Aromatization of Hantzsch 1,4-dihydropyridines by hydrogen peroxide in the presence of cobalt(II) acetate

Article abstract of DOI:10.1007/s00706-002-0487-6

Hydrogen peroxide readily oxidizes Hantzsch type 1,4-dihydropyridines in the presence of cobalt(II) acetate as catalyst at room temperature. No evidence of a dealkylation process for 4-alkyl 1,4-dihydropyridines has been observed.

Full text of DOI:10.1007/s00706-002-0487-6

Monatshefte f€ur Chemie 134, 107–110 (2003)
DOI 10.1007/s00706-002-0487-6
Short Communication
Aromatization of Hantzsch
1,4-Dihydropyridines by Hydrogen
Peroxide in the Presence
of Cobalt(II) Acetate
ꢀ
Mohammed M. Hashemi , Yusef Ahmadibeni, and Hossien Ghafuri
Department of Chemistry, Sharif University of Technology, Tehran, Iran
Received January 16, 2002; accepted (revised) April 20, 2002
Published online November 18, 2002 # Springer-Verlag 2003
Summary. Hydrogen peroxide readily oxidizes Hantzsch type 1,4-dihydropyridines in the presence of
cobalt(II) acetate as catalyst at room temperature. No evidence of a dealkylation process for 4-alkyl
1,4-dihydropyridines has been observed.
Keywords. Hantzsch type 1,4-dihydropyridines; Hydrogen peroxide; Cobalt(II) acetate; Aromatiza-
tion; Catalytic oxidation.
Introduction
The oxidation of 1,4-dihydropyridines has gained interest in recent years due to the
fact that 1,4-dihydropyridines based antihypertensive drugs (calcium antagonists)
are oxidatively converted to pyridine derivatives by cytochrom P-450 in liver [1, 2].
Consequently, this oxidation reaction continues to attract the attention of research-
ers for the discovery of milder and general procedure applicable to a wide range of
1,4-dihydropyridines. Many of the reported oxidation procedures either suffer from
the use of strong oxidants (HNO3 [2], KMnO4 [3], CrO3 [4], Bi(NO3)3 [5], nico-
tinium dichromate [6]), require severe conditions (S [7], Pd=C dehydrogenation
[8]), or need excess of the oxidants (CAN [9], PCC [10]).
In connection with our interest in the chemistry of 1,4-dihydropyridines and
oxidation procedures, we have used zinc chlorochromate [11], molecular oxygen
in the presence of cobalt and manganese salts of 4-amino benzoicacid supported
on silica gel [12], and sodium hypochlorite=Dowex 1X8-200 [13]. We became
ꢀ
Corresponding author. E-mail: mhashemi@sharif.ac.ir

108
M. M. Hashemi et al.
Table 1. Oxidation of 1,4-dihydropyridines to pyridine derivatives using hydrogen peroxidea
1,4-DHP
R
Time
(min)
Oxidized
product
Yield (%)
1a
1b
1c
1d
1e
1f
H
15
90
60
30
150
75
60
70
65
65
2a
2b
2c
2d
2e
2f
98
95
97
97
92
96
97
96
98
98
CH3
CH3CH2
C6H5
3-NO2C6H4
2-furyl
1g
1h
1i
4-ClC6H4
2-ClC6H4
C6H5CH¼CH
4-CH3C6H4
2g
2h
2i
1j
2j
a
All reactions were carried out at room temperature in methanol using a molar ratio of 1:1 for
DHP:cobalt(II) acetate
interested in developing another convenient and environmentally friendly method
for the oxidation of 1,4-dihydropyridines.
Results and Discussion
A commercially available 30% solution of hydrogen peroxide serves as an excel-
lent oxidant for a variety of 1,4-dihydropyridines as shown in the formula scheme.
The results are collected in Table 1.
Following experiments have been performed to check the efficiency of our
method. Cobalt(II) acetate alone does not oxidize dihydropyridines. When reaction
of dihydropyridines and hydrogen peroxide is done without cobalt(II) acetate, it is
a slow and low yield reaction. When cobalt acetate is used as catalyst, oxidation of
dihydropyridines with hydrogen peroxide occurrs in excellent yields.
The data provided are optimum conditions such as quantity of catalyst, time
and solvent, for all the reactions. Hydrogen peroxide in the presence of cobalt(II)
acetate is a mild and effective alternative for the oxidation of 1,4-dihydropyridines
to the corresponding pyridine derivatives in high yields without formation of side
products.
Experimental
Chemicals were purchased from Merck, Aldrich and Riedel Dehaen AG chemical companies and were
used without further purification. IR spectra were recorded on FT-IR Unicam Mattson 1000 Spectro-
photometer. 1H-NMR spectra were recorded on Brucker AC-80 (80 MHz) spectrometer in CDCl3 and

Aromatization of 1,2-Dihydropyridines
109
chemical shifts are listed in ꢀ ppm. All products are known compounds and they were identified by
1
their mp, IR, and H-NMR spectroscopic properties. All yields refer to the isolated products and all
reactions were stirred at room temperature until the substrates were completely consumed. The crude
products obtained upon extractive work-up were purified by short silica gel column chromatography or
crystallization. Hantzsch 1,4-dihydropyridines were synthesized according to the standard procedure
[14].
Oxidation of diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate
Typical procedure
The Hantzsch 1,4-dihydropyridine 1, (0.253g, 1 mmol) was dissolved in 25ml methanol and cobalt(II)
acetate tetrahydrate (0.249 g, 1 mmol) was added to this solution and then 0.15ml hydrogen peroxide
30% was added in portions over 15 min at room temperature along with stirring of the reaction
mixture. Then 25ml water was added to the reaction mixture and it was treated by 10% sodium
bicarbonate solution. The product was extracted with 3Â 10ml Et2O, dried over Na2SO4 and evapo-
rated to dryness. After crystallization of the product in ethanol, 0.250 g (99% yield) of diethyl-2,6-
dimethyl-3,5-pyridine dicarboxylate was obtained.
The oxidations of the other 1,4-dihydropyridines were carried out in a similar procedure. The time
of reactions and the yields of the isolated products are compiled in Table 1.
Diethyl-2,6-dimethyl-3,5-pyridine dicarboxylate (2a; C13H17NO4)
Mp 68–70ꢁC (Ref. [15], 71ꢁC); FT-IR (KBr): 2976, 1723, 1592, 1446, 1222cmÀ 1; 1H-NMR (CDCl3)
ꢀ 4-R: 8.6 (s, 1H).
Diethyl-2,6-dimethyl-4-methyl-3,5-pyridine dicarboxylate (2b; C14H19NO4)
1
Oil (Ref. [15], oil); FT-IR (neat): 2984, 1730, 1569, 1453, 1238cmÀ 1; H-NMR (CDCl3) ꢀ 4-R: 2.1
(s, 3H).
Diethyl-2,6-dimethyl-4-ethyl-3,5-pyridine dicarboxylate (2c; C15H21NO4)
1
Oil (Ref. [15], oil); FT-IR (neat): 2974, 1730, 1569, 1453, 1238cmÀ 1; H-NMR (CDCl3) ꢀ 4-R: 2.8
(2H), 1.2–0.8 (3H).
Diethyl-2,6-dimethyl-4-phenyl-3,5-pyridine dicarboxylate (2d; C19H21NO4)
1
Mp 60–61ꢁC (Ref. [16], 60–61ꢁC); FT-IR (KBr): 2976, 1723, 1561, 1230, 1100 cmÀ 1; H-NMR
(CDCl3) ꢀ 4-R: 7.2 (s, 5H).
Diethyl-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate (2e; C19H20N2O6)
1
Mp 62–64ꢁC (Ref. [16], 61–62ꢁC); FT-IR (KBr): 3061, 2984, 1730, 1530, 1246 cmÀ 1; H-NMR
(CDCl3) ꢀ 4-R: 7.9 (m, 2H), 7.3 (m, 2H).
Diethyl-2,6-dimethyl-4-(2-furyl)-3,5-pyridine dicarboxylate (2f; C17H19NO5)
Mp 40–42 (Ref. [15], oil); FT-IR (neat): 3123, 2984, 1730, 1561, 1107, 1046 cmÀ 1; 1H-NMR (CDCl3)
ꢀ 4-R: 7.3 (m, 1H), 6.5–6.2 (m, 2H).

110
M. M. Hashemi et al.: Aromatization of 1,2-Dihydropyridines
Diethyl-2,6-dimethyl-4-(4-chlorophenyl)-3,5-pyridine dicarboxylate (2g; C19H20ClNO4)
1
Mp 66–68ꢁC (Ref. [17], 65–67ꢁC); FT-IR (KBr): 2976, 1730, 1561, 1238, 1107 cmÀ 1; H-NMR
(CDCl3) ꢀ 4-R: 7.2–7.3 (m, 4H).
Diethyl-2,6-dimethyl-4-(2-chlorophenyl)-3,5-pyridine dicarboxylate (2h; C19H20ClNO4)
1
Mp 61–63ꢁC (Ref. [16], 61–62ꢁC); FT-IR (KBr): 2984, 1730, 1561, 1238, 1115 cmÀ 1; H-NMR
(CDCl3) ꢀ 4-R: 7.1–7.2 (m, 4H).
Diethyl-2,6-dimethyl-4-(4-cinamyl)-3,5-pyridine dicarboxylate (2i; C21H23NO4)
Mp 162–164ꢁC (Ref. [15], 162–163ꢁC); FT-IR (KBr): 2930, 1730, 1561, 1115, 1046 cmÀ 1; 1H-NMR
(CDCl3) ꢀ 4-R: 7.1–7.2 (m, 7H).
Diethyl-2,6-dimethyl-4-(4-methylphenyl)-3,5-pyridine dicarboxylate (2j; C20H23NO4)
1
Mp 72–73ꢁC (Ref. [15], 72–73ꢁC); FT-IR (KBr): 2976, 1730, 1561, 1246, 1107 cmÀ 1; H-NMR
(CDCl3) ꢀ 4-R: 7.1 (s, 4H), 2.3 (s, 3H).
1H-NMR (CDCl3) ꢀ 2,6-CH3: 2.4 (s, 6H) for 2b–j and 3.0 (s, 6H) for 1a, ꢀ COOC2H5: 4.2 (q, 4H)
and 1.2 (t, 6H) for 2a–j.
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