Aromatization of 1,4-dihydropyridines in the presence of methanesulfonic acid/NaNO2/Wet SiO2 under both heterogeneous and solvent free conditions

Article abstract of DOI:10.1002/jhet.5570430131

A combination of methanesulfonic acid and sodium nitrite in the presence of wet SiO₂ was used as an effective oxidizing agent for the oxidation of 1,4-dihydropyridines to the corresponding pyridine derivatives under mild and heterogeneous condi

Full text of DOI:10.1002/jhet.5570430131

Jan-Feb 2006
Aromatization of 1,4-Dihydropyridines in the Presence of
Methanesulfonic Acid/NaNO /Wet SiO under Both Heterogeneous
199
2
2
and Solvent Free Conditions
a,
b
a
Khodabakhsh Niknam, * Mohammah Ali Zolfigol, Seyed Mehdi Razavian
c
and Iraj Mohammahpoor-Baltork
aChemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr 75168, Iran
bChemistry Department, College of Science, Bu-Ali Sina University, Hamadan, 65174, Iran
cChemistry Department, College of Science, Isfahan University, Isfahan, Iran
Received May 6, 2005
A combination of methanesulfonic acid and sodium nitrite in the presence of wet SiO was used as an
2
effective oxidizing agent for the oxidation of 1,4-dihydropyridines to the corresponding pyridine derivatives
under mild and heterogeneous conditions in excellent yields.
J. Heterocyclic Chem., 43, 199 (2006).
Introduction.
remarkably practical use of O gas as a clean and efficient
2
oxidant for this purpose [1]. Also, Ohsawa et al reported a
remarkably practical use of NO gas as a clean and efficient
oxidant for this conversion [2].
4
-Substituted Hantsch dihydropyridines (1) are analogues
of NADH coenzymes and an important class of drugs [1].
The oxidation of dihydropyridines is an old reaction in gen-
eral organic chemistry. In the human body, it has been
observed that these compounds undergo oxidation to form
pyridine derivatives. These oxidized compounds are largely
devoid of the pharmacological activity of the parent com-
pounds. Additionally, dihydropyridines are often produced
in a synthetic sequence, and have to be oxidized to pyridines
Although a variety of reagents are capable of affecting
these oxidations [1-39], as far as we know this transforma-
tion is not so easy and is a tricky step because these com-
pounds (they have different functional 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 desired
products. Another major drawback to the older procedures
is their use of reagents which are either highly toxic or pre-
sent 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 effective hood with
caution [2]. Therefore, we decided to choose a new reagent
or reagent systems to overcome the above limitations. In
addition, for our propose both clean and easy work-up
were also important.
[
2]. Numerous reagents and procedures have been recom-
mended 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], bismuth nitrate pentahydrate [8], PCC [9],
tetrakis-pyridine cobalt(II) dicromate (TPCD) [10], nico-
tinium dichromate [11], S-nitrosoglutathion [12], N O
compelex of 18-crown-6 [13], diphenylpicrylhydrazyl and
benzoyl peroxide as free radical oxidizing agents [14],
KMnO [15], CrO [16], HNO [17], HNO [18], tert-butyl-
2
4
4
3
3
2
In this article, we would like to report a simple, cheap
and convenient method for effective conversion of 1,4-
hydroperoxide [19], silica gel supported ferric nitrate (sil-
fen) [20], N O [21], photochemical oxidation [22],
2
3
dihydropyridine (1) with CH SO H/NaNO into their cor-
3
3
2
H O /Co(OAc) [23], peroxydisulfate-cobalt(II) [24],
2
2
2
responding pyridine derivatives (2 or 3) under mild, het-
erogeneous and solvent free conditions via in situ genera-
Zr(NO ) [25], hypervalent iodine reagents [26], Co(II) cat-
alyzed auto oxidation [27], anodic oxidation [28], I -MeOH
29], inorganic acidic salts or heteroply acid and sodium
nitrite or nitrate [30-38], selenium dioxide [39].
3
4
2
-
tion of NOX (X= CH SO ), (Scheme 1).
[
3
3
Different type of dihydropyridines (1) were subjected
to oxidation in the presence of CH SO H (I), NaNO
3
3
2
Results and Discussion.
(
II), and wet SiO (50% w/w) under solvent free condi-
2
Recently, Hayashi et al reported an excellent procedure
for this transformation. They have demonstrated the
tions or in dichloromethane (Table 1). It was also
observed that the oxidation of 1,4-dihydropyridines

2
00
K. Niknam, M. Ali Zolfigol, S. M. Razavian and I. Mohammahpoor-Baltork
Vol. 43
Scheme 1
1
a
,2
R1
R2
H
1,2
R1
R2
1,2
q
R1
R2
Me
Ph
COOEt
COOEt
i
COOEt 2,5-(MeO)2-
C H -
COOEt
COMe
COMe
6
3
b
c
Me
j
r
COOEt
COOEt
Et
k
l
COOEt
s
t
COMe
COMe
4-MeO-
C H -
6
4
d
Ph
COOEt
2-MeO-
C H -
6
4
e
f
COOEt
COOEt
4-Br-
m
n
COOEt
COOEt
i-Pr
u
v
COMe
COMe
2,5-(MeO)2-
C H -
C H -
6
4
6 3
2-NO2-
2-Py
C H -
6
4
g
COOEt
COOEt
3-NO2-
C H -
o
COOEt
COMe
4-Py
H
w
x
COMe
COMe
6
4
h
2-MeO-
C H -
p
6
4
(
Table 1, entry 13) bearing alkyl substituent (alkyl moi-
Scheme 2
eties may be responsible for generating stable carboca-
tions) at the 4-position gave only the dealkylated pyridine
derivative (3). This is in agreement with the observation
made by other employing different oxidative conditions
[
(
2]. However, aryl substituted 1,4-dihydropyridines
Table 1, entries 4-12, 14, 15, 18-24) furnished the corre-
sponding pyridine derivatives.
Acid
CH SO H
Time(h)
72
Conversion%
40
It is worth mentioning, that these reactions were accom-
plished faster and with higher yields under solvent free
conditions (Table 1). For example, for pyridine substituted
in the 4-position (entries 14, 15, Table 1) the oxidation
complete after 15 min at room temperature. However,
these reactions did not occur with the same molar ratio of
oxidizing agent in dichloromethane solution at room tem-
perature (Table 1).
3
3
1,4-Dihydropyridines (Table 1, 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 pyri-
dine derivative (2) confirming that these compounds have
not been nitrosated or nitrated (or both) during the oxida-
tion reaction. Therefore, this system behaves chemoselec-
The oxidation reaction did not occur in the absence of
wet SiO . This observation suggests that the water mole-
2
+
cule is essential for such processes. The presence of wet
tively and NO attacks only the nitrogen site of the sec-
SiO thus provides an effective heterogeneous surface area
ondary amines in 1,4-dihydropyridines [30].
2
for in situ generation of NOX [36]. It also eases the reac-
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 nitration side-prod-
ucts is avoided. We believe that the present methodology
could be an important addition to existing methodologies.
tion work-up. Oxidation reaction by using MeSO H and
3
without applying NaNO preceded very slowly for exam-
2
ple; conversion of 1d was about 40% after 72 h.
(
Scheme 2). In this reaction the molar ratio of acid was the
same with that used in Tables 1.

Jan-Feb 2006
Aromatization of 1,4-Dihydropyridines in the Presence of Methanesulfonic Acid
201
Table 1
3
Oxidation of 1,4-dihydropyridines (1) to their corresponding pyridine derivatives (2 or 3) with a combination of MeSO H
(
I), NaNO
2
(II) and wet SiO
2
(50% w/w) under solvent free conditions or in dichloromethane at room temperature
a
Entry
Substrate
Product
Reagent/Substrate (mmol)
II
Solvent Free
2 2
CH Cl
I
Conditions
Solution
b
b
Time (Min) Yield
Time (Min) Yeild
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
3a
2b
2c
2d
2e
2f
2
1.5
3
3
6
92
90
89
90
85
89
90
91
91
89
87
88
83
89
88
92
90
90
89
89
90
88
87
86
5
10
15
8
92
87
85
87
83
84
88
90
90
88
86
86
83
3
3
3
10
5
4.5
4.5
5.5
5.5
3
4.5
4.5
5.5
5.5
3
10
5
17
10
10
5
1g
1h
1i
2g
2h
2i
5
3
3
3
10
15
14
7
15
25
25
13
25
-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1j
2j
4
4
1k
1l
2k
2l
5.5
5.5
3
5.5
5.5
3
1m
1n
1o
1p
1q
1r
3m
2n
2o
3p
2q
2r
13
15
15
3
c
17
17
-
c
17
2
17
2
-
-
25
10
12
25
20
20
20
25
15
90
89
88
87
89
90
88
85
85
3
4.5
3
4.5
4
8
1s
1t
2s
2t
3
3
15
12
10
12
5
3
3
1u
1v
1w
1x
2u
2v
2w
2x
3
3
4.5
5.5
5.5
4.5
5.5
5.5
10
a
b
c
2
Wet SiO : substrate (0.2 g : 1 mmol); Isolated yields. Reaction did not occur.
EXPERIMENTAL
0.192 g), sodium nitrite (1.5 mmol, 0.104 g), and wet SiO (0.2 g,
2
5
0% w/w) was stirred magnetically at room temperature. The
progress of the reaction was followed by TLC. After 3 minutes
the reaction was completed. The residue was washed with
dichloromethane (2x20 mL), then a solution of sodium bicarbon-
ate 10% (20 mL) was added and extracted. To the organic layer
General.
Methanesulfonic acid and other chemicals were purchased
from Fluka, Merck and Aldrich chemicals companies. The prod-
ucts were characterized by comparing of their spectral (IR, H
1
anhydrous Na SO (10 g) was added and filtered after 20 min.
2
4
NMR), TLC and physical data with authentic samples.
The solvent was evaporated and a crystalline pale yellow solid of
diethyl-2,6-dimethyl pyridine-3,5-dicarboxylate (3a) 0.233 g
General Procedure for the Oxidation of 1,4-Dihydropyridines (1)
to the Corresponding Pyridine Derivatives (2 or 3) under Solvent
Free conditions.
1
(
92%) obtained, mp 68-69 °C (Lit. [6] mp 69-70 °C). H NMR: δ
1
.2 (t, 6H), 3.0 (s, 6H), 4.36 (q, 4H), 8.69 (s, 1H) (Lit. [6]).
A suspension of compound 1 (1 mmol), CH SO H (I), sodium
General Procedure for the Oxidation of 1,4-Dihydropyridines (1)
to the Corresponding Pyridine Derivatives (2 or 3) in
Dichloromethane.
3
3
nitrite (II), [the molar ratio of CH SO H and sodium nitrite to the
3
3
substrate 1 was optimized, Table 1], and wet SiO (0.2 g, 50%
2
w/w) was stirred magnetically at room temperature. The progress
of the reaction was followed by TLC. After completion of the
reaction, the residue was washed with dichloromethane (2x20
mL), then a solution of sodium bicarbonate 10% (20 mL) was
A suspension of compound 1 (1 mmol), CH SO H (I),
3
3
sodium nitrite (II), [the molar ratio of CH SO H and sodium
3
3
nitrite to the substrate 1 was optimized, Table 1], and wet SiO2
0.2 g, 50% w/w) in dichloromethane (8 mL) was stirred mag-
netically at room temperature. The progress of the reaction
was followed by TLC. The reaction mixture was filtered after
completion of the reaction. The residue was washed with
(
added and extracted. To the organic layer anhydrous Na SO (10
2
4
g) was added and filtered after 20 min. The solvent was evapo-
rated and pyridine derivatives (2) obtained. If further purification
is needed, flash chromatography on silica gel [eluent:
acetone/petroleum ether (10:90)] provides pure (2) derivatives.
CH Cl (20 mL), then a solution of sodium bicarbonate 10%
2
2
(
20 mL) was added and extracted. To the organic layer anhy-
drous Na SO (10 g) was added and filtered after 20 min. The
Typical Procedure.
2
4
solvent was evaporated and pyridine derivatives (2) obtained.
If further purification is needed, flash chromatography on sil-
ica gel [eluent: acetone/petroleum ether (10:90)] provides
pure (2) derivatives.
Diethyl-2,6-dimethylpyridine-3,5-dicarboxylate (3a).
A suspension of diethyl-2,6-dimethyl-1,4-dihydropyridine-
3
,5-dicarboxylate (1) (1 mmol, 0.253 g), CH SO H (2 mmol,
3 3

202
K. Niknam, M. Ali Zolfigol, S. M. Razavian and I. Mohammahpoor-Baltork
Vol. 43
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