Functionalization of benzo[b][1,6]naphthyridine derivatives

Article abstract of DOI:10.1023/A:1024725811506

Two routes to consecutive functionalization of 3-chloro-4-cyanobenzo[b][1, 6]naphthyridine (1a) at positions 3 and 10 were developed. Oxidation of compound 1a with m-chloro-perbenzoic acid in acetone leads to 3-chloro-4-cyano-10-oxobenzo[b][1,6]naphthyrid

Full text of DOI:10.1023/A:1024725811506

1182
Russian Chemical Bulletin, International Edition, Vol. 52, No. 5, pp. 1182—1189, May, 2003
Functionalization of benzo[b][1,6]naphthyridine derivatives
ꢀ
A. S. Ivanov, N. Z. Tugusheva, L. M. Alekseeva, and V. G. Granik
The State Scientific Center of the Russian Federation
"Scientific Research Institute of Organic Intermediates and Dyes" (NIOPIK),
1/4 ul. B. Sadovaya, 123995 Moscow, Russian Federation.
Fax: +7 (095) 254 6574. Eꢀmail: aivanov@email.ru
Two routes to consecutive functionalization of 3ꢀchloroꢀ4ꢀcyanobenzo[b][1,6]naphthyriꢀ
dine (1a) at positions 3 and 10 were developed. Oxidation of compound 1a with mꢀchloroꢀ
perbenzoic acid in acetone leads to 3ꢀchloroꢀ4ꢀcyanoꢀ10ꢀoxobenzo[b][1,6]naphthyridine, while
in acetic acid, the reaction gives 3ꢀchloroꢀ4ꢀcyanoꢀ10ꢀ(3ꢀchlorobenzoyloxy)ꢀ5ꢀhydroxyꢀ5,10ꢀ
dihydrobenzo[b][1,6]naphthyridine. The reactions of 1a with some Cꢀnucleophiles give
σꢀadducts at position 10. The reactions of N,Nꢀdimethylamide acetals with chloride 1a leads to
4ꢀcyanoꢀ3ꢀdimethylaminobenzo[b][1,6]naphthyridine.
Key words: benzo[b][1,6]naphthyridines, nucleophilic addition to πꢀdeficient azines, oxiꢀ
dation, Thorpe—Ziegler cyclization, hetarylation of amide acetals.
Previously, it was shown1 that 3ꢀchloroꢀ4ꢀcyanoꢀ
benzo[b][1,6]naphthyridine (1a) reacts with various Sꢀ,
Cꢀ, and Nꢀnucleophiles to give σꢀadducts 2 at position 10
(Scheme 1).
AcOH). When oxidation with MCPBA was carried out at
∼20 °C in AcOH, compound 4 was isolated in a moderate
1
yield. In addition, as shown by H NMR spectroscopy,
the mother liquor contained 10ꢀacetoxyꢀ3ꢀchloroꢀ4ꢀ
cyanoꢀ5ꢀhydroxyꢀ5,10ꢀdihydrobenzo[b][1,6]naphthyriꢀ
dine (5), which we described previously,1 and tricyclic
derivative 3 (Scheme 2).
Scheme 1
Scheme 2
It is known2 that σꢀadducts formed by nucleophiles
with noncharged azines are unstable and, as a rule, they
can be detected only by physical methods at low temperaꢀ
tures. However, σꢀadducts 2 prove to be rather stable and
can be isolated and identified. This indicates that their
formation is not very unfavorable from the energy standꢀ
point, and the addition at position 10 of the tricyclic
system 1a may underlie a convenient synthetic strategy
for further functionalization of this system. The purpose
of this study is to explore the possibility of the synthesis of
3,10ꢀdisubstituted 4ꢀcyanobenzo[b][1,6]naphthyridines
with different substituents in these positions of the rings.
The oxidation of compound 1a with mꢀchloroperꢀ
benzoic acid (MCPBA) on refluxing in acetone was studꢀ
ied. This reaction gave 10ꢀoxo derivative 3 in a good yield
(previously,1 we described the preparation of this comꢀ
pound in a 0.4% yield by oxidation of 1a with H2O2 in
To elucidate the reasons of this crucial dependence of
the oxidation route of compound 1a on the properties of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1120—1126, May, 2003.
1066ꢀ5285/03/5205ꢀ1182 $25.00 © 2003 Plenum Publishing Corporation

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 5, May, 2003
1183
the medium, a special investigation is required, which is
planned for the future.
On refluxing in POCl3 in the presence of Et3N•HCl,
the oxo group in compound 3 was replaced by a Cl atom,
which afforded 3,10ꢀdichloroꢀ4ꢀcyanobenzo[b][1,6]naphꢀ
thyridine (11) (Scheme 4). It is noteworthy that recording
The structure of compound 3 shows that it can react
with nucleophiles at position 3, while position 10 would
remain intact. Subsequently, position 10 can be activated,
for example, by transforming the obtained compounds
into 10ꢀchloro derivatives, which could provide a pathway
to 3,10ꢀdisubstituted derivatives of the system under study.
At the first stage, it was shown that the Cl atom in position
3 of compound 3 can be smoothly replaced by amino
groups to give 3ꢀamino derivatives 6a—c (Scheme 3). On
refluxing with hydrazine hydrate, the Cl atom is replaced
by the hydrazine residue, which is followed by cyclization
of the intermediate hydrazine 7 involving the nitrile group
and giving rise to 1ꢀaminoꢀ6ꢀoxoꢀ3,11ꢀdihydroꢀ6Hꢀ
benzo[b]pyrazolo[3,4ꢀh][1,6]naphthyridine (8). 1ꢀAminoꢀ
2ꢀethoxycarbonylꢀ6ꢀoxoꢀ6,11ꢀdihydrobenzo[b]thieꢀ
no[2,3ꢀh][1,6]naphthyridine (9) was prepared by refluxꢀ
ing compound 3 with methyl mercaptoacetate in the
presence of MeONa as a basic catalyst. By analogy
with the synthesis of 2ꢀsubstituted 1ꢀaminobenzo[b]thieꢀ
no[2,3ꢀh][1,6]naphthyridines,1 it can be assumed that the
thiolate anion attacks position 3 to yield 3ꢀmethoxyꢀ
carbonylmethylthio derivative 10, which subsequently unꢀ
dergoes the Thorpe—Ziegler cyclization3 to give tetracyclic
product 9.
1
the H NMR spectrum in DMSOꢀd6 containing a small
amount of water resulted in hydrolysis of compound 11 to
the initial tricyclic structure 3. This indicates that the Cl
atom in position 10 possesses a higher mobility than the
3ꢀCl atom. Due to the low solubility of compounds 3
and 11 in other solvents (CDCl3, CD2Cl2, C6D6), lowꢀ
polar solvents cannot be used for recording the spectra.
Therefore, the purity of product 11 was established relyꢀ
ing on TLC, IR spectroscopy, and mass spectrometry. In
the resulting dichloroꢀsubstituted compound 11, both Cl
atoms are readily substituted by piperidine residues, which
gives rise to bisꢀamino derivative 12 with identical subꢀ
stituents in positions 3 and 10 (see Scheme 4).
We also attempted to obtain benzo[b][1,6]naphthyriꢀ
dine derivatives containing different substituents in posiꢀ
tions 3 and 10. To this end, the oxo group in position 10
of compound 6а was replaced by chlorine on refluxing the
starting compound in POCl3 in the presence of Et3N•HCl
with subsequent evaporation of POCl3 in vacuo and treatꢀ
ment of the resulting chloroxide complex4 with a sodium
carbonate solution. As expected, the product isolated
in this way was 10ꢀchloroꢀ3ꢀpiperidinoꢀ4ꢀcyanobenꢀ
Scheme 3

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 5, May, 2003
Ivanov et al.
Scheme 4
zo[b][1,6]naphthyridine (13). In this compound, as in 11,
the Cl atom in position 10 is rather active and susceptible
for hydrolysis, which affords the starting tricyclic comꢀ
pound 6а. The reaction of compound 13 with morpholine
yielded 10ꢀmorpholino derivative 14. In addition, prodꢀ
uct 13 was converted into bis(piperidine) derivative 12 by
an alternative synthetic route (see Scheme 4).
pared by an alternative protocol, i.e., by the reaction of
chloro derivative 1a with dimethylamine (Scheme 6).
Scheme 6
Another approach to the synthesis of 3,10ꢀdisubstiꢀ
tuted benzo[b][1,6]naphthyridines was also studied. Now
the goal was to introduce a heteronucleophile (e.g., amino
or mercapto group) in position 3 and a Cꢀnucleophile in
position 10. As previously,1 the synthetic strategy was
based on the possibility of formation of σꢀcomplexes at
position 10 of the benzonaphthyridine molecule, but
Cꢀnucleophiles were employed as the reagents.
The first nucleophiles chosen were dimethyl and diꢀ
ethyl acetals of N,Nꢀdimethylacetamide (15a,b), which
are known5 to behave as enamines in various reactions
due to the ternary equilibrium (Scheme 5).
Scheme 5
R = Me (a), Et (b, c); R´ = Me (a, b), H (c)
The alkylation of amide acetals is known6 to involve
the N atom. Since the Cl atom in compound 1a is quite
mobile due to the presence of the electronꢀwithdrawing
cyano group and the fused quinoline ring, one can assume
that arylation of amide acetals by chloro derivative 1a
would also follow this route giving intermediates 19a—c.
The reaction of chloride 1a and acetal 15b proceeding
according to this pattern should be accompanied by ethyl
acetate evolution; this was really established by GLC (see
Scheme 6).
Since the attempt of using acetals 15a,b as enamꢀ
ines has not met with success, we used indole as the
Cꢀnucleophile. This compound is known to exhibit propꢀ
erties of an enamine in many respects.7 It was found
that refluxing compound 1a with indole in PriOH furꢀ
R = Me (a), Et (b)
However, the reaction between acetals 15a,b and triꢀ
cyclic compound 1a gave an unexpected result. 3ꢀDiꢀ
methylamino derivative 17 was formed as the only prodꢀ
uct. In order to verify whether αꢀalkoxyenamine 16 parꢀ
ticipates in this unusual transformation, a similar reaction
was carried out with DMF diethyl acetal (18). In this
case, too, compound 17 was isolated in a high yield. For
confirming the structure, this compound was also preꢀ

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 5, May, 2003
1185
Scheme 7
R = Cl (a), SPh (b); X =
(a), SPh (b)
nishes the σꢀadduct whose structure is described as
3ꢀchloroꢀ4ꢀcyanoꢀ10ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ5,10ꢀdihydroꢀ
benzo[b][1,6]naphthyridine (20a) (Scheme 7). 4ꢀ Cyanoꢀ
3ꢀphenylthiobenzo[b][1,6]naphthyridine (1b), reported in
our previous publication,1 does not react with indole unꢀ
der these conditions; however, when the conditions are
made more drastic (refluxing in BunOH), σꢀadduct 20b
appears. In compounds 20a,b, position 3 of indole molꢀ
ecule is linked to position 10 of the initial compounds
(1Hꢀindolꢀ3ꢀyl)ꢀ3ꢀmorpholinobenzo[b][1,6]naphthyriꢀ
dine (23а), while the reaction with benzenethiol in the
presence of AcONa gave rise to 4ꢀcyanoꢀ10ꢀ(1Hꢀindolꢀ
3ꢀyl)ꢀ3ꢀphenylthiobenzo[b][1,6]naphthyridine (23b) (see
Scheme 7).
Thus, new approaches to the synthesis of 3,10ꢀfuncꢀ
tionally substituted benzo[b][1,6]naphthyridines with eiꢀ
ther identical or different substituents in positions 3 and
10 have been developed on the basis of nucleophilic addiꢀ
tion to the electronꢀdeficient C atom in a πꢀdeficient
aromatic system.
1
1a,b (see Scheme 7), which was proved by H NMR
spectroscopy. The spectra exhibit a doublet correspondꢀ
ing to the indole fragment, which can be assigned to the
H(2´) atom relying on the chemical shifts (δ 7.20 and
7.16) and spinꢀspin coupling constant (J = 2.4—2.7 Hz).8
The reaction of compound 1a with dimedone (refluxing
in PriOH) was also studied. This reaction results in the
corresponding σꢀadduct having the structure of 3ꢀchloroꢀ
4ꢀcyanoꢀ10ꢀ(2ꢀhydroxyꢀ4,4ꢀdimethylꢀ6ꢀoxoꢀ1ꢀcycloꢀ
hexenyl)ꢀ5,10ꢀdihydrobenzo[b][1,6]naphthyridine (21)
(see Scheme 7).
In order to prepare a fully aromatic compound conꢀ
taining an indole residue in position 10, σꢀadduct 20a had
to be oxidized. For this purpose, the adduct was reꢀ
fluxed with K3[Fe(CN)6] in aqueous PriOH, which gave
3ꢀchloroꢀ4ꢀcyanoꢀ10ꢀ(1Hꢀindolꢀ3ꢀyl)benzo[b][1,6]naphꢀ
thyridine (22), in which the active Cl atom in position 3 is
retained (see Scheme 7). The use of [Ag(Py)2]MnO4 as a
mild oxidant in this reaction7,9 also led to product 22.
Compound 22 reacts with nucleophilic reagents; this
was used to prepare derivatives having other 3ꢀsubstituꢀ
ents. The reaction with morpholine gave 4ꢀcyanoꢀ10ꢀ
Experimental
IR spectra were recorded on a Perkin—Elmer 457 instruꢀ
ment in mineral oil, mass spectra (EI) were run on a Finnigan
SSQꢀ710 mass spectrometer with direct sample injection into
the ion source. The 1H NMR spectra were measured on a Varian
Unity 400 and Bruker АCꢀ200 spectrometers in DMSOꢀd6. The
reactions were monitored and the purity of the compounds was
checked by TLC on Silufol UVꢀ254 plates (using AcOEt for
elution and UV light for visualization). Melting points were
determined on a Electrothermal 9100 instrument (UK). Physiꢀ
cochemical characteristics and the data of elemental analysis
for the synthesized compounds are listed in Table 1 and the
1H NMR spectra are in Table 2. In the synthesis of compounds 3
and 4, 50—55% MCPBA (Lancaster) was used containing 10%
of mꢀchlorobenzoic acid and water.
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀoxoꢀ5,10ꢀdihydrobenzo[b][1,6]naphꢀ
thyridine (3). 50% MCPBA (15 g) was added in portions over a
period of 18 h to a suspension of compound 1a (6 g, 25.1 mmol)
in 200 mL of acetone stirred at reflux. Then the mixture was
refluxed for additional 5 h. Acetone was evaporated to 2/3 its

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Ivanov et al.
Table 1. Melting points and elemental analysis data for compounds 4, 6a—c, 8, 9, 11, 12, 14, 17, 20—23
Comꢀ
pound
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
N
C
H
S (Cl)*
4
242—243.5
(benzene)
58.36
58.27
2.76
2.69
10.21
10.20
16.89
17.20
C20H11Cl2N3O3
C18H16N4O
C17H14N4O2
C22H16N4O
C13H9N5O
6a
6b
6c
8
270—271.5
(BuOH)
71.28
71.03
5.39
5.30
18.29
18.41
—
—
—
—
281—282.5
(PriOH)
66.60
66.65
4.60
4.61
18.26
18.29
288.5—289.5
(DMF)
75.26
74.98
4.67
4.58
15.96
15.90
>400
(DMF)
61.80
62.14
3.62
3.61
27.46
27.88
9
278.5—279.5
(AcOH)
59.38
59.07
3.36
3.41
12.57
12.92
09.78
09.85
C16H11N3O3S
C13H5Cl2N3
C23H25N5
11
12
14
17
20a
20b
21
22
23a
23b
257—260
(acetone)
57.21
56.96
1.77
1.84
15.21
15.33
25.72
25.87
215.5—216.5
(PriOH)
74.78
74.36
6.73
6.78
19.00
18.86
—
—
—
269—270
(PriOH)
70.57
70.76
6.46
6.21
18.78
18.75
C22H23N5O
C15H12N4
210.5—212
(CH2Cl2—AcOEt)
73.11
72.56
4.83
4.87
22.46
22.57
251—251.5
(PriOH)
70.25
70.69
3.82
3.67
15.83
15.70
09.87
09.94
C21H13ClN4
C27H18N4S
C21H18ClN3O2
C21H11ClN4
C25H19N5O
C27H16N4S
218.5—219.5
(PriOH)
75.61
75.33
4.13
4.21
13.12
13.01
07.68
07.45
263—265
(DMF)
66.51
66.40
4.86
4.78
11.01
11.06
09.18
09.33
383.5—384.5
(DMF)
71.23
71.09
3.13
3.13
15.82
15.79
09.93
09.99
281—282.5
(PriOH)
73.75
74.05
4.72
4.72
17.15
17.28
—
320—323
(PriOH)
75.70
75.68
3.67
3.76
12.99
13.08
07.43
07.48
* See the molecular formula.
initial volume and the precipitate was filtered off, washed with
acetone and benzene, and dried to give product 3 as fine lightꢀ
yellow needles. Yield 4.86 g (76%). The melting point of a mixed
sample with the compound prepared by a previously described
procedure1 was undepressed. The IR spectra of both samples
were identical.
1 H, NOH). MS, m/z (Irel (%)): 412 [M]+ (7), 255 [M –
mꢀClꢀC6H4CO2H]+ (97), 239 [M – mꢀClꢀC6H4CO3H]+ (71),
220 (55), 156 [mꢀClꢀC6H4ꢀCO2]+ (55).
Synthesis of compounds 6a—c (general procedure). Comꢀ
pound 3 (1 mmol) and the corresponding amine (2 mmol) in
4 mL of DMF were stirred for 4 h at 40 °C, 10 mL of water was
added, and the precipitate was filtered off, washed with water
and ether, and dried.
4ꢀCyanoꢀ10ꢀoxoꢀ3ꢀpiperidinoꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (6a). Yield 83%. IR, ν/cm–1: 3271 (NH),
2200 (CN), 1627 (CO). MS, m/z (Irel (%)): 304 [M]+ (100), 275
[M – C2H5]+ (96), 262 [M – (CH2)3]+ (90), 249 (73), 236 (28),
221 [M – piperidine + 2 H]+ (94).
4ꢀCyanoꢀ3ꢀmorpholinoꢀ10ꢀoxoꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (6b). Yield 92%. MS, m/z (Irel (%)):
306 [M]+ (90), 275 (80), 261 (80), 249 [M – C3H5O]+ (100),
221 [M – morpholine + 2 H]+ (85).
3ꢀChloroꢀ10ꢀ(3ꢀchlorobenzoyloxy)ꢀ4ꢀcyanoꢀ5ꢀhydroxyꢀ
5,10ꢀdihydrobenzo[b][1,6]naphthyridine (4). A solution of comꢀ
pound 1a (0.25 g, 1.044 mmol) and 50% aqueous MCPBA
(0.72 g) in 10 mL of AcOH was stirred for 2 h at ∼20 °C, and the
precipitate was filtered off, washed with EtOH, and dried to give
0.12 g (28%) of benzonaphthyridine 4. 1H NMR, δ: 6.92 (d,
1 H, H(9), Jo = 7.2 Hz); 6.97 (t, 1 H, H(8), Jo = 7.2 Hz); 7.15 (t,
1
1 H, H(7), Jo = 7.2 Hz); 7.33 (s, 1 H, H(10), JC,H = 178 Hz);
7.48 (t, 1 H, H(5´), Jo = 8.0 Hz); 7.57 (d, 1 H, H(6), Jo =
7.2 Hz); 7.57 (s, 1 H, H(2´)); 7.68 (d, 2 H, H(4´), H(6´), Jo =
1
8.0 Hz); 8.48 (s, 1 H, H(1), JC,H = 186.1 Hz); 9.42 (br.s,

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 5, May, 2003
1187
Table 2. 1H NMR spectra of compounds 6а, 12, 14, 20—22, and 23b
Comꢀ
pound
δ (J/Hz)
H(1)
H arom.
C(3)ꢀR, C(10)ꢀRa
NH
(s, 1 H)
(H(6), H(7), H(8), H(9))
(br.s, 1 H)
6a
12
8.97
7.32, 7.72 (both t, 1 H each, Jo = 8.4); 1.69 (br.s, 6 H, 2 H(3´), 2 H(4´), 2 H(5´));
7.92, 8.13 (both d, 1 H each, Jo = 8.4) 3.86 (br.s, 4 H, 2 H(2´), 2 H(6´))
11.20
(1JC,H = 181.7)
9.35
7.40, 7.75 (both t, 1 H each, Jo = 8.4); 1.71 (br.s, 6 H, 2 H(3´), 2 H(4´), 2 H(5´));
7.83, 8.16 (both d, 1 H each, Jo = 8.4) 1.83 (br.s, 6 H, 2 H(3″), 2 H(4″), 2 H(5″));
3.80 (br.s, 4 H, 2 H(2´), 2 H(6´));
—
3.96 (br.s, 4 H, 2 H(2″), 2 H(6″))
14
9.42
7.42, 7.80 (both t, 1 H each, Jo = 8.6); 1.71 (br.s, 6 H, 2 H(3´), 2 H(4´), 2 H(5´));
7.88, 8.21 (both d, 1 H each, Jo = 8.6) 3.82—3.95 (m, 12 H, 2 H(2´), 2 H(6´),
2 H(2″), 2 H(3″), 2 H(5″), 2 H(6″))
—
20a
20b
21
7.96
7.01, 7.14 (both t, 1 H each, Jo = 8.0); 5.67 (s, H(10), 1JC,H = 132.3); 6.85, 6.89
7.06, 7.40 (both d, 1 H each, Jo = 8.0) (both t, 1 H each, Jo = 8.6); 7.27, 7.32 (both d, 10.98 (H(1´))
1 H each, Jo = 8.6); 7.20 (d, 1 H, Jo = 2.4)
10.12 (H(5));
(1JC,H = 182.0)
7.91
(1JC,H = 181.0)
7.02, 7.17 (both t, 1 H each, Jo = 8.0); 5.60 (s, H(10), 1JC,H = 132.3); 6.87, 6.89
9.79 (H(5));
10.87 (H(1´))
7.08 (d, 1 H, Jo = 8.0)b
(both m, 1 H each); 7.30, 7.34 (both d,
1 H each, Jo = 8.4); 7.16 (d, 1 H, Jo = 2.7)b
7.59
(1JC,H = 180.0)
6.82 (m, 2 H, H(8), H(9), Jo = 8.0);
7.02 (t, 1 H, H(7));
7.21 (d, 1 H, H(6))
0.94 (s, 6 H, 2 Me); 2.21 (br.s, 4 H,
2 H(3´), 2 H(5´)); 5.50 (s, 1 H, H(10),
1JC,H = 131.5); ∼11.0 (br.s, OH)
9.78
12.14 (H(1´))
12.04
22
9.38
(1JC,H = 186)
7.08, 7.27 (both t, 1 H each, Jo = 8.0); 7.69, 8.10 (both t, 1 H each, Jo = 8.7);
7.23, 7.65 (both d, 1 H each, Jo = 8.0) 8.18, 8.30 (both d, 1 H each, Jo = 8.7);
8.03 (d, 1 H, Jo = 2.4)
23b
9.20
7.02, 7.23 (both t, 1 H each, Jo = 8.2); 8.07, 8.21 (both d, 1 H each, Jo = 8.8);
7.16 (d, 1 H, Jo = 8.2)b,c
7.97 (m, 2 H)b
a In numbering of substituents, a prime corresponds to C(3)ꢀR and two primes, to C(10)ꢀR.
b The other signals are at about δ 7.40—7.70.
c All m (each 1 H).
4ꢀCyanoꢀ3ꢀ[3,4ꢀdihydroꢀ2(1H)ꢀisoquinolinyl]ꢀ10ꢀoxoꢀ
5,10ꢀdihydrobenzo[b][1,6]naphthyridine (6c). Yield 92%. MS,
m/z (Irel (%)): 352 [M]+ (100), 338 [M –NH]+ (62), 261 [M –
PhCH2]+ (31), 237 (48), 236 (52), 221 [M – dihydroisoꢀ
quinoline]+ (82).
(both t, each 1 H, H(8), H(9), Jo = 8.2 Hz); 7.91, 8.22 (both d,
each 1 H, H(7), H(10), Jo = 8.2 Hz); 7.40 (br.s, NH + NH2);
9.22 (s, 1 H, H(5)). MS, m/z (Irel (%)): 325 [M]+ (87), 293
[M – S or M – MeOH]+ (100), 267 [M – MeOH – CN]+ (50),
220 [M – SCH2COOMe]+ (46).
1ꢀAminoꢀ6ꢀoxoꢀ3,11ꢀdihydroꢀ6Hꢀbenzo[b]pyrazoꢀ
lo[3,4ꢀh][1,6]naphthyridine (8). A mixture of compound 3
(0.25 g, 0.979 mmol) and 10 mL of hydrazine hydrate was reꢀ
fluxed for 4 h with stirring and the reaction mixture was cooled
3,10ꢀDichloroꢀ4ꢀcyanoꢀ5,10ꢀdihydrobenzo[b][1,6]naphꢀ
thyridine (11). A mixture of compound 3 (1.5 g, 5.87 mmol) and
Et3N•HCl (0.7 g) in 20 mL of POCl3 was stirred with reflux for
18 h, POCl3 was evaporated in vacuo, and the residue was trituꢀ
rated in a cooled aqueous solution of Na2CO3. The precipitate
was filtered off, thoroughly washed with water, and dried to give
1.45 g (90%) of compound 11. MS, m/z (Irel (%)): 273 [M – H]+
(100), 238 [M – HCl]+ (26), 202 [M – 2 Cl]+ (17), 176 [M –
2 Cl – CN]+ (41).
4ꢀCyanoꢀ3,10ꢀdipiperidinoꢀ5,10ꢀdihydrobenzo[b][1,6]naphꢀ
thyridine (12). А. A mixture of compound 11 (0.25 g, 0.921 mmol)
and piperidine (4 mL) was stirred for 5 h at ∼20 °C, piperidine
was evaporated in vacuo, the dry residue was triturated in a 1 N
aqueous solution of KOH, and the precipitate was filtered off,
washed with water and hexane, and dried to give 0.09 g (26%) of
compound 12. MS, m/z (Irel (%)): 371 [M]+ (100), 275 (88), 203
[M – (piperidinyl)2]+ (96).
and filtered off to give 0.23 g (94%) of compound 8. IR, ν/cm–1
:
3416, 3310, 3197 (NH, NH2), 1627 (CO). 1H NMR, δ: 6.05
(br.s, 2 H, NH2); 7.40 (m, 1 H, H(8)); 7.79 (m, 2 H, H(7),
H(9)); 8.22 (d, 1 H, H(10), Jo = 8.2 Hz); 9.09 (s, 1 H, H(5));
10.91 (br.s, 1 H, NH(3)); 12.60 (br.s, 1 H, NH(11)). MS,
m/z (Irel (%)): 251 [M]+ (100), 235 [M – NH2]+ (12), 209 [M –
CH2N2]+ (12).
1ꢀAminoꢀ2ꢀmethoxycarbonylꢀ6ꢀoxoꢀ6,11ꢀdihydrobenꢀ
zo[b]thieno[2,3ꢀh][1,6]naphthyridine (9). Methyl mercaptoꢀ
acetate (0.09 mL, 1.11 mmol) was added with stirring to a soluꢀ
tion of MeONa (from 0.022 g of Na and 8 mL of MeOH). Then
compound 3 (0.25 g, 0.979 mmol) was added, the mixture was
stirred with reflux for 1.5 h and poured into 20 mL of water, and
the precipitate was filtered off to give 0.30 g (94%) of comꢀ
pound 9. IR, ν/cm–1: 3403, 3351 (NH, NH2), 1683 (ester C=O),
1644 (C(6)=O). 1H NMR, δ: 3.81 (s, 1 H, OMe); 7.40, 7.81
B. A mixture of compound 13 (0.20 g, 0.620 mmol) and
1.5 mL of piperidine was stirred for 1 h at ∼20 °C, piperidine was
evaporated in vacuo, the dry residue was triturated in 1 N aqueꢀ

1188
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 5, May, 2003
Ivanov et al.
ous KOH, and the precipitate was filtered off, washed with
water and hexane, and dried to give 0.13 g (56%) of comꢀ
pound 12. The melting point of a mixed sample with the comꢀ
pound prepared by procedure А was undepressed. The IR specꢀ
tra of both samples were identical.
10ꢀChloroꢀ4ꢀcyanoꢀ3ꢀpiperidinoꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (13). A mixture of compound 6a (0.3 g,
0.987 mmol) and Et3N•HCl (0.3 g) in 24 mL of POCl3 was
stirred with reflux for 4 h, POCl3 was evaporated in vacuo, and
the precipitate was triturated in a solution of sodium carbonate
in 10% aqueous acetone. The precipitate was filtered off, washed
with water and hexane, and dried in vacuo over P4O10 to give
0.26 g (82%) of crude product 13, which was used subsequently
without further purification. MS, m/z (Irel (%)): 322 [M]+ (100),
293 [M – Et]+ (65), 267 [M – C4H7]+ (40), 239 [M –
piperidinyl + H]+ (37).
4ꢀCyanoꢀ10ꢀmorpholinoꢀ3ꢀpiperidinoꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (14). Compound 13 (0.3 g, 0.932 mmol)
was stirred with morpholine (2 mL) for 1 h at ∼20 °C, morpholine
was evaporated in vacuo, the dry residue was triturated in 1 N
aqueous KOH, and the precipitate was filtered off, washed with
water and hexane, and dried to give 0.22 g (63%) of comꢀ
pound 14. MS, m/z (Irel (%)): 373 [M]+ (100), 344 [M – CHO]+
(46), 330 [M – CHO – CH2]+ (41), 317 (63), 305 (61), 290
[M – piperidinyl + H]+ (59).
with PriOH, and dried to give 0.26 g (87%) of product 20a as
fine white crystals slowly oxidized in air. IR, ν/cm–1: 3112,
3290, 3192 (2 NH), 2227 (CN). MS, m/z (Irel (%)): 356 [M]+
(100), 240 [M – indolyl]+ (53), 204 [M – indolyl – HCl]+ (27),
178 [M – indolyl – HCl – CN]+ (15), 117 [indole]+ (24).
4 ꢀ C y a n o ꢀ 1 0 ꢀ ( 1 H ꢀ i n d o l ꢀ 3 ꢀ y l ) ꢀ 3 ꢀ p h e n y l t h i o b e n ꢀ
zo[b][1,6]naphthyridine (20b). A mixture of compound 1b (0.2 g,
0.64 mmol) and indole (0.09 g, 0.77 mmol) in 8 mL of BunOH
was stirred with reflux for 6 h. The solution was cooled to ∼20 °C
and the precipitate was filtered off, washed with hexane, and
dried to give 0.22 g (80%) of product 20b. MS, m/z (Irel (%)):
430 [M]+ (88), 312 [M – indole]+ (100), 117 [indole]+ (83).
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀ(2ꢀhydroxyꢀ4,4ꢀdimethylꢀ6ꢀoxoꢀ1ꢀ
cyclohexenyl)ꢀ5,10ꢀdihydrobenzo[b][1,6]naphthyridine (21).
A
mixture of compound 1a (3 g, 12.53 mmol) and dimedone
(2.28 g, 16.28 mmol) in 200 mL of PriOH was stirred with reflux
for 17 h and the precipitate was filtered off, washed with PriOH,
and dried to give 4.39 g (92%) of product 21. MS, m/z (Irel (%)):
379 [M]+ (5), 344 [M – Cl]+ (3), 239 [M – dimedone]+ (100),
204 [M – dimedone – Cl]+ (59), 177 [M – dimedone – Cl –
HCN]+ (57), 140 [dimedone]+ (53).
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀ(1Hꢀindolꢀ3ꢀyl)benzo[b][1,6]naphꢀ
thyridine (22). А. A mixture of compound 20a (0.25 g,
0.701 mmol) and K3[Fe(CN)6] (0.5 g, 1.52 mmol) in 10 mL of
50% aqueous PriOH was stirred with reflux for 60 h, the precipiꢀ
tate was filtered off, and extracted with boiling DMF. The exꢀ
tract was passed through a paper filter and the product was
precipitated by 50% aqueous EtOH. The precipitate was filtered
off, washed with EtOH, and dried to give 0.11 g (44%) of comꢀ
pound 22 as brightꢀred fine crystals. MS, m/z (Irel (%)): 354 [M]+
(100), 319 [M – Cl]+ (50), 291 [M – HCl – HCN]+ (13), 177
[M – indolyl – Cl – CN]+ (16), 117 [indole]+ (57).
B. A solution of [Ag(Py)2]MnO4 (0.32 g, 0.841 mmol) in
3 mL of pyridine was added to a solution of compound 20a
(0.2 g, 0.561 mmol) in 2 mL of pyridine and the mixture was
stirred for 1 h at ∼20 °C. The reaction mixture was diluted with
water and left for ∼12 h in a refrigerator for aggregation of the
precipitate. The precipitate was filtered off, washed with EtOH,
dried, and extracted with hot DMF (2×5 mL), and the extract
was filtered through a paper filter. A 50% aqueous solution of
EtOH (15 mL) was added to the filtrate, and the mixture was
cooled. The precipitate was filtered off, washed with EtOH, and
dried to give 0.11 g (55%) of compound 22. The melting point of
a mixed sample with the compound prepared by procedure А
was undepressed.
4ꢀCyanoꢀ10ꢀ(1H ꢀindolꢀ3ꢀyl)ꢀ3ꢀmorpholinobenꢀ
zo[b][1,6]naphthyridine (23a). A mixture of compound 22
(0.25 g, 0.705 mmol) and morpholine (0.25 g) in 5 mL of DMF
was stirred for 20 h at ∼20 °C and poured in 20 mL of water. The
precipitate was filtered off, washed with water, and dried to give
0.25 g (88%) of compound 23a. MS, m/z (Irel (%)): 405 [M]+
(100), 348 (95) [M – C3H5O]+, 320 [M – morpholyl]+ (86), 319
[M – morpholine]+ (96).
4ꢀCyanoꢀ3ꢀdimethylaminobenzo[b][1,6]naphthyridine (17).
A. A mixture of compound 1a (0.2 g, 0.835 mmol) and ∼70%
alcohol solution (0.57 g) of N,Nꢀdimethylformamide diethyl
acetal (18) in 10 mL of anhydrous EtOH was stirred with reflux
for 33 h, 1 mL of water was added, and the precipitate was
filtered off, washed with EtOH, and dried to give 0.18 g (87%) of
product 17. An analytic grade sample was obtained by passing a
solution of compound 17 through a silica gel layer (elution with
CH2Cl2—AcOEt, 1 : 1). IR, ν/cm–1: 2196 (CN). 1H NMR, δ:
3.45 (s, 6 H, NMe2); 7.55, 7.91 (both t, each 1 H, H(7), H(8),
Jo = 8.0 Hz); 7.99, 8.12 (both d, each 1 H, H(6), H(9), Jo =
1
8.0 Hz); 9.12 (s, 1 H, H(10), JC,H = 165.9 Hz); 9.36 (s, 1 H,
1
H(1), JC,H = 183.3 Hz). MS, m/z (Irel (%)): 248 [M]+ (100),
233 [M – Me]+ (81), 219 [M – Et]+ (93), 205 [M – NMe2]+
(74), 179 (48).
B. A mixture of compound 1a (0.3 g, 0.835 mmol) and a
∼70% alcohol solution (0.47 g) of N,Nꢀdimethylacetamide diꢀ
methyl acetal (15a) in 12 mL of MeOH was stirred with reflux
for 7 h and cooled, and the precipitate was filtered off, washed
with EtOH, and dried to give 0.17 g (55%) of product 17. Furꢀ
ther purification was the same as in procedure А. The same
reaction was carried out with diethyl acetal of N,Nꢀdimethylꢀ
acetamide (15b) in anhydrous EtOH.
C. A mixture of compound 1a (0.1 g, 0.418 mmol) and
a 30% aqueous solution (0.28 mL) of dimethylamine was
stirred for 4 h at ∼20 °C, and the precipitate was filtered off,
washed with water, and dried to give 0.1 g (97%) of product 17.
Further purification was the same as in procedure А. A mixꢀ
ture of samples prepared by methods A, B, and C shows an
undepressed melting point. The IR spectra of these samples
were identical.
4 ꢀ C y a n o ꢀ 1 0 ꢀ ( 1 H ꢀ i n d o l ꢀ 3 ꢀ y l ) ꢀ 3 ꢀ p h e n y l t h i o b e n ꢀ
zo[b][1,6]naphthyridine (23b). A mixture of compound 22
(0.25 g, 0.705 mmol), benzenethiol (0.08 mL, 0.775 mmol), and
AcONa (0.1 g) in 10 mL of PriOH was refluxed with stirring for
2 h, and the precipitate was filtered off, washed with water and
PriOH, and dried to give 0.21 g (70%) of compound 23b. MS,
m/z (Irel (%)): 428 [M]+ (100), 402 [M – CN]+ (9), 318 [M –
PhSH]+ (11), 280 [M – indolyl – S]+ (29).
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (20a). A mixture of compound 1a
(0.20 g, 0.835 mmol) and indole (0.5 g, 0.919 mmol) in 15 mL of
PriOH was stirred with reflux for 45 min. The reaction mixture
was cooled to ∼20 °C and the precipitate was filtered off, washed

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 5, May, 2003
1189
5. V. G. Granik, A. N. Zhidkova, and R. G. Glushkov, Usp.
Khim., 1977, 46, 685 [Russ. Chem. Rev., 1977, 46 (Engl.
Transl.)].
The authors are grateful to N. P. Solov´eva for assisꢀ
tance in recording the NMR spectra.
6. H. Meerwein, W. Florian, and N. Schön, Ann. Chem.,
1961, 641, 1.
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Received November 27, 2002;
in revised form January 22, 2003