Microwave-assisted synthesis of dihydropyrimidin-2(1H)-ones using graphite supported lanthanum chloride as a mild and efficient catalyst

Article abstract of DOI:10.1016/j.bmcl.2007.10.087

Graphite supported lanthanum chloride efficiently catalyzes the three-component coupling of β-ketoesters, aldehydes and urea/thiourea to afford corresponding dihydropyrimidinones in good yields under microwave irradiation.

Full text of DOI:10.1016/j.bmcl.2007.10.087

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 278–280
Microwave-assisted synthesis of dihydropyrimidin-2(1H)-ones
using graphite supported lanthanum chloride as a mild
and efficient catalyst
Hojatollah Khabazzadeh, Kazem Saidi* and Hassan Sheibani
Department of Chemistry, Shahid Bahonar University of Kerman, 76169 Kerman, Iran
Received 5 August 2007; revised 1 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—Graphite supported lanthanum chloride efficiently catalyzes the three-component coupling of b-ketoesters, aldehydes and
urea/thiourea to afford corresponding dihydropyrimidinones in good yields under microwave irradiation.
Ó 2007 Published by Elsevier Ltd.
Dihydropyrimidinones (DHPMs) named Biginelli com-
pounds are known to exhibit a wide range of biological
activities such as antiviral, antitumour, antibacterial and
anti-inflammatory actions.1–3 Appropriately functional-
ized DHPMs have emerged as potent calcium channel
blockers,4 antihypertensive agents5 a1a adrenergic antag-
onists.6 Several marine alkaloids containing the DHPM
core unit have shown interesting biological properties.
In particular, batzelladine alkaloids have been found
to be potent HIV gp-120-CD4 inhibitors.7
In order to improve the efficiency of the Biginelli reac-
tion different Lewis catalysts such as ZrCl4,10 BiCl3,11
LiBr,12 Mn(OAc)3Æ2H2O,13 InCl3,14 Cu(OTf)2,15
19
Zn(OTf)2,16 FeCl3Æ6H2O,17 LiClO4,18 CuCl2 and chlo-
roacetic acid20 have been reported.
Microwave heating has emerged as a powerful technique
to promote a variety of chemical reactions.21 Microwave
reactions under solvent-free conditions and/or in the
presence of a solid support, such as clays, alumina, silica
and graphite, resulting in shorter reaction times and
higher product yields than those obtained by using con-
ventional heating offer low cost together with simplicity
in processing and handling.22
The original one-pot synthesis of 3,4-dihydropyrimidin-
2(1H)-ones was first reported by Pietro Biginelli in 1893
performing the three-component cyclocondensation
reaction of ethyl acetoacetate, benzaldehyde and urea
under Bro¨nsted acid catalysis. However, this reaction
suffers from the harsh conditions, high reaction times
and frequently low yields.8
In continuation of our interest in microwave-assisted syn-
thesis,23 we wish to report the LaCl3-graphite catalyst sys-
tem catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-
ones 4 under microwave conditions (Scheme 1).
This has led to multi-step synthetic strategies that pro-
duce somewhat better yields but lack the simplicity of
one-pot synthesis.9
The selection of LaCl3 as a catalyst is done on the basis
of report of Lu et al., in which they obtained dihydro-
In recent years, new methods for the synthesis of 3,4-
dihydropyrimidin-2-(1H)-ones have been developed by
different groups.
O
O
1
O
R
OEt
O
1
H
X
2
LaCl3-graphite
EtO
N
1
R
H
X
solvent free
microwave
H3C
N
H
4
H2N
NH2
Keywords: Dihydropyrimidine; Lanthanum chloride; Biginelli reaction;
Microwave.
3
*
Corresponding author. Tel./fax: +98 341 3222033; e-mail: saidik@
mail.uk.ac.ir
Scheme 1.
0960-894X/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.10.087

H. Khabazzadeh et al. / Bioorg. Med. Chem. Lett. 18 (2008) 278–280
279
Table 1. Graphite supported lanthanum chloride synthesis of dihydropyrimidin-2(1H)-ones and thiones under microwave irradiation
Entry
Product
R1
X
Yield (%)
Mp (°C)
Observed
Reported
1
4a
4b
4c
4d
4e
4f
Ph
O
O
O
O
O
O
O
O
O
S
85
80
65
75
80
75
60
58
50
86
80
74
80
84
196–198
208–210
211–214
202–204
209–212
225–228
255–258
177–179
194–196
198–200
106–108
202–204
180–183
185–188
198–20020
211–21320
216–21828
205–20728
213–21620
229–23027
260–26227
180–18220
196–19720
202–20420
109–11130
206–20728
184–18520
189–19229
2
4-ClC6H4
2-ClC6H4
4-O2NC6H4
4-CH3C6H4
3-O2NC6H4
2-CH3OC6H4
CH3CH2CH2
(CH3)2CH
Ph
3
4
5
6
7
4g
4h
4i
8
9
10
11
12
13
14
4j
4k
4l
4-O2NC6H4
3-O2NC6H4
4-ClC6H4
4-CH3C6H4
S
S
4m
4n
S
S
LaCl3
X
This method not only preserved the simplicity of Bigi-
nelli’s one-pot condensation but also improved the
yields of dihydropyrimidinones in shorter reaction time
as against the longer reaction times required for other
catalysts.
2+
La
Cl3La
X
H
O
O
O
1
N
NH2
-H2O
OEt
+
NH2
R
H
H2N
1
R
H
5
1
1
O
R
O
R
The procedure gives the products in good yields and
avoids problems associated with solvent use such as
cost, handling, specifically safety, because of fire hazard
due to occurrence of sparks in microwave ovens.
H
N
N
EtO
-H2O
EtO
H3C
X
H3C
O
X
N
H
4
H2N
Scheme 2.
Acknowledgment
The authors express their gratitude to the Shahid Baho-
nar University of Kerman Faculty Research Grant for
its support of this investigation.
pyrimidinones in long reaction time (5 h).24 Therefore,
we developed the catalyst by impregnation of LaCl3
on graphite support25 which is a strong microwave
absorbent and enhances the reaction temperature rap-
idly and subsequently increases the yield of products.
References and notes
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1:1.2:1.5 mol ratios of aldehyde, 1,3-dicarbonyl urea/
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To study the generality of this process, several examples
were studied and are summarized in Table 1. In all cases
studied, the three-component reaction proceeded fastly
to give the corresponding 3,4-dihydropyrimidin-2(1H)-
ones in good yields.
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5,31 formed by the reaction of the aldehyde and urea
which was catalyzed by HCl and stabilized by LaCl3.
Subsequent addition of b-ketoester enolate to the acyl-
imine, followed by cyclization and dehydration, afforded
the corresponding dihydropyrimidinones (Scheme 2).32
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the reaction mixture and catalyst was removed by filtra-
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32. Spectral data for selected compounds:5-(Ethoxycar-
bonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one
(4a). IR (KBr): 3230, 3131, 2982, 1699, 1650 cmÀ1 1H
,
24. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron
Lett. 2000, 41, 9075.
NMR (DMSO-d6, 500 MHz): d = 1.10 (t, J = 7.1 Hz, 3H,
CH3), 2.25 (s, 3H, CH3), 3.99 (q, J = 7.1 Hz, 2H, CH2),
5.15 (d, J = 3.2 Hz, 1H, CH), 7.23–7.34 (m, 5H, arom
CH), 7.73 (s, 1H, NH), 9.18 (s, 1H, NH). 13C NMR
(DMSO-d6, 125 MHz) d = 14.94, 18.64, 54.83, 60.04,
100.13, 127.11, 128.12, 129.25, 145.73, 149.22, 152.99,
166.20. 5-(Ethoxycarbonyl)-6-methyl-4-(4-methylphenyl)-
3,4-dihydropyrimidin-2(1H)-thione (4n). IR (KBr): 3329,
25. General procedure for the preparation of catalyst. LaCl3Æ7-
H2O (10 mmol, 3.70 g) was dissolved in 10 ml H2O and
then graphite (1.85 g) in 5 ml EtOH was added. The
catalyst was collected after evaporating the solvent and
dried at 100 °C for 1 h.
26. General procedure for the preparation of 3,4-dihydropyrim-
idin-2(1H)-ones/thiones. A mixture of appropriate alde-
hyde (10 mmol), ethylacetoacetate (12 mmol), urea/
thiourea (15 mmol), catalyst (1.5 g, ꢀ35 mol%) and one
drop conc HCl was placed in an erlenmeyer flask. The
mixture was placed in a microwave oven (Butane) and
irradiated for a period of 1 min at a time. After each
irradiation the reaction mixture was removed from the
microwave oven for shaking. The total period of micro-
1
3180, 3156, 2982, 1691, 1592 cmÀ1, H NMR (DMSO-d6,
500 MHz): d = 1.11 (t, J = 7.1 Hz, 3H, CH3), 2.27 (s, 3H,
CH3), 2.30 (s, 3H, CH3), 4.01 (q, J = 7.1 Hz, 2H, CH2),
5.14 (d, J = 3.0 Hz, 1H, CH), 7.11 (d, J = 8.0 Hz, 2H,
arom CH), 7.15 (d, J = 8.0 Hz, 2H, arom CH), 9.61 (s, 1H,
NH), 10.30 (s, 1H, NH). 13C NMR (DMSO-d6, 125 MHz)
d = 14.89, 18.01, 21.53, 54.61, 60.42, 101.70, 127.16,
129.92, 137.76, 141.47, 145.73, 166.01, 175.03.