A one-pot Biginelli synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones catalyzed by triphenylphosphine as Lewis base

Article abstract of DOI:10.1016/j.tetlet.2008.08.016

We report herein the use of triphenylphosphine (TPP) as a new catalyst for the one-pot Biginelli reaction coupling of β-ketoesters, aldehydes and urea (or thiourea) to afford the corresponding dihydropyrimidinones/thiones.

Full text of DOI:10.1016/j.tetlet.2008.08.016

Tetrahedron Letters 49 (2008) 6119–6121
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A one-pot Biginelli synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones
catalyzed by triphenylphosphine as Lewis base
a
a
a
b
Abdelmadjid Debache a, , Mouna Amimour , Ali Belfaitah , Salah Rhouati , Bertrand Carboni
*
a Laboratoire des Produits Naturels D’origine Végétale et de Synthèse Organique, Faculté des Sciences, Université Mentouri de Constantine, 25000 Constantine, Algeria
b Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the use of triphenylphosphine (TPP) as a new catalyst for the one-pot Biginelli reaction
coupling of b-ketoesters, aldehydes and urea (or thiourea) to afford the corresponding dihydropyrimid-
inones/thiones.
Received 7 June 2008
Revised 29 July 2008
Accepted 5 August 2008
Available online 8 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
3,4-Dihydropyrimidinones/thiones
Biginelli reaction
Triphenylphosphine
Multicomponent reaction
In 1893, Petro Biginelli reported the first synthesis of 3,4-dihy-
dropyrimidin-2(1H)-one (DHPM) of type 4 by a very simple one-
pot condensation reaction of an aromatic aldehyde 1, b-ketoesters
2 and urea 3 under strongly acidic conditions.1 However, this
protocol often provides only low to moderate yields of the desired
target molecules.
ing CeCl3/InCl3 or Yb(OTF)3 in the presence of chiral ligands have
been investigated recently.21,22 Further, aluminium hydrogen sul-
fate Al(HSO4)3 and potassium hydrogen sulfate KHSO4 were ap-
plied with success as a source of both protic and metallic Lewis
acids.23,24 Many combinatorial approaches towards DHPMs have
been advanced using solid phase25 or fluorous phase26 reaction
conditions. Several improved procedures have been reported using
heteropoly acids27 such as H3PW12O40, H3PMo12O40, H3PMo11VO40
and propane phosphoric acid.28 On the other hand, this condensa-
tion was found to be equally effective when Lewis acids were
replaced by a strong Brönsted base (KOH), but in this case the
reaction involves two steps.29
In recent years, interest in these compounds has increased rap-
idly, mainly due to the apparent structural similarity of DHPMs to
the well-known dihydropyridine calcium channel modulators of
the Hantzsh type.2 In addition, several alkaloids containing the
dihydropyrimidine core unit, exhibiting interesting biological
properties, have been isolated from marine source.3–5 Among these
the crambine3 and batzelladine alkaloids4 were found to be potent
HIVgp-120-CD4 inhibitors. The scope of this pharmacophore has
been increased further by the identification of the 4-(3-hydroxy-
phenyl)-2-thione derivative ( )-4i called monastol,6 as a novel
cell-permeable lead molecule for the development of anticancer
drugs. Due to the importance of the Biginelli reaction products,
much work on improving the yields and reaction conditions has
been actively pursued. For example, modification and improve-
ments include using Lewis acids such as BF3ÁOEt2,7 FeCl3 and
HCl,8 LaCl3Á7H2O,9 La(OTf)3,10 Yb(OTf)3,11 ZrCl4,12 BiCl3,13
As part of our continued interest in the Biginelli reaction,30 we
report here our preliminary investigation dealing with the use of
triphenylphosphine as a Lewis base catalyst under neutral condi-
tions preserving the simplicity of Biginelli’s one-pot reaction
(Scheme 1).
Ar
O
O
Ar
R
H
O
1
PPh3
R
NH
+
NH2
X
Solvent-free, 100 °C
Mn(OAc)3,14 LiClO4,15 H3BO3 and polyphosphorate ester.17 Many
16
O
Me
N
H
X
H2N
other synthetic methods for preparing these compounds have been
reported including classical conditions with microwave18 and
ultrasound irradiation.19,20 Also, two asymmetric syntheses utiliz-
Me
4
3
2
R=OEt, CH3
X=O, S
* Corresponding author. Tel./fax: +213 31 81 88 62.
E-mail address: a_debache@yahoo.fr (A. Debache).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.016

6120
A. Debache et al. / Tetrahedron Letters 49 (2008) 6119–6121
Table 1
O
O
H
O
H
TPP-catalyzed synthesis of DHPM 4 in different solventsa and under solvent-free
conditions at 100 °Cb
Ar
O
R
O
O
H
Me
R
-H2O Ar
N
Ar
H
+
H
H2N
X
+
+
Entry
Solvent
Amount of TPP (mol %)
Time (h)
Yield (%)
Me
O
NH2
X
TPP
H
1
2
3
4
5
6
7
8
Ethanol
Dioxane
Toluene
MeCN
Solvent-free
Solvent-free
Solvent-free
Solvent-free
10
10
10
10
10
15
20
5
18
18
18
18
10
10
10
10
Trace
Trace
25
H2N
Ar
TPP
16
35, 54c
31
O
Ar
O
Ar
NH
28
10
-H2O
R
NH
X
R
Me
X
Me
N
O
H2N
a
H
Reflux temperature.
2-Thiophenecarboxaldehyde/ethyl acetoacetate/urea, 1:1:1.5.
2-Thiophenecarboxaldehyde/ethyl acetoacetate/urea, 1:1.25:1.25.
b
c
Scheme 2.
through acylimine formation between an aldehyde and urea. Sub-
sequent addition of the enolate of the b-keto-ester to the acylimine
followed by cyclodehydration would afford dihydropyrimidinone-
(1H)-one 4. The b-ketoester enolate31 can be formed by coordinat-
ing the aldehyde with TPP which promotes deprotonation of the
b-ketoester (Scheme 2).
In summary, we have described a novel method for the prepa-
ration of substituted dihydropyrimidinones catalyzed by triphen-
ylphosphine (TPP) as Lewis base under neutral and solvent-free
conditions. Moderate to good yields of the corresponding DHPM
were obtained from readily available starting materials. Further
studies to confirm our mechanistic hypothesis and to extend these
results to others Lewis bases and chiral trialkylphosphines deriva-
tives are underway.
General procedure for the preparation of 3,4-dihydropyrimidinon-
es/thiones 4: A mixture of aldehyde 1 (2 mmol), ethyl acetoacetate
2 (2.5 mmol), urea/thiourea 3 (2.5 mmol) and triphenylphosphine
(0.2 mmol) was heated with stirring at 100 °C for 10 h. After cool-
ing, the reaction mixture was poured into crushed ice with stirring.
The crude product was filtered, washed with cold water, dried and
recrystallized from 95% ethanol or ethyl acetate to give pure prod-
ucts 4 (42–70%). All compounds were fully characterized by mp, IR,
1H and 13C NMR spectroscopy.
We started our study of the three-component Biginelli conden-
sation using TPP as the catalyst (Scheme 1), by examining the con-
ditions for the reaction using 2-thiophenecarboxaldehyde, ethyl
acetoacetate and urea to afford the corresponding DHPM product
(Table 1).
We first examined the reaction in different solvents including
acetonitrile, ethanol, dioxane, toluene and solvent-free at 100 °C.
The best results were obtained under solvent-free conditions
(entry 5).
Next, we optimized the amount of TPP required (entries 5-8)
and the optimum amount was found to be 10 mol %.
Finally, in order to improve the yields, we performed the reac-
tions using different quantities of reagents. The best results were
obtained with a 1:1.25:1.25:0.1 ratio of 2-thiophenecarboxalde-
hyde, urea, b-ketoester and TPP, respectively.
In order to investigate the scope of these conditions, several
examples were studied and are summarized in Table 2. In all cases,
the three-component reaction proceeded smoothly to give the cor-
responding 3,4-dihydropyrimidin-2(1H)-ones/thiones in moderate
to good yields (entries 1–12). The reaction with both aromatic
aldehydes carrying electron-donating substituents (entries 1–6)
and heteroaromatic aldehyde (entry 8) gave the corresponding
DHMP products in good yields and in high purity (purity was
determined by 1H NMR analysis). However, the yield decreased
significantly in the reaction involving cinnamaldehyde (entry 7).
In a similar manner, thiourea and 2,4-pentandione were also used
to provide the corresponding Biginelli products in moderate yields
(entries 9–12).
5-Ethoxycarbonyl-4-(2-methoxyphenyl)-6-methyl-3,4-dihydropyr-
imidin-2(1H)-one 4c: Mp: 255–257 °C. IR (KBr)
mmax: 3240, 3117,
2960, 1693, 1643, 1514, 1462 cmÀ1 1H NMR (DMSO-d6): dH 9.14
.
(1H, br s, NH), 7.31 (1H, br s, NH), 7.24 (1H, m, CH), 7.05 (1H, d,
3J = 6.2 Hz, CH), 6.99 (1H, d, 3J = 8.2 Hz, CH), 6.88 (1H, m, CH),
5.49 (1H, d, 3J = 2.9 Hz, CH), 3.92 (2H, q, 3J = 7.1 Hz, OCH2) , 3.94
(3H, s, OCH3), 2.28 (3H, s, CH3), 1.03 (3H, t, 3J = 7.1 Hz, CH3). 13C
NMR (DMSO-d6): dC 165.8, 156.9, 152.6, 149.3, 132.0, 129.1,
127.5, 120.6, 111.5, 98.0, 59.4, 55.7, 49.3, 18.1, 14.4. HRMS (EI)
calcd for C15H18N2O4 [M]+.: 290.12666, found: 290.1276.
Unlike most of the reported methods, under the present reac-
tion conditions, aromatic aldehydes carrying either electron-with-
drawing substituents such as Cl and Br afforded a mixture of
bisureide and DHPM products, while nitrobenzaldehyde gave only
the corresponding bisureide product. The reaction may proceed
Table 2
TPP-catalyzed synthesis of dihydropyrimidinones/thiones 4
Entry
Product
Ar
R
X
Yielda (%)
Mp (°C)
Found
Lit.
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
O
O
O
O
O
O
O
O
O
O
S
70
58
51
62
66
55
38
54
62
58
50
42
200–202
202–203
255–257
216–217
208–209
225–226
223–225
213–214
234–235
168–170
202–204
191–193
202–20432
202–20432
—
4-(MeO)–C6H4
2-(MeO)–C6H4
4-(Me) –C6H4
3-(Me)–C6H4
4-(HO)–C6H4
C6H5CH@CH
2-Thienyl
C6H5
4-(MeO)–C6H4
C6H5
215–21632
207–20833
227–22834
225–22732
215–21732
233–23611
166–16836
206–20735
192–19432
10
11
12
4j
4k
4l
Me
OEt
OEt
4-(Me)–C6H4
S
a
Isolated yields.

A. Debache et al. / Tetrahedron Letters 49 (2008) 6119–6121
19. Li, J. T.; Ham, J. F.; Yang, J. H.; Li, T. S. Ultrason. Sonochem. 2003, 10, 119.
6121
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