3-Amino-3-thioxopropanamide in the synthesis of functionally substituted nicotinamides

Article abstract of DOI:10.1023/B:RUJO.0000010189.83376.ca

Derivatives of ethoxymethylenemalonic acids by condensation with 3-amino-3-thioxopropanamide in the presence of sodium ethylate furnished chalcogenopyridines and polyfunctionally substituted dienes which were converted into nicotinamide derivatives.

Full text of DOI:10.1023/B:RUJO.0000010189.83376.ca

Russian Journal of Organic Chemistry, Vol. 39, No. 8, 2003, pp. 1174 1179. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 8, 2003,
pp. 1245 1250.
Original Russian Text Copyright
2003 by Dyachenko, Tkachev.
3-Amino-3-thioxopropanamide in the Synthesis
of Functionally Substituted Nicotinamides
V. D. Dyachenko and R. P. Tkachev
Lugansk State Pedagogical University, Lugansk, 91011 Ukraine, e-mail: dvd_lug@online.lg.ua
Received November 15, 2002
Abstract Derivatives of ethoxymethylenemalonic acids by condensation with 3-amino-3-thioxopropanamide
in the presence of sodium ethylate furnished chalcogenopyridines and polyfunctionally substituted dienes
which were converted into nicotinamide derivatives.
The nicotinamide is among the most important
biologically active substances, and the synthesis of
its substituted analogs is one of the most promising
synthetic lines in preparation of compounds with
predetermined pharmacological properties. In this
connection we developed a procedure for preparation
of new substituted nicotinamide derivatives and
investigated their properties.
course of reaction SNVin to isolate free compounds
IV it is presumable that the formation of pyridines
III and V is preceded by the corresponding acyclic
structures IV. The information on acyclic or hetero-
cyclic structure of the product obtained in the SNVin
reaction is provided by IR spectra. In the IR spectra
of compounds IV appears a signal of a conjugated
1
cyano group in the region 2218 2224 cm , whereas
in the IR spectra of pyridines III such absorption
bands are lacking. These characteristics also confirm
the regioselectivity of the intramolecular hetero-
cyclization of compounds IV involving the cyano
group.
A convenient reagent for preparation of nicotin-
amide derivatives is 3-amino-3-thioxopropanamide
(I) that by reaction with activated olefins provides
various pyridinechalcogenones: 4,6-diaryl-3-thio-
carbamoyl-3,4-dihydropyridin-2(1H)-ones [1, 2],
3-carbamoyl-5-(pyrid-4-yl)pyridine-2(1H)-thione [3],
6-amino-4-aryl-3-carbamoyl-5-cyano-1,4-dihydro-
pyridine-2-thiolates [4], piperidinium 5-carbamoyl-2-
oxo-4-phenyl-3-cyano-3,4-dihydro-6(1H)-thiolate [5].
We prepared formerly 2-alkylsulfanyl-6-amino-5-
phenylcarbamoyl-3-cyanopyridines by alkylation of
N-methylmorpholinium 1-amino-4-phenylcarbamoyl-
2,4-dicyano-1,3-butadiene-1-thiolate [6].
The formation of nicotinethioamide V and not of
substituted nicotinamide III in reaction of propan-
amide I with diethyl ethoxymethylenemalonate (IIi)
1
was proved by H NMR spectrum of the product. In
the spectrum of compound V were observed signals
of two protons belonging to thioamide group as two
broadened singlets at 10.0 and 10.5 ppm, whereas
the signals of two protons from an amide group
appeared commonly more upfield (6.6 7.7 ppm for
compounds III, IV) in agreement with the published
data [2, 5, 7].
In the present study we involved 3-amino-3-thi-
oxopropanamide (I) into a reaction of nucleophilic
vinyl substitution (SNVin). In reaction with ethoxy-
olefins II in the presence of a base compound I plays
the part of a CH-acid and affords nicotinamides III,
polyfunctionally substituted dienes IV, or nicotine-
Thus in the ring closure involving a cyano group a
thiocarbamoyl group is more nucleophilic than a
carbamoyl one. At the same time in intramolecular
cyclization with an ester group the amide group is
more reactive than the thioamide one. These differ-
ences can be rationalized basing on steric reasoning.
The cyano group with the sp-hybridized carbon atom
is digonal, and the approach thereto of a bulky thio-
carbamoyl group (which in this case is apparently
more nucleophilic than carbamoyl group) is not
hampered. The ethoxycarbonyl group containing sp2-
hybridized carbon is trigonal, and the nucleophile
attack is subject to special steric requirements. The
1
thioamides V. H NMR spectra both of pyridines III
and compounds IV contain proton signals from two
amino groups in the region 6.6 8.2 ppm, a proton
signal from the =CH group at 8.5 9.1 ppm. and also
signals from the electron-acceptor group X in the
appropriate regions. IR spectra of compounds III, IV
contain a set of bands characteristic of amino group
1
(3100 3470 cm ), and also characteristic signals of
the stretching vibrations of the NHCO group at
1
1660 1690 cm . Since we have been able in the
1070-4280/03/3908-1174$25.00 2003 MAIK Nauka/Interperiodica

3-AMINO-3-THIOXOPROPANAMIDE
1175
II, III, Y = CN, X = o-MeC6H4NHCO (a), m-MeC6H4NHCO (b), o-MeOC6H4NHCO (c), m-MeOC6H4NHCO (d),
-naphthylcarbamoyl (e), 4-phenyl-1,3-thiazol-2-yl (f), PhNHCO (g), EtOOC (h); Y = X = EtOOC (i). IV, X =
PhNHCO (a); EtOOC (b). VI, Hlg = Cl, Z = Ph (a); Hlg = Br, Z = CH=CH2 (b), C(O)Ph (c); Hlg = I, Z =
(CH2)3CH3 (d), H (e). VII, X = o-MeC6H4NHCO, Z = (CH2)3CH3 (a), CH= CH2 (b); X = o-MeOC6H4NHCO,
Z = (CH2)3CH3 (c), C(O)Ph (d); X = m-MeOC6H4NHCO, Z = (CH2)3CH3 (e); X = -naphthylcarbamoyl, Z =
(CH2)3CH3 (f); X = 4-phenyl-1,3-thiazol-2-yl, Z = (CH2)3CH3 (g), CH=CH2 (h), Ph (i); X = PhNHCO, Z =
(CH2)3CH3 (j). XI, Z = CH=CH2 (a), H (b).
attack of carbamoyl group having smaller volume
than the thiocarbamoyl group occurs easier at the
electrophilic site of the ester group. The results
obtained are well consistent with the data of [8] where
has been demonstrated that under similar conditions
the 6-exo-dig-process has an advantage over 6-exo-
trig-process.
The acylation of mercaptopyridine IIIf in excess
acylating agent occurs both at NH2 and SH groups
yielding
3-carbamoyl-6-methylcarboxamido-5-(4-
phenyl-1,3-thiazol-2-yl)-2-pyridylethanethioate
(IX), and bromination of compound VIIj proceeds
regioselectively at the benzene ring and affords deriv-
ative X.
Pyridines III undergo alkylation at SH group by
halides VIa d affording organic sulfides VII. The
alkylation of compound IVa also gives N3-phenyl-2-
amino-6-pentylmercaptopyridine-3,5-dicarboxamide
VIIj, whereas in reaction of compound IVb with
methyl iodide we succeeded to isolate acyclic sulfide
VIII. This alkylation product unlike pyridines VII
contained in the IR spectrum the band belonging to
The alkylation of pyridone V also occurs regio-
selectively under mild conditions at the sulfur atom,
similarly to alkylation of the substituted 3-amino-
(thioxo)methyl-3,4-dihydropyridin-2(1H)-one [2]. But
in our case the carbimine group does not undergo
hydrolysis, and the reaction stops at the stage of
5-alkylmercapto(imino)methylpyridines (XI) forma-
tion. The obtained previously unknown ethyl 5-alkyl-
mercapto(imino)methyl-6-hydroxy-2-oxo-1,2-dihydro-
pyridine-3-carboxylates are of great synthetic and
1
the conjugated cyano group (2216 cm ) that confirm-
ed its acyclic structure.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003

1176
DYACHENKO, TKACHEV
pharmacological interest and require further investig-
ation.
H 4.52; N 18.39. C14H14N4O2S. Calculated, %:
C 55.61; H 4.67; N 18.53.
N3-(o-Anisyl)-2-amino-6-mercaptopyridine-
3,5-dicarboxamide (IIIc). Yield 2.52 g (79%),
mp 284 286 C. IR spectrum, cm : 3166, 3330,
3466 [ (NH2)], 1666 [ (C=O)], 1622 [ (NH2)].
1H NMR spectrum, , ppm: 3.98 s (3H, OCH3),
6.89 7.19 m (4H, Harom), 6.91 and 7.17 both br.s
(2H, CONH2), 8.00 br.s (2H, NH2), 8.50 s (1H,
C4H), 8.92 s (1H, SH), 11.06 s (1H, CONH).
Found, %: C 52.91; H 4.29; N 17.72. C14H14N4O3S.
Calculated, %: C 52.82; H 4.43; N 17.60.
EXPERIMENTAL
1
IR spectra were recorded on spectrophotometer
IKS-40 from mulls in mineral oil. H NMR spectra
1
were registered from solutions in DMSO-d6 on
spectrometers Bruker DRX500 (500.13 MHz) (com-
pounds IIIa, N, VIIb, XI), and Gemini-200
(199.975 MHz) (compounds IIIb f, IVa, b, VIIa,
c j, VIII, IX, X), internal reference TMS. Mass
spectra were measured on Kratos MS-890 instrument
(70 eV). The melting points were determined on
Koeffler heating block. The reaction progress was
monitored and the homogeneity of the compounds
obtained was checked by TLC on Silufol UV-254
plates, eluent acetone hexane, 3: 5, development in
iodine vapor.
N3-(m-Anisyl)-2-amino-6-mercaptopyridine-
3,5-dicarboxamide (IIId). Yield 2.90 g (91%),
1
mp 310 312 C. IR spectrum, cm : 3174, 3330,
3430 [ (NH2)], 1670 [ (C=O)], 1630 [ (NH2)].
1H NMR spectrum, , ppm: 3.79 s (3H, OCH3), 6.53
and 6.95 both br.s (2H, CONH2), 7.10 7.38 m (4H,
Harom), 7.41 br.s (2H, NH2), 8.65 s (1H, C4H),
9.91 s (1H, SH), 10.98 s (1H, CONH). Found, %:
C 52.69; H 4.25; N 17.71. C14H14N4O3S. Calculat-
ed, %: C 52.82; H 4.43; N 17.60.
Compounds IIIa f. To a solution of 0.68 g
(10 mmol) of sodium ethylate in 15 ml of ethanol was
added at 20 C 1.18 g (10 mmol) of 3-amino-3-thi-
oxopropanamide (I), and the mixture was stirred for
5 min till dissolution of all components. Then to the
reaction mixture was added 10 ml of an appropriate
olefin II, and the stirring was continued for 10 min.
At the same time a precipitate separated. The mixture
was left standing for 2 h, and then compounds IIIa f
were filtered off.
N3-(o-Tolyl)-2-amino-6-mercaptopyridine-
3,5-dicarboxamide (IIIa). Yield 2.63 g (87%), mp
333 335 C. Mass spectrum, m/z (Irel, %): 259 (2.5),
250 (2.5), 233 (3), 153 (20), 126 (26), 106 (100),
N3-( -Naphthyl)-2-amino-6-mercaptopyridine-
3,5-dicarboxamide (IIIe). Yield 2.33 g (69%), mp
1
328 330 C. IR spectrum, cm : 3316, 3394
1
[ (NH2)], 1672 [ (C=O)], 1648 [ (NH2)]. H NMR
spectrum, , ppm: 6.98 and 7.31 both br.s (2H,
CONH2), 7.38 7.62 m (7H, Harom), 8.18 br.s (2H,
NH2), 8.95 s (1H, C4H), 10.20 s (1H, SH), 10.85 s
(1H, CONH). Found, %: C 60.39; H 4.09; N 16.47.
C17H14N4O2S. Calculated, %: C 60.34; H 4.17;
N 16.56.
1
2-Amino-6-mercapto-3-(4-phenyl-1,3-thiazol-2-
89 (15), 77 (28), 53 (20), 34 (27). IR spectrum, cm :
3108, 3332, 3448 [ (NH2)], 1676 [ (C=O)], 1648
[ (NH2)]. H NMR spectrum, , ppm: 2.22 s (3H,
yl)pyridine-5-carboxamide (IIIf). Yield 3.02 g
1
1
(92%), mp 308 310 C. IR spectrum, cm : 3118,
3292, 3434[ (NH2)], 1661 [ (C=O)], 1632 [ (NH2)].
1H NMR spectrum, , ppm: 7.11 and 7.42 both br.s
(2H, CONH2), 7.35 d.d (1H, Harom, J 6.7 Hz),
7.43 d.d (2H, Harom), 7.81 br.s (2H, NH2), 7.82 s
(1H, C5H), 7.92 d (2H, Harom, J 7.2 Hz), 8.52 s
(1H, C4H), 10.92 s (1H, SH). Found, %: C 54.63;
H 3.34; N 16.89. C15H12N4OS2. Calculated, %:
C 54.86; H 3.68; N 17.06.
CH3), 6.65 and 7.28 both br.s (2H, CONH2),
7.06 d.d (1H, Harom, J 7.5 Hz), 7.12 d.d (1H, Harom
,
J 8.0 Hz), 7.16 d (1H, Harom, J 8.5 Hz), 7.20 d (1H,
Harom), 7.34 br.s (2H, NH2), 8.69 s (1H, C4H),
9.67 s (1H, SH), 10.85 s (1H, CONH). Found, %:
C 55.80; H 4.43; N 18.38. C14H14N4O2S. Calculat-
ed, %: C 55.61; H 4.67; N 18.53.
N3-(m-Tolyl)-2-amino-6-mercaptopyridine-
3,5-dicarboxamide (IIIb). Yield 2.33 g (77%), mp
Compounds IVa, b were prepared similarly to
mercaptopyridines IIIa f from compounds IIg, h.
1
325 327 C. IR spectrum, cm : 3168, 3316, 3420
N1-Phenyl-4-(1-amino-1-mercaptomethylidene)-
2-cyanopent-2-enediamide(IVa). Yield2.45g(85%),
1
[ (NH2)], 1666 [ (C=O)], 1626 [ (NH2)]. H NMR
spectrum, , ppm: 2.30 s (3H, CH3), 6.77 and 7.11
both br.s (2H, CONH2), 7.09 7.51 m (4H, Harom),
7.50 br.s (2H, NH2), 8.63s (1H, C4H), 9.83 s (1H,
SH), 11.01 s (1H, CONH). Found, %: C 55.71;
1
mp 330 335 C. IR spectrum, cm : 3144, 3310,
3378[ (NH2)], 2224[ (C N)], 1674, 1720 [ (C=O)],
1
1644 [ (NH2)]. H NMR spectrum, , ppm: 7.04 d.d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003

3-AMINO-3-THIOXOPROPANAMIDE
1177
(1H, Harom, J 7.5 Hz), 7.23 and 7.56 both br.s (2H,
CONH2), 7.27 d.d (2H, Harom), 7.62 d (2H, Harom, J
8.0 Hz), 7.64 br.s (2H, NH2), 8.70 s (1H, CH=),
9.81 s (1H, CONH), proton signal of SH group was
not detected apparently due to fast exchange with
protons of water present in the solvent. Found, %:
C 54.47; H 4.09; N 19.77. C13H12N4O2S. Calculated,
%: C 54.15; H 4.20; N 19.43.
N3-(o-Tolyl)-6-allylmercapto-2-aminopyridine-
3,5-dicarboxamide (VIIb). Yield 1.42 g (83 %), mp
184 185 C (AcOH). Mass spectrum, m/z (Irel, %):
342 (75) [M]+ , 327 (32), 309 (68), 301 (80), 236
1
(100), 167 (71), 107 (58), 41(61). IR spectrum, cm :
3208, 3306, 3424 [ (NH2)], 1696 [ (C=O)], 1646
1
[ (NH2)]. H NMR spectrum, , ppm: 2.27 s (3H,
CH3), 3.72 d (2H, SCH2, J 6.3 Hz), 5.04 d (1H,
=CH2, Jcis 9.6 Hz), 5.28d (1H, =CH2, Jtrans
16.3 Hz), 5.92 m (1H, CH=), 7.02 and 7.08 both
br.s (2H, CONH2), 7.14 d.d (1H, Harom, J 8.0 Hz),
7.19 d.d (1H, Harom, J 8.0 Hz), 7.23 d (1H, Harom),
7.29 d (1H, Harom, J 8.5 Hz), 7.30 br.s (2H, NH2),
8.39 s (1H, C4H), 9.46 s (1H, CONH). Found, %:
C 59.39; H 5.48; N16.12. C17H18N4O2S. Calculated,
%: C 59.63; H 5.30; N 16.36.
Ethyl-5-amino-4-(1-amino-1-mercaptomethylid-
ene)-5-oxo-2-cyanopent-2-enoate (IVb). Yield 1.78g
1
(74%), mp 220 222 C. IR spectrum, cm : 3186,
3350 [ (NH2)], 2218 [ (C N)], 1694 [ (C=O)],
1
1646 [ (NH2)]. H NMR spectrum, , ppm: 1.31 t
(3H, CH3CH2), 4.28 q (2H, CH2), 7.52 and 7.71
both br.s (2H, CONH2), 8.04 br.s (2H, NH2), 9.07 s
(1H, CH=), 9.79 s (1H, SH). Found, %: C 44.49;
H 4.85; N 17.23. C9H11N3O3S. Calculated, %:
C 44.80; H 4.60; N 17.42.
N3-(o-Anisyl)-2-amino-6-pentylmercapto-
pyridine-3,5-dicarboxamide (VIIc). Yield 1.39 g
1
(72%), mp 201 203 C (EtOH). IR spectrum, cm :
Ethyl-5-amino(thioxo)methyl-6-hydroxy-2-oxo-
1,2-dihydropyridine-3-carboxylate (V) was obtained
similarly to compounds IIIa f from compound IIi.
Yield 2.06 g (85%), mp 226 228 C. IR spectrum,
3172, 3334, 3438 [ (NH2)], 1714 [ (C=O)], 1642
1
[ (NH2)]. H NMR spectrum, , ppm: 0.90 t (3H,
CH3, J 6.9 Hz), 1.37 m (4H, SCH2CH2CH2CH2),
1.60 m (2H, SCH2CH2), 3.00 t (2H, SCH2,
1
cm : 3084, 3428 [ (NH2)], 1706 [ (C=O)], 1624
J 7.0 Hz), 3.84 s (3H, OCH3), 6.91 d.d (1H, Harom
,
[ (NH2)]. 1H NMR spectrum, ppm: 1.33 t (3H,
CH3), 4.21 q (2H, CH2, J 7.1 Hz), 6.71 br.s (1H,
NH), 8.79 s (1H, C4H), 10.00 br.s and 10.50 br.s
(on 1H, NH2), proton signal of OH group was not
detected apparently due to fast exchange with protons
of water present in the solvent. Found, %: C 44.73;
H 4.08; N 11.42. C9H10N2O4S. Calculated, %:
C 44.62; H 4.16; N 11.57.
J 7.6 Hz), 6.98 d (1H, Harom), 7.01 and 7.47 both
br.s (2H, CONH2), 7.11 d.d (1H, Harom, J 7.8 Hz),
7.33 br.s (2H, NH2), 7.64 d (1H, Harom), 8.30 s
(1H, C4H), 9.12 s (1H, CONH). Found, %: C 58.15;
H 6.40; N 14.16. C19H24N4O3S. Calculated, %:
C 58.74; H 6.23; N 14.42.
N3-(o-Anisyl)-2-amino-6-benzoylmethyl-
mercaptopyridine-3,5-dicarboxamide (VIId). Yield
1.92 g (88%), mp 250 252 C (AcOH). IR spectrum,
Compounds VIIa j. To a suspension of 5 mmol
of mercaptopyridine III or pentene IVa in 10 ml of
ethanol was added at stirring 2.8 ml (5 mmol) of 10%
solution of KOH. To the solution formed was added
5 mmol of an appropriate alkyl halide VI, and the
mixture was stirred for 1 h. The separated precipitate
was filtered off and recrystallized from ethanol or
glacial acetic acid.
1
cm : 3195, 3330, 3396 [ (NH2)], 1688 [ (C=O)],
1
1652 [ (NH2)]. H NMR spectrum, , ppm: 3.84 s
(3H, OCH3), 4.53 s (2H, SCH2), 6.89 d. d (1H,
H
arom, J 7.2 Hz), 6.97 d (1H, Harom, J 7.1 Hz), 7.05
and 7.12 both br.s (2H, CONH2), 7.06 d.d (1H,
arom), 7.09 d.d (1H, Harom), 7.44 br.s (2H, NH2),
7.48 d.d (2H, Harom, J 7.6 Hz), 7.63 d (1H, Harom
H
,
N3-(o-Tolyl)-2-amino-6-pentylmercaptopyridine-
3,5-dicarboxamide (VIIa). Yield 1.69 g (91%), mp
J 8.1 Hz), 8.04 d (2H, Harom, J 7.1 Hz), 8.39 s (1H,
C4H), 9.08 s (1H, CONH). Found, %: C 60.88;
H 4.71; N 12.56. C22H20N4O4S. Calculated, %:
C 60.54; H 4.62; N 12.84.
1
180 182 C (AcOH). IR spectrum, cm : 3210, 3304,
1
3434 [ (NH2)], 1700 [ (C=O)], 1644 [ (NH2)]. H
NMR spectrum, , ppm: 0.93 t (3H, CH3), 1.41 m
(4H, SCH2CH2CH2CH2), 1.63 m (2H, SCH2CH2),
2.27s (3H, CH3), 3.05 t (2H, SCH2, J 7.6 Hz), 6.99
7.25 m (4H, Harom), 7.00 and 7.14 both br.s (2H,
CONH2), 7.21 br.s (2H, NH2), 8.39 s (1H, C4H),
9.45 s (1H, CONH). Found, %: 61.49; H 6.71;
N 14.87. C19H24N4O2S. Calculated, %: C 61.26;
H 6.49; N 15.04.
N3-(m-Anisyl)-2-amino-6-pentylmercapto-
pyridine-3,5-dicarboxamide (VIIe). Yield 1.26 g
(65%), mp 194 196 C (EtOH). IR spectrum, cm :
3334, 3444 [ (NH2)], 1666 [ (C=O)], 1628 [ (NH2)].
1HNMR spectrum, , ppm:0.89t(3H, CH3, J 7.0 Hz),
1.36 m (4H, SCH2CH2CH2CH2), 1.61 m (2H,
SCH2CH2), 2.99 t (2H, SCH2, J 7.6 Hz), 3.75 s
1
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DYACHENKO, TKACHEV
(3H, OCH3), 6.54 d (1H, Harom, J 7.5 Hz), 7.01 and
7.19 d.d (1H, Harom, J 7.0 Hz), 7.22 d.d (1H, Harom,
7.18 both br.s (2H, CONH2), 7.08 7.20 m (2H,
J 7.0 Hz), 7.28 d.d (2H, Harom, J 7.6 Hz), 7.35 d.d
(2H, Harom, J 7.1 Hz), 7.48 d (2H, Harom), 7.92 d
(2H, Harom), 7.98 s (1H, C5H), 8.09 br.s (2H, NH2),
8.19 s (1H, C4H). Found, %: C 63.04; H 4.19;
N 13.53. C22H18N4OS2. Calculated, %: C 63.13;
H 4.33; N 13.39.
H
arom), 7.21 br.s (2H, NH2), 7.33 s (1H, Harom),
8.26 s (1H, C4H), 9.66 s (1H, CONH). Found, %:
C 58.97; H 6.49; N 14.58. C19H24N4O3S. Calculated,
%: C 58.74; H 6.23; N 14.42.
N3-( -Naphthyl)-2-amino-6-pentylmercapto-
pyridine-3,5-dicarboxamide (VIIf). Yield 1.49 g
N3-Phenyl-2-amino-6-pentylmercaptopyridine-
1
(73%), mp 204 206 C (AcOH). IR spectrum, cm :
3,5-dicarboxamide (VIIj). Yield 1.39 g (78%), mp
1
3180, 3390 [ (NH2)], 1696 [ (C=O)], 1650
198 200 C (AcOH). IR spectrum, cm : 3334, 3452
1
1
[ (NH2)]. H NMR spectrum, , ppm: 0.94 t (3H,
[ (NH2)], 1664 [ (C=O)], 1626 [ (NH2)]. H NMR
CH3, J 6.9 Hz), 1.39 s (4H, SCH2CH2CH2CH2),
1.62m (2H, SCH2CH2), 3.06t (2H, SCH2, J 7.0 Hz),
7.06 and 7.50 both br.s (2H, CONH2), 7.41 br.s (2H,
NH2), 7.49 8.05 m (7H, Harom), 8.57 s (1H, C4H),
10.03 s (1H, CONH). Found, %: C 64.30; H 5.74;
N 13.45. C22H24N4O2S. Calculated, %: C 64.68;
H 5.92; N 13.72.
spectrum, , ppm: 0.93 t (3H, CH3, J 6.9 Hz),
1.39 m (4H, SCH2CH2CH2CH2), 1.63 m (2H,
SCH2CH2), 3.03 t (2H, SCH2, J 7.0 Hz), 7.02 and
7.27 both br.s (2H, CONH2), 7.06 d.d (1H, Harom
,
J 7.0 Hz), 7.31 d.d (2H, Harom, J 7.6 Hz), 7.63 d
(2H, Harom), 7.64 br.s (2H, NH2), 8.31 s (1H, C4H),
9.83 s (1H, CONH). Found, %: C 60.21; H 6.34;
N 15.93. C18H22N4O2S. Calculated, %: C 60.31;
H 6.19; N 15.63.
2-Amino-6-pentylmercapto-3-(4-phenyl-1,3-thi-
azol-2-yl)pyridine-5-carboxamide (VIIg). Yield
1.65 g (83%), mp 210 212 C (AcOH). IR spectrum,
Ethyl-5-amino-4-carbamoyl-5-methylsylfanyl-
2-cyanopenta-2,4-dienoate (VIII).To a solution of
2.41 g (10 mmol) of pentene IVb in 20 ml of ethanol
a 20 C was added 0.62ml(10mmol) of methyl iodide.
The mixture was left standing at room temperature
for 2 days. The separated precipitate was filtered off,
washed with ethanol and hexane. Yield 1.61 g (63%),
1
cm : 3172, 3298, 3368 [ (NH2)], 1661 [ (C=O)],
1646[ (NH2)]]. 1HNMR spectrum, , ppm: 0.94t(3H,
CH3, J 7.1 Hz), 1.43 m (4H, SCH2CH2CH2CH2),
1.67 m (2H, SCH2CH2), 3.13 t (2H, SCH2, J 7.1
Hz), 7.01 and 7.57 both br.s (2H, CONH2), 7.34 d.d
(1H, Harom, J 7.2 Hz), 7.46 d.d (2H, Harom),
7.82 br.s (2H, NH2), 7.94 d (2H, Harom, J 6.9 Hz),
7.96 s (1H, C5H), 8.14 s (1H, C4H). Found, %:
C 60.42; H 5.39; N 14.27. C20H22N4OS2. Calculat-
ed, %: C 60.27; H 5.57; N 14.06.
1
mp 212 214 C. IR spectrum, cm : 3172, 3346,
3420 [ (NH2)], 2216 [ (C N)], 1696 [ (C=O)],
1
1652 [ (NH2)]. H NMR spectrum, , ppm: 1.33 t
(3H, CH2CH3, J 7.1 Hz), 2.35 s (3H, SCH3), 4.26 q
(2H, CH2), 6.95 br.s (2H, NH2), 7.25 br.s and
7.58br.s (1H each, NH2), 8.23s (1H, CH=). Found,
%: C 46.92; H 5.21; N 16.28. C10H13N3O3S. Cal-
culated, %: C 47.05; H 5.13; N 16.46.
6-Allylmercapto-2-amino-3-(4-phenyl-1,3-thiazol-
2-yl)pyridine-5-carboxamide (VIIh). Yield 1.66 g
1
(90%), mp 215 217 C (AcOH). IR spectrum, cm :
3214, 3302, 3394 [ (NH2)], 1662 [ (C=O)], 1632
1
[ (NH2)]. H NMR spectrum, ppm: 3.78 d (2H,
3-Carbamoyl-6-methylcarboxamido-5-(4-phenyl-
1,3-thiazol-2-yl)-2-pyridylethanethioate (IX). To a
solution of 1.64 g (5 mmol) of thiol (IIIf) in 10 ml
of acetic anhydride was added 0.10 ml of pyridine,
and the mixture was boiled for 3 h and then left stand-
ing at room temperature for 24 h. The precipitate
formed was filtered off, washed with ethanol. Yield
SCH2, J 7.0 Hz), 5.05 d (1H, =CH2, Jcis 9.9 Hz),
5.30 d (1H, =CH2, Jtrans 17.1 Hz), 5.94 m (1H,
CH=), 7.02 and 7.62 both br.s (2H, CONH2),
7.33 d.d (1H, Harom, J 7.1 Hz), 7.45 d.d (2H, Harom
,
J 7.6 Hz), 7.92 br.s (2H, NH2), 7.93 d (2H, Harom),
7.95 s (1H, C5H), 8.17 s (1H, C4H). Found, %:
C 58.29; H 4.59; N 15.03. C18H16N4OS2. Calculated,
%: C 58.67; H 4.38; N 15.21.
1
1.71 (83%), mp 210 212 C. IR spectrum, cm :
3103, 3172, 3399 [ (NH2)], 1682, 1748 [ (C=O)],
1
1610 [ (NH2)]]. H NMR spectrum, , ppm: 2.29 s
2-Amino-6-benzylmercapto-3-(4-phenyl-1,3-thi-
azol-2-yl)pyridine-5-carboxamide (VIIi). Yield
1.56 g (75%), mp 230 233 C (EtOH). IR spectrum,
and 2.41 s (…o 3H, both CH3), 7.37 7.93 m (7H,
Ph and NH2), 8.18 s (1H, C5H), 8.72 s (1H, C4H),
12.76 s (1H, NH). Found, %: C 55.48; H 3.77;
N 13.49. C19H16N4O3S2. Calculated, %: C 55.32;
H 3.91; N 13.58.
1
cm : 3180, 3350 [ (NH2)], 1671 [ (C=O)], 1642
1
[ (NH2)]. H NMR spectrum, , ppm: 4.36 s (2H,
SCH2), 7.02 and 7.36 both br.s (2H, CONH2),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003

3-AMINO-3-THIOXOPROPANAMIDE
1179
N3-(4-Bromophenyl)-2-amino-6-pentylmer-
captopyridine-3,5-dicarboxamide (X). To a solution
of 1.79 g (5 mmol) of pyridine VIIj in 10 ml of
glacial acetic acid was added while stirring dropwise
0.26 ml (5 mmol) of Br2. The separated precipitate
was filtered off, washed with ethanol and hexane.
Yield 1.99 g (91%), mp 210 212 C. IR spectrum,
Ethyl-6-hydroxy-5-imino(methylmercapto)-
methyl-2-oxo-1,2-dihydropyridine-3-carboxylate
(XIb). Yield 1.10 g (86%), mp 214 216 C. IR spec-
1
trum, cm : 3174, 3372 [ (NH2)], 1740 [ (C=O)],
1
1644[ (NH2)]. HNMR spectrum, , ppm: 1.41t(3H,
CH2CH3), 2.45s (3H, SCH3), 4.38 q (2H, CH2CH3),
7.20 br.s (1H, N1H), 7.60 br.s (1H, =NH), 8.32 s
(1H, C4H), 11.49 br.s (1H, OH). Found, %: C 47.12;
H 4.85; N 11.05. C10H12N2O4S. Calculated, %:
C 46.86; H 4.72; N 10.93.
1
cm : 3184, 3286, 3380 [ (NH2)], 1690 [ (C=O)],
1656[ (NH2)]. 1HNMR spectrum, , ppm: 0.92 t (3H,
CH3, J 6.9 Hz), 1.38 m (4H, SCH2CH2CH2CH2),
1.64m(2H, SCH2CH2), 3.07 t (2H, SCH2, J 7.0 Hz),
7.29 br.s (4H, 2 NH2), 7.40 d and 7.74 d (on 2H,
Harom, J8.8 Hz), 8.18s (1H, C4H), 10.13s (1H, NH).
Found, %: C 49.31; H4.92; N12.65. C18H21BrN4O2S.
Calculated, %: C 49.43; H 4.84; N 12.81.
REFERENCES
1. Krauze, A.A., Liepin,sh, E.E., Dubur, G.Ya. Khim.
Geterotsikl. Soed., 1987, p. 994.
2. Krauze, A.A., Liepin,sh, E.E., and Dubur, G.Ya.,
Khim. Geterotsikl. Soed., 1989, p. 787.
3. Krauze, A.A., Rumler, A., Khagen, F., Ensh,, Kh.-I.,
Shturm, I.G., and Dubur, G.Ya. Khim. Geterotsikl.
Soed., 1992, p. 75.
Compounds XIa, b were obtained analogously to
alkylmercaptopyridines VIIa j from pyridone V
Ethyl-5-allylmercapto(imino)methyl-6-hydroxy-
2-oxo-1,2-dihydropyridine-3-carboxylate
(XIa).
Yield 1.27 g (90%), mp 323 325 C. IR spectrum,
4. Rodinovskaya, L.A., Shestopalov, A.M., and Neste-
rov, V.N. Khim. Geterotsikl. Soed., 1996, p. 1376.
5. Krauze, A.A., Duburs, G.Ya. Khim. Geterotsikl.
Soed., 1999, p. 506.
1
cm : 3210, 3262, 3400 [ (NH2)], 1680 [ (C=O)],
1
1644 [ (NH2)]. H NMR spectrum, , ppm: 1.23 t
(3H, CH3, J 7.1 Hz), 3.60 d (2H, SCH2, J 6.9 Hz),
4.10 q (2H, CH2CH3), 4.97 d (1H, =CH2, Jcis
9.9 Hz), 5.16 d (1H, =CH2, Jtrans 16.1 Hz), 5.87 m
(1H, CH=), 6.79 br.s (1H, N1H), 6.86 br.s (1H,
=NH), 8.05 s (1H, C4H), proton signal of OH group
was not detected apparently due to fast exchange with
protons of water present in the solvent. Found, %:
C 50.82; H 4.88; N 10.21. C12H14N2O4S. Calculat-
ed, %: C 51.05; H 5.00; N 9.93.
6. Dyachenko, V.D., Tkachev, R.P. Zh. Org. Khim.,
2002, vol. 38, p. 768.
7. Gordon, A.J. and Ford, R.A., The Chemist,s
Companion, New York: Wiley, 1972. Translated
under the title Sputnik khimika, Moscow: Mir, 1976,
pp. 200 225.
8. Lorente, A., Vaquerizo, L., Martin, A., and
Gomez-Sal, P. Heterocycles, 1995, vol. 41, p. 71.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003