Synthesis, structure, and electrochemical characteristics of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid nitriles

Article abstract of DOI:10.1007/s10593-005-0156-x

We have obtained 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4- dihydropyridine-3-carboxylic acid nitriles by S-alkylation of the corresponding 2-thioxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid nitrile by iodoacetamide or one-pot multicomponent synthesis methods: condensation of 2-arylidene-acetoacetic acid ethyl ester, 2-cyanothioacetamide, piperidine, and iodoacetamide; acetoacetic acid ethyl ester, 3-aryl-2-cyanothioacrylamide, piperidine, and iodoacetamide; acetoacetic acid ethyl ester, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and iodoacetamide. We have carried out a comparative analysis of the capability of 2-alkylthio-4-aryl-5- ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid nitriles for electrochemical oxidation as a function of the electronic properties of the aryl substituent in the 4 position of the heterocycle and the 2-alkylthio substituent. X-ray diffraction data indicate the existence of a hydrogen bond between the C=O of the 2-carbamoylmethylthio substituent and the NH of the hydrogenated heterocycle, which explains the more facile oxidation of the studied compounds compared with 2-methylthio-substituted 1,4-dihydropyridines.

Full text of DOI:10.1007/s10593-005-0156-x

Chemistry of Heterocyclic Compounds, Vol. 41, No. 3, 2005
SYNTHESIS, STRUCTURE, AND ELECTROCHEMICAL
CHARACTERISTICS OF 4-ARYL-2-CARBAMOYLMETHYLTHIO-
5-ETHOXYCARBONYL-1,4-DIHYDROPYRIDINE-
3-CARBOXYLIC ACID NITRILES*
L. Baumane, A. Krauze, S. Belyakov, L. Sile, L. Chernova, M. Griga, G. Duburs, and J. Stradins
We have obtained 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic
acid nitriles by S-alkylation of the corresponding 2-thioxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid
nitrile by iodoacetamide or one-pot multicomponent synthesis methods: condensation of 2-arylidene-
acetoacetic acid ethyl ester, 2-cyanothioacetamide, piperidine, and iodoacetamide; acetoacetic acid
ethyl ester, 3-aryl-2-cyanothioacrylamide, piperidine, and iodoacetamide; acetoacetic acid ethyl ester,
an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and iodoacetamide. We have carried out a
comparative analysis of the capability of 2-alkylthio-4-aryl-5-ethoxycarbonyl-1,4-dihydropyridine-3-
carboxylic acid nitriles for electrochemical oxidation as a function of the electronic properties of the
aryl substituent in the 4 position of the heterocycle and the 2-alkylthio substituent. X-ray diffraction data
indicate the existence of a hydrogen bond between the C=O of the 2-carbamoylmethylthio substituent
and the NH of the hydrogenated heterocycle, which explains the more facile oxidation of the studied
compounds compared with 2-methylthio-substituted 1,4-dihydropyridines.
Keywords: 1,4-dihydropyridines, hydrogen bond, one-pot multicomponent method, electrochemical
oxidation, X-ray diffraction analysis.
Nitriles of 2-alkylthio-4-aryl-1,4-dihydropyridine-3-carboxylic acids are of interest as potential
antioxidants [1, 2] that are also distinguished by cardiovascular [3, 4] and hepatoprotective [5] activity.
Continuing a study of the chemical and electrochemical properties of 2-alkylthio-1,4-dihydropyridines
[4, 6] and methods for obtaining them [7, 8], we have synthesized a series of novel 4-aryl-2-
carbamoylmethylthio-5-ethoxycarbonyl-6-methyl-1,4-dihydropyridine-3-carboxylic acid nitriles 1, in which we
varied the substituents on the 4-phenyl ring over a broad range. We carried out a comparative analysis of the
capability for electrochemical oxidation of 2-alkylthio-4-aryl-5-ethoxycarbonyl-1,4-dihydropyridine-3-
carboxylic acid nitriles 1 and 4 as a function of the electronic properties of the aryl substituent on the 4 position
of the heterocycle and the 2-alkylthio substituent, since the corresponding values of the potentials quantitatively
characterize the antioxidant properties of the compounds. The electrochemical oxidation data were used for a
more targeted search for biologically active substances.
_______
* Dedicated to Academician V. Minkin to show our appreciation for his contribution to organic chemistry and
his wonderful humanity, remembering his collaboration with his colleagues from Riga.
_________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: lbaumane@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 416-428, March, 2005. Original article submitted
October 29, 2004.
362
0009-3122/05/4103-0362©2005 Springer Science+Business Media, Inc.

4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid nitriles 1 were
obtained by condensation of: A) 2-arylidene acetoacetic acid ethyl ester, 2-cyanothioacetamide, piperidine, and
iodoacetamide; B) acetoacetic acid ethyl ester, 3-aryl-2-cyanothioacrylamide, piperidine, and iodoacetamide; C)
acetoacetic acid ethyl ester, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and iodoacetamide, and D)
by alkylation of 4-aryl-2-thioxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid nitriles 2 by iodoacetamide
(Scheme 1). For the comparative analysis, we obtained compound 1g by all four methods. Multicomponent
synthesis methods A (yields of compounds calculated based on the aldehyde, 47%-60%), B (54%-62%), and C
(68%-85%) have advantages over method D (stepwise synthesis, 33%-50%). The five-component method C
proved to be the most efficient and the most "green" in the studied cases (the need to synthesize lacrimators,
3-aryl-2-cyanothioacrylamides, was dropped).
These observations are consistent with data on synthesis of 2-methylthio-1,4-dihydropyridine-3-
carboxylic acid nitriles 4. It has been established [4] that design of the 1,4-dihydropyridine-2(3H)-thione ring is
a very complicated problem, since these compounds are readily oxidized in dilute solutions (compound 1d
cannot be obtained by method D). We need to find conditions allowing them to be rapidly separated from the
reaction medium or transformed to more stable 2-alkylthio-1,4-dihydropyridines, which is possible when using
methods A-C. On the other hand, 2-arylideneacetoacetic acid ethyl esters, obtained from an aromatic aldehyde
and acetoacetic acid ethyl ester (the starting materials for method A), are formed as a mixture of cis and trans
isomers [9], and their separation is occasionally prolonged and labor-intensive, since upon heating the products
of further Michael reaction are formed with participation of acetoacetic acid ethyl ester as the methylene
component. The lacrimators 3-aryl-2-cyanothioacrylamides, obtained from an aromatic aldehyde and
2-cyanothioacetamide (the starting materials for method B), tend toward dimerization in the presence of bases
[10]. Furthermore, 2-arylideneacetoacetic acid ethyl esters and 3-aryl-2-cyanothioacrylamides, in contrast to
aromatic aldehydes, are not oxidized during storage and therefore in a number of cases are used as the starting
components when using less efficient synthesis methods (A, B, or D).
Application of methods A-C leads to formation of 1,4-dihydropyridines 1 with 6-hydroxy-1,4,5,6-
tetrahydropyridines 3 as an impurity. When the reaction mixture containing compounds 1 and 3 is acidified, final
dehydration of hydroxy derivatives 3 occurs with formation of exclusively 1,4-dihydropyridines 1.
The structure of compounds 1 is proved spectroscopically. In the IR spectra, the most characteristic
features are absorption bands for the stretching vibrations of the cyano groups at 2190-2200 cm-1 and the three
bands for the C=O groups at 1686-1707 cm-1 (COOEt), 1670-1692 cm-1 (CONH2), and 1632-1652 cm-1. The
latter band may be assigned to stretching vibrations of the C=O of the amide group, which takes part in hydrogen
bond formation. In the 1H NMR spectra, we observe signals from the H-4 protons at 4.42-5.12 ppm, confirming
the 1,4-dihydropyridine structure of compounds 1.
1
The characteristics of the synthesized compounds and the IR and H NMR spectral data are shown in
Tables 1 and 2.
During electrochemical oxidation of compounds 1a-j in anhydrous acetonitrile on a stationary glassy
carbon electrode, we recorded one oxidation peak in the potential range from 1.18 V to 1.29 V relative to the
aqueous saturated calomel electrode. For compound 1a, we also recorded electrochemical oxidation polarograms
on a rotating disk electrode, and on a ring electrode we recorded the reduction waves for the oxidized products.
We found that electrochemical oxidation occurs along previously established pathways [6]: on the disk electrode
we recorded one oxidation wave with half-wave potential E1/2 = 1.09 V, and on the ring electrode we recorded a
reduction wave for the product (the protonated pyridine) at a potential E1/2 = -1.12 V (relative to Ag/AgNO3).
The electrochemical oxidation potentials of compounds 1a-j are not very sensitive to a change in the
electron-donor properties of the substituent on the phenyl ring, in the 4 position of the 1,4-dihydropyridine ring.
Going from a clearly electron-donor substituent para-OCH3 (compound 1c) to a strong electron-acceptor para-
NO2 (compound 1h) increases the electrochemical oxidation potential by only 60 mV (Table 3). The same
363

Scheme 1
R
O
R
CN
S
+
O
+
R
O
O
O
H2N
CN
S
O
O
+
1) B:
CN
S
C
H2N
+
O
NH2
O
I
2)
O
B
H N
O
2
1) B:
R
NH2
2)
I
A
1) B:
O
O
NH2
2)
I
CN
S
O
O
NH2
N
HO
H
3
O
+
H
R
R
R
1) B:
O
O
NH2
O
I
2)
CN
S
CN
S
O
D
O
CN
S
O
O
NH2
N
N
N
H
4
H
H
O
1
2
а R = H, b R = 4-OH; c R = 4-OMe; d R = 2-OMe; e R = 4-Cl; f R = 3-Cl; g R = 2-Cl; h R = 4-NO2; i R = 3-NO2; j R = 4-CN; B: = piperidine

TABLE 1. Characteristics of Synthesized Compounds 1
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield,
%*
mp, °С
Method
C
H
N
S
1a
1b
1c
1d
C18H19N3O3S
194-196
[7]
A
D
75 (60)
79 (50)
C18H19N3O4S·
1/2 H2O
56.31
56.53
5.27
5.27
10.92
10.98
8.49
8.38
202-204
B
B
B
94 (54)
83 (60)
84 (60)
C19H21N3O4S
173-175
[4]
203-205
C19H21N3O4S
58.88
58.90
5.42
5.46
10.81
10.84
8.25
8.28
С
68 (68)
72 (54)
1e
1f
C18H18ClN3O3S
C18H18ClN3O3S
C18H18ClN3O3S
54.81
55.17
55.17
55.17
55.21
55.17
4.66
4.63
4.48
4.63
4.52
4.63
10.58
10.72
10.78
10.72
10.75
10.72
8.07
8.18
8.19
8.18
8.19
8.18
193-195
189-191
193-195
A
C
A
85 (85)
84 (60)
1g
B
C
D
84 (62)
82 (82)
87(33)
1h
1i
C18H18N4O5S
C18H18N4O5S
53.68
53.72
4.38
4.51
13.80
13.92
7.99
7.97
185-187
A
71 (47)
184-186
[7]
D
84 (41)
1j
C19H18N4O3S
184-186
[8]
C
D
73 (73)
73 (49)
_______
* Calculated based on the aldehyde.
TABLE 2. Spectral Characteristics of Compounds 1
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz)
1
2
3
1a
1b
1c
1d
1e
1642, 1676, 1700 (C=O); 1.00 and 3.91 (5H, t and q, ОC2H5); 2.24 (3H, s, CH3-6);
2195 (C≡N); 3160, 3328
(NH, NH2)
3.55 and 3.68 (2Н, d and d, J = 14.4, SCH2); 4.47 (1H, s, H-4);
7.1-7.3 (5Н, m, C6H5); 7.58 and 7.88 (2H, br. s and br. s,
CONH2); 10.40 (1H, s, NH)
1637, 1670, 1686 (C=O), 1.10 and 3.97 (5H, t and q, ОC2H5); 2.30 (3H, s, CH3-6);
2190 (C≡N), 3270, 3360, 3.63 and 3.72 (2Н, d and d, J = 14.4, SCH2); 4.42 (1H, s, H-4);
3458 (NH, NH2, OH )
6.72 and 6.98 (4H, d and d, C6H4), 7.62 and 7.92 (2H,
br. s and br. s, CONH2); 9.34 (1H, s, OH); 10.32 (1H, s, NH)
1652, 1678, 1700 (C=O), 1.10 and 3.92 (5H, t and q, ОC2H5); 2.28 (3H, s, CH3-6);
2200 (C≡N), 3214, 3362
(NH, NH2)
3.58 and 3.72 (2Н, d and d, J = 14.6, SCH2); 3.68 (3H, s,
OCH3); 4.54 (1H, s, H-4); 6.84 and 7.07 (4Н, d and d, C6H4);
7.57 and 7.86 (2H, br. s and br. s, CONH2); 10.32 (1H, s, NH)
1645, 1675, 1690 (C=O), 1.02 and 3.88 (5H, t and q, ОC2H5); 2.33 (3H, s, CH3-6);
2190 (C≡N), 3165, 3198, 3.58 and 3.70 (2Н, d and d, J = 14.4, SCH2); 3.76 (3H, s,
3350 (NH, NH2)
OCH3); 4.97 (1H, s, H-4); 6.8–7.3 (4Н, m, C6H4);
7.60 and 7.88 (2H, br. s and br. s, CONH2); 10.33 (1H, s, NH)
1643, 1688, 1707 (C=O), 1.08 and 3.97 (5H, t and q, ОC2H5); 2.32 (2H, s, CH3-6);
2198 (C≡N), 3160, 3338
(NH, NH2)
3.62 and 3.74 (2H, d and d, J = 14.4, SCH2); 4.54 (1H, s, H-4);
7.72 and 7.38 (4H, d and d, C6H4); 7.58 and 7.87 (2H, s and s,
CONH2); 10.42 (1H, s, NH)
365

TABLE 2 (continued)
1
2
3
1f
1650, 1672, 1700 (C=O), 1.08 and 3.96 (5H, t and q, ОC2H5); 2.32 (2H, s, CH3-6);
2190 (C≡N), 3180, 3350
(NH, NH2)
3.62 and 3.74 (2H, d and d, J = 14.4, SCH2); 4.56 (1H, s, H-4);
7.05-7.45 (4H, m, C6H4); 7.60 and 7.90 (2H, s and s, CONH2);
10.45 (1H, s, NH)
1g
1h
1i
1643, 1692, 1705 (C=O), 1.00 and 3.86 (5H, t and q, ОC2H5); 2.34 (2H, s, CH3-6);
2196 sh, 2200 (C≡N),
3150, 3330 (NH, NH2)
3.60 and 3.72 (2H, d and d, J = 14.8, SCH2); 5.12 (1H, s, H-4);
7.2-7.5 (4H, m, C6H4); 7.62 and 7.90 (2H, s and s, CONH2);
10.44 (1H, s, NH)
1647, 1680, 1707 (C=O), 1.08 and 3.97 (5H, t and q, ОC2H5); 2.36 (2H, s, CH3-6);
2190 (C≡N) 3160, 3340
(NH, NH2)
3.56 and 3.78 (2H, d and d, J = 14.4, SCH2); 4.74 (1H, s, H-4);
7.52 and 8.26 (4H, d and d, C6H4); 7.66 and 7.96 (2H, s and s,
CONH2); 10.58 (1H, s, NH)
1632, 1671, 1686 (C=O); 1.09 and 3.95 (5H, t and q, ОC2H5); 2.31 (3H, s, CH3-6);
2192 (C≡N); 3140, 3208, 3.75 and 3.64 (2Н, d and d, J = 14.4, SCH2); 4.70 (1H, s, H-4);
3318, 3342 (NH, NH2)
7.1-8.1 (4Н, m, C6H4); 7.56 and 7.87 (2H, br. s and br. s,
CONH2); 10.42 (1H, s, NH)
1j
1646, 1683, 1704 (C=O); 1.07 and 3.95 (5H, t and q, ОC2H5); 2.35 (3H, s, CH3-6);
2196, 2228 (C≡N); 3160, 3.64 and 3.74 (2Н, d and d, J = 14.8, SCH2); 4.64 (1H, s, H-4);
3348 (NH, NH2)
7.38 and 7.78 (4Н, m, C6H4); 7.62 and 7.90 (2H, br. s
and br. s, CONH2); 10.49 (1H, s, NH)
TABLE 3. Values of the Oxidation Peak Potentials for Cyclic Potential
Scanning on a Stationary Electrode (En) for Compounds 1a-j in Acetonitrile
in the Supporting Electrolyte 0.1 M (C4H9)4NPF6*
Compound
Еп, V
Compound
Еп, V
1a
1b
1c
1d
1e
1f
1.26
1.23
1.22
1.18
1.28
1.27
1.28.
1.28
1.29
1.28
4a
4b
4c
4d
4e
4f
1.32
1.32
1.33
1.28
1.42
1.42
1.36
1.44
1.42
1.42
1g
1h
1i
4g
4h
4i
1j
4j
_______
* For comparison, we give the values of the electrochemical oxidation
potentials for compounds 4a-j [4].
replacement of substituents in 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid
nitriles 4 shifts the oxidation potential toward the positive region by 110 mV [4], in symmetric 4-aryl-3,5-
di(ethoxyethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridines, by 120 mV [1], and in 4-aryl-3,5-
di(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridines, by 240 mV [12]. The low sensitivity and the poor
correlation of the electrochemical oxidation potentials with the Hammett's σ*-constants for compounds 1
indicate a role for new effects besides a purely electronic effect.
All the studied 2-carbamoylmethylthio-1,4-dihydropyridines 1a-j have one common feature: they are
more readily oxidized than the corresponding 2-methylthio-1,4-dihydropyridines 4a-j [4,6]. For the 4-phenyl
derivative 1a, the difference in the potentials for the corresponding compounds of the two series is 60 mV, and
366

as the electron-donor or electron-acceptor properties of the substituent on the phenyl ring increase, the difference
becomes as much as 160 mV (see Table 3 and [4]). This is not consistent with ideas about the effect of donor or
acceptor properties of a substituent on the electrochemical oxidation potentials of the starting compounds, since
the carbamoyl group in the 2 position of the 1,4-dihydropyridine ring has electron-acceptor properties and
should hinder abstraction of the first electron in the electrochemical process. 2-Methylthio-1,4-dihydropyridines
4 [4] were studied in acetonitrile with camphor as an additive; in this work, there was no need for such an
addition due to the low adsorbability of the substance on the electrode surface. We established that the values of
the oxidation peak potentials in pure acetonitrile and in acetonitrile with camphor additive coincide for
compounds 1a and 1j. Consequently, we should look elsewhere for the reasons for the anomaly found.
We carried out X-ray diffraction analysis for representatives of the series of compounds to be compared.
Single crystals were grown for 2-carbamoylmethylthio-1,4-dihydropyridine 1e and its analog 2-methylthio-1,4-
dihydropyridine 4e. Three-dimensional models of the compounds 1e and 4e are shown in Figs. 1 and 2; the bond
lengths and bond angles in the molecules of both compounds as well as some parameters characterizing the
conformation of these molecules are given in Table 4. X-ray diffraction analysis clearly shows that there is a
hydrogen bond in the molecule of compound 1e, in contrast to 4e. By means of an intramolecular hydrogen bond
N(1)–H(1)···O(10), in the molecule of compound 1e a seven-membered ring is formed that is condensed with the
dihydropyridine ring. The length of the hydrogen bond is 2.789(12) Å (H(1)···O(10) = 2.0(1) Å, the angle N(1)–
H(1)···O(10) = 168(9)°), which corresponds to a hydrogen bond of average strength [13]. The dihydropyridine
rings in the 1e and 4e molecules have a flattened boat conformation and in molecule 1e the degree of flattening
is higher, which probably is promoted by intramolecular hydrogen bond formation.
Fig. 1. Three-dimensional molecular model of compound 1e, designating the atoms
and showing their thermal vibration ellipsoids.
367

Fig. 2. Three-dimensional molecular model of compound 4e, designating the atoms
and showing their thermal vibration ellipsoids.
In the studied crystals of both compounds, there are also intermolecular hydrogen bonds (Table 6). In the
structure of compound 1e, the lengths of the intermolecular hydrogen bonds are close to the statistical average
values for hydrogen bonds of the NH···O and NH···N type [14]. In the structure of 4e, the hydrogen bond is
forked, so the corresponding N···O and N···Cl distances are longer than the statistical average values [19]. Figs. 3
and 4 illustrate the packing of the molecules in crystals of 1e and 4e. In the crystal structure of 1e, there is the
disordered ethanol C2H5OH molecule (single crystals of 1e were grown in an acetone–ethanol mixture, 1:1). For
all the atoms of the ethanol molecule, the g-factors are equal to 0.5.
In the course of the X-ray diffraction studies of compound 1e, we observed an intramolecular hydrogen
bond between the proton on the nitrogen atom in the heterocycle and the oxygen atom of the carbamoyl group,
while this was absent for compound 4e, which probably explains the indicated effect of ease of electrochemical
oxidation for compound 1e. The lower bond multiplicity at the nitrogen atom in the 1 position and at the carbon
atom in the 4 position of the heterocycle indicates a decrease in conjugation between the 1 position, where the
electron density is concentrated, and the 4 position of the 1,4-dihydropyridine ring. N-Substituted
1,4-dihydropyridines are more readily oxidized electrochemically than N-unsubstituted derivatives. Thus the
oxidation potential of 3,5-di(ethoxycarbonyl)-2,6-dimethyl-4-phenyl-1,4-dihydropyridine is 90 mV higher than
for its N–CH3 derivative [15, 16]; the oxidation potential for 3,5-di(methoxycarbonyl)-4-(4-methoxyphenyl)-2,6-
dimethyl-1,4-dihydropyridine is 61 mV higher than for its N–CH2CH3 derivative [17]; and for 4-(4-nitrophenyl)-
1,4-dihydropyridine, it is 57 mV higher than for the N–CH2CH3-substituted derivative [17]. On the other hand,
the substituent on the nitrogen atom creates steric hindrances to free rotation of the substituents in the
368

TABLE 4 Bond Lengths (l) and Bond Angles (ω) of the Molecules of
Compounds 1e and 4e*
l, Å
Bond
1е
4е
N(1)–C(2)
N(1)–C(6)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
C(2)–S(7)
Angle
1.382(9)
1.388(9)
1.355(10)
1.528(10)
1.518(10)
1.345(10)
1.752(7)
1.374(3)
1.383(4)
1.351(4)
1.526(4)
1.525(4)
1.354(4)
1.763(3)
ω, deg.
C(2)–N(1)–C(6)
N(1)–C(2)–C(3)
N(1)–C(2)–S(7)
C(3)–C(2)–S(7)
C(2)–C(3)–C(4)
C(3)–C(4)–C(5)
C(4)–C(5)–C(6)
C(5)–C(6)–N(1)
C(2)–S(7)–C(8)
∆N(1), Å
121.9(7)
120.0(7)
119.7(6)
120.1(6)
122.6(6)
109.7(6)
122.6(7)
120.6(7)
104.5(4)
0.079(7)
0.199(7)
0.200(2)
6.8(4)
123.2(3)
119.2(2)
119.2(2)
121.3(2)
122.0(2)
109.9(2)
121.1(2)
119.8(2)
102.4(2)
0.114(3)
0.274(3)
0.3098(8)
10.1(2)
∆C(4), Å
∆S(7), Å
ϕ1, deg.
ϕ2, deg.
13.2(3)
18.2(2)
_______
* ∆N(1), ∆C(4), ∆S(7) are the deviations of the corresponding atoms from
the C(2), C(3), C(5), C(6) plane; ϕ1 is the dihedral angle between the C(2),
N(1), C(6) and C(2), C(3), C(5), C(6) planes; ϕ2 is the dihedral angle
between the C(3), C(4), C(5) and C(2), C(3), C(5), C(6) planes.
TABLE 5. Crystallographic Data and Refinement Parameters of the Crystal
Structures of 1e and 4e
Characteristic
1
1e
4e
2
3
Empirical formula
[С18H18ClN3O3S]·[C2H5OH]1/2
Colorless
С17H17ClN2O2S
Yellow
Color of crystals
Size of single crystal, mm
0.04 × 0.13 × 0.37
Triclinic
0.12 × 0.23 × 0.35
Monoclinic
Crystal system
Crystal lattice parameters,
Å, degrees
a
8.413(1)
10.403(2)
14.168(3)
68.482(7)
87.997(8)
68.23(1)
1063.9(3)
P⎯1
13.1194(7)
9.8636(7)
13.4731(9)
90
b
c
α
β
γ
104.225(3)
90
Unit cell volume V, Å3
Space group
1690.0(2)
P 21/n
369

TABLE 5 (continued)
1
2
3
Z
2
4
F(000)
434
728
Density, Dx, g/cm3
µ, mm-1
1.295
0.30
50.0
1.371
0.36
55.0
2θ max, °
Number of reflections
measured
5537
3506
6402
4136
independent
used in least-squares method
Number of refined parameters
R-factor
1605 (I > 2σI)
255
2535 (I > 3σI)
276
0.089
0.052
wR2
0.226
0.207
∆ρmax, е/Å3
0.32
0.41
∆ρmin, е/Å3
-0.25
-0.53
positions 2 and 6 and the for substituents in the 3 and 5 positions of the heterocycle. The hydrogen bond
H···O=C(NH2)– weakens the N–H bond, thus facilitating the process of deprotonation and abstraction of an
electron. Consequently, the presence of a hydrogen bond at the nitrogen atom may be a factor promoting
abstraction of an electron in compounds 1 with a thiomethylcarbamoyl group compared with compounds 4,
having a thiomethyl group in the 2 position of the 1,4-dihydropyridine ring.
Fig. 3. Three-dimensional model of molecular packing in the unit cell of 1e crystals.
370

Fig. 4. Crystal structure of 4e in the projection on the (010) crystallographic plane.
TABLE 6. Parameters of Intermolecular Hydrogen Bonds in the Crystal
Structures of 1e and 4e
Length
of H-bond
D···A, Å
Angle,
D–H···A,
deg.
Com-
pound
Distance
D···A, Å
Symmetry
of A atoms
Bond D–H···A
1е
4е
N(11)–H(111)···O(10) 2.896(12)
N(11)–H(112)···N(13) 3.019(13)
1.84(7)
2.05(8)
165(5)
173(6)
2 − x, -y, -z
1 − x, 1 − y, -z
3/2 − x, 1/2 + y, 3/2 − z
1/2 + x, 1/2 + y, 3/2 + z
N(1)–H(1)···O(19)
N(1)–H(1)···Cl(17)
3.060(4)
3.715(3)
2.40(4)
3.30(3)
142(3)
116(2)
EXPERIMENTAL
1
The IR spectra were taken on a Perkin-Elmer 580B spectrometer in vaseline oil. The H NMR spectra
were recorded on a WH 90/DC (90 MHz) spectrometer in DMSO-d6, internal standard HMDS (δ, 0.05 ppm).
The course of the reaction and the purity of the substances were monitored using TLC on Silufol UV-254 plates;
eluent, chloroform–hexane–acetone 2:1:1. The compounds were recrystallized from ethanol. The synthesis of
compounds 1a (method A and D) and 1i (method D) is described in [7]; the synthesis of 1c (method B) is
described in [4], and the synthesis of 1j (method D) is described in [8]. The starting 2-arylideneacetoacetic acid
ethyl esters were synthesized according to the organic chemistry laboratory manual [18], while the 3-aryl-2-
cyanothioacrylamides were synthesized as in [10]. Product yields: 2-benzylideneacetoacetic acid ethyl ester,
371

80%; 2-(4-chlorobenzylidene)acetoacetic acid ethyl ester, 75%; 2-(2-chlorobenzylidene)acetoacetic acid ester,
72%; 2-(4-nitrobenzylidene)acetoacetic acid ester, 66%; 2-(3-nitrobenzylidene)acetoacetic acid ethyl ester, 80%;
2-cyano-3-(4-hydroxyphenyl)thioacrylamide,
57%;
2-cyano-3-(4-methoxyphenyl)thioacrylamide,
81%;
2-cyano-3-(2-methoxyphenyl)thioacrylamide, 72%; and 3-(2-chlorophenyl)-2-cyanothioacrylamide, 76%.
The cyclic voltammetric curves were recorded with a PAR-170 electrochemical system, using a three-
electrode cell on a stationary glassy carbon electrode. The reference electrode was an aqueous saturated calomel
electrode fitted with a bridge junction for working in nonaqueous solvents. Electrochemical studies using the
rotating ring-disk electrode method with a ring were conducted on an apparatus consisting of a Ring–Disk-
Electrode System Model 636 (PAR) electrode rotation system and a Bruker E-350 dual potentiostat. The disk
and ring electrodes were made from glassy carbon. The calculated electrode efficiency coefficient was 0.39 [19],
the electrode rotation speed was 2000 min-1. All the potentials were measured relative to a 0.1 N silver reference
electrode (Ag/AgNO3). All the studies were conducted in anhydrous acetonitrile purified by the procedure in
[20]. The depolarizer concentration was 5·10-4 mol·l-1. The supporting electrolyte was
1·10-1 mol·l-1 tetrabutylammonium hexafluorophosphate.
For the X-ray diffraction analysis, single crystals of compound 1e were grown in a mixture of solvents,
acetone–ethanol (1:1), and single crystals of compound 4e were grown in chloroform. The crystal structure of
compounds 1e and 4e were determined using a Nonius KappaCCD automatic diffractometer (the data collection
were taken at room temperature, molybdenum radiation with λ = 0.71073 Å, graphite monochromator, ϕ and ω
scanning). The structures were solved by the procedure in [21] and refined by the full-matrix least-squares
method using the program in [22] (for 1e) and [23] (for 4e). The main crystallographic characteristics for 1e and
4e are given in Table 5.
General Methods for Synthesis of 4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-methyl-1,4-
dihydropyridine-3-carboxylic Acid Nitriles (1). A. A mixture of 2-arylideneacetoacetic acid ethyl ester
(5 mmol), 2-cyanothioacetamide (5 mmol) in ethanol (15-20 ml), and piperidine (6 mmol) was heated briefly
until dissolved, and then after 10 min iodoacetamide (5.5 mmol) was added. The mixture was boiled for 1-2 min
on a water bath and then 3 M HCl in ethanol (2 ml) was added. The precipitate formed was filtered out and then
washed with ethanol (5-10 ml) (cooled down to 0°C) and water (10 ml). Compounds 1a,e,g,h were obtained.
B. A mixture of acetoacetic acid ethyl ester (5 mmol), 3-aryl-2-cyanothioacrylamide (5 mmol) in ethanol
(15-20 ml), and piperidine (6 mmol) was heated briefly until dissolved, and then after 10 min iodoacetamide (5.5
mmol) was added. The mixture was boiled for 5 min on a water bath and 3 M HCl in ethanol (2 ml) was added.
The precipitate formed was filtered out and then washed with ethanol (cooled down to 0°C) (5-10 ml) and water
(10 ml). Compounds 1b-d,g were obtained.
C. A mixture of an aromatic aldehyde (5 mmol), 2-cyanothioacetamide (5 mmol) in ethanol (15-20 ml),
and piperidine (1 mmol) was heated briefly until dissolved. Then, while the reaction mixture was stirred at room
temperature, acetoacetic acid ethyl ester (5 mmol) and piperidine (5 mmol), and (after 10 min) iodoacetamide
(5.5 mmol) were added. The mixture was boiled for 5 minutes on a water bath, and then 3 M HCl in ethanol
(2 ml) was added. The precipitate formed was filtered out and then washed with ethanol (cooled down to 0°C)
(5-10 ml) and water (10 ml). Compounds 1d,f,g were obtained.
D. A mixture of 2-thioxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid nitrile 2 (10 mmol), piperidine
(11 mmol), and iodoacetamide (11 mmol) in ethanol (20-40 ml) was boiled for 2-5 min on a water bath and
stirred for 5-10 min at room temperature. The precipitate formed was filtered out and then washed with ethanol
(cooled down to 0°C) (5-10 ml) and water (10 ml). Compounds 1a,g,i,j were obtained.
The characteristics of the synthesized compounds are given in Tables 1 and 2.
372

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