An efficient and environmentally friendly method for synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by Bi(NO3) 3·5H2O

Article abstract of DOI:10.1081/SCC-120030742

Bismuth nitrate pentahydrate catalyzes the three component condensation reaction of an aromatic aldehyde, urea and a β-ketoester or a β-diketone under solvent-free conditions to afford the corresponding dihydropyrimidinones (DHPMs) in high yields. The pre

Full text of DOI:10.1081/SCC-120030742

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An Efficient and Environmentally Friendly Method
for Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones
Catalyzed by Bi(NO ) · 5H O
3
3
2
a
a
a
Mohammad Mehdi Khodaei , Ahmad Reza Khosropour & Mojtaba Beygzadeh
a
Department of Chemistry, Razi University, Kermanshah, 67149, Iran
Published online: 16 Aug 2006.
To cite this article: Mohammad Mehdi Khodaei , Ahmad Reza Khosropour & Mojtaba Beygzadeh (2004): An Efficient and
Environmentally Friendly Method for Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones Catalyzed by Bi(NO ) · 5H O, Synthetic
3
3
2
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:9, 1551-1557
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 9, pp. 1551–1557, 2004
An Efficient and Environmentally
Friendly Method for Synthesis of
3
,4-Dihydropyrimidin-2(1H)-ones
.
Catalyzed by Bi(NO ) 5H O
3
3
2
*
*
Mohammad Mehdi Khodaei, Ahmad Reza Khosropour,
and Mojtaba Beygzadeh
Department of Chemistry, Razi University, Kermanshah, Iran
ABSTRACT
Bismuth nitrate pentahydrate catalyzes the three component condensation
reaction of an aromatic aldehyde, urea and a b-ketoester or a b-diketone
under solvent-free conditions to afford the corresponding dihydropyrimi-
dinones (DHPMs) in high yields. The present method is also effective for
the selective condensation of aryl aldehydes in the presence of aliphatic
aldehydes.
.
3 3
)
Key Words: Aldehydes; Lewis acids; Catalysts; Biginelli; Bi(NO
O.
5H
2
*
Correspondence: Mohammad Mehdi Khodaei and Ahmad Reza Khosropour, Depart-
ment of Chemistry, Razi University, Kermanshah 67149, Iran; Fax: þ98-831-4223306;
E-mail: mmkhoda@razi.ac.ir and arkhosropour@razi.ac.ir.
1
551
DOI: 10.1081/SCC-120030742
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Khodaei, Khosropour, and Beygzadeh
INTRODUCTION
As green chemistry has become a major concern to organic chemists in
present years, reactions under solvent-free conditions with a solid catalysts
have received much attention. These reactions offer several advantages in pre-
parative procedures such as environmentally friendly, simplifying work-up,
formation of cleaner products, enhanced selectivity, and much improved
[
1]
reaction rates.
Dihydropyrimidinones (DHPMs) are important classes of heterocycles
that have attracted much synthetic interest and their derivatives have pharma-
cological and biological properties, as the antihypertensive agents, calcium
channel blockers, a-1a-antagonists, neuropeptide Y(NPY) antagonists, anti-
[2–5]
tumor, antibacterial, and antiinflammatory behaviors.
Recently, the bat-
zelladine alkaloids containing the dihydropyrimidinone-5-carboxylate core,
are the most notably, which have been found to be potent HIV-gp-120-CD4
[
6]
inhibitors. In addition, due to the importance of these compounds as syn-
thons in organic synthesis many synthetic methods for preparing such com-
pounds have been developed and Biginelli reaction has gained an active
[
7]
ongoing research. However, there are several disadvantages associated
with these methodologies including unsatisfactory yields, long conversion
times, difficult handling of reagents, toxic and inflammable organic solvents,
and incompatibility with other functions in the molecules that limited these
methods to small-scale synthesis. Thus, development of facile and environ-
mental friendly synthetic methods to the DHPMs, is demanded.
The application of bismuth(III) salts as catalysts in organic synthesis has
[8,9]
been investigated extensively.
In line with the recent surge in activity in
the use of Bi(NO ) 5H O, we now report a simple, efficient, selective, and
[
10]
.
3
3
2
environmentally benign method for the synthesis of 3,4-dihydropyrimidin-
-ones from aryl aldehydes with b-dicarbonyl compounds and urea under
solvent-free conditions (Sch. 1).
2
Various substituted aromatic aldehydes reacted well with b-dicarbonyl
.
compounds and urea in the presence of a catalytic amount of Bi(NO3)3 5H O
2
under solvent-free conditions to give the corresponding DHPMs in 78–97%
yields (Table 1).
Scheme 1.

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Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
1553
a
Table 1. Formation of DHPMs catalyzed by Bi(NO
conditions.
.
3
)
3
5H
2
O under solvent-free
M.p. (8C)
Time
(min)
Yield
b
(%)
Entry
R
1
R
2
Found
Reported
c
[7c]
1
2
3
4
5
6
7
8
9
C H
6
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
Me
10
10
10
10
25
10
30
10
25
10
10
30
30
20
10
10
10
25
10
10
20
20
30
96/89
91
202–203 203–204
169–171 170–171
201–202 201–203
257–269 256–258
213–212 213–215
231–232 232–233
207–209 206–208
227–228 226–227
210–211 209–210
175–177 175–177
213–215 212–214
249–251 249–250
233–234 232–235
247–249 247–248
212–214 210–212
195–196 194–195
202–203 202–204
237–239 236–238
204–206 203–205
233–235 233–236
169–170 168–170
5
[
7h]
4-CH
4-CH
3
C
6
H
4
c
[7c]
3
OC
6
H
4
90/87
95
[
[
[
[
[
[
[
7b]
7f]
7c]
7i]
4-NMe C H
2
6
4
3-OHC H
6
90
4
4-OH, 3-CH
3
OC
6
H
3
87
2-NO
3-NO C H
2
C
6
H
4
4
4
78
92
7c]
7c]
7g]
2
6
4-NO
4-FC
4-ClC H
2
C
6
H
85
90
1
1
1
1
1
1
1
1
1
1
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
6
H
4
c
c
[7c]
7b]
[7g]
90/86
80
6
4
[
2,4-Cl
CH 55 CHC
a-Naphthyl
2
C
6
H
3
2
6
H
4
83/79
80
[
[
[
[
[
[
7h]
7c]
7c]
7a]
7c]
7c]
C
6
H
5
93
4-CH
4-CH
3
OC
6
H
4
91
90
3
C
6
H
4
4-NO C H
6 4
85
2
4-ClC
6
H
4
92
c,d
[7g]
[7g]
[7g]
C
4-CH OC H
6
H
5
97/95
d
Me
83
3
6
4
d
4-O
2-O
2
NC
6
6
H
4
Me
Me
82
79
233 (dec) 230 (dec)
227 (dec) 225 (dec)
d
[7e]
2
NC
H
4
a
All products were characterized by comparison of their physical and spectral data with
those of authentic samples.
b
Isolated yields.
Isolated yields with reused catalyst.
c
d
Under 608C was performed.
Most importantly, aromatic aldehydes carrying either electron-donating
or electron-withdrawing substituents reacted very well and gave good to
excellent yields. Aliphatic aldehydes were also used in Biginelli reaction,
but their yields were not satisfactory even after 3 h. In fact, more than 70%
of the parent aldehydes were recovered and only less than 30% of the
desired products obtained. Acid-sensitive substrates like cinnamaldehyde
are also reacted in high yields without the formation of any side products.

ORDER
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554
Khodaei, Khosropour, and Beygzadeh
The tolerance of various functional groups under the present reaction con-
ditions has been examined by reacting the substrates bearing methoxy,
nitro, hydroxy, and olefinic groups. In comparison, this reaction was examined
in different solvents and indicated that the reaction was performed better in
neat conditions (Table 2).
In order to show the selectivity of the desired method we have also inves-
tigated the competitive reactions in the presence of this catalyst and found that
aromatic aldehydes react selectively in the presence of aliphatic aldehydes
(
Sch. 2).
Under the reaction conditions employed, thiourea did not undergo the
Biginelli reaction and the starting materials were recovered unchanged.
These may be considered as a useful practical achievement in Biginelli reac-
tion. Moreover, this catalyst has been recovered almost quantitatively and has
been reused for second cyclocondensation reaction and the yields of the
second runs were comparable to those of the first run (Table 1, products 1,
3
, 11, 13, and 20).
.
In conclusion, we have demonstrated the use of Bi(NO3)3 5H O as a
2
low toxic, inexpensive, oxygen and moisture tolerant catalyst that could
be readily recovered and reused for the one-pot formation of DHPMs under
solvent-free conditions. In addition, high chemoselectivity, low reaction
times, high yields of the products, easy work-up, and ecologically clean
procedure, make the present method as a useful addition to the present
methodologies.
EXPERIMENTAL
1
Products were characterized by comparison of their spectral data ( H-NMR,
IR) and physical data with those reported in the literature.
Table 2. Formation of DHPMs in different solvents and no solvent.
Entry
Solvent
Time (hr)
Yield (%)
1
2
3
4
5
6
7
Methanol
Ethanol
Water
4
75
80
5
4
2
Ethanol/water (1 : 1 v/v)
Acetonitrile
4
25
55
40
90
5
Dichloromethane
Solvent free
5
0.16

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Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
1555
Scheme 2.
General Procedure for the Preparation of DHPMs
To a solution of aryl aldehyde (1 mmol), b-dicarbonyl compound
.
1 mmol) and urea (1.3 mmol) was added Bi(NO3)3 5H O (0.1 mmol). The
2
(
mixture was stirred at reflux conditions for an appropriate time (Table 1).
After completion of the reaction, as indicated by TLC, ethanol (20 mL) was
added, filtered and the filterate cooled until the product was crystallized.
The product was washed with a mixture of (1 : 1) water/ethanol and then
dried. The pure product was obtained by recrystallization from ethanol in
78–97% yields. The catalyst was washed with 95% ethanol and reused for
another reaction.
ACKNOWLEDGMENT
We are grateful to the Razi University Research Council for partial sup-
port of this work.
REFERENCES
1. Tanaka, K.; Toda, F. Solvent free organic synthesis. Chem. Rev. 2000,
100, 1025.
2. (a) Atwal, K.S.; Rovnyak, G.C.; O’Reilly, B.C.; Schwartz, J. Substituted
1
1
,4-dihydropyrimidines. 3. Synthesis of selectively functionalized 2-hetero
,4-dihydropyrimidines. J. Org. Chem. 1989, 54, 5898; (b) Rovnyak, G.C.;
Kimball, S.D.; Beyer, B.; Cucinotta, G.; Dimarco, J.D.; Gougoutas, J.;
Hedberg, A.; Malley, M.; McCarthy, J.P.; Zhang, R.; Moreland, S. Calcium
entry blockers and activators: conformational and structural determinants
of dihydropyrimidine calcium channel modulators. J. Med. Chem. 1995,
38, 119.

ORDER
REPRINTS
1
556
Khodaei, Khosropour, and Beygzadeh
3
. (a) Kappe, C.O.; Fabian, W.M.F.; Semones, M.A. Conformational anal-
ysis of 4-aryl-dihydropyrimidine calcium channel modulators. A com-
parison of ab-initio, semiemperical, and x-ray crystallographic studies.
Tetrahedron 1997, 53, 2803; (b) Hu, E.H.; Sidler, D.R.; Dolling, U.H.
Unprecedented catalutic three component one-pot condensation reaction:
an efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-
2(1H)-ones. J. Org. Chem. 1998, 63, 3454.
4
. Atwal, K.S.; Swanson, B.N.; Unger, S.E.; Floyd, D.M.; Moreland, S.;
Hedberg, A.; O’Reilly, B.C. Dihydropyrimidine calcium channel block-
ers. 3,3-carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidine car-
boxylic acid esters as orally efffective antihypertensive agents. J. Med.
Chem. 1991, 34, 806.
5
. Grover, G.J.; Dzwonczyk, S.; McMullen, D.M.; Normadinam, C.S.;
Sleph, P.G.; Moreland, S.J. J. Cardiovasc. Pharmacol. 1995, 26, 289.
. (a) Overman, L.E.; Rabinowitz, M.H.; Renhowe, P.A. Enantioselective
total synthesis of (2)-ptibmycalin A. J. Am. Chem. Soc. 1995, 117,
6
2657; (b) Snider, B.; Shi, Z. Biomimetic synthesis of (0 + 0)-crambines
A, B, C1, and C2. Revision of the structure of crambines B and C1. J. Org.
Chem. 1993, 58, 3828.
7
. (a) Fan, X.; Zhang, X.; Zhang, Y. Samarium chloride catalyzed Biginelli
reaction: one-pot synthesis of 3, 4-dihydropyrimidin-2(1H)-ones. J. Chem.
Res. (S) 2002, 436; (b) Lu, J.; Bai, Y. Catalysis of the Biginelli reaction by
ferric and nickel chloride hexahydrates. one-pot synthesis of 3,4-dihydro-
pyridine-2-(1H)-ones. Synthesis 2002, 466; (c) Jin, T.; Zhang, S.; Guo, J.;
Li, T. A simple and efficient synthesis of 3,4-dihydropyrimidin-
2-ones catalyzed by amidosulfonic acid. J. Chem. Res. (S) 2002, 37;
(
d) Varala, R.; Alam, M.M.; Adapa, S.R. Bismuth triflate catalyzed
one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones: an improved pro-
tocal for the Biginelli reaction. Synlett. 2003, 67; (e) Kiran Kumar
Reddy, G.S.; Srinivas Reddy, Ch.; Yadav, J.S.; Sabitha, G. One-pot syn-
thesis of dihydropyrimidinones using iodotrimethylsilane; facile and
new improved protocal for the Biginelli reaction at room temperature.
Synlett. 2003, 858; (f) Ranu, B.C.; Hajra, A.; Jana, U. Indium(III)
chloride-catalyzed one-pot synthesis of dihydropyrimidinones by a
three-component coupling of 1,3-dicarbonyl compounds, aldehydes,
and urea: an improved procedure for the Biginelli reaction. J. Org.
Chem. 2000, 65, 6270; (g) Yun, M.; Changtao, Q.; Limin, W.; Min, Y.
Lanthanide triflate catalyzed Biginelli reaction. One-pot synthesis of
dihydropyrimidinone under solvent-free conditions. J. Org. Chem.
2000, 65, 3864; (h) Yadav, J.S.; Subba Reddy, B.V.; Srinivas, R.;
Venugopal, C.; Ramalingam, T. LiClO -catalyzed one-pot synthesis
of dihydropyrimidinones: an improved protocal for Biginelli reaction.
4

ORDER
REPRINTS
Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
1557
Synthesis 2001, 1341; (i) Bose, D.S.; Fatima, L.; Mereyala, H.B. Green
chemistry approaches to the synthesis of 5-alkoxycarbonyl-4-aryl-3,4-
dihydropyrimidin-2(1H)-ones by a three component coupling of one-pot
condensation reaction: comparison of ethanol, water, and solvent-free
conditions. J. Org. Chem. 2003, 68, 587.
8
. (a) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. Highly efficient and
versatile acylation of alcohols with Bi(OTf) as catalyst. J. Org. Chem.
3
2001, 26, 8926; (b) Bhatia, K.A.; Eash, K.J.; Leonard, N.M.;
Oswald, M.C.; Mohan, R.S. A facile and efficient method for the
rearrangement of aryl-substituted epoxides to aldehydes and ketones
using bismuth triflate. Tetrahedron Lett. 2001, 46, 8129; (c) Roux, C.L.;
Dubac, J. Bismuth(III) chloride and triflate: novel catalysts for acylation
and sulfonylation reactions. Survey and mechanistic aspects. Synlett.
2002, 2, 181.
9
. (a) Mohammadpoor-Baltork, I.; Khosropour, A.R. Efficient and selective
conversion of trimethylsilyl and tetrahydropyranyl ethers to their corre-
sponding acetates and benzoates catalyzed by bismuth(III) salts.
Monatshefte f u¨ r Chemie 2002, 133, 189; (b) Mohammadpoor-Baltork, I.;
Aliyan, H.; Khosropour, A.R. Bismuth(III) salts as convenient and efficient
catalysts for the selective acetylation and benzoylation of alcohols and phe-
nols. Tetrahedron 2001, 57, 5851; (c) Mohammadpoor-Baltork, I.;
Khosropour, A.R.; Aliyan, H. A convenient and chemoselective acetylation
and formylation of alcohols and phenols using acetic acid and ethyl formate
in the presence of Bi(III) salts. J. Chem. Research(S) 2001, 7, 780;
(d) Mohammadpoor-Baltork, I.; Khosropour, A.R. Bi(TFA) and catalyzed
3
conversions of epoxides to thiiranes with ammonium thiocyanate and
thiourea under non-aqueous conditions. Molecules 2001, 6, 996;
(
e) Mohammadpoor-Baltork, I.; Khosropour, A.R. Bi(III) salts as new cat-
alysts for the selective conversion of trimethylsilyl and tetrahydropyranyl
ethers to their corresponding acetates and formates. Synth. Commun.
2001, 21, 3411.
1
0. (a) Cunha, S.; Lima, B.R.; Souza, A.R. Bismuth nitrate pentahydrate: a
new and enviromentally benign reagent for guanidylation of N-benzoyl-
thioureas. Tetrahedron Lett. 2002, 43, 49; (b) Mohammadpoor-Baltork, I.;
Khodaei, M.M.; Nikoofar, K. Bismuth(III) nitrate pentahydrate: a
convenient and selective reagent for conversion of thiocarbonyls to
their carbonyl compounds. Tetrahedron Lett. 2003, 44, 591 and references
therein.
Received in the UK September 3, 2003

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