One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using lanthanum chloride as a catalyst

Article abstract of DOI:10.1016/S0040-4039(00)01645-2

An efficient synthesis of 3,4-dihydropyrimidinones using lanthanum chloride heptahydrate as a catalyst from an aldehyde, β-keto ester and urea or thiourea in ethanol is described. Compared to the classical Biginelli reaction conditions, this new method co

Full text of DOI:10.1016/S0040-4039(00)01645-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9075–9078
One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using
lanthanum chloride as a catalyst
Jun Lu,* Yinjuan Bai, Zhenjun Wang, Bingqin Yang and Huairang Ma
Department of Chemistry, Northwest University, Xi’an 710069, PR China
Received 3 August 2000; revised 14 September 2000; accepted 20 September 2000
Abstract
An efficient synthesis of 3,4-dihydropyrimidinones using lanthanum chloride heptahydrate as a catalyst
from an aldehyde, b-keto ester and urea or thiourea in ethanol is described. Compared to the classical
Biginelli reaction conditions, this new method consistently has the advantage of good yields (56–97%).
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Biginelli reaction; dihydropyrimidinones; lanthanum chloride heptahydrate; one-pot condensation; synthe-
sis.
During recent years, the use of lanthanide(III) compounds as catalysts or promoters in
organic synthesis has attracted great interest from many chemists.1 Lanthanide additives or
complexes can enhance the reactivity and selectivity of many types of reaction, such as
reduction, carbonꢀcarbon bond formation, aldol condensation, cycloaddition, ring-opening and
polymerization.
The Biginelli reaction was first reported more than a century ago and recently reviewed,2 and
involves the synthesis of 3,4-dihydropyrimidin-2(1H)-ones of type 4 by a very simple one-pot
condensation reaction of ethyl acetoacetate 1, benzaldehyde 2 and urea 3 in ethanol. However,
this one-pot, one-step protocol often provides only low to moderate yields of the desired target
molecules 4 (Scheme 1), in particular when substituted aromatic or aliphatic aldehydes are
employed.
In the past decade, dihydropyrimidine derivatives have exhibited important pharmacological
properties, e.g. as the integral backbones of several calcium channel blockers, antihypertensive
agents, alpha-1a-antagonists, and neuropeptide Y (NPY) antagonists.3 Therefore, the discovery
of milder and practical routes for the synthesis of dihydropyrimidin-2(1H)-ones by the Biginelli
reaction continues to attract the attention of researchers. Several improved procedures for the
preparation of DHPMs (‘Biginelli compounds’) have recently been reported, either by modifica-
* Corresponding author. Tel: 86-29-8302604; fax: 86-29-8303798; e-mail: lujunyue@hotmail.com
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01645-2

9076
Scheme 1.
tion of the classical one-pot Biginelli approach itself,4–8 or by the development of novel, but
more complex multistep strategies.9 In addition, several combinatorial approaches towards
DHPMs 4 have been advanced using solid-phase or fluorous phase reaction conditions.10
Here we wish to report our preliminary investigation concerning the direct synthesis of
3,4-dihydropyrimidin-2(1H)-ones. In this paper, we describe a general and practical route for
the Biginelli cyclocondensation reaction using lanthanum chloride heptahydrate as the catalyst
(Method A).11 This is a novel, one-pot combination that not only preserves the simplicity of
Biginelli’s one-pot reaction but also consistently produces excellent yields of the dihydropyrimi-
din-2(1H)-ones. In the presence of the LaCl3·7H2O (5 mmol), the reaction of b-keto ester 1 (10
mmol), aldehyde 2 (10 mmol), and urea or thiourea 3 (15 mmol) was carried out in a one-pot
condensation employing refluxing EtOH, which has previously been employed successfully in the
Biginelli condensation as solvent. After the reaction was completed, the dihydropyrimidinones
4a–t precipitated from the reaction mixture. Even for aliphatic aldehydes (i.e. butyraldehyde and
iso-butyraldehyde), which normally show extremely poor yields in the Biginelli reaction,12 60
and 56% yields of the corresponding dihydropyrimidin-2(1H)-ones 4j and 4k could be obtained
(Table 1).
Recently, the mechanism of the Biginelli reaction was reinvestigated in detail by Kappe.16 He
proposed and established that the first step in this reaction, the acid-catalyzed formation of an
acyl imine intermediate formed by reaction of the aldehyde with urea, is the key rate-limiting
step. Interception of the iminium ion by ethyl acetoacetate produces an open-chain ureide 7
which subsequently cyclizes to the dihydropyrimidinones 4. Because of the 4f empty orbital in
the lanthanum ion, a complex 6 can be formed through a coordinative bond and stabilized by
lanthanum. So we propose a mechanism for the lanthanum promoted Biginelli reaction as
follows (Scheme 2):
Scheme 2.

9077
Table 1
DHPMs 4 synthesized using LaCl3·7H2O versus classical Biginellis’ conditions
DHPM
X
R1
R2
Yield (%)
Bb
Aa
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Et
C6H5
95
93
91
92
89
80
92
87
97
60
56
76
67
93
97
82
96
68
96
7813
6113
4913
4313
6713
5813
564
4-(CH3O)-C6H4
3,4-(OCH2O)-C6H3
4-(OH)-3-(CH3O)-C6H3
4-(OH)-C6H4
4-(NO2)-C6H4
4-(Cl)-C6H4
3-(Cl)-C6H4
3-(Br)-C6H4
CH3CH2CH2
(CH3)2CH
2-(OH)-C6H4
Furyl-
2,4-(Cl)2-C6H3
C6H5
4-(CH3O)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
C6H5
568
588
1512
1012
1913
3613
69c
424
284
564
414
70,14
4213
8014
4t
S
Et
4-(CH3O)-C6H4
85
a Method A: new reaction conditions (cat. LaCl3·7H2O/HCl in EtOH, reflux 5 h).11
b Method B: classical Biginelli conditions (cat. HCl in EtOH reflux 18 h).13–15
c This work.
In conclusion, we have developed a simple and efficient method for the direct preparation of
substituted dihydropyrimidinones using lanthanum chloride heptahydrate as a catalyst in good
yields from readily available starting materials.
Acknowledgements
This work was supported by the science foundation of Northwest University (98NW07F).

9078
References
1. (a) Imamoto, T. In Lanthanides in Organic Synthesis, Academic Press: New York, 1994. (b) Kobayashi, S. Synlett
1994, 689. (c) Molander, G. A. Chem. Rev. 1992, 92, 29.
2. (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) For a review of the Biginelli reaction, see Kappe, C. O.
Tetrahedron 1993, 49, 6937.
3. (a) 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. J. Med. Chem. 1995, 38, 119. (b) Atwal, K. S.; Rovnyak,
G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K.
M.; Malley, M. F. J. Med. Chem. 1990, 33, 2629. (c) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu,
M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.; Ishihara, T.;
Funahashi, K.; Satah, F.; Morita, M.; Noguchi, T. J. Med. Chem. 1989, 32, 2399. (d) Grover, G. J.; Dzwonczyk,
S.; McMullen, D. M.; Normadinam, C. S.; Sleph, P. G.; Moreland, S. J. J. Cardiovasc. Pharmacol. 1995, 26, 289.
(e) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.;
Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254. (f) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd,
D. M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 34, 806. (g) Wong, W. C.; Lagu, B.;
Nagarathnam, D.; Marzabadi, M. R.; Gluchowski, C. PCT Int. Appl. WO 98 51,311. (h) Sidler, D. R.; Larsen,
R. D.; Chartrain, M.; Ikemoto, N.; Roberge, C. M.; Taylor, C. S.; Li, W.; Bills, G. F. PCT Int. WO 99 07,695.
(i) Bruce, M. A.; Pointdexter, G. S.; Jonhson, G. PCT Int. Appl. WO 98 33,791.
4. Hu, E. H.; Sidler, D. R.; Dolling, Ulf-H. J. Org. Chem. 1998, 63, 3454.
5. Kappe, C. O.; Falsone, S. F. Synlett 1998, 718.
6. Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1999, 40, 3465.
7. Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron 1999, 55, 12873.
8. Lu, J.; Ma, H. Synlett 2000, 63.
9. (a) O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185. (b) Atwal, K. S.; O’Reilly, B. C.; Gougoutas, J. Z.;
Malley, M. F. Heterocycles 1987, 26, 1189. (c) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org.
Chem. 1989, 54, 5898. (d) Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P. L. Ind. J. Chem. 1995, 34B, 151. (e)
Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999, 1799.
10. (a) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819. (b) Studer, A.; Hadida, S.; Ferritto, R.; Kim,
S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823. (c) Studer, A.; Jeger, P.; Wipf, P.; Curran, D.
P. J. Org. Chem. 1997, 62, 2917.
11. General procedure for LaCl3·7H2O—mediated preparation of pyrimidines 4: a solution of b-keto ester (1, 10
mmol), the appropriate aldehyde (2, 10 mmol), urea or thiourea (3, 15 mmol), LaCl3·7H2O (1.85 g, 5 mmol) and
conc. HCl (1–2 drops) in EtOH (20 mL) was heated under reflux for 5 h. After cooling, the reaction mixture was
poured onto 50 g of crushed ice. Stirring was continued for several minutes; the solid products were filtered,
washed with cold water (2×50 mL) and a mixture (1:1) of ethanol–water (2×20 mL) and subsequently dried. All
1
the products (except 4n) are known compounds which were characterized by IR and H NMR spectral data and
their mps compared with literature reported mps. Data for 4n: mp 248–250°C. IR (KBr): 3219, 3104, 2969, 1699,
1
1641 cm−1. H NMR (DMSO-d6, 300 MHz): 9.33 (br s, N1-H), 7.77 (br s, N3-H), 7.31–7.57 (m, Ar-H), 5.60 (s,
C4-H), 3.90 (q, OCH2CH3, J=7.2 Hz), 2.29 (s, C6-CH3), 1.02 (t, OCH2CH3, J=7.2 Hz). MS m/e 328 (M+, 6.69),
330 (M++2, 4.10), 299 (47.18), 293 (68.72), 255 (40.00), 183 (100.00), 155 (32.82), 137 (25.64). Anal. calcd for
C14H14Cl2N2O3: C, 51.06; H, 4.26; N, 8.51. Found: C, 51.32; H, 4.43; N, 8.24.
12. Eynde, J. J. V.; Audiart, N.; Canonne, V.; Michel, S.; Haverbeke, Y. V.; Kapple, C. O. Heterocycles 1997, 45,
1967.
13. Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55, 2886.
14. Akhtar, M. E.; Seth, M.; Bahaduri, A. P. Indian J. Chem. 1987, 26B, 556.
15. Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem. Soc. 1932, 54, 3751.
16. Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
.