New synthesis of benzo[b][1,6]naphthyridines and pyrido[4,3-b]benz[f] azepines from lactim ethers of 3,4-dihydrocarbostyril and 1H-2,3,4,5- tetrahydrobenz[b]azepin-2-one

Article abstract of DOI:10.1007/s11172-007-0155-4

Condensation of lactim ethers of 3,4-dihydrocarbostyril and 1H-2,3,4,5-tetrahydrobenz[b]azepin-2-one with malonodinitrile, cyanoacetamide, and ethyl cyanoacetate gave the corresponding 2-methylidene derivatives. Their reactions with dimethylformamide diethyl acetal followed by cyclization into benzo[b][1,6]naphthyridines and pyrido[4,3-b]benz[f ]azepines were studied.

Full text of DOI:10.1007/s11172-007-0155-4

Russian Chemical Bulletin, International Edition, Vol. 56, No. 5, pp. 1032—1040, May, 2007
1032
New synthesis of benzo[b][1,6]naphthyridines
and pyrido[4,3ꢀb]benz[ f ]azepines from lactim ethers of
3,4ꢀdihydrocarbostyril and 1Hꢀ2,3,4,5ꢀtetrahydrobenz[b]azepinꢀ2ꢀone
T. V. Golovko,a O. B. Smirnova,a N. P. Solov´eva,b O. S. Anisimova,b and V. G. Granika
ꢀ
aState Research Center of Antibiotics,
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Fax: +7 (495) 231 4284. Eꢀmail: vggranik@mail.ru
bAllꢀRussian Research Chemical Pharmaceutical Institute,
7 ul. Zubovskaya, 119815 Moscow, Russian Federation.
Fax: +7 (495) 246 7805
Condensation of lactim ethers of 3,4ꢀdihydrocarbostyril and 1Hꢀ2,3,4,5ꢀtetrahydroꢀ
benz[b]azepinꢀ2ꢀone with malonodinitrile, cyanoacetamide, and ethyl cyanoacetate gave the
corresponding 2ꢀmethylidene derivatives. Their reactions with dimethylformamide diethyl
acetal followed by cyclization into benzo[b][1,6]naphthyridines and pyrido[4,3ꢀb]benz[ f ]azeꢀ
pines were studied.
Key words: 3,4ꢀdihydrocarbostyril, 1Hꢀ2,3,4,5ꢀtetrahydrobenz[b]azepinꢀ2ꢀone, dimethylꢀ
formamide diethyl acetal, cyanoacetic acid derivatives, benzo[b][1,6]naphthyridines, pyriꢀ
do[4,3ꢀb]benz[ f ]azepines.
Scheme 1
Proceeding further in our investigations into the
synthesis of heterocyclic oxindoleꢀbased systems,1 we
used in the present work the homologous benzolactams
3,4ꢀdihydrocarbostyril (1) and 1Hꢀ2,3,4,5ꢀtetrahydroꢀ
benz[b]azepinꢀ2ꢀone as the starting reagents. In oxindole,
the 3ꢀmethylene fragment is activated by both the carboꢀ
nyl group and the annulated benzene ring, while the corꢀ
responding activation in the above lactams is only due to
the lactam CO group. Because of this, condensation at
the 3ꢀCH2 group could be expected to be substantially
more difficult. Indeed, compound 1 does not react with
dimethylformamide diethyl acetal (2) either in boiling
ethanol, benzene, or toluene (oxindole reacts with acꢀ
etal 2 at room temperature) or with AlCl3 as a catalyst.2
Only when refluxing lactam 1 in excess acetal 2 for 5 h
in the presence of catalytic amounts of piperidine, we
obtained 3ꢀdimethylaminomethylidene derivative 3 in
low yield (22%) (Scheme 1). The catalytic effect of piꢀ
peridine is associated with the formation of intermediate
N,Oꢀacetal 4. This acetal is much more reactive than
amide acetals of the type 2 because of the substantially
better stabilization of amidinium cation 5 compared to
imino ether cation 6 (its stabilization determines the elecꢀ
trophilic properties of amide acetals).
1
According to the H NMR spectrum, compound 3 in
DMSOꢀd6 exists as one geometric isomer. In terms of
molecular models, one can assume the formation of the
Eꢀisomer, in which the H(3´) proton and the CO group
are close to each other. Enamino amide 3 was subjected
to transamination, which is the most representative reacꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 995—1002, May, 2007.
1066ꢀ5285/07/5605ꢀ1032 © 2007 Springer Science+Business Media, Inc.

Benzonaphthyridines and pyridobenzazepines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1033
Scheme 3
tion of enamines. A reaction with benzylamine gave a
multicomponent mixture. Its mass spectrum shows two
molecular ion peaks with m/z 264 and 262 due to the
expected 3ꢀbenzylaminomethylideneꢀ1,2,3,4ꢀtetrahydroꢀ
quinolinꢀ2ꢀone 7 and its dehydrogenation product 8. The
1H NMR spectrum of this mixture contains signals for
two geometric isomers (Eꢀ7 and Zꢀ7) in the ratio 4 : 1 (the
presence of the Zꢀisomer is due to its stabilization by
intramolecular hydrogen bonding) and signals for deꢀ
hydrogenated derivative 8, which exists in DMSOꢀd6 in
the enol form (Scheme 2).
Scheme 2
X = CN (10a,b), CONH2 (11a,b), COOEt (12);
n = 1 (9a—11a, 12), 2 (9b—11b)
(1.25 mmol) was heated at 120—125 °C until ethanol was
1
completely removed. According to the H NMR specꢀ
trum, the resulting mixture contained compounds 9a, 9b,
10a, 10b, and 1Hꢀ2,3,4,5ꢀtetrahydrobenz[b]azepinꢀ2ꢀone
in the ratio 41 : 46 : 10 : 2 : 1; i.e., the condensation rate of
the sixꢀmembered lactim ether is ~5 times higher than
that of the sevenꢀmembered ether. The ratio of the comꢀ
ponents in the reaction mixture was assessed from the
integral intensities of the signals for the ring methylene
protons and the methyl protons in the lactim ethers. This
reaction outcome can be explained by a reaction mechaꢀ
nism in which addition of the CH acid anion to position 2
of the lactim ethers is a rateꢀlimiting step. The formation
of intermediate 13 (see Scheme 3) involves a transformaꢀ
tion of the sp2ꢀhybridized C(2) atom into the sp3ꢀhybridꢀ
ized state, which is thermodynamically much more favorꢀ
able for a sixꢀmembered ring than for a sevenꢀmemꢀ
bered one.3
Since the aforementioned synthesis of compound 3 is
unsuitable for preparative purposes, we followed an alterꢀ
native route involving condensation of lactim ethers 9a,b
with cyanoacetic acid derivatives. We could expect that
introduction of a methylene fragment with two strong
electronꢀwithdrawing βꢀsubstituents into position 2 of
tetrahydroquinoline and 1Hꢀ2,3,4,5ꢀtetrahydrobenzꢀ
azepine would greatly activate the 3ꢀCH2 group and allow
their reactions with amide acetal.
Reactions of lactim ethers 9a,b with malonodinitrile
with removal of ethanol during the condensation gave the
corresponding βꢀdicyanomethylidene derivatives 10a,b
(Scheme 3). The removal of ethanol began at 95—100 °C
for sixꢀmembered lactim ether 9a and at 120—125 °C for
sevenꢀmembered ether 9b. Condensation with cyanoꢀ
acetamide occurred at a higher temperature (165—175 °C)
to give βꢀcarbamoylꢀβꢀcyanomethylidene derivaꢀ
tives 11a,b. A still higher temperature (225—230 °C) was
required for reactions with ethyl cyanoacetate: in this case,
only compound 12 was isolated in the individual state.
One can see that condensation with active methylene
compounds occurs for lactim ether 9a containing the sixꢀ
membered ring more easily than for sevenꢀmembered
ether 9b. For quantitative estimation of the tendency of
ethers 9a,b toward condensation of this type, a mixture of
lactim ethers 9a,b (5 mmol each) and malonodinitrile
As expected, condensation of compounds 10a,b with
acetal 2 proceeded smoothly enough to yield diene diꢀ
amines 14a,b (Scheme 4).
Scheme 4
n = 1 (a), 2 (b)

1034
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Golovko et al.
1
The H NMR spectra of compounds 3, 7, 8, 10a,b,
11a,b, 12, and 14a,b are given in Tables 1 and 2.
ened signal at δ 120.1 (CN) and a highꢀfield signal for the
quaternary sp2ꢀhybridized C(2´) atom (δ 38.6), which is
due to the strong electronꢀdonating effects of the endoꢀ
The characteristic features of the 13C NMR spectrum
of compound 14a (see Experimental) include a broadꢀ
1
cyclic NH group and the NMe2 fragment. The H NMR
Table 1. 1H NMR spectra of compounds 3, 7, 8, and 14a,b in DMSOꢀd6
Comꢀ
pound
δ (J/Hz)
CH2
H(3´)
H arom.
(m)
N(1)H
(br.s, 1 H)
Other
protons
3
3.96 (s, 2 H, H(4))
3.55 (s, 2 H, H(4))
7.21 (t, 1 H,
4JH(3´),H(4) = 1.5)
7.30 (dt, 1 H,
6.70—7.07
(4 H, H(5)—H(8))
6.75—7.10
9.25
9.25
3.04 (s, 6 H, NMe2)
Eꢀ7a
6.95 (dt, 1 H, NHCH2Ph,
3JH(3´),NH = 12.2,
4JH(3´),H(4) = 2.0)
(4 H, H(5)—H(8))
3JNH,СH = 5.2); 4.36 (d, 2 H,
2
NHCH2Ph); 6.75—7.36
(m, 5 H, Ph)
Zꢀ7a
3.52 (s, 2 H, H(4))
—
—
6.75—7.10
(H(5)—H(8))
9.28
—
4.32 (d, 2 H, NHСH2Ph,
b
3JNH,СH = 6.4)c; 6.75—7.36
2
(m, 5 H, Ph)
8
8.70 (t, 1 H,
7.15—7.82
(4 H, H(5)—H(8))
4.80 (d, 2 H, CH2Ph); 6.75—7.36
(m, 5 H, Ph); 8.49 (s, 1 H, H(4));
12.05 (br.s, 1 H, OH)
4JH(3´),СH = 1.5)
2
14а
3.63 (br.s, 2 H,
H(4))
2.36 (m, 2 H, H(4));
2.78 (m, 2 H, H(5))
2.70 (m, 2 H, H(4));
2.86 (m, 2 H, H(5))
7.41 (s, 1 H)
5.54 (s, 1 H)
6.37 (s, 1 H)
6.95—7.15
(4 H, H(5)—H(8))
6.70—7.16
(H(6)—H(9))
6.70—7.16
10.03
7.30
9.60
3.16 (s, 6 H, NMe2)
Eꢀ14bd
Zꢀ14bd
~3.20 (br.s, 6 H, NMe2)
3.13, 3.24 (both s, 3 H each, NMe2)
(H(6)—H(9))
a The relative contents of the Eꢀ and Zꢀisomers are 80 and 20%, respectively.
b The signals are masked by a multiplet for the aromatic protons in the components of the mixture under analysis.
c The signal for NHCH2Ph overlaps with a multiplet for the aromatic protons.
d The relative contents of the Zꢀ and Eꢀisomers are 60 and 40%, respectively.
Table 2. 1H NMR spectra of compounds 10a,b, 11a,b, 12, and 15 in DMSOꢀd6
Comꢀ
pound
δ (J/Hz)
CH2
H arom. (m)
N(1)H
Other protons
—
10a
10b
2.84 (m, 4 H, H(3), H(4))
7.00—7.35
(4 H, H(5)—H(8))
7.20—7.32
11.06
(br.s, 1 H)
10.79
2.18 (quint, 2 H, H(4),
—
3JH(3),H(4) = 3JH(4),H(5) = 7.2);
2.38 (t, 2 H, H(3), 3JH(3),H(4) = 7.2);
2.65 (t, 2 H, H(5), 3JH(4),H(5) = 7.2)
2.85 (m, 4 H, H(3), H(4))
(4 H, H(6)—H(9))
(br.s, 1 H)
11a
11b
6.95—7.20
(6 H, H(5)—H(8), NH2)*
7.15—7.30
12.55
(s, 1 H)
12.26
—
2.20 (quint, 2 H, H(4),
~7.20*
3JH(3),H(4) = 3JH(4),H(5) = 7.2);
2.40 (t, 2 H, H(3), 3JH(3),H(4) = 7.2);
2.70 (t, 2 H, H(5), 3JH(4),H(5) = 7.2)
2.80—2.95 (m, 4 H, H(3), H(4))
(6 H, H(6)—H(9), NH2)*
(s, 1 H)
3
12
15
7.05—7.23
(4 H, H(5)—H(8))
7.00—7.20
11.41
(s, 1 H)
12.93
1.25 (t, 3 H, Me, J = 7.2);
4.16 (q, 2 H, СH2, 3J = 7.2)
8.50 (s, 1 H, N=CH); 3.08,
2.87 (m, 4 H, H(3), H(4))
(4 H, H(5)—H(8))
(br.s, 1 H) 3.18 (both s, 3 H each, NMe2)
* The protons of the CONH2 fragment are manifested by two strongly broadened signals that overlap with a multiplet for the
aromatic protons, making its integral intensity equal to 6 H.

Benzonaphthyridines and pyridobenzazepines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1035
Scheme 5
spectrum of this compound contains one set of signals
(see Table 1). To determine the configuration of this comꢀ
pound, we carried out a nuclear Overhauser effect (NOE)
experiment. Irradiation at the frequency of the signal for
the Me2N group (δ 3.16) increased the intensity of the
narrow singlet for the vinylic proton (δ 7.41, NOE 28%)
and slightly (but distinctly) increased the intensity of the
singlet for the methylene protons (δ 3.63, NOE 3%). Such
an insignificant effect for the 4ꢀCH2 group is probably
associated with the inversion of the tetrahydropyridine
ring that causes broadening of this singlet. Irradiation at
the frequency of the singlet for the 4ꢀCH2 protons inꢀ
creased the intensity of the doublet for the H(5) proton
(δ 7.10, NOE 9%). Thus, the NOE experiment reꢀ
vealed that compound 14a have spatially close Me2N and
4ꢀCH2 groups and hence exists (like compound 3) in the
Eꢀconfiguration.
n = 1 (a), 2 (b)
The 1H NMR spectrum of compound 14b in
DMSOꢀd6 (see Table 1) shows a double set of signals
indicating the presence of a mixture of geometric isomers
in solution. The largest difference between the chemical
shifts relates to the vinylic protons (δ 6.37 for Zꢀisomer
(60%) and δ 5.54 for Eꢀisomer (40%); ∆δ = 0.83 ppm). In
CD3OD, the equilibrium shift to the major isomer (76%)
is more pronounced. The correctness of our assignment
of the signals to the Eꢀ and Zꢀisomers is evident from a
good agreement between the chemical shifts of the meꢀ
thylene protons in the sevenꢀmembered ring in the major
Zꢀisomer of compound 14b (δ 2.70 (H(4)) and 2.86
(H(5))) and in compound 16b (δ 2.74 and 2.92; see beꢀ
low), as well as from an appreciable difference between
these values and the chemical shifts of the methylene
protons of the sevenꢀmembered ring in the minor Eꢀisoꢀ
mer (δ 2.36 and 2.78).
A NOE experiment (Table 4) via irradiation at the
frequency of the signal for the N(2)H group caused an
increase in the intensity of the signal for the H(1) proton
(by 17.5%) in the spectrum of compound 16a. Therefore,
we can assign to this compound a pyridone rather than
iminopyran structure. Unambiguous chemical proof of
the structure of tricyclic product 16a was obtained by
highꢀtemperature cyclization of enamino acylamidine 15
from which no iminopyran can form. According to
1
the H NMR spectra, the final reaction mixture conꢀ
tains compound 16a and resinification products (see
Scheme 5).
Cyclization of diene diamine 14a under other condiꢀ
tions (heating with sodium methoxide in methanol) gave
3ꢀmethoxydihydrobenzonaphthyridine 17 (Scheme 6).
To reliably distinguish between tricyclic structure 17 and
an alternative structure (methoxymethylidene derivaꢀ
1
tive 18), we examined the H and 13C NMR spectra (see
Table 3 and Experimental) and carried out a NOE experiꢀ
ment. Irradiation at the frequency of the signal for the
C(10)H2 protons (δ 3.97) increased the intensity of the
signal for the H(1) proton (δ 7.87) by 25% and the intenꢀ
sity of the doublet for the H(9) proton (δ 7.09) by 20%.
Based on the signal multiplicity for the C atoms in the
13C NMR spectrum recorded without proton decoupling,
we made an unambiguous choice for the tricyclic strucꢀ
ture. First, in the case of bicyclic structure 18, the comꢀ
ponents of the quartet for the methoxy C atom should be
split because of a spinꢀspin coupling with the H(3´) proꢀ
Note that the reaction of acetal 2 with enamino amide
11a occurs at the carbamoyl NH2 group rather than the
3ꢀCH2 fragment. The resulting enamino acylamidine 15
easily undergoes hydrolysis in boiling water to give the
starting compound 11a (Scheme 5).
Then we studied heterocyclization of diene diꢀ
amines 14a,b. Heating of the
ton. The actual spectrum shows a quartet (1JC,H
=
latter in acetic acid yielded
tricyclic products 16a,b (see
Scheme 5). The 1H NMR
147.3 Hz) characteristic of structure 17. Second, the mulꢀ
tiplicity of the signal at δ 148.6 for the C(1) atom, which is
a doublet of triplets arising from spinꢀspin couplings with
3
spectra of compounds 16a,b
the H(10) protons (1JC(1),H = 178.5 Hz, JC(1),H(10)
=
(Table 3) do not contradict
structure A as well.
3.1 Hz) is evidence for structure 17. In the case of strucꢀ
ture 18, the C(3´) atom would couple with the OMe proꢀ

1036
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Golovko et al.
Table 3. 1H NMR spectra of compounds 16a,b, 17, 19, 20a, and 21 in DMSOꢀd6
Comꢀ
poꢀ
und
δ (J/Hz)
CH2
H arom.
N(5)H
(1 H)
N(2)H
H(1) H of the substituꢀ
(br.s, 1 H) (s, 1 H) ent in position 3
16a
16b
3.81
(s, 2 H, H(10))
6.95 (t, 1 H, 3J = 9.3); 7.09 (d, 1 H, 3J = 9.3);
7.15 (t, 1 H, 3J = 9.3); 7.35 (d, 1 H, 3J = 9.3)
(H(6)—H(9))
9.60 (s)
11.40
11.48
7.36
7.34
—
—
2.74, 2.92
6.92—7.20 (m, 3 H); 7.30 (d, 1 H, 3J = 8.3)
8.40 (s)
(both m, 2 H each,
H(10), H(11))
(H(6)—H(9))
17
3.97
(s, 2 H, H(10))
7.09 (m, 2 H, H(9), H(7)); 6.92 (t, 1 H, H(8),
9.48 (s)
9.76 (s)
—
—
—
7.87
8.03
7.74
3.88 (с,
3 H, ОMe)
3
3J = 7.7); 7.24 (d, 1 H, H(6), J = 7.7)
19
4.05
(s, 2 H, H(10))
6.93 (t, 1 H, H(8), 3J = 8.0); 7.10 (m, 2 H,
H(9), H(7)); 7.30 (d, 1 H, H(6), 3J = 8.0)
—
20а
3.85
(s, 2 H, H(10))
6.81—7.30 (m, 10 H)*
9.14
(br.s)
4.55 (d, 2 H,
NCH2,
3JСH ,NH = 5.7)
2
21
3.85
(s, 2 H, H(10))
6.88, 7.05 (both t, 1 H each, 3J = 9.3);
7.07, 7.20 (both d, 1 H each, J = 9.3)
9.07 (s)
—
7.71
6.37 (br.s,
2 H, NH2)
3
(H(6)—H(9))
* The multiplet is due to the aromatic H(6)—H(9) protons, the protons of the Ph group, and the NH protons of the substituent in
position 3.
Table 4. NOE data for compound 16a
Signal, δ Increase in the intensity
Reflux of compound 16a with POCl3 afforded chloro
derivative 19, which reacted with various amines to give
amino derivatives 20a—d (Scheme 7).
of the observed signal (%)
irradiation
observation
Scheme 7
3.81 (H(10))
7.09 (H(9))
7.36 (H(1))
30
36
7.36 (H(1))
9.60 (N(5)H)
11.40 (N(2)H)
7.35 (H(6))
6.5
16
11.40 (N(2)H) 7.36 (H(1))
17.5
tons and the signal would appear as a doublet of multiꢀ
plets.
Scheme 6
R = CH2Ph (a), (CH2)2C6H3ꢀ3,4ꢀ(OMe)2 (b), (CH2)2NEt2 (c), Bu (d)
By treating compound 14a with an ethanolic solution
of ammonia, we obtained tricyclic product 21. Apparꢀ
ently, the reaction proceeds via transamination followed
by cyclization involving the amino and cyano groups
(Scheme 8).
1
The H and 13C NMR spectra of tricyclic product 21
are similar to those of compound 17 (see Table 3 and
Experimental) and substantially differ from the spectra
of bicyclic compounds 14 (see Table 1). This makes

Benzonaphthyridines and pyridobenzazepines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1037
Scheme 8
Scheme 10
structure 21 preferred to isomeric intermediate 22. The
13C NMR spectrum of compound 21 shows a characterꢀ
istic doublet for the C(3) atom because of a spinꢀspin
Experimental
1
H and 13C NMR spectra were recorded on a Varian
Unity 400 spectrometer (400 (1H) and 100 MHz (13C)) in
DMSOꢀd6 with Me4Si as the internal standard. Mass spectra
(EI and CI) were recorded on a SSQꢀ710 FinniganꢀMAT inꢀ
strument (direct inlet probe, ionizing voltage 70 eV, ionization
chamber temperature 150 °C). Melting points were determined
on a Boetius hot stage.
coupling with the aromatic H(1) proton (3JC(3),H(1)
=
13.4 Hz).
Compound 21 readily undergoes dehydrogenation
(Scheme 9). For instance, even on heating in acetic acid
(80 °C, 1.5 h), its degree of dehydrogenation was 10%
1
(the H NMR spectrum of compound 23 is given in
Experimental). A mixture of compounds 23 and 21
(83 and 17%, respectively) was obtained by vacuum subliꢀ
mation of compound 21 at 260—265 °C.
The physicochemical constants and yields of the compounds
obtained are summarized in Table 5; their spectroscopic characꢀ
teristics are given in Tables 1—4 and 6.
Lactim ethers were prepared as described earlier.4
3ꢀ(N,NꢀDimethylamino)methylideneꢀ1,2,3,4ꢀtetrahydroꢀ
quinolinꢀ2ꢀone (3). A mixture of 1,2,3,4ꢀtetrahydroquinolinꢀ2ꢀ
one (1) (0.74 g, 5 mmol), N,Nꢀdimethylformamide diethyl acetal
(2) (10 mL), and piperidine (0.05 mL) was refluxed for 5 h and
kept at ~20 °C for 15 h. The precipitate of compound 3 that
formed was filtered off.
Scheme 9
Transamination of compound 3 with benzylamine. A mixture
of compound 3 (0.4 g, 2 mmol) and benzylamine (0.32 g, 3 mmol)
was refluxed in toluene (10 mL) for 3 h. The solvent was reꢀ
moved in vacuo and the residue was triturated with light petroꢀ
leum and dissolved in ethyl acetate. The solution was filtered
and cooled. The resulting precipitate of 3ꢀ(benzylamino)methylꢀ
ideneꢀ1,2,3,4ꢀtetrahydroquinolinꢀ2ꢀone (7) and 3ꢀ(benzylꢀ
amino)methylꢀ2ꢀhydroxyquinoline (8) was filtered off, m.p.
160—163 °C.
`2ꢀDicyanomethylideneꢀ1,2,3,4ꢀtetrahydroquinoline (10a),
2ꢀdicyanomethylideneꢀ1Hꢀ2,3,4,5ꢀtetrahydrobenz[b]azepine
(10b), 2ꢀ(1ꢀcarbamoylꢀ1ꢀcyanomethylidene)ꢀ1,2,3,4ꢀtetrahydroꢀ
quinoline (11a), 2ꢀ(1ꢀcarbamoylꢀ1ꢀcyanomethylidene)ꢀ1Hꢀ
2,3,4,5ꢀtetrahydrobenz[b]azepine (11b), and 2ꢀ(1ꢀcyanoꢀ1ꢀ
ethoxycarbonylmethylidene)ꢀ1,2,3,4ꢀtetrahydroquinoline (12)
(general procedure). A mixture of lactim ether 9a or 9b and an
appropriate cyanoacetic acid derivative in the molar ratio 1 : 1
was heated with removal of liberated ethanol at 95—100
(for 10a), 120—125 (10b), 165—170 (11a), 170—175 (11b), and
225—230 °C (12) until the reaction was completed (ceasing of
the removal). The reaction mixture was cooled and washed with
ether to give compounds 10a,b and 11a,b. In the case of comꢀ
pound 12, the reaction mixture was cooled, the precipitate was
triturated with light petroleum, and the product was extracted
A reaction of compound 21 with acetal 2 gave
amidine 24 (see Scheme 9). Its attempted highꢀpressure
cyclization by heating in a methanolic solution of ammoꢀ
nia failed: a 3 : 2 mixture of compounds 21 and 23 was
isolated. Obviously, the reaction is accompanied by elimiꢀ
nation of N,Nꢀdimethylformamidine (Scheme 10).
To sum up, we found that the lactim ethers of 3,4ꢀdiꢀ
hydrocarbostyril and, to a lesser degree, 1Hꢀ2,3,4,5ꢀtetraꢀ
hydrobenz[b]azepinꢀ2ꢀone are convenient starting reꢀ
agents for various heterocyclization reactions. Based on
them, we discovered a new route to benzonaphthyridines
and pyridobenzazepines.

1038
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Golovko et al.
Table 5. Yields, melting points, and elemental analysis data for
compounds 3, 10a,b, 11a,b, 12, 14a,b, 15, 16a,b, 17, 19, 20a—d,
21, and 24
with ether. The resulting solution was concentrated to 1/3 of the
initial volume and cooled and the precipitate of compound 12
that formed was filtered off.
2ꢀDicyanomethylideneꢀ3ꢀdimethylaminomethylideneꢀ1,2,3,4ꢀ
tetrahydroquinoline (14a). A mixture of compound 10a (0.58 g,
3 mmol) and acetal 2 (0.53 g, 3.6 mmol) was stirred in toluene
(15 mL) at 90 °C for 30 min. Then an additional portion of
acetal 2 (0.3 g) was added and stirring was continued for 40 min.
The reaction mixture was cooled to 0 °C and the precipitate
of quinoline 14a that formed was filtered off. 13C NMR
(DMSOꢀd6), δ: 26.7 (C(4)); 38.6 (C(2´)); 43.8 (NMe2); 89.6
(C(3)); 117.1, 123.9, 127.3, 127.8 (C(5)—C(8)); 120.1 (CN);
124.8 (C(4a)); 136.0 (C(8a)); 153.3 (C(3´)); 164.1 (C(2)).
2ꢀDicyanomethylideneꢀ3ꢀdimethylaminomethylideneꢀ1Hꢀ
2,3,4,5ꢀtetrahydrobenz[b]azepine (14b). A mixture of compound
10b (1.04 g, 5 mmol), acetal 2 (5 mL), and a catalytic amount of
piperidine was heated at 80—90 °C for 30 min. The reaction
mixture was concentrated, the residue was successively trituꢀ
rated with light petroleum and ether—ethyl acetate, and the
precipitate of benzazepine 14b was filtered off.
2ꢀ{1ꢀCyanoꢀ1ꢀ[(dimethylamino)methylideneaminocarboꢀ
nyl]methylidene}ꢀ1,2,3,4ꢀtetrahydroquinoline (15). A mixture of
compound 11a (2.6 g, 12.2 mmol) and acetal 2 (2.14 g,
14.6 mmol) was refluxed in methanol (30 mL) for 1 h and then
with an additional portion of acetal 2 (0.5 g) for 2 h. The reacꢀ
tion mixture was filtered and cooled to ~15 °C. The precipitate
of quinoline 15 that formed was filtered off.
Hydrolysis of compound 15. Compound 15 (0.15 g, 0.7 mmol)
was refluxed in water (20 mL) for 30 min and filtered. On coolꢀ
ing, the precipitate of compound 11a that formed was filtered off.
Extraction from the aqueous mother liquor with chloroform
gave an additional crop of compound 11a.
4ꢀCyanoꢀ3ꢀoxoꢀ2,3,5,10ꢀtetrahydrobenzo[b][1,6]naphthyriꢀ
dine (16a). A. A mixture of compound 14a (9.77 g, 31.1 mmol)
and glacial acetic acid (115 mL) was stirred at 85—90 °C for 4 h.
On cooling, the precipitate of compound 16a was filtered off
and washed with water and isopropyl alcohol.
Comꢀ Yield
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
N
poꢀ
(%)
und
C
H
3
22
90
91
97
90
23
67
34
52
83
202—205
(AcOEt)
71.19 7.20 13.74 C12H14N2O
71.26 6.98 13.85
10а
10b
11a
11b
12
233—234
(PriOH)
73.90 4.61 21.45 C12H9N3
73.83 4.65 21.53
229—230
(MeOH)
217—220a
(ЕtOH)
74.64 5.51 20.37 C13H11N3
74.62 5.30 20.08
67.37 5.20 19.48 C12H11N3O
67.59 5.20 19.71
160—165
(PriOH)
68.53 6.00 18.07 C13H13N3O
68.70 5.77 18.49
88—92
(Et2O)
69.50 6.00 11.32 C14H14N2O2
69.40 5.83 11.56
14a
14b
15
226—229
(PriOH)
72.00 5.67 22.44 C15H14N4
71.98 5.64 22.38
138—142
(PriOH)
72.43 6.45 20.98 C16H16N4
72.70 6.10 21.20
168—172
(PriOH)
66.86 6.02 20.80 C15H16N4O
67.14 6.01 20.88
16ab
>270
68.59 4.33 18.73 C13H9N3O•
(DMF—H2O, 68.56 4.21 18.75 •0.25 H2O
1 : 1)
16b
81
>270
70.94 4.77 17.75 C14H11N3O
(DMF—H2O, 70.87 4.67 17.71
1 : 1)
17
76
91
91
65
52
228—230
(MeCN)
245—249a
(MeCN)
70.86 4.68 17.64 C14H11N3O
70.87 4.67 17.71
B. Compound 15 (0.06 g) was heated at 185—190 °C for
45 min. The reaction mixture was triturated with isopropyl alcoꢀ
hol and the precipitate of quinolone 16a was filtered off.
4ꢀCyanoꢀ3ꢀoxoꢀ2Hꢀ3,5,10,11ꢀtetrahydrobenzo[ f ]pyriꢀ
do[4,3ꢀb]azepine (16b) was obtained analogously from comꢀ
pound 14b (method A, 95—100 °C, 4.5 h).
19 c
20a
20b
20c
64.44 3.42 17.47 C13H8ClN3
64.61 3.34 17.39
216—219
(MeCN)
76.43 5.32 18.21 C20H16N4
76.90 5.16 17.94
154—156
(AcOEt)
71.62 5.88 14.00 C23H22N4O2
71.48 5.74 14.50
4ꢀCyanoꢀ3ꢀmethoxyꢀ5,10ꢀdihydrobenzo[b][1,6]naphthyriꢀ
dine (17). Compound 14a (0.625 g, 2.5 mmol) was refluxed for
1.5 h in a methanolic solution of sodium methoxide prepared
from metallic sodium (0.06 g) and methanol (10 mL). On coolꢀ
108—110
(aqueous
45% PriOH)
70.92 7.15 21.75 C19H23N5
71.00 7.21 21.79
ing, the precipitate of compound 17 was filtered off. 13C NMR
1
(DMSOꢀd6), δ: 26.4 (split t, C(10)); 54.2 (q, OMe, JC,H
=
20d
21
53
59
90
126—129
(heptane)
260—263a
(МеОН)
73.26 6.34 20.02 C17H18N4
73.35 6.52 20.13
147.3 Hz); 77.5 (s, C(4)); 110.4 (m, C(10a)); 114.5 (s, CN);
120.2 (m, C(9a)); 116.2, 123.1, 127.6, 129.8 (C(6)—C(9)); 137.0
(t, C(5a)); 148.6 (dt, C(1), 1JC,H = 178.5 Hz); 150.6 (d, C(4a));
164.2 (m, C(3)).
3ꢀChloroꢀ4ꢀcyanoꢀ5,10ꢀdihydrobenzo[b][1,6]naphthyridine
(19). A mixture of compound 16a (7.2 g, 32.3 mmol), triethylꢀ
amine hydrochloride (3.82 g, 27.3 mmol), and POCl3 (65 mL)
was refluxed for 6 h. On cooling, the precipitate of compound 19
was filtered off and washed successively with water, aqueous
K2CO3, again water, and isopropyl alcohol.
70.10 4.49 25.35 C13H10N4
70.25 4.54 25.21
24
252—254
(MeCN)
69.27 5.35 25.00 C16H15N5
69.29 5.45 25.25
a Decomp.
b Found (%): H2O, 1.83. Calculated (%): H2O, 1.98.
c Found (%): Cl, 14.72. Calculated (%): Cl, 14.67.

Benzonaphthyridines and pyridobenzazepines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1039
Table 6. Selected mass spectra of the compounds obtained
Comꢀ
pound
MS, m/z
(Irel (%))
7 + 8a
11аb
11b
264 [M1]+ (10), 263 [M1 – H]+ (11), 262 [M2]+ (12), 261 [M2 – H]+ (13), 173 [M1 – CH2Ph]+ (20),
171 [M2 – CH2Ph]+ (22), 159 [PhCH2NHCH=C=C=O]+ (25), 106 [PhCH2NH2]+ (18),
91 [CH2Ph]+ (100), 65 [C5H5]+ (20)
213 [M]+ (100), 196 [M – NH3]+ (87), 195 [M – H2O]+ (42), 168 [M – NH3 – CO]+ (30),
167 [M – NH3 – HCO]+ (18), 140 [M – NH3 – HCO – HCN]+ (16), 130 [M – CNCHCONH2]+ (18),
106 [CH2C6H4NH2]+ (7), 77 [C6H5]+ (10)
227 [M]+ (81), 210 [M – NH3]+ (100), 181 [M – NH3 – HCO]+ (20), 154 [M – NH3 – HCO – HCN]+ (10),
144 [M – СN – CНСОNH2]+ (26), 127 [M – NH3 – HCO – 2 HCN]+ (8), 106 [CH2C6H4NH2]+ (8),
91 [C6H4NH]+ (9)
14a
250 [M]+ (100), 235 [M – CH3]+ (13), 220 [M – 2 CH3]+ (10), 207 [M – CH2NCH3]+ (83),
206 [M – NMe2]+ (52), 193 [M – CHNMe2]+ (20), 185 [M – CH(CN)2]+ (40), 179 [M – NMe2 – HCN]+
(57), 152 [M – NMe2 – 2 HCN]+ (10), 140 [M – NMe2 – C3H2N2]+ (8), 128 [M – NMe2 – C4H2N2]+ (8)
264 [M]+ (82), 249 [M – CH3]+ (8), 236 [M – C2H4]+ (10), 221 [M – CH2=NCH3]+ (18),
220 [M – NMe2]+ (24), 207 [M – CHNMe2]+ (6), 199 [M – CH(CN)2]+ (100), 193 [M – NMe2 – HCN]+
(12), 106 [CH2C6H4NH2]+ (22), 82 [CH≡C—CH=NMe2]+ (23)
14bc
15d
268 [M]+ (96), 242 [M – CN]+ (5), 224 [M – NMe2]+ (36), 197 [M – N=CHNMe2]+ (20),
196 [M – NH=CHNMe2]+ (33), 168 [M – CONHCHNMe2]+ (20), 141 [M – CONHCHNMe2 – HCN]+ (15),
140 [M – CONHCHNMe2 – C2H4]+ (32), 130 [M – CNCHCONCHNMe2]+ (20), 99 [CON=CHNMe2]+ (100),
73 [H2N+=CHNMe2] (96)
16a
223 [M]+ (23), 222 [M – H]+ (53), 194 [M – H – CO]+ (10), 167 [M – CONHCH]+ (20),
140 [M – CONHCH – HCN]+ (37), 128 [M – CHNHCOCHCN]+ (10), 113 [M – CONHCH – 2 HCN]+ (12),
101 [M – CHNHCOCHCN – HCN]+ (11), 89 [C7H5]+ (23), 77 [C6H5]+ (50), 76 [C6H4]+ (60),
66 [O=C=C+—C≡N]+ (47), 63 [C5H3]+ (66), 52 [CH=CH—CN]+ (100)
16be
17
237 [M]+ (100), 236 [M – H]+ (62), 222 [M – CH3]+ (13), 208 [M – H – CO]+ (10), 182 [M – CO – HCN]+
(10), 181 [M – H – CO – HCN]+ (13), 154 [M – CH – NHCO – HCN]+ (8)
237 [M]+ (56), 236 [M – H]+ (100), 222 [M – CH3]+ (5), 193 [M – H – COCH3]+ (10),
181 [M – OCH2 – CN]+ (6), 140 [M – CHNCOCH3 – HCN]+ (6)
19f
241 [M]+ (60), 240 [M – H]+ (100), 204 [M – H – HCl]+ (10), 177 [M – H – HCl – HCN]+ (16),
153 [M – N≡CCl – HCN]+ (10), 103 [C8H7]+ (15), 89 [C7H5]+ (12), 76 [C6H4]+ (10)
312 [M]+ (100), 311 [M – H]+ (85), 235 [M – Ph]+ (8), 207 [M – NH=CHPh]+ (12), 206 [M – NHCH2Ph]+
(19), 179 [M – NHCH2Ph – HCN]+ (8), 156 [M – CN – C≡C – NHCH2Ph]+ (9), 106 [NHCH2Ph]+ (48),
91 [CH2Ph]+ (45), 65 [C5H5]+ (10)
20a
24
277 [M]+ (100), 276 [M – H]+ (48), 262 [M – CH3]+ (52), 233 [M – NMe2]+ (15), 221 [M – NC3H6]+ (40),
207 [M – C3H6N2]+ (21), 206 [M – C3H7N2]+ (20), 179 [M – C3H7N2 – HCN]+ (12)
a The mixture was obtained as the result of transamination of compound 3. The peaks with M1 and M2 relate to products 7 and 8,
respectively; the other signals are shared by both compounds.
b The spectrum also contains a peak with m/z 143 (1).
c CIMS, m/z: 265 [MH]+.
d Evaporation of the sample upon an increase in the temperature gives rise to peaks with m/z 223 ([M´]+) and 196 ([M´ – HCN]+);
the intensity of the latter increases from 33 to 100%. Apparently, they are due to thermal transformations of compound 15 in the
mass spectrometer.
e The spectrum also contains a peak with m/z 255 ([M]+) due to hydrolysis of the CN group of compound 16b.
f For chlorineꢀcontaining fragments, the mass numbers of 35Clꢀcontaining ions are given.
3ꢀBenzylaminoꢀ4ꢀcyanoꢀ5,10ꢀdihydrobenzo[b][1,6]naphꢀ
thyridine (20a). A mixture of compound 19 (0.6 g, 2.48 mmol)
and benzylamine (1.96 g, 18.3 mmol) was heated at 115 °C for
1.5 h. The reaction mixture was diluted with water and the
precipitate of compound 20a was filtered off.
4ꢀCyanoꢀ3ꢀ[2ꢀ(3,4ꢀdimethoxyphenyl)ethylamino]ꢀ5,10ꢀdiꢀ
hydrobenzo[b][1,6]naphthyridine (20b). A mixture of comꢀ
pound 19 (0.5 g, 2.06 mmol) and homoveratrylamine (3 g,
16.6 mmol) was heated at 165—170 °C for 2 h. The reaction
mixture was cooled and triturated with heptane and isopropyl
alcohol to give compound 20b.
4ꢀCyanoꢀ3ꢀ[2ꢀ(diethylamino)ethylamino]ꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (20c). A mixture of compound 19 (0.5 g,
2.06 mmol) and βꢀdiethylaminoethylamine (2 g, 17.2 mmol)
was heated at 150 °C for 30 min. The reaction mixture was
cooled and washed with water. The product was extracted with
chloroform. The organic layer was dried over Na2SO4 and conꢀ
centrated in vacuo. The residue was triturated with light petroꢀ
leum and the precipitate of compound 20c was filtered off.
3ꢀButylaminoꢀ4ꢀcyanoꢀ5,10ꢀdihydrobenzo[b][1,6]naphthyriꢀ
dine (20d). A mixture of compound 19 (0.5 g, 2.06 mmol) and
butylamine (10 mL) was heated in a closed steel vessel at

1040
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Golovko et al.
110—120 °C for 4.5 h. The reaction mixture was concentrated
and washed with water. The product was extracted from the
residue with chloroform. The extract was dried over Na2SO4
and concentrated. Recrystallization of the residue from heptane
gave compound 20d.
3ꢀAminoꢀ4ꢀcyanoꢀ5,10ꢀdihydrobenzo[b][1,6]naphthyridine
(21). A. Compound 14a (0.25 g, 1 mmol) and a saturated soluꢀ
tion of ammonia in methanol (15 mL) were stirred at 20 °C for
12 h. The precipitate of compound 21 was filtered off. 13C NMR
(DMSOꢀd6), δ: 26.4 (split t, C(10)); 73.5 (br.s, C(4)); 104.5 (m,
C(10a)); 116.1 (s, CN); 120.6 (m, C(9a)); 116.2, 122.7, 127.4,
128.8 (C(6)—C(9)); 137.7 (m, C(5a)); 149.9 (m, C(4a)); 151.2
(dt, C(1), 1JC,H = 173.0 Hz); 160.9 (d, C(3)).
4ꢀCyanoꢀ3ꢀ[(dimethylamino)methylidene]aminoꢀ5,10ꢀdiꢀ
hydrobenzo[b][1,6]naphthyridine (24). A mixture of comꢀ
pound 21 (0.4 g, 1.8 mmol) and acetal 2 (0.5 g, 3.4 mmol) was
refluxed in stirred toluene (15 mL) for 6 h, while adding acetal
(0.5 mL) every 2 h. On cooling, the precipitate of compound 24
was filtered off.
Reaction of compound 24 with a saturated solution of ammoꢀ
nia in methanol. Compound 24 (0.35 g, 1.26 mmol) and a satuꢀ
rated solution of ammonia in methanol (35 mL) were heated in
a closed steel vessel at 105—110 °C for 7 h. On cooling, the
precipitate was filtered off and recrystallized from DMF (18 mL).
A mixture of compounds 21 (60%) and 23 (40%) was obtained
(1H NMR). The total yield was 0.14 g.
B. Compound 14a (6 g, 24 mmol) and a saturated solution
of ammonia in methanol (200 mL) were heated in a closed steel
vessel 50 °C for 5.5 h. The precipitate of compound 21 was
filtered off.
References
1. T. V. Golovko, N. P. Solov´eva, and V. G. Granik,
Khim.ꢀFarm. Zh., 1996, 30, No. 10, 32 [Pharm. Chem. J.,
1996, 30, No. 10, 637 (Engl. Transl.)].
2. V. G. Granik, N. I. Smetskaya, N. A. Mukhina, I. V.
Persianova, and V. G. Klimenko, Khim. Geterotsikl. Soedin.,
1983, 1279 [Chem. Heterocycl. Compd., 1983, 19 (Engl.
Transl.)].
3. V. G. Granik, Usp. Khim., 1982, 51, 207 [Russ. Chem. Rev.,
1982, 51 (Engl. Transl.)].
4. R. G. Glushkov and V. G. Granik, Adv. Heterocycl. Chem.,
1970, 12, 185.
Dehydrogenation of compound 21. A. A mixture of comꢀ
pound 21 (0.25 g, 1.13 mmol) and glacial acetic acid (6 mL) was
heated at 80 °C for 1.5 h. On cooling, the precipitate that formed
was filtered off. According to 1H NMR data, the precipitate
contained compound 21 (90%) and 3ꢀaminoꢀ4ꢀcyanobenꢀ
1
zo[b][1,6]naphthyridine (23) (10%). Compound 23. H NMR,
δ: 7.52 (t, 1 H, H(8), 3J = 8.8 Hz); 7.84 (br.s, 2 H, NH2); 7.90 (t,
3
3
1 H, H(7), J = 8.8 Hz); 8.00 (d, 1 H, H(6), J = 8.8 Hz); 8.12
(d, 1 H, H(9), 3J = 8.8 Hz); 9.20 (s, 1 H, H(10)); 9.40
(s, 1 H, H(1)).
B. Compound 21 (0.9 g, 4.05 mmol) was sublimed in vacuo
(15 Torr) at 260—265 °C. A mixture of compounds 21 (17%)
and 23 (83%) was obtained (1H NMR).
Received December 22, 2006;
in revised form February 28, 2007