The Biginelli condensation: A novel and efficient regioselective synthesis of dihydropyrimidin-2(1H)-ones using lithium bromide

Article abstract of DOI:10.1246/cl.2002.1038

Various substituted 3,4-dihydropyrimidin-2(1H)-ones were synthesised in one-pot reaction of aldehydes, β-ketoesters and urea using LiBr in tetrahydrofuran in excellent yields without any side reactions as observed by Biginelli and others.

Full text of DOI:10.1246/cl.2002.1038

1038
Chemistry Letters 2002
The Biginelli Condensation: A Novel and Efficient Regioselective Synthesis
of Dihydropyrimidin-2(1H)-ones Using Lithium Bromide
Partha P. Baruah, Sunil Gadhwal, Dipak Prajapati, and Jagir S. Sandhuꢀ
Regional Research Laboratory, Jorhat 785006, Assam, India
(Received June 17, 2002;CL-020507)
Various substituted 3,4-dihydropyrimidin-2(1H)-ones were
O
synthesised in one-pot reaction of aldehydes, ꢀ-ketoesters and
urea using LiBr in tetrahydrofuran in excellent yields without any
side reactions as observed by Biginelli and others.
O
O
O
+
R
R
H
Me
R'
R'
NH
LiBr
THF,
1
R' = OEt, Me
Me
+
O
N
H
2
O
In recent years attention has been focused particularly on
dihydropyrimidinones (DHPMs) which are an important class of
compounds due to their therapeutic and pharmacological proper-
ties.1 They have emerged as integral backbones of several
calcium channel blockers (e.g., nifedipine), antihypertensive
agents and alpha1-a-antagonists,2 Moreover, alkaloids containing
the dihydropyrimidine unit have been isolated from marine
sources3 and among these are the batzelladine alkaloids which
were found to be potent HIV gp-120-CD4 inhibitors.4 This is an
impressive profile that bodes well for the interaction of this
heterocyclic building block with a variety of biological targets of
interests in medicinal chemistry. Thus synthesis of this hetero-
cyclic nucleus is of continuing interest. The most convenient
Biginelli’s one-pot reaction for the synthesis of DHPMs, first
described more than a century ago1a (1893) and reviewed1b
recently, involves condensation of ꢀ-dicarbonyl compounds with
aldehydes and ureas or thioureas. The reaction is commonly
performed in refluxing ethanolic HCl or THF. However the main
drawback of Biginelli reaction is low yields in case of substituted
aromatic and aliphatic aldehydes5 and sensitive functional groups
are lost during the reaction.6 Several improvements including
combination of Lewis acids with transition metal salts or
BF3ꢁOEt27 or KSF8 or InCl39 and polyphosphate ester10 recently
mediated Biginelli reaction to greatly improve the yield of the
process.11 But the practical application of these methods suffer
from disadvantages such as the use of expensive or less easily
available reagents, vigorous reaction conditions, prolonged
standing or heating at moderately high temperatures and tedious
manipulations in the isolation of the pure products. Consequently
there is a need for the development of protocol using readily
available and safer reagents which lead to high yields of
dihydropyrimidinone derivatives.
4
H2N
NH2
3
Scheme 1.
4 h under nitrogen atmosphere. After completion (monitored by
TLC), the reaction was cooled to room temperature and poured
into water (200 ml). The solid separated was filtered, washed with
water and then recrystallized from isopropanol to afford pure
product 4a, mp 201–202 ꢂC (lit.12 mp 202 ꢂC) in 96% yield.
Similarly other substituted aldehydes, ꢀ-dicarbonyl compound
and urea are reacted together by this procedure to produce the
corresponding dihydropyrimidin-2(1H)-ones. The results are
summarised in the Table 1. Under this condition, the yields were
significantly improved to 80–96% for the classical Biginelli
method, and the reaction time was reduced. A number of
substituted aromatic, aliphatic and heterocyclic aldehydes have
been employed successfully. Acetylacetone has also been
employed with similar success as ethyl acetoacetate. This
condensation procedure is fairly general and several functional-
Table 1. LiBr-mediated synthesis of dihydropyrimidin-2-(1H)-
ones
Reaction
time/h
Entry Product
R
R0
Yielda/%
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
OEt
OEt
OEt
OEt
OEt
OEt
4
4.5
4
4
6
6.5
4
4.5
6
6.5
6
5
90
82
80
83
80
84
85
80
95
85
80
82
80
82
4-(OCH3)C6H4
4-(OH)-C6H4
4-(NO2)-C6H4
3-(NO2)
2,3-(Cl2)-C6H3
3,4-(OCH3)2-C6H3 OEt
4-(Cl)-C6H4
Ph
4-(Cl)-C6H4
PhCH ¼ CH
2-Furyl
Herein we report an efficient advancement of Biginelli
reaction using lithium bromide as promoter for the one-pot
conversion of 1,3-dicarbonyl compound, aldehyde and urea to
dihydropyrimidin-2-(1H)-ones. The reaction is complete within
4–6.5 h, workup is simple, the reagents are readily available, the
yields are excellent and the method is applicable to aliphatic,
aromatic and heterocyclic aldehydes.
In a typical case, a solution of ethyl acetoacetate (1.30 g,
10 mmol), benzaldehyde (1.06 g, 10 mmol) and urea (0.6 g,
10 mmol) in THF (25 ml) was stirred for 5 min at room
temperature. To this solution lithium bromide (1.72 g, 20 mmol)
was added and the resulting mixture was heated under reflux for
OEt
Me
Me
OEt
OEt
OEt
OEt
9
10
11
12
13
14
4j
4k
4l
4m 2-Pyridyl
4n n-Pr
5
6
aYields refer to pure isolated products, characterised by mp
and spectral (IR, 1H NMR, and MS) data.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1039
ities including nitro, chloro, hydroxy, methoxy and conjugated
carbon-carbon double bond do survive during the course of the
reaction. Attempts to perform this reaction using ꢀ-keto aldehyde
in THF for 4 h was fruitless even when a large excess of LiBr was
used under refluxing conditions. Further increase of reaction time
gave no significant improvement, rather decomposition of
starting materials occurred. Also the reaction did not proceed in
the absence of lithium bromide. The reaction proceeds effectively
with AlCl3, or CeCl3, but do not give comparable results to LiBr.
Similarly other salts like KBr or NaBr or LiCl do not give
satisfactory results (yield hardly 30–40%). In case of MgSO4 and
Na2SO4 the reaction does not proceed even after 33 h of refluxing.
Roughly 1.5 equivalent of LiBr was found to be sufficient for
these reactions and use of less than 1.5 equivalent is not optimal
one. The use oflarge amount of LiBris alsofound tobe not fruitful
i.e. it does not increased the yields. All the compounds obtained
were characterised fully by comparison of spectral data (IR, 1H
NMR, Mass) and mp with those of authentic samples. Although
the detailed mechanism of this reaction is not clear at this stage, it
is likely that the reaction may proceed through the acylimine
intermediate formed in situ and the subsequent addition of the ꢀ-
keto ester enolate to the acylimine followed by cyclisation and
dehydration as proposed using Lewis-acids.7;9 Further investiga-
tions of the scope and mechanism of the reaction are under way.
2
a) K. S. Atwal, G. C. Rovnyak, B. C. O’Relly, and J. Schwartz,
J. Org. Chem., 54, 5898 (1989). b) K. S. Atwal, B. N.
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and B. C. O’Relly, J. Med. Chem., 34, 806 (1991). c) G. C.
Rovnyak, K. S. Atwal, A. Hedberg, S. D. Kimball, S.
Moreland, J. Z. Gougoutoy, B. C. O’Relly, J. Schwartz, and
M. F. Malley, J. Med. Chem., 35, 3254 (1992). d) C. O. Kappe,
W. M. F. Fabian, Tetrahedron, 53, 2803 (1997).
3
4
L. E. Overman, M. H. Rabinowitz, and P. A. Renhowe, J. Am.
Chem. Soc., 117, 2657 (1995).
a) A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Ben, A. J.
Freyer, C. DeBrosse, S. Mai, A. Truneh, D. J. Faulkner, B.
Carte, A. L. Breen, R. P. Hertzberg, R. K. Johnson, J. W.
Westley, and B. C. M. Potts, J. Org. Chem., 60, 1182 (1995).
b) B. Snider, J. Chen, A. D. Patial, and A. Freyer, Tetrahedron
lett., 37, 6977 (1996). c) A. V. R. Rao, M. K. Gurjar, and J.
Vasudevan, J. Chem. Soc., Chem. Commun., 1995, 1369.
a) K. Folkers, H. J. Harwood, and T. B. Johnson, J. Am. Chem.
Soc., 54, 3751 (1932). b) S. I. Zavyalov and L. B. Kulikova,
Khim.-Farm. Zh., 126, 116 (1992). c) R. Gupta, A. K. Gupta,
S. Paul, and P. L. Kachroo, Ind. J. Chem., 34B, 151 (1995). d)
E. H. Hu, D. R. Sidler, U. H. Dolling, and M. A. Patane, PCT
Int. Appl. WO 97 21,687 (Cl. C 07 D 239/36) 19 June 1997;
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5
6
7
8
9
For a study of the pH dependence of the reaction see: A. Elison
and Karimullah, Pak. J. Sci. Int. Res., 66, 83 (1967).
E. H. Hu, D. R. Sidler, and U. H. Dolling, J. Org. Chem., 63,
3454 (1998).
F. Bigi, S. Carloni, B. Frullanti, R. Maggi, and G. Sartori,
Tetrahedron Lett., 40, 3465 (1999).
In conclusion the present method employing LiBr for the
synthesis of various dihydropyrimidine-2(1H)-ones provides an
efficient advancement of Biginelli’s reaction. In addition to its
simplicity and selectivity this reaction has one salient feature in its
ability to tolerate a variey of aldhydes and constitute a useful
alternative to the commonly accepted procedures.
B. C. Ranu, A. Hajra, and U. Jano, J. Org. Chem., 65, 6270
(2000).
References
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12 K. Folkers, H. J. Harwood, and T. B. Johnson, J. Am. Chem.
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