Ultrasound mediated, green innovation for the synthesis of polysubstituted 1,4-dihydropyridines

Article abstract of DOI:10.1039/c6ra05441b

An elegant, atom efficient protocol via a one-pot four-component cyclocondensation reaction of aromatic aldehydes, malononitrile, acetylenedicarboxylates and arylamines catalyzed by copper(I) iodide in aqueous medium under ultrasound irradiation has been developed for the synthesis of a series of novel pharmacologically interesting polysubstituted 1,4-dihydropyridines. In comparison with the reported methods, our approach is expedient and offers several advantages such as: a shorter reaction time, excellent yields, milder conditions, convenience and environmental benignity. We have herein successfully demonstrated the utility of sonication in a multicomponent reaction (MCR), which exhibits a better functional group tolerance, and straightforward product isolation and purification by precipitation.

Full text of DOI:10.1039/c6ra05441b

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PAPER
Ultrasound mediated, green innovation for the synthesis of
polysubstituted 1,4-dihydropyridines
Received 00th December 20xx,
Accepted 00th January 20xx
Sumaiya Tabassum, Santhosh Govindaraju, Riyaz-ur-Rahaman Khan and M. A. Pasha*
DOI: 10.1039/x0xx00000x
An elegant, atom efficient protocol for the synthesis of a series of novel pharmacologically interesting polysubstituted 1,4-
dihydropyridines has been developed via a one-pot four-component cyclocondensation reaction of aromatic aldehydes,
malononitrile, acetylenedicarboxylates and arylamines catalyzed by copper (I) iodide in aqueous medium under ultrasound
irradiation. In comparison with the reported methods, our approach is expedient and offers several advantages such as:
shorter reaction time, excellent yields, milder conditions, convenient and is environmentally benign. We have herein
successfully demonstrated the utility of sonication in a multicomponent reaction (MCR), which exhibits a better functional
www.rsc.org/
group
tolerance,
straightforward
product
isolation
and
the
purification
is
by
precipitation
nifedipine and nicardipine is well known (Figure 1) [5]. The
classical methods for the synthesis of 1,4-dihydropyridines
usually involve Hantzsch reaction [6], cycloaddition reactions
[7], Michael condensation [8], Huisgen dipolar additions [9]
and others [10].
Introduction
In the last two decades, enormous thrust and exploration
towards inculcating the green chemistry practices have been
taking place steadily. Multi-component reactions (MCRs) are
one of the major contributions to the field of green chemistry,
which have time and again served as the best tools to gain an
access into biologically active heterocyclic molecules of
interesting properties [1] by a one-pot, single-step process.
This approach offers several potential advantages over
conventional synthesis. Assembling of N-heterocycles via
multi-component strategy is one of the vital areas in synthetic
organic chemistry.
Cl
O-
N+
Cl
O
O
O
O
O
O
O
O
O
N
N
H
H
Felodipine
Nifedipine
These heterocycles are a remarkable scaffold of prime
importance to mankind. These heterocyclic skeletons are often
an enticing framework for synthetic organic chemists,
pharmaceutical and agricultural industries to design
compounds of immense chemical and biological interest [2].
Accordingly, molecules containing 1,4-dihydropyridine scaffold
are an important class of privileged heterocycles that have
been enjoying a relative renaissance of interest owing to the
abundance of these components in various natural products,
new materials and pharmaceuticals. These ubiquitous motifs
are endowed with a wide range of biological applications [3].
They are often used in the treatment of cardiovascular
diseases, angina pectoris, Alzheimer’s disease and
hypertension [4]. Their presence in prominent commercially
available drug molecules such as felodipine, amlodipine,
Cl
O
-O
O
N+
N
O
O
O
O
O
N
H
O
O
O
N
H
NH2
Amlodipine
Nicardipine
Figure 1. Some biologically potent 1,4 DHPs
A rigorous literature survey reveals that, a few synthetic
methodologies have been reported recently which employ
varied catalysts and solvents such as: nano particles [11],
meglumine [12], KF/Al2O3 [13], triethylamine [14], NaOH [15],
polyethylene glycol (PEG), ethanol [16], grinding condition
[17], trifluoroacetic acid [18], (NH4)2HPO4 [19], Cu(OTf)2 [20]
and Sc(OTf)3 [21]. Although a variety of approaches have been
documented and are found to have their unique advantages,
they suffer from one or the other drawbacks such as
preparation of the catalyst, use of expensive catalysts, organic
bases and organic solvents, prolonged reaction times,
exposure to chemicals leading to environmental concerns
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Journal Name
during grinding in grindstone method, require expensive conditions, high purity of the product, enhance catalyst
starting materials, unsatisfactory yields and lack of generality. efficiency and safety of the technique are the essence of
Owing to the prominent aforementioned medicinal profile sonochemical reactions. These characteristics place
of 1,4-dihydropyridines, search for the development of better sonochemistry amongst the elite of green chemical methods
eco sustainable, economical and energy efficient methods [30]. Since water is non-toxic, abundant natural resource,
remain a challenging task and therefore has attracted keen inexpensive, non-flammable, eco-compatible and is known to
attention of synthetic and medicinal chemists in designing facilitate excellent cavitation up to 50–60 °C, it is emerging as
them.
Another noteworthy recent finding includes the
the solvent of choice in sonochemistry [31]. As a result of inter
and intra molecular non covalent interactions, it causes special
effects in reactions leading to assembly processes. Copper (I)
iodide, a versatile Lewis acid catalyst has found applications in
numerous organic transformations [32]. It holds a great
promise for future research as it offers beneficial advantages
such as remarkable catalytic activity, operational simplicity,
commercial availability, inexpensive, non-corrosive and less
toxic nature.
identification of benzofuran and Huisgen’s dipole chemistry
because of their relevance as building blocks in drug design.
Benzofuran is
a very prevalent basic core unit of
pharmaceutical interest which is found in many natural
products (such as moracin, egonol and homoegonol), bioactive
molecules and other compounds [22]. Due to their profound
chemotherapeutic and physiological properties [23], this
scaffold constitutes an integral part of chemical, medicinal and
life sciences that has led to a considerable amount of modern
research being pursued in many parts of the world. This
heterocycle can also serve as versatile biodynamic motif that
can be used to construct novel active therapeutic agents [24].
The increasing enthusiasm into this nucleus is due to their
ability to display an array of valuable pharmacological activities
such as immunomodulatory, anticancer, antihyperglycemic,
antiparasitic, kinase inhibitor activities and with applications
such as brightening agents, fluorescent sensors, drugs,
antioxidants and oxidants [25]. They are regarded as potential
medicinal leads in developing therapeutic agents.
To the best of our knowledge, there are no reports in the
literature on the use of copper iodide in water under sonic
condition for the synthesis of these nitrogen heterocycles.
Encouraged by all these findings, substantial efforts have been
made by us to meticulously design a library of diversified
potent 1,4-dihydropyridines via a one-pot four-component
cyclocondensation reaction of
aromatic
aldehydes,
malononitrile, acetylenedicarboxylates and arylamines
catalyzed by copper (I) iodide in aqueous medium under
ultrasound irradiation as shown in the Scheme 1
.
R
R1OOC
R1OOC
CN
R2
COOR1
CN
CN
Furthermore, the highly active nature of the Huisgen’s
dipoles play a crucial role in organic synthesis as they are very
receptive to participate as key substrates in many kinds of
multi-component reactions and have lead to a library of
structurally diverse heterocyclic and carbocyclic molecules
[26]. They can be conveniently generated by the addition of
amines to electron-deficient alkynes which upon further
treatment with various electrophiles and other reagents would
furnish a number of C-C and C-N bond formation reactions
[27].
R
CuI
H2O, ))))
N
NH2
CHO
COOR1
NH2
R2
4(a-f)
3(a-b)
5(a-r)
2
1
Scheme 1: Preparation of polysubstituted 1,4-dihydropyridines 5(a-r)
Results and discussion
To explore the feasibility and generality of copper (I) iodide
catalyzed sonicated domino MCR, the reaction variables
including catalyst, reaction solvent, feed ratio of catalyst and
energy efficiency were optimized to observe their roles in
enhancing the rates and yield of the products. Benzofuran-2-
carboxaldehyde, malononitrile, aniline and DMAD were chosen
as model substrates.
As part of green chemistry concept, catalysis in aqueous
system under sonochemical condition has become an
irresistible method after more than two decades of extensive
studies in this domain [28]. This approach has proven to be
fast, efficient, clean and reliable in chemical laboratories when
compared to the traditional methods. Sonochemistry,
a
A variety of catalysts were explored under different
reaction conditions (room temperature, reflux temperature of
the solvent, microwave and ultrasonic irradiation) and the
results are presented in Table 1. To rationalize the influence of
the catalyst, the four component reaction was first carried out
in the absence of catalyst wherein a maximum yield of only
40% could be recorded and most of the starting materials were
recovered (Table 1, Entry 1). It was further observed that the
yield of the reaction hardly improved in the presence of other
catalysts which included amino acid (ʟ-Proline), organic
nitrogen bases (DBU, piperidine, Et3N), Lewis acids (InCl3,
frontier area in chemical research has been used increasingly
in organic synthesis as it facilitates unusual mechanism for
generating high-energy chemistry. The phenomenon of
acoustic cavitation, indeed, the backbone of sonochemistry
offers immense potentiality in the intensification of reaction
rates that can be attributed to the mechanical effects of sound
waves (heterogeneous processes) and chemical induction
(homogeneous processes) in an energy-efficient manner. It is
during the cavitation bubble collapse that immense pressures,
temperatures and the extraordinary heating and cooling rates
sets in to drive the reactions towards completion in very short
times [29]. Rapid reaction rate, simplicity, controllable reaction
.
Cu(OTf)2, CuO, CuSO4 5H2O, CuCN, CuCl, CuBr, CuNO3), amino
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sugar (Meglumine) and inorganic bases (K2CO3, NaOH) (Table Entry 13). Hence, CuI under ultrasonic irradiation was
, Entries 2−12, 14−17) whereas the use of CuI proved to be preferred for our further studies.
superior, as it gave the best yield of 5a in 30 min (Table 1
1
,
Table 1: Optimization of catalyst for the synthesis of 5a a
Reaction Condition
RT (25 °C)
Reflux (80 °C)
MW
US
Entry
Catalyst
Time
Yield
(%) b
Time
Yield
(%) b
Time
(min)
Yield
(%) b
Time
(min)
Yield
(%) b
(min)
600
600
600
600
600
600
600
600
600
600
600
600
600
600
600
600
600
(min)
600
600
600
600
600
600
600
600
600
600
600
600
600
600
600
600
600
1
2
No Catalyst
10
10
10
10
15
25
60
85
85
70
75
65
60
40
45
50
62
15
35
25
30
30
35
62
80
86
75
80
70
67
40
50
60
65
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
40
50
50
50
50
50
65
75
80
70
70
50
84
45
53
63
68
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
40
50
55
60
60
65
67
60
78
78
70
55
96
47
55
67
72
L-Proline
3
DBU
4
Piperidine
Et3N
5
6
InCl3
7
K2CO3
8
Meglumine
NaOH
9
10
11
12
13
14
15
16
17
Cu(OTf)2
CuO
.
CuSO4 5H2O
CuI
CuCN
CuCl
CuBr
CuNO3
aReaction conditions: benzofuran-2-carboxaldehyde (1 mmol), malononitrile (1 mmol), aniline (1 mmol),
DMAD (1 mmol), catalyst (0.20 mmol) and H2O (3 mL).
bIsolated yields.
Varied solvents (nonpolar, polar aprotic and polar protic
solvents) were assessed in order to substantiate the best nonpolar solvents made the reactions very lethargic and low
choice and the results of the findings are tabulated in Table 2 yields were isolated (Table 2, Entries 2−3), whereas in the case
We, initially probed this experiment under solvent-free of polar aprotic solvents, moderate yields were obtained
condition and observed that, sonication gave the maximum Table 2, Entries 4−8) and to our delight, polar protic solvents
yield (45%) of 5a whereas unsatisfactory yields were obtained gave very high yields (Table 2, Entries 9−10).
under other conditions even after prolonged time (Table 2
Furthermore, the studies revealed that, the use of
.
(
,
Entry 1).
Table 2: Optimization of solvent for the synthesis of 5a a
Reaction Condition
RT (25 °C)
Reflux
MW
US
Entry
Solvent
Time
Yield
(%) b
15
Yield
(%) b
20
Time
Yield
(%) b
25
Time
(min)
30
Yield
(%) b
45
Time(min)
(min)
600
600
600
600
600
600
600
600
600
600
(min)
30
1
2
No Solvent
Toluene
n-Hexane
DCM
600
600
600
600
600
600
600
600
600
600
16
25
30
35
30
45
3
15
25
30
40
30
50
4
18
30
30
45
30
55
5
THF
12
35
30
40
30
50
6
DMSO
CH3CN
DMF
12
25
30
30
30
58
7
10
20
30
35
30
60
8
05
15
30
30
30
55
9
Ethanol
10
20
30
80
30
87
10
H2O
25
50
30
82
30
96
a Reaction conditions: benzofuran-2-carboxaldehyde (1 mmol), malononitrile (1 mmol), aniline (1 mmol),
DMAD (1 mmol), CuI (0.20 mmol) and solvent (3 mL).
bIsolated yields.
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_______________________________________________________________________________________
aldehydes, malononitrile, diverse substituted aromatic amines
(bearing electron donating, electron withdrawing groups), and
non-aromatic amines, dialkyl acetylenedicarboxylate (DMAD,
DEAD) and CuI as catalyst in water for the tandem one-pot
multi-component synthesis of fifteen novel polysubstituted
1,4-dihydropyridines assisted by ultrasound. Gratifyingly, in all
the cases these four components congregated successfully into
Table 3: Optimization of the amount of CuI for the synthesis of 5a a
Amount of CuI
(mmol)
0.05
Time
(min)
30
Yield b
(%)
50
Entry
1
2
3
4
0.10
30
70
0.15
30
82
the
corresponding
5-cyano-1,4-dihydropyridine-2,3-
0.20
30
96
dicarboxylate analogs in good to excellent yields (Table 4
,
a Reaction conditions: benzofuran-2-carboxaldehyde (1 mmol),
malononitrile (1 mmol), aniline (1 mmol), DMAD (1 mmol),
catalyst and H2O (3 mL).
Entries 1−14). Furthermore, the protocol was successfully
extended to a series of substituted aromatic aldehydes and
excellent yields were obtained (Table 4, Entries 15−19). To our
disappointment, complex mixtures of products were observed
bIsolated yields.
when non-aromatic amines such as
n-hexylamine, cyclohexyl
amine, ethyl amine and iso-propyl amine were used (Table 4
,
Entries 19−22). It was also noted that, the electronic effects of
the substituents tethered on the aromatic ring showed
marginal effect on the reactivity and did not have much impact
on the product yields.
100
80
60
40
20
0
All the products were fully characterized by IR, 1H NMR, 13C
NMR, ESI-MS and by elemental analysis. In the IR spectrum of
compound 5a, a stretching band at 2187 cm-1 appeared which
confirms the presence of nitrile group in the product. In the 1H NMR
spectrum, three singlets appeared at 3.45, 3.69 and 4.23 ppm
indicating the presence of –CH3 protons of the two –COOMe
groups and the –NH2 protons of the amino group at C-2 carbon
respectively. The proton at the fourth position of the
dihydropyridine appeared as a singlet at 4.92 ppm confirming the
fusion of malanonitrile and DMAD. The 13C NMR spectrum further
confirmed the formation of dihydropyridine by exhibiting a signal at
165.3 ppm for the C-2 carbon of 5a. The mass spectrometry data
showed a peak at m/z 430.1 [M+H]+ which corresponds to the
expected formula of the isolated 1,4-dihydropyridine. All these
1
2
3
4
5
Number of Runs
Figure 2. Reusability of CuI for the synthesis of 5(a–r)
With the expectation to maximize the product yield in
short reaction time, the amount of catalyst required to
promote this successful transformation was ascertained and
the results are summarized in Table 3. When the reaction was
carried out using 0.05 mmol, 0.10 mmol, 0.15 mmol and 0.20
mmol of the catalyst, the rate of the reaction progressed
steadily with lower to good yields. To our pleasure, an
excellent chemical yield of 96% was obtained when 0.20 mmol
of the catalyst was employed (Table 3, Entry 4). Further
addition of the catalyst did not show any significant
enhancement in the yield of the desired product.
Consequently, the best results were achieved by using 0.20
mmol of CuI as catalyst, water as green solvent in the presence
evidences are in the favour of structure 5a
.
Further, the chemical structure of the representative
compounds 5b and 5f were unequivocally confirmed by single-
crystal X-ray diffraction studies as shown in Figures 3 and
The compounds 5b and 5f were recrystallized in ethanol.
4.
of ultrasonic waves for the synthesis of 5a
.
The possibility of recycling the catalyst was then examined.
After completion of the reaction (30 min), the reaction mixture
was treated with EtOAc (5 mL) to dissolve the product formed,
and filtered through a pre-weighed sintered glass crucible. The
solid (CuI) present in the sintered glass crucible was repeatedly
washed with water and dried in a hot air oven, the crucible
was weighed, and the solid (19 mg) was collected and kept
aside for reuse. In the present reaction, it was found that 20
mol% of CuI was reusable without appreciable loss of activity
for four runs. From the Figure 2, it can be seen that, in the first
four runs the activity was more or less maintained but after
the fourth run the yields were low, which may be due to loss
of the catalyst during recovery.
Figure 3. ORTEP plot of compound 5b
Figure 4. ORTEP plot of compound 5f
To broaden the scope of the designed protocol, we
subjected benzofuran-2-carboxaldehyde and other aromatic
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Table 4: Synthesis of 5(a–r) using ultrasounda
Aldehyde
R
Time
(min)
Yield b
(%)
Melting Point
(°C)
R1
R2
Product
Entry
1
2
CH3
C2H5
CH3
H
5a
5b
5c
5d
5e
5f
30
30
30
30
30
30
30
30
30
30
30
30
30
96
93
91
92
93
93
89
90
90
94
92
87
90
193−194
182–183
163–164
151–152
133–134
218–219
159–160
148–149
203–204
172– 173
160–161
144–145
177–178
H
3
4-Cl
4
C2H5
CH3
4-Cl
5
4-CH3
4-CH3
4-NO2
4-NO2
2-Cl
6
C2H5
CH3
7
5g
5h
5i
O
8
C2H5
CH3
9
10
11
12
13
14
C2H5
CH3
2-Cl
5j
4-OCH3
4-OCH3
3-Cl
5k
5l
C2H5
CH3
5m
C2H5
CH3
CH3
CH3
CH3
3-Cl
4-Cl
4-CH3
4-Cl
5n
5o
5p
5q
5r
30
30
30
30
30
85
90
87
87
96
161–162
217–218
187−188 [16a]
128–129 [14b]
213–214 [14b]
15
16
17
18
3,4,5 (OCH3)3C6H2
4-ClC6H4
4-ClC6H4
3-NO2C6H4
4-CH3
Intractable
mixture
Intractable
mixture
Intractable
mixture
Intractable
mixture
19
20
21
22
4-ClC6H4
CH3
CH3
CH3
CH3
n-hexylamine
cyclohexylamine
ethylamine
30
30
30
30
–
–
–
–
–
–
–
–
3-NO2C6H4
3,4,5 (OCH3)3C6H2
3,4,5 (OCH3)3C6H2
Iso-propylamine
a Reaction conditions: aromatic aldehyde (1 mmol), malononitrile (1 mmol), aniline/amine (1 mmol), DMAD/DEAD (1 mmol),
CuI (0.20 mmol), H2O (3 mL) and temp 25 °C (35 kHz constant frequency, 80W).
b Isolated yields.
Generally, when ultrasound is passed through a liquid–
In conclusion, the present study deals with the
solid system, bubble cavitation ascends due to variation in bulk development of an efficient synthetic strategy to construct
pressure and causes a series of unique physical phenomena complex 1,4-dihydropyridines that could further streamline
that can affect the solid. Asymmetric bubble collapse occurs at their syntheses with the aid of greener and harmless sound
the interface generating high-pressure/high-velocity microjets energy technique.
and high energetic shockwaves leading to intermolecular
The attractive features of this procedure are the use of
reactions in short times. These jets trigger the solid catalyst, inexpensive starting materials, high atom efficiency, clean
causes disruption of the interfacial boundary, intensifies the reaction profiles, use of ecofriendly solvent, mild reaction
contact through efficient mixing. As a result localized erosion, conditions, it is general and very high yields are obtained,
particle fragmentation by overall particle size reduction, involes use of an energy efficient techinque which meets the
disengagement of heterogeneous reactants, intermediates, essential precepts of a green chemical approaches. These
product take place enhancing the overall heat and mass pharmacophoric frameworks may hopefully provide insights
transfer [28b, 33]. Also, the implosive bubble collapse induces for medicinal chemists to explore their virtue in developing
extremely high temperatures (as much as 4700
°C) and novel pharmaceutical agents to tackle the varied pathological
pressures (10 Pa) in a microscopic region of the sonicated aspects and modify the disease processes. These analogs are
liquid [28c]. As a result the rate of the chemical reaction of particular interest, as they contain reactive handles and as
increases by many folds, which is termed “false such could be used as a foundation for the synthesis of more-
sonochemistry” Therefore, it is feasible to assume that these complex biologically important molecules.
effects are responsible for the chemical enhancement of
reactions.
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Yellow crystal; m.p 182–183 °C; IR (ν cm-1): 3325, 2952, 2190, 1752,
Experimental section
Material and methods
1651, 1221; 1H NMR (500 MHz, CDCl3):
δ
1.19−1.22 (t,
J
J
= 7.0 Hz, 3H,
= 7.0 Hz, 4H,
Reagents and solvents were purchased from Sigma Aldrich.
All materials were of commercial reagent grade. Melting
points were determined using Thiele’s apparatus (con. H2SO4)
with a calibrated thermometer. The progress of the reaction
and the purity of the compounds were monitored by TLC
[analytical silica gel plates (Merck60 F254)]. Infrared (IR) spectra
were recorded using an Agilent Cary 630 FT-IR
Spectrophotometer. 1H NMR spectra were recorded on an
Advance Bruker instrument operating at 400, 500 MHz and 13C
NMR spectra were recorded at 100 MHz in CDCl3. Chemical
shifts were reported in ppm. ESI-MS analysis was carried out
using ESI-Q TOF instrument. CHN analysis was performed using
Elementar vario MICRO cube analyzer. Sonication was
performed using SIDILU Indian make sonic bath operating at
35 kHz (constant frequency, 80W) maintained at 25 °C by
circulating water.
−4.25 (q,
-CH3), 1.39
−1.42 (t,
J
= 7.0 Hz, 3H, -CH3), 4.20
-CH2), 4.85 (s, 2H, -NH2), 5.19 (s, 1H, -CH), 6.56 (s, 1H, Ar-H),
7.13−7.55 (m, 9H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
14.6,
δ
15.3, 30.7, 56.9, 60.3, 61.7, 99.4, 107.0, 110.6, 113.5, 114.1, 118.5,
121.0, 123.2, 126.0, 127.6, 129.6, 131.2, 142.9, 149.8, 156.1, 163.6,
166.9, 169.2 ppm; ESI-MS, m/z: 458.1 [M+H]+; Anal. Calc. for
C26H23N3O5 (%): C, 68.26, H, 5.07, N, 9.19; found: C, 68.34, H, 5.02,
N, 9.11.
Dimethyl-6-amino-4-(benzofuran-2-yl)-1-(4´-chlorophenyl)-5-
cyano-1,4-dihydropyridine-2,3-dicarboxylate (5c)
Brown powder; m.p 118–119 °C; IR (ν cm-1): 3380, 2945, 2181,
1743, 1621, 1205; 1H NMR (400 MHz, CDCl3):
3.51 (s, 3H, -CH3),
3.69 (s, 3H, -CH3), 4.46 (s, 2H, -NH2), 5.29 (s, 1H, -CH), 6.57 (s, 1H,
Ar-H), 7.19−7.54 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
:
δ
δ
32.9, 52.4, 52.9, 59.9, 102.4, 111.3, 119.8, 121.1, 122.8, 124.0,
128.5, 130.4, 131.5, 133.1, 133.8, 137.0, 142.4, 151.0, 155.2, 158.2,
163.2, 165.2 ppm; ESI-MS, m/z: 464.0 [M+H]+; Anal. Calc. for
C24H18ClN3O5 (%): C, 62.14, H, 3.91, N, 9.06; found: C, 62.19, H, 3.98,
N, 9.03.
General procedure for the synthesis of polysubstituted 1,4-
dihydropyridines 5(a-r)
A
50mL flask was charged with benzofuran-2-
carboxaldehyde/aromatic aldehyde (1 mmol), malononitrile (1
mmol), copper iodide (0.20 mmol) in water (3 mL) and
sonicated (35 kHz) at 25 °C for 10 min. Then a solution of
acetylenedicarboxylate/s (1 mmol) and aniline or non-aromatic
amine (1 mmol) in water (3 mL) was added to the above flask
and the resulting mixture was further sonicated (35 kHz) at 25
°C for an additional 20 min. After completion of the reaction
[monitored by TLC, using hexane:ethyl acetate (9:1) as eluent],
the reaction mixture was treated with EtOAc (5 mL) to dissolve
the product formed, and filtered through a pre-weighed
sintered glass crucible. The solid (CuI) present in the sintered
glass crucible was repeatedly washed with water and dried in a
hot air oven, the crucible was weighed, the solid (19 mg) was
collected and kept aside for reuse. The filtrate was then taken
into a separating funnel, the organic layer was separated, and
dried over anhydrous Na2SO4 to get the crude compound
which was then recrystallized from ethanol to get the pure
product. The structures of all the products were confirmed by
IR, 1H NMR, 13C NMR, ESI-MS and CHN analyses.
Diethyl-6-amino-4-(benzofuran-2-yl)-1-(4´-chlorophenyl)-5-cyano-
1,4-dihydropyridine-2,3-dicarboxylate (5d):
Yellow crystal; m.p 151–152 °C;IR (ν cm-1): 3390, 2983, 2105, 1745,
1668, 1217;1H NMR (400 MHz, CDCl3):
δ
1.21−1.25 (t,
J
J
= 6.8 Hz, 3H,
= 6.8 Hz, 4H,
-CH3), 1.37−1.40 (t,
J
= 6.8 Hz, 3H, -CH3), 4.07−4.12 (q,
-CH2), 4.85 (s, 2H, -NH2), 5.19 (s, 1H, -CH), 7.25−7.65 (m, 9H, Ar-H)
ppm;13C NMR (100 MHz, CDCl3):
13.7, 14.3, 29.0, 57.1, 60.1, 62.2,
δ
94.9, 106.3, 112.4, 112.5, 113.7, 119.4, 122.3, 123.3, 124.8, 127.3,
129.1, 130.2, 143.7, 148.6, 156.9, 163.3, 167.0, 168.5 ppm; ESI-MS,
m/z: 492.1 [M+H]+; Anal. Calc. for C26H22ClN3O5 (%): C, 63.48, H,
4.51, N, 8.54; found: C, 63.55, H, 4.59, N, 8.59.
Dimethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-
p-tolyl-1,4-
dihydropyridine-2,3-dicarboxylate (5e):
Yellow powder; m.p 133–134 °C; IR (ν cm-1): 3325, 2978, 2105,
1755, 1632, 1219; 1H NMR (400 MHz, CDCl3):
2.36 (s, 3H, -CH3),
δ
3.10 (s, 3H, -CH3), 3.47 (s, 3H, -CH3), 4.54 (s, 2H, -NH2), 4.80 (s, 1H, -
CH), 6.82 (s, 1H, Ar-H), 7.20−7.62 (m, 8H, Ar-H) ppm; 13C NMR (100
MHz, CDCl3):
δ 24.5, 31.1, 51.5, 52.1, 58.8, 103.1, 112.4, 120.0,
122.8, 124.2, 126.4, 128.7, 130.6, 131.4, 132.6, 133.7, 137.3, 143.6,
149.5, 153.7, 156.9, 161.8, 163.9 ppm; ESI-MS, m/z: 444.1 [M+H]+;
Anal. Calc. for C25H21N3O5 (%): C, 67.71, H, 4.77, N, 9.48; found: C,
67.79, H, 4.85, N, 9.42.
Spectral data
Dimethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (5a):
Yellow crystal; m.p 193–194 °C; IR (ν cm-1): 3336, 2975, 2187, 1740,
Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-
p-tolyl-1,4-
1
1653, 1217; H NMR (500 MHz, CDCl3):
δ 3.45 (s, 3H, -CH3), 3.69 (s,
dihydropyridine-2,3-dicarboxylate (5f):
Yellow crystal; m.p 218–219 °C;IR (ν cm-1): 3397, 2938, 2143, 1751,
1653, 1981; 1H NMR (400 MHz, CDCl3):
0.92−0.95 (t, = 6.8 Hz, 3H,
-CH3), 1.26−1.29 (t, = 6.8 Hz, 3H, -CH3), 2.39 (s, 3H, -CH3),
4.19−4.24 (q, = 6.8 Hz, 4H, -CH2), 4.59 (s, 2H, -NH2), 4.79 (s, 1H, -
CH), 6.84 (s, 1H, Ar-H), 7.21−7.59 (m, 8H, Ar-H) ppm; 13C NMR (100
MHz, CDCl3): 14.9, 15.6, 30.5, 55.5, 61.3, 62.5, 101.7, 108.0, 110.7,
3H, -CH3), 4.23 (s, 2H, -NH2), 4.92 (s, 1H, -CH), 6.57 (s, 1H, Ar-H),
7.19−7.55 (m, 9H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
32.4,
δ
δ
J
51.5, 52.1, 59.9, 103.6, 112.6, 118.9, 120.5, 122.5, 125.0, 127.7,
129.7, 131.2, 132.2, 135.1, 137.1, 141.3, 150.1, 154.3, 157.5, 163.0,
165.3 ppm; ESI-MS, m/z: 430.1 [M+H]+; Anal. Calc. for C24H19N3O5
(%): C, 67.13, H, 4.46, N, 9.79; found: C, 67.18, H, 4.41, N, 9.74.
Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (5b):
J
J
δ
113.7, 115.5, 118.0, 120.6, 123.2, 125.0, 128.6, 131.8, 135.1, 142.9,
150.5, 155.5, 162.7, 166.7, 169.2 ppm; ESI-MS, m/z: 472.1 [M+H]+;
6 | RSC Advances., 2015, 00, 1-9
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Anal. Calc. for C27H25N3O5 (%): C,68.78, H, 5.34, N, 8.91; found: C, 121.8, 123.0, 124.5, 128.7, 130.9, 131.6, 133.2, 134.0, 138.0, 140.9,
68.69, H, 5.38, N, 8.98.
149.9, 156.4, 159.5, 162.2, 164.6 ppm; ESI-MS, m/z: 460.1 [M+H]+;
Dimethyl 6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4´-nitrophenyl)- Anal. Calc. for C25H21N3O6 (%): C, 65.35, H, 4.61, N, 9.15; found: C,
1,4-dihydropyridine-2,3-dicarboxylate (5g): 65.21, H, 4.66, N, 9.17.
Yellow powder; m.p 159–160 °C; IR (ν cm-1): 3341, 2930, 2176, Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4´-
1752, 1634, 1203; 1H NMR (400 MHz, CDCl3):
δ 3.45 (s, 3H, -CH3), methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5l):
3.70 (s, 3H, -CH3), 4.37 (s, 2H, -NH2), 5.29 (s, 1H, -CH), 6.62 (s, 1H, Yellow powder; m.p 144–145 °C; IR (ν cm-1): 3357, 2917, 2182,
Ar-H), 7.24−7.72 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
δ
1746, 1616, 1211; H NMR (400 MHz, CDCl3):
δ
0.90−0.94 (t,
= 6.8 Hz, 3H, -CH3), 2.29 (s, 3H, -OCH3),
= 6.8 Hz, 4H, -CH2), 4.53 (s, 2H, -NH2), 4.82 (s, 1H, -
162.2, 164.2 ppm; ESI-MS, m/z: 475.1 [M+H]+; Anal. Calc. for CH), 6.84 (s, 1H, Ar-H), 7.21−7.59 (m, 8H, Ar-H) ppm; 13C NMR (100
C24H18N4O7 (%): C, 60.76, H, 3.82, N, 11.81; found: C, 60.84, H, 3.89, MHz, CDCl3): 13.0, 13.7, 28.4, 52.7, 55.5, 61.6, 62.5, 99.2, 106.6,
J = 6.8
1
32.9, 52.3, 52.8, 58.5, 104.1, 112.4, 121.4, 122.7, 123.8, 124.6, Hz, 3H, -CH3), 1.26−1.29 (t,
125.5, 127.1, 128.2, 130.1, 131.9, 137.1, 143.6, 151.0, 155.0, 158.7, 4.12−4.16 (q,
J
J
δ
N, 11.88.
112.5, 114.0, 115.1, 118.4, 121.5, 123.4, 125.0, 128.0, 130.4, 134.2,
143.6, 151.7, 157.1, 163.8, 166.1, 167.8 ppm; ESI-MS, m/z: 488.1
[M+H]+;
Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4´-nitrophenyl)-
1,4-dihydropyridine-2,3-dicarboxylate (5h):
Yellow powder; m.p 148–149 °C; IR (ν cm-1): 3322, 2943, 2195, Anal. Calc. for C27H25N3O6(%): C, C, 66.52, H, 5.17, N, 8.62; found: C,
1748, 1670, 1233; 1H NMR (400 MHz, CDCl3):
δ
1.12−1.15 (t,
J
= 6.8 66.59, H, 5.12, N, 8.60.
Hz, 3H, -CH3), 1.28−1.31 (t, = 6.8 Hz, 3H, -CH3), 4.16−4.21 (q,
J
J
= 6.8 Dimethyl-6-amino-4-(benzofuran-2-yl)-1-(3´-chlorophenyl)-5-
Hz, 4H, -CH2), 5.43 (s, 1H, -CH), 6.85 (s, 2H, -NH2), 7.22−7.72 (m, 9H, cyano-1,4-dihydropyridine-2,3-dicarboxylate (5m):
Ar-H) ppm; 13C NMR (100 MHz, CDCl3): 15.0, 15.1, 29.4, 57.4, 60.3, Yellow powder; m.p 177–178 °C; IR (ν cm-1): 3356, 2957, 2128,
61.5, 101.0, 106.5, 112.0, 112.6, 116.1, 119.6, 123.5, 125.1, 126.9, 1751, 1676, 1219; 1H NMR (400 MHz, CDCl3):
3.51 (s, 3H, -CH3),
129.1, 130.2, 135.4, 144.0, 148.3, 156.6, 163.8, 166.6, 167.5 ppm; 3.68 (s, 3H, -CH3), 4.96 (s, 2H, -NH2), 5.29 (s, 1H, -CH), 6.73 (s, 1H,
ESI-MS, m/z: 503.1 [M+H]+; Anal. Calc. for C26H22N4O7 (%): C, 62.15, Ar-H), 7.20−7.49 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
δ
δ
δ
H, 4.41, N, 11.15; found: C, 62.21, H, 4.47, N, 11.17.
Dimethyl-6-amino-4-(benzofuran-2-yl)-1-(2´-chlorophenyl)-5-
cyano-1,4-dihydropyridine-2,3-dicarboxylate (5i):
33.8, 53.4, 54.1, 62.3, 103.6, 112.5, 119.4, 121.1, 124.2, 125.8,
128.5, 130.1, 132.0, 133.1, 134.5, 137.00, 141.5, 151.5, 154.7,
159.3, 162.1, 166.5 ppm; ESI-MS, m/z: 464.0 [M+H]+; Anal. Calc. for
Golden yellow powder; m.p 203–204 °C; IR (ν cm-1): 3327, 2938, C24H18ClN3O5 (%): C, 2.14, H, 3.91, N, 9.06; found: C, 62.11, H, 3.97,
1
2185, 1747, 1631, 1246; H NMR (500 MHz, CDCl3):
δ 3.47 (s, 3H, - N, 9.01.
CH3), 3.68 (s, 3H, -CH3), 4.19 (s, 2H, -NH2), 4.88 (s, 1H, -CH), 6.61 (s, Diethyl-6-amino-4-(benzofuran-2-yl)-1-(3´-chlorophenyl)-5-cyano-
1H, Ar-H), 7.19−7.62 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3): 1,4-dihydropyridine-2,3-dicarboxylate (5n):
δ
33.5, 52.6, 53.2, 60.1, 103.6, 110.5, 118.7, 120.8, 122.5, 124.7, Yellow powder; m.p 161–162 °C; IR (ν cm-1): 3319, 2979, 2167,
1
128.5, 130.0, 132.6, 135.5, 137.1, 142.3, 146.9, 150.6, 155.5, 157.5, 1742, 1636, 1269; H NMR (400 MHz, CDCl3):
162.5, 165.4 ppm; ESI-MS, m/z: 464.0 [M+H]+; Anal. Calc. for Hz, 3H, -CH3), 1.33−1.36 (t,
δ
1.17−1.21 (t,
J
= 6.8
= 6.8
J
= 6.8 Hz, 3H, -CH3), 4.10−4.15 (q, J
C24H18ClN3O5 (%): C, 62.14, H, 3.91, N, 9.06; found: C, 62.19, H, 3.98, Hz, 4H, -CH2), 4.79 (s, 2H, -NH2), 5.05 (s, 1H, -CH), 6.62 (s, 1H, Ar-H),
N, 9.02.
7.20−7.45 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
δ 15.3,
Diethyl-6-amino-4-(benzofuran-2-yl)-1-(2´-chlorophenyl)-5-cyano-
16.1, 30.6, 56.4, 60.3, 61.5, 99.7, 107.9, 111.5, 113.8, 115.6, 119.5,
120.7, 123.6, 127.6, 131.7, 133.4, 136.4, 142.7, 148.9, 157.3, 163.8,
1,4-dihydropyridine-2,3-dicarboxylate (5j):
Golden yellow powder; m.p 172–173 °C; IR (ν cm-1): 3321, 2943, 165.6, 170.2 ppm; ESI-MS, m/z: 492.1 [M+H]+; Anal. Calc. for
2156, 1739, 1669, 1287; 1H NMR (500 MHz, CDCl3):
δ
1.18−1.21 (t,
J
J
C26H22ClN3O5 (%): C, 63.48, H, 4.51, N, 8.54; found: C, 63.43, H, 4.48,
N, 8.59.
= 7.0 Hz, 3H, -CH3), 1.36−1.39 (t, = 7.0 Hz, 3H, -CH3), 4.07−4.12 (q,
J
= 7.0 Hz, 4H, -CH2), 4.42 (s, 2H, -NH2), 4.78 (s, 1H, -CH), 6.46 (s, 1H, Dimethyl-6-amino-1-(4´-chlorophenyl)-5-cyano-4-(3´´,4´´,5´´-
Ar-H), 7.09−7.73 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
trimethoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5o):
13.9, 14.5, 30.0, 56.8, 60.2, 61.4, 99.5, 107.3, 111.6, 112.5, 115.0, Yellow powder; m.p 217–218 °C; IR (ν cm-1): 3319, 2979, 2167,
119.7, 121.3, 123.0, 119.7, 121.3, 123.0, 125.1, 125.7, 129.6, 131.6, 1742, 1636, 1269; 1H NMR (400 MHz, CDCl3):
3.53 (s, 3H, -CH3),
δ
δ
143.0, 148.6, 157.1, 163.7, 166.6, 168.4 ppm; ESI-MS, m/z: 492.1 3.65 (s, 3H, -CH3), 3.86 (s, 3H, -OCH3), 3.90 (s, 6H, -OCH3), 4.63 (s,
[M+H]+; Anal. Calc. for C26H22ClN3O5 (%): C, 63.48, H, 4.51, N, 8.54; 2H, -NH2), 5.31 (s, 1H, -CH), 6.59 (s, 2H, Ar-H), 7.25−7.49 (m, 4H, Ar-
found: C, 63.42, H, 4.50, N, 8.59.
H) ppm; 13C NMR (100 MHz, CDCl3):
δ 38.0, 55.1, 55.2, 62.0, 62.6,
Dimethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4-
63.0, 103.4, 105.3, 115.1, 120.1, 127.7, 130.9, 138.0, 140.6, 141.9,
methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5k):
150.1, 153.0, 160.9, 163.8, 165.5 ppm; ESI-MS, m/z: 514.1 [M+H]+;
Yellow powder; m.p 160–161 °C; IR (ν cm-1): 3314, 2955, 2163, Anal. Calc. for C25H24ClN3O7 (%): C, 58.43, H, 4.71, N, 8.18; found: C,
1
1745, 1638, 1209; H NMR (400 MHz, CDCl3):
δ 3.50 (s, 3H, -OCH3), 58.31, H, 4.80, N, 8.29.
3.68 (s, 3H, -CH3), 3.85 (s, 3H, -CH3), 4.20 (s, 2H, -NH2), 4.91 (s, 1H, - Dimethyl-6-amino-4-(4´-chlorophenyl)-5-cyano-1-
CH), 6.56 (s, 1H, Ar-H), 7.18−7.54 (m, 8H, Ar-H) ppm; 13C NMR (100 dihydropyridine-2,3-dicarboxylate (5p):
p-tolyl-1,4-
MHz, CDCl3):
δ 33.4, 51.6, 52.3, 56.3, 60.0, 103.9, 112.0, 120.6,
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Yellow powder; m.p 187–188 °C; IR (ν cm-1): 3363, 2921, 2110,
(b) A. Boumendjel, H. Baubichon-Cortay, D. Trompier, T.
Perrotton and A. Di Pietro, Med. Res. Rev., 2005, 25, 453−472;
(c) C. Avendano and J. C. Menendez, Med. Res. Rev., 2004, 1,
1735, 1659, 1227; 1H NMR (400 MHz, CDCl3):
δ
2.4 (s, 3H, -CH3),
3.45 (s, 3H, -OCH3), 3.59 (s, 3H, -OCH3), 4.11 (s, 2H, -NH2), 4.68 (s,
1H, -CH), 7.18−7.29 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
419‒444;
δ
(d) A. Hilgeroth and H. Lilie, Eur. J. Med. Chem., 2003, 38, 495‒
22.0, 38.5, 52.6, 62.6, 105.6, 112.6, 121.1, 128.5, 129.3, 130.3,
131.1, 132.5, 133.1, 141.0, 142.0, 142.8, 149.1, 162.1, 165.6 ppm;
ESI-MS, m/z: 438.1 [M+H]+; Anal. Calc. for C23H20ClN3O4 (%): C,
63.09, H, 4.60, N, 9.60; found: C, 63.18, H, 4.67, N, 9.72.
Dimethyl-6-amino-1,4-bis(4´-chlorophenyl)-5-cyano-1,4-
dihydropyridine-2,3-dicarboxylate (5q):
499;
(e) D. J. Triggle, Biochem Pharmacol., 2007, 74, 1−9;
(f) S. Bahekar and D. Shinde, Acta pharmaceut., 2002, 52, 281‒
287;
(g) S. Gullapalli and P. Ramarao, Neuropharmacology, 2002, 42
467−475;
(h) E. Fasani, M. Fagnoni, D. Dondi and A. Albini, J. Org. Chem.
2006, 71, 2037‒2045.
4. (a) J. Marco-Contelles, R. Leon, C. de los Rios, A. Samadi, M.
Bartolini, V. Andrisano, O. Huertas, X. Barril, F. J. Luque and M. I.
Rodriguez-Franco, J. Med Chem., 2009, 52, 2724‒2732;
,
,
Yellow powder; m.p 128–129 °C; IR (ν cm-1): 3360, 2989, 2119,
1746, 1643, 1210; 1H NMR (400 MHz, CDCl3):
δ
3.41 (s, 3H, -CH3),
3.69 (s, 3H, -CH3), 4.13 (s, 2H, -NH2), 4.63 (s, 1H, -CH), 7.22−7.47 (m,
8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
18.8, 36.7, 50.5, 51.1,
δ
(b) N. Edraki, A. R. Mehdipour, M. Khoshneviszadeh and R. Miri,
Drug Discov. Today., 2009, 14, 1058‒1066;
(c) D. J. Triggle, D. A. Langs and R. A. Janis, Med. Res. Rev., 1989,
56.4, 61.8, 104.6, 120.5, 127.7, 128.4, 129.9, 130.0, 130.7, 131.4,
132.1, 132.6, 134.0, 135.8, 140.8, 141.2, 143.5, 149.7, 157.2, 159.2,
163.9, 164.7 ppm; ESI-MS, m/z: 458.1 [M+H]+; Anal. Calc. for
C22H17Cl2N3O4 (%): C, 57.66, H, 3.74, N, 9.17; found: C, 57.50, H,
4.03, N, 8.95.
9
, 123‒180;
5. (a) K. Aouam and A. Berdeaux, Therapie, 2003, 58, 333‒339;
(b) A. Hilgeroth, Mini. Rev. Med. Chem., 2002, , 235‒245;
2
Dimethyl-6-amino-5-cyano-4-(3´-nitrophenyl)-1-
p-tolyl-1,4-
(c) C. O. Kappe, W. M. Fabian and M. A. Semones, Tetrahedron
,
dihydropyridine-2,3-dicarboxylate (5r):
1997, 53, 2803‒2816;
Yellow powder; m.p 213–214 °C; IR (ν cm-1): 3382, 2942, 2120,
1749, 1610, 1237; 1H NMR (400 MHz, CDCl3):
2.49 (s, 3H, -CH3),
3.46 (s, 3H, -OCH3), 3.59 (s, 3H, -OCH3), 4.18 (s, 2H, -NH2), 4.82 (s,
1H, -CH), 7.26−8.28 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz, CDCl3):
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129.3, 130.1, 130.7, 131.5, 132.6, 134.1, 141.1, 142.5, 146.7, 148.1,
151.9, 162.4 163.9 ppm; ESI-MS, m/z: 449.1 [M+H]+; Anal. Calc. for
C23H20N4O6 (%): C, 61.60, H, 4.50, N, 12.49; found: C, 61.49, H, 4.85,
N, 12.11.
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Acknowledgements
The authors gratefully acknowledge the financial assistance by
the VGST, Dept. of IT, BT and Science
& Technology,
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2009, 74, 2862‒2865;
,
Government of Karnataka for the CESEM Award Grant No. 24
(2010-2011). We also acknowledge the NMR centers, IISc,
Bangalore for providing 1H and 13C NMR spectra.
(b) N. M. Evdokimov, I. V. Magedov, A. S. Kireev and A.
Kornienko, Org. Lett., 2006, , 899‒902.
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and M. Asgari-Kheirabadi, RSC Adv., 2015, , 18145‒18152.
8
5
Appendix A. Supporting Information
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1362.
The detailed spectroscopic data of all the new compounds are
available free of charge via the Internet. Single crystal data for
compounds 5b (CCDC 1423053) and 5f (CCDC 1423055) have
been deposited in the Cambridge Crystallographic Data Center.
13. S. Pal, M. N. Khan and L. H. Choudhury, J. Heterocycl. Chem.
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