Chemistry Letters Vol.33, No.9 (2004)
1169
well, affording excellent yields in high purity. Very highlight of
this procedure is the tolerance of acid sensitive aldehydes such as
furfural and cinnamaldehyde (4k and 4e) without formation of
side products. Also the additional advantage of this protocol is
volatile propionaldehyde (4j) yield the corresponding DHPM
in excellent yield. Thiourea also gives the corresponding dihy-
dropyrimidin-2(1H)-thiones (Entries 4w–4z) which are also of
much interest with regard to biological activity.1a And also a
wide variety of ꢀ-ketone esters (4w–4y) and aliphatic ꢀ-dike-
tones (4s–4v, 4z) were participated in this reaction. Thus, varia-
tions in all the three components have been accommodated very
comfortably. This protocol utilizes the use of just 10 mol % of
L-proline under solvent-free conditions at ambient temperature.
In addition no additive or protic/Lewis acid is necessary in this
procedure. The crude products obtained are of high purity
(>95% by 1H NMR). Another important feature of this protocol
is survival of a variety of functional groups such as OCH3, OH,
NO2, F, Cl, and conjugated C=C double bond under the reaction
conditions.
2
3
a) K. S. Atwal, G. C. Rovnyak, B. C. O’Reilly, and J.
Schwartz, J. Org. Chem., 54, 5898 (1989). b) G. J. Grover,
S. Dzwonczyk, D. M. McMullen, D. E. Normandin, C. S.
Arham, P. G. Sleph, and S. Moreland, J. Cardiovasc. Phar-
macol., 26, 289 (1995) and references cited therein.
a) C. O. Kappe, W. M. F. Fabian, and M. A. Semones, Tet-
rahedron, 53, 2803 (1997). b) J. C. Barrow, P. G. Nantermet,
H. G. Selnick, K. L. Glass, K. E. Rittle, R. M. Freidinger, R.
W. Ransom, S. S. O’Malley, P. Eppert, D. Nagarathnam, and
C. Forray, J. Med. Chem., 43, 2703 (2000) and references
cited therein.
a) B. B. Snider and Z. Shi, J. Org. Chem., 58, 3828 (1993)
and references cited therein. b) L. E. Overman, M. H.
Rabinowitz, and P. A. Renhowe, J. Am. Chem. Soc., 117,
2657 (1995). c) Review: L. Heys, C. G. Moore, and P.
Murphy, Chem. Soc. Rev., 29, 57 (2000).
a) A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Bean, A. J.
Freyer, C. De Brosse, S. Mai, A. Truneh, and D. Faulkner,
J. Org. Chem., 60, 1182 (1995). b) A. V. Rama Rao, M. K.
Gurjar, and J. Vasudevan, J. Chem. Soc., Chem. Commun.,
1995, 1369. c) B. B. Snider, J. Chen, A. D. Patil, and A.
Freyer, Tetrahedron Lett., 37, 6977 (1996).
a) T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King,
S. L. Screiber, and T. J. Mitchison, Science, 286, 971
(1999). b) S. J. Haggarty, T. U. Mayer, D. T. Miyamoto,
R. Fathi, R. W. King, T. J. Mitchison, and S. L. Screiber,
Chem. Biol., 7, 275 (2000).
a) P. Biginelli, Ber., 24, 1317 (1891). b) P. Biginelli, Ber.,
26, 447 (1893). c) P. Biginelli, Gazz. Chim. Ital., 23, 360
(1893).
a) J. Barluenga, M. Tomas, A. Ballesteros, and L. A. Lopez,
Tetrahedron Lett., 30, 4573 (1989). b) K. S. Atwal, G. C.
Rovnyak, B. C. O’Reilly, and J. Schwartz, J. Org. Chem.,
54, 5898 (1989).
a) B. C. O’Reilly and K. S. Atwal, Heterocycles, 26, 1185
(1987). b) K. R. Reddy, Ch. V. Reddy, M. Mahesh, P. V.
K. Raju, and V. V. N. Reddy, Tetrahedron Lett., 44, 8173
(2003).
4
5
We propose the mechanism based on an elegant mechanism
proposed by List13 for the direct asymmetric three-component
Mannich reaction. The most plausible mechanism of the L-pro-
line catalyzed three components Biginelli reaction is depicted
in Figure 1.
6
X
X
O
- H2O
NH2
N
+
R1
O
H2N
NH2
H
O
R1
N
CO2H
R2
H
O
R2
R3
7
8
R3
- H2O
+
N
-
CO2
O
N
CO2H
R2
R3
H
R1
NH
.
.
N
X
+H2O
H2
-
N
CO2
R2
H
O
NH
R1
O
R3
R1
9
N
H
X
NH
R3
R2
N
X
H
Figure 1. Plausible mechanism (X = oxygen or sulphur).
10 a) Review: C. O. Kappe, Tetrahedron, 49, 6937 (1993). b) A.
Shaabani, A. Bazgir, and F. Teimouri, Tetrahedron Lett., 44,
857 (2003) and references cited therein. c) J. T. Li, J. F. Han,
J. H. Yang, and T. S. Li, Ultrason. Sonochem., 10, 119
(2003). d) D. Alessandro, M. Alessandro, S. Simona, and
B. Valerio, J. Org. Chem., 67, 6979 (2003). e) D. Alessandro,
M. Alessandro, M. Erik, S. Simona, and B. Valerio, J. Org.
Chem., 67, 6172 (2003).
11 B. List, Synlett, 2001, 1675 and references cited therein.
12 a) A. Bogevig, N. Kumaragurubaran, K. Juhl, W. Zhuang,
and K. A. Jorgensen, Angew. Chem., Int. Ed. Engl., 41,
1790 (2002). b) N. Kumaragurubaran, K. Juhl, W. Zhuang,
A. Bogevig, and K. A. Jorgensen, J. Am. Chem. Soc., 124,
6254 (2002). c) B. List, J. Am. Chem. Soc., 124, 5656 (2002).
13 B. List, P. Pojarliev, W. T. Biller, and H. J. Martin, J. Am.
Chem. Soc., 124, 827 (2002).
In summary, we have developed a novel and simple proto-
col, for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by
L-proline catalyzed condensation of ꢀ-dicarbonyl compound, al-
dehyde, and urea under solvent-free condition provided an effi-
cient, eco-friendly and much improved modification of classical
Biginelli reaction. We believe, our procedure will find an impor-
tant application in the synthesis of DHPMs to fulfill the needs of
academia as well as pharmaceutical industries.
SPK, GK, and RSR thank CSIR, New Delhi, for the award
of fellowships.
References and Notes
1
a) Review: C. O. Kappe, Tetrahedron, 49, 6937 (1993). b)
Review: C. O. Kappe, Acc. Chem. Res., 33, 879 (2000). c)
Review: C. O. Kappe, Eur. J. Med. Chem., 35, 1043 (2000).
14 The racemic nature of DHPMs confirmed by HPLC analysis.
Published on the web (Advance View) August 14, 2004; DOI 10.1246/cl.2004.1168