Ruthenium(III) chloride-catalyzed one-pot synthesis of 3,4- dihydropyrimidin-2-(1H)-ones under solvent-free conditions

Article abstract of DOI:10.1055/s-2005-869899

Ruthenium(III) chloride efficiently catalyzes the three-component Biginelli reaction of an aldehyde, a β-keto ester, and urea or thiourea under solvent-free conditions to afford the corresponding 3,4-dihydropyrimidine-2-(1H) -ones in excellent yields. Geo

Full text of DOI:10.1055/s-2005-869899

1748
SHORT PAPER
Ruthenium(III) Chloride-Catalyzed One-Pot Synthesis of 3,4-Dihydro-
pyrimidin-2-(1H)-ones under Solvent-Free Conditions
Synthesis of
D
u
ihydropyrim
r
idinones
y
under
S
olve
a
nt-Fre
e
Condition
K
s
. De,* Richard A. Gibbs
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue Cancer Center, Purdue University,
West Lafayette, IN 47907, USA
Fax +1(765)4941414; E-mail: skd125@pharmacy.purdue.edu
Received 4 January 2005
In this communication, we report a simple and efficient
Abstract: Ruthenium(III) chloride efficiently catalyzes the three-
method for the synthesis of dihydropyrimidinones using a
catalytic amount of RuCl3 at 100 °C under solvent-free
component Biginelli reaction of an aldehyde, a b-keto ester, and
urea or thiourea under solvent-free conditions to afford the corre-
conditions. Recently, we have reported that RuCl3 is a
mild Lewis acid for both the acetylation of alcohols16 and
the chemoselective synthesis of acetals from aldehydes.17
The reaction of benzaldehyde and urea with ethyl aceto-
acetate in the presence of a catalytic amount of RuCl3 at
100 °C afforded the desired dihydropyrimidinone in 91%
yield (Scheme 1). We also examined this reaction in dif-
ferent solvents, but the reaction gave better yields under
neat conditions (Table 1). Thus, several activated and de-
activated aromatic aldehydes and aliphatic aldehydes un-
derwent the reaction to give the corresponding
dihydropyrimidinones in good yields. The experimental
procedure is very simple, convenient, and has the ability
to tolerate a variety of other functional groups such as
methoxy, nitro, hydroxy, halides, and olefins under the re-
action conditions. Thiourea was used as one of the ingre-
dients with similar success to provide the corresponding
3,4-dihydropyrimidin-2(1H)-thiones, which are also of
interest with respect to their biological activities. For in-
stance, monastrol (entry 18, Table 2), a mitotic kinesin
Eg5 motor protein inhibitor and a potential anticancer
drug lead, was obtained in 89% yield.18,19 The results have
been summarized in Table 2, which clearly indicates the
generality and scope of the reaction with respect to vari-
ous aromatic, heterocyclic, unsaturated, and aliphatic al-
dehydes.
sponding 3,4-dihydropyrimidine-2-(1H)-ones in excellent yields.
Key words: pyrimidinones, ruthenium, aldehyde, Biginelli reac-
tion, solvent-free conditions, heterocycles
At the beginning of the new century, green chemistry has
become a major driving force for organic chemists to de-
velop environmentally benign routes to a myriad of mate-
rials.1 The possibility of performing multi-component
reactions under solvent-free conditions with solid cata-
lysts could enhance their efficiency from an economic as
well as ecological point of view, so solvent free chemical
reactions have received much attention. These reactions
offer several advantages in preparative procedures, such
as environmental compatibility, simplifying work-up, for-
mation of cleaner products, enhanced selectivity, reduc-
tion of byproducts, a reduction in the waste produced, and
much improved reaction rates.2
Dihydropyrimidinones and their sulfur analogs have been
reported to possess diverse pharmacological properties
such as antiviral, antibacterial, and antihypertensive activ-
ity, as well as efficacy as calcium channel modulators, and
a-1a-antagonists.3–6 The batzelladine alkaloids containing
the dihydropyrimidine core unit are particularly notable,
as they recently were found to be potent HIV gp-120-CD4
inhibitors.7 Therefore, due to the importance of these
compounds as synthons in organic synthesis, many meth-
ods for preparing such compounds have been developed,
and the Biginelli reaction has gained particular impor-
tance for ongoing research programs.8–15 However, many
of these reported methods have drawbacks such as long
reaction times, low yields of products, harsh reaction con-
ditions, the use of stoichiometric reagents, difficulties in
work-up, the use of toxic and inflammable solvents, and
incompatibility with other functional groups in the mole-
cules. Therefore, there is a need to develop new methods
using less hazardous solvents, or even better, those that do
not need solvents at all.
R
EtO2C
O
O
O
RuCl3 (cat.)
100 °C
NH
+
+
RCHO
N
NH2
OEt H2
N
O
H
Scheme 1
We propose a mechanism of the Ru(III)-catalyzed reac-
tion as shown in Scheme 2. The aldehyde reacts with urea
to form an acyl imine intermediate 6, which is activated
by Ru(III). Subsequent addition of the b-carbonyl com-
pound, followed by cyclization and dehydration, affords
the dihydropyrimidinone 4.
In summary, we have developed a simple and efficient
method for the synthesis of dihydropyrimidinones using a
catalytic amount of RuCl3 under solvent-free conditions.
Moreover, the mild reaction conditions, short reaction
SYNTHESIS 2005, No. 11, pp 1748–1750
Advanced online publication: 18.05.2005
DOI: 10.1055/s-2005-869899; Art ID: M00305SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

SHORT PAPER
Synthesis of Dihydropyrimidinones under Solvent-Free Conditions
1749
Table 2 RuCl3-Catalyzed Synthesis of Dihydropyrimidinones and
Thio-Derivatives
R
H
R
OH
O
O
–H2O
RCHO
+
N
NH2
HN
NH2
R
H2N
NH2
+
Ru3
O
R
EtO2C
X
O
O
NH
5
6
(cat.)
RuCl3
100 °C
NH2
+
+
RCHO
R
H2N
OEt
N
X
Ru 3+
O
1
H
3
2
4
EtO2C
–H2O
EtO2C
NH
O
NH
Entry
1
R
X
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Time (min) Yielda (%)
O
O
OEt
N
H
O
H2N
Ph
30
45
40
72
85
50
55
78
40
55
70
45
90
95
50
50
60
65
91
93
87
84
80
90
87
85
92
89
86
90
76
74
86
89
91
89
7
4
2
4-MeOC6H4
4-ClC6H4
Scheme 2
3
4
4-NO2C6H4
4-HOC6H4
4-MeC6H4
3-MeOC6H4
4-NO2C6H4
Table 1 Formation of DHPM in Different Solventsa and Solvent-
Free Conditionsb
5
Entry
Solvent
MeCN
EtOH
Time (h)
Yieldc (%)
6
1
2
3
4
5
6
8
9
78
62
46
25
40
91
7
8
CH2Cl2
H2O
10
6
9
2,4-(OMe)2C6H3
PhCH=CH
1-Naphthyl
2-Furfuryl
n-Pentyl
10
11
12
13
14
15
16
17
18
THF
10
0.5
solvent-free
a Reflux temperature.
b 100 °C.
c Benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (1.5
mmol), and RuCl3 (5 mol%) were used.
n-Hexyl
Ph
3-MeOC6H4
4-ClC6H4
3-HOC6H4
S
times, high yields of the products, ease of work-up, com-
patibility with various functional groups, and the ecologi-
cally clean procedure, will make the present method a
useful and important addition to the present methodolo-
gies for heterocyclic synthesis.
S
S
a Yields refer to isolated products that were characterized by compar-
ison of their mp, IR and 1H NMR spectra with those of authentic sam-
ples.
NMR spectra were recorded on a Bruker ARX 300 (300 MHz) in-
strument. Low resolution MS (CI, EI) were recorded on a Finnigan
4000 mass spectrometer. HRMS (EI, CI, ESI) were recorded on a
Finnigan MAT XL95 mass spectrometer. The reactions were mon-
itored by TLC, and visualized with UV light followed by develop-
ment using phosphomolybdic acid (15%) in EtOH. All solvents and
reagents were purchased from Aldrich in high-grade quality, and
used without any further purification. All yields refer to isolated
products. All products are known and were identified by compari-
son of their spectral data and physical properties with those of au-
thentic samples.3–15
Selected Spectral Data
5-Ethoxycarbonyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydro-
pyrimidin-2(1H)-one (Entry 2, Table 2)
1H NMR (300 MHz, DMSO-d6): d = 1.16 (t, J = 7.2 Hz, 3 H), 2.24
(s, 3 H), 3.76 (s, 3 H), 3.98 (q, J = 7.2 Hz, 2 H), 5.10 (d, J = 3.2 Hz,
1 H), 6.79 (d, J = 8.7 Hz, 2 H), 7.17 (d, J = 8.7 Hz, 2 H), 7.25 (br s,
1 H), 8.94 (br s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 13.8, 17.6, 53.4, 54.7, 58.6,
99.5, 113.3, 127.1, 136.9, 147.5, 152.1, 158.3, 165.2.
General Procedure
MS: m/z = 290 (M+), 261, 217, 155, 77, 42.
A mixture of aldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea
(1.5 mmol), and RuCl3 (5 mol%) was heated with stirring at 100 °C
for an appropriate time (Table 2). After completion of the reaction
(TLC), the reaction mixture was cooled to r.t., and then poured onto
crushed ice (5 g). The solid separated was filtered under suction,
washed with ice-cold H2O. Finally, solid product was recrystallized
from hot EtOH to give the pure product.
5-Ethoxycarbonyl-4-(4-nitrophenyl)-6-methyl-3,4-dihydropy-
rimidin-2(1H)-one (Entry 4, Table 2)
1H NMR (300 MHz, DMSO-d6): d = 1.10 (t, J = 7.2 Hz, 3 H), 2.27
(s, 3 H), 3.98 (q, J = 7.2 Hz, 2 H), 5.29 (d, J = 3.2 Hz, 1 H), 7.51 (d,
J = 9 Hz, 2 H), 7.89 (br s, 1 H), 8.19 (d, J = 9 Hz, 2 H), 9.33 (br s,
1 H).
Synthesis 2005, No. 11, 1748–1750 © Thieme Stuttgart · New York

1750
S. K. De, R. A. Gibbs
SHORT PAPER
5-Ethoxycarbonyl-4-(3-methoxyphenyl)-6-methyl-3,4-dihydro-
pyrimidin-2(1H)-thione (Entry 16, Table 2)
(6) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Mereland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem.
1991, 34, 806.
1H NMR (300 MHz, DMSO-d6): d = 1.13 (t, J = 6.2 Hz, 3 H), 2.28
(s, 3 H), 3.74 (s, 3 H), 4.01 (q, J = 6.2 Hz, 2 H), 5.18 (d, J = 2.8 Hz,
1 H), 6.85 (m, 3 H), 7.28 (t, J = 9 Hz, 1 H), 9.70 (br s, 1 H), 10.37
(br s, 1 H).
(7) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am.
Chem. Soc. 1995, 117, 2657.
(8) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270.
(9) Verala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 67.
(10) Lu, J.; Bai, Y.; Wang, L.; Yang, B.; Ma, H. Tetrahedron
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13C NMR (75 MHz, DMSO-d6): d = 14.3, 17.6, 54.3, 55.3, 59.9,
101.2, 112.8, 118.6, 130.4, 145.2, 145.7, 159.6, 165.3, 174.4.
(11) Reddy, C. V.; Mahesh, M.; Raju, P. V.; Babu, T.; Reddy, V.
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Synthesis 2005, No. 11, 1748–1750 © Thieme Stuttgart · New York