Cerium (IV) ammonium nitrate as an efficient Lewis acid for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones and their corresponding 2-(1H) thiones

Article abstract of DOI:10.1002/jhet.259

(Chemical Equation Presented) A simple and highly efficient procedure for the Biginelli condensation reaction of aldehydes, b-ketoesters, urea, or thiourea catalyzed by Ceric ammonium nitrate (CAN) as a Lewis-acid at ambient temperature is described. The

Full text of DOI:10.1002/jhet.259

284
Cerium (IV) Ammonium Nitrate as an Efficient Lewis Acid for
the One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and
Their Corresponding 2-(1H) Thiones
Vol 47
Kamal Usef Sadek,a* Fawzia Al-Qalaf,b Mervat Mohammed Abdelkhalik,b and
Mohamed Hilmy Elnagdic
aFaculty of Science, Chemistry Department, El-Minia University, El-Minia 61519, Egypt
bApplied Science Department, College of Technological Studies, Public Authority for Applied
Education and Training, Safat 13060, Kuwait
cFaculty of Science, Chemistry Department, Kuwait University, Safat 13060 Kuwait
*E-mail: kusadek@yahoo.com
Received July 7, 2009
DOI 10.1002/jhet.259
Published online 22 February 2010 in Wiley InterScience (www.interscience.wiley.com).
A simple and highly efficient procedure for the Biginelli condensation reaction of aldehydes,
b-ketoesters, urea, or thiourea catalyzed by Ceric ammonium nitrate (CAN) as a Lewis-acid at ambient
temperature is described. The procedure proved to be simple and of high yield.
J. Heterocyclic Chem., 47, 284 (2010).
INTRODUCTION
Very recently, an efficient synthesis of DHPMs utilizing
CaF2 in refluxing EtOH [25], Cu(NH2SO3)2 in refluxing
acetic acid [26] and the use of etidronic acid catalyst
[27] were reported. However, many drawbacks were
associated with such synthesis such as the use of expen-
sive reagents, strong acidic conditions, long reaction
times, and low to moderate yields. Consequently, there
is a need to develop a new efficient and simple method
using inexpensive and environmentally benign catalyst.
Ceric ammonium nitrate (CAN) was tested as an alter-
native catalyst. It is worth mentioning that the
CeCl3ꢀ7H2O or Ce(NO3)3ꢀ6H2O catalyzed synthesis of
DHMPs suffers from some drawbacks such as the use of
fairly high amounts of catalysts (100–20 mol %) or
heating at 80ꢁC.
Dihydropyrimidines (DHPMs) and their derivatives
are class of heterocycles that posses a wide range of bi-
ological and therapeutic properties. They act as calcium
channel blockers, antihypertensive agents, and a-la-
antagonists and neuropeptide Y (NPY) antagonists [1–
3]. Furthermore, several bioactive isolated marine alka-
loids, in particular, the batzelladine alkaloids were found
to contain 2-amino-1,4-dihydropyrimidine carboxylate
core that have been found to be potent HIV gp-120-
CD4 inhibitors [4–6]. They also have known to posses
antibacterial, antiviral, antitumor and anti-inflammatory
activities [7,8]. Thus, a synthesis of these heterocyclic
molecules has been of much importance in current
years.
Ceric ammonium nitrate (CAN) is a convenient and
widely used reagent for affecting a broad spectrum of
synthetic transformations due to its many advantages
such as solubility in water and various organic solvents,
inexpensiveness, ecofriendly nature, uncomplicated han-
dling, fast conversions, and convenient work-up proce-
dure which make CAN a potent catalyst in organic syn-
thesis. Although DHMPs has been previously synthe-
sized utilizing CAN as one electron oxidant [28] under
ultrasound irradiation, we found that there is no need
for sonification as the reaction proceeds smoothly at am-
bient temperature. Also, we do believe that CAN acts as
a Lewis acid catalyst because of the applicability of our
protocol for the synthesis of DHMP thiones. The use of
CAN as a Lewis-acid catalyst in CAN bond formation
The most simple and direct method for their synthesis
was first reported by Biginelli [9] since more than 100
years ago; it involves a three one-pot condensation of
benzaldehyde, ethyl acetoacetate, and urea under strong
acidic conditions with a low yield. In the past 10 years,
several one-pot methodologies for the synthesis of
DHPM derivatives were developed. This involves the
use of several catalysts such as lanthanide triflates [10],
ZrCl4 [11], VCl3 [12], PPh3 [13], InBr3 [14], GaX3 [15],
H3BO3 [16], KAl(SO4)2ꢀ12H2O supported on silica [17],
Y(NO3)3ꢀ6H2O [18], Ce(NO3)3ꢀ6H2O [19], CeCl3 and
InCl3 [20], Nafion-H [21]. Microwave heating [22],
ultrasound irradiation [23], and ionic liquids [24] were
also performed as green techniques for their synthesis.
C
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2010 HeteroCorporation

March 2010
Cerium (IV) Ammonium Nitrate as an Efficient Lewis Acid for the One-Pot Synthesis
of 3,4-Dihydropyrimidin-2(1H)-ones and Their Corresponding 2-(1H) Thiones
285
Scheme 1
in heterocyclic chemistry is somehow limited [29].
Thus, in continuation to our efforts in the synthesis of
azoles and azines [30,31] via simple and high-yielding
protocol, we report herein and for the first time a novel
three component one-pot synthesis of Biginelli 3,4-dihy-
dropyrimidine-2(1H)-ones and 2-(1H)-thiones in high
yields via the reaction of aromatic aldehydes, ethyl ace-
toacetate, urea, or thiourea using CAN as catalyst at am-
bient temperature.
smoothly in a high yield with a slight decrease in the
yield when the aryl substituent involves a strong elec-
tron donating group. However, attempts to apply this to
simple aliphatic aldehydes were unsuccessful (Table 1).
A proposed mechanism to account for the formation
of 4 is demonstrated in Scheme 2.
CONCLUSIONS
In conclusion, a catalytic amount of ceric ammonium
nitrate (CAN) efficiently catalyzes the three component
one-pot synthesis of Biginelli condensation product in
MeOH at ambient temperature. The procedure proved to
be simple, highly efficient, produces excellent yields
which make it a useful and important addition to the
well-known Biginelli reaction.
RESULTS AND DISCUSSION
When aryl aldehydes 1 was treated with ethyl aceto-
acetate 2 and urea or thiourea 3 in MeOH (10 mL) in
the presence of CAN (10 mol %) at ambient tempera-
ture (27ꢁC), and the reaction mixture was left overnight,
the dihydropyrimidinones/thiones 4 were obtained in a
high yield (cf. Scheme 1). The optimization of the reac-
tion was investigated. For this goal, we explored the
effect of catalyst molar ratio and solvent effect on the
overall yield. Our investigation clearly revealed that
addition of (10 mol %) of CAN to the reaction mixture
containing 1:1:1.2 molar ratio of 1:2:3 at ambient tem-
perature was optimal for the formation of the condensa-
tion products. In addition, MeOH was found to be the
best solvent among those tested (H2O, EtOH, THF).
To study the scope of the procedure, a variety of aro-
matic, heteroaromatic, and a,b-unsaturated aldehydes
were utilized. In all cases, the reaction proceeds
EXPERIMENTAL
Melting points were determined on a Shimadzu-Gallenkamp
apparatus and are uncorrected. Elemental analyses were
obtained on a LECO CHNS-932 Elemental Analyzer. Infrared
spectra were recorded in KBr on a Perkin-Elmer 2000 FTIR
system. 1H-NMR and 13C-NMR (DMSO-d6) spectra were
determined on a Bruker DPX spectrometer operating at 400
MHz for 1H-NMR and 100 MHz for 13C-NMR in DMSO-d6
as solvents and TMS as internal standard; chemical shifts are
reported in d (ppm). Mass spectra were measured on VG
Autospec Q MS 30 and MS 9 (AEI) spectrometers, with EI
70 eV.
Table 1
Scheme 2
CAN catalyzed one-pot synthesis of Biginelli 3,4-dihydropyridin-
2(1H)-ones and their corresponding 2-(1H)-thiones.
mp (ꢁC)
Yield
Entry
Ar
X
(%)
Found
Lit.
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
O
O
O
O
O
O
O
S
95
93
94
96
93
88
84
94
92
93
202–203 201–204 [26]
203–205 204–206 [26]
213–215 212–213 [26]
225–227 226–228 [26]
4-CH3OC6H4
4-CH3C6H4
3-NO2C6H4
4-ClC6H4
212–214
204–206
212–214 [5]
205–207 [5]
2-Furyl
C6H5CH¼CH
241–242 241–243 [28]
207–209 207–209 [26]
150–152 150–152 [32]
108–110 109–111 [32]
C6H5
4-CH3OC6H4
4-NO2C6H4
S
S
4j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

286
K. U. Sadek, F. Al-Qalaf, M. M. Abdelkhalik, and M. H. Elnagdi
Vol 47
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Acknowledgments. This research was done by the financial sup-
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet