A simple one-pot synthesis of new 4-unsubstituted 2-oxo(thioxo)-1,2-dihydropyridine-3-carbonitriles, -3-carboxamides, and -3-carboxylic acid esters and 2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles

Article abstract of DOI:10.1134/S1070428015090146

One-pot condensations of formaldehyde with CH acids and enamines afforded new 4-unsubstituted derivatives of 2-oxo(thioxo)-1,2-dihydropyridine-3-carbonitrile, 2-oxo(thioxo)-1,2-dihydropyridine-3-carboxamide, ethyl 2-oxo(thioxo)-1,2-dihydropyridine-3-carboxylate, and 2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3- carbonitrile, which were subjected to alkylation.

Full text of DOI:10.1134/S1070428015090146

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 9, pp. 1293–1300. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © I.V. Dyachenko, V.D. Dyachenko, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 9, pp. 1319–1325.
A Simple One-Pot Synthesis of New 4-Unsubstituted
2-Oxo(thioxo)-1,2-dihydropyridine-3-carbonitriles,
-3-carboxamides, and -3-carboxylic Acid Esters
and 2-Thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles
I. V. Dyachenko and V. D. Dyachenko
Taras Shevchenko Lugansk University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
e-mail: dyachvd@mail.ru
Received March 6, 2015
Abstract—One-pot condensations of formaldehyde with CH acids and enamines afforded new 4-unsubstituted
derivatives of 2-oxo(thioxo)-1,2-dihydropyridine-3-carbonitrile, 2-oxo(thioxo)-1,2-dihydropyridine-3-carbox-
amide, ethyl 2-oxo(thioxo)-1,2-dihydropyridine-3-carboxylate, and 2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-
carbonitrile, which were subjected to alkylation.
DOI: 10.1134/S1070428015090146
Compounds exhibiting antibacterial [1] and anti-
tumor activity [2] were found among 2-oxo(thioxo)-
nicotinic acid derivatives having no substituent on C4.
Some of them can be used for the treatment and pro-
phylactics of human central nervous system disorders
[3]. 4-Unsubstituted 2-oxo(thioxo)nicotinic acid deriv-
atives are generally synthesized by recyclization of
2,6-diamino-4H-thiopyran-3,5-dicarbonitrile [4] and
nucleophilic vinylic substitution in reactions of ethoxy-
[5–8] or phenylaminomethylidene derivatives of CH
acids [9] with CH acids.
phenacyl bromides 5a and 5b in DMF in the presence
of alkali afforded the corresponding sulfides 6a and
6b, which confirmed the structure of 4 [15, 16].
6-Amino-2-thioxo-1,2-dihydropyridine-3,5-dicar-
bonitrile (7) was obtained by condensation of formal-
dehyde (1) with 2 equiv of thioamide 2 in ethanol at
20°C in the presence of morpholine. Likewise, the re-
action involves intermediate formation of Knoevenagel
product A and Michael adduct C. Chemoselective
intramolecular cyclization of the latter yields 7. By
alkylation of 7 with α-halo ketones 8a and 8b (DMF,
KOH) we synthesized sulfides 9a and 9b. If 2 equiv of
aqueous potassium hydroxide was used in the alkyla-
tion process, the products were thieno[2,3-b]pyridine
derivatives 10a–10c (Scheme 1).
The condensation of formaldehyde (1) with cyano-
thioacetamide (2) and ethyl 3-(morpholin-4-yl)but-2-
enoate (11) led to the formation of morpholinium
3-cyano-5-ethoxycarbonyl-6-methylpyridine-2-thiolate
(12). The reaction direction did not radically change
when enamine 11 was replaced by diethyl malonate
(13). Heterocyclization of Michael adduct D gave ethyl
5-cyano-2-oxo-6-sulfanyl-1,2,3,4-tetrahydropyridine-
3-carboxylate E which was readily oxidized (presum-
ably, with atmospheric oxygen) to the corresponding
1,2-dihydropyridine derivative 14. Alkylation of the
latter with α-halo ketones 8e and 8f regioselectively
involved the sulfur atom through hypothetic thiolate F
despite the presence in molecule 14 of several nucleo-
In continuation of our studies on the chemical prop-
erties of 4-unsubstituted 2-oxo(thioxo)nicotinic acid
derivatives [10–12], in the present article we describe
a new method of synthesis of such compounds via
three-component condensations of formaldehyde (1)
with CH acids and enamines. The reaction of formal-
dehyde (1) with 2-cyanoethanethioamide (2) and
4-(cyclohex-1-en-1-yl)morpholine (3) in ethanol in the
presence of morpholine at 20°C gave 2-thioxo-
1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (4).
A probable mechanism is shown in Scheme 1. It is
reasonable to assume intermediacy of 2-cyanoprop-2-
enethioamide A resulting from the Knoevenagel con-
densation of formaldehyde with CH acid 2. Next fol-
lows Stork alkylation of enamine 3 with alkene A [13],
and adduct B thus formed undergoes intramolecular
transamination [14] and dehydrogenation, yielding
compound 4 as final product. The alkylation of 4 with
1293

I. DYACHENKO, V. DYACHENKO
1294
Scheme 1.
CH2
O
NH2
NC
NH2
+
NC
–H2O
H
H
S
S
1
2
A
CN
S
CN
S
A
··
H2N
N
O
N
–HN
O
N
H
O
–2[H]
3
B
4
CN
Hlg
4-HlgC6H4C(O)CH2Br (5a, 5b)
KOH
–H2O, –KBr
N
S
O
6a, 6b
NC
CN
S
8a, 8b
R
H2N
N
NC
CN
NC
HlgCH2C(O)R
CN
S
O
8a–8d
A
9a, 9b
2
–H2S, –2[H]
NH2
H2N
S
··
NH2
H2N
N
H
S
NC
R
8b–8d, KOH
C
7
S
O
H2N
N
10a–10c
O
Me
OEt
H
H
CN
N
A
Et
N
O
O
O
Me
N
O
S–
12
11
O
O
O
O
CN
S
CN
CN
SH
A
EtO
EtO
EtO
–EtOH
–2[H]
EtO
OEt
EtO
··
O
N
SH
O
N
O
NH2
H
H
13
D
E
14
O
O
O
O
CN
CN
HlgCH2C(O)R (8e, 8f)
KOH
EtO
EtO
–H2O
R
N
S– K+
N
S
H
H
O
F
15a, 15b
5, 6, Hlg = Cl (a), Br (b); 8, Hlg = Cl, R = 1,3-thiazol-2-ylamino (a), i-PrO (b), quinolin-8-ylamino (e), 6,8-dibromo-2-oxo-2H-
chromen-3-yl (f); Hlg = Br, R = 4-MeOC6H4 (c), 2,4,5-Me3C6H2 (d); 9, R = 1,3-thiazol-2-ylamino (a), i-PrO (b); 10, R = i-PrO (a),
4-MeOC6H4 (b), 2,4,5-Me3C6H2 (c); 15, R = quinolin-8-ylamino (a), 6,8-dibromo-2-oxo-2H-chromen-3-yl (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015

A SIMPLE ONE-POT SYNTHESIS OF NEW 4-UNSUBSTITUTED 2-OXO(THIOXO)-...
1295
Scheme 2.
Me Me
O
N
O
Me
Me
O
S
O
O
S
O
Piperidine
17
+
1
··
NH2
H2N
NH2
H2N
H2N
NH2
N
CH2
S
O
16
G
H
O
Me
O
O
O
8c or ClCH2CN (19)
NH2
Me
NH2
NH
–
, –2[H]
Me
N
H
S
Me
N
S
R
O
18
20a, 20b
S
O
(1)
(21), piperidine
O
O
S
O
O
H2N
(2) 17
OEt
Cl
5a, KOH
Me
OEt
Me
OEt
1
Me
N
N
H
Me
N
S
O
22
23
Ph
S
S
S
Piperidine
Ph
1
+
N
H2N
S
H2N
CH2
24
I
O
S
O
O
S
(25)
Ph
Ph
NC
OEt
EtO
N
N
EtO
H2N
–2[H]
··
H2N
S
N
S
N
H
J
26
O
O
S
O
S
Ph
Ph
13
–EtOH, –2[H]
MeI, KOH
–KI, –H2O
N
N
SMe
EtO
EtO
N
H
SH
O
N
H
K
27
20, R = 4-MeOC6H4C(O) (a), CN (b).
philic centers (SH, NH, C=O), and the products were
sulfides 15a and 15b.
Formaldehyde (1) reacted with 3-amino-3-thioxo-
propanamide (16) and enamine 17 derived from acetyl-
acetone to produce 5-acetyl-6-methyl-2-thioxo-1,2-
dihydropyridine-3-carboxamide (18) (Scheme 2). The
reaction is likely to proceed through intermediates G
and H. Compound 18 was alkylated with p-methoxy-
phenacyl bromide (8c) and chloroacetonitrile (19)
(DMF, KOH) to obtain sulfides 20a and 20b. The
condensation of 1 with enamine 17 and ethyl 3-amino-
3-thioxopropanoate (21) (instead of 16) under analo-
gous conditions resulted in the formation of ethyl
5-acetyl-6-methyl-2-thioxo-1,2-dihydropyridine-3-car-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015

I. DYACHENKO, V. DYACHENKO
1296
399.97 MHz from solutions in DMSO-d6 using tetra-
methylsilane as internal standard. The mass spectra
(electron impact, 70 eV) were obtained on an MKh-
1321 instrument with direct sample admission into the
ion source (compounds 7, 14, 15a, and 15b) and on
an Agilent Series LC/MS instrument with a mass-
selective detector (other compounds; samples were
introduced in CF3COOH solution). The elemental
compositions were determined on a Perkin Elmer CHN
analyzer. The melting points were measured on
a Kofler hot stage. The progress of reactions and the
purity of products were monitored by TLC on Silufol
UV-254 plates using acetone–hexane (3:5) as eluent;
spots were detected by treatment with iodine vapor and
by UV irradiation.
boxylate (22). Presumably, the reaction path is analo-
gous to that leading to compound 18. The presence of
a thioxo group in molecule 22 was confirmed by al-
kylation with p-chlorophenacyl bromide (5a), which
gave sulfide 23. This way of synthesis of organic
sulfides serves as a “qualitative test” for 2-sulfanyl-
substituted pyridines [17].
By condensation of formaldehyde (1) with CH acid
(24) and ethyl cyanoacetate (25) in DMF at 20°C in
the presence of piperidine we obtained ethyl 2-amino-
6-thioxo-5-(4-phenyl-1,3-thiazol-2-yl)-1,6-dihydro-
pyridine-3-carboxylate (26), a potential precursor of
drugs for the treatment of cardiovascular diseases [18]
and tumors [19]. The reaction is likely to involve
intermediate formation of Knoevenagel alkene I and
Michael adduct J. The latter undergoes chemoselective
intramolecular cyclization to tetrahydropyridine deriv-
ative which is oxidized to compound 26 (presumably,
with atmospheric oxygen). Analogous three-compo-
nent condensation with diethyl malonate (13) instead
of CH acid 25, followed by treatment with equimolar
amounts of 10% aqueous potassium hydroxide and
methyl iodide, afforded ethyl 6-(methylsulfanyl)-2-
oxo-5-(4-phenyl-1,3-thiazol-2-yl)-1,2-dihydropyridine-
3-carboxylate (27), assumingly through intermediates
I, J, and K.
2-Thioxo-5,6,7,8-tetrahydroquinoline-3-carbo-
nitrile (4). Three drops of morpholine were added
under stirring at 20°C to a mixture of 0.73 mL
(10 mmol) of 37% aqueous formaldehyde and 1.0 g
(10 mmol) of 2-cyanoethanethioamide (2) in 20 mL of
ethanol. The mixture was stirred for 15 min, 1.67 g
(10 mmol) of enamine 3 was added, and the mixture
was stirred for 1 h and left overnight. The mixture was
diluted with 10% aqueous HCl to pH 5 and left to
stand for 48 h. The precipitate was filtered off and
washed with water, ethanol, and hexane. Yield 1.5 g
(78%), yellow powder, mp 249–251°C (from AcOH);
published data [26]: mp 250–252°C.
The structure of newly synthesized compounds 4, 6,
7, 9, 10, 12, 14, 15, 18, 20, 22, 23, 26, and 27 was
confirmed by spectral data. Their IR spectra contained
absorption bands typical of stretching vibrations of
conjugated cyano and carbonyl groups, as well as of
stretching and bending vibrations of the amino group.
Substituted tetrahydroquinolines 6a and 6b
(general procedure). Aqueous potassium hydroxide
(10%), 5.6 mL (10 mmol), was added under stirring at
20°C to a mixture of 1.9 g (10 mmol) of compound 4
and 15 mL of DMF, 10 mmol of phenacyl bromide 5a
or 5b was then added, and the mixture was stirred for
5 h and diluted with an equal volume of water. The
precipitate was filtered off and washed with water,
ethanol, and hexane.
1
In the H NMR spectra of these compounds we ob-
served signals from protons in the substituents on the
pyridine ring and a singlet at δ 6.54–8.88 ppm due to
4-H, which is typical of such compounds [20–22]. The
1H NMR spectrum of sulfide 15b characteristically
displayed nonequivalence of the SCH2 protons which
appeared as two doublets at δ 3.50 and 4.05 ppm with
2-[2-(4-Chlorophenyl)-2-oxoethylsulfanyl]-
5,6,7,8-tetrahydroquinoline-3-carbonitrile (6a).
Yield 2.6 g (75%), yellow powder, mp 137–139°C
(from AcOH). IR spectrum, ν, cm–1: 2224 (C≡N), 1702
2
a geminal coupling constant J of 16.8 Hz. Presum-
ably, rotation of the coumarin fragment about the single
bonds is restricted for steric reasons. Analogous pat-
terns were observed by us previously for other pyri-
dine-3-carbonitrile derivatives [23, 24]. The presence
of the [M + 2]+ ion peak in the mass spectrum of 26
confirmed that its molecule contains sulfur atoms [25].
1
(C=O). H NMR spectrum, δ, ppm: 3.52–3.76 m (4H,
CH2), 4.00 t (2H, CH2, J = 6.5 Hz), 4.23 t (2H, CH2,
J = 5.3 Hz), 4.71 s (2H, SCH2), 7.48 d (2H, Harom, J =
8.3 Hz), 7.95 d (2H, Harom, J = 8.3 Hz), 8.03 s (1H,
4-H). Mass spectrum, m/z: 343 (Irel 100%) [M + 1]+.
Found, %: C 62.95; H 4.33; N 8.02. C18H15ClN2OS.
Calculated, %: C 63.06; H 4.41; N 8.17. M 342.85.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Perkin
1
Elmer Spectrum One spectrometer. The H NMR
2-[2-(4-Bromophenyl)-2-oxoethylsulfanyl]-
5,6,7,8-tetrahydroquinoline-3-carbonitrile (6b).
spectra were measured on a Varian-400 instrument at
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015

A SIMPLE ONE-POT SYNTHESIS OF NEW 4-UNSUBSTITUTED 2-OXO(THIOXO)-...
1297
Yield 2.8 g (72%), yellow crystals, mp 153–155°C
10% aqueous potassium hydroxide and 10 mmol of
(from AcOH). IR spectrum, ν, cm–1: 2220 (C≡N), 1698
α-halo ketone 8b–8d, the mixture was stirred for 2 h,
an additional 5.6 mL (10 mmol) of 10% aqueous
potassium hydroxide was added, and the mixture was
stirred for 2 h and diluted with an equal volume of
water. The precipitate was filtered off and washed with
water, ethanol, and hexane.
1
(C=O). H NMR spectrum, δ, ppm: 3.52–3.77 m (4H,
CH2), 3.99 t (2H, CH2, J = 6.2 Hz), 4.25 t (2H, CH2,
J = 5.6 Hz), 4.72 s (2H, SCH2), 7.62 d (2H, Harom, J =
8.5 Hz), 7.89 d (2H, Harom, J = 8.5 Hz), 8.09 s (1H,
4-H). Mass spectrum, m/z 388 (Irel 100%) [M + 1]+.
Found, %: C 55.70; H 3.78; N 7.05. C18H15BrN2OS.
Calculated, %: C 55.82; H 3.90; N 7.23. M 387.301.
Isopropyl 3,6-diamino-5-cyanothieno[2,3-b]pyr-
idine-2-carboxylate (10a). Yield 2.1 g (75%), yellow
powder, mp 257–258°C (from AcOH); sublimes at
200°C. IR spectrum, ν, cm–1: 3333, 3270, 3195 (N–H),
2220 (C≡N), 1716 (C=O), 1648 (δNH). 1H NMR spec-
trum, δ, ppm: 1.31d (6H, Me, J = 5.0 Hz), 5.02–5.14 m
(1H, OCH), 6.77 br.s (2H, 3-NH2), 6.95 br.s (2H,
6-NH2), 8.54 s (1H, 4-H). Mass spectrum: m/z 277
(Irel 100%) [M + 1]+. Found, %: C 52.08; H 4.26;
N 20.12. C12H12N4O2S. Calculated, %: C 52.16;
H 4.38; N 20.28. M 276.32.
6-Amino-2-thioxo-1,2-dihydropyridine-3,5-di-
carbonitrile (7) was synthesized as described above
for compound 4, but 1.0 g (10 mmol) of 2-cyano-
ethanethioamide (2) was used instead of enamine 3.
Yield 1.23 g (70%), yellow fine crystalline powder,
mp 210–212°C (from AcOH); published data [27]:
mp 208–210°C. Mass spectrum, m/z (Irel, %): 178 (4)
[M + 2]+, 177 (8) [M + 1]+, 176 (100) [M]+, 149 (25)
[M – HCN]+, 132 (41) [M –HCN – NH3]+, 118 (20), 84
(73), 55 (25), 45 (18) [HCS]+, 44 (17) [C=S]+, 33 (9)
[HS]+, 28 (26) [H2CN]+. Calculated: M 176.201.
3,6-Diamino-2-(4-methoxybenzoyl)thieno[2,3-b]-
pyridine-5-carbonitrile (10b). Yield 2.6 g (81%),
yellow crystals, mp 285–286°C (from AcOH);
sublimes at 230°C. IR spectrum, ν, cm–1: 3352, 3290,
3202 (NH); 2225 (C≡N), 1702 (C=O), 1633 (δNH).
1H NMR spectrum, δ, ppm: 3.84 s (3H, Me), 7.04 d
(2H, Harom, J = 8.6 Hz), 7.58 br.s (2H, 3-NH2), 7.72 d
(2H, Harom, J = 8.6 Hz), 8.29 br.s (2H, 6-NH2), 8.74 s
(1H, 4-H). Mass spectrum: m/z 325 (Irel 100%) [M + 1]+.
Found, %: C 59.14; H 3.66; N 17.18. C16H12N4O2S.
Calculated, %: C 59.25; H 3.73; N 17.27. M 324.362.
6-Amino-2-(acylmethylsulfanyl)pyridine-3,5-dicar-
bonitriles 9a and 9b were synthesized as described
above for compounds 6 from 1.8 g (10 mmol) of 7 and
10 mmol of 8a or 8b.
2-(6-Amino-3,5-dicyanopyridin-2-ylsulfanyl)-N-
(1,3-thiazol-2-yl)acetamide (9a). Yield 2.6 g (81%),
yellow powder, mp 177–179°C (from BuOH). IR spec-
trum, ν, cm–1: 3341, 3270, 3232 (NH), 2222 (C≡N),
1
1672 (C=O), 1636 (δNH). H NMR spectrum, δ, ppm:
4.12 s (2H, CH2), 7.15 d (1H, 5′-H, J = 2.5 Hz), 7.44 d
(1H, 4′-H, J = 2.5 Hz), 7.87 br.s and 7.94 br.s (1H
each, NH2), 8.24 s (1H, 4-H), 12.15 br.s (1H, NH).
Mass spectrum: m/z 317 (Irel 100) [M + 1]+. Found, %:
C 45.41; H 2.39; N 26.48. C12H8N6OS2. Calculated, %:
C 45.56; H 2.52; N 26.56. M 316.365.
3,6-Diamino-2-(2,4,5-trimethylbenzoyl)thieno-
[2,3-b]pyridine-5-carbonitrile (10c). Yield 2.7 g
(79%), yellow–brown powder, mp 244–246°C (from
BuOH). IR spectrum, ν, cm–1: 3342, 3285, 3196
(N–H); 2226 (C≡N), 1698 (C=O), 1637 (δ NH2).
1H NMR spectrum, δ, ppm: 2.19 s (3H, Me), 2.21 s
(3H, Me), 2.26 s (3H, Me), 7.02 s (1H, Harom), 7.06 s
(1H, Harom), 7.36 br.s (2H, 3-NH2), 8.11 br.s (2H,
6-NH2), 8.70 s (1H, 4-H). Mass spectrum: m/z 337
(Irel 100%) [M + 1]+. Found, %: C 64.12; H 4.87;
N 16.56. C18H16N4OS. Calculated, %: C 64.27; H 4.79;
N 16.65. M 336.184.
Isopropyl 2-(6-amino-3,5-dicyanopyridin-2-yl-
sulfanyl)acetate (9b). Yield 2.0 g (74%), yellow
cotton wool-like crystals, mp 151–152°C (from
AcOH). IR spectrum, ν, cm–1: 3335, 3260, 3190
(N–H), 2219 (C≡N), 1714 (C=O), 1638 (δ NH).
1H NMR spectrum, δ, ppm: 1.25 d (6H, Me, J =
5.1 Hz), 4.03 s (2H, CH2), 4.86–4.94 m (1H, OCH),
7.73 br.s (2H, NH2), 8.11 s (1H, 4-H). Mass spectrum,
m/z 277 (Irel 100%) [M + 1]+. Found, %: C 52.03;
H 4.25; N 20.11. C12H12N4O2S. Calculated, %:
C 52.16; H 4.38; N 20.28. M 276.32.
Morpholinium 3-cyano-5-ethoxycarbonyl-6-
methylpyridine-2-thiolate (12). Yield 2.4 g (78%),
yellow fine crystalline powder, mp 208–210°C;
sublimes at 140°C. IR spectrum, ν, cm–1: 3300 (N–H),
1
2210 (C≡N), 1717 (C=O). H NMR spectrum, δ, ppm:
3,6-Diamino-2-acyl-5-cyanothieno[2,3-b]pyri-
dines 10a–10c (general procedure). To a mixture of
1.8 g (10 mmol) of compound 7 and 20 mL of DMF
we added at 20°C under stirring 5.6 mL (10 mmol) of
1.29 t (3H, MeCH2, J = 6.2 Hz), 2.54 s (3H, Me),
3.04 t (4H, CH2NCH2, J = 4.4 Hz), 3.73 t (4H,
CH2OCH2, J = 4.4 Hz), 4.16 q (2H, OCH2, J = 6.2 Hz),
+
7.90 s (1H, 4-H). No NH2 signal was observed,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015

I. DYACHENKO, V. DYACHENKO
1298
presumably because of fast H–D exchange. Found, %:
C 54.28; H 6.04; N 13.42. C14H19N3O3S. Calculated,
%: C 54.35; H 6.19; N 13.58.
16.8 Hz), 4.15 q (2H, OCH2, J = 6.1 Hz), 7.95 s (1H,
4-H), 8.20 s (1H, Harom), 8.23 s (1H, Harom), 8.31 s (1H,
4′-H), 8.81 br.s (1H, NH). Mass spectrum, m/z (Irel, %):
570 (5) [M + 2]+, 569 (31) [M + 1]+, 568 (100) [M]+,
567 (50) [M – 1]+, 269 (10), 236 (14), 176 (19), 156
(10), 138 (92), 111 (79), 99 (97), 97 (25), 94 (13).
Found, %: C 42.19; H 2.02; N 4.85. C20H12Br2N2O6S.
Calculated, %: C 42.28; H 2.13; N 4.93. M 568.2.
Ethyl 5-cyano-2-oxo-6-sulfanyl-1,2-dihydropyri-
dine-3-carboxylate (14) was synthesized as described
above for compound 4 using 0.73 mL (10 mmol) of
37% aqueous formaldehyde (1), 1.0 g (10 mmol) of
thioamide 2, and 1.6 mL (10 mmol) of diethyl malo-
nate (13). Yield 1.64 g (73%), yellow fine crystalline
powder, mp 318–320°C (from AcOH). IR spectrum, ν,
cm–1: 3315 (N–H), 2220 (C≡N), 1712 (C=O), 1670
5-Acetyl-6-methyl-2-thioxo-1,2-dihydropyridine-
carboxamide (18) was synthesized as described above
for compound 4 from 0.73 g (10 mmol) of 37%
aqueous formaldehyde, 1.2 g (10 mmol) of 3-amino-
3-thioxopropanamide (16), and 1.7 g (10 mmol) of
enamine 17 in the presence of three drops of piper-
idine. Yield 1.5 g (69%), yellow powder, mp 322–
324°C (from AcOH). IR spectrum, ν, cm–1: 3315,
3290, 3200 (N–H); 1702 (C=O), 1668 (CONH).
1H NMR spectrum, δ, ppm: 2.56 s (3H, Me), 2.71 s
(3H, Me), 7.91 br.s (1H, NH2), 8.88 s (1H, 4-H),
9.90 br.s (1H, NH2), 13.97 br.s (NH). Mass spectrum:
m/z 211 (Irel 100%) [M + 1]+. Found, %: C 51.36;
H 4.68; N 13.22. C9H10N2O2S. Calculated, %: C 51.41;
H 4.79; N 13.32. M 210.256.
1
(CONH). H NMR spectrum, δ, ppm: 1.30 t (3H, Me,
J 7.0 Hz), 4.14 q (2H, CH2, J = 7.0 Hz), 7.91 s (1H,
4-H), 11.26 br.s (1H, NH). No SH signal was observed,
presumably because of fast H–D exchange. Mass spec-
trum, m/z (Irel, %): 224 (4) [M]+, 206 (75) [M – H2O]+,
178 (100) [M – H2O – H2CN]+, 165 (43), 147 (98), 124
(42), 103 (11), 96 (18), 91 (14), 86 (5), 70 (10), 64
(63), 52 (12), 44 (95) [C=S]+, 37 (10). Found, %:
C 48.07; H 3.49; N 12.33. C9H8N2O3S. Calculated, %:
C 48.21; H 3.60; N 12.49. M 224.239.
Substituted ethyl 6-(acylmethylsulfanyl)-5-
cyano-2-oxopyridine-3-carbocylates 15a and 15b
were synthesized as described above for compounds 6
from 2.24 g (10 mmol) of 14 and 10 mmol of 8e or 8f.
2-(Alkylsulfanyl)-5-acetyl-6-methylpyridine-
3-carboxamides 20a and 20b were synthesized as
described above for compound 6 from 2.1 g (10 mmol)
of 18 and 10 mmol of 8c or 9.
2-(5-Cyano-3-ethoxycarbonyl-2-oxo-1,2-dihydro-
pyridin-6-ylsulfanyl)-N-(quinolin-8-yl)acetamide
(15a). Yield 2.9 g (70%), yellow powder, mp 247–
249°C (from BuOH). IR spectrum, ν, cm–1: 3348
(N–H), 2223 (C≡N), 1715 (C=O), 1671 (CONH).
1H NMR spectrum, δ, ppm: 1.18 t (3H, Me, J =
6.8 Hz), 4.21 s (2H, SCH2), 4.34 q (2H, OCH2, J =
6.8 Hz), 7.41–7.63 m (2H, Harom), 7.94 s (1H, 4-H),
8.27 d (1H, quinoline, J = 8.2 Hz), 8.39 d (1H, quino-
line, J = 7.9 Hz), 8.62 d (1H, quinoline, J = 7.0 Hz),
8.87 d (1H, quinoline, J = 8.0 Hz), 8.96 br.s (1H,
CONH), 10.75 br.s (1H, 1-H). Mass spectrum, m/z
(Irel, %): 408 (6) [M]+, 394 (8), 171 (100) [quinoline-8-
ylcarbamoyl]+, 144 (43) [8-aminoquinoline]+, 116 (12),
89 (5), 77 (3), 45 (4) [HCS]+, 44 (3) [C=S]+, 34 (9)
[H2S]+, 33 (5) [HS]+. Found, %: C 58.72; H 3.83;
N 13.66. C20H16N4O4S. Calculated, %: C 58.81;
H 3.95; N 13.72. M 408.44.
5-Acetyl-2-[2-(4-methoxyphenyl)-2-oxoethylsul-
fanyl]-6-methylpyridine-3-carboxamide (20a).
Yield 2.7 g (74%), yellow powder, mp 200–202°C
(from DMF). IR spectrum, ν, cm–1: 3342, 3280, 3205
1
(N–H); 1711, 1716 (C=O); 1669 (CONH). H NMR
spectrum, δ, ppm: 2.33 s (3H, Me), 2.55 s (3H, Me),
3.87 s (3H, MeO), 4.48 s (2H, CH2), 6.99 d (2H, Harom
,
J = 8.8 Hz), 7.48 br.s (1H, NH2), 7.99 d (2H, Harom, J =
8.8 Hz), 8.09 br.s (1H, NH2), 8.37 s (1H, 4-H). Mass
spectrum: m/z 359 (Irel 100%) [M + 1]+. Found, %:
C 60.24; H 4.97; N 7.70. C18H18N2O4S. Calculated, %:
C 60.32; H 5.06; N 7.82. M 358.419.
5-Acetyl-2-(cyanomethylsulfanyl)-6-methylpyri-
dine-3-carboxamide (20b). Yield 1.8 g (72%), yellow
crystals, mp 243‒245°C (from AcOH). IR spectrum, ν,
cm–1: 3338, 3291, 3199 (N–H); 2246 (C≡N), 1716
Ethyl 5-cyano-6-[2-(6,8-dibromo-2-oxo-2H-
chromen-3-yl)-2-oxoethylsulfanyl]-2-oxopyridine-3-
carboxylate (15b). Yield 4.7 g (83%), yellow powder,
mp 223–225°C (from DMF). IR spectrum, ν, cm–1:
3378, 3188 (N–H); 2228 (C≡N), 1738 (C=O), 1684
1
(C=O), 1665 (CONH). H NMR spectrum, δ, ppm:
2.62 s (3H, Me), 2.70 s (3H, Me), 4.07 s (2H, CH2),
7.73 br.s and 8.33 br.s (1H each, NH2), 8.54 s (1H,
4-H). Mass spectrum: m/z 250 (Irel 100%) [M + 1]+.
Found, %: C 52.91; H 4.30; N 16.75. C11H11N3O2S.
Calculated, %: C 53.00; H 4.45; N 16.86. M 249.293.
1
(CONH). H NMR spectrum, δ, ppm: 1.18 t (3H, Me,
2
J = 6.1 Hz), 3.50 d and 4.05 d (1H each, SCH2, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015

A SIMPLE ONE-POT SYNTHESIS OF NEW 4-UNSUBSTITUTED 2-OXO(THIOXO)-...
1299
Ethyl 5-acetyl-6-methyl-2-thioxo-1,2-dihydro-
pyridine-3-carboxylate (22) was synthesized as
described above for compound 4 from 0.73 mL
(10 mmol) of 37% aqueous formaldehyde, 1.5 g
(10 mmol) of CH acid 21, and 1.7 g of enamine 17 in
the presence of three drops of piperidine. Yield 1.7 g
(70%), yellow powder, mp 212–214°C (from AcOH).
IR spectrum, ν, cm–1: 3322 (N–H); 1714, 1722 (C=O).
1H NMR spectrum, δ, ppm: 1.40 t (3H, MeCH2, J =
7.2 Hz), 2.44 s (3H, Me), 2.58 s (3H, Me), 4.46 q (2H,
CH2, J = 7.2 Hz), 8.55 s (1H, 4-H); no NH signal was
observed, presumably because of fast H–D exchange.
Mass spectrum: m/z 240 (Irel 100%) [M + 1]+. Found,
%: C 55.08; H 5.33; N 5.71. C11H13NO3S. Calculated,
%: C 55.21; H 5.48; N 5.85. M 239.296.
to a mixture of 0.73 mL (10 mmol) of 37% aqueous
formaldehyde and 2.34 g (10 mmol) of CH acid 24 in
20 mL of DMF, the mixture was stirred for 30 min,
1.6 mL (10 mmol) of diethyl malonate (13) was added,
and the mixture was stirred for 1 h and left overnight.
The mixture was treated in succession under stirring
with 5.6 mL (10 mmol) of 10% aqueous potassium
hydroxide and 0.62 mL (10 mmol) of methyl iodide,
stirred for 5 h, and diluted with an equal volume of
water. The precipitate was filtered off and washed with
water, ethanol, and hexane. Yield 2.3 g (67%),
mp 145–146°C (from AcOH). IR spectrum, ν, cm–1:
1
3118 (N–H), 1711 (C=O), 1668 (CONH). H NMR
spectrum, δ, ppm: 1.42 t (3H, Me, J = 7.1 Hz), 2.62 s
(3H, SMe), 4.40 q (2H, CH2, J = 7.1 Hz), 7.22–7.68 m
(3H, Ph), 7.93–8.17 m (3H, 4-H, Ph), 8.48 s (1H,
5′-H), 11.70 br.s (1H, NH). Mass spectrum: m/z 373
(Irel 100%) [M + 1]+. Found, %: C 57.93; H 4.18;
N 7.42. C18H16N2O3S2. Calculated, %: C 58.05;
H 4.33; N 7.52. M 372.468.
Ethyl 5-acetyl-2-[2-(4-chlorophenyl)-2-oxoethyl-
sulfanyl]-6-methylpyridine-3-carboxylate (23) was
synthesized as described above for compound 6 from
2.4 mL (10 mmol) of 22 and 2.3 g (10 mmol) of
p-chlorophenacyl bromide (5a). Yield 3.0 g (77%),
yellow crystals, mp 219–221°C (from AcOH). IR spec-
trum, ν, cm–1: 1718, 1711, 1695 (C=O). 1H NMR spec-
trum, δ, ppm: 1.19 t (3H, MeCH2, J = 6.8 Hz), 2.53 s
(3H, Me), 3.51 s (3H, Me), 4.22 q (2H, OCH2, J =
6.8 Hz), 5.51 s (2H, SCH2), 7.69 d (2H, Harom, J =
8.6 Hz), 7.91 d (2Harom, J = 8.6 Hz), 8.57 s (1H, 4-H).
Mass spectrum: m/z 392 (Irel 100%) [M + 1]+. Found,
%: C 58.15; H 4.52; N 3.41. C19H18ClNO4S. Calculat-
ed, %: C 58.24; H 4.63; N 3.57. M 391.877.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015