4-(3-Cyanopyridin-2-ylthio)acetoacetates in synthesis of heterocycles

Article abstract of DOI:10.1023/B:RUCB.0000011877.60574.34

Substituted 2-ammo-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d] pyrido[3′,2′:4,5]thieno[3,2-b]pyridines were synthesized by the reactions of 4-hydroxy-1H-thieno[2,3-b;4,5-b]dipyridin-2-ones with arylidenemalononitriles or by the three-component reactions of hydroxythienodipyridinones with aldehydes and malononitrile in DMF in the presence of Methylamine. Methods for syntheses of substituted 3-alkoxycarbonyl-6-amino-4-aryl-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans were developed on the basis of the reactions of 4-(3-cyanopyridin-2-ylthio) acetoacetates and arylidenemalononitriles or aldehydes and malononitrile. Ethyl 4-(3-cyanopyridin-2-ylthio)acetoacetate and 4-methoxybenzyl- idenecyanothioacetamide were used for the synthesis of 6-(pyridin-2- ylthiomethyl)-3-cyanopyridine-2(1H)-thione.

Full text of DOI:10.1023/B:RUCB.0000011877.60574.34

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2185—2196, October, 2003
2185
4ꢀ(3ꢀCyanopyridinꢀ2ꢀylthio)acetoacetates in synthesis of heterocycles
L. A. Rodinovskaya,ꢀ A. M. Shestopalov, and A. V. Gromova
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
Substituted
2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrano[2,3ꢀd]pyriꢀ
do[3´,2´:4,5]thieno[3,2ꢀb]pyridines were synthesized by the reactions of 4ꢀhydroxyꢀ1Hꢀ
thieno[2,3ꢀb;4,5ꢀb]dipyridinꢀ2ꢀones with arylidenemalononitriles or by the threeꢀcomponent
reactions of hydroxythienodipyridinones with aldehydes and malononitrile in DMF in the
presence of triethylamine. Methods for syntheses of substituted 3ꢀalkoxycarbonylꢀ6ꢀaminoꢀ4ꢀ
arylꢀ2ꢀ(3ꢀcyanopyridinꢀ2ꢀylthiomethyl)ꢀ4Hꢀpyrans were developed on the basis of the reacꢀ
tions of 4ꢀ(3ꢀcyanopyridinꢀ2ꢀylthio)acetoacetates and arylidenemalononitriles or aldehydes
and malononitrile. Ethyl 4ꢀ(3ꢀcyanopyridinꢀ2ꢀylthio)acetoacetate and 4ꢀmethoxybenzylꢀ
idenecyanothioacetamide were used for the synthesis of 6ꢀ(pyridinꢀ2ꢀylthiomethyl)ꢀ3ꢀ
cyanopyridineꢀ2(1H )ꢀthione.
Key words: malononitrile, arylidenemalononitriles, 3ꢀcyanopyridineꢀ2(1H )ꢀthiones, substiꢀ
tuted 5,6ꢀdihydroꢀ5ꢀoxoꢀ4Hꢀpyrano[2,3ꢀd]pyrido[3´,2´:4,5]thieno[3,2ꢀb]pyridines, 4ꢀhydroxyꢀ
1Hꢀthieno[2,3ꢀb;4,5ꢀb]dipyridinꢀ2ꢀones, 4ꢀ(3ꢀcyanopyridinꢀ2ꢀylthio)acetoacetates, 3ꢀalkoxyꢀ
carbonylꢀ6ꢀaminoꢀ4ꢀarylꢀ2ꢀ(3ꢀcyanopyridinꢀ2ꢀylthiomethyl)ꢀ4Hꢀpyrans, 3ꢀcyanopyridineꢀ6ꢀ
(pyridinꢀ2ꢀylthiomethyl)ꢀ2(1H )ꢀthione.
We have previously1 established that 4ꢀ(3ꢀcyanoꢀ
pyridinꢀ2ꢀylthio)acetoacetates are convenient starting
reactants in the syntheses of inaccessible 4ꢀhydroxyꢀ
1Hꢀthieno[2,3ꢀb;4,5ꢀb]dipyridinꢀ2ꢀones. Since esters of
4ꢀ(3ꢀcyanopyridinꢀ2ꢀylthio)acetoacetic acid contain sevꢀ
eral reaction centers, we studied these compounds in difꢀ
ferent reactions and developed methods for syntheses of
various inaccessible heterocycles, including new heteroꢀ
cyclic systems. An interest in these compounds is evoked,
first, by the high physiological activity of such their anaꢀ
logs as hydroxy(oxo)pyridines with different biological
activities2,3 and 2ꢀaminoꢀ4Hꢀpyrans patented as mediꢀ
cines, pesticides, and other practically significant comꢀ
pounds.4—6 Therefore, it seems of interest to obtain subꢀ
stances, whose molecules simultaneously contain pyriꢀ
dine and pyran cycles.
Substituted 4ꢀ(3ꢀcyanopyridinꢀ2ꢀylthio)acetoacetates
(3) can easily be synthesized from 3ꢀcyanopyridineꢀ
2(1H )ꢀthiones 1 and 4ꢀchloroacetoacetates 2 and further
transformed into 4ꢀhydroxyꢀ1Hꢀthieno[2,3ꢀb;4,5ꢀb]diꢀ
pyridinꢀ2ꢀones 4 by two successive intramolecular
Thorpe—Ziegler and Guareschi—Thorpe1 ring closures
(Scheme 1).
Nꢀmethylmorpholine in dimethylformamide to form
2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ5,6ꢀdihydroꢀ5ꢀoxoꢀ4Hꢀpyraꢀ
no[2,3ꢀd]pyrido[3´,2´:4,5]thieno[3,2ꢀb]pyridines 8a—c
(method A). Compounds 8b—d were also synthesized by
the threeꢀcomponent reaction of thienodipyridinones
4b,c, aromatic aldehydes 9a—c, and malononitrile 10
(method B). This method is simpler in the preparative
variant and does not need preliminary synthesis of
arylidenemalononitriles 5, which are lacrimators. It is most
likely that the reaction occurs stepwise. Michael adduct 6
is primarily formed and then undergoes ring closure to
iminopyrane 7, and the latter is further transformed into
annelated 2ꢀaminoꢀ4Hꢀpyran 8 (see Scheme 1).
A similar scheme of the reaction was proposed for the
formation of 6ꢀaminoꢀ4ꢀarylꢀ5ꢀcyanoꢀ2,4ꢀdihydropyraꢀ
no[2,3ꢀc]pyrazoles from carbonyl compounds, malonoꢀ
nitrile, and pyrazolonꢀ5ꢀones,9—11 where the correspondꢀ
ing Michael adducts were isolated and characterized.
The data of instrumental methods of analysis of
pyranopyridothienopyridines 8 indicate that the reactions
are highly regioselective. Compounds 8 are highly meltꢀ
ing powders, stable in air, and poorly soluble in the maꢀ
jority of organic solvents except DMF and DMSO.
For example, the 1H NMR spectra of compounds
8a—d, along with signals of aliphatic and aromatic
protons, contain signals of H(4) of the pyran ring at
4.50—4.92 ppm in the form of singlets and signals as
singlets characteristic of the NH2 group at 7.09—7.25 ppm
We used thienopyridinones 4 for the synthesis of
annelated pyrans 8, viz., previously unknown heteroꢀ
cyclic system. As 4ꢀhydroxyquinolinꢀ2(1H )ꢀone,7,8 comꢀ
pounds 4a—c, being CH acids, react with arylideneꢀ
malononitriles 5a—c in the presence of triethylamine or
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2069—2080, October, 2003.
1066ꢀ5285/03/5210ꢀ2185 $25.00 © 2003 Plenum Publishing Corporation

2186
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Rodinovskaya et al.
Scheme 1
and of the NH group at 11.04—12.78 ppm. The IR spectra
of compounds 8 contain bands corresponding to stretchꢀ
ing vibrations of the nitrile group at 2200—2204 cm–1 and
absorption bands characteristic of the amino group correꢀ
sponding to stretching vibrations at 3168—3468 cm–1 and
of the amide groups corresponding to bending vibraꢀ
tions at 1604—1668 cm–1. A similar situation in the IR
and 1H NMR spectra has been observed previously
for 2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀ
pyrano[3,2ꢀc]quinoline8 and other annelated 2ꢀaminoꢀ4ꢀ
arylꢀ3ꢀcyanoꢀ4Hꢀpyrans.9—13
Pyridinylthioacetoacetates 3 are also involved in inꢀ
termolecular reactions with electrophilic reactants. The
reactions of esters 3a—i with arylidenemalononitriles

4ꢀ(3ꢀCyanopyridinꢀ2ꢀylthio)acetoacetates
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2187
Scheme 1 (continued)
1
a
b
c
d
e
f
R1
Me
Me
H
H
H
R2
H
Me
H
R3
OH
Me
Me
2
a
b
c
R4
Et
Me
Pri
3
a
b
c
d
e
f
R1
Me
Me
Me
H
H
R2
H
Me
Me
H
R3
OH
Me
Me
Me
R4
Et
Et
Pri
Me
Et
(CH2)5
(CH2)3
H
H
2ꢀC4H3S
2ꢀC4H3S
H
H
4ꢀC5H4N
4ꢀClC6H4
Et
g
h
H
H
(CH2)6
CH2N(Me)CH2CH2
g
h
i
j
k
l
H
H
H
Me
H
H
(CH2)5
(CH2)5
(CH2)5
Me
Et
8
a
b
c
d
R1
2ꢀC4H3S
Me
H
Me
R2
R3
Ar
2ꢀClC6H4
Ph
Pri
Me
Et
R1
2ꢀC4H3S
Me
R2
R3
(CH2)4
(CH2)5
H
Me
4
a
b
c
H
H
Me
(CH2)3
(CH2)3
(CH2)4
(CH2)4
(CH2)5
3ꢀC4H3O
Pri
Pri
H
Me
Me3ꢀClC6H4
m
H
H
5
a
b
c
d
e
f
g
h
i
Ar
9
a
b
c
d
e
f
g
h
i
Ar
Ph
3ꢀC4H3O
3ꢀClC6H4
3ꢀC5H4N
9
Ar
13
a
b
c
d
e
f
g
h
i
R4
Et
Et
Et
Me
Et
Ar
Ph
2ꢀIC6H4
2ꢀC4H3S
4ꢀEtC6H4
4ꢀClC6H4
2ꢀClC6H4
Ph
3ꢀC4H3O
2ꢀIC6H4
2ꢀC4H3S
4ꢀEtC6H4
j
k
l
m
n
o
p
q
r
2ꢀC4H3S
4ꢀEtC6H4
4ꢀClC6H4
3ꢀMeOC6H4
3ꢀBrC6H4
2ꢀFC6H4
2ꢀ(5ꢀNO2C4H2S)
4ꢀNO2C6H4
2ꢀClꢀ5ꢀNO2C6H3
4ꢀ(COOMe)C6H4
2ꢀIC6H4
Me 3ꢀMeOC6H4
Pri 4ꢀNO2C6H4
Me
Et
Me
Et
3ꢀ(OCH2Ph)C6H4
3ꢀBrC6H4
2ꢀ(5ꢀNO2C4H2S)
3,5ꢀ(MeO)2C6H3
2ꢀCF3C6H4
3,5ꢀ(MeO)2C6H3
2ꢀNO2ꢀ4,5ꢀ(OCH2O)C6H2
3ꢀBrꢀC6H4
3ꢀC5H4N
2ꢀFC6H4
j
j
k
2ꢀCF3C6H4
12
a
b
c
d
e
f
g
h
i
R1
Me
Me Me
Me Me
Me Me
R2
H
R3
R4
Et
Et
Pri
Pri
Me
Ar
Ph
2ꢀIC6H4
2ꢀC4H3S
2ꢀIC6H4
4ꢀEtC6H4
12
m
n
o
p
q
r
s
t
u
v
w
x
R1
H
H
H
H
R2
R3
R4
Pri
Pri
Pri
Pri
Et
Ar
OH
Me
Me
Me
Me
(CH2)3
(CH2)3
(CH2)3
(CH2)4
4ꢀNO2C6H4
2ꢀClꢀ5ꢀNO2C6H3
4ꢀ(COOMe)C6H4
2ꢀClꢀ5ꢀNO2ꢀC6H3
2ꢀC4H3S
4ꢀClC6H4
3ꢀMeOC6H4
3ꢀC5H4N
H
H
H
H
H
Me Me
Me
2ꢀC4H3S Et
2ꢀC4H3S Et
(CH2)5 Me
Et
3ꢀ(OCH2Ph)C6H4
2ꢀC4H3S
H
H
H
H
H
H
H
H
4ꢀC5H4N Et
4ꢀClC6H4
(CH2)3
(CH2)5
(CH2)6
Me
Et
Me
Me
Et
H
H
H
Me
H
3ꢀBrC6H4
(CH2)5
(CH2)5
2ꢀ(5ꢀNO2C4H2S)
3,5ꢀ(MeO)2C6H3
3ꢀC5H4N
3ꢀBrC6H4
2ꢀFC6H4
2ꢀCF3C6H4
j
k
l
Pri
Me
Et
CH2N(Me)CH2CH2
CH2N(Me)CH2CH2
(CH2)5
H
Me
(CH2)3
2ꢀ(5ꢀNO2C4H2S)
Pri 2ꢀNO2ꢀ4,5ꢀ(OCH2O)C6H2
5b,d—j are regioselective only at one of the available acꢀ
tive methylene groups, namely, at the CH2COOR group
and not at the SCH2 group, resulting in the formation
(likely, through intermediates 11) of substituted 2ꢀaminoꢀ
4Hꢀpyrans 12a—j (method A) (see Scheme 1).
isolation of arylidenemalononitriles 5 in the threeꢀcomꢀ
ponent reaction of compound 3j—m, the corresponding
aromatic aldehyde 9d—h, and malononitrile 10 in ethaꢀ
nol in the presence of a base (method B).
The structures of some compounds 12 were conꢀ
firmed by the "encounter" synthesis. The reaction of esꢀ
ters 2a—c, malononitrile (10), and corresponding aldeꢀ
In some cases, pyranopyridines 12k—p were syntheꢀ
sized by the simplified procedure without intermediate

2188
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Rodinovskaya et al.
Scheme 2
hydes 9a,d,f,i—p in ethanol in the presence of triꢀ
ethylamine afforded pyrans 13a—k. The further reaction
of pyrans 13a—k with pyridineꢀ2(1H )ꢀthiones 1a—h
is regioselective and affords pyranopyridines
12a,b,e,h,m,q—w (method C).
Taking into account the regioselectivity of formation
of compounds 3 and 12, it would be reasonable to assume
that pyrans 12 can be obtained by a simpler method withꢀ
out preliminary isolation and purification of pyridinylꢀ
thioacetoacetic esters 3 (method D). Esters 3 were generꢀ
ated by the reactions of pyridinethiones 1d,e,h and esters
2a—c in ethanol in the presence of an equimolar amount
of КOH. Then equimolar amounts of aromatic aldehyde
9d,m,p—r and malononitrile 10 and a catalytic amount of
triethylamine were added to the reaction mixture. Alꢀ
though the yield of compounds 12j,s,t,w,x obtained by
method D is 48—64%, this approach is in the last analysis
the most convenient and economic.
It is noteworthy that esters of acetoacetic acid have
been applied previously7,14 for the synthesis of 5ꢀalkoxyꢀ
carbonylꢀ2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ6ꢀmethylꢀ4Hꢀpyrans.
However, we studied for the first time the use of esters of
4ꢀ(3ꢀcyanopyridinꢀ2ꢀylthio)acetoacetic acid with the
ambident properties for the synthesis of the correspondꢀ
ing pyrans 12.
As a rule, compounds 12 are white crystalline subꢀ
stances highly soluble in the majority of organic solvents.
The 1H NMR spectra of these compounds contain the
characteristic signals of H(4) of the pyran ring in the
region of δ 4.25—4.99 (in the case of 12x, 5.26 ppm) and
protons of the amino group at δ 6.64—7.33. The position
of the methylenic protons bonded to the sulfur atom in
the region of δ 4.46—4.97 is also characteristic. The sigꢀ
nals of the methylenic protons mainly appear as either a
singlet or a doublet of doublets, and the spinꢀspin couꢀ
pling constant for the latter is approximately unchanged
and ranges within 13.0—15.1 Hz.
The IR spectra of compounds 12 are characterized by
the presence of two absorption bands of the nitrile groups
of the pyran and pyridine fragments at 2184—2208 and
2216—2228 cm–1, respectively. The characteristic absorpꢀ
tion bands of the carbonyl group lie at 1700—1724 cm–1
(in the case of compound 12j, at 1688 cm–1). The IR
spectra of compounds 12 also contain the absorption bands
of the amino group characteristic of bending vibrations in
the region of 1668—1692 cm–1 and stretching vibrations
in the form of two or three (due to the formation of
venient reactants for the regioselective synthesis of funcꢀ
tionally substituted heterocycles.
Experimental
IR spectra of the compounds were obtained on
Perkin—Elmerꢀ577 and Specord Mꢀ82 instruments in KBr pelꢀ
lets with a concentration of 0.01 mol L–1. 1H NMR spectra were
recorded on Bruker AMꢀ300 (300 MHz) and Bruker WMꢀ250
(250 MHz) instruments for 5—12% solutions in DMSOꢀd6 usꢀ
ing Me4Si as the internal standard. Elemental analysis was carꢀ
ried out on a Perkin—Elmer C,H,Nꢀanalyzer instrument. The
course of reactions and individual character of the synthesized
compounds were monitored by thinꢀlayer chromatography on
the Silufol UVꢀ254 plates using hexane—acetone (5 : 3) mixꢀ
tures as the eluent. Iodine vapors were used for developing TLC
spots.
associates) bands at 3168—3484 cm–1
.
Similarly, the intermolecular reaction of 4ꢀ(pyridinꢀ
2ꢀylthio)acetoacetate 3b with 4ꢀmethoxybenzylideneꢀ
cyanothioacetamide 14 proceeds through the Michael adꢀ
duct 15 affording pyridineꢀ2(1H )ꢀthione 16 (Scheme 2).
Thus, it is established that 3ꢀcyanopyridinylthioꢀ
acetoacetates with several highly reactive centers are conꢀ

4ꢀ(3ꢀCyanopyridinꢀ2ꢀylthio)acetoacetates
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2189
Table 1. Physicochemical characteristics of 4ꢀ(3ꢀcyanopyridinꢀ2ꢀylꢀthio)acetoacatates 3
Comꢀ M.p.
pound /°C
Yield Found
Molecular
formula
Comꢀ M.p.
pound /°C
Yield Found
Molecular
formula
(%)
N
(%)
N
(%)
Calculated
(%)
Calculated
C
H
C
H
3a
3b
3c
3d
3e
147—149
91—93
85
61
86
66
85
52.78 4.64 9.24 C13H14N2O4S
53.05 4.79 9.52
57.82 5.75 8.92 C15H18N2O3S
58.08 5.92 9.14
59.73 6.14 8.55 C16H20N2O3S
59.98 6.29 8.74
54.35 4.43 10.32 C12H12N2O3S
54.53 4.58 10.60
3g
3i
93—94
86—87
73
75
86
87
81
60.14 5.52 8.63 C16H18N2O3S
60.36 5.70 8.80
62.28 6.29 7.81 C18H22N2O3S
62.40 6.40 8.09
55.83 4.86 9.83 C13H14N2O3S
56.10 5.07 10.06
60.19 5.58 8.65 C16H18N2O3S
60.36 5.70 8.80
85—86
3j
82—83
76—77
3l
117—118
94—95
104—105
55.25 6.27 7.84 C16H14N2O4S2
55.47 6.40 8.09
3m
61.67 6.19 8.72 C17H20N2O3S
61.42 6.06 8.43
Table 2. Spectroscopic characteristics of 4ꢀ(3ꢀcyanopyridinꢀ2ꢀylthio)acetoacetates 3
Comꢀ
pound
IR,
ν/cm–1
1H NMR (300 MHz, DMSOꢀd6),
δ (J/Hz)
CN
C=O
R1
R2
R3
R4
SCH2
CH2
(s, 2 H)
(s, 2 H)
3a
2216 1664 br, 2.20 (s, 3 H,
6.03 (s, 1 H) 7.66 (s, 1 H)
1.13 (t, 3 H,
Me, J = 7.1);
4.02 (q, 2 H, CH2,
J = 7.1)
3.79 (d, 1 H,
J = 15.7);
3.93 (d,
1 H,
J = 14.2)
4.21
3.49 (d,
1 H,
J = 15.7);
3.50 (d, 1 H,
J = 14.2)
3.78
1720
Me)
3b
3c
2220
2224
1724,
1736
2.46 (s, 3 H,
Me)
2.17 (s, 3 H, 2.40 (s, 3 H,
1.20 (t, 3 H,
Me, J = 7.1);
4.10 (q, 2 H,
CH2, J = 7.1)
1.19, 1.21
(both s, 3 H each,
Me); 4.94 (m,
1 H, CH)
Me)
Me)
1728,
1748
2.48 (s, 3 H,
Me)
2.17 (s, 3 H, 2.41 (s, 3 H,
Me) Me)
4.21
3.75
3d
3e
2224
2220
1720,
1748
1724,
1744
7.99 (d, 1 H,
J = 7.8)
8.21 (d, 1 H,
J = 8.8)
7.14 (d, 1 H, 2.53 (s, 3 H,
J = 7.8) Me)
7.82 (d, 1 H, 7.25 (m, 1 H);
J = 8.2) 7.81, 8.00
3.68 (s, 3 H, Me)
4.20
4.22
3.77
3.78
1.02 (t, 3 H, Me,
J = 7.2); 4.01 (q,
(both d, 1 H each, 2 H, CH2,
J = 4.2)
J = 7.2)
3g
3i
2228
2220
1724,
1744
7.95 (s, 1 H)
7.83 (s, 1 H)
1.60 (m, 4 H, CH2);
1.83, 2.25, 2.98
(all m, 2 H each, CH2)
1.63 (m, 4 H, CH2);
1.86, 2.78, 3.00
3.64 (s, 3 H, Me)
4.25
4.17
3.82
3.67
1724,
1744
1.22, 1.24 (both s,
3 H each, Me);
(all m, 2 H each, CH2)
4.96 (m, 1 H, CH)
3.68 (s, 3 H, Me)
3j
3l
2220
2224
1720,
1744
1724,
1744
2.47 (s, 3 H,
Me)
7.91 (s, 1 H)
7.03 (s,
1 H)
2.44 (s, 3 H,
Me)
4.17
4.17
3.74
3.68
2.13 (m, 2 H, CH2);
2.90—3.00 (m,
1.23, 1.25 (both s,
3 H each, Me); 4.96
(m, 1 H, CH)
4 H, CH2)
3m
2220
1724,
1744
7.81 (s, 1 H)
1.77, 1.85, 2.72, 2.85
(all m, 2 H each, CH2)
1.22, 1.25 (both s,
3 H each, Me); 4.96
(m, 1 H, CH)
4.11
3.69

2190
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Rodinovskaya et al.
Table 3. Physicochemical characteristics of 2ꢀaminoꢀ4ꢀarylꢀ
3ꢀcyanoꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrano[2,3ꢀd]pyridoꢀ
[3´,2´:4,5]thieno[3,2ꢀb]pyridines 8
morpholine (0.1 mL) were added to a suspension of compound 4
(0.01 mol) in DMF (or in an ethanol—dioxane (1 : 1) mixture).
The reaction mixture was refluxed for 2—3 h (chromatographic
monitoring). After cessation of the reaction, concentrated HCl
(1 mL) was added to the mixture. A precipitate formed was
separated and washed successively with water, ethanol, and
hexane. All compounds 8 had m.p. higher than 300 °C. The
characteristics of compounds 8 are presented in Tables 3 and 4.
B. Aldehyde 9 (0.01 mol), malononitrile (10) (0.66 g,
0.01 mol), and triethylamine or Nꢀmethylmorpholine (0.1 mL)
were added to a suspension of compound 4 (0.01 mol) in DMF.
Then the reaction was carried out similarly to method A.
3ꢀAlkoxycarbonylꢀ6ꢀaminoꢀ4ꢀarylꢀ5ꢀcyanoꢀ2ꢀ(3ꢀcyanopyriꢀ
dinꢀ2ꢀylthiomethyl)ꢀ4Hꢀpyrans 12. A. Arylidenemalononitrile 5
(0.01 mol) and triethylamine (0.1 mL) were added with stirring
to a suspension of ester 3 (0.01 mol) in ethanol (15—20 mL),
and the mixture was refluxed for 3—5 min. After cooling, water
(5 mL) was added to the solution, and the resulting mixture was
left for 16 h. A precipitate that formed was separated and washed
with cool ethanol and hexane.
Comꢀ Yield
pound (%)
(method)
Found
Calculated
(%)
Molecular
formula
C
H
N
8a*
8b
63 (A)
60.74 4.19 8.67
60.90 4.31 8.88
C28H19ClN4O2S2•
•C4H8O2
75 (A), 65.55 3.88 13.64 C22H16N4O2S
71 (B) 65.98 4.03 13.99
90 (A), 63.92 4.12 12.93 C23H18N4O3S
8c
83 (B)
83 (B)
64.17 4.21 13.01
60.57 3.24 12.56 C22H15ClN4O2S
60.76 3.48 12.88
8d
* The complex with one dioxane molecule.
4ꢀ(3ꢀCyanopyridinꢀ2ꢀylthio)acetoacetates 3 were synthesized
by a described method.1 The characteristics of undescribed1
compounds 3 are presented in Tables 1 and 2.
2ꢀAminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyraꢀ
no[2,3ꢀd]pyrido[3´,2´:4,5]thieno[3,2ꢀb]pyrimidines 8. A. Arylꢀ
idenemalononitrile 5 (0.01 mol) and triethylamine or Nꢀmethylꢀ
B. Aldehyde 9 (0.01 mol) malononitrile (10) (0.66 g,
0.01 mol), and triethylamine (0.1 mL) were added with stirring
to a suspension of ester 3 (0.01 mol) in ethanol or methanol
(15—20 mL), and the mixture was refluxed for 5—12 min. After
cooling, water (5 mL) was added to the solution, and the mixꢀ
Table 4. Spectroscopic characteristics of 2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrano[2,3ꢀd]pyrido[3´,2´:4,5]thieꢀ
no[3,2ꢀb]pyridines 8
Comꢀ
pound
IR,
ν/cm–1
1H NMR (DMSOꢀd6),
δ (J/Hz)
CN
CONH,
NH2
R1
R2
R3
Ar
C(4)H
NH2
NH
(s, 1 H) (s, 2 H) (s, 1 H)
8aa
8b
2200
1648 (δ),
1668 (δ),
3176,
3352,
3448
1632 (δ),
1668 (δ),
3180,
7.09—7.95
(m, 3 H,
C4H3S)
1.76 (d, 2 H, CH2);
1.88, 2.63, 3.08
(all m, 2 H each, CH2)
7.09—7.95
4.92
4.64
7.09b
12.76
(m, 4 H, C6H4)b
2200
2.58
(s, 3 H,
Me)
7.28c
(s, 1 H)
2.90
(s, 3 H,
Me)
7.20—7.32c
(m, 5 H, Ph)
7.11
11.04
3288,
3364,
3420
8c
8d
2200
2204
1640 (δ),
1668 (δ),
3168,
3320,
3444
1636 (δ),
1668 (δ),
3184,
8.45
(s, 1 H)
1.66 (m, 4 H, CH2CH2);
1.85, 2.89, 3.11
(all m, 2 H each, CH2)
6.39 (s, 1 H);
7.53 (d, 2 H,
J = 8.1)
4.50
4.68
7.25
12.78
11.05
2.59
(s, 3 H,
Me)
7.26c
(s, 1 H)
2.90
(s, 3 H,
Me)
7.17—7.37c,d
(m, 4 H,
C6H4)
7.21d
3324,
3468
a The complex with one dioxane molecule; for dioxane δH (300 MHz, DMSOꢀd6) 3.07 (s, 8 H, 2 (—CH2CH2—)). Mass spectrum for
compound 8a, m/z (Irel (%)): 542 [M – dioxane]+ (7), 507 (49), 442 (100), 354 (20), 252 (15), 188(19), 89 [dioxane + H] (12), 66 (89).
b The signals of the protons of 2ꢀC4H3S, 2ꢀClC6H4, and 2ꢀNH2 are overlapped.
c The signals of the protons of C(8)H and Ar are overlapped.
d The signals of the protons of 2ꢀNH2 and Ar are overlapped.

4ꢀ(3ꢀCyanopyridinꢀ2ꢀylthio)acetoacetates
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2191
Table 5. Physicochemical characteristics of 3ꢀalkoxycarbonylꢀ6ꢀaminoꢀ4ꢀarylꢀ5ꢀcyanoꢀ2ꢀ(3ꢀcyanopyridinꢀ2ꢀylthiomethyl)ꢀ4Hꢀpyrans 12
Comꢀ M.p.
pound /°C
Yield Found
Molecular
formula
Comꢀ M.p.
pound /°C
Yield Found
Molecular
formula
(%)
N
(%)
N
(%)
Calculated
(%)
Calculated
(method)
(method)
C
H
C
H
12a 120—121 80 (A) 61.32 4.25 12.57 C23H20N4O4S
71 (C) 61.59 4.49 12.49
12m 211—213 58 (B), 60.30 4.29 13.19 C26H23N5O5S
75 (C) 60.34 4.48 13.53
12b 202—203 85 (A), 51.46 4.11 10.07 C25H23IN4O3S
94 (C) 51.20 3.95 9.55
12n 227—228 72 (B) 56.85 3.94 12.42 C26H22ClN5O5S
56.57 4.02 12.69
12c 183—184 87 (A) 60.14 5.16 11.83 C24H24N4O3S2
59.98 5.03 11.66
12o 172—174 38 (B) 63.12 4.73 10.31 C28H26N4O5S
63.38 4.94 10.56
12d 216—217 89 (A) 51.84 4.12 9.14 C26H25IN4O3S
52.01 4.20 9.33
12p 136—137 35 (B) 57.26 4.18 12.15 C27H24ClN5O5S
57.29 4.27 12.37
12e 102—103 77 (A), 64.37 4.75 12.37 C24H22N4O3S
58 (C) 64.56 4.97 12.55
12q 195—196 71 (C) 59.02 4.63 12.12 C23H22N4O3S2
59.21 4.75 12.01
12f
171—172 78 (A) 65.44 4.18 9.07 C33H26N4O4S2
12r
183—184 64 (C) 60.95 3.67 13.03 C27H20ClN5O3S
65.53 4.32 9.23
61.19 3.80 13.21
12g 204—205 69 (A) 58.19 3.27 8.83 C30H21ClN4O3S3
58.38 3.43 9.08
12s 191—192 98 (C) 63.12 4.42 11.52 C25H22N4O4S
65 (D) 63.28 4.67 11.81
12h 204—205 72 (A), 56.41 3.94 9.81 C26H23BrN4O3S
77 (C) 56.63 4.20 10.16
12t
157—158 67 (C) 63.83 4.92 14.05 C26H25N5O3S
55 (D) 64.05 5.17 14.36
12i
178—180 56(A) 55.68 4.16 12.81 C25H23N5O5S2
55.85 4.31 13.03
12u 167—168 65 (C) 57.32 4.20 9.57 C27H25BrN4O3S
57.35 4.46 9.91
12j
175—177 63 (A), 64.02 5.46 10.00 C30H32N4O5S
48 (D) 64.27 5.75 9.99
12v 140—142 59 (C) 61.36 4.26 13.92 C25H22FN5O3S
61.09 4.51 14.25
12k 216—217 83 (B) 60.73 4.24 15.92 C22H19N5O3S
12w 157—158 90 (C) 58.09 4.11 12.30 C27H24F3N5O3S
49 (D) 58.37 4.35 12.61
60.96 4.42 16.16
12l
218—219 79 (B) 54.03 3.47 13.47 C23H19N5O5S2
12x 199—201 51 (D) 59.39 4.46 11.51 C29H27N5O7S
59.07 4.62 11.88
54.21 3.76 13.74
Table 6. Spectroscopic characteristics of 3ꢀalkoxycarbonylꢀ6ꢀaminoꢀ4ꢀarylꢀ5ꢀcyanoꢀ2ꢀ(3ꢀcyanopyridinꢀ2ꢀylthiomethyl)ꢀ4Hꢀpyrans 12
Comꢀ
pound
IR,
ν/cm–1
1H NMR (300 MHz, DMSOꢀd6),
δ (J/Hz)
CN C=O NH2
R1
R2
R3
—
R4
Ar
NH2
(s, 2 H)
H(4)
SCH2
(2 H)
12a
12b
2196, 1716 1676 (δ), 2.33
2216
6.45
1.03 (t, 3 H,
Me, J = 7.2)
4.00 (q, 2 H,
CH2, J = 7.2)
1.00 (t, 3 H,
Me, J = 7.3);
3.99 (q, 2 H,
CH2, J = 7.3)
7.10—7.47 (m,
5 H, Ph)
6.84
4.34 4.50, 4.62
(both d,
3200, (s, 3 H, (s, 1 H,
3328,
3392
Me)
CH)
1 H each,
J = 13.4)
2204, 1720 1684 (δ), 2.42a
2.17
2.42a
6.96 (dd, 1 H,
C6H4, J = 7.9,
J = 7.3);
6.78
4.78 4.61, 4.72
(both d,
2220
3180, (s, 3 H, (s, 3 H, (s, 3 H,
3312,
3448
Me)
Me)
Me)
1 H each,
J = 14.0)
7.03 (d, 1 H,
C6H4, J = 7.3);
7.37 (t, 1 H,
C6H4, J = 7.3);
7.81 (d, 1 H,
C6H4, J = 7.9)
6.84 (d, 1 H,
12c
2204, 1712 1684 (δ), 2.46
2216
2.18
2.41
1.08 (d, 3 H,
Me, J = 6.6);
1.19 (d, 3 H,
Me, J = 6.6);
4.95 (m,
7.00
4.68 4.57, 4.71
(both d,
3180, (s, 3 H, (s, 3 H, (s, 3 H,
C(3)H, C4H3S,
J = 3.6); 6.93
(dd, 1 H, C(4)H,
C4H3S, J = 3.6,
J = 4.9); 7.37 (d,
1 H, C(5)H,
3312,
3484
Me)
Me)
Me)
1 H each,
J = 14.2)
1 H, CH)
C4H3S, J = 4.9)
(to be continued)

2192
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Rodinovskaya et al.
Table 6 (continued)
Comꢀ
pound
IR,
ν/cm–1
1H NMR (300 MHz, DMSOꢀd6),
δ (J/Hz)
CN C=O NH2
R1
R2
R3
R4
Ar
NH2
(s, 2 H)
H(4)
SCH2
(2 H)
12d
2208, 1716 1680 (δ), 2.46
2220
2.20
2.42
0.78, 1.20
(both d,
3 H each,
Me, J = 6.6);
4.85 (m,
6.97 (t, 1 H,
C6H4, J = 8.0);
7.06 (d, 1 H,
C6H4, J = 8.0);
7.30 (t, 1 H,
C6H4, J = 8.0);
7.82 (d, 1 H,
C6H4, J = 8.0)
1.16 (t, 3 H,
Me, J = 7.5);
2.56 (q, 2 H,
CH2, J = 7.5);
6.99 (d, 1 H,
C6H4, J = 7.5);
7.20 (d, 1 H,
C6H4, J = 7.5)
5.06 (s, 2 H,
OCH2);
6.76
6.83
6.78c
4.77 4.60, 4.78
(both d,
3180, (s, 3 H, (s, 3 H, (s, 3 H,
3324,
3476
Me)
Me)
Me)
1 H each,
J = 13.2)
1 H, CH)
12e
2196, 1720 1680 (δ), 8.10
2220
7.10
2.55
3.59 (s, 3 H,
Me)
4.27
4.69 (s)
3188, (d, 1 H, (d, 1 H, (s, 3 H,
3328,
CH,
CH,
Me)
3444 J = 8.0) J = 8.0)
12f
2196, 1716 1680 (δ), 8.21
2220
7.82
7.23b
1.02 (t, 3 H,
4.36 4.72, 4.83
(both d,
3196, (d, 1 H, (d, 1 H, (m, 1 H, Me, J = 7.2);
3328 CH, CH, C4H3S); 4.01 (q, 2 H,
3448 J = 8.9) J = 8.9)
(m, 2 H,
C6H4); 6.90
(d, 1 H,
C6H4, J = 8.4);
7.23b (m, 1 H,
C6H4);
1 H each,
J = 14.3)
7.81
(d, 1 H,
C4H3S,
J = 4.0);
8.00
CH2, J = 7.2)
(d, 1 H,
C4H3S,
J = 4.4)
6.95
7.32—7.48
(m, 5 H,
Ph)
6.89 (d, 1 H,
C4H3S,
12g
2184, 1716 1668 (δ), 7.68
2220
7.92
1.15 (t, 3 H,
6.99
4.75 4.72, 4.84
(both d,
1632 sh (d, 2 H, (s, 1 H, (dd, 1 H, Me, J = 6.7);
(δ),
C6H4,
CH)
C4H3S,
J = 2.4,
J = 4.9);
7.38
(d, 1 H,
C4H3S,
J = 4.9);
8.12
4.12 (q, 2 H,
CH2, J = 6.7)
J = 1.8);
1 H each,
J = 14.0)
3176, J = 7.9);
3332, 7.77 (d,
3452 2 H, C6H4,
J = 8.5)
7.25 (dd, 1 H,
C4H3S, J = 4.9,
J = 1.8);
7.92 (d, 1 H,
C4H3S,
J = 4.9)
(d, 1 H,
C4H3S,
J = 2.4)
12h
12i
2208, 1720 1688 (δ), 7.81
2216 3184, (s, 1 H,
1.62 (m, 4 H,
CH2, CH2);
1.83, 2.77,
2.92 (all m,
2 H each,
3.62 (s,
3 H, Me)
7.11 (d, 1 H,
C6H4, J = 7.5);
7.20 (m, 2 H,
C6H4);
7.34 (d, 1 H,
C6H4, J = 8.1)
6.97, 7.96d
6.71
7.33
4.31 4.64, 4.76
(both d,
3312,
3460
CH)
1 H each,
J = 14.3)
CH2)
2188, 1700 1668 (δ), 7.96d
2220 3184, (s, 1 H,
1.42—1.53 (m,
4 H, CH2);
1.76, 2.72, 2.89
(all m, 2 H
each, CH2)
1.18 (t,
3 H, Me,
J = 7.9);
4.14 (q, 2 H,
CH2, J = 7.9)
4.73 4.51, 4.92
(both d,
(both d, 1 H each,
C4H2S, J = 4.1)
3300,
3348
CH)
1 H each,
J = 13.6)
(to be continued)

4ꢀ(3ꢀCyanopyridinꢀ2ꢀylthio)acetoacetates
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2193
Table 6 (continued)
Comꢀ
pound
IR,
ν/cm–1
1H NMR (300 MHz, DMSOꢀd6),
δ (J/Hz)
CN C=O NH2
R1
R2
R3
R4
Ar
NH2
(s, 2 H)
H(4)
SCH2
(2 H)
12j
2192, 1688 1668 (δ), 7.93
2216 3216, (s, 1 H,
1.58 (m, 4 H,
CH2); 1.80,
2.77, 2.97
(all m,
2 H each, CH2) 4.87 (m, 1 H,
CH)
1.00, 1.16
(both d,
3 H each,
Me, J = 5.9);
3.69 (s, 6 H,
2 MeO); 6.26
(s, 2 H,
C6H3); 6.36
(s, 1 H,
6.73
4.25 4.63, 4.71
(both d,
3332,
3408
CH)
1 H each,
J = 13.8)
C6H3)
12k
2192, 1724 1680 (δ), 2.33
2220 3308, (s, 3 H, (s, 1 H,
3372 Me) CH)
7.12
2.42 (s,
3 H,
Me)
3.54 (s,
3 H,
Me)
7.30 (dd, 1 H,
C5H4N, J = 4.3,
J = 8.0); 7.45
(d, 1 H,
7.05
4.38 4.63, 4.74
(both d,
1 H each,
J = 14.5)
C5H4N, J = 8.0);
8.34 (s, 1 H,
C5H4N);
8.43 (d, 1 H,
C5H4N, J = 4.3)
6.95, 7.86
(both d, 1 H each,
C4H2S, J = 4.8)
12l
2204, 1720 1676 (δ), 7.89
2224 3188, (s, 1 H,
2.09 (m, 2 H,
CH2);
2.84—2.93
(m, 4 H,
CH2)
1.21 (t, 3 H,
Me, J = 7.1);
4.22 (q, 2 H,
CH2, J = 7.1)
7.12
4.68 4.56, 4.76
(both d,
3352,
3452
CH)
1 H each,
J = 14.3)
12m
12n
2196, 1704 1692 (δ), 7.93
2224 3320, (s, 1 H,
2.08 (m, 2 H,
CH2);
2.76—2.98
(m, 4 H,
CH2)
2.02 (m, 2 H,
CH2);
2.54—2.91
(m, 4 H,
CH2)
1.00, 1.18
(both d, 3 H each, (both d, 2 H each,
7.37, 8.12
6.88
6.96
4.46 4.65, 4.73
(both d,
3336,
3412
CH)
Me, J = 6.6);
4.90 (m, 1 H,
CH)
0.93 (d, 3 H,
Me, J = 6.6);
1.19 (d, 3 H,
Me, J = 5.1);
4.87 (m, 1 H,
CH)
C6H4, J = 7.9)
1 H each,
J = 14.4)
2204, 1720 1680 (δ), 7.82
2228 3184, (s, 1 H,
7.67, 8.04
4.98 4.52, 4.92
(both d,
(both d, 2 H each,
C6H3, J = 8.5);
7.90 (s, 1 H,
C6H3)
3360,
3460
CH)
1 H each,
J = 13.8)
12o
12p
12q
2200, 1708 1680 (δ), 7.91
2228 3220, (s, 1 H,
2.07 (m, 2 H,
CH2);
2.71—2.98
(m, 4 H,
CH2)
0.97 (d, 3 H,
Me, J = 5.9);
1.16 (d, 3 H,
Me, J = 6.6);
4.88 (m, 1 H,
CH)
0.90 (d, 3 H,
Me, J = 6.6);
1.21 (d, 3 H,
Me, J = 5.9);
4.89 (m, 1 H,
CH)
3.87 (s, 3 H,
6.77
6.93
6.91
4.37
4.67 (s)
Me); 7.22, 7.86
(both d, 2 H each,
C6H4, J = 7.9)
3184,
3332,
3428
CH)
2200, 1716 1676 (δ), 7.80d
2220 3316, (s, 1 H,
3480 CH)
1.70 (m, 2 H,
CH2);
2.45, 2.69
(m, 4 H,
CH2)
7.68, 8.05
4.99 4.46, 4.97
(both d,
(both d, 1 H each,
C6H3, J = 8.5);
7.80d (s, 1 H,
C6H3)
1 H each,
J = 14.4)
2200, 1720 1676 (δ), 2.44
2220 3184, (s, 3 H, (s, 3 H, (s, 3 H,
2.18
2.40
1.16 (t, 3 H,
Me, J = 7.5);
4.15 (q, 2 H,
CH2, J = 7.5)
6.83 (d, 1 H,
C4H3S, J = 2.4);
6.93 (m, 1 H,
C4H3S);
4.57 4.59, 4.70
(both d,
3328,
3476
Me)
Me)
Me)
1 H each,
J = 13.2)
7.35 (d, 1 H,
C4H3S,
J = 4.9)
(to be continued)

2194
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Rodinovskaya et al.
Table 6 (continued)
Comꢀ
pound
IR,
ν/cm–1
1H NMR (300 MHz, DMSOꢀd6),
δ (J/Hz)
CN C=O NH2
R1
R2
R3
R4
Ar
NH2
(s, 2 H)
H(4)
SCH2
(2 H)
12r
2200, 1704 1668 (δ), 8.30
2224
7.99 8.06, 8.71 1.09 (t, 3 H,
Me, J = 7.4);
7.16, 7.37
(both d,
6.64
4.39 4.82, 4.92
(both d,
3300, (d, 1 H, (d, 1 H, (both d,
3348
CH,
CH, 2 H each, 4.02 (q, 2 H,
2 H each,
C6H4,
J = 7.9)
3.69 (s, 3 H,
MeO); 6.59
(s, 1 H, C6H4);
6.67, 6.79
(both d, 1 H each,
C6H4, J = 7.9);
7.17 (t, 1 H,
1 H each,
J = 14.4)
J = 8.4) J = 8.4) C5H4N,
J = 5.3)
CH2,
J = 7.4)
3.61 (s, 3 H,
Me)
12s
2208, 1728 1676 (δ), 8.01
2220 3184, (s, 1 H,
2.03 (m,
2 H, CH2);
2.74—2.90
(m, 4 H,
CH2)
6.82
4.26 4.61, 4.71
(both d,
3296,
3452
CH)
1 H each,
J = 14.4)
C6H4, J = 7.9)
7.26 (dd, 1 H,
C5H4N, J = 4.4,
J = 8.1); 7.44
(d, 1 H, C5H4N,
J = 8.1); 8.33
(s, 1 H, C5H4N);
8.40 (m, 1 H,
C5H4N)
12t
2192, 1700 1676 (δ), 7.83
2228 3244, (s, 1 H,
1.62 (m, 4 H,
CH2); 1.84,
2.77, 2.92
(all m,
1.10 (t, 3 H,
Me, J = 7.5);
4.06 (q, 2 H,
CH2 each,
J = 7.5)
6.80
4.36
4.70 (s)
3372,
3444
CH)
2 H, CH2)
12u
12v
12w
2204, 1720 1684 (δ), 7.48
2220 3180, (s, 1 H,
1.35, 1.67,
2.75, 2.82
(all m, 2 H
each, CH2)
3.62 (s, 3 H,
Me)
7.12 (d, 1 H,
C6H4, J = 7.5);
7.21 (m, 2 H,
C6H4); 7.35
(d, 1 H,
C6H4, J = 7.9)
7.07—7.25
6.75
6.91
6.69
4.32 4.66, 4.74
(both d,
3316,
3460
CH)
1 H each,
J = 14.3)
2204, 1720 1668 (δ), 7.97
2224 3184, (s, 1 H,
2.36 (s,
3 H, Me);
2.62—2.84
(m, 4 H,
CH2); 3.50
(s, 2 H, CH2)
2.42 (s, 3 H,
Me); 2.71 (m,
2 H, CH2);
2.88 (m, 2 H,
CH2); 3.53
(s, 2 H, CH2)
3.57 (s, 3 H,
Me)
4.61 4.62, 4.72
(both d,
(m, 4 H, C6H4)
3320,
3448
CH)
1 H each,
J = 14.3)
2200, 1712 1668 (δ), 7.88
2228 3184, (s, 1 H,
0.94 (t, 3 H,
Me, J = 7.2);
3.98 (q, 2 H,
CH2, J = 7.2)
7.29 (d, 1 H,
C6H4, J = 7.5);
7.38—7.52
(m, 1 H each,
C6H4); 7.63
(d, 1 H, C6H4,
J = 8.0)
4.77 4.63, 4.73
(both d,
3324,
3376
CH)
1 H each,
J = 14.5)
12x
2204, 1708 1680 (δ), 7.84
2228 3184, (s, 1 H,
1.62 (m, 4 H,
CH2); 1.85,
2.77, 2.94
(all m,
0.95, 1.12
(both d, 3 H each, OCH2O);
Me, J = 5.9);
4.86 (m,
6.15 (s, 2 H,
6.79
5.26 4.67, 4.74
(both d,
3324,
3476
CH)
6.63, 7.40
(both s,
1 H each,
J = 14.4)
2 H each, CH2) 1 H, CH)
1 H each, C6H2)
а The signals of the protons of the methyl groups are overlapped.
b The signals of the protons of the aryl substituents are overlapped.
c The signals of the proton of the amino group are overlapped with the signals of the protons of the aryl substituent.
d The signal of the proton of the pyridine ring is overlapped with the signals of the protons of the aryl substituent.

4ꢀ(3ꢀCyanopyridinꢀ2ꢀylthio)acetoacetates
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2195
Table 7. Physicochemical characteristics of 5ꢀalkoxycarbonylꢀ2ꢀaminoꢀ4ꢀarylꢀ6ꢀchloromethyleneꢀ5ꢀcyanoꢀ1Hꢀpyrans 13
Comꢀ M.p. Yield
pound /°C (%)
Found
Calculated
Molecular
formula
Comꢀ M.p. Yield
pound /°C (%)
Found
Calculated
Molecular
formula
(%)
N
(%)
N
C
H
C
H
13a 161—162 86
13b 184—186 91
13c 175—177 84
13d 147—148 39
13e 152—154 90
60.56 4.83 8.94 C16H15ClN2O3
60.29 4.74 8.79
43.04 3.05 6.07 C16H14ClIN2O3
43.22 3.17 6.30
52.04 4.36 8.95 C14H13ClN2O3S
51.77 4.03 8.63
61.64 5.04 8.12 C17H17ClN2O3
61.36 5.15 8.42
13g 106—107 65
13h 170—171 58
53.82 4.14 10.85 C17H16ClN3O5
54.05 4.27 11.12
46.72 3.01 7.05 C15H12BrClN2O3
46.96 3.15 7.30
56.17 4.20 12.82 C15H14ClN3O3
56.35 4.41 13.14
55.97 3.72 8.75 C15H12ClFN2O3
55.83 3.75 8.68
13i
13j
184—186 94
179—180 53
54.36 3.84 7.70 C16H14Cl2N2O3
54.41 4.00 7.93
13k 161—162 65
52.53 3.44 7.02 C17H14ClF3N2O3
52.79 3.65 7.24
13f
173—174 49
57.18 4.36 8.12 C16H15ClN2O4
57.41 4.52 8.37
Table 8. Spectroscopic characteristics of 5ꢀalkoxycarbonylꢀ2ꢀaminoꢀ4ꢀarylꢀ6ꢀchloromethyleneꢀ5ꢀcyanoꢀ1Hꢀpyrans 13
Comꢀ
pound
IR,
ν/cm–1
1H NMR (300 MHz, DMSOꢀd6),
δ (J/Hz)
CN
C=O
NH2
CH2Cl
(s, 2 H)
NH2
(br.s)
R4
C(4)H
(s)
Ar
13a
13b
2188
2196
1696 1676 (δ),
3412, 3332
1704 1680 (δ),
3416, 3328
4.71
4.73
6.95
1.08 (t, 3 H, Me, J = 7.1);
4.03 (q, 2 H, CH2, J = 7.1)
4.48
4.83
7.12—7.38 (m, 5 H)
6.99* 1.03 (t, 3 H, Me, J = 7.1);
4.00 (q, 2 H, CH2, J = 7.1)
6.99* (m, 1 H);
7.12 (d, 1 H, J = 8.1);
7.39 (m, 1 H);
7.33 (d, 1 H, J = 7.4)
6.87 (d, 1 H, C(3)H, J = 2.9);
6.96 (m, 1 H, C(4)H);
7.49 (d, 1 H, C(5)H, J = 7.1)
1.18 (t, 3 H, Me, J = 7.2);
2.58 (q, 2 H, CH2, J = 7.2);
7.06, 7.17 (both d, 2 H each,
J = 7.9)
13c
13d
2192
2192
1696 1676 (δ),
4.68
4.70
7.01
6.92
1.18 (t, 3 H, Me, J = 7.1);
4.14 (q, 2 H, CH2, J = 7.1) 4.73
3408, 3328
1704 1680 (δ),
3.60 (s, 3 H, Me)
4.34
4.40
4.47
4.57
4.41
4.47
3416, 3336
13e
13f
13g
13h
13i
2196
2196
2196
2192
2200
1700 1680 (δ),
4.67, 4.75
(both d,
1 H each,
J = 12.9)
4.69, 4.75
(both d,
1 H each,
J = 12.9)
4.70, 4.79
(both d,
1 H each,
J = 11.8)
4.68, 4.75
(both d,
1 H each,
J = 12.9)
4.67, 4.78
(both d,
1 H each,
J = 11.4)
7.04
7.01
7.05
7.08
7.00
1.07 (t, 3 H, Me, J = 7.1);
4.04 (q, 2 H, CH2, J = 7.1)
7.19, 7.40 (both d,
2 H each, J = 7.1)
3408, 3332
1704 1680 (δ),
3.60 (s, 3 H, Me)
3.74 (s, 3 H, Me);
6.69 (s, 1 H);
6.74, 6.84 (both d, 1 H each,
J = 8.5); 7.35 (t, 1 H, J = 8.5)
7.46, 8.21 (both d,
3408, 3328
1724 1688 (δ),
0.95 (d, 3 H, Me, J = 5.9);
1.16 (d, 3 H, Me, J = 6.6);
4.85 (m, 1 H, СH)
3330, 3376
2 H each, J = 8.5)
1704 1672 (δ),
3.61 (s, 3 H, Me)
7.18 (d, 1 H, J = 8.5);
7.32 (m, 1 H);
7.46 (d, 1 H, J = 8.5)
3412, 3328
1724 1684 (δ),
1.08 (t, 3 H, Me, J = 7.3);
4.06 (q, 2 H, CH2, J = 7.3)
7.48 (m, 1 H, C(5)H);
7.57 (d, 1 H, C(4)H, J = 7.8);
8.41 (s, 1 H, C(2)H);
3352, 3304
8.46 (d, 1 H, C(6)H, J = 4.3)
(to be continued)

2196
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Rodinovskaya et al.
Table 8 (continued)
Comꢀ
pound
IR,
ν/cm–1
1H NMR (300 MHz, DMSOꢀd6),
δ (J/Hz)
CN
C=O
NH2
CH2Cl
(s, 2 H)
NH2
(br.s)
R4
C(4)H
(s)
Ar
13j
2200
2212
1704 1680 (δ),
3416, 3332
1724 1684 (δ),
3480, 3320
4.72
4.71
6.93
3.58 (s, 3 H, Me)
4.69
4.79
7.10—7.34 (m, 4 H)
13k
6.95
0.92 (t, 3 H, Me, J = 7.2);
3.97 (q, 2 H, CH2, J = 7.2)
7.37 (d, 1 H, J = 7.9);
7.46 (t, 1 H, J = 7.9);
7.67 (m, 2 H)
* The signals of the protons are overlapped.
ture was left for 16 h. A precipitate that formed was separated
and washed with cool ethanol and hexane.
References
C. Pyran 13 (0.01 mol) was added with stirring to a suspenꢀ
sion of pyridinethione 1 (0.01 mol) in ethanol or methanol
(15—20 mL), and the mixture was stirred for 0.5—1 h at
40—45 °C. After cooling, water (5 mL) was added to the soluꢀ
tion, and the mixture was left for 16 h. A precipitate formed was
separated and washed with cool ethanol and hexane.
D. 4ꢀChloroacetoacetate 2 (0.042 mol) was added with stirꢀ
ring to a suspension of pyridinethione 1 (0.004 mol) in ethaꢀ
nol or methanol (15—20 mL), and stirring was continued at
40—45 °C for 12—15 min. Then aldehyde 9 (0.0043 mol),
malononitrile (10) (0.28 g, 0.0043 mol), and triethylamine
(0.1 mL) were added to the solution, and the mixture was reꢀ
fluxed for 3—5 min. After cooling, water (5 mL) was added to
the solution, and the mixture was stored for 16 h. A precipitate
of compound 12 was separated and washed with cool ethanol
and hexane.
Compounds 12 were recrystallized from ethanol or methanol.
The characteristics of compounds 12 are presented in
Tables 5 and 6.
5ꢀAlkoxycarbonylꢀ2ꢀaminoꢀ4ꢀarylꢀ6ꢀchloromethyleneꢀ5ꢀ
cyanoꢀ1Hꢀpyrans 13. Triethylamine (0.1 mL) was added to a
suspension of ester 2a—c (0.01 mol), aldehyde 9 (0.01 mol), and
malononitrile (10) (0.66 g, 0.01 mol) in ethanol or methanol.
The mixture was refluxed for 5—7 min and stored at ∼20 °C for
10—12 h. A precipitate formed was separated and washed with
ethanol or hexane.
1. L. A. Rodinovskaya and A. M. Shestopalov, Izv. Akad. Nauk,
Ser. Khim., 2000, 347 [Russ. Chem. Bull., Int. Ed., 2000,
49, 348].
2. The Merck Index, Ed. V. J. O´Neil, Merck and Co., Inc.,
Whitehouse Station, NJ, 2001, 1818 p.
3. V. P. Litvinov, R. A. Rodinovskaya, Yu. A. Sharanin, A. M.
Shestopalov, and A. Senning, Sulfur Reports, 1992, 13, 1.
4. K. Urbahns, H.ꢀG. Heine, B. Junge, F. Mauler, R. Wittka,
and J.ꢀM.ꢀV. Dr. De Vry, Eur. Pat. 758647; Chem. Abstrs.,
1997, 126, 225216v.
5. K. T. Tanaka, Sh. K. Makino, I. T. Oshio, T. T. Shimotori,
Yu. T. Aikawa, T. N. Inaba, C. T. Yoshida, S. M. Takano,
and Y. T. Taniguchi, Eur. Pat. 695547; Chem. Abstrs., 1996,
124, 23835c.
6. S. J. Ambler, W. F. Jr. Heath, J. P. Singh, C. W. Smith, and
L. E. Stramm, Eur. Pat. 619314, Chem. Abstrs., 1995, 122,
31327d.
7. Yu. A. Sharanin, M. P. Goncharenko, and V. P. Litvinov,
Usp. Khim., 1998, 67, 442 [Russ. Chem. Rev., 1998, 67 (Engl.
Transl.)].
8. A. G. A. Elagamey, S. Z. A. Sowellim, F. M. A. A. ElꢀTaweel,
and M. H. Elnagdi, Coll. Czechosl. Chem. Commun., 1988,
53, 1534.
9. L. G. Sharanina, V. K. Promonenkov, V. P. Marshtupa,
A. V. Pashchenko, V. V. Puzanova, Yu. A. Sharanin, N. A.
Klyuev, L. F. Gusev, and A. P. Gagusin, Khim. Geterotsikl.
Soedin., 1982, 801 [Chem. Heterocycl. Comp., 1982, 18, 607
(Engl. Transl.)].
The data on compounds 13 are presented in Tables 7 and 8.
5ꢀCyanoꢀ3ꢀethoxycarbonylꢀ2ꢀ(3ꢀcyanopyridinꢀ2ꢀylthioꢀ
methylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ4,5,6ꢀtrimethyl)pyridineꢀ6(1H )ꢀ
thione 16. Morpholine (0.17 mL, 0.002 mol) was added to a
suspension of ester 3b (0.61 g, 0.002 mol) and 4ꢀmethoxyꢀ
benzylidenecyanothioacetamide 14 (0.44 g, 0.002 mol) in ethaꢀ
nol (20 mL), and the mixture was refluxed for 2 h. The reaction
mixture was stored for 16 h in a refrigerator. A precipitate formed
was filtered off and crystallized from ethanol. Compound 16
(0.54 g, 54%) was obtained as a yellow powder with m.p.
206—208 °C. Found (%): C, 62.02; H, 4.84; N, 12.89; S, 12.55.
C26H24N4O3S2. Calculated (%): C, 61.89; H, 4.79; N 11.12;
10. A. M. Shestopalov, Yu. M. Emeliyanova, A. A. Shestopalov,
L. A. Rodinovskaya, Z. I. Niazimbetova, and D. H. Evans,
Org. Lett., 2002, 4(3), 423.
11. A. M. Shestopalov, A. P. Yakubov, V. V. Tsyganov, Yu. M.
Emeliyanova, and V. N. Nesterov, Khim. Geterotsikl. Soedin.,
2002, 1345 [Chem. Heterocycl. Comp., 2002 (Engl. Transl.)].
12. Yu. A. Sharanin, L. Yu. Sukharevskaya, and V. V. Shelyakin,
Zh. Org. Khim., 1998, 34, 586 [Russ. J. Org. Chem., 1998, 34,
552 (Engl. Transl.)].
13. M. Z. Piao and K. Imafuku, Tetrahedron Lett., 1997,
38, 5301.
1
S, 12.71. IR, ν/cm–1: 2220, 2225 (CN); 1716 (CO). H NMR
(250 MHz, DMSOꢀd6), δ: 0.84 (t, 3 H, Me, J = 7.2 Hz); 2.20,
2.40, 2.59 (all s, 3 H each, Me); 3.72 (s, 3 H, MeO); 3.88 (q,
2 H, CH2O, J = 7.2 Hz); 4.64 (s, 2 H, CH2S); 7.04, 7.37 (both d,
2 H each, Ar, J = 7.9 Hz). MS, m/z (Irel (%)): 504 [M]+ (7), 458
[M – EtOH]+ (18), 328 (85), 178 (120), 134 (87%).
14. A. M. Shestopalov, Z. I. Niazimbetova, D. H. Evans, and
M. E. Niazimbetov, Heterocycles, 1999, 5, 1101.
Received March 6, 2003;
in revised form July 11, 2003