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

Article abstract of DOI:10.1016/S0040-4039(02)02612-6

Ammonium chloride as a very inexpensive and readily available reagent, and efficiently catalyzes one-pot, three component, Biginelli condensation reactions of aldehydes, 1,3-dicarbonyl compounds and urea or thiourea under solvent-free conditions to afford the corresponding 3,4-dihydropyrimidin-2-(1H)-ones in high yields at 100°C.

Full text of DOI:10.1016/S0040-4039(02)02612-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 857–859
Ammonium chloride-catalyzed one-pot synthesis of
3,4-dihydropyrimidin-2-(1H)-ones under solvent-free conditions
Ahmad Shaabani,* Ayoob Bazgir and Fatemeh Teimouri
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
Received 14 October 2002; revised 6 November 2002; accepted 15 November 2002
Abstract—Ammonium chloride as a very inexpensive and readily available reagent, and efficiently catalyzes one-pot, three
component, Biginelli condensation reactions of aldehydes, 1,3-dicarbonyl compounds and urea or thiourea under solvent-free
conditions to afford the corresponding 3,4-dihydropyrimidin-2-(1H)-ones in high yields at 100°C. © 2003 Elsevier Science Ltd.
All rights reserved.
It is well known that 3,4-dihydropyrimidin-2-(1H)-ones
and related compounds exhibit a wide range of biologi-
cal activities1 such as antiviral, antitumor, antibacterial
and antiflammatory properties. In addition, the 2-
oxodihydropyrimidine-5-carboxylate core unit is found
in nature2 and in potent HIVgp-120-CD4 inhibitors.
acidic conditions, long reaction times, high tempera-
tures and stoichiometric amounts of catalysts, and give
unsatisfactory yields. Therefore, the discovery of a new
and an inexpensive catalyst for the preparation of
3,4-dihydropyrimidin-2-(1H)-ones under neutral and
mild conditions is of prime importance.
Recently, many synthetic methods for preparing these
compounds have been reported including classical con-
ditions, with microwave and ultrasound irradiation and
by using Lewis acids as well as protic acid promoters
such as: zirconium(IV) chloride,3 indium(III) bromide,4
In connection with our previous work on solid state
organic transformations19–21 using ammonium chloride
as a catalyst,22 we wish to report the results obtained
from a study of the preparation 3,4-dihydropyrimidin-
2-(1H)-ones with NH4Cl as a very inexpensive and
easily available catalyst under neutral and solvent-free
conditions (Scheme 1).
ytterbium(III)-resin,5
1-n-butyl-3-methylimidazolium
tetrafluoroborate (BMImBF4) or hexafluorophosphor-
ate (BMImPF6),6 ceric ammonium nitrate (CAN),7
Mn(OAc)3·2H2O,8 lanthanide triflate,9 indium(III) chlo-
ride,10 lanthanum chloride,11 H2SO4,12 HOAc,13 mont-
morillonite KSF,14 polyphosphate ester (PPE),15
BF3–OEt2/CuCl/HOAc,16 and conc. HCl.17,18
The procedure gives the products in good yields and
avoids problems associated with solvent use (cost, hand-
ling, safety and pollution). Decreased reaction times are
also realized because of the increased reactivity of the
reactant in the solid state and the fact that the other
reaction product, water, evaporates at the reaction tem-
perature of 100°C.
However, in spite of their potential utility, many of
these methods involve expensive reagents, strongly
Scheme 1.
Keywords: Biginelli reaction; dihydropyrimidinones; ammonium chloride; one-pot condensation; solvent-free.
* Corresponding author. Fax: +98-21-2403041; e-mail: a-shaabani@cc.sbu.ac.ir
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02612-6

858
A. Shaabani et al. / Tetrahedron Letters 44 (2003) 857–859
Table 1. Ammonium chloride-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions at 100°C
DHMP
R1
R2
R3
X
Yield (%)a
Mp (°C)
Reported
Found
1
2
3
4
5
6
7
8
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2-Thienyl
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
90
84
83
83
80
85
81
42
78
65
92
79
90
85
85
80
79
86
83
88
86
78
80
75
89
77
200–202
199–201
209–211
205–207
225–227
216–218
207–208
186–188
155–157
154–156
207–209
234–236
192–193
204–206
252–253
279–280
232–235
177–179
229 (dec.)
205–206
138–140
206–207
165–166
186–187
98–101
201–203b
199–201b
210–212b
207–210b
226–228c
215–218c
208–210d
189–190e
153–155f
157–158b
207–210b
235–237b
191–193b
204–207g
–
4-OMe-C6H4
4-Cl-C6H4
4-NO2-C6H4
3-NO2-C6H4
2-Cl-C6H4
2-Me-C6H4
CH3
C3H7
C4H9
C6H5
4-NO2-C6H4
4-OMe-C6H4
4-Cl-C6H4
2-Cl-C6H4
3-NO2-C6H4
C6H5
4-OMe-C6H4
4-NO2-C6H4
C6H5
4-OMe-C6H4
3-NO2-C6H4
C6H5
4-OMe-C6H4
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
–
233–236b
178–180b
230 (dec.)b
205–207c
140h
Me
Me
OEt
OEt
OEt
OBn
OBn
CF3
OEt
S
S
O
O
O
O
206–207c
–
–
99–102b
157–159g
C6H5
158–160
a Isolated yield.
b Ref. 9.
c Ref. 15.
d Ref. 4.
e Ref. 24.
f Ref. 23.
g Ref. 16.
h Ref. 11.
Experimental
In order to improve the yields, we performed reactions
using different quantities of reagents. The best results
were obtained with a 0.5:1:1:1.5 ratio of ammonium
chloride, aldehyde, 1,3-dicarbonyl compound and urea
or thiourea.
Ammonium chloride-catalyzed synthesis of 5-ethoxycar-
bonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-one, (4d) under solvent-free conditions
A mixture of 4-nitrobenzaldehyde (0.30 g, 2 mmol),
ethyl acetoacetate (0.26 g, 2 mmol), urea (0.18 g, 3
mmol) and NH4Cl (0.05 g, 0.8 mmol) was heated with
stirring at 100°C for 3 h. After cooling, the reaction
mixture was washed with cold water (2×50 mL) and
residue recrystallized from ethyl acetate:n-hexane (1:3)
to afford the pure product 4 (0.51g, 1.7 mmol, 83%).
Mp 205–207°C; IR (KBr) (wmax, cm−1): 3215, 1731,
1707, 1641; 1H NMR (DMSO-d6): lH 1.07 (3H, t, 3J 6.8
As can be seen from Table 1, aldehydes, 1,3-dicarbonyl
compounds and urea or thiourea in the presence of
NH4Cl gave the corresponding 3,4-dihydropyrimidin-2-
(1H)-ones under neutral conditions in good yields after
3 h. Even aliphatic aldehydes, which normally show
extremely poor yields in the Biginelli reaction,23 gave
42–78% yields of the corresponding dihydropyirimidin-
2-(1H)-ones 8, 9 and 10 (Table 1). Furthermore, aro-
matic aldehydes carrying either electron-donating or
electron-withdrawing substituents reacted well, giving
moderate to excellent yields.
3
Hz, CH3), 2.26 (3H, s, CH3), 3.97 (2H, q, J 5.4 Hz,
OCH2), 5.27 (1H, s, CH), 7.50 (2H, d, 3J 7.3 Hz,
arom.), 7.87 (1H, s, NH), 8.20 (2H, d, 3J 7.2 Hz,
arom.), 9.33 (1H, s, NH); 13C NMR: lC 14.5, 18.3,
54.2, 59.8, 98.7, 124.2, 128.1, 147.2, 149.8, 152.2, 152.5,
165.5; MS (m/z,%) 305 (M+, 25), 276 (M+−C2H5, 92),
260 (M+−C2H5CO2, 20), 183 (100).
In summary, we have developed an economically and
environmentally friendly procedure for the synthesis of
3,4-dihydropyrimidin-2-(1H)-ones with short reaction
times. This involves the use of NH4Cl as a very inex-
pensive and easily available catalyst and neutral and
solvent-free conditions.
All the products (except 15, 16, 23 and 24) are known
compounds which were characterized by IR and 1H

A. Shaabani et al. / Tetrahedron Letters 44 (2003) 857–859
859
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Acknowledgements
Financial support by the Research Council of Shahid
Beheshti University is acknowledged.
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