N,N′-ethylene-bis(benzoylacetoniminato) copper (II), Cu(C 22H22N2O2), a new reagent for aromatization of Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.3390/12030433

A variety of Hantzsch 1,4-dihydropyridines were oxidized to their corresponding pyridines in high yields in the presence of Cu(C ₂₂H₂₂N₂O₂) in refluxing acetic acid.

Full text of DOI:10.3390/12030433

Molecules 2007, 12, 433-438
molecules
ISSN 1420-3049
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Full Paper
N,N'-Ethylene-bis(benzoylacetoniminato) Copper (II),
Cu(C H N O ), a New Reagent for Aromatization of Hantzsch
2
2
22
2
2
1
,4-Dihydropyridines
∗
∗
Saeed Dehghanpour , Majid M. Heravi and Fatemeh Derikvand
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
*
Authors to whom correspondence should be addressed. E-mails: dehganpour_farasha@yahoo.com;
mmh1331@yahoo.com
Received: 7 January 2007; in revised form: 6 February 2007 / Accepted: 10 February 2007 /
Published: 12 March 2007
Abstract: A variety of Hantzsch 1,4-dihydropyridines were oxidized to their
corresponding pyridines in high yields in the presence of Cu(C22
acetic acid.
22 2 2
H N O ) in refluxing
22 2 2
Keywords: Cu(C22H N O ), Hantzsch 1,4-dihydropyridines, aromatization, oxidation,
solid reagents.
Introduction
Hantzsch 1,4-dihydropyridines (1,4-DHPs) and their derivatives are an important class of bioactive
molecules in the pharmaceutical field [1]. The DHP heterocyclic ring is a common feature of a variety
of bioactive compounds including anticonvulsant, antidiabetic, antianxiety, antidepressive, antitumor,
analgesic, seditative, vasodilator, bronchodilator, hypnotic and anti-inflammatory agents [2]. DHPs are
commercially used as calcium channel blockers for the treatment of cardiovascular diseases, including
hypertension [3]. The oxidation of DHPs to the corresponding pyridine derivatives constitutes the
principal metabolic pathway in biological systems [4], as well as providing facile access to the
corresponding pyridine derivatives, which show antihypoxic and antiischemic activities [5], from the
easily available DHPs [6]. Therefore, oxidative aromatization of DHPs has attracted continuing
interests of organic and medicinal chemists and a plethora of protocols has been developed [7-9]. Early
experiments mostly used strong oxidants, such as HNO [7], KMnO [8], cerium ammonium nitrate
3
4

Molecules 2007, 12
CAN) [9] or I –MeOH [10]. New more efficient and environmentally benign methods, such as
4
34
(
2
electrochemical oxidation [11] and catalytic aerobic oxidation using RuCl
carbon [14] or Fe(ClO ) [15] have also been reported.
3
[12], Pd/C [13], activated
4
3
In recent years considerable emphasis has been placed on diminishing the environmental impact of
industrial processes [16] and it is well recognized that solid acid catalysts and reagents can play a
significant role in the development of cleaner technologies [17].
Copper(II) complexes of N O ligands have generated considerable interest because of their
2
2
interesting physio-chemical properties, potentially useful in catalytical reaction and biological
activities [18]. Recently we have reported the synthesis and structure of N,N'-ethylene-bis(benzoyl-
acetoniminato) copper (II), Cu(C H N O ) [19].
2
2
22
2
2
Based on our previous studies on the use of solid acid catalysts [20-25] and reagents [26-28] for
carrying out organic reactions and our interest in aromatization of Hantzsch 1,4-dihydropyridines [26-
2
9], we have examined the possibility of using Cu(C22
H
22
N
2
O
2
) as a novel solid reagent to effect the
aromatization of Hantzsch 1,4-dihydropyridines. (Scheme 1)
Scheme 1.
R
H
H
R
N
EtOOC
COOEt Cu(C H N O )
22 22 2 2
EtOOC
COOEt EtOOC
COOEt
CH3
+
H C
N
CH3
AcOH, reflux
3
H C
CH3
H C
N
3
3
H
Results and Discussion
In order to determine the best reaction conditions, the efficiency of a variety of solvents in the
oxidation of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate as a model reaction was
studied. First we carried out the model reaction under solvent-free conditions at room temperature. The
temperature of the reaction mixture started to rise but the reaction was not complete after 24 h. Then
we decided to examine the effect of the solvent on the reaction. As shown in Table 1, the best results in
terms of yield and time were obtained in refluxing acetic acid.
Table 1. The effect of the solvent on the oxidation of 2,6-dimethyl-4-phenyl-1,4-
22 2 2
dihydropyridine-3,5-dicarboxylate, in the presence of Cu(C22H N O ).
Solvent
Dichloromethan Chloroform Ethanol Water Acetonitrile Acetic acid
e
Time (h)
Yield(%)
24
24
24
24
24
1
a
20
20
25
35
40
90
a) Yields were analyzed by GC.
In order to establish the scope of this novel oxidation protocol, we tested a variety of 1,4-DHPs
under the optimized reaction conditions. As shown in Table 2 the presence of both electron donating

Molecules 2007, 12
4
35
and electron withdrawing substituents on the precursors afforded the corresponding pyridines in good
to excellent yields. In the presence of excess reagent the corresponding products were obtained in
shorter times. (cf. entries 8 and 9, Table 2). As expected, in the case of a 1,4-DHP bearing an isopropyl
group in the 4-position, a pyridine derivative resulting from the elimination of isopropyl group was
formed. This may be attributed to the stability of the isopropyl cation (Table 2, entry 10).
The oxidizing species in the reaction is the copper(II) complex and it can be reduced to Cu(I)
during the reaction. As Cu(I) prefers the tetrahedral structure and we believe it is unstable in it’s
complex form, so, after reduction, the complex will be decomposed. The produced species are soluble
in acetic acid and ethanol and could be separated by recrystallization from ethanol or chromatography.
Table 2. Oxidation of Hantzsch 1,4-dihydropyridines in the presence of Cu(C H N O )
2
2
22
2
2
in refluxing acetic acid.
o
m.p ( C)
a
Entry R
Time (min) Yield (%)
b
Found
68-70
Oil
Reported [Ref.]
69-70[30]
Oil[4]
1
2
3
4
5
6
7
8
9
1
H-
40
50
45
60
55
50
45
65
40
40
89
88
90
90
87
88
75
80
80
Me-
Et-
Oil
Oil[4]
Ph
60-62
72-73
50
61-62[4]
72-73[11]
50[12]
4-Me-Ph
4-MeO-Ph
4-Cl-Ph
64-66
62-63
62-63
68-70
65-66[31]
61-63[30]
61-63[30]
69-70[30]
3-NO
2
2
-Ph
-Ph
c
3-NO
d
0
Isopropyl-
85
a) Yields were analyzed by GC.
b) Products exhibited physical properties in accordance with the assigned structures.
c) The reaction was carried out in the presence of 1.2 equivalents of the reagent.
d) The product resulting from the elimination of isopropyl group was formed.
Conclusions
In summary, we have developed the use of Cu(C22
22 2 2
H N O ) as an easy to handle, non-corrosive
and environmentally benign reagent for the aromatization of Hantzsch 1,4-dihydropyridines. The
advantages of the present procedure are simplicity of operation and the good yields of the products.
Experimental Section
General
Melting points were measured by using the capillary tube method with an Electrothermal 9200
1
apparatus. H-NMR spectra were recorded on a Bruker AC-80 MHZ spectrometer using TMS as an

Molecules 2007, 12
internal standard (CDCl solution). IR spectra were recorded using KBr disks on a Bruker Tensor
4
36
3
2
7FT-IR instrument. GC spectra were recorded on an Agilent 5973 GC instrument. All products were
characterized by spectra and physical data. Silica gel 60 for column chromatography was purchased
from Merck. The Cu(II) reagent [19] was prepared as follows: the Schiff base N,N’-ethylene-
bis(benzoyl-acetoniminate) (2 mmol) was dissolved in boiling methanol (20 mL) and mixed with a
solution of copper(II) acetate (2 mmol) in the same volume of solvent. The mixture was heated on a
water bath for about 3 min and then left to stand overnight. The crystals which had formed were
filtered off, washed with methanol and dried. All the dihydropyridines were prepared according to the
literature procedure [32], using the appropriate aldehydes, ammonia, and ethyl acetoacetate.
Aromatization of Hantzsch 1,4-dihydropyridines: General procedure
22 2 2
The Hantzsch 1,4-dihydropyridine (1 mmol) was reacted with Cu(C22H N O ) (1 mmol) in
refluxing acetic acid (3 mL). The progress of the reaction was monitored by TLC using 80:20
petroleum ether-ethyl acetate as eluent. After completion of the reaction, diethyl ether (5 mL) was
added to the mixture. The solution obtained was washed successively with 5% NaHCO (10 mL) and
3
4
brine (10 mL) and dried over MgSO . The solvent was evaporated under reduced pressure to yield the
crude products. Further purification was achieved by recrystallization from ethanol (in the case of solid
products) and flash chromatography. Yields were obtained using GC analysis. All products were
known compounds and their physical and spectroscopic data were compared with those of authentic
samples [4,11,12,30,31] and found to be identical.
Acknowledgments
The Authors are thankful for the partial financial assistance from Azzahra University Research
Council.
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Sample Availability: Samples of selected compounds (1-5, 7, 8, 10) are available from authors.
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