Catalytic effect of basic alumina in the dehydrogenation of 1,4-Dihydropyridines with tetrabutylammonium peroxydisulfate

Article abstract of DOI:10.1515/znb-2010-0914

4-Alkyl- or 4-aryl-1, 4-dihydropyridine derivatives were oxidized to the pyridine derivatives by tetrabutylammonium peroxydisulfate (n-Bu ₄N)₂S₂O₈ (TBAPD) in combination with basic alumina in refluxing acetonitr

Full text of DOI:10.1515/znb-2010-0914

Catalytic Effect of Basic Alumina in the Dehydrogenation of
1,4-Dihydropyridines with Tetrabutylammonium Peroxydisulfate
Hamid R. Memarian and Behjat Barati
Catalysis Division, Department of Chemistry, Faculty of Science, University of Isfahan,
Isfahan, 81746-73441, I. R. Iran
Reprint requests to Prof. H. R. Memarian. Fax: +98-311-668 9732. E-mail: memarian@sci.ui.ac.ir
Z. Naturforsch. 2010, 65b, 1143 – 1147; received March 11, 2010
4-Alkyl- or 4-aryl-1,4-dihydropyridine derivatives were oxidized to the pyridine derivatives by
tetrabutylammonium peroxydisulfate (n-Bu4N)2S2O8 (TBAPD) in combination with basic alumina
in refluxing acetonitrile and also in the absence or presence of basic alumina under microwave irra-
diation. The presence of basic alumina plays an important role in the reaction mechanism. Whereas
oxidation under thermal condition is assumed to occur through an ionic mechanism, ionic and also
radical mechanisms are proposed for the reactions under microwave irradiation.
Key words: 1,4-Dihydropyridines, Heterocycles, Oxidation, Peroxydisulfates, Pyridines
Introduction
interest in the chemistry of 1,4-dihydropyridines, es-
pecially oxidation and photo-oxidation of these com-
pounds [16], we were also interested to find an efficient
and especially inexpensive oxidant for the conversion
of these compounds to pyridine derivatives.
1,4-Dihydropyridines (1,4-DHPs) are well-known
compounds of considerable interest as pharmaceuticals
which have been described more than one century ago
by Arthur Hantzsch [1]. These compounds are analogs
of NADH coenzymes and an important class of drugs
which are potent blockers of calcium channels with rel-
evant applications in various cardiovascular diseases
[2, 3]. It has been observed that in the human body
1,4-DHPs are generally oxidized to their correspond-
ing pyridines [4 – 8]. Due to the biological importance
of the oxidation step of 1,4-dihydropyridines, oxida-
tion of these compounds has been the subject of a
large number of studies and is still under investigation
[9, 10].
In recent years, application of microwave irradiation
for the optimization and acceleration of organic reac-
tions has rapidly increased [11 – 13]. In organic synthe-
sis especially it leads to shorter reaction times, higher
yields, easier work-up, and environmental friend-
liness.
Recently, we have reported on the oxidation of var-
ious 1,4-dihydropyridines to pyridine derivatives us-
ing tetrabutylphosphonium dichromate (TBPDC) un-
der conventional heating and microwave irradiation
[14], and also on the electron transfer-induced oxida-
tion of these compounds by 2,3-dichloro-5,6-dicyano-
p-benzoquinone (DDQ) at room temperature and un-
der microwave irradiation [15]. Due to our general
Tetrabutylammonium peroxydisulfate (TBAPD) is
easily prepared by reaction of tetrabutylammoniumhy-
drogensulfate and potassium peroxydisulfate in aque-
ous solution [17]. This reagent has been extensively
used for a variety of transformations of functional
groups in organic synthesis such as the one-pot syn-
thesis of nitriles from primary alcohols [18] and alde-
hydes [19], as a selective approach to the oxidative de-
protection of allyl ethers [20] and O-benzyl protective
groups [21], epoxidation of α,β-unsaturated ketones
[22], and iodination of aromatic compounds [23, 24].
In contrast to K2S2O8, Na2S2O8or (NH4)2S2O8, this
reagent is easily soluble in various organic solvents
such as acetonitrile, acetone, methanol, and dichloro-
methane.
The aim of the present work has been to investi-
gate the oxidation of 1,4-dihydropyridines by using
tetrabutylammonium peroxydisulfate (TBAPD) as oxi-
dant in combination with a suitable catalyst to enhance
its oxidizing ability. For this reason, TBAPD alone
or in combination with various Lewis acids has been
used for the oxidation of 1,4-dihydropyridine-3,5-di-
esters (Scheme 1) and 3,5-diacetyl-1,4-dihydropyrid-
ines (Scheme 2) under conventional heating or mi-
crowave irradiation.
c
0932–0776 / 10 / 0900–1143 $ 06.00 ꢀ 2010 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Unauthenticated
Download Date | 5/3/17 10:45 AM

1144
H. R. Memarian – B. Barati · Catalytic Effect of Basic Alumina
Scheme 1.
Scheme 2.
Table 1. The effect of the catalyst on the rate of oxidation of
1e by TBAPD in refluxing acetonitrile.
Results and Discussion
At first we have carried out the thermal oxidation
of diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-
3,5-dicarboxylate (1e) as a model substance in the
presence of TBAPD alone or in combination with
AlCl3, acidic Al2O3, basic Al2O3,ormontmorillonitein
acetonitrile. The results presented in Table 1 show that
basic Al2O3 is the most suitable catalyst for this pur-
Catalyst
–
AlCl3
Acidic Al2O3
Basic Al2O3
Montmorillonite
Time (h)
8
5.5
3.5
1
Conversion (%)
0
100
100
100
∼ 40
5
It is interesting to compare the effect of the pres-
pose. Since the nature of the solvent has a great effect ence or absence of the catalyst under both reaction con-
on the solubility of the oxidant, and since its boiling ditions. Since the thermal reaction without using of a
point can also affect the rate of oxidation under ther- catalyst does not work, we will propose a mechanism
mal condition, we studied also the oxidation of 1e in for the thermal reaction (Scheme 3).
the presence of TBAPD and basic alumina in a ratio
According to the proposed mechanism, nucleophilic
of 1 : 1 : 0.5 in different solvents such as acetone, ace- attack of basic alumina occurs at the sulfur atom of
tonitrile, chloroform, and dichloromethane under re- the oxidant (path 1), followed by a heterolytic cleavage
flux conditions. It was found that acetonitrile is the best of the peroxydisulfate anion (path 2). The deprotona-
solvent for this purpose.
tion at the more acidic site of the 1,4-dihydropyridine
A comparison of the results obtained under re- by this reactive anion species and the following expul-
flux condition and under microwave irradiation (Ta- sion of 4-H (as H−) or 4-R (as R−) result in the for-
bles 2 and 3) shows that i) the same product(s) are ob- mation of the pyridine derivative (path 3). The attack
tained in both reactions, ii) the reaction times are much of hydride or alkyl ions of the aluminum complex re-
shorter under microwave irradiation, and iii) oxidation leases the basic alumina, which goes back to the re-
of 1,4-DHPs also occurrs under microwave irradiation action cycle (path 4). This argument is supported by
even in the absence of basic alumina, but at a slower the formation of tributylamine, which is detected by
rate.
the GC analysis of the reaction mixture. It is impor-
The loss of the substituent in position 4 has earlier tant to note that this amine was also formed by treat-
been observed in photochemical reactions of Hantzsch ment of the oxidant with sodium hydride (as a hydride
esters only in the cases of carboxyl groups [25], some source) and basic alumina, as confirmed by the GC
heterocyclic groups [26, 27], and secondary alkyl and analyses. The anionic species formed in path 3 pos-
benzyl groups. Thermal oxidation of Hantzsch esters sibly are converted to water or alcohol and the sul-
with expulsion of benzylic and secondary alkyl sub- fate anion (path 5). This explains the use of equimo-
stituents in position 4 by various oxidants has been lar amounts of the oxidant. In the case of acidic alu-
cited [28]. We have also reported earlier the expulsion mina, Al-OH can attack the peroxydisulfate, which
of the 4-substituent on photochemical reaction of some is not more nucleophilic compared with basic alu-
keto-dihydropyridines [28].
mina (AlO−); therefore, a slower reaction (longer re-
Unauthenticated
Download Date | 5/3/17 10:45 AM

H. R. Memarian – B. Barati · Catalytic Effect of Basic Alumina
1145
Table 2. Aromatization of 1,4-dihydropiridine-3,5-diesters 1a – m using tetrabutylammonium peroxydisulfate and basic alu-
mina in refluxing acetonitrile and under microwave irradiation.
Thermal
Microwave irradiation
Time (sec)b without cat. Time (sec)b with cat.
1
a
b
c
d
e
f
g
h
i
j
k
l
m
a
R
H
CH3
CH3CH2CH2
Ph(CH)CH3
C6H5
2-ClC6H4
4- ClC6H4
4-CH3C6H4
2,5-(CH3O)2C6H3
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-Furyl
Product
2a
Yield (%)a
Time (min)b
Productc
2a
95
2.5/92
93
88
93
90
87
93
86
89
86
90
76
25
75
90
100
60
150
120
100
45
60
135
150
170
120
260
220
170
100
150
240
270
310
30
80
90
110
60
160
100
120
70
2a/2b
2c
2b
2c
2a
2a
2e
2e
2f
2f
2g
2g
2h
2h
2i
2i
2j
75
2j
90
2k
150
180
65
2k
2l
160
165
170
2l
2m
2m
b
c
Isolated yield; the times are given for total disappearance of 1a – m; the products have not been isolated, and only their TLC was
compared with that of authentic samples.
Table 3. Aromatization of 3,5-diacetyl-1,4-dihydropyridines 3a – j using tetrabutylammonium peroxydisulfate and basic alu-
mina in refluxing acetonitrile and under microwave irradiation.
Thermal
Microwave irradiation
Time (sec)b without cat.
3
a
b
c
d
e
f
g
h
i
j
a
R
H
CH3
C6H5
2-ClC6H4
4- ClC6H4
4-CH3C6H4
2-CH3OC6H3
3-NO2C6H4
4-NO2C6H4
2-Furyl
Producta
4a
Time (min)b
Producta
4a
Time (sec) with cat.b
5
40
35
80
70
25
4
60
65
120
40
130
90
210
190
80
15
80
50
140
130
50
80
80
110
70
4b
4b
4c
4c
4d
4d
4e
4e
4f
4f
4g
4g
115
140
180
130
4h
4h
4i
4i
4j
4j
b
The products have not been isolated, and only their TLC was compared with that of authentic samples; the times are given for total
disappearance of 3a – j.
action time) is expected in the case of acidic alumina Conclusion
(Table 1).
In conclusion, we have found that tetrabutylam-
It is interesting to compare the results obtained un-
der microwave irradiation in the presence or in the ab-
sence of the catalyst. Since the presence of the catalyst
increases the rate of oxidation, a heterolytic cleavage
of the oxidant as mentioned for the thermal reaction
(Scheme 3) and also a homolytic cleavage (Scheme 4)
for the oxidation under microwave irradiation are pro-
posed.
monium peroxysulfate in the presence of basic alu-
mina in acetonitrile under thermal condition and/or
microwave irradiation, and with or without this cata-
lyst, is a suitable oxidant for the aromatization of 1,4-
dihydropyridines. The nature of the 4-substituent plays
an important role regarding the rate of oxidation.
Experimental Section
According to this mechanism, homolytic cleavage
of the peroxy bond of the oxidant results in the for-
mation of two sulfate radicals (path 6). This reactive
species can abstract hydrogen either from 1- or 4-
positions under formation of dihydropyridyl radicals
(path 7). Elimination of a hydrogen or alkyl radical
from dihydropyridyl radicals leads to the formation of
pyridines (path 8).
1,4-Dihydropyridines were synthesized according to the
Hantzsch procedure [1]. Tetrabutylammonium peroxydisul-
fate (TBAPD) was prepared according to the known pro-
cedure [17]. Microwave irradiation was carried out us-
ing a commercial microwave oven (National) operating at
2450 MHz (900 W). All products were known, and their
physical and spectroscopic data were compared with those
of authentic samples. The spectroscopic data of the starting
Unauthenticated
Download Date | 5/3/17 10:45 AM

1146
H. R. Memarian – B. Barati · Catalytic Effect of Basic Alumina
Scheme 3.
Scheme 4.
materials and also the products have been reported earlier Thermal reactions
[27, 28 – 30]. Preparative layer chromatography (PLC) was
In an optimized reaction, a mixture of 1a – m (0.3 mmol)
carried out on 20 × 20 cm2 plates, coated with a 1 mm layer
of Merck silica gel PF254, prepared by applying the silica as
slurry and drying in air.
or 3a – j (0.3 mmol), TBAPD (0.3 mmol) and basic alumina
(0.15 mmol) in acetonitrile (10 mL) was refluxed until to-
tal disappearance of 1,4-dihydropyridine (TLC). After com-
Unauthenticated
Download Date | 5/3/17 10:45 AM

H. R. Memarian – B. Barati · Catalytic Effect of Basic Alumina
1147
pletion of the reaction, the solvent was evaporated, and the without a catalyst in acetonitrile (0.5 mL) was irradiated with
product was isolated by PLC.
microwaves until all of the dihydropyridine was consumed.
Acknowledgement
Microwave irradiation
We are thankful to the Center of Excellence (Chemistry)
and Research Council of the University of Isfahan and the
(0.1 mmol) and basic alumina as catalyst (0.05 mmol) or Office of Graduate Studies for their financial support.
A mixture of 1a – m or 3a – j (0.1 mmol), TBAPD
[1] A. Hantzsch, Justus Liebigs Ann. Chem. 1882, 215, 1 –
82.
[15] H. R. Memarian, M. Ghazaie, S. Kakhki Mehneh,
Z. Naturforsch. 2009, 64b, 1187 – 1192.
[16] H. R. Memarian, M. Abdoli-Senejani, D. Do¨pp, J.
Chin. Chem. Soc. 2007, 54, 131 – 139.
[2] R. A. Janis, D. J. Triggle, J. Med. Chem. 1983, 26,
775 – 785.
[3] X. Y. Wei, A. Rutledge, D. J. Triggle, Mol. Pharmacol.
1989, 35, 541 – 542.
[4] R. H. Bocker, F. P. Guengerich, J. Med. Chem. 1986,
29, 1596 – 1603.
[17] J. C. Jung, H. C. Chai, Y. H. Kim, Tetrahedron Lett.
1993, 34, 3581 – 3584.
[18] F.-E. Chen, Y.-Y. Li, M. Xu, H.-Q. Jia, Synthesis 2002,
1804 – 1806.
[5] H. Meyer, E. Wehinger, F. Bossert, D. Scherling,
Arzneim.-Forsch. 1983, 33, 106 – 112.
[6] F. P. Guengerich, W. R. Brian, M. Iwasaki, M. A. Sari,
C. Ba¨a¨rnhielm, P. Berntsson, J. Med. Chem. 1991, 34,
1838 – 1844.
[7] F. de Matteis, C. Hollands, A. M. Gibbs, N. de Sa,
M. Rizzardini, FEBS Lett. 1982, 145, 87 – 92.
[8] S. A. Mc Cluskey, D. S. Riddick, J. E. Mackie, S. M.
Kimmet, R. A. Whitney, G. S. Marks, Can. J. Physiol.
Pharmacol. 1992, 70, 1069 – 1074.
[19] F.-E. Chen, H. Fu, G. Meng, Y. Cheng, Y.-X. Lu¨, Syn-
thesis 2000, 1519 – 1520.
[20] F.-E. Chen, X.-H. Ling, Y.-H. He, X.-H. Peng, Synthe-
sis 2001, 1772 – 1774.
[21] S. G. Yang, M. Y. Park, Y. H. Kim, Synlett 2002, 492 –
494.
[22] Y. H. Kim, J. P. Hwang, S. G. Yang, Tetrahedron Lett.
1997, 38, 3009 – 3012.
[23] S. G. Yang, Y. H. Kim, Tetrahedron Lett. 1999, 40,
6051 – 6054.
[9] H. R. Memarian, I. Mohammadpoor-Baltork, M. M.
Sadeghi, Z. S. Samani, Indian J. Chem. 2001, 40B,
727 – 728, and refs. cited therein.
[10] M. Anniyappan, D. Muralidharan, P. T. Perumal, Tetra-
hedron 2002, 58, 5069 – 5073.
[11] C. O. Kappe, Angew. Chem. 2004, 116, 6408 – 6443;
Angew. Chem. Int. Ed. 2004, 43, 6250 – 6284.
[12] H. R. Memarian, A. Saffar-Teluri, J. Mol. Catal. A:
Chem. 2007, 274, 224 – 230.
[13] H. R. Memarian, H. Sabzyan, A. Farhadi, Z. Natur-
forsch. 2009, 64b, 532 – 540.
[24] J. P. Whang, S. G. Yang, Y. H. Kim, Chem. Commun.
1997, 1355 – 1356.
[25] J. F. Biellman, H. J. Callot, W. R. Pilgrim, Tetrahedron
1972, 28, 5911 – 5921.
[26] H. R. Memarian, M. M. Sadeghi, A. R. Momeni, Indian
J. Chem. 1999, 38B, 800 – 804.
[27] H. R. Memarian, A. Mirjafari, Bioorg. Med. Chem.
Lett. 2005, 15, 3423 – 3425.
[28] H. R. Memarian, M. M. Sadeghi, A. R. Momeni,
D. Do¨pp, Monatsh. Chem. 2002, 133, 661 – 667.
[29] H. R. Memarian, M. M. Sadeghi, H. Aliyan, Indian J.
Chem. 1998, 37B, 219 – 223.
[30] H. R. Memarian, M. Bagheri, D. Do¨pp, Monatsh.
Chem. 2004, 135, 833 – 838.
[14] H. R. Memarian, I. Mohammadpoor-Baltork, M. Java-
hery, J. Chin. Chem. Soc. 2006, 53, 511 – 514.
Unauthenticated
Download Date | 5/3/17 10:45 AM