Facile synthesis of Hantzsch 1,4-dihydropyridines with unsymmetrical 2,6-and 3,5-substituents

Article abstract of DOI:10.3184/174751913X13843392957323

A facile synthesis of Hantzsch 1,4-dihydropyridines with unsymmetrical 2,6- and 3,5-substituents in a one-pot two-step tandem reaction under solvent-free conditions, promoted by microwave irradiation, has been developed. No catalysts are used and the work-up is easy. This approach provides a convenient, efficient and practical synthesis of 1,4-dihydropyridines having non-identical substituents at the 2,6- and 3,5- positions, which are not easily accessed by the classical Hantzsch synthesis.

Full text of DOI:10.3184/174751913X13843392957323

748 RESEARCH PAPER
DECEMBER, 748–750
JOURNAL OF CHEMICAL RESEARCH 2013
Facile synthesis of Hantzsch 1,4-dihydropyridines with unsymmetrical 2,6-
and 3,5-substituents
Zhen Wang, Qingjian Liu*, Wenwen Zhang and Qing Chen
College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Engineering Research Center
of Pesticide and Medicine Intermediate Clean Production, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of
Fine Chemicals, Shandong Normal University, Jinan 250014, P.R. China
A facile synthesis of Hantzsch 1,4-dihydropyridines with unsymmetrical 2,6- and 3,5-substituents in a one-pot two-step tandem
reaction under solvent-free conditions, promoted by microwave irradiation, has been developed. No catalysts are used and the
work-up is easy. This approach provides a convenient, efficient and practical synthesis of 1,4-dihydropyridines having non-
identical substituents at the 2,6- and 3,5- positions, which are not easily accessed by the classical Hantzsch synthesis.
Keywords: 1,4-dihydropyridines, Hantzsch reaction, one-pot two-step synthesis, microwave irradiation, solvent-free reaction
1,4-Dihydropyridines (DHPs), in particular 4-aryl-1,4-
dihydropyridines, are an important class of organic compounds
in the field of drugs and pharmaceuticals.1,2 The DHP moiety is
common in numerous bioactive compounds that include various
antihypertensive, vasodilator, antimutagenic, bronchodilator,
The classical synthesis of symmetrically substituted
1,4-dihydropyridines is the Hantzsch reaction, a one-pot
three-component condensation of an aldehyde, β-ketoester,
and ammonia catalysed by an acid. This reaction is usually
conducted in refluxing ethanol.17 However, this method cannot
be applied for the preparation of differently substituted 1,4-
DHPs because with two different types of β-ketoesters the
Hantzsch reaction will give rise to a mixture of the DHP
products. Several modifications have been made for this
classical procedure.12,18–24 Microwave irradiation has been
successfully employed to accelerate the Hantzsch condensation
reaction of 1,4-DHPs.25–29 However, few reports on using a
one-pot procedure for the preparation of unsymmetrically
substituted 1,4-DHPs have been found. Hence, the development
of new methods leading to DHPs with different substituents
at the 2,6- and 3,5-positions on the dihydropyridine ring by a
convenient and efficient way is of great interest for medicinal
and synthetic organic chemists.
A survey of the Hantzsch reaction mechanism reveals the
intermediacy of the Knoevenagel condensation product between
the aldehyde and β-ketoester and the 3-aminocrotonate resulting
from the reaction of the β-ketoester with ammonia. This
implies that the synthesis of 1,4-DHPs with non-identical
substituents at the 2,6- or 3,5-positions might be achieved by
the reaction of the two types of intermediate products bearing
different ester groups. Such an approach, however, includes
the independent formation and separation of the Knoevenagel
condensation product and the 3-aminocrotonate as starting
materials, respectively, which is obviously complicated and
inconvenient. We report here a new synthetic procedure for the
straightforward synthesis of 1,4-DHPs with different 2,6- and
3,5-substituents.
hepatoprotective,
antiatherosclerotic,
antitumour,
geroprotective, and antidiabetic agents.3–11 The most important
class of calcium channel modulators is represented by nifedipine
(I), a well-known commercialised calcium channel blocker of
a unsymmetrically substituted 4-aryl-1,4-dihydropyridine.12–14
1,4-Dihydropyridines with non-identical 3,5-ester groups
on the ring are in many cases superior to those with identical
ester group substitution.12 In fact, installation of different
ester groups in the 3,5-positions of the DHP ring leads to the
second generation of drugs for the treatment of cardiovascular
and hypertension diseases, such as nitrendipine (II)
(antihypertensive), nimodipine (III) (cerebral vasodilator),
and nicardipine (cerebral vasodilator) (IV).12 Some of these
1,4-DHPs are known to be useful for the regeneration of the
reduced form of nicotinamine adenine dinucleotide (NADH),
an essential compound for living organisms.15,16
NO2
NO2
O
O
MeO2C
CO2Me
O
O
O
N
H
N
H
I. Nifedipine
(calcium antagonist)
III. Nimodipine
(cerebral vasodilator)
Results and discussion
NO2
NO2
This one-pot two-step protocol for the preparation of
unsymmetrically substituted 1,4-DHPs can be carried out by
first reacting ethyl benzoylacetate with ammonium acetate,
and then methyl (ethyl) acetoacetate with an aromatic aldehyde
being added. All the reactions are finished in one-pot with
two steps under solvent-free conditions and are promoted by
microwave irradiation without using any catalyst as shown in
Scheme 1.
The results of the reactions are presented in Table 1. It is
thought that the reaction proceeds first with the formation of
aminocinnamate A from ethyl benzoylacetate and ammonium
acetate; it is then followed by the Knoevenagel condensation of
methyl or ethyl acetoacetate with the aromatic aldehyde leading
to arylmethylideneacetoacetate B (Scheme 2).
N
O
O
O
O
O
O
O
O
N
N
H
H
II. Nitrendipine
(antihypertensive)
IV. Nicardipine
(cerebral vasodilator)
Fig. 1 Substituted 1,4-dihydropyridines used as drugs.
* Correspondent. E-mail: liuqj@sdnu.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2013 749
O
Ar
O
O
O
O
O
NH4OAc
EtO
OR
OR
MWI, 10 min
ArCHO
MWI, 10-20 min
R = Me, Et; Ar = Ph or substituted phenyl
Ph
OEt
Ph
N
H
Scheme 1 One-pot two step synthesis of an unsymmetrically substituted 1,4-dihydropyridine DHP.
O
O
NH2
O
-H2O
-H2O
+
NH4OAc
A
B
Ph
H
OEt
Ph
Ar
OEt
O
O
Ar
+
OR
OR
Ar
O
O
O
Ar
O
O
O
O
-H2O
OR
EtO
EtO
OR
+
NH2
MWI, 10-20 min
O
Ph
Ph
N
H
A
B
DHP
R = Me, Et; Ar = Ph or substituted phenyl
Scheme 2 Formation route of unsymmetrically substituted 1,4-dihydropyridine DHP.
The conjugate addition of aminocinnamate
A
to
Table 1 One-pot two-step synthesis of mixed 2,6- and 3,5-substituted
1,4-DHPs
arylmethylideneacetoacetate B and subsequent intramolecular
cyclisation affords the final products, namely 4-aryl-2-methyl-
6-phenyl-1,4-dihydropyridine-3,5-dicarboxylates in moderate
to high yields. The successive preparation procedure of one-pot
with two steps reactions in the same pot eliminates the necessity
of separating the two intermediate products A and B and averts
the problem of forming mixed DHP products. Table 1 shows
that a wide range of substituents can be incorporated in the
4-aryl ring, including the hydroxyl and the azido groups.
Time Yield
Entry
Ar
R
M.p./˚C
/min
20
20
20
20
20
30
25
20
20
20
20
20
25
20
20
20
20
20
20
25
20
20
20
20
20
20
20
25
30
20
20
20
20
20
20
20
20
/%
81
85
86
85
80
62
86
85
85
83
86
81
75
87
81
80
76
81
82
75
76
76
74
70
1
2
3
4
5
6
7
8
9
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
156–157
169–170
168–169
154–156
167–169
142–144
170–171
112–114
234–235
218–210
158–159
169–171
169–170
197–199
180–182
132–134
153–155
158–160
126–128
119–121
136–138
161–163
156–157
144–146
4-FC6H4
4-ClC H4
4-BrC66H4
4-IC H4
2-O 6NC H
3-O2NC6H4
4-O22NC66H44
3-HOC H
10 4-HOC6H44
11 4-MeO6C H
12 3,4-Cl2C66H34
13 4-Me NC6H
14 4-HO2-3-Me4OC6H3
15 3,5-Br -4-HOC6H2
16 2-Fura2nyl
17 3-ClC6H4
Conclusions
In summary, we have presented a facile protocol for the
straightforward synthesis of Hantzsch 1,4-DHPs with
unsymmetrical 2,6- and 3,5-substituents, which is characterised
by a one-pot, two-step and four-component tandem reactions
under solvent-free conditions promoted by microwave
irradiation. No catalysts are used and the work-up is easy. This
provides a convenient, efficient and practical synthesis to the
differently substituted 2,6- and 3,5-dihydropyridines, which
are otherwise difficult to access by the classical Hantzsch
1,4-dihydropyridine synthesis. Further expanding the reaction
scope, the applications of this strategy in the synthesis of
biologically active asymmetrically substituted DHP derivatives
and the reaction mechanism will be investigated.
18 3-N C H
19 4-N3C66H44
20 C6H35
21 4-FC6H4
Et
22 4-ClC H4
Et
23 4-BrC66H4
Et
24 4-IC H4
Et
25 3-O 6NC H
26 4-O22NC66H44
27 3-HOC H
Et
76 199–202, 200–20130
Et
75
78
75
71
83
72
74
75
77
79
89
76
135–137
131–133
180–182
178–180
130–132
152–154
168–170
124–126
108–109
175–176
177–179
105–106
Et
28 4-HOC66H4
29 4-Me NC64H4
30 4-Me2OC H
31 3,4-Cl C6H34
32 3-ClC62H46
Et
Experimental
1H and 13C NMR spectra were determined with a Bruker Avance 300
Et
Et
spectrometer in DMSO-d6 solutions unless otherwise stated with
Et
1
TMS as internal reference (300 MHz for H and 75 MHz for 13C).
Et
The chemical shifts (δ) are reported in ppm and coupling constants
(J) are given in Hz. IR spectra were recorded on a Bruker Tensor
27 spectrometer in KBr plates. Mass spectra were recorded with an
Agilent 5973N MSD spectrometer in EI mode at 70 eV. Elemental
analyses were carried out on a Perkin-Elmer PE-2400 II HONS
33 3-N C H
Et
34 4-N33C6H4
Et
35 4-HO-63-4MeOC6H3
36 3,5-Br -4-HOC6H2
37 2-Fura2nyl
Et
Et
Et
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750 JOURNAL OF CHEMICAL RESEARCH 2013
analyser. Melting points are uncorrected. 2-Furaldehyde, ethyl and
methyl acetoacetate, and ethyl benzoylacetate were all reagent grades
and were redistilled in vacuo before use. The synthetic reactions
were carried out in a Computer Microwave Solid-Liquid Synthesizer/
Extraction Work Station XH-200A (0–1000 W and 0–300 °C) (Beijing
Xianghu Science and Technology Development Company, Ltd.) and
performed in open vessels. The reaction temperature was set as needed
and monitored automatically.
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9.11 (s, 1 H, NH), 7.28 (m, 10 H, ArH), 4.97 (s, 1 H, CH), 3.68 (q, 2 H,
J=6.9 Hz, OCH2), 3.58 (s, 3 H, OCH3), 2.30 (s, 3 H, CH3), 0.69 (t, 3 H,
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Received 29 July 2013; accepted 6 October 2013
Paper 1302094 doi: 10.3184/174751913X13843392957323
Published online: 6 December 2013
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