A Facile and Efficient One-Pot Synthesis of Dihydropyrimidinones Catalyzed by Magnesium Bromide under Solvent-Free Conditions

Article abstract of DOI:10.1081/SCC-120027250

Magnesium bromide efficiently catalyzes the three-component condensation reaction of aldehyde, β-diketon and urea/thiourea under solvent-free conditions to afford the corresponding dihydropyrimidinones in high yields and short reaction time.

Full text of DOI:10.1081/SCC-120027250

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A Facile and Efficient One‐Pot Synthesis of
Dihydropyrimidinones Catalyzed by Magnesium
Bromide Under Solvent‐Free Conditions
a
a
Hojatollah Salehi & Qing‐Xiang Guo
a
Department of Chemistry , University of Science and Technology of China , 96 JinZhai
Road, Hefei, 230026, China
Published online: 16 Aug 2006.
To cite this article: Hojatollah Salehi & Qing‐Xiang Guo (2004) A Facile and Efficient One‐Pot Synthesis of
Dihydropyrimidinones Catalyzed by Magnesium Bromide Under Solvent‐Free Conditions, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:1, 171-179, DOI: 10.1081/
SCC-120027250
To link to this article: http://dx.doi.org/10.1081/SCC-120027250
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 1, pp. 171–179, 2004
A Facile and Efficient One-Pot Synthesis of
Dihydropyrimidinones Catalyzed by
Magnesium Bromide Under
Solvent-Free Conditions
*
Hojatollah Salehi and Qing-Xiang Guo
Department of Chemistry, University of Science and Technology
of China, Hefei, China
ABSTRACT
Magnesium bromide efficiently catalyzes the three-component conden-
sation reaction of aldehyde, b-diketon and urea/thiourea under solvent-
free conditions to afford the corresponding dihydropyrimidinones in high
yields and short reaction time.
Key Words: One-pot synthesis; Magnesium bromide; Dihydropyrimi-
dinones; Biginelli reaction.
*
Correspondence: Qing-Xiang Guo, Department of Chemistry, University of Science
and Technology of China, 96 JinZhai Road, Hefei 230026, China; Fax: 86-551-360-
689; E-mail: qxguo@ustc.edu.cn.
6
1
71
DOI: 10.1081/SCC-120027250
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

1
72
Salehi and Guo
Dihydropyrimidinone derivatives have attracted considerable interest
recently because of their promising activities as calcium channel blockers,
[1]
antihypertensive agents and a-1a-antagonists. Morever, several alkaloids
containing the dihydropyrimidine unit have been isolated from marine
[2,3]
sources, and exhibit interesting biological properties.
Recently several
isolated marine alkaloids with biological activities were also found containing
the dihydropyrimidinones core. Most notably among them are betzelladine
alkaloids, which have been found to be potent HIVgp-120-CD4 inhibi-
[
4–6]
tors.
Thus, synthesis of this heterocyclic nucleus is of much current
important. The most simple and straightforward procedure, reported by
Biginelli in 1893, involves one-pot condensation of ethyl acetoacetate,
[7]
benzaldehyde and urea under strongly acidic conditions.
However, one serious drawback of Biginelli’s reaction is low yields
[8]
obtained in the case of substituted aromatic and aliphatic aldehydes. This
has led to the development of multistep strategies that produce somewhat
[9–11]
higher overall yields but lack the simplicity of the one-pot synthesis.
The art of performing efficient chemical transformation coupling three
or more components in a single operation by a catalytic process avoiding
stoichiometric toxic reagents, large amount of solvents and expensive
purification technique, represent a fundamental target of the modern organic
[
12]
synthesis.
midinones has received renewed interest. Several improved procedures have
Thus, Biginelli’s reaction for the synthesis of dihydropyri-
[
13–25]
recently been reported. It has been reported that Lewis acids (such as
in combination with transition metals and a proper proton
source were effective catalyst for this reaction. Dihydropyrimidinones were
[
13]
.
BF3 OEt2)
[
23]
[19]
also synthesized by using various protic acids such as HCl,
under microwave irradiation. More recently, ionic liquids,
and AcOH,
[17]
montmor-
[25]
[
20]
[21]
illonite KSF,
polyphosphate ester(PPE),
and lanthanide triflate,
as
catalysts for the one-pot solvent-free synthesis of dihydropyrmidinones have
also been reported. However, in spite of their potential utility, many of these
methods involve expensive reagents, strongly acidic conditions, long
reaction time, unsatisfactory yields and cumbersome product-isolation pro-
cedures. Consequently, there are scopes for further renovation toward milder
reaction conditions, variations of substituents in all three components and
better yields.
In recent years magnesium bromide has received considerable attention as
a powerful reaction medium for effecting various transformations
[26–31]
such
as condensation reactions, cyclization reaction, polymerization, Diels-Alder
reactions, anti-Aldol reactions and acylation of alcohols. The challenge for a
sustainable environment calls for clean procedures that can avoid using
[
32]
harmful organic solvents. Reactions under solvent-free or so-called dry
media conditions are especially appealing as they provide an opportunity to

Dihydropyrimidinones
173
Scheme 1.
work with open vessels, thus avoiding the risk of high pressure development
[33–35]
and with the possibility of upscaling the reactions to larger scale.
Here, we wish to report a facile and efficient method for the one-pot
synthesis of dihydropyrimidinones using magnesium bromide as catalyst
under solvent free conditions (Sch. 1).
A wide range of substituted aldehydes and several b-diketones and urea/
thiourea were subjected to this procedure to produce the corresponding
dihydropyrimidinones (Table 1). The procedure gives the products in good to
excellent yields and avoids problems associated with solvent use (cost,
handling, safety and pollution). Decreased reaction times are also realized
because of the increased reactivity of the reactant in the solid state and the fact
Table 1. Magnesium bromide-catalyzed one-pot synthesis of dihydropyrimidinones
under solvent-free conditions at 1008C.
a
Product R1
R2
R3
X
Time (min) Yield (%)
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
OMe
OMe
Me
C
6
H
5
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
S
45
90
60
90
90
90
45
45
90
90
90
90
90
60
45
90
90
82
88
86
82
79
92
94
84
86
91
85
81
90
91
86
3-(NO
C H
2 6 4
)-C H
6
5
C
C
6
H
H
5
5
4-(OMe)-C
2,4-(Cl) -C
4-(OH)-C H
6 4
H
6
2
6
H
3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
6
4
g
h
i
6 5
C H
4-(OMe)-C
2-Furyl
6
H
4
j
3-(NO )-C H
2
6
4
k
l
4-(OH)-C
2,4-(Cl) -C
6
H
4
2
6
H
3
m
n
o
p
C H CH 55 CH
6
5
C
6
H
5
4-(OMe)-C
C H
6
H
4
S
S
6
5
a
Isolated yields.

1
74
Salehi and Guo
that the other reaction product, water, evaporates at the reaction temperature
of 1008C. Most literature examples of the Biginelli variants used simple b-
ketoesters in the condensation reaction. Besides the b-ketoester, the b-
diketone can also be employed. Thiourea and N-methylurea have been used
with similar success to provide the corresponding dihydropyrimidinones,
[1]
which are also of much interest with regard to biological activity. No
additive or protic acid is necessary in this procedure. Another important aspect
of this procedure is survival of a variety of functional groups, such as NO , Cl,
2
OH, OMe, and C 55 C under the experimental conditions. Furthermore,
aromatic aldehydes bearing either electron-donating or electron-withdrawing
substituents all worked well, giving good to excellent yields. In addition, acid
sensitive aldehydes, such as furfural reacted well without any side products,
which normally reacted either in the presence of portic or Lewis acids. The
reaction may proceed through the acylimine intermediate (formed in situ by
reaction of the aldehyde with urea), which is stabilized by the magnesium ion,
and the subsequent addition of the b-diketon enolate to the acylimine,
followed by cyclization and dehydration, affords the corresponding
dihydropyrimidinones (Sch. 2).
In conclusion, we developed an environmentally friendly procedure for
the synthesis of dihydropyrimidinones by using magnesium bromide as an
inexpensive and easily available catalyst under solvent-free conditions. In
addition to its simplicity and mild reaction conditions, it tolerates a wide
variety of substitutions in all three components. The adopted procedure is
convenient, involves simple experimental procedure and product isolation;
hence, it is a useful addition to the existing methods.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were run on a Bruker
2
spectrometer and expressed in cm (KBr). H and C NMR spectra were
1
1
13
recorded on a Bruker AVMCE-300 MHz in DMSO-d solutions. Elemental
6
analysis was performed by the Elementar Vario EL-III. High resolution mass
spectra were obtained with a Micromass GCT TOF mass spectrometer.
Scheme 2.

Dihydropyrimidinones
175
General Procedure for the One-Pot Synthesis of
Dihydropyrimidinones Under Solvent-Free Conditions
Representative procedure for 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-
dihydropyrimidin-2 (1H)-one (4g). Ethyl acetoacetate (10 mmol), benzal-
dehyde (10 mmol), urea (15 mmol) and magnesium bromide (1 mmol,
10 mol%) were heated at 1008C under stirring for 45 min. After cooling, the
reaction mixture was poured onto crushed ice (50 g) and stirred for 5–10 min.
The solid separated was filtered under suction, washed with ice-cold water
(2 Â 50 mL) and then recrystallized from ethanol to afford pure product. All
the products were characterized by mp, spectral and analytical data. 4e and 4f
are new compounds.
4
a. m.p. 214–2168C. IR (KBr): n ¼ 3333, 3226, 3106, 2950, 1696,
2
1 1
1
5
9
668 cm . HNMR (DMSO-d ): d ¼ 2.24 (s, 3H, CH ), 3.52 (s, 3H, CH ),
6
3
3
.12 (d, 1H, J ¼ 3.18, H-4), 7.21–7.34 (m, 5H, H
), 7.76 (brs, 1H, NH),
.22 (brs, 1H, NH). MS: m/z ¼ 246.09 (M ), 231, 214, 187, 169, 137, 77, 43.
21 1
arom
þ
4
b. m.p. . 2508C. IR (KBr): n ¼ 3357, 3219, 3101, 2957, 1695, 1642,
1
5
8
2
535 cm . HNMR (DMSO-d ): d ¼ 2.28 (s, 3H, CH ), 3.54 (s, 3H, CH ),
6
3
3
.29 (d, 1H, J ¼ 3.19, H-4), 7.62–7.70 (m, 2H, H
), 7.93 (brs, 1H, NH),
arom
þ
.08–8.15 (m, 2H, H
32, 186, 169, 137, 58, 43.
), 9.40 (brs, 1H, NH). MS: m/z ¼ 291.08 (M ), 274,
arom
2
1
4
c. m.p. 242–2448C. IR (KBr): n ¼ 3260, 2923, 1702, 1675, 1599 cm
.
1
HNMR (DMSO-d ): d ¼ 2.10 (s, 3H, CH ), 2.28 (s, 3H, CH ), 5.25 (brs, 1H,
6
3
3
H-4), 7.25–7.32 (m, 5H, H
), 7.83 (brs, 1H, NH), 9.19 (brs, 1H, NH). MS:
arom
þ
m/z ¼ 230.1 (M ), 229, 215, 211, 187, 153, 144, 115, 110, 77.
4
d. m.p. 236–2388C. IR (KBr): n ¼ 3351, 3282, 2926, 1709, 1673,
2
1 1
1
5
632 cm . HNMR (DMSO-d ): d ¼ 1.66 (s, 3H, CH ), 3.70 (s, 3H, CH ),
6
3
3
.23 (d, 1H, J ¼ 2.91, H-4), 6.84 (d, 2H, J ¼ 8.64, H
), 7.09 (d, 2H,
), 7.72 (brs, 1H, NH), 9.13 (brs, 1H,
arom
arom
J ¼ 8.64, H
), 7.42–7.53(m, 5H, H
NH). MS: m/z ¼ 322.1 (M ), 321, 307, 291, 217, 215, 185, 105, 77, 43.
arom
þ
2
1
4
e. m.p. 232–2348C. IR (KBr): n ¼ 3290, 1697, 1655, 1615, 1592 cm
.
1
HNMR (DMSO-d ): d ¼ 1.67 (s, 3H, CH ), 5.70 (d, 1H, J ¼ 2.6, H-4), 7.40–
6
3
1
3
7
.52 (m, 8H, H
), 7.73 (brs, 1H, NH), 9.24 (brs, 1H, NH). CNMR
arom
(
DMSO-d ): d ¼ 18.6, 52.8, 107.5, 127.7, 127.8, 128.6, 128.9, 130.6, 131.6,
6
1
32.6, 140.0, 140.8, 146.1, 151.4, 193.8. Anal. Calcd. For C H N2Cl O : C,
18 14 2 2
5
9.85; H, 3.90; N, 7.75; Found: C, 59.74; H, 3.92; N, 7.83. MS: m/z ¼ 361.03
þ
(
M ), 325, 255, 241, 215, 105, 77.
4
f. m.p. 178–1808C. IR (KBr): n ¼ 3280, 3098, 2985, 1703, 1667,
2
1 1
1
626 cm . HNMR (DMSO-d ): d ¼ 1.11 (t, 3H, J ¼ 6.96, CH ), 2.46 (s, 3H,
6
3
CH ), 3.08 (s, 3H, NCH ), 4.02 (q, 2H, J ¼ 7.08, CH ), 5.03 (d, 1H, J ¼ 3.21,
3
3
2
H-4), 6.66 (d, 2H, J ¼ 8.19, H
), 6.98 (d, 2H, J ¼ 8.34, H
), 7.83 (brs,
arom
arom
1
3
1
H, NH), 9.34 (s, 1H, OH). CNMR (DMSO-d ): d ¼ 14.0, 16.0, 18.5, 29.6,
6

1
76
Salehi and Guo
51.9, 56.0, 59.4, 102.9, 115.0, 127.2, 134.6, 149.9, 153.1, 156.6, 165.6. Anal.
Calcd. For C H N O : C, 62.05; H, 6.24; N, 9.64; Found: C, 61.93; H, 6.27;
1
5 18 2 4
þ
N, 9.44. MS: m/z ¼ 290.1 (M ), 275, 261, 217, 197, 169, 151, 94, 56.
21 1
4
g. m.p. 2068C. IR (KBr): n ¼ 3245, 3118, 2978, 1725, 1701,
1
649 cm . HNMR (DMSO-d ): d ¼ 1.06 (t, 3H, J ¼ 6.84, CH ), 2.24 (s,
6
3
3
H, CH ), 3.94 (q, 2H, J ¼ 6.75, CH ), 5.13 (d, 1H, J ¼ 3.06, H-4), 7.21–7.37
3
2
(
m, 5H, H
M ), 232, 231, 213, 187, 183, 155, 137, 115, 102, 77.
), 7.73 (brs, 1H, NH), 9.19 (brs, 1H, NH). MS: m/z ¼ 260.1
arom
þ
(
4
h. m.p. 198–2008C. IR (KBr): n ¼ 3436, 3247, 3113, 2929, 1724,
2
1 1
1
705, 1649 cm . HNMR (DMSO-d ): d ¼ 1.10 (t, 3H, J ¼ 7.08 CH ), 2.17
6
3
(
s, 3H, CH ), 3.71 (s, 3H, CH ), 3.96 (q, 2H, J ¼ 7.14, CH ), 5.07 (d, 1H,
3
3
2
J ¼ 2.97, H-4), 6.85 (d, 2H, J ¼ 8.49, H
), 7.12 (d, 2H, J ¼ 8.55, H
),
arom
arom
7
.67 (brs, 1H, NH), 9.15 (brs, 1H, NH).
4
i. m.p. 206–2088C. IR (KBr): n ¼ 3342, 3242, 3117, 2985, 1700,
2
1 1
1
645 cm . HNMR (DMSO-d ): d ¼ 1.05 (t, 3H, J ¼ 7.08, CH ), 2.22 (s,
6
3
3
H, CH ), 3.98 (q, 2H, J ¼ 6.99, CH ), 5.19 (d, 1H, J ¼ 3.0, H-4), 6.08 (d, 1H,
3
2
J ¼ 2.94, H
), 6.35 (s, 1H, H
), 7.55 (s, 1H, H
), 7.76 (brs, 1H, NH),
arom
arom
arom
þ
9
.25 (brs, 1H, NH). MS: m/z ¼ 250.09 (M ), 233, 221, 205, 177, 176, 124.
4
j. m.p. 226–2288C. IR (KBr): n ¼ 3422, 3104, 2964, 1708, 1690, 1630,
2
1 1
1
3
526 cm . HNMR (DMSO-d ): d ¼ 1.08 (t, 3H, J ¼ 7.02, CH ), 2.27 (s,
6 3
H, CH ), 3.98 (q, 2H, J ¼ 4.57, CH ) 5.30 (d, 1H, J ¼ 2.69, H-4), 7.63-7.72
3
2
(
m, 2H, H
), 7.93 (brs, 1H, NH), 8.09–8.16 (m, 2H, H
), 9.40 (brs, 1H,
arom
arom
þ
NH). MS: m/z ¼ 305.1 (M ), 289, 288, 276, 260, 232, 183, 155, 137, 110.
4
k. m.p. 2328C. IR (KBr): n ¼ 3511, 3278, 3123, 2975, 1686,
2
1 1
1
3
2
647 cm . HNMR (DMSO-d ): d ¼ 1.07 (t, 3H, J ¼ 6.90, CH ), 2.22 (s,
6
3
H, CH ), 3.93 (q, 2H, J ¼ 6.98, CH ) 5.03 (d, 1H, J ¼ 2.76, H-4), 6.67 (d,
3
2
H, J ¼ 8.25, H
), 7.01 (d, 2H, J ¼ 8.32, H
), 7.62 (brs, 1H, NH), 9.12
arom
arom
(
brs, 1H, NH), 9.32 (brs, 1H, OH).
4
l. m.p. 248–2508C. IR (KBr): n ¼ 3359, 3220, 3105, 2971, 1698, 1644,
2
1 1
1
590 cm . HNMR (DMSO-d ): d ¼ 1.04 (t, 3H, J ¼ 7.04, CH ), 2.28 (s,
6
3
3
H, CH ), 3.87 (q, 2H, J ¼ 6.99, CH ), 5.59 (brs, 1H, H-4), 7.29 (d, 1H,
3
2
J ¼ 8.26, H
), 7.39 (d, 1H, J ¼ 8.27, H
), 7.55 (brs, 1H, H
), 7.77
arom
arom
arom
(
brs, 1H, NH), 9.33 (brs, 1H, NH). MS: m/z ¼ 300, 299, 293, 263, 257, 255,
1
83, 155, 137, 110, 58, 43.
4
m. m.p. 240–2428C. IR (KBr): n ¼ 3247, 3115, 2928, 1720, 1701,
2
1 1
1
3
652 cm . HNMR (DMSO-d ): d ¼ 1.17 (t, 3H, J ¼ 7.05, CH ), 2.19 (s,
3 2
6
3
H, CH ), 4.06 (q, 2H, J ¼ 7.17, CH ) 4.72 (brs, 1H, H-4), 6.20 (dd, 1H,
J ¼ 5.86, J ¼ 6, 55 CH), 6.33 (d, 1H, J ¼ 15.86, 55 CH), 7.22–7.41 (m, 5H,
þ
H
), 7.56 (brs, 1H, NH), 9.15 (brs, 1H, NH). MS: m/z ¼ 286.1 (M ), 258,
arom
2
57, 240, 213, 211, 183, 155, 137, 104, 103, 91, 78.
n. m.p. 206–2088C. IR (KBr): n ¼ 3328, 3173, 3104, 2979, 1670,
4
2
1 1
1
573, 1465 cm . HNMR (DMSO-d ): d ¼ 1.07 (t, 3H, J ¼ 7.08, CH ), 2.28
6
3

Dihydropyrimidinones
177
(
s, 3H, CH ), 3.97 (q, 2H, J ¼ 7.02, CH ) 5.15 (d, 1H, J ¼ 3.57, H-4), 7.20–
3
2
7
.35 (m, 5H, H
), 9.66 (brs, 1H, NH), 10.34 (brs, 1H, NH).
arom
4
o. m.p. 1528C. IR (KBr): n ¼ 3445, 3315, 3175, 2965, 1667, 1617,
2
1 1
1
575, 1510 cm . HNMR (DMSO-d ): d ¼ 1.08 (t, 3H, J ¼ 6.93 CH ), 2.28
6
3
(
s, 3H, CH ), 3.72 (s, 3H, CH ), 3.96 (q, 2H, J ¼ 7.17, CH ), 5.10 (d, 1H,
3
3
2
J ¼ 3.6, H-4), 6.87 (d, 2H, J ¼ 8.64, H
), 7.09 (d, 2H, J ¼ 8.64, H
),
arom
arom
9
.60 (brs, 1H, NH), 10.28 (brs, 1H, NH).
4
p. m.p. 236–2388C. IR (KBr): n ¼ 3296, 3203, 2994, 1610, 1577,
21 1
1
5
1
462cm . HNMR (DMSO-d ): d ¼ 2.15 (s, 3H, CH ), 2.33 (s, 3H, CH ),
6 3 3
.28 (d, 1H, J ¼ 3.57, H-4), 7.21–7.37 (m, 5H, H ), 9.76 (brs, 1H, NH),
arom
þ
0.29 (brs, 1H, NH). MS: m/z ¼ 246.08 (M ), 245, 231, 203, 169, 144, 77, 43.
ACKNOWLEDGMENT
This work was supported by the CAS, MOST, NSFC and the University
of Science and Technology of China.
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Received in Japan May 27, 2003