Phenylboronic acid as a mild and efficient catalyst for Biginelli reaction

Article abstract of DOI:10.1016/j.tetlet.2006.06.015

The synthesis of 3,4-dihydropyrimidinone derivatives was achieved in good to excellent yields using phenylboronic acid as catalyst to promote the Biginelli three-component condensation of a diversity of aromatic aldehydes, ethyl acetoacetate and urea or t

Full text of DOI:10.1016/j.tetlet.2006.06.015

Tetrahedron Letters 47 (2006) 5697–5699
Phenylboronic acid as a mild and efficient catalyst for
Biginelli reaction
a,
a
a
a
*
Abdelmadjid Debache, Boudjemaa Boumoud, Mouna Amimour, Ali Belfaitah,
a
b
Salah Rhouati and Bertrand Carboni
a
Laboratoire des produits naturels d’origine v e´ g e´ tale et de synth e` se organique, D e´ partement de Chimie, Facult e´ des Sciences,
Universit e´ Mentouri de Constantine, 25000 Constantine, Algeria
Sciences Chimiques de Rennes, UMR 6226 CNRS-Universit e´ de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
b
Received 14 April 2006; revised 30 May 2006; accepted 2 June 2006
Abstract—The synthesis of 3,4-dihydropyrimidinone derivatives was achieved in good to excellent yields using phenylboronic acid
as catalyst to promote the Biginelli three-component condensation of a diversity of aromatic aldehydes, ethyl acetoacetate and urea
or thiourea.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
Ar
+
Ar CHO
OEt
H2N
3
,4-Dihydropyrimidinones (DHPMs) constitute a very
PhB(OH)2
1
2
EtO
NH
important class of organic compounds due to their
attractive pharmacological properties, including anti-
viral, antitumour, antibacterial activities. The dihydro-
pyrimidinone core is also found in many natural
products that explained the important efforts devoted
X
CH CN, Δ
3
N
H
X
+
NH2
4
3
1
to the synthesis of these heterocycles. The one-pot,
Scheme 1.
three-component Biginelli condensation provides cer-
tainly the most efficient access to DHMP derivatives
due to its atom economy feature and the availability
and the diversity of the building blocks engaged in this
reaction (Scheme 1). In the past few years, the Biginelli
reaction has received renewed interest and several im-
7
ported catalysts. The use of two boron compounds,
Et OBF in the presence of CuCl and acetic acid in
2
3
8
refluxing THF and boric acid in glacial acetic at
100 °C has also been reported. Two asymmetric synthe-
ses using CeCl /InCl or Yb(OTF) in the presence of
9
2
proved procedures have been reported. There is a vari-
3
3
3
1
0,11
ety of suitable reaction conditions, traditionally with
strong Brønsted acid, but nowadays, more frequently,
with Lewis acids, such as LiClO , LaCl –7H O, InCl ,
chiral ligands were recently investigated.
4
3
2
3
Boronic acids are effective catalysts for several organic
transformations, such as Mukayama aldol condensation
or amidation of carboxylic acids with amines, for exam-
ple. The synthetic interest of these catalysts is greatly en-
hanced by the possible use of chiral derivatives, such as
acyloxyboranes or alkyldichloroboranes. They have
been successfully applied to asymmetric Diels Alder cyclo-
additions or enantioselective allylation reactions. To
our knowledge, neither boronic acid nor its derivatives
have been hitherto tested as catalysts in the Biginelli
reaction.
Bi(OTf) , BiCl , Mn(OAc) , Cu(OTf) , FeCl –6H O,
3
3
3
2
3
2
3
ZrCl or SnCl Æ2H O, for example. Other works have
been devoted to the use of ionic liquids, microwave
irradiation, solid phase reagents, and polymer-sup-
4
2
2
4
5
6
1
2
Keywords: Biginelli; Boronic acid; 3,4-Dihydropyrimidinone; Three-
component condensation.
*
Corresponding author. Tel./fax: +213 31 61 46 22; e-mail: bertrand.
carboni@univ-rennes1.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.015

5698
A. Debache et al. / Tetrahedron Letters 47 (2006) 5697–5699
Table 1. Phenylboronic acid catalysed synthesis of dihydropyrimidinones 4
Entry
Product
Ar
X
Yields (%)
Mp (°C) [Lit.]
8
8
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
C
6
H
5
O
O
O
O
O
O
O
O
O
O
S
87
76
80
78
97
91
70
75
75
82
60
75
200–202 [202–204]
195–196 [193–195]
>300
6 4
3-Cl–C H
3,5-Cl
3,4-Cl
4-MeO–C
4-HO–C H
4-Me–C
3-Me–C
3-NO
2-Thienyl
6 5
C H
4-MeO–C
2
–C
–C
6
H
3
2
6
H
3,5
>300
8
1
1
1
1
1
1
1
6
H
4
202–203 [201–203]
198–200 [198–200]
213–214 [215–216]
204–205 [207–208]
227–228 [229–231]
207–208 [207–208]
204–205 [206–207]
150–152 [150–152]
3
4
5
4
6
6
4
6
4
4g
4h
4i
6
H
H
4
6
4
2
–C
6
H
4
1
1
1
0
1
2
4j
4k
4l
6
H
4
S
NH2
O
sponding 3,4-dihydroxypyrimidinone was formed in
very low yield (20%) that was currently observed in
the classical Biginelli reaction conditions.
H
NH2
H
H N
2
Ph
N
O
Ph
O
PhB(OH)2
H
These results suggest a mechanism wherein the in situ
acylimine intermediate, generated from the aldehyde
and urea, is activated, either by protonation or
coordination with boron, the phenyl boronic acid being
able to act as a Lewis or a Brønsted acid.1 It was
followed by the addition to the boron enolate derived
NH2
H
NH2
or Ph
N
O
Ph
N
H
O
2
.
PhB (OH)2
1
7
from ethyl acetoacetate, cyclisation and dehydration
(Scheme 2).
O
O
PhB(OH)2
B
O
O
OR
O
In conclusion, we have developed a simple and efficient
method for a one-pot three-component synthesis of 3,4-
dihydropyridiminone derivatives using phenylboronic
acid as catalyst in refluxing acetonitrile and neutral
media. Further studies to confirm our mechanistic
hypothesis and to extend these results to chiral organo-
boranes derivatives are underway.
OR
Ph
O
Ph
O
O
-
H2O
RO
NH
RO
N
H
NH2
N
H
O
Scheme 2.
2. Experimental
General procedure for the synthesis of 3,4-dihydropyr-
imidinones 4. A solution of ethyl acetoacetate 1
(2 mmol), aldehyde 2 (2 mmol), urea 3 (3 mmol) and
phenylboronic acid (0.2 mmol) in acetonitrile (10 ml)
was heated under reflux for 18 h. The reaction mixture
was poured into crushed ice with stirring. The crude
product was filtered, washed with 95% ethanol, dried
and recrystallised from hot ethanol to give 4. All com-
In the following, we report our preliminary investiga-
tions dealing with the use of a boronic acid, PhB(OH)2,
a commercially available, nontoxic and cheap reagent,
as catalyst in these synthetically useful three-component
condensation (Scheme 1).
The optimised conditions utilise a 1:1:1.5:0.1 ratio of
ethyl acetoacetate 1, aldehyde 2, urea 3 and phenyl-
boronic in acetonitrile as solvent at reflux temperature
1
13
pounds are fully characterised by mp, IR, H and
C
spectroscopy.
(
Table 1). Aromatic aldehydes carrying either electron-
donating or electron-withdrawing substituents afforded
high yields of products (entries 1–9). Acid sensitive
aldehydes, such as 2-thiophenecarboxaldehyde, reacted
without the formation of any side product and gave
the 3,4-dihydropyrimidinone derivative in 82% yield
Selected data for 4e: 5-Ethoxycarbonyl-4-(4-methoxy-
phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one. Mp:
202–203 °C; IR (KBr): 3246, 3111, 2985, 2956, 2931,
1
1730, 1703, 1651, 1514. H NMR (DMSO-d
): d 9.14
6
(s, 1H, NH); 7.67 (s, 1H, NH); 7.15 (d, J = 8.6 Hz,
(
entry 10). Thiourea has also been frequently employed
2H); 6.88 (d, J = 8.7 Hz, 2H); 5.10 (d, J = 3.2 Hz, 1H);
to provide the 3,4-dihydropyrimidinethiones. In our
experimental conditions, the cyclisation took place in
moderate to good yields (entries 11 and 12). With
3.98 (q, J = 7.1 Hz, 2H, OCH
1.10 (t, J = 7.1 Hz, 3H, CH
165.8; 158.8; 152.6; 148.4; 137.4; 127.8; 114.1; 100.0;
59.6, 55.4; 53.7; 18.1; 14.5.
2
); 3.74 (s, 3H, OCH
3
);
1
3
). C (DMSO-d
): d
3
6
2
-methylpropanal, an aliphatic aldehyde, the corre-

A. Debache et al. / Tetrahedron Letters 47 (2006) 5697–5699
5699
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