Study of the reactions of 3-chloro-4-cyanobenzo[b][1,6]naphthyridine with nucleophilic reagents

Article abstract of DOI:10.1023/A:1021636632164

The reactions of 3-chloro-4-cyanobenzo[b][1,6]naphthyridine (4) with S-, C-, and N-nucleophiles afford stable σ-adducts at position 10. In the base-catalyzed reactions of compound 4 with thiols, the resulting σ-complexes are rearranged into sulfides 14a - c. Sulfides 14b,c undergo the Thorpe - Ziegler cyclization to give 1-aminobenzo[b]thieno[2,3-h][1,6]naphthyridine derivatives 15a,b. The reaction of naphthyridine 4 with aniline affords a mixture of σ-adducts of the C - N and C - C types, while those with aliphatic amines yield 3-amino derivatives 17a - c. In the presence of H₂O₂, benzonaphthyridine 4 adds peroxycarboxylic acids to give compounds 8a,b. In alkaline medium, adduct 8a is rearranged into 4-aminopyridine-3-carbaldehyde derivative 10.

Full text of DOI:10.1023/A:1021636632164

Russian Chemical Bulletin, International Edition, Vol. 51, No. 11, pp. 2121—2128, November, 2002
2121
Study of the reactions of 3ꢀchloroꢀ4ꢀcyanobenzo[b][1,6]naphthyridine
with nucleophilic reagents
A. S. Ivanov,a N. Z. Tugusheva,a N. P. Solov´eva,b and V. G. Granika
ꢀ
aState Scientific Center of the Russian Federation
"Organic Intermediate Products and Dyes Institute" (NIOPIK),
1/4 ul. Bol´shaya Sadovaya, 103787 Moscow, Russian Federation.
Fax: +7 (095) 254 6574. Eꢀmail: aivanov@email.ru
bCenter of Drug Chemistry,
AllꢀRussian Research Chemical Pharmaceutical Institute,
7 Zubovskaya pl., 119815 Moscow, Russian Federation.
Fax: +7 (095) 246 7805
The reactions of 3ꢀchloroꢀ4ꢀcyanobenzo[b][1,6]naphthyridine (4) with Sꢀ, Cꢀ, and
Nꢀnucleophiles afford stable σꢀadducts at position 10. In the baseꢀcatalyzed reactions of
compound 4 with thiols, the resulting σꢀcomplexes are rearranged into sulfides 14a—c. Sulfides
14b,c undergo the Thorpe—Ziegler cyclization to give 1ꢀaminobenzo[b]thieno[2,3ꢀh][1,6]naphꢀ
thyridine derivatives 15a,b. The reaction of naphthyridine 4 with aniline affords a mixture of
σꢀadducts of the C—N and C—C types, while those with aliphatic amines yield 3ꢀamino
derivatives 17a—c. In the presence of H2O2, benzonaphthyridine 4 adds peroxycarboxylic acids
to give compounds 8a,b. In alkaline medium, adduct 8a is rearranged into 4ꢀaminopyridineꢀ
3ꢀcarbaldehyde derivative 10.
Key words: benzo[b][1,6]naphthyridine, 2ꢀchloroꢀ3ꢀcyanoꢀ5ꢀformylꢀ4ꢀ(2ꢀhydroxyꢀ
anilino)pyridine, benzo[b]thieno[2,3ꢀh][1,6]naphthyridine, Thorpe—Ziegler cyclization.
Earlier, it was shown that hydrolytic opening of
5ꢀcyanoꢀ6ꢀ(2ꢀdimethylaminovinyl)ꢀ1ꢀphenylpyrimidinꢀ
4ꢀone (1) is followed by recyclization, which gives
4ꢀanilinoꢀ3ꢀcyanopyridinꢀ2ꢀone (2) in alkaline medium1
and 4ꢀanilinoꢀ3ꢀcyanoꢀ5ꢀformylpyridinꢀ2ꢀone (3) in
acidic media.2 It was also found2 that heating of formylꢀ
pyridone 3 in POCl3 in the presence of Et3N•HCl
smoothly affords 3ꢀchloroꢀ4ꢀcyanobenzo[b][1,6]naphꢀ
thyridine (4) (Scheme 1).
In the present study, we found that the recyclization
of pyrimidinone 1 in aqueous AcOH yields both pyridones
2 and 3 in the ratio ∼1 : 2, while the major recyclizaꢀ
tion product in glacial AcOH is 4ꢀcyanoꢀ3ꢀoxobenꢀ
zo[b][1,6]naphthyridine (5). In the latter case, intermeꢀ
diate Nꢀformyl amide 6 undergoes cyclization into 3ꢀoxoꢀ
benzonaphthyridine 5, which is convertible by reaction
with POCl3 into the known2 3ꢀchloro derivative 4.
One can believe that a partial positive charge in triꢀ
cyclic compound 4 is localized at position 10.
Hence, this position can be attacked by various nuꢀ
cleophiles. Reactions of this type, which afford correꢀ
sponding σꢀcomplexes,3 are well studied for azines. In a
relevant review,3 neutral azine derivatives were mentioned
among possible substrates for these reactions. However,
corresponding azinium cations or Nꢀoxides are certainly
more reactive in such transformations. Because of this,
the goal of this work was to study the reactions of nucleoꢀ
philes with both compound 4 proper and its Nꢀoxide.
However, oxidation of compound 4 with H2O2 in hot
AcOH gave 10ꢀacetyloxyꢀ3ꢀchloroꢀ4ꢀcyanoꢀ5ꢀhydroxyꢀ
5,10ꢀdihydrobenzo[b][1,6]naphthyridine (8a) rather than
the expected 5ꢀNꢀoxide; i.e., the acetate anion is added at
position 10 (Scheme 2). An analogous reaction in propiꢀ
onic acid afforded corresponding 10ꢀpropionyloxy deꢀ
rivative 8b. 3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀoxoꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (9) was isolated as a byꢀproduct
in these reactions.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1966—1973, November, 2002.
1066ꢀ5285/02/5111ꢀ2121 $27.00 © 2002 Plenum Publishing Corporation

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002
Ivanov et al.
Scheme 1
1H NMR spectra of the compounds obtained, signals for
all aromatic protons are significantly shifted upfield comꢀ
pared to those for the starting benzonaphthyridine 4 *; in
addition, they show narrow singlets at δ ∼7.00 for the
Scheme 2
methine protons (1J13
= 175 Hz), signals for the proꢀ
C,H
tons of the acyloxy groups, and broadened singlets at
δ ∼9.40 for the N—OH protons (Table 1). The NOE exꢀ
periment for Nꢀhydroxynaphthyridine 8a revealed a 20%
intensification of the singlet at δ 8.38 for the H(1) proton
upon irradiation of the signal at δ 7.00. When the singlet
at δ 8.38 was irradiated, the signal at δ 7.00 becomes, in
turn, more intense by 12%. These data indicate a spatial
vicinity of the H(1) and H(10) protons, which correlates
with the proposed structure 8a. Analogously, irradiation
of the broadened singlet at δ 9.41 intensifies the signal at
δ 7.52 for the H(6) atom by 10%, thus confirming the
presence of the N(5)—OH fragment in the molecule. The
structure of compound 8a was unambiguously proved by
13C NMR data (see Experimental). The 13C NMR specꢀ
trum contains a signal δ 93.5 for the C(10) atom (dd,
3
1JC,H = 175 Hz, JH(1),C(10) = 4.6 Hz). The signals for
C(4a) and C(4) were found to be sensitive to deuteration
of the N(5)—OH fragment. Addition of a D2O—water
mixture (four to five drops) to the solution under study
caused these signals to shift by 0.11 and 0.06 ppm, respecꢀ
8: R = Me (a), Et (b)
Apparently, intermediate Nꢀoxide 7, in which posiꢀ
tion 10 is activated for nucleophilic attack, is initially
protonated at the O atom. This is followed by addition of
an acyloxy anion at position 10 to give compound 8a,b.
The structures of the latter were unambiguously deterꢀ
mined from their 1H and 13C NMR spectra. In the
* Naphthyridine 4: 1H NMR (DMSOꢀd6), δ: 7.85, 8.17 (both t,
1 H each, H(7), H(8)); 8.31, 8.40 (both d, 1 H each, H(6),
1
H(9)); 9.68 (br.s, 1 H, H(10), JC,H = 169.3 Hz); 9.83 (s, 1 H,
H(1), 1JC,H = 189.1 Hz).

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002 2123
Table 1. 1H NMR spectra of compounds 8a,b, 9, 13a—c, 16, and 18
Comꢀ
pound
δ (J/Hz)
H(1)
(s, 1 H)
H(10)
(s, 1 H)
H arom. (1 H each,
H(6), H(7), H(8), H(9))
Substituent at
the C(10) atom
N(O)—H(5)
(s, 1 H)
8a
8.38
7.00
6.90, 7.52
(both d, Jo = 8.0);
7.06, 7.16
(both t, Jo = 8.0)
6.90, 7.52
(both d, Jo = 8.0);
7.05, 7.16
(both t, Jo = 8.0)
7.44, 7.85
(both t, Jo = 8.4);
8.00, 8.20
(both d, Jo = 8.4)
7.07, 7.25
(both t, Jo = 8.0);
7.34 (d, Jo = 8.0)b
1.94 (s, 3 H, Me)
9.41 a
9.43 a
12.13 a
10.17
(1JC,H = 185.0)
(1JC,H = 175.0)
8b
8.38
(1JC,H = 185.0)
7.04
(1JC,H = 175.6)
0.84 (t, 3 H, CH2Me, Jo = 7.6);
2.20 (sym.m, 2 H, CH2Me,
Jo = 7.6)
9
9.18
—
—
13a
13b
13c
7.78
(1JC,H = 184.0)
5.93
(1JC,H = 153.6)
7.04 (d, 2 H, H(2´), H(6´),
Jo = 7.2); 7.27 (t, 2 H, H(3´),
H(5´), Jo = 7.2); 7.38 (t, 1 H,
H(4´), Jo = 7.2)
8.26
(1JC,H = 183.8)
5.64
(1JC,H = 151.0)
7.10, 7.30
(both t, Jo = 7.6);
7.34, 7.44
(both d, Jo = 7.6)
7.10, 7.28
(both t, Jo = 7.8);
7.39, 7.44
(both d, Jo = 7.8)
1.14 (t, 3 H, CH2Me, Jo = 7.2);
10.40
3.20 (q, 2 H, SCHAB,
2JH B = 15.8); 3.94
,H
(q, А2 H, CH2Me, Jo = 7.2)
8.32
(1JC,H = 184.7)
5.71
(1JC,H = 152.0)
3.18 (q, 2 H, SСHAB
,
10.37
2JH B = 14.6); 7.04 (t, 1 H,
,H
А
H(4´)); 7.28 (t, 2 H, H(3´),
H(5´)); 7.49 (d, 2 H, H(2´),
H(6´)); 9.99 (s, 1 H, CONH)
5.09 (d, 1 H, HC(CN)2,
3JH(10),H = 5.3)
16
18
8.38
(1JC,H = 181.6)
5.19 c
(1JC,H = 148.2)
7.19, 7.39
(both t, Jo = 7.2);
7.47, 7.51
(both d, Jo = 7.2)
6.96, 7.16
(both t, Jo = 7.4);
7.06, 7.40
(both d, Jo = 7.4)
10.49
10.01
8.03
(1JC,H = 181.4)
5.22
(1JC,H = 134.0)
4.98 (br.s, 2 H, NH2); 6.41
(d, 2 H, Ph, H(3´), H(5´),
Jo = 8.8); 6.75 (d, 2 H, Ph,
H(2´), H(6´), Jo = 8.8)
a Br.s.
b 2 H (H(6), H(9)).
c Doublet.
tively. The signals for the C(5a), C(6), C(9), and C(10)
atoms are less sensitive to the deuteration, simply becomꢀ
ing noticeably broader. Thus, this effect is mainly conꢀ
fined to the atoms in the vicinity of the N—OH group.
Alkaline hydrolysis of compound 8a occurs in a rather
unusual way (Scheme 3). Cleavage of the C(9a)—C(10)
and N—OH bonds is followed by migration of the OH
group to the orthoꢀposition of the benzene ring to give
2ꢀchloroꢀ3ꢀcyanoꢀ5ꢀformylꢀ4ꢀ(2ꢀhydroxyanilino)pyriꢀ
dine (10) (1H and 13C NMR data).
aromatic protons at δ 6.80 and 7.18 (both t, 1 H each,
H(4´), H(5´), Jo = 7.2 Hz) and δ 6.97 and 7.27 (both d,
1 H each, H(3´), H(6´), Jo = 7.2 Hz). The signal at
δ 10.32 becomes even broader at 60 °C and is shifted to
δ 10.20, while the position of the lowerꢀfield signal
(δ 10.55) remains unchanged. Based on these data, we
assigned the singlet at δ 10.02 to the aldehyde proton, the
signal at δ 10.32 to the OH proton, and the broadened
signal at δ 10.55 to the NH proton involved in intramoꢀ
lecular hydrogen bonding. Selective decoupling experiꢀ
ment enabled us to assign signals in the 13C NMR specꢀ
The 1H NMR spectrum of compound 10 contains two
1
narrow singlets at δ 8.72 (1 H, JC,H = 184.7 Hz) and
trum. The lowestꢀfield doublet at δ 194.3 (1J13
=
C,H
δ 10.02 (1 H, 1JC,H = 185.4 Hz), two broadened singlets at
δ 10.32 (1 H) and δ 10.55 (1 H), and multiplets for four
185.4 Hz) belongs to the CH=O group. Its components
are additionally split because of spinꢀspin coupling

2124
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002
Ivanov et al.
Scheme 3
an adduct at position 5, while replacement of the Cl atom
by the ethylamino group requires a prolonged reacꢀ
tion time.5
Compound 4 reacts with thiophenol (12a), ethyl
thioglycolate (12b), and Nꢀphenylthioglycolamide (12c)
under mild conditions (DMF, 20 °C or in boiling PriOH)
to give adducts at position 10 (13a—c) in good yields
(Scheme 4). Their structures were unambiguously conꢀ
firmed by 1H and 13C NMR data. In the 1H NMR spectra
of compounds 13a—c (as in those of 8a,b), signals for the
aromatic protons are noticeably shifted upfield compared
to analogous signals for the starting benzonaphthyridine 4.
A singlet for the methine H(10) proton in compounds
13a—c appears at δ 5.60—6.00. The presence of the asymꢀ
metric C(10) atom in the naphthyridine in question makes
the S—CH2 protons nonequivalent (quartets at δ 3.20
(2JH ,H = 15.8 Hz) for 13b and δ 3.18 (2JH ,HB = 14.6 Hz)
A
B
A
for 13c). Selective decoupling from the H(10) and H(1)
protons was used to assign signals in the 13C NMR specꢀ
trum of compound 13b (see Experimental). In the proꢀ
tonꢀnondecoupled spectrum, a doublet for the C(10) atom
at δ 41.2 (1JC,H = 151.0 Hz) is additionally split into a
triplet because of a spinꢀspin coupling with the CH2—S
protons (3JC(10),H CS ≈ 4.4 Hz). A signal for CH2—S apꢀ
pears at δ 31.9 (td2, 1JC,H = 138.6 Hz), its shape being due
to a spinꢀspin coupling with the methine H(10) proton.
Selective decoupling from the H(10) proton reduces the
multiplicity of signals for the aromatic protons at the C(9),
C(9a), C(5a), C(10a), C(4a), and C(1) atoms. It is sigꢀ
nificant that the mass spectra of σꢀadducts 13a—c conꢀ
tain no molecular ion peaks and correspond to the startꢀ
ing compound 4.
1
with the C(6)H proton (δ 159.7, J13
= 184.7 Hz,
C,H
3J(C=O),H(6) = 5.4 Hz). A high geminal heteroconstant
(δ13C 115.8 (C(5)), 2JC(5),CHO = 22.9 Hz) is characteristic
of an aldehyde fragment.4 The CN fragment gives a sinꢀ
glet at δ 113.0, while the signal for the C(3) atom apꢀ
pears at δ 93.6 (3JC(3),NH = 7.7 Hz). Signals at δ 159.2
3
3
(d, JC(2),H(6) = 14.5 Hz) and δ 154.5 (t, JC(4),HOC
≈
3JC(4),H(6) ≈ 6 Hz) were unambiguously assigned to the
C(2) and C(4) atoms, respectively. Signals at δ 116.1,
119.3, 128.3, and 129.7 correspond to the benzene CH
groups. The two remaining signals at δ 123.2 (m) and
∑
153.4 (t, JC,HC = 17 Hz) can be assigned to the C(1´)
and C(2´) atoms of the 2´ꢀhydroxyphenyl substituent. The
last signal assignment was verified against the chemical
shifts for the C(1´) and C(2´) atoms in a model comꢀ
pound 3 (δC(2´) 126.0, δC(1´) 136.1). In addition, the exꢀ
Scheme 4
pected δ13 values for the C(1´) and C(2´) atoms in the
C
orthoꢀhydroxyphenyl fragment (δ 124.1 and 153.0, reꢀ
spectively), which were calculated with the use of increꢀ
ments for an OH group in the benzene series,4 proved to
be very close to the experimental data (δ 123.2 and 153.4).
The presence of the formyl group in compound 10 was
also confirmed by the synthesis of pꢀnitrophenylhydrꢀ
azone 11 (see Scheme 3).
The mechanism of the unusual 8а
10 transforꢀ
mation calls for further investigation.
Easy addition of a nucleophile to Nꢀoxide 7 motivated
us to study the reactions of tricyclic compound 4 with
various nucleophilic reagents. In this case, replacement
of the Cl atom and addition of a nucleophile at posiꢀ
tion 10 are both possible. Earlier,3,5 such substrates were
already used. Thus the reaction of ethylamine with
7ꢀchloropteridine in the presence of KMnO4 initially gives
R = Ph (a), CH2COOEt (b), CH2CONHPh (c);
R´ = COOEt (a), CONHPh (b)

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002 2125
Table 2. 1H NMR spectra of compounds 14a—c and 17a
Comꢀ
pound
δ (J/Hz)
H(1)
(s, 1 H)
H(10)
(s, 1 H)
H arom. (1 H each,
H(6), H(7), H(8), H(9))
Substituent at
the C(3) atom
14a
14b
9.59
9.45
7.75, 8.03 (both t, Jo = 8.4); 7.48—7.53 (m, 3 H, Ph);
(1JC,H = 187.1)
9.73
(1JC,H = 168.1) 8.21, 8.30 (both d, Jo = 8.4) 7.63—7.65 (m, 2 H, Ph)
9.49
7.73, 8.06 (both t, Jo = 8.0); 1.20 (t, 3 H, CH2Me, Jo = 7.2);
(1JC,H = 185.6)
(1JC,H = 168.0) 8.20, 8.30 (both d, Jo = 8.0) 4.14 (q, 2 H, CH2Me, Jo = 7.2);
1
4.34 (s, 2 H, CH2S, JC,H = 143.5)
14c
17a
9.74
9.47
7.73, 8.19, 8.29
(all d, Jo = 8.4);
8.06 (t, Jo = 8.4)
4.45 (s, 2 H, CH2S, 1JC,H = 142.1);
7.05 (t, 1 H, H(4´), Jo = 7.6); 7.30
(t, 2 H, H(3´), H(5´), Jo = 7.6);
7.59 (d, 2 H, H(2´), H(6´), Jo = 7.6);
10.40 (s, 1 H, CONH)
(1JC,H = 186.9)
(1JC,H = 168.1)
9.42
(1JC,H = 183.4)
9.09
7.51, 7.88 (both t, Jo = 8.0); 0.92 (t, 3 H, Me, Jo = 7.2); 1.36
(1JC,H = 165.2) 7.97, 8.09 (both d, Jo = 8.0) (m, 2 H, CH2Me); 1.62 (quintet, 2 H,
CH2Et, Jo = 7.2); 3.62 (q, 2 H,
CH2Pr, Jo = 7.2); 7.80 (br.s,
1 H, NH)
Heating of compound 4 with thiols 12a,c (or heating
of adduct 13b without thiols) in PriOH in the presꢀ
ence of AcONa afforded 3ꢀalkyl(aryl)thioꢀ4ꢀcyanobenꢀ
zo[b][1,6]naphthyridines 14a—c. There is no doubt that
the thiol is eliminated from adducts 13 under these condiꢀ
tions and slowly but irreversibly replaces the Cl atom.
It is of interest to compare the 1H NMR data for
σꢀadducts 13a—c and benzonaphthyridines 14a—c (see
Tables 1, 2). Signals for the methylene protons in comꢀ
pounds 14b,c (as opposed to 13b,c) appear as singlets at
δ 4.34 (14b) and 4.45 (14c) since their molecules contain
no asymmetric centers.
piperidine, and morpholine) are known7 to yield 3ꢀaminoꢀ
benzo[b][1,6]naphthyridines. In the present work, we disꢀ
covered that naphthyridine 4 reacts with butylamine,
2ꢀaminobutanol, and hexahydroazepine to give correꢀ
sponding compounds 17a—c in high yields, as well
(Scheme 6).
Scheme 6
When compound 4 is refluxed with methyleneꢀactive
thiols 12b,c in PriOH in the presence of K2CO3, products
14b,c undergo in situ Thorpe—Ziegler cyclization6 to give
benzo[b]thieno[2,3ꢀh][1,6]naphthyridines 15a,b (see
Scheme 4).
We also found that the reaction of compound 4 with
malononitrile affords adduct 16, which was isolated as a
mixture with the starting benzonaphthyridine 4 (∼10%).
1
The structure of the adduct was confirmed by H NMR
spectra (see Table 1, Scheme 5).
R1 = Bu, R2 = H (a); R1 = CH(Et)CH2OH, R2 = H (b);
R1, R2 = (CH2)6 (c)
Scheme 5
Previously, it was shown that the reactions of azines
(particularly acridines as quaternary salts3,8) with aniline
derivatives afford unstable Nꢀadducts, which exist only at
low temperatures. Above 0 °C, they change into thermoꢀ
dynamically stable Cꢀadducts; the latter can be oxidized
into pꢀaminophenylacridinium halides.8
The reactions of compound 4 with highꢀbasic amines
(βꢀphenylethylamine, homoveratrylamine, benzylamine,
These results motivated us to carry out a reaction of
compound 4 with aniline in boiling PriOH for a proꢀ

2126
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002
Ivanov et al.
ion source). 1H and 13C NMR spectra were recorded on a Varian
Unityꢀ400 spectrometer in DMSOꢀd6. The course of the reacꢀ
tion was monitored and the purity of individual compounds was
checked by TLC on Silufol UVꢀ254 plates in AcOEt (visualizaꢀ
tion under UV light). Melting points were determined on a
Boetius stage. Spectral and physicochemical characteristics and
elemental analysis data for the compounds obtained are given in
Tables 1—3.
longed time. The reaction afforded 10ꢀ(4ꢀaminophenyl)ꢀ
3ꢀchloroꢀ4ꢀcyanobenzo[b][1,6]naphthyridine (18) in
good yield. The crude product contains aniline and adꢀ
duct 19 (∼16%) (1H NMR data). Obviously, the latter is
much more stable than the aforementioned Nꢀadducts of
acridinium ions (probably, because of the electronꢀwithꢀ
drawing groups in its pyridine ring).
4ꢀCyanoꢀ3ꢀoxoꢀ2,3ꢀdihydrobenzo[b][1,6]naphthyridine (5).
A. Pyrimidinone 1 1 (30 g, 0.11 mol) was stirred in 70 mL of
glacial AcOH containing 0.5 mL of water at ∼20 °C for 24 h. The
precipitate that formed was filtered off, washed with distilled
water and EtOH, and dried to give benzonaphthyridinone 5
(15.3 g, 61%), m.p. >350 °C.
Experimental
IR spectra were recorded on a Perkin—Elmer 457 instruꢀ
ment (Vaseline oil). Mass spectra were obtained with a Finnigan
SSQꢀ710 massꢀspectrometer (EI, direct inlet of samples into the
Table 3. Melting points and elemental analysis data for compounds 8a,b, 9—11, 13a—c,
14a—c, 15a,b, and 17a—c
Comꢀ
pound
M.p./°C
(solvent)
Found
Calculated
(%)
Molecular
formula
C
H
Cl
N
S
8a
109—110
(PriOH)
155.5—158
(PriOH)
—*
57.07
57.05
58.15
58.28
60.80
61.07
57.17
57.05
55.44
55.46
65.53
65.25
57.17
56.75
62.25
61.99
72.73
72.82
—
3.26 11.22
3.17 11.25
3.65 11.09
3.67 10.75
2.24 12.73
2.37 13.86
3.28 12.95
2.94 12.95
13.01
13.31
12.95
12.74
16.58
16.44
15.08
15.35
18.40
18.48
12.26
12.01
11.62
11.68
14.00
14.00
13.86
13.41
12.85
12.99
15.30
15.12
12.85
12.99
14.82
15.12
20.33
20.27
19.17
19.15
18.47
18.53
16.80
16.84
0—
C15H10ClN3O3
C16H12ClN3O3
C13H6ClN3O
C13H8ClN3O2
8b
0—
0—
0—
0—
9
10
—*
(EtOH)
—*
(EtOH)
277—278
(MeCN)
274—276
(MeCN)
203—205
(MeCN)
262—267
(Me2CO)
202—204
(MeCN)
11**
13a
13b
13c
14a
14b
14c
15a
15b
17a
17b
17c
18
4.09
4.18
8.15
7.81
C19H13ClN6O3•
•C2H5OH
C19H12ClN3S
3.39 10.33
3.43 10.14
3.85 10.18
9.32
9.17
8.95
8.89
7.91
7.91
10.28
10.23
9.93
9.92
8.51
8.66
9.89
9.92
8.52
8.66
0—
C17H14ClN3O2S
C21H15ClN4OS
C19H11N3S
3.92
3.88
3.72
3.46
3.54
3.97
4.05
3.76
3.81
4.14
4.05
3.96
3.81
5.88
5.84
5.52
5.52
6.32
6.00
9.85
8.55
8.55
0—
0—
0—
0—
0—
0—
0—
0—
C17H13N3O2S
C21H14N4OS
C17H13N3O2S
C21H14N4OS
C17H16N4
277.5—278
(PriOH—DMF)
195.5—196
(BunOH)
256.5—258
(BunOH)
245.6—246
(PriOH)
169.5—170.5
(PriOH—H2O)
168—169
(PriOH)
67.88
68.09
62.93
63.14
67.98
68.09
74.15
73.89
69.85
69.90
75.40
75.47
69.09
68.57
0—
0—
0—
C17H16N4O
C19H18N4
247 (decomp.)
(MeCN)
3.86 10.56
3.94 10.66
C19H13ClN4
* No characteristic melting point.
** Solvate with EtOH (1 : 1).

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002 2127
B. Compound 4 (0.1 g, 0.42 mmol) was refluxed in 10 mL
of glacial AcOH and cooled. The precipitate that formed
was filtered off, washed with water, and dried to give comꢀ
pound 5 (0.04 g, 43%). MS, m/z (Irel (%)): 221 [M]+ (100), 193
[M – CO]+ (91), 165 [M – CO – HCN]+ (16), 140 (15). IR,
ν/cm–1: 2220 (CN), 1640 (CO). The melting point of a mixture
with the sample obtained by method A was not depressed.
Benzonaphthyridines 8a,b and 9 (general procedure). An
eightfold excess of 38% H2O2 was added to compound 4 in
acetic (for 8a) or propionic acid (for 8b). The reaction mixture
was stirred at 80 °C for 1.5 h and then cooled to ∼20 °C. The
precipitate of benzonaphthyridinone 9 was filtered off. Aqueous
25% EtOH was added to the mother liquor, and the precipitate
that formed was filtered off, washed with aqueous EtOH, and
dried to give benzonaphthyridines 8a,b.
10ꢀAcetyloxyꢀ3ꢀchloroꢀ4ꢀcyanoꢀ5ꢀhydroxyꢀ5,10ꢀdihydroꢀ
benzo[b][1,6]naphthyridine (8a). The yield was 26%. MS,
m/z (Irel (%)): 315 [M]+ (29), 273 [M – CH2CO]+ (100), 256
[M – CH2CO – OH]+ (40). IR, ν/cm–1: 3329 (OH), 2232
(CN), 1760 (CO). 13C NMR, δ: 20.6 (Me); 93.5 (C(10)); 95.4
(C(4)); 114.2 (CN); 118.5 (C(10a)); 122.1, 122.95, 124.8, 125.6
(C(6), C(7), C(8), C(9)); 132.8 (C(9a)); 143.6 (C(5a)); 151.1
(C(1)); 151.5 (C(4a)); 154.6 (C(3)); 168.3 (CO).
Table 4. Reaction conditions and the yields of compounds
13a—c, 14a,c, 15a,b, 17a,b, and 18
Proꢀ t*/h
T/°C
Catalyst
Reagent
Yield
duct
(excess (mol.%)) (%)
13a
13b
13c
14a
14c
15a
15b
17a
17b
24
72
5
20
20
—
—
—
12a (20)
12b (20)
12c (10)
12a (20)
12c (15)
96
93
59
96
68
83
84
87
Refluxing
1.5 The same AcONa
5
1.5
2.5
25
»
»
»
»
»
AcONa
K2CO3
K2CO3
—
12b (15)
12c (10)
BuNH2 (400)
HOCH2CH(Et)NH2 82
(300)
27
—
18
56
»
—
PhNH2 (400)
78
* Reaction duration.
washed with PriOH (and with water for 14a,c, 15a,b, 17a,c,
and 18), and dried to give benzonaphthyridines 13a—c, 14a,c,
15a,b, 17a—c, and 18.
3ꢀChloroꢀ4ꢀcyanoꢀ5ꢀhydroxyꢀ10ꢀpropionyloxyꢀ5,10ꢀdiꢀ
hydrobenzo[b][1,6]naphthyridine (8b). The yield was 24%. MS,
m/z (Irel (%)): 329 [M]+ (54), 273 [M – CH2CH2CO]+ (100),
256 [M – CH2CH2CO – OH]+ (70), 244 (50), 220 (37). IR,
ν/cm–1: 3327 (OH), 2229 (CN), 1756 (CO).
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀphenylthioꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (13a). MS, m/z (Irel (%)): 239
[M – PhS]+ (100), 204 [M – PhS – Cl]+ (12), 177 [M – PhS –
Cl – HCN]+ (18), 110 [PhS]+ (72). IR, ν/cm–1: 3305 (NH),
2225 (CN).
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀoxoꢀ5,10ꢀdihydrobenzo[b][1,6]naphꢀ
thyridine (9). The yield was 0.4%. MS, m/z (Irel (%)): 255 [M]+
(100), 220 [M – Cl]+ (93), 191 [M – Cl – CHO]+ (35), 165
[M – Cl – CHO – CN]+ (59). IR, ν/cm–1: 3251, 3168 (NH),
2229 (CN), 1624 (CO).
2ꢀChloroꢀ3ꢀcyanoꢀ5ꢀformylꢀ4ꢀ(2ꢀhydroxyanilino)pyridine
(10). A solution of NaOH (0.1 g, 2.5 mmol) in 15 mL of anꢀ
hydrous EtOH was slowly added to naphthyridine 8a (0.3 g,
0.85 mmol) in 10 mL of anhydrous EtOH. The reaction mixture
was stirred at 0 °C for 1.5 h and acidified with HCl. The precipiꢀ
tate that formed was filtered off and dried to give pyridine 10
(0.18 g, 71%). MS, m/z (Irel (%)): 273 [M]+ (100), 244
[M – CHO]+ (38), 232 (49), 180 [M – C6H4OH]+ (54), 94
[M – C6H4OH]+ (77). IR, ν/cm–1: 3289, 3215, 3135 (OH,
NH), 2220 (CN), 1659 (CO).
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀethoxycarbonylmethylthioꢀ5,10ꢀdiꢀ
hydrobenzo[b][1,6]naphthyridine (13b). MS, m/z (Irel (%)): 239
[M – SCH2COOEt]+ (100), 204 [M – SCH2COOEt – Cl]+
(64), 177 [M – SCH2COOEt – Cl – HCN]+ (68). IR, ν/cm–1
:
3288 (NH), 2231 (CN), 1724 (CO). 13C NMR, δ: 14.2 (Me);
31.9 (CH2S); 41.2 (C(10)); 61.3 (CH2Me); 92.2 (C(4)); 114.0
(CN); 116.0 (C(10a)); 119.9 (C(9a)); 116.9, 124.1, 129.2, 129.4
(C(6), C(7), C(8), C(9)); 136.6 (C(5a)); 149.0 (C(4a)); 151.2
(C(1)); 151.8 (C(3)); 169.8 (CO).
10ꢀAnilinocarbonylmethylthioꢀ3ꢀchloroꢀ4ꢀcyanoꢀ5,10ꢀdiꢀ
hydrobenzo[b][1,6]naphthyridine (13c). MS, m/z (Irel (%)): 239
[M – SCH2CONHPh]+ (100), 204 [M – SCH2CONHPh –
Cl]+ (18), 177 [M – SCH2CONHPh – Cl – HCN]+ (19), 93
[PhNH2]+ (37). IR, ν/cm–1: 3291, 3223, 3193, 3120 (NH),
2232 (CN), 1650 (CO).
2ꢀChloroꢀ3ꢀcyanoꢀ4ꢀ(2ꢀhydroxyanilino)ꢀ5ꢀ[(4ꢀnitropheꢀ
nyl)hydrazono]methylpyridine (11). pꢀNitrophenylhydrazine
(0.11 g, 0.73 mmol) and a drop of AcOH were added to aldehyde
10 (0.1 g, 0.37 mmol) in 7 mL of PriOH. The reaction mixture
was refluxed for 11 h. The precipitate that formed was filtered
off, washed with PriOH and ether, and dried to give solvate
11•EtOH (1 : 1) (0.08 g, 53%). MS, m/z (Irel (%)): 408 [M]+
(21), 406 [M – 2 H]+ (30), 378 [M – NO]+ (7), 306 (51), 256
[M – NHNHC6H4NO2]+ (100). 1H NMR, δ: 6.84, 7.13 (both t,
1 H each, H(4´), H(5´), Jo = 7.2 Hz); 6.97, 7.30 (both d,
1 H each, H(3´), H(6´), Jo = 7.2 Hz); 7.13 (d, 2 H, H arom., J =
9.2 Hz); 8.15 (d, 2 H, H arom., J = 9.2 Hz); ∼10.2, 10.53, 11.55
(all br.s, 2 NH, OH).
4ꢀCyanoꢀ3ꢀ(phenylthio)benzo[b][1,6]naphthyridine (14a).
MS, m/z (Irel (%)): 313 [M]+ (95), 312 [M – H]+ (100), 287
[M – CN]+ (33).
4ꢀCyanoꢀ3ꢀethoxycarbonylmethylthiobenzo[b][1,6]naphꢀ
thyridine (14b). Sodium acetate (0.3 g) was added to compound
13b (0.2 g, 0.84 mmol) in 15 mL of PriOH. The reaction mixture
was refluxed with stirring for 4.5 h. The precipitate that formed
was filtered off, washed with PriOH and water, and dried to give
compound 14b (0.11 g, 61%). MS, m/z (Irel (%)): 323 [M]+
(30), 250 [M – COOEt]+ (100). IR, ν/cm–1: 2218 (CN),
1728 (CO).
3ꢀAnilinocarbonylmethylthioꢀ4ꢀcyanobenzo[b][1,6]naphthyrꢀ
idine (14c). MS, m/z (Irel (%)): 370 [M]+ (23), 278 [M – NHPh]+
(100), 250 [M – CONHPh]+ (44). IR, ν/cm–1: 3316 (NH),
2229 (CN), 1672 (CO).
Benzonaphthyridines 13a—c, 14a,c, 15a,b, 17a—c, and 18
(general procedure). The reaction conditions are specified in
Table 4. A mixture of compound 4 (0.2 g), a thiol or amine, and
a catalyst (if necessary) was stirred in 15 mL of PriOH (in 10 mL
of DMF for 17c). The precipitate that formed was filtered off,
1ꢀAminoꢀ2ꢀethoxycarbonylbenzo[b]thieno[2,3ꢀh][1,6]naphꢀ
thyridine (15a). MS, m/z (Irel (%)): 323 [M]+ (100), 295
[M – C2H4]+ (50), 277 [M – EtOH]+ (75), 250 [M – COOEt]+

2128
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002
Ivanov et al.
(80), 205 (62). IR, ν/cm–1: 3451, 3384, 3322, 3275 (NH2), 1670
(CO). 1H NMR, δ: 1.33 (t, 3 H, Me, Jo = 7.2 Hz); 4.32 (q, 2 H,
CH2, Jo = 7.2 Hz); 7.35, 8.65 (both br.s, 2 H, NH2); 7.75 (t,
1 H, H(8), Jo = 8.0 Hz); 8.03 (t, 1 H, H(9), Jo = 8.0 Hz); 8.31
(d, 2 H, H(10), H(7), Jo = 8.0 Hz); 9.47 (s, 1 H, H(6)); 9.53
(s, 1 H, H(5)).
240 [M – NHPh]+ (100). IR, ν/cm–1: 3392, 3307, 3220 (NH),
2225 (CN). Compound 18 contains impurities of aniline and
adduct 19 (∼16%) (1H NMR data). Adduct 19: 1H NMR, δ: 5.10
(s, 1 H, H(10)); 6.90 (t, 1 H, H(4´), J = 8.8 Hz); 6.95 (t, 1 H,
H(8), J = 7.4 Hz); 7.05 (d, 1 H, H(9), J = 7.4 Hz); 7.12 (t, 1 H,
H(7), J = 7.4 Hz); 7.22 (t, 2 H, H(3´), H(5´), J = 8.8 Hz); 7.36
(d, 1 H, H(6), J = 7.4 Hz); 7.49 (t, 2 H, H(2´), H(6´)); 7.70 (s,
1 H, H(1)); 8.70 (s, 1 H, NHPh); 9.50 (s, 1 H, NH(5)).
1ꢀAminoꢀ2ꢀanilinocarbonylbenzo[b]thieno[2,3ꢀh][1,6]naphꢀ
thyridine (15b). MS, m/z (Irel (%)): 370 [M]+ (40), 278
[M – NHPh]+ (100). IR, ν/cm–1: 3456, 3384, 3334 (NH2, NH),
1
1637 (CO). H NMR, δ: 7.08 (t, 1 H, H(4´), Jo = 7.6 Hz); 7.34
References
(t, 2 H, H(3´), H(5´), Jo = 7.6 Hz); 7.74 (d, 2 H, H(2´), H(6´),
Jo = 7.6 Hz); 7.78 (t, 1 H, H(8), Jo = 8.0 Hz); 8.07 (t, 1 H, H(9),
Jo = 8.0 Hz); 8.23 (br.s, 2 H, NH2); 8.35, 8.36 (both d, 1 H each,
1. V. G. Granik and S. I. Kaimanakova, Khim. Geterotsikl.
Soedin., 1983, 816 [Chem. Heterocycl. Compd., 1983, 19, 714
(Engl. Transl.)].
2. N. Z. Yalysheva, N. P. Solov´eva, V. V. Chistyakov, Yu. N.
Sheinker, and V. G. Granik, Khim. Geterotsikl. Soedin.,
1986, 1118 [Chem. Heterocycl. Compd., 1986, 22, 910 (Engl.
Transl.)].
3. O. N. Chupakhin, V. N. Charushin, and H. C. van der Plas,
Tetrahedron, 1988, 1.
4. G. Levy and G. Nelson, in Carbonꢀ13 Nuclear Magnetic Resoꢀ
nance for Organic Chemists, WileyꢀInterscience, Division of
J. Wiley and Sons, Inc., New York—London—Sydney—
Toronto, 1972.
5. H. Hara and H. C. van der Plas, J. Heterocycl. Chem., 1982,
19, 1527.
6. V. G. Granik, A. V. Kadushkin, and J. Liebsher, Adv.
Heterocycl. Chem., 1998, 72, 79.
7. N. Z. Tugusheva, L. V. Ershov, V. G. Granik, G. Ya. Shvarts,
R. D. Syubaev, and M. D. Mashkovskii, Khim.ꢀFarm. Zh.,
1986, 20, No. 7, 830 [Pharm. Chem. J., 1986, 20, No. 7, 483
(Engl. Transl.)].
8. O. N. Chupakhin and I. Ya. Postovskii, Usp. Khim., 1976, 45,
908 [Russ. Chem. Rev., 1976, 45, 454 (Engl. Transl.)].
1
H(7), H(10), Jo = 8.0 Hz); 9.51 (br.s, 1 H, H(6), JC,H
=
1
166.2 Hz); 9.56 (s, 1 H, H(5), JC,H = 184.7 Hz); 9.63
(br.s, 1 H, NH).
3ꢀChloroꢀ4ꢀcyanoꢀ10ꢀdicyanomethylꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (16). A mixture of compound 4 (0.2 g,
0.84 mmol) and malononitrile (0.06 g, 0.84 mmol) in 10 mL of
DMF was stirred for five days and then diluted with water
(20 mL). The precipitate that formed was filtered off, washed
with water and ethanol, and dried to give crude adduct 16 (0.24 g,
94%). The product recrystallized from MeCN contains the startꢀ
ing compound 4 (∼10%) (1H NMR data), m.p. 285—290 °C
(decomp.).
3ꢀButylaminoꢀ4ꢀcyanobenzo[b][1,6]naphthyridine (17a).
MS, m/z (Irel (%)): 276 [M]+ (24), 233 [M – (CH2)2Me]+ (100).
4ꢀCyanoꢀ3ꢀ[1ꢀ(hydroxymethyl)propyl]aminobenꢀ
zo[b][1,6]naphthyridine (17b). MS, m/z (Irel (%)): 292 [M]+
(50), 261 [M – CH2OH]+ (100).
4ꢀCyanoꢀ3ꢀ(hexahydroazepino)benzo[b][1,6]naphthyridine
(17c). A mixture of compound 4 (0.2 g, 0.84 mmol) and
hexahydroazepine (0.25 g, 2.51 mmol) in 5 mL of DMF was
stirred at 40 °C for 40 min and then diluted with water (20 mL).
The precipitate that formed was filtered off, washed with water
and EtOH, and dried to give compound 17c (0.20 g, 79%). MS,
m/z (Irel (%)): 302 [M]+ (100), 259 [M – (CH2)Me]+ (71).
10ꢀ(4ꢀAminophenyl)ꢀ3ꢀchloroꢀ4ꢀcyanoꢀ5,10ꢀdihydrobenꢀ
zo[b][1,6]naphthyridine (18). MS, m/z (Irel (%)): 332 [M]+ (84),
Received January 11, 2002;
in revised form March 29, 2002