Ionic liquids catalyzed Biginelli reaction under solvent-free conditions

Article abstract of DOI:10.1016/S0040-4039(01)01139-X

3,4-Dihydropyrimidin-2(1H)-ones were synthesised in high yields by one-pot three-component Biginelli condensation in the presence of room temperature ionic liquids such as 1-n-butyl-3-methylimidazolium tetrafluoroborate (BMImBF₄) or hexafluorop

Full text of DOI:10.1016/S0040-4039(01)01139-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5917–5919
Ionic liquids catalyzed Biginelli reaction under solvent-free
conditions
Jiajian Peng and Youquan Deng*
State Key Laboratory for Oxo Synthesis and Selective Oxidation and Centre for Ecological and Green Chemistry,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
Received 23 April 2001; revised 18 June 2001; accepted 22 June 2001
Abstract—3,4-Dihydropyrimidin-2(1H)-ones were synthesised in high yields by one-pot three-component Biginelli condensation in
the presence of room temperature ionic liquids such as 1-n-butyl-3-methylimidazolium tetrafluoroborate (BMImBF4) or
hexafluorophosphorate (BMImPF6) as catalysts under solvent-free and neutral conditions. © 2001 Elsevier Science Ltd. All rights
reserved.
Recently, the interest in synthesis of 3,4-dihydropyrim-
idin-2(1H)-ones (denoted as Biginelli compounds) and
their derivatives is increasing tremendously because of
their therapeutic and pharmacological properties and
also because of interesting biological activities of sev-
eral marine alkaloids which contain the dihydropyrim-
idine nucleus.1–4 Synthetic strategies for the
dihydropyrimidine nucleus involves one-pot to multi-
step approaches. The classical Biginelli synthesis is a
one-pot condensation using b-dicarbonyl compounds
with aldehydes (aromatic and aliphatic aldehydes) and
urea or thiourea in ethanol solution containing catalytic
amounts of acid.5 This method, however, involves long
reaction times, harsh reaction conditions and unsatis-
factory yields. Improvements in such syntheses have
been sought continuously. Recently, it was reported
that Lewis acids (such as BF3·OEt2) in combination
with transition metals and a proper proton source were
effective catalysts for this reaction.2 Dihydropyrimidi-
nes were also synthesized in high yields by one-pot
cyclocondensation of aldehydes, acetoacetates and urea
using various acid catalysts like Amberlyst-15, Nafion-
H, KSF clay and dry acetic acid under microwave
irradiation.6,7 More recently, lanthanide triflate,1 lan-
thanum chloride,8 ferric chloride hexahydrate,9 and
indium chloride10 as catalysts for the one-pot syntheses
of dihydropyrimidinones were also reported.
On the other hand, because of the great potential of
room temperature ionic liquids as environmentally
benign media for catalytic processes, much attention
has currently been focused on organic reactions cata-
lyzed by ionic liquids, several organic reactions cata-
lyzed by ionic liquids have been reported with high
performance.11–16 This offered some new clues that
using ionic liquids as catalysts for those traditionally
acid–base synthetic reactions may not only be possible
but also practical and even highly efficient.
Our new approach reported herein involves the use of
room temperature ionic liquids based on 1-n-butyl-3-
methylimidazolium tetrafluoroborate (BMImBF4) or
hexafluorophosphorate (BMImPF6)17 as catalysts for
the Biginelli condensation reaction under solvent-free
conditions.
Keywords: ionic liquid; Biginelli reaction; 3,4-dihydropyrimidin-
2(1H)-ones; one-pot process.
* Corresponding author. Fax: +86-931-8277088; e-mail: ydeng@
ns.lzb.ac.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01139-X

5918
J. Peng, Y. Deng / Tetrahedron Letters 42 (2001) 5917–5919
1-n-Butyl-3-methylimidazolium
tetrafluoroborate
With 0.4 mol% of BMImBF4 as catalyst, aromatic
(BMImBF4) and hexafluorophosphorate (BMImPF6)
ionic liquids were, respectively, synthesized according
to the procedures reported in previous literatures.17
aldehydes with either electron-donating or electron-
withdrawing substituents (entries 5, 6 and 7) were also
used as one of the substrates. It can be seen that all
reacted very well and the yields achieved from the
aromatic aldehydes with electron-donating substituents
were slightly higher than aromatic aldehydes with elec-
tron withdrawing substituents.
Typical experimental procedures were as follows: Alde-
hyde (25.0 mmol), b-dicarbonyl compound (25.0
mmol), urea (37.5 mmol) and BMImBF4 (0.05–0.2
mmol) were successively charged into a 50 ml round-
bottomed flask with a magnetic stirring bar. Then the
reaction proceeded at 100°C for 30 min during which
time a solid product gradually formed. After the reac-
tion, the resulting solid product with pale yellow color
was crushed, washed with water, filtered and dried in
vacuo to afford the primary product. A pure product
was obtained by further recrystallization of the primary
product with ethyl acetate. The characterization of the
products is well known, therefore only the basic iden-
Under the same reaction conditions and substrates as
entries 3, 5, 6 and 7, BMImPF6 as catalyst was also
examined (entries 8, 9, 10 and 11). Even higher yields,
i.e. 94, 98, 98 and 92%, respectively, were obtained in
comparison with BMImBF4 as catalyst, indicating that
−
−
the BF4 and PF6 anions have some impact on the
−
catalytic performance, and the PF6 anion is more
favorable for such reactions.
1
tifications including FT-IR (IFS 120HR, Bruker), H
Under the same reaction conditions as entry 3, n-hexyl
aldehyde, which replaced the aromatic aldehyde as one
of the substrates, was tested and 4-n-pentyl-5-(ethoxy-
carbonyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
was produced in 93% yield (entry 12). This shows that
aliphatic aldehydes exhibit analogous behavior to that
of aromatic aldehydes, and this characteristic was simi-
lar to that of lanthanide triflate as catalyst.1 Further-
more, the experimental results showed that besides
ethyl acetoacetate, acetylacetone can also be used as
one of the substrates. The highest yield was obtained
for the benzaldehyde, acetylacetone and urea three-
component Biginelli condensation (entry 13), and the
corresponding yield was also improved for the 4-nitro-
benzaldehyde, acetylacetone and urea three-component
Biginelli condensation (entry 14), in comparison with
the result of entry 7. For the purpose of comparison,
toluene (10 ml, entry 15) was added into the reaction
system, which was employed in entry 14, and the
possible influence of solvent was examined. The reac-
tion was refluxed at 100°C for 2 h, and the yield was
NMR (FT-80A, using TMS as internal standard) and
melting points measurements, were conducted.
The results of ionic liquids catalyzed Biginelli reactions
are shown in Table 1. Firstly, no desirable product
could be detected when a mixture of benzaldehyde,
ethyl acetoacetate and urea (mole rate 1:1:1.5) was
heated at 100°C for 30 min in the absence of ionic
liquids (entry 1), indicating a catalyst must be needed
for the Biginelli reaction. Then, the condensation reac-
tion of benzaldehyde, ethyl acetoacetate in stoichiomet-
ric ratio and urea in slightly excess amount was tested
in the presence of different amounts of BMImBF4, i.e.
0.2, 0.4 and 0.8 mol% BMImBF4 relative to the amount
of benzaldehyde (entries 2, 3 and 4) at 100°C without
any additional solvent. Isolated yields of 85, 92 and
95%, respectively, could be achieved after the reaction
had only proceeded for 30 min. This indicates that the
conversion was increased with increasing amounts of
ionic liquid.
Table 1. Ionic liquids catalyzed Biginelli reactions under solvent-free conditionsa
Entry
Ionic liquid (mmol)
Amount of ionic liquid (mol%)
R
R1
Isolation yield (%)
0
1
None
0
C6H5
OC2H5
2
3
4
5
6
7
8
9
10
11
12
13
14
15b
16
17
BMImBF4 (0.05)
BMImBF4 (0.1)
BMImBF4 (0.2)
BMImBF4 (0.1)
BMImBF4 (0.1)
BMImBF4 (0.1)
BMImPF6 (0.1)
BMImPF6 (0.1)
BMImPF6 (0.1)
BMImPF6 (0.1)
BMImBF4 (0.1)
BMImBF4 (0.1)
BMImBF4 (0.1)
BMImBF4 (0.1)
BMImCl (0.1)
n-Bu4NCl (0.1)
0.2
0.4
0.8
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
C6H5
C6H5
C6H5
OC2H5 85
OC2H5 92
OC2H5 95
OC2H5 95
OC2H5 96
OC2H5 90
OC2H5 94
OC2H5 98
OC2H5 98
OC2H5 92
OC2H5 93
4-(CH3O)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
C6H5
4-(CH3O)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
n-Pentyl
C6H5
CH3
CH3
CH3
99
92
77
4-(NO2)-C6H4
4-(NO2)-C6H4
C6H5
OC2H5 56
OC2H5
C6H5
0
Reaction conditions: RCHO 25.0 mmol, CH3COCH2COR1 25.0 mmol, urea 37.5 mmol, 100°C, 0.5 h.
a All products were characterized by FT-IR, 1H NMR and their melting points in comparison with that of previous literatures.
b Refluxed in toluene (10 ml) in the presence of BMImBF4 (0.1 mmol) for 2 h.

J. Peng, Y. Deng / Tetrahedron Letters 42 (2001) 5917–5919
2000, 65, 3864 and references cited therein.
5919
lower than that obtained in entry 14. Finally, the
catalytic performances of two kinds of quaternary
ammonium salts used as catalyst were also tested
(entries 16 and 17). Low reaction yield was obtained,
and the reaction of Biginelli condensation could almost
not be observed when the BMImCl (1-n-butyl-3-
methylimidazolium chloride) and n-Bu4NCl was used
as catalyst, respectively. This indicated that both cation
and anion in the ionic liquids played an important role
as the catalyst towards the Biginelli condensation.
2. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem.
1998, 63, 3454.
3. Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828.
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In summary, a novel method for the synthesis of dihy-
dropyrimidinones by three-component Biginelli conden-
sations of aldehydes with b-dicarbonyl compounds and
urea using room temperature ionic liquids as catalyst
under solvent-free and neutral conditions was devel-
oped on high yield for the first time. The main advan-
tages of this methodology are: (1) relatively simple
catalyst system; (2) shorter reaction times; (3) higher
yields; (4) free of organic solvent, and (5) easy synthetic
procedure. Further investigations of the scope and
mechanism of this reaction are under way.
13. Xu, L.; Chen, W.; Xiao, J. Organometallics 2000, 19,
1123.
14. Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 403.
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Acknowledgements
16. Lee, C. Tetrahedron Lett. 1999, 40, 2461.
17. BMImBF4 and BMImPF6 were prepared according to
This work was financially supported by Science Foun-
dation of the Personal Ministry of China.
.
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