Oxidative aromatization of Hantzsch 1,4-dihydropyridines in the presence of mixed-addenda vanadomolybdophosphate heteropolyacid, H6PMo9V3O40

Article abstract of DOI:10.1016/j.bmcl.2007.04.002

A variety of Hantzsch 1,4-dihydropyridines were oxidized to the corresponding pyridines in high yields in the presence of H₆PMo₉V₃O₄₀, a Keggin type heteropolyacid, in refluxing acetic acid. The heteropolyacid w

Full text of DOI:10.1016/j.bmcl.2007.04.002

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3305–3309
Oxidative aromatization of Hantzsch 1,4-dihydropyridines
in the presence of mixed-addenda vanadomolybdophosphate
heteropolyacid, H PMo V O
6
9 3 40
a,
a
a
a
*
Majid M. Heravi, Fatemeh Derikvand, Shahla Hassan-Pour, Khadijeh Bakhtiari,
b
a
Fatemeh F. Bamoharram and Hossein A. Oskooie
a
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
b
Department of Chemistry, Islamic Azad University—Mashhad Branch, Mashhad, Iran
Received 27 November 2006; revised 21 February 2007; accepted 3 April 2007
Available online 6 April 2007
Abstract—A variety of Hantzsch 1,4-dihydropyridines were oxidized to the corresponding pyridines in high yields in the presence of
H PMo V O , a Keggin type heteropolyacid, in refluxing acetic acid. The heteropolyacid was found to be reusable.
6
9
3
40
Ó 2007 Elsevier Ltd. All rights reserved.
8
e
1,4-Dihydropyridines (1,4-DHPs) are a class of model
compounds of NADH coenzyme, and calcium channel
I2–MeOH. Recently, attention has been paid to more
efficient and environmentally benign methods, such as
1
9
antagonists (CCAs). These compounds have been
established as one of the first line drugs for treatment
of hypertension because of their promising depressor
electrochemical oxidation and catalytic aerobic oxida-
1
0a
10b
10c
tion using RuCl3,
Pd/C
and activated carbon
as the catalyst. Despite these intensive efforts, most of
the reported oxidation procedures require long reaction
times, utilize strong oxidants in large excess, afford
products with only modest yields, and non-reusability
of the catalyst. Therefore, the development of more
effective methods for aromatization of 1,4-dihydropyri-
dines is still necessary.
2
effect and relatively good tolerability. 1,4-Dihydropyri-
dines have been extensively studied in view of the bio-
logical pertinence of these compounds to the NADH
3
redox process, and their therapeutic functions for treat-
4
ment of a variety of diseases, such as cardiovascular
4
a
4b
4c
disorders, cancer and AIDS. In the human body,
these compounds are oxidized to pyridine derivatives
5
by the action of cytochrome P-450 in the liver. These
Recently, there has been considerable interest in the use
of heteropolyacids as environmentally benign catalysts
due to their unique properties such as high thermal sta-
bility, low cost, ease of preparation and ease of recycla-
bility. Numerous chemical reactions can be carried out
oxidized compounds are largely devoid of the pharma-
cological activity of the parent compounds. The oxida-
tion of 1,4-DHPs to the corresponding pyridine
derivatives constitutes the principal metabolic route in
1
,3
11
biological systems, as well as a facile access to the cor-
responding pyridine derivatives, which show anti-hyp-
in the presence of heteropolyacids.
6
oxic and anti-ischemic activities, from the easily
7
Based on our previous studies on the use of heteropoly-
12–23
acids as catalyst for carrying out organic reactions
and continuing our interest in aromatization of Han-
tzsch 1,4-dihydropyridines, we examined the possibil-
ity of using a mixed addenda heteropolyacid to effect
the oxidative aromatization of Hantzsch 1,4-dihydro-
pyridines (Scheme 1).
available DHPs. Therefore, oxidative aromatization
of DHPs has attracted continuing interests of organic
and medicinal chemists and a plethora of protocols
2
4
8
–10
has been developed.
oxidants, such as HNO3, KMnO4, or CAN and
Early works mostly used strong
8c
8
b
8d
In order to get the best reaction condition the efficiency
of a variety of solvents and heteropolyacids in the oxida-
tion of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate as a model reaction was studied.
Keywords: Aromatization; Hantzsch 1,4-dihydropyridine; Mixed-add-
enda vanadomolybdophosphate; H
*
6 9 3
PMo V O40; Reusable catalyst.
Corresponding author. Fax: +98 2188047861; e-mail: mmh1331@
yahoo.com
0
960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.002

3306
M. M. Heravi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3305–3309
O
1 H
O
O
1 H
R
O
Because of large negative charge of polyoxoanions, all
of the HOMOs and LUMOs of them have very high en-
ergy levels. Heteropolyanions are reducible easily and it
is necessary in oxidative catalytic reactions. The LUMO
must be sufficiently low to accept the electrons in oxida-
tive catalytic reactions. The solvent molecules can place
these molecular orbitals at the appropriate level. It is
suggested that the solvent effects are dominated by the
electrostatic component-the interactions of the polarized
polyanions with the charge distribution of the solvent,
to place the molecular orbitals at the appropriate level
and or to lower the activation energy. In this research,
with respect to the Table 1 it seems likely that this effect
is higher for the acetic acid.
R
R2O
2
OR
2
HPA
R O
OR2
Me
N
Me
ACOH, reflux
Me
N
Me
H
H
Scheme 1.
First we carried out the model reaction under solvent-
free condition at room temperature. The reaction was
not completed. The temperature of the reaction mixture
started to rise but the reaction was not completed after
4 h. Then we decided to examine the effect of the
solvent on the reaction. The results are summarized in
Table 1.
2
The effect of a variety of heteropolyacids including
H PW O , H P W O , H PMo V O , H PMo
11-
One of the important factors affecting the oxidation
capacity of plyanions is the energy gap between the
highest occupied molecular orbital (HOMO) and
the lowest unoccupied orbital (LUMO). The heteropoly
anions are easily reducible chemical species, thus the
energy of the LUMO must be sufficiently low. The sol-
vent molecules can stabilize these anions and place
molecular orbitals at the appropriate level. Therefore
both yields and reaction times can be affected by varying
the solvent. By taking a look to the results of Table 1, we
can see the highest yield of product has been obtained
with acetic acid as solvent. In solutions, the acid proper-
ties of heteropolyacids have been characterized in terms
of dissociation constants and Hammett acidity func-
3
12 40
6
2
18 6 2
5
10
2
40
4
VO40 and H PMo O in the oxidation of 2,6-di-
3
12 40
methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate(A)
and 2,6-dimethyl-4-ethyl-1,4-dihydropyridine-3,5-dicarb-
oxylate(B) in refluxing acetic acid was also explored.
The results are shown in Table 2. Among Keggin type
heteropolyacids H PMo V O gave the best results in
6
9
3
40
terms of yields and times. It is difficult to clarify the dif-
ferent activity between these anions clearly. Obviously
there is a complex relationship between the activity
and structure of polyanions. Transition metal cations
have an important effect on the properties of these com-
pounds when they substitute molybdenum cations in the
Keggin units or when they are present as counter cat-
ions. The case of vanadium, which can occupy both an-
ionic and cationic positions, is more complex. The
introduction of vanadium (V) into the Keggin frame-
2
5
tion. As heteropolyacids have different dissociation
2
5–28
constants and Hammett acidity in various solvents
and therefore, show different behaviors for dissociation
2
6,27
29
of protons in different solvents.
less polar acetic acid, Keggin-type acids behave as 1–1
In this area, in the
work is beneficial for redox catalysis, shifting its reac-
tivity from acid to redox-dominated. One of the
difficulties encountered in interpreting data obtained
from reactions of vanadomolybdophosphate anions is
that in solution, a mixture of heteropoly anions are
usually present. In addition positional isomers of the
polyvanadium anions are also apparent. Another
complication inherent in the study of multi electron
2
5
27
electrolytes. From the conductivity study, it was in-
ferred that in polar nonaqueous solvents heteropolyac-
ids are fully ionized, so the solvated protons are
loosely bound to the anion as a whole rather than to a
certain oxygen atom in the anion, in contrast to the crys-
talline acid.
Table 1. The effect of the solvent on the oxidation of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate, (entry 5, Table 3) in the presence
of catalytic amount of H
6 9 3 40
PMo V O
Solvent
Dichloromethane
Chloroform
Ethanol
Water
Acetonitrile
Acetic acid
Time (min)
a
Yield (%)
70
20
70
20
70
25
70
35
70
40
70
96
a
Yields were analyzed by GC.
Table 2. Oxidation of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate(A) (entry 1, Table 3) and 2,6-dimethyl-4-ethyl-1,4-dihydropyri-
dine-3,5-dicarboxylate(B) (entry 5, Table 3), using a catalytic amount of different heteropolyacids (1 mol%) in refluxing acetic acid
a
Entry
Heteropolyacid
Time (min)
Yield (%)
A
B
A
B
1
2
3
4
5
6
H
3
H
6
H
3
H
4
H
5
H
6
PW12
O
40
62
40
240
240
225
80
240
240
80
10
15
95
95
80
96
12
15
96
98
98
99
P
2
W
18
O
PMo12
PMo11VO40
PMo10
PMo
O
130
35
V
2
O
40
80
9
V
O
3 40
70
20
a
Yields were analyzed by GC.

M. M. Heravi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3305–3309
3307
6
1
þ
xꢁ8
40
ꢁ
þ
oxidations by polyvanadium-containing anions is the
capacity of these oxidants to be reduced by one or more
electrons (reduction of each V(V) ion to V(IV)).
½XM O ꢀ þ pe þ qH
6
2
þ
5þ
xþqꢁpꢁ8
40
3
0,31
! Hq½XM
2,33
Mp O ꢀ
ð1Þ
12ꢁp
3
where q 6 p.
Considering the real oxidant in these reactions one can
tell, redox chemistry of polyoxometalates is extremely
Redox properties of the mixed-addenda anions
PMo1 V O ] have been studied in considerable de-
tail, especially in connection with their application for
3
2,33
diverse.
[
2ꢁn
n
40
3
2,34
According to Pope,
polyoxometalates, regarding
35–37
catalytic oxidation.
These anions are remarkable
their redox abilities, can be divided into two groups-
mono-oxo, (type I) and, cis-dioxo, (type II). This classi-
fication is based on the number of terminal oxygen
atoms attached to each addenda atom, for example,
molybdenum or tungsten, in the polyanion. Examples
of type I polyanions are the Keggins, the Wells–Daw-
sons and their derivatives that have one terminal oxygen
atom M@O per each addenda atom. Type II polyanions
can be represented by the Dexter–Silverton anion which
has two terminal oxygens in cis positions on each adden-
da atom.
because they posses not only a fairly high oxidation po-
tential (ca. 0.7 V)but also their reduced forms are very
easily reoxidised by oxygen (air) in solution. These re-
dox reactions can be represented by Eqs. 2 and 3.
þ
½PMo12ꢁn
V
n
O
40ꢀþRedþmH ! H
m
½PMo12ꢁn
V
n
O40ꢀþOx
ð2Þ
H ½PMo
m
12ꢁn
V O ꢀþðm=4ÞO ! ½PMo
n
40
2
12ꢁn
V O ꢀþðm=2ÞH O ð3Þ
n
40
2
Electron-transfer reactions of Keggin polyoxometalates
in solution can be viewed as the outer-sphere electron
3
8–41
transfers, which is in line with their very low solva-
tion energies as well as their weakness as ligands.
In type I octahedral MO , the lowest unoccupied
6
In our reactions, the heteropolyacid, oxidizes the sub-
strate and then, in a separate step, is reoxidised by O2.
Either step can be rate-determining to control the over-
all reaction rate.
molecular orbital (LUMO) is a nonbonding metal-cen-
tered orbital, whereas the LUMO for type II octahe-
dral is antibonding with respect o the terminal
M@O bonds. Consequently, type I polyoxometalates
are reduced easily and frequently reversibly to form
mixed-valence species, heteropoly blues, which can
act as an oxidant. In contrast, type II polyoxometa-
lates are reduced with more difficultly and irreversibly
In order to establish the scope of this novel oxidation
protocol, we tested a variety 1,4-DHPs under the opti-
4
6
mized reaction conditions. As shown in Table 3 both
electron donating and electron withdrawing substituents
on the precursors afforded the corresponding pyridines
in good to excellent yields. In the presence of more
amount of the catalyst the corresponding products of
3
2,34
to complexes with yet unknown structures.
For
this reason, only type I heteropoly compounds, by
and large the Keggins, are of interest for oxidation
catalysis.
1
,4-dihydropyridines containing electron-withdrawing
groups were obtained in shorter reaction times (Table
, entries 10 and 12).
The total number of accepted electrons on reduction of
type I polyoxometalates can be quite high. As the anion
structure retains upon this process, the additional
negative charge is compensated for by protonation of
the anion from solvent. Thus, the reduction is frequently
pH-dependent. This can be represented by Eq. 1. Also,
this point shows the importance of solvent in these
reactions (Table 1).
3
All compounds were known and their physical and spec-
troscopic data were compared with those of authentic
3
b,10a,42,43
samples and found to be identical.
Yields were
obtained using GC analysis. The reusability of the cata-
lyst was also studied. After completing the model
Table 3. Oxidation of Hantzsch 1,4-dihydropyridines in the presence of catalytic amount of H
6
PMo
9
V
3
O40 in refluxing acetic acid
1
R
2
R
a
Entry
Time (min)
Yield (%)
mp (°C)
b
Found
Reported
2
9
1
2
3
4
5
6
7
8
9
H-
Me-
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
30
70
98
97
68–70
Oil
Oil
69–70
3
b
Oil
Oil
3
b
Et-
Isopropyl-
ph
20
15
99
94
1
3
9
0a
b
70–72
60–62
72–73
50
70–71
61–62
72–73
70
75
96
98
h
4-Me-ph
4-MeO-ph
4-Cl-ph
10a
50
97
80
50
3
2
0
9
300
720
240
240
120
64–66
62–63
62–63
104–105
104–105
65–66
61–63
61–63
3-NO
3-NO
2-NO
2-NO
2
2
2
2
-ph
-ph
-ph
-ph
100
80
c
29
1
1
1
0
1
2
9
d
80
100
104–105
104–105
c
9d
a
b
c
Yields were analyzed by GC.
Products exhibited physical properties in accordance with the assigned structures.
The reactions were carried out in the presence of 2 mol% of the catalyst.

3308
M. M. Heravi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3305–3309
reaction, the catalyst was removed and washed with
diethyl ether and subjected to a second run of the reac-
tion process with the same substrate. The results of the
first experiment and subsequent were maintaining more
than 90% yield.
G.; Thomas, H. J.; Autino, J. C. Tetrahedron Lett. 2003,
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4
1
1
1
1
Acknowledgment
5. Bamoharram, F. F.; Heravi, M. M.; Roshani, M.;
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252, 90.
The authors are thankful from Azzahra Research Coun-
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1
1
6. Heravi, M. M.; Motamedi, R.; Seifi, N.; Bamoharram, F.
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according to the literature procedure, using the
appropriate aldehydes, ammonia, and ethyl acetoace-
1
4
4
tate. Hantzsch 1,4-dihydropyridine (1 mmol) in acetic
acid (3 mL) was treated with a catalytic amount of
heteropolyacid (1 mol%) under refluxing condition.
The progress of the reaction was monitored by
TLC using petroleum ether: ethyl acetate as eluent.
After completion of the reaction the catalyst was
filtered off and diethylether (5 mL) was added to the
mixture. The obtained solution was washed with 5%
4
4
4
0. Eberson, L. New J. Chem. 1992, 16, 151.
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Haverbeke, Y. Tetrahedron 1995, 51, 6511.
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3. Sabitha, G.; Reddy, G. S.; Reddy, C. S.; Fatima, N.;
Yadav, J. S. Synthesis 2003, 8, 1267.
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4. Hantzsch, A. Verbindungen. Ber. 1881, 14, 1637.
5. Kozhevnikov, I. V. Catalysts for Fine Chemicals. In
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NaHCO
dried over MgSO
3
(10 mL) and brine (10 mL) successively and
. The solvent was evaporated under
4
reduced pressure to yield the crude products. Further
purification was obtained by flash chromatography.
Heteropolyacids were prepared according to the
2
, pp 47–54.
4
6. Aromatization of Hantzsch 1,4-dihydropyridines: general
procedure: All the dihydropyridines were prepared
4
5
literature.