Sulfated zirconia-catalyzed one-pot benign synthesis of 3,4-dihydropyrimidin-2(1H)-ones under microwave irradiation

Article abstract of DOI:10.1246/cl.2006.1074

Sulfated zirconia has been demonstrated as an efficient catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under microwave irradiation and conventional heating. The solid acid catalyst is found to be highly active for the one-pot condensation o

Full text of DOI:10.1246/cl.2006.1074

1074
Chemistry Letters Vol.35, No.9 (2006)
Sulfated Zirconia-catalyzed One-pot Benign Synthesis
of 3,4-Dihydropyrimidin-2(1H)-ones under Microwave Irradiation
Dalip Kumar,ꢀ M. Swapna Sundaree, and Braja Gopal Mishraꢀ
Chemistry Group, Birla Institute of Technology & Science, Pilani-333031, India
(Received June 21, 2006; CL-060703; E-mail: dalipk@bits-pilani.ac.in)
.
Sulfated zirconia has been demonstrated as an efficient cat-
BF3 OEt, FeCl3, InCl3, BiCl3, LaCl3, LiClO4, Iodine, clays,
etc.16 Some of these methods suffer from drawbacks such as
stoichiometric amounts of catalysts, purification of products,
extended reaction time and moderate yields. Recently, use of
microwave irradiation as an unconventional energy source has
greatly improved the time and yield of Biginelli reaction under
solvent-free conditions.17,18 In view of environment constraints
and biological importance of 3,4-dihydropyrimidin-2(1H)-ones,
a rapid protocol that proceeds under catalytic condition and in
quantitative yield is highly desirable.
alyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones un-
der microwave irradiation and conventional heating. The solid
acid catalyst is found to be highly active for the one-pot conden-
sation of aldehydes, urea and ꢀ-dicarbonyl compound, affording
variety of 3,4-dihydropyrimidin-2(1H)-ones in excellent yields
with high purity. The low cost catalyst has exhibited remarkable
reactivity and recycled without any significant loss of activity.
In recent years, organic synthesis involving greener process
is being explored world wide due to stringent environment reg-
ulations.1,2 Homogeneous, corrosive liquid acid catalysts, such
as H2SO4, HCl, and complexes of BF3 are frequently used in or-
ganic synthesis. However, processes involving conventional
acids are inherently associated with problems such as high tox-
icity, corrosion, catalyst waste, difficulty in separation and re-
covery. Replacement of these conventional acids by solid cata-
lyst is highly desirable to achieve effective catalyst handling,
product purification and to decrease waste production. In the last
decade, sulfated metal oxides have received considerable atten-
tion as potentially benign solid acid catalysts that possess very
high catalytic activity and even superacidity.1–3 Sulfated zirco-
nia has been demonstrated to be efficient catalyst for several in-
dustrially important reactions under mild reaction conditions.2–8
The sulfated zirconia catalyst is known to possess both Brønsted
and Lewis acidity, the relative concentration of which depends
on the procedure of preparation and the pretreatment tempera-
ture.2,3 Generation of acidic sites on sulfated oxides thought to
proceed by a two-stage reaction mechanism involving grafting
of the sulfate species during impregnation step followed by de-
hydration of the grafted species at higher temperatures.2,9 The
strength of the surface acidic sites in case of sulfated zirconia
has been found to be greater than many conventional solid acid
catalysts such as silica–alumina, clays, and zeolites.1–3
Synthesis of 3,4-dihydropyrimidin-2(1H)-ones has received
significant attention in natural and synthetic organic chemistry
because of their promising therapeutic and pharmacological
properties.10–12 Some of 3,4-dihydropyrimidin-2(1H)-ones has
been evaluated as antihypertensive agents, calcium channel
blockers, and ꢁ1a antagonists. Recently, monastrol has been
identified as a lead compound of a new class of anticancer
agents.13 Several marine alkaloids bearing the dihydropyrimi-
done nucleus with interesting biological activities have also been
isolated.14 First synthesis of these dihydropyrimidones was re-
ported by Biginelli involving one-pot condensation of ꢀ-dicar-
bonyl compound, aldehyde, and urea under strongly acidic
conditions.15 The major drawback of this method was the low
to moderate yields that are frequently encountered when using
substituted aromatic aldehydes. Since then various reagents have
been employed for this conversion includes, among others:
Considering the vast scope of sulfated zirconia for acid-cat-
alyzed organic reactions, we have described herein the potential
of this solid acid catalyst for the synthesis of aforementioned
3,4-dihydropyrimidin-2(1H)-ones in a multi-component conden-
sation approach. Using sulfated zirconia we obtained 3,4-dihy-
dropyrimidin-2(1H)-ones in high yields from a neat mixture of
aryl aldehyde, urea and ꢀ-dicarbonyl compound (Scheme 1).
Initially we varied the amount of sulfated zirconia catalyst and
observed that 100 mg was sufficient for effective conversion.
Excessive amount of the catalysts does not increase the yields
significantly. The microwave-accelerated condensation of three
components was found to complete in a time span of 90–120 s.
Under similar condition, aromatic aldehydes and heteroarylalde-
hyde afforded the corresponding 3,4-dihydropyrimidin-2(1H)-
ones in high yields and purity. The ꢀ-dicarbonyl compounds
such as acetylacetone and benzoylacetone were also found
equally effective as ethyl acetoacetate, and corresponding prod-
ucts were achieved in high yields. Furthermore, replacing urea
with thiourea, thio analogues of 3,4-dihydropyrimidin-2(1H)-
ones were obtained. Variation of different substituents and func-
tional groups in the substrates, demonstrates the generality of
this procedure. The sulfated zirconia catalyst was easily separat-
ed by taking the neat reaction mixture into methanol and fol-
lowed by simple filtration.
The reaction (Sl No.1, Table 1) was also performed in differ-
ent solvent such as methanol, acetonitrile, and tetrahydrofuran at
80 ꢁC. We found that in methanol, the conversion was fastest
(2 h) with 90% yield of the product. Whereas, the condensation
of the three components in acetonitrile (70%, 6 h), tetrahydro-
furan (64%, 10 h) and under neat condition (89%, 3 h) at 80 ꢁC
afforded product in moderate to good yield.
The used sulfated zirconia catalyst was reactivated by heat
treatment at 400 ꢁC for 1 h in air. The regenerated catalyst was
R1
CHO
O
O
O
X
R3
NH
Sulfated Zirconia
R2
R3
H2
N
NH2
R2
N
X
R1
H
Scheme 1.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.9 (2006)
1075
Table 1. Sulfated zirconia-catalyzed one-pot synthesis of 3,4-
dihydropyrimidin-2(1H)-ones under microwave irradiation
condition. The final product was recovered from the solution
which upon recrystallization from ethyl acetate afforded the
pure ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (Sr No. 3) in 91% yield, mp 228–
229 ꢁC (lit. mp 226–227 ꢁC).17 IR (KBr): 3300, 3120, 1710,
Sr
Time Yield
/%b
R1
H
R2
R3
X
Mp16/ꢁC
Noa
/s
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me OEt
O
O
O
O
O
O
S
90
60
86
94
91
91
79
90
90
83
90
91
84
94
88
81
93
198–200
206–207
228–229
213–215
199–201
201–202
194–196
130–132
210–212
233–234
167–170
230–232
203–204
218–220
229–231
1
1690, 1630 cmꢂ1. H NMR (DMSO-d6) ꢂ 1.12 (t, 3H, J ¼ 7:5
p-NO2 Me OEt
m-NO2 Me OEt
p-Cl
p-OMe Me OEt
Hz, CH3), 2.28 (s, 3H, CH3), 4.03 (q, 2H, J ¼ 7:5 Hz, OCH2),
5.33 (d, 1H, J ¼ 3:0 Hz, H-4), 7.62–7.75 (m, 2H, Ar–H), 7.96
(brs, 1H, NH), 8.07–8.18 (m, 2H, Ar–H), 9.34 (brs, 1H, NH).
Synthesis of ethyl 6-methyl-4-phenyl-2-oxo-1,2,3,4-tetra-
90
90
Me OEt
120
120
120
120
120
90
o-OH
Me OEt
Me OEt
p-OMe Me OEt
hydropyrimidine-5-carboxylate in solution:
A methanolic
H
solution (5 mL) of benzaldehyde (1 mmol), ethyl acetoacetate
(1 mmol), urea (1.5 mmol), and sulfated zirconia (100 mg) was
heated at 80 ꢁC for 2 h. After completion of reaction, sulfated zir-
conia was removed by simple filteration under hot conditions.
The methanol was distilled off and the residue obtained was
recrystallised from ethanol to afford the pure product.
In conclusion, we have described a novel application of
sulfated zirconia catalyst for a facile and rapid synthesis of struc-
turally diverse 3,4-dihydropyrimidin-2(1H)-ones. Furthermore,
this method is suitable for generating diverse libraries of poten-
tially biological active 3,4-dihydropyrimidin-2(1H)-ones.
S
2-furyl Me OEt
H
O
O
O
O
O
O
S
Me Me
p-OMe Me Me
p-NO2 Me Me
120
90
H
Me Ph
p-OMe Me Ph
Me Ph
90
90
90
H
aAll the products were identified by their physical and spec-
b
tral data (1H NMR and IR). Isolated yields.
Financial support from the institute is gratefully acknowl-
edged.
Zr4+
Zr4+
O
O
X
H
CHO
Zr4+
X
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R2
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its activity (Sl No. 2, yields, 94%, 1st; 91%, 2nd; 89%, 3rd).
Mechanistically, initial condensation of the aldehyde and
urea probably leads to acyl iminium intermediate. It is likely that
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Published on the web (Advance View) August 26, 2006; doi:10.1246/cl.2006.1074