Reactions of cyclic enaminoketones with benzylidenemalononitriles. Synthesis of new fused heterocyclic systems containing the 1,4-dihydropyridine fragment

Article abstract of DOI:10.1023/A:1015056117968

The reactions of cyclic cnaminoketones with benzylidenemalononitriles were examined and a new procedure was developed for the synthesis of fused heterocyclic systems containing the 1,4-dihydropyridine ring, viz., thienopyrimidoquinolines and furopyrimidoq

Full text of DOI:10.1023/A:1015056117968

2428
Russian Chemical Bulletin, International Edition, Vol. 50, No. 12, pp. 2428—2432, December, 2001
Reactions of cyclic enaminoketones with benzylidenemalononitriles.
Synthesis of new fused heterocyclic systems containing
the 1,4-dihydropyridine fragment
B. V. Lichitsky, S. N. Ivanov, A. A. Dudinov, S. A. Woznesensky, and M. M. Krayushkin«
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. E-mail: mkray@ioc.ac.ru
The reactions of cyclic enaminoketones with benzylidenemalononitriles were examined
and a new procedure was developed for the synthesis of fused heterocyclic systems
containing the 1,4-dihydropyridine ring, viz., thienopyrimidoquinolines and furopyrimido-
quinolines. The characteristic features of the reactions and the structures of the resulting
compounds were investigated.
Key words: cyclic enaminoketones, benzylidenemalononitriles, fused 1,4-dihydropyridines,
thienopyrimidoquinolines, furopyrimidoquinolines, Michael reaction.
Scheme 1
1,4-Dihydropyridines and their fused derivatives have
attracted considerable recent attention due to their high
biological activities.1—4 As a continuation of our studies
on the synthesis of 1,4-dihydropyridine-containing sys-
tems,5,6 we examined the reactions of N-hetaryl-substi-
tuted enaminoketones with benzylidenemalononitriles
giving rise to new heterocyclic structures in which the
dihydropyridine ring is annelated with the thieno-
pyrimidine or furopyrimidine fragment.
O
X
(CH2)n
NH2
+
R
S
O
R
O
Cyclic enaminoketones have promise as the starting
compounds for the synthesis of the above-mentioned
compounds. The use of these compounds allows one to
prepare fused 1,4-dihydropyridines containig substitu-
ents at the ring nitrogen atom introduced in a stage of
the synthesis of enaminoketones. For example, the reac-
tions of 3-anilino-5,5-dimethylcyclohexen-2-one with
benzylidenemalononitriles in the presence of a base
afford substituted hexahydroquinolines.7 The use of func-
tionally substituted heterocyclic amines in these reac-
tions makes it possible to substantially extend the range
of new 1,4-dihydropyridine-containing systems.
R
R
X
(CH2)n
N
H
S
1a—c, 2a—c
2
1
R
n
1
1
2
X
R
n
1
1
2
X
a
b
c
Me
H
CN
CN
CN
Me
H
CO2Et
CO2Et
CO2Et
The starting enaminoketones 1 and 2 were prepared
by the reactions of aminothiophenes with cyclic β-di-
ketones (Scheme 1).
Me
Me
Enaminones 1 readily react with benzylidene-
malononitriles. Depending on the reaction conditions,
two different types of products can be obtained. Thus
heating of the reactants in ethanol over a short period
(15—20 min) in the presence of a catalytic amount of
piperidine afforded hexahydroquinolines 3, the reactions
proceeding readily even in the case of deactivated ben-
zylidene derivatives to give products in rather high yields
(85—95%) (Scheme 2).
ence of DBU as a catalyst, the reaction was not termi-
nated at the stage of formation of hexahydroquinolines 3
and was completed with intramolecular cyclization to
form fused thienopyrimidoquinolines 4.
It should be noted that compounds 4 can also be
obtained as minor products along with products 3 using
piperidine as a catalyst and upon prolonged reflux-
ing (24 h).
Presumably, the formation of thienopyrimido-
quinolines 4 involves the generation of the enamino-
ketone anion under the action of a base, the Michael
When a mixture of enaminoketones 1 and benzyl-
idenemalononitriles was refluxed for 4—5 h in the pres-
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2319—2323, December, 2001.
1066-5285/01/5012-2428 $25.00 © 2001 Plenum Publishing Corporation

Thieno- ad furopyrimidinoquinolines
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 12, December, 2001 2429
Scheme 2
Scheme 3
O
O
Ar
N
O
Ar
N
O
Ar
N
CN
Ar
CN
CN
CN
CN
EtOH,
piperidine
R
R
R
R
–
NH
NH2
X
NH2
CN
NH
R
R
R
R
B:
X
CN
S
S
S
S
(CH2)n
1a—c, 2a—c
(CH2)n
3a—c, 5a,b
(CH2)n
(CH2)n
3a—c
CN
Ar
EtOH,
DBU
Ar
O
CN
CN
N
X = CN
X = CO2Et
R
N
R
Ar
N
Ar
N
O
O
NH2
S
CN
N
CN
NH
R
R
(CH2)n
4a—c
R
R
NH2
O
S
S
Thus refluxing of the reactants in EtOH over a short
period (15—20 min) in the presence of a catalytic amount
of piperidine yielded hexahydroquinolines 5a,b, whereas
fused thienopyrimidoquinolines 6a—c, which are ana-
logs of compounds 4a—c, were the major reaction prod-
ucts upon prolonged refluxing (2—3 h).
(CH2)n
4a—c
(CH2)n
6a—c
3, 4 R
n
1
1
2
n
1
1
Ar
Ph
X = CN
a
b
c
5
a
b
Me
H
Me
R
C6H4Cl-4
C6H4OMe-4
Ar
Compounds 6a—c were also obtained upon heating
of the reactants in EtOH over a short period (25—30 min)
in the presence of DBU or upon refluxing of hexa-
hydroquinolines 5a,b in EtOH with piperidine or DBU.
Apparently, the scheme of the synthesis of thieno-
pyrimidoquinolines 6a—c is analogous to that consid-
ered above for compounds 4a—c. However, it should be
noted that the last stage in the latter case proceeded
more readily than in the case of nitrile analogs 2a—c.
Intermediate hexahydroquinolines 5a,b can be isolated
in the pure form only with the use of benzylidene-
malonodinitriles containing electron-withdrawing sub-
stituents in the aromatic ring. In the other cases, exclu-
sively the final reaction products 6a—c were obtained.
Thienopyrimidoquinolines 4a—c and 6a—c are high-
melting (m.p. > 300 °C) yellow crystalline compounds
poorly soluble in organic solvents.
The reaction under consideration is common to het-
erocyclic amines containing the cyano or ester group in
the position 4 with respect to the amino group. Thus the
use of readily accessible cyclic enaminoketones 7 gener-
ated from substituted aminofurans made it possible
to synthesize fused furopyrimidoquinolines 8a—c
(Scheme 4).
X = CO2Et
6
a
b
c
R
Me
H
n
1
1
2
Ar
Me
H
C6H4Cl-4
C6H4NO2-3
C6H4Cl-4
Ph
C6H4OMe-4
Me
addition of the anion to benzylidenemalononitrile, in-
tramolecular cyclization to form intermediate hexahydro-
quinolines 3, and the final base-catalyzed cyclization
involving the cyano group (Scheme 3).
Compounds 4a—c were generated not only in the
direct reactions of enaminoketones 1a—c with benzyl-
idenemalonodinitriles, but also from intermediate
hexahydroquinolines 3a—c, which have been prepared
according to a standard procedure with the use of piperi-
dine. However, the transformations of products 3a—c
into thienopyrimidoquinolines 4a—c upon refluxing in
ethanol in the presence of a catalytic amount of DBU
proceeded slowly (8—10 h). This is probably associated
with poor solubilities of both the starting compounds
3a—c and the final products 4a—c in ethanol, i.e., with
the heterogeneity of the reaction mixture.
The reactions of enaminoketones 2a—c with benzyl-
idenemalononitriles also afforded two types of products.

2430
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 12, December, 2001
Lichitsky et al.
Scheme 4
2.60—2.80 (m, 4 H, 2 CH2); 5.15 (s, 1 H, CH); 9.20
(br.s, 1 H, NH).
2-[(3-Oxocyclohexen-1-yl)amino]-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carbonitrile (1b) was prepared analo-
gously from cyclohexane-1,3-dione (3.36 g, 0.03 mol) and
2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene8 (5.34 g,
0.03 mol) in a yield of 6.94 g (85%), m.p. 165—166 °C.
Found (%): C, 65.91; H, 6.07; N, 10.47; S, 11.61. C15H16N2OS.
Calculated (%): C, 66.15; H, 5.92; N, 10.28; S, 11.77.
1H NMR, δ: 1.75 (m, 4 H, 2 CH2); 1.95, 2.20, and 2.55
(all m, 2 H each, CH2); 2.60—2.75 (m, 4 H, 2 CH2); 5.20 (s,
1 H, CH); 9.25 (br.s, 1 H, NH).
O
O
Me
Me
NH2
O
NH
Me
Me
NC
NC
O
O
2-[(5,5-Dimethyl-3-oxocyclohexen-1-yl)amino]-5,6,7,8-
tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (1c) was
prepared analogously from dimedone (4.20 g, 0.03 mol) and
2-amino-3-cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thio-
phene8 (5.76 g, 0.03 mol) in a yield of 8.29 g (88%), m.p.
195—197 °C. Found (%): C, 68.94; H, 6.88; N, 9.12; S, 10.03.
C18H22N2OS. Calculated (%): C, 68.75; H, 7.05; N, 8.91;
CN
CN
7
Ar
DBU
Ar
O
1
S, 10.20. H NMR, δ: 1.05 (s, 6 H, 2 Me); 1.60 (m, 4 H,
CN
2 CH2); 1.85, 2.15, and 2.40 (all s, 2 H each, CH2); 2.60—2.80
(m, 4 H, 2 CH2); 5.20 (s, 1 H, CH); 9.25 (br.s, 1 H, NH).
2-Amino-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thien-
2-yl)-7,7-dimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (3a). Several drops of piperidine were
added to a solution of enaminoketone 1a (0.60 g, 0.002 mol)
and benzylidenemalonodinitrile (0.31 g, 0.002 mol) in EtOH
(7 mL). The reaction mixture was refluxed for 20 min and then
cooled. The precipitate that formed was filtered off and washed
on a filter with a small amount of EtOH. Hexahydroquinoline
3a was obtained in a yield of 0.83 g (91%), m.p. 275—276 °C.
Found (%): C, 71.47; H, 5.69; N, 12.57; S, 6.88. C27H26N4OS.
Calculated (%): C, 71.34; H, 5.76; N, 12.32; S, 7.05. 1H NMR,
δ: 0.80 and 1.00 (both s, 3 H each, Me); 1.75—2.45 (m, 8 H,
4 CH2); 2.65—2.90 (m, 4 H, 2 CH2); 4.45 (s, 1 H, CH); 6.05
(br.s, 2 H, NH2); 7.10—7.35 (m, 5 H, H arom.).
Me
Me
N
N
NH2
O
8a—c
Ar = Ph (a), C6H4Cl-4 (b), C6H4OMe-4 (c)
To summarize, the examination of the characteristic
features of the reactions of N-hetaryl-substituted
enaminoketones with benzylidenemalononitriles allowed
us to develop a simple regioselective procedure for the
synthesis of functionally substituted fused heterocycles
4a—c, 6a—c, and 8a—c containing the 1,4-dihydro-
pyridine fragments.
2-Amino-4-(4-chlorophenyl)-1-(3-cyano-4,5,6,7-tetra-
hydrobenzo[b]thien-2-yl)-5-oxo-1,4,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (3b) was obtained analogously from
enaminoketone 1b (0.54 g, 0.002 mol) and 4-chlorobenzyl-
idenemalonodinitrile (0.38 g, 0.002 mol) in a yield of 0.87 g
(95%), m.p. 288—290 °C. Found (%): C, 65.39; H, 4.73;
Cl, 7.41; N, 12.31; S, 7.18. C25H21ClN4OS. Calculated (%):
1
C, 65.14; H, 4.59; Cl, 7.69; N, 12.15; S, 6.96. H NMR, δ:
Experimental
1.50—2.45 (m, 10 H, 5 CH2); 2.70—2.95 (m, 4 H, 2 CH2);
4.50 (s, 1 H, CH); 6.10 (br.s, 2 H, NH2); 7.20 and 7.35
(both d, 2 H each, H arom., J = 8 Hz).
1
The H NMR spectra were recorded on Bruker AM-300
(300.13 MHz) and Bruker WM-250 (250.13 MHz) instruments
in DMSO-d6. The melting points were measured on a Boetius
heating stage and were not corrected. The reaction mixtures
were analyzed and the purities of the products were monitored
by TLC on Silufol UV-254 plates in a 3 : 1 EtOAc—hexane
solvent system.
2-Amino-1-(3-cyano-5,6,7,8-tetrahydro-4H-cyclo-
hepta[b]thien-2-yl)-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (3c) was pre-
pared analogously from enaminoketone 1c (0.63 g, 0.002 mol)
and 4-methoxybenzylidenemalonodinitrile (0.37 g, 0.002 mol)
in a yield of 0.85 g (85%), m.p. 281—283 °C. Found (%):
C, 70.04; H, 5.90; N, 10.97; S, 6.68. C29H30N4O2S. Calcu-
2-[(5,5-Dimethyl-3-oxocyclohexen-1-yl)amino]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carbonitrile (1a). A solution of
dimedone (4.20 g, 0.03 mol), 2-amino-3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophene8 (5.34 g, 0.03 mol), and TsOH
(0.2 g, 0.0011 mol) in benzene (70 mL) was refluxed using a
Dean—Stark trap for 5 h. The reaction mixture was cooled,
and the precipitate of the product that formed was filtered off
and washed on a filter with a small amount of benzene.
Enaminoketone 1a was obtained in a yield of 8.35 g (93%),
m.p. 227—228 °C. Found (%): C, 68.13; H, 6.58; N, 9.17;
S, 10.93. C17H20N2OS. Calculated (%): C, 67.97; H, 6.71;
1
lated (%): C, 69.85; H, 6.06; N, 11.24; S, 6.43. H NMR, δ:
0.80 and 0.95 (both s, 3 H each, Me); 1.75—2.45 (m, 10 H,
5 CH2); 2.65—2.90 (m, 4 H, 2 CH2); 3.75 (s, 3 H, OMe); 4.35
(s, 1 H, CH); 5.90 (br.s, 2 H, NH2); 6.80 and 7.15 (both d,
2 H each, H arom., J = 8 Hz).
8-Amino-2,2-dimethyl-4-oxo-5-phenyl-1,3,4,5,9,10,11,12-
octahydro-2H-benzo[4´,5´]thieno[3´,2´:5,6]pyrimi-
do[1,2-a]quinoline-6-carbonitrile (4a). Several drops of DBU
were added to a solution of enaminoketone 1a (0.60 g,
0.002 mol) and benzylidenemalonodinitrile (0.31 g, 0.002 mol)
in EtOH (7 mL). The reaction mixture was refluxed for 5 h
and then cooled. The precipitate that formed was filtered off
1
N, 9.32; S, 10.67. H NMR, δ: 1.05 (s, 6 H, 2 Me); 1.75 (m,
4 H, 2 CH2); 2.10 and 2.40 (both s, 2 H each, CH2);

Thieno- ad furopyrimidinoquinolines
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 12, December, 2001 2431
and washed on a filter with a small amount of EtOH.
Thienopyrimidoquinoline 4a was obtained in a yield of 0.86 g
(94%), m.p. > 320 °C. Found (%): C, 71.58; H, 5.85; N, 12.09;
S, 7.18. C27H26N4OS. Calculated (%): C, 71.34; H, 5.76;
N, 12.32; S, 7.05. 1H NMR, δ: 0.95 and 1.15 (both s,
3 H each, Me); 1.60—1.95 (m, 4 H, 2 CH2); 2.20 (d, 1 H,
CH2, J = 18 Hz); 2.55—2.90 (m, 7 H, CH2); 4.65 (s, 1 H,
CH); 7.05—7.35 (m, 7 H, NH2 + H arom.).
8-Amino-5-(4-chlorophenyl)-4-oxo-1,3,4,5,9,10,11,12-
octahydro-2H-benzo[4´,5´]thieno[3´,2´:5,6]pyrimi-
do[1,2-a]quinoline-6-carbonitrile (4b) was prepared analo-
gously from enaminoketone 1b (0.54 g, 0.002 mol) and
4-chlorobenzylidenemalonodinitrile (0.38 g, 0.002 mol) in a
yield of 0.86 g (93%), m.p. > 320 °C. Found (%): C, 65.31;
H, 4.45; Cl, 7.95; N, 11.92; S, 7.18. C25H21ClN4OS. Calcu-
lated (%): C, 65.14; H, 4.59; Cl, 7.69; N, 12.15; S, 6.96.
1H NMR, δ: 1.50—2.45 (m, 8 H, 5 CH2); 2.70—2.95 (m, 6 H,
2 CH2); 4.70 (s, 1 H, CH); 7.15 (d, 2 H, H arom., J = 8 Hz);
7.35 (m, 4 H, NH2 + H arom.).
4 H, 2 CH2); 4.25 (q, 2 H, MeCH2, J = 7 Hz); 5.55 (s, 1 H,
CH); 9.80 (s, 1 H, NH).
Ethyl 2-[(5,5-dimethyl-3-oxocyclohexen-1-yl)amino]-
5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate
(2c) was prepared analogously from dimedone (4.20 g, 0.03 mol)
and ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thio-
phene-3-carboxylate8 (7.17 g, 0.03 mol) in a yield of 6.73 g
(62%), m.p. 124—126 °C. Found (%): C, 66.70; H, 7.41;
N, 3.72; S, 9.08. C20H27NO3S. Calculated (%): C, 66.45;
1
H, 7.53; N, 3.87; S, 8.87. H NMR, δ: 1.05 (s, 6 H, 2 Me);
1.35 (t, 3 H, MeCH2, J = 7 Hz); 1.65 (m, 4 H, 2 CH2); 1.80
(m, 2 H, CH2); 2.05 and 2.45 (both s, 2 H each, CH2);
2.60—2.80 (m, 4 H, 2 CH2); 4.25 (q, 2 H, MeCH2, J = 7 Hz);
5.60 (s, 1 H, CH); 9.80 (s, 1 H, NH).
Ethyl 2-[2-amino-4-(4-chlorophenyl)-3-cyano-7,7-di-
methyl-5-oxo-1,4,5,6,7,8-hexahydro-1-quinolinyl]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (5a). Several drops
of piperidine were added to a solution of enaminoketone 2a
(0.69 g, 0.002 mol) and 4-chlorobenzylidenemalonodinitrile
(0.38 g, 0.002 mol) in EtOH (5 mL). The reaction mixture was
refluxed for 15 min and then cooled. The precipitate that
formed was filtered off and washed on a filter with a small
amount of EtOH. Hexahydroquinoline 5a was obtained in a
yield of 0.81 g (76%), m.p. 245—246 °C. Found (%): C, 65.15;
H, 5.78; Cl, 6.48; N, 7.71; S, 6.17. C29H30ClN3O3S. Calcu-
lated (%): C, 64.97; H, 5.64; Cl, 6.61; N, 7.84; S, 5.98.
1H NMR, δ: 0.80 (s, 3 H, Me); 1.00 (s, 1 H, Me); 1.25 (t,
3 H, MeCH2, J = 7 Hz); 1.75—2.35 (m, 8 H, 4 CH2);
2.70—2.85 (m, 4 H, 2 CH2); 4.25 (q, 2 H, MeCH2, J = 7 Hz);
4.45 (s, 1 H, CH); 5.55 (s, 2 H, NH2); 7.15—7.40 (m, 4 H,
H arom.).
Ethyl 2-[2-amino-3-cyano-4-(3-nitrophenyl)-5-oxo-
1,4,5,6,7,8-hexahydro-1-quinolinyl]-4,5,6,7-tetrahydroben-
zo[b]thiophene-3-carboxylate (5b) was prepared analogously
from enaminoketone 2b (0.64 g, 0.002 mol) and 3-nitrobenzyl-
idenemalonodinitrile (0.40 g, 0.002 mol) in a yield of 0.86 g
(83%), m.p. 268—269 °C. Found (%): C, 62.38; H, 4.98;
N, 10.98; S, 6.34. C27H26N4O5S. Calculated (%): C, 62.53;
H, 5.05; N, 10.80; S, 6.18. 1H NMR, δ: 1.25 (t, 3 H, MeCH2,
J = 7 Hz); 1.50—2.45 (m, 10 H, 5 CH2); 2.70—2.85 (m, 4 H,
2 CH2); 4.25 (q, 2 H, MeCH2, J = 7 Hz); 4.55 (s, 1 H, CH);
5.60 (s, 2 H, NH2); 7.50—8.20 (m, 4 H, H arom.).
2,2-Dimethyl-5-(4-chlorophenyl)-4,8-dioxo-1,3,4,5,7,
8,9,10,11,12-decahydro-2H-benzo[4´,5´]thieno[3´,2´:5,6]pyri-
mido[1,2-a]quinoline-6-carbonitrile (6a). Several drops of DBU
were added to a solution of enaminoketone 2a (0.69 g,
0.002 mol) and 4-chlorobenzylidenemalonodinitrile (0.38 g,
0.002 mol) in EtOH (8 mL). The reaction mixture was re-
fluxed for 30 min and then cooled. The precipitate that formed
was filtered off and washed on a filter with a small amount of
EtOH. Thienopyrimidoquinoline 6a was obtained in a yield of
0.91 g (93%), m.p. > 320 °C. Found (%): C, 66.35; H, 5.09;
Cl, 7.17; N, 8.72; S, 6.43. C27H24ClN3O2S. Calculated (%):
C, 66.18; H, 4.94; Cl, 7.32; N, 8.58; S, 6.54. 1H NMR, δ: 1.00
(s, 3 H, Me); 1.15 (s, 1 H, Me); 1.70—1.85 (m, 4 H, 2 CH2);
2.15 (d, 1 H, CH2, J = 18 Hz); 2.55—2.95 (m, 7 H, CH2);
4.70 (s, 1 H, CH); 7.10 and 7.35 (both d, 2 H each, H arom.,
J = 8 Hz); 11.15 (s, 1 H, NH).
4,8-Dioxo-5-phenyl-1,3,4,5,7,8,9,10,11,12-decahydro-2H-
benzo[4´,5´]thieno[3´,2´:5,6]pyrimido[1,2-a]quinoline-6-carbo-
nitrile (6b) was prepared analogously from enaminoketone 2b
(0.64 g, 0.002 mol) and benzylidenemalonodinitrile (0.31 g,
0.002 mol) in a yield of 0.77 g (90%), m.p. > 320 °C.
Found (%): C, 70.05; H, 5.02; N, 9.66; S, 7.71. C25H21N3O2S.
Calculated (%): C, 70.24; H, 4.95; N, 9.83; S, 7.50. 1H NMR,
δ: 1.50—2.45 (m, 10 H, 5 CH2); 2.60—2.85 (m, 4 H, CH2);
8-Amino-5-(4-methoxyphenyl)-2,2-dimethyl-4-oxo-
1,3,4,5,10,11,12,13-octahydro-2H,9H-cyclohepta[4´,5´]thi-
eno[3´,2´:5,6]pyrimido[1,2-a]quinoline-6-carbonitrile (4c) was
prepared analogously from enaminoketone 1c (0.63 g,
0.002 mol) and 4-methoxybenzylidenemalonodinitrile 0.37 g
(0.002 mol) in a yield of 0.96 g (96%), m.p. > 320 °C.
Found (%): C, 69.57; H, 6.21; N, 11.42; S, 6.28. C29H30N4O2S.
Calculated (%): C, 69.85; H, 6.06; N, 11.24; S, 6.43. 1H NMR,
δ: 0.90 and 1.15 (both s, 3 H each, Me); 1.60—1.95 (m, 6 H,
3 CH2); 2.20 (d, 1 H, CH2, J = 18 Hz); 2.55—3.05 (m, 7 H,
CH2); 3.70 (s, 3 H, OMe); 4.60 (s, 1 H, CH); 6.80 and 6.95
(both d, 2 H each, H arom., J = 8 Hz); 7.25 (br.s, 2 H, NH2).
Transformation of hexahydroquinoline 3a into thieno-
pyrimidoquinoline 4a. Several drops of DBU were added to a
suspension of hexahydroquinoline 3a (0.45 g, 0.001 mol) in
boiling EtOH (8 mL). The reaction mixture was refluxed for
8 h and then cooled. The precipitate that formed was filtered
off and washed on a filter with a small amount of EtOH.
Thienopyrimidoquinoline 4a was obtained in a yield of 0.41 g
1
(91%), m.p. > 320 °C. According to the H NMR spectro-
scopic data, thienopyrimidoquinoline 4a was identical with
that prepared according to a procedure described above.
Ethyl 2-[(5,5-dimethyl-3-oxocyclohexen-1-yl)amino]-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (2a).
A solution of dimedone (4.20 g, 0.03 mol), ethyl 2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate8 (6.75 g,
0.03 mol), and TsOH (0.2 g, 0.0011 mol) in benzene (70 mL)
was refluxed using a Dean—Stark trap for 10 h. Then the
reaction mixture was cooled, the solvent was evaporated, and
the residue was recrystallized from an ethyl acetate—heptane
mixture. Enaminoketone 2a was obtained in a yield of 7.52 g
(72%), m.p. 155—156 °C. Found (%): C, 65.89; H, 7.11;
N, 3.85; S, 9.01. C19H25NO3S. Calculated (%): C, 65.68;
1
H, 7.25; N, 4.03; S, 9.23. H NMR, δ: 1.05 (s, 6 H, 2 Me);
1.35 (t, 3 H, MeCH2, J = 7 Hz); 1.75 (m, 4 H, 2 CH2); 2.05
and 2.45 (both s, 2 H each, CH2); 2.60—2.80 (m, 4 H,
2 CH2); 4.25 (q, 2 H, MeCH2, J = 7 Hz); 5.60 (s, 1 H, CH);
9.85 (s, 1 H, NH).
Ethyl 2-[(3-oxocyclohexen-1-yl)amino]-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxylate (2b) was prepared analogously
from cyclohexane-1,3-dione (3.36 g, 0.03 mol) and ethyl
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate8
(6.75 g, 0.03 mol) in a yield of 6.51 g (68%), m.p. 136—137 °C.
Found (%): C, 64.21; H, 6.78; N, 4.12; S, 9.82. C17H21NO3S.
Calculated (%): C, 63.92; H, 6.63; N, 4.38; S, 10.04. 1H NMR,
δ: 1.35 (t, 3 H, MeCH2, J = 7 Hz); 1.75 (m, 4 H, 2 CH2);
1.95, 2.20, and 2.55 (all m, 2 H each, CH2); 2.60—2.80 (m,

2432
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 12, December, 2001
Lichitsky et al.
4.65 (s, 1 H, CH); 7.10—7.30 (m, 5 H, H arom.); 11.10
(s, 1 H, NH).
4-Amino-7-(4-chlorophenyl)-10,10-dimethyl-2,3-diphenyl-
8-oxo-8,9,10,11-tetrahydro-7H-furo[3´,2´:5,6]pyrimi-
do[1,2-a]quinoline-6-carbonitrile (8b) was prepared analo-
gously from enaminoketone 7 (0.38 g, 0.001 mol) and 4-chloro-
benzylidenemalonodinitrile (0.19 g, 0.001 mol) in a yield of
0.32 g (56%), m.p. 334—335 °C. Found (%): C, 73.45;
H, 7.89; Cl, 6.54; N, 9.97. C35H27ClN4O2. Calculated (%):
5-(4-Methoxyphenyl)-2,2-dimethyl-4,8-dioxo-1,3,4,5,
7,8,10,11,12,13-decahydro-2H,9H-cyclohepta[4´,5´]thi-
eno[3´,2´:5,6]pyrimido[1,2-a]quinoline-6-carbonitrile (6c) was
prepared analogously from enaminoketone 2c (0.72 g,
0.002 mol) and 4-methoxybenzylidenemalonodinitrile (0.37 g,
0.002 mol) in a yield of 0.86 g (86%), m.p. > 320 °C.
Found (%): C, 69.49; H, 5.97; N, 8.65; S, 6.54. C29H29N3O3S.
Calculated (%): C, 69.72; H, 5.85; N, 8.41; S, 6.42. 1H NMR,
δ: 1.00 (s, 3 H, Me); 1.15 (s, 1 H, Me); 1.60—1.85 (m, 6 H,
3 CH2); 2.15 (d, 1 H, CH2, J = 18 Hz); 2.55—3.00 (m, 7 H,
CH2); 3.75 (s, 3 H, OCH3); 4.55 (s, 1 H, CH); 6.80 and 7.00
(both d, 2 H each, H arom., J = 8 Hz); 11.10 (s, 1 H, NH).
Transformation of hexahydroquinoline 5a into thieno-
pyrimidoquinoline 6a. Several drops of DBU were added to a
solution of hexahydroquinoline 5a (0.54 g, 0.001 mol) in
boiling EtOH (8 mL). The reaction mixture was refluxed for
2 h and then cooled. The precipitate that formed was filtered
off and washed on a filter with a small amount of EtOH.
Thienopyrimidoquinoline 6a was obtained in a yield of 0.47 g
1
C, 73.61; H, 7.77; Cl, 6.21; N, 9.81. H NMR, δ: 1.00 and
1.20 (both s, 3 H each, Me); 2.20, 2.55, 2.85, and 3.50 (all d,
1 H each, CH2, J = 18 Hz); 4.70 (s, 1 H, CH); 4.85
(br.s, 1 H, NH); 7.20—7.75 (m, 14 H, H arom.); 8.10
(br.s, 1 H, NH).
4-Amino-7-(4-methoxyphenyl)-10,10-dimethyl-2,3-diphe-
nyl-8-oxo-8,9,10,11-tetrahydro-7H-furo[3´,2´:5,6]pyrimi-
do[1,2-a]quinoline-6-carbonitrile (8c) was prepared analo-
gously from enaminoketone 7 (0.25 g, 0.65 mmol) and
4-methoxybenzylidenemalonodinitrile (0.12 g, 0.65 mol) in a
yield of 0.20 g (55%), m.p. 298—299 °C. Found (%): C, 76.22;
H, 5.41; N, 9.62. C36H30N4O3. Calculated (%): C, 76.31;
H, 5.34; N, 9.89. 1H NMR, δ: 1.00 and 1.15 (both s,
3 H each, Me); 2.20, 2.55, 2.80, and 3.50 (all d, 1 H each,
CH2, J = 18 Hz); 3.70 (s, 3 H, OCH3); 4.60 (s, 1 H, CH);
4.80 (br.s, 1 H, NH); 6.80 and 7.10 (both d, 2 H each,
H arom., J = 8 Hz); 7.20—7.65 (m, 10 H, H arom.); 8.00
(br.s, 1 H, NH).
1
(96%), m.p. > 320 °C. According to the H NMR spectro-
scopic data, the product was identical with thienopyrimido-
quinoline 6a, which was prepared as described above.
2-[(5,5-Dimethyl-3-oxocyclohexen-1-yl)amino]-4,5-di-
phenylfuran-3-carbonitrile (7). A solution of dimedone (0.42 g,
0.003 mol), 2-amino-3-cyano-4,5-diphenylfuran9 (0.78 g,
0.003 mol), and TsOH (0.02 g, 0.0001 mol) in benzene
(10 mL) was refluxed using a Dean—Stark trap for 5 h and
then cooled. The precipitate that formed was filtered off and
washed on a filter with a small amount of benzene.
Enaminoketone 7 was obtained in a yield of 0.95 g (83%),
m.p. 182—183 °C. Found (%): C, 78.32; H, 5.75; N, 7.17.
C25H22N2O2. Calculated (%): C, 78.51; H, 5.80; N, 7.32.
1H NMR, δ: 1.05 (s, 6 H, 2 Me); 2.15 and 2.55 (both s,
2 H each, CH2); 5.80 (s, 1 H, CH); 7.25—7.55 (m, 10 H,
H arom.); 10.45 (s, 1 H, NH).
References
1. S. Goldmann and J. Stoltefuss, Angew. Chem., Int. Ed.
Engl., 1991, 30, 1559.
2. V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim., 1998, 2123
[Russ. Chem. Bull., 1998, 47, 2953 (Engl. Transl.)].
3. WO Pat. 9528388; Chem. Abstrs., 1996, 124, 175860.
4. US Pat. 5455253; Chem. Abstrs., 1996, 124, 86828.
5. B. V. Lichitsky, V. N. Yarovenko, I. V. Zavarzin, and
M. M. Krayushkin, Izv. Akad. Nauk, Ser. Khim., 2000, 1254
[Russ. Chem. Bull., Int. Ed., 2000, 49, 1251].
6. B. V. Lichitsky, V. N. Nesterov, A. A. Dudinov, and M. M.
Krayushkin, Izv. Akad. Nauk, Ser. Khim., 2000, 1320 [Russ.
Chem. Bull., Int. Ed., 2000, 49, 1318].
7. M. Hammouda, M. Mashaly, and E. M. Afsah, Pharmazie,
1994, 49, 365.
8. K. Gewald, E. Schinke, and H. Bottcher, Chem. Ber.,
1966, 99, 94.
9. T. Hayashi and M. Kagawa, Bull. Chem. Soc. Jpn., 1970,
43, 3290.
4-Amino-10,10-dimethyl-8-oxo-2,3,7-triphenyl-8,9,10,11-
tetrahydro-7H-furo[3´,2´:5,6]pyrimido[1,2-a]quinoline-6-
carbonitrile (8a). Several drops of DBU were added to a
solution of enaminoketone 7 (0.25 g, 0.65 mmol) and
benzylidenemalonodinitrile (0.10 g, 0.65 mmol) in EtOH
(4 mL). The reaction mixture was refluxed for 4 h and then
cooled. The precipitate that formed was filtered off and washed
on a filter with a small amount of EtOH. Furopyrimidoquinoline
8a was obtained in a yield of 0.24 g (68%), m.p. 295—296 °C.
Found (%): C, 78.21; H, 5.31; N, 10.72. C35H28N4O2. Calcu-
lated (%): C, 78.34; H, 5.26; N, 10.44. 1H NMR, δ: 1.00 and
1.20 (both s, 3 H each, Me); 2.20, 2.55, 2.85, and 3.50 (all d,
1 H each, CH2, J = 18 Hz); 4.70 (s, 1 H, CH); 4.85
(br.s, 1 H, NH); 7.10—7.65 (m, 15 H, H arom.); 8.05
(br.s, 1 H, NH).
Received March 13, 2001;
in revised form June 20, 2001