Convenient one-pot heterogeneous catalytic method for the preparation of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1080/00397910500330858

A new, simple, environmentally friendly synthesis of dihydropyrimidinones from aromatic and aliphatic aldehydes, ethyl acetoacetate, and urea or thiourea using a small-pore-size zeolite as catalyst is described. Compared with the classical Biginelli react

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Convenient One‐Pot Heterogeneous
Catalytic Method for the Preparation of
3,4‐Dihydropyrimidin‐2(1H)‐ones
Adrienn Hegedüs a , Zoltán Hell a & Ilona Vígh a
a Department of Organic Chemical Technology, Budapest University of
Technology and Economics, Budapest, Hungary
Available online: 21 Aug 2006
To cite this article: Adrienn Hegedüs, Zoltán Hell & Ilona Vígh (2006): Convenient One‐Pot Heterogeneous
Catalytic Method for the Preparation of 3,4‐Dihydropyrimidin‐2(1H)‐ones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:1, 129-136
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Synthetic Communicationsw, 36: 129–136, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500330858
Convenient One-Pot Heterogeneous
Catalytic Method for the Preparation
of 3,4-Dihydropyrimidin-2(1H)-ones
´
´
Adrienn Hegedu¨s, Zoltan Hell, and Ilona Vıgh
Department of Organic Chemical Technology, Budapest University
of Technology and Economics, Budapest, Hungary
Abstract: A new, simple, environmentally friendly synthesis of dihydropyrimidinones
from aromatic and aliphatic aldehydes, ethyl acetoacetate, and urea or thiourea using a
small-pore-size zeolite as catalyst is described. Compared with the classical Biginelli
reaction conditions, this method has the advantage of high yield, shorter reaction
time, and recyclable and reusable catalyst.
Keywords: Biginelli reaction, green chemistry, heterocycles, multicomponent
reaction, zeolites
INTRODUCTION
Aryl-substituted 3,4-dihydropyrimidin-2(1H)-one and their derivatives are an
important class of substances in organic and medicinal chemistry. They are
found as core units in many marine alkaloids (Batzelladine, Crambine),
which have been found to be potent HIV gp-120CD4 inhibitors.[1] Most of
the dihydropyrimidinones are found to exhibit a wide range of biological
activities[2] such as antibacterial, antitumor, antiviral, and antiinflammatory
properties. These compounds are medicinally important as calcium channel
blockers, a1a-antagonists, and neuropeptide Y(NPY) antagonists.[3]
The simplest method for the synthesis of 3,4-dihydropyrimidin-2(1H)-
ones is the Biginelli reaction. It is a three-component, one-pot condensation
Received in the UK June 1, 2005
´
Address correspondence to Zoltan Hell, Department of Organic Chemical Techno-
logy, Budapest University of Technology and Economics, H-1521 Budapest, Hungary.
Tel.: þ36-1-463-1414; Fax: þ36-1-463-3648; E-mail: zhell@mail.bme.hu
129

´
A. Hegedu¨s, Z. Hell, and I. Vıgh
130
of an aldehyde, b-ketoester, and urea or thiourea in the presence of an acid
catalyst.[4] The reaction reported by Biginelli was carried out in the
presence of catalytic amount of hydrochloric acid at reflux temperature for
18 h. The drawbacks of the classical Biginelli reaction are the poor yield
and the long reaction time.
In recent years, several protocols for preparing of dihydropyrimidinones
have been reported using Lewis acids as well as protic acids as catalysts, such
[6]
as concentrated HCI,[5] BF3 OEt2,
LaCl3,[7] InCl3,[8] H2SO4,[9]
.
Mn(OAC)3,[10] BiCl3,[11] LiClO4,[12] FeCl3,[13] ZrCl4,[14] Bi(OTf)3,[15] dry
acetic acid under microwave irridation,[16] and so forth. Most of these
catalysts are harmful, toxic, dangerous as chemicals, and dangerous for the
environment, too. Therefore, attempts were made for the development of
new methods using less harmful catalysts. Thus, ion-exchange resin[17] or
montmorillonite[18] were also used. Meanwhile, to find a new and inexpensive,
environmentally friendly catalyst would be an important synthetic goal.
Ersorb-4 (E4) is a clinoptylolite-type zeolite material with high silicium
content (Si/Al ratio 5 : l).[19] The original mineral is modified with ion
exchanges and with other water-phase technologies followed by a thermal
˚
treatment, yielding a Ca-K mixed cation–based adsorbent with 4 A pore
size. The composition of E4 can be described as follows: SiO2 73.0%,
Al2O3 11.2%, Fe2O3 1.17%, K2O 5.12%, Na2O 0.38%, CaO 2.20%, and
MgO 0.44%. The XRD spectrum of E4 was identical with the spectrum of
clinoptylolite. It has a specific surface of 40 m2/g (determined by the BET
method with nitrogen at the temperature of liquid nitrogen). E4 has a
slightly surfacial acidic character. The pH of its aqueous suspension is
about 6. The high silicium content yields high chemical resistance. It is
stable until 500–6008C. It can adsorb small molecules such as water, hydro-
chloric acid, ammonia, methanol, and so forth. It is environmentally friendly,
nontoxic, recoverable, reusable, and inexpensive. Recently we reported that
E4 showed good activity in different condensation reactions such as cycli-
zation of b-aminoalcohols with carboxylic acids yielding oxazoline
derivatives,[20] synthesis of 2-arylimidazoline and 2-arylbenzoxazole deri-
vative,[21] and tetrahydropyranylation of alcohols and phenols.[22] E4a has
an enhanced acidity (pH ca. 3–4). It showed good activity in the preparation
of 1-substituted tetrahydroisoquinolines via the Pictet–Spengler reaction.[23]
Based on these results, we examined the Biginelli reaction under mild
reaction conditions.
EXPERIMENTAL
The commercial starting materials were purchased from Merck-Hungary Ltd.
´´ ´
1
except E4a, which is the product of Erdokemia-ker Ltd., Hungary. H NMR
spectra were made on Bruker Avanche 300 spectrometer in DMSO-d6 using
TMS as internal standard.

Dihydropyrimidinone Synthesis
Pretreatment of the Catalyst
131
Before each experiment the sample of E4a was powdered and heated at 1208C
for 2 h.
Typical Protocol for the Reaction of Aromatic Aldehydes
A mixture of aromatic aldehyde (5 mmol), ethyl acetoacetate (0.65 g, 0.63 mL,
5 mmol), urea (0.36 g, 6 mmol)/thiourea (0.46 g, 6 mmol), and E4a (1 g) in
ethanol (10 mL) was heated at 808C for 8 h. The solid was filtered out, the
filtrate was evaporated, and the residue was purified by recrystallization
from ethanol and characterized.
Typical Protocol for the Reaction of Aliphatic Aldehydes
A mixture of aliphatic aldehyde (5 mmol), ethyl acetoacetate (0.65 g, 0.63 mL,
5 mmol), urea (0.36 g, 6 mmol)/thiourea (0.46 g, 6 mmol), and E4a (1 g) in
ethanol (10 mL) was heated at a temperature indicated in Table 2 for 8 h.
The solid was filtered out, the filtrate was evaporated, and the residue was
purified by recrystallization from ethanol and characterized.
All 3,4-dihydropyrimidin-2(1H)-one derivatives are known compounds
1
and were characterized by H NMR spectroscopy and their melting points.
Selected data for 5-ethoxycarbonyl-4-(4-methoxyphenyl)-6-methyl-3,
4-dihydropyrimidin-2(1H)-one (Table 1, entry 10): mp 201–2038C
(ethanol); 1H NMR (300 MHz, DMSO-d6): d ¼ 1.14 (t, J ¼ 7.1 Hz, 3H,
CH3), 2.25 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.1 (q, J ¼ 7.2 Hz, 2H,
OCH2), 5.15 (d, J ¼ 1.1 Hz, 1H, CH), 6.82 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.2
(d, J ¼ 8.6 Hz, 2H, Ar-H), 7.71 (br s, lH, NH), 8.98 (br s, lH, NH).
RESULTS AND DISCUSSION
The reaction of 4-chlorobenzaldehyde, ethyl acetoacetate, and urea in the
presence of E4a in ethanol resulted in the appropriate 5-ethoxycarbonyl-4-
(4-chlorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one in one step and
good yield (Scheme 1). We examined the reaction of ethyl acetoacetate
with different aromatic aldehydes and urea or thiourea. The results are sum-
marized in Table 1.
Longer reaction time resulted in higher yield (Table 1, entries 1–4);
the optimal reaction time was 8 h. Ortho-substituted benzaldehyde deriva-
tives gave poorer yields, probably because of steric hindrance (Table 2,
entries 15–17, 24, and 25). When a weakly acidic E4 was used instead
of E4a in the reaction, the yield was significantly poorer (Table 2, entry 7).
The workup of the reaction mixture was very simple: the catalyst was

´
A. Hegedu¨s, Z. Hell, and I. Vıgh
132
Table 1. Synthesis of dihydropyrimidinones from aromatic aldehydes in the presence
of E4a
Entry
R
X
Yield (%)a
Mp (8C)
Lit. mp (8C)
1
2
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
C6H5
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
89
209–210
209–210
209–210
209–210
209–210
209–210
209–210
205
210–212[24]
210–212[24]
210–212[24]
210–212[24]
210–212[24]
210–212[24]
210–212[24]
206[25]
69b
70c
87d
88e
89 f
52g
93
3
4
5
6
7
8
9
C6H5
90e
91
205
206[25]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-CH3O-C6H4
4-(CH3)2N-C6H4
3-NO2-C6H4
3-CH3O-C6H4
3-OH-C6H4
2-Cl-C6H4
2-Br-C6H4
2-OH-C6H4
C6H5
203–205
230–231
227–229
205–207
166
203–205[26]
229–232[17]
229–231[27]
207–208[10]
164–166[10]
216–218[28]
206–208[24]
200–202[28]
207–208[29]
209–210[29]
209–210[29]
150–152[26]
198[30]
89
84
79
—
75
74
216–217
209
69
81
200–201
209
4-Cl-C6H4
4-Cl-C6H4
4-CH3O-C6H4
4-(CH3)2N-C6H4
3-NO2-C6H4
2-Cl-C6H4
2-OH-C6H4
S
83
207–208
207–208
154
S
82e
83
S
S
84
76
196–198
205
S
206–207[29]
168[31]
186[32]
S
68
66
164–165
183–185
S
aIsolated yield.
bReaction time 5 h.
cReaction time 6 h.
dReaction time 10 h.
eRecycled E4a.
fThird use of E4a.
gE4 catalyst instead of E4a.
filtered out and the solvent was evaporated. The catalyst was reusable after a
simple treatment (washing with acetone then heating at 1208C for 4 h) without
significant loss of activity (Table 1, entries 5, 9, and 20).
Aliphatic aldehydes gave similar results as shown in Table 2. In these
cases the reaction temperature was determined by the boiling point of the
aldehyde, which implicitly had an influence on the yield, too.
The catalytic activity of E4a can be explained with the known fact that
the metal ions of the zeolites can interact with electron-rich systems such as
an aromatic ring or a heteroatom. The compounds such fixed onto the

Dihydropyrimidinone Synthesis
133
Table 2. Synthesis of dihydropyrimidinones from aliphatic aldehydes in the presence
of E4a
Entry
R
X
R. temp. (8C) Yield(%)a Mp (8C)
Lit. mp (8C)
1
2
(CH3)2CH
CH3
C2H5
O
O
O
O
O
S
60
r.t.
50
70
60
60
r.t.
50
70
70
81
60
63
77
79b
64
57
61
77
77b
193–195 194–195[24]
192–194 194–195[27]
210–211 212–214[33]
3
4
n-C3H7
(CH3)2CH
(CH3)2CH
CH3
186
193–195 194–195[24]
184.5–185[34]
5
6
190
191–192[29]
7
S
190–192 191[33]
8
C2H5
n-C3H7
n-C3H7
S
148–149 150.5–151.5[36]
9
10
S
165
165
163[35]
163[35]
S
aIsolated yield.
bRecycled E4a.
Scheme 1.
surface of the zeolites are in an appropriate position for the condensation
reactions and the deliberated water can be immediately adsorbed into the
small pores.
CONCLUSION
The modified zeolite-type adsorbent E4a is a suitable catalyst for the synthesis
of 3,4-dihydropyrimidin-2(1H)-ones. The method is simple, convenient,
cheap, and environmentally friendly, and the catalyst can be easily recycled
without any loss of activity.
ACKNOWLEDGMENTS
This work was supported by the Hungarian Scientific Research Fund
Programs (OTKA Grant No. T 037757).

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A. Hegedu¨s, Z. Hell, and I. Vıgh
134
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