Cellulose sulfuric acid: An efficient biodegradable and recyclable solid acid catalyst for the one-pot synthesis of 3,4-dihydropyrimidine-2(1H)-ones

Article abstract of DOI:10.1080/00397910802517871

Biosupported cellulose sulfuric acid has been found to be an efficient solid acid catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)- ones. The advantages of this method are avoidance of harsh reaction conditions, ecofriendly chemistry, oper

Full text of DOI:10.1080/00397910802517871

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Cellulose Sulfuric Acid: An
Efficient Biodegradable and
Recyclable Solid Acid Catalyst
for the One-Pot Synthesis of
3,4-Dihydropyrimidine-2(1H)-
ones
a
a
P. Narsimha Reddy , Y. Thirupathi Reddy , M.
a
a
a
Nikhil Reddy , B. Rajitha & Peter A. Crooks
a
Department of Pharmaceutical Sciences, College
of Pharmacy, University of Kentucky, Lexington,
Kentucky, USA
Version of record first published: 04 Mar 2009.
To cite this article: P. Narsimha Reddy, Y. Thirupathi Reddy, M. Nikhil Reddy,
B. Rajitha & Peter A. Crooks (2009): Cellulose Sulfuric Acid: An Efficient
Biodegradable and Recyclable Solid Acid Catalyst for the One-Pot Synthesis of 3,4-
Dihydropyrimidine-2(1H)-ones, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:7, 1257-1263
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1
Synthetic Communications , 39: 1257–1263, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802517871
Cellulose Sulfuric Acid: An Efficient
Biodegradable and Recyclable Solid Acid
Catalyst for the One-Pot Synthesis of
3
,4-Dihydropyrimidine-2(1H)-ones
P. Narsimha Reddy, Y. Thirupathi Reddy, M. Nikhil Reddy,
B. Rajitha, and Peter A. Crooks
Department of Pharmaceutical Sciences, College of Pharmacy,
University of Kentucky, Lexington, Kentucky, USA
Abstract: Biosupported cellulose sulfuric acid has been found to be an efficient
solid acid catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones.
The advantages of this method are avoidance of harsh reaction conditions,
ecofriendly chemistry, operational simplicity, high yield, and reusable catalyst.
Keywords: Biginelli reaction, biosupported catalyst, cellulose sulfuric acid (CSA),
3
,4-dihydropyrimidin-2(1H)-ones, one-pot synthesis
Dihydropyrimidinones exhibit an attractive pharmacological profile as
calcium channel blockers, antihypertensive agents, a -antagonists,
1
a
[
1–3]
and neuropeptide Y (NPY) antagonists
; they also exhibit other bio-
logical activities such as antifungal, antiviral, anticancer, antibacterial,
[
4,5]
and anti-inflammatory effects.
analogs of folic acid have been screened for antitumor activity.
Recently, pyrimido[4,5-d]pyrimidine
[
6]
Thus, 3,4-dihydropyrimidin-2(1H)-ones and their derivatives have
emerged as potential therapeutic molecules. Biginelli condensation is
the most common acid- catalyzed procedure for the synthesis of
[
7–32]
3
,4-dihydropyrimidin-2(1H)-ones.
Even though various procedures
Received August 27, 2008.
Address correspondence to Peter A. Crooks, Department of Pharmaceutical
Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536,
USA. E-mail: pcrooks@email.uky.edu
1
257

1258
P. N. Reddy et al.
have been reported for this condensation reaction, several disadvan-
tages, including low yields, prolonged reactions times, use of an excess
of reagents=catalysts, and use of toxic organic solvents, necessitate the
development of more efficient and economical routes for the synthesis
of 3,4-dihydropyrimidin-2(1H)-ones.
Cellulose is one of the most abundant natural biopolymers in the
world and has been widely studied during the past several decades because
it is a biodegradable material and a renewable resource. Its unique proper-
ties make it an attractive alternative as a conventional organic or inor-
ganic support in catalytic applications. Recently, the direction of science
and technology has been shifting more toward ecofriendly, natural pro-
duct resources and reusable catalysts in organic synthesis. Thus, natural
biopolymers are attractive candidates in the search for such solid support
[
33,34]
catalysts.
promising biopolymeric solid support acid catalyst for acid-catalyzed
Recently, cellulose sulfuric acid (CSA) has emerged as a
[
35]
[36]
reactions, such as the synthesis of a-aminonitriles,
and quinolines. CSA can be easily prepared by the reaction of inexpen-
sive cellulose with chlorosulfonic acid; the number of acidic (H ) sites in
[
the cellulose sulfuric acid product is 0.5 meq=g.
We now report a new and efficient method for the synthesis of
imidazoazines,
[37]
þ
32]
3
,4-dihydropyrimidin-2(1H)-ones via the one-pot condensation of an
aldehyde, a b-keto ester, and urea using CSA (Scheme 1). To the
best of our knowledge, the use of CSA as a catalyst for the synthesis of
3
,4-dihydropyrimidin-2(1H)-ones has not been previously reported.
Initially, the condensation of benzaldehyde and urea with ethyl acet-
oacetate was conducted in the presence of a catalytic amount of CSA in
refluxing ethanol (Table 1). When 1.0 mmol of benzaldehyde, 1.0 mmol
of ethyl acetoacetate, 1.5 mmol of urea, and 0.1 g of CSA were utilized,
the reaction was complete within 2 h to afford the corresponding 3,4-
dihydropyrimidin-2(1H)-one product in 96% yield (entry 1). Further-
more, the effect of solvent was examined, and the results showed that
the efficiency and the reaction yield in ethanol were higher than those
Scheme 1. Synthesis of 3,4-dihydropyrimidine-2(1H)-ones using cellulose sulfuric
acid (CSA).

3
-4-Dihydropyrimidine-2(1H)-ones
1259
Table 1. Effect of solvent on 3,4-dihydropyrimidin-
(1H)-one yield
2
a
Entry
Solvent
Yield (%)
1
2
3
4
5
EtOH
MeOH
CH CN
3
96
86
82
68
73
2 2
CH Cl
Toluene
a
Isolated yield.
obtained in other polar solvents, such as methanol and acetonitrile
entries 2 and 3), and in nonpolar solvents such as dichloromethane
and toluene (entries 4 and 5).
(
The efficiency of the CSA reagent compared to various sulfur analog
acidic catalysts was also examined (Table 2). In this study, it was found
that CSA is a more efficient and superior catalyst (entry 1) compared to
other acidic catalysts such as silica sulfuric acid and p-toluene sulfonic
acid (entries 2 and 3) with respect to reaction time and yield of the desired
3
3
,4-dihydropyrimidin-2(1H)-one. It was also observed that the yield of
,4-dihydropyrimidin-2(1H)-one was only 10% in the absence of the
CSA reagent (entry 4).
Several syntheses of 3,4-dihydropyrimidin-2(1H)-one derivatives
from the condensation of urea or thiourea with methyl acetoacetate or
ethyl acetoacetate and a wide range of aromatic aldehydes were examined
utilizing CSA in refluxing ethanol. All reactions were complete within
2
–3 h, as indicated in Table 3. In all cases, the reactions afforded the
desired products in excellent yields (89–96%). It is important to note
that the recovered catalyst can be utilized at least two more times in
Table 2. Effect of catalyst on 3,4-dihydropyrimidin-
2(1H)-one yield
a
Entry
Catalyst
Yield (%)
1
2
3
4
Cellulose sulfuric acid
Silica sulfuric acid
p-Toluene sulfonic acid
No catalyst
96
91
85
10
a
Isolated yield.

1260
P. N. Reddy et al.
Table 3. Cellulose sulfuric acid–catalyzed synthesis of dihydropyrimidin-
(1H)-ones
2
1
a
Product
R
R
X
Time (h)
Yield (%)
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
C
6
H
5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
2.0
3.0
4.0
3.0
2.5
3.5
4.0
2.0
3.0
3.5
4.0
3.0
3.0
3.5
2.5
3.0
3.0
3.5
96
92
91
93
94
93
91
95
90
91
89
93
94
92
91
92
90
92
3-(NO )-C
4-(NO )-C H
4-(OCH
3-(Cl)-C
4-(Cl)-C H
2
6
H
4
4
2
6
3
)-C
6
H
4
6
H
4
4
6
g
h
i
4-(OH)-C
6
H
4
C
6
H
5
3-(NO )-C
4-(NO )-C H
4-(OCH
3-(Cl)-C
4-(Cl)-C H
2
6
H
4
4
j
2
6
k
l
3
6 4
)-C H
6
H
4
m
n
o
p
q
r
6
4
4-(OH)-C
6
H
4
C
6
H
5
C H
6
OMe
OEt
OEt
S
S
S
5
4-(OCH
4-(Cl)-C
3
)-C
6
H
4
6
H
4
a
Yields refer to pure solid products; all products were reported in the literature
and were characterized by comparison of their physical and spectral data with
those previously reported.
subsequent reactions without significant loss in product yield. All pro-
1
ducts were characterized by comparison of their H NMR, Infrared
(IR), and mass spectra (MS) with those of authentic samples.
General Procedure for Synthesis of Dihydropyrimidinones (4a–r)
A mixture of aldehyde (1 mmol), b-keto ester (1 mmol), urea (1.5 mmol),
and CSA (0.1 g) in 5 mL of dry ethanol was stirred at reflux temperature
for the appropriate time, according to Table 3. After completion of the
reaction (as indicated by silica-gel thin-layer chromatography (TLC)
utilizing ethyl acetate–n-hexane, 2:3, as developing solvent), the react-
ion mixture was filtered while hot, and the CSA catalyst was recovered.
The filtrate was concentrated to dryness and chromatographed over silica
gel, employing EtOAc–hexane (1:4, v=v), to afford the pure product.
Further purification was achieved by crystallization from ethanol to
afford analytically pure 4a as pale yellow crystals.

3
-4-Dihydropyrimidine-2(1H)-ones
1261
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