KHSO4 supported onto bentonite, a versatile reagent for aromatization of Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.1002/jccs.200700083

Aromatization of Hantzsch 1,4-dihydropyridines was promoted by KHSO ₄, a relatively green chemical, supported onto bentonite to yield the corresponding pyridine derivatives in excellent yields. The reaction was carried out under mild and conven

Full text of DOI:10.1002/jccs.200700083

Journal of the Chinese Chemical Society, 2007, 54, 579-581
579
Communication
KHSO Supported onto Bentonite, A Versatile Reagent for Aromatization
4
of Hantzsch 1,4-Dihydropyridines
Majid M. Heravi,* Khadijeh Bakhtiari and Hossein A. Oskooie
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
4
Aromatization of Hantzsch 1,4-dihydropyridines was promoted by KHSO , a relatively green chemi-
cal, supported onto bentonite to yield the corresponding pyridine derivatives in excellent yields. The reac-
tion was carried out under mild and convenient conditions.
4
Keywords: Hantzsch 1,4-dihydropyridines; Bentonite; Aromatization; KHSO .
Several 1,4-dihydropyridines (1,4-DHPs) are impor-
is used as a highly efficient, mild and the sole oxidizing
1
8
tant cardiovascular drugs due to their calcium antagonistic
1
effect. In the human body, it has been observed that these
agent in many organic reagents.
Very recently, we have reported the use of KHSO
an efficient catalyst for the synthesis of 1,1-diacetates un-
4
as
compounds are oxidized. They are serving as effective re-
dox catalysts under mild conditions, modeling the NAD(P)H
coenzyme to study its oxidation mechanism in living sys-
1
9
der solvent-free conditions. Synthesis of 2-arylsubsti-
tuted benzimidazoles by oxidative condensation of alde-
2
,3
tems and in seeking new drugs for treating heart vascular
hydes with o-phenylenediamine in the presence of KHSO
4
20
4
,5
disease. In addition recent studies have suggested that
,4-dihydropyridines also provides an antioxidant protec-
tive effect that may contribute to their pharmacological ac-
has also been reported. As part of our research in aro-
2
1-29
1
matization of Hantzsch 1,4-dihydropyridines,
we ex-
and
amined the possibility of using a mixture of KHSO
4
6
2+
tivity. This effect is not due to the Ca antagonist effect
but is related to the reactivity of these compounds toward
Bentonite to effect the aromatization of Hantzsch 1,4-di-
hydropyridines. We wish to report that the reaction can be
performed in chloroform under reflux condition to afford
pyridine derivatives in excellent yields.
7
radical species. On the other hand, the oxidation of the
dihydropyridine ring is the main metabolic route for these
compounds.
We describe in this article a new approach to easy and
efficient conversion of Hantzsch 1,4-dihydropyridines into
Aromatization of Hantzsch 1,4-dihydropyridines is
an important method for the preparation of pyridine deriva-
tives. Development of efficient, mild and reliable reagents
for this propose has been an objective of synthetic chem-
ists, and over the years a large number of such reagents
the corresponding pyridine derivatives using KHSO
ported onto bentonite as catalyst.
4
sup-
4
We have found that KHSO supported onto bentonite
can serve as a mild, fast and efficient oxidant for the aro-
matization of Hantzsch 1,4-dihydropyridines to pyridines.
8
-17
have been reported.
Each method using these reagents encounters at least
one of the following drawbacks: long reaction times, unsat-
isfactory yields, harsh reaction conditions, expensive or
not readily available reagents, inconvenient preparation of
reagents and tedious workup procedures. Considering these
facts, there is still a need for new reagents for this conver-
sion.
4
In terms of reaction time, KHSO supported onto bentonite
seems to be one of the most efficient oxidants for the 1,4-
DHPs among known oxidants, to our best knowledge.
We first performed the aromatization reaction of 1,4-
4
DHPs in the presence of KHSO (0.5 mmol) under reflux
conditions. After 2 hours 40% yield of the product was ob-
tained. In order to reduce the reaction time we decided to
perform the reaction in the presence of a solid support.
Among the various solid supports examined such as mont-
KHSO
4
is one of the components of a triple salt with
.KHSO .K SO a so-called oxone which
formula 2KHSO
5
4
2
4
*
Corresponding author. E-mail: mmh1331@yahoo.com

5
80 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Heravi et al.
morilonite K-10, kaolin, silica gel and bentonite, the latter
proved to be superior in terms of yield and reaction time.
Surprisingly, we found that in the presence of a mixture of
in the 4-position. Dealkylation of 4-ethyl derivative, which
11b
was observed during other oxidation process, did not oc-
cur in the present case.
KHSO
also yields of products increased up to 96-99%.
In fact refluxing the mixture of KHSO (0.5 mmol),
bentonite (0.2 g) and 1,4-DHP (1 mmol) within a short time
Table 1) gave after simple filtration, the desired pyridine
4
and bentonite not only reaction time decreased but
Compared to some previously reported reagents with
major and minor drawbacks, several noteworthy features of
this reaction are apparent: easy workup procedure, avail-
ability of the reagents, use of inexpensive reagents, and
high yield of products in considerably shorter reaction
times.
4
(
derivatives in very high yields (Scheme I).
In conclusion, the present procedure for oxidation of
1
,4-DHPs provides an easy, mild, efficient, and general
Scheme I
methodology for the preparation of pyridine derivatives
from 1,4-DHPs. The method has advantages in terms of
high yields, high selectivity, short reaction times, ease of
operation, and use of relatively non-toxic, available and in-
expensive catalysts. We feel that it may be a suitable addi-
tion to the currently available methodologies.
As shown in Table 1, the oxidation of 1,4-DHPs in the
presence of KHSO
pleted within just a few minutes in CHCl
ditions, requiring no activation such as ultrasound[8] or mi-
4
supported onto bentonite was com-
under reflux con-
EXPERIMENTAL
3
11b
crowave irradiation.
All the dihydropyridines were prepared according to
This reagent was found to be equally effective for the
the literature procedure, using the appropriate aldehydes,
3
ammonia and ethyl acetoacetate.
1
aromatization of 1,4-DHPs bearing an alkyl or aryl group
Table 1. Oxidation of 1,4-DHPs using KHSO supported onto bentonite
4
m.p./b.p. (°C)
Entry
R
Time (min) Yield (%)
Found
Reported
29
1
2
3
H
2
5
2
99
99
96
70
liq
liq
69-70
5
Liq
Me
Et
5
liq
5
4
5
98
61
61-62
30
5
10
99
60-62
61-63
O N
2
1
2
6
7
8
MeO
5
5
5
99
98
97
48-50
39-40
65
50
3
3
0
0
38-41
66-67
O
Cl
a) Yields analyzed by GC.
b) Products exhibited physical properties in accordance with the assigned structures.

Aromatization of Hantzsch 1,4-Dihydropyridines
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 581
2
006, 14, 2720.
Melting points were measured by using the capillary
1
tube method with an electro thermal 9100 apparatus. H
9. Moghadam, M.; Nasr-Esfahani, M.; Tangestaninejad, Sh.;
Mirkhani, V. Bioorg. Med. Chem. Lett. 2006, 16, 2026.
NMR spectra were recorded on a Bruker DRX-90 AVANCE
1
0. Ko, K.-Y.; Kim, J.-Y. Tetrahedron Lett. 1999, 40, 3207.
1. (a) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21.
b) Varma, R. S.; Kumar, D. J. Chem. Soc., Perkin Trans. 1,
999, 1755.
12. Mashraqui, S. H.; Karnik, M. A. Tetrahedron Lett. 1998, 39,
895.
3
by using TMS as an internal standard (CDCl solution). IR
1
spectra were recorded as a KBr disk on the FT-IR Bruker
Tensor 27. All products were known; their physical and
spectroscopic data were compared with those of authentic
(
1
5
,12,30
4
samples and found to be identical.
1
1
3. Mashraqui, S. H.; Karnik, M. A. Synthesis 1998, 713.
4. Han, B.; Liu, Zh.; Liu, Q.; Yang, L.; Liu, Zh.-L.; Yu, W. Tet-
rahedron 2006, 62, 2492.
Aromatization of 1,4-dihydropyridines: General Pro-
cedure
1
1
5. Itoh, T.; Nagata, K.; Okada, M.; Ohsawa, A. Tetrahedron
Lett. 1995, 36, 2269.
4
To a solution of KHSO (0.5 mmol) in chloroform (5
mL) bentonite (0.2 g) was added. The mixture was stirred at
room temperature for about 5 min. 1,4-Dihydropyridine (1
mmol) was then added and refluxed for the specified time
6. Amriappan, P. J. Tetrahedron 2002, 58, 5069.
17. Khadikar, B.; Borkat, S. Synth. Commun. 1998, 28, 207.
1
8. (a) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B.
Org. Lett. 2003, 5, 1031. (b) Bolm, C.; Magnus, A. S.;
Hildebrand, J. P. Org. Lett. 2000, 2, 1173. (c) Thottumkara,
A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett. 2005, 7, 2933.
9. Heravi, M. M.; Bakhtiari, Kh.; Taheri, Sh.; Oskooie, H. A.
Green Chem. 2005, 7, 867.
(
Table 1). The progress of the reaction was monitored by
TLC using petroleum ether-ethyl acetate as eluent. Upon
completion of the reaction, the mixture was filtered and
1
2
2
2
2
2
3
washed with CHCl . The filtrate was evaporated to dryness
under reduced pressure to afford the pure product. The re-
sults are summarized in Table 1.
0. Ma, H. Q.; Wang, Y. L.; Wang, J. Y. Heterocycles 2006, 68,
1669.
1. Heravi, M. M.; Behbahani, F. K.; Oskooie, H. A.; Hekmatshoar,
R. Tetrahedron Lett. 2005, 46, 2775.
2. Heravi, M. M.; Ghassemzadeh, M. Phosphorus Sulfur and
Silicon 2005, 180, 347.
Received August 22, 2006.
3. Heravi, M. M.; Dirkwand, F.; Oskooie, H. A.; Ghassemzadeh,
M. Heterocyclic Commun. 2005, 11, 75.
REFERENCES
4. Heravi, M. M.; Moosavi, F. S. S.; Beheshtiha, Y. S.;
Ghassemzadeh, M. Heterocyclic Commun. 2004, 10, 415.
1
. Janis, R. A.; Triggle, D. J. J. Med. Chem. 1983, 26, 775.
. (a) Meijer, H. P.; Pandit, U. K. Tetrahedron 1985, 41, 467.
25. Heravi, M. M.; Ghassemzadeh, M. Heterocyclic Commun.
2004, 10, 465.
2
(
b) Zhu, Y. Q.; Liu, Y. C.; Cheng, J. P. J. Org. Chem. 1999,
4, 8980.
. Lu, Y.; Cheng, J. P. Chim. Sci. Bull (Engl. Ed) 1996, 41,
881.
26. Tajbakhsh, M.; Heravi, M. M.; Hosseini, A.; Shahrezaiee, A.
Phosphorus Sulfur and Silicon 2003, 178, 773.
27. Heravi, M. M.; Derikvand, F.; Oskooie, H. A.; Hekmatshoar,
R. J. Chem. Res. 2006, 168.
6
3
1
4
. Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
28. Heravi, M. M.; Derikvand, F.; Oskooie, H. A.; Hekmatshoar,
R. Synth. Commun. 2006, 36, 77.
5
. Bocker, R. H.; Guengerich, F. P. J. Med. Chem. 1986, 29,
1
596.
29. Fotouhi, L.; Khaleghi, S.; Heravi, M. M. Lett. Org. Chem.
2006, 3, 111.
6
7
8
. Toniolo, R.; Di Narda, F.; Bontempelli, G.; Ursini, F.
Bioelectrochem. 2000, 51, 193 and references cited therein.
. Mason, R. P.; Mak, I. T.; Trumbore, N. W.; Mason, P. E. Am.
J. Cardiol. 1999, 84, 16L.
30. Eynde, J. J. V.; Delfosse, F.; Mayence, A.; Haverbeke, Y. V.
Tetrahedron 1995, 51, 6511.
31. Hantzsch, A. Condensationprodukte aus Aldehydammoniak
und Ketoniartigen Verbindungen. Ber. 1881, 14, 1637.
. Nasr-Esfahani, M.; Moghadam, M.; Tangestaninejad, Sh.;
Mirkhani, V.; Momeni, A. R. Bioorg. Med. Chem. Lett.