Bronsted acidic ionic liquid: An efficient and reusable catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1080/00397910600588488

A novel ionic liquid, 3-carboxymethyl-1-methylimidazolium bisulfate (CMImHSO₄), was synthesized and used as a recyclable catalyst for the Biginelli reaction under solvent-free conditions. High yields of various substituted 3,4-dihydropyrimidin-

Full text of DOI:10.1080/00397910600588488

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Brønsted Acidic Ionic Liquid: An Efficient
and Reusable Catalyst for the Synthesis of
3
,4‐Dihydropyrimidin‐2(1H)‐ones
a a a a
Renwei Zheng , Xiaoxia Wang , Hui Xu & Jingxing Du
a
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College
of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, P. R.
China
Version of record first published: 21 Aug 2006.
To cite this article: Renwei Zheng, Xiaoxia Wang, Hui Xu & Jingxing Du (2006): Brønsted Acidic Ionic
Liquid: An Efficient and Reusable Catalyst for the Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones, Synthetic
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Synthetic Communications , 36: 1503–1513, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600588488
Brønsted Acidic Ionic Liquid: An Efficient
and Reusable Catalyst for the Synthesis
of 3,4-Dihydropyrimidin-2(1H)-ones
Renwei Zheng, Xiaoxia Wang, Hui Xu, and Jingxing Du
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces,
College of Chemistry and Life Sciences, Zhejiang Normal University,
Jinhua, P. R. China
Abstract: A novel ionic liquid, 3-carboxymethyl-1-methylimidazolium bisulfate
(
4
CMImHSO ), was synthesized and used as a recyclable catalyst for the Biginelli
reaction under solvent-free conditions. High yields of various substituted 3,4-dihydro-
pyrimidin-2(1H)-ones (or thiones) were obtained. The ionic liquid can be recovered
and recycled easily without loss of activity.
Keywords: Biginelli reaction, Brønsted acidic ionic liquid, dihydropyrimidinone,
recyclable catalyst
INTRODUCTION
In the past decades, the dihydropyrimidiones (DHPMs) and their derivatives
have attracted increasing interest in the realms of natural and synthetic
organic chemistry because of their diverse therapeutic and pharmacological
[
1]
properties. These nonplanar heterocyclic compounds have emerged as the
[
2]
integral backbones of calcium channel modulators,
[
antihypertensive
agents, a -adrenergic receptor antagonists, neuropeptide Y (NPY) antag-
3]
[4]
1
a
[5]
[6]
onists, mitotic kinesin inhibitors, and hepatitis B virus replication inhibi-
[7]
tors. In addition, several marine-derived natural products such as Crambine,
Received in Japan September 20, 2005
Address correspondence to Renwei Zheng, Zhejiang Key Laboratory for Reactive
Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang
Normal University, Jinhua 321004, P. R. China. E-mail: sky31@zjnu.cn
1
503

1
504
R. Zheng et al.
Batzelladine B (potent HIV gp-120CD inhibitors), and Ptilomycalin alkaloids
4
[8]
have been reported to contain DHPM moiety. Consequently, synthesis of
this heterocyclic core is currently of much importance.
A simple and direct method, first reported by Biginelli in 1893, involves a
three-component, one-pot condensation of an aldehyde, a b-ketoester, and
[9]
urea (or thiourea) under strongly acidic conditions. Though simple, the
original Biginelli reaction suffered from low yields (20–50%), especially
when substituted aromatic or aliphatic aldehydes were used as the sub-
[
10]
strates.
produced relatively higher overall yields but lack the simplicity of the one-
This has led to the development of multistep strategies that
[
11]
pot Biginelli synthesis.
As a result, many improved procedures for the
preparation of DHPMs have recently been reported, either by modification
of the catalyst or by employment of novel experimental techniques. The
[
12]
[13]
former involves using such catalysts as Lewis acids,
[
protic acid,
Instead of strong acid, and the latter includes
14]
[15]
triflate,
applying microwave irradiation,
and others.
[14e,16]
[17]
ultrasound irradiation,
and so on. In spite of their respective advantage and potential
solid-phase
[
18]
reaction,
utility, some of the reported methods suffer from drawbacks such as longer
reaction times, higher temperatures, expensive catalysts, unsatisfactory
yields, cumbersome product-isolation procedures, and environmental
pollution problems.
In recent years, ionic liquids (ILs) have been widely used for various
[
19]
organic reactions. The increased interest of the researchers lies mainly in
their green characteristics, such as being chemical and thermal stable, nonvo-
[20]
latile, designable, nonflammable, etc. In addition, they can facilitate the
isolation of products and are readily recycled. Recently, Peng and Deng
reported that 1-n-butyl-3-methyl-imidazolium tetrafluoroborate (BMImBF4)
[21]
and hexfluorophosphorate (BMImPF ) were effective catalysts for the
6
[22]
Biginelli reaction. More recently, Shaabani and Rahmati
also reported
that 1,1,3,3-tetramethyl-guanidinium trifluoroacetate (TMGT) is a very
efficient promoter for this reaction. Herein, we report a simple and effective
approach to the Biginelli condensation reaction using
catalyst, 3-carboxymethyl-1-methylimidazolium bisulfate (CMImHSO , 2),
a reusable
4
a new Brønsted acidic ionic liquid. The route for its synthesis is shown in
Scheme 1.
Scheme 1.

Brønsted Acidic Ionic Liquid
1505
CMImHSO (compound 2), melting at about 458C, was obtained as a pale
4
yellow liquid of low viscosity in the synthetic procedure reported here. It rep-
resents a new Brønsted acidic ionic liquid and was easily available from N-
methylimidazole, chloro ethylacetate, and sulfuric acid under mild reaction
conditions. It can dissolve in water, ethanol, DMSO, and DMF, can partly
dissolve in dichloromethane, and is insoluble in diethyl ether, acetone,
THF, ethyl acetate, cyclohexane, and chloroform. Therefore, the acidic
ionic liquid is separated readily from the insoluble product in cold water.
The Biginelli reaction catalyzed by the ionic liquid 2 afforded an
excellent yield of DHPMs under solvent-free conditions (Scheme 2 and
Table 1).
It can be concluded from Table 1 that when aromatic aldehydes were used
as substrates, satisfactory yields could always be obtained, though aromatic
aldehydes with a strong electron-withdrawing group (such as nitro group)
required relatively longer time (25 min) for the reaction to be complete
(entries 6b, 6l, 6p). Aromatic aldehydes carrying electron-donating substitu-
ents (entries 6d–g) produced excellent yields of DHPMs even more
smoothly, and thus pharmacologically relevant substitution patterns on the
4
-aryl group can be introduced efficiently. Aliphatic aldehydes such as
butanal and isobutanal also react well with b-ketoester compounds (entries
i, 6j) and urea in the presence of CMImHSO , giving the corresponding
6
4
DHPMs in high yields, though longer reaction time and more amount of
catalyst were required. However, such aldehydes normally afforded
[9]
extremely poor yields in the Biginelli reaction, which shows that aliphatic
aldehydes exhibit analogous activity to that of aromatic aldehydes here.
Thiourea has been used with the same success to provide the correspond-
ing dihydro-pyrimidin-2(1H)-thiones (entries 6k–n, 6t), which are also of
[1]
much interest with regard to biological activity. The scope of the meth-
odology was demonstrated as a variety of 1,3-dicarbonyl compounds
proved effective with this protocol (entries 6o–t). Another important
aspect of the procedure is the survival of a variety of functional groups
such as NO , Cl, OH, and OCH and a conjugated C 55 C bond under
2
3
the reaction conditions.
The catalyst is reusable and can be applied several times without any
decrease in the yield of the reaction. Take the synthesis of 6a, for example.
CMImHSO was reused five times to get the yields of 6a in 93%, 90%,
4
Scheme 2.

1
506
R. Zheng et al.
(5 mol%)-catalyzed synthesis of dihydropyrimidinones
Mp(8C)
Reported
Table 1. CMImHSO
4
a
1
2
b
Entry
R
R
X
Product Yield (%)
Found
c
66 ,87 ,90 201–203 202.4
d
e
[23]
[23]
1
2
EtO
EtO
C
C
6
H
H
5
5
O
6a
6a
f
93, 90 , 92, 201–203 202.4
6
O
8
9, 91
g
[23]
3
4
5
6
7
8
EtO 4-NO
EtO 4-ClC
EtO 2-HOC H
2
C
6
H
4
O
O
O
O
O
O
6b
6c
6d
6e
6f
91
89
92
96
94
89
206–207 207–208.5
[
[
[
[
23]
6
H
4
210–212 213–215
201–203 201–202
199–201 201–202
170–172 172–173
23]
6
4
23]
EtO 4-CH
EtO 4-CH
3
3
OC
6
H
4
12a]
C
6
H
4
EtO 2-HO-3-
CH OC H
6 4
6g
232–233
—
3
[
23]
9
EtO PhCH 55 CH
EtO n-Pr
EtO i-Pr
O
O
O
S
6h
6i
88
89
85
90
93
88
93
96
93
91
90
95
93
238–240 238–239.5
h
h
[23]
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
156–157 151–152
191–193 195–196
206–207 206–207
209–212 210–213
180–181 180–182
[24]
6j
6k
[
24]
EtO
EtO 4-NO
EtO 4-ClC H
C
6
H
5
g
6i
[23]
2
C
6
H
4
S
[
23]
S
6m
7b
6n
6o
6
4
EtO 2-HOC
6
H
4
S
178–179
—
[
[
23]
25]
EtO 4-CH
CH3 C H
3
OC
6
H
4
S
138–140 136–138
232–234 233–236
O
O
O
O
O
6
5
g
[25]
CH
CH
CH
3
3
3
4-NO
4-ClC
4-CH
2
C
6
H
4
6p
228dec
230dec
[
[
22]
6
H
4
6q
6r
6s
224–226 226–227
181–182 178–180
25]
3
OC
6
H
4
CH3 2-HO-3-
CH OC
4-ClC
CH3 2-HOC H
235–236
—
3
6 4
H
[
23]
2
2
3
CH
3
6
H
4
S
S
6t
7a
87
91
224–226 224–225
242–243
2
—
6
4
a
Typical reaction conditions were used unless otherwise specified: 5 mol%
CMImHSO relative to aldehyde; 808C; 15 min, and no solvent. The molar ratio of
4
aldehyde/b-ketoester of b-dicarbonyl compound/urea or thiourea ¼ 1:1:1.5.
b
Isolated yield.
c
Compound 1 as catalyst, 808C, 40 min.
1
d
0 mL of ethanol was added as solvent.
e
f
1
2
0 mL of H O was added as solvent.
Isolated yield with reused catalyst.
g
h
5
1
mol% catalyst, 808C, 25 min.
0 mol% catalyst, 808C, 40 min.
92%, 89%, and 91%, respectively, exhibiting the same catalytic activity (entry
2). It should be noted that only 66% isolated yield could be produced when
compound 1 were used as a catalyst in ethanol (entry 1). From entry 1,
although water and ethanol as solvent afforded also the product in high

Brønsted Acidic Ionic Liquid
1507
yields, solvent-free conditions were employed for more environmental accept-
ability. We studied also the effect of the amount of catalyst on the yields of
product. Use of just 5 mol% of CMImHSO4 relative to the amount of
aldehyde is sufficient to push the reaction forward. High amounts of the
catalyst did not improve the result to a large extent.
In the course of our studies, we found that the products derived from the
condensation reaction involving salicylaldehyde, acetylacetone (or ethyl
acetoacetate), and thiourea gave an NMR spectrum different from that of
the expected dihydropyrimidinthione 6. The exact structures were character-
ized by IR, NMR, and elemental analysis to be diazatricyclo structures 7a
and 7b, which are formed from further intramolecular Michael addition of
the hydroxyl to the electron-deficient C 55 C existing in compound 6 under
CMImHSO catalysis (Scheme 3).
4
In summary, the present procedure for the synthesis of dihydropyrimidi-
nones by a novel Brønsted acidic ionic liquid (CMImHSO )–catalyzed
4
condensation provides an efficient modification of the original Biginelli
reaction. Moreover, this method offers several advantages including
high yields, short reaction times, simple workup procedures, solvent-
free conditions, and reusable catalyst. It is a useful addition to the existing
methods.
EXPERIMENTAL
Melting points were measured on an electrothermal digital melting-point
apparatus and are uncorrected. NMR spectra were recorded on a Brucker
1 13
AC-400 instrument at 400 MHz for H and 100 MHz for C using d6-
DMSO or D O as solvent. Chemical shifts (s) are reported in ppm and
2
coupling constants (J ) are given in Hz. IR spectra were obtained as KBr
plates on a Bruker Vector-22 infrared spectrometer. Elemental analyses
were performed on an EA-1110 instrument. The reaction was routinely
monitored by thin-layer chromatography (TLC) on silica-gel plates.
Scheme 3.

1
508
R. Zheng et al.
Typical Procedure for the Preparation of CMImHSO Ionic Liquid
4
Methylimidazole (8.2 g, 0.1 mol), anhydrous ethanol (100 mL), and ethyl
chloroacetate (18.4 g, 0.15 mol) were added to a 250 mL round-bottom flask
containing a stirring bar. After stirring at 608C (water-bath temperature) for
3
days (TLC monitoring), ethanol was then removed under reduced
pressure; the residue was purified by washing with dry diethyl ether and
toluene repeatedly and then dried in vacuum to obtain a pale yellow liquid
(
compound 1: 3-ethoxycarbonylethyl-1-methyl-imidazolium chloride)
1
(
13.7 g, 62%). H NMR (D O): d (ppm) 1.20 (t, 3H, J ¼ 7.2 Hz, CH CH ),
2
2
3
3
7
3
.86 (s, 3H, CH ), 4.21 (q, 2H, J ¼ 7.2 Hz, CH CH ), 5.08 (s, 2H, CH ),
3
2
3
2
1
.36 (m, 2H, arom CH), 8.63 (s, 1H, arom CH). C NMR (D O): d 13.2,
3
2
5.9, 51.6, 63.6, 123.5, 123.6, 137.4, 168.2.
A stoichiomeric amount of 65% sulfuric acid was added to compound 1 and
stirred for at least 4 h at 508C. The solution was evaporated at the rotary evapor-
ator under reduced pressure to remove ethanol and water. The ionic liquid phase
was then washed repeatedly with toluene and ether to remove nonionic residue
and dried in vacuum to give a pale yellow liquid with low viscosity (compound
2
1
: 3-carboxymethyl-1-methylimidazoliurn bisulfate). H NMR (d -DMSO): d
6
(ppm) 3.90 (s, 3H, CH ), 5.14 (s, 2H, CH ), 7.70 (m, 1H, arom CH), 7.78
3 2
(m, 1H, arom CH), 9.13 (s, 1H, arom CH), 10.15 (s, 1H, HSO ), 12.90 (s, 1H,
COOH). C NMR (d -DMSO): 36.3, 501, 123.6, 124.2, 138.1, 168.6.
4
1
3
6
General Procedure for the Preparation of DHPMs
A mixture of b-ketoester or b-dicarbonyl compound 3 (25 mmol), aldehydes 4
(25 mmol), urea or thiourea 5 (37.5 mmol), and CMImHSO 2 (1.25 mmol,
4
5
mol% with respect to aldehyde) was heated with stirring at 808C for 15min
monitored by TLC). During the reaction process, a solid product spontaneously
(
formed. After cooling, the solid product was poured into ice water (30 mL) and
stirred for 5–10min. The separated solid was suction filtered, washed with ice
water, and recrystallized from hot ethanol to obtain the pure product 6. The
water layer was washed with ethyl ether several times to remove unreacted
starting materials and other organic contaminations. The water was then evap-
orated under reduced pressure. The ionic liquid thus recovered can be reused.
Data
5
-Ethoxycarbonyl-6-methyl-4-(2-hydroxyl-3-methoxyphenyl)-3,4-dihydro-
1
pyrimidin-2(1H)-one (6g): pale brown solid, mp: 232–2338C; H NMR: d
9.08 (s, 1H,OH), 8.72 (brs, 1H, NH), 7.05 (brs, 1H, NH), 6.84 (dd, J 8.0 Hz,
1H, arom CH), 6.69 (q, 1H, J 7.7 Hz, arom CH), 6.61 (q, 1H, J
7.7 Hz, arom CH), 5.51 (d, 1H, J 2.8 Hz, CH), 3.93 (q, 2H, J 6.8 Hz,

Brønsted Acidic Ionic Liquid
1509
OCH ), 3.94 (s, 3H, OCH ), 2.26 (s, 3H, CH ), 1.04 (t, 3H, J 6.8 Hz,
2
3
3
1
OCH CH ); C NMR: 165.9, 152.6, 148.9, 148.0, 144.0, 131.0, 119.5,
3
2
3
2
1
1
3
5
19.0, 111.3, 98.5, 59.4, 56.3, 49.2, 18.1, 14.5. vmax(KBr)/cm : 3536,
343, 3113, 2975, 1689, 1643, 1479. Anal. calcd. for C H N O : C,
1
5 18 2 5
8.82; H, 5.92; N, 9.15. Found: C, 58.75; H, 5.90; N, 9.03.
5
-Acetyl-6-methyl-4-(2-hydroxy-3-methoxyphenyl)-3,4-dihydropyrimi-
1
dine-2(1H)-one (6t): white solid, mp 235–2368C; H NMR: d 9.10 (5, 1H,
OH), 8.93 (brs, 1H, NH), 7.70 (brs, 1H, NH), 6.85–6.58 (m, 3H, arom CH),
5
.16 (d, 1H J 3.1 Hz, CH), 3.73 (s, 3H, OCH ), 2.27 (s, 3H, CH ), 2.06
3 3
1
s, 3H, CH3); C NMR: 195.0, 152.5, 148.1, 147.9, 146.4, 135.6, 118.9,
3
(
2
1
1
3
5
15.8, 111.7, 109.7, 56.1, 54.2, 30.5, 19.2. vmax(KBr)/cm : 3320, 3220,
115, 2968, 1700, 1617, 1524. Anal. calcd. for C H N O : C, 60.86; H,
1
4 16 2 4
.84; N, 10.14. Found: C, 60.92; H, 5.79; N, 10.18.
2
3-Acety-9-methyl-11-thio-8-oxa-10,12-diazatricyclo[7.3.1.0 ]trideca-2,4,
.7
1
6
1
-triene (7a): red–brown solid, mp 242–2438C; H NMR: d 9.05 (brs, 1H,
NH), 9.00 (brs, 1H, NH), 7.21–6.82 (m, 4H, arom CH), 4.75 (m, 1H, CH),
1
3
3
2
2
.43 (d, 1H, J 3.0 Hz), 2.28 (s, 3H, CH ), 1.68 (s, 3H, CH ); C NMR:
3 3
03.9, 177.0, 151.1, 130.1, 129.4, 127.7, 121.1, 116.9, 82.0, 48.5, 47.9,
2
9.6, 23.3. vmax(KBr)/cm : 3228, 3147, 2955, 1715, 1609, 1565. 1511.
1
Anal. calcd. for C H N O S: C, 59.52; H, 5.38; N, 10.68. Found: C,
1
3 14 2 2
5
9.44; H, 5.35; N, 10.73.
2
.7
1
3-Ethoxycarbonyl-9-methyl-11-thio-8-oxa-10,12-diazatricyclo[7.3.1.0
]
1
trideca-2,4,6-triene (7b): pale brown solid, mp 197–1988C; H NMR: d 9.80
brs, 1H, NH), 9.15 (brs, 1H, NH), 7.24–6.72 (m, 4H, arom CH), 4.58 (d, 1H,
J 2.4 Hz CH), 4.16 (q, 2H, J 7.6 Hz, CH ), 3.30 (d, 1H, J 2.2 Hz), 1.78 (s, 3H,
(
2
1
3
CH ), 1.23 (t, 3H, J 7.6 Hz, CH CH ); C NMR: 76.5, 167.9, 150.5, 129.7,
3
2
3
2
1
1
28.8, 123.8, 120.9, 116.5, 81.4, 60.8, 48.2, 42.3, 23.4, 14.0. vmax(KBr)/cm
416, 3326, 3013, 2960, 1722, 1665, 1508. Anal. calcd. for C H N O S:
:
3
C, 57.52; H, 5.52; N, 9.58. Found: C, 57.60; H, 5.54; N, 9.50.
1
4 16 2 3
ACKNOWLEDGMENT
We are grateful to the Education Foundation of Zhejiang Province (Project
No. 20040847) for financial support.
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