Synthesis and alkylation of N(3)-aryl-N(5)-phenyl-6- amino-4-aryl(2-furyl)-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamide

Article abstract of DOI:10.1007/s10593-008-0114-5

N₍₃₎-Aryl-N₍₅₎-phenyl-6-amino-4-aryl(2-furyl)-2- thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides have been obtained by the interaction of N-phenyl-3-aryl(2-furyl)-2-cyanoacrylamides with 3-amino-3-thioxopropananilides under the

Full text of DOI:10.1007/s10593-008-0114-5

Chemistry of Heterocyclic Compounds, Vol. 44, No. 7, 2008
SYNTHESIS AND ALKYLATION
OF N(3)-ARYL-N(5)-PHENYL-6-AMINO-
4-ARYL(2-FURYL)-2-THIOXO-
1,2,3,4-TETRAHYDROPYRIDINE-
3,5-DICARBOXAMIDE
V. D. Dyachenko, D. A. Krasnikov, and M. V. Khorik
N(3)-Aryl-N(5)-phenyl-6-amino-4-aryl(2-furyl)-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides
have been obtained by the interaction of N-phenyl-3-aryl(2-furyl)-2-cyanoacrylamides with 3-amino-
3-thioxopropananilides under the conditions of the Michael reaction. N(3)-Aryl-N(5)-phenyl-2-alkylthio-
6-amino-4-aryl(2-furyl)-3,4-dihydropyridine-3,5-dicarboxamides and N(3),N(5)-diphenyl-6-benzylthio-
4-(2-furyl)-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides were synthesized by alkylation of the
products.
Keywords: dihydropyridines, tetrahydropyridines, alkylation, heterocyclization, Michael reaction.
Derivatives of 3,5-dicarbamoyl-substituted partially hydrogenated pyridines attract the attention of
investigators in connection with the discovery of a series of biologically active compounds among them, in
particular, calcium channel antagonists [1-5].
Previously we obtained for the first time 3-carbamoyl-6-methyl-5-phenyl-2-thioxocarbamoyl-1,2,3,4-
tetrahydropyridine-4-spirocyclohexane [6] by the Michael reaction and 6-amino-2-mercaptopyridine-
3,5-dicarboxamides by the SNvin reaction [7].
In the present work the interaction has been investigated of N-phenyl-3-aryl(2-furyl)-2-cyano-
acrylamides 1a-d with 3-amino-3-thioxopropanilides 2a-b in absolute ethanol at 20oC in the presence of sodium
ethylate. It was shown that this reaction leads to the formation of N(3)-aryl-N(5)-phenyl-6-amino-4-aryl(2-furyl)-
2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides 3a-e (Table 1). The pathway for this process probably
includes the formation of the appropriate Michael adducts 4, readily converting under the conditions of the
reaction by intramolecular chemoselective heterocyclization into the substituted partially hydrogenated
pyridines 3a-e.
The
corresponding
N(3)-aryl-N(5)-phenyl-2-alkylthio-6-amino-4-aryl(2-furyl)-3,4-dihydropyridine-
3,5-dicarboxamides 6a-c were synthesized on interacting compounds 3 with alkyl halides 5a,b in ethanol in the
presence of sodium ethylate. Replacement of sodium ethylate in this reaction by aqueous KOH solution and
heating the reaction mixture to 50°C is accompanied not only by the formation of the corresponding organic
sulfide but also by hydrolysis of the amino group. N(3),N(5)-Diphenyl-6-benzylthio-4-(2-furyl)-2-oxo-1,2,3,4-
tetrahydropyridine-3,5-dicarboxamide (7) was obtained in this way.
__________________________________________________________________________________________
Lugansk Taras Shevchenko National Pedagogical University, Lugansk 91011, Ukraine; e-mail:
dvd_lug@online.lg.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1018-1023, July,
2008. Original article submitted March 22, 2007.
0009-3122/08/4407-0815©2008 Springer Science+Business Media, Inc.
815

1
A characteristic of the H NMR spectra of compounds 3a-e is the presence of all the proton signals of
the substituents of the tetrahydropyridine nucleus in the appropriate regions (Table 2), and also of signals of the
H-3 and H-4 protons as singlets at 4.07-4.25 and 5.01-5.09 ppm respectively. The absence of splitting of these
signals into the expected doublets may be explained by the formation of a conformation of the
tetrahydropyridine ring in which the dihedral angle of the H–C(3)–C(4)–H fragment, described by the Karplus
equation, approaches 90o [8].
O
NHAr
O
S
O
R
O
R
O
S
NH2
S
2a,b
NHAr
PhHN
PhHN
H2N
NHAr
. .
C
N
N
H
H2N
3a–e
4
R1
5b
Hal
5a,b
O
O
R
O
O
O
O
CHR
CN
PhHN
H2N
NHPh
R1
PhHN
PhHN
NHPh
Ph
N
S
O
N
H
S
1a–d
6a–c
7
1 a R = 2-furyl, b R = Ph, c R = 4-MeC6H4, d R = 4-ClC6H4; 2 а Ar = Ph, b Ar = 3-MeC6H4;
3 a–d Ar = Ph; a R = 2- furyl, b R = Ph, c R = 4-MeC6H4, d R = 4-ClC6H4, e Ar = 3-MeC6H4,
R = 4-ClC6H4; 5 a Hal = I, R1 = H, b Hal = Cl, R1 = Ph; 6 a R = 2-furyl,
R1 = H, b R = R1 = Ph, c R = 4-MeC6H4, R1 = Ph
TABLE 1. Characteristics and Data of Elemental Analysis of Compounds
3a-e, 6a-c, 7
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
C23H20N4O3S
63.79
63.87
67.70
67.85
68.18
68.40
62.76
62.95
63.42
63.60
64.63
64.56
72.13
72.16
72.39
72.50
4.72
4.66
5.12
5.01
5.12
5.30
4.29
4.44
4.52
4.72
4.81
4.97
5.28
5.30
5.32
5.53
12.78
12.95
12.50
12.66
12.09
12.27
11.58
11.75
11.29
11.41
12.35
12.55
10.41
10.52
10.08
10.25
230-233
195-197
208-210
190-192
193-195
204-206
207-209
173-175
224-226
72
86
82
85
79
70
77
79
58
3a
3b
3c
3d
3e
6a
6b
6c
7
C25H22N4O2S
C26H24N4O2S
C25H21ClN4O2S
C26H23ClN4O2S
C24H22N4O3S
C32H28N4O2S
C33H30N4O2S
C30H25N3O4S
68.68
68.82
4.76
4.81
8.18
8.03
816

TABLE 2. 1H NMR Spectrum of Compounds 3a-e, 6a-c, and 7
Com-
pound
Chemical shifts, δ, ppm, J (Hz)
3a
4.24 (1H, s, Н-3); 5.09 (1Н, s, Н-4); 5.99 (1Н, d, J = 2.6, Н-3 furan);
6.34 (1Н, dd, J = 2.6, J = 1.6, Н-4 furan); 6.90 (1Н, t, J = 7.2, Harom);
7.05 (1Н, t, J = 7.4, Harom); 7.20-7.54 (9Н, m, Н-5 furan and Harom);
8.25 and 9.57 (both 1Н, both br. s, NH2);
10.52 and 10.57 (both 1Н, both br. s, 2NHCO); 13.18 (1H, br. s, N(1)H)
3b
3c
4.11 (1H, s, Н-3); 5.06 (1H, s, Н-4); 6.90 (1H, t, J = 7.0, Harom); 7.07 (1H, t, J = 7.0, Harom);
7.20 (4H, m, Harom); 7.31-7.38 (5H, m, Harom); 7.54 (2H, d, J = 7.5, Harom);
7.58 (2H, d, J = 7.5, Harom); 8.17 and 9.41 (both 1H, both br. s, NH2);
10.52 and 10.54 (both 1H, both br. s, 2NHCO); 13.33 (1H, br. s, N(1)H)
2.25 (3Н, s, СН3); 4.07 (1H, s, Н-3); 5.01 (1H, s, Н-4); 6.90 (1H, t, J = 6.7, Harom);
7.07 (1Н, t, J = 6.7, Harom); 7.12 (2H, d, J = 6.9, Harom); 7.20 (2H, t, J = 7.0, Harom);
7.24 (2H, d, J = 6.9, Harom); 7.32 (2H, t, J = 6.6, Harom); 7.53 (2H, d, J = 7.8, Harom);
7.58 (2H, d, J = 7.8, Harom); 8.13 and 9.38 (both 1Н, both br. s, NH2);
10.49 and 10.51 (both 1Н, both br. s, 2NHCO); 13.32 (1Н, br. s, N(1)H)
3d
4,25 (1Н, s, Н-3); 5.02 (1Н, s, Н-4); 6.89 (1Н, t, J = 7.1, Harom); 7.05 (1Н, t, J = 7.2, Harom);
7.19 (2Н, t, J = 7.7, Harom); 7.30 (2Н, t, J = 7.7, Harom); 7.38 (2Н, d, J = 8.3, Harom);
7.47 (2Н, d, J = 8.3, Harom); 7.53 (2Н, d, J = 8.0, Harom); 7.65 (2Н, d, J = 8.1, Harom);
8.92 and 9.91 (both 1Н, both br. s, NH2); 10.52 and 10.96 (both 1Н, both br. s, 2CONH);
13.35 (1Н, br. s, N(1)H)
3e
6a
2.21 (3Н, s, СН3); 4.25 (1H, s, Н-3); 5.01 (1H, s, Н-4); 6.72 (1H, d, J = 6.8, Harom);
7.03-7.10 (2H, m, Harom); 7.28-7.48 (8H, m, Harom); 7.65 (2H, d, J = 8.4, Harom);
8.88 and 9.88 (both 1Н, both br. s, NH2); 10.52 and 10.95 (both 1Н, both br. s, 2NHCO);
13.30 (1Н, br. s, N(1)H)
2.43 (3Н, s, СН3); 3.96 (1H, c, Н-3); 4.74 (1H, s, Н-4); 6.11 (1H, d, J = 2.0, Н-3 furan);
6.34 (1H, dd, J = 2.0, J = 1.5, Н-4 furan); 6.92 (1H, t, J = 7.3, Harom);
7.05 (1H, t, J = 7.3, Harom); 7.19 (2H, t, J = 7.8, Harom); 7.30 (2H, t, J = 7.8, Harom);
7.52 (2H, d, J = 7.7, Harom); 7.56-7.60 (3Н, m, Harom and Н-5 furan); 7.78 (2Н, br. s, NH2);
8.40 and 10.25 (both 1Н, both br. s, 2NHCO)
6b
6c
7
3.60 (1Н, s, Н-3); 4.23 and 4.37 (both 1Н, both d, 2J = 13.1, CH2); 4.66 (1Н, s, Н-4);
6.92 (1Н, t, J = 7.2, Harom); 7.08 (1Н, t, J = 7.2, Harom); 7.14–7.35 (12Н, m, Harom);
7.39 (2Н, d, J = 8.0, Harom); 7.44 (2Н, d, J = 8.1, Harom); 7.56 (2Н, br. s, NH2);
7.61 (2Н, d, J = 8.0, Harom); 8.89 and 9.91 (both 1Н, both br. s, 2NHCO)
2.25 (3Н, s, СН3); 3.57 (1Н, s, Н-3); 4.24 and 4.37 (both 1H, both d, 2J = 13.2, СН2);
4.62 (1Н, s, Н-4); 6.93 (1Н, t, J = 6.5, Harom); 7.06–7.50 (16Н, m, Harom);
7.56 (2Н, br. s, NH2); 7.61 (2Н, d, J = 7.5, Harom);
8.84 and 9.88 (both 1Н, both br. s, 2NHCO)
3.90 (1H, d, J = 5.3, Н-3); 4.12 and 4.24 (both 1H, both d, 2J = 12.1, СН2);
4.70 (1H, d, J = 5.3, Н-4); 6.20 (1H, d, J = 3.0, Н-3 furan);
6.35 (1H, dd, J = 3.0, J = 1.9, Н-4 furan); 7.00 (1H, t, J = 7.3, Harom);
7.07 (1H, t, J = 7.3, Harom); 7.20-7.35 (10Н, m, Harom); 7.44 (1H, d, J = 7.9, Harom);
7.56-7.60 (3Н, m, Н-5 furan and Harom); 9.58 (1Н, br. s, N(1)H);
10.30 and 10.32 (both 1Н, both br. s, NHCO)
We also noted the presence of signals of the amino group protons displayed as two broadened singlets at
8.31-8.92 and 9.38-9.91 ppm respectively. These data show the nonequivalence of the NH2 group protons,
caused probably by intramolecular hydrogen bonds. Previously, according to X-ray structural data, we detected
the presence of an extremely strong intramolecular hydrogen bond, closing a six-membered ring between a
hydrogen atom of the amino group and the oxygen atom of an amide fragment in pyridine, in which the amino
group and the arylcarbamoyl fragment are disposed vicinally [9].
The mass spectra of the substituted tetrahydropyridine-2-thiones 3a-e are characterized by the presence
of a peak for the molecular ion at an even number, which corresponds to the "nitrogen rule" [10], and also by the
presence of an [M+2]+ ion which may indicate the content in the molecule of one sulfur atom [11] (Table 3).
A special feature of the 1H NMR spectra of substituted 3,4-dihydropyridines 6a,b and tetrahydropyridin-
2-one 7 is the splitting of the SCH2Ph methylene group proton signals into two doublets, which indicates their
nonequivalence, caused by the absence of rotation of the alkyl substituent around the S–CH2Ph bond. This fact,
known in a series of partially hydrogenated 2-alkylthiopyridines [12, 13], enables 2J be recorded for the SCH2Ph
group, which is within the limits 12.1-13.2 Hz (Table 2).
817

TABLE 3. IR and Mass Spectra of Compounds 3a-e, 6a-c, and 7
Com-
pound
IR spectrum, ν, cm-1
Mass spectrum, m/z (Irel, %)
CONH, δNH
NH2, NH
2
434 (14) [M+2]+, 432 [M]+ (62), 430 [M−2]+ (100),
3380,
3296,
3161
1684,
1656
3a
3b
3c
3d
3e
6a
6b
6c
7
356 (19), 312 (14), 218 (9), 193 (7), 124 (6), 84 (5)
3302,
3268
2965
1684,
1654
444 [M+2]+ (9), 442 [M] (49), 440 [M−2]+ (100), 366 (12),
322 (10), 280 (6), 188 (15), 154 (7), 106 (9), 85 (16)
3359,
3177,
2963
1687,
1622
458 [M+2]+ (11), 456 [M]+ (65), 454 [M−2]+ (100), 428 (6),
380 (8), 352 (12), 188 (15), 159 (13), 122 (10), 84 (17)
3350,
3294,
3134
1696,
1662
479 [M+2]+ (48); 477 [M]+ (100), 384 (18), 356 (9),
239 (11), 186 (5), 94 (16)
3318,
3296,
2956
1686,
1631
492 [M+1]+ (61), 491 (100) [M]+, 459 (10), 398 (14),
296 (5), 220 (19), 180 (11), 83 (10)
3342,
3218,
2995
1698,
1653
448 [M+2]+ (37), 447 [M+1]+ (100), 428 (5), 354 (10),
260 (8), 157 (50), 99 (11)
3365,
3300,
3115
1684,
1637
534 [M+2]+ (50), 533 [M+1]+ (100), 440 (12), 295 (16),
157 (48), 94 (22)
3352,
3205,
3199
1683,
1653
546 [M]+ (48), 544 [M−2]+ (100), 388 (11), 261 (9),
136 (15), 106 (4), 84 (7)
3310,
3214,
2965
1685,
1647
524 [M+1]+ (100), 432 (15), 157 (14), 94 (12)
EXPERIMENTAL
1
The IR spectra of the synthesized compounds were recorded on a IKS-40 instrument in nujol. The H
NMR spectra were recorded on a Varian Mercury 400 (400 MHz) instrument in DMSO-d6 solution, internal
standard was TMS. The mass spectra were obtained on a Chrommass GC/MS instrument Hewlett-Packard
5890/5972, on a HP-5 column MS (70 eV) in methylene chloride solution. Melting points were determined on a
Kofler block. A check on the progress of reactions and the purity of the substances obtained was effected by
TLC on Silufol UV-254 plates, eluent was an acetone–hexane mixture, 3:5, visualization with iodine vapor and
UV light.
N(3),N(5)-Diphenyl-6-amino-4-(2-furyl)-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamide (3a),
N(3),N(5),4-Triphenyl-6-amino-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-carboxamide (3b), N(3),N(5)-Diphenyl-
6-amino-2-thioxo-4-(4-tolyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxamide (3c), N(3),N(5)-Diphenyl-6-amino-
4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamide (3d), and N(3)-(3-Tolyl)-N(5)-
phenyl-6-amino-4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamide
(3e).
The
CH-acid 2a,b (5 mmol) was added at 20°C to a stirred solution of metallic sodium (0.115 g, 5 mmol) in absolute
ethanol (30 ml) and stirred for 10 min to form a homogeneous phase. The appropriate acrylamide 1a-d (5 mmol)
was then added, the mixture stirred for 2 h, after which the mixture was diluted with 10% hydrochloric acid to
pH 6, and left at room temperature. After 1 day the solid which formed was filtered off, washed with ethanol and
with hexane, and recrystallized from ethanol (Tables 1-3).
N(3),N(5)-Diphenyl-6-amino-4-(2-furyl)-2-methylthio-3,4-dihydropyridine-3,5-dicarboxamide (6a),
N(3),N(5),4-Triphenyl-6-amino-2-benzylthio-3,4-dihydropyridine-3,5-dicarboxamide (6b), and N(3),N(5)-
818

6-amino-2-benzylthio-4-(4-tolyl)-3,4-dihydropyridine-3,5-dicarboxamide (6c). A solution of metallic sodium
(0.115 g, 5 mmol) in absolute ethanol (15 ml) was added to a stirred suspension of compound 3a-c (5 mmol) in
absolute ethanol (15 ml) at 20°C, and stirred for 10 min to obtain a homogeneous phase. Alkyl halide 5a,b (5
mmol) was added to the reaction mixture, which was stirred for 1 h, and then left for 2 days at room
temperature. The solid formed was filtered off, washed with ethanol, and with hexane, and recrystallized from
ethanol (Tables 1-3).
N(3),N(5)-Diphenyl-6-benzylthio-4-(2-furyl)-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamide (7). A
10% aqueous solution of KOH (1.68 ml, 3 mmol) was added to a stirred suspension of compound 3a (1.30 g,
3 mmol) in ethanol (30 ml), and the mixture was stirred at 50oC until complete solution. Benzyl chloride 5b
(0.35 ml, 3 mmol) was added to the obtained solution, and the mixture was left for 2 days. The resulting solid
was filtered off, washed with ethanol, and with hexane, and recrystallized from ethanol (Tables 1-3).
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