7
78
S. L. Jain, V. B. Sharma, and B. Sain
Vol 43
Kappe, Eur. J. Med. Chem., 35, 1043 (2000).
out under similar reaction conditions using benzaldehyde,
ethyl acetoacetate and urea as substrates. The reaction
was found to be very slow in the absence of catalyst. The
use of acetyl acetone as 1,3-dicarbonyl moiety in place of
ethyl acetoacetate also gave similar results Table (entry
[
[
2] P. Biginelli, Gazz. Chim. Ital., 23, 360 (1893).
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Ramesh, and V. V. N. Reddy, Tetrahedron Lett., 43, 2657 (2002); N. Y.
Fu, Y. F. Yuan, Z. Cao, S. W. Wang, J. T. Wang, and C. Peppe,
Tetrahedron, 58, 4801 (2002); K. Ramalinga, P. Vijyalakshmi, and T. N.
B. Kaimal, Synlett, 863 (2001); J. S. Yadav, B. V. S. Reddy, R. Srinivas,
C. Venugopal, and T. Ramalingam, Synthesis, 1341 (2001); E. H. Hu, D.
R. Sidler, and U. H. Dolling, J. Org. Chem., 63, 3454 (1998) ; J. Lu and
Y. Bai, Synthesis, 466 (2002).
1
1-14). The effect of various solvents was also studied
for the formation of dihydropyrimidinone using benzal-
dehyde, ethyl acetoacetate and urea as substrates. Among
the various solvents such as THF, acetonitrile, ethanol and
benzene studied, ethanol was found to be the best solvent.
Although the detail mechanism of this reaction is not
clear at this stage the reaction probably involves the in
situ formation of acylimine intermediate by the reaction
of urea and aldehyde, which undergoes the subsequent
addition to ꢀ-dicarbonyl compound followed by
cyclization and dehydration to yield dihydropyrimidinone
[
4] S. R. Adapa, M. M. Anan, and R. Varala, Synlett, 67 (2003);
A. S. Paraskar, G. K. Dewkar, and A. Sundailai, Tetrahedron Lett., 44,
305 (2003).
[5] P. Salehi, M. Dabiri, M. Ali Zolfigol, and M. A. B. Fard,
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46, 1159 (2005).
3
[
2
[
[8] R. V. Yarapathi, S. Kurya, and S. Tammishetti, Catal.
Commun., 5, 511 (2004).
4
as proposed using lewis acids [17].
[
9] J. S. Yadav, S. P. Kumar, G. Kondaji, R. S. Rao, and K.
In conclusion the present procedure describes for the
Nagaiah, Chem. Lett., 33, 1168 (2004).
first time the use ruthenium tichloride as an extremely
mild and high efficient catalyst for the synthesis of a
variety of 3,4-dihydropyrimidin-2(1H)-ones in excellent
yield under mild conditions by three component
condensation of an aldehyde, 1,3-dicarbonyl compound
and urea in one-pot. The simplicity of the system, easy
workup and excellent yields make this method an
attractive and facile tool for the Biginelli reaction.
We are thankful to the Director, IIP for his kind
permission to publish these results. Suman L. Jain and
Vishal B. Sharma are thankful to CSIR, New Delhi for the
award of Research Fellowships.
[10] J. S. Yadav, B. V. S. Reddy, P. Sridhar, J. S. S. Reddy, K.
Nagaiah, N. Lingaiah, and P. S. Saiprasad, Eur. J. Org. Chem., 552
(
2004).
[
11] T. Naota, H. Takaya, and S. Murahashi, Chem. Rev., 98, 2599
(1998); A. Miyata, M. Murakami, R. Irie, and T. Katsuki, Tetrahedron
Lett., 42, 7067 (2001); T. Kondo, T. Okada, and T. Mitsudo, J. Am.
Chem. Soc., 124, 186 (2002).
[
12] S. L. Jain and B. Sain, Angew. Chem. Int. Ed., 42, 1265
(2003); S. L. Jain and B. Sain, Chem. Commun., 1040 (2002); V. B.
Sharma, S. L. Jain, and B. Sain, Tetrahedron Lett., 44, 383 (2003); S. L.
Jain and B. Sain, J. Mol. Catal., 176, 101 (2001); V. B. Sharma, S. L.
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Sharma, and B. Sain, Tetrahedron Lett., 44, 4385 (2003); S. L. Jain, V.
B. Sharma, and B. Sain,. Tetrahedron Lett., 45, 1233 (2004).
[13] Typical experimental procedure: A solution of benzaldehyde
(5 mmol, 535 mg), urea (5 mmol, 300 mg) and ethylacetoacetate (5
mmol, 650 mg) in ethanol (10 ml) was stirred until urea got dissolved
completely. Ruthenium trichloride hydrate (5 mol %, 0.25 mmol, 52
mg) was then added to the reaction mixture and it was further stirred for
5 min. followed by refluxing for 4 h under nitrogen blanket. The
REFERENCES AND NOTES
[
1] Review: C. O. Kappe, Tetrahedron, 43, 6937 (1993);
Review: C. O. Kappe, Acc. Chem. Res., 33, 879 (2000); Review: C. O.
2
progress of the reaction was monitored by TLC (SiO ) using ethyl
Table
Ruthenium-catalyzed Synthesis of Dihydropyrimidin-2(1H)-ones
a
Entry
Product
R
R’
Reaction
time/h
Yield
(%)
Mp (°C)
Found (lit) [ref]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
C
6
H
5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
4.0
4.5
4.5
5.0
4.5
5.0
6.0
4.5
5.5
6.5
4.5
5.0
5.0
6.0
95
85
82
80
79
75
75
83
75
70
94
82
79
80
201(202) [14]
214-15 (215) [3]
199-200 (201) [15]
208-09 (210) [15]
211 (212-13) [15]
222 (223-4) [15]
151-2 (153-55) [3]
204-05 (205) [14]
193-4 (195) [15]
156 (157-8) [15]
208 (209-12) [14]
234-5 (235-7) [15]
189-90 (190-93) [15]
209-10 (210-12) [16]
4-CH
4-CH OC
4-NO
3
C
6
H
4
3
6
H
4
2
C
6
H
4
4-ClC
2-ClC
6
H
H
4
6
4
n-CH
2-Furyl
(CH CH
n-CH (CH2) CH
2
3 2 2
CH CH
3 2
)
1
1
1
1
1
0
1
2
3
4
3
2
6 5
C H
4-NO
4-CH OC
2-Furyl
2
C
6
H
4
Me
Me
Me
3
6
H
4
[a] Isolated Yields.