Silica chloride/NaNo2 as a novel heterogeneous system for the oxidation of 1,4-dihydropyridines under mild conditions via in situ generation of NOCl

Article abstract of DOI:10.1080/10426500307836

A combination of silica chloride and sodium nitrite in the presence of wet SiO₂ were used as an effective oxidizing agent for the oxidation of dihydropyridines to their corresponding pyridine derivatives under mild and heterogeneous conditions

Full text of DOI:10.1080/10426500307836

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Silica Chloride/NaNO 2 as a Novel Heterogeneous
System for the Oxidation of 1,4-Dihydropyridines
Under Mild Conditions via In Situ Generation of NOCl
Mohammad Ali Zolfigol a , Farhad Shirini b , Arash Ghorbani Choghamarani a & Iraj
Mohammadpoor-Baltork c
a Bu-Ali Sina University , Hamadan, Iran
b Gilan University , Rasht, Iran
c Isfahan University , Isfahan, Iran
Published online: 27 Oct 2010.
To cite this article: Mohammad Ali Zolfigol , Farhad Shirini , Arash Ghorbani Choghamarani & Iraj Mohammadpoor-Baltork
(2003) Silica Chloride/NaNO 2 as a Novel Heterogeneous System for the Oxidation of 1,4-Dihydropyridines Under Mild
Conditions via In Situ Generation of NOCl, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:8, 1709-1715, DOI:
10.1080/10426500307836
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Phosphorus, Sulfur, and Silicon, 178:1709–1715, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390220853
SILICA CHLORIDE/NaNO2 AS A NOVEL
HETEROGENEOUS SYSTEM FOR THE OXIDATION
OF 1,4-DIHYDROPYRIDINES UNDER MILD
CONDITIONS VIA IN SITU GENERATION OF NOCl
Mohammad Ali Zolfigol,a Farhad Shirini,b Arash Ghorbani
Choghamarani,a and Iraj Mohammadpoor-Baltorkc
Bu-Ali Sina University, Hamadan, Iran;a Gilan University,
Rasht, Iran;b and Isfahan University, Isfahan, Iranc
(Received February 18, 2003)
A combination of silica chloride and sodium nitrite in the presence of
wet SiO2 were used as an effective oxidizing agent for the oxidation
of dihydropyridines to their corresponding pyridine derivatives under
mild and heterogeneous conditions in moderate to excellent yields.
Keywords: 1,4-Dihydropyridines; oxidation; pyridines; silica chloride
4-Substituted Hantzsch dihydropyridines (1) are analogues of NADH
coenzymes and an important class of drugs.1 For example, amlodepine
besylate, nifedepine, and related dihydropyridines are Ca2+ channel
blockers, and are rapidly emerging as one of the most important classes
of drugs for the treatment of cardiovascular diseases including hyper-
tension. In the human body, it has been observed that these compounds
undergo oxidation to form pyridine derivatives. These oxidized com-
pounds largely are devoid of the pharmacological activity of the par-
ent compounds. Additionally, dihydropyridines often are produced in
a synthetic sequence and have to be oxidized to pyridines.2 Numer-
ous reagents and procedures have been recommended for this purpose,
such as ferric or cupric nitrates on a solid support (clayfen or claycop),3
ceric ammonium nitrate,4 clay-supported cupric nitrate accompanied
by ultrasound-promotion,5 manganese dioxide or DDQ,6 nitric oxide,7
Bu-Ali Sina University, Hamadan, Iran, is gratefully acknowledged for financial sup-
port for this work.
Address correspondence to Mohammad Ali Zolfigol, Chemistry Department, Col-
lege of Science, Bu-Ali Sina University, Hamadan 65174, Post Box No. 4135, I.R. Iran.
E-mail: Zolfi@basu.ac.ir
1709

1710
M. A. Zolfigol et al.
bismuth nitrate pentahydrate,8 PCC,9 tetrakis-pyridine cobalt(II)
dichromate (TPCD),10 nicotinium dichromate,11 S-nitrosoglutathion,12
N2O4 compelex of 18-crown-6,13 diphenylpicrylhydrazyl and benzoyl
peroxide as free radical oxidizing agents,14 KMnO4,15 CrO3,16 HNO3,17
HNO2,18 tert-butylhydroperoxide,19 silica gel supported ferric nitrate
(silfen),20 N2O3,21 photochemical oxidation,22 inorganic acidic salts and
sodium nitrite or nitrate.23−26
Recently, Ohsawa et al. reported an excellent procedure for this
transformation. They have demonstrated the remarkably practical use
of NO gas as a clean and efficient oxidant for this purpose.2
Although a variety of reagents is capable of effecting these oxida-
tions,1−26 as far as we know this transformation is not easy and is a
complicated step because these compounds (which have different func-
tional groups within the molecule) are very sensitive to the oxidizing
agents and reaction conditions. Most of the reported reagents produce
by-products which are difficult to remove from the desired products. An-
other major drawback to the older procedures is their use of reagents
which are either highly toxic or present serious disposal problems (or
both). For example, we know that the NO gas is corrosive and highly
toxic and must be used under Ar atmosphere and an effective hood with
caution.2 Therefore, we decided to choose a new reagent or reagent sys-
tems to overcome the above limitations. In addition, for our propose
both clean and easy work-up were also important.
On the other hand, any reduction in the amount of liquid acids needed
and any simplification in handling procedures would be highly conve-
nient in terms of risk reduction, economic advantage, and environment
protection.27 Also there is intense current research and general inter-
est in heterogeneous systems because of the perceived opportunities
such systems present for basic research and because of the unques-
tioned importance such systems have in industry and in developing
technologies.28 In continuation of our studies on the application of het-
erogeneous systems,29,30 we found that the silica chloride31 (I) is an
excellent source for generation of HCl. It is interesting to note that
the addition of wet SiO2 to the reaction mixture containing of silica
chloride could in situ generate HCl. Therefore, we were interested in
using this inorganic acidic resin (I) as a new hydrochloric acid function
immobilized on the surface of silica gel via covalent bonding for the
in situ generation of NOCl (as an efficient oxidizing agent) when used
in conjunction with NaNO2, wet SiO2 (Scheme 1). We report a simple
method for the effective oxidation of 1,4-dihydropyridines (1) to their
corresponding pyridine derivatives (2 or 3) under mild and heteroge-
neous conditions via in situ generation of NOCl (Scheme 2).

Silica Chloride/NaNO as a Novel Heterogeneous System
2
1711
SCHEME 1
SCHEME 2

1712
M. A. Zolfigol et al.
Different types of dihydropyridines (1) were subjected to the oxida-
tion reaction in the presence of silica chloride (I), NaNO2 (II), and wet
SiO2 (50% w/w) in dichloromethane (Scheme 2). The oxidation reactions
were performed under mild and completely heterogeneous conditions
at room temperature and take place with moderate to excellent yields
(Table I).
It also was observed that the oxidation of 1,4-dihydropyridines (Ta-
ble I, entry 13) bearing alkyl substituent (alkyl moieties may be re-
sponsible for generating stable carbocations) at the 4-position gives only
dealkylated pyridine derivative (2). This is in agreement with the obser-
vation made by other employing different oxidative conditions.2,19,23−26
TABLE I Oxidation of 1,4-Dihydropyridines (1) to Their Corresponding
Pyridine Derivatives (2 or 3) with a Combination of Silica Chloride (I), NaNO2
(II), and wet SiO2 (50% w/w) in Dichloromethane at Room Temperature
Reagent/Substratea
(mmol)
Time
Entry
Substrate
Product
I
II
1.5
1.75
1.75
4.125
4.5
5.5
5.5
1.5
(min)
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
0.2
30
30
30
60
45
45
30
90
45
45
45
45
30
135
75
30
45
120
75
60
45
75
75
75
92
92
99
92
99
96
99
90
90
99
92
95
99
86
90
91
98
91
99
98
97
96
96
96
0.25
0.25
0.55
0.6
0.75
0.75
0.2
0.3
0.5
0.6
0.6
0.25
1.05
0.95
0.2
0.25
0.55
0.4
0.4
0.4
0.6
0.6
2.25
3.75
4.5
1j
1k
1l
2j
2k
2l
4.5
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
1x
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
1.75
7.875
7.125
1.5
1.75
4.125
3
3
3
4.5
4.5
0.6
4.5
aWet SiO2: substrate (0.4 g: 1 mmol), I–II refer to mmol of the silica chloride and
NaNO2.
bIsolated yields.

Silica Chloride/NaNO as a Novel Heterogeneous System
1713
2
However, aryl substituted 1,4-dihydropyridines (Table I, entries 4–12,
14, 15, 18–24) furnished the corresponding pyridine derivatives.
This present oxidation reaction can be carried out readily by placing
silica chloride (I), NaNO2 (II), 1,4-dihydropyridine (1), wet SiO2 (50%
w/w), and CH2Cl2 as the solvent in a reaction vessel and efficiently
stirring the resulting heterogeneous mixture at room temperature. The
pyridine derivatives (2 or 3) can be obtained simply by filtration and
evaporation of the solvent. The results and reaction conditions are given
in the Table I.
The oxidation reaction did not occur in the absence of wet SiO2. This
observation suggests that the water molecule is essential for such pro-
cesses. The presence of wet SiO2 thus provides an effective heteroge-
neous surface area for in situ generation of NOCl.32 It also eases the
reaction work-up.
1,4-Dihydropyridines (Table I, entries 5, 8–9, 19–22) bearing very
electron rich aryl or thienyl substituents (these compounds also are very
susceptible to electrophilic aromatic substitution) at the 4-position give
only the pyridine derivative (3) confirming that these compounds have
not been nitrosated or nitrated (or both) during the oxidation reaction.
Therefore, this system behaves chemoselectively and NO+ attacks only
the nitrogen site of the secondary amines in 1,4-dihydropyridines.24
In conclusion, the low cost and availability of the reagents, easy and
clean work-up, and high yields make this an attractive methodology.
This simple procedure is highly selective and contamination by nitra-
tion side-products is avoided. We believe that the present methodology
could be an important addition to existing methodologies.
EXPERIMENTAL SECTION
General: Chemicals were purchased from Fluka, Merck, Riedel-de
Haen AG and Aldrich chemical companies. Yields refer to isolated
products. Silica chloride was synthesised according to the reported
prosedures.33,34 The oxidation products were characterized by compari-
son of their spectral data (IR, 1H-NMR) with the reported physical data
in the literature. All Hantzsch 1,4-dihydropyridines were synthesized
by the reported procedures.18
Oxidation of Dihydropiridine (1a) to Substituted Pyridine
(2a). A Typical Procedure
A suspension of compound 1a (0.331 g, 1 mmol), silica chloride (0.2 g),
wet SiO2 (50% w/w, 0.4 g), and NaNO2 (0.1035 g, 1.5 mmol) in CH2Cl2
(6 mL) was stirred at room temperature for 30 min (the progress of

1714
M. A. Zolfigol et al.
the reaction was monitored by TLC) and then filtered. The residue was
washed with CH2Cl2 (20 mL). Anhydrous Na2SO4 (5 g) was added to the
filtrate and filtered after 20 min. Dichloromethane was removed. The
yield was 0.3312 g, (92%) of crystalline pale yellow solid (2a), m.p. 70–
1
72◦C [Lit.3 m.p. 72–73◦C]. H-NMR (FT-NMR 90 MHz, CDCl3)/TMS):
1.42 (t, 6 H), 2.86 (s, 6 H), 4.36 (q, 4 H), 8.69 (s, 1 H) [Lit.9].
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