Synthesis of derivatives of a new heterocyclic system, indolo[2,3-f][1,7] naphthyridine

Article abstract of DOI:10.1023/B:RUCB.0000011871.28637.78

3-(N′-Aryl-N′-chloroacetyl)amino-2-formylindoles were converted into 3-amino-1-aryl-2-oxo-1,2-dihydropyrido[3,2-b]indoles, which were used to synthesize derivatives of a new heterocyclic system, namely, indolo[2,3-f][1,7]naphthyridine. The structures of the resulting compounds were proved by IR and ¹H NMR spectroscopy and mass spectrometry.

Full text of DOI:10.1023/B:RUCB.0000011871.28637.78

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2149—2156, October, 2003
2149
Synthesis of derivatives of a new heterocyclic system,
indolo[2,3ꢀf ][1,7]naphthyridine
N. A. Rastorgueva, S. Yu. Ryabova, E. A. Lisitsa, L. M. Alekseeva, and V. G. Granikꢀ
Federal State Unitary Enterprise State Scientific Center
"Scientific Research Institute of Organic Intermediates and Dyes",
1, building 4 ul. Bolshaya Sadovaya, 123995 Moscow, Russian Federation.
Fax: +7 (095) 254 6574. Eꢀmail: vggranik@mail.ru
3ꢀ(N´ꢀArylꢀN´ꢀchloroacetyl)aminoꢀ2ꢀformylindoles were converted into 3ꢀaminoꢀ1ꢀarylꢀ
2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]indoles, which were used to synthesize derivatives of a new
heterocyclic system, namely, indolo[2,3ꢀf ][1,7]naphthyridine. The structures of the resulting
1
compounds were proved by IR and H NMR spectroscopy and mass spectrometry.
Key words: 3ꢀ(N´ꢀarylꢀN´ꢀchloroacetyl)aminoꢀ2ꢀformylindoles, pyrido[3,2ꢀb]indoles,
indolo[2,3ꢀf ][1,7]naphthyridines, functionalization.
Known highly efficient drugs include a group of comꢀ
pounds that belong to the βꢀ and γꢀcarboline series
(incazan, carbidine, dimebon, diazoline).1 However, the
chemistry and biology of substituted pyrido[3,2ꢀb]indoles
has not been adequately studied. Recently,2 we developed
a new approach to the synthesis of previously inaccessible
3ꢀamino derivative of pyrido[3,2ꢀb]indole. The present
study was focused on extending this approach to the synꢀ
thesis of other 3ꢀaminoꢀ1ꢀarylpyrido[3,2ꢀb]indoles and
using the resulting compounds for the preparation of
annelated heterocycles.
3ꢀ(N´ꢀArylꢀN´ꢀchloroacetyl)aminoꢀ2ꢀformylindoles
1a—d were used as the key compounds.3,4 It was found
that irrespective of the substituent in the aryl fragment,
these compounds react with pyridine with cyclization leadꢀ
ing smoothly not only to known2 compound 2a but also to
other (1ꢀarylꢀ2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]indolꢀ3ꢀ
yl)pyridinium chlorides 2b—d (Scheme 1). Without furꢀ
ther purification, chlorides 2a—d were treated with
benzylamine in methanol at reflux. This resulted in openꢀ
ing of the pyridinium ring followed by complete degradaꢀ
tion of the azapolyene fragment (these processes were
Scheme 1
R = H (a), 4ꢀCl (b), 4ꢀOEt (c), 4ꢀNO2 (d)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2036—2042, October, 2003.
1066ꢀ5285/03/5210ꢀ2149 $25.00 © 2003 Plenum Publishing Corporation

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Rastorgueva et al.
described in detail for another system, 1ꢀ(3ꢀcyanoꢀ5ꢀ
nitropyridinꢀ2ꢀyl)pyridinium chloride5) giving rise to
amino derivatives 3a 2 and 3b—d. Compounds 3a,d were
also characterized as acetyl derivatives 4a,d.
The reaction of 3ꢀaminopyrido[3,2ꢀb]indoles 3a—d
with ester 9 smoothly afforded the corresponding enamꢀ
ines 10a—d in good yields. The intramolecular cyclizaꢀ
tion of compounds of this type requires fairly drastic conꢀ
ditions (heating in diphenyl at 270 °C)7,8 (Scheme 3).
Under similar conditions, we synthesized derivatives of a
new heterocyclic system, namely ethyl 6ꢀarylꢀ1,5ꢀdioxoꢀ
4,5,6,11ꢀtetrahydroꢀ1Hꢀindolo[2,3ꢀf ][1,7]naphthyridineꢀ
2ꢀcarboxylates (11a—d).
An alternative approach developed to synthesize
3ꢀaminopyrido[3,2ꢀb]indole derivatives involves the reꢀ
action of chloroacyl derivatives 1a—d with sodium nitrite
to yield 1ꢀarylꢀ3ꢀnitroꢀ2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]inꢀ
doles (5a—d), which are subsequently subjected to reducꢀ
tion. As in the case of reaction with pyridine, the intermeꢀ
diate ωꢀnitroꢀsubstituted compounds 6a—d cyclize as early
as during the reaction to afford pyrido[3,2ꢀb]indoles 5a—d.
It is noteworthy that the presence of the electronꢀwithꢀ
drawing nitro group in the pyridone ring induces a subꢀ
stantial downfield shift of the H(4) signal in the 1H NMR
spectrum (the positions of this signal for the nitro and
amino derivatives differ by ∆δ ≈ 2). The reduction of nitro
derivative 5a with zinc in acetic acid was shown to lead
smoothly to the previously described acylamine 4a.2
The amino group in pyrido[3,2ꢀb]indoles 3a—d occuꢀ
pies position 3 of the pyridine ring and, hence, it particiꢀ
pates rather easily in reactions with electrophilic reagents.
Indeed, treatment of compounds 3a,b with benzaldehyde
yields Schiff´s bases 7a,b, while condensation of 3a with
dimethylformamide diethyl acetal results in amidine 8a
(Scheme 2).
Scheme 3
Scheme 2
R = H (a), 4ꢀCl (b), 4ꢀOEt (c), 4ꢀNO2 (d)
It is worth noting that cyclization of enamine 10a is
accompanied by partial decarbethoxylation of the resultꢀ
ing ester 11a, apparently, through the attack of the ester
carbonyl by the alcohol molecule liberated upon cyclizaꢀ
tion. This yields target tetracyclic ester 11a with an adꢀ
mixture of 1,5ꢀdioxoꢀ6ꢀphenylꢀ4,5,6,11ꢀtetrahydroꢀ1Hꢀ
indolo[2,3ꢀf ][1,7]naphthyridine (12) (minor product).
The composition of the mixꢀ
ture was derived from examiꢀ
1
nation of the H NMR specꢀ
trum of the crude product. The
spectrum (DMSOꢀd6) exhibits
signals for 11a (δ): 1.35 (t, 3 H,
COOCH2CH3); 4.30 (q, 2 H,
COOCH2CH3, J = 7.0 Hz);
R = H (a), 4ꢀCl (b)
In order to prepare angular polyannelated heterocycles,
the synthesized aminopyrido[3,2ꢀb]indoles were introꢀ
duced in the condensation reaction with diethyl ethoxyꢀ
methylenemalonate (9). It is known that the reaction of
aromatic or heteroaromatic amine with this reagent is the
first stage in the synthesis of a vast group of medical
preparations, namely, quinolonecarboxylic acids exhibitꢀ
ing a high antibacterial activity, for example, oxolinic and
nalidixic acids and numerous fluoroquinolonecarboxylic
acids.6,7
5.93 (d, 1 H, H(7), J7,8
=
8.2 Hz); 6.74 (t, 1 H, H(8), J8,7 = J8,9 = 8.2 Hz); 7.17 (t,
1 H, H(9), J9,8 = J9,10 = 8.2 Hz); 7.57—8.43 (m, 6 H,
H(10), Ph); 8.43 (s, 1 H, H(3)); 11.97 (br.s, 1 H, N(4)H);
12.53 (br.s, 1 H, N(11)H); and 12: 6.45 (d, 1 H, H(2),
J2,3 = 8.2 Hz); 11.75 (br.s, 1 H, N(4)H); 12.10 (br.s, 1 H,
N(11)H). The other proton signals of compound 12 coinꢀ
cide with those of compound 11a, while the signal for the

Indolo[2,3ꢀf ][1,7]naphthyridine
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2151
H(3) proton of compound 12 falls in the region containꢀ
ing the signals from the aromatic protons of the benzene
ring (δ 7.57—8.43). The ratio of compounds in the mixꢀ
ture (5 : 1) was determined from the intensity of the
N(11)H signals.
Thus, this study presents the synthesis of previously
inaccessible 1ꢀarylꢀ3ꢀaminoꢀ and 3ꢀnitropyrido[3,2ꢀb]inꢀ
doles. We synthesized representatives of a new heteroꢀ
cyclic system, indolo[2,3ꢀf ][1,7]naphthyridine, and creꢀ
ated the grounds for preparing its functionally substituted
derivatives that present interest for synthetic, physicoꢀ
chemical, and biological research.
A similar cyclization of compounds 10b—d can be
carried out with retention of the ethoxycarbonyl group
in position 2; in this case, the reaction furnishes tetraꢀ
cyclic esters 11b—d, which are individual compounds
according to spectral characteristics. It is difficult to puꢀ
rify these products by recrystallization, and only comꢀ
pounds 11c,d have been obtained in an analytically
pure state (Tables 2—4, Experimental). Therefore, furꢀ
ther evidence for the structure of indolonaphthyridines
11a,b was gained from their subsequent transformations.
The corresponding 1ꢀchloro derivatives were prepared by
the reactions of 11a,b with the Vilsmeier reagent;9 this
gave rise to ethyl 6ꢀarylꢀ1ꢀchloroꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ
11Hꢀindolo[2,3ꢀf ][1,7]naphthyridineꢀ2ꢀcarboxylates
(13a,b) (Scheme 4). The structure of these compounds
can be unambiguously deduced from the data of 1H NMR
and IR spectroscopy and mass spectrometry (see Exꢀ
perimental), although we were unable to prepare them
as analytically pure products. The chlorine atom in
compounds 13a,b is rather active, which creates condiꢀ
tions for the synthesis and biological study of functionally
substituted indolonaphthyridines. For example, treatꢀ
ment of compounds 13a,b with piperidine in DMF furꢀ
nished ethyl 6ꢀarylꢀ5ꢀoxoꢀ1ꢀpiperidinoꢀ5,6ꢀdihydroꢀ11Hꢀ
indolo[2,3ꢀf ][1,7]naphthyridineꢀ2ꢀcarboxylates (14a,b),
which were characterized by spectral data and elemental
analysis.
Experimental
The IR spectra of compounds were measured on a
PerkinꢀElmer 457 instrument in mineral oil. Mass spectra were
recorded on a JSQꢀ900 mass spectrometer with direct sample
injection into the ion source. 1H NMR spectra were run on a
Bruker ACꢀ200 spectrometer in DMSOꢀd6. The reactions were
monitored and the purity of compounds was checked by TLC on
Silufol UVꢀ254 plates using a 10 : 1 chloroform—methanol (for
compounds 2b—d, 3b—d, 4d, 5a—d, 8a, 10a—d, 11a,b, 13a,b,
and 14a,b), a 5 : 3 : 1 ethyl acetate—propanꢀ2ꢀol—ammonia sysꢀ
tem (for compound 7a,b, 11c), and chloroform (for compound
11d) as eluents. The 1H NMR spectra of compounds 2d, 3b—d,
4d, 5a—d, 7a,b, 8a, and 10a—d are presented in Table 1, those
of compounds 11b—d, 13a,b, and 14a,b are listed in Table 2.
The physicochemical characteristics and the yields of compounds
3b—d, 4d, 5a—d, 7a,b, 8a, 10a—d, 11c,d, and 14a,b are preꢀ
sented in Table 3 and the spectral characteristics of these comꢀ
pounds are in Table 4. Compounds 1a,b,3,4 1c,d,4 2a, 3a, and
4a 2 were described in our previous study.
3ꢀAminoꢀ1ꢀarylꢀ2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]indoles
3b—d (general procedure). A mixture of aldehyde 1b—d (8 mmol)
and pyridine (19 mL) was stirred at a temperature of 20 °C (see
Ref. 2) to give (1ꢀarylꢀ2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]indolꢀ3ꢀ
yl)pyridinium chlorides 2b—d: 3.19 g (98%) of salt 2b, m.p.
252—254 °C; 2.85 g (84%) of salt 2c, m.p. ∼300 °C; or 3.06 g
(90%) of salt 2d, m.p. ∼300 °C. IR, ν/cm–1: 1638 (CO), 3562,
3112, 3068 (NH).
Scheme 4
Then benzylamine (1.25 mL, 6 mmol) was added to a soluꢀ
tion of 2 mmol of the corresponding salt 2b—d in 30 mL of
methanol and the mixture was refluxed for 3 h and cooled. The
precipitate was filtered off and washed with methanol to give
0.62 g of compound 3b, 0.86 g of compound 3c, and 0.53 g of
compound 3d.
3ꢀAcetylaminoꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2ꢀdihydropyrido[3,2ꢀb]inꢀ
dole (4a). A suspension of compound 5a (0.23 g, 0.75 mmol) in
7 mL of AcOH was heated to boiling with stirring, zinc dust
(0.24 g, 3.8 mmol) was added in portions, and the mixture was
refluxed for 2 h and cooled. The precipitate was filtered off,
washed with water, and dried to give 0.21 g (74%) of monoacetyl
derivative 4a, m.p. 356—358 °C (Ref. 2: m.p. 358—360 °C). IR,
ν/cm–1: 1675 (CO), 3273, 3223 (NH).
3ꢀAcetylaminoꢀ1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyriꢀ
do[3,2ꢀb]indole (4d). A suspension (0.1 g, 0.3 mmol) of 3ꢀamino
derivatives 3d in 2 mL of Ac2O was stirred for 18 h at 20 °C. The
precipitate was filtered off and washed with Ac2O and ether to
give 0.1 g of compound 4d.
1ꢀArylꢀ3ꢀnitroꢀ2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]indoles 5a—d
(general procedure). Sodium nitrite (0.12 g, 1.7 mmol), potasꢀ
sium iodide (0.17 g, 1 mmol), and 3 drops of triethylamine were
added to a solution of aldehyde 1a—d in 6 mL of ethyl acetate.
R = H (a), 4ꢀCl (b), 4ꢀOEt (c), 4ꢀNO2 (d)

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Rastorgueva et al.
Table 1. 1H NMR spectra of 3ꢀsubstituted 1ꢀarylꢀ2ꢀoxoꢀ1,2ꢀdihydropyrido[3,2ꢀb]indoles 3b—d, 4d, 5a—d, 7a,b, 8a, and 10a—d
Comꢀ
poꢀ
und
δ, J/Hz
H(4), N(5)H, H(6), d,
br.s J6,7 = 8.2
H(7), t,
J7,6
J7,8 = 8.2 J8,9 = 8.2
H(8), t, H(9), d,
C6H4—R
Other signals
s
=
J8,7
=
J9,8 = 8.2
3b
3c
6.96 10.91
7.00 11.02
7.29
7.36
6.96
7.04
6.67
6.73
6.02
6.02
7.44, 7.65 (both m, 4 H, C6H4Cl)
1.46 (t, 3 H, OCH2Me,
5.22 (br.s, 2 H, NH2)
5.41 (br.s, 2 H, NH2)
J = 7.0); 4.21 (d, 2 H,
OCH2Me, J = 7.0);
7.19, 7.36 (both m, 4 H, C6H4OEt)
3d
4d
6.98 11.13
8.85 11.51
7.34
7.45
7.00
7.17
6.70
6.77
6.00
6.10
7.79, 8.49 (both m, 4 H, C6H4NO2) 5.48 (br.s, 2 H, NH2)
7.86, 8.52 (both m, 4 H, C6H4NO2) 2.20 (s, 3 H, NHCOMe);
9.36 (br.s, 1 H,
NHCOMe)
5a
5b
5c
5d
7a
8.87 11.84
8.96 11.85
8.87 11.80
8.95 11.90
7.85 11.52
*
7.36
7.41
7.38
7.41
7.20
6.81
6.91
6.87
6.87
6.75
5.97
6.12
6.10
6.13
5.96
7.50—7.70 (both m, 6 H, H(6), Ph)
7.62, 7.80 (both m, 4 H, C6H4Cl)
7.20, 7.55 (both m, 4 H, C6H4OEt)
7.91, 8.55 (both m, 4 H, C6H4NO2)
7.53, 7.70 (both m, 5 H, Ph)
—
—
—
—
7.58
7.55
7.58
7.47
7.53, 7.92 (m, 5 H,
N=CHPh); 9.40 (s, 1 H,
N=CH Ph)
7b
7.84 11.47
7.27 11.17
8.02 11.46
*
7.22
7.07
7.17
6.83
6.67
6.75
6.14
5.89
5.95
7.56, 7.74 (both m, 4 H, C6H4Cl)
7.42, 7.64 (both m, 5 H, Ph)
7.49, 7.68 (both m, 5 H, Ph)
7.53, 7.92 (m, 5 H,
N=CHPh); 9.39 (s, 1 H,
N=CH Ph)
8a
7.37
7.46
2.96 (s, 6 H,
N=CHN(Me)2); 8.50
(s, 1 H, N=CHN(Me)2)
1.26, 1.29
10a
(both t, 3 H each,
(COOCH2Me)2, J = 7.0);
4.19 (m, 4 H,
(COOCH2Me)2); 8.58
(d, 1 H, CH=, J = 11.2);
11.04 (d, 1 H, NH)
1.26, 1.29
(both t, 3 H each,
(COOCH2Me)2, J = 7.0);
4.20 (m, 4 H,
(COOCH2Me)2); 8.59
(d, 1 H, CH=, J = 11.2);
11.04 (d, 1 H, NH)
1.26, 1.29
(both t, 3 H each,
(COOCH2Me)2, J = 7.0);
4.19 (m, 4 H,
(COOCH2Me)2); 8.59
(d, 1 H, CH=, J = 11.2);
11.05 (d, 1 H, NH)
1.27, 1.29
(both t, 3 H each,
(COOCH2Me)2, J = 7.0);
4.22 (m, 4 H,
10b
10c
10d
8.03 11.51
8.01 11.45
8.06 11.56
7.48
7.47
7.50
7.20
7.19
7.21
6.83
6.80
6.81
6.10
6.10
6.12
7.58 (m, 2 H, H(3´)H(5´));
7.76 (m, 2 H, H(2´), H(6´))
1.42 (t, 3 H, OCH2Me),**
7.19 (m, 2 H, H(3´)H(5´));
7.40 (m, 2 H, H(2´), H(6´))
7.88 (m, 2 H, H(3´)H(5´));
8.53 (m, 2 H, H(2´), H(6´))
(COOCH2Me)2); 8.60
(d, 1 H, CH=, J = 11.2);
11.03 (d, 1 H, NH)
* The H(6) signal falls in the region containing the signals of the aromatic protons of the benzene ring.
** The (OCH2Me) signals fall in the region of the (COOCH2Me)2 multiplet with δ 4.19.

Indolo[2,3ꢀf ][1,7]naphthyridine
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2153
Table 2. 1H NMR spectra of indolo[2,3ꢀf ][1,7]naphthyridine derivatives 11b—d, 13a,b, and 14a,b
Comꢀ
poꢀ
und
δ, J/Hz
H(3), N(4)H, H(7), d
br.s J7,8 = 8.2
H(8), t
J8,7
J8,9 = 8.2 J9,10 = 8.2
H(9), t
H(10), d N(11)H,
J10,9 = 8.2
C6H4ꢀR
Other signals
s
=
J9,8
=
s
11b
11c
8.43 11.94
8.43 11.88
6.10
6.12
6.84
6.81
7.21
7.19
7.72
12.49 7.65, 7.79 (both m,
4 H, C6H4Cl)
1.35 (t, 3 H, COOCH2Me,
J = 7.0); 4.30 (q, 2 H,
COOCH2Me)
7.70
12.45 1.43 (t, 3 H,
OCH2Me, J = 7.0); 1.35 (t, 3 H, COOCH2Me
4.20 (q, 2 H,
OCH2Me); 7.21,
7.47 (m, 4 H,
J = 7.0); 4.30 (q, 2 H,
COOCH2Me)
C6H4OEt)
11d
13a
13b
14a
8.43 12.01
6.10
5.88
6.02
5.94
6.82
6.73
6.87
6.79
7.21
7.21
7.28
7.23
7.73
*
12.50 7.94, 8.56 (both m,
4 H, C6H4NO2)
1.35 (t, 3 H, COOCH2Me,
J = 7.0); 4.30 (q, 2 H,
COOCH2Me)
8.97
9.02
8.71
—
—
—
11.59 7.51—7.70 (m, 6 H, 1.42—1.48 (t, 3 H,
Ph, H(10))
COOCH2Me, J = 7.0);
4.50 (q, 2 H, COOCH2Me)
*
11.62 7.61—7.80 (m, 5 H, 1.42—1.48 (t, 3 H,
C6H4Cl, H(10))
COOCH2Me, J = 7.0);
4.50 (q, 2 H, COOCH2Me)
7.75
10.56 7.54—7.74 (m, 5 H, 1.42—1.48 (t, 3 H,
Ph)
COOCH2Me, J = 7.0);
4.50 (q, 2 H,
COOCH2Me); 1.70, 1.96
(both br.s, 2 H and 4 H each,
2 H(4″), 2 H(3″), 2 H(5″))**
1.42—1.48 (t, 3 H,
COOCH2Me, J = 7.0);
4.50 (q, 2 H,
14b
8.70
—
6.08
6.87
7.25
*
10.57 7.61, 7.75 (both m,
4 H, C6H4Cl)
COOCH2Me); 1.70, 1.95
(both br.s, 2 H and 4 H each,
2 H(4″), 2 H(3″), 2 H(5″))**
* The H(10) signal falls in the region of aromatic protons of the benzene ring.
** The 2 H(2″) and 2 H(6″) signals in the spectrum recorded in DMSOꢀd6 are covered by the solvent water signals. In the spectrum
recorded in DMSOꢀd6 + CCl4, the 2 H(2″) and 2 H(6″) signals occur at δ 3.26.
The mixture was refluxed for 7 h. The precipitate was filtered
off, washed with water and methanol, and dried to give 0.22 g of
compound 5a, 0.25 g of compound 5b, 0.11 g of compound 5c,
or 0.2 g of compound 5d.
1ꢀArylꢀ3ꢀ(N´ꢀbenzylidene)aminoꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyrido[3,2ꢀb]indoles 7a,b (general procedure). Benzaldehyde
(0.1 mL, 1.1 mmol) was added to a solution of amine 3a,b
(1 mmol) in 5 mL of DMF and the mixture was refluxed for 3 h
and cooled. The precipitate was filtered off, washed with methaꢀ
nol, and dried to give 0.15 g of compound 7a or 0.27 g of
compound 7b.
3ꢀAminoꢀ3ꢀ(N´,N´ꢀdimethylaminomethylamino)ꢀ2ꢀoxoꢀ1ꢀ
phenylꢀ1,2ꢀdihydropyrido[3,2ꢀb]indole (8a). Dimethylformamide
diethyl acetal (0.2 mL, 1.2 mmol) was added to a solution of
3ꢀaminopyrido[3,2ꢀb]indole 3a (0.3 g, 1 mmol) in 3 mL of DMF,
and the mixture was refluxed for 3 h, cooled, and concentrated
to dryness. The precipitate was triturated with acetone, filtered,
and dried to give 0.16 g of amidine 8a.
1ꢀArylꢀ3ꢀ(β,βꢀdiethoxycarbonylethenyl)aminoꢀ2ꢀoxoꢀ1,2ꢀ
dihydropyrido[3,2ꢀb]indoles 10a—d (general procedure). A mixꢀ
ture of amine 3a—d (1.6 mmol), DMF (5 mL), and ethyl
ethoxymethylenemalonate (0.34 mL, 1.7 mmol) (9) was refluxed
for 2 h and cooled. The precipitate was filtered off, washed with
DMF and methanol, and dried to give 0.65 g of compound 10a,
0.56 g of compound 10b, 0.66 g of compound 10c, and 0.69 g of
compound 10d.
Ethyl
6ꢀarylꢀ1,5ꢀdioxoꢀ4,5,6,11ꢀtetrahydroꢀ1Hꢀindoꢀ
lo[2,3ꢀf ][1,7]naphthyridineꢀ2ꢀcarboxylate 11a—d (general proꢀ
cedure). A mixture of enamine 10a—d (0.3 g, 0.6 mmol) and
diphenyl (2 g) was heated on a Wood´s alloy bath at 270 °C for
1.5 h; during this period, boiling of the reaction mixture was
observed. The mixture was cooled and diphenyl was washed out
with boiling light petroleum (40—70 °C) to give 0.22 g of comꢀ
pound 11a with an admixture of 1,5ꢀdioxoꢀ6ꢀphenylꢀ4,5,6,11ꢀ
tetrahydroꢀ1Hꢀindolo[2,3ꢀf ][1,7]naphthyridine 12; 0.18 g (69%)
of compound 11b, which could not be purified for elemental

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Rastorgueva et al.
Table 3. Physicochemical characteristics of the synthesized compounds 3b—d, 4d, 5a—d, 7a,b, 8a, 10a—d, 11c,d, and 14a,b
Comꢀ Yield
M.p./°C
Solventa
M
Found
Calculated
Molecular
formula
(%)
poꢀ
(%)
und
С
H
N
Cl
3b
77
78
83
92
47
53
32
51
47
88
44
92
73
84
90
38
38
13
6
333—335
298—301
326—329
∼400
PriOH
309
319
320
362
305
339
349
350
363
397
330
445
479
489
490
443
444
466
500
65.97
65.92
71.25
71.45
63.88
63.75
63.07
62.98
67.04
66.88
59.98
60.10
65.52
65.32
58.35
4.04
3.90
5.27
5.37
3.56
3.78
3.98
3.90
3.79
3.63
2.97
2.97
4.54
4.33
2.94
58.29
4.63
4.72
4.00
4.05
5.28
5.50
5.21
5.20
4.53
4.62
5.72
5.56
4.42
4.52
4.87
4.77
3.84
3.73
5.77
5.62
4.99
5.03
13.32
11.42
11.45
—
C17H12N3OCl
C19H17N3O2
C17H12N4O3
C19H14N4O4
C17H11N3O3
C17H10N3O3Cl
C19H15N3O4
C17H10N4O5
C24H17N3O
13.57
12.93
13.16
17.62
17.49
15.59
15.46
13.99
13.76
12.11
12.37
12.03
12.03
15.71
2.88
11.56
11.56
10.57
10.56
16.67
16.96
9.49
3c
MeOH—DMF,
9 : 0.1
MeCN—DMF,
9 : 1
3d
—
—
—
4d
DMF
5a
362—364
382—384
394—396
356—358
362—364
326—328
266—268
262—264
260—264
269—270)
285—287
366—368
362—364
158—160
252—254
DMF
DMF
DMF
5b
10.43
10.44
5c
5d
MeCO2—DMF,
2 : 1
—
16.00
—
7a
DMF
78.81
79.32
72.74
72.46
72.71
72.70
66.89
67.40
61.83
62.57
65.90
66.24
61.23
61.22
67.91
67.71
60.73
61.44
71.87
72.08
67.20
67.13
7b
DMF
DMF
PriOH
PriOH
8.77
8.91
—
C24H16N3OCl
C20H18N4O
8a
10a
10b
10c
10d
11c
11d
14a
14b
—
C25H23N3O5
C25H22N3O5Cl
C27H27N3O6
C25H22N4O7
C25H21N3O5
C23H16N4O6
C28H26N4O3
C28H25N4O3Cl
9.45
8.30
8.76
8.84
7.39
7.38
—
DMF—Me2CO,
1 : 1
PriOH—DMF,
1 : 1
8.58
11.34
11.42
9.33
—
—
—
—
DMF
9.48
DMF, AcOHb
toluene
11.98
12.20
11.35
12.01
11.12
11.18
DMF
7.07
7.08
a The solvent used for recrystallization is given in parentheses.
b Analysis is related to 1/4 moles of AcOH.
analysis, m.p. 254—256 °C. C23H16N3O4Cl. MS, m/z (Irel (%)):
433 [M]+ (7), 389 [M – C2H4O]+ (9), 361 [M – COOC2H5]+
(100), 333 [M – COOC2H5 – CO]+ (12). IR, ν/cm–1: 1716
(COOC2H5), 1643 (CO), 3313 (NH); 0.22 g of compound 11c;
or 0.29 g of compound 11d.
Purification of compound 11c for analysis: 0.22 g of crude
11c was dissolved in 12 mL of boiling DMF. The mixture
was cooled and the gelꢀlike precipitate was filtered off and
triturated on the filter with acetone to give 0.12 g of a subꢀ
stance, which was recrystallized from 8 mL of DMF. The gelꢀ
like precipitate that formed was cooled on an ice bath for
5 h with stirring. The resulting crystals were filtered off and
washed with acetone to give 0.1 g of compound 11c of analytiꢀ
cal grade.
Purification of compound 11d for analysis: 0.29 g of crude
11d was dissolved in 10 mL of boiling DMF, and the solution
was filtered and cooled. The resulting gelꢀlike precipitate (which
did not form crystals even after a 3ꢀday storage in a refrigerator)
was mixed with ∼5 mL of water and triturated. The precipitate
that formed was filtered off, washed with acetone, and then
refluxed with acetone. The hot solution was filtered to give 0.2 g
of a product, which was refluxed in 10 mL of AcOH. The hot
suspension was filtered, washed with AcOH, water, and acꢀ
etone, and dried in a Fischer apparatus at 110 °C over P2O5 to

Indolo[2,3ꢀf ][1,7]naphthyridine
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2155
Table 4. Spectral characteristics of the synthesized compounds 3b—d, 4d, 5a—d, 7a,b, 8a, 10a—d, 11c,d, and 14a,b
Comꢀ
poꢀ
MS, m/z
(Irel (%))
IR,
max/cm–1
ν
und
NH (NH2)
CO
1633
3b
3c
3d
309 [M]+ (100), 281 [M – CO]+ (15)
3431, 3344,
3257, 3092
3428, 3340,
3217
3432, 3361,
3306, 3171
3302, 3206
3175
319 [M]+ (100), 291 [M – C2H4]+ (26), 262 [M – C2H4 – HCO]+ (21),
235 [M – C2H4 – HCO – HCN]+ (34)
320 [M]+ (98), 290 [M – NO]+ (27), 274 [M – NO2]+ (100)
1637
1632
4d
5a
362[M]+(100), 320 [M – COCH2]+ (82), 274 [M – COCH2 – NO2]+ (27)
305 [M]+ (48), 275 [M – NO]+ (100), 231 [M – CO – NO2]+ (33),
170 [M – CO – C6H5]+(57)
1676, 1629
1650
5b
339 [M]+ (18), 309 [M – NO]+ (100), 265 [M – CO – NO2]+ (15),
170 [M – NO – CO – C6H4Cl]+ (33)
3172
1644
5c
5d
349 [M]+ (85), 169 [M – C6H4OC2H5 – HCO – NO]+ (25)
350 [M]+ (31), 320 [M – NO]+ (100), 290 [M – 2NO]+ (31),
274 [M – NO – NO2]+ (42)
3230
3338
1655
1651
7a
7b
363 [M]+ (100), 260 [M – C6H5CN]+ (93)
3151, 3057
3217
1625
1618
397 [M]+ (84), 294 [M – CN – C6H5]+ (100), 266 [M – CN – C6H5 – CO]+ (55),
231 [M – CN – C6H5 – CO – Cl]+ (37), 155 [M – CN – C6H5 – CO – C6H4Cl]+ (32)
330 [M]+ (100), 288 [M – CO – CH2]+(66)
8a
10a
3239, 3056
3325
1621
1682, 1641
445 [M]+ (12), 399 [M – C2H5OH]+ (100), 353 [M – 2C2H5OH]+ (56),
299 [M – 2COOC2H5]+ (34)
10b
10c
10d
11c
11d
433 [M – C2H5OH]+ (100), 387 [M – 2C2H5OH]+ (41),
361 [M – OC2H4 – CO]+ (66)
3258, 3053
3273
1735, 1695,
1636
1715, 1638
489 [M]+ (24), 443 [M – C2H5OH]+ (100), 369 [M – 2C2H5OH – CO]+ (90),
343 [M – 2COOC2H5]+ (73)
490 [M]+ (89), 444 [M – C2H5OH]+ (100), 370 [M – 2C2H5OH – CO]+ (72),
344 [M – 2COOC2H5]+ (77)
3528, 3378,
3270
3304, 3195,
3071
3529, 3370,
3181
3414, 3276
3414, 3325
1673, 1641
1717, 1647
1711, 1649
443 [M]+ (100), 397 [M – C2H5OH]+ (38), 372 [M – HCO – CH2=CHNH2]+ (84),
341 [M – C2H5OH – 2CO]+ (36)
444 [M]+ (100), 398 [M – C2H5OH]+ (39)
14a
14b
466 [M]+ (100), 437 [M – HCO]+ (13)
500 [M]+ (100), 471 [M – HCO]+ (27), 344 [M – COOC2H4 – C5H10N]+ (11)
1723, 1656
1730, 1656
give 0.1 g of compound 11d of analytical grade, which contained
0.25 mol of AcOH according to H NMR data.
320—322 °C. C23H16N3O3Cl. MS, m/z (Irel (%)): 417 [M]+
(100), 389 [M – C2H4]+ (34), 345 [M – COOC2H4]+ (10). IR,
ν/cm–1: 1650, 1713, 1727 (CO), 3189, 3393 (NH).
1
Ethyl 1ꢀchloroꢀ5ꢀoxoꢀ6ꢀphenylꢀ6,11ꢀdihydroꢀ5Hꢀindoꢀ
lo[2,3ꢀf ][1,7]naphthyridineꢀ2ꢀcarboxylate (13a). Crude prodꢀ
uct (11a + 12) (0.3 g, 0.75 mmol) was added with stirring at
20 °C to a Vilsmeier reagent prepared from POCl3 (0.7 mL,
7.5 mmol) and DMF (2.23 mL, 30 mmol), and the mixture was
heated to 60 °C, stirred at this temperature for 2 h, and poured
into 350 mL of an aqueous solution (рH 8) of sodium bicarbonꢀ
ate with ice. The resulting mixture was stirred for 40 min, and
the precipitate was filtered off, washed with water, and dried
to give 0.28 g (89%) of compound 13a, m.p. 328—330 °C.
Ethyl 6ꢀarylꢀ5ꢀoxoꢀ1ꢀpiperidinoꢀ6,11ꢀtetrahydroꢀ5Hꢀindoꢀ
lo[2,3ꢀf ][1,7]naphthyridineꢀ2ꢀcarboxylates (14a,b) (general proꢀ
cedure). Piperidine (0.25 mL, 2.5 mmol) was added to chloro
derivative 13a or 13b (1 mmol) in 15 mL of DMF and the
mixture was stirred at 20 °C for 4.5 h and poured into 50 mL of
water. The resulting precipitate was filtered off, washed with
water, and dried. After recrystallization from toluene, compound
14a was refluxed with 15 mL of ethyl acetate and the hot soluꢀ
tion was filtered. This gave 0.06 g of pure compound 14a. Reꢀ
crystallization of 14b from DMF gave 0.03 g of pure comꢀ
pound 14b.
C
23H16N3O3Cl. MS, m/z (Irel (%)): 417 [M]+ (100), 389
[M – C2H4]+ (34), 345 [M – COOC2H4]+ (10). IR, ν/cm–1
:
1650, 1713, 1727 (CO), 3189, 3393 (NH).
Ethyl 1ꢀchloroꢀ6ꢀ(4ꢀchlorophenyl)ꢀ5ꢀoxoꢀ6,11ꢀdihydroꢀ5Hꢀ
indolo[2,3ꢀf ][1,7]naphthyridineꢀ2ꢀcarboxylate (13b) was preꢀ
pared similarly to compound 13a with the difference that crude
11b containing no impurities was used and the mixture was kept
at 75 °C for 16 h. This gave 0.42 g (80%) of compound 13b, m.p.
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Received April 28, 2003;
in revised form June 23, 2003