Bismuth(III)-catalyzed synthesis of dihydropyrimidinones: Improved protocol conditions for the Biginelli reaction

Article abstract of DOI:10.1055/s-2001-14587

An efficient synthesis of 3,4-dihydropyrimidines using bismuth chloride as a catalyst from an aldehyde, β-keto ester and urea in acetonitrile is described. Compared to the classical Biginelli reaction conditions, this new method consistently has the advan

Full text of DOI:10.1055/s-2001-14587

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LETTER
863
Bismuth(III)-Catalyzed Synthesis of Dihydropyrimidinones: Improved
Protocol Conditions for the Biginelli Reaction
K. Ramalinga, P. Vijayalakshmi, T. N. B. Kaimal*
Oils & Fats Division, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91-40-7173370; E-mail: kaimal@iict.ap.nic.in
Received 4 April 2001
Over recent years, the catalytic activity of bismuth(III)
chloride has emerged as powerful Lewis acid catalyst im-
parting high regio- and chemoselectivity in various chem-
ical transformations.8 Our own work also found BiCl3 to
be a very efficient catalyst for two and three component
coupling reactions.9 We wish to report another remarkable
catalytic activity of BiCl3 for the one-pot condensation of
1,3-dicarbonyl compounds, aldehydes and urea to form
dihydropyrimidin-2(1H)-ones.
Abstract: An efficient synthesis of 3,4-dihydropyrimidines using
bismuth chloride as a catalyst from an aldehyde, -keto ester and
urea in acetonitrile is described. Compared to the classical Biginelli
reaction conditions, this new method consistently has the advantage
of good yields (56-97%).
Key words: Biginelli reaction, dihydropyrimidinones, bismuth
chloride, one-pot condensation, synthesis
Dihydropyrimidinone derivatives have attracted consider-
able interest in recent times because of their promising ac-
tivities as calcium channel blockers, antihypertensive
agents and -1a-antagonists.1 Moreover, several alkaloids
containing the dihydropyrimidine unit have been isolated
from marine sources, and exhibit interesting biological
properties.2 Thus, synthesis of this heterocyclic nucleus is
of much current importance. The most simple and
straightforward procedure, reported by Biginelli in 1893,
involves one-pot condensation of ethyl acetoacetate, ben-
zaldehyde and urea under strongly acidic conditons.3
However, one serious drawback of Biginelli’s reaction is
the low yields obtained in the case of substituted aromatic
and aliphatic aldehydes.4 This has led to the development
of multistep strategies that produce somewhat higher
overall yields but lack the simplicity of the one-pot, one-
step synthesis4,5 (Scheme 1).
Here we wish to report our preliminary investigation con-
cerning the direct synthesis of 3,4-dihydropyrimidin-
2(1H)-ones. In this paper, we describe a general and prac-
tical route for the Biginelli cyclocondensation reaction us-
ing bismuth chloride as the catalyst.10 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 dihydropyrmidin-2(1H)-ones. In
the presence of BiCl3 (0.3 mmol), the reaction of -keto
ester 1 (2.5 mmol), aldehyde 2 (2.5 mmol), and urea 3 (3.7
mmol) was carried out in a one-pot condensation employ-
ing refluxing CH3CN, which has previously been em-
ployed successfully in the Biginelli condensation as
solvent. After the reaction was complete, the dihydropyri-
midinones 4a-t precipitated from the reaction mixture.
Even for aliphatic aldehydes (i.e., butyraldehyde, iso-bu-
tyraldehyde and heptanal), which normally show ex-
tremely poor yields in the Biginelli reaction,11 72%, 54%
and 50% yields, respectively, of the corresponding dihy-
dropyrimidin-2(1H)-ones (4k, 4l and 4m) could be ob-
tained (Table).
Performing efficient chemical transformations, coupling
three or more components in a single operation by a cata-
lytic process avoiding stoichiometric, toxic reagents,
large amount of solvents and expensive purification tech-
nique, represents a fundamental target of the modern or-
ganic synthesis.6 Thus, Biginelli’s reaction for the
synthesis of dihydropyrimidinone has received renewed
interest and several improved procedures have recently
been reported,3b,7 although some of these methods involve
strong Lewis acids such as BF3,7e protic acids such as
HCl,7h AcOH7e and additives.7e Consequently, there is
scope for further improvement toward milder reaction
conditions, variations of substituents in all three compo-
nents and better yields.
We propose a mechanism similar to that of Folkers and
Johnson,12-14 Kappe15 and Hu7 for the Biginelli reaction
and the first step in this reaction involves the acid-cata-
lyzed formation of acyl imine intermediate formed by re-
action of the aldehyde with urea and stabilized by
bismuth, is the key rate-limiting step. Interception of the
iminium ion 6 by ethyl acetoacetate enolate produces an
open-chain ureide 7 which subsequently cyclizes to the di-
hydropyrimidinones 4 (Scheme 2).
Scheme 1
Synlett 2001 No. 6, 863–865 ISSN 0936-5214 © Thieme Stuttgart · New York

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864
K. Ramalinga et al.
Table 1 BiCl3-Catalyzed Efficient Synthesis of Dihydropyrmidinones
LETTER
1
a Yield refer to pure solid products, properly characterized by m.p. spectral (IR, H NMR) and
analytical data.
In conclusion, the present procedure for the synthesis of
dihydropyrimidin-2(1H)-ones by bismuth(III)chloride
catalyzed condensation of 1,3-dicarbonyl compound, al-
dehyde and urea provides an efficient and much improved
modification of Biginelli’s reaction. In addition to its sim-
plicity and milder reaction conditions, this method has the
ability to tolerate a wide variety of substituents in the car-
bonyl components, which is lacking in the existing proce-
dures.7 Thus this procedure offers easy access to
substituted dihydropyrimidin-2(1H)-ones in very high
yields. We believe, our procedure will find important ap-
plications in the synthesis of dihydropyrimidinones to ca-
ter for the needs of academia as well as pharmaceutical
industries.
References and Notes
†
IICT Communication No. 4713.
(1) a) 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.
b) 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 and references cited therein.
(2) Overman, L.E.; Rabinowitz, M.H.; Renhowe, P.A. J. Am.
Chem. Soc. 1995, 117, 2657.
(3) a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. b) Kappe, C.O.
Tetrahedron. 1993, 49, 6937.
(4) a) Atwal, K.S.; Rovnyak, G.C.; O’Reilly, B.C.; Schwartz, J. J.
Org. Chem. 1989, 54, 5898. b) Barluenga, J.; Tomas, M.;
Ballesteros, A.; Lopez, L.A. Tetrahedron Lett. 1989, 30, 4573.
Synlett 2001, No. 6, 863–865 ISSN 0936-5214 © Thieme Stuttgart · New York

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LETTER
Bismuth(III)-Catalyzed Synthesis of Dihydropyrimidinones
865
Scheme 2
(5) O’Reilly, B.C.; Atwal, K.S. Heterocycles 1987, 26, 1185.
(6) Mizuno, N.; Misono, M. Chem. Rev. 1998, 98, 199.
(7) a) Gupta R.; Gupta, A.K.; Paul, S.; Kachroo, P.L. Indian J.
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1998, 63, 3454. f) Kappe, C.O.; Falsone, S.F. Synlett 1998,
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Synlett 2000, 63.
(8) a) Komatru, N.; Uda, M.; Suzuth, H.; Takahashi; Domae, T.;
Wada, M. Tetrahedron Lett. 1997, 7215. b) Le Roux, C.;
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Mandrou, S.; Dubac, J. J. Org. Chem. 1996, 61, 3885. d) Le
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(9) Unpublished results.
solid products were filtered, washed with cold water (2 50
mL) and subsequently dried. All the products (except 4n and
4o) are known compounds which were characterized by mp
and IR spectral data.
Spectral data for 4n : m.p. 179-180 °C; 1H NMR (DMSO-
d6): 1.20 (t, 3H, J = 6.8 Hz), 2.30 (s, 3H), 3.80 (s, 3H), 3.85
(s, 6H), 4.15 (q, 2H, J = 6.8 Hz), 5.30 (d, 1H, J = 2.7 Hz), 5.8
(brs, NH), 6.50 (s, 2H), 8.30 (brs, NH); EIMS : m/z 349 M+;
IR (KBr) : 3199, 3069, 2910, 2810, 1962, 1713, 1651, 1587,
1281, 1125, 1092, 840; Anal. Calcd. for C17H21N2O6: C,
58.45; H, 6.01; N, 8.02. Found : C, 58.50; H, 6.21; N, 8.10.
Spectral data for 4o : m.p. 236-237 °C; 1H NMR (DMSO-
d6): 1.15 (m, 4H), 1.30 (t, 3H, J = 7.0 Hz), 1.50 (m, 3H), 1.80
(m, 4H), 2.35 (s, 3H), 4.20 (m, 3H), 6.20 (brs, NH), 8.50 (brs,
NH); EIMS : m/z 266 M+; IR (KBr) : 3210, 3075, 2910,
2840, 1730, 1702, 1650, 1430, 1245, 1080, 810. Anal. Calcd.
for C14H22N2O3: C, 63.15; H, 8.27; N, 10.52. Found : C, 63.20;
H, 8.30; N, 10.60.
(11) Eynde, J.J.V.; Audirat, N.; Canonne, N.; Michel, S.;
Haverbeke, Y.V.; Kappe, C.O. Heterocycles 1997, 45, 1967.
(12) Folkers, K.; Harwood, H.J.; Johnson, T.B. J. Am. Chem. Soc.
1932, 54, 3751.
(13) Folkers, K.; Johnson, T.B. J. Am. Chem. Soc. 1933, 55, 2886.
(14) Folkers, K.; Johnson, T.B. J. Am. Chem. Soc. 1933, 55, 3784.
(15) Kappe, C.O. J. Org. Chem. 1997, 62, 7201.
(10) General procedure for BiCl3-mediated preparation of
pyrmidines 4: A solution of -keto ester (1, 2.5 mmol),
appropriate aldehyde (2, 2.5 mmol), urea (3, 3.7 mmol) BiCl3
(0.3 mmol), in CH3CN (20 mL) was heated under reflux for 5
h. The solution was cooled to room temperature and poured
into water. Stirring was continued for several minutes. The
Article Identifier:
1437-2096,E;2001,0,06,0863,0865,ftx,en;D04601ST.pdf
Synlett 2001, No. 6, 863–865 ISSN 0936-5214 © Thieme Stuttgart · New York