An efficient one-pot synthesis of dihydropyrimidinones catalyzed by zirconium hydrogen phosphate under solvent-free conditions

Article abstract of DOI:10.3906/kim-0912-357

A simple, efficient, and practical procedure for the Biginelli reaction using zirconium hydrogen phosphate [Zr(H₂ PO₄) ₂] as a novel solid acid catalyst is described under solvent-free conditions in high yields. The cataly

Full text of DOI:10.3906/kim-0912-357

Turk J Chem
4 (2010) , 411 – 416.
3
¨ ˙
ꢀ
c TUBITAK
doi:10.3906/kim-0912-357
An efficient one-pot synthesis of dihydropyrimidinones
catalyzed by zirconium hydrogen phosphate under
solvent-free conditions
1
¨
¨
2
˙
˘
2,∗
˙
2
S¸ enol BE S¸ OLUK , Mustafa KU C¸ UKISLAMOGLU , Mustafa ZENGIN
˙
˘
2
Mustafa ARSLAN , Mehmet NEBIOGLU
1
Department of Science Education, Faculty of Education, Sakarya University,
Sakarya 54300, TURKEY
2
Department of Chemistry, Faculty of Art and Science, Sakarya University,
Sakarya 54140, TURKEY
e-mail: mustafak@sakarya.edu.tr
Received 09.12.2009
A simple, efficient, and practical procedure for the Biginelli reaction using zirconium hydrogen phosphate
Zr(H PO ] as a novel solid acid catalyst is described under solvent-free conditions in high yields. The
[
2
4 2
)
catalyst exhibited remarkable reactivity and it is reusable.
Key Words: Biginelli reaction; solvent-free; zirconium hydrogen phosphate; dihydropyrimidinones, recy-
clable catalyst
Introduction
Several dihydropyrimidinones and their derivatives are pharmacologically potent calcium channel blockers,
1
antihypertensive agents, α-adrenergic antagonists, and neuropeptide Y(NPY) antagonists. These compounds
2
also exhibit a broad range of biological activities such as antiviral, antitumor, antibacterial, anti-inflammatory,
antioxidant, and FATP4 inhibitor properties. Furthermore, the 2-oxodihydropyrimidine-5-carboxylate core
unit is found in many marine natural products including batzelladine alkaloids, which have been found to
3
be HIV-gp-120 CD4 inhibitors. Therefore, the preparation of this heterocyclic core unit has attracted the
4
attention of many organic chemists. The simple and direct method originally reported by Biginelli involves
∗
Corresponding author
4
11

An efficient one-pot synthesis of dihydropyrimidinones..., S¸ . BE S¸ OLUK, et al.,
the one-pot condensation of β-ketoester with an aldehyde and urea under strongly acidic conditions, but the
reaction suffered from drawbacks such as low yields, long reaction time, and strong corrosion equipment. For
5
4
6
3,
7
8
this transformation, several methods were improved, such as using ZrCl InBr Mn(OAc)3 .2H2 O, ZnCl2 ,
,
9
10
11
TMSCl, FeCl 3 /Si-MCM-41, and ionic liquid. However, some of these one-pot procedures generally require
strong protic or Lewis acids, prolonged reaction times, and high temperature. Consequently, there is scope for
further modification towards mild reaction conditions, increased variation of the substituents, and improved
yields.
Solvent-free conditions are especially important for providing an eco-friendly system. Currently, much
emphasis has been given to the use of inorganic reagents in organic reactions, as these reactions often provide
1
2
the milder conditions and easier work up than similar reactions using organic reagents.
1
3
In the recent past, metal phosphates have attracted considerable attention as solid acid catalysts. The
activity of these materials is attributed to the Brønsted acidity of hydroxyl groups and the Lewis acidity of
the metal center. In particular, zirconium phosphates have been used in catalytic reactions such as esterifi-
1
4
cation, dehydration of alcohols, isomerization of olefins, and Aza-Diels-Alder reactions. Zirconium hydrogen
phosphate [Zr(H2 PO4)2 ] is a new water-tolerant solid acid catalyst that possesses high activity, is stable in
the presence of excess water, is recoverable by simple filtration, and is reusable without any treatments such as
1
5
calcination.
In continuation of our studies on the development of novel synthetic methodologies in a heterogeneous
1
6
system,
we report herein the synthesis of a variety of 3,4-dihydropyrimidin-2(1H)-ones using zirconium
hydrogen phosphate as a water-tolerant solid acid catalyst in the condensation reaction of β-ketoester with
urea (or thiourea) and various aromatic aldehydes without any solvent (Scheme).
O
R1
O
O
X
Zr(H PO ) 7 mol%
2 4 2
R2
1
NH
R CHO
+
+
R2
Solvent-free
H N
2
NH2
N
H
X
1
2
3
X= O, S 4a-y
Scheme
Experimental
Melting points were recorded using an Electrothermal IA 9100 melting point apparatus and are uncorrected.
1
13
H- and C-NMR spectra were recorded in DMSO-d6 and CDCl3 on a Varian Mercury Plus 300 MHz and mass
spectra were taken by Micromass Quattro LC-MS-MS instruments. Benzaldehyde was purified by distillation.
The other chemicals were of commercial grade and used without further purification.
1
5
General Procedure for the Synthesis of DHPMs: Catalyst was prepared according to the literature.
A
mixture of benzaldehyde (3 mmol, 0.32 g), ethyl acetoacetate (3 mmol, 0.39 g), urea (4.5 mmol, 0.27 g), and
◦
the catalyst (7% mmol) was finely mixed together in a test tube at 90 C for 1 h. After cooling, the reaction
mixture was poured onto crushed ice (50 g) and stirred for 10 min. The precipitate was filtered under suction
4
12

An efficient one-pot synthesis of dihydropyrimidinones..., S¸ . BE S¸ OLUK, et al.,
and washed with cold water (20 mL) to remove excess urea. After that the solid was dissolved in ethanol and
filtered to remove the catalyst and purified further by recrystallization (hot ethanol).
5
-Ethoxycarbonyl-4-(2,4-dimethoxyphenyl)-6-methyl-3,4-dihydro-pyrimidin-2(1H)-one (4g)
1
H-NMR (300 MHz, CDCl3): δ 1.11 (3H, t, J=7.03 Hz, CH3 CH2 O), 2.39 (3H, s, CH3), 3.77 (3H, s,
CH3 O), 3.83 (3H, s, CH3 O), 4.05 (2H, q, J=7.03 Hz, CH3 CH2 O), 5.64 (1H, d, J=2.93 Hz, CH), 5.77 (1H, s,
NH), 6.37 (1H, dd, J=8.2 Hz, J=2.34 Hz, Ar-H), 6.44 (1H, d, J=2.34 Hz, Ar-H), 6.94 (1H, d, J=8.2 Hz, Ar-H),
1
3
8
1
.45 (1H, s, NH). C-NMR (75 MHz, CDCl3): δ 14.43, 18,73, 49.78, 55.57, 55.59, 60.08, 98.75, 98.96, 103.91,
+
22.77, 127.48, 148.36, 154.15, 158.01, 160.75, 166.17. MS, m/z: [M+1] 321.17.
5
-Ethoxycarbonyl-4-(2,3-dimethoxyphenyl)-6-methyl-3,4-dihydro-pyrimidin-2(1H)-one (4h)
1
H-NMR (300 MHz, CDCl3): δ 1.11 (3H, t, J=7.03 Hz, CH3 CH2 O), 2.39 (3H, s, CH3), 3.86 (3H, s,
CH3 O), 3.90 (3H, s, CH3 O), 4.04 (2H, q, J=7.03 Hz, CH3 CH2 O), 5.65 (1H, s, NH), 5.70 (1H, d, J=2.63 Hz,
1
3
CH), 6.71 (1H, dd, J=7.91, J=1.46 Hz, Ar-H), 6.84-6.98 (2H, m, Ar-H), 8.56 (1H, s, NH). C-NMR (75 MHz,
CDCl3): δ 14.42, 18,77, 50.38, 56.06, 60.09, 60.94, 98.73, 112.55, 118.96, 124.40, 136.07, 146.52, 148.54, 152.96,
+
1
53.61, 166.02. MS, m/z: [M+1] 321.10.
5
-Ethoxycarbonyl-4-(3,4-dihydroxyphenyl)-6-methyl-3,4-dihydro-pyrimidin-2(1H)-one (4j)
1
H-NMR (300 MHz, DMSO-d6): δ 1.11 (3H, t, J=7.03, CH3 CH2 O), 2.22 (3H, s, CH3), 3.98 (2H, q,
J=7.03, CH3 CH2 O), 4.98 (1H, d, J=3.23, CH), 6.47-6.65 (3H, Ar-H), 7.60 (1H, s, NH), 8.78 (1H, s, -OH), 8.88
1
3
(
1H, s, -OH), 9.10 (1H, s, NH). C-NMR (75 MHz, DMSO-d6): δ 14.81, 18,43, 54.18, 59.80, 100.51, 114.38,
+
1
15.84, 117.83, 136.68, 145.17, 145.63, 148.18, 152.90, 166.15. MS, m/z: [M+1] 293.01.
5
-Ethoxycarbonyl-4-(2,4,6-trimethoxyphenyl)-6-methyl-3,4-dihydro-pyrimidin-2(1H)-one (4m)
1
H-NMR (300 MHz, DMSO-d6): δ 0.99 (3H, t, J=7.03 Hz, CH3 CH2 O), 2.14 (3H, s, CH3), 3.70 (6H,
s, 2 × CH3 O), 3.74 (3H, s, CH3 O), 3.82 (2H, q, J=7.03 Hz, CH3 CH2 O), 5.74 (1H, d, J=1.17, CH), 6.16 (2H,
1
3
s, Ar-H), 6.91 (1H, s, NH), 8.95 (1H, s, NH). C-NMR (75 MHz, DMSO-d6): δ 14.63, 18,46, 45.58, 55.78,
+
5
6.19, 59.11, 91.38, 96.74, 114.22, 148.58, 152.80, 159.62, 160.62, 166.52. MS, m/z: [M+1] 351.13.
5
-Ethoxycarbonyl-4-(2,4,5-dimethoxyphenyl)-6-methyl-3,4-dihydro-pyrimidin-2(1H)-one (4n)
1
H-NMR (300 MHz, DMSO-d6): δ 1.05 (3H, t, J=7.03 Hz, CH3 CH2 O), 2.25 (3H, s, CH3), 3.35 (3H,
s, CH3 O), 3.62 (3H, s, CH3 O), 3.76 (3H, s, CH3 O), 3.92 (2H, q, J=7.03 Hz, CH3 CH2 O), 5.38 (1H, d, J=3.07,
1
3
CH), 6.62 (1H, s, Ar-H), 6.67 (1H, s, Ar-H), 7.22 (1H, s, NH), 9.90 (1H, s, NH). C-NMR (75 MHz, DMSO-d6):
δ 14.78, 18,36, 50.03, 56.48, 56.93, 57.27, 59.61, 98.45, 99.24, 113.61, 124.20, 142.76, 149.04, 149.85, 151.99,
+
1
52.79, 166.07. MS, m/z: [M+1] 351.12.
5
-Ethoxycarbonyl-4-(2,4-dimethoxyphenyl)-6-methyl-3,4-dihydro-pyrimidin-2(1H)-thione (4u)
1
H-NMR (300 MHz, DMSO-d6): δ 1.02 (3H, t, J=7.03 Hz, CH3 CH2 O), 2.24 (3H, s, CH3), 3.69 (3H, s,
CH3 O), 3.73 (3H, s, CH3 O), 3.88 (2H, q, CH3 CH2 O), 5.37 (1H, d, J=3.52, CH), 6.42 (1H, dd, J=8.20, J=2.05,
1
3
Ar-H), 6.50 (1H, J=2.05, Ar-H), 6.89 (1H, d, J=8.20, Ar-H), 9.18 (1H, s, NH), 10.17 (1H, s, NH). C-NMR
(
75 MHz, DMSO-d6): δ 14.66, 17.69, 49.67, 55.86, 56.16, 60.01, 99.11, 100.25, 105.20, 123.91, 129.18, 145.61,
+
1
58.34, 160.89, 165.90, 174.64. MS, m/z: [M+1] 337.14.
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13

An efficient one-pot synthesis of dihydropyrimidinones..., S¸ . BE S¸ OLUK, et al.,
Results and discussion
Zirconium hydrogen phosphate [Zr(H2 PO4)2 ] is a new water-tolerant solid acid catalyst. The activity of this
material is attributed to the Brønsted acidity of dihydrogenphosphate groups and the Lewis acidity of zirconium
metal.
A number of aromatic and aliphatic aldehydes were used with ethyl acetoacetate and urea or thiourea to
illustrate the generality of the condensation. These results are summarized in the Table.
Table. Zirconium hydrogen phosphate-catalyzed synthesis of dihydropyrimidinones under solvent-free conditions.
1
2
a
◦
◦
Entry
R
R
X
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Time (h) Yield (%) Mp( C) found Mp( C) reported
1
7
4
4
a
C6H5-
EtO-
EtO-
EtO-
EtO-
EtO-
EtO-
EtO-
EtO-
EtO-
EtO-
EtO-
1
1
88
81
92
77
58
86
91
85
94
89
82
89
76
80
95
92
97
73
82
79
93
43
67
207-208
216-217
214-215
210-211
184-186
236-237
210-211
185-186
214-216
243-244
256-257
238-239
255-256
208-209
236-237
230-231
228-230
233-235
208-209
192-193
163-164
210-211
191-193
206
1
1
1
1
1
8
7
7
7
9
b
4-(Me)-C6H4-
4-(Cl)-C6H4-
215-216
213-215
209-212
167-170
236-238
-
4
c
1
4
d
4-(NO2)-C6H4-
3-(OH)-C6H4-
4-(OH)-C6H4-
2,4-(MeO)-C6H3-
2,3-(MeO)-C6H3-
2,5-(MeO)-C6H3-
3,4-(OH)-C6H3-
4-NMe2-C6H4-
1
4
4
e
1
f
1
4
4
g
1
h
1
-
1
0
4
4
i
1
212
-
j
1
2
2
1
2
4
k
1
257-258
232-233
-
4
l
3-(MeO)-4-(OH)-C6H3- EtO-
1
4
m
2,4,6-(MeO)-C6H2-
2,4,5-(MeO)-C6H2-
C6H5-
EtO-
EtO-
Me-
1
4
n
o
p
q
1
-
2
2
2
3
3
3
4
1
234-235
228-229
215-216
4
4
4-(Me)-C6H4-
4-(Cl)-C6H4-
C6H5-
Me-
1
Me-
1
1
7
4r
4s
4t
Me-
1,5
2
183(dec.)
1
8
8
C6H5-
EtO-
EtO-
EtO-
EtO-
-OEt
S
208-210
192-194
-
1
4-(Me)-C6H4-
2,4-(MeO,)-C6H4-
CH2CH2-
S
2
4
4
4
u
v
y
S
2
2
4
O
O
1
212-214
2
5
(CH3)2CH-
1
194
a
Isolated yield.
The procedure gives products in good yields and avoids problems associated solvent use (cost, handling,
safety, pollution). Decreased reaction times are also realized because of increased reactivity of the reactants in
the solid state and the fact that water as a reaction product is evaporated at the reaction temperature at 90
◦
C. Importantly, aromatic aldehydes carrying either electron-donating or electron-withdrawing substituents all
reacted very well, giving moderate-to-excellent yields of the desired products using the catalyst. The activity
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14

An efficient one-pot synthesis of dihydropyrimidinones..., S¸ . BE S¸ OLUK, et al.,
of the recycled Zr(H2 PO4)2 was also examined according to the typical experimental conditions. We obtained
the desired products in 88%, 87%, and 85% yields after 1-3 runs, respectively (entry 4a).
In conclusion, we have described a simple and general method for the synthesis of dihydro- pyrimidinones
by using a reusable Zr(H2 PO4)2 solid acid catalyst. The method offer several advantages including high yields,
environmentally friendly procedure, short reaction times, simple work-up procedure, and easy isolation, making
it a useful process for the synthesis of DHPMs. Moreover, the catalysis is not affected by water released from
the reaction.
Acknowledgment
The authors thank to Professor Nurettin Yaylı (Karadeniz Technical University) for the mass spectra, and the
Scientific Research and Project Council of Sakarya University (Research Grant 06-FBD-013) for its financial
support.
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