Substituted 3- and 5-formylpyridin-2-ones in the synthesis of 1-aryl-1,6-naphthyridinone derivatives

Article abstract of DOI:10.1007/s11172-009-0325-7

New 1-aryl-6-[2-(dimethylamino)vinyl]-4-oxo-1,4-dihydropyrimidine-5- carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbonitriles containing electron-withdrawing substituents in the benzene ring were synthesized from enamino amides and dimethyl

Full text of DOI:10.1007/s11172-009-0325-7

Russian Chemical Bulletin, International Edition, Vol. 58, No. 11, pp. 2336—2246, November, 2009
2336
Substituted 3ꢀ and 5ꢀformylpyridinꢀ2ꢀones in the synthesis of
1ꢀarylꢀ1,6ꢀnaphthyridinone derivatives
M. I. Medvedeva,a N. Z. Tugusheva,b L. M. Alekseeva,b M. I. Evstratova,b S. S. Kiselev,b
V. V. Chernyshev,c G. V. Avramenko,a and V. G. Granikb
aD. Mendeleyev University of Chemical Technology of Russia,
9 pl. Miusskaya, 125047 Moscow, Russian Federation.
Eꢀmail: marinacasper@gmail.com
bState Research Center of Antibiotics (SRCA),
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Eꢀmail: vggranik@mail.ru
cDepartment of Chemistry, M. V. Lomonosov Moscow University,
Build. 3, 1 Leninskie Gory, 119992 Moscow, Russian Federation.
Eꢀmail: cher@biocryst.phys.msu.su
New 1ꢀarylꢀ6ꢀ[2ꢀ(dimethylamino)vinyl]ꢀ4ꢀoxoꢀ1,4ꢀdihydropyrimidineꢀ5ꢀcarbonitriles and
4ꢀarylaminoꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitriles containing electronꢀwithdrawing
substituents in the benzene ring were synthesized from enamino amides and dimethylformamide
dialkylacetals. The influence of various dimethylformamide acetals on the yield of 3ꢀ(4ꢀchloroꢀ
anilino)ꢀ2ꢀcyanoꢀ5ꢀ(dimethylamino)pentaꢀ2,4ꢀdienoic acid Nꢀ(dimethylamino)methylꢀ
ideneamide was investigated in the reaction of these acetals with 3ꢀ(4ꢀchloroanilino)ꢀ
2ꢀcyanocrotonamide. New 4ꢀarylaminoꢀ5ꢀformylꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitriles
and 4ꢀarylaminoꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbaldehydes containing electronꢀwithdrawꢀ
ing substituents in the benzene ring were synthesized. The latter compounds were converted
into new substituted 1,6ꢀnaphthyridinones by the action of various CH acids. A new approach
to the synthesis of 4ꢀ(4ꢀfluoroanilino)ꢀ5ꢀformylꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile
using dimethylformamide diisopropylacetal under mild conditions was developed. The comꢀ
parative reactivity of the formyl group in the reactions of 4ꢀarylaminoꢀ5ꢀformylꢀ2ꢀoxoꢀ
1,2ꢀdihydropyridineꢀ3ꢀcarbonitriles and in 4ꢀarylaminoꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbꢀ
aldehydes with malononitrile was determined using HPLC.
Key words: enamino amides, dimethylformamide acetals, 4ꢀarylaminoꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyridineꢀ3ꢀcarbonitriles, 3ꢀarylaminoꢀ2ꢀcyanoꢀ5ꢀdimethylaminoꢀNꢀ[(dimethylamino)methylꢀ
idene]pentaꢀ2,4ꢀdien amides, 4ꢀarylaminoꢀ5ꢀformylꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboꢀ
nitriles, 4ꢀarylaminoꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbaldehydes, 1ꢀarylꢀ3,8ꢀdicyanoꢀ
2ꢀiminoꢀ1,6ꢀnaphthyridineꢀ2,5(1H,6H)ꢀdiones, 1ꢀarylꢀ5ꢀchloroꢀ3ꢀnitroꢀ1,6ꢀnaphthyridineꢀ
2(1H)ꢀones, the Knoevenagel reaction, Xꢀray diffraction, HPLC.
Enamines are important compounds usable in various
Earlier,5,6 the procedure for the synthesis of various
1ꢀalkylꢀ and 1ꢀarylꢀ6ꢀ[2ꢀ(N,Nꢀdimethylamino)vinyl]ꢀ
4ꢀoxoꢀ1,4ꢀdihydropyrimidineꢀ5ꢀcarbonitriles 1 has been
developed based on the reactions of amide acetals with
the amino group of primary amides and the methyl group
of 3ꢀarylaminoꢀ2ꢀcyanocrotonamides 2. Pyrimidinones 1
were found5—8 to undergo recyclization to form 4ꢀarylꢀ
aminoꢀ3ꢀcyanoꢀ5ꢀformylpyridinꢀ2ꢀones 3 under condiꢀ
tions of both basic and acid hydrolysis (Scheme 1).
At present, it has been proven8 that it is acylamidines 4
that undergo cyclization in an acid medium to form
5ꢀformylpyridinꢀ2ꢀones 5. Nevertheless, isolation of pure
acylamidines of type 4 is rather difficult since, as a rule,
they are formed in a mixture with pyrimidinones 1.
fields of organic and medicinal chemistry. A number
of reviews is devoted to their properties.1,2 Numerous
methods of synthesis of various heterocyclic compounds
including those with pronounced biological activity are
developed on the basis of enamines.
Recently,3 a new approach to the synthesis of 1ꢀpheꢀ
nylꢀ1,6ꢀnaphthyridines has been developed by us when
studying reactions of CH acids with 4ꢀanilinoꢀ3ꢀ and
ꢀ5ꢀformylꢀpyridones (see also Ref. 4). The general charꢀ
acter of the methods proposed and possibility of extenꢀ
sion of their scope with the purpose of obtaining a number
of new 1ꢀarylꢀ1,6ꢀnaphthyridines substituted in paraꢀpoꢀ
sition of the benzene ring are shown in the present study.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2265—2274, November, 2009.
1066ꢀ5285/09/5811ꢀ2336 © 2009 Springer Science+Business Media, Inc.

1ꢀArylꢀ1,6ꢀnaphthyridinone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009 2337
Scheme 1
R1 = Cl (a), F (b), H (c); R2 = Et (a), Me (b), Pri (c)
However, it was found7 that individual condensation
product 4a can be isolated in high yield from the reaction
of (pꢀchloroanilino)enamide 2а with dimethylformamide
diethylacetal (6а).
losses. Therefore, a more efficient procedure for the prepaꢀ
ration of 5ꢀformylpyridone 5a involved evaporation
in vacuo of an excess of the acetal and the solvent folꢀ
lowed by acid hydrolysis of the reaction mixture without
isolation of the individual acylamidine 4а. 5ꢀFormylꢀ
pyridone 5a was thus obtained in a yield of 35%.
Using the known procedure,5,9 we have synthesized
enaminoamides 2a,b by refluxing enaminoamide 7
with pꢀchloroaniline and pꢀfluoroaniline in acetic acid.
Dimethylformamide dimethylacetal (6b) was used to preꢀ
pare acylamidine 4а. As it turned out, the crude condenꢀ
sation product of enaminoamide 2a with acetal 6b is a
mixture of acylamidine 4а and pyrimidinone 1а, as has
been noted earlier8 for phenylꢀ and tolylꢀsubstituted
derivatives. To clarify the influence of the nature of the
acetal (6a or 6b) on the yield of acylamidine 4а, we carꢀ
ried out a comparative experiment: enaminoamide 2a
was refluxed in ethanol for 40 min with dimethylformꢀ
amide dimethylacetal and diethylacetal. The ratios of
acylamidine 4а and pyrimidinone 1а in the crude prodꢀ
ucts are approximately equal (1Н NMR): 79 : 21 for the
experiment with acetal 6а and 75 : 25 for the experiment
with acetal 6b. Sufficiently pure acylamidine 4а could not
be obtained upon recrystallization without considerable
On the contrary, the use of (pꢀfluoroanilino)enamide
2b in the reaction with dimethylformamide dimethylacetal
(6b) under similar conditions (shortꢀtime refluxing in
EtOH) leads only to pyrimidinone 1b, which does not
allow one to synthesize 5ꢀformylpyridone 5b. Probably,
intermediate acylamidine 4b transforms fast into pyriꢀ
midinone 1b on heating. In the present study, we someꢀ
what changed the method developed earlier8 with the
purpose of preparing compound 5b. First, the reaction of
enaminoamide 2b with acetal 6b was carried out in dry
toluene at 52 °С and amidine 8b was obtained in high
yield (65%). Thus, the primary amino group of the amide
is more prone to the attack of acetal ambident cation
under given conditions than the methyl group. Then
amidine 8b reacted with dimethylformamide diisopropylꢀ
acetal (6с) under mild conditions. We failed to isolate

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009
Medvedeva et al.
compound 4b in the individual state because of its low
stability under the reaction conditions and its transformaꢀ
tion into pyrimidinone 1b. However, 5ꢀformylpyridone
5b was isolated in a yield of 26% by treatment of the
reaction mixture, following its concentration in vacuo,
with 90% aqueous acetic acid. Compound 5b can only be
formed from acylamidine 4b,8 hence it is possible to
synthesize compound 4b using such an approach. It should
be noted that it was proved necessary to use dimethylꢀ
formamide diisopropylacetal (6с) rather then usually
employed amide acetals (6а,b) since its higher reactivity
due to better stabilization of the ambident cation10 (the
reactive species in the reactions with nucleophiles) allows
reduction of the condensation temperature. This fact
points to the possibility of using other, more reactive amide
acetals in similar syntheses. This can lead to the systems
that are inaccessible under common condensation condiꢀ
tions because of alternative directions of the heteroꢀ
cyclization.
elucidation of structure—activity relationships. At the
same time, such 5ꢀsubstituted pyridones can serve as preꢀ
cursors for various annulated heterocycles. Therefore, we
carried out reactions of compound 5а with various CH
acids (Scheme 2). Thus naphthyridinone 9a was obtained
in a yield of 74% by the reaction of 5ꢀformylpyridone 5a
with malononitrile in pyridine at 20 °C in the presence
of triethylamine. Earlier,3 it has been found that comꢀ
pound 9c has the naphthyridine structure. The evidence
of bicyclic structure was the presence of signals for the
C atoms of two (rather then three) nitrile groups in
13С NMR spectrum. In contrast to the reaction with
malononitrile, the reaction of aldehyde 5a with ethyl
cyanoacetate does not result in the cyclization of the
Knoevenagel reaction product: substituted vinylpyridone
10 was isolated in a yield of 72%. Earlier,3 it has been
established that compound analogous to compound 10
(a phenyl substituent at the N(1) atom) has the pyridone
structure. Hydrolysis of the ethoxycarbonyl group to
the carboxyl group and subsequent cyclization into
naphthyridinone 11 took place upon refluxing of isolated
vinylpyridone 10 in a basic medium (NaOH in aqueous
methanol).
5ꢀFormylpyridones synthesized are promising as
starting compounds for the preparation of 4ꢀarylaminoꢀ
pyridones derivatives containing various substituents in
position 5, which are of interest from the point of view of
Scheme 2
R1 = Cl (a), H (c)

1ꢀArylꢀ1,6ꢀnaphthyridinone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009 2339
Scheme 3
As was mentioned, recyclization of pyrimidinones
under conditions of alkaline hydrolysis affords substituted
4ꢀaminopyridones.5—7 Compounds comprising a 4ꢀaminoꢀ
pyridine or 4ꢀaminopyridone fragment are of considerꢀ
able interest due to their potential biological (including
psychotropic, nootropic, etc.) activity.11—13 It is sufficient
to note that this class of compounds includes the wellꢀ
known drugs tacrine and amiridine, which are used in
the therapy of such a serious neurodegenerative disease
as Alzheimer’s disease.14
Tacrine
Amiridine
R1 = Cl (a), F (b)
Another line of investigation of the present study was
the preparation and studies of properties of other aldeꢀ
hydes, viz., 3ꢀformylpyridones.
Reagents and conditions: i. 85% HCOOH, Ni—Al alloy;
ii. 50% HCOOH, Ni—Al alloy; iii. PriOH + piperidine.
To this end, pyrimidinones 1a,b were used, which
have been obtained by refluxing enaminoamides 2a,b
with dimethylformamide dimethylacetal (6b) in dry
toluene and in anhydrous ethanol, respectively. Pyridones
3а,b can be prepared by both hydrolysis of the isolated
pure pyrimidinones and treatment of the reaction mixture
without their isolation in pure state. Compound 3а was
formed as a result of condensation of enaminoamide 2а
with dimethylformamide dimethylacetal (6b) followed by
the treatment of reaction mixture concentrated in vacuo
with 4% aqueous NaOH without isolation of the correꢀ
sponding pyrimidinone 1a. In contrast to 3a, compound
3b was obtained by alkaline hydrolysis of compound 1b.
It is known15 that aromatic nitriles can be transformed
into aldehydes with a large excess of a Ni—Al alloy in
75% HCOOH. Refluxing of 3ꢀcyanopyridones 3a,b
in 50% HCOOH with Ni—Al alloy (1 gram per gram of
the nitrile) afforded only pure formyl derivatives 12a,b
in 43 and 45% yield, respectively (Scheme 3). The reacꢀ
tion of 3ꢀcyanopyridones 3a,b with this alloy in 85%
HCOOH afforded not only 3ꢀformylpyridones 12a,b, but
also tricyclic products 13а,b. 3ꢀFormylpyridones 12а,b
readily undergo cyclization to tricyclic compounds 13a,b
upon refluxing in isopropyl alcohol in the presence of
piperidine.
Scheme 4
R1 = Cl (a), F (b), H (c)
Compounds А and 14 are isomers. The mass specꢀ
trum (ES) of compound 14а shows peaks with m/z 297
[M + H]+•, 319 [M + Na]+•, 615 [2 M + Na]+•. The
mass spectrum (ES) of compound 14b shows peaks with
In other words, it is possible to direct reactions to
the preferred formation of either formylpyridones 12 or
substituted benzonaphthyridines 13 under appropriate
conditions.
Compounds 14a,b were obtained upon reflux of 3ꢀ
formylpyridones 12a,b with malononitrile in anhydrous
ethanol in the presence of triethylamine. One could supꢀ
pose that the Knoevenagel reaction affords substituted
vinylpyridone (A) or naphthyridinone (14) (Scheme 4).
m/z 281 [M + H]+•, 303 [M + Na]+•, 561 [2 M + Na]+•
.
Data from 1H NMR spectroscopy do not allow deterꢀ
mination of the exact structure of compounds 14a,b as
well. For unambiguous elucidation of their structures,
Xꢀray diffraction analysis of compound 14а was carried
out. All geometrical characteristics of the molecule in
the crystal structure of 14а (Fig. 1) have values similar to
those found in Cambridge Crystallographic Database

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009
Medvedeva et al.
C(7)
in 78 and 86% yields upon refluxing 3ꢀformylpyridones
12а,b with ethyl nitroacetate in isopropyl alcohol in the
presence of a secondary amine (morpholine) (Scheme 5).
3ꢀNitroꢀ1ꢀphenylꢀ1,6ꢀnaphthyridineꢀ2,5(1Н,6Н)ꢀdione
(15c) has been prepared earlier.3
C(8)
N(6)
C(17i)
C(16i)
C(10)
C(18)
C(17)
C(9)
C(5)
C(4)
O(11)
N(1)
C(3)
Cl
C(15)
Scheme 5
C(16)
C(2)
C(13)
N(14)
N(12)
Fig. 1. Molecular structure and atom numeration of compound
14а [code of symmetry (i) x, 1/2 – y, z]. Spheres of atom disꢀ
placements are presented with 50% probability for nonhydrogen
atoms.
Table 1. Characteristics of hydrogen bonds in compound 14a
D—H...A
d/Å
D—H...A
angle/deg
D—H H...A D...A
N(6)—H(6)...N(12)
N(12)—H(12)...O(11) 0.86 2.18 2.913(7)
0.86 2.02 2.789(8)
149
143
c
0
b
R1 = Cl (a), F (b), H (c)
a
The corresponding 5ꢀchloroꢀ3ꢀnitroꢀsubstituted naphꢀ
thyridinones 16a—с were isolated by the treatment of
compounds 15a—c with phosphoryl chloride in the presꢀ
ence of triethylamine hydrochloride. Triethylamine
hydrochloride was used as an additional source of the
chloride anions. Reactions of compounds 16a—с with
morpholine in refluxing isopropyl alcohol afforded comꢀ
pounds 17a—с in high yields, this reaction was underꢀ
taken to test the ability of chlorine atom in the naphthyrꢀ
idine structure to undergo the nucleophilic substitution.
It was of interest to compare the reactivity of both
types of the obtained pyridinecarbaldehydes with respect
to nucleophilic reagents (malononitrile was chosen as
the CH acid). Certainly, the presence of the electronꢀ
withdrawing nitrile group in position 3 of 5ꢀformyl
derivatives favors their enhanced reactivity. However, it
should be taken into account that in this compound the
cyano and formyl groups are in metaꢀposition relative
to each other and only inductive effects influence their
interaction. One should not expect for considerable differꢀ
Fig. 2. Fragments of crystal packing of 14а: molecule chains
linked by hydrogen bonds (indicated by dashed lines).
(CCDC).16 Almost all the atoms except for С(16) and
С(17) with attached protons are in the mirror symmetry
plane m. In the crystal, the amine and imine protons are
involved in the intermolecular hydrogen bonds N—H...N
and N—H...O (Table 1). These bonds bind the moleꢀ
cules in chains that are parallel to the axis c of the unit
cell (Fig. 2). All structural data were deposited with the
Cambridge Crystallographic Database (CCDC 692639)*.
1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀnitroꢀ1,6ꢀnaphthyridineꢀ
2,5(1Н,6Н)ꢀdione (15а) and 1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀnitroꢀ
1,6ꢀnaphthyridineꢀ2,5(1Н,6Н)ꢀdione (15b) were prepared
* Copies can be obtained, free of charge, on application to the
Cambridge Crystallographic Data Centre (CCDC), 12 Union
Road, Cambrige CB2 1EZ, UK. Fax: +44 (0) 1223 336033.
Eꢀmail: deposit@ccdc.cam.ac.uk.

1ꢀArylꢀ1,6ꢀnaphthyridinone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009 2341
Scheme 6
of the reactions was monitored, and the purity of the compounds
was checked, by TLC on Merсk Silica gel 60 F254 plates
(chloroform, chloroform—ethanol (10 : 1), ethyl acetate—
ethanol (10 : 1), acetone). The melting points were determined
on an Electrotermal 9100 instrument (UK). The following
N,Nꢀdimethylformamide acetals were used: dimethyl (6b) (purity
97%, Lancaster), diethyl (6а) (purity 94%, Lancaster), diisoꢀ
propyl (6с) (purity 94%, Lancaster). Ni—Al alloy was used (Alfa
Aesar, mass ratio 1 : 1).
ence in the rates of reactions of 3ꢀ and 5ꢀformylpyridones
with malononitrile. A comparision of the reaction rates
was carried out by HPLC under competitive process
conditions: DMSO, 20 °C, the ratio 5с (or 5а) : 12с (or
12а) : malononitrile was 1 : 1 : 0.25. The samples were
withdrawn 2 h after beginning of the reaction. In the case
of phenylderivatives (5с and 12с), the ratio of the reacꢀ
tion products (9с : 14с) was 94 : 6, and in the case of
chlorophenylderivatives (5а and 12а) the ratio of the
reaction products (9а : 14а) was 98 : 2. Therefore, in the
reaction with malononitrile the reactivity of 5ꢀformyl
derivatives was considerably higher than that of 3ꢀformyl
derivatives. It can be related to the steric effects: in the
case of 3ꢀaldehyde the first step of condensation leads
to a more steric hindered compound than in the case of
5ꢀaldehyde (Scheme 6).
Thus, new 1ꢀarylpyrimidinꢀ4ꢀone derivatives with a
halogen substituent in the benzene ring were synthesized.
Its behavior under conditions of alkaline and acid hyꢀ
drolysis was studied. 4ꢀAnilinoꢀ5ꢀformylꢀ2ꢀpyridones and
4ꢀanilinoꢀ3ꢀformylꢀ2ꢀpyridones were obtained. A series
of substituted 1,6ꢀnaphthyridines were synthesized by
the Knoevenagel reaction on the basis of these 3ꢀ and
5ꢀformylpyridones.
Analysis of the reaction mixtures by HPLC was carried out
on a Water Breeze system consisted of a gradient pump (Waters
1525), twoꢀwavelength detector (Waters 2487), and a manual
injector Rheodyne. Software Empower, an analytical column
Phenomenex Luna C 18(2), 150×4.6 mm, and a UV detector
(254 nm) were used. The eluent flow rate was 1 mL min–1
,
temperature of the column was 20 °С, time of differentiation
was 10 min. The mobile phase was methanol—buffer solution
(20 : 80 for the mixture of 9c and 14c or 50 : 50 for the mixture
9a and 14a). Buffer was prepared by addition of nꢀpropylamine
to 0.01% aqueous formic acid to рН 5.2. Samples of the analyzed
compounds and the reaction mixtures were obtained by dissolving
the corresponding samples in a mixture DMSO—methanol
and by dilution with the mobile phase up to 5—10 mg L–1
concentration, the retention time (τ/min–1) was 6.8 (9c),
3.8 (14c), 2.5 (9a), and 4.4 (14a).
1ꢀ(4ꢀChlorophenyl)ꢀ6ꢀ[2ꢀ(dimethylamino)vinyl]ꢀ4ꢀoxoꢀ
1,4ꢀdihydropyrimidineꢀ5ꢀcarbonitrile (1a). A mixture of enaminoꢀ
amide 2а (0.200 g, 0.85 mmol) and dimethylformamide dimethyl
acetal (6b) (0.459 g, 3.85 mmol) in dry toluene (0.9 mL) was
refluxed for 6 h (TLC). The reaction mixture was kept at 20 °C
for 12 h, triturated, the precipitate was filtered off, washed with
toluene and dried. Compound 1а was obtained in a yield of
Experimental
The IRꢀspectra were recorded on an FSMꢀ1201 instrument
in Nujol mulls. The electron impact (EI) mass spectra (70 eV)
were obtained on a Finnigan SSQꢀ710 mass spectrometer using
a direct intel system, the electrospray ionization (ESI) mass
spectra were recorded on a Waters ZQꢀ2000 mass spectrometer
using a direct intel system without a chromatographic column.
The 1H NMR spectra were recorded on a Bruker ACꢀ300
spectrometer in DMSOꢀd6 and DMSOꢀd6—CCl4. The course
0.100 g (45%). M.p. 261.6—263.5 °С (PriOH). IR, ν/сm–1
:
2178 (CN); 1628 (CO). ES MS, m/z: 301 [M + Н]+•, 323
1
[M + Na]+•, 601 [2 M + Н]+•, 623 [2 M + Na]+•. Н NMR
(DMSOꢀd6), δ: 2.61, 3.10 (both br.s, 3 Н each, NMe2); 4.02
(d, 1 H, H(6´), Jo = 12.86 Hz); 7.54, 7.63 (А2В2, 4 Н, Ar,
Jo = 8.71 Hz); 7.94 (d, 1 H, H(6″), Jo = 12.80 Hz); 8.13 (s, 1 Н,

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Medvedeva et al.
Н(2)). Found (%): N, 18.60. С15H13ClN4O. Calculated (%):
N, 18.63.
and dimethylformamide dimethyl acetal (6b) (16.320 g,
136.9 mmol) in dry toluene (30 mL) was refluxed for 2.5 h
(TLC). The precipitate that formed after cooling the reaction
mixture to 20 °C was filtered off, washed with dry toluene and
petroleum ether. Pyrimidinone 3b was obtained in a yield of
2.753 g (71%). Aqueous solution of NaOH (4%, 27.5 mL) was
added to the precipitate obtained, the mixture was refluxed for
1 h. The reaction mixture was cooled, diluted with 3 volumes
of water and neutralized with concentrated HCl (20 mL). The
precipitate that formed was filtered off, washed with water to
pH 7, and dried. Compound 3b was obtained in a yield of 2.109 g
(95% with respect to 1b, 67% with respect to 2b). The mother
liquor of the reaction with acetal was concentrated in vacuo
almost to dryness. Aqueous solution of NaOH (4%, 11.5 mL)
was added to the semicrystalline residue, the mixture was refluxed
for 1 h, cooled, diluted with 3 volumes of water, and neutralized
with concentrated HCl (5 mL). The precipitate that formed was
filtered off, washed with water to pH 7, and dried. Additional
crop of compound 3b was obtained (0.666 g (21%)). Total yield
was 89%. M.p. 285.9—287.2 °С (PriOH). IR, ν/сm–1: 3266,
3146 (NH, NH); 2224 (CN); 1665 (CONH); 1636 (С=С).
6ꢀ[2ꢀ(Dimethylamino)vinyl]ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4ꢀoxoꢀ
1,4ꢀdihydropyrimidineꢀ5ꢀcarbonitrile (1b). A mixture of enaminoꢀ
amide 2b (0.100 g, 0.46 mmol) and dimethylformamide dimethyl
acetal (6b) (0.544 g, 4.57 mmol) in absolute ethanol (2 mL)
was refluxed for 2 h (TLC). The reaction mixture was cooled,
the precipitate that formed was filtered off and washed with
ethanol. Compound 1b was obtained in a yield of 0.078 g (61%).
M.p. 262.5—263.2 °С (PriOH). IR, ν/сm–1: 2205 (CN); 1643
(CO). ES MS, m/z: 285 [M + Н]+•, 307 [M + Na]+•, 569
1
[2 M + Н]+•, 591 [2 M + Na]+•. Н NMR (DMSOꢀd6), δ:
2.59, 3.09 (both br.s, 3 Н each, NMe2); 4.01 (d, 1 H, H(6´),
Jo = 12.92 Hz); 7.41 (t, 2 Н, Н(3´), Н(3″), Jo = 8.65 Hz);
7.55—7.59 (m, 2 H, Н(2´), Н(2″)); 7.92 (d, 1 H, H(6″),
Jo = 12.83 Hz); 8.14 (s, 1 Н, Н(2)). Found (%): N, 19.76.
С15H13FN4O. Calculated (%): N, 19.71.
3ꢀ(4ꢀChloroanilino)ꢀ2ꢀcyanocrotonamide (2а). A mixture of
2ꢀcyanoꢀ3ꢀdimethylaminocrotonamide (7) (5.000 g, 33 mmol)
and pꢀchloroaniline (4.630 g, 36 mmol) in glacial acetic acid
(50 mL) was refluxed for 3 h. The reaction mixture was kept at
20 °C for 12 h. White crystals that formed were filtered off,
washed with ethyl acetate, and dried. The mother liquor was
concentrated in vacuo, the crystalline residue was washed
with water, filtered off, washed with ethyl acetate, and dried.
Compound 2а was obtained in a total yield of 4.590 g (80%).
M.p. 225.5—226.0 °С (EtOH) (cf. Ref. 7: m.p. 234 °C (EtOH)).
IR, ν/сm–1: 3368, 3196 (NH, NH2); 2200 (CN); 1654 (CONH2).
ES MS, m/z: 230 [M + Н]+•, 252 [M + Na]+•, 459 [2 M + Н]+•
,
481 [2 M + Na]+•. 1Н NMR (DMSOꢀd6), δ: 5.72 (d, 1 H, H(5),
Jo = 7.50 Hz); 7.13—7.27 (m, 5 Н, Н(6), Ar); 9.16 (br.s, 1 H,
NHC(4)); 11.26 (br.s, 1 H, N(1)Н). Found (%): С, 63.02; Н,
3.75; N, 18.34. С12H8FN3O. Calculated (%): C, 62.88; Н, 3.52;
N, 18.33.
3ꢀ(4ꢀChloroanilino)ꢀ2ꢀcyanoꢀ5ꢀ(dimethylamino)pentaꢀ
2,4ꢀdienoic acid Nꢀ[(dimethylamino)methylidene]amide (4а).
A mixture of enaminoamide 2а (3.530 g, 15 mmol) and dimethylꢀ
formamide dimethyl acetal (6b) (5.360 g, 45 mmol) in absolute
ethanol (30 mL) was refluxed for 50 min. The reaction mixture
was cooled, the precipitate that formed was filtered off, washed
with absolute ethanol. A mixture of compound 4а and pyrimidinꢀ
one 1а was obtained in a yield of 3.364 g. M.p. 170—172 °C. The
mass spectrum of this product coincides with that of compound
1а. 1Н NMR (DMSOꢀd6), δ: 2.89 (br.s, 6 Н, NMe2); 3.06, 3.15
(both br.s, 3 H each, NMe2); 4.74 (d, 1 H, H(4), Jo = 13.12 Hz);
7.21, 7.32 (А2В2, 4 Н, Ar, Jo = 8.50 Hz); 7.41 (d, 1 Н, Н(5),
Jo = 13.10 Hz); 8.37 (s, 1 Н, NCHNMe2); 12.44 (br.s, 1 H, NH).
4ꢀ(4ꢀChloroanilino)ꢀ5ꢀformylꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ
3ꢀcarbonitrile (5a). A mixture of enaminoamide 2а (0.606 g,
4 mmol) and dimethylformamide dimethyl acetal (6b) (5.380 g,
41 mmol) was refluxed for 15 min at 76 °C. The reactin mixture
was cooled to 20 °C, and concentrated in vacuo. Glacial acetic
acid (6 mL) and water (0.6 mL) were added to the dry residue.
The yellow solution that formed was kept at 20 °С for 3 days.
The precipitate that formed was filtered off and washed with
ethyl acetate. Compound 5a was obtained in a yield of 0.368 g
(35%). M.p. 285.9—287.2 °C (DMF) (cf. Ref. 17: m.p. 290 °С
(decomp., PriOH—DMF, 3 : 2)). IR, ν/сm–1: 3198, 3090 (NH);
2218 (CN); 1692 (СОН); 1645 (CONH). ES MS, m/z: 296
1
ES MS, m/z: 258 [M + Na]+•, 493 [2 M + Na]+•. Н NMR
(DMSOꢀd6), δ: 2.22 (s, 3 H, Me); 6.80, 7.10 (both br.s, 1 H
each, CONH2); 7.26, 7.42 (А2В2, 4 Н, Ar, Jo = 8.60 Hz); 12.71
(br.s, 1 H, NH).
2ꢀCyanoꢀ3ꢀ(4ꢀfluoroanilino)crotonamide (2b) was prepared
analogously to 2a from compound 7 and 4ꢀfluoroaniline. The
yield was 84%. M.p. 211.5—212.4 °С (EtOH). IR, ν/сm–1: 3399,
3184 (NH, NH2); 2195 (CN); 1670 (CONH2). ES MS, m/z: 242
[M + Na]+•, 461 [2 M + Na]+•. 1Н NMR (DMSOꢀd6), δ: 2.17
(s, 3 H, Me); 6.80, 7.10 (both br.s, 1 H each, CONH2); 7.20,
7.28 (both m, 2 H each, Ar); 12.60 (br.s, 1 H, NH). Found (%):
N, 19.34. С11H10FN3O. Calculated (%): N, 19.17.
4ꢀ(4ꢀChloroanilino)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboꢀ
nitrile (3a). A mixture of enaminoamide 2а (3.000 g, 12.74 mmol)
and dimethylformamide dimethyl acetal (6b) (4.550 g,
38.2 mmol) in absolute ethanol (26 mL) was refluxed for 4.5 h
(TLC). The reaction mixture was cooled to 20 °С, the solvent
was evaporated in vacuo, an aqueous solution of NaOH (4%,
40 mL) was added to the semicrystalline residue, and the mixture
was refluxed for 1 h. The reaction mixture was cooled, diluted
with 3 volumes of water, neutralized with concentrated HCl
(5 mL). The precipitate that formed was filtered off, washed
with water to pH 7, and dried. Compound 3а was obtained in
a yield of 1.649 g (55%). M.p. 278.3—279.1 °С (DMF—PriOH,
1 : 3) (cf. Ref. 7: m.p. 279—281 °С (aqueous DMF)). IR, ν/сm–1
:
[M + Na]+•, 569 [2 M + Na]+•, 244 [M – CHO]+•
.
3258, 3140 (NH, NH); 2226 (CN); 1661 (CONH); 1628 (С=С).
EI MS, m/z (Irel (%)): 245 [M]+• (100), 217 [M – CO]+• (9),
127 [C6H4ClNH2]+• (16), 111 [C6H4Сl]+• (57). 1Н NMR
(DMSOꢀd6), δ: 5.75 (d, 1 H, H(5), Jo = 7.47 Hz); 7.16, 7.30
(А2В2, 4 H, Ar, Jo = 8.55 Hz); 7.21 (d, 1 H, H(6), Jo = 7.53 Hz);
9.20 (br.s, 1 H, NHС(4)); 11.28 (br.s, 1 H, N(1)H).
4ꢀ(4ꢀFluoroanilino)ꢀ5ꢀformylꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ
3ꢀcarbonitrile (5b). Dimethylformamide diisopropyl acetal (6с)
(1.68 mL, 0.765 mmol) was added to a suspension of acylamidine
8b (0.700 g, 0.255 mmol) in dry toluene (5 mL). The mixture
obtained was stirred for 2 h at 52—54 °C. The precipitate that
formed was filtered off, the starting acylamidine 8b was recovered
in a yield of 0.340 g. The mother liquor was concentrated
in vacuo almost to dryness. Aqueous acetic acid (90%, 1 mL)
4ꢀ(4ꢀFluoroanilino)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboꢀ
nitrile (3b). A mixture of enaminoamide 2b (3.000 g, 13.7 mmol)

1ꢀArylꢀ1,6ꢀnaphthyridinone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009 2343
was added to the oily residue. The yellow solution that formed
was kept at 20 °С for 2 days. White precipitate that formed
was filtered off. Compound 5b was obtained in a yield of
0.170 g (26% relative to the original amount of compound 8b).
M.p. 322.5 °С (decomp., PriOH—DMF (3 : 2)). ES MS, m/z:
258 [M + Н]+•, 280 [M + Na]+•, 537 [2 M + Na]+•. 1Н NMR
(DMSOꢀd6), δ: 7.20, 7.38 (both m, 2 H each, Ar); 8.39 (s, 1 Н,
С(6)); 9.59 (s, 1 H, COH); 10.51 (br.s, 1 H, N(1)H); 12.32
(br.s, 1 H, NHС(4)). Found (%): С, 60.63; Н, 3.13; N, 16.33.
С13H8FN3O2. Calculated (%): C, 60.70; Н, 3.14; N, 16.34.
NꢀDimethylaminomethylideneꢀ3ꢀ(4ꢀchloroanilino)ꢀ2ꢀcyanoꢀ
crotonamide (8а). Dimethylformamide dimethyl acetal (6b)
(1.67 mL, 12.484 mmol) was added to a suspension of enaminoꢀ
amide 2а (0.490 g, 2.081 mmol) in absolute ethanol (7 mL). The
solution obtained was stirred for 3.5 h at 54 °С. The precipitate
that formed after cooling of the reaction mixture was filtered
off and washed with absolute ethanol. Compound 8а was
obtained in a yield of 0.453 g (75%). M.p. 128.5—129.2 °С
(EtOH). IR, ν/сm–1: 3400 (NH), 2205 (CN), 1630 (CO).
2214 (CN); 1697 (CONH). ES MS, m/z: 369 [M + Н]+•, 391
[M + Na]+•, 759 [2 M + Na]+•. 1Н NMR (DMSOꢀd6), δ: 1.39
(t, 3 H, СООСН2СН3, Jo = 7.10 Hz); 4.35 (q, 2 H, СООСН2СН3,
Jo = 7.10 Hz); 7.59, 7.69 (А2В2, 4 H, Ar, Jo = 8.44 Hz); 8.65,
8.73 (both br.s, 1 H each, H(5´), H(6)); 9.50 (br.s, 1 Н, NH(1)).
Found (%): N, 15.14. С18H13ClN4O3. Calculated (%): N, 15.19.
1ꢀ(4ꢀChlorophenyl)ꢀ8ꢀcyanoꢀ2,7ꢀdioxoꢀ1,2,6,7ꢀtetrahydroꢀ
1,6ꢀnaphthyridineꢀ3ꢀcarboxylic acid (11). Compound 10
(0.150 g, 0.407 mmol) was added to 10 mL of solution of NaOH
(2 g) in methanol (20 mL) and water (10 mL). The mixture
obtained was refluxed for 10.5 h. The reaction mixture
was cooled to 20 °С. The solution of sodium salt obtained was
acidified with concentrated HCl to pH 1 and kept for 0.5 h. The
precipitate that formed was filtered off, and washed with
water. Compound 11 was obtained in a yield of 0.110 g (80%).
M.p. 369.6—371.2 °С (PriOH—DMF, 6 : 1). IR, ν/сm–1
:
3490 (ОН); 3270 (NH); 2216 (CN); 1742 (COОH); 1682
(СО). ES MS, m/z: 342 [M + Н]+•, 364 [M + Na]+•, 705
[2 M + Na]+•. 1Н NMR (DMSOꢀd6), δ: 7.45, 7.57 (А2В2, 4 Н,
Ar, Jo = 8.83 Hz); 8.71, 8.77 (both s, 1 Н each, Н(4), Н(5)).
Found (%): N, 12.03. С16H8ClN3O4. Calculated (%): N, 12.30.
4ꢀ(4ꢀChloroanilino)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbꢀ
aldehyde (12а). An Ni—Al alloy (1 g) was added to a suspension
of pyridone 3а (1 g, 4.073 mmol) in 50 % HCOOH ( 35 mL).
The reaction mixture was refluxed with stirring for 6 h (TLC).
The precipitate was filtered off after cooling the reaction mixture
to 20 °С, washed with small amount of 50% HCOOH and
water. The crude precipitate that represented a mixture of
inorganic salts and the reaction product was extracted with DMF
(4×20 mL), the solids were filtered off, the filtrate was conꢀ
centrated in vacuo to dryness, the residue (crystalline precipitate)
was triturated with petroleum ether, filtered off, and washed
with petroleum ether. Compound 12a was obtained in a yield of
0.433 g (43%). M.p. 301—303 °С (DMF). (We succeeded in
isolation of only small amounts of the starting pyridone from
ES MS, m/z: 291 [M + Н]+•, 581 [2 M + Н]+• 1Н NMR
.
(DMSOꢀd6), δ: 2.27 (s, 3 H, С(4)H3); 3.08, 3.20 (both s, 3 Н
each, NMe2); 7.27, 7.42 (А2В2, 4 Н, Ar, Jo = 8.61 Hz); 8.45 (s,
1 Н, NCHNMe2); 12.99 (br.s, 1 H, NH). Found (%): С, 57.85;
Н, 5.46; N, 19.14. С14H15ClN4O. Calculated (%): C, 57.83;
Н, 5.20; N, 19.27.
NꢀDimethylaminomethylideneꢀ3ꢀ(4ꢀfluoroanilino)ꢀ2ꢀcyanoꢀ
crotonamide (8b). Dimethylformamide dimethyl acetal (6b)
(7.32 mL, 54.792 mmol) was added to a suspension of enaminoꢀ
amide 2b (2.000 g, 9.132 mmol) in dry toluene (25 mL).
The solution obtained was stirred for 1.5 h at 52 °С. White
precipitate that formed was filtered off and washed with dry
toluene. Compound 8b was obtained in a yield of 1.616 g (65%).
M.p. 141.3—142.1 °С (EtOH). IR, ν/сm–1: 3400 (NH), 2199
(CN), 1626 (C=С). ES MS, m/z: 275 [M + Н]+•, 297
1
[M + Na]+•, 549 [2 M + Н]+•. Н NMR (DMSOꢀd6), δ: 2.21
(s, 3 H, С(4)H3); 3.02, 3.16 (both s, 3 Н each, NMe2);
7.25, 7.34 (both m, 2 H each, Ar); 8.47 (s, 1 Н, NCHNMe2);
12.88 (br.s, 1 H, NH). Found (%): С, 61.38; Н, 5.56; N, 20.48.
С14H15FN4O. Calculated (%): C, 61.30; Н, 5.51; N, 20.43.
1ꢀ(4ꢀChlorophenyl)ꢀ3,8ꢀdicyanoꢀ2ꢀiminoꢀ1,6ꢀnaphthyridinꢀ
7(1H,6H)ꢀone (9a). Malononitrile (0.013 g, 0.2 mmol) and
triethylamine (0.02 mL, 0.2 mmol) were added to a suspension
of 5ꢀformylpyridone 5а (0.038 g, 0.139 mmol) in pyridine
(0.38 mL). The reaction mixture was kept for 3 days at 20 °С
(TLC). The precipitate that formed was filtered off and washed
with propanꢀ2ꢀol. Compound 9a was obtained in a yield of
0.033 g (74%). M.p. 287.1—287.5 °С (PriOH—DMF (5 : 1)).
IR, ν/сm–1: 3312, 3289 (NH); 2228, 2210 (CN); 1663 (CONH),
the mother liquor of the reaction mixture.) IR, ν/сm–1
:
3146, 3057 (NH); 1651 (СОН); 1620 (CONH). ES MS, m/z:
249 [M + Н]+•, 271 [M + Na]+•, 519 [2 M + Na]+•, 767
1
[3 M + Na]+•. Н NMR (DMSOꢀd6), δ: 5.87 (d, 1 H, Н(5),
Jo = 7.53 Hz); 7.32, 7.47 (А2В2, 4 Н, Ar, Jo = 8.70 Hz); 7.38
(d, 1 Н, Н(6), Jo = 7.50 Hz); 10.03 (s, 1 Н, СОН); 11.17 (br.s,
1 H, NH(1)); 11.63 (br.s, 1 H, NHС(4)). Found (%): С, 57.94;
Н, 3.77; N, 11.38. С12H9ClN2O2. Calculated (%): C, 57.96;
Н, 3.65; N, 11.27.
4ꢀ(4ꢀFluoroanilino)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbꢀ
aldehyde (12b) was prepared analogously to 12a from comꢀ
pound 3b. The reaction time was 26 h. The yield was 45%.
M.p. 386.5 °С (EtOH). IR, ν/сm–1: 3140, 3065 (NH); 1647
(СОН); 1624 (CONH). ES MS, m/z: 233 [M + Н]+•, 255
1616 (С=С). ES MS, m/z: 322 [M + Н]+•, 344 [M + Na]+•
,
665 [2 M + Na]+•. Н NMR (DMSOꢀd6), δ: 7.45, 7.62 (А2В2,
4 Н, Ar, Jo = 8.34 Hz); 8.17 (s, 1 Н, Н(4)); 8.29 (s, 1 H, H(5)).
Found (%): С, 59.77; Н, 2.90; N, 21.82. С16H8ClN5O. Calculꢀ
ated (%): C, 59.73; Н, 2.51; N, 21.77.
[M + Na]+•, 487 [2 M + Na]+•, 719 [3 M + Na]+•. Н NMR
1
1
(DMSOꢀd6), δ: 5.78 (d, 1 H, Н(5), Jo = 7.53 Hz); 7.18—7.33
(m, 5 H, H(6), Ar); 10.02 (s, 1 Н, СОН); 11.08 (br.s, 1 H,
NH(1)); 11.62 (br.s, 1 H, NHС(4)). Found (%): С, 62.14;
Н, 4.48; N, 12.37. С12H9FN2O2. Calculated (%): C, 62.07;
Н, 3.91; N, 12.06.
8ꢀChloroꢀ1,2ꢀdihydrobenzo[b]ꢀ1,6ꢀnaphthyridineꢀ1ꢀone
(13а). Piperidine (0.26 mL, 3.06 mmol) was added to a solution
of 3ꢀformylpyridone 12а (0.150 g, 0.602 mmol) in propanꢀ2ꢀol
(6 mL). The reaction mixture was refluxed for 25 h (TLC). The
precipitate that formed after cooling the reaction mixture to
20 °С was filtered off and washed with PriOH. Compound 13а
4ꢀ(4ꢀChloroanilino)ꢀ5ꢀ(2ꢀcyanoꢀ2ꢀethoxycarbonylvinyl)ꢀ
2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (10). A mixture of
5ꢀformylpyridone 5а (0.500 g, 1.83 mmol), ethyl cyanoacetate
(0.207 g, 1.83 mmol), and triethylamine (0.18 mL) in pyridine
(5 mL) was kept for 48 h at 20 °С (TLC). The precipitate that
formed was filtered off, washed with propanꢀ2ꢀol, and benꢀ
zene. Compound 10 was obtained in a yield of 0.345 g (72%).
M.p. 296.7—297.1 °С (DMF). IR, ν/сm–1: 3306, 3164 (NH);

2344
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009
Medvedeva et al.
was obtained in a yield of 0.130 g (94%). M.p. 357.5 °С (DMF).
IR, ν/сm–1: 3165 (NH); 1665 (CONH). ES MS, m/z: 231
by the modified Voight function24 taking into account anisoꢀ
tropy of the peak broadening.25 Texture effects caused by prior
alignment of crystals were considered within the limits of the
March—Dollas model26 (the direction of the prior alignment
was 010, refined value of parameter r was 1.022(8)) In the
refinement, restriction to the permissible deflections of the
interatomic distances in the molecule and to the planarity of
the rings were applied. Parameters of thermal fluctuations
of nonhydrogen atoms were refined in an isotropic approxiꢀ
mation. After the first cycle of refinement, the crystal strucꢀ
ture was transformed into centrosymmetrical threeꢀdimensional
P21/m group using the PLATON27 program; after that refinement
was continued. Hydrogen atoms were placed at the calculated
positions and were not refined. The principal crystallographic
characteristics and experimental parameters of compound 14а
are given in Table 2. The experimental powder diagram and the
difference curve as a result of refinement using the Rietveld
method are shown in Fig. 3.
1
[M + Н]+•, 253 [M + Na]+•, 483 [2 M + Na]+•. Н NMR
(DMSOꢀd6), δ: 6.63 (d, 1 Н, Н(4), Jo = 7.5 Hz); 7.41, 7.81, 8.03
(all m, 1 Н each, Н(3), Н(7), Н(6)); 8.26 (s, 1 Н, Н(9)); 9.18
(s, 1 Н, Н(10)); 11.32 (br.s, 1 Н, N(2)H). Found (%): С, 62.49;
Н, 3.37; N, 12.12. С12H7ClN2O. Calculated (%): С, 62.49;
Н, 3.06; N, 12.15.
8ꢀFluoroꢀ1,2ꢀdihydrobenzo[b]ꢀ1,6ꢀnaphthyridineꢀ1ꢀone
(13b). Method A. An Ni—Al alloy (0.2 g) was added to a
suspension of pyridone 7b (0.2 g, 0.873 mmol) in 80% HCOOH
(19 mL), the reaction mixture was refluxed with stirring for 35 h.
Solids were filtered off after cooling the reaction mixture to
20 °С, washed with small amount of 85% HCOOH. The mother
liquor was concentrated in vacuo to dryness. Water (3 mL) was
added to the crystalline residue and the mixture was kept at
20 °С for 2 days. The precipitate that formed (a mixture of
compounds 12b and 13b, TLC), was filtered off. The yield
of this mixture was 0.070 g. The filtrate was concentrated
in vacuo to dryness, the residue was triturated with acetone.
The precipitate was filtered off, washed with acetone. The
yield of compound 13b was 0.040 g (22.4%). ES MS, m/z: 215
3ꢀCyanoꢀ1ꢀ(4ꢀfluorophenyl)ꢀ2ꢀiminoꢀ1,6ꢀnaphthyridinꢀ
5(2Н,6Н)ꢀone (14b) was prepared analogously to 14а
from compound 12b. The yield was 97%. M.p. 302 °С (DMF).
IR, ν/сm–1: 3281, 3070 (NH); 2222 (CN); 1672 (СО); 1634
(CONH). ES MS, m/z: 281 [M + H]+•, 303 [M + Na]+•, 561
[M + Н]+•, 237 [M + Na]+•, 253 [M + К]+•
.
1
Method B is analogous to the method of preparation of
compound 13а. The reaction time was 40 h. The yield was
91%. M.p. 270.2—270.6 °С (EtOH). IR, ν/сm–1: 3169 (NH);
[2 M + Na]+. Н NMR (DMSOꢀd6), δ: 5.19 (d, 1 Н, Н(8),
Jo = 6.87 Hz); 6.32, 7.17 (both br.s, 1 Н, NH=C(2)); 7.37 (d,
1 Н, Н(7), Jo = 7.50 Hz); 7.48 (m, 4 Н, Ar); 8.14 (s, 1 Н,
Н(4)); 11.68 (br.s, 1 Н, NН(6)). Found (%): С, 64.19; Н, 3.38;
N, 19.97. С15H9FN4O. Calculated (%): C, 64.29; Н, 3.24;
N, 19.99.
1
1665 (CONH). Н NMR (DMSOꢀd6), δ: 6.63 (d, 1 Н, Н(4),
Jo = 7.50 Hz); 7.37, 7.72, 7.91, 8.08 (all m, 1 Н each, Н(6),
Н(3), Н(9), Н(7)); 9.19 (s, 1 Н, Н(10)); 11.28 (br.s, 1 Н,
N(2)H). Found (%): С, 67.15; Н, 3.62; N, 13.05. С12H7FN2O.
Calculated (%): С, 67.29; Н, 3.29; N, 13.08.
1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀcyanoꢀ2ꢀiminoꢀ1,6ꢀnaphthyridinꢀ
5(2Н,6Н)ꢀone (14a). Malononitrile (0.067 g, 1.007 mmol)
and triethylamine (0.05 mL) were added to a suspension of
3ꢀformylpyridone 12а (0.100 g, 0.402 mmol) in absolute ethanol
(3 mL). The reaction mixture was refluxed for 12 h (TLC).
The precipitate that formed was filtered off and washed with
ethanol. Compound 14а was obtained in a yield of 0.084 g (71%).
M.p. 300 °С (DMF). IR, ν/сm–1: 3279, 3123 (NH); 2224 (CN);
Table 2. Crystallographic characteristics of comꢀ
pound 14а
Parameter
Value
Molecular formula
Crystal system
Space group
a/Å
b/Å
c/Å
C15H9ClN4O
Monoclinic
P21/m
11.9604(11)
6.7697(5)
8.8512(8)
90
1672 (CONH); 1634 (C=С). ES MS, m/z: 297 [M + H]+•
,
319 [M + Na]+•, 615 [2 M + Na]+. Н NMR (DMSOꢀd6), δ:
5.20 (d, 1 Н, Н(8), Jo = 7.44 Hz); 6.39, 7.17 (both br.s, 1 Н,
NH=C(2)); 7.36 (d, 1 Н, Н(7), Jo = 7.44 Hz); 7.45, 7.72 (А2В2,
4 Н, Ar, Jo = 8.58 Hz); 8.16 (s, 1 Н, Н(4)); 11.78 (br.s, 1 Н,
NН(6)). Found (%): С, 60.74; Н, 3.08; N, 18.79. С15H9ClN4O.
Calculated (%): C, 60.72; Н, 3.06; N, 18.88.
1
α/deg
β/deg
109.765(12)
90
674.45(10)
29
γ/deg
V/Å3
M20
*
The structure of compound 14а was established by powder
Xꢀray diffraction.18 Powder diagram was measured in the Guinier
camera "Huber G670" containing bent germanium monoꢀ
chromator. The positions of first 22 peaks were refined on
the powder diagram. Using these positions, indicating in the
monoclinic cell was carried out with the TREOR90 program.19
Systematical reductions revealed by refinement of the powder
diagram using the Pauli method20 by the MRIA21 program were
consistent with two space groups: P21 and P21/m. The crystal
structure of compound 14a was solved by the method of
systematic search22 in the P21 group. Rigid threeꢀdimensional
molecule model obtained as a result of the optimization by the
density functional method using the PRIRODA23 program was
used. Then the solution obtained was refined by the Rietveld
method using the MRIA program, peak profiles were described
F30*
Z
dcalc/g cm–3
Radiation
Wavelength/Å
2θmin—2θmax/deg
Step of measurement/deg
Rp*
55 (0.010, 37)
2
1.461
CuꢀKα
1
1.5406
4.00—100.50
0.01
0.0237
0.0325
0.0100
9.345
Rwp
*
Rexp
χ *
*
2
* Indicators of indication quality M20 (see
Ref. 28) and F30 (see Ref. 29) were determined
previously, Rp, Rwp, Rexp and χ — see Ref. 30.
2

1ꢀArylꢀ1,6ꢀnaphthyridinone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 11, November, 2009 2345
I (rel. units)
8.97 (s, 1 Н, Н(4)). Found (%): С, 49.91; Н, 2.11; N, 12.56.
С14H7Cl2N3O3. Calculated (%): C, 50.03; Н, 2.10; N, 12.50.
5ꢀChloroꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀnitroꢀ1,6ꢀnaphthyridinꢀ
2(1Н)ꢀone (16b) was prepared analogously to 16а from
compound 15b. The yield was 88%. M.p. 230 °С (PriOH). IR,
ν/сm–1: 1697, 1688 (CO); 1616 (С=С); 1532 (NO2). ES MS,
m/z: 320 [M + H]+•, 342 [M + Na]+•, 661 [2 M + Na]+.
1Н NMR (DMSOꢀd6), δ: 6.57 (d, 1 Н, Н(8), Jo = 6.10 Hz); 7.44
(m, 4 Н, Ar); 8.30 (d, 1 Н, Н(7), Jo = 5.98 Hz); 8.95 (s, 1 Н,
Н(4)). Found (%): С, 52.60; Н, 2.22; N, 13.19. С14H7FClN3O3.
Calculated (%): C, 52.60; Н, 2.21; N, 13.14.
15•104
×4
1
5ꢀChloroꢀ3ꢀnitroꢀ1ꢀphenylꢀ1,6ꢀnaphthyridinꢀ2(1Н)ꢀone
(16c) was prepared analogously to 16а from compound 15с
(see Ref. 3). The yield was 70%. M.p. 180—181.5 °С (PriOH).
0
2
ES MS, m/z: 302 [M + H]+•, 324 [M + Na]+•, 625 [2 M + Na]+,
255 [M – NО2]+. 1Н NMR (DMSOꢀd6), δ: 6.52 (d, 1 Н, Н(8),
Jo = 6.03 Hz); 7.46, 7.66 (both m, 2 Н each, 3 Н, Ph); 8.34 (d,
1 Н, Н(7), Jo = 6.02 Hz); 9.05 (s, 1 Н, Н(4)). Found (%):
N, 14.13. С14H8ClN3O3. Calculated (%): N, 13.93.
10 20 30 40 50 60 70 80
2θ/deg
Fig. 3. The result of elucidation of crystal structure of compound
14а by the Rietveld method: experimental curve (1), the differꢀ
ence between the experimental and calculated curves as a result
of refinement (2); highꢀangle area (2θ > 40°) is presented on a
large scale. The calculated positions of reflexes are indicated as
vertical segments.
1ꢀ(4ꢀChlorophenyl)ꢀ5ꢀmorpholinoꢀ3ꢀnitroꢀ1,6ꢀnaphthyridinꢀ
2(1Н)ꢀone (17a). Morpholine (0.104 g, 1.19 mmol) was added
to a suspension of compound 16а (0.100 g, 0.299 mmol) in
PriOH (2 mL). The reaction mixture was refluxed for 1.5 h
(TLC). The precipitate that formed after cooling the reaction
mixture to 20 °С was filtered off and washed with PriOH.
Compound 17а was obtained in a yield of 0.104 g (91%).
1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀnitroꢀ1,6ꢀnaphthyridineꢀ2,5(1Н,6Н)ꢀ
dione (15a). A mixture of 3ꢀformylpyridone 12а (0.100 g,
0.402 mmol), ethyl nitroacetate (0.107 g, 0.803 mmol), and
morpholine (0.086 g, 0.987 mmol) in PriOH (7 mL) was refluxed
for 6 h (TLC). The reaction mixture was cooled to 20 °С. The
precipitate was filtered off, and washed with PriOH. Compound
15а was obtained in a yield of 0.100 g (78%). M.p. 325 °С
(PriOH). IR, ν/сm–1: 3194 (NH); 1697, 1672 (СОNH); 1618
(С=С); 1518 (NO2). ES MS, m/z: 318 [M + H]+•, 340
M.p. 231.0—231.8 °С (PriOH—DMF, 10 : 1). IR, ν/сm–1
:
1692 (CO); 1518 (NO2). ES MS, m/z: 387 [M + H]+•, 409
[M + Na]+•, 795 [2 M + Na]+. 1Н NMR (DMSOꢀd6), δ:
3.47 (t, 4 Н, N(CH2)2, Jo = 4.02 Hz); 3.82 (t, 4 Н, O(CH2)2,
Jo = 4.13 Hz); 6.07 (d, 1 Н, Н(8), Jo = 5.90 Hz); 7.40, 7.67
(А2В2, 4 Н, Ar, Jo = 8.43 Hz); 8.12 (d, 1 Н, Н(7), Jo = 5.98 Hz);
8.78 (s, 1 Н, Н(4)). Found (%): С, 56.04; Н, 4.05; N, 14.41.
С18H15ClN4O4. Calculated (%): C, 55.90; Н, 3.91; N, 14.49.
1ꢀ(4ꢀFluorophenyl)ꢀ5ꢀmorpholinoꢀ3ꢀnitroꢀ1,6ꢀnaphthyridinꢀ
2(1Н)ꢀone (17b) was prepared analogously to 17а from
compound 16b. The yield was 89%. M.p. 217.7—218 °С (PriOH).
IR, ν/сm–1: 1680 (CO); 1535 (NO2). ES MS, m/z: 371
[M + H]+•, 393 [M + Na]+•, 763 [2 M + Na]+. 1Н NMR
(DMSOꢀd6), δ: 3.46 (t, 4 Н, N(CH2)2, Jo = 4.52 Hz); 3.83 (t,
4 Н, O(CH2)2, Jo = 4.23 Hz); 6.06 (d, 1 Н, Н(8), Jo = 6.00 Hz);
7.42 (m, 4 Н, Ar); 8.13 (d, 1 Н, Н(7), Jo = 5.90 Hz); 8.79 (s,
1 Н, Н(4)). Found (%): С, 58.00; Н, 4.12; N, 14.73. С18H15FN4O4.
Calculated (%): C, 58.38; Н, 4.08; N, 15.13.
[M + Na]+•, 657 [2 M + Na]+. Н NMR (DMSOꢀd6), δ: 5.43
1
(d, 1 Н, Н(8), Jo = 7.47 Hz); 7.41, 7.67 (А2В2, 4 Н, Ar, Jo = 8.28
Hz); 7.51 (d, 1 Н, Н(7), Jo = 7.29 Hz); 8.89 (s, 1 Н, Н(4)); 12.07
(br.s, 1 Н, NH(6)). Found (%): С, 52.90; Н, 2.70; N, 13.29.
С14H8ClN3O4. Calculated (%): C, 52.93; Н, 2.54; N, 13.23.
1ꢀ(4ꢀFluorophenyl)ꢀ3ꢀnitroꢀ1,6ꢀnaphthyridineꢀ2,5(1Н,6Н)ꢀ
dione (15b) was prepared analogously to 15а from compound
12b. The yield was 86%. M.p. 350.3 °С (PriOH). IR, ν/сm–1
:
3237 (NH); 1699, 1672 (СОNH); 1618 (С=С); 1512 (NO2).
ES MS, m/z: 302 [M + H]+•, 324 [M + Na]+•, 625 [2 M + Na]+.
1Н NMR (DMSOꢀd6), δ: 5.41 (d, 1 Н, Н(8), Jo = 7.49 Hz); 7.42
(m, 4 Н, Ar); 7.51 (d, 1 Н, Н(7), Jo = 7.51 Hz); 8.89 (s, 1 Н,
Н(4)); 12.07 (br.s, 1 Н, NH(6)). Found (%): С, 55.63; Н, 2.78;
N, 13.87. С14H8FN3O4. Calculated (%): C, 55.82; Н, 2.68;
N, 13.95.
5ꢀMorpholinoꢀ3ꢀnitroꢀ1ꢀphenylꢀ1,2ꢀdihydroꢀ1,6ꢀnaphthyridinꢀ
2(1Н)ꢀone (17с) was prepared analogously to 17а from comꢀ
pound 16с. The yield was 32%. M.p. 227—228 °С (PriOH). IR,
ν/сm–1: 1688 (CO); 1518 (NO2). ES MS, m/z: 353 [M + H]+•
,
5ꢀChloroꢀ1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀnitroꢀ1,6ꢀnaphthyridinꢀ
2(1Н)ꢀone (16a). A mixture of compound 15а (0.100 g,
0.315 mmol), triethylamine hydrochloride (0.043 g, 0.313 mmol),
and phosphoryl chloride (1.2 mL) was refluxed for 4 h (TLC).
The reaction mixture was cooled to 20 °С, and concentrated
in vacuo to dryness. The residue was triturated with toluene
and concentrated in vacuo to dryness. The residue was triturated
with small amount of propanꢀ2ꢀol and kept at 20 °С for 24 h.
The precipitate was filtered off, compound 16а was obtained in
375 [M + Na]+•, 705 [2 M + H]+, 727 [2 M + Na]+. 1Н NMR
(DMSOꢀd6), δ: 3.46 (t, 4 Н, N(CH2)2, Jo = 4.02 Hz); 3.83 (t,
4 Н, O(CH2)2, Jo = 4.91 Hz); 6.03 (d, 1 Н, Н(8), Jo = 5.91 Hz);
7.33, 7.63 (both m, 2 Н each, 3 Н, Ph); 8.10 (d, 1 Н, Н(7),
Jo = 5.86 Hz); 8.78 (s, 1 Н, Н(4)). Found (%): С, 60.92;
Н, 4.60; N, 15.39. С18H16N4O4. Calculated (%): C, 61.36;
Н, 4.58; N, 15.90.
a yield of 0.075 g (71%). M.p. 290—292 °С (PriOH). IR, ν/сm–1
:
References
1703 (CON); 1622 (С=С); 1530 (NO2). ES MS, m/z: 336
[M + H]+•, 358 [M + Na]+•, 693 [2 M + Na]+. 1Н NMR
(DMSOꢀd6), δ: 6.59 (d, 1 Н, Н(8), Jo = 5.98 Hz); 7.46, 7.70
(А2В2, 4 Н, Ar, Jo = 8.53 Hz); 8.31 (d, 1 Н, Н(7), Jo = 6.01 Hz);
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Received December 10, 2008;
in revised form June 22, 2009