Water-tolerant and reusable lewis acid catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2-(1h)- ones under solvent-free conditions

Article abstract of DOI:10.1080/10826060903558562

3,4-Dihydropyrimidin-2-(1H)-ones were synthesized in high yields by a one-pot cyclocondensation of an aldehyde, a 1,3-dicarbonyl compound, and urea using copper methanesulfonate (2 mol %) as a recyclable catalyst under solvent-free conditions in short rea

Full text of DOI:10.1080/10826060903558562

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WATER-TOLERANT AND REUSABLE LEWIS
ACID CATALYST FOR THE ONE-POT
SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2-
(1H)-ONES UNDER SOLVENT-FREE
CONDITIONS
a
b
c
c
Min Wang , Zhiguo Song , Heng Jiang & Hong Gong
a
College of Chemistry and Chemical Engineering, Bohai University ,
Jinzhou, Liaoning, P. R. China
b
Center for Science & Technology Experiment, Bohai University ,
Jinzhou, Liaoning, P. R. China
c
Liaoning Shihua University , Fushun, Liaoning, P. R. China
Published online: 08 Mar 2010.
To cite this article: Min Wang , Zhiguo Song , Heng Jiang & Hong Gong (2010) WATER-TOLERANT AND
REUSABLE LEWIS ACID CATALYST FOR THE ONE-POT SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2-(1H)-ONES
UNDER SOLVENT-FREE CONDITIONS, Preparative Biochemistry and Biotechnology, 40:2, 101-106, DOI:
10.1080/10826060903558562
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Preparative Biochemistry & Biotechnology, 40:101–106, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 1082-6068 print/1532-2297 online
DOI: 10.1080/10826060903558562
WATER-TOLERANT AND REUSABLE LEWIS ACID CATALYST FOR
THE ONE-POT SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2-(1H)-
ONES UNDER SOLVENT-FREE CONDITIONS
1
Min Wang, Zhiguo Song, Heng Jiang, and Hong Gong
2
3
3
1
College of Chemistry and Chemical Engineering, Bohai University, Jinzhou,
Liaoning, P. R. China
2
Center for Science & Technology Experiment, Bohai University, Jinzhou,
Liaoning, P. R. China
3
Liaoning Shihua University, Fushun, Liaoning, P. R. China
&
3,4-Dihydropyrimidin-2-(1H)-ones were synthesized in high yields by a one-pot cyclocondensa-
tion of an aldehyde, a 1,3-dicarbonyl compound, and urea using copper methanesulfonate
2 mol %) as a recyclable catalyst under solvent-free conditions in short reaction time (1–2 h).
(
Keywords Biginelli reaction, copper methanesulfonate, dihydropyrimidin-2-(1H)-one,
one-pot synthesis
INTRODUCTION
Dihydropyrimidinones (DHPMs) and their derivatives have important
pharmaceutical and therapeutic properties such as antitumor effects, anti-
viral, antibacterial, anticarcinogenic, antihypertensive, and antiinflamma-
[
1]
tory activities.
Several alkaloids with interesting biological activities
were isolated from marine sources recently. Most notable among them
are the batzelladine alkaloids, which have been found to be potent
[
2]
HIVgp-120-CD4 inhibitors.
Thus, syntheses of these heterocyclic
compounds are of much importance.
The classical synthesis of DHPMs was reported first by Pietro Biginelli in
1
893, involving a one-pot condensation of an aldehyde, a b-ketoester, and
[3]
urea under strongly acidic conditions.
This method suffers from low
yields, long reaction time, and severe corrosion of equipment. Many
Address correspondence to Min Wang, College of Chemistry and Chemical Engineering, Bohai
University, Jinzhou, Liaoning, P. R. China. E-mail: minwangzg@yahoo.com.cn

102
M. Wang et al.
SCHEME 1 CMS-catalyzed the Biginelli reaction.
[4]
improved procedures including protonic acids such as HClO , chloro-
4
[
5]
[6]
[7]
[8]
acetic acid,
Lewis acids such as TiCl ,
CdCl ,
M(HSO ) ,
4 n
4
2
[
9]
[10]
[11]
[12]
Sm(NO ) ꢀ 6H O,
InCl3,
Mn(OAc) ꢀ 2H O,
Sc(OTf) ,
and
Nafion
3
3
2
3
2
3
13]
[
other types of catalysts such as 12-tungstophosphoric acid,
[14]
[15]
[16]
NR-50,
metallophthalocyanine,
and HEU type zeolite
were
developed. However, most methods have not been entirely satisfactory
because of several drawbacks such as the expensive and hazardous reagents,
large excess of catalyst, long reaction time, harsh reaction condition, and
harmful organic solvent. Therefore, finding a mild and environmentally
friendly protocol has become increasingly important.
Copper methanesulfonate (CMS) is a green, water-tolerant Lewis acid,
[
17]
[18]
which has been used successfully in esterification,
and tetrahydropyranylation reactions.
diacetylation,
[19]
Properties such as low toxicity,
moisture tolerance, and reusability make it an attractive alternative to
conventional Lewis acids. In the course of our study on the green organic
synthesis, we developed an ideal route to carry out the Biginelli reaction
by using an inexpensive and reusable CMS (2 mol%) as catalyst in a highly
efficient manner (Scheme 1). This method not only preserves the sim-
plicity of the one-pot Biginelli reaction, but also produces excellent yields
of the products. Following this protocol, a variety of reactants were
converted to their corresponding dihydropyrimidin-2-(1H)-ones in
short reaction time (1–2 h). After reaction, the catalyst can be separated
easily and reused up to four times. Three new compounds were reported
at first.
EXPERIMENTAL
Melting points were determined using RY-1 micromelting point appar-
atus and were uncorrected. Infrared spectra were recorded on a Spectrum
1
GX series Fourier Transform instrument of Perkin Elmer. H NMR spectra
were recorded on a Bruker ARX-600 spectrometer in DMSO-d using TMS
6
as an internal standard. Elemental analyses were carried out on an EA
2400II elemental analyzer (Perkin-Elmer).

Water-Tolerant and Reusable Lewis Acid
103
General Procedure for the Synthesis of DHPMs
A mixture of aldehyde (20 mmol), 1,3-dicarbonyl compound (24 mmol),
ꢁ
urea (1.80 g, 30 mmol), and CMS (0.4 mmol) was heated with stirring at 90 C
for an appropriate time. After completion (monitored by TLC), the reaction
mixture was cooled to room temperature, and then poured onto crushed
ice. The solid products were filtered under suction, washed thoroughly with
cold water and 20% ethanol (v), and subsequently dried and recrystallized
from ethanol to give the pure DHPMs. All the pure products were character-
1
ized by Mp, IR, H NMR, and elemental analysis. Spectral data for the new
compounds:
5
-Methoxycarbonyl-6-methyl-4-(2-hydroxyphenyl)-3,4-dihydropyrimidin-2-
(1H)-one (4s)
Pale green solid. IR (KBr): 3232 (N-H), 1742 (C¼O, acyl), 1692 (C¼O,
ꢂ1 1
ring) cm . H NMR (600 MHz, DMSO-d ) d: 7.61 (s, 1H, NH), 7.23 (s, 1H,
6
NH), 7.21–6.78 (m, 4H, arom.), 4.47 (s, 1H, OH), 3.70 (s, 3H, CH OCO),
3
3
.31 (d, 1H, J ¼ 13.0 Hz, CH), 1.73 (s, 3H, CH ). Anal. calcd. for
3
C H N O : C, 59.53; H, 5.38; N, 10.68. Found: C, 59.50; H, 5.39; N,
1
3
14
2
4
10.67%.
5
-Methoxycarbonyl-6-methyl-4-(2-furyl)-3,4-dihydropyrimidin-2-(1H)-one (4v)
Pale brown solid. IR (KBr): 3244 (N-H), 1706 (C¼O, acyl), 1651 (C¼O,
ꢂ1 1
ring) cm . H NMR (600 MHz, DMSO-d ) d: 9.27 (s, 1H, NH), 7.79 (s, 1H,
6
NH), 7.56 (d, 1H, J ¼ 0.6 Hz, furyl), 6.34 (s, 1H, furyl), 6.10 (d, 1H,
J ¼ 3.1 Hz, furyl), 5.20 (d, 1H, J ¼ 3.4 Hz, CH), 3.57 (s, 3H, OCH ), 2.21
3
(
s, 3H, CH ). Anal. calcd. for C H N O : C, 55.93; H, 5.12; N, 11.86.
3 11 12 2 4
Found: C, 55.91; H, 5.11; N, 11.87%.
5-Aceto-6-methyl-4-(2-hydroxyphenyl)-3,4-dihydropyrimidin-2-(1H)-one (4z)
Pale yellow solid. IR (KBr): 3238 (N-H), 1697 (C¼O, acyl), 1610 (C¼O,
ꢂ1 1
ring) cm . H NMR (600 MHz, DMSO-d ) d: 7.48 (s, 1H, NH), 7.20 (s, 1H,
6
NH), 7.18–6.76 (m, 4H, arom.), 4.64 (s, 1H, OH), 3.37 (s, 1H, CH), 2.49 (s,
3H, CH CO), 1.64 (s, 3H, CH ). Anal. calcd. for C H N O : C, 63.40; H,
3 3 13 14 2 3
5.73; N, 11.37. Found: C, 63.36; H, 5.72; N, 11.39%.
RESULTS AND DISCUSSION
The solvent-free Biginelli reaction has drawn much attention recently.
The procedure avoids problems associated with solvent use (cost, handling,
safety, and pollution). Herein, we report a simple and efficient one-pot
three-component synthesis of 3,4-dihydropyrimidin-2-(1H)-ones from an

104
M. Wang et al.
aldehyde (aromatic, aliphatic or heterocyclic aldehyde), a 1,3-dicarbonyl
compound (ethyl acetoacetate, methyl acetoacetate or pentanedione),
and urea using CMS as catalyst under solvent-free conditions (Table 1).
All reactions proceeded smoothly in moderate to high yields within 2 h.
Aromatic aldehydes carrying either electron-withdrawing groups or
electron-donating groups all reacted well. The position of the substituents
on the aromatic ring shows no obvious effects on this conversion. Acid
sensitive aldehyde such as furfural worked well without the formation of
any by-products. Aliphatic aldehydes afford moderate yields of products
too. The by-product of the Biginelli reaction is water. Especially for com-
pounds 4h and 4t, they derived from 40% aqueous acetaldehyde, which
shows CMS did not hydrolyze encounter the water. The use of methyl
TABLE 1 CMS Catalysed One-pot Synthesis of DHPMs (4)
ꢁ
Mp ( C)
a
DHPMs (4)
R
R
1
Time (h)
Yield (%)
Found
Reported
b
[20]
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
C
6
H
5
C
C
C
C
C
C
C
C
C
C
C
C
C
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
H
H
H
H
H
5
5
5
5
5
5
5
5
5
5
5
5
5
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2
1.5
2
1.5
1
2
2
2
2
2
2
2
2
2
2
2
1.6
1
1.3
2
94,92,89,85
93
205–206
219–220
210–212
241–244
221–224
202–203
203–205
180–182
180–181
179–180
193–195
117–119
206–207
202–204
218–220
250–253
273–275
204–206
199–201
167–169
179–181
205–207
236–238
254–256
221–223
208–210
170–172
203–205
205–206
218–220
208–209
246–248
228–230
205–206
188–190
185–187
179–181
179–180
195–197
118–119
203–205
214–215
226–229
252–253
[
[
[
[
[
[
6]
2-(Cl)-C
4-(Cl)-C
2,4-Cl
3-NO
4-CH
6
H
H
4
20]
5]
6
4
92
88
91
89
81
60
61
73
45
70
80
92
89
83
90
93
92
42
84
91
96
93
92
83
2
-C
-C
O-C
6
H
H
3
6]
2
6
4
20]
20]
3
6
H
4
2-OH-C
CHc
6
H
4
[21]
3
[
[
[
[
[
[
[
[
21]
21]
21]
21]
20]
20]
9]
CH
3
CH
(CH
CH
(CH
Furyl
2
CH
3
2
)
2
(CH
CH
3
)
2
3
2
)
6
C
6
H
5
3
3
3
3
3
3
3
3
3
2-Cl-C
2,4-Cl
3-NO
4-CH
2-OH-C
CH
CH
Furyl
6
H
4
5]
2
-C
-C
O-C
6
H
H
3
[13]
2
6
4
279
[
22]
3
6
H
4
205–208
-
s
t
6
H
4
c
[21]
3
167–169
184–185
–
[21]
u
v
w
x
y
3
CH
2
2
1.5
1.5
1.3
1
1.7
2
[
[
[
20]
20]
20]
C
6
H
5
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
232–234
252–254
218–220
–
2-Cl-C
4-Cl-C
2-OH-C
CH CH
Furyl
6
H
H
4
6
4
z
a
b
6
H
4
0
0
[21]
3
2
40
94
173–175
210–212
[10]
1.4
a
b
Isolated yield.
Reuse of catalyst.
c
Using 40% aqueous acetaldehyde.

Water-Tolerant and Reusable Lewis Acid
105
acetoacetate and pentanedione as 1,3-dicarbonyl moieties in place of ethyl
acetoacetate also gave satisfactory results. Another important aspect of this
procedure is the survival of a variety of functional groups such as –Cl,
–
NO , –CH O, and –OH. From the above observations, it is very clear that
2 3
this methodology is applicable to a wide range of reactants with different
functional groups. Many pharmacologically relevant substitution patterns
of the DHPMs can thus be introduced with high efficiency.
After completion of the reaction, the reaction mixture was cooled and
the ensuing solid contents were treated with hot ethyl acetate. The catalyst
could be recovered quantitatively from the reaction mixture by simple
filtration and washed with CH Cl , and could be reused for subsequent
2
2
reactions. For example, the catalyst was reused in the case of benzaldehyde
for four times without obvious loss of activity (Entry 4a).
CONCLUSIONS
In conclusion, we have described a simple and efficient method for the
synthesis of dihydropyrimidiones by using a water tolerant and reusable
Lewis acid, CMS, as catalyst. The method offers several advantages includ-
ing high yields, shorter reaction time, reusable catalyst, and environmen-
tally friendly procedures, which make it is a useful and important
addition to the existing methods.
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