Synthesis of 1,4-dihydropyridine derivatives via one pot multicomponent condensation in water

Article abstract of DOI:10.2174/15701786113109990012

A facile and efficient one-pot preparation of a new series of 1,4-dihydropyridines has been reported via a threecomponent reaction of nano aluminum nitride, aromatic aldehydes and benzyl-3-oxobutanoate or 2-methoxyethyl-3-oxobutanoateat 80°C in water. Using this methodology, Hantzsch1,4-dihydropyridine derivatives were synthesized in a simple pathway without the use of a catalyst or an organic solvent.

Full text of DOI:10.2174/15701786113109990012

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562
Letters in Organic Chemistry, 2013, 10, 562-567
Synthesis of 1,4-dihydropyridine Derivatives via One Pot Multicomponent
Condensation in Water
Arash Ghorbani-Choghamarani* and Masoomeh Norouzi
Department of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
Received March 15, 2013: Revised June 08, 2013: Accepted June 10, 2013
Abstract: A facile and efficient one-pot preparation of a new series of 1,4-dihydropyridines has been reported via a three-
component reaction of nano aluminum nitride, aromatic aldehydes and benzyl-3-oxobutanoate or 2-methoxyethyl-3-
oxobutanoateat 80 °C in water. Using this methodology, Hantzsch1,4-dihydropyridine derivatives were synthesized in a
simple pathway without the use of a catalyst or an organic solvent.
Keywords: 1,4-Dihydropyridine, Hantzsch reaction, One-pot condensation, Multicomponent, Aluminum nitride.
INTRODUCTION
These examples clearly show the remarkable potential of
new dihydropyridine derivatives as a source of valuable drug
candidates, due to the potential importance of 1,4-
dihydropyridyl compounds from a pharmaceutical, industrial
and synthetic point of view [13].
Multi-component reactions (MCRs) have emerged as an
efficient and powerful tool in modern synthetic organic
chemistry allowing the facile creation of several new bonds
in a one-pot transformation [1]. The sequencing of mul-
ticomponent reactions (MCRs) and subsequent cyclization
reactions is a powerful stratagem for the rapid synthesis of
diverse heterocyclic structures [2].
Dihydropyridines are also important because of their ap-
plications in synthesis. Thus, some types of 1,4-
dihydropyridines behave as mimics of the coenzymes
NADH and NADPH and can therefore be employed as hy-
drogen transfer reagents. Furthermore, dihydropyridines
have also been widely used as synthetic intermediates espe-
cially in the preparation of libraries of alkaloid-like com-
pounds and related heterocyclic systems [14].
As a one-pot reaction, MCRs generally afford good
yields and are fundamentally different from two-component
and stepwise reactions in several aspects and permit a rapid
access to combinatorial libraries of complex organic mole-
cules for an efficient lead structure identification and optimi-
zation in drug discovery [3].
Dihydropyridines are often obtained by reduction of
pyridinium salts, which in turn need to be prepared by N-
alkylation of pyridines. A better approach would be one
based on the direct construction of the dihydropyridine
framework from acyclic precursors. The best known of these
dihydropyridine syntheses is the Hantzsch reaction involving
a multicomponent condensation of an aldehyde with a 1,3-
dicarbonyl compound and ammonia [15-19].
Hantzsch 1,4-dihydropyridines (1,4-DHPs) are a very
important class of compounds which can be found in numer-
ous biologically active compounds. For example, some of
these compounds are calcium-channel modulators blocker
and show antihypertensive effects [4].
Also these heterocyclic compounds are interesting exam-
ple of a useful scaffold, because of their ability to act as
NAD(P)H analog of 1,4-dihydronicotinamide.
Interestingly, these heterocycles have been found to be
the structural feature of several compounds belonging to
different bio-active classes such as vasodilator, antitumor,
bronchodilator, analgesic, anti-inflammatory, antithrombotic,
anticonvulsant, hepato-protective, radioprotective, antiathe-
rosclerotic, and antidiabetic agents. They were also reported
to exhibit anticancer, antitubercular, antibacterial, and antivi-
ral, activities. 1,4-DHPs are also known to act as HIV prote-
ase inhibitors and chemosensitizersin MDR tumor therapy
[5-12].
RESULTS & DISCUSSION
In continuing our investigations on the synthetic organic
reactions [20-23], in efforts to develop an efficient and envi-
ronmentally-friendly procedure for the synthesis of 1,4-
dihydropyridine derivatives, we have decided to prepare a
new type of 1,4-dihydropyridines 4a-h via one-pot and
three-component condensation of nano aluminum nitride, a
variety of aldehydes and 1,3-dicarbonyl compounds. It was
found that benzyl-3-oxobutanoate 2 or 2-methoxyethyl-3-
oxobutanoate 3 could be condensed with aromatic aldehydes
1a-e and nano aluminum nitride (as a source of ammonia) to
smoothly afford 1,4-dihydropyridines with excellent yields
at 80°C in water solvent (Scheme 1).
*Address correspondence to this author at the Department of Chemistry,
Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran;
Tel/Fax: +98 841 2227022; E-mails: arashghch58@yahoo.com or
a.ghorbani@mail.ilam.ac.ir
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

Synthesis of 1,4-dihydropyridine Derivatives via one Pot Multicomponent
Letters in Organic Chemistry, 2013, Vol. 10, No. 8 563
O
R
O
H
CH3COCH2COOCH2Ph (2 )
PhH2CO
OCH2Ph
AlN
H2O, 80 °C
Me
N
H
Me
RCHO
4a-d
1a: R= -C6H4OMe
1b: R= -C6H4Me
1c: R= -C6H4Cl
R
O
O
H
1d: R= -C6H4Br
CH3COCH2COOCH2CH2OCH3
(3 )
1e: R= -C6H4F
H3COC2H4O
OC2H4OCH3
AlN
Me
N
H
Me
4e-h
H2O, 80 °C
Scheme 1. Synthesis of 1,4-dihydropyridine derivatives.
100
90
80
70
60
50
40
30
20
10
0
Crude yield (4b)
Pure yield (4b)
Crude yield (4f)
Pure yield (4f)
0.5
1
1.5
2
2.5
3
3.5
Amount of AlN (mmol)
Fig. (1). Optimization of the amount of aluminum nitride for the synthesis of 1,4-dihydropyridine derivatives.
mmol of benzyl-3-oxobutanoate 2 or 2-methoxyethyl-3-
oxobutanoate 3 in the presence of different amounts of nano
aluminum nitride in water (5 mL) at 80°C was conducted.
The results of the preparation of dibenzyl 4-(4-bromophenyl)-
1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate 4b and
bis(2-methoxyethyl) 1,4-dihydro-4-(4-methoxyphenyl)-2,6-
dimethylpyridine-3,5-dicarboxylate 4f as a function of the
amounts of aluminum nitride are shown in (Fig. 1).
In view of these results, the optimal value for aluminum
nitride was 3 mmol, which was subsequently applied for all
cases.
The morphology of aluminium nitride was also observed
by scanning electron microscopy (Fig. 2). SEM image
showed diameters of approximately 40nm.
Eventually, these optimized conditions were applied to
the reaction of a variety of aldehydes and benzyl-3-
oxobutanoate 2 or 2-methoxyethyl-3-oxobutanoate 3, alumi-
num nitride and water in a sealed tube at 80°C, for 6 h,
(There was no increase in the yield of the product after
longer reaction times). The results for these condensations
are summarized in (Table 1).
Fig. (2). SEM image of nano aluminium nitride.
To study the conditional aspects of Hantzch reaction we
used aluminum nitride as alternative nitrogen source to im-
prove the reaction conditions.
Initially, in order to determine the optimal amount of
In all cases, crude products were obtained by extracting
the reaction mixtures with dichloromethane, and then puri-
fied by preparative TLC.
aluminum nitride, the reaction of
1
mmol of 4-
bromobenzaldehyde 1d or 4-methoxybenzaldehyde 1a, 2.2

564 Letters in Organic Chemistry, 2013, Vol. 10, No. 8
Ghorbani-Choghamarani and Norouzi
Table 1. One-pot Synthesis of 1,4-dihydropyridine Derivatives a
Entry
Compound
R1
R2
Product
Yield Ab (B)c %
OMe
O
O
1
4a
OCH2Ph
4-MeO-C6H4
96(45)
PhH2CO
OCH2Ph
Me
N
H
Me
Br
O
O
2
3
4
5
6
OCH2Ph
4-Br-C6H4
88(60)
95(56)
93(41)
87(56)
75(45)
4b
4c
4d
4e
4f
PhH2CO
OCH2Ph
Me
N
H
Me
Cl
O
O
OCH2Ph
4-Cl-C6H4
PhH2CO
OCH2Ph
Me
N
H
Me
Me
O
O
OCH2Ph
4-Me-C6H4
PhH2CO
OCH2Ph
Me
N
H
Me
Cl
O
O
OC2H4OCH3
4-Cl-C6H4
H3COC2H4O
OC2H4OCH3
Me
N
H
Me
OMe
O
O
OC2H4OCH3
4-MeO-C6H4
H3COC2H4O
OC2H4OCH3
Me
N
H
Me

Synthesis of 1,4-dihydropyridine Derivatives via one Pot Multicomponent
Letters in Organic Chemistry, 2013, Vol. 10, No. 8 565
Table 1. Contd…..
Entry
Compound
R1
R2
Product
Yield Ab (B)c %
F
O
O
7
4g
OC2H4OCH3
4-F-C6H4
72(50)
H3COC2H4O
OC2H4OCH3
Me
N
H
Me
Me
O
O
8
4h
OC2H4OCH3
4-Me-C6H4
76(41)
H3COC2H4O
OC2H4OCH3
Me
N
H
Me
aMolar ration of the reagents: ꢀ-dicarbonylcompound/ aldehyde/ aluminum nitride= (2.2 mmol/ 1 mmol/ 3 mmol);b Crude isolated yield. c Yield of pure product (Purified by P-TLC).
O
O
R2
H
COR1
R2-CHO
H2O
+
(1)
+
R1
COCH3
A
(2)
3NH3
+
Al(OH)3
AlN
NH3
+
H2O
NH2
O
O
O
(3)
H2O
R1
+
R1
+
B
R2
R2
R2
R1OC
H3C
R1OC
COR1
COR1
CH3
COR1
CH3
R1OC
Cyclization
Dehydration
CH3
O
NH2
NH2
H3C
H3C
N
H
O
-
D
B
A
C
Scheme 2. Possible mechanism.
A second key intermediate B is an enamine, which is
As can be seen from (Table 1), the experimental proce-
dure is simple and mild and has the ability to tolerate a vari-
ety of functional groups such as methoxy, methyl, and hal-
ides under the reaction conditions.
produced by condensation of the of ꢀ-dicarbonylcompound
with NH3. Then, Michael addition between these two frag-
ments (A and B) gives the 1,4-dihydropyridine derivative D
(Scheme 2).
According to the results, the reaction can be mechanisti-
cally considered to proceed via the initial formation of the
intermediates A (equation 1) through a Knoevenagel con-
densation of an aldehyde with ꢀ-dicarbonyl compound.
In conclusion, we have described a successful strategy,
an efficient and convenient green synthesis for the prepara-
tion of Hantzch 1,4-dihydropyridines 4a-h in three-
component cyclocondensation reaction of different alde-
hydes, benzyl-3-oxobutanoate
2
or 2-methoxyethyl-3-
Aluminum nitride contributes to generate a solution of
ammonia via hydrolysis, which is known reaction (equation
2) [24-26].
oxobutanoate 3 and nano aluminium nitride in water.
Hantzsch 1,4-dihydropyridine derivatives were synthesized

566 Letters in Organic Chemistry, 2013, Vol. 10, No. 8
Ghorbani-Choghamarani and Norouzi
in a simple pathway without the use of metal as a catalyst or
an organic solvent. Thus, this is an ecofriendly and environ-
mentally friendly procedure for the synthesis of 1,4-
dihydropyridine derivatives.
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The authors confirm that this article content has no con-
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