Magnesium chloride hexahydrate catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)ones under solvent-free conditions

Article abstract of DOI:10.1081/SCC-200050956

3,4-Dihydropyrimidin-2-(1H)-one were prepared by Biginelli condensation of aldehyde, 1,3-dicarbonyl compound and urea under solvent-free condition at 80°C with magnesium chloride hexahydrate as catalyst.

Full text of DOI:10.1081/SCC-200050956

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Magnesium Chloride Hexahydrate
Catalyzed One‐Pot Synthesis of
3,4‐Dihydropyrimidin‐2‐(1H)ones Under
Solvent‐Free Conditions
a
a b c
Guo‐Lin Zhang & Xiao‐Hua Cai
a
Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu,
China
b
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences ,
Chengdu, China
c
Graduate School of the Chinese Academy of Sciences , Beijing, China
Published online: 20 Aug 2006.
To cite this article: Guo‐Lin Zhang & Xiao‐Hua Cai (2005) Magnesium Chloride Hexahydrate Catalyzed One‐Pot
Synthesis of 3,4‐Dihydropyrimidin‐2‐(1H)ones Under Solvent‐Free Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:6, 829-833, DOI: 10.1081/
SCC-200050956
To link to this article: http://dx.doi.org/10.1081/SCC-200050956
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Synthetic Communications , 35: 829–833, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050956
Magnesium Chloride Hexahydrate
Catalyzed One-Pot Synthesis of
,4-Dihydropyrimidin-2-(1H)ones Under
Solvent-Free Conditions
3
Guo-Lin Zhang
Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu, China
Xiao-Hua Cai
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu, China and Graduate School of the Chinese Academy of
Sciences, Beijing, China and Chengdu Institute of Biology, Chinese
Academy of Sciences, Chengdu, China
Abstract: 3,4-Dihydropyrimidin-2-(1H)-one were prepared by Biginelli condensation
of aldehyde, 1,3-dicarbonyl compound and urea under solvent-free condition at 808C
with magnesium chloride hexahydrate as catalyst.
Keywords: Biginelli reaction, dihydropyrimidinones, magnesium chloride hexahy-
drate, one-pot condensation, solvent-free
3,4-Dihydropyrimidin-2-(1H)-ones (DHPMs, 4) and related compounds
possess diverse biological properties, such as antiviral, antitumor, antihyper-
[
1]
tensive, and antibacterial effects.
blockers, and a-adrenergic and neuropetide Y (NPY) antagonists.
They are potential calcium-channel
[2]
Received in Japan October 15, 2004
Address correspondence to Guo-Lin Zhang, Chengdu Institute of Biology, Chinese
Academy of Sciences, Chengdu 610041, China. Fax: þ86-28-85225401; E-mail:
ZHANGGL@cib.ac.cn

8
30
G.-L. Zhang and X.-H. Cai
In addition, several marine alkaloids with interesting biological properties
[3]
contain 3, 4-dihydropyrimidinone-5-carboxylate moiety. The simple and
direct method for the synthesis of DHPMs reported by Biginelli in 1893
involves the one-pot condensation of aldehyde, b-keto ester, and urea under
[
4]
strongly acidic condition. This method suffers from low yields, especially
in the cases of aliphatic and some substituted aromatic aldehydes. Recently,
many improved procedures were reported for the preparation of DHPMs
[
5]
[6]
[7]
[8]
.
FeCl3 6H O or
2
using Bi(OTf) ,
3
ZrCl ,
4
InCl3,
.
LiClO4,
Bi(OTf)3,
[
NiCl 6H O, p-TsOH,
9]
[10]
[11]
[12]
[13]
.
LaCl3 7H O,
2
KHSO4,
ionic
[16]
or TMSOTf
2
2
[14]
liquids (BMImPF and BMImBF ),
[15]
.
Mn(OAc) 2H O,
6
4
3
2
as the catalyst. However, some of the catalysts are expensive, complex or
unavailable, and some of these methods require vigorous reactions, prolonged
standing and tedious manipulations to isolation the products. Organic solvents
are always used. Therefore, the inexpensive and environmentally friendly
procedure for the preparation of DHPMs under mild conditions is of prime
importance.
The solvent-free Biginelli reaction has attracted much attention and good
results were reported recently. Under solvent-free conditions, N-butyl-N, N
dimethyl-a-phenylethyl ammonium bromide could catalyze the Biginelli
reaction to afford corresponding products in 86ꢀ99% yields at 1008C
[
17]
. .
CuCl 2H O or CuSO 5H O as the catalyst gives Biginelli
2 2 4 2
within 1 h.
condensation products in 80ꢀ99% yields at 1008C for 60ꢀ110 min under
[
18]
solvent-free conditions.
or environmentally unfriendly catalysts. Ammonium chloride was used as
However, these procedures involved expensive
[19]
the catalyst under solvent-free conditions, but the yields are not satisfactory
42ꢀ92%) and longer reaction time (3 h) is required. Magnesium chloride has
(
been used to catalyze the acylation of b-keto esters. Here we would like to
report a new economic approach for the synthesis of DHPMs by Beginelli
[20]
.
reaction using MgCl2 6H O as the catalyst under solvent-free conditions
2
(Scheme 1).
Biginelli condensation was performed using hydrous Lewis acid as the
.
.
.
3
catalyst, such as FeCl3 6H O, NiCl 6H O, and LaCl 7H O in higher
2
2
2
2
yields in an organic solvent. We studied the Biginelli condensation using
hydrous salt as catalyst under solvent-free conditions. Then, we selected
Scheme 1.

3,4-Dihydropyrimidin-2-(1H)Ones
831
Table 1. Biginelli condensation of benzaldehyde, ethyl acetoace-
tate, and urea under different conditions
Isolated
yield (%)
Entry
Catalyst
Time
.
1
2
3
4
NiCl2 6H O
2
1 h
1 h
1 h
2 h
90
86
96
81
.
FeCl
MgCl
none
3
6H
.
2
O
2
2
6H O
.
.
.
3
inexpensive and available NiCl2 6H O, MgCl 6H O, and FeCl 6H O
2
2
2
2
(20 mol%) as catalysts to the three-component Biginelli condensation under
solvent-free conditions at 808C, and the results obtained are exhibited in
Table 1. Entry 3 shows that magnesium chloride hexahydrate gave the best
results among the three salts. To optimize the reaction conditions, the conden-
sation reaction of benzaldehyde, ethyl acetoacetate, and urea was selected as a
model to examine the effects of the catalyst (0, 10, 20, and 30 mol%) and
Table 2. Magnsium chloride hexahydrate catalyzed solvent-free synthesis of
3,4-dihydropyrimidin-2-(1H)-one at 808C
Time Yield
b
(min) (%)
a
DHMP
R
1
R
2
Mp (8C) Lit. mp (8C)
[
[
[
[
[
[
[
[
[
[
18]
18]
21]
22]
25]
23]
24]
23]
26]
18]
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
Me
C H
6
60
50
40
60
60
45
60
30
60
90
40
50
60
90
50
90
96
95
92
89
90
93
95
96
97
85
88
90
94
92
91
90
203–204 200–202
200–202 198–200
185–187 185–187
230–232 231–232
228–230 227–229
213–215 209–212
223–225 222–223
183–186 182–184
207–209 205–206
210–212 208–209
190–191 186–188
195–196 190–192
229–230 229–231
173–174 170–172
5
4-(MeO)-C
3-(HO)-4-(MeO)-C
4-(HO)-3-(MeO)-C H
6 5
H
6
H
5
5
6
4-(HO)-C
4-(Cl)-C
3,4-(2-Cl)-C H
6 5
H
6 5
H
g
h
i
6
5
4-(F)-C
6 5
H
2-(NO
2-furyl
Me
2
)-C
6 5
H
j
c
[19]
[18]
k
d
l
3 2
(CH )
CH
[
[
23]
23]
m
n
6 5
C H
Me
4-(MeO)-C H
6 5
o
Me
Me
4-(F)-C
2-furyl
6
H
5
217–218
212–213
—
210–212
[
7]
p
a
b
c
d
1
All products were characterized by IR, H NMR, and MS spectral data.
Isolated yield.
Room temperature.
508C.

8
32
G.-L. Zhang and X.-H. Cai
quantities of reagents at different reaction temperature (50, 80, and 1008C).
The best results were obtained with a 1:1:1.5:0.2-mol ratio of aldehyde,
ethyl acetoacetate, urea, and magnesium chloride hexahydrate under
solvent-free conditions at 808C for 1 h.
In a typical procedure, a mixture of ethyl acetoacetate (0.65 g, 5 mmol),
benzaldehyde (0.503 g, 5 mmol), urea (0.45 g, 7.5 mmol), and magnesium
chloride hexahydrate (0.20 g, 1 mmol) was heated to 808C for 1 h. After com-
pletion (monitored by TLC), the reaction mixture was cooled to room
temperture and poured into water (30 mL). The solid was separated by
filtration, washed with water, and then recrystallized from ethanol to afford
[
18]
4
a, mp 203ꢀ2048C (lit.
mp 200ꢀ2028C) in 96% yield. Similarly, substi-
tuted aldehyde, and 1,3-dicarbonyl compound were together heated with
urea to give the corresponding 3,4-dihydropyrimidin-2-(1H)-ones, which
were purified by recrystallizing from ethanol or washing three times with
cool ethyl acetate. The results are summarized in Table 2. Apparently, the
procedure gave the products in high yields (85ꢀ97%) within 1.5 h at 808C
and solvent was not necessary. Moreover, the separation and purification of
the products is simple.
In conclusion, an economically and environmentally friendly procedure for
the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones using magnesium chloride
hexahydrate as catalyst was developed. The synthetic procedure provides an
efficient and attractive method to synthesize DPHMs by Biginelli condensation
in good to excellent yields under solvent-free conditions.
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