Novel bipodal, tripodal, and tetrapodal 1,4-dihydropyridines - Microwave-assisted synthesis and structural confinements

Article abstract of DOI:10.1139/v11-088

The one pot, three component reaction of p-hydroxy benzaldehyde, β-ketoester, and ammonium acetate afforded the corresponding monopodal 1,4-dihydropyridines as building blocks, which in turn converted into diversified novel bipodal, tripodal, and tetrapodal 1,4-dihydropyridines with different alkylating agents through conventional as well as microwave assisted reactions. The unambiguous structural confinements of the all the synthesized compounds were drawn out with the help of 2D NMR (H-H COSY and C-H COSY).

Full text of DOI:10.1139/v11-088

1236
Novel bipodal, tripodal, and tetrapodal 1,4-
dihydropyridines — Microwave-assisted synthesis
and structural confinements
Kancherla Rajesh, Bandapalli Palakshi Reddy, and Vijayaparthasarathi Vijayakumar
Abstract: The one pot, three component reaction of p-hydroxy benzaldehyde, b-ketoester, and ammonium acetate afforded
the corresponding monopodal 1,4-dihydropyridines as building blocks, which in turn converted into diversified novel bipo-
dal, tripodal, and tetrapodal 1,4-dihydropyridines with different alkylating agents through conventional as well as microwave
assisted reactions. The unambiguous structural confinements of the all the synthesized compounds were drawn out with the
help of 2D NMR (H-H COSY and C-H COSY).
Key words: bipodal-tripodal-tetrapodal 1,4-dihydropyridines, Hantzsch pyridines, microwave irradiation.
Résumé : La réaction monotope, à trois composants, du p-hydroxybenzaldéhyde, d′un b-cétoester et de l′acétate d′ammo-
nium conduit aux 1,4-dihydropyridines correspondantes, des synthons monopodes qui, par le biais de réactions normales ou
assistées par des microondes, peuvent être transformées à leur tour en nouvelles 1,4-dihydropyridines bipodes, tripodes et té-
trapodes portant divers agents alkylants. Les confinements structuraux non ambiguës de tous les composés synthétisés ont
été délimités à l′aide de la RMN 2D (COSY H-H et COSY C-H).
Mots‐clés : 1,4-dihydropyridines bipodes, tripodes ou tétrapodes, pyridines de Hantzsch, irradiation microonde.
[Traduit par la Rédaction]
and applications has been of continuing interest, which led
to the development of novel synthetic strategies. So far the
attention has mainly been paid to the synthesis of monopodal
1,4-DHP derivatives, and the highly functional ones are sel-
dom investigated. A series of bis-1,4-DHP derivatives was
synthesized by Songlei Zhu et al. by the reaction of
p-phenylenedialdehyde or m-phenylenedialdehyde and active
methylene compounds.10 Mohammad Ali Zolfigol et al. syn-
thesized new tripodal 1,4-DHPs under solvent-free conditions
by the reaction of a mixture of b-ketoester and tri-aldehydes
in the presence of ammonium fluoride.11 Although the meth-
ods described above have been beneficial in the specific ex-
amples for which they were developed, they do not show
much scope for the synthesis of varyingly substituted bipo-
dal, tripodal, and tetrapodal 1,4-DHPs, where synthesis by
the former methods requires bis, tris, and tetra aldehydes,
which is a costlier approach and not applicable in some
cases. A retro synthetic analysis approach (Scheme 1) for tar-
get bipodal 1,4-DHPs has shown that the simple monopodal
1,4-DHPs can serve as building blocks for the construction of
the target molecules.
Introduction
The synthesis of 1,4-dihydropyridines (1,4-DHPs) via a
three-component cyclocondensation reaction of acetoacetic
ester, arylaldehyde, and ammonia was first reported by
Arthur Hantzsch in 1882.1 Since then a lot of new variants
of the original method have been developed, allowing the
synthesis of different substituted 1,4-DHPs, which have now
been recognized as vital drugs in the treatment of angina and
hypertension. Some of the representatives like nifedipine,2 fe-
lodipine,3 nicardipine,4 amlodipine,5 and manidipine hydro-
chloride (Fig. 1), have been commercialized and have proven
their pharmaceutical action in binding to the voltage depend-
ent L-type calcium channel, thus decreasing the passage of
calcium ions into the cell. The result is the relaxation of
smooth muscle cells and the lowering of blood pressure.
Studies revealed that 1,4-DHPs exhibit several other me-
dicinal applications, which include neuroprotectant6 and pla-
telet antiaggregatory activity,7 in addition to acting as a
cerebral anti-ischemic agent in the treatment of Alzheimer’s
disease8 and as a chemosensitizer in tumor therapy.9 The ex-
amples clearly demonstrate the potential of novel DHP deriv-
atives as a source of valuable drug candidates. A recent
computational analysis of the compressive medicinal chemis-
try database found that the DHP framework to be among the
most prolific chemo-types. Thus, the synthesis of molecules
containing this heterocyclic nucleus with diverse properties
The synthesis of monopodal 1,4-DHP building blocks in-
volves one-pot multicomponent coupling reactions (MCRs),
where several organic moieties coupled in one step for car-
bon–carbon and carbon–heteroatom bond formation, which
is an attractive synthetic strategy for the synthesis of small
molecule libraries with several degrees of structural diver-
Received 10 January 2011. Accepted 4 June 2011. Published at www.nrcresearchpress.com/cjc on 7 September 2011.
K. Rajesh, B. Palakshi Reddy, and V. Vijayakumar. Synthetic Organic Chemistry Research Laboratory, Organic Chemistry Division,
School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India.
Corresponding author: Vijayaparthasarathi Vijayakumar (e-mail: kvpsvijayakumar@gmail.com).
Can. J. Chem. 89: 1236–1244 (2011)
doi:10.1139/V11-088
Published by NRC Research Press

Rajesh et al.
1237
Fig. 1. Biologically active 1,4-dihydropyridines.
Cl
Cl
O
NO2
O
H3C
H3COOC
COOCH3
O
O
CH3
H3C
N
H
CH3
H3C
N
H
CH3
Nifedipine
Felodipine
NO2
Cl
COOC2H5
CH3
N
O
H3COOC
H3COOC
O
O
Ph
H3C
N
H
NH2
H3C
N
H
CH3
Amlodipine
Nicardipine
NO2
N
O
N
COOCH3
O
H3C
N
H
CH3
Manidipine Hydrochloride
Fig. 2. Structural correlation of the synthesized bipodal 1,4-DHP 13 with the nifedipine.
N
O
O
NO2
O
O
O
O
O
O
O
O
O
O
O
N
H
HN
O
NH
Nifedipine
13
sities.12–14 The synthesis mainly involves the dehydration of
arylaldehydes, b-ketoester or diketone, and ammonium ace-
tate.
The present work describes a direct approach, where the
monofunctional 1,4-DHPs, thus synthesized according to the
literature,15,16 serve as building blocks for the construction of
novel bipodal, tripodal, and tetrapodal 1,4-DHPs by the con-
ventional methods and by microwave irradiation, which is
hitherto unreported in the literature, and all the results were
best executed. The structural correlation of the synthesized
bipodal 1,4-DHP 13 with nifedipine (vital drug in treatment
of angina and hypertension) can be seen in Fig. 2.
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Can. J. Chem. Vol. 89, 2011
Scheme 1. Retrosynthetic analysis approach for bipodal 1,4-DHPs.
O
R
O
O
O
R
R
O
O
O
O
O
O
NH
HN
R
Path- B
Path- A
NH4OAc
NH4OAc
O
R
O
O
Br
Br
O
R
O
O
R
O
O
HO
OH
O
O
O
O
O
CHO
R
OHC
O
O
R
R
O
O
O
O
R
O
NH
O
N
H
O
R
CHO
OH
OHC
R
O
O
HO
CHO
OH
O
R
O
Br
Br
O
O
NH4OAc
Scheme 2. Synthetic scheme for bipodal p-substituted 1,4-DHPs 7–8.
17
17'
16'
OH
15
15'
16
Br
O
O
R10'
R
17'
17
14
13'
14
9'
13
13'
12'
12' O
O
O
K2CO3
mw
13
R10'
12
11
+
8'
11
O
O
9
12
R
O
O
9'
4
5
R
O
8'
4
3
O
O
8
10
O
6
3
N
H
5
6
7'
Br
8
2
9
O
2
NH
1
7
4 R= -CH3
5 R= -H
6
N1
H
R10
7 R= -CH3
7'
7
8
R= -H
Results and discussion
using di-bromo, tri-bromo, or tetra-bromo benzenes with
p-hydroxybenzaldehyde, which can further be reacted with
b-ketoester and ammonium acetate to give the desired poly-
podals, but large amounts of di-bromo, tri-bromo, and tetra-
bromo benzenes are needed to carry out the first step, which
is a costlier approach. So, Path-A was chosen for convenience,
where a mixture of p-hydroxy benzaldehyde, b-ketoester, and
ammonium acetate in ethanol were heated to give the desired
1,4-DHPs (4, 5) in a first step (Table 1). The structure of the
As part of the continuing interest in the synthesis of 1,4-
DHP nucleus17–20 and heterocyclic compounds bearing bipo-
dal and tripodal moieties,21–23 we synthesized novel bipodal,
tripodal, and tetrapodal 1,4-DHPs by the reaction of mono-
functional 1,4-DHP (4, 5) with different alkylating agents by
using powdered K2CO3 as mild base (Schemes 2–6).
The two possible retro synthetic analysis approaches, Path-
A and Path-B for bipodal 1,4-DHPs, are given in Scheme 1.
In case of Path-A, as a part of a first step, the desired 1,4-
DHPs (4, 5) have to be synthesized, which may then be re-
acted with di-bromo, tri-bromo, or tetra-bromo benzenes to
give the desired polypodals by using a mild base. Alterna-
tively, this can also be achieved via Path-B, where bis, tris,
and tetrakis aldehydes have to be synthesized in a first step
1
products 4 and 5 have been characterized using H NMR and
HRMS data. The melting point, retention factor, Rf (the re-
tention factor value of the synthesized sample was compared
with that of the sample commercially sourced from Sigma-
Aldrich), and spectral data were found to be in accord with
the literature.15,16
Published by NRC Research Press

Rajesh et al.
1239
Scheme 3. Synthetic scheme for bipodal m-substituted 1,4-DHPs 10–13.
16
15
15'
10'
X
R
9'
O
OH
O
17
17'
18'
13
14
14
13'
9
18
O 12
10R
R
13'
12'
12'O
8'
13
19
O
8
11
O
R10'
12
O
O
3
4
11
K2CO3
mw
4
5
+
O
O
2
O
8'
6
X
5
9'
3
7
R
O
O
7
7'
8
Br
Br
9
HN
6
NH
1
2
O
N
H
1
10R
7'
4 R= -CH3
5 R= -H
9a X= -CH
9b X= -N
10
R= -CH3; X= -CH
R= -CH3; X= -N
R= -H; X= -CH
11
12
13 R= -H; X= -N
Scheme 4. Synthetic scheme for bipodal o-substituted 1,4-DHPs 15–16.
18
18'
17
17'
OH
16
16'
R
O
O
15'
13
14
15
R
9
O 12
10R
13'
12'
O
K2CO3
mw
O
O
O
O
8
+
R10'
3
4
11
O
O
2
R
O
8'
Br
Br
5
9'
O
7
N
H
HN
6
NH
O
1
O
7'
14
4 R= -CH3
5 R= -H
R
15
R= -CH3
R= -H
16
Scheme 5. Synthetic scheme for tripodal 1,4-DHPs 18–21.
7
10
1
2
R
HN
O
8
7'
3
9
6
4
5
O
O
12
11
8' O
13
12'
13'
9'
OH
Br
R
14
10'
10'R
15''
9'
O
R
18'
18''
O
16''
X
8'
X
X
K2CO3
mw
13' 12'O
X
17'
16'
15'
O
O
7'
+
17''
O 14
6
5
11
4
15
Br
16
17
R
O
O
13
NH
12
3
8
1
X
O
18
13 14
O
N
H
Br
X
2
9
O 12
10R
7
13'
O
9
O
R10'
9'
8
12'
3
4
4 R= -CH3
5 R= -H
17a X= -H
17b X= -CH3
11
5
R10
2
O
8'
7
18 R= -CH3; X= -H
19
HN
6
O
1
7'
R= -CH3; X= -CH3
20 R= -H; X= -H
21 R= -H; X= -CH3
ture (60 °C) lead to the formation of 7 and its subsequent de-
rivatives very smoothly.
The compounds 4, 5 were converted into the desired poly-
podals by reacting it with di-bromo, tri-bromo, and tetra-
bromo benzenes using powdered K2CO3/Na2CO3 as mild
base. Initially the reaction was carried by using sodium hy-
dride/THF, which promoted the reaction but with lowered
yields (Method-A). This is because of the strong basic nature
of NaH, which allows the maximum reactivity of –OH, –NH,
and esters over 1,4-DHP towards 6, resulting in undesired
side products, which in turn effect the yield of the final prod-
uct. This led us to quantitatively investigate an efficient ap-
proach to synthesize 7 and its derivatives. The use of
powdered Na2CO3 or K2CO3 in DMF at controlled tempera-
In the case of ethoxy substituent, a maximum yield of 67%
was achieved for the bipodal para isomer 7, and the other
two meta substituted bipodal molecules 10 and 11 showed
closely adjusted yields of 19% and 67%, respectively
(Table 2). A yield of 10% was achieved for bipodal ortho iso-
mer 15, whereas the tripodal 18 and 19 showed yields of
67% and 50%, respectively. A yield of 49% was achieved for
tetrapodal 23. In the case of methoxy substituent, a maximum
yield of 72% was achieved for the bipodal para isomer 8, and
the other two meta substituted bipodal molecules 12 and 13
Published by NRC Research Press

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Can. J. Chem. Vol. 89, 2011
Scheme 6. Synthetic scheme for tetrapodal 1,4-DHPs 23–24.
10R
7
2
7'
6
9
1
O
8
1
O
8'
HN
NH
9'
3
5
O
12
10'
R
O
12'
11
7
2
7'
6
4
11
4
5
3
13
14
13'
12
O
O
8'
9'
8
OH
O
12'
O
Br
O 14
9
R10
13
13'
O
15
Br
+
R10'
R
O
17
16
16'
16
15
K2CO3
mw
O
O
10'R
15
15
16'
9'
17'
R
O
13'
9
13
O
14
R
O 14
10
12'
O 12
8'
Br
O
O
N
H
Br
22
O
8
13'
13
5
4
3
6
11
7'
4
11
10'
R
12'
12
2
4 R= -CH3
3
7
O
O
8'
5
9'
NH
5
8
R= -H
HN
1
2
6
1
O
9
O
7'
7
10
R
23 R= -CH3
24 R= -H
Table 1. Reaction of p-hydroxybenzaldehyde, ammonium acetate and b-ketoester leading to monopodal 1,4-DHPs.
Mp (°C)
Entry
1
Aldehyde
Ester
O
Product
Found
228–230
Reported
230–23217
OH
O
OH
O
O
O
OHC
O
O
N
H
4
231–23318
OH
OH
O
O
2
230–232
O
O
O
OHC
O
O
N
H
5
showed closely adjusted yields of 64% and 59%, respectively.
A yield of 52% was achieved for the bipodal ortho isomer 16,
whereas tripodal 20 and 21 showed 69% and 63% yield, re-
spectively. A yield of 54% was achieved for tetrapodal 24.
The marked differentiation in yields was expected because of
a high steric hindrance over the molecule, especially for 10
and 15. Better results were observed in powdered Na2CO3 or
K2CO3 over the granular forms because of the larger surface
area, which allows maximum reactivity of the alkylating
agent towards hetero atoms.
The reaction was expected to proceed via a SN2 mecha-
nism. The use of elevated temperatures may produce higher
impurity levels, which is consistent with the carbocation
mechanism. The stronger activation may result in faster gen-
eration of carbocation and has a propensity to undergo side
reactions. Thus, we are confined to carry the reactions under
controlled temperatures, typically at 60 °C using K2CO3 as
mild base. Rather than changing the base and reaction tem-
perature, we thought to change the methodology. Micro-
wave-assisted synthesis of bipodal, tripodal, and tetrapodal
1,4-DHPs were also carried out to produce the reaction with
better yield. Microwave irradiation of a mixture of diethyl or di-
methyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate, alkylating agent, powdered K2CO3, and 5
to 6 drops of DMF, at 30% power, was applied for 12 min
(six pulses each of 2 min), resulting in product formation
with good purity and yield (Table 2). The synthesized com-
pounds were subjected to LC-MS as crude to find the pres-
ence of mono-substituted products instead of bis, tris, and
tetrakis substitutions. But it was very clear that the mono-
substituted compounds were not found, and the unambigu-
ous structural confinements for the synthesized compounds
were drawn out with the help of 2D NMR (H-H COSY
and C-H COSY).
Conclusion
In conclusion, the mono functional 1,4-DHPs served as
building blocks for the construction of novel bipodal, tripo-
dal, and tetrapodal 1,4-DHPs by conventional method and by
Published by NRC Research Press

Rajesh et al.
1241
Table 2. Reaction of 1,4-DHP with alkylating agents in the presence of K2CO3 under conventional and solvent free microwave Irra-
diation.
Yield (%)a
Entry
1
2
3
4
5
6
7
8
Alkylating agent
1,4-DHP
Product
7
8
Conv.b
67
72
19
67
64
59
10
52
67
50
69
63
49
54
Mwc
81
87
39
83
80
78
31
71
82
77
85
79
72
80
a,a′-Dibromo-p-xylene 6
4
5
4
4
5
5
4
5
4
4
5
5
4
5
a,a′-Dibromo-p-xylene 6
a,a′-Dibromo-m-xylene 9a
10
11
12
13
15
16
18
19
20
21
23
24
2,6-Bis(bromomethyl)pyridine 9b
a,a′-Dibromo-m-xylene 9a
2,6-Bis(bromomethyl)pyridine 9b
a,a′-Dibromo-o-xylene 14
a,a′-Dibromo-o-xylene 14
9
1,3,5-Tris(bromomethyl)benzene 17a
2,4,6-Tris(bromomethyl)mesitylene 17b
1,3,5-Tris(bromomethyl)benzene 17a
2,4,6-Tris(bromomethyl)mesitylene 17b
1,2,4,5-Tetrakis(bromomethyl)benzene 22
1,2,4,5-Tetrakis(bromomethyl)benzene 22
10
11
12
13
14
aThe yields refer to the isolated pure products.
bReaction carried under conventional heating.
cReaction carried under microwave irradiation.
microwave irradiation. The microwave mehtod exhibited sev-
eral advantages over conventional heating by significantly re-
ducing the reaction time and improving the reaction yield,
owing to a specific non-thermal microwave effect. The meth-
odology employed for this synthesis shows much scope not
only for the synthesis of bipodal and tripodal 1,4-DHPs but
also for tetrapodal moieties, which is not possible to do by
the methods in the literature.
was monitored by TLC. After completion of the reaction, the
reaction mixture was left aside for the formation of product,
filtered to remove the insoluble solids and then the filter cake
was washed with diethyl ether. The solid was recrystallized
from absolute ethanol to yield respective 1,4-dihydropyridine
derivatives as a yellow solid.
Diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4)
Yellow solid (recrystallized from ethanol). Rf (pet. ether/
EtOAc, 6:4) = 0.83. Mp 228–230 °C (Lit. 230–232 °C).15
IR (KBr, cm–1): 3345, 2981, 1662, 1486. 1H-NMR
(200 MHz, CDCl3) d: 0.88 (t, J = 7.5 Hz, 6H), 2.77 (s, 6H),
3.66–3.76 (q, J = 6.0 Hz, 4H), 4.49 (s, 1H), 6.30 (d, J =
8.0 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 7.60 (s, -NH, 1H),
8.27 (s, -OH, 1H). HRMS: m/z 345.1582 (M+).
Experimental section
General
Solvents and reagents were commercially sourced and used
without further purification, with the exception of THF,
which was freshly distilled over sodium. Melting points were
taken with a Elchem microprocessor-based DT apparatus in
open capillary tubes and are corrected with benzoic acid. IR
spectra were obtained on an Avatar-330 FTIR spectropho-
tometer (Thermo Nicolet) using KBr pellets, and only note-
worthy absorption levels (reciprocal centimetres) are listed.
The NMR spectra were recorded on a Bruker 300 and
500 MHz spectrometer, using TMS as internal standard
(chemical shifts d in ppm). Mass spectra were recorded on
HRMS and LCMS by an Agilent 1200 series LC and Micro-
mass zQ spectrometer. Microwave oven used is of synthetic
microwave, CATA R with the maximum power of 700 W at
100% power level. All reactions were carried at 30% power
level, which produces power of 210 W. Thin-layered chroma-
tography (TLC) was performed on preparative plates of silica
gel (s.d. fine). Visualization was made with an iodine cham-
ber. Column chromatography was performed by using silica
gel (60–120 mesh).
Dimethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (5)
Yellow solid (recrystallized from ethanol). Rf (pet. ether/
EtOAc, 6:4) = 0.8. Mp 230–232 °C (Lit. 231–233 °C).16 IR
1
(KBr, cm–1): 3339, 3003, 2950, 1680, 1647, 1611. H-NMR
(200 MHz, CDCl3) d: 2.86 (s, 6H), 3.28 (s, 6H), 4.51 (s,
1H), 6.31 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H),
7.73 (s, -NH, 1H), 8.35 (s, -OH, 1H). HRMS: m/z 317.1270
(M+).
Representative procedure for preparation of bipodal,
tripodal, and tetrapodal 1,4-DHP derivatives
Method A (Classical method using NaH)
To a slurry of 22 mmol of NaH in 20 mL of dry THF in a
three-necked round bottom flask under an N2 atmosphere,
2 mmol of diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (4) dissolved in 30 mL of
dry THF was added dropwise and the mixture was refluxed
for 1 h. a,a′-Dibromo-p-xylene (6) (1.1 mmol) was dissolved
in 100 mL of THF and added to the above reaction mixture
General procedure for synthesis of 1,4-DHPs (4, 5)
A mixture of p-hydroxybenzaldehyde (10 mmol, 1.0
equiv.), b-ketoester (20 mmol, 2.0 equiv.) and ammonium
acetate (12 mmol, 1.2 equiv.) were heated for 15 min in the
presence of ethanol (10 mL). The progress of the reaction
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1242
Can. J. Chem. Vol. 89, 2011
with stirring for 12 h and then at reflux for a further 12 h.
The reaction mixture quenched with aq NH4Cl solution to re-
move excess NaH, and THF was removed under reduced
pressure. The residue was extracted with CHCl3 and dried
over anhydrous Na2SO4. The crude product was purified by
column chromatography on silica gel, using pet. ether/EtOAc
(8:2) as eluent to give tetraethyl 4,4′-(4,4′-(1,4-phenylenebis
(methylene)) bis(oxy)bis(4,1-phenylene))bis(2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate) (7) in 32% yield.
140.67 (C-11), 143.85 (C-2, 6), 157.10 (C-14), 167.79 (C-8,
8′). LC-MS: m/z 793.2 (M+1). Anal. calcd. for C46H52N2O10:
C, 69.68; H, 6.61; N, 3.53. Found: C, 69.50; H, 6.81; N,
3.45.
Tetramethyl 4,4′-(4,4′-(1,4-phenylenebis(methylene))bis
(oxy)bis(4,1-phenylene))bis(2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate) (8)
White solid (recrystallized from diethyl ether/methanol,
5:5). Mp 282–284 °C; IR (KBr, cm–1): 3344, 2947, 1701,
1
Method B (Classical method using powdered K2CO3)
To a suspension of 1.05 equiv. of diethyl or dimethyl 4-
(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-di-
carboxylate (4 or 5) in 10 volumes of dry DMF, 3.0 equiv.
of powdered K2CO3 was added, stirred well for 15 min at
just above room temperature (40 °C). To that, alkylating
agent (0.5 equiv. in case of 6, 9a, 9b, and 14; 0.333 equiv.
in case of 17a and 17b;; 0.25 equiv. in case of 22) dis-
solved in minimum amount of DMF was added drop wise
for 1 h with stirring at 50 °C. After the complete addition,
the reaction mixture heated at 60 °C with stirring for 48 h.
The completion of reaction was monitored by TLC. Then
the reaction mixture was allowed cool to room temperature,
filtered to remove the insoluble solids, and then the filter
cake was washed with DMF. Excess solvents were removed
under reduced pressure and then quenched with ice-cold
water; the obtained crude products were purified by column
chromatography (60–120 mesh), which produced the prod-
ucts in good to moderate yields.
1650. H-NMR (500 MHz, DMSO-d6) dH: 2.25 (s, 12 pro-
tons at H-7, 7′), 3.32 (s, 12 protons at H-9, 9′), 4.82 (s, 2
protons at H-4), 5.02 (s, 4 protons at H-15, 15′), 6.84 (d, J =
10 Hz, 4 arom.protons at H-13, 13′), 7.03 (d, J = 8.5 Hz, 4
arom. protons at H-12, 12′), 7.42 (s, 4 arom. protons at H-17,
17′), 8.82 (s, 2protons at -NH). LC-MS: m/z 735.4 (M–1),
759.4 (M+Na). Anal. calcd. for C42H44N2O10: C, 68.46; H,
6.02; N, 3.80. Found: C, 69.16; H, 5.91; N, 3.77.
Tetraethyl 4,4′-(4,4′-(1,3-phenylenebis(methylene))bis(oxy)
bis(4,1-phenylene))bis(2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate) (10)
Pale yellow solid (recrystallized from pet. ether/EtOAc,
8:2). Mp 106–108 °C. IR (KBr, cm–1): 3341, 3091, 2982,
1
1697, 1647. H-NMR (300 MHz, CDCl3) dH: 1.22 (t, J =
7.05 Hz, 12 protons at H-10, 10′), 2.32 (s, 12 protons at H-
7, 7′), 4.09 (q, 8 protons at H-9, 9′), 4.93 (s, 2 protons at H-
4), 5.00 (s, 4 protons at H-15, 15′), 5.64 (bs, 2 protons at
-NH), 6.81 (d, J = 8.4 Hz, 4 arom. protons at H-13, 13′),
7.14–7.45 (m, 8 arom. protons at H-12, 12′, 16, 18, 18′, 19).
LC-MS: m/z 793.3 (M+1). Anal. calcd. for C46H52N2O10: C,
69.68; H, 6.61; N, 3.53. Found: C, 70.24; H, 6.24; N, 3.40.
Method C (Microwave irradiation)
A mixture of 1.05 equiv. of diethyl or dimethyl 4-(4-hy-
droxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbox-
ylate (4 or 5), alkylating agent (0.5 equiv. in the case of 6,
9a, 9b, and 14; 0.333 equiv. in case of 17a and 17b;; 0.25
equiv. in case of 22), 3.0 equiv. of powdered K2CO3, and 5
to 6 drops of DMF, which acts as homogenizer were finely
ground. Microwave irradiation at 30% power was applied for
12 min (six pulses each of 2 min). The progress of the reac-
tion was followed by TLC. After the completion of reaction,
the reaction mixture poured into ice-cold water; the obtained
solid was filtered, washed with water, and air dried to afford
the desired product. The obtained crude products were puri-
fied by column chromatography on silica gel (60–120 mesh),
which obtained the products in good to moderate yields.
Tetraethyl 4,4′-(4,4′-(pyridine-2,6-diylbis(methylene))bis
(oxy)bis(4,1-phenylene))bis(2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate) (11)
White solid (recrystallized from pet ether/EtOAc, 7.5:2.5).
Mp 100–102 °C. IR (KBr, cm–1): 3337, 3096, 2979, 1693,
1
1608. H-NMR (300 MHz, CDCl3) dH: 1.21 (t, J = 7.05 Hz,
12 protons at H-10, 10′), 2.32 (s, 12 protons at H-7, 7′), 4.08
(q, 8 protons at H-9, 9′), 4.93 (s, 2 protons at H-4), 5.14 (s, 4
protons at H-15, 15′), 5.69 (bs, 2protons at -NH), 6.82 (d, J =
8.7 Hz, 4 arom. protons at H-13, 13′), 7.20 (d, J = 8.4 Hz, 4
arom. protons at H-12, 12′), 7.43 (d, J = 7.8 Hz, 2 arom.
protons at H-18, 18′), 7.71 (t, J = 7.5 Hz, 1 arom. proton at
H-19). 13C-NMR (75 MHz, CDCl3) dC: 14.23 (C-10, 10′),
19.56 (C-7, 7′), 38.72 (C-4), 59.67 (C-9, 9′), 70.43 (C-15,
15′), 104.27 (C-3, 5), 114.04 (C-13, 13′), 119.99 (C-18,
18′), 129.03 (C-12, 12′), 140.17 (C-19), 140.79 (C-11),
143.58 (C-2, 6), 156.67 (C-17, 17′), 156.95 (C-14) 167.65
(C-8, 8′). LC-MS: m/z 792.5 (M–1), 816.4 (M+Na). Anal.
calcd. for C45H51N3O10: C, 68.08; H, 6.47; N, 5.29. Found:
C, 68.64; H, 6.90; N, 5.18.
Tetraethyl 4,4′-(4,4′-(1,4-phenylenebis(methylene))bis(oxy)
bis(4,1-phenylene))bis(2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate) (7)
Pale yellow solid (recrystallized from pet. ether/EtOAc,
8:2). Mp 102–104 °C. IR (KBr, cm–1): 3337, 3097, 2979,
1
2929, 1678, 1505. H-NMR (300 MHz, CDCl3) dH: 1.22 (t,
J = 6 Hz, 12 protons at H-10, 10′), 2.32 (s, 12 protons at
H-7, 7′), 4.09 (q, 8 protons at H-9, 9′), 4.92 (s, 2 protons at
H-4), 5.00 (s, 4 protons at H-15, 15′), 5.61 (bs, 2protons at
-NH), 6.81 (d, J = 9 Hz, 4 arom. protons at H-13, 13′), 7.19
(d, J = 6 Hz, 4 arom. protons at H-12, 12′), 7.41 (s, 4 arom.
protons at H-17, 17′). 13C-NMR (75 MHz, CDCl3) dC: 14.28
(C-10, 10′), 19.50 (C-7, 7′), 38.72 (C-4), 59.72 (C-9, 9′),
69.66 (C-15, 15′), 104.17 (C-3, 5), 114.09 (C-13, 13′),
127.69 (C-17, 17′), 128.98 (C-12, 12′), 136.93 (C-16, 16′),
Tetramethyl 4,4′-(4,4′-(1,3-phenylenebis(methylene))bis
(oxy)bis(4,1-phenylene))bis(2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate) (12)
White solid (recrystallized from pet. ether/EtOAc, 8:2).
1
Mp 116–118 °C. H-NMR (300 MHz, CDCl3) dH: 2.30 (s,
12 protons at H-7, 7′), 3.63 (s, 12 protons at H-9, 9′), 4.93
(s, 2 protons at H-4), 4.98 (s, 4 protons at H-15, 15′), 5.84
Published by NRC Research Press

Rajesh et al.
1243
(bs, 2protons at -NH), 6.80 (d, J = 6.9 Hz, 4 arom. protons
at H-13, 13′), 7.16 (d, J = 8.4 Hz, 4 arom. protons at H-12,
12′), 7.25–7.47 (m, 4 arom. protons at H-16, 18, 18′, 19).
128.78 (C-17, 17′), 135.24 (C-16, 16′), 140.28 (C-11, 11′),
144.20 (C-2, 6), 157.03 (C-14), 168.14 (C-8, 8′). LC-MS:
m/z 735.1 (M–1). Anal. calcd. for C42H44N2O10: C, 68.46;
H, 6.02; N, 3.80. Found: C, 69.47; H, 5.67; N, 3.66.
13C-NMR (75 MHz, CDCl3) dC: 19.52 (C-7, 7′), 38.35 (C-
4), 50.98 (C-9, 9′), 69.77 (C-15, 15′, 103.94 (C-3, 5),
114.28 (C-13, 13′), 126.49 (C-16), 126.96 (C-18,
18′),128.59 (C-12, 12′), 128.77 (C-19), 137.57 (C-11),
140.20 (C-17, 17′), 144.07 (C-2, 6), 157.16 (C-14), 168.11
(C-8, 8′). LC-MS: m/z 735.5 (M–1). Anal. calcd. for
C42H44N2O10: C, 68.46; H, 6.02; N, 3.80. Found: C, 69.47;
H, 5.70; N, 4.05.
Hexaethyl 4,4′,4″-(4,4′,4″-(benzene-1,3,5-triyltris
(methylene))tris(oxy)tris(benzene-4,1-diyl))tris(2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) (18)
White solid (recrystallized from pet. ether/EtOAc, 7:3).
Mp 124–126 °C. IR (KBr, cm–1): 3336, 3096, 2978, 2932,
1
1677. H-NMR (300 MHz, CDCl3) dH: 1.23 (18 protons at
H-10, 10′), 2.31 (s, 18 protons at H-7, 7′), 4.09 (12 protons
at H-9, 9′), 4.99 (s, 9 protons at H-4, 15, 15′, 15″), 6.34 (bs,
3 protons at -NH), 6.82–7.41 (m, 15 arom. protons at H-12,
12′, 13, 13′, 17, 17′, 17″). 13C-NMR (75 MHz, CDCl3) dC:
14.28 (C-10, 10′), 19.42 (C-7, 7′), 38.69 (C-4), 59.72 (C-9,
9′), 69.67 (C-15, 15′, 15″), 104.04 (C-3, 5), 114.13 (C-13,
13′), 125.98 (C-17, 17′, 17″), 128.94 (C-12, 12′), 137.95 (C-
11), 140.72 (C-16, 16′, 16″), 144.00 (C-2, 6), 157.03 (C-14),
167.82 (C-8, 8′). HRMS: m/z 1149.5192 (M+). Anal. calcd.
for C66H75N3O15: C, 68.91; H, 6.57; N, 3.65. Found: C,
68.43; H, 6.86; N, 3.58.
Tetramethyl 4,4′-(4,4′-(pyridine-2,6-diylbis(methylene))bis
(oxy)bis(4,1-phenylene))bis(2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate) (13)
White solid (recrystallized from pet. ether/EtOAc, 8:2).
1
Mp 118–120 °C. H-NMR (300 MHz, CDCl3) dH: 2.31 (s,
12 protons at H-7, 7′), 3.63 (s, 12 protons at H-9, 9′), 4.93
(s, 2 protons at H-4), 5.13 (s, 4 protons at H-15, 15′), 5.75
(bs, 2protons at -NH), 6.81 (d, J = 8.4 Hz, 4 arom. protons
at H-13, 13′), 7.16 (d, J = 8.1 Hz, 4 arom. protons at H-12,
12′), 7.42 (d, J = 7.8 Hz, 2 arom. protons at H-18, 18′), 7.70
(t, J = 7.5 Hz, 1 arom. proton at H-19). 13C-NMR (75 MHz,
CDCl3) dC: 19.55 (C-7, 7′), 38.35 (C-4), 50.97 (C-9, 9′),
70.42 (C-15, 15′), 103.93 (C-3, 5), 114.23 (C-13, 13′),
119.99 (C-18, 18′), 128.65 (C-12, 12′), 133.99 (C-11, 11′),
135.73 (C-19), 143.99 (C-2, 6), 154.85 (C-17, 17′), 156.75
(C-14), 168.06 (C-8, 8′). LC-MS: m/z 736.5 (M–1); Anal.
calcd. for C41H43N3O10: C, 66.72; H, 5.87; N, 5.70. Found:
C, 66.61; H, 5.58; N, 5.46.
Hexaethyl 4,4′,4″-(4,4′,4″-(2,4,6-trimethylbenzene-1,3,5-
triyl)tris(methylene)tris(oxy)tris (benzene-4,1-diyl))tris
(2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) (19)
White solid (recrystallized from pet. ether/EtOAc,
6.5:4.5). Mp 120–122 °C. IR (KBr, cm–1): 3338, 3096,
1
2979, 1678, 1607. H-NMR (300 MHz, CDCl3) dH: 1.22 (t,
J = 9.4 Hz, 18 protons at H-10, 10′), 2.30 (s, 18 protons at
H-7, 7′), 2.35 (s, 9 protons at H-18, 18′, 18″), 4.08 (bs,12
protons at H-9, 9′), 4.93 (s, 3 protons at H-4), 4.98 (s, 6
protons at H-15, 15′, 15″), 5.94 (bs, 3 protons at -NH),
6.83 (d, J = 6.8 Hz, 6 arom. protons at H-13, 13′), 7.20 (d,
J = 6.8 Hz, 6 arom. protons at H-12, 12′). 13C-NMR
(75 MHz, CDCl3) dC: 15.62 (C-10, 10′), 15.99 (C-18, 18′,
18″), 19.27 (C-7, 7′), 38.60 (C-4), 59.63 (C-9, 9′), 64.67
(C-15, 15′, 15″), 103.96 (C-3, 5), 113.79 (C-13, 13′),
128.78 (C-12, 12′), 131.37 (C-17, 17′, 17″), 139.04 (C-16,
16′, 16″), 140.52 (C-11),143.96 (C-2, 6), 157.34 (C-14),
167.76 (C-8, 8′). MS: m/z 1190.54 (M–1). Anal. calcd. for
C69H81N3O15: C, 69.50; H, 6.85; N, 3.52. Found: C, 68.89;
H, 7.00; N, 3.44.
Tetraethyl 4,4′-(4,4′-(1,2-phenylenebis(methylene))bis(oxy)
bis(4,1-phenylene))bis(2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate) (15)
Yellow solid (recrystallized from pet. ether/EtOAc, 8:2).
Mp 112–114 °C. IR (KBr, cm–1): 3347, 2986, 1661, 1635.
1H-NMR (300 MHz, CDCl3) dH: 1.22 (t, J = 6.9 Hz, 12 pro-
tons at H-10, 10′), 2.33 (s, 12 protons at H-7, 7′), 4.09 (q, 8
protons at H-9, 9′), 4.84 (s, 2 protons at H-4), 4.92 (s, 4 pro-
tons at H-15, 15′), 5.54 (bs, 2 protons at -NH), 6.66 (d, J =
8.4 Hz, 4 arom. protons at H-13, 13′), 7.14 (d, J = 8.4 Hz, 4
arom. protons at H-12, 12′), 7.26–7.28 (m, 4 arom. protons
at H-17, 17′, 18, 18′). HRMS: m/z 792.3620 (M+); Anal.
calcd. for C46H52N2O10: C, 69.68; H, 6.61; N, 3.53. Found:
C, 69.26; H, 6.46; N, 3.47.
Hexamethyl 4,4′,4″-(4,4′,4″-(benzene-1,3,5-triyltris
(methylene))tris(oxy)tris(benzene-4,1-diyl))tris(2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) (20)
Yellow solid (recrystallized from pet. ether/EtOAc, 6:4).
Tetramethyl 4,4′-(4,4′-(1,2-phenylenebis(methylene))bis
(oxy)bis(4,1-phenylene))bis(2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate) (16)
1
Mp 140–142 °C. H-NMR (300 MHz, CDCl3) dH: 2.31 (s,
18 protons at H-7, 7′), 3.63 (s, 18 protons at H-9, 9′), 4.94
(s, 3 protons at H-4), 4.98 (s, 6 protons at H-15, 15′, 15″),
6.01 (bs, 3 protons at -NH), 6.79 (d, J = 8.4 Hz, 6 arom.
protons at H-13, 13′), 7.17 (d, J = 8.1 Hz, 6 arom. protons
at H-12, 12′), 7.38 (s, 3 arom. protons at H-17, 17′, 17″).
Yellow solid (recrystallized from pet. ether/EtOAc, 8:2).
1
Mp 134–136 °C. H-NMR (300 MHz, CDCl3) dH: 2.31 (s,
12 protons at H-7, 7′), 3.64 (s, 12 protons at H-9, 9′), 4.94
(s, 2 protons at H-4), 5.08 (s, 4 protons at H-15, 15′), 5.97
(bs, 2 protons at -NH), 6.81 (d, J = 8.4 Hz, 4 arom. protons
at H-13, 13′), 7.17 (d, J = 8.4 Hz, 4 arom. protons at H-12,
12′), 7.34–7.49 (m, 4 arom. protons at H-17, 17′, 18, 18′).
13C-NMR (75 MHz, CDCl3) dC: 19.46 (C-7, 7′), 38.31 (C-
4), 50.98 (C-9, 9′), 69.64 (C-15, 15′, 15″), 103.82 (C-3, 5),
114.32 (C-13, 13′), 125.90 (C-17, 17′, 17″), 128.57 (C-12,
12′), 137.96 (C-11), 140.25 (C-16, 16′, 16″), 144.21 (C-2,
6), 157.08 (C-14), 168.15 (C-8, 8′). HRMS: m/z 1065.4260
13C-NMR (75 MHz, CDCl3) dC: 19.48 (C-7, 7′), 38.30 (C-
4), 50.99 (C-9, 9′), 67.72 (C-15, 15′), 103.86 (C-3, 5),
114.26 (C-13, 13′), 128.27 (C-18, 18′), 128.57 (C-12, 12′),
Published by NRC Research Press

1244
Can. J. Chem. Vol. 89, 2011
(M+). Anal. calcd. for C60H63N3O15: C, 67.59; H, 5.96; N,
3.94. Found: C, 67.71; H, 6.05; N, 3.86.
Supplementary data
Supplementary data for this article are available on the
journal Web site (www.nrcresearchpres.com/cjc).
Hexamethyl 4,4′,4″-(4,4′,4″-(2,4,6-trimethylbenzene-
1,3,5triyl)tris(methylene)tris(oxy)tris(benzene-4,1-diyl))tris
(2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate)(21)
Yellow solid (recrystallized from pet. ether/EtOAc, 6:4).
Acknowledgements
This work was supported by Department of Science &
Technology, Government of India (Grant No. SR/FTP/CS-
108/2006) and are gratefully acknowledged. The authors are
also thankful to the VIT University management for their
generous support and facilities.
1
Mp 138–140 °C. H-NMR (300 MHz, CDCl3) dH: 2.32 (s,
18 protons at H-7,7′), 2.37 (s, 9 protons at H-18, 18′, 18″),
3.65 (s, 18 protons at H-9, 9′), 4.96 (s, 3 protons at H-4),
5.00 (s, 6 protons at H-15, 15′, 15″), 5.91 (bs, 3 protons at
-NH), 6.86 (d, J = 7.5 Hz, 6 arom. protons at H-13, 13′),
7.21 (d, J = 6.9 Hz, 6 arom. protons at H-12, 12′). 13C-
NMR (75 MHz, CDCl3) dC: 15.79 (C-18, 18′, 18″), 19.50
(C-7, 7′), 38.36 (C-4), 51.00 (C-9, 9′), 64.67 (C-15, 15′,
15″), 103.94 (C-3, 5), 114.00 (C-13, 13′), 128.55 (C-12,
12′), 131.76 (C-17, 17′, 17″), 139.16 (C-16, 16′, 16″),
140.12 (C-11), 144.12 (C-2, 6), 157.46 (C-14), 168.13 (C-8,
8′). HRMS: m/z 1107.4721 (M+). Anal. calcd. for
C63H69N3O15: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.88;
H, 6.12; N, 3.68.
References
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Octaethyl 4,4′,4″,4′′′-(4,4′,4″,4′′′-(benzene-1,2,4,5-
tetrayltetrakis(methylene))tetrakis(oxy) tetrakis(benzene-
4,1-diyl))tetrakis(2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate) (23)
White solid (recrystallized from pet. ether/EtOAc, 6:4).
(6) Klusa, V. Drugs Future 1995 20 (2), 135.
1
Mp 174–176 °C. H-NMR (300 MHz, CDCl3) dH: 1.21 (t, J =
(7) Bretzel, R. G.; ; Bollen, C. C.; Maeser, E.; Federlin, K. F. Am.
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6 Hz, 24 protons at H-10, 10′), 2.31 (s, 24 protons at H-7,
7′), 4.08 (q, 16 protons at H-9, 9′), 4.92 (s, 4 protons at H-
4), 5.07 (s, 8 protons at H-15, 15′, 15″, 15′′′), 5.90 (bs, 4
protons at -NH), 6.79 (d, J = 6 Hz, 8 arom. protons at H-
13, 13′), 7.18 (d, J = 7.2 Hz, 8 arom. protons at H-12, 12′),
7.61 (s, 2 arom. protons at H-17, 17′). 13C-NMR (75 MHz,
CDCl3) dC: 14.25 (C-10, 10′), 19.50 (C-7, 7′), 38.60 (C-4),
59.69 (C-9, 9′), 67.52 (C-15, 15′, 15″, 15′′′), 104.14 (C-3,
5), 114.12 (C-13, 13′), 127.51 (C-17, 17′), 128.91 (C-12,
12′), 136.92 (C-11), 140.68 (C-16, 16′, 16″, 16′′′), 143.81
(C-2, 6), 156.89 (C-14), 167.70 (C-8, 8′). MS: m/z 1505.60
(M–1). Anal. calcd. for C86H98N4O20: C, 68.51; H, 6.55; N,
3.72. Found: C, 69.32; H, 6.70; N, 3.64.
(11) Zolfigol, M. A.; Kolvari, E.; Abdoli, A.; Shiri, M; ., ; Mol Divers, .
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Octamethyl 4,4′,4″,4′′′-(4,4′,4″,4′′′-(benzene-1,2,4,5-
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dicarboxylate) (24)
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1
Mp 160–162 °C. H-NMR (300 MHz, CDCl3) dH: 2.30 (s,
24 protons at H-7, 7′), 3.62 (s, 24 protons at H-9, 9′), 4.93
(s, 4 protons at H-4), 5.05 (s, 8 protons at H-15, 15′, 15″,
15′′′), 6.11 (bs, 4 protons at -NH), 6.77 (d, J = 8.1 Hz, 8
arom. protons at H-13, 13′), 7.14 (d, J = 8.1 Hz, 8 arom.
protons at H-12, 12′), 7.58 (s, 2 arom. protons at H-17, 17′).
13C-NMR (75MHz, CDCl3) dC: 19.45 (C-7, 7′), 38.27 (C-4),
51.00 (C-9, 9′), 67.51 (C-15, 15′, 15″, 15′′′), 103.77 (C-3,
5), 114.33 (C-13, 13′), 124.92 (C-17, 17′, 17″, 17′′′), 128.55
(C-12, 12′), 135.26 (C-11), 140.32 (C-16, 16′, 16″, 16′′′),
144.32 (C-2, 6), 156.94 (C-14), 168.17 (C-8, 8′). MS: m/z
1393.53 (M–1). Anal. calcd. for C78H82N4O20: C, 67.13; H,
5.92; N, 4.01. Found: C, 67.86; H, 5.65; N, 3.94.
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