Substituted 4-(3-cyanopyridin-2-ylthio)acetoacetates: New convenient reagents for the synthesis of heterocycles

Article abstract of DOI:10.1055/s-2006-942433

Polyfunctional 4-(3-cyanopyridin-2-ylthio)acetoacetates were used in the synthesis of 4-hydroxy-1H-thieno[2,3-b:4,5-b]dipyridin-2-ones. The latter were used in reactions with arylidene-malononitriles or in three-component reactions with aldehydes and malo

Full text of DOI:10.1055/s-2006-942433

PAPER
2357
Substituted 4-(3-Cyanopyridin-2-ylthio)acetoacetates: New Convenient
Reagents for the Synthesis of Heterocycles
Synthesis of
He
y
terocycles
U
u
sing 4-(3-Cy
d
anopyridin-2
m
-ylthio)acetoacetate
i
s
la Rodinovskaya,* Anatoliy Shestopalov, Anna Gromova, Alexander Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russia
E-mail: shchem@dol.ru
Received 31 January 2006; revised 16 March 2006
of type 6, which represent a novel heterocyclic system.9
Compounds 4, similar to 4-hydroxyquinolin-2(1H)-
one,10,11 react as CH-acids with arylidenemalononitriles 5
in the presence of triethylamine or N-methylmorpholine
Abstract: Polyfunctional 4-(3-cyanopyridin-2-ylthio)acetoacetates
were used in the synthesis of 4-hydroxy-1H-thieno[2,3-b:4,5-
b]dipyridin-2-ones. The latter were used in reactions with arylidene-
malononitriles or in three-component reactions with aldehydes and
malononitrile to give 2-amino-4-aryl-3-cyano-5-oxo-5,6-dihydro- in DMF to afford 2-amino-4-aryl-3-cyano-5,6-dihydro-5-
4H-pyrano[2,3-d]pyrido[3¢,2¢:4,5]thieno[3,2-b]pyridines. Utilizing
oxo-4H-pyrano[2,3-d]pyrido[3¢,2¢:4,5]thieno[3,2-b]pyri-
4-(3-cyanopyridin-2-ylthio)acetoacetates and arylidenemalononi-
triles or aldehydes and malononitrile, we developed a method for
obtained by three-component reaction of thienodipyridi-
the synthesis of substituted 3-alkoxycarbonyl-6-amino-4-aryl-2-(3-
dines 6a–e (method A). Compounds 6a–d were also
nones 4, aromatic aldehydes 7, and malononitrile 8 (meth-
od B) (Scheme 1).
cyanopyridin-2-ylthiomethyl)-4H-pyrans. Reactions of substituted
4-(3-cyanopyridin-2-ylthio)acetoacetates with hydrazine hydrate
yielded substituted 3-hydroxypyrazoles, which were further used
for the preparation of 6-amino-4-aryl-5-cyano-3-(pyrid-2-ylthio-
methylene)-2,4-dihydropyrano[2,3-c]pyrazoles. Analogously, eth-
yl 4-(3-cyano-1,4-dihydropyridin-2-ylthio)acetoacetates were used
for the synthesis of substituted 2-amino-4H-pyrans.
R1
N
R2
R3
C
S
OEt
Cl
+
N
H
O
O
Key words: 2-amino-4H-pyrans, thienopyridines, 4-(3-cyanopyri-
din-2-ylthio)acetoacetates, pyranopyridines, multi-component re-
actions
1
2a
R1
O
R1
N
N
R2
R3
HN
C
R2
R3
We have previously reported that 4-(3-cyanopyridin-2-
ylthio)acetoacetates (3) are convenient starting reagents
for the syntheses of 4-hydroxy-1H-thieno[2,3-b:4,5-
b]dipyridin-2-ones that are otherwise difficult to prepare.1
Considering that compounds of type 3 contain several re-
action centers, we decided to study the ability of these
compounds to undergo a range of reactions in order to de-
velop new routes to relatively inaccessible heterocycles,
including new heterocyclic systems. Products of these re-
actions are of interest for several reasons, but mainly be-
cause of their similarity to the highly physiologically
active hydroxy(oxo)pyridines2,3 and 2-amino-4H-pyrans,
which are licensed as drugs, pesticides, and other practi-
cally significant compounds.4–8 It therefore seemed of
practical interest to prepare substances containing simul-
taneously both pyridine and pyran rings.
OEt
N
S
O
OH
S
O
3
CN
CN
4a–d
(5a–d)/DMF, Et3N
Ar
method À
Ar
O
R1
HN
DMF, Et3N
method B
4a–c + ArCHO (7a–d)
+ NCCH2CN (8)
R2
R3
CN
O
S
N
NH2
6a–e
Scheme 1 (4a) R1 = Me, R2 = H, R3 = Me; (4b) R1 = H, R2 = H,
R3 = 4-MeOC6H4; (4c) R1 = H, R2-R3 = (CH2)5; (4d) R1 = H, R2-
R3 = -CH2N(Me)CH2CH2-; (6a) R1 = Me, R2 = H, R3 = Me, Ar = 4-
MeC6H4; (6b) R1 = Me, R2 = H, R3 = Me, Ar = 3-C5H4N; (6c)
R1 = H, R2 = H, R3 = 4-MeOC6H4, Ar = 4-FC6H4; (6d) R1 = H,
Substituted 4-(3-cyanopyridin-2-ylthio)acetoacetates 3,
can be readily synthesized from 3-cyanopyridine-2(1H)-
thiones 1 and 4-chloroacetates 2 and can be further trans-
formed into 4-hydroxy-1H-thieno[2,3-b:4,5-b]dipyridin-
2-ones 4 by successive Thorpe–Ziegler and Guareschi–
Thorpe1 intramolecular ring closures (Scheme 1).
R2-R3 = (CH2)5, Ar = 4-i-PrOC6H4; (6e) R1 = H, R2-R3
=
-CH2N(Me)CH2CH2-, Ar = 4-F-C6H4; (5a, 7a) Ar = 4-MeC6H4; (5b,
7b) Ar = 3-C5H4N; (5c, 7c) Ar = 4-FC6H4; (5d, 7d) Ar = 4-i-
PrOC6H4
We decided to use thienodipyridinones 4 and their hydro-
genated analogues for the synthesis of annealated pyrans
The data of physicochemical analysis of pyranopyri-
dothienopyridines 6 (Tables 1 and 2) indicate that the re-
actions leading to their formation are highly
regioselective. Compounds 6 are high-melting microcrys-
tals, which are stable under normal conditions, and poorly
SYNTHESIS 2006, No. 14, pp 2357–2370
x
x.
x
x
.
2
0
0
6
Advanced online publication: 26.06.2006
DOI: 10.1055/s-2006-942433; Art ID: Z02706SS
© Georg Thieme Verlag Stuttgart · New York

2358
L. Rodinovskaya et al.
PAPER
soluble in most of the organic solvents, excluding DMF Compounds 10b,c were dissolved in hot ethanol, and a
and DMSO.
two-fold excess of base was added to the solution. The re-
action mixture was then refluxed, cooled to room temper-
ature and acidified with hydrochloric acid to precipitate
The 1H NMR spectra of compounds 6a–e show character-
istic singlets of 4-H protons of the pyran ring at 4.43–4.71
ppm, and singlets of the NH2 and NH protons at 7.09–7.25
ppm and 11.08–12.84 ppm, respectively. The IR spectra
of compounds 6 are characterized by absorption bands of
stretching vibrations of the nitrile group at 2184–2208
1
compounds 12 which, according to the IR and H NMR
spectra, were formed in the reaction instead of the expect-
ed 4-hydroxy-1,2-dihydro-2-[2¢,3¢:4,5]thieno[2,3-b]py-
ridines 11 (Scheme 2).
cm–1, and by absorption bands of stretching vibrations Annelated thienopyridines 12a and 12b were also synthe-
(3164–3468 cm–1) and bending vibrations (1632–1676 sized in one step, without preliminary isolation of com-
cm–1) of the amino and amide groups. Similar IR and 1H pounds 10, by refluxing a mixture consisting of equimolar
NMR spectra were previously observed for 2-amino-4- amounts of salt 9b,c and 2a in ethanol in the presence of
aryl-3-cyano-5,6-dihydro-5-oxo-4H-pyrano[3,2-c]quino-
a two-fold excess of base. Compounds 12a,b are stable
line11 and other annelated 2-amino-4-aryl-3-cyano-4H- and poorly soluble in the majority of organic solvents.
pyrans.12–16
The IR spectra of compounds 12a,b contain no signals
These types of transformations were extended by us to in- from the CN groups, but do contain the characteristic sig-
clude hydrogenated pyridinethiones (Scheme 2). Thus, 4- nals of the NHCO and OH groups. The 1H NMR spectra
(1,4-dihydropyridin-2-ylthio)acetoacetates 10a–c were of these compounds show signals corresponding to the
obtained by the alkylation of morpholinium 1,4-dihydro- aryl protons and from the ArNH group (in regions 10.45
pyridinethiolates 9a–c with ethyl chloroacetoacetate (2a) and 10.41 ppm). The signal from the 3-H proton of 12a
in ethanol. Compound 10a was isolated as an amorphous and 12b was observed at 5.86 ppm and 6.19 ppm, respec-
substance, by precipitating a resinous residue from the so- tively. The signal of the N1H proton was observed at 12.05
lution with water, followed by extraction with diethyl ppm and 11.69 ppm, respectively, which is characteristic
ether.
for pyridin-2(1H)-ones.1 It proved difficult to assign the
signal from the OH proton due to deuterium exchange that
takes place in DMSO-d6 and the poor solubility of 12 in
other solvents used in 1H NMR spectroscopy.
1
The H NMR spectra of compounds 10 (Tables 3 and 4)
contain the characteristic singlets of NH and 4-H protons
of the pyridine ring at 9.25–9.56 and 4.48–4.83 ppm, re-
spectively. The signals of the methylene atoms were ob- On heating in DMF in the presence of N-methylmorpho-
served at 4.11–4.21 ppm (CH2S) and at 3.65–3.75 ppm line, thienopyridine 12a reacts with 4-fluorobenzylidene-
(CH2O). Compounds 10b and 10c showed signals corre- malononitrile (5c) to form the tetracyclic-condensed
sponding to the CONH protons at 8.97 ppm and 9.10 ppm, system 13. The IR spectrum of 13 contains the character-
respectively. The IR spectra of compounds 10b and 10c istic absorption band of the CN group at 2210 cm–1, a
showed absorption bands of the CN group at 2205 cm–1 broadened absorption band at 1640 cm–1 corresponding to
and 2218 cm–1 and of the CO group in the region of 1730– bending vibrations of the NH2 group, and an absorption
1
1740 cm–1.
band of the CO group at 1670 cm–1. The H NMR spec-
trum of 13 contains the characteristic signals from the
NH2 and NH protons at 7.53 ppm and 10.40 ppm, respec-
tively.
Esters 10 were used to prepare synthetically challenging
4-hydroxy-2-oxopyrido[2¢,3¢:4,5]thieno[2,3-b]pyridines.
O
Ar1
O
Ar1
N
N
OEt
C
S
C
S
R1
2a
R1
O
O
Me
N
H
Me
N
H
H2N
O
9a–c
10a–c
1) 2 KOH
2) HCl
2a
(R1 = NHPh)
2 KOH,
(for 9b,c)
O
Ar1
O
Ar1
H
O
PhHN
Me
H
O
H
F
N
O
O
N
N
[O]
5c
PhHN
PhHN
N
S
Me
N
H
Me
N
12a,b
S
S
O
OH
OH
CN
13
11
NH2
Scheme 2 (9a, 10a) R1 = OMe, Ar1 = 3,4,5-(MeO)3C6H2; (9b, 10b) R1 = NHC6H4, Ar1 = Ph; (9c, 10c) R1 = NHC6H4, Ar1 = 3-C5H4N; (12a)
Ar1 = Ph; (12b) Ar1 = 3-C6H4N
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocycles Using 4-(3-Cyanopyridin-2-ylthio)acetoacetates
2359
Intermolecular reactions involving electrophilic and nu- In some cases, pyranopyridines 15g–i were prepared us-
cleophilic reactants with pyridinylthioacetoacetates 3 ing a simplified procedure without isolation of intermedi-
were also considered (Scheme 3).9 The reaction of esters ates 5 by a three-component reaction of compounds 3g–i,
3a–f with arylidenemalononitriles 5b,e–g occurs regiose- aromatic aldehydes 7e–g, and malononitrile 8 in ethanol
lectively only at one of the two available methylene-active in the presence of bases (method B).
groups (CH2COOR group) and affords the substituted 2-
amino-4H-pyrans 15a–f (method A).
The structures of compounds 15 were also confirmed by a
counter synthesis. The reaction of pyrans 16a–f with the
corresponding pyridine-2(1H)-thiones 1a–g regioselec-
tivly gave pyranopyridines 15b,c,i–n (method C).
OR4
O
R1
N
Taking into account that the formation of compounds 3
and 15 was highly regioselective, it was reasonable to as-
sume that pyrans 15 could be synthesized by a simpler
method without preliminary isolation and purification of
pyridylthioacetoacetic esters 3 (method D). Esters 3 were
generated by reaction of pyridinethiones 1c–e and esters
2a–c in ethanol (or methanol) in the presence of an
equimolar amount of KOH, and then equimolar amounts
of the corresponding aromatic aldehyde 7h,i and malono-
nitrile 8 and a catalytic amount of triethylamine were add-
ed to the reaction mixture to produce compounds 15.
Despite the moderate yields of compounds 15f,j,k in
method D (48–57%), this approach was found to be both
the most convenient and the more economic route.
N
C
N
R2
R3
C
CN
CN
O
R1
R2
Ar
S
OH
Ar
N
5b,e–g
S
N
O
method A
CN
R3
OR4
3a–f
14
3g–i + ArCHO (7e–g)
+ NCCH2CN (8)
method B
NH2
CN
Ar
O
Ar
O
O
O
CN
R4O
Cl
1a–g, KOH, DMF
CN
method C
Generally, compounds 15 are colorless, crystalline sub-
R1
R2
NH2
S
OR4
16a–f
stances, which are well soluble in most organic solvents.
1
R1
N
The H NMR spectra of these compounds (Tables 5
R2
CN
S
and 6) contain the characteristic signals of the 4-H proton
of the pyran ring at d = 4.25–4.88 ppm and protons of the
amino group at d = 6.63–7.00 ppm. The methylene atoms
of the CH2S group were observed in the region of
d = 4.60–4.96 ppm. Generally, signals from the methyl-
ene protons are present in the form of either a singlet or a
doublet of doublets. For the latter, the spin-spin coupling
constant ranges from 13.7–15.1 Hz.
1. 2a–c, EtOH, KOH
2. 7h,i, 8, Et3N/∆
R3
15a–n
R3
N
H
method D
1c–e
Scheme 3 (1a) R1 = R2 = H, R3 = Ph; (1b) R1 = R2 = H, R3 = 4-
C5H4N; (1c) R1 = H, R2-R3 = (CH2)5; (1d) R1 = H, R2 = Me, R3 = Et;
(1e) R1 = H, R2-R3 = (CH2)5 (1f) R1 = H, R2-R3 = -CH2N(Me)CH2CH2-;
(1g) R1 = 4-MeO-C6H4, R2-R3 = -CH2CH(t-Bu)CH2CH2-; (2a)
R4 = Et; (2b) R4 = Me; (2c) R4 = i-Pr; (3a) R1 = R2 = H,
R3 = R4 = Me; (3b) R1 = R2 = H, R3 = Ph, R4 = Et; (3c) R1 = R2 = H,
R3 = 4-C5H4N, R4 = Et; (3d) R1 = 4-ClC6H4, R2 = H, R3 = 2-C4H3S,
R4 = Et; (3e) R1 = H, R2-R3 = (CH2)3, R4 = Me; (3f) R1 = H, R2-
R3 = (CH2)5, R4 = i-Pr; (3g) R1 = Me, R2 = H, R3 = R4 = Me; (3h)
R1 = H, R2-R3 = (CH2)4, R4 = i-Pr; (3i) R1 = H, R2-R3 = (CH2)5,
R4 = Et; (5b) Ar = 3-C5H4N; (5e) Ar = 2-ClC6H4; (5f) Ar = 4-EtC6H4;
(5g) Ar = 4-C5H4N; (7c) Ar = 4-FC6H4; (7e) Ar = 2-FC6H4; (7f)
Ar = 4-NO2C6H4; (7g) Ar = 3-C4H3S; (7h) Ar = 2-C4H3S (7i) Ar = 4-
C5H4N; (15a) R1 = R2 = H, R3 = R4 = Me, Ar = 2-ClC6H4; (15b)
R1 = R2 = H, R3 = Ph, R4 = Et, Ar = 3-C5H4N; (15c) R1 = R2 = H,
R3 = 4-C5H4N, R4 = Et, Ar = 3-C5H4N; (15d) R1 = 4-ClC6H4, R2 = H,
R3 = 2-C4H3S, R4 = Et, Ar = 3-C5H4N; (15e) R1 = H, R2-R3 = (CH2)3,
R4 = Me, Ar = 4-EtC6H4; (15f) R1 = H, R2-R3 = (CH2)5, R4 = i-Pr,
Ar = 4-C5H4N; (15g) R1 = Me, R2 = H, R3 = R4 = Me, Ar = 2-FC6H4;
(15h) R1 = H, R2-R3 = (CH2)4, R4 = i-Pr, Ar = 4-NO2C6H4; (15i)
R1 = H, R2-R3 = (CH2)5, R4 = Et, Ar = 3-C4H3S; (15j); R1 = H,
R2 = Me, R3 = R4 = Et, Ar = 2-C4H3S; (15k) R1 = H, R2-R3 = (CH2)6,
R4 = Me, Ar = 4-C5H4N; (15l) R1 = H, R2-R3 = -CH2N(Me)CH2CH2-,
R4 = Me, Ar = 4-FC6H4; (15m) R1 = H, R2-R3 = -CH2N(Me)CH2CH2-,
R4 = Et, Ar = 4-ClC6H4; (15n) R1 = 4-MeOC6H4, R2-R3 = -CH2CH(t-
Bu)CH2CH2-, R4 = Et, Ar = 2-C4H3S; (16a) R4 = Et, Ar = 3-C5H4N;
(16b) R4 = Et, Ar = 3-C4H3S; (16c) R4 = Et, Ar = 2-C4H3S; (16d)
R4 = Me, Ar = 4-C5H4N; (16e) R4 = Me, Ar = 4-FC6H4; (16f) R4 = Et,
Ar = 4-Cl-C6H4
The IR spectra of compounds 15 were characterized by
two absorption bands of the nitrile groups of the pyran and
pyridine rings at 2188–2204 cm–1 and 2216–2240 cm–1,
respectively. The absorption bands of the carbonyl group
lie in a region of 1704–1728 cm–1. The IR spectra of com-
pounds 15 also show absorption bands of the amino group
at 1668–1688 cm–1 for bending vibrations and as two or
three (due to the formation of associates) bands at 3168–
3472 cm–1 for stretching vibrations.
Similar transformations were carried out for hydrogenat-
ed pyridine derivatives (Scheme 4). In this case, the pyri-
dine ring was not dehydrogenated, and 2-(6-amino-3-
carbethoxy-5-cyano-4H-pyran-2-ylmethylenethio)-3-cy-
ano-1,4-dihydropyridines 17 were obtained. For example,
the reaction of ester 10a with 4-methoxybenzylidenema-
lononitrile 5h in ethanol in the presence of triethylamine
gave compound 17a (method A). Since isolation in the
pure state and the work with resin-like esters 10 was dif-
ficult and decreased the yield of the target compounds, we
generated esters 10 in the reaction mixture and then intro-
duced them, without isolation, into the reaction with
arylidenenemalononitriles 5c,h. In this manner, com-
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

2360
L. Rodinovskaya et al.
PAPER
O
Ar1
O
Ar1
N
N
OEt
O
C
S
C
S
R1
R1
Me
+
2a
Me
N
H
H2N
N
H
O
O
9
10
NC
Ar
CN
O
Ar
O
CN
EtO
Cl
ArCHO (7k)
NCCH2CN (8)
5c,h
NH2
16g,h
method C
method B
method D
OMe
MeO
OMe
O
Ar1
N
O
C
N
C
R1
Me
5 h
MeO
O
NH2
CN
N
H
S
method A
Me
N
S
O
H
OEt
O
OEt
Ar
O
10a
17a–e
Scheme 4 (5c) Ar = 4-FC6H4; (5h) 4-MeOC6H4; (7k) Ar = 4-MeOC6H4; (9a) R1 = OMe, Ar1 = 3,4,5-(MeO)3C6H2; (9d) R1 = OMe, Ar1 = 3,4-
(MeO)2C6H3; (9e) R1 = OEt, Ar1 = 2-C4H3S; (9f) R1 = OEt, Ar1 = 4-(MeO2C)C6H4; (16g) Ar = 4-MeOC6H4; (16h) Ar = 4-FC6H4; (17a) Ar = 4-
MeOC6H4, R1 = OMe, Ar1 = 3,4,5-(MeO)3C6H2; (17b) Ar = 4-MeOC6H4, R1 = OMe, Ar1 = 3,4-(MeO)2C6H3; (17c) Ar = 4-MeOC6H4,
R1 = OEt, Ar1 = 2-C4H3S; (17d) Ar = 4-MeOC6H4, R1 = OEt, Ar1 = 4-(MeO2C)C6H4; (17e) Ar = 4-F-C6H4, R1 = OEt, Ar1 = 2-C4H3S
pounds 17b,c,e were obtained in good yields of ~70% the same side by 0.10 and 0.24 Å, respectively. In the ba-
(method B).
sis molecule, the C(12) atom has the R configuration but
molecules of compound 15a are crystallized in the achiral
space group P21/n. The structure of compound 15a is lay-
ered and a projection along axis [100] is presented in
Figure 2. Both hydrogen atoms of the amino group are in-
volved in the formation of the N(3)–H(1)···O(3) (x + 1/2,
–y + 1/2, z + 1/2) [N(3)–H(1) 0.85(3), H(1)···O(3)
2.01(3), N(3)···O(3) 2.806(3) Å, angle N(3)–H(1)···O(3)
155(2)°], N(3)–H(2)···N(4) (–x + 2, –y, –z + 1) [N(3)–
H(2) 0.85(3), H(2)···N(4) 2.25(3), N(3)···N(4) 3.055(3) Å,
angle N(3)–H(2)···N(4) 158(2)°] hydrogen bonds, which
unify molecules 15a to form layers parallel to the (1 0 –1)
plane.
At the next stage this synthesis was simplified. After ester
10 was generated in the reaction mixture from salt 9e
(Ar1 = 2-C4H3S) and ester 2a, 4-methoxybenzaldehyde
7k, malononitrile 8, and triethylamine were added to the
solution. After brief heating of the multi-component reac-
tion mixture, compound 17c was obtained in 57% yield
(method C). Furthermore, the reaction of salts 9a,e,f with
pyrans 16g,h was carried out in ethanol without catalysts
to obtain compounds 17a,c–e in 42–50% yield (method
D).
The structures of compounds 17 were confirmed by the IR
and 1H NMR spectra (Tables 9 and 10). The IR spectra of
compounds 17 contain the characteristic signals of the ni-
trile group of the pyran at 2202–2215 cm–1 and dihydro-
The presence of electrophilic carbonyl carbon atoms in
the acetoacetic ester fragment together with nucleophilic
centers in the molecule, prompted us to study their reac-
tion with hydrazine, since 4-(3-cyanopyridin-2-ylthio)ac-
etoacetates 3 have been recognized as convenient reagents
for syntheses of substituted pyrazoles.17 For example, the
reaction of ester 3j with hydrazine gives 2-(3-hydroxy-
1H-pyrazolyl-5-methylthio)pyridine 18 (Scheme 5).
pyridine at 2174–2195 cm–1. The H NMR spectra show
1
signals of the 4-H proton of the pyran in a region of
d = 4.24–4.34 and 1,4-dihydropyridine at d = 4.43–4.83
ppm, as well as the characteristic signals of the protons of
the CH2S methylene group as a doublet of doublets at
d = 4.00–4.70 ppm. Probably, this multiplicity is related
to the hindered rotation of the pyran ring around the S– As pyrazoles are convenient reagents for the synthesis of
CH2 bond. The 1H NMR spectra also contain signals cor- 6-amino-5-cyano-2,4-dihydropyrano[2,3-c]pyra-
responding to the amino group at d = 6.50–6.82 ppm zoles,10,13,14,17 we decided to apply this reaction to com-
along with signals of the NH proton at d = 9.40–9.80 ppm. pound 18 in order to synthesize pyrano[2,3-c]pyrazoles
20a,b. The reaction of pyrazole 18 with arylidenemalono-
nitriles 5c,h in ethanol in the presence of catalytic
amounts of triethylamine yielded pyrazolopyrans 20a,b.
It is most probable that the reaction proceeds through the
corresponding Michael adduct 19, whose subsequent ring
closure affords pyrano[2,3-c]pyrazoles 20.
The structure of compound 15a was confirmed by X-ray
diffraction analysis as 6-amino-4-(2-chlorophenyl)-5-cy-
ano-3-methoxycarbonyl-2-(3-cyano-6-methylpyridin-2-
ylthiomethyl)-4H-pyran, the molecular structure of which
is shown in Figure 1. In the 4H-pyran ring, the olefinic
carbon atoms lie in one plane with an accuracy of 0.02 Å,
and the O(1) and C(12) atoms deviate from this plane to
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocycles Using 4-(3-Cyanopyridin-2-ylthio)acetoacetates
2361
Figure 2 Projection of the structure of 6-amino-4-(2-chlorophe-
nyl)-5-cyano-3-methoxycarbonyl-2-(3-cyano-6-methylpyridin-2-
ylthiomethyl)-4H-pyran (15a) along axis [100]
We also synthesized pyrano[2,3-c]pyrazole from hydro-
genated pyridines (Scheme 6). The reaction of ester 10c
with hydrazine hydrate gave 2-(pyrazolyl-5-methylthio)-
1,4-dihydropyridine 21, which was used in a reaction with
4-fluorobenzylidenemalononitrile (5c) in ethanol in the
presence of N-methylmorpholine to give the pyrazolopyr-
an 22.
Figure 1 Molecular structure of 6-amino-4-(2-chlorophenyl)-5-cy-
ano-3-methoxycarbonyl-2-(3-cyano-6-methylpyridin-2-ylthiometh-
yl)-4H-pyran (15a)
The structures of pyranopyrazoles 20 were confirmed by
spectroscopic methods. In addition to other characteristic
proton signals, the 1H NMR spectra of compounds 20a,b
contained singlets from the NH protons at 12.49 ppm and
12.44 ppm, the NH2 group at 6.90 ppm and 6.83 ppm, as
well as protons corresponding to the 4-H-pyran ring at
4.76 ppm and 4.67 ppm, respectively. The IR spectra of
compounds 20a,b showed two sets of absorption bands
from the CN group of the pyridine and the pyran at 2224
cm–1, 2232 cm–1 and 2184 cm–1, 2188 cm–1, respectively.
In conclusion, we found that 3-cyanopyridinylthioace-
toacetates 3 and 10, containing several highly reactive
centers are convenient reagents for the regioselective syn-
thesis of functionally substituted heterocycles.
Nucleophilic properties of the molecules 3 and 10 are re-
alized in two distinctive pathways (Scheme 7, pathways a
and b). We found that either reaction pathway can occur,
CN
CN
R
NC
OEt
(5c,h)/ EtOH, Et3N
N2H4⋅H2O
CN
N
S
N
S
N
O
O
18
3j
OH
H
N
R
R
CN
S
CN
S
CN
NH2
N
N
N
N
N
OH
N
O
F
H
N
H
N
19
20a,b
Scheme 5 (5c, 20a) R = F; (5h, 20b) R = MeO
N
N
N
O
O
O
N2H4⋅H2O
5c
N
CN
C
CN
S
PhHN
PhHN
PhHN
CN
NH2
OEt
Me
N
S
Me
N
H
S
Me
N
H
H
N
N
O
O
O
OH
H
H
N
N
22
10c
21
Scheme 6
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

2362
L. Rodinovskaya et al.
PAPER
5
CN
AlkO
NH2
Ar
O
CN
N
N
b
b
a
a
OAlk
O
N
2
4
O
S
1
3
S
S
O
O
AlkO
CN
c
c
3, 10
O
Ar
NH2 NH2
H
N
O
5
c
S
4, 12
OH
CN
Ar
CN
N
5
CN
N
Ar
O
Ar
O
NH2
CN
HN
S
S
CN
S
CN
AlkO
HN
OH
N
18, 21
15, 17
OH
O
Ar
N
O
Ar
HN
S
N
Ar
CN
CN
NH2
S
O
NH2
HN
O
N
20, 22
6, 13
Scheme 7
a = 11.1247(8) Å, b = 13.7795(14) Å, c = 14.7256(13) Å,
b = 103.40(2)°; V = 2195.9(3) A3; rcalcd = 1.370 gcm–3; Z = 4;
Crystal size 0.4 × 0.4 × 0.4 mm; m = 0.300 mm–1; Reflections col-
lected 8972. Independent reflections 5281; Collected at 23 °C on a
Enraf Nonius CAD-4 diffractometer (MoKa radiation, graphite
monochromator, /2 scan mode to qmax = 28°). Number of indepen-
dent reflection with I>2s(I) is 2902. The structure was solved by di-
rect methods.19 All hydrogen atoms were localized from the
difference Fourier synthesis; refinement method anisotropic-isotro-
pic (hydrogen atoms) least-squares. The final R factors were
R1 = 0.0438, wR2 = 0.1186 (2902 independent reflections) and
R1 = 0.1069, wR2 = 0.1431 (all reflections); Goodness-of-
fit = 1.022. All calculations were performed using the SHELXL97
program.20
depending upon the sequence of the reagent addition and
the reaction conditions. Thus, if a base and then aryliden-
emalononitriles 5 are added to esters 3 or 10, the reaction
leads to pyrans 6 or 13, respectively (pathway a). But if
esters 3 or 10 are first added to the unsaturated nitriles 5,
followed by catalytic base, the reaction takes pathway b
and leads to pyrans 15 or 17, respectively.
Finally, if esters 3 or 10 are first combined with hydrazine
followed by subsequent nitrile 5 addition, then during the
first step of the reaction, the esters realize their electro-
philic properties (pathway c) to give pyrans 20 or 22 as fi-
nal products.
4-(3-Cyanopyridin-2-ylthio)acetoacetates (3)
The analytical data for compounds 3a,b,d,f–j are presented in the
references.1,9
Melting points were determined on a Kofler stage. Infrared spectra
were obtained using a Perkin-Elmer 577 and Specord M82 instru-
1
ments in KBr pellets at a concentration of 0.01 mol/L. H and 13
C
NMR spectra were recorded using a Bruker WM-250 instrument
(250 and 63 MHz, respectively) and Bruker AM-300 (300 MHz) in-
strument in DMSO-d6 solutions. Mass spectra were obtained on a
MAT INCOS-50 instrument (Finnigan) (ionizing energy 70 eV).
Elemental analysis was carried out on a Perkin-Elmer CHN analyz-
er. The reactions’ progress and composition were monitored by
TLC on Silufol UV-254 plates (n-hexane–acetone, 5:3) and iodine
vapor as a developer.
Ethyl 4-[3-Cyano-6-(4-pyridyl)-pyridin-2-ylthio]acetoacetates
(3c)
Yield: 59%; mp 141–142 °C.
IR (KBr): 1728, 1748 (CO), 2220 (CN) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.10 (t, J = 7.2 Hz, 3 H,
CH3CH2), 3.83 (s, 2 H, CH2), 4.04 (q, J = 7.2 Hz, 2 H, CH3CH2),
4.47 (s, 2 H, SCH2), 8.04 (m, 3 H, 5-H of pyridine, 2-H, 6-H of 4-
C5H4N), 8.40 (d, J = 8.4 Hz, 1 H, 4-H of pyridine), 8.76 (d, J = 4.8
Hz, 2 H, 3-H, 5-H of 4-C5H4N).
4-(3-cyanopyridin-2-ylthio)acetoacetates (3) and 4-hydroxy-1H-
thieno[2,3-b:4,5-b¢]dipyridin-2-ones (4) were synthesized using a
described procedure.1
X-ray crystal data18 for 15a; Empirical formula C19H14N2O2; Crys-
tal system = monoclinic; Space group P21/n; Unit cell dimensions
Anal. Calcd for C17H15N3O3S: C, 59.81; H, 4.43; N, 12.31. Found:
C, 59.64; H, 4.23; N, 12.10.
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocycles Using 4-(3-Cyanopyridin-2-ylthio)acetoacetates
2363
Methyl 4-(3-Cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-2-
ylthio)acetoacetates (3e)
Yield: 85%; mp 109–110 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.70 (s, 3 H, CH3), 5.86 (s,
1 H, 3-H), 6.95–7.69 (10 H, m, 2 × C6H5), 10.45 (s, 1 H, NHC6H5),
12.05 (s, 1 H, N1H).
IR (KBr): 1724, 1748 (CO), 2224 (CN) cm–1.
Anal. Calcd for C24H17N3O3S: C, 67.43; H, 4.01; N, 9.83. Found: C,
67.22; H, 4.18; N, 9.74.
1H NMR (300 MHz, DMSO-d6): d = 2.09 (m, 2 H, CH2), 2.91 (m,
4 H, CH2CH2), 3.62 (s, 3 H, CH3), 3.83 (s, 2 H, CH2), 4.25 (s, 2 H,
SCH2), 8.02 (s, 1 H, 4-H).
4-Hydroxy-7-methyl-2-oxo-9-(pyridin-3-yl)-1,2-dihydro-
thieno[2,3-b;4,5-b¢]dipyridine-8-carboxylic Acid Phenyl-
amide (12b)
Anal. Calcd for C14H14N2O3S: C, 57.92; H, 4.86; N, 9.65. Found: C,
58.09; H, 4.74; N, 9.78.
Yield: 2.44 g (57%) by method A and 2.1 g (48%) by method B; mp
>300 °C.
2-Amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-
d]pyrido[3¢,2¢:4,5]thieno[3,2-b]pyridines (6,13); General Proce-
dure
IR (KBr): 1600–1651 (CO), 3400, 3340, 3040 (CONH, OH) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.71 (s, 3 H, CH3), 6.19 (s,
1 H, 3-H), 7.00–8.70 (m, 9 H, C6H5, 3-C5H4N), 10.41 (s, 1 H,
NHC6H5), 11.69 (s, 1 H, N1H).
Method A: The arylidenemalononitrile 5 (0.01 mol) and Et3N or
N-methylmorpholine (0.1 mL) were added to a suspension of the
corresponding compound 4,12a (0.01 mol) in DMF. The reaction
mixture was refluxed for 2–3 h (monitored by TLC), then concd
HCl (1 mL) was added and the precipitate formed was filtered off
and successively washed on the filter with H2O (2 × 10 mL), EtOH
(2 × 5 mL), and hexane (2 × 10 mL). All compounds 6 have
mp>300 °C. The analytical data for compounds 6,13 are shown in
Tables 1 and 2.
Anal. Calcd for C23H16N4O3S: C, 64.48; H, 3.76; N, 13.08. Found:
C, 64.50; H, 3.89; N, 12.92.
3-Alkoxycarbonyl-6-amino-4-aryl-5-cyano-2-(3-cyanopyridin-
2-ylthiomethyl)-4H-pyrans (15); General Procedure
Method A: The corresponding arylidenemalononitrile 5 (0.01 mol)
and Et3N (0.1 mL) were added to a stirred suspension of the corre-
sponding ester 3 (0.01 mol) in EtOH or MeOH (15–20 mL), and the
mixture was boiled for 3–5 min. After cooling to r.t., the solution
was quenched with H2O (5 mL), and the mixture was left overnight.
The precipitate formed was filtered off and washed on the filter with
cold EtOH (2 × 5 mL) and hexane (2 × 7 mL).
Method B: Equimolar amounts (0.01 mol) of the corresponding al-
dehyde 7, malononitrile 8, and Et3N were added to a suspension of
the corresponding 4 (0.01 mol) in DMF and the reaction was con-
ducted as described in method A.
Ethyl 4-(4-Aryl-3-cyano-6-methyl-1,4-dihydropyridin-2-yl-
thio)acetoacetates (10); General Procedure
Method B: Aldehyde 7 (0.01 mol), malononitrile 8 (0.66 g, 0.01
mol), and Et3N (0.1 mL) were added to a stirred suspension of the
corresponding ester 3 (0.01 mol) in EtOH or MeOH (15–20 mL),
and the reaction mixture was boiled for 5–10 min. After cooling to
r.t., the solution was quenched with H2O (5 mL), and the resulting
mixture was left overnight. The precipitate formed was filtered off
and washed on the filter with cold EtOH (2 × 5 mL) and hexane (2
× 7 mL).
Ethyl 4-chloroacetoacetate (2a) (1.4 mL, 0.01 mol) was added to a
stirred solution of the corresponding salt 9 (0.01 mol) in EtOH (15–
20 mL), and stirring was continued at 40–45 °C for 0.5–1 h. The
mixture was quenched with H2O (5 mL), and the resulting solution
was kept for 1–3 h in the refrigerator. The precipitate formed was
filtered off and washed with H2O (2 × 5 mL), EtOH (2 × 5 mL), and
hexane (2 × 10 mL). In the case of compound 10a, the formed resi-
due was separated, washed with H2O (2 × 10 mL), and extracted
with Et2O (2 × 15 mL). The organic layer was then evaporated un-
der reduced pressure to give the final product in pure state. The an-
alytical data for compounds 10 are presented in Tables 3 and 4.
Method C: Pyran 16 (0.01 mol) was added to a stirred suspension of
the corresponding pyridinethione 1 (0.01 mol) in EtOH or MeOH
(15–20 mL), and the mixture was stirred at 40–45 °C for 0.5–1 h.
After cooling to r.t., the solution was quenched with H2O (5 mL),
and left overnight. The precipitate formed was filtered off and
washed on the filter with cold EtOH (2 × 5 mL) and hexane (2 × 7
mL).
4-Hydroxy-1H-thieno[2,3-b:4,5-b]dipyridin-2-ones (12); Gen-
eral Procedure
Method A: The corresponding ester 10b,c (0.01 mol) was dissolved
on heating in EtOH (30 mL) and a solution of KOH (1.12 g) in
EtOH (20 mL) was added to the resulting solution. The reaction
mixture was boiled for 5 min then, after cooling to r.t., it was acid-
ified with concd. HCl (3 mL) to pH 2. The precipitate formed was
filtered off, and successively washed on the filter with H2O (2 × 10
mL), EtOH (2 × 5 mL), and hexane (2 × 10 mL).
Method D: The ester of 4-chloroacetoacetic acid 2 (0.042 mol) was
added to a stirred suspension of the corresponding pyridinethione 1
(0.004 mol) in EtOH or MeOH (15–20 mL), and stirring was con-
tinued at 40–45 °C for 10–15 min. To the resulting solution was
added aldehyde 7 (0.0043 mol), malononitrile 8 (0.28 g, 0.0043
mol), and Et3N (0.1 mL), and the mixture was boiled for 3–5 min.
After cooling to r.t., the solution was quenched with H2O (5 mL)
and left overnight. The precipitate of compound 15 was filtered off
and washed on the filter with cold EtOH (2 × 5 mL) and hexane (2
× 7 mL). Compounds 15 were recrystallized from EtOH or MeOH.
The analytical data for compounds 15 are shown in Tables 5 and 6.
Method B: Ethyl 4-chloroacetoacetate (2a) (1.4 mL, 0.01 mol) was
added to a suspension of the corresponding salt 9b,c (0.01 mol) in
EtOH (20 mL), and the reaction mixture was heated until the start-
ing materials dissolved. A soln of aq KOH (10%, 1.12 mL) was add-
ed, and the mixture was stirred for 0.5 h under reflux. After cooling
to r.t., the reaction mixture was acidified with concd. HCl (3 mL).
The precipitate formed was filtered off, and successively washed
with H2O (2 × 5 mL), EtOH (2 × 5 mL), and hexane (2 × 10 mL).
5-Alkoxycarbonyl-2-amino-4-aryl-6-chloromethylene-3-cyano-
1H-pyrans (16); General Procedure
Et3N (0.1 mL) was added to a suspension of ester 2a,b (0.01 mol),
aldehyde 7 (0.01 mol), and malononitrile 8 (0.66 g, 0.01 mol) in
EtOH or MeOH (15–20 mL). The reaction mixture was boiled for
5–7 min and left at r.t. for 10–12 h. The precipitate formed was fil-
tered off and washed on the filter with EtOH (2 × 3 mL) and hexane
(2 × 5 mL). Compounds 16 were recrystallized from EtOH or
MeOH. The analytical data for compounds 16 are presented in
Tables 7 and 8.
4-Hydroxy-7-methyl-2-oxo-9-phenyl-1,2-dihydrothieno[2,3-
b:4,5-b¢]dipyridine-8-carboxylic Acid Phenylamide (12a)
Yield: 3.5 g (82%) by method A and 2.7 g (64%) by method B; mp
>300 °C.
IR (KBr): 1600–1650 (CO), 3370, 3050 (CONH, OH) cm–1.
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

2364
L. Rodinovskaya et al.
PAPER
2-(6-Amino-4-aryl-5-cyano-3-ethoxycarbonyl-4H-pyran-2-yl-
methylthio)-4-aryl-3-cyano-6-methyl-1,4-dihydropyridine (17)
Method A: 4-Methoxybenzylidenemalononitrile 5h (0.01 mol) and
Et3N (0.1 mL) were added to a stirred suspension of the ester 10a
(0.01 mol) in EtOH (15 mL), and the mixture was boiled for 5 min.
After cooling to r.t., the solution was quenched with H2O (5 mL),
and the mixture was left overnight. The formed precipitate was fil-
tered off and washed on the filter with cold EtOH (2 × 3 mL) and
hexane (2 × 5 mL).
6-Amino-5-cyano-3-(3-cyano-6,7-dihydro-5H-cyclopenta[b]py-
ridin-2-ylthio)methyl)-4-(4-fluorophenyl)-2,4-dihydropyra-
no[2,3-c]pyrazole (20a)
Yield: 0.56 g (63%); mp 231–232 °C.
IR (KBr): 2184, 2224 (CN, pyrane, pyridine), 1644 (d), 3288, 3406
(NH, NH2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.11 (m, 2 H, CH2), 2.90 (m,
2 H, CH2), 3.01 (m, 2 H, CH2), 4.10 (d, J = 14.7 Hz, 1 H, SCH2),
4.18 (d, J = 14.7 Hz, 1 H, SCH2), 4.76 (s, 1 H, 4-H of pyrane), 6.90
(s, 2 H, NH2), 7.03 (m, 2 H, 3-H, 5-H of 4-F-C6H4), 7.15 (m, 2 H, 2-
H, 4-H of 4-F-C6H4), 7.98 (s, 1 H, 4-H of pyridine), 12.49 (s, 1 H,
NH of pyrazole).
Method B: Ethyl 4-chloroacetoacetate (2a) (1.4 g, 0.01 mol) was
added to a stirred suspension of the corresponding salt 9 (0.01 mol)
in EtOH (15–20 mL), and stirring was continued at 40–45 °C for
10–15 min. The corresponding arylidenemalononitrile 5c,h (0.01
mol) and Et3N (0.1 mL) were added to the solution, and the reaction
mixture was boiled for 3–5 min. After cooling to r.t., the solution
was quenched with H2O (5 mL), and the mixture was left overnight.
The precipitate formed was filtered off and washed on the filter with
cold EtOH (2 × 3 mL) and hexane (2 × 5 mL).
Anal. Calcd for C23H17FN6OS: C, 62.15; H, 3.86; N, 18.91. Found:
C, 62.27; H, 3.71; N, 18.74.
6-Amino-5-cyano-3-(3-cyano-6,7-dihydro-5H-cyclopenta[b]py-
ridin-2-ylthio)methyl)-4-(4-methoxyphenyl)-2,4-dihydropyra-
no[2,3-c]pyrazole (20b)
Method C: Ethyl 4-chloroacetoacetate (2a) (1.4 mL, 0.01 mol) was
added to a stirred suspension of the salt 9e (3.93 g, 0.01 mol) in
EtOH (15–20 mL), and stirring was continued at 40–45 °C for 10–
15 min. Aldehyde 7k (1.24 mL, 0.01 mol), malononitrile (8) (0.66
g, 0.01 mol), and Et3N (0.1 mL) were added to the solution, and the
reaction mixture was boiled for 3–5 min. After cooling to r.t., the so-
lution was quenched with H2O (5 mL), and the mixture was left
overnight. The precipitate of compound 17c formed was filtered off
and washed on the filter with cold EtOH (2 × 3 mL) and hexane (2
× 5 mL).
Yield: 0.62 g (68%); mp 245–247 °C.
IR (KBr): 2188, 2232 (CN, pyrane, pyridine), 1632 (d), 3288, 3320,
3432 (NH, NH2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.12 (m, 2 H, CH2), 2.90 (m,
2 H, CH2), 3.03 (m, 2 H, CH2), 3.84 (s, 3 H, CH3O), 4.08 (d,
J = 14.0 Hz, 1 H, SCH2), 4.16 (d, J = 14.0 Hz, 1 H, SCH2), 4.67 (s,
1 H, 4-H of pyrane), 6.78 (d, J = 8.5 Hz, 2 H,3-H, 5-H of 4-CH3O-
C6H4), 6.83 (s, 2 H, NH2), 7.04 (d, J = 8.5 Hz, 2 H, 2-H, 6-H of 4-
CH3O-C6H4), 7.99 (s, 1 H, 4-H of pyridine), 12.44 (s, 1 H, NH of
pyrazole).
Method D: The corresponding pyran 16g,h (0.01 mol) was added to
a stirred suspension of the corresponding salt 9a,e,f (0.01 mol) in
EtOH (15–20 mL). The mixture was stirred at 40–45 °C for 0.5–1 h.
After cooling to r.t., the solution was quenched with H2O (5 mL),
and the mixture was left overnight. The precipitate formed was fil-
tered off and washed on the filter with cold EtOH (2 × 3 mL) and
hexane (2 × 5 mL). Compounds 17 were recrystallized from EtOH.
The analytical data for compounds 17 are shown in Tables 9 and 10.
Anal. Calcd for C24H20N6O2S: C, 63.14; H, 4.42; N, 18.41. Found:
C, 63.29; H, 4.53; N, 18.31.
5-Cyano-6-(3-hydroxy-1H-pyrazol-5-ylmethylthio)-2-methyl-
3-(N-phenylcarbamoyl)-4-(pyrid-3-yl)-1,4-dihydropyridine
(21)
Hydrazine hydrate (0.5 mL) was added to a solution of ester 10c
(2.37 g, 0.005 mol) in EtOH (30 mL). The reaction mixture was
boiled for 1–2 min and left overnight. The precipitate formed was
filtered off and washed on the filter with H2O (2 × 5 mL), EtOH (2
× 3 mL), and hexane (2 × 5 mL).
3-Cyano-2-(3-hydroxy-1H-pyrazol-5-ylmethylthio)-6,7-dihy-
dro-5H-cyclopenta[b]pyridine (18)
Hydrazine hydrate (0.5 mL) was added to a solution of ester 3j (1.52
g, 0.005 mol) in EtOH (15 mL). The reaction mixture was boiled for
1–2 min and left overnight at r.t.. The precipitate formed was fil-
tered off and washed with H2O (2 × 5 mL), EtOH (2 × 3 mL), and
hexane (2 × 5 mL).
Yield: 1.53 g (69%); colorless powder; mp 185–187 °C.
IR (KBr): 2210 (CN), 1658 (d, CO), 3300, 3460 (NH) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.11 (s, 3 H, CH3), 4.14 (s,
2 H, SCH2), 4.82 (s, 1 H, 4-H of pyridine), 5.39 (s, 1 H, 4-H of pyra-
zole), 7.00 (t, J = 7.1 Hz, 1 H, C6H5), 7.23 (t J = 7.1 Hz, 2 H, C6H5),
7.36 (m, 1 H, 5-H of 3-C5H4N), 7.50 (d, J = 7.1 Hz, 3 H, C6H5, 6-H
of 3-C5H4N), 8.37 (s, 1 H, 2-H of 3-C5H4N,), 8.42 (d, J = 3.2 Hz,
1 H, 4-H of 3-C5H4N), 9.32 (br s, 1 H, NH), 9.64 (s, 1 H, NH of
pyrazole), 11.56 (br s, 1 H, NH of pyridine).
Yield: 88% (1.19 g); slightly yellow powder; mp 257–258 °C.
IR (KBr): 2216 (CN), 3344 (NH) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.10 (m, 2 H, CH2), 2.90 (m,
2 H, CH2), 3.02 (m, 2 H, CH2), 4.38 (s, 2 H, CH2S), 5.39 (s, 1 H, 4-
H of pyrazole), 8.02 (s, 1 H, 4-H of pyridine), 11.36 (s, 1 H, NH).
Anal. Calcd for C13H12N4OS: C, 57.34; H, 4.44; N, 20.57. Found:
C, 57.42; H, 4.53; N, 20.66.
Anal. Calcd for C23H20N6O2S: C, 62.15; H, 4.54; N, 18.91. Found:
C, 62.27; H, 4.31; N, 19.01.
6-Amino-4-aryl-5-cyano-3-(3-cyanopyridin-2-ylthiomethyl)-
2,4-dihydropyrano[2,3-c]pyrazoles (20); General Procedure
A mixture of pyrazolylmethylthiopyridine 18 (0.55 g, 0.002 mol),
the corresponding arylidenemalononitrile 5c,h (0.002 mol), and
Et3N (0.1 mL) in EtOH (20 mL) was boiled for 10 min, and then
kept overnight at r.t.. The precipitate formed was filtered off,
washed on the filter with EtOH (2 × 3 mL) and hexane (2 × 5 mL),
and recrystallized from 1,4-dioxane or EtOH.
6-{6-Amino-5-cyano-4-(4-fluorophenyl)-2,4-dihydropyra-
no[2,3-c]pyrazol-3-ylthiomethyl}-5-cyano-2-methyl-4-(pyrid-3-
yl)-1,4-dihydropyridine (22)
A mixture of the corresponding pyrazolylmethylthiopyridine 21
(0.89 g, 0.002 mol), 4-fluorobenzylidenemalononitrile (5c) (0.34 g,
0.002 mol), and N-methylmorpholine (0.1 mL) was refluxed in
EtOH (20 mL) for 10 min. After 24 h, the precipitate formed was
filtered off, washed with EtOH (2 × 3 mL) and hexane (2 × 3 mL),
and recrystallized from 1,4-dioxane.
Yield 0.60 g (49%); mp 198–200 °C.
IR (KBr): 1638 (d, NH2), 1710 (CO), 2192, 2200 (CN), 3440 (NH)
cm–1.
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocycles Using 4-(3-Cyanopyridin-2-ylthio)acetoacetates
2365
1H NMR (300 MHz, DMSO-d6): d = 2.08 (s, 3 H, CH3), 4.15 (d,
J = 14.7 Hz, 1 H, SCH2), 4.35 (d, J = 14.7 Hz, 1 H, SCH2), 4.80 (s,
1 H, 4-H of pyridine), 4.89 (m, 1 H, 4-H of pyran), 6.73–7.67 and
8.40 (m, 15 H, C6H5, 4-F-C6H4, 3-C5H4N, NH2), 9.01 (s, 1 H, NH),
9.67 (s, 1 H, NH of pyrazole), 12.48 (s, 1 H, NH of pyridine).
Anal. Calcd for C33H25FN8O2S: C, 64.27; H, 4.09; N, 18.17. Found:
C, 64.03; H, 4.17; N, 18.29.
Table 1 2-Amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d]pyrido[3¢,2¢:4,5]thieno[3,2-b]pyridines (6, 13)
Compound Yield (%) (method) Molecular formula Found/Calculated (%)
IR (cm–1)
CN
C
H
N
CONH, NH2
6a
6b
6c
77 (A), 71 (B)
84 (A), 80(B)
92 (A), 73 (B)
84 (A), 78 (B)
72 (A)
C23H18N4O2S
C21H15N5O2S
C27H17FN4O3S
C28H26N4O3S
C24H18FN5O2S
C34H23FN5O3S
66.87
66.65
4.59
4.38
13.80
13.52
2208
2184
2200
2188
2200
2210
1632 (d), 1672, 3184, 3284, 3420
62.74
62.83
3.52
3.77
17.33
17.45
1664 (d), 3320, 3356, 3408
65.50
65.31
3.52
3.45
11.40
11.28
1640 (d), 1676, 3192, 3324, 3412
1640 (d), 1676, 3164, 3316, 3440
1636 (d), 1668, 3168, 3300, 3468
1640 (d), 1670, 3130, 3300, 3370
6d
6e
67.21
67.45
5.18
5.26
11.03
11.24
62.51
62.73
3.71
3.95
15.02
15.24
13a
39 (A)
68.10
67.99
4.03
3.86
11.38
11.66
a Mp 230–231 °C.
Table 2 2-Amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d]pyrido[3¢,2¢:4,5]thieno[3,2-b]pyridines (6, 13)
1
Compound H NMR d [DMSO-d6, J (Hz)]
R1
R2
R3
Ar
4-H
NH2
NH
(1 H, s) (2 H, s) (1 H, s)
6aa
6bb
2.58 (3 H, s) 7.20 (1 H, s)
2.58 (3 H, s) 7.20 (1 H, s)
2.89 (3 H, s)
2.88 (3 H, s)
2.25 (3 H, s, CH3), 7.06–7.17 (4 H, 4.58 7.09
m)
11.08
11.17
7.32 (1 H, t, J = 3.9), 7.59 (1 H, d,
J = 4.7), 8.43 (1 H, d, J = 7.8), 8.51
(1 H, s)
4.71 7.25
4.55 7.11c
4.43 7.23
6c
8.74 (1 H, d, 8.11 (1 H, d,
3.86 (3 H, s, OCH3),
7.24c (2 H, d, J = 8.1),
8.18 (2 H, d, J = 8.1)
7.11c (2 H, m), 7.32c (2 H, m)
12.84
12.81
J = 8.1)
J = 8.1)
6dd
8.44 (1 H, s) 1.67 (4 H, m), 1.86 (2 H, m), 2.89 (2 H, m),
3.12 (2 H, m)
1.23 (3 H, d, CH3, J = 2.7), 1.24
(3 H, d, CH3, J = 2.7), 4.53 (1 H, m,
CHO), 6.82 (2 H, d, J = 8.1), 7.97
(2 H, d, J = 9.5)
6e
13
8.48 (1 H, s) 2.71 (3 H, s, N-CH3), 2.52e (2 H, m), 3.25 (2 H, 7.11 (m, 2 H), 7.30 (m, 2 H)
m), 4.15 (2 H, s)
4.54 7.24
4.44 7.53c
12.77
7.95
7.04–7.57c
(5 H, m)
7.04–7.57c (5 H, m, 2.72 (3 H, s)
C6H5), 10.40 (1 H,
s, NH)
7.04–7.57c (4 H, m)
a 13C NMR (63 MHz, DMSO-d6): d = 18.95, 20.54, 23.77, 36.38, 58.41, 100.40, 119.65, 121.91, 122.13, 127.15, 127.26, 127.37, 128.69,
128.80, 128.91, 135.71, 141.54, 144.98, 150.96, 158.00, 158.60, 159.67, 160.28.
b 13C NMR(63 MHz, DMSO-d6): d = 18.67, 23.52, 34.42, 57.41, 102.65, 109.41, 118.98, 121.70, 121.84, 122.36, 123.31, 134.74, 139.48,
144.78, 147.60, 148.59, 150.94, 157.92, 158.61, 159.67, 160.23.
c The signal is overlapped with the signal of another fragment.
d MS (EI, 70 eV): m/z (%) = 432 (14) [M – NCCH2CN]+, 389 (52), 373 (5), 363 (8), 286 (20), 170 (39).
e The signal is overlapped with the signal for the protons of DMSO.
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

2366
L. Rodinovskaya et al.
PAPER
Table 3 Ethyl 4-(4-Aryl-3-cyano-6-methyl-1,4-dihydropyridin-2-ylthio)acetoacetates (10)
Compound Mp (°C)
Yield (%) Molecular formula Found/Calculated (%)
IR (cm–1)
C
H
N
CN
CO, NH
a
10a
10b
10c
–
60
C24H28N2O8S
C26H25N3O4S
C25H24N4O4S
57.05
57.13
5.89
5.59
5.34
5.55
146–147 73
149–150 67
65.42
65.67
5.38
5.30
8.70
8.84
2205
2218
1740 (d), 1720 (d), 1645 (d,CONH), 3290,
3320
62.91
63.01
5.22
5.08
11.51
11.76
1730 (d), 1710 (d), 1628 (d,CONH), 3360
a Amorphous substance.
Table 4 Ethyl 4-(4-Aryl-3-cyano-6-methyl-1,4-dihydropyridin-2-ylthio)acetoacetates (10)
1
Compound H NMR d [DMSO-d6, J (Hz)]
R1
CH2CO 6-CH3
(2 H, s) (3 H, s)
OC2H5
Ar
4-H
SCH2
NH
(1 H, s)
(1 H, s) (2 H, s)
10a
10b
10c
3.59 (3 H, s)
3.65
3.75
3.74
3.32
2.08
2.07
1.25 (3 H, t,
3.59 (3 H, s, CH3O), 3.70 (3 H, 4.48 4.11a
9.25
J = 7.2), 4.11 (2 H, s, CH3O), 3.78 (3 H, s, CH3O),
q, J = 7.2)a
6.39 (2 H, s)
8.97 (1 H, s, NH),
6.95–7.55,b (5 H, m,
C6H5)
1.22 (3 H, t,
J = 7.1), 4.10 (2 H,
q, J = 7.1)
6.95–7.55 (m, 5 H, C6H5)b
4.79 4.20 (d, 9.56
J = 3.9)
9.09 (1 H, s, NH),
7.00–7.49,b (5 H, m,
C6H5)
1.20 (3 H, t,
7.36 (1 H, dd, J = 5.2, J = 7.8),b 4.82 4.20 (d, 9.65
J = 3.9)
J = 7.1), 4.12 (2 H, 7.60 (1 H, d, J = 7.8), 8.42 (1 H,
m) s), 8.45 (1 H, m)
a The signals of the protons of the methylene groups are overlapped.
b The signals of the protons of the aryl substituents are overlapped.
Table 5 3-Alkoxycarbonyl-6-amino-4-aryl-5-cyano-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans (15)
Compound Mp (°C) Yield (%) (method) Molecular formula Found/Calculated (%)
IR (cm–1)
CN
C
H
N
C=O NH2
15a
15b
15c
15d
15e
15f
15g
15h
15i
209–211 77 (A)
C22H17ClN4O3S
C27H21N5O3S
C26H23N6O3S
C31H22ClN5O3S2
C26H24N4O3S
C27H27N5O3S
C23H19FN4O3S
C27H25N5O5S
C25H24N4O3S2
58.61
58.34
3.84
3.78
12.01
12.37
2196, 2220 1712 1672 (d), 3196, 3328,
3416
116–118 67 (A), 58 (C)
157–158 60 (A), 54 (C)
160–162 59 (A)
65.32
65.44
4.23
4.27
14.03
14.13
2200, 2228 1716 1680 (d), 3168, 3316,
3344
62.64
62.89
3.89
4.06
16.73
16.92
2200, 2224 1712 1676 (d), 3124, 3296,
3352
61.01
60.83
3.45
3.62
11.23
11.44
2196, 2220 1724 1684 (d), 3180, 3328,
3452
164–165 87 (A)
66.28
66.08
5.20
5.12
12.02
11.86
2188, 2224 1716 1684 (d), 3160, 3312,
3384
174–175 67 (A), 48 (D)
203–204 77 (B)
64.33
64.65
5.26
5.43
13.58
13.96
2196, 2240 1728 1676 (d), 3172, 3320,
3380
61.14
61.32
4.11
4.25
12.19
12.44
2204, 2224 1724 1680 (d), 3192, 3316,
3388
187–188 42 (B)
60.79
61.00
4.61
4.74
12.91
13.17
2196, 2228 1712 1684 (d), 3180, 3324,
3472
111–112 65 (B), 74 (C)
60.55
60.95
4.72
4.91
11.13
11.37
2188, 2220 1704 1668 (d), 3188, 3316,
3384
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocycles Using 4-(3-Cyanopyridin-2-ylthio)acetoacetates
2367
Table 5 3-Alkoxycarbonyl-6-amino-4-aryl-5-cyano-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans (15) (continued)
IR (cm–1)
Compound Mp (°C) Yield (%) (method) Molecular formula Found/Calculated (%)
15j
173–175 89 (C), 57 (D)
146–147 79 (C), 57 (D)
122–123 51 (C)
C23H22N4O3S2
C26H25N5O3S
C25H22FN5O3S
C26H24ClN5O3S
C35H36N4O4S2
59.07
59.21
4.58
4.75
11.80
12.01
2204, 2216 1720 1688 (d), 3184, 3316,
3460
15k
15l
63.80
64.05
4.89
5.17
14.04
14.36
2196, 2228 1716 1676 (d), 3176, 3300,
3404
60.82
61.09
4.26
4.51
14.04
14.25
2200, 2228 1716 1684 (d), 3348, 3472
2196, 2228 1716 1680 (d), 3360, 3428
15m
15n
162–163 54 (C)
59.62
59.82
4.52
4.63
13.04
13.42
212–214 60 (C)
65.95
65.60
5.43
5.66
8.34
8.74
2200, 2223 1716 1680 (d), 3196, 3324,
3392
Table 6 3-Alkoxycarbonyl-6-amino-4-aryl-5-cyano-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans (15)
1
Compound H NMR d [DMSO-d6, J (Hz)]
R1
R2
R3
R4
Ar
NH2
4-H
SCH2
(2H, s) (1H, s) (2H)
15a
15b
15c
15d
8.11 (1 H, d,
J = 7.5)
7.21 (1 H, d, 2.42 (3 H, s)
3.54 (3 H, s)
7.08 (1 H, m), 7.21
(2 H, m),a 7.38 (1 H, d,
J = 6.2)
6.92
6.81
4.88
4.42
4.41
4.47
4.72 (s)
J = 7.5)a
8.20 (1 H, d,
J = 8.1)
7.85 (1 H, d, 7.49 (3 H, m),
1.10 (3 H, t,
J = 7.5), 4.00
(2 H, q, J = 7.5)
7.25 (1 H, m), 7.52
(1 H, m), 8.40 (2 H, m)
4.83, 4.96
(both d of
1H, J = 13.7)
J = 8.1)
8.14 (2 H, m)
8.31 (1 H, d,
J = 8.3)
8.00 (1 H, d, 8.06 (2 H, d,
1.08 (3 H, t,
J = 7.4), 4.02
(2 H, q, J = 7.4)
7.25 (1 H, dd, J = 3.9, 6.78
J = 7.9), 7.51 (1 H, d,
J = 7.9), 8.40 (2 H, m)
4.84, 4.96
(both d of
1H, J = 13.8)
J = 8.3)
J = 5.3), 8.70
(2 H, d, J = 5.3)
7.67 (2 H, q,
J = 8.3), 7.78
(2 H, q,
7.91 (1 H, s) 7.26 (1 H, t,
1.03 (3 H, t,
J = 7.2), 4.02
7.35 (1 H, dd, J = 6.1, 6.94
J = 8.3), 7.57 (1 H, d,
J = 8.3), 8.42 (1 H, s),
8.45 (1 H, d, J = 6.1)
4.77, 4.89
(both d of
1H, J = 14.3)
J = 4.4), 7.82
(1 H, d, J = 4.4), (2 H, q, J = 7.2)
8.11 (1H, d,
J = 8.3)
J = 4.4)
15e
15f
8.02 (1 H, s)
7.96 (1 H, s)
2.03 (2 H, m), 2.71–2.92 (4 H, m) 3.60 (3 H, s)
1.16 (3 H, t, J = 7.2),
2.56 (2 H, q, J = 7.2),
6.97 (1 H, d, J = 7.9),
7.08 (1 H, d, J = 7.9)
6.84
4.25
4.36
4.65 (s)
4.71 (s)
1.57 (4 H, m), 1.80 (2 H, m),
2.77 (2 H, m), 2.93 (2 H, m)
0.92 (3 H, d,
J = 5.9), 1.14 (3 H, 8.47 (2 H, d, J = 5.9)
7.12 (2 H, d, J = 5.9),
6.94
d, J = 5.9), 4.84 (1
H, m)
15g
15h
2.34 (3 H, s)
7.83 (1 H, s)
7.11 (1 H, s) 2.42 (3 H, s)
1.76 (4 H, m), 2.70 (4 H, m)
3.57 (3 H, s)
7.06–7.30 (4 H, m)
6.97
6.87
4.62
4.46
4.64, 4.75
(both d of
1H, J = 14.5)
0.97 (3 H, d,
J = 6.3), 1.19 (3 H, 8.12 (2 H, d, J = 8.7)
7.37 (2 H, d, J = 8.7),
4.62, 4.73
(both d of
d, J = 6.3), 4.88 (1
1H, J = 13.8)
H, m)
15i
15j
7.95 (1 H, s)
7.95 (1 H, s)
1.55 (4 H, m), 1.79 (2 H, m),
2.77 (m, 2 H), 2.94 (2 H, m)
1.12 (3 H, t,
J = 7.2), 4.06 (2 H, (1 H, d, J = 1.3), 7.4 (1
q, J = 7.2)
6.8 (1 H, d, J = 4.6), 7.1 6.88
4.44
4.69
4.60, 4.73
(both d on
1H, J = 14.4)
H, dd, J = 4.6, J = 1.3)
6.84 (1 H, d, J = 2.7),
2.27 (3 H, s) 1.21 (3 H, t,
J = 8.4), 2.78
1.15 (3 H, t,
J = 7.2), 4.12 (2 H, 6.94 (1 H, dd, J = 2.7,
6.90
4.62, 4.75
(both d of
(2 H, q, J = 8.4)
q, J = 7.2)
J = 4.9), 7.46 (1 H, d,
J = 4.9)
1H, J = 13.7)
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

2368
L. Rodinovskaya et al.
PAPER
Table 6 3-Alkoxycarbonyl-6-amino-4-aryl-5-cyano-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans (15) (continued)
1
Compound H NMR d [DMSO-d6, J (Hz)]
R1
R2
R3
R4
Ar
NH2
4-H
SCH2
(2H, s) (1H, s) (2H)
15k
7.84 (1 H, s)
1.36 (4 H, m), 1.68 (4 H, m),
2.76 (2 H, m), 2.86 (2 H, m)
3.60 (3 H, s)
7.00 (2 H, m), 7.14
(2 H, m)
6.63
4.34
4.62, 4.75
(both d of
1H, J = 14.3)
15l
7.95 (1 H, s)
7.95 (1 H, s)
2.37 (3 H, s), 2.65–2.91 (4 H, m), 3.59 (3 H, s)
3.50 (2 H, s)
7.12 (4 H, m)
6.85
6.89
4.33
4.33
4.65 (s)
15m
2.36 (3 H, s), 2.61–2.90 (4 H, m), 1.06 (3 H, t,
7.06 (2 H, d, J = 7.7),
4.60, 4.70
3.48 (2 H, s)
J = 7.2), 4.04 (2 H, 7.31 (2 H, d, J = 7.7)
q, J = 7.2)
(both d of
1H, J = 13.8)
15n
3.84 (3 H, s), 0.8 (9 H, s), 1.34, 1.95, 2.22,
1.17 (3 H, t,
6.83 (1 H, d, J = 3.9),
7.00
4.69
4.62, 4.72
7.09 (2 H, d,
2.40, 2.89 (7 H, m)
J = 6.8), 4.16 (2 H, 6.92 (1 H, dd, J = 3.9,
(both d of
J = 9.2), 7.31
(2 H, d, J = 9.2)
q, J = 6.8)
J = 4.5), 7.35 (1 H, d,
J = 4.5)
1H, J = 15.1)
a The signal is overlapped with the signal of another fragment.
Table 7 5-Alkoxycarbonyl-2-amino-4-aryl-6-chloromethylene-3-cyano-1H-pyrans (16)
Compound Mp (°C) Yield (%) Molecular formula Found/Calculated (%)
IR (cm–1)
CN
C
H
N
CO
NH2
16a
16b
16c
16d
16e
16f
184–186
178–179
175–177
118–119
177–178
152–154
94
68
84
53
43
90
C15H14ClN3O3
C14H13ClN2O3S
C14H13ClN2O3S
C14H12ClN3O3
C15H12ClFN2O3
C16H14Cl2N2O3
56.17
56.35
4.22
4.41
12.84
13.14
2200
2196
2192
2196
2196
2196
1724
1696
1696
1728
1708
1700
1684 (d), 3352, 3304
1676 (d), 3404, 3332
1676 (d), 3408, 3328
1672 (d), 3368, 3320
1680 (d), 3420, 3336
1680 (d), 3408, 3332
51.40
51.77
3.83
4.03
8.39
8.63
52.01
51.77
4.40
4.03
8.85
8.63
55.37
55.00
3.81
3.96
13.42
13.74
55.64
55.83
3.54
3.75
8.39
8.68
54.35
54.41
3.83
4.00
7.70
7.93
16g
16h
150–151
153–155
93
98
C17H17ClN2O4
C16H14ClFN2O3
58.26
58.54
4.71
4.91
7.97
8.03
2196
2188
1704
1696
1680 (d), 3416, 3328
1676 (d), 3412, 3332
56.90
57.07
4.04
4.19
8.09
8.32
Table 8 5-Alkoxycarbonyl-2-amino-4-aryl-6-chloromethylene-3-cyano-1H-pyrans (16)
Compound 1H NMR d [DMSO-d6, J (Hz)]
CH2Cl (2 H, s)
NH2 (2 H, s) R4
4-H (1 H, s) Ar
16a
16b
16c
4.67, 4.78 (both d of 1 H,
J = 11.4)
7.00
6.87a
7.01
1.08 (3 H, t, J = 7.3), 4.06
(2 H, q, J = 7.3)
4.47
4.52
4.73
7.48 (1 H, m), 7.57 (1 H, d, J = 7.8),
8.41 (1 H, s), 8.46 (1 H, d, J = 4.3)
4.63, 4.73 (both d of 1 H,
J = 13.6)
1.14 (3 H, t, J = 7.2), 4.11
(2 H, q, J = 7.2)
6.90 (1 H, m),a 7.18 (1 H, d, J = 3.6),
7.46 (1 H, m)
4.68
1.18 (3 H, t, J = 7.1), 4.14
(2 H, q, J = 7.1)
6.87 (1 H, d, J = 2.9), 6.96 (1 H, dd,
J = 2.9, J = 7.1), 7.49 (1 H, d, J = 7.1)
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocycles Using 4-(3-Cyanopyridin-2-ylthio)acetoacetates
2369
Table 8 5-Alkoxycarbonyl-2-amino-4-aryl-6-chloromethylene-3-cyano-1H-pyrans (16) (continued)
Compound 1H NMR d [DMSO-d6, J (Hz)]
CH2Cl (2 H, s)
NH2 (2 H, s) R4
4-H (1 H, s) Ar
16d
16e
16f
4.69, 4.78 (both d of 1 H,
J = 11.8)
7.09
6.96
7.04
6.84
7.02
3.60 (3 H, s)
4.47
4.10
4.40
4.33
4.40
7.27 (2 H, d, J = 5.3), 8.58 (2 H, d,
J = 5.3)
4.67, 4.72 (both d of 1 H,
J = 11.8)
3.60 (3 H, s)
7.18 (4 H, m)
4.67, 4.76 (both d of 1 H,
J = 12.9)
1.07 (3 H, t, J = 7.1), 4.04
(2 H, q, J = 7.1)
7.19 (2 H, d, J = 7.1), 7.40 (2 H, d,
J = 7.1)
16g
16h
4.70
1.10 (3 H, t, J = 7.2), 4.05
(2 H, q, J = 7.2)
3.74 (3 H, s, OCH3), 6.89 (2 H, d,
J = 7.8), 7.08 (2 H, d, J = 7.8)
4.67, 4.75 (both d of 1 H,
J = 12.9)
1.07 (3 H, t, J = 7.1), 4.04
(2 H, q, J = 7.1)
7.15–7.21 (4 H, m)
a The signal is overlapped with the signal of another fragment.
Table 9 2-(6-Amino-4-aryl-5-cyano-3-ethoxycarbonyl-4H-pyran-2-ylmethylthio)-4-aryl-3-cyano-6-methyl-1,4-dihydropyridine (17)
Compound Mp (°C)
Yield (%) (method) Molecular formula Found/Calculated (%)
IR (cm–1)
C
H
N
CN (pyridine, CO, NH
pyrane)
NH2 (d)
17a
17b
17c
210–211 69 (A)
C35H36N4O9S
C34H34N4O8S
C31H30N4O6S2
60.92
61.04
5.34
5.27
8.24
8.13
2195, 2215
2183, 2203
2178, 2215
1675, 1690, 3320 1600
50 (D)
190–191 72 (B)
61.77
61.99
5.13
5.20
8.42
8.51
1640, 1720, 3315 1625
227–228 71 (B)
57 (C)
60.29
60.18
4.94
4.89
8.85
9.06
1675, 1705, 3380 1608
45 (D)
17d
17e
118–120 42 (D)
C35H34N4O8S
62.50
62.68
5.00
5.11
8.47
8.35
2176, 2216
2174, 2202
3352-2952, 1696, 1616
1656
151–152 69 (B)
46 (D)
C30H27FN4O5S2
59.31
59.39
4.53
4.49
3.41
3.13
1665, 1705, 3420 1605
Table 10 2-(6-Amino-4-aryl-5-cyano-3-ethoxycarbonyl-4H-pyran-2-ylmethylthio)-4-aryl-3-cyano-6-methyl-1,4-dihydropyridine (17)
1H NMR d [DMSO-d6, J (Hz)]
Com- R1
pound
OC2H5
6-CH3 SCH2
(3 H, s) (2 H, s)
4-H pyrane 4-H pyridine Ar
Ar1
NH2
(2 H, s) (1 H, s)
NH
(1 H, s)
(1 H, s)
17a 3.56
1.07 (3 H, t, 2.28
J = 7.2),
4.00 (1 H,
m),a 4.60
(1 H, d,
4.26
4.46
6.81 (2 H, d,
J = 8.3), 7.09
(2 H, d,
J = 8.3), 3.89
(3 H, s, CH3O)
6.98 (2 H, s), 3.76
(9 H, s, 3 CH3O)
6.54
9.45
9.40
9.80
(3 H, s)
4.00
(2 H, m)a
J = 14.4)
17b 3.52
(3 H, s)
1.07 (3 H, t, 2.27
J = 7.1),
3.97 (2 H, m)
4.04, 4.58
(both d of 1
H, J = 14.3)
4.25
4.25
4.42
4.80
6.77 (2 H, d,
6.64 (1 H, m), 6.72 6.61
J = 8.4),a 7.05 (1 H, d, J = 7.2),
(2 H, d,
J = 8.4), 3.71
(3 H, s, CH3O) (3 H, s, CH3O)
6.78 (1 H, s),a 3.74
(3 H, s, CH3O), 3.75
17c
1.14
3 H, t,
1.00 (3 H, t, 2.36
J = 7.4),
4.00 (1 H,
m),a 4.70
(1 H, d,
6.78 (2 H, d,
J = 8.4), 7.10
(2 H, d,
J = 8.4), 3.72
(3 H, s, CH3O) J = 4.0)
6.82 (1 H, d,
6.82b
J = 3.2),b 6.93 (1 H,
dd, J = 3.2, 4.0),
7.35 (1 H, d,
J = 7,1), 4.00
4.00
(2 H, m)a
J = 14.2)
(2 H, m)a
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York

2370
L. Rodinovskaya et al.
PAPER
Table 10 2-(6-Amino-4-aryl-5-cyano-3-ethoxycarbonyl-4H-pyran-2-ylmethylthio)-4-aryl-3-cyano-6-methyl-1,4-dihydropyridine (17) (continued)
1H NMR d [DMSO-d6, J (Hz)]
Com- R1
pound
OC2H5
6-CH3 SCH2
(3 H, s) (2 H, s)
4-H pyrane 4-H pyridine Ar
Ar1
NH2
(2 H, s) (1 H, s)
NH
(1 H, s)
(1 H, s)
17d 1.08
1.08 (3 H, t, 2.32
J = 7.2),a
(d,
4.07 (1 H,
m), 4.50
4.27 (d,
J = 12.4) J = 12.4)
4.62 (d,
6.77 (2 H, d,
J = 8.5), 7.08
(2 H, d,
J = 8.5), 3.73
(3 H, d,
7.28 (2 H, d,
J = 7.3), 7.88 (2 H, (d,
d, J = 7.3), 3.86
(3 H, d, J = 3.2,
CH3OOC)
6.51
9.46
(d,
(3 H, t,
J = 7.2),a 3.95
J = 11. (1 H, m)
J = 15. J = 10.
8)
3.95
(2 H, m)b
5)
5)
(2 H m)b
J = 5.9, CH3O)
17e
1.20
(3 H, t,
J = 7.5), 4.02
1.06 (3 H, t, 2.27
J = 7.2),
4.63 (1 H,
d,J = 14.3),
4.05
4.33
4.81
7.02 (2 H, t,
J = 8.7), 7.22
(2 H, m)b
6.81 (1 H, d,
6.50
9.58
J = 3.1), 6.90 (1 H,
t, J = 3.7), 7.22
(1 H, m)b
4.02 (2
(2 H, m)a
(1 H, m)a
H, m)a
a,b The signal is overlapped with the signal of another fragment.
(11) Elagamey, A. G. A.; Sowellim, S. Z. A.; El-Taweel, F. M. A.
A.; Elnagdi, M. H. Collect. Czech. Chem. Commun. 1988,
53, 1534.
(12) Sharanina, L. G.; Promonenkov, V. K.; Marshtupa, V. P.;
Pashchenko, A. V.; Puzanova, V. V.; Sharanin, Y. A.;
Klyuev, N. A.; Gusev, L. F.; Gnatusina, A. P. Chem.
Heterocycl. Compd. 1982, 18, 607.
(13) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A.
A.; Rodinovskaya, L. A.; Niazimbetova, Z. I.; Evans, D. H.
Org. Lett. 2002, 4, 423.
(14) Shestopalov, A. M.; Yakubov, A. P.; Tsyganov, V. V.;
Emel’yanova, Y. M.; Nesterov, V. N. Chem. Heterocycl.
Compd. 2002, 38, 1180.
References
(1) Rodinovskaya, L. A.; Shestopalov, A. M. Russ. Chem. Bull.
Int. Ed. 2000, 49, 348.
(2) The Merck Index, 13th ed.; Merck and Co.: Whitehouse
Station NJ / USA, 2001, 1818.
(3) Litvinov, V. P.; Rodinovskaya, L. A.; Sharanin, Y. A.;
Shestopalov, A. M.; Senning, A. Sulfur Rep. 1992, 13, 1.
(4) Urbahns, K.; Heine, H.-G.; Junge, B.; Mauler, F.; Wittka, R.;
De Vry, J.-M.-V. Eur. Pat. 758647, 1997; Chem. Abstr.
1997, 126, 225216v.
(5) Tanaka, K. T.; Makino, S. K.; Oshio, I. T.; Shimotori, T. T.;
Aikawa, Y. T.; Inaba, T. N.; Yoshida, C. T.; Takano, S. M.;
Taniguchi, Y. T. Eur. Pat. 695547, 1996; Chem. Abstr. 1996,
124, 23835c.
(6) Ambler, S. J.; Heath, W. F. Jr.; Singh, J. P.; Smith, C. W.;
Stramm, L. E. Eur. Pat. 619314, 1995; Chem. Abstr. 1995,
122, 31327d.
(7) Joshi, K. C.; Jain, R.; Arora, S. J. Indian Chem. Soc. 1988,
65, 277.
(8) Panda, D.; Singh, J. P.; Wilson, L. J. Biol. Chem. 1997, 272,
7681.
(9) Rodinovskaya, L. A.; Shestopalov, A. M.; Gromova, A. V.
Russ. Chem. Bull. Int. Ed. 2003, 52, 2185.
(10) Sharanin, Y. A.; Goncharenko, M. P.; Litvinov, V. P. Russ.
Chem. Rev. (Engl. Transl.) 1998, 67, 393.
(15) Sharanin, Y. A.; Sukharevskaya, L. Y.; Shelyakin, V. V.
Russ. J. Org. Chem. 1998, 34, 552.
(16) Piao, M. Z.; Imafuku, K. Tetrahedron Lett. 1997, 38, 5301.
(17) Rodinovskaya, L. A.; Gromova, A. V.; Shestopalov, A. M.;
Nesterov, V. N. Russ. Chem. Bull. Int. Ed. 2003, 52, 2207.
(18) The X-ray diffraction study was performed by Doct. Sci.
(Chem.) V. S. Sergienko at the N. S. Kurnakov Institute of
General and Inorganic Chemistry (Moscow).
(19) Sheldrick, G. M. SHELXS97. Program for the Solution of
Crystal Structures; University of Göttingen: Germany,
1997.
(20) Sheldrick, G. M. SHELXL97. Program for the Refinement of
Crystal Structures; University of Göttingen: Germany,
1997.
Synthesis 2006, No. 14, 2357–2370 © Thieme Stuttgart · New York