Novel Biginelli-like three-component cyclocondensation reaction: Efficient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2004.08.107

Iron (III) catalyzed the three-component Biginelli-like cyclocondensation reaction efficiently in acetonitrile to afford the corresponding 5-unsubstituted 3,4-dihydropyrimidin-2-(1H)-ones in high yields. The first Biginelli-like reactions of urea, aldehyd

Full text of DOI:10.1016/j.tetlet.2004.08.107

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7951–7953
Novel Biginelli-like three-component cyclocondensation
reaction: efficient synthesis of 5-unsubstituted
3,4-dihydropyrimidin-2(1H)-ones
a,
a,
*
Zong-Ting Wang,a,b Li-Wen Xu,a,* Chun-Gu Xia and Han-Qing Wang
*
aState key laboratory of Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, PR China
bDepartment of Applications Chemistry, University of Petroleum (East China), Dongying, Shandong 257062, PR China
Received 9 July 2004; revised 17 August 2004; accepted 19 August 2004
Available online 11 September 2004
Abstract—Iron (III) catalyzed the three-component Biginelli-like cyclocondensation reaction efficiently in acetonitrile to afford the
corresponding 5-unsubstituted 3,4-dihydropyrimidin-2-(1H)-ones in high yields. The first Biginelli-like reactions of urea, aldehydes
and ketones were furnished important new 3,4-dihydropyrimidin-2-(1H)-ones derivatives suitable for further study.
Ó 2004 Elsevier Ltd. All rights reserved.
O
There is considerable current interest in the Biginelli
reaction, because 3,4-dihydropyrimidin-2-(1H)-ones
and their derivatives have attracted great attention
recently in synthetic organic chemistry due to their
pharmacological and therapeutic properties such as
antibacterial and antihypertensive activity as well as
behaving as calcium channel blockers, a-1a-antagonists
and neuropeptides Y (NPY) antagonists.1 The Biginelli
reaction is one of the multicomponent reactions (MCRs)
and the most important procedures for the synthesis of
3,4-dihydropyrimidin-2-(1H)-ones. In general, Biginelli
reactions are simple one-pot but low-yielding condensa-
tions of b-dicarbonyl compounds with aldehydes and
urea, and strong acids and Lewis acids such as BF3ÆOEt2,
LaCl3, La(OTf)3, Yb(OTf)3, InX (X = Cl, Br), ZrCl4,
BiCl3, LiClO4, etc. have been employed for this transfor-
mation (Scheme 1).2,3 However, many of these reagents
or catalysts are expensive, harmful and difficult to handle
especially on a large scale.
Ph
O
EtO
FeCl3.6H2O
NH
CH3COCH2COOEt
H2N
NH2
PhCHO/CH3CN
O
N
H
89%
Scheme 1. Biginelli reaction catalyzed by FeCl3Æ6H2O.
ambient temperature. In continuation of interest in
the use of Lewis acid catalyst or reagent4 and our inter-
est in the preparation of new 3,4-dihydropyrimidin-2-
(1H)-ones derivatives led us to attempt the extension
of this versatile reaction to other substrates.
At first, we found the Biginelli reaction of acetoacetate,
benzylaldehyde and urea could be catalyzed by FeCl3Æ
6H2O in the absence of any additives, and the desired
product was obtained in high yield under reflux for 3h
(89%). The good results prompted us to investigate
new substrate for the extension of this versatile Biginelli
reaction Leading directly to 5-unsubstituted 3,4-dihydro-
pyrimidin-2(1H)-ones. At present, there are few articles
describing the synthesis of certain 5-unsubstituted 3,4-
dihydropyrimidin-2(1H)-ones.5 And previous reported
methods have typically accomplished the synthesis of
5-unsubstituted dihydropyrimidinones in a multistep
fashion via the saponification of the C-5 ester on the
preassembled pyrimidinone followed by thermal decarb-
oxylation.6,7 These harsh and inefficient methods have
Previous reported protocols normally required pro-
longed reaction times and high temperature with moder-
ate yields, so there has been considerable interest to
explore mild, rapid, and higher yielding protocol at
Keywords: Three component; Biginelli-like reaction; Cyclocondensa-
tion; One pot; Iron.
*
Corresponding authors. Tel.: +86 931 4968056; fax: +86 931
8277088; e-mail: liwenxulicp@hotmail.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.107

7952
Z.-T. Wang et al. / Tetrahedron Letters 45 (2004) 7951–7953
Table 1. Iron catalyzed three-component Biginelli-like cycloconden-
sation reaction9
R1
O
Entrya
Aldehydes
Ketones
Yieldb/%
82
CHO
urea/FeCl3
reflux
R1
NH
R2
CHO
O
1
N
O
R2
H
O
O
CHO
CHO
Scheme 2. Biginelli-like reaction.
2
3
0c
86
resulted in low-yielding transformations and multiple
side products.
O
O
CHO
4
5
83
The use of ketones gave us the opportunity to prepare
corresponding new 5-unsubstituted 3,4-dihydropyrimi-
din-2-(1H)-ones derivatives (Scheme 2). And the Bigin-
elli-like reactions of ketones with single carbonyl
group provide a useful 5-unsubstituted 3,4-dihydropyri-
midin-2-(1H)-ones. Herein we continued to describe a
simple and efficient protocol for the Biginelli-like
three-component cyclocondensation reactions of alde-
hydes, ketones and urea for the synthesis of 5-unsubsti-
tuted 3,4-dihydropyrimidin-2-(1H)-ones using very
cheap FeCl3Æ6H2O under mild conditions.
H3C
CHO
CHO
88
86
Cl
O
6
O2N
H3CO
O
CHO
Cl
7
8
78
85
O
CHO
Cl
Cl
H3CO
O
In the primary study, we found only FeCl3Æ6H2O used as
catalyst in this reaction gave few products. However, the
addition of TMSCl accelerated the Biginelli-like reac-
tion and gave good results. For example, the TMSCl-
mediated Biginelli-like reaction of acetophenone, benz-
aldehyde, and urea gave corresponding product in high
yield at reflux for 12h (Table 1, entry 1). The role of
TMSCl is not completely understood, it may be ex-
plained in terms of hard–soft acid, which activates the
carbonyl group (ketone).8
CHO
9
89
75
O
CHO
Cl
10
O
O
CHO
11
81
O
a Reaction conditions: aldehyde (1mmol), urea (1.5mmol), and
ketones (1mmol) in CH3CN (3mL), FeCl3Æ6H2O (0.1mmol), TMSCl
(1mmol), reflux, 12h.
Then the Biginelli-like reactions of other various alde-
hydes and ketones were general run under established
protocol wherein we used a 1:1:1.5 ratio of ketones,
aldehyde, and urea, respectively. After the completion
of the reaction, as indicated by TLC, and the crude
products were directly filtrated through a sintered
funnel. The crude product was further purified by
recrystallization (EtOH) to afford products as indicated
in Table 1. In all cases studied, the three-component
reaction proceeded smoothly to give the corresponding
5-unsubstituted 3,4-dihydropyrimidin-2-(1H)-ones in
high yields. Especially, aromatic aldehydes carrying
either electron-donating or electron-withdrawing substi-
tutents reacted efficiently to give good yields. Although
TMSCl was used as additive, the three-component
cyclocondensation products were generally obtained in
good yields under mild conditions.
b Isolated yield.
c At room temperature.
lyzed by FeCl3Æ6H2O but also extend the utility of ke-
tones in Biginelli reactions.
Acknowledgements
This work was financially supported in part by the
Natural Science Founder of China (29933050 and
20373082).
References and notes
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three-component cyclocondensation reaction to ketones
other than activated b-dicarbonyl compounds (acetoace-
tate) for the synthesis of interesting 5-unsubstituted 3,4-
dihydropyrimidin-2-(1H)-ones. These results not only
provide a new aspect of catalytic organic reaction cata-
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