aldehyde, 1,3-dicarbonyl compound, and urea to afford the corresponding dihydropyrimidinones in good yields under solvent-free conditions. The catalysts could be re

Full text of DOI:10.1080/00397910902774042

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One-Pot Synthesis of 3,4-
Dihydropyrimidin-2(1H)-ones
Catalyzed by Acidic Ionic
Liquids Under Solvent-Free
Conditions
Jianzhou Gui a , Dan Liu a , Chan Wang a , Feng Lu a
Jingzhao Lian a , Heng Jiang a & Zhaolin Sun a
,
a College of Chemistry and Materials Science,
Liaoning Shihua University, Fushun, Liaoning, China
Version of record first published: 04 Sep 2009.
To cite this article: Jianzhou Gui, Dan Liu, Chan Wang, Feng Lu, Jingzhao Lian,
Heng Jiang & Zhaolin Sun (2009): One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-
ones Catalyzed by Acidic Ionic Liquids Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:19, 3436-3443
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Synthetic Communications1, 39: 3436–3443, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902774042
One-Pot Synthesis of 3,4-Dihydropyrimidin-
2(1H)-ones Catalyzed by Acidic Ionic Liquids
Under Solvent-Free Conditions
Jianzhou Gui, Dan Liu, Chan Wang, Feng Lu, Jingzhao Lian,
Heng Jiang, and Zhaolin Sun
College of Chemistry and Materials Science, Liaoning Shihua University,
Fushun, Liaoning, China
Abstract: The acidic ionic liquids were new catalysts for the one-pot Biginelli
reaction coupling of aldehyde, 1,3-dicarbonyl compound, and urea to afford
the corresponding dihydropyrimidinones in good yields under solvent-free condi-
tions. The catalysts could be recycled and reused five times without a noticeable
decrease in catalytic activity.
Keywords: Acidic ionic liquid, Biginelli reaction, synthesis
INTRODUCTION
Dihydropyrimidinone derivatives (DHPMs) have attracted considerable
interest because of therapeutic and pharmacological properties. To
improve the efficiency of the Biginelli reaction, recently many synthetic
methods for preparing these compounds, such as use of heteropoly
acids,[1] CuCl2 Á H2O,[2] l-proline,[3] praseodymium methanesulfonate,[4]
chloroacetic acid,[5] and so on, have been developed. The search for the
new, readily available, and green catalysts is still being actively pursued.
Because of the great potential of room-temperature ionic liquids
(ILs) as environmentally benign media for catalytic processes, much
Received November 17, 2008.
Address correspondence to Jianzhou Gui, College of Chemistry and Materials
Science, Liaoning Shihua University, Fushun 113001, Liaoning, China. E-mail:
jzgui@hotmail.com; guijz@lnpu.edu.cn
3436

Biginelli Reaction in Acidic Ionic Liquids
3437
Figure 1. Structure of the acidic liquids in the study.
Scheme 1. The synthesis of 3,4-dihydropyrimidin-2(1H)-ones.
attention has currently been focused on the organic reactions catalyzed
with or in ILs, and many organic reactions, especially in the reactions
promoted with acid–base catalysts, were performed in ILs. In recent
years, the acidic ILs, which were stable and reusable, have emerged as
a powerful alternative to conventional chloroaluminate ILs.[6] The acidic
ILs have also been used as catalysts for the Biginelli reaction.[7] Some of
them are really good; however, some drawbacks still remain. For exam-
ple, reaction temperature of some catalytic systems is relatively high.
Furthermore, the anionic portion consisting of halogen containing anions
(such as PF6ꢀ, BF4ꢀ, [CF3SO3]ꢀ, and [(CF3SO2)2N]ꢀ) can easily yield
white fumes of hydrogen fluoride (HF) or hydrate precipitates. To follow
the generally recognized safe rule to avoid toxicological and environmen-
tal hazards, there is still much room for the development of more efficient
methods.
In our previous work, our group had synthesized and characterized
several Brønsted acid sites functionalized ILs.[8] In continuation of our
interest in acidic ILs and the synthesis of 3,4-dihydropyrimidin-2-
(1H)-ones,[4] in this communication, we describe them (Fig. 1) as catalysts
for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones under
solvent-free conditions (Scheme 1).
EXPERIMENTAL
All solvents and chemicals in the experiment were commercially available
and used without further purification unless otherwise stated. The C, N,

3438
J. Gui et al.
and H elemental analyses were performed on an Elementar Vario EL
element analyzer. Infrared (IR) spectra were recorded on a PE
SpectrumTM GX Fourier transform (FT-IR) spectrometer using liquid
film or KBr tablet. 1H NMR (300 MHz) was obtained on Varian
Mercury-plus 300BB instruments as solutions in deuterium-substituted
reagent. Chemical shifts were reported in parts per million (ppm, d).
Aldehyde (20 mmol), 1,3-dicarbonyl (20 mmol), urea (24 mmol), and
ILs (0.3 mmol) were heated to 75ꢁC while being stirred for 0.5–1.5 h, then
5 mL ice–cold water were added. The products were filtered out and
washed with ice–cold water to afford pure 3,4-dihydropyrimidin-2-
(1H)-ones. The IL was reused after removal of water under vacuum
(0.01 torr) at 130ꢁC for 3 h.
RESULTS AND DISCUSSION
The catalytic activity of the different acidic liquids was first examined in
the model reaction of benzaldehyde, methyl acetoacetate, and urea
under the same conditions. It can be seen that all ILs exhibit good
catalytic effects with yields greater than 84% (Table 1). The data in
entries 1–4 (Table 1) indicate that the yields of DHPMs in IL1 and
IL3 are considerably more than those in IL2 and IL4. It is suggested
that the IL’s anion has a significant impact on its catalytic activity. This
phenomenon can be explained in terms of the different Brønsted
acidities of the anions.
After reaction, the mixture was poured into ice water. The product
4A that precipitated was isolated by simple filtration. The IL remaining
in the aqueous phase was reused after removal of water under vacuum
(0.01 torr) at 130ꢁC for 3 h. It is to be noted that IL3 can indeed be reused
five times without visible loss of activity (Table 1, entry 5). This indicated
that IL3 as catalyst for the Biginelli reaction was recyclable.
Then, three-component Biginelli condensation of aldehyde,
1,3-dicarbonyl, and urea was catalyzed by IL3. In all cases studied,
the three-component reaction proceeded smoothly to give the corre-
sponding DHPMs in satisfactory yields.[20] Aromatic aldehydes carrying
either electron-donation or electron-withdrawing substituents (func-
tional groups including ethers, nitro, hydroxyl, and halides) afforded
good yields of DHPMs in high purity (entries 6–20). Most importantly,
aliphatic aldehydes, which usually show extremely poor yields in the
Biginelli reaction, afforded good yields of products too (entries
21–29). It showed that aliphatic aldehyde exhibited behavior analogous
to that of aromatic aldehydes, which demonstrated IL3 is efficient for
the Biginelli reaction.

Biginelli Reaction in Acidic Ionic Liquids
3439
Table 1. Synthesis of DHPMs catalyzed by acidic ionic liquid under solvent-free
conditionsa
Mp (ꢁC)
DHP
Entry Ms
Time Yield
IL (h) (%)b Found Reported
R1
R2
1
2
3
4
5c
6
7
8
9
4A
4A
4A
4A
4A
4B
4S
4De
4E
C6H5
C6H5
C6H5
C6H5
C6H5
CH3O IL1 0.5 87.5
CH3O IL2 0.5 84.6
CH3O IL3 0.5 88.7 210–212
CH3O IL4 0.5 85.2
CH3O IL3 0.5 88.0
210[9]
4-(CH3O)-C6H4 CH3O IL3
1
1
1
1
94.6 191–193 191–193[10]
88.8 236–238 237–238[11]
96.5 205–208 206–208[12]
90.5 253–256 254–255[13]
4-(NO2)-C6H4
4-(Cl)-C6H4
2,4-(Cl)2-C6H3
4-OH-3-
CH3O IL3
CH3O IL3
CH3O IL3
10
4F
CH3O IL3 0.5 67.4 249–251
=
(OMe)-C6H3
2-(OH)-C6H4
C6H5
4-(CH3O)-C6H4 C2H5O IL3
4-(NO2)-C6H4
2,4-(Cl)2-C6H3 C2H5O IL3
C6H5
4-(CH3O)-C6H4
4-(NO2)-C6H4
4-(Cl)-C6H4
2,4-(Cl)2-C6H3
CH3
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
4G
4H
4I
CH3O IL3
C2H5O IL3
1
1
1
77.6 229–231
=
97.0 205–207 201–203[14]
97.8 201–203 201–202[15]
4J
C2H5O IL3 0.5 96.4 206–208 208–209[16]
4K
4M
4N
4O
4P
4Q
4R
4S
4T
4U
4V
4W
4X
4Y
4Z
1
1
1
1
94.8 237–239 238–240[17]
85.1 235–237 235–236[9]
83.7 164–166 165–168[11]
78.1 227–229 227–229[11]
CH3 IL3
CH3 IL3
CH3 IL3
CH3 IL3 0.5 92.9 214–216 215–216[18]
CH3 IL3
1
94.5 228–230
=
C2H5O IL3 1.5 83.0 186–189 186–188[19]
CH3CH2
C2H5O IL3
C2H5O IL3
CH3O IL3 1.5 73.2 168–170
CH3O IL3
CH3O IL3
CH3 IL3 1.5 74.1 186–188
CH3 IL3 1.5 73.7 174–176
1
1
90.0 180–183 179–181[9]
89.0 158–159 155–157[19]
n-CH3(CH2)2
CH3
CH3CH2
n-CH3(CH2)2
CH3
CH3CH2
=
1
1
84.6 184–186 184–185[9]
[9]
89.3 172–175 174–175
=
=
[9]
n-CH3(CH2)2
CH3 IL3 1.5 77.5 149–151 151–152
aAldehyde, 20 mmol; 1,3-dicarbonyl, 20 mmol; urea, 24 mmol; and ILs,
0.3 mmol. Reactions were run in a thermostated oil bath at 75ꢁC, variation ꢂ2ꢁC.
bIsolated yields.
cIL3 was reused five times.

3440
J. Gui et al.
CONCLUSION
In summary, an efficient procedure for synthesizing DHPMs from
aromatic and aliphatic aldehydes catalyzed by acidic ILs was developed.
After the reaction, the catalyst can be easily recovered and reused without
distinct decrease in reactive activity. The procedure is free of organic sol-
vent, has a short reaction time, and requires a low reaction temperature.
Therefore, it is a useful and environmentally friendly process.
Spectral Data for Selected Compounds
5-Methoxycarbonyl-6-methyl-4-(4-hydroxy-3-methoxyphenyl)-3,4-
dihydropyrimidin-2-(1H)-one (4F)
1
IR (KBr) n=cmꢀ1: 3258, 1675, 1649; H NMR (DMSO-d6) 9.18 (s, 1H),
8.92 (s, 1H), 7.62 (s, 1H), 6.83 (d, J ¼ 1.7 Hz, 1H), 6.69–6.67 (d,
J ¼ 8.1 Hz, 1H), 3.74 (s, 3H), 3.54 (s, 3H), 2.24 (s, 3H). C14H16O5N2
(292.16) calcd.: C, 57.55; H, 5.48; N, 9.58. Found: C, 57.70; H, 5.41;
N, 9.52.
5-Aceto-6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-2-(1H)-one (4O)
IR (KBr) n=cmꢀ1: 3255, 1673, 1607; 1H NMR (DMSO-d6) d: 9.36 (s, 1H),
8.21–8.20 (d, J ¼ 8.5 Hz), 8.0 (s, 1H), 7.51–7.50 (d, J ¼ 8.2 Hz, 2H),
5.39–5.38 (d, 3.6, 1H), 2.30 (s, 3H), 2.16 (s, 3H). C13H13O4N3 (275.16)
calcd.: C, 56.74; H, 4.72; N, 15.27. Found: C, 56.70; H, 4.80; N, 15.21.
5-Aceto-6-methyl-4-(2,4-dichlorophenyl)-3,4-dihydropyrimidin-2-
(1H)-one (4Q)
IR (KBr) n=cmꢀ1: 3340, 1713, 1668; 1H NMR (DMSO-d6) d: 9.31(1H, s),
7.81 (s, 1H), 7.61 (d, J ¼ 2.1 Hz, 1H), 7.41–7.39 (q, J ¼ 10.5 Hz, 1H),
7.26–7.24(d, J ¼ 8.4 Hz, 1H), 5.65 (d, J ¼ 3.1 Hz, 1H), 2.35 (s, 3H), 2.07
(s, 3H). C13H12O2N2Cl2 (315.05) calcd.: C, 49.56; H, 3.81; N, 8.89.
Found: C, 49.50; H, 3.87; N, 8.88.
5-Ethoxycarbonyl-6-methyl-4-propyl-3,4-dihydropyrimidin-
2-(1H)-one (4T)
IR (KBr) n=cmꢀ1: 3251, 1720, 1647; 1H NMR (DMSO-d6) d: 8.93 (s, 1H),
7.33 (s, 1H), 4.10–4.04 (q, J ¼ 4.7 Hz, 3H), 2.16 (s, 3H), 1.26–1.40 (m,
J ¼ 4.7 Hz, 4H), 1.21–1.16 (t, J ¼ 3.2 Hz, 3H), 0.87–0.83 (t, J ¼ 6.9 Hz,

Biginelli Reaction in Acidic Ionic Liquids
3441
3H). C11H18O3N2 (226.13) calcd.: C, 58.42; H, 7.96; N, 12.39. Found: C,
58.41; H, 8.01; N 12.31.
5-Methoxycarbonyl-4,6-dimethyl-3,4-dihydropyrimidin-2-(1H)-one (4U)
1
IR (KBr) n: 3248, 3115, 2954, 1710, 1658 cmꢀ1; H NMR (DMSO-d6) d:
9.08 (s, 1H), 7.23 (s, 1H), 4.18 (q, J ¼ 6.3 Hz, 1H), 3.66 (s, 3H), 2.18
(s, 3H), 1.17 (t, J ¼ 6.5 Hz, 3H). C8H12N2O3 (184.1) calcd.: C, 52.19; H,
6.52; N, 15.22. Found: C, 52.15; H, 6.59; N, 15.26.
5-Aceto-4,6-dimethyl-3,4-dihydropyrimidin-2-(1H)-one (4X)
1
IR (KBr) n: 3308, 3090, 2978, 1698, 1615 cmꢀ1; H NMR (DMSO-d6) d:
9.07 (s, 1H), 7.32 (s, 1H), 4.25 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.07 (t,
J ¼ 6.3 Hz, 3H). C8H12N2O2 (168.1) calcd.: C, 57.18; H, 7.20; N, 16.59.
Found: C, 57.22; H, 7.24; N, 16.53.
5-Aceto-6-methyl-4-ethyl-3,4-dihydropyrimidin-2-(1H)-One (4Y)
1
IR (KBr) n: 3246, 3122, 2974, 1707, 1682 cmꢀ1; H NMR (DMSO-d6) d:
8.94 (s, 1H), 7.40 (s, 1H), 4.08 (t, J ¼ 5.3 Hz, 1H), 2.20 (s, 6H), 1.39 (m,
J ¼ 6.4, 2H, J ¼ 7.4 Hz), 0.81 (t, 3H, J ¼ 7.4 Hz). C9H14N2O2 (182.11)
calcd.: C, 59.32; H, 7.54; N, 15.43. Found: C, 59.23; H, 7.69; N, 15.44.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Natural
Science Foundation of China (No. 20706027) and The Education Depart-
ment of Liaoning (No. 2009A430).
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