Synthesis and electrochemical oxidation of nitriles of 4-aryl-2- carbamoylmethylthio-5-ethoxy-carbonyl-1,4-dihydropyridine-3-carboxylic acids

Article abstract of DOI:10.1023/B:COHC.0000018336.52691.a7

Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-1,4,5, 6-tetrahydropyridine-3-carboxylic acids were obtained by the alkylation of 1,4,5,6-tetrahydropyridine-2-thiolate with iodoacetamide or by a three-component synthesis by condensing 2-arylmethylene-1,3-dicarbonyl compounds with 2-cyanothioacetamide in the presence of piperidine with subsequent reaction with iodoacetamide. Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4- dihydropyridine-3-carboxylic acids were obtained by the dehydration of 6-hydroxy-1,4,5,6-tetrahydropyridines or with a one-reactor three-component system from 2-cyano-3-(4-methoxyphenyl)thioacrylamide, 1,3-dicarbonyl compounds, and iodoacetamide. The electrochemical oxidation of the synthesized nitriles was investigated and it was established that derivatives of 1,4,5,6- tetrahydropyridine as a rule are oxidized readily to the corresponding 1,4-dihydropyridines. A comparative analysis has been carried out of the ability of hydrogenated pyridines to be oxidized electrochemically depending on the electron-withdrawing properties of the substituents in the heterocycle.

Full text of DOI:10.1023/B:COHC.0000018336.52691.a7

Chemistry of Heterocyclic Compounds, Vol. 39, No. 12, 2003
SYNTHESIS AND ELECTROCHEMICAL
OXIDATION OF NITRILES OF 4-ARYL-
2-CARBAMOYLMETHYLTHIO-5-ETHOXY-
CARBONYL-1,4-DIHYDROPYRIDINE-
3-CARBOXYLIC ACIDS
L. Baumane, A. Krauze, L. Chernova, L. Sile, G. Duburs, and J. Stradins
Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-1,4,5,6-tetrahydropyridine-3-
carboxylic acids were obtained by the alkylation of 1,4,5,6-tetrahydropyridine-2-thiolate with
iodoacetamide or by a three-component synthesis by condensing 2-arylmethylene-1,3-dicarbonyl
compounds with 2-cyanothioacetamide in the presence of piperidine with subsequent reaction with
iodoacetamide. Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-
carboxylic acids were obtained by the dehydration of 6-hydroxy-1,4,5,6-tetrahydropyridines or with a
one-reactor three-component system from 2-cyano-3-(4-methoxyphenyl)thioacrylamide, 1,3-dicarbonyl
compounds, and iodoacetamide. The electrochemical oxidation of the synthesized nitriles was
investigated and it was established that derivatives of 1,4,5,6-tetrahydropyridine as a rule are oxidized
readily to the corresponding 1,4-dihydropyridines. A comparative analysis has been carried out of the
ability of hydrogenated pyridines to be oxidized electrochemically depending on the electron-
withdrawing properties of the substituents in the heterocycle.
Keywords: 6-hydroxy-1,4,5,6-tetrahydropyridines, 1,4-dihydropyridines, one-reactor three-component
synthesis, electrochemical oxidation.
Many of the esters of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylic acids possess a cardiovascular
action [1], consequently their antioxidant and antiradical activity have been investigated [2], as also the
interconnection of these forms of activity with cardiovascular properties [3, 4]. Unsymmetrical 2-alkylthio-1,4-
dihydropyridines have been studied less, however marked cardiovascular [5], hepato-protecting [6], antioxidant
[7], and antiradical [8] activity have also appeared among them.
In continuation of investigations on the synthesis and properties of 2-alkylthio-1,4-dihydropyridines
[9,10] and condensed heterocycles based on them [11], we have synthesized a series of new nitriles of 4-aryl-2-
carbamoylmethylthio-5-ethoxycarbonyl-6-methyl(phenyl or p-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acids
(see Scheme) and have investigated their electrochemical oxidation. Data on electro-chemical oxidation are
important as a quantitative characteristic of the ability of compounds to be oxidized, which enables a more
purpose-directed search for biologically active substances to be carried out.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: lbaumane@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1808-1818, December, 2003. Original article submitted
October 10, 2003.
0009-3122/03/3912-1591$25.00©2003 Plenum Publishing Corporation
1591

R
O
O
CN
S
CN
O
NH2
O
+
+
+
I
+
_
HO
Ph
H2N
N
H
NH2
O
O
N
H
S
1
1
R
+
NH2
H
I
O
R
R
+
O
O
1
H
CN
CN
S
O
O
1
NH2
NH2
R
R
N
H
3a–i
S
N
H
HO
O
O
O
2b,d,e,g
NaNO2
+
H
O
O
CN
O
CN
S
O
NH2
+
+
+
I
NH2
1
R
O
N
N
S
O
H2N
H
O
4a
a,d,g R = H, b,e,h R = NO , c,f,i R = OMe; a c R1 = Me, d f R1 = Ph, g i R1 = p-O NC H
−
−
−
2
2
6
4
2-Carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-4,6-diphenyl-1,4,5,6-tetrahydropyridine-3-carboxylic
acid nitrile (2d) was obtained in 87% yield by the alkylation of 1,4,5,6-tetrahydropyridine-2-thiolate 1 with
iodoacetamide.
6-Hydroxytetrahydropyrimidines 1 and 2 are unstable compounds on the whole, having a tendency to
eliminate a molecule of water [12]. For this reason in certain cases it was not possible to isolate compound 1
from the reaction mixture. The nitriles of 1,4,5,6-tetrahydropyrimidine-3-carboxylic acids 2b and 2e were
obtained with the aid of a one-reactor three-component synthesis. The advantage of this method is that the
unstable intermediates of the reaction of 1 are not isolated. Compound 2b was obtained only in this way. The
low yield is explained by the fact that pure 6-hydroxytetrahydropyridine 2b was obtained after fractional
crystallization of the resulting mixture of 2b with dihydropyridine 3b.
The nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid 3
were obtained by three methods: A) by the dehydration of tetrahydropyridines 2 (compounds 3d,e) or by a one-
reactor three-component synthesis; B) by the condensation of 2-arylmethylene-1,3-dicarbonyl compounds with
1592

2-cyanothioacetamide in the presence of piperidine with subsequent reaction with iodoacetamide and
acidification of the reaction mixture under mild conditions (1,4-dihydropyridines 3b and 3d in yields of 77 and
69%); C) by the condensation of 2-cyano-3-(4-methoxyphenyl)thioacrylamide with 1,3-dicarbonyl compounds
in the presence of piperidine, with subsequent reaction with iodoacetamide and acidification of the reaction
mixture under mild conditions (1,4-dihydropyridines 3c and 3f in yields of 83 and 70%), which is a new
convenient method for obtaining nitriles of 2-carbamoylmethylthio-1,4-dihydropyridine-3-carboxylic acid 3.
The structures of compounds 2 and 3 were demonstrated spectroscopically. In the IR spectra of 2 and 3
the absorption bands of the stretching vibrations of the cyano groups at 2182-2212 cm-1 and the absorption
bands of the stretching vibrations of the carbonyl group were the most characteristic. In the 1H NMR spectra of
compounds 2 the most characteristic signals were those of the 4- and 5-H protons as doublets with coupling
constants 12-13 Hz, which indicates the trans-diaxial disposition of these protons. Consequently the bulky
4-aryl and 5-ethoxycarbonyl substituents are orientated trans-equatorially. In the 1H NMR spectra of compounds
3 the most characteristic were the signals of 4-H at 4.48-4.74 ppm and the signals of the S-CH2 groups as an AB
quartet with J ~ 15 Hz, which shows the nonequivalence of the CH2 protons due to the presence in the molecule
of the asymmetric center at 4-C.
The electrochemical oxidation of compounds 2 and 3 was carried out in anhydrous acetonitrile at a
rotating disk electrode with a ring and stationary glass-graphite electrode. When oxidizing the derivatives of
1,4-dihydropyridine 3a-i and of 1,4,5,6-tetrahydropyridine 2b,d,e,g at the rotating disc electrode one or two
polarographic waves were observed. Waves for the electrochemical reduction of the oxidized products were
recorded at the ring electrode. The potentials of the oxidation peaks of compounds were determined by cyclic
voltammetry at the stationary electrode and the reversibility of the oxidation–reduction reactions was checked. It
was established that all the compounds are oxidized irreversibly at room temperature. The results of the
investigations are given in Table 1.
By analogy with the data obtained by various authors [13-17] when studying the mechanism of
oxidation of 1,4-dihydropyridine derivatives, we propose that compounds 3a-i are oxidized to the corresponding
pyridines with separation of two electrons and two protons by a ECEC scheme. The values of the reduction
potentials at the ring electrode of the products formed at the disc electrode indicate this, particularly the wave in
the potential range -1.7 to -2.4 V, corresponding to the reduction of pyridine, and the wave in the potential range
from -0.8 to -1.1 V which belongs to the reduction of the protonated form of pyridine. The oxidized form 4a of
1,4-dihydropyridine 3a was synthesized and an electrochemical reduction of it was carried out at the rotating
ring electrode. The half-wave potential E1/2 = -2.36 V coincides with the reduction potential of one of the
products of the electrooxidation of compound 3a. The wave at potential ~1 V shows the presence of the
protonated form of the pyridine, the possibility of forming which for N-unsubstituted 1,4-dihydro-pyridines has
been studied in more detail in [16].
For compounds 3d-i containing a phenyl or p-nitrophenyl substituent at position 6 of the
1,4-dihydropyridine ring, a second oxidation wave was recorded at the disc electrode more or less clearly
displayed. At the potentials of this wave in the case of compound 3g a product was formed capable of being
reduced electro-chemically at a more positive potential than the reduction potential of the corresponding
protonated pyridine (see Table 1). The nature of the product is still not clear. Possibly this indicates a further
oxidation process affecting the sulfur atom and heterocyclization with the formation of 4,7-dihydrothieno-
[2,3-b]pyridine [18] or further oxidation of some other product.
For 1,4,5,6-tetrahydropyridine derivatives 2b,d,e two electrooxidation waves were also recorded at the
disk electrode. The values of the potentials of the first wave for compounds 2b,d,e were greater than for the
corresponding 1,4-dihydropyridines. Compound 2g is oxidized in acetonitrile with the formation of one
extremely sloping polarographic wave, the half-wave potential (1.25 V) is displaced into the positive region
compared with the potential of the corresponding 1,4-dihydropyridine (Table 1). However, if the surface active
substance camphor (up to 0.1%) is added to the solution, then the wave is split and it is possible to determine
approximately two values for the half-wave potentials, viz. 1.0 and 1.4 V. For comparison we recorded the
1593

TABLE 1. Values of Potentials for Compounds 3 and 2 in Acetonitrile on a
Base of 0.1 M (C4H9)4PF6*
Com-
Е
1/2, V*2
1.04
n
Е, V
-Е1/2, V
Еp, V*2
pound
1.6
1.3-1.9
0
1.1-1.8
1.1-1.9
1.5-1.9
1.12, 2.36
2.36
1.11, 1.98
0.82, 1.73
0.41, 2.04
1.26
3а
4а
3b
3c
3d
1.09
0.88
1.4
1.6
Σ1.4
1.28
1.22
1.32
1.03
1.46
1.04
1.2
1.3
1.3-1.9
0.77, 1.89
0.86, 2.27
1.37
1.32
3e
3е
0.94
1.8
1.64
1.2
0.95
1.51
0.7
1.3
1.3
1.8
0.99
0.53
1.36
3f
0.93
1.34
3g
1.50
1.19
1.2
1.2-1.9
1.2-1.9
0.78
0.71
1.45
1.42
3h
3i
1.04
1.2
1.68
2.0
0.85
1.50
1.0
1.1
1.2
1.9
1.12
0.76
1.10
1.80
2b
2d
2e
2g
0.97
1.0
1.2
0.89, 1.9
1.34
~1.8
?
2.0
0.69
1.78
0.95
1.38
1.0
1.2
1.2-1.9
0.96
1.33
1.25
1.4
1.2
1.7
1.2
1.7
1.15, 1.72
0.69
1.10
1.38
1.36
1.03
1.40
1.19, 1.72
0.77
_______
* E1/2 is the half-wave potentials for electrochemical oxidation, where n is
the number of electrons transferred at the rotating disk electrode; -E1/2 is the
half-wave potential for the electrochemical reduction at the rotating ring
electrode of the products formed at potential E at the disk electrode; Ep is
the potential of oxidation peaks on cyclic scanning (0.1 V/sec) at the
stationary electrode. For compounds 3g and 2g values given in italics were
obtained with the addition of 0.1% camphor to the solution being
investigated.
*2 The numerical values of potentials E1/2 and Ep differ due to the use of
different reference electrodes.
electrochemical characteristics of dihydropyridine 3g under the same conditions. In all cases tetrahydropyridine
2g is oxidized with more difficulty than dihydropyridine 3g. The first polarographic waves of compounds 2b,d,e
correspond in height to the transfer of one electron, however in the cyclic voltammetric curves at a potential
scanning rate up to 1 V/sec no reversibility of the electrochemical process was observed in any case.
At constant potential E at the disk electrode, corresponding to the potential for the limiting current of
each of the polarographic waves, products were detected for compound 2 capable of being reduced
electrochemically. As in the case of the corresponding 1,4-dihydropyridines a product is formed at the first stage
of electrooxidation which is reduced at a potential of ~1 V, and in the second a product that is reduced more
readily (Table 1). In addition to the oxidation products proposed for compound 3g tetrahydropyridines may, as a
result of dehydration, form either 1,4- or 3,4-dihydropyridine structures [12]. In the present work new data are
1594

presented on the electrochemical oxidation of tetrahydropyridines 2 for which conjugation between the COOEt
group in position 5 and the N atom of the heterocycle is impossible. Such a system may be converted by
elimination of water into a dihydropyridine 3 (tetrahydropyridine 2b is oxidized more readily than the
corresponding 1,4-dihydropyridine 3b and at the first stage products are formed which are reduced at the same
potential). Compounds 2d and 2e are also oxidized more readily than their dihydro analogs, however the
corresponding pyridine analogs were not recorded at the ring electrode. In the case of tetrahydropyridine 2g
oxidation proceeds with more difficulty than for dihydropyridine 3g and reduction of the protonated pyridine
was also not detected. From the data given it is impossible to establish a route for the oxidation of
tetrahydropyridines 2. They are mainly oxidized more readily than dihydropyridines 3. For a detailed study of
the mechanism of reduction of tetrahydropyridine derivatives it is necessary to use subjects which are not
clogged with various electroreactive substituents, to synthesize additional model compounds, and to apply more
contemporary methods of investigation, such as electrochemical oxidation with simultaneous detection and
identification of the resulting intermediate products by chromato-mass spectrometry (CMS). In our case the
waves of the electroreduction of the nitro groups of the initial compounds and the series of possible conversions
of the substituents in positions 2 and 3 of the heterocycle significantly hinder the polarographic study of the
mechanism of electrooxidation.
The effect of the donor–acceptor properties of substituents in positions 4 and 6 has been studied on the
ease of electrochemical oxidation of 1,4-dihydropyridine derivatives 3a-i. When comparing the numerical
values of the electrooxidation potentials the values of Ep obtained from cyclic voltammetric curves were used,
since in certain cases it is difficult to determine on the polarograms the precise values of the half-wave
potentials due to their merging into one slanting wave or there is no clear plateau of limiting current.
If R1 = Me (compounds 3a-c) or R1 = Ph (compounds 3d-i), the detachment of the first electron is
hindered by an increase in the electron-withdrawing properties of the substituent R. If a strong electron-
withdrawing group is introduced into position 6 (compounds 3g-i) then the ability of compounds to be oxidized
electrochemically falls in the series 3g < 3i < 3h and does not comply with the Hammett equation LSE (values
of E1/2 change in the same sequence). On the other hand, if compounds with unchanged substituent R in position
4 of the heterocycle are compared then in all cases the electrochemical oxidation potential is displaced towards
the region of more positive values with the growth in electron-withdrawing properties of the substituent R1,
which is in agreement with the LSE principle. On comparing the results with the data of [13] we established that
replacement of a methyl group by an alkylthio group in position 2 and an ethoxycarbonyl group by a cyano
group in position 3 of the heterocycle hinders detachment of the first electron for compound 3c by 220, for
compound 3a by 120, and for compound 3b by only 20 mV. If the electrooxidation potentials of certain
symmetrical 4-aryl- and 4-(p-nitrophenyl)-2,6-dimethyl-3,5-X-1,4-dihydropyridines [14] are compared with the
electrooxidation potentials of compounds 3a and 3b then these compounds may be arranged in series according
to electro-oxidation potential (∆E, V is the difference in the numerical values of the electro-oxidation
potentials).
for R = H
X = COCH3 < COOC2H5 < COOCH3 < 3a < CN
∆E = 0.20 0.12 0.08 -0.12
X = COCH3 < COOC2H5 < COOCH3 < 3b < CN
∆E = 0.12 0.02 0.01 -0.16
0
for R = NO2
0
The introduction of a strong electron-withdrawing group (R = NO2) into the substituent at position 4 of
the heterocycle narrows the gap of oxidation potentials ∆E of the compounds being compared from 320 to
280 mV. In its series compound 3b becomes more susceptible towards electrooxidation than compound 3a in its
series.
1595

TABLE 2. Characteristics of the Synthesized Compounds 2 and 3
Found, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
Calculated, %
mp, °С
C
H
N
S
C18H20N4O6S
C23H23N3O4S
C23H22N4O6S
C18H18N4O5S
C19H21N3O4S
C23H21N3O3S
51.32
51.42
4.68
4.79
13.16
13.33
7.56
7.63
152-153
148-150
203-205
185-187
173-175
223-226
11
87
2b
2d
2e
3b
3c
3d
62.91
5.21
9.72
7.45
63.14
5.30
9.60
7.33
57.13
57.27
4.47
4.59
11.51
11.61
6.56
6.65
31
53.52
4.29
13.80
7.99
77 (B)
83 (C)
53.72
4.51
13.92
7.97
58.56
58.90
5.36
5.46
10.69
10.84
8.36
8.28
65.49
4.81
10.11
7.75
72 (A)
69 (B)
65.85
5.05
10.02
7.64
C23H20N4O5S
C24H23N3O4S
59.10
59.47
4.21
4.34
12.05
12.06
6.86
6.90
198-200
205-207
75 (A)
3e
3f
64.11
5.15
9.38
7.14
70 (C)
64.13
5.16
9.35
7.13
On comparing values of electrochemical oxidation potentials of the corresponding di- and
tetrahydropyridines it is evident that tetrahydropyridine 2b, containing an electron-donating, low-volume methyl
substituent in position 6 of the heterocycle, is oxidized 240 mV more readily than the corresponding
dihydropyridine 3b. However, if the methyl group in position 6 is replaced by a bulky phenyl substituent then
the electron-withdrawing nitro group in position 4 hinders the electrooxidation of the dihydropyridine by 50 mV
(Ep, compounds 3d, 3e) and the opposite is observed for tetrahydropyridine derivatives. The nitrophenyl
derivative 2e is oxidized 10 mV more readily than the phenyl derivative 2d. If compounds 3b,d,g and 2b,d,g are
compared then it is evident that replacement of the methyl group in position 6 of the heterocycle by phenyl and
then by nitrophenyl gradually hinders electrooxidation in the compound 3 series, however in the compound 2
series transfer from a methyl to a phenyl substituent introduces the the main contribution.
The results given indicate that according to the values of both E1/2 and Ep the tetrahydropyridines 2 are
oxidized more readily than the corresponding dihydropyridines 3 (except for 2g the oxidation peak of which at
Ep = 1.1 V is not caused by the oxidation of the starting material). The tetrahydropyridine has one electron-
withdrawing substituent, the cyano group, in the conjugated system, while the conjugated system of the
dihydropyridine contains a second electron-withdrawing substituent, the ethoxycarbonyl group. This confirms
the hypothesis that electron-withdrawing substituents in the conjugated system of hydrogenated pyridines hinder
detachment of an electron and the process of electrochemical oxidation. The information given above on the
noncorrespondance of the values of the electro-oxidation potentials with the LSE principle indicates only that
the susceptibility of compounds of type 2 and 3 towards electrochemical oxidation is determined not only by
donor–acceptor properties but also by additional effects such as steric hindrance to the access of the molecule to
the electrode. The mechanism of electrochemical oxidation of tetrahydropyridines requires further study. It
should be noted that the instability of the compounds hindered the work. They were fairly readily
dehydrogenated in the air being converted into dihydropyridines.
EXPERIMENTAL
The electrochemical investigations by the rotating disk electrode with a ring electrode were carried out
in equipment consisting of a PAR Ring–Disk–Electrode System Model 636 (USA) and a Bruker E 350 double
potentiostat. The disk and ring electrodes were prepared from glass-graphite. The efficiency coefficient of the
1596

TABLE 3. Spectral Characteristics of Compounds 2 and 3
Com-
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)
pound
1690 (C=O); 2182
(C≡N);
0.98 and 3.90 (5H, t and q, J = 7, ОC2H5);
2b
1.52 (3H, s, 6-CH3); 2.82 and 4.12 (2H, d and d, J ~ 13,
5-Н and 4-Н); 3.62 (2Н, s, SCH2); 6.04 (1Н, s, ОH);
7.60 and 8.20 (4Н, d and d, J = 7, C6H4);
3180, 3350 (NH, NH2)
7.58 and 7.88 (2Н, s an s, NH2); 8.88 (1Н, s, NH)
1673, 1731 (C=O);
2196 (C≡N); 3190, 3342,
3500 (NH, NH2, ОН)
0.48 and 3.42 (5H, t and q, J = 7, ОC2H5);
2.90 and 4.10 (2H, d and d, J ~ 12, 5-Н and 4-Н);
3.60 (2Н, s, SCH2); 6.40 (1Н, s, ОH);
7.1-7.9 (12Н, complection, 2 C6H5 and NH2);
9.14 (1Н, s, NH)
2d
1674, 1730 (C=O);
2192 (C≡N);
0.48 and 3.47 (5H, t and q, J = 7, ОC2H5);
2e
3b
3c
3.06 and 4.30 (2H, d and d, J ~ 13, 5-Н and 4-Н);
3.62 (2Н, s, SCH2); 6.54 (1Н, s, ОH); 7.4-8.2 (11Н,
complection, C6H5, C6H4 and NH2); 9.34 (1Н, s, NH)
3186, 3346 (NH, NH2)
1647, 1680, 1707 (C=O); 1.08 and 3.97 (5H, t and q, J = 7, ОC2H5);
2.36 (3H, s, 6-CH3); 3.56 and 3.78 (2H, d and d, J ~ 15,
SCH2); 4.74 (1Н, s, 4-Н); 7.52 and 8.26 (4Н, d and d, C6H4);
7.66 and 7.96 (2Н, br. s and br. s, NH2); 10.58 (1Н, s, NH)
2190 (C≡N);
3160, 3342 (NH, NH2)
1651, 1678, 1700 (C=O); 1.10 and 3.92 (5H, t and q, J = 7, ОC2H5); 2.28 (3H, s,
6-CH3); 3.58 and 3.72 (2H, d and d, J ~ 15, SCH2);
3.68 (3Н, s, ОСН3); 4.54 (1Н, s, 4-Н);
2200 (C≡N);
3214, 3362 (NH, NH2)
6.84 and 7.07 (4Н, and dd, C6H4);
7.57 and 7.86 (2Н, br. s and br. s, NH2); 10.32 (1Н, s, NH)
1673, 1710 (C=O);
2194, 2204 (C≡N);
3170, 3340,
0.70 and 3.70 (5H, t and q, J = 7, ОC2H5);
3d
3e
3.64 and 3.88 (2H, d and d, J ~ 15, SCH2); 4.56 (1Н, s, 4-Н);
7.2-7.5 (10Н, complection, 2 C6H5);
7.58 and 7.90 (2Н, s and s, NH2); 10.74 (1Н, s, NH)
3414 (NH, NH2)
1666, 1694 (C=O);
2198, 2204 (C≡N);
3200, 3370 (NH, NH2)
0.70 and 3.72 (5H, t and q, J = 7, ОC2H5);
3.70 and 3.94 (2H, d and d, J ~ 15, SCH2);
4.70 (1Н, s, 4-Н); 7.48 (5Н, m, C6H5);
7.60 and 7.97 (2Н, s and s, NH2);
7.64 and 8.80 (4Н, d and d, J = 7, C6H4); 10.96 (1Н, s, NH)
1667, 1688 (C=O);
2205, 2212 (C≡N);
3205, 3380 (NH, NH2)
0.70 and 3.92 (5H, t and q, J = 7, ОC2H5); 3.64 and 3.82
(2H, d and d, J ~ 15, SCH2); 3.70 (3Н, s, ОСН3);
4.48 (1Н, s, 4-Н); 6.90 and 7.18 (4Н, dd and dd, J = 8, C6H4);
7.40 (5Н, m, C6H5); 7.53 and 7.88 (2Н, br. s and br. s, NH2);
10.70 (1Н, s, NН)
3f
electrodes of 0.39 was calculated by the procedure of [19], and the rotation rate of the electrodes was
2000 min-1. All potentials were measured relative to a 0.1 N silver reference electrode (Ag/AgNO3). Cyclic
volt-ampere curves were recorded with the aid of a PAR 170 (USA) electrochemical system using a three-
electrode cell and a stationary glass-graphite electrode. The reference electrode was a saturated aqueous calomel
electrode fitted with a connecting bridge for working in nonaqueous solvents. All investigations were carried
out in anhydrous acetonitrile purified by the method of [20]. The depolarizer concentration was 5·10-4 M , base
electrolyte was tetrabutylammonium hexafluorophosphate (1·10-1 M).
The IR spectra of the starting materials were taken on a Perkin–Elmer 580B spectrometer in Nujol. The
1H NMR spectra were recorded on a WH 90/DC (90 Hz) spectrometer in DMSO-d6, internal standard was TMS.
A check on the course of reactions and the homogeneity of substances was effected by TLC on Silufol UV 254
plates, eluent was chloroform–hexane–acetone, 2:1:1. Compounds were recrystallized from ethanol. The
synthesis of compounds 2g and 3g-i has been described in [10], and of 3a and 4a in [11].
The physicochemical and spectral characteristics of compounds 2 and 3 are given in Tables 2 and 3.
1597

2-Carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-6-methyl-4-(4-nitrophenyl)-1,4,5,6-tetra-
hydropyridine-3-carboxylic Acid Nitrile (2b). 2-(4-Nitrophenylmethylene)acetoacetic acid ethyl ester (1.32 g,
5 mmol) and 2-cyanothioacetamide (0.5 g, 5 mmol) were dissolved in ethanol (20 ml) by heating, then the
solution was cooled to 30-40°C, and piperidine (0.6 ml, 0.5 mmol) was added. After 15 min stirring at room
temperature iodoacetamide (1.11 g, 6 mmol) was added. The solid formed was filtered off after 1 h, washed
with ethanol (10 ml) cooled to 0°C, and with water (20 ml). A mixture (0.96 g) of compounds 2b and 3b was
obtained. Pure colorless compound 2b (0.22 g, 11%) was obtained by recrystallization from ethanol. On
acidifying the filtrates compound 3b (1.23 g, 61%) was isolated. Colorless compound 2e (31%) was obtained
analogously on using the ethyl ester of 2-(4-nitrophenylmethylene)benzoylacetic acid.
2-Carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-4,6-diphenyl-1,4,5,6-tetrahydropyridine-3-
carboxylic Acid Nitrile (2d). Finely powdered 1,4,5,6-tetrahydropyridine-2-thiolate 1 [12] (2.33 g, 5 mmol)
and iodoacetamide (1.02 g, 5.5 mmol) were dissolved with heating in ethanol (20 ml). The solution was stirred
at room temperature for 15 min, the resulting solid was filtered off, washed with ethanol (10 ml) cooled to 0°C,
and with water (20 ml). Colorless compound 2d (1.90 g, 87%) was obtained.
Synthesis of 6-Substituted Nitriles of 4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-
1,4-dihydropyridine-3-carboxylic Acids 3. A. 1,4,5,6-Tetrahydropyridine 2d (0.44 g, 1 mmol) was dissolved
with brief heating in 0.5 M HCl in ethanol (10 ml), and the solution stirred for 1 h at room temperature. The
solid formed was filtered off, washed with ethanol (10 ml) cooled to 0°C, and colorless compound 3d (0.30 g,
72%) was obtained.
Colorless compound 3e was obtained analogously by the dehydration of tetrahydropyridine 2e in 75%
yield.
B. 2-(4-Nitrophenylmethylene)acetoacetic acid ethyl ester (1.32 g, 5 mmol) and 2-cyanothioacetamide
(0.5 g, 5 mmol) were dissolved by heating in ethanol (20 ml). Piperidine (0.6 ml, 0.5 mmol) was added to the
obtained solution, and after stirring for 15 min iodoacetamide (1.11 g, 6 mmol) was added. After 10 min, 1 M
HCl in ethanol (10 ml) was poured in, the mixture was briefly heated to boiling and stirred for 1 h at ~20°C. The
resulting precipitate was filtered off, and washed with ethanol (10 ml) cooled to 0°C, and with water (20 ml).
Colorless compound 3b (1.55 g, 77%) was obtained.
Colorless compound 3d was obtained analogously in 69% yield using 2-(4-nitrophenylmethylene)-
benzoylacetic acid ethyl ester.
C. 2-Cyano-3-(4-methoxyphenyl)thioacrylamide (1.09 g, 5 mmol) and acetoacetic acid ethyl ester
(0.65 g, 5 mmol) were dissolved with heating in ethanol (20 ml). Piperidine (0.6 ml, 0.5 mmol) was added to the
obtained solution, and after stirring for 15 min iodoacetamide (1.02 g, 5.5 mmol) was added. After 10 min 1 M
HCl in ethanol (10 ml), was added, the mixture was heated briefly to boiling, then stirred for 1 h at ~20°C. The
precipitate formed was filtered off, and washed with ethanol (10 ml) cooled to 0°C, and with water (20 ml).
Colorless compound 3c (1.60 g, 83%) was obtained.
Colorless compound 3f was obtained analogously in 70% yield using benzoylacetic acid ethyl ester.
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