Synthesis and characterization of poly(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)arenes as novel multi-armed molecules

Article abstract of DOI:10.1016/j.tetlet.2015.11.015

A new series of poly(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)arenes were synthesized in good yields using a one-pot, acid-catalyzed cyclocondensation reaction of the appropriate poly(aldehydes) with 3-aminobut-2-enenitrile in acetic acid at reflux.

Full text of DOI:10.1016/j.tetlet.2015.11.015

Tetrahedron Letters 56 (2015) 7085–7088
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterization of poly(2,6-dimethyl-4-phenyl-1,4-
dihydropyridinyl)arenes as novel multi-armed molecules
⇑
Ismail A. Abdelhamid, Ahmed F. Darweesh, Ahmed H. M. Elwahy
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of poly(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)arenes were synthesized in good yields
using a one-pot, acid-catalyzed cyclocondensation reaction of the appropriate poly(aldehydes) with
3-aminobut-2-enenitrile in acetic acid at reflux.
Received 30 May 2015
Revised 3 October 2015
Accepted 5 November 2015
Available online 10 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Poly(aldehydes)
3-Aminobut-2-enenitrile
Poly-dihydropyridines
Cyclocondensation
Alkylation
Since the first reported synthesis of 1,4-dihydropyridines (1,4-
DHPs) by Arthur Hantzsch in 1881, there has been a great deal of
interest in this area.1 This is mainly due to the fact that the 1,4-
DHP motif has been found to exhibit significant biological activities
in the treatment of cardiovascular disease and as calcium channel
blockers.2 More than twelve commercial, clinically important
drugs such as Nifedipin 1, Felodipine 2, Nicardipine 3, and Nimodi-
pin 4 (Fig. 1), containing the 1,4-DHP parent nucleus have been
manufactured and used worldwide.3 These compounds also exhibit
a variety of biological activities such as vasodilator, branchodilator,
antitheroselerotic, antitumour, antidiabatic, hepatoprotective,
geroprotective, and antituberclosis activities.4
Benzene cores appended by six flexible arms, each terminated by
an anionic group, have recently been shown to form micelles in
aqueous solutions.7a,7b Multi-armed molecules, in which the arms
contain suitable donor functionalities, have been used as ligands
for metal ion complexation.8 Multi-armed arenes have also been
frequently used as core units for dendrimers.9
In connection with these findings, we report herein, the synthe-
sis of novel three-, four-, and sixfold branched dihydropyridine-
3,5-dicarbonitriles linked to a benzene core via phenoxylmethyl
spacers. To the best of our knowledge, very little is known about
the synthesis and properties of multi-armed dihydropyridine-3,5-
dicarbonitrile derivatives.10
Therefore, the preparation of novel 1,4-DHP derivatives is a rea-
sonable target in medicinal and synthetic organic chemistry.
Numerous attempts to improve the Hantzsch reaction using alter-
native catalysts and green reaction methods have been investi-
gated.5 Multicomponent reactions (MCRs) are among the most
efficient strategies for the synthesis of 1,4-DHPs in terms of
providing both sufficient structural diversity and a large number
of compounds for libraries.6
Furthermore, over recent years there has been an increasing
number of reports regarding so-called ‘multi-armed’ molecules7
which are of interest in a range of contexts. For example, multi-
armed molecules, in which an aromatic core is appended by long
aliphatic arms, has found use as discotic liquid crystals.7q
Two strategies were investigated for the synthesis of the target
compounds. In the first strategy (Scheme 1) we studied the
synthesis of 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropy-
ridine-3,5-dicarbonitrile 7 via the cyclocondensation of p-hydroxy-
benzaldehyde 5 with 3-aminobut-2-enenitrile 6 in acetic acid at
reflux according to the method described by Kuthan et al.11
Subsequent reaction of three equivalents of the potassium salt of
7 with 1,3,5-tris-bromomethylbenzene12 in DMF unfortunately
did not lead to the clean formation of the corresponding tris
(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)benzene 9a. The
reaction instead gave a mixture of products that were not easily
handled and were not characterized.
In search for an alternative pathway to prepare the target tris
(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)benzenes 9a,b, our
attention turned to utilizing tris-aldehydes 10a,b as precursors
which could then undergo acid-catalyzed condensation with
⇑
Corresponding author.
E-mail address: aelwahy@hotmail.com (A.H.M. Elwahy).
http://dx.doi.org/10.1016/j.tetlet.2015.11.015
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

7086
I. A. Abdelhamid et al. / Tetrahedron Letters 56 (2015) 7085–7088
NO2
13, respectively. Similarly, hexakis(4-formylphenoxymethyl)ben-
zenes 16 and 17 were prepared in 80% and 84% yields, respectively,
by sixfold substitution of hexakis(bromomethyl)benzenes 1212
with six equivalents of the potassium salt of 4-hydroxybenzalde-
hyde and salicylaldehyde, respectively, (Scheme 3).13
The same methodology was extended to the preparation of tet-
rakis- and hexakis(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)
benzenes 18a,b and 19a,b, respectively.13 Thus, acid-catalyzed
condensation of the appropriate poly(aldehyde) derivative 14–17
with eight or twelve equivalents, respectively, of 3-aminobut-2-
enenitrile in acetic acid at reflux afforded 18a,b and 19a,b, respec-
tively, in 74–82% yield (Scheme 4).13
NO2
COOMe
MeOOC
MeOOC
COO(CH 2)2N(CH 3)CH 2Ph
N
H
N
H
(1)
(3)
Nifedipine
Nicardipine
O
Cl
NO2
Cl
Cl
MeOOC
COO(CH 2)2N(CH 3)CH 2Ph
O
It was noteworthy that the amount of acetic acid used in the
above reactions played an important role in determining the reac-
tionproducts. For examplein thepresenceof excess aceticacid, most
of the reactions gave a mixture of products. Analysis of the 1H NMR
spectra of the reaction products indicated the presence of the target
productstogether withadditionalsignals for thecorrespondingben-
zylidene-3-oxobutanenitrile derivatives as well as other unknown
by-products. Fortunately, (benzene-1,2,4,5-tetrayltetrakis-(methy-
lene))tetrakis-(oxy)tetrakis(benzene-2,1-diyl))tetrakis-(methan-1-
yl-1-ylidene)tetrakis(3-oxobutanenitrile) 20 was isolated as a single
product in 73% yield upon treatmentof 15 with3-aminobut-2-enen-
itrile 6 in excess acetic acid (Scheme 5). On the other hand, 18b was
obtained as the sole product in high yields by carrying out the same
reaction using catalytic acetic acid.
N
H
Cl
N
H
Felodipine (2)
Nimodipine (4)
Figure 1. 1,4-DHPs used as clinical drugs.
3-aminobut-2-enenitrile 6 to yield the target molecules. Thus, tris
(4-formylphenoxymethyl)benzenes 10a,b were prepared by react-
ing the potassium salt of 4-hydroxybenzaldehyde 5 or salicylalde-
hyde with tris(bromomethyl)benzene in DMF at reflux.13 In the
next step, acid-catalyzed condensation of each of the tris-aldehy-
des 10a and 10b with six equivalents of 3-aminobut-2-enenitrile
gave the corresponding tris(2,6-dimethyl-4-phenyl-1,4-dihy-
dropyridinyl)benzenes 9a and 9b in 78% and 76% yields, respec-
tively, as pale yellow crystals (Scheme 2).13
Tetrakis(4-formylphenoxymethyl)benzenes 14 and 15 were pre-
pared in 79% and 82% yields, respectively, by fourfold substitution of
tetrakis(bromomethyl)benzene 1112 with four equivalents of the
potassium salt of 4-hydroxybenzaldehyde 5 and salicylaldehyde
The structures of the newly synthesized compounds were con-
firmed by IR, NMR, mass spectra, and elementary analysis.14,15 The
symmetry of compounds 9a,b, 18a,b, and 19a,b manifested as a
single set of signals in the NMR spectra that were characteristic
of the equivalent OCH2, CH, NH and Me groups.
H
Me
NC
N
Me
CN
Br
OH
Br
Br
OH
O
CN
8
AcOH
+
2
x
NC
Me
CN
Me
H N
2
Me
KOH, DMF
O
O
CHO
CN
Me
CN
N
H
7
Me
HN
Me
NH
Me
5
6
CN
NC
9a
,
p-isomer
Scheme 1.
H
N
Me
NC
Me
CN
CHO
O
O
CN
Me
AcOH
CN
CN
+ 6
x
O
O
O
O
Me
HN
Me
NH
Me
CHO
H N
2
OHC
NC
CN
10a, p-isomer
b, o-isomer
6
9a, p-isomer (78%)
b, o-isomer (76%)
Me
Scheme 2.

I. A. Abdelhamid et al. / Tetrahedron Letters 56 (2015) 7085–7088
7087
OHC
CHO
CHO
OHC
Br
Br
Br
Br
O
O
O
O
O
O
O
O
or
11
OHC
CHO
CHO
OHC
14 (79%)
15 (82%)
i) KOH / EtOH
ii) DMF
CHO
or
CHO
HO
OHC
Br
OHC
OHC
O
CHO
CHO
CHO O
OHC
5, p-isomer
13, o-isomer
Br
Br
Br
Br
O
O
O
O
O
O
O
O
or
O
O
Br
CHO
OHC
CHO
12
CHO
16 (80%)
17 (84%)
Scheme 3.
H
N
Me
NC
Me
CN
Me
NH
NC
Me
CN
Me
CN
Me
CN
Me
CN
CN
HN
Me
O
NC
O
CN
HN
Me
NH
O
Me
CN
O
O
O
O
Me
NH
Me
O
O
CN
CN
CN
Me
O
NC
Me
HN
Me
NH
Me
Me
HN
CN
NC
CN
NC
Me
CN
Me
Me
N
H
18a, p-isomer (77%)
b, o-isomer (81%)
19a, p-isomer (74%)
b, o-isomer (82%)
Scheme 4.
unusual molecules and for their promising pharmacological and
biological activities. They offer the advantage of easy synthesis
using a simple one step procedure from inexpensive starting mate-
rials. Studies directed at examining the biological activities and
inclusion behavior of these compounds as well as to extend the
scope of the described synthetic method to additional multi-armed
heterocyclic compounds are currently in progress.
NC
COCH 3
COCH3
NC
NC
O
O
O
O
Acknowledgments
COCH 3 NC
COCH 3
The authors gratefully acknowledge the Alexander von Hum-
boldt Foundation for a research fellowship.
20 (73%)
Scheme 5.
References and notes
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as building blocks for novel (2,6-dimethyl-4-phenyl-1,4-dihy-
dropyridinyl)arenes has also been investigated. These new classes
of 1,4-dihydropyridines are interesting both in their own right as
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ˇ
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5126. Typical experimental procedure for the synthesis of poly
(dihydropyridinyl)arenes 9a,b, 18a,b and 19a,b: To a warm solution of the
appropriate poly-aldehyde 10a, 10b, 14, 15, 16 and 17 (10 mmol) in glacial
acetic (5 mL), 3-aminobut-2-enenitrile 6 (6, 8 and 12 equiv, respectively) was
added. The resulting yellowish solution was heated at reflux for 2 h then
allowed to cool to room temperature. The formed precipitate was filtered,
dried, and purified by recrystallization from acetic acid to afford pale yellow
crystals of 9a,b, 18a,b, and 19a,b, respectively. Compound (9a): Pale yellow
solid (78%); m.p. = 286–288 °C. IR (KBr)
m .
= 3356 (NH), 2202 (CN) cmÀ1 1H
NMR (DMSO-d6) d 2.03 (s, 18H), 4.34 (s, 3H), 5.15 (s, 6H), 7.06 (d, 6H, J = 6.8
Hz), 7.20 (d, 6H, J = 6.8 Hz), 7.54 (s, 3H), 9.45 (s, 3H); 13C NMR (DMSO-d6) d
17.7, 40.0, 69.2, 83.0, 115.0, 119.3, 126.5, 128.8, 136.7, 137.7, 146.4, 157.9.
Compound (18a): Pale yellow solid (77%); m.p. 294–296 °C; IR (KBr)
(NH), 2198 (CN) cmÀ1 1H NMR (DMSO-d6) d 2.02 (s, 24H), 4.32 (s, 4H), 5.26 (s,
8H), 7.04 (d, 8H, J = 8.4 Hz), 7.18 (d, 8H, J = 8.4 Hz), 7.75 (s, 2H), 9.44 (s, 4H); 13
m 3358
;
C
NMR (DMSO-d6) d 17.7, 40.2, 66.9, 82.9, 115.0, 119.3, 128.7, 130.6, 135.0,
136.7, 146.3, 157.7. Compound (19a): Pale yellow solid (74%); m.p. 238–
240 °C; IR (KBr)
m ;
3352 (NH), 2202 (CN) cmÀ1 1H NMR (DMSO-d6) d 2.01 (s,
36H), 4.26 (s, 6H), 5.29 (s, 12H), 6.93 (d, 12H, J = 8.7 Hz), 7.13 (d, 12H, J = 8.7
Hz), 9.42 (s, 6H); 13C NMR (DMSO-d6) d 17.7, 40.0, 63.9, 82.9, 115.1, 119.3,
128.8, 136.9, 137.6, 146.4, 157.7.
14. The infrared spectra were recorded on potassium bromide disks using a Pye
Unicam SP 3–300 and Shimadzu FTIR 8101 PC infrared spectrophotometer. The
1H NMR spectra were determined on
a Varian Mercury VX 300 NMR
spectrometer using TMS as an internal standard and DMSO-d6 as a solvent.
Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 eV.
15. All new compounds gave correct analytical data (1H NMR, 13C NMR, IR, MS, and
elemental analyses).