Synthesis of 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones

Article abstract of DOI:10.1023/A:1023483521652

The reactions of 1-substituted 2-nitro-3-phenylaminoprop-2-en-1-ones with cyanothioacetamide afforded the corresponding 6-substituted 3-cyano-5- nitropyridine-2(1H)-thiones, which were used for the synthesis of 6-substituted 3-cyano-2-methylthio-5-nitropyridines and 7-substituted 4-hydroxy-8- nitropyrido[2′,3′:4,5]thieno[2,3-b]pyridin-2(1H)-ones.

Full text of DOI:10.1023/A:1023483521652

Russian Chemical Bulletin, International Edition, Vol. 52, No. 2, pp. 447—450, February, 2003
447
Synthesis of 6ꢀsubstituted 3ꢀcyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀthiones
K. S. Chunikhin, L. A. Rodinovskaya, and A. M. Shestopalovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: shchem@dol.ru
The reactions of 1ꢀsubstituted 2ꢀnitroꢀ3ꢀphenylaminopropꢀ2ꢀenꢀ1ꢀones with cyanoꢀ
thioacetamide afforded the corresponding 6ꢀsubstituted 3ꢀcyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀ
thiones, which were used for the synthesis of 6ꢀsubstituted 3ꢀcyanoꢀ2ꢀmethylthioꢀ5ꢀ
nitropyridines and 7ꢀsubstituted 4ꢀhydroxyꢀ8ꢀnitropyrido[2´,3´:4,5]thieno[2,3ꢀb]pyridinꢀ
2(1H )ꢀones.
Key words: cyanothioacetamide, 1ꢀsubstituted 2ꢀnitroꢀ3ꢀphenylaminopropꢀ2ꢀenꢀ1ꢀones,
3ꢀcyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀthiones, 3ꢀcyanoꢀ2ꢀmethylthioꢀ5ꢀnitropyridines, pyriꢀ
do[2´,3´:4,5]thieno[2,3ꢀb]pyridinꢀ2(1H )ꢀones.
The use of substituted 3ꢀcyanopyridinethiones in the
synthesis of practically important compounds, viz., dyes,
drugs, pesticides, etc., gives impetus to the extensive
development of procedures for their preparation.1—3
βꢀEnaminocarbonyl compounds serve as convenient reꢀ
agents for the regioselective synthesis of substituted
3ꢀcyanopyridineꢀ2(1H )ꢀthiones and their hydrogenated
analogs.4,5 Thus, the reactions of βꢀenaminocarbonyl
compounds with cyanothioacetamide afforded various
3ꢀcyanopyridineꢀ2(1H )ꢀthiones containing the acetyl,
alkoxycarbonyl, or cyano group at position 5. The reacꢀ
tion of the sodium salt of nitromalondialdehyde with
cyanothioacetamide6 was the only example of the syntheꢀ
sis of 3ꢀcyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀthiones published
in the literature. Because of this, the chemical properties
of nitroꢀsubstituted 3ꢀcyanopyridineꢀ2(1H )ꢀthiones reꢀ
mained virtually unknown.
6ꢀsubstituted 3ꢀcyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀthiones
5a—d in 95—98% yields. The reactions proceeded regioꢀ
selectively at 40—45 °C through, apparently, the formaꢀ
tion of intermediate 3 followed by cyclization to give
thiolate 4.
Scheme 1
In the present study, we carried out the regioselective
synthesis of substituted 3ꢀcyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀ
thiones based on βꢀenaminocarbonyl compounds and
studied some chemical transformations of nitroꢀcontainꢀ
ing pyridinethiones.
We used 1ꢀsubstituted 1ꢀnitroꢀ2ꢀphenylaminoethylꢀ
enes 1a—d as βꢀenaminocarbonyl compounds. These
enamines were prepared according to a known proceꢀ
dure7 by condensation of the corresponding αꢀnitroꢀ
carbonyl compounds, trimethyl orthoformate, and aniline.
We chose compounds 1a—d as enamines because they are
more stable and can be more easily isolated than free
nitrodicarbonyl compounds.
We found that the reactions of enamines 1a—d with
cyanothioacetamide 2 in water in the presence of a
10% KOH solution (Scheme 1) followed by acidification
of the reaction mixture with hydrochloric acid afforded
R = EtO (1a), OH (5a), Ph (1b, 5b), 4ꢀMeC6H4 (1c, 5c),
4ꢀMeOC6H4 (1d, 5d)
The structures of the compounds thus synthesized were
confirmed by 1H NMR and IR spectroscopy and elemenꢀ
tal analysis. The1H NMR spectra of compounds 5a—d
have characteristic singlets for the H(4) protons of the
pyridine ring at δ 8.26—8.67. The IR spectra have absorpꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 428—430, February, 2003.
1066ꢀ5285/03/5202ꢀ447 $25.00 © 2003 Plenum Publishing Corporation

448
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
Chunikhin et al.
Scheme 2
The reactions of compounds 5a—d with iodomethane in
ethanol in the presence of an equivalent amount of KOH
produced substituted 2ꢀ(methylthio)pyridines 6a—d.
3ꢀCyanoꢀ5ꢀnitropyridineꢀ2(1H)ꢀthiones 5a—c were used
also in the synthesis of difficultly accessible annelated
nitropyridines 7a—c according to a procedure described
earlier.8 This procedure involved alkylation of ethyl
4ꢀchloroacetoacetate (8) followed by cyclization of interꢀ
mediate ethyl 4ꢀ(pyridylthio)acetoacetates 9 and ethyl
3ꢀ(3ꢀaminothieno[2,3ꢀb]pyridꢀ2ꢀyl)ꢀ3ꢀoxopropionates 10
in the presence of an excess of KOH.
1
The H NMR spectra of compounds 7a—c have sinꢀ
glets at δ 5.69—5.85 belonging to the C(3)H protons and
singlets at δ 12.10—12.25 belonging to the N(1)H proꢀ
tons. These signals are characteristic of 4ꢀhydroxyꢀ
pyrido[2´,3´:4,5]thieno[2,3ꢀb]pyridinꢀ2(1H )ꢀones.1,8
The assignment of the signals of the hydroxy groups in the
1H NMR spectra of compounds 7a—c presented difficulꢀ
ties due, apparently, to association of these compounds
with water, deuterium exchange in DMSOꢀd6, and low
solubility in other solvents used in NMR spectroscopy.
Experimental
The melting points were measured on a Kofler hotꢀstage
apparatus. The IR spectra were recorded on a Perkin—Elmer 577
1
instrument (in KBr). The H NMR spectra were measured on a
Bruker WMꢀ250 instrument in DMSOꢀd6. The mass spectra
were obtained on a MAT INCOSꢀ50 Finnigan instrument (enꢀ
ergy of ionizing electrons was 70 eV). Elemental analysis was
performed on a Perkin—Elmer C,H,N analyzer.
6, 7: R = OH (a), Ph (b), 4ꢀMeC6H4 (c), 4ꢀMeOC6H4 (d)
Synthesis of compounds 5a—d (general procedure). A 10%
aqueous solution of KOH (2.35 mL) was added dropwise with
stirring to a suspension of compounds 1a—d (3 mmol) and
cyanothioacetamide (2) (0.31 g, 3.1 mmol) in water (3 mL) at
30—35 °C for 5 min. The resulting solution was stirred at
40—45 °C for 20 min, cooled to 20 °C, and acidified with conꢀ
centrated HCl (0.5 mL). The precipitate that formed was filꢀ
tered off, washed with water and hexane, and recrystallized from
tion bands of the cyano groups at 2224—2240 cm–1, which
are characteristic of 3ꢀcyanopyridineꢀ2(1H )ꢀthiones,
and intense absorption bands at 1564—1592 and
1324—1328 cm–1 corresponding respectively to symmetriꢀ
cal and asymmetrical vibrations of the nitro group.
Compounds 5a—d undergo chemical transformations
(Scheme 2) typical of 3ꢀcyanopyridineꢀ2(1H )ꢀthiones.
Table 1. Characteristics of 6ꢀsubstituted 3ꢀcyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀthiones 5a—d
Comꢀ
pound
R
Yield
(%)
Found
Calculated
Molecular
formula
IR,
1H NMR,
MS
[M]+
m/z
(%)
ν/cm–1
δ, 3J/Hz
C
H
N
S
CN
NO2
H(4)
Other signals
(s, 1 H)
5a
5b
ОH
Ph
98
97
36.71 1.56 21.10 16.12 C6H3N3O3S
36.55 1.53 21.31 16.26
56.14 2.82 16.69 12.23 C12H7N3O2S
56.02 2.74 16.33 12.46
57.68 3.45 15.78 11.78 C13H9N3O2S
57.56 3.32 15.49 11.82
2224 1328,
1564
2240 1328,
1584
2232 1324,
1588
8.26
8.67
8.65
11.78 (s, 1 H, NH, ОH)
7.56 (m, 5 H, Ph)
—
257
271
5c 4ꢀMeC6H4 96
5d 4ꢀMeOC6H4 95
2.41 (s, 3 H, Me);
7.29, 7.36 (both d,
2 H each, J = 8.2)
3.85 (d, 3 H, MeO);
7.02, 7.43 (both d,
2 H each, J = 8.3)
54.63 3.17 14.79 11.23 C13H9N3O3S
54.35 3.16 14.63 11.16
2224 1324,
1592
8.57
287

3ꢀCyanoꢀ5ꢀnitropyridineꢀ2(1H )ꢀthiones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
449
Table 2. Characteristics of 6ꢀsubstituted 3ꢀcyanoꢀ2ꢀmethylthioꢀ5ꢀnitropyridines 6a—d
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Molecular
formula
IR,
ν/cm–1
1H NMR,
δ, 3J/Hz
MS
[M]+
(%)
m/z
C
H
N
S
CN
NO2
H(4)
SMe
Other
(s, 1 H) (s, 3 H)
signals
6a
6b
6c
40
50
63
271
40.09 2.42 19.70 15.08 C7H5N3O3S
2224 1304, 8.13
1576
2224 1340, 8.36
1540
2.41
2.75
2.71
11.65 (s,
1 H, NH, OH)
7.56 (m,
5 H, Ph)
2.39 (s,
211
271
285
(decomp.) 39.81 2.39 19.90 15.18
129—
—130
130—
—131
57.51 3.44 15.61 11.69 C13H9N3O2S
57.56 3.34 15.49 11.82
59.11 4.01 14.78 11.36 C14H11N3O2S 2224 1336, 8.87
58.94 3.89 14.73 11.24 1584
3 H, Me);
7.31 (d, 2 H,
C6H4, J = 8.4);
7.52 (d, 2 H,
C6H4, J = 8.4)
3.85 (s,
3 H, MeO);
7.05 (d, 2 H,
C6H4, J = 8.4);
7.62 (d, 2 H,
C6H4, J = 8.4)
6d
76
132—
—133
55.79 3.73 14.12 10.78 C14H11N3O3S 2224 1340, 8.81
55.81 3.84 13.95 10.64 1568
2.72
301
Table 3. Characteristics of 7ꢀsubstituted 4ꢀhydroxyꢀ8ꢀnitropyrido[2´,3´:4,5]thieno[2,3ꢀb]pyridinꢀ2(1H )ꢀones 7a—c
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Molecular
formula
IR,
ν/cm–1
1H NMR,
δ, 3J/Hz
(%)
C
H
N
S
CONH,
NO2
H(3) H(9) NH
Other
OH, etc.
(OH) signals
s, 1 Н
7a
7b
40
86
>300
>300
42.97 1.78 14.82 11.32 C10H5N3O5S
43.02 1.80 15.05 11.48
1656,
3648,
1380,
1548
3632
1372,
1540
3376,
3056
1344,
1544
3240,
3580
5.69 9.31 12.10 7.91 (s,
1 H, OH)
56.69 2.72 12.29 9.32
56.63 2.67 12.38 9.45
C16H9N3O4S
1640,
3592,
5.85 9.32 12.25 7.61 (m,
5 H, Ph)
7c
88
>300
57.90 3.17 11.78 9.11
57.79 3.14 11.89 9.07
C17H11N3O4S 1640,
3056,
5.82 9.32 12.22 2.39 (s,
3 H, Me);
7.29 (d,
2 H, C6H4,
J = 8.2);
7.47 (d,
2 H, C6H4,
J = 8.2)
EtOH. The characteristics of compounds 5a—d are given in
Table 1.
Synthesis of compounds 7a—c (general procedure). A 10%
aqueous solution of KOH (0.56 mL) was added dropwise with
stirring to a suspension of compounds 5a—c (1 mmol) in EtOH
(3 mL). Then ethyl 4ꢀchloroacetoacetate (8) (0.14 mL, 1 mmol)
was added and the reaction mixture was kept for 5 min, after
which a precipitate formed. A 10% aqueous solution of KOH
(0.84 mL) was added to the resulting mixture and the mixture
was heated until a transparent solution was obtained. The soluꢀ
Synthesis of compounds 6a—d (general procedure). A 10%
aqueous solution of KOH (0.56 mL) and MeI (0.1 mL, 1.4 mmol)
were successively added dropwise to a suspension of compounds
5a—d (1 mmol) in EtOH (3 mL). After 1 h, the precipitate that
formed was filtered off and recrystallized from hexane. The charꢀ
acteristics of compounds 6a—d are given in Table 2.

450
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Chunikhin et al.
tion was cooled to ∼20 °C and then concentrated HCl (0.15 mL)
was added. The precipitate that formed was filtered off and
washed successively with EtOH, water, and hexane. The charꢀ
acteristics of compounds 7a—d are given in Table 3.
organicheskom sinteze," [Abstrs. of Papers, I Urals Conf. "Enamꢀ
ines in Organic Synthesis], Perm, 1986, 5 (in Russian).
5. L. A. Rodinovskaya, Dr. Sc. (Chem.) Thesis, N. D. Zelinsky
Institute of Organic Chemistry, Russian Academy of Sciences,
Moscow, 1994 (in Russian).
6. US Pat. 3624877 (Cl. 424/263, A 01n); Chem. Abstr., 1972,
77, 88314.
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Received February 18, 2002;
in revised form November 11, 2002