Synthesis and reactions of 1-R-3-benzoyl-5-ethoxycarbonyl-6-oxo-1,2,3,6- tetrahydropyridine-2-thiones

Article abstract of DOI:10.1007/s10593-007-0218-3

Cycloacylation of N-R-3-oxo-3-phenylpropanethioamides by diethyl ethoxymethylenemalonate occurs selectively to form 1-R-3-benzoyl-5- ethoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-thiones which are convenient starting materials for the synthesis of bi-and tricyclic hetero systems including the previously unknown 9-R-7-ethoxycarbonyl-5-phenyl-8,9- dihydropyrido[2,3-d][1,2,4]triazolo[1,5-a]-pyrimidin-8-ones.

Full text of DOI:10.1007/s10593-007-0218-3

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
SYNTHESIS AND REACTIONS
OF 1-R-3-BENZOYL-5-ETHOXY-
CARBONYL-6-OXO-1,2,3,6-TETRA-
HYDROPYRIDINE-2-THIONES
V. N. Britsun, A. N. Esipenko, A. N. Chernega,
E. B. Rusanov, and M. O. Lozinskii
Cycloacylation of N-R-3-oxo-3-phenylpropanethioamides by diethyl ethoxymethylenemalonate occurs
selectively to form 1-R-3-benzoyl-5-ethoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-thiones which are
convenient starting materials for the synthesis of bi- and tricyclic hetero systems including the previously
unknown 9-R-7-ethoxycarbonyl-5-phenyl-8,9-dihydropyrido[2,3-d][1,2,4]triazolo[1,5-a]-pyrimidin-8-ones.
Keywords: 1-R-3-benzoyl-5-ethoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-thiones, diethyl
ethoxymethylenemalonate, 6-ethoxycarbonyl-2-imino-8-methyl-4-phenyl-1,2,7,8-tetrahydropyrido[2,3-d]-
pyrimidin-7-one, 5-ethoxycarbonyl-7-methy-3-phenyl-6,7-dihydroisoxazolo[3,4-b]pyridine-6-one, N-R-3-
oxo-3-phenylpropanethioamides, 9-R-7-ethoxycarbonyl-5-phenyl-8,9-dihydropyrido[2,3-d][1,2,4]triazolo-
[1,5-a]pyrimidin-8-ones, X-ray structural analysis, cycloacylation.
The cycloacylation of thioamides by unsaturated carboxylic acid derivatives is a convenient and
practical method for the synthesis of sulfur containing azoles and azines [1-5].
One of these reagents is diethyl ethoxymethylenemalonate, the ethoxy group of which has good
nucleofuge properties. None the less, there are only two studies in which the cyclocondensation of this
compound with thioamides is discussed [6, 7]. It is likely that the low interest of investigators in this area of
reactions is explained by the fact that the reaction is carried out under forcing conditions [7] and forms two [7] or
three products [6].
The aim of this work was the discovery of conditions for the cycloacylation of the N-R-3-oxo-
3-phenylpropanethioamides 1a,b by diethyl ethoxymethylenemalonate 2 and the exploitation of the synthetic
potential of the products obtained.
It was found that the N-R-3-oxo-3-phenylpropanethioamides 1a,b condense with diethyl
ethoxymethylenemalonate 2 in the presence of sodium ethylate. The reaction occurs selectively and its products
are the 1-R-3-benzoyl-5-ethoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-thiones 3a,b.
In all likelihood the high selectivity of the process is explained by the high CH-acidity of the thioamides
1a,b [8] when compared with the N-aryl-2-thiocarbamoylacetamides. The latter react with diethyl
ethoxymethylenemalonate non selectively to give three products [6].
__________________________________________________________________________________________
Organic Chemistry Institute, National Academy of Sciences of Ukraine, Kiev 02660; e-mail:
bvn1967@rambler.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1660-1669,
November, 2007. Original article submitted July 10, 2007.
0009-3122/07/4311-1411©2007 Springer Science+Business Media, Inc.
1411

EtO
CO2Et
O
O
Ph
S
EtO2C
O
S
2
EtO
O
R
Ph
N
H
N
R
1a,b
3a,b
O
1. KOH
MeI
2.
Ar
CH2Br
5a,b
Ph
O
O
O
O
Ph
O
EtO
Ar
EtO
N
R
SMe
S
N
R
O
4a,b
6a,b
1, 3, 4, 6 а R = Me, b R = Et; 5, 6 a Ar = Ph, b Ar = 4-ClC6H4
The yields of the compounds synthesized, melting points, and elemental analytical data are given in
Table 1. The 1H NMR and IR spectra are given in Table 2 and 13C NMR spectra in Table 3. The structure of the
products 3a,b was proved by their reactions to the S-methyl derivatives 4a,b and 2-aroyl-5-ethoxycarbonyl-
3-phenyl-7-R-6,7-dihydrothieno[2,3-b]pyridine-6-ones 6a,b (using methyl iodide and the arylbromomethyl
ketones 5a,b respectively).
Because the 1-R-1,2,3,6-tetrahydropyridine-2-thiones 3a,b are structurally similar to β-thioxoketones [9]
and can exist as an equilibrium mixture of the ketone 3, enol 3', and enethiol 3" forms as a result of the
formation of intramolecular hydrogen bonds the spectra of compound 3b were also recorded in CDCl3
(1H NMR) and CCl4 (IR) to identify the structure of the dominant tautomer.
O
Ph
O
O
Ph
Ph
EtO
O
EtO
EtO
O
H
O
O
N
R
3
S
O
N
O
N
SH
S
R
R
3'
3"
Analysis of the IR spectra showed that both in the solid state and in CCl4 solution the 1-R-1,2,3,6-
tetrahydropyridine-2-thiones 3a,b occur in the enol form 3' stabilized by a medium intensity hydrogen bond (νOH
3300 cm-1) and the absorption for the mercapto group at 2500 cm-1 is absent. It did not prove possible to identify
the ketonic form from the carbonyl group absorption bands because there are three carbonyl groups present in
compounds 3a,b, two of which do not take part in the formation of an intramolecular hydrogen bond.
1
The H NMR spectra of compound 3a,b recorded in DMSO-d6 do not show signals for the OH or SH
1
group protons probably as a result of deuterium exchange whereas the H NMR spectrum of the products 3a,b
show a proton signal at 14.14-14.60 ppm in CDCl3 solution. Since the chemical shifts of chelated OH and SH
1412

are at 12-18 and 4.5-7.5 ppm [10] the range of chemical shifts 14.14-14.60 ppm can most probably be assigned
both to that of an enolic OH group signal and to the mean value of the enolic OH and enethiol SH form with a
predominance of enol form 3'.
The 1-R-3-benzoyl-5-ethoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-thiones 3a,b and 1-R-5-
benzoyl-3-ethoxycarbonyl-6-methylthio-1,2-dihydropyridin-2-ones 4a,b are polyfunctional compounds and this
makes them valuable starting materials for subsequent reactions. In contrast to 1,2,3,6-tetrahydropyridine-2-
thiones 3a,b we have found that the 1,2-dihydropyridine-2-ones 4a,b readily take part in [3+2] and [3+3]
cyclocondensations with nitrogen containing 1,2- and 1,3-dinucleophiles to give bi- and tricyclic heterocycles. It
should be noted that these reactions occur selectively involving the methylthio- and phenylcarbonyl groups of
the 1,2-dihydropyridine-2-ones 4a,b and are accompanied by the evolution of methyl mercaptan and water. The
product yields are preparative (60-78%).
We have used hydrazine and hydroxylamine as the 1,2-dinucleophiles. The 1,2-dihydropyridin-2-one 4a
reacts rapidly and unambiguously with hydrazine to give 5-ethoxycarbonyl-7-methyl-3-phenyl-6,7-dihydro-
1
1H-pyazolo[3,4-b]pyridine-6-one 7. It structure was confirmed using H NMR and IR spectroscopy and
composition from elemental analytical data.
Treatment of 1,2-dihydropyridin-2-ones 4a,b with hydroxylamine can give the two products
6,7-dihydroisoxazolo[3,4-b]pyridine-6-ones and 6,7-dihydroisoxazolo[5,4-b]pyridine-6-ones. To clarify which
of the reaction centers of the 1,2-dihydropyridin-2-ones 4a,b (the methylthio or phenylcarbonyl group) primarily
undergo nucleophilic attack we studied the reaction of the starting compound 4a with aromatic amines. In the
latter role we have used aniline and p-anisidine since their pKa values (4.58 and 5.29 respectively) are close to
that of hydroxylamine (5.97) [11]. As might be expected, methyl mercaptan is eliminated more readily than
water to give the 6-arylamino-5-benzoyl-3-ethoxycarbonyl-1-methyl-1,2-dihydropyridine-2-ones 9a,b.
O
O
Ph
Ph
EtO
EtO
O
H
N
N
N
O
N
O
N
H
Ar
ArNH2
R
9a,b
R
N2H4
8a,b
7
Ph
O
O
O
.
(H N) C=NH
2
Ph
N
2
2
N
NH2OH
EtO
.
H2CO3
EtO
4a,b
O
N
NH
O
N
R
N
N
R
10a,b
H
N
N
R2
R 1
11
H2N
H2N
N
H
14a,b
12a,b
Ph
O
O
O
Ph
OH
N
R 2
N
N
EtO
EtO
N
N
R1
O
N
N
N
R
R
13a,b
15a,b
8, 9 a Ar = Ph, b Ar = 4-MeOC6H4; 7, 9a,b, 10a, 11, 13a,b, 15a R = Me;
10b, 15 b R = Et; 12, 13 a R1 = H, b R1 = SMe; 14, 15 a R2 = H, b R2 = Me
1413

Since the reaction of the 1,2-dihydropyridine-2-ones 4a,b with hydroxylamine occurs selectively it can
be established on the basis of the above results that the products of this reaction are the 7-R-5-ethoxycarbonyl-
3-phenyl-6,7-dihydroisoxazolo[3,4-b]pyridine-6-ones 10a,b.
We have also studied the cyclocondensation of 1,2-dihydropyridin-2-ones 4a,b with such nitrogen
containing 1,3-dinucleophiles as guanidine carbonate, 5-R1-3-amino-1,2,4-triazoles 12a,b, and 5-R2-2-
aminopyridines 14a,b.
Fig. 1. Overall view of the 7-ethoxycarbonyl-9-methyl-5-phenyl-8,9-dihydropyrido[2,3-d]-
[1,2,4]triazolo[1,5-a]pyrimidin-8-one molecule 13a. Selected bond lengths and angles:
С(3)–N(5) 1.381(3), С(3)–С(4) 1.425(3), С(4)–С(8) 1.425(3), С(4)–С(5) 1.377(3),
С(5)–N(1) 1.357(2), N(1)–C(2) 1.386(3), С(2)–N(4) 1.344(3), N(4)–С(3) 1.323(2),
С(2)–N(3) 1.329(3), N(3)–C(1) 1.350(3), C(1)–N(2) 1.322(3), N(2)–N(1) 1.373(2) Å;
N(5)C(3)N(4) 117.42(18), N(5)C(3)C(4) 118.25(17), C(8)C(4)C(3) 118.79(17),
C(8)C(4)C(5) 121.75(17), C(4)C(5)N(1) 115.34(17), C(3)N(4)C(2) 115.49(17),
N(4)C(2)N(1) 122.34(18), N(4)C(2)N(3) 128.4(2), N(1)C(2)N(3) 109.3(2),
N(1)N(2)C(1) 100.2(2), N(2)C(1)N(3) 118.4(2), C(1)N(3)C(2) 102.0(2)°.
It should be noted that the lower basicity 1,3-nucleophiles 2-aminopyrimidine and 5-aminotetrazole do
not react with the dihydropyridin-2-ones 4a,b.
The reaction of 1,2-dihydropyridin-2-one 4a with guanidine gives only the 6-ethoxycarbonyl-2-imino-
8-methyl-4-phenyl-1,2,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one 11 in 70% yield whereas treatment of 4a,b
with 5-R2-2-aminopyridines 14a,b (5-R1-3-amino-1,2,4-triazoles 12a,b) can give two (four) isomeric
heterocycles. However, these reactions occur selectively. The structure of the condensation products of 4a with
5-R1-3-amino-1,2,4-trazoles 12a,b could not be determined by spectroscopic means hence their structures were
studied using X-ray investigation. The X-ray data study for compound 13a unambiguously shows that is
7-ethoxycarbonyl-9-methyl-5-phenyl-8,9-dihydropyrido[2,3-d][1,2,4]triazolo[1,5-a]pyrimidin-8-one.
The overall view of the compound 13a molecule and the bond lengths and valence angles are given in
Figure 1. The central tricyclic system N1-5C1-8 is virtually planar (the deviation from the mean square plane not
exceeding 0.07 Å) and the dihedral angles between the heterocycle C(4)C(3)N(4)C(2)N(1)C(5) and the systems
1414

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
3a
C16H15NO4S
60.72
60.56
61.85
61.62
61.41
61.62
62.42
62.59
68.83
69.05
64.55
64.44
64.86
64.64
70.29
70.20
68.13
67.97
64.16
64.42
65.19
65.38
63.12
62.96
62.05
61.89
57.90
57.71
67.07
66.83
67.58
67.51
4.89
4.76
4.88
5.17
5.28
5.17
5.73
5.54
4.32
4.59
4.60
4.33
4.82
5.09
5.18
5.36
5.21
5.46
4.95
4.73
4.98
5.16
5.22
4.97
4.48
4.33
4.06
4.33
4.80
5.07
5.13
5.41
4.20
4.41
3.94
4.23
4.42
4.23
3.85
4.06
3.12
3.36
2.88
3.01
13.89
14.13
7.71
7.44
7.05
6.89
9.11
9.39
9.25
8.97
17.52
17.27
19.82
20.05
17.93
17.71
10.84
11.13
10.52
10.74
185-187
135-137
130-132
98-100
63
68
72
76
85
81
86
79
82
75
87
70
66
69
60
64
3b
C17H17NO4S
C17H17NO4S
C18H19NO4S
C24H19NO4S
C25H20ClNO4S
C16H15N3O3
C22H20N2O4
C23H22N2O5
C16H14N2O4
C17H16N2O4
C17H16N4O3
C18H15N5O3
C19H17N5O3S
C21H19N3O4
C22H21N3O4
4a
4b
6a
186-188
170-173
240-242
159-161
185-187
128-130
85-87
6b
7
9a
9b
10a
10b
11
176-178
228-230
260-262
248-250
213-215
13a
13b
15a
15b
C(4)C(8)C(7)C(6)N(5)C(3) and N(1)C(2)N(3)C(1)N(2) are 2.8 and 1.2º. The atoms N(1) and N(5) have planar trigonal
coordination and the sum of the valence angles for these atoms is 360.0º. For steric reasons the benzene ring
C(10)-C(15) is twisted by 61.0º relative to the central fragment. It should be noted that, according to the Cambridge
structural data bank [12], similar tricyclic systems have not been investigated by structural methods before.
In contrast to the reaction above, cyclocondensation of the 1,2-dihydropyridin-2-ones 4a,b with the
5-R2-2-aminopyridines 14a,b cannot be accompanied by the separation of water and so its products can be
1
compounds with both acyclic and cyclic structures. H NMR and IR spectroscopic data were insufficient for an
unambiguous identification of the reaction products hence their structure was determined using 13C NMR
spectroscopy.
It is known that the signal of a phenylcarbonyl group carbon atom occurs in the region 192.6-198.1 ppm
13
in the 13C NMR spectrum (Table 2, compounds 4b,9b and the spectroscopic data in the study [13]). The C
NMR spectrum of compound 15a does not show signals in the region but shows a signal for an sp3-hybridized
C–N carbon [14] with a chemical shift of 88.8 ppm. The latter can only be assigned to the C(5) atom of the 1-R-
8-R2-3-ethoxycarbonyl-5-hydroxy-5-phenyl-1,5-dihydro-2H-dipyrido[1,2-a:2,3-d]pyrimidin-2-ones 15a,b.
Hence the cycloacylation of N-R-3-oxo-3-phenylpropanethioamides by diethyl ethoxy-
methylenemalonate occurs selectively and is a preparative method for obtaining 1-R-3-benzoyl-5-ethoxy-
carbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-thiones. These are valuable starting compounds for the preparation
of bi- and tricyclic hetero systems including the previously unknown 9-R-7-ethoxycarbonyl-5-phenyl-
8,9-dihydropyrido[2,3-d][1,2,4]triazolo[1,5-a]pyrimidin-8-ones.
1415

1
TABLE 2. H and 13C NMR Spectroscopic Characteristics of the
Compounds Synthesized
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz)
1
2
3
3a
3300, 3000, 1660, 1620, 1.27 (3Н, t, J = 6.6, СН3СН2); 3.63 (3Н, s, NCH3);
1550, 1450, 1390, 1380, 4.25 (2Н, q, J = 6.6, СН3СН2); 7.40 (2Н, m, C6H5);
1350, 1310
7.49 (1Н, m, C6H5); 7.71 (2Н, m, C6H5); 7.74 (1Н, s, H-4)
[1.41 (3Н, t, J = 5.7, СН3СН2); 3.96 (3Н, s, NCH3);
4.44 (2Н, q, J = 5.7, СН3СН2); 7.48-7.61 (3Н, m, C6H5);
7.76 (1Н, s, H-4); 7.90 (2Н, m, C6H5);
14.60 (1Н, br. s, ОН)]*
3b*2
3300, 3050, 3000, 2900, 1.19 (3Н, t, J = 7.2, СН3СН2N); 1.28 (3Н, t, J = 7.5,
1670, 1620, 1550, 1430, СН3СН2O); 4.26 (2Н, q, J = 7.5, СН3СН2O); 4.38 (2Н, q,
1390, 1360, 1270, 1210, J = 7.2, СН3СН2N); 7.43 (2Н, m, C6H5); 7.56 (1Н, m, C6H5);
1180
7.70 (2Н, m, C6H5); 7.73 (1Н, s, H-4)
[1.37 (6Н, m, 2СН3СН2); 4.39 (2Н, q, J = 7.2, СН3СН2);
4.74 (2Н, q, J = 6.9, СН3СН2); 7.46 (2Н, m, C6H5);
7.56 (1Н, m, C6H5); 7.74 (1Н, s, H-4); 7.85 (2Н, m, C6H5);
14.14 (1Н, br. s, ОН)]*
4a
4b
3050, 3000, 1720, 1650, 1.25 (3Н, t, J = 6.9, СН3СН2); 2.32 (3H, s, SCH3); 3.72 (3H,
1600, 1520, 1450, 1410, s, NCH3); 4.21 (2Н, q, J = 6.9, СН3СН2); 7.53 (2Н, m, C6H5);
1380, 1350, 1310
7.67 (1Н, m, C6H5); 7.85 (2Н, m, C6H5); 7.89 (1Н, s, H-4)
3000, 2950, 1690, 1670, 1.29 (6Н, m, 2СН3СН2); 2.35 (3H, s, SCH3); 4.19 (2Н, q,
1650, 1580, 1490, 1460, J = 7.2, СН3СН2O); 4.36 (2Н, q, J = 6.6, СН3СН2N);
1380, 1350, 1310
7.55 (2Н, m, C6H5); 7.68 (1Н, m, C6H5); 7.84 (2Н, m, C6H5);
7.87 (1Н, s, H-4)
6a
3100, 3000, 1730, 1660, 1.24 (3Н, t, J = 7.2, СН3СН2); 3.70 (3H, s, NCH3);
1620, 1590, 1520, 1490, 4.20 (2Н, q, J = 7.2, СН3СН2); 7.16-7.25 (7Н, m, C6H5);
1440, 1380, 1340, 1300, 7.32 (1Н, m, C6H5); 7.43 (2Н, m, C6H5); 8.00 (1Н, s, H-4)
1260, 1200
6b
7
3100, 3000, 2900, 1700, 1.24 (3Н, t, J = 7.2, СН3СН2N); 1.38 (3Н, t, J = 6.9,
1675, 1630, 1590, 1520, СН3СН2O); 4.21 (4Н, m, 2СН3СН2); 7.14-7.28 (7Н, m, HAr);
1480, 1450, 1390, 1310
7.41 (2Н, d, J = 8.9, 4-С6Н4); 8.00 (1Н, s, H-4)
3200, 3000, 1710, 1690, 1.30 (3Н, t, J = 7.2, СН3СН2); 3.53 (3Н, s, NCH3);
1610, 1530, 1490, 1410, 4.24 (2Н, q, J = 7.2, СН3СН2); 7.55 (3Н, m, C6H5);
1370, 1360
7.82 (2Н, m, C6H5); 8.46 (1Н, s, H-4); 14.01 (1Н, br. s, NH)
9a
9b
3100, 3000, 1700, 1680, 1.22 (3Н, t, J = 6.6, СН3СН2); 3.26 (3Н, s, NCH3);
1600, 1550, 1490, 1450, 4.20 (2Н, q, J = 6.6, СН3СН2); 6.96 (2Н, m, C6H5);
1400, 1360
7.08 (1Н, s, C6H5); 7.23 (2Н, m, C6H5); 7.45 (4Н, m, C6H5);
7.54 (1H, m, C6H5); 8.20 (1Н, s, H-4); 10.69 (1Н, s, NH)
3100, 3000, 1720, 1650, 1.20 (3Н, t, J = 7.2, СН3СН2); 3.18 (3Н, s, NCH3);
1610, 1560, 1520, 1470, 3.73 (3H, s, OCH3); 4.13 (2Н, q, J = 7.2, СН3СН2);
1370, 1330
6.83 (2Н, d, J = 8.1, 4-С6Н4); 7.01 (2Н, d, J = 8.1, 4-С6Н4);
7.45-7.56 (5Н, m, C6H5); 8.20 (1Н, s, H-4); 11.04 (1Н, s, NH)
10a
10b
11
3100, 3000, 1700, 1670, 1.31 (3Н, t, J = 6.6, СН3СН2); 3.43 (3Н, s, NCH3);
1630, 1540, 1480, 1450, 4.30 (2Н, q, J = 6.6, СН3СН2); 7.64 (3Н, m, C6H5);
1400, 1370
8.02 (2Н, m, C6H5); 8.52 (1Н, s, H-4)
3100, 3000, 2950, 1730, 1.32 (6Н, m, 2СН3СН2); 4.03 (2Н, q, J = 6.9, СН3СН2N);
1640, 1540, 1480, 1460, 4.29 (2Н, q, J = 6.9, СН3СН2O); 7.65 (3Н, m, C6H5);
1390, 1340
8.01 (2Н, m, C6H5); 8.51 (1Н, s, H-4)
3400, 3280, 3000, 1690, 1.23 (3Н, t, J = 7.3, СН3СН2); 3.56 (3Н, s, NCH3);
1660, 1600, 1550, 1470, 4.17 (2Н, q, J = 7.3, СН3СН2); 6.92 (1Н, s, NH);
1420, 1380
7.59 (5Н, m, C6H5); 7.71 (1Н, s, HN=); 8.19 (1Н, s, H-5)
13a
3100, 3000, 1730, 1660, 1.24 (3Н, t, J = 6.6, СН3СН2); 3.71 (3Н, s, NCH3);
1630, 1600, 1550, 1530, 4.25 (2Н, q, J = 6.6, СН3СН2); 7.74 (5Н, m, C6H5);
1490, 1450, 1380
8.03 (1Н, s, H-6); 8.61 (1Н, s, H-2)
_______
* Spectrum obtained in CDCl3
*2 IR spectrum of compound 3b in CCl4 (concentration 0.1 M): 3300,
3100, 3000, 2950, 1660, 1620, 1560, 1430, 1380, 1361, 1270, 1215.
1416

TABLE 2. (continued)
1
2
3
13b
3100, 3000, 1740, 1670
1.24 (3Н, t, J = 7.2, СН3СН2); 2.58 (3H, s, SCH3);
1620, 1600, 1560, 1500, 3.68 (3Н, s, NCH3); 4.23 (2Н, q, J = 7.2, СН3СН2);
1430, 1385, 1370, 1300 7.74 (5Н, m, C6H5); 7.99 (1Н, s, H-6)
15a
15b
3100, 3000, 1720, 1640, 1.15 (3Н, t, J = 6.9, СН3СН2); 3.54 (3Н, s, NCH3); 4.09 (2Н,
1620, 1580, 1560, 1480, q, J = 6.9, СН3СН2); 6.74 (1H, m, H-8); 7.08 (1H, d, J = 9.0,
1370, 1300
H-10); 7.31-7.47 (5Н, m, C6H5); 7.58 (1Н, s, ОН);
7.62 (1Н, m, Н-9); 7.71 (1Н, d, J = 6. 6, Н-7); 8.59 (1Н, s, H-4)
3100, 3000, 1720, 1640, 1.19 (6Н, m, 2СН3СН2); 2.05 (8-CH3); 4.08 (2Н, q, J = 6.9,
1610, 1580, 1490, 1460, СН3СН2O); 4.29 (2Н, q, J = 7.2, СН3СН2 N); 7.00 (1H, d,
1370, 1340
J = 9.6, H-9); 7.33 (2H, m, Ar); 7.38-7.44 (3Н, m, Ar);
7.49 (2H, m, Ar); 7.57 (1Н, s, ОН); 8.46 (1Н, s, H-4)
TABLE 3. 13C NMR Spectra of Compounds 4b, 9b, and 15a
Com-
pound
Chemical shifts (DMSO-d6), δ, ppm.
4b
13.6 (NCH2CH3), 14.0 (OCH2CH3); 20.2 (SCH3); 41.8 (NCH2CH3), 60.6 (OCH2CH3);
118.6, 121.7, 128.7, 129.6, 133.6, 138.8, 141.1, 151.6 (Ar); 157.9 (O=C−N);
163.9 (O=C−OEt); 192.6 (C6H5–C=O)
9b
14.2 (OCH2CH3); 33.1 (NCH3); 55.3 (OCH3); 59.7 (OCH2CH3);
102.4, 105.7, 114.4, 124.4, 128.3, 128.4, 131.6, 132.0, 138.2, 147.6, 156.0, 156.8 (Ar);
158.8 (O=C−N); 164.2 (O=C−OEt); 193.0 (C6H5–C=O)
15a
14.18 (OCH2CH3); 28.2 (NCH3); 59.2 (OCH2CH3); 88.8 (C-5);
100.4, 107.8, 113.5, 123.3, 125.7, 128.5, 128.6, 135.6, 139.3, 141.9, 145.4,
149.9, 151.3 (Ar); 158.8 (O=C−N); 164.7 (O=C−OEt)
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Varian 300 instrument (300 and 75 MHz respectively)
using TMS as internal standard. IR spectra were taken on a UR-20 instrument for KBr tablets.
X-ray Structural Investigation of Compound 13a Single Crystal with a linear size of
0.38×0.25×0.20 mm was prepared by a method of slow cooling of an ethanol solution and measured at room
temperature on a Bruker Apex II automatic CCD diffractometer (MoKα radiation, λ = 0.71069 Å, θmax = 26.62º,
spherical segment -9 ≤ h ≤ 12, -18 ≤ k ≤ 21, -24 ≤ l ≤ 15). In all, 11,993 reflections were collected (3247
independent reflections, Rint = 0.0305). Crystals of compound 13a are orthorhombic with a = 10.1548(7),
b = 16.9036(11), c = 19.354(2) Å, V = 3322.2(5) Å3, M = 349.35, Z = 8, dcalc = 1.397 g/cm3, µ = 0.099 cm-1,
F(000) = 1456, space group Pbca (No. 61). The structure was solved by a direct method and refined in a least
squares analysis full matrix anisotropic approximation using the SHELXS97 [15] and SHELXL97 [16]
programs. 3247 reflections were used in the refinement (2115 reflections with I > 2σ(I)) (295 refinement
parameters, number of reflections per parameter 7.17). All of the hydrogen atoms were revealed in electron
density difference synthesis and included in the refinement with fixed positions and thermal parameters. A
2
2
weighting scheme was used with w = 1/[s2(F0 ) + (0.0754P)2 + 0.5696P], where P = (F0 + 2Fc2)/3. The final
difference factors were R1(F) = 0.0481 and wR2(F2) = 0.1207 and GOF = 1.002. The residual electron density
from the Fourier difference series was -0.272 and 0.215 e/Å3. The full set of structural data for compound 13a
has been deposited in the Cambridge structural data bank (CCDC 653195).
1417

1-R-3-Benzoyl-5-ethoxycarbonyl-6-oxo-1,2,3,6-tetrahydropyridine-2-thiones 3a,b. A solution of
sodium ethylate (0.1 mol), the thioamide 1a,b (0.1 mol), and diethyl ethoxymethylenemalonate 2 (21.6 g,
0.1 mol) in anhydrous ethanol (100 ml) was refluxed with a reflux condenser for 2 h and then cooled.
Hydrochloric acid (6%, 100 ml) was added and the precipitate was filtered off, dried, and recrystallized from
ethanol (3a) or 2-propanol (3b).
1-R-5-Benzoyl-3-ethoxycarbonyl-6-methylthio-1,2-dihydropyridin-2-ones 4a,b. A solution of KOH
(1.12 g, 0.02 mol), the tetrahydropyridine-2-thione 3a,b (0.02 mol), and methyl iodide (3.408 g, 0.024 mol) in
ethanol (90%, 50ml) was refluxed with a reflux condenser for 1 h and then cooled. Water (80 ml) was added and
the precipitated 4a,b were filtered off, dried, and recrystallized from 2-propanol.
7-R-2-Aroyl-5-ethoxycarbonyl-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-6-ones 6a,b. A solution
of KOH (0.56 g, 0.01 mol), the tetrahydropyridine-2-thione 3a,b (0.1 mol), and the arylbromomethyl ketone
5a,b (0.01 mol) in ethanol (85%, 15 ml) was refluxed for 1 h, cooled and water (30 ml) was added. The
precipitated 6a,b were filtered off, dried, and crystallized from AcOH.
5-Ethoxycarbonyl-7-methyl-3-phenyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-one 7. A solution of
the 1,2-dihydropyridin-2-one 4a (1.655 g, 0.005 mol) and hydrazine monohydrate (0.25 g, 0.005 mol) in
2-propanol (8 ml) was refluxed with a reflux condenser for 30 min and cooled. The precipitated product 7 was
filtered off, dried, and recrystallized from DMSO.
6-Arylamino-5-benzoyl-3-ethoxycarbonyl-1-methyl-1,2-dihydropyridin-2-ones 9a,b. A mixture of
the 1,2-dihydropyridin-2-one 4a (1.655 g, 0.005 mol) and arylamine 8a,b (0.005 mol) was fused at 140ºC for
20 min and then cooled. The product 9a,b was recrystallized from ethanol.
5-Ethoxycarbonyl-7-methyl-3-phenyl-6,7-dihydroisoxazolo[3,4-b]pyridin-6-ones 10a,b. A solution
of hydroxylamine hydrochloride (0.348 g, 0.005 mol), KOH (0.28 g, 0.005 mol), 1,2-dihydropyridin-2-one 4a,b
(0.005 mol) and ethanol (5 ml) was refluxed with a reflux condenser for 1 h. The solution was separated from the
KCl precipitate, cooled, and the product 10a,b filtered.
6-Ethoxycarbonyl-2-imino-8-methyl-4-phenyl-1,2,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (11).
A mixture of the 1,2-dihydropyridin-2-one 4a (1.655 g, 0.005 mol) and guanidine carbonate (0.54 g, 0.003 mol)
was fused at 140ºC for 30 min, cooled, the reaction mixture dissolved in 2-propanol (6 ml), filtered from the
unreacted guanidine carbonate, and cooled. The precipitate of 11 was separated and recrystallized from
2-propanol.
2-R1-7-Ethoxycarbonyl-9-methyl-5-phenyl-8,9-dihydropyrido[2,3-d][1,2,4]triazolo[1.5-a]pyrimi-
din-8-ones (13a,b). A solution of the 1,2-dihydropyridin-2-one 4a (1.655 g, 0.005 mol) and 5-R-3-amino-1,2,4-
triazole 12a,b (0.005 mol) in 2-propanol (6 ml) was refluxed for 1 h and then cooled. The product 13a,b was
filtered off, dried, and recrystallized from ethanol (13a) or DMSO (13b).
1-R-8-R2-3-Ethoxycarbonyl-5-hydroxy-5-phenyl-1,5-dihydro[1,2-a:2,3-d]pyrimidin-2-ones (15a,b).
A solution of the 1,2-dihydropyridin-2-one 4a,b (0.005 mol) and 2-amino-5-R2-pyridine 14a,b (0.005 mol) in
2-propanol (5 ml) was refluxed with a reflux condenser for 1 h and then cooled. The product 15a,b was filtered
off, dried, and recrystallized from DMSO.
REFERENCES
1.
2.
3.
4.
N. A. Danilkina, L. E. Mikhailov, and B. A. Ivin, Zh. Org. Khim., 42, 807 (2006).
A. N. Borisevich, V. N. Britsun, and M. O. Lozinskii, Zh. Org. Farm. Khim., 4, 3 (2006).
V. N. Britsun, A. N. Borisevich, L. S. Samoilenko, and M. O. Lozinskii, Zh. Org. Khim., 41, 292 (2005).
V. N. Britsun, A. N. Borisevich, A. N. Esipenko, and M. O. Lozinskii, Khim. Geterotsikl. Soedin., 623
(2006). [Chem. Heterocycl. Comp., 42, 546 (2006)].
1418

5.
6.
A. D. Dyachenko, S. M. Desenko, V. D. Dyachenko, and A. N. Chernega, Khim. Geterotsikl. Soedin.,
1171 (2004). [Chem. Heterocycl. Comp., 40, 1009 (2004).
R. P. Tkachev, O. S. Bityukova, V. D. Dyachenko, V. P. Tkacheva, and A. D. Dyachenko, Zh. Obshch.
Khim., 77, 125 (2007).
7.
8.
J. P. Clayton, P. J. O’Hanlon, and T. J. King, J. Chem. Soc., Perkin Trans. 1, 1352 (1980).
V. N. Britsun, V. O. Doroshuk, N. V. Bogdan, V. M. Zaitsev, and M. O. Lozinskii, Ukr. Khim. Zh., 73,
No. 5, 40 (2007).
9.
10.
11.
F. Duus, J. Amer. Chem. Soc., 108, 630 (1986).
U. Berg, J. Sandstrom, L. Carlsen, and F. Duus, J. Chem. Soc., Perkin Trans. 2, 1321 (1983).
A. Albert and E. P. Sergeant, Ionization Constants of Acids and Bases, [Russian translation], Khimiya,
Moscow, Leningrad (1964), p. 139.
12.
13.
Cambridge Crystallographic Data Base, release 2007.
V. N. Britsun, A. N. Borisevich, L. S. Samoilenko, A. N. Chernega, and M. O. Lozinskii, Izv. Akad.
Nauk, Ser. Khim., 757 (2005).
13
14.
15.
16.
E. Breitmaier and W. Voelter, C NMR Spectroscopy, 2nd Edition, Verlag Chemie, Weinheim (1978),
p. 183.
G. M. Sheldrick, SHELXS97. A Program for the Solution of Crystal Structures, Göttingen University,
Germany (1997).
G. M. Sheldrick, SHELXL97. A Program for the Refinement of Crystal Structures, Göttingen University,
Germany (1997).
1419