Ammonium dihydrogen phosphate catalyst for one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/S1872-2067(11)60355-0

A one-pot three component Biginelli condensation of different substituted aromatic and aliphatic aldehydes with ethyl acetoacetate and urea to the respective 3,4-dihydropyrimidin-2-(1H)-ones under solvent-free conditions that is simple, effective, and env

Full text of DOI:10.1016/S1872-2067(11)60355-0

CHINESE JOURNAL OF CATALYSIS
Volume 33, Issue 4, 2012
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2012, 33: 659–665.
ARTICLE
Ammonium Dihydrogen Phosphate Catalyst for One-pot
Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
Reza TAYEBEE*, Behrooz MALEKI, Malihe GHADAMGAHI
Department of Chemistry, School of Sciences, Hakim Sabzevari University, Sabzevar 96179-76487, Iran
Abstract: A one-pot three component Biginelli condensation of different substituted aromatic and aliphatic aldehydes with ethyl aceto-
acetate and urea to the respective 3,4-dihydropyrimidin-2-(1H)-ones under solvent-free conditions that is simple, effective, and environ-
mentally friendly was shown. Ammonium dihydrogen phosphate (NH4H2PO4) was used as a non-toxic, inexpensive, and easily available
catalyst. The facile reaction condition and simple isolation and purification procedures of this method make it a good option for the syn-
thesis of dihydropyrimidinones.
Key words: 3,4-dihydropyrimidin-2-(1H)-one; ammonium dihydrogen phosphate; solvent free; condensation
3,4-Dihydropyrimidin-2(1H)-ones have a wide range of
therapeutic and pharmacological properties [1], such as anti-
viral [2], antibiotic [3], anticarcinogenic [4], antihypertensive
[5], and anti-inflammatory properties. Moreover, several
natural marine alkaloids, most notably batzelladine, have in-
teresting biological activities that are mainly attributed to the
presence of a dihydropyrimidinone moiety [6]. The simplest
and the most straightforward approach for the synthesis of
3,4-dihydropyrimidin-2(1H)-ones, which was first reported by
Biginelli [7], involves the one-pot reaction of ꢀ-ketoester or
ꢀ-diketone, aryl-aldehyde, and urea. However, this reaction
needs harsh conditions and long time, and gives low yields [8].
Multi-component condensation constitutes an attractive syn-
thetic strategy because the products are formed in a single step.
Several complex multi-step procedures have been reported to
give high yields of 3,4-dihydropyrimidin-2(1H)-ones. How-
ever, many of these methods lack the simplicity of the original
one-pot Biginelli protocol.
[19], Mn(OAc)3 [20], and many ionic salts were established as
effective catalysts [21]. However, most of these protocols
involve expensive reagents, strongly acidic conditions, long
reaction time, high temperatures, and stoichiometric amounts
of catalysts, and give unsatisfactory yields. Therefore, the
discovery of a new and inexpensive catalyst for the preparation
of 3,4-dihydropyrimidin-2(1H)-ones under mild conditions is
important.
From our research on the development of useful synthetic
methodologies [22–30] and interest in NH4H2PO4 catalyzed
reactions, we have found a convenient and practical one-pot
three component procedure for the preparation of
3,4-dihydropyrimidin-2(1H)-one derivatives under sol-
vent-free condition with the use of ammonium dihydrogen
phosphate as a non-toxic, inexpensive, and easily available
catalyst (Scheme 1). The heterogenization of NH4H2PO4 on
mesoporous silica as support was further investigated to im-
prove the catalytic reaction conditions, recoverability, and
reusability of the catalyst.
Biginelli’s reaction has received renewed interest and sev-
eral improved reaction protocols have recently been reported
[9,10]. Different acid catalysts including chiral phosphoric
acids [11], inorganic solid acids such as zeolite [12],
mesoporous silica [13], and Lewis acids as well as protic acids
such as concentrated HCl [14], BF3 [15], polyphosphonate ester
[16], montmorillonite [17], InCl3 [18], ceric ammonium nitrate
1 Experimental
1.1 Preparation of NH4H2PO4/SiO2
The catalyst was prepared by mixing silica gel (1.5 g, Merck
Received 12 October 2011. Accepted 18 December 2011.
*Corresponding author. Tel: +98-571-4410310; Fax: +98-571-4410300; E-mail: rtayebee@yahoo.com
This work was partially supported by the Research Council of Hakim Sabzevari University.
Copyright © 2012, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(11)60355-0

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 659–665
O
R
O
C
O
O
C
O
C
EtO
H3C
NH
or
NH4H2PO4
NH4H2PO4/SiO2
100 oC
+
C
+
R
H
OEt
H2N
NH2
H3C
N
H
O
R = aryl, alkyl
Scheme 1. Three component condensation of urea, aldehyde, and ethyl acetoacetate.
1
grade 60, 230–400 mesh) with a solution of NH4H2PO4 (0.6 g,
5 mmol) in distilled water (10 ml). The resulting mixture was
stirred for 30 min to adsorb the ammonium dihydrogen phos-
phate on the surface of silica gel (Scheme 2). After the slow
removal of water, the solid powder was dried at 120 oC for 4 to
5 h. The drying temperature was maintained below the de-
composition temperature of the ammonium salt [31]. The het-
eropolyacid catalysts were prepared and characterized ac-
cording to the literature procedure [30].
2958, 1726, 1703, 1639, 1487, 1286. H NMR (DMSO-d6): ꢁ
1.04 (t, 3H, CH3), 2.27 (s, 3H, CH3), 3.789 (s, 3H, CH3), 3.93
(q, 2H, CH2), 5.50 (d, 1H, H-4), 6.87–7.28 (m, 4H, Harom, 1H,
NH), 9.1 (s, 1H, NH). 13C NMR (DMSO-d6): ꢁ 14.5, 18.2, 49.3,
55.8, 59.4, 98.0, 111.6, 120.6, 127.5, 129.1, 132.1, 149.3,
152.7, 157.0, 165.8.
Ethyl-6-methyl-4-(2-chlorophenyl)-2-oxo-1,2,3,4-tetrahydr
opyrimidine-5-carboxylate. IR (KBr, cm–1): ꢀ 3354, 3236,
1
3111, 2978, 1693, 1641, 1226, 1095. H NMR (DMSO-d6): ꢁ
0.99 (t, 3H, CH3), 2.30 (s, 3H, CH3), 3.90 (q, 2H, CH2), 5.63 (d,
1H, H-4), 7.25–7.41 (m, 4H, Harom), 7.71 (s, 1H, NH), 9.27 (s,
1H, NH). 13C NMR (DMSO-d6): ꢁ 14.4, 18.1, 51.9, 59.5, 98.3,
128.2, 129.2, 129.5, 129.8, 132.1, 142.2, 149.8, 151.8, 165.4.
1.2 Preparation of 3,4-dihdropyrimidin-2(1H)-ones
A solution of ethyl acetoacetate (0.26 g, 2 mmol), aldehyde
o
(2 mmol), and urea (2.5 mmol) was heated to 100 C under
Ethyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1,
2,
3,
solvent-free condition in the presence of NH4H2PO4 (0.01 g, 5
mol %). The reaction was monitored by thin layer chroma-
tography (TLC). At the end of the reaction, the resulting mix-
ture was poured into cold water and the solid product was
separated by filtration. Impure product was re-crystallized
from n-hexane/ethyl acetate (3:1) when necessary. Infrared
spectra were recorded on a 8700 Shimadzu Fourier Transform
spectrophotometer. Silica gel 60 (230–400 mesh) was used for
the column chromatography. The spectral data of some selected
compounds [32] are listed as follows.
4-tetrahydropyrimidine-5-carboxylate. IR (KBr, cm–1): ꢀ 3215,
1
1731, 1707, 1641. H NMR (DMSO-d6): ꢁ 1.07 (t, 3H, 3J 6.8
Hz, CH3), 2.26 (s, 3H, CH3), 3.97 (q, 2H, 3J 5.4 Hz, OCH2),
5.27 (s, 1H, CH), 7.50 (d, 2H, 3J 7.3 Hz, Harom.), 7.87 (s, 1H,
NH), 8.20 (d, 2H, 3J 7.2 Hz, Harom.), 9.33 (s, 1H, NH). 13C NMR
(DMSO-d6): ꢁ 14.5, 18.3, 54.2, 59.8, 98.7, 124.2, 128.1, 147.2,
149.8, 152.2, 152.5, 165.5.
Ethyl-6-methyl-4-(4-methylphenyl)-2-oxo-1,2,3,4-tetrahydr
opyrimidine-5-carboxylate. IR (KBr, cm–1): ꢀ 3326, 3152,
1691, 1562, 1232, 1051, 783. 1H NMR (DMSO-d6): ꢁ 1.12 (t, J
= 7.5 Hz, 3H), 2.28, 2.30 (s, 3H), 4.00 (q, J = 7.5 Hz, 2H), 5.11
(d, J = 3.0 Hz, 1H), 7.25 (m, 4H), 7.70 (brs, 1H, NH), 9.19 (brs,
1H, NH).
Ethyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidi
ne-5-carboxylate. IR (KBr, cm–1): ꢀ 3238, 3113, 2980, 1724,
1
1649, 1465, 1290. H NMR (DMSO-d6): ꢁ 1.09 (t, 3H, CH3),
2.24 (s, 3H, CH3), 3.99 (q, 2H, CH2), 5.13 (d, 1H, H-4),
7.21–7.34 (m, 5H, Harom), 7.73 (s, 1H, NH), 9.19 (s, 1H, NH).
13C NMR (DMSO-d6): ꢁ 14.5, 18.2, 54.5, 59.7, 99.8, 126.7,
127.7, 128.8, 145.3, 148.8, 152.8, 165.8.
Ethyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro
pyrimidine-5-carboxylate. IR (KBr, cm–1): ꢀ 3300, 3120, 1710,
1
1690, 1630. H NMR (DMSO-d6): ꢁ 1.11 (t, J = 7.5 Hz, 3H),
2.29 (s, 3H), 4.02 (q, J = 7.5 Hz, 2H), 5.31 (d, J = 3.0 Hz, 1H),
7.65–7.75 (m, 2H), 7.95 (brs, 1H), 8.09–8.20 (m, 2H), 9.34
(brs, 1H).
Ethyl-6-methyl-4-(2-methoxyphenyl)-2-oxo-1,2,3,4-tetrahy
dropyrimidine-5-carboxylate. IR (KBr, cm–1): ꢀ 3267, 3109,
Ethyl-6-methyl-4-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydr
opyrimidine-5-carboxylate. IR (KBr, cm–1): ꢀ 3220, 3100,
1720, 1700. 1H NMR (DMSO-d6): ꢁ 1.10 (t, J = 7.2, 3H), 22 (s,
3H), 3.96 (q, J = 7.2, 2H), 5.02 (s, J = 3.2, 1H), 6.64 (d, J = 8.4,
2H), 7.02 (d, J = 8.4, 2H), 7.57 (s, 1H), 9.07 (s, 1H).
O
P
O
P
OH
O
OH
OH
NH4
OH
HO
OH
OH
O
OH
O
+
NH3
2 Results and discussion
H2O
OH
O
OH
OH
The optimization of the three-component Biginelli conden-
sation of ethyl acetoacetate, benzaldehyde, and urea in the
presence of 5 mol% NH4H2PO4 under solvent-free condition
resulted in 80% yield of 3,4-dihydropyrimidin-2(1H)-one after
P
OH
Scheme 2. Immobilization of NH4H2PO4 on mesoporous silica.

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 659–665
Table
1
Effect of NH4H2PO4 amount on the condensation of
100
80
60
40
20
0
4-nitrobenzaldehyde with ethyl acetoacetate and urea
Entry
NH4H2PO4 amount (mol%)
Time (h)
8.0
3.0
Yield (%)
< 10 (very impure)
1
2
3
4
5
6
7
0
0.5
2
47
87
90
93
78
68
2.5
5
2.0
10
30
40
2.5
4.0
4.0
0
1
2
3
4
5
Reaction conditions: 4-nitrobenzaldehyde 0.30 g (2 mmol), ethyl aceto-
acetate 0.26 g (2 mmol), urea 0.15 g (2.5 mmol), 100 oC.
Urea concentration (mmol)
Fig. 2.
Effect of urea concentration on the condensation of
2 h. The condition was that the condensation reaction was
performed with a low catalyst concentration at ambient condi-
tion, and it was selective and led to a high yield of the
3,4-dihydropyrimidin-2(1H)-one.
4-nitrobenzaldehyde with ethyl acetoacetate and urea after 3 h.
three component condensation of 4-nitrobenzaldehyde, ethyl
acetoacetate, and urea was studied. The production of the cor-
responding dihydropyrimidinone was increased with a larger
urea from 2 to 2.5 mol%. The desired product was obtained in
90% yield in the presence of 2.5 mmol of urea after 2 h, while
only 67% yield was achieved by 2 mmol of urea after 5 h. A
further increase in urea concentration only reduced the time
(1.2 h) needed to reach the maximum conversion of 73%–84%
(Fig. 2).
The catalytic efficiency of ammonium dihydrogen phos-
phate for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
was studied with various amount of NH4H2PO4 (Table 1). To
determine the role of the catalyst, a blank reaction of
4-nitrobenzaldehyde, ethyl acetoacetate, and urea was carried
out in the absence of catalyst. The reaction did not give the
desired product efficiently in the absence of catalyst, and it
gave many impurity byproducts after an extended time of 8 h
(entry 1). The presence of the catalyst, only 0.5 mol% of
NH4H2PO4, gave 47% conversion after 3 h (entry 2), which
showed that the catalyst has high catalytic activity. Table 1
shows that increasing catalyst amount initially led to high yield
at short reaction time. However, 5 mol% of the catalyst was
enough for the reaction. With more catalyst (10 mol%), the
yield progressed very smoothly to 93% without decreasing the
reaction time (entry 5). Even more catalyst (>10 mol%) not
only failed to improve the yield, but also decreased the effi-
ciency of the catalytic system (Fig. 1). This behavior was ex-
plained by the changes in polarity, pH, and components of the
reaction mixture in the solvent-free system. Thus, 5 mol% of
NH4H2PO4 was selected for all the reactions.
The effect of ethyl acetoacetate concentration on the effi-
ciency of the catalytic system (Table 2) was also investigated.
Increasing ethyl acetoacetate concentration decreased the ef-
ficacy of the reaction. On increasing the concentration of this
reagent from 2 to 5 mmol, the reaction time was prolonged
more than five times in order to get ~82% conversion.
The effect of the reaction temperature on the three compo-
nent condensation of urea with 4-nitrobenzaldehyde and ethyl
acetoacetate to synthesize the corresponding 3,4-dihydro-
pyrimidin-2(1H)-one in the presence of 5 mol% NH4H2PO4
was studied. The yield and reaction time were markedly in-
fluenced by temperature. Increasing the reaction temperature
o
from 50 to 80 C enhanced the conversion ~2.2 times and
reduced the required time about 1.4 times (Fig. 3). More in-
crease in reaction temperature slightly affected the yield. In-
creasing the reaction temperature from 100 to 140 oC led to the
reduction of reaction time to reach 90% of conversion from 2 to
1.2 h. From technical considerations, a reaction temperature of
100 oC was selected for all the reactions.
The effect of urea concentration on the efficiency of the
100
80
60
40
20
0
Table 3 compares the efficiency of the present catalyst,
Table 2 Effect of ethyl acetoacetate concentration on the condensation
with benzaldehyde and urea in the presence of NH4H2PO4
Ethyl acetoacetate (mmol)
Time (h)
Yield (%)
2
3
5
2
9
10
90
81
82
0
5
10 15 20 25 30 35 40 45
Catalyst amount (mol%)
Fig. 1. Effect of catalyst amount on the condensation of 4-nitroben-
zaldehyde with ethyl acetoacetate and urea after 2 h.
Reaction conditions: 4-nitrobenzaldehyde
NH4H2PO4 5 mol%, 100 oC.
2
mmol, urea 2.5 mmol,

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 659–665
three phosphates was NH4H2PO4 > NaH2PO4 > KH2PO4. The
100
80
60
40
20
0
–
sodium and potassium salts of H2PO4 were clearly more ef-
2–
fective than the HPO4 counterparts. Another distinct feature
of Table 3 was the catalytic activity of NH4H2PO4 supported on
silica gel. Only 2.5 mmol of ammonium dihydrogen phosphate
in supported form was enough to be efficient. 88% of conver-
sion was obtained with 21 mg of NH4H2PO4/SiO2 after 4 h
(entry 7), but a lower conversion (79%) was attained with the
higher amount of 42 mg in the same time. The study of the
catalytic efficiency of supported NH4H2PO4 on different solid
materials is under investigation.
0
20
40
60
80
100
120
140
Temperature (oC)
The catalytic activity of the complex metal-oxo structured
heteropolyacids is the highlight in Table 3 (entries 14–16).
They showed very good catalytic activity and only 2 mol% led
to complete conversion. Among the heteropolyacids,
H6P2W18O62 (2 mol%) with a Wells-Dawson structure showed
the best catalytic activity, giving 98% ethyl-6-methyl-4-
(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbox
ylate after 40 min. The most familiar Keggin type heter-
opolyacid, H3PW12O40, gave 97% of the desired product after
2.3 h. The mixed metal vanadium substituted heteropolyacid,
H5SiW9Mo2VO40, showed less catalytic activity and gave about
the same conversion in the longer time of 4 h.
After optimizing the reaction conditions, the generality of
the protocol was evaluated by the reaction of several substi-
tuted aliphatic and aromatic aldehydes with different electron
withdrawing and electron releasing substituents on the phenyl
ring in the presence of 5 mol% of NH4H2PO4 catalyst (Table 4).
Aromatic aldehydes with either electron donating or with-
drawing substituents gave high yields of products in high pu-
rity. Aliphatic aldehydes, which normally show extremely poor
yields in the acid catalyzed Biginelli reaction due to decom-
position or polymerization under acidic conditions [33], were
also converted to their corresponding 3,4-dihydropyrimidin-2-
(1H)-ones, but with lower yields after longer reaction time than
the aromatic aldehydes. The procedure not only preserved the
simplicity of the Biginelli reaction, but also gave good yields of
3,4-dihydropyrimidin-2(1H)-ones.
The superiority of the present method over other reported
protocols can be seen by comparing the present results with
those reported previously (Table 5). The three component
condensation of urea, acetoacetate, and 4-nitrobenzaldehyde to
ethyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyri
midine-5-carboxylate was selected as a model reaction and the
comparison was made in terms of the catalyst, reaction time,
and percentage yield. Although some of the other catalysts
gave marginally higher conversions, however, they required
long reaction time and a higher amount of catalyst. The present
method used a small amount (5 mol%) of a cheap and envi-
ronmentally friendly catalyst under solvent-free condition and
required a relatively short reaction time.
Fig. 3. Effect of reaction temperature on the three component condensa-
tion of urea with 4-nitrobenzaldehyde and ethyl acetoacetate after 3 h.
Reaction conditions: 4-nitrobenzaldehyde 2 mmol, urea 2.5 mmol, ethyl
acetoacetate 2 mmol, NH4H2PO4 5 mol%.
NH4H2PO4, with different simple metal oxides and complex
metal-oxo compounds, and heteropolyacids. It can be seen that
5 mol% of ammonium dihydrogen phosphate was sufficient for
good conversion at 2 h (entry 1). Zinc, zirconium, and titanium
oxide were less effective and needed longer time and higher
amount of catalyst. Among the simple transition metal oxides
examined, ZrOCl2 gave the highest yield (94%) but with 10
mol% of catalyst and a long time of 4.5 h (entry 10). Among
the catalysts, NH4H2PO4 was the best since it is commercially
cheap and easily available.
The catalytic activities of various phosphates (5 mol%) with
different cations were investigated and the results are given in
Table 3. NH4H2PO4 gave the best result. KH2PO4 and NaH2PO4
were less efficient. The order of the catalytic activities of these
Table 3 Three component condensation of urea, ethyl acetoacetate, and
4-nitrobenzaldehyde to the corresponding 3,4-dihydropyrimidin-
2(1H)-one catalyzed by different catalysts
Catalyst
amount (mol%)
Time
(h)
Yield
(%)
Entry
Catalyst
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
NH4H2PO4
KH2PO4
NaH2PO4
Na2HPO4
K2HPO4
NH4H2PO4/SiO2
NH4H2PO4/SiO2
ZnO
5
5
5
5
5
2.0
6.3
5.3
5.0
5.0
4.0
4.0
5.0
8.5
4.5
8.5
5.0
8.5
0.7
2.3
4.0
90
74
65
62
very impure
42 mg
21 mg
5
10
10
10
0.7
0.7
2
79
88
53
74
94
84
58
61
98
97
98
ZrO2
ZrOCl2
TiO2
nano-ZnO
nano-CuO
H6P2W18O62
H3PW12O40
H5SiW9Mo2VO40
2
2
Reaction conditions: 4-nitrobenzaldehyde 2 mmol, ethyl acetoacetate 2
mmol, urea 2.5 mmol, 100 oC.
The stability of the catalyst was evaluated by reusing the
recycled catalyst in the three component condensation of urea,

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 659–665
Table 4 Three component condensation of urea, ethyl acetoacetate, and
different aldehydes to 3,4-dihydropyrimidin-2(1H)-ones catalyzed by
Table 5 Comparison of the activity of NH4H2PO4 with some other cata-
lysts used for the synthesis of ethyl-6-methyl-4-(4-nitrophenyl)-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
NH4H2PO4
R
NO
2
O
O
H
O
O
H
O
C
O
O
O
C
NH4H2PO4
EtO
NH
O
O
+
+
H C
o
100 C
+
+
H C
EtO
H C
NH
NH
OEt
2
H N
NH
3
2
OEt
H N
2
2
H C
N
O
3
3
H
R
O
NO
N
H
2
3
Time Yield
(h)
Melting point (oC)
Found Reported
Entry
1
Aldehyde
C
Catalyst
amount (mol%)
Time
(h)
2
5
3
10
4
6
Yield
(%)
Catalyst
Ref.
(%)
90
80
83
85
78
88
H
NH4H2PO4
LaClꢀ·7H2O
NH4Cl
NBS
InCl3
5
50
40
20
10
10
this work
[39]
[21]
[40]
[38]
2.0
85 201–203 200–201 [34]
90 203–206 205–207 [35]
O
H
2
3
C
O2N
2.0
5.0
O
H
ZrCl4
[41]
C
74 225–227 227–228 [36]
O
NO2
run. The catalyst was found to be reusable for at least seven
cycles without loss of activity. The catalytic activity of the used
catalyst was as good as the freash catalyst, demonstrating the
stability of the catalyst (Fig. 4). The FT-IR spectrum of the
recovered NH4H2PO4 after the fifth run did not reveal any
significant change in the structure of ammonium dihydrogen
phosphate, that is, the identity of the catalyst was retained (Fig.
5).
H
4
5
C
3.0
3.5
91 254–257 258–259 [37]
75 206–208 207–208 [18]
O
OMe
H
C
O
MeO
MeO
MeO
H
6
7
C
6.0
4.5
70 202–204
—
O
100
80
60
40
20
0
H
C
C
78 191–193 193–195 [38]
O
Cl
H
8
9
4.5
73 215–218 215–216 [36]
69 208–210 209–211 [35]
O
Cl
H
Cl
C
5.5
5.0
1
2
3
4
5
6
7
O
H
Cycle
10
11
Br
C
94 209–211
80 198–201
—
—
Fig. 4. Reusability of NH4H2PO4 in the three component condensation
of urea, ethyl aetoacetate, and 4-nitrobenzaldehyde.
O
H
C
5.0
O
Br
H
Fresh catalyst
12
13
Me
C
5.0
6.5
82 211–214 212–214 [39]
56 176–178 153–155 [39]
O
O
CH3CH2CH2C
Recycled catalyst
H
Reaction conditions: aldehyde 2 mmol, ethyl acetoacetate 2 mmol, urea
2.5 mmol, NH4H2PO4 5 mol%, 100 oC.
acetoacetate, and 4-nitrobenzaldehyde. For this purpose, the
catalyst was separated from the reaction mixture and washed
with chloroform. Then, it was dried under vacuum and reused
for a fresh catalytic run. When the reaction was repeated with
recovered NH4H2PO4, the conversion was similar to the first
4000 3500 3000 2500 2000 1500 1000 500
Wavenumber (cmꢀ1)
Fig. 5. FT-IR spectra of fresh and recycled NH4H2PO4 catalyst after the
seventh run

Reza TAYEBEE et al. / Chinese Journal of Catalysis, 2012, 33: 659–665
R
O
O
EtO2C
H
O
+
N
C
C
H
H2N
NH2
H
R
HO
Me
H2O
N
H
H2O
O
P
R
O
ꢀ
OH
CH
HO
OH
O
EtO2C
Me
R
NH
N
C
NH2
O
R
H
O
+NH
H ..
2
EtO2C
Me
H
N
C
NH4H2PO4
N
H
O
NH4H2PO4
H+
R
O
H2O
H
ꢀ
EtO2C
Me
R
C
H2PO4
NH
N
NH2
O
O
C
O
C
(H2O4P)
O
H
NH2
OEt
Me
OPO3H
H+
Scheme 3. Proposed mechanism for the three component condensation of urea, ethyl acetoacetate, and aldehyde to 3,4-dihydropyrimidin-2(1H)-one in
the presence of NH4H2PO4.
2
3
Kappe C O. Eur J Med Chem, 2000, 35: 1043
The Biginelli reaction mechanism has been studied exten-
sively by several research groups [41]. A pathway for the three
component condensation of urea, ethyl acetoacetate, and al-
dehyde to 3,4-dihydropyrimidin-2(1H)-one in the presence of
NH4H2PO4 is given in Scheme 3. The first step is the formation
of an acyl imine intermediate formed by the reaction of the
aldehyde with urea in the presence of the catalyst. Then, the
iminium ion intermediate interacts with ethyl acetoacetate to
produce an open chain ureide that subsequently cyclizes to the
dihydropyrimidinone by removing a water molecule from it.
The empty 3d orbitals of the phosphorous atom in NH4H2PO4
stabilize the iminium ion intermediate by the formation of
coordinative bonds.
Kamal A, Shaheer Malik M, Bajee S, Azeeza S, Faazil S, Rama-
krishna S, Naidu V G M, Vishnuwardhan M V P S. Eur J Med
Chem, 2011, 46: 3274
Akhaja T N, Raval J P. Eur J Med Chem, 2011, 46: 5573
Russowsky D, Canto R F S, Sanches S A A, D'Oca M G M, de
Fátima A, Pilli R A, Kohn L K, Antônio M A, de Carvalho J E.
Bioorg Chem, 2006, 34: 173
Fattorusso E, Taglialatela-Scafati O eds. Modern Alkaloids:
Structure, Isolation, Synthesis and Biology. Weinheim:
Wiley-VCH, 2008
4
5
6
7
8
9
Biginelli P. Gazz Chim Ital, 1893, 23: 360
Wipf P, Cunningham A. Tetrahedron Lett, 1995, 36: 7819
Hajipour A R, Seddighi M. Syn Commun, 2012, 42: 227
10 Yu J, Shi F, Gong L-Z. Acc Chem Res, 2011, 44: 1156
11 Li N, Chen X-H, Song J, Luo S-W, Fan W, Gong L-Z. J Am
Chem Soc, 2011, 132: 10953
3 Conclusions
12 Radha Rani V, Srinivas N, Radha Kishan M, Kulkarni S J,
Raghavan K V. Green Chem, 2001, 3: 305
13 Choudhary V R, Tillu V H, Narkhede V S, Borate H B, Wak-
harkar R D. Catal Commun, 2003, 4: 449
14 Saloutin V I, Burgart Y V, Kuzueva O G, Kappe C O, Chupakhin
O N. J Fluor Chem, 2000, 103: 17
15 Hu E H, Sidler D R, Dolling U H. J Org Chem, 1998, 63: 3454
16 Kappe C O, Falsone S F. Synlett, 1998: 718
An economic and environmentally benign procedure was
developed for the one pot synthesis of 3,4-dihydropyrimidin-
2-(1H)-ones in a short reaction time. The method offers several
advantages including high yield of product and easy workup. In
many cases, the products were crystallized directly from the
reaction mixture in high purity. Since a non toxic and com-
mercially available catalyst was used, the procedure should
find important applications in the synthesis of
3,4-dihydropyrimidin-2(1H)-ones.
17 Bigi F, Carloni S, Frullanti B, Maggi R, Sartori G. Tetrahedron
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