A Novel Cu-catalysed Three-component One-pot Synthesis of Dihydropyrimidin-2(1H)-ones Using Microwaves under Solvent-free Conditions

Article abstract of DOI:10.1055/s-2003-43374

Cupric chloride dihydrate catalyzes the three-component Biginelli condensation between an aldehyde, a β-ketoester and urea or thiourea under microwave irradiation in the absence of solvent to yield various substituted 3,4-dihydropyrimidin-2(1H)-ones. The

Full text of DOI:10.1055/s-2003-43374

LETTER
235
A Novel Cu-catalysed Three-component One-pot Synthesis of Dihydro-
pyrimidin-2(1H)-ones Using Microwaves under Solvent-free Conditions
C
u-catalysed Three-c
o
u
m
ponent
O
n
k
-pot
S
ynthe
u
sis of Dihydr
t
opyrimidin-2
G
(1
H
)-ones ohain,a Dipak Prajapati,*a Jagir S. Sandhub
a
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat – 785 006, India
Fax +91(376)2370011; E-mail: dr_dprajapati@yahoo.co.uk; E-mail: drugs@csir.res.in
b
Department of Chemistry, Panjabi University, Patiala-147 002
Received 4 September 2003
application of these methods suffer from disadvantages
such as the use of expensive or less easily available re-
agents, vigorous reaction conditions, prolonged standing
and tedious manipulations in the isolation of the pure
Abstract: Cupric chloride dihydrate catalyzes the three-component
Biginelli condensation between an aldehyde, a b-ketoester and urea
or thiourea under microwave irradiation in the absence of solvent to
yield various substituted 3,4-dihydropyrimidin-2(1H)-ones. The
reaction is also effective when performed at room temperature in products. Therefore, a need still exists for versatile, sim-
acetonitrile or at 100 °C in a solvent free approach, without any side
reactions as observed by Biginelli and others.
ple and environmentally friendly processes whereby
DHPMs may be obtained under milder conditions.
Key words: Biginelli condensation, cupric chloride, cupric sul-
A very recent report by Sudalai and his co-workers14b
phate, dihydropyrimidinones,, three-component reactions
prompted us to disclose our results on the three-compo-
nent Biginelli reaction using cupric chloride dihydrate in
a solvent-free condition under microwave irradiations.
In recent years attention has been focused particularly on
The reaction also proceeded efficiently at room tempera-
dihydropyrimidinones (DHPMs), which are an important
ture in acetonitrile and the corresponding DHPMs were
class of compounds due to their therapeutic and pharma-
obtained in 80–94% yields. Further, the condensation was
cological properties.1 They have emerged as integral
found to be equally effective when CuCl2·2H2O was re-
backbones of several calcium channel blockers (e.g. nife-
placed by CuSO4·5H2O and the corresponding DHPMs
dipine), antihypertensive agents and alpha-1a-antagonists
were obtained in almost comparable yields. Sudalai et al.
have synthesised various dihydropyrimidin-2(1H)-ones in
60–95% yields using expensive Cu(OTf)2 and various
and neuropeptide antagonists.2 Alkaloids containing the
dihydropyrimidine unit have been isolated from marine
sources3 and among these are the batzelladine alkaloids
other copper salts. Among the copper salts screened in-
which were found to be potent HIV gp-120-CD4 inhibi-
cluding CuSO4·5H2O, Cu(OTf)2 showed excellent activi-
tors.4 This is an impressive profile that bodes well for the
ty in terms of yields in producing the required product at
interaction of this heterocyclic building block with a vari-
25–70 °C in 4–12 hours. But with 5 mol% of cuprous
ety of biological targets of interests. Thus synthesis of this
chloride and copper sulphate, they got the corresponding
heterocyclic nucleus is of continuing interest. The most
DHPMs in 20% and 0% yields respectively. In contrast,
convenient Biginelli’s one-pot reaction first described
we have performed the Biginelli reaction in presence of
more than a century ago1a and reviewed1b,c recently in-
CuCl2·2H2O and CuSO4·5H2O in solvent free conditions,
and isolated the corresponding DHPMs in 80–99% yields.
volves condensation of an aldehyde, a b-dicarbonyl com-
pound and urea or thiourea under strongly acidic
The reaction was very fast when carried out under micro-
conditions. However, the main drawback of Biginelli re-
wave irradiations (1–1.5 min) and took 1–2 hours on heat-
action is low yields5 and sensitive functional groups are
ing at 100 °C. We employed microwave energy because
lost during the reaction conditions.6 This has led to the dis-
the potential application of microwave technology in or-
covery of multi-step strategies7 that produce somewhat
ganic synthesis17 particularly in solid state is increasing
higher yields but lack the simplicity of the original Bigi-
rapidly due to its reaction simplicity, less polluting and
nelli one-pot synthesis. Several improvement includes
minimum reaction time providing rapid access to large
combination of Lewis acids with transition metal salts or
libraries of diverse small molecules (Scheme 1).
8
10
BF3·OEt2 or KSF9 or InX3 (X = Cl, Br) or CAN11 or
Yb(OTf)312 and poly- phosphate ester13 mediates Biginelli
reaction was applied recently to greatly improve the
yield of the process. Even during last two years several
improved protocols14 by the modification of the classical
one-pot approach8,9,13,15 and complex multi-step
strategies2a,7,16 have been published. But the practical
SYNLETT 2004, No. 2, pp 0235–0238
0
2.
0
2.
2
0
0
4
Advanced online publication: 18.12.2003
DOI: 10.1055/s-2003-43374; Art ID: D22403ST.pdf
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

236
M. Gohain et al.
LETTER
In a typical procedure, a mixture of ethyl acetoacetate in 98% yield. Similarly other substituted aldehydes, b-di-
(1.30 g, 10 mmol), benzaldehyde (1.06 g, 10 mmol), urea carbonyl compounds and urea were reacted together to
(0.6 g, 10 mmol) and cupric chloride dihydrate (0.17 g, 1 produce the corresponding dihydropyrimidin-2(1H)-ones.
mmol) was placed in an Erlenmeyer flask and heated in a The results are summarized in Table 1. Under this condi-
microwave oven at power 60%, (operating at 2450 MHz tion, the yields were significantly improved to 80–99%
frequency) for 1.5 minutes. After completion (monitored and the reaction time was reduced dramatically. A number
by TLC), the reaction was cooled to room temperature and of substituted aromatic, aliphatic and heterocyclic alde-
poured into water (30 mL). The solid separated was fil- hydes have been employed successfully. Acetylacetone
tered, washed with water and then recrystallised from eth- and thiourea were also used with similar success to
anol to afford pure 4a, mp 201–202 °C (lit.18 mp 202 °C) provide the corresponding 3,4-dihydropyrimidin-2(1H)-
Table 1 CuCl2·2H2O/CuSO4·5H2O Catalysed Synthesis of Dihydropyrimidin-2-(1H)-ones 4
Entry Prod- R1
uctsa
R2
X
Catalyst
Reactionb Yieldc Reactionb
Yieldc Mp (°C)
Lit. mp (°C)
time (min) (%)
thermal
time (min) (%)
microwave
1
2
4a
4b
4c
4d
4e
4f
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
CH3
CH3
CH3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
CH3
CH3
O
O
O
O
O
O
O
O
O
O
S
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
60
60
60
60
60
60
60
100
110
112
60
75
60
60
65
60
70
60
70
70
70
96
97
96
90
95
80
86
82
80
80
97
95
92
96
93
80
96
97
96
90
80
82
85
97
96
80
1
98
96
99
92
97
82
88
85
80
82
88
97
90
98
95
80
98
96
99
92
82
85
88
88
98
80
200–202
215–216
198–200
206–208
214–215
208–209
227–228
231–232
156–157
190–192
208–209
191–192
214–216
207–209
192–193
236–238
200–202
215–216
198–200
206–208
208–209
231–232
156–157
208–209
207–209
236–238
202–20414b
213–2158
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
4-CH3C6H4
2-Furyl
1
3
1.5
1
201–20214b
207–20814b
215–21614b
209–21114b
226–22722a
232–23512
157–15812
194–19512
208–21014b
192–19514b
215–21714b
209–2128
4
5
1
6
1.5
1.5
1
7
4g
4h
4i
3-NO2C6H4
C6H4-CH=CH
n-Bu
8
9
1.5
1.5
1.5
1.5
1.5
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4j
(CH3)2CH-
Ph
4k
4l
4-ClC6H4
2-Thienyl
Ph
S
4m
4n
4o
4p
4a
4b
4c
4d
4f
S
O
O
O
O
O
O
O
O
O
O
S
4-MeC6H4
4-NO2C6H4
Ph
1.5
1.5
1
192–19414b
235–23714b
202–20414b
213–2158
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
2-Furyl
1
1.5
1
201–20214b
207–20814b
209–21114b
232–23512
157–15812
208–21014b
209–2128
1.5
1
4h
4i
C6H4-CH=CH
n-Bu
CuSO4·5H2O 110
CuSO4·5H2O 110
1.5
1.5
2
4k
4n
4p
Ph
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
70
70
70
Ph
O
O
4-NO2C6H4
1.5
235–23714b
a All the compounds were characterized by IR, NMR, MS and mp.
b At r.t., the reaction time is 2–3 h and the yield is 80–94%.
c Isolated yields.
Synlett 2004, No. 2, 235–238 © Thieme Stuttgart · New York

LETTER
Cu-catalysed Three-component One-pot Synthesis of Dihydropyrimidin-2(1H)-ones
237
thiones.19 Thus variation in all three components have
been accommodated very comfortably. This condensation
procedure is fairly general and several functionalities in-
cluding nitro, chloro, hydroxyl, methoxy and conjugated
carbon-carbon double bond do survive during the course
of the reaction. However, under the present reaction con-
dition b-ketoaldehyde do not produce the corresponding
dihydropyrimidinones, instead they lead to multiple prod-
ucts. Meanwhile, even for aliphatic aldehyde such as bu-
tyraldehyde and iso-butyraldehyde which normally show
extremely poor yields in the Biginelli reaction, the corre-
sponding dihydropyrimidinones could be obtain in 80–
82% yields20 (Table 1). Acid sensitive aldehydes such as
furfural also worked well without the formation of any
side products. Roughly 0.1 equivalent of CuCl2 was found
to be sufficient for these reactions and use of less than 0.1
equivalent was not optimal one. The use of large amount
of CuCl2·2H2O is also found to be not fruitful i.e. does not
increase the yields. Notably, with CuSO4, 0.05 equivalent
of the catalyst was sufficient to perform the condensation.
Also, the reagents employed for this process were inex-
pensive and anhydrous conditions were not required. All
the reactions were very fast, clean and high yielding using
1 or 0.5 mol% of the catalyst. In a recent solvent-free
approach12 by Yang et al. the heterogeneous mixture of b-
ketoesters, aldehydes and urea were refluxed for 10 hours
in the presence of 30 mol% of CeCl3·7H2O to get the cor-
responding DHPMs in 65–80% yields. In contrast, using
CuCl2·2H2O or CuSO4·5H2O in a solvent-free approach
we got the corresponding DHPMs in 80–99% yields when
carried out in a microwave oven or by heating the hetero-
geneous mixture at 100 °C.
Scheme 2
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In conclusion, the present method discloses a new and
simple modification of the Biginelli reaction by using in-
expensive CuCl2·2H2O or CuSO4·5H2O as a catalyst in
solvent-free conditions under microwave irradiations.
The yield of the DHPMs can be increased from 20–50%8
to 80–99% while the reaction time was reduced dramati-
cally from 18–48 hours to 1–1.5 minutes. It not only led
to economical automation but also reduces hazardous pol-
lution to achieve environmentally friendly processes. This
Cu-catalysed one-pot synthesis of DHPMs is therefore,
simple, high yielding, time saving and environment
friendly. In addition to its simplicity and selectivity this
reaction has one salient feature in its ability to tolerate a
variety of aldehydes and constitute a useful alternative to
the commonly accepted procedures.
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Synlett 2004, No. 2, 235–238 © Thieme Stuttgart · New York

238
M. Gohain et al.
LETTER
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Synlett 2004, No. 2, 235–238 © Thieme Stuttgart · New York