One-pot construction of dihydropyrimidinones in ionic liquids

Article abstract of DOI:10.1070/MC2004v014n05ABEH001895

The use of the ionic liquid [bmim]Cl·2AlCl₃ for the preparation of dihydropyrimidinones is described.

Full text of DOI:10.1070/MC2004v014n05ABEH001895

,
2004, 14(5), 210–212
One-pot construction of dihydropyrimidinones in ionic liquids
a
b
b
Sushilkumar S. Bahekar, Sandip A. Kotharkar and Devanand B. Shinde*
a
Department of Chemistry, National Cheng Kung University, Tainan-701, Taiwan, R.O.C.
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS) – 431004, India.
b
Fax: +091 240 401833; e-mail: ssbahekar@rediffmail.com
DOI: 10.1070/MC2004v014n05ABEH001895
The use of the ionic liquid [bmim]Cl·2AlCl for the preparation of dihydropyrimidinones is described.
3
In 1893, the Italian chemist Pietro Biginelli reported that the
acid-catalysed one-pot cyclocondensation of ethyl acetoacetate,
benzaldehyde and urea gave multifunctionalised dihydro-
or the development of novel but more complex multistep
strategies.1
1–14
In addition, several combinatorial solid-phase
approaches have been reported that use microwave condi-
1
15,16
pyrimidones (DHPMs). After nearly 100 years, a resurgence
tions.
of interest occurred as evidenced by an increase in the number
The Biginelli synthesis is an example of the use of less toxic
chemicals. Thus, the use of catalysts that contain both Lewis
2
–4
of publications and patents on both the synthesis
and
biological activity5 of these compounds. Antiviral, antitumor,
antibacterial, potent calcium channel blocking and anti-
inflammatory activities were ascribed to DHPMs. However, the
Biginelli synthesis of DHPMs suffers from relatively low yields
of products, in particular, when substituted aromatic aldehydes
–10
acid and transition metal salts, e.g., BF –OEt , montmoril-
17
3
2
1
8
19
lonite(KSF), polyphosphate ester and reagents such as
InCl3,20 LiBr, CeCl ·H O and Mn(OAc) ·2H O gave better
21
22
23
3
2
3
2
yields of DHPMs.
Ionic liquids are environmentally benign alternative solvents
for various chemical processes. They have attracted the atten-
3
,11–14
or thioureas are employed.
This has led to the recent dis-
closure of several improved synthetic protocols for DHPMs,
tion of chemists owing to their unique physical and chemical
which involve either modification of the Biginelli synthesis11
properties.
24,25
Because of their low vapour pressure, ionic
2
10 Mendeleev Commun. 2004

,
2004, 14(5), 210–212
a
Table 1 Dihydropyrimidinones 4a–s produced according to Scheme 1.
R1
R2
X
t/min
Yield (%)
b
Found mp /°C
c
Reported mp/°C
Entry
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
4-NO C H
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
80
90
75
50
60
70
90
80
55
80
60
45
60
90
70
60
75
80
90
97
95
94
98
92
95
94
89
90
93
97
90
91
96
88
96
87
95
91
231–232 (decomp.)
268–270 (decomp.)
151–152
235–236
239–240 (decomp.)
237–239
210–213
226–228
184–186
173–175
194–196
205–207
227–229
202–204
214–216
179–183
185–186
209–212
230 (decomp.)13
2
6
4
4
3
3
1
1
3-NO C H
267–269 (decomp.)
2
6
3
1
1
3
Pr
Ph
152–154
235–236
3-NO C H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
240–241 (decomp.)
2
6
4
4
2
1
3
3
3
1
2
2
3
2
9
3
2
1
1
3
3
3
1
3
4-NO C H
235–237
209–216
226–229
184–185
174–175
191–193
203–205
227–228
201–202
214–215
2
6
Ph
2-ClC H
6
4
Et
Pr
4-MeOC H
6
4
Ph
3-NO C H
2
6
4
4-NO C H
2
6
4
2-ClC H
6
4
2
3
Et
179
2
1
3
3
3
2
Me CHCH
185–186
207–210
208–210
2
2
4-MeOC H
6
4
Ph
209–211
a
1
13
b
All compounds are characterised by IR, H and C NMR spectroscopy and mass spectrometry. The optimised yield is based on the crystalline product
c
obtained. Melting points are uncorrected.
species do not contribute to volatile organic compound emis-
R1
O
sion. They have also been referred to as ‘designer solvents’26
since their properties can be altered by the fine tuning of
parameters such as the choice of the organic cation, inorganic
anion and alkyl chain attached to the organic cation. These
structural variations provide an opportunity to devise the most
idealised solvent needed for a particular chemical process. Several
O
O
O
X
R2
NH
R2
R1
H
H N
2
NH2
X
N
H
1
2
3
4
Scheme 1
2
7
reactions have been carried out in ionic liquids including the
Biginelli, Diels–Alder, Wittig and Pechman reactions, the benzoin
5-Methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-3,4-dihydropyrimidin-
1
2
condensation, catalytic hydrogenation and several enzyme cata-
2(1H)-one 4e: mp 239–240 °C (decomp.). H NMR ([ H ]DMSO,
6
lysed reactions.28
300 MHz) d: 9.31 (s, 1H, NH), 8.09–8.13 (m, 2H, Ar–H), 7.85 (s, 1H,
NH), 7.63–7.70 (m, 2H, Ar–H), 5.31 (d, 1H, H-4, J 3.0 Hz), 3.35 (s, 3H,
COOMe, J 3.0 Hz), 2.28 [s, 3H, C(6)–Me]. C NMR, d: 165.5, 151.7,
149.6, 147.8, 146.6, 132.8, 130.1, 122.3, 120.8, 98.0, 53.3, 50.8, 17.8.
IR (KBr, n/cm ): 3358, 3244, 3102, 2957, 1701, 1641. MS (70 eV, EI),
Chloroaluminate ionic liquids have been used in Friedel–
Crafts and other reactions where they play the dual role of both
1
3
2
7
the Lewis acid catalyst and the solvent. Thus, we decided to
investigate the Biginelli synthesis under these conditions. Here
we report a new synthesis of DHPMs in the presence of the
–
1
+
m/z: 291 (M , 5.86%).
5
-Methoxycarbonyl-4-(2-chlorophenyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one 4h: mp 226–228 °C. H NMR ([ H ]DMSO, 300 MHz) d:
.21 (s, 1H, NH), 7.59 (s, 1H, NH), 7.25–7.40 (m, 4H, Ar–H), 5.62 (d,
1H, H-4, J 2.5 Hz), 3.45 (s, 3H, COOMe), 2.30 [s, 3H, C(6)–Me].
13C NMR, d: 165.4, 151.3, 149.3, 141.4, 131.6, 129.4, 129.0, 128.6,
127.6, 97.6, 51.3, 50.6, 17.6. IR (KBr, n/cm ): 3367, 3221, 3103, 2948,
Lewis acid [bmim]Cl·2AlCl ionic liquid.
1
2
3
6
The composition of ionic liquids is expressed as the apparent
9
mole fraction of AlCl , N. Accordingly, they are classified as
3
basic, neutral and acidic liquids when N is 0–0.5, 0.5 and
–
1
0
.5–0.67, respectively. The reaction of (thio)ureas, aldehydes
+
and α-ketoesters was carried out in liquids with N = 0.33, 0.5
and 0.67, respectively. Positive results were obtained only in
case of acidic ionic liquids as expected.
1714, 1698. MS (70 eV, EI), m/z: 280 (M , 5.13%).
5-Methoxycarbonyl-4-ethyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one
i: mp 184–186 °C. H NMR ([ H ]DMSO, 300 MHz) d: 8.96 (s, 1H,
NH), 7.30 (s, 1H, NH), 4.01 (m, 1H, H-4), 3.59 (s, 3H, COOMe), 2.16
s, 3H, C(6)–Me], 1.39 (q, 2H, CH Me, J 7.5 Hz), 0.77 (t, 3H, CH Me,
J 7.5 Hz). C NMR, d: 165.9, 152.7, 148.6, 98.5, 51.3, 50.7, 29.5, 17.7,
.4. IR (KBr, n/cm ): 3249, 3118, 2961, 1728, 1708, 1680. MS (70 eV,
EI), m/z: 198 (M , 0.59%).
-Methoxycarbonyl-4-propyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one
1
2
4
6
In order to study the effect of substituents on the reactivity
of the reactants, a variety of aliphatic and aromaic aldehydes
[
2
2
1
3
†
were used. The results are given in Table 1. In comparison
–
1
8
2
9
with reported procedures, the reaction time for the complete
+
5
†
1
2
The purity of compounds was checked by TLC. The IR spectra were
4j: mp 173–175 °C. H NMR ([ H ]DMSO, 300 MHz) d: 8.94 (s, 1H,
6
recorded on a JASCO spectrophotometer (Japan) using KBr pellets. The
NH), 7.31 (s, 1H, NH), 4.03 (t, 1H, H-4, J 3.2 Hz), 3.59 (s, 3H,
COOMe), 2.15 [s, 3H, C(6)–Me], 1.19–1.40 (m, 4H, CH CH Me), 0.82
1
13
H and C NMR spectra in CDCl were measu red on a FT-NMR
3
2
2
1
3
spectrophotometer model Ac-300 F (Bruker, Germany) at 300 MHz using
TMS as an internal standard. Satisfactory microanalysis data (±0.4% of
calculated values) were obtained for all the compounds.
(t, 3H, CH CH Me, J 6.7 Hz). C NMR, d: 165.8, 152.6, 148.3, 99.1,
2 2
–
1
50.6, 49.8, 17.6, 16.9, 13.6. IR (KBr, n/cm ): 3442, 3252, 3123, 2957,
1726, 1708, 1653. MS (70 eV, EI), m/z: 212 (M , 0.43%).
+
Typical experimental procedure. To a stirred mixture of urea or thio-
urea (2.6 mmol), an appropriate α-ketoester (2 mmol) and an aldehyde
5-Ethoxycarbonyl-4-ethyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4p:
1
2
mp 185–186 °C. H NMR ([ H ]DMSO, 300 MHz) d: 8.82 (s, 1H, NH),
6
(
2 mmol), the ionic liquid [bmim]Cl·2AlCl (11 mmol) was added, and
7.18 (s, 1H, NH), 4.03–4.09 (m, 3H, H-4 and OCH Me), 2.16 [s, 3H,
3
2
the reaction mixture was stirred for an appropriate time at room tem-
perature. The reaction mixture was quenched with cold 6 M HCl (15 ml).
The precipitate was filtered off, and the solid was purified by column
C(6)–Me], 1.41 (m, 2H, CH Me), 1.17 (t, 3H, OCH Me, J 6.0 Hz), 0.78
2
3
2
1
(t, 3H, CH Me, J 7.5 Hz). C NMR, d: 165.3, 152.6, 148.1, 98.7, 58.8,
2
–
1
51.2, 29.4, 17.5, 14.0 and 8.31. IR (KBr, n/cm ): 3250, 3123, 2962,
1723, 1703, 1675. MS (70 eV, EI), m/z: 212 (M , 0.43%).
1
+
chromatography (ethyl acetate–hexane) and characterised by IR, H and
13
C NMR spectroscopy and mass spectrometry.
5-Ethoxycarbonyl-4-isobutyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one
1
2
5
-Aceto-4-propyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4c: mp 151–
4q: mp 185–186 °C. H NMR ([ H ]DMSO, 300 MHz) d: 8.86 (s, 1H,
6
1
2
1
1
52 °C. H NMR ([ H ]DMSO, 300 MHz) d: 8.94 (s, 1H, NH), 7.42 (s,
NH), 7.32 (s, 1H, NH), 4.01–4.10 (m, 3H, H-4 and OCH Me), 2.16 [s,
6
2
H, NH), 4.09 (t, 1H, H-4, J 3.2 Hz), 2.18 (s, 3H, COMe), 2.16 [s, 3H,
3H, C(6)–Me], 1.69 (m, 1H, CH CHMe ), 1.35 (m, 1H, CH CHMe ),
2
2
2
2
C(6)–Me], 1.20 (m, 4H, CH CH Me), 0.82 (t, 3H, CH CH Me, J
1.17 (t, 3H, OCH Me, J 7.0 Hz), 1.10 (m, 1H, CH CHMe ), 0.85 (d, 6H,
2
2
2
2
2
2
2
1
3
13
7
1
.0 Hz). C NMR, d: 194.5, 153.3, 147.8, 111.1, 50.5, 30.6, 19.3, 17.6,
CH CHMe , J 6.5 Hz). C NMR, d: 165.1, 152.6, 147.9, 100.2, 58.8,
2 2
–
1
–1
4.2. IR (KBr, n/cm ): 3247, 3113, 2956, 1723, 1625. MS (70 eV, EI),
48.1, 45.8, 23.5, 22.7, 21.3, 17.4, 14.0. IR (KBr, n/cm ): 3447, 3244,
+
+
m/z: 196 (M , 1.27%).
3112, 2951, 1701, 1652. MS (70 eV, EI), m/z: 241 (M + 1, 1.08%).
Mendeleev Commun. 2004 211

,
2004, 14(5), 210–212
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highest purity. Furthermore, the ionic system used acted as both
a Lewis acid catalyst and a solvent, which is important in reac-
tions where stoichiometric amounts are used.
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Received: 26th January 2004; Com. 04/2221
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12 Mendeleev Commun. 2004