4-Alkyl-6-amino-N 3,N 5-diaryl-2-thioxo-1,2,3,4- tetrahydropyridine-3,5-dicarboxamides: II. Synthesis and selected reactions

Article abstract of DOI:10.1134/S1070363213090156

New 4-alkyl-6-amino-N ³,N ⁵-diaryl-2-thioxo-1,2,3,4- tetrahydropyridine-3,5-dicarboxamides have been prepared via enantioselective reaction of 3-amino-N-aryl-3-thioxopropanamides with N-aryl-2-cyanoacetamide and aliphatic aldehydes.

Full text of DOI:10.1134/S1070363213090156

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 9, pp. 1716–1723. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © V.D. Dyachenko, E.N. Karpov, I.A. Feskov, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 9, pp. 1496–1503.
4-Alkyl-6-amino-N3,N5-diaryl-2-thioxo-1,2,3,4-
tetrahydropyridine-3,5-dicarboxamides:
II.1 Synthesis and Selected Reactions
V. D. Dyachenko, E. N. Karpov, and I. A. Feskov
Taras Shevchenko Luhansk National University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
e-mail: chem@luguniv.edu.ua
Received August 20, 2012
Abstract—New 4-alkyl-6-amino-N3,N5-diaryl-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides have been
prepared via enantioselective reaction of 3-amino-N-aryl-3-thioxopropanamides with N-aryl-2-cyanoacetamide
and aliphatic aldehydes. The prepared products can be regioselectively alkylated at sulfur atom.
DOI: 10.1134/S1070363213090156
The 5-carbamoyl-substituted nicotinic acid nitriles
form a well-studied class of organic compounds [2–5].
Their preparation methods have been developed, and
some of the chemical and biological properties have
been explored [6–13]. The most striking of the
properties are hepatoprotective activity [14], potential
antiviral activity towards a group of arboviruses, and
good antioxidant activity [4]. However, the attempts to
replace the cyano group in the position 3 with a less
toxic amide fragment are scarce [4, 15, 16], and 3,5-
diarylcarbamoylpyridine-2(1H)-thiones have been
considered in a few works only [4, 17, 18]. Carbamoyl
substituent, in contrast to the nitrile one, reduces the
compound toxicity; however, preparation of such
derivatives from nitriles is problematic because under
severe conditions the regioselectivity of the synthesis
is poor, and the yield decreases due to the formation of
side products [19, 20]. Replacement of the 4-aryl
substituent of the pyridine ring with an alkyl should
also reduce the toxicity, and increase the lipophilicity
of the final product [9, 21]. However, of the
corresponding examples, only 3-carbamoyl-6-methyl-
2-thioxo-5-phenylcarbamoyl-1,2,3,4-tetrahydropyridine-
4-spiro-cyclohexane [18] has been known; recently,
we have prepared 4-alkyl-3,5-diarylcarbamoylpyridine-
2-thiones [1].
amide fragment of the initial CH-acid being retained in
the pyridine nucleus.
The known methods for the preparation of 6-amino-
3,5-dicarbamoyl-2-thioxodihydropyridines boil down
to sequential reaction of three components: an al-
dehyde reacts with a cyanoacetanilide via the
Knoevenagel reaction, and the alkene formed reacts
with a thioxopropanamide [4]. However, in the case
addressed in this work, the described approach was not
applicable due to a number of reasons, such as the
instability of the in situ formed alkene and its sub-
sequent dimerization [22–24], the exchange of me-
thylene components [25], the release of the Michael
adduct [26], and the aldol condensation in the basic
medium, leading to tarring of the reaction mixture
[27].
In this paper we propose a method of new 4-alkyl-
6-amino-N3,N5-diaryl-2-thioxo-1,2,3,4-tetrahydropyridine-
3,5-dicarboxamides (Ia–Ig) preparation consisting in
the interaction of an aliphatic aldehyde IIa–IIg with a
thiocarbamoylacetanilide IIIa–IIIc. The reaction pro-
ceeded, apparently, via the formation of the
Knoevenagel condensation product A, which reacted
with the second mole of a reagent IIIa–IIIc to form
the Michael adduct B, giving finally the product Ia–Ig
via intramolecular cyclocondensation.
The aim of this study was to investigate the ways of
the partially hydrogenated pyridines synthesis, the
The target products I were formed independently of
the reagents ratio in the original mixture. For example,
we studied the reaction at IId: IIIa ratio ranged from
1
For communication I, see [1].
1716

4-ALKYL-6-AMINO-N3,N5-DIARYL-2-THIOXO-1,2,3,4-TETRAHYDROPYRIDINE-… : II.
1717
Ar
O
Alk O
Ar
NH
O
S
O
NH
Ar
Ar
Ar
O
Alk
IIIа_IIIc
EtONa/EtOH
_H2O
N
N
H
Alk
+
H
NH2
S
NH2
H2N
H2N
S
S
IIа_IIg
IIIа_IIIc
А
B
Alk
H
Alk
Alk
O
O
O
O
S
O
O
Ar
Ar
Ar
Ar
Ar
KOH
_H2O
N
N
N
N
N
H
N
H
H
H
H
H
H
S
_H2S
K+
H2N
N
SH
H2N
N
H2N
N
H
Iа_Ig
IV
C
Z
Hlg
Z
Hlg
Vа_Ve
Vа_Ve
Alk
O
O
Alk
O
O
Ar
Ar
Z
Ar
Ar
N
N
N
N
H
H
H
H
H2N
N
S
H2N
N
S
Z
VIа_VIg
VII
I, Alk = i-Bu, Ar = Ph (a); i-Pr, Ph (b); Et, Ph (c); (CH2)5Me, Ph (d); (CH2)6Me, 2-MeC6H4 (e); CH2CH(Ph)CH3, Ph (f); Et,
3-MeC6H4 (g); II, Alk = Et (a); i-Pr (b); i-Bu (c); (CH2)5Me (d); (CH2)6Me (e); CH(Ph)CH3 (f); CH2CH(Ph)CH3 (g); III,
Ar = Ph (a); 2-MeC6H4 (b); 3-MeC6H4 (c); V, Z = CH=CH2, Hlg = Br (а); Н, I (b); (CH2)7Me, I (c); Ph, Cl (d);
4-MeOC6H4NHCO, Cl (e); VI, Alk = i-Bu, Ar = Ph, Z = CH=CH2 (a); (CH2)5Me, Ph, CH=CH2 (b); i-Pr, Ph, CH=CH2 (c);
(CH2)5Me, Ph, (CH2)7Me (d); (CH2)5Me, Ph, Ph (e); i-Pr, Ph, Н (f); (CH2)6Me, 2-MeC6H4, 4-MeOC6H4NHCO (g).
1:2 to 4:1. In all the cases, the major product was 4-
alkyltetrahydropyridine-3,5-dicarboxanilide (Id), but
not the expected alkene (A).
Taking into account the above-mentioned facts, the
possible structure of the compounds I could be re-
presented as pair of prototropic thione-thiol tautomers
1
I and IV. The H NMR patterns of those forms should
The Michael adduct (B) formation followed by
cyclization proceeded enantioselectively. The only
isomers isolated were σ-diastereomers with trans-
location of arylcarbamoyl and alkyl substituents at C3
and C4 of the pyridine ring, respectively. That conclu-
be nearly identical. In the crystalline state, the thione
form should exist exclusively, as evidenced by the
valence vibration bands of C=S at 1166–1193 cm–1 in
the IR spectrum [29]. Likely, the same form was
1
1
present in DMSO-d6 solution (at the conditions of H
sion was based on H NMR data taking into account
NMR spectra recording). However, in the GS–MS
spectra several molecular ion peaks with the same
molecular mass were observed, thus indicating possible
tautomerization in CH2Cl2 solution (at the conditions
of GS–MS experiment).
results of the previous studies [1, 4]. In particular, in
the 1H NMR spectrum of compounds Ia–Ig the protons
at C3 and C4 coupling constants were less than 1 Hz,
and the signals were practically not split into multi-
plets. This could be due to several factors, including
the C3–C4 bond elongation due to steric hindrance,
increasing the C3C4H and C4C3H bond angles, and the
implementation of the cycle conformation with the
dihedral angle HC3C4H close to 90° as derived from
the Karplus equation [28].
The regioselective alkylation of the prepared dihyd-
ropyridines with alkyl halides V occurred at sulfur
atom to give thioesters VI, being in agreement with the
previously reported results on the alkylation of 4-aryl
analogues of VI [3]. The set of the spectral data did not
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 9 2013

1718
DYACHENKO et al.
allow discrimination the real structure of the com-
pounds between the two possible tautomers, VI and
VII. In [1], the tautomer VI was shown and its
structure was proved by X-ray diffraction with Alk =
i-Bu, Ar = 3-MeC6H4, Z = CH=CH2. The reaction was
carried out in ethanol in the presence of 10% aqueous
KOH solution. Apparently, under those conditions the
thiol tautomer IV readily formed salt B, further
reacting with alkyl halide in basic medium.
was formed in situ, and then the second equivalent of
another CH-acid (IIIb or IIIc) was added to it.
However, according to the GS–MS results, a complex
mixture of the products was formed, including Ia,
VIII, IX, and the product of methylenes exchange X
likely formed via the reversible reactions through the
intermediates E–H. In the intermediate E, two ways
the nucleophilic attack were possible (paths a and b),
resulting in the formation of isomeric products VIII
and IX. The alkylation of the so obtained mixture of
Ia, VIII, IX, and X with allyl bromide occurred at S
atom and led to the mixture of VIa, XI, XII, and XIII.
The latter mixture was reflected in the GC-MS spectra
by three molecular ions peaks with the masses differing
In the further part of the study, we focused at prepara-
tion of tetrahydropyridines I analogs containing various
arylcarbamoyl substituents at positions 3 and 5. First,
the Knoevenagel condensation product, alkene (D),
IIIb
O
O
S
O
or
O
IIIc
EtONa
N
NH
Ph
NH
Ph
H3C
а
IIc IIIa
+
N
H3C
H
_IIIa
EtOH
H
H2N
H2N
S
H2N
S
H2N
S
D
b
E
F
_H2S
IIIb or IIIc
IIIa
CH3
H3C
O
O
O
O
_H2S
Ph
Ph
N
N
H
N
H
H2N
N
H
H
S
S
H2N
H2N
H2N
S
a
b
S
H
G
_H2S
_H2S
CH3
H3C
CH3
CH3
O
O
O
O
S
O
S
O
Ph
N
H
N
Ia
+
N
NH
N
N
+
+
H
H
H
H
Ph
H2N
N
H
S
H2N
N
H
N
NH2
H
IXа, IXb
Xа, Xb
VIIIа, VIIIb
KOH
Br
CH3
H3C
CH3
CH3
O
O
S
O
S
O
O
O
Ph
VIa +
Ph
N
+
+
N
N
N
N
N
H
H
H
H
H
H
IX
H2N
N
N
NH2
XIIа, XIIb
2-МеС6Н4 (а), 3-МеС6Н4 (b).
H2N
N
S
XIIIа, XIIIb
XIа, XIb
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4-ALKYL-6-AMINO-N3,N5-DIARYL-2-THIOXO-1,2,3,4-TETRAHYDROPYRIDINE-… : II.
1719
by one CH2 group as a result of presence or absence of
the tolyl fragment; thus, the initial mixture composi-
tion was confirmed. In the H NMR spectrum of the
An alternative solution to the stated problem could
be a three-component interaction of aldehyde II,
tiocarbamoylacetanilide III, and cyanoacetanilide
XIV. That approach was successfully applied in the
case of aromatic aldehydes [4, 30]. In our case, it was
not applicable due to the methylene components
exchange and in situ formation of alkylmethylene-
cyanoacetanilide, further dimerizing as described in
[22]. However, in the case of 2-phenylpropanal IIe, the
alkene J was stabilized by the phenyl substituent and
gave the target XV through the adduct (K). The
alkylation of XV resulted in thioester XVI.
1
VIa + XI + XII + XIII mixture, the following signals
were identified: δ of 0.75–1.74 ppm (aliphatic substi-
tuent protons), 2.16–2.27 ppm (methyl substituent in
aromatic ring), 3.36–3.40 (characteristic multiplets of
allyl fragment), 3.71–3.74 ppm (methylene protons),
4.85, 5.07–5.09, and 5.8–5.82 ppm (vinyl group protons),
6.81–7.61 ppm (aromatic protons and protons of the
amino group), and 8.76–9.61 ppm (several broad
singlet of amide protons). We failed to isolate the
mixture components by fractional crystallization.
O
N
Ph
Ph
H
O
O
CN
O
EtONa
XIV
Ph
Ph
IIе IIIa
+
N
N
EtOH
N
H
H
H
S
NC
H2N
O
S
H2N
J
K
Ph
Ph
O
O
S
O
Br
Ph
Ph
N
N
N
N
H
H
H
H
H2N
N
H2N
N
S
H
XV
XVI
EXPERIMENTAL
Synthesis of compounds I (general procedure).
5 mmol (0.115 g) of sodium was dissolved in 20 ml of
anhydrous ethanol, then 5 mmol of the corresponding
3-amino-N-aryl-3-thioxopropanamide IIIa–IIIc and
5 mmol of aldehyde IIa–IIg were added upon stirring.
After 10 min, another 5 mmol of IIIa–IIIc was added,
and the mixture was left for 48 h at room temperature.
The precipitate was filtered off, washed with water,
cold ethanol, and hexane.
1H NMR spectra were recorded with Bruker
AVANCE DRX-500 (500 MHz) (compounds Id, Ie,
Ig; VId, VIf, and VIg; mixture Ia + VIIIb + IXb +
Xb) and Bruker AVANCE II-400 (400 MHz)
(compounds Iа–Ic, If; VIa–VIc, VIe; XV, and XVI;
mixtures Ia + VIIIa + IXa + Xa, VIa + XIа + XIIа +
XIIIа, and VIа + XIb + XIIb + XIIIb) instruments, in
DMSO-d6 (with TMS as internal standard). Mass
spectra were recorded with Chrommas GC/MS-
Hewlett-Packard 5890/5972 instrument with HP-5MS
column (CI, 70 eV). IR spectra were recorded with
FIR Spectrum One (Perkin-Elmer) instrument in KBr
pellets. Melting points were measured with Kofler
bench. Reaction monitoring and the compounds purity
check were performed by TLC (Silufol UV-254 plates,
in acetone–hexane 3:5 mixture, developers were iodine
vapor and UV irradiation).
Compound Ia. Yield 1.46 g (69%). Yellow powder,
mp 178–180°C (EtOH). IR spectrum, ν, cm–1: 3143–
3527 (NH, NH2), 1688, 1658 (СОNH), 1623 [δ(NH2)],
1
1180 (С=S). H NMR spectrum, δ, ppm: 0.89 d (3Н,
СН3, J 6.4 Hz), 0.97 d (3Н, СН3, J 6.4 Hz), 1.02–1.29
m (2Н, СН2), 1.46–1.66 m (1Н, СНМе2), 3.78 d (1Н,
С4Н, J 4.4 Hz), 3.81 s (1Н, С3Н), 6.91 t (1Н, Нarom
,
J 6.9 Hz), 7.06 t (1Н, Нarom, J 6.9 Hz), 7.22 t (2Н,
arom, J 6.8 Hz), 7.30 t (2Н, Нarom, J 6.8 Hz), 7.49–7.57
Н
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 9 2013

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DYACHENKO et al.
6.77–7.51 m (9Н, 7Нarom and NH2), 8.19 d (1Н, Нarom
m (4Н, Нarom), 7.60 br.s (2Н, NH2), 10.27 br.s (2Н,
2NHСО), 13.22 br.s (1Н, N1H). Маss spectrum, m/z
(Irel, %): 423.2 (100) [М + 1]+. Found, %: С 65.22; Н
6.14; N 13.19. С23H26N4O2S. Calculated, %: С 65.38;
Н 6.20; N 13.26. М 422.54.
,
J 7.5 Hz), 9.76 br.s (1Н, NHСО), 10.28 br.s (1Н,
NHСО), 12.47 br.s (1Н, N1H). Маss spectrum, m/z
(Irel, %): 493.2 (100) [М + 1]+. Found, %: С 68.20; Н
7.29; N 11.20. С28H36N4O2S. Calculated, %: С 68.26;
Н 7.37; N 11.37. М 492.676.
Compound Ib. Yield 0.85 g (42%). Yellow powder,
mp 184–186°C (EtOH). IR spectrum, ν, cm–1: 3155–
3540 (NH, NH2), 1685, 1662 (СОNH), 1619 [δ(NH2)],
Compound If. Yield 0.18 g (7%). Yellow powder,
mp 225–227°C (EtOH). IR spectrum, ν, cm–1: 3120–
3480 (NH, NH2), 1668, 1656 (СОNH), 1616 [δ(NH2)],
1
1166 (С=S). H NMR spectrum, δ, ppm: 0.72–1.02 m
1
(6Н, 2СН3), 1.52–1.73 m (1H, СНМе2), 3.53 d (1H,
1192 (С=S). H NMR spectrum, δ, ppm: 1.31 d (3Н,
С4Н, J 6.0 Hz), 4.08 s (1H, С3Н), 6.90 t (1Н, Нarom
,
СН3, J 6.4 Hz), 1.39–1.49 m (1Н, СН2), 1.50–1.61 m
(1Н, СН2), 2.84–2.96 m (1Н, СНМе2), 3.84 t (1Н,
J 6.8 Hz), 7.05 t (1Н, Нarom, J 6.8 Hz), 7.15–7.35 m
(4Н, Нarom), 7.52–7.65 m (4Н, Нarom), 8.42 br.s (1Н,
NH2), 9.86 br.s (1Н, NH2), 10.26 br.s (1Н, NHСО),
10.40 br.s (1Н, NHСО), 13.34 br.s (1Н, N1H). Маss
spectrum, t/z (Irel, %): 409.2 (100) [М + 1]+. Found, %:
С 64.55; Н 5.76; N 13.64. C22H24N4O2S. Calculated,
%: С 64.68; Н 5.92; N 13.71. М 408.517.
С4Н, J 6.8 Hz), 3.89 s (1Н, С3Н), 6.93 t (1Н, Нarom
,
J 6.9 Hz), 7.07 t (1Н, Нarom, J 6.8 Hz), 7.11–7.40 m
(9Н, Нarom), 7.44–7.63 m (4Н, Нarom), 8.22 br.s (1Н,
NH2), 9.51 br.s (1Н, NH2), 10.18 br.s (1Н, NHСО),
10.39 br.s (1Н, NHСО), 13.22 s (1Н, N1H). Маss
spectrum, m/z (Irel, %): 485.2 (100) [М + 1]+. Found,
%: С 69.23; Н 5.76; N 11.38. С28H28N4O2S.
Calculated, %: С 69.40; Н 5.82; N 11.56. М 484.613.
Compound Ic. Yield 0.30 g (15%). White powder,
mp 202–204°C (i-PrOH). IR spectrum, ν, cm–1: 3120–
3490 (NH, NH2), 1690, 1670 (СОNH), 1621 [δ(NH2)],
Compound Ig. Yield 0.40 g (19%). White powder,
mp 218–220°C (EtOH). IR spectrum, ν, cm–1: 3146–
3512 (NH, NH2), 1684, 1667 (СОNH), 1628 [δ(NH2)],
1
1193 (С=S). H NMR spectrum, δ, ppm: 0.82 t (3Н,
СН3, J 6.9 Hz), 1.22–1.43 m (2H, СН2), 3.53–3.65 m
(1H, С4Н), 4.01–4.07 m (1H, С3Н), 6.82–6.93 m (2Н,
1188 (С=S). H NMR spectrum, δ, ppm: 0.88 t (3Н,
1
Н
Н
arom), 6.97–7.12 m (1Н, Нarom), 7.14–7.32 m (3Н,
arom), 7.46 br.s (1Н, NH2), 7.52–7.67 m (4Н, Нarom),
СН3, J 7.4 Hz), 1.29–1.35 m (1H, СН2), 1.39–1.47 m
(1H, СН2), 2.24 s (3Н, СН3), 2.26 s (3Н, СН3), 3.70 t
(1H, С4Н, J 6.2 Hz), 3.78 s (1H, С3Н), 6.74 d (1Н,
7.90 br.s (1Н, NH2), 10.11 br.s (1Н, NHСО), 10.62
br.s (1Н, NHСО), 13.56 br.s (1Н, N1H). Маss
spectrum, t/z (Irel, %): 395.2 (100) [М + 1]+. Found, %:
С 63.85; Н 5.47; N 14.12. C21H22N4O2S.
Нarom, J 7.6 Hz), 6.88 d (1Н, Нarom, J 7.8 Hz), 7.10 t
(1Н, Нarom, J 7.6 Hz), 7.18 t (1Н, Нarom, J 7.8 Hz), 7.32
d (1Н, Нarom, J 8.5 Hz), 7.36 d (1Н, Нarom, J 8.5 Hz),
7.40 s (1Н, СНarom), 7.42 s (1Н, СНarom), 8.23 br.s (1Н,
NH2), 9.48 br.s (1Н, NH2), 10.16 br.s (1Н, NHСО),
10.36 br.s (1Н, NHСО), 13.10 br.s (1Н, N1H). Маss
spectrum, t/z (Irel, %): 423.2 (100) [М + 1]+. Found, %:
С 65.25; Н 6.12; N 13.12. C23H26N4O2S. Calculated,
%: С 65.38; Н 6.20; N 13.26. М 422.543.
Compound Id. Yield 1.28 g (29%). Yellow powder,
mp 191–193°C (EtOH). IR spectrum, ν, cm–1: 3137–
3510 (NH, NH2), 1672, 1658 (СОNH), 1620 [δ(NH2)],
1
1174 (С=S). H NMR spectrum, δ, ppm: 0.86 t (3Н,
СН3, J 6.14 Hz), 1.07–1.46 m (10Н, 5СН2), 3.72 br.s
(1Н, С4Н), 3.91 s (1Н, С3Н), 6.92 t (1Н, Нarom, J 6.8 Hz),
7.05 t (1Н, Нarom, J 6.8 Hz), 7.22 t (2Н, Нarom, J 7.6 Hz),
7.29 t (2Н, СНarom, J 7.6 Hz), 7.51–7.70 m (4Н,
СНarom), 8.58 br.s (1Н, NH2), 9.57 br.s (1Н, NH2),
10.37 br.s (2Н, 2NHСО), 13.28 br.s (1Н, N1H). Маss
spectrum, m/z (Irel, %): 451.2 (100) [М + 1]+. Found,
%: С 66.47; Н 6.67; N 12.37. С25H30N4O2S.
Calculated, %: С 66.64; Н 6.71; N 12.43. М 450.596.
Synthesis of compounds VIa–VIg and XVI
(general procedure). 0.5 mmol (0.26 ml) of 10%
aqueous KOH solution was added upon stirring to a
suspension of 0.5 mmol of the compound Ia–Ig or XV
in 15 ml of ethanol; after 10 min, 0.5 mmol of the
appropriate alkyl halide was added. The mixture was
left for 24 h, the precipitate was filtered off, washed
with water, cold methanol, and ethanol. The product
was dried under vacuum.
Compound Ie. Yield 0.60 g (24%). Yellow powder,
mp 169–171°C (EtOH). IR spectrum, ν, cm–1: 3135–
3527 (NH, NH2), 1680, 1655 (СОNH), 1612 [δ(NH2)],
Compound VIa. Yield 0.11 g (49%). White
powder, mp 152–154°C (EtOH). IR spectrum, ν, cm–1:
3180–3430 (NH, NH2), 1670, 1652 (СОNH), 1614
1
1182 (С=S). H NMR spectrum, δ, ppm: 0.87 t (3Н,
СН3, J 6.15 Hz), 1.11–1.45 m (12Н, 6СН2), 2.12 s
(3Н, СН3), 2.33 s (3Н, СН3), 3.88 br.s (2Н, С3Н, С4Н),
[δ(NH2)]. H NMR spectrum, δ, ppm: 0.88 d (6Н,
1
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4-ALKYL-6-AMINO-N3,N5-DIARYL-2-THIOXO-1,2,3,4-TETRAHYDROPYRIDINE-… : II.
1721
2СН3, J 4.0 Hz), 1.00–1.14 m (1Н, СН2), 1.26–1.38 m
(1Н, СН2), 1.69 s (1Н, СНМе2), 3.31 s (1Н, С3Н),
3.35–3.43 m (2Н, С4Н and SСН2), 3.73 d.d (1Н, SСН2,
2J 13.2, 3J 6.4 Hz), 4.84 d (1Н, =СН2, Jcis 9.8 Hz), 5.06
d (1Н, =СН2, Jtrans 17.0 Hz), 5.73–5.88 m (1Н, СН=),
7.00 t (1Н, Нarom, J 7.2 Hz), 7.06 t (1Н, Нarom, J 7.2 Hz),
7.27 t (2Н, Нarom, J 7.6 Hz), 7.32 t (2Н, Нarom, J 7.6 Hz),
7.40 br.s (1Н, NH2), 7.49 br.s (1Н, NH2), 7.54–7.68 m
(4Н, 4Нarom), 9.32 br.s (1Н, NHСО), 9.78 br.s (1Н,
NHСО). Маss spectrum, m/z (Irel, %): 463.2 (100)
[М + 1]+. Found, %: С 67.43; Н 6.39; N 12.06.
С26H30N4O2S. Calculated, %: С 67.50; Н 6.54; N 12.11.
М 462.607.
1.03–1.55 m (24Н, 12СН2), 2.64–2.74 (1Н, SСН2),
3.00–3.09 m (1Н, SСН2), 3.27 t (1Н, С4Н, J 6.5 Hz),
3.32 s (1Н, С3Н), 7.00 t (1Н, Нarom, J 7.2 Hz), 7.05 t
(1Н, Нarom, J 7.2 Hz), 7.19–7.46 m (6Н, 4Нarom and
NH2), 7.60 t (4Н, Нarom, J 8.2 Hz), 9.39 br.s (1Н,
NHСО), 9.71 br.s (1Н, NHСО). Маss spectrum, m/z
(Irel, %): 577.4 (100) [М + 1]+. Found, %: С 70.90; Н
8.49; N 9.82. С34H48N4O2S. Calculated, %: С 70.79; Н
8.39; N 9.71. М 576.836.
Compound VIe. Yield 0.17 g (64%). White powder,
mp 181–183°C (EtOH). IR spectrum, ν, cm–1: 3157–
3458 (NH, NH2), 1666, 1656 (СОNH), 1621 [δ(NH2)].
1H NMR spectrum, δ, ppm: 0.83 t (3Н, СН3, J 6.18 Hz),
1.00–1.51 m (10Н, 5СН2), 3.38–3.50 m (2Н, С3Н,
Compound VIb. Yield 0.047 g (19%). White
powder, mp 151–153°C (EtOH). IR spectrum, ν, cm–1:
3164–3412 (NH, NH2), 1668, 1650 (СОNH), 1612
2
С4Н), 4.10 d (1Н, SСН2, J 13.0 Hz), 4.32 d (1Н,
2
SСН2, J 13.0 Hz), 6.97 t (1Н, Нarom, J 7.0 Hz), 7.06 t
1
(1Н, Нarom, J 7.2 Hz), 7.11–7.71 m (15Н, 13Нarom and
NH2), 9.06 br.s (1Н, NHСО), 9.81 br.s (1Н, NHСО).
Маss spectrum, m/z (Irel, %): 541.2 (100) [М + 1]+.
Found, %: С 71.23; Н 6.64; N 10.18. С32H36N4O2S.
Calculated, %: С 71.08; Н 6.71; N 10.36. М 540.72.
[δ(NH2)]. H NMR spectrum, δ, ppm: 0.75–0.90 m
(3Н, СН3), 1.05–1.47 m (10Н, 5СН2), 3.28–3.32 m
(1Н, С4Н), 3.34 s (1Н, С3Н), 3.44 d.d (1Н, SСН2,
2J 13.1, 3J 7.6 Hz), 3.74 d.d (1Н, SСН2, 2J 13.1, 3J 6.5 Hz),
4.89 d (1Н, =СН2, Jcis 9.9 Hz), 5.10 d (1Н, =СН2, Jtrans
17.1 Hz), 5.78–5.93 m (1Н, СН=), 7.00 t (1Н, Нarom
J 7.1 Hz), 7.06 t (1Н, Нarom, J 7.1 Hz), 7.27 t (2Н,
arom, J 7.6 Hz), 7.32 t (2Н, Нarom, J 7.6 Hz), 7.41 br.s
(2Н, NH2), 7.52–7.63 m (4Н, 4Нarom), 9.18 br.s (1Н,
NHСО), 9.63 br.s (1Н, NHСО). Маss spectrum, m/z
(Irel, %): 491.2 (100) [М + 1]+. Found, %: С 68.40; Н
6.82; N 11.25. С28H34N4O2S. Calculated, %: С 68.54;
Н 6.98; N 11.42. М 490.66.
,
Compound VIf. Yield 0.07 g (32%). White
powder, mp 214–216°C (EtOH). IR spectrum, ν, cm–1:
3189–3432 (NH, NH2), 1672, 1662 (СОNH), 1627 [δ
(NH2)]. 1H NMR spectrum, δ, ppm: 0.91 d (6Н, 2СН3,
J 6.0 Hz), 1.54–1.69 m (1Н, СНМе2), 2.24 s (3Н,
SСН3), 3.11 d (1Н, С4Н, J 6.8 Hz), 3.47 s (1Н, С3Н),
6.99 t (1Н, Нarom, J 7.6 Hz), 7.06 t (1Н, Нarom, J 7.4 Hz),
7.26 t (2Н, Нarom, J 7.8 Hz), 7.31 t (2Н, Нarom, J 7.8 Hz),
7.37 br.s (2Н, NH2), 7.59 d (2Н, Нarom, J 8.0 Hz), 7.62
d (2Н, Нarom, J 8.0 Hz), 9.21 br.s (1Н, NHСО), 9.66
br.s (1Н, NHСО). Маss spectrum, m/z (Irel, %): 423.1
(100) [М + 1]+. Found, %: С 65.25; Н 6.03; N 13.11.
С23H26N4O2S. Calculated, %: С 65.38; Н 6.20; N 13.26.
М 422.543.
Н
Compound VIc. Yield 0.014 g (6%). White powder,
mp 183–185°C (EtOH). IR spectrum, ν, cm–1: 3176–
3422 (NH, NH2), 1656, 1648 (СОNH), 1615 [δ(NH2)].
1H NMR spectrum, δ, ppm: 0.91 d (6Н, 2СН3, J 6.3 Hz),
1.55–1.69 m (1Н, СНМе2), 3.08 d (1Н, С4Н, J 7.3 Hz),
2
3
3.38 d.d (1Н, SСН2, J 13.3, J 7.8 Hz), 3.45 s (1Н,
2
3
С3Н), 3.73 d.d (1Н, SСН2, J 13.3, J 6.4 Hz), 4.84 d
(1Н, =СН2, Jcis 9.9 Hz), 5.06 d (1Н, =СН2, Jtrans 17.1 Hz),
5.72–5.88 m (1Н, СН=), 7.00 t (1Н, Нarom, J 7.2 Hz),
7.07 t (1Н, Нarom, J 7.2 Hz), 7.27 t (2Н, Нarom, J 7.6 Hz),
7.32 t (2Н, Нarom, J 7.6 Hz), 7.45 br.s (2Н, NH2), 7.51–
7.72 m (4Н, Нarom), 9.29 br.s (1Н, NHCO), 9.58 br.s
(1Н, NHСО). Маss spectrum, m/z (Irel, %): 449.2 (100)
[М + 1]+. Found, %: С 66.80; Н 6.39; N 12.32.
С25H28N4O2S. Calculated, %: С 66.94; Н 6.29; N 12.49.
М 448.58.
Compound VIg. Yield 0.13 g (40%). White powder,
mp 186–188°C (EtOH). IR spectrum, ν, cm–1: 3132–
3421 (NH, NH2), 1678, 1650 (СОNH), 1618 [δ(NH2)].
1H NMR spectrum, δ, ppm: 0.85 t (3Н, СН3, J 6.28 Hz),
1.19–1.53 m (12Н, 6СН2), 2.13 s (3Н, СН3), 2.19 s
(3Н, СН3), 3.37–3.40 m (1Н, С4Н), 3.48 s (1Н, С3Н),
2
3.66 d (1Н, SСН2, J 14.0 Hz), 3.69 s (3Н, ОСН3),
2
3.87 d (1Н, SСН2, J 14.2 Hz), 6.74 d (2Н, Нarom, J
8.9 Hz), 7.01–7.25 m (7Н, Нarom), 7.33 d (2Н, Нarom, J
8.9 Hz), 7.37 d (2Н, Нarom, J 7.7 Hz), 7.74 d (2Н, NH2,
J 21.3 Hz), 8.81 br.s (1Н, NHСО), 9.06 br.s (1Н,
NHСО), 9.91 br.s (1Н, NHСО). Маss spectrum, m/z
(Irel, %): 656.4 (100) [М + 1]+. Found, %: С 67.60; Н
6.76; N 10.51. С37H45N5O4S. Calculated, %: С 67.76;
Н 6.92; N 10.68. М 655.849.
Compound VId. Yield 0.098 g (34%). White powder,
mp 152–154°C (EtOH). IR spectrum, ν, cm–1: 3138–
3415 (NH, NH2), 1668, 1643 (СОNH), 1608 [δ(NH2)].
1H NMR spectrum, δ, ppm: 0.74–0.92 m (6Н, 2СН3),
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DYACHENKO et al.
Compound XVI. Yield 0.08 g (31%). White powder,
7.50–7.58 m (9Н, Нarom), 8.25 br.s, 9.51 br.s (2Н,
NH2), 10.07 br.s, 10.15 br.s, 10.31 br.s (2Н, 2NHСО),
13.14 br.s, 13.19 br.s (1Н, N1H). Маss spectrum, m/z
(Irel, %): 423.2 (43) [М + 1]+ (Iа), 437.2 (100) [М + 1]+
(VIIIb, IXb), 451.2 (49) [М + 1]+ (Xb).
mp 193–195°C (EtOH). IR spectrum, ν, cm–1: 3124–
3446 (NH, NH2), 1669, 1658 (СОNH), 1626 [δ(NH2)].
1H NMR spectrum, δ, ppm: 1.27 d (3Н, СН3, J 6.6 Hz),
2.26 s (3Н, СН3), 2.68–2.81 m (1Н, СНМе), 3.45 d.d
2
3
(1Н, SСН2, J 13.0, J 7.5 Hz), 3.47 br.s (1Н, С4Н),
The mixtures VIa + XIa + XIIa + XIIIa and VIa +
XIb + XIIb + XIIIb were prepared similarly to VI.
3.52 s (1Н, С3Н), 3.69 d.d (1Н, SСН2, J 13.0, J 6.6
Hz), 4.88 d (1Н, =СН2, Jcis 9.8 Hz), 5.10 d (1Н, =СН2,
Jtrans 16.9 Hz), 5.68–5.81 m (1Н, СН=), 6.82–7.48 m
(16Н, 14Нarom and NH2), 8.43 br.s (1Н, NHСО), 9.28
br.s (1Н, NHСО). Маss spectrum, m/z (Irel, %): 525.2
(100) [М + 1]+. Found, %: С 71.13; Н 6.10; N 10.52.
С31H32N4O2S. Calculated, %: С 70.96; Н 6.15; N
10.68. М 524.676.
2
3
The mixture of compounds VIa, XIa, XIIa, and
1
XIIIa. H NMR spectrum, δ, ppm: 0.77–1.02 m (6Н,
2СН3), 1.05–1.19 m (1Н, СН2), 1.25–1.37 m (1Н,
СН2), 1.62–1.76 m (1Н, СНМе2), 2.16 s and 2.23 s
(3Н, СН3), 3.34–3.51 m (3Н, С3Н, С4Н, SСН2), 3.68–
3.79 m (1Н, SСН2), 4.78–4.91 m (1Н, =СН2), 4.99–
5.18 m (1Н, =СН2), 5.75–5.87 m (1Н, СН=), 6.88–
7.75 m (11Н, 9Нarom and NH2), 8.76 br.s, 8.87 br.s,
8.91 br.s, 9.17 br.s, 9.30 br.s, 9.57 br.s, 9.61 br.s (2Н,
2NHСО). Маss spectrum, m/z (Irel, %): 463.2 (20)
[М + 1]+ (VIа), 477.2 (100) [М + 1]+ (XIа, XIIа),
491.2 (70) [М + 1]+ (XIIIа).
Compound XV was prepared similarly to I using
5 mmol (0.97 g) of 3-amino-N-phenyl-3-thioxopropan-
amide (III), 5 mmol (0.67 g) of 2-phenylpropanal
(IIf), and 5 mmol (0.87 g)of N-(m-tolyl)-2-cyano-
acetamide (XIV). Yield 0.14 g (6%). Yellow powder,
mp 167–169°C (Me 2 SO). IR spectrum, ν, cm–1:
3186–3390 (NH, NH2), 1668 (СОNH), 1615 [δ(NH2)],
The mixture of compounds VIa, XIb, XIIb, and
1
1
XIIIb. H NMR spectrum, δ, ppm: 0.76–0.96 m (6Н,
1208 (С=S). H NMR spectrum, δ, ppm: 1.25 d (3Н,
2СН3), 1.00–1.16 m (1Н, СН2), 1.22–1.35 m (1Н, СН2),
1.59–1.75 m (1Н, СНМе2), 2.27 s (3Н, СН3), 3.25–3.46 m
(3Н, С3Н, С4Н, SСН2), 3.67–3.80 m (1Н, SСН2), 4.81–
4.89 m (1Н, =СН2), 5.07 d (1Н, =СН2, Jtrans 16.8 Hz),
5.72–5.82 m (1Н, СН=), 6.76–7.65 m (11Н, 9Нarom
and NH2), 9.19 br.s, 9.22 br.s, 9.28 br.s, 9.32 br.s, 9.71
br.s, 9.80 br.s (2Н, 2NHСО). Маss spectrum, m/z (Irel,
%): 463.2 (100) [М + 1]+ (VIа), 477.2 (100) [М + 1]+
(XIb, XIIb), 491.2 (100) [М + 1]+ (XIIIb).
СН3, J 6.3 Hz), 2.25 s (3Н, СН3), 2.86–2.98 m (1Н,
СН), 3.90 s (1Н, С3Н), 4.06 d (1Н, С4Н, J 4.6 Hz),
6.84–7.00 m (2Н, Нarom), 7.09–7.58 m (12Н, Нarom),
7.90 br.s (1Н, NH2), 9.32 br.s (1Н, NH2), 9.80 br.s
(1Н, NHСО), 10.07 br.s (1Н, NHСО), 13.18 br.s (1Н,
N1H). Маss spectrum, m/z (Irel, %): 485.2 (100) [М + 1]+.
Found, %: С 69.24; Н 5.68; N 11.49. С28H28N4O2S.
Calculated, %: С 69.40; Н 5.82; N 11.56. М 484.613.
The mixtures Ia + VIIIa + IXa + Xa, and Ia +
VIIIb + IXb + Xb were prepared similarly to I, using
5 mmol of 3-amino-N-aryl-3-thioxopropanamides (IIIa–
IIIc) and 5 mmol (0.535 ml) of 3-methylbutanal (IIb).
REFERENCES
1. Dyachenko, V.D. and Karpov, E.N., Russ. J. Gen.
Chem., 2013, vol. 83, no. 7, pp. 1394–1401.
2. Brytsun, V.N., 2-Funktsionalizirovannye metilenaktivnye
tioatsetamidy (2-Functionalized Methylene Thioacetamide),
Kiev: CP “Komprint,” 2012.
3. Dyachenko, V.D., Doctoral (Chem.) Dissertation,
Moscow, 1998.
4. Krasnikov, D.A., Candidate Sci. (Chem.) Dissertation,
The mixture of compounds Ia, VIIIa, IXa, and
Xa. H NMR spectrum, δ, ppm: 0.84–1.04 m (6Н,
1
2СН3), 1.09–1.34 m (2Н, СН2), 1.52–1.67 m (1Н,
СНМе2), 2.06–2.15 m (3Н, СН3), 3.68–3.94 m (2Н,
С3Н, С4Н), 6.76–8.26 m (11Н, NH2, Нarom), 9.52 br.s,
9.67 br.s, 10.19 br.s, 10.35 br.s (2Н, 2NHСО), 12.41
br.s, 13.20 br.s (1Н, N1H). Маss spectrum, m/z (Irel,
%): 423.2 (55) [М + 1]+ (Iа), 437.2 (100) [М + 1]+
(VIIIа, IXa), 451.2 (51) [М + 1]+ (Xа).
Khar’kov, 2011.
5. Litvinov, V.P., Russ. Chem. Rew., 2006, vol. 75, no. 7,
pp. 577–600.
6. Dyachenko, V.D., Russ. J. Gen. Chem, 2005, vol. 75,
no. 3, pp. 440–446.
7. Krauze, A. and Duburs, G., Chem. Heterocycl. Comp.,
The mixture of compounds Ia, VIIIb, IXb, and
1
Xb. H NMR spectrum, δ, ppm: 0.90 d, 0.98 d, 1.05 d
(6Н, 2СН3, J 6.0 Hz), 1.09–1.27 m (2Н, СН2), 1.53–
1.68 m (1Н, СНМе2), 2.24 s, 2.26 s (3Н, СН3), 3.71 d,
3.74–3.86 m, 4.30 d (2Н, С3Н, С4Н, J 4.0 Hz), 6.74 d,
6.88 d, 6.91 t, 7.03–7.12 m, 7.15–7.25 m, 7.28–7.42 m,
1999, no. 4, pp. 446–449.
8. Skudarnova, T.I., Burova, O.A., Smirnova, N.M.,
Chelysheva, G.M., and Safonova, T.S., Pharm. Chem. J.,
1994, vol. 28, no. 3, pp. 185–188.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 9 2013

4-ALKYL-6-AMINO-N3,N5-DIARYL-2-THIOXO-1,2,3,4-TETRAHYDROPYRIDINE-… : II.
1723
9. Dyachenko, V.D. and Karpov, E.N., Russ. J. Org.
Chem., 2011, vol. 47, no. 1, pp. 1–29.
20. Deyanov, A.B., Kon’shin, M.E., and Semenova, Z.N.,
Chem. Heterocycl. Comp., 2004, no. 12, pp. 1560–1563.
10. Dyachenko, V.D., Nikishin, A.A., and Dyachenko, I.E.,
Russ. J. Org. Chem., 2011, vol. 47, no. 8, pp. 1214–
1221.
21. Dyachenko, V.D., Nesterov, V.N., Krivokolysko, S.G.,
and Litvinov, V.P., Russ. Chem. Bull., 1997, vol. 46,
no. 1, pp. 192–194
11. Rodinovskaya, L.A., Shestopalov, A.M., and Neste-
rov, V.N., Chem. Heterocycl. Comp., 1996, no. 10,
pp. 11182–1188.
22. Dyachenko, V.D. and Rusanov, E.B., Chem. Hetero-
cycl. Comp., 2003, no. 5, pp. 645–690.
23. Dyachenko, V.D. and Chernega, A.N., Russ. J. Gen.
Chem., 2005, vol. 75, no. 6, pp. 952–960.
12. Dyachenko, A.D., Desenko, S.M., Dyachenko, V.D.,
Chem. Heterocycl. Comp., 2004, no. 8, p. 1009–1016.
13. Elkholy E.M., Abu-Shanab F.A., Erian A.W., Phosph.,
Sulfur, Silicon, Relat. Elem., 2000, vol. 167, p. 151.
14. Krauze, A.A., Odinets, A.G., Verreva, A.A., Ger-
mane, S.K., Kozhukhov, A.N., and Dubur, G.Ya.,
Pharm. Chem. J., 1991, vol. 25, no. 7, pp. 477–481.
15. Dyachenko, V.D. and Tkachev, R.P., Russ. J. Org.
Chem., 2003, vol. 39, no. 8, pp. 1174–1179.
24. Dyachenko, V.D. and Chernega, A.N., Russ. J. Org.
Chem., 2006, vol. 42, no. 4, pp. 567–576.
25. Dyachenko, V.D. and Krasnikov, D.A., Ukr. Khim. Zh.,
2005, vol. 71, no. 6, p. 86.
26. Hagiwara, H., Miya, S., Suzuki, T., Ando, M.,
Hamamoto, I., and Kato, M., Heterocycles, 1999,
vol. 51, no. 3, p. 493.
27. Comprehensive Organic Chemistry, Barton, D. and
16. Dyachenko, V.D. and Tkachov, R.P., Vіsn. Harkіv.
Nats. Unіv., Ser. Khіm., 2002, vol. 31, no. 8, p. 50.
Ollis. W.D., Eds., Oxford: Pergamon Press, 1979,
28. Praktikum po organicheskoi khimii (Workshop on
Organic Chemistry), Zefirov, N.S., Ed., Moscow:
BINOM. Laboratoriya Znanii, 2010, p. 102.
17. Dyachenko, A.D., Desenko, S.M., Dyachenko, V.D.,
and Chernega, A.N., Chem. Heterocycl. Comp., 2004,
no. 5, pp. 650–659.
29. Pretsch, E., Bühlmann, P., and Affolter, C., Structure
Determination of Organic Compounds: Tables of
Spectral Data, Berlin: Springer, 2000.
18. Dyachenko, A.D., Desenko, S.M., Dyachenko, V.D.,
and Rusanov, E.B., Chem. Heterocycl. Comp., 2003,
no. 6, pp. 744–748.
30. Dyachenko, V.D., Krasnikov, D.A., and Khorik, M.V.,
19. Li, X., Song, L., Xing, Ch., Tetrahedron., 2006, vol. 62,
Chem. Heterocycl. Comp, 2008, no. 7, pp. 815–819.
no. 10, p. 2255.
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