An efficient Co(II) catalyzed auto oxidation of 1,4-dihydropyridines

Article abstract of DOI:10.1081/SCC-120018693

An efficient Co(II) catalyzed auto oxidation of 1,4-dihydropyridines to pyridines in good to excellent yield is described.

Full text of DOI:10.1081/SCC-120018693

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An Efficient Co(II) Catalyzed Auto Oxidation of 1,4-
Dihydropyridines
Subhash P. Chavan a , Rajendra K. Kharul a , Uttam R. Kalkote a & I. Shivakumar a
a Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune, India
Published online: 15 Aug 2006.
To cite this article: Subhash P. Chavan , Rajendra K. Kharul , Uttam R. Kalkote & I. Shivakumar (2003) An Efficient
Co(II) Catalyzed Auto Oxidation of 1,4-Dihydropyridines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:8, 1333-1340, DOI: 10.1081/SCC-120018693
To link to this article: http://dx.doi.org/10.1081/SCC-120018693
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 8, pp. 1333–1340, 2003
An Efficient Co(II) Catalyzed Auto Oxidation
of 1,4-Dihydropyridines
*
Subhash P. Chavan, Rajendra K. Kharul,
Uttam R. Kalkote, and I. Shivakumar
Division ofOrganic Chemistry: Technology,
National Chemical Laboratory, Pune, India
ABSTRACT
An efficient Co(II) catalyzed auto oxidation of1,4-dihydropyridines
to pyridines in good to excellent yield is described.
Key Words: Auto oxidation; 1,4-Dihydropyridines; Pyridines.
*Correspondence: Subhash P. Chavan, Division ofOrganic Chemistry:
Technology, National Chemical Laboratory, Pune 411 008, India.
1333
DOI: 10.1081/SCC-120018693
Copyright & 2003 by Marcel Dekker, Inc.
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1334
Chavan et al.
INTRODUCTION
The aryldihydropyridines, first prepared by Hantzsch[1] almost more
than 100 years ago. Substantial research activities have been devoted
recently to the chemistry and biology ofthe Hantzsch dihydropyridine
derivatives (e.g., Hantzsch esters) because oftheir wide applications in
[2]
hot areas such as synthesis ofsubstituted pyridines, serving as effective
redox catalysts under mild conditions, modeling the NAD(P)H coenzyme
to study its oxidation mechanism in living system[3] and emerging as highly
effective calcium channel antagonist[4] with suitable pharmacological
profiles. Hantzsch 1,4-dihydropyridine (DHP) nucleus is common to
numerous bioactive compounds, which include various vasodilator,[5a]
antihypertensive,[5b] bronchodilator,[5c] antiatherosclerotic, hepatoprotec-
tive, antitumor, antimutagenic, geroprotective, and antidiabetic agents.
DHPs have found commercial utility as calcium channel blockers, as
exemplified by therapeutic agents such as Nifedipine,[5d] Nitrendipine,[5e]
Nimodipine,[5f] and Amlodipine.
In the human body, these 1,4-dihydropyridine based drugs are
oxidatively converted to the corresponding pyridine derivatives by the
action ofcytochrome P-450 or other related enzymes in the liver.
Dihydropyridines are often produced in synthetic sequence, which have
to be oxidized to pyridines; and provide the easiest method to obtain
selectively substituted pyridine derivatives.
From the literature review,[2] it is evident that the oxidation of
1,4-dihydropyridines to the corresponding pyridine derivatives is well
documented. However, many ofthe reported oxidation procedures
either suffer from strong oxidants (HNO3,[3a] CrO3,[2k] and KMnO4[2b]),
require severe conditions (S[2p] and Pd/C dehydrogenations[2q]), need
[2a]
excess ofthe oxidants (CAN,
PCC[2l]) or cumbersome workup.[2f,2g]
RESULTS AND DISCUSSIONS
In view ofthe above limitations, and our interest in development of
efficient catalytic protocols, we decided to develop a practical, mild and
general approach for this oxidative transformation. Herein, we wish to
report an efficient Co(II) catalyzed auto oxidation of1,4-dihydropyri-
dines to pyridines in good to excellent yields. Metal catalysis for the
oxidation ofvarious organic substrates is ofsynthetic as well as
[6]
ofbiological interest. Currently, there is an ongoing interest in
developing catalytic oxidation methods using metals in their higher

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Auto Oxidation of 1,4-Dihydropyridines
1335
oxidation states [(e.g., Co(III), Mn(III), Ce(IV), Ru(III)] along with a
suitable cooxidant to reoxidize the reduced metal species.[6a,7]
Activation ofoxygen catalyzed by metals to effect a variety oforganic
transformations is a subject of topical interest.[8] Molecular oxygen when
activated under appropriate conditions is one ofthe most versatile reactive
species known to organic chemists for oxidations. Under appropriate
conditions, it combines chemically with organic compounds.
A wide range oforganic compounds, particularly having one hydrogen
atom bonded to a sp3 hybridized carbon atom will undergo auto oxidation
easily catalyzed by transition metal salts. Compounds having allylic or
benzylic hydrogens are especially prone to auto oxidation.
Keeping metal catalysis in mind, we decided to study auto oxidation of
1,4-dihydropyridines using Co-naphthenate as catalyst. Co-naphthenate
is a cobalt salt ofnaphthenic acids. The naphthenic acids are obtained as
byproducts in petroleum refining and are cyclopentane and cyclohexane
derivatives.
A variety of1,4-dihydropyridines were subjected to auto oxidation
catalyzed by Co-naphthenate in chloroform at its reflux temperature to
yield corresponding pyridine derivatives. The presence ofthe metal
catalyst is essential for the success of the reaction. This was confirmed
by performing the auto oxidation of (1e) without the catalyst (Sch. 1).
It was found to be too sluggish (137 h) from practical point of view.
The product thus obtained was characterized by IR, 1H & 13C NMR,
1
and mass spectroscopy analysis. In H NMR, the disappearance ofthe
singlet at ꢀ ¼ 5.0–5.3 (DHP CH-4) was diagnostic ofthe oxidation.
In order to prove the generality ofthe above protocol, a variety
of1,4-DHPs were auto oxidized under the identical reaction conditions
as for the model 1,4-DHP (1e). The results have been summarized in
Table 1.
It was observed that, during auto oxidation reaction of1,4-dihydro-
pyridines (Entries 5–10) bearing aryl substitution at 4-position furnished
corresponding pyridine derivatives (2a–f), however, alkyl substitution at
4-position (Entries 1–4) gave dealkylated pyridine derivative (3). This
dealkylation is in agreement with the literature.[2b,2d]
Scheme 1.

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1336
Chavan et al.
Table 1.
Yield
1,4-DHP Product Time/h (%) M.p. (Lit. M.p.)ꢀC
Entry
R
1
2
H
-CH2CH3
1a
1b
1c
3
2.50
2.50
2.50
2.50
8.00
89
84
90
91
100 (101)[5j]
100 (101)[5j]
100 (101)[5j]
100 (101)[5j]
3
3
3
-CH2CH2CH3
-CH(CH3)2
C6H5-
40-OCH3-C6H4-
40-Cl-C6H4-
20-Cl-C6H4-
40-NO2-C6H4-
20-NO2-C6H4-
4
1d
1e
3
2a
5
92 136–138 (135–136)[3a]
115
6
1f2b
1g
1h
1i
8.00
2c
67
7
8.00
9.00
73
68
91
137–139
70 (69–70)[5a]
148
8
2d
2e
9
10
17.00
[5a]
1j
2f23.00
88
104–105 (106)
CONCLUSIONS
1. Co(II) catalyst has been used effectively to oxidize 1,4-dihydro-
pyridines to pyridines.
2. A variety ofDHPs have been oxidized in good to excellent
yield.
3. 4-Alkyl substituted DHP suffered dealkylation to furnish the
pyridines.
4. A general protocol for obtaining differently substituted pyridine
derivatives.
5. A very simple, efficient protocol has been devised.
6. Co-naphthenate is cheap and available readily.
EXPERIMENTAL
General Information
IR spectra were recorded on Mattson, UK, model: Research series
FT-IR. 1H and 13C were recorded on Bruker AC 200 spectrometers. The
chemical shifts are reported in ppm (ꢀ) using tetramethyl silane as internal
standard. Mass spectra were recorded on a Finnigan MAT-1020-B-70 eV
mass spectrometer. 1,4-Dihydropyridines were prepared according to the
literature procedure.[4c]

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Auto Oxidation of 1,4-Dihydropyridines
General Procedure
1337
In a typical experiment, molecular oxygen was bubbled through
a mixture of2,6-dimethyl-1,4-dihydro-4-phenyl-3,5-pyridinedicarboxylic
acid, dimethyl ester (1e, 0.6 g, 2.0 mmol) and Co-naphthenate (9%
Co(II), 0.6 mL) in chloroform at its reflux temperature using Vodnar
apparatus.[10] The reaction was monitored by TLC. After completion,
the reaction mixture was cooled to room temperature, diluted with
chloroform. The organic layer was washed with brine (2 Â 4 mL) and
then dried over sodium sulphate, filtered and concentrated in vacuum.
The product was purified by column chromatography (eluent: 20:80 ethyl
acetate:pet ether).
2,6-Dimethyl-3,5-pyridinedicarboxylic Acid, Dimethyl
Ester (3)
Mol. formula: C11H13NO4, yield: 90%, m.p.: 100ꢀC, Lit.[2a] m.p.:
101ꢀC, IR (CHCl3) cmÀ1: 3040, 1725, 1410, 1390, 1220, 1110, 750.
1H NMR: 2.83 (s, 6H); 3.91 (s, 6H); 8.67 (s, 1H). 13C NMR: 24.08 (q),
51.42 (q); 121.71 (s); 140.14 (d); 161.78 (s), 165.23 (s). Mass (m/z): 223
(Mþ, 61), 192 (78), 164 (28), 149 (13), 120 (14), 104 (17), 91 (21), 57 (100).
2,6-Dimethyl-4-phenyl-3,5-pyridinedicarboxylic Acid,
Dimethyl Ester (2a)
Mol. formula: C17H17NO4, yield: 92%, m.p.: 136–138ꢀC, Lit.[2a]
m.p.: 135–136ꢀC, IR (CHCl3) cmÀ1: 3040, 1740, 1640, 1600, 1410,
1
1250, 1200, 760. H NMR: 2.84 (s, 6H); 3.56 (s, 6H); 7.22 (m, 2H); 7.47
(m, 3H). 13C NMR: 18.31 (q); 52.86 (q); 126.96 (d); 128.62 (d); 129.98 (d);
130.44 (s); 133.67 (s); 152.78 (s); 153.09 (s); 164.19 (s). Mass (m/z): 299
(Mþ, 92), 284 (7), 268 (52), 236 (100), 224 (15), 208 (22), 180 (23), 153
(23), 139 (39), 115 (21), 91 (18), 91 (17).
2,6-Dimethyl-4-(4-methoxyphenyl)-3,5-
pyridinedicarboxylic Acid, Dimethyl Ester (2b)
Mol. formula: C18H19NO5, Anal. calculated for C18H19NO5 C:
65.65%, H: 5.77, N: 4.27. Found: C: 65.56, H: 6.16, N: 4.24. Yield: 67%,
m.p.: 115ꢀC, IR (CHCl3) cmÀ1: 3040, 1730, 1370, 1220, 760. 1H NMR: 2.55

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1338
Chavan et al.
(s, 6H); 3.55 (s, 6H); 3.81 (s,3H); 6.90 (d, 2H, J ¼ 10 Hz); 7.17 (d, 2H,
J ¼ 8 Hz). 13C NMR: 22.40 (q), 51.77 (q), 54.68 (q), 96.91 (s), 113.27 (d),
127.26 (s), 129.23 (s), 130.13 (d), 146.18 (s), 155.98 (s), 161.12 (s).
Mass (m/z): 329 (Mþ, 100), 298 (18), 267 (74), 266 (76), 254 (12), 238
(14), 212 (11), 195 (9), 168 (11), 149 (21), 135 (23), 99 (26), 77 (22), 57 (24).
2,6-Dimethyl-4-(4-chlorophenyl)-3,5-
pyridinedicarboxylic Acid, Dimethyl Ester (2c)
Mol. formula: C17H16ClNO4, Anal. calculated for C17H16ClNO4
C: 61.17, H: 4.78, Cl: 10.64, N: 4.19. Found: C: 61.29, H: 4.91, Cl:
11.10, N: 4.04. Yield: 73%, m.p.: 137–139ꢀC, IR (CHCl3) cmÀ1: 3040,
1
1730, 1370, 1220, 760. H NMR: 2.59 (s, 6H); 3.56 (s, 6H); 6.90 (d, 2H,
J ¼ 10 Hz); 7.17 (d, 2H, J ¼ 8 Hz). 13C NMR: 22.79 (q), 51.92 (q), 122.99
(d), 126.09 (s), 128.52 (d), 142.82 (s), 143.92 (s), 147.02 (s), 154.92 (s),
167.87 (s). Mass (m/z): 299 [(M À Cl)þþ1, 33] 298 [(M À Cl)þ, 100], 282
(3), 252 (7), 251(7), 224 (7), 223 (7), 180 (5), 152 (6), 127 (7), 77 (7), 59 (8).
2,6-Dimethyl-4-(2-chlorophenyl)-3,5-pyridinedicarboxylic
Acid, Dimethyl Ester (2d)
Mol. formula: C17H16ClNO4, yield: 68%, m.p.: 69–70ꢀC, Lit.[2a]
m.p.: 69–71ꢀC, IR (CHCl3) cmÀ1: 3040, 1725, 1560, 1380, 1220, 1110,
1
1050, 760. H NMR: 2.55 (s, 6H); 3.43 (s, 6H); 7.08 (m, 1H); 7.18 (m,
2H); 7.32 (m, 1H). 13C NMR: 23.69 (q), 52.26 (q), 126.48 (d), 126.77 (s),
129.38 (d), 130.1 (d), 130.34 (d), 133.02 (s), 135.92 (s), 145.00 (s), 156.83 (s),
167.71 (s). Mass (m/z) : 299 [(M À Cl)þþ1, 33] 298 [(M À Cl)þ, 100], 266
(3), 224 (2), 196 (3), 152 (4), 139 (5), 59 (7).
2,6-Dimethyl-4-(4-nitrophenyl)-3,5-pyridinedicarboxylic
Acid, Dimethyl Ester (2e)
Mol. formula: C17H16N2O6, yield: 91%, m.p.: 148ꢀC, Lit.[2r] m.p.:
147–149ꢀC IR (CHCl3) cm –1: 3040, 1730, 1380, 1200, 750. H NMR:
1
2.59 (s, 6H); 3.53 (s, 6H); 7.42 (d, 2H, J ¼ 8 Hz); 8.26 (d, 2H, J ¼ 10
Hz). 13C NMR: 22.77 (q), 52.10 (q), 123.01 (d), 125.82 (s), 128.74 (d),
143.01 (s), 144.06 (s), 148.00 (s), 155.62 (s), 168.23 (s). Mass (m/z): 344
(Mþ, 79), 313 (100), 297 (32), 280 (32), 267 (18), 236 (20), 209 (21), 181
(19), 140 (31), 77 (30), 59 (88).

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Auto Oxidation of 1,4-Dihydropyridines
1339
2,6-Dimethyl-4-(2-nitrophenyl)-3,5-
pyridinedicarboxylic Acid, Dimethyl Ester (2f )
Mol. formula: C17H16N2O6, yield: 88%, m.p.: 105ꢀC, Lit.[2a] m.p.:
106ꢀC. IR (CHCl3) cmÀ1: 3040, 2980, 1705, 1530, 1290, 1150, 1110, 750.
1H NMR: 2.64 (s, 6H); 3.50 (s, 6H); 7.21 (d, 1H, J ¼ 8 Hz); 7.60 (m, 2H);
8.17 (d, 1H, J ¼ 10 Hz). 13C NMR: 22.24 (q), 50.86 (q), 125.08 (d), 125.37
(s), 127.98 (s), 128.61 (d), 128.94 (d), 132.00 (s), 134.96 (s), 145.98 (s),
155.82 (s), 166.92 (s). Mass (m/z): 344 (Mþ, 68), 313 (100), 297 (28), 280
(28), 267 (18), 236 (20), 209 (16), 181 (14), 139 (36), 77 (22), 59 (36).
ACKNOWLEDGMENT
RKK thanks CSIR, New Delhi for senior research fellowship.
Funding from Young Scientist Award, CSIR, New Delhi is also greatfully
acknowledged.
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Received in the USA January 2, 2002