Microwave-assisted copper(ii)-catalyzed one-pot four-component synthesis of multifunctionalized dihydropyridines

Article abstract of DOI:10.1021/cc100060s

A fast and highly efficient copper-catalyzed multicomponent synthesis of 1,4-dihydropyridines under microwave irradiation is described. The protocol utilizes mild reaction conditions with low catalytic loading, leading to high yields. This methodology pro

Full text of DOI:10.1021/cc100060s

J. Comb. Chem. 2010, 12, 577–581
577
Microwave-Assisted Copper(II)-Catalyzed One-Pot Four-Component
Synthesis of Multifunctionalized Dihydropyridines
Kalyan Kumar Pasunooti, Chantel Nixon Jensen, Hua Chai, Min Li Leow,
Da-Wei Zhang, and Xue-Wei Liu*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical, Sciences,
Nanyang Technological UniVersity, Singapore 637371, Singapore
ReceiVed April 6, 2010
A fast and highly efficient copper-catalyzed multicomponent synthesis of 1,4-dihydropyridines under
microwave irradiation is described. The protocol utilizes mild reaction conditions with low catalytic loading,
leading to high yields. This methodology provides us with biologically active 1,4-dihydropyridine library
for medicinal chemistry applications.
Introduction
Multicomponent reactions have proven to be a valuable
asset in medicinal chemistry, drug design, and drug discovery
because of their simplicity, efficiency, and high selectivity.
Such protocols can reduce the number of steps and present
advantages, such as low energy consumption and little to
no waste production, leading to desired environmentally
friendly processes. The multicomponent symmetrical 1,4-
dihydropyridine yielding Hantzsch reaction was first estab-
lished by Hantzsch in 1881 and has attracted considerable
attention over the years because of its efficiency to yield
bioactive dihydropyridines.20 However, the classic reaction
using aldehyde, ethylacetoacetate, and ammonia under acetic
condition suffers from disadvantages, such as high temper-
atures, long reaction times, harsh reaction conditions, and
incomplete conversion of reactants. Thus, over recent years
significant effort has been made to find efficient procedures
that maintain the simplicity of the Hantzsch reaction but
produce better yields. A large number of optimized proce-
dures have been reported by many research groups, the
majority of them employed catalytic methods to synthesize
DHPs. These protocols utilize ionic liquids,21 triphenyl
phospine,22 iodine,23 Baker’s yeast,24 silica-supported acids,25
ceric ammonium nitrate (CAN),26 organo-catalysts,27-29
polymers,30,31 and metal-triflates.32-34 However, many of
the methods still suffer from drawbacks, such as high reaction
temperatures, incomplete conversion of reactants, expensive
metal precursors, stoichiometric amounts of catalyst, envi-
ronmentally toxic catalysts, or prolonged reaction time. In
contrast, copper catalysts have become increasingly appealing
because of their affordability, high activity, and low toxicity.
Synthesis of bioactive molecules should preferably be
facile, fast, and efficient with minimal workup.1 To suite
such requirements, multicomponent reactions that directly
yield target molecules have attracted considerable attention
in both organic and medicinal chemistry.2 Many chemical
processes require a large amount of energy from heating,
which can have considerable adverse effects on the environ-
ment. Therefore, microwave technology is becoming increas-
ingly attractive as an alternative energy source to assist
reactions under milder conditions.3 Microwave irradiation
is an extremely powerful tool for reducing reaction time and
increasing desired product yields, thus producing many
efficient organic reactions.4,5 Over the past few years our
group has extensively focused on the development of new
facile and efficient methodologies to synthesize bioactive
compounds for medicinal chemistry applications.6-8
Multisubstituted 1,4-dihydropyridines (1,4-DHPs) are ana-
logues of NADH coenzymes and have a wide range of
biological activity with such derivatives proving to act as
vasodilator, bronchodilator, antiatherosclerotic, antitumor,
geroprotective, hepatoprotective, and antidiabetic agents.9-14
The major biological significance of 1,4-DHPs is that they
act as Ca2+ channel blockers enabling them to be important
drugs in the treatment of cardiovascular disease including
hypertension, as exemplified by nifedipine and nicardipine
(Figure 1).15,16 Recent studies have shown that these 1,4-
DHP pharmacophores possess neuroprotectant and platelet
antiaggregatory activities.17,18 In addition, it has also been
indicated that DHPs can be used in the treatment of
Alzheimer’s disease because of their antiischemic activity
and can also be used as chemosensitizers in tumor therapy.19
Hence, the development of new methods that lead to
multisubstituted DHPs via an efficient and convenient
procedure are of great interest for medicinal chemists.
* To whom correspondence should be addressed. E-mail: xuewei@
ntu.edu.sg. Phone: +65 6316 8901. Fax: +65 6791 1961.
Figure 1. Biologically active dihydropyridines.
10.1021/cc100060s  2010 American Chemical Society
Published on Web 06/07/2010

578 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Table 1. Optimization of the Hantzsch Reactiona
Pasunooti et al.
Table 2. Cu(OTf)2 Catalyzed Hantzsch Synthesis of
Dihydropyridine Derivatives from Substituted Aromatic
Aldehydes
Cu(OTf)2
temperature
catalyst
(mol %)
yield
(%)
entry
R1
R2
R3
product
yield (%)
95
quantitative
91
98
92
90
quantitative
88
98
95
88
92
82
90
entry
solvent
(°C)
time
24 h
12 h
24 h
12 h
1 h
24 h
12 h
12 h
1 h
1 h
1 h
30 min
15 min
5 min
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
5a
5b
5c
5d
5e
5f
5g
5h
5i
1
2
3
DCM
DCM
ACN
ACN
ACN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
rt
50
rt
70
80
rt
70
70
80
80
80
80
100
120
10
10
10
10
10
10
10
5
10
5
2
2
2
38
52
45
55
65
55
82
82
95
95
95
95
95
65
4-MeC6H4
4-NO2C6H4
4-OMeC6H4
4-CO2MeC6H4
4-ClC6H4
4-SMeC6H4
3,4-Me2C6H3
3-OHC6H4
2-CF3C6H4
2-furyl
3-thiophenyl
n-pentyl
cyclohexyl
2-NO2C6H4
1-naphthyl
C6H5
4-MeC6H4
4-NO2C6H4
4-OMeC6H4
4-ClC6H4
4-SMeC6H4
3,4-Me2C6H3
3-OHC6H4
2-CF3C6H4
C5H4N
4
5b
6
7
8
9
9b
10b
11b
12b
13b
14b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
5j
5k
5l
5m
5n
5o
5p
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
2
82
92
96
a Reaction conditions using benzaldehyde (1.0 mmol), ethyl
acetoacetate (1.0 mmol), dimedone (1.0 mmol), ammonium acetate (1.0
mmol), solvent (2 mL) and Cu(OTf)2 (0.1, 0.05, and 0.02 mmol).
b Reactions under microwave irradiation, 200 W.
quantitative
92
quantitative
98
Copper can be used with considerable advantages including
mild reaction conditions, high catalytic efficiency, shorter
reaction times and no formation of byproduct. Recently, our
group has developed a copper-catalyzed one-pot three-
component synthesis of homoallylamines with great suc-
cess.35 In this study, we focus on the development of a new,
fast, and efficient methodology utilizing microwave technol-
ogy with a copper catalyst for the preparation of biologically
active 1,4-dihydropyridine derivatives via a one step mul-
ticomponent reaction.
quantitative
92
90
87
85
93
86
94
88
81
91
2-furyl
3-thiophenyl
n-pentyl
cyclohexyl
2-NO2C6H4
1-naphthyl
6m
6n
6o
6p
the reaction led to decomposition of the product, therefore
producing low yields (55%); however, ethanol produced the
desired DHPs in a significantly higher yield (82%). We then
focused on lowering the reaction time from 12 h, in which
microwave irradiation was used because of its ability to lower
reaction times and increase yields. A range of temperatures,
times, and the amounts of catalysts were screened to optimize
the one-pot multicomponent reaction. For both acetonitrile
and ethanol, the reaction was then carried out using
microwave irradiation at 80 °C for 1 h at 200 W. The reaction
utilizing acetonitrile as a solvent suffered from incomplete
conversion of reactants, as indicated by TLC monitoring and
thus the reaction in ethanol produced the desired product in
much higher yield (95%) than acetonitrile did (65%), proving
ethanol to be the most effective solvent. At the same time,
decreasing the amount of copper catalyst from 10 to 5 and
2 mol % did not show any significant impact on the product
yield. The investigation at this point indicated that ethanol
at 80 °C in the presence of 2 mol % Cu(OTf)2 with a reaction
time of 1 h under microwave irradiation were the appropriate
conditions for the one-pot synthesis.
Results and Discussion
First, the establishment of the reaction conditions was
undertaken by investigating the effect of different solvents,
temperatures, reaction times and amounts of catalyst using
benzaldehyde, ethylacetoacetate, dimedone, and ammonium
acetate as standard components (Table 1).36 Initially, a
mixture of benzaldehyde, ethylacetoacetate, dimedone and
ammonium acetate in dichloromethane was stirred in the
presence of Cu(OTf)2 (10 mol %) at room temperature for
24 h and the dihydropyridine product was produced in a low
yield (38%) due to incomplete conversion of the reactants,
leading to the assumption that more thermal energy may be
needed. To focus on the effect of temperature and time, the
reaction was carried out at 50 °C for 12 h, which allowed
the heterocyclic product to form with a slightly higher yet
unsatisfactory yield (52%).
Our attention then moved on to investigate the effect of
solvents on the product yields, and dichloromethane was
replaced by acetonitrile and ethanol. The reactions were
stirred for 24 h at room temperature, and both solvents
resulted in incomplete conversion of reactants; ethanol,
however, gave higher yields. The temperature was then raised
to 70 °C for both acetonitrile and ethanol and the mixture
was stirred for 12 h. In the case of acetonitrile as the solvent,
Next, we proceeded to lower the reaction time further to
speed up the reaction and produce desirable yields therefore
producing a more efficient reaction. The reaction mixture
of benzaldehyde, ethylacetoacetate, dimedone, ammonium

Multifunctionalized Dihydropyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 579
Scheme 1. Cu(OTf)2 Catalyzed Hantzsch Synthesis of Dihydropyridine Derivatives
acetate, and Cu(OTf)2 (2 mol %) in ethanol was stirred under
microwave irradiation at 80 °C for 30 min, and the DHP
product was produced with a similar yield (95%). The
temperature was then raised to 100 °C and the reaction
mixture was stirred for 15 min. Such changes produced the
product in similar yields as comparing to that running at 80
°C (95%). When the reaction time was then lowered to 5
min at a temperature of 120 °C the resulting DHP product
was obtained in a lower yield (65%), suggesting that the
temperature was too high which led the components to
decompose. From the above investigations, ethanol at 100
°C in the presence of 2 mol % Cu(OTf)2 with a reaction
time of 15 min under microwave irradiation at a power of
200 W was established as the optimized reaction conditions
for the four-component, one-step synthesis.
Under the optimized conditions the copper-catalyzed
reactions of a variety of substituted aldehydes were under-
taken and a small library of DHPs was created (Table 2).

580 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Pasunooti et al.
The reactions of different aldehydes possessing a range of
substituents from electron-withdrawing (6c) to electron-
donating (6d) produced the heterocyclic products in excellent
yields, ranging from 82% to quantitative yields. Unsubsti-
tuted (6a), heteroaromatic (6k), and bulky aldehydes such
as naphthal (6p) were also investigated and led to the
production of the corresponding DHPs in excellent yields
(81-96%). The use of aldehydes with electron-withdrawing
substituents showed no significant effect on the yields of the
corresponding DHPs when compared to reactions utilizing
aldehydes, which possessed electron-donating substituents
(compare compounds 6c and 6d) and also when compared
to those that were unsubstituted and those possessing bulky
substituents (compare compounds 6c and 6a, 6c, and 6p).
We then proceeded to replace the dimedone with 1,3-
cyclohexanedione and repeated the reaction with the same
substituted aldehydes. Compared with the initial reaction
utilizing dimedone, the reactions involving 1,3-cyclohex-
anedione produced the corresponding DHPs in equally high
yields (82% to quantitative yields) (comparing compounds
5b and 6b) and similarly the nature of the aldehyde
substituents showed no significant effect on the yields
(compare compounds 5c and 5d, 5c and 5a, 5c and 5p).
Figure 2. X-ray crystal structure of ethyl 4-cyclohexyl-2-methyl-
5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5n).
droquinoline-3-carboxylate motif was further confirmed by
X-ray crystallography (Figure 2, 5n).
Conclusion
In conclusion, we have developed a simple and efficient
method to generate a range of DHP analogues in excellent
yields via a microwave-assisted one-pot four-component
reaction. The protocol utilizes Cu(OTf)2 in small quantities
and mild reaction conditions avoiding workup and column
purification. Reaction times were considerably reduced and
product yields increased up to quantitative yields under
microwave irradiation. This methodology can be exploited
to construct new multisubstituted DHPs, which are of great
interest due to their extensive pharmaceutical and biological
applications. Currently, biological tests of the synthesized
1,4-DHP analogues are in progress in our laboratory.
Our attention then focused on replacing ethylacetoacetate
in the one-step synthesis (Scheme 1). In the reaction of
benzaldehyde, ethyl acetoacetate, dimedone, and ammonium
acetate the ꢀ-ketoester was replaced by ethyl propionylacetate
and the corresponding DHP (7b) was produced in quantita-
tive yields. At the same time, ethyl butyrylacetate was
employed to replace ethyl acetoacetate, and the corresponding
DHP, 7a, was formed in similarly high yields (95%). This
methodology was also tested with electron-donating (OMe)
and electron-withdrawing (NO2) substituted benzaldehydes
which yielded the desired products, 7e, 7f, 7i, and 7j, in
noticeably high quantities (89% to quantitative). The electron-
withdrawing NO2 group seemed to have little effect on the
DHP yield when compared to the electron donating OMe
product and also the unsubstituted product (compare com-
pounds 7f and 7j, 7f, and 7b).
Acknowledgment. Financial support from Nanyang Techno-
logical University (RG50/08) and the Ministry of Health (NMRC/
H1N1R/001/2009), Singapore, are gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Multifunctionalized Dihydropyridines
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CC100060S