Electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines

Article abstract of DOI:10.1007/s10593-009-0211-0

The electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines has been studied in an aprotic medium and in the presence of pyridine. In an aprotic medium the products of oxidation are both 4-alkyl-substituted and 4-unsubstituted pyridines

Full text of DOI:10.1007/s10593-009-0211-0

Chemistry of Heterocyclic Compounds, Vol. 44, No. 12, 2008
ELECTROCHEMICAL OXIDATION
OF 4-MONOALKYL-SUBSTITUTED
1,4-DIHYDROPYRIDINES
B. Turovska, I. Goba, I. Turovskis, S. Grinberga, S. Belyakov,
S. Stupnikova, E. Liepinsh, and J. Stradins
The electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines has been studied in an
aprotic medium and in the presence of pyridine. In an aprotic medium the products of oxidation are
both 4-alkyl-substituted and 4-unsubstituted pyridines or mixtures of them. On oxidation in acetonitrile
of 4-Et-, 4-n-Pr-, and 4-i-Bu-substituted dihydropyridines, 2-methylene-1,2,3,4-tetrahydropyridines
were obtained in addition to the oxidized forms. In the presence of base the products of preparative
electrolysis of the studied compounds were 4-alkyl-substituted pyridines. The exception was the 4-i-Pr-
substituted dihydropyridine which was dealkylated on oxidation even in the presence of base.
Keywords: 4-alkyl-substituted pyridines, 1,4-dihydropyridines, alkyl radicals, exocyclic double bond,
electrochemical oxidation.
Dihydropyridines are one of the most investigated classes of organic compounds. The synthesis and
reactions of 1,4-dihydropyridines have been examined in detail in reviews [1-4]. Many compounds of this series
possess pharmacological activity. A series of pharmaceuticals [5] has been developed based mainly on 4-aryl-
substituted 1,4-dihydropyridines. Antioxidant properties have also been confirmed for the heterocycle itself in
reactions with various radicals [6, 7]. On the other hand study of the redox reaction of the dihydropyridine ring
is also important for the reason that its oxidation is the main metabolism of dihydropyridines.
The attention of electrochemists is mainly attracted [8-13] by the oxidation of 4-methyl-, 4-aryl-1,4-di-
hydropyridines or those unsubstituted in position 4. In all the mentioned cases proton is split off from the
position 4 of the ring on oxidation.
H
R
MeOOC
Me
COOMe
Me
N
H
1–5
1 R = Me, 2 R = Et, 3 R = n-Pr, 4 R = i-Pr, 5 R = i-Bu
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: turovska@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1829-1838, December 2008. Original article submitted
November 11, 2008.
0009-3122/08/4412-1483©2008 Springer Science+Business Media, Inc.
1483

The electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines 1-5 by cyclic
voltamperometry and preparative electrolysis has been studied in this work. In addition the rotating disk
electrode was used to determine oxidation potentials and limiting current values.
In aprotic medium the oxidation of all the compounds studied proceeds in one irreversible step (Fig. 1)
at potentials ~1 V (Table 1). Preparative electrolysis at a controlled potential was carried out to clarify the
1
products of electrochemical oxidation of dihydropyridines 1-5. Analysis of H NMR spectra of the reaction
mixture directly after evaporation of the solvent showed that the main oxidation products of compounds 1-5
were the corresponding pyridinium perchlorates. The deprotonated reaction mixture was analyzed by GC-MS
with subsequent isolation of products.
a
b
I×10–5, A
I×10–5, A
E, V
E, V
Fig. 1. Electrochemical oxidation of 1,4-dihydropyridines 2 (a) and 4 (b)
(concn. = 5×10-4 M) at the stationary glass-graphite electrode. Base electro-
lyte 0.1 M NaClO4/MeCN
According to literature data [14-18], the substituent in position 4 of the oxidized form of the heterocycle
is retained on electrochemical and chemical oxidation of 4-methyl-substituted 1,4-dihydropyridines. Moreover
on oxidation of 4,4-dimethyl-substituted dihydropyridines in an aprotic medium the sole product is a stable
cation-radical [19].
The methyl group is also retained on electrochemical oxidation of 4-methyl-substituted dihydropyridine
1 and 3,5-dimethoxycarbonyl-2,4,6-trimethylpyridine (1a) is the sole product (95.7%) of electrolysis.
TABLE 1. Oxidation Potentials (Eox), Limiting Current Values (I) and the
Coulometrically Determined Number of Electrons (n) on Oxidation of
Dihydropyridines 1-5 in 0.1 M NaClO4/MeCN
Еох, V
Stationary
glassy carbon electrode
Еох, V
I, µA
I, µA (Py)
Compound
n, F/mol
Rotating disk electrode
1
2
3
4
5
1.03
1.02
1.01
1.03
1.03
1.10
1.00
1.00
0.97
0.97
110
78
78
126
137
108
117
145
1.15
0.69
0.84
1.50
1.04
124
94
1484

TABLE 2. Products and Yields on Electrochemical Oxidation of
4-Monosubstituted 1,4-Dihydropyridines in Acetonitrile
Com-
pound
Yield, %
2а
3а
5а
2b
3b
5b
6
2
3
5
18.5
—
—
46.6
—
—
—
12.9
—
—
19.4
—
—
—
61.1
27.3
46.1
—
36.7
—
7.5
Me
H Me
MeOOC
Me
COOMe
Me
MeOOC
Me
COOMe
Me
MeCN
N
N
H
1
1a
However the products of electrochemical oxidation of dihydropyridines 2, 3, and 5 contain both
4-substituted pyridines (2a, 3a, 5a) and also 4-unsubstituted pyridine (6). In addition to both oxidized forms,
tetrahydropyridines 2b, 3b, 5b were isolated from the reaction mixture.
2, 3, 5
MeCN
R
H
H
R
MeOOC
Me
COOMe
R
MeOOC
Me
COOMe
Me
MeOOC
Me
COOMe
Me
+
+
N
H
CH2
N
N
6
2a, 3a, 5a
2b, 3b, 5b
2 R = Et; 3 R = n-Pr; 5 R = i-Bu
The formation of a similar exocyclic C=C bond was noted only on trying to alkylate N-substituted
1,4-dihydropyridines in the presence of a strong base (lithium diisopropylamide) [20] capable of deprotonating a
methyl group. In some cases the presence of 2-methylene-1,2,3,4-tetrahydropyridines was also demonstrated as
an intermediate products in the Hantzsch synthesis of N-substituted, as well as N-unsubstituted,
dihydropyridines according to [21-24].
The formation of similar tetrahydropyridines on electrochemical oxidation of 4-monoalkyl-substituted
dihydropyridines 2, 3, and 5 may be explained in two ways. After removing the first electron the alkyl group is
eliminated as a carbocation, and on its subsequent attack on a double bond in the dihydropyridine molecule,
ejection of proton from the 2-methyl group of the heterocycle must follow. This is extremely improbable since
the acidity of the N–H proton is significantly greater than the acidity of methyl group protons.
H
COOMe
COOMe
MeOOC
Me
H
+
N
Me
–
Me
ClO4
7
1485

In addition no formation of an exocyclic bond was observed [25] in the protonated dihydroderivative 7.
3,4,5-Trimethoxycarbonyl-1,2,6-trimethyl-3,4-dihydropyridinium perchlorate is a stable compound which is
deprotonated in the presence of water regenerating the initial dihydropyridine.
If the primary product of anodic oxidation of dihydropyridine, the cation-radical, eliminates an alkyl
radical from position 4 then, on attacking it at the double bond of the dihydropyridine molecule, fission of an H
atom from the methyl group in position 2 of the heterocycle seems more realistic.
2-Methylene-substituted tetrahydropyridines 2b (Fig. 2), 3b, and 5b are stable compounds, which in
solution are slowly converted into 3,4-dihydropyridines 2c, 3c, and 5c.
R
R
H
H
MeOOC
Me
COOMe
MeOOC
Me
COOMe
R
R
N
Me
N
H
CH2
2c, 3c, 5c
2b, 3b, 5b
On electrochemical oxidation of 4-i-Pr-substituted dihydropyridine 4 the substituent at position 4 of the
heterocycle is lost and the sole product of electrolysis is the pyridine 6 (92.8%), corresponding to literature data
[26-29] on the oxidation of dihydropyridines of such a type. In addition to the oxidized form the presence of
nitrilium perchlorate 8, was proved in the solution by a counter-synthesis [30].
Fig. 2. Structure of the 2b molecule with numbering and thermal vibration
ellipsoids of atoms.
Compared to other alkyl radicals the isopropyl radical is more stable, its subsequent oxidation at the
anode to carbocation is therefore possible. It then attacks an acetonitrile molecule.
Preparative electrolysis in mixed solvent (MeCN–C5H5N, 1:1) was carried out to investigate the
products obtained on electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines 1-5 in the
presence of base. The oxidation products after workup of the anolyte were also analyzed by GC-MS. In the
presence of base the 4-alkyl-substituted pyridine derivatives 1a-3a, 5a were the sole products of the electrolysis
of dihydropyridines 1-3, 5, respectively.
1486

TABLE 3. Crystallographic Data for Compound 2b
Empirical formula
Molecular mass, M
Crystal system
C15H23NO4
281.352
Triclinic
–
1
Space group
P
Parameters of unit cell:
a, Å
b, Å
c, Å
α, deg
β, deg
γ, deg
8.6672(4)
8.8310(4)
10.2452(4)
81.868(2)
89.108(2)
80.558(2)
Volume of unit cell, V, Å3
Number of molecules in unit cell, Z
Density of crystals, D, g/cm3
Absorption coefficient, µ, mm-1
Number of reflections with I > 3σ(I)
Number of parameters refined
Final divergence factor, R
765.74(6)
2
1.220
0.088
2586
273
0.047
SIR97 [33], maXus [34]
Programs used
Me
MeCN
+
–
ClO4
6
Me
C
N
CH
Me
4
+
8
Even in the presence of base the mechanism of oxidation of dihydropyridine 4 was unchanged, and in
this case the sole electrolysis product was the dealkylated pyridine 6. The 4-i-Pr-substituted pyridine 4a (25%)
was only obtained on carrying out the electrolysis in pyridine, but in this case too the main product was the
dealkylated pyridine 6 (68%). In the products of electrolysis of 4-i-Pr-substituted dihydropyridine 4 in pyridine,
or in the presence of pyridine, the formation of isopropylpyridine 9 was demonstrated by GC-MS.
-i
Pr
-i
Pr
MeOOC
Me
COOMe
Me
Py
4
+
+
6
N
N
4a
9
The results obtained indicate that in aprotic medium 4-monoalkyl-substituted 1,4-dihydropyridines
undergo a one-electron oxidation (Table 1) with subsequent fission of an alkyl radical, with the exception of the
4-methyl-substituted analog 1. Depending on the substituent in position 4 of the dihydropyridine the place of
attack of the eliminated alkyl radical may be sterically screened, as was observed in the case of the oxidation of
the 4-i-Pr-substituted dihydropyridine 4. In the presence of base the mechanism of oxidation is changed and the
yield of 4-alkyl-substituted pyridines depends on the basicity of the medium.
EXPERIMENTAL
Cyclic voltamperograms were taken on a PARSTAT 2273 electrochemical system. Oxidation potentials
were determined at the stationary glass-graphite electrode (d = 6 mm). All potentials were measured relative to a
saturated calomel electrode fitted with a salt bridge. A Pt wire served as auxiliary electrode.
1487

Preparative oxidation of dihydropyridines 1-5 was carried out using a PAR-170 electrochemical system.
Oxidation of dihydropyridines 1-5 was carried out in an H-shaped cell at a potential of +1.20 V in acetonitrile,
prepared according to the method of [31]. Anhydrous NaClO4, dried in vacuum at 40oC, was used as base
electrolyte. The cell was filled with 0.1 M solution of base electrolyte (100 ml), and into the anode space
compounds 1-5, 0.80 g, 3.3 mmol, 0.81 g, 3.2 mmol, 0.80 g, 3.0 mmol, 0.88 g, 3.3 mmol, and 0.58 g, 2.1 mmol,
respectively, were introduced. Platinum gauze (3.5 x 2.5 cm) served as anode and cathode and argon was blown
through the anode space throughout electrolysis. After the end of the electrolysis, the reaction mixture was
evaporated, the residue treated with water, and extracted with chloroform. The chloroform was evaporated, and
the residue subjected to column chromatography.
Preparative oxidation of dihydropyridine 4 (0.5 g, 1.8 mmol) was also carried out in pyridine, using
anhydrous LiClO4 dried in vacuum at 40oC as base electrolyte. Electrolysis and processing of anolyte was in
accordance with that mentioned above.
Silica gel type Acros (0.060-0.200 mm) was used for preparative column chromatography (column 2×70
cm), eluent was chloroform–hexane–acetone, 9:7:1.
1H NMR spectra were recorded on a Bruker WH 90 (90 MHz) in CDCl3 (compounds 1, 1a, 2, 2a-c, 3,
3a-c, 4, 4a, 5, 5a-c), internal standard was TMS.
Mass spectra were recorded on a HP 6890 GC-MS chromato-mass spectrometer with energy of ionizing
electrons 70 eV.
For the X-ray crystallographic analysis the diffraction picture of a monocrystal of compound 2b
(obtained by crystallization from methylene chloride) of size 0.15×0.28×0.44 mm, was taken on a Nonius
KappaCCD automatic diffractometer to 2θmax = 55o (λMo = 0.71073 Å). The main crystallographic characteristics
of compound 2b, and also the parameters of the refined structure are given in Table 3. The crystal structure has
been deposited in the Cambridge structural data bank (CCDC 707926).
4-Monoalkyl-substituted 1,4-dihydropyridines 1-5 were obtained by the procedure of [32].
1
3,5-Dimethoxycarbonyl-2,4,6-trimethyl-1,4-dihydropyridine (1). H NMR spectrum, δ, ppm (J, Hz):
0.94 (3H, d, 3J = 6.4, 4-CH3); 2.26 (6H, s, 2,6-CH3); 3.70 (6H, s, 3,5-COOCH3); 3.80 (1H, q, 3J = 6.4, H-4); 5.87
(1H, s, NH).
1
3,5-Dimethoxycarbonyl-2,4,6-trimethylpyridine (1a). H NMR spectrum, δ, ppm: 2.24 (3H, s,
4-CH3); 2.50 (6H, s, 2,6-CH3); 3.92 (6H, s, 3,5-COOCH3). Mass spectrum, m/z (Irel, %): 237 [M]+ (46), 222 [M-
Me]+ (63), 206 (100), 190 (16), 178 [M-CO2Me]+ (31).
4-Ethyl-3,5-dimethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (2). 1H NMR spectrum, δ, ppm (J,
3
Hz): 0.72 (3H, t, J = 7.0, 4-CH2CH3); 1.34 (2H, m, 4-CH2CH3); 2.25 (6H, s, 2,6-CH3); 3.65 (6H, s,
3,5-COOCH3); 3.87 (1H, t, 3J = 5.0, H-4); 5.43 (1H, s, NH).
1
4-Ethyl-3,5-dimethoxycarbonyl-2,6-dimethylpyridine (2a). H NMR spectrum, δ, ppm (J, Hz): 1.14
(3H, t, 3J = 7.0, 4-CH2CH3); 2.49 (6H, s, 2,6-CH3); 2.58 (2H, q, 3J = 7.0, 4-CH2CH3); 3.92 (6H, s, 3,5-COOCH3).
Mass spectrum, m/z (Irel, %): 251 [M]+ (13), 236 [M-Me]+ (100), 220 (39), 204 (35), 160 (22), 91 (18).
3,4-Diethyl-3,5-dimethoxycarbonyl-6-methyl-2-methylene-1,2,3,4-tetrahydropyridine (2b). 1H
NMR spectrum, δ, ppm (J, Hz): 0.81 (6H, m, 3,4-CH2CH3); 1.62 (4H, m, 3,4-CH2CH3); 2.36 (3H, s, 6-CH3);
3
3.10 (1H, t, J = 5.0, H-4); 3.70 (3H, s, 3-COOCH3); 3.76 (3H, s, 5-COOCH3); 4.50, 4.98 (2H, two s, =CH2);
5.78 (1H, s, NH). Mass spectrum, m/z (Irel, %): 281 [M]+ (44), 266 [M-Me]+ (16), 252 [M-Et]+ (77), 222
[M-CO2Me]+ (100), 208 (54), 192 (70), 59 (66).
1
3,4-Diethyl-3,5-dimethoxycarbonyl-2,6-dimethyl-3,4-dihydropyridine (2c). H NMR spectrum, δ,
ppm (J, Hz): 0.81 (6H, m, 3,4-CH2CH3); 1.26 (4H, m, 3,4-CH2CH3); 2.27 (3H, s, 2-CH3); 2.53 (3H, s, 6-CH3);
2.98 (1H, t, 3J = 5.0, H-4); 3.70 (3H, s, 3-COOCH3); 3.76 (3H, s, 5-COOCH3).
1
3,5-Dimethoxycarbonyl-2,6-dimethyl-4-propyl-1,4-dihydropyridine (3). H NMR spectrum, δ, ppm
(J, Hz): 0.81 (3H, t, 3J = 7.0, 4-CH2CH2CH3); 1.23 (4H, m, 4-CH2CH2CH3); 2.25 (6H, s, 2,6-CH3); 3.67 (6H, s,
3,5-COOCH3); 3.91 (1H, t, 3J = 5.0, H-4); 5.69 (1H, s, NH).
1488

1
3,5-Dimethoxycarbonyl-2,6-dimethyl-4-propylpyridine (3a). H NMR spectrum, δ, ppm (J, Hz): 0.87
3
(3H, t, J = 7.0, 4-CH2CH2CH3); 1.54 (4H, m, 4-CH2CH2CH3); 2.49 (6H, s, 2,6-CH3); 3.93 (6H, s, 3,5-COOCH3).
Mass spectrum, m/z (Irel, %): 265 [M]+ (11), 250 [M-Me]+ (59), 234 (100), 218 [M-Pr]+ (43), 202 (25), 177 (22), 77
(24).
3,5-Dimethoxycarbonyl-6-methyl-2-methylene-3,4-dipropyl-1,2,3,4-tetrahydropyridine (3b). 1H
NMR spectrum, δ, ppm (J, Hz): 0.80 (6H, m, 3,4-CH2CH2CH3); 1.51 (8H, m, 3,4-CH2CH2CH3); 2.27 (3H, s,
3
6-CH3); 3.12 (1H, t, J = 5.0, H-4); 3.67 (3H, s, 3-COOCH3); 3.72 (3H, s, 5-COOCH3); 4.49, 5.00 (2H, two s,
=CH2); 5.83 (1H, s, NH). Mass spectrum, m/z (Irel, %): 309 [M]+ (42), 280 [M-Et]+ (71), 266 [M-Pr]+ (38), 250
[M-CO2Me]+ (35), 224 (100), 192 (39), 59 (53).
1
3,5-Dimethoxycarbonyl-2,6-dimethyl-3,4-dipropyl-3,4-dihydropyridine (3c). H NMR spectrum, δ,
ppm (J, Hz): 0.80 (6H, m, 3,4-CH2CH2CH3); 1,14 (8H, m, 3,4-CH2CH2CH3); 2.29 (3H, s, 2-CH3); 2.51 (3H, s,
6-CH3); 2.89 (1H, t, 3J = 5.0, H-4); 3.75 (3H, s, 3-COOCH3); 3.76 (3H, s, 5-COOCH3).
1
4-Isopropyl-3,5-dimethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (4). H NMR spectrum, δ,
ppm (J, Hz): 0.71 (6H, d, 3J = 6.4, 4-CH(CH3)2); 1.84 (1H, m, 4-CH(CH3)2); 2.29 (6H, s, 2,6-CH3); 3.70 (6H, s,
3,5-COOCH3); 3.87 (1H, d, 3J = 5.6, H-4); 5.60 (1H, s, NH).
4-Isopropyl-3,5-dimethoxycarbonyl-2,6-dimethylpyridine (4a). 1H NMR spectrum, δ, ppm (J, Hz): 1.25
(6H, d, 3J = 6.4, 4-CH(CH3)2); 2.44 (6H, s, 2,6-CH3); 2.90 (1H, m, 4-CH(CH3)2); 3.91 (6H, s, 3,5-COOCH3). Mass
spectrum, m/z (Irel, %): 265 [M]+ (5), 250 [M –Me]+ (100), 234 (24), 200 (96), 91 (16), 77 (20).
1
4-Isobutyl-3,5-dimethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (5). H NMR spectrum, δ, ppm
3
3
(J, Hz): 0.83 (6H, d, J = 5.6, 4-CH2CH(CH3)2); 1.08 (2H, t, J = 6.0, 4-CH2CH(CH3)2); 1.41 (1H, m,
4-CH2CH(CH3)2); 2.31 (6H, s, 2,6-CH3); 3.67 (6H, s, 3,5-COOCH3 ); 3.94 (1H, t, 3J = 6.4, H-4); 5.71 (1H, s, NH).
1
4-Isobutyl-3,5-dimethoxycarbonyl-2,6-dimethylpyridine (5a). H NMR spectrum, δ, ppm (J, Hz):
3
0.82 (6H, d, J = 5.6, 4-CH2CH(CH3)2); 1.66 (3H, m, 4-CH2CH(CH3)2 + 4-CH2CH(CH3)2); 2.48 (6H, s,
2,6-CH3); 3.89 (6H, s, 3,5-COOCH3). Mass spectrum, m/z (Irel, %): 279 [M]+ (5), 264 [M-Me]+ (26), 248 (100),
222 [M-Bu]+ (94), 206 (52), 177 (26), 77 (30).
3,4-Diisobutyl-3,5-dimethoxycarbonyl-6-methyl-2-methylene-1,2,3,4-tetrahydropyridine (5b). 1H
NMR spectrum, δ, ppm (J, Hz): 0.85 (12H, m, 3,4-CH2CH(CH3)2); 1.53 (4H, m, 3,4-CH2CH(CH3)2); 1.68 (2H,
m, 3,4-CH2CH(CH3)2); 2.25 (3H, s, 6-CH3); 3.13 (1H, m, H-4); 3.66 (3H, s, 3-COOCH3); 3.69 (3H, s,
5-COOCH3); 4.53, 5.20 (2H, two s, =CH2); 5.80 (1H, s, NH). Mass spectrum, m/z (Irel, %): 337 [M]+ (6), 294
[M-Pr]+ (68), 262 (25), 224 (100), 41 (30).
3,4-Diisobutyl-3,5-dimethoxycarbonyl-2,6-dimethyl-3,4-dihydropyridine (5c). 1H NMR spectrum, δ,
ppm: 0.85 (12H, m, 3,4-CH2CH(CH3)2); 1.53 (4H, m, 3,4-CH2CH(CH3)2); 1.68 (2H, m, 3,4-CH2CH(CH3)2);
2.25 (3H, s, 2-CH3); 2.46 (3H, s, 6-CH3); 2.82 (1H, m, H-4); 3.71 (3H, s, 3-COOCH3); 3.74 (3H, s, 5-COOCH3).
1
3,5-Dimethoxycarbonyl-2,6-dimethylpyridine (6). H NMR spectrum (CDCl3), δ, ppm: 2.82 (6H, s,
1
2,6-CH3); 3.91 (6H, s, 3,5-COOCH3); 8.66 (1H, s, H-4). H NMR spectrum (DMSO-d6), δ, ppm: 2.71 (6H, s,
2,6-CH3); 3.85 (6H, s, 3,5-COOCH3); 8.50 (1H, s, H-4). Mass spectrum, m/z (Irel, %): 223 [M]+ (55), 192 (100),
164 [M-CO2Me]+ (40), 77 (28), 63 (33).
1
Isopropylnitrilium Perchlorate (8). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.00 (6H, d,
3J = 7.0, CH(CH3)2); 1.76 (3H, s, CH3); 3.74 (1H, m, CH(CH3)2).
The work was carried out with the support of the Latvian Council of Science (grant 05.1787).
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