Synthesis and functionalization of 4-arylamino-2-pyridone derivatives

Article abstract of DOI:10.1007/s11172-006-0443-4

New approaches to the synthesis of the previously unknown pyrimidine, 4-amino-2-pyridone, and 4-aminopyridine derivatives were developed based on the reactions of enaminoamides with dimethylformamide dimethyl acetal. New structural modifications of 4-amin

Full text of DOI:10.1007/s11172-006-0443-4

Russian Chemical Bulletin, International Edition, Vol. 55, No. 8, pp. 1475—1486, August, 2006
1475
Synthesis and functionalization of 4ꢀarylaminoꢀ2ꢀpyridone derivatives
N. Z. Tugusheva,a L. M. Alekseeva,a A. S. Shashkov,b V. V. Chernyshev,c and V. G. Granika
ꢀ
aState Research Center of Antibiotics,
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Fax: +7 (495) 231 4284. Еꢀmail: vggranik@mail.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328
cDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 3654. Eꢀmail: cher@biocryst.phys.msu.su
New approaches to the synthesis of the previously unknown pyrimidine, 4ꢀaminoꢀ2ꢀ
pyridone, and 4ꢀaminopyridine derivatives were developed based on the reactions of
enaminoamides with dimethylformamide dimethyl acetal. New structural modifications of
4ꢀaminoꢀ2ꢀpyridone derivatives were performed. Numerous compounds of this type, which are
of interest for biological studies, were prepared.
Key words: amide acetals, 3ꢀcyanoꢀ2ꢀoxoꢀ5ꢀRꢀ4ꢀ(phenylamino)ꢀ1,2ꢀdihydropyridines,
4ꢀarylaminoꢀ3,5ꢀdicyanopyridines, acidic hydrolysis, NMR spectroscopy, Xꢀray diffraction
analysis.
Earlier, a procedure has been developed for the synꢀ
thesis of various 1ꢀalkylꢀ and 1ꢀarylꢀ5ꢀcyanoꢀ(2ꢀN,Nꢀdiꢀ
methylaminovinyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydropyrimidines1,2
based on the reactions of amide acetals at the priꢀ
mary amide amino group and at the methyl group of
3ꢀarylaminoꢀ2ꢀcyanocrotonamides. These pyrimidinoꢀ
nes were found1—4 to undergo recyclization to form
4ꢀalkyl(aryl)aminoꢀ3ꢀcyanopyridinꢀ2ꢀones under condiꢀ
tions of both alkaline and acidic hydrolysis.
The aim of the present study was to synthesize new
1ꢀarylpyrimidinꢀ4ꢀone derivatives containing ortho subꢀ
stituents in the phenyl ring and investigate their behavior
under conditions of acidic and alkaline hydrolysis, as well
as to prepare 4ꢀarylaminoꢀ5ꢀformylꢀ2ꢀpyridones and inꢀ
vestigate their properties. It should be emphasized that
recyclization of these pyrimidinones would be expected
to give substituted 4ꢀaminopyridines, and this class of
compounds is of considerable interest in searching for
compounds acting on the central nervous system. It is
sufficient to note that this class includes the wellꢀknown
drugs tacrine and amiridine, which are used in the therapy
of the neurodegenerative disease, such as Alzheimer's
disease.5—7
Scheme 1 presents the synthesis of pyrimidinones 4a,b
by the method developed earlier.1,4 In the first step,
transamination of enaminoamide 1 with orthoꢀsubstiꢀ
tuted anilines in acetic acid gives, via compounds 3a,b,
enaminoamides 2a,b in high yields, and refluxing of the
latter in DMF acetal (or in toluene in the presence of
a threefold excess of DMF acetal) affords pyrimidiꢀ
nones 4a,b.
Alkaline hydrolysis of compounds 4a,b yields 3ꢀcyꢀ
anoꢀ4ꢀ(2ꢀmethoxyphenylamino)ꢀ and 3ꢀcyanoꢀ4ꢀ(2,5ꢀ
dimethoxyphenylamino)pyridinꢀ2ꢀone 5a,b, as observed
earlier in analogous reactions with various 1ꢀalkylꢀ and
1ꢀarylꢀsubstituted pyrimidinꢀ4ꢀones.1—4 This process inꢀ
volves the pyrimidine ring opening accompanied by elimiꢀ
nation of HCOOH followed by recyclization through inꢀ
tramolecular transamination to form 3ꢀcyanopyridones 5.
Acidic hydrolysis of pyrimidinꢀ4ꢀones gives rise to a
mixture of compounds, different products being isolated
depending on the reaction conditions and the nature of
substituents in the benzene ring. For example, refluxing
of pyrimidinones 4a,b in glacial acetic acid affords bicyꢀ
clic compounds 6a and 6b in 41 and 78% yields, respecꢀ
tively, the pyrimidine ring remaining intact. Heating of
pyrimidinone 4a in a stronger acid (1 M HCl, 70 °C, 4 h)
gives rise to a mixture of two products, viz., Nꢀformylꢀ
carbamoylpyridone 7a and 3ꢀcarbamoylpyridone 8a. We
Tacrine
Amiridine
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1421—1432, August, 2006.
1066ꢀ5285/06/5508ꢀ1475 © 2006 Springer Science+Business Media, Inc.

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Tugusheva et al.
Scheme 1
2: Ar = 2ꢀMeOC6H4 (a), 2,5ꢀ(MeO)2C6H3 (b), 4ꢀClC6H4 (c)
3, 9: R1 = H, R2 = Ph (a); R1 = H, R2 = 4ꢀClC6H4 (b); R1 = R2 = Me (c)
4—8: R3 = H, R4 = OMe (a); R3 = R4 = OMe (b); R3 = R4 = H (c)
isolated compound 7a from this mixture in individual
form in 21% yield. 3ꢀCarbamoylꢀ4ꢀ(2ꢀmethoxyphenylꢀ
amino)ꢀ2ꢀpyridone (8a) was also prepared in 82% yield
by direct hydrolysis of pyrido[4,3ꢀd]pyrimidineꢀ4,5ꢀdione
6a with 1 M KOH. Apparently, heating of pyrimidinone
4a in 1 M HCl first leads to cyclization giving rise to
pyrido[4,3ꢀd]pyrimidine 6a with the involvement of the
enamine and cyano groups followed by the pyrimidine
ring opening to form compound 7a, which is transformed
into carbamoylpyridone 8a. Such transformations have
been observed earlier8 for 1ꢀbenzylꢀsubstituted pyrimidiꢀ
none of type 4 under both acidic and alkaline conditions.
Heating (70 °C, 1 h) of pyrimidinone 4b containing
the 2,5ꢀdimethoxyphenyl substituent or prolonged storꢀ
age of this compound at 20 °C in 1 M HCl also affords a
mixture of products (bicyclic compound 6b, Nꢀformylꢀ
carbamoylpyridone 7b, and an impurity of 5b (TLC)).
Storage of this mixture at 20 °C in 1 M KOH led to the
formation of 3ꢀcarbamoylpyridone 8b in 74% yield (see
Scheme 1). NꢀFormylcarbamoylpyridone 7b, which is an
intermediate product of recyclization of pyrimidinone 4b
into carbamoylpyridone 8b, was also isolated in individual
form in 13% yield from an analogous mixture, which was
prepared by moderate heating (at 70 °C for 3 h or at 40 °C
for 6 h) of pyrimidinone 4b in 99% acetic acid.
In addition, we studied the properties of 5ꢀformylꢀ
substituted pyridinꢀ2ꢀones. Earlier, it has been found that
the reactions of amide acetals with enaminoamides iniꢀ
tially afford compounds 3 as condensation products at
both the amide and methyl groups followed by cyclization
to give pyridinones. It was established that it is these
compounds 3 that give 4ꢀarylaminoꢀ3ꢀcyanoꢀ5ꢀformylꢀ
pyridinꢀ2ꢀones in acidic media.4 The drawback of this
method is that compounds 3 are difficult to prepare in
individual form. However, the use of Nꢀ(pꢀchlorophenyl)ꢀ
substituted enaminoamide 2c in the reaction with DMF
acetal made it possible to isolate compound 3c,3 whose
hydrolysis in 90% acetic acid according to the known
method4 produced 4ꢀ(4ꢀchlorophenylamino)ꢀ3ꢀcyanoꢀ5ꢀ
formylpyridinꢀ2ꢀone 9b. 5ꢀFormylꢀ4ꢀphenylaminoꢀ and
4ꢀdimethylaminoꢀ5ꢀformylpyridones 9a,c4 were syntheꢀ
sized analogously (see Scheme 1).

Synthesis of 4ꢀarylaminoꢀ2ꢀpyridone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
1477
Scheme 2
9, 13: R1 = H, R2 = Ph (a); R1 = H, R2 = 4ꢀClC6H4 (b)
10: R3 = CH2Ph (a), (CH2)3COOH (b), 3,4ꢀ(MeO)2C6H3(CH2)2 (c), Ph (d)
12: R4 = Ph, R5 = H (a); R4 = 4ꢀHOC6H4, R5 = H (b); R4 = 3ꢀMeOꢀ4ꢀHOC6H3, R5 = H (c); R4 = 4ꢀMeOC6H4, R5 = H (d); R4 + R5 = (CH2)5 (e)
Earlier,9 we have synthesized 4ꢀ(arylamino)ꢀ3ꢀcyanoꢀ
pyridinꢀ2ꢀones unsubstituted at position 5 of the pyridine
ring and studied their biological properties. 5ꢀFormylꢀ
pyridinones prepared in our study allow one to synthesize
compounds containing various substituents at position 5,
which are of interest from the point of view of elucidaꢀ
tion of structure—activity relationships. The reaction of
5ꢀformylpyridone 9a with amines produced Schiff bases
10a—d (Scheme 2). The ease of the reaction is to a large
extent associated with the basicity of the amine used. The
reaction with γꢀaminobutyric acid proceeds very slowly
(product 10b was isolated in low yield), whereas the reacꢀ
tion with benzylamine readily affords target product 10a
in high yield. The reaction of 5ꢀformylpyridine 9a with
hydrazine hydrate also proceeds readily to give comꢀ
pound 11, whose reactions with various aldehydes proꢀ
duce hydrazones 12a—e in high yields.
nucleophile (piperidine) unexpectedly does not occur at
position 2 of the pyridinium fragment of salt 15 but leads
to its replacement. As a result, 5ꢀpiperidinomethylꢀ
pyridone 16 was synthesized (in 36% yield based on conꢀ
sumed alcohol).
Scheme 3
The aldehyde group in 5ꢀformylpyridines 9a,b is reꢀ
duced with NaBH4 to give alcohols. These reactions afꢀ
forded 4ꢀphenylaminoꢀsubstituted 5ꢀhydroxymethylꢀ
pyridones 13a,b in 70—72% yields (see Scheme 2).
The "benzyl" alcoholic group in pyridone 13a is rather
reactive. The reaction of compound 13a with urea in
AcOH produces 5ꢀureidomethyl derivative 14 (Scheme 3)
in high yield (89%). Various ureido derivatives can exhibit
anticonvulsant and antihypoxic activities.10,11 The transꢀ
formation of 5ꢀhydroxymethylꢀ4ꢀphenylaminopyridone
13a into the chloro derivative followed by treatment with
pyridine gave pyridinium salt 15 (1H NMR spectroscopic
data, see the Experimental section). Such pyridinium salts
were demonstrated12 to form amino derivatives in the
reactions with primary and secondary amines. However,
in the reaction under consideration, the attack of the
Reagents and conditions. i. H2NCONH2; ii. 1) SOCl2, 2) pyriꢀ
dine; iii. Piperidine.
The reactions of 5ꢀformylpyridones 9a—c with hyꢀ
droxylamine hydrochloride in pyridine under mild condiꢀ
tions produce oximes 17a—c (Scheme 4).
Some cyanopyridines exhibit considerable antiꢀ
bradykinin, analgetic, and antihypertensive effects.1,9
5ꢀFormylpyridines can be used to synthesize compounds

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Tugusheva et al.
Scheme 4
9,17: R1 = H, R2 = Ph (a); R1 = H, R2 = 4ꢀClC6H4 (b); R1 = R2 = Me (c)
18—20, 22: R3 = H (a), Cl (b)
21: R3 = R4 = H (a); R3 = H, R4 = CH2Ph (b); R3 = H, R4 = Ph (c); R3 = H, R4 = 4ꢀMeOC6H4 (d); R3 = H, R4 = 4ꢀClC6H4 (e);
R
3 = H, R4 = 4ꢀMeC6H4 (f); R3 = Cl, R4 = 4ꢀClC6H4 (g)
containing electronꢀreleasing substituted amino groups
and two electronꢀwithdrawing cyano groups. Alternative
methods for the synthesis of such compounds are lacking,
and these compounds are virtually inaccessible with the
use of conventional methods of pyridine synthesis. We
succeeded in preparing a series of such compounds with
the use of methods for the transformation of the aldehyde
moiety into the nitrile group.13 The treatment of 4ꢀpheꢀ
nylaminoꢀsubstituted 5ꢀformylpyridones with hydroxyꢀ
lamine hydrochloride in pyridine followed by heating of
the reaction mixture in acetic anhydride afforded 3,5ꢀdiꢀ
cyanopyridones 19a,b in high yield. Apparently, the startꢀ
ing compounds 9a,b are initially transformed into oximes
17a,b, which are rapidly transformed into acetyl derivaꢀ
tives 18a,b under the action of acetic anhydride. At higher
temperature (110—115 °C), compounds 18a,b eliminate
the acetic acid molecule to give dicyanopyridones 19a,b.
We succeeded in synthesizing acetyl derivatives from
both oximes 17a,b and 5ꢀformylpyridones 9a,b. As exꢀ
pected, storage of these compounds in acetic anhydride at
110—115 °C afforded dicyanopyridones 19a,b, whose reꢀ
actions with phosphorus oxychloride in the presence of
triethylamine hydrochloride produced 2ꢀchloroꢀ3,5ꢀ
dicyanoꢀ4ꢀ(4ꢀRꢀphenylamino)pyridines 20a,b in high
yield (see Scheme 4).
The Cl atom in these compounds is rather labile and
can be replaced by the NH2 or RNH group. This method
was used to synthesize diamino derivatives of dicyanoꢀ
pyridones 21a—g. The replacement of the Cl atom by the
amino group was performed by the reaction of chloroꢀ
pyridine 20a with ethanolic ammonia in an autoclave (see
Scheme 4).
It should be noted that heating of acetyl derivatives
18a,b in dimethylformamide or pyridine leads to their
cyclization to give 7ꢀcyanoꢀ6ꢀoxoꢀ1ꢀ(4ꢀRꢀphenylamino)ꢀ
5,6ꢀdihydroꢀ1Hꢀpyrazolo[4,3ꢀc]pyridines 22a,b. In the
case of 4ꢀanilinoꢀsubstituted 18a, cyclization is accomꢀ
panied by the formation of dicyanopyridone 19a (which is
observed by chromatography), whereas 4ꢀchloroꢀsubstiꢀ
tuted 5ꢀformylpyridone undergoes only cyclization (see
Scheme 4).
This cyclization is very unusual. Hence, we studied
the structures of the resulting bicyclic compounds in deꢀ
tail by spectroscopy (the NMR spectra of compounds
22a,b with the complete assignment of the 1H and
13C signals are given in the Experimental section).
The structure of compound 22b was established by
the HMBC (heteronuclear multipleꢀbond connectivity)
technique. The correlations peaks at δ 8.41/112.1
(H(3)/C(3a)), 8.41/146.8 (H(3)/C(7a)), 8.73/112.1

Synthesis of 4ꢀarylaminoꢀ2ꢀpyridone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
1479
of 3ꢀcyanopyridine 5c in 85% HCOOH in the presence of
this catalyst produced not only 3ꢀformylpyridone 23 but
also tricyclic product 24 (Scheme 5).
C(2)
N(7)
Scheme 5
N(12)
O(10)
Fig. 1. Intermolecular hydrogen bonds in the crystal structure
of 22b.
(H(4)/C(3a)), 8.73/139.8 (H(4)/C(3)), 8.73/146.8
(H(4)/C(7a)), and 8.73/161.4 (H(4)/C(6)) are consistent
with the proposed structure.
The NMR spectroscopic data were supported by Xꢀray
diffraction data for bicyclic compound 22b (see the Exꢀ
perimental section).
The crystal packing of compound 22b is stabilized by
intermolecular N—H...O and C—H...N hydrogen bonds
(Fig. 1). The geometric characteristics of these bonds are
given in Table 1.
26: R = OH (a), NHC6H4NO2 (b)
As mentioned above, pyrimidinones 4 are transformed
into 3ꢀcyanopyridones 5 under the action of alkali. It is
known14 that aromatic nitriles can be transformed into
aldehydes in 75% HCOOH in the presence of a large
excess of a Ni—Al2 alloy as the catalyst. The reaction with
3ꢀcyanopyridine was documented. The yield achieved in
this reaction is substantially lower than that in the reacꢀ
tions with aromatic nitriles (37% and 70—97%, respecꢀ
tively). It was of interest to study the behavior of cyano
derivatives of 4ꢀaminophenylpyridines under these conꢀ
ditions. Refluxing of 3ꢀcyanopyridine 5c, which was preꢀ
pared according to a procedure described earlier,3 in
50% HCOOH in the presence of a large excess (gram per
gram of nitrile) of a Ni—Al2 alloy as the catalyst afforded
only pure formyl derivative 23 in 53% yield. The reaction
Reagents and conditions. i. 63% H2SO4; ii. Raney Ni,
HCOOH; iii. PriOH + piperidine; iv. HONH2HCl or
NH2NHC6H4NO2.
3ꢀFormylpyridone 23 readily undergoes cyclization to
form tricyclic compound 24 upon refluxing in isopropyl
alcohol in the presence of piperidine.
Refluxing of compound 5c (40 min) in 63% H2SO4
leads to hydrolysis of the nitrile group to form the carboxy
group followed by decarboxylation with the simultaneous
sulfonation at the para position of the phenyl ring to give
finally compound 25 in 60% yield (see Scheme 5).
3ꢀFormylpyridone 23 is readily involved in condensaꢀ
tion. Refluxing in ethanol with hydroxylamine hydroꢀ
chloride or pꢀnitrophenylhydrazone affords oxime 26a
and hydrazone 26b in 63 and 68% yields, respectively.
To summarize, we developed procedures for the synꢀ
thesis of various 4ꢀaminopyridine derivatives, performed
modifications of these structures, and prepared numerous
compounds, which are of interest for biological studies.
Table 1. Geometric characteristics of hydrogen bonds in comꢀ
pound 22b
D—H...A
Bond length/Å
D—H...A angle
/deg
D—H H...A D...A
Experimental
N(7)—H(7)...O(10)i
0.86 1.96 2.617(8)
133
138
O(18)—H(18)...O(12)ii 0.93 2.46 3.210(8)
The IR spectra were recorded on a FSMꢀ1201 instrument in
Nujol mulls. The H NMR spectra were measured on Bruker
ACꢀ300 and Bruker DRXꢀ500 spectrometers in DMSOꢀd6
1
Note. The symmetry codes: (i) –x, 0.5 + y, 0.5 – z;
(ii) 1 + x, 1 + y, z.

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Tugusheva et al.
and DMSOꢀd6—CCl4. The HMBC spectra were recorded on
a Bruker DRXꢀ500 spectrometer in DMSOꢀd6. The electron
impact (EI) mass spectra (70 eV) were obtained on a Finnigan
SSQꢀ710 mass spectrometer using a direct inlet system. The
electrospray—ionization (ESI) mass spectra were recorded on a
Waters ZQꢀ2000 mass spectrometer using a direct inlet system
without a chromatographic column. The course of the reactions
was monitored and the purity of the compounds was checked by
TLC on Merck 60 F254 plates (ethyl acetate—ethanol, 10 : 1,
as the eluent). The melting points were determined on an
Electrotermal 9100 instrument (UK). The melting points and
the yields of the reaction products are given in Table 2.
Table 2. Melting points and elemental analysis data for compounds 2a,b, 4a,b, 5a,b, 6a, 7a,b, 8b, 9b, 10a—c, 11, 12b,c,e, 13a,b, 14,
17a—c, 18a, 19a,b, 20a,b, 21a—g, 22b, 23, 24, and 26a,b
Comꢀ
pound
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
Comꢀ
pound
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
N
(%)
N
C
H
C
H
2a
186—187
(DMF)
177—178
(PriOH)
259—262
62.65 5.76 18.05 C12H13N3O2
62.33 5.67 18.17
59.73 5.87 16.06 C13H15N3O3
59.76 5.79 16.08
17aa
17b
17c
18a
19a
19b
20ab
20b
21a
21b
21c
21d
21ec
21f
261—263
(MeOH)
293—294
(PriOH)
203—204
(PriOH)
286—288
(DMF)
59.73 4.20 21.66 C13H10N4O2•
60.35 4.06 21.24 •0.25H2O
54.50 2.91 19.57 C13H8N4O2Cl
54.28 2.80 19.48
52.54 4.69 27.16 C9H10N4O2
52.42 4.89 27.17
60.76 4.01 18.52 C15H12N4O3
60.81 4.05 18.92
65.74 3.47 23.41 C13H8N4O
66.10 3.39 23.73
57.43 2.75 20.67 C13H7N4OCl
57.69 2.61 20.70
61.67 2.66 22.16 C13H7N4Cl
61.30 2.75 22.00
53.89 2.20 19.31 C13H6N4Cl2
54.01 2.09 19.38
2b
4a
65.05 5.59 18.72 C16H16N4O2
(PriOH—DMF) 64.85 5.44 18.91
4b
205—206
62.51 5.41 16.90 C17H18N4O3
(PriOH—DMF) 62.57 5.56 17.17
5a
241—242
64.76 4.64 17.36 C13H11N3O2
323—324
(MeOH)
335
(PriOH—DMF) 64.72 4.60 17.42
5b
275—277
62.06 4.98 15.15 C14H13N3O3
(PriOH—DMF) 61.99 4.83 15.49
(MeOH)
192—194
(EtOH)
240—241
(MeOH)
225—226
(EtOH)
219—220
(EtOH)
234—236
(MeOH)
203—204
(MeOH)
218—220
(EtOH)
224—226
(EtOH)
222—226
6a
280—284
61.95 4.07 14.89 C14H11N3O3
(PriOH—DMF) 62.45 4.12 15.61
7a
208—211
58.72 4.56 14.44 C14H13N3O4
(PriOH—DMF) 58.53 4.56 14.63
7b
208—211
57.10 4.69 13.02 C15H15N3O5
66.35 3.72 30.06
66.38 3.83 29.79
74.24 4.70 21.87
73.85 4.62 21.54
73.37 4.20 22.44
73.31 4.18 22.51
C13H9N5
C20H15N5
C19H13N5
(PriOH—DMF) 56.78 4.76 13.24
8b
280
58.31 5.44 14.26 C14H15N3O4
(PriOH—DMF) 58.13 5.23 14.53
9b
290
57.02 2.65 15.39 C13H8N3O2Cl
(PriOH—DMF) 57.05 2.95 15.35
10a
10b
10c
11
229—230
(MeOH)
207—209
(MeOH)
202—204
(EtOH)
>320
(DMF)
290—292
(DMF)
292—293
(DMF)
290—291
(EtOH)
222—223
73.27 4.84 17.21 C20H16N4O
73.17 4.88 17.07
62.60 4.83 16.95 C17H16N4O3
62.96 4.94 17.28
68.51 5.58 13.98 C23H22N4O3
68.66 5.47 13.93
61.78 4.54 27.50 C13H11N5O
61.66 4.35 27.67
66.93 4.49 19.51 C20H15N5O2
67.23 4.20 19.61
64.98 4.67 18.26 C21H17N5O3
65.12 4.39 18.09
68.37 5.72 21.16 C19H19N5O
68.47 5.71 21.02
70.36 4.40 20.49 C20H15N5O
70.38 4.40 20.53
65.99 3.40 20.37 C19H12N5Cl
65.99 3.47 20.26
73.70 4.51 21.38
73.85 4.62 21.54
C20H15N5
21g
22b
23
59.81 2.77 18.47 C19H11N5Сl2
(decomp., EtOH) 60.02 2.92 18.42
12b
12c
12e
13a
13b
14
>350
(DMF)
57.73 2.77 20.81 C13H7N4OCl
57.69 2.61 20.70
67.53 4.91 13.30 C12H10N2O2
67.28 4.70 13.08
73.31 4.09 14.12 C12H8N2O
73.46 4.11 14.28
62.80 4.85 18.22 C12H11N3O2
62.87 4.84 18.33
61.61 4.59 19.93 C18H15N5O3
61.89 4.33 20.05
241—242
(PhCH3)
330—331
(MeOH)
234—236
(MeOH)
361—362
(DMF)
24
64.70 4.79 17.48 C13H11N3O2
26a
26b
(PriOH—DMF) 64.72 4.60 17.42
261—264
57.07 3.98 15.38 C13H10N3O2Cl
(PriOH—DMF) 56.64 3.66 15.24
247—250
59.59 4.99 24.61 C14H13N5O2
(PriOH—DMF) 59.36 4.63 24.72
a Found (%): H2O, 1.53. Calculated (%): H2O, 1.74.
b Found (%): Cl, 14.08. Calculated (%): Cl, 13.95.
c Found (%): Cl, 10.42. Calculated (%): Cl, 10.27.

Synthesis of 4ꢀarylaminoꢀ2ꢀpyridone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
1481
1ꢀCyanoꢀ2ꢀ(2ꢀmethoxyphenylamino)crotonamide
(2a).
3ꢀCyanoꢀ4ꢀ(2,5ꢀdimethoxyphenyl)aminoꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyridinꢀ2ꢀone (5b) was prepared analogously to compound 5a
from pyrimidinone 4b. The yield was 76%, m.p. 275—277 °C
A mixture of enaminoamide 1 (0.3 g, 0.002 mol) and
orthoꢀanisidine (0.34 g, 0.028 mol) in AcOH (5 mL) was reꢀ
fluxed for 6 h. The reaction mixture was concentrated in vacuo,
the residue was triturated in water, and the precipitate that
formed was filtered off and washed with water. Compound 2a
was obtained in a yield of 0.3 g (67%), m.p. 186—187 °C (PriOH).
IR, ν/cm–1: 3357, 3184 (NH); 2194 (CN); 1656 (CO); 1606
(C=C). EI MS, m/z (Irel (%)): 231 [M]+• (91), 214 [M – NH3]+•
(72), 199 [M – MeOH]+• (48), 185 [M – CONH2 – 2 H]+•
1
(PriOH—DMF, 2 : 1). H NMR (DMSOꢀd6), δ: 3.72 (s, 6 H,
2 OMe); 5.53 (d, 1 H, H(5), Jo = 7.4 Hz); 6.85 (m, 2 H, H(4´),
H(6´)); 7.05 (d, 1 H, H(3´), Jo = 8.4 Hz); 7.25 (d, 1 H, H(6),
Jo = 7.4 Hz); 8.66 (br.s, 1 H, C(4)NH); 11.09 (br.s, 1 H, N(1)H).
EI MS, m/z (Irel (%)): 271 [M]+• (100), 256 [M – Me]+• (47),
228 [M – Me – CO]+• (45).
1ꢀ(2ꢀMethoxyphenyl)ꢀ4,5ꢀdioxoꢀ1,4,5,6ꢀtetrahydropyriꢀ
do[4,3ꢀd]pyrimidine (6a). A solution of compound 4a (0.3 g,
1 mmol) in glacial AcOH (4 mL) was refluxed for 7 h. The
reaction mixture was cooled to 5 °C, and the precipitate that
formed was filtered off and washed with ethyl acetate. Comꢀ
pound 6a was obtained in a yield of 0.11 g (41%), m.p.
(39), 171 [M
–
CONH2
–
CH4]+• (54), 148
[M – NCCH=CONH2]+• (100), 123 [M – C6H4OMe]+• (87),
108 [Ph(OMe)]+• (71).
1ꢀCyanoꢀ2ꢀ(2,5ꢀdimethoxyphenylamino)crotonamide (2b)
was prepared analogously to compound 2a from enaminoamide
1 and 2,5ꢀdimethoxyaniline. The yield was 55%, m.p.
1
280—282 °C (PriOH—DMF, 1 : 1). H NMR (DMSOꢀd6), δ:
1
177—178 °C (PriOH). H NMR (DMSOꢀd6), δ: 2.17 (s, 3 H,
3.81 (s, 1 H, OMe); 5.43 (s, 1 H, H(8), Jo = 7.2 Hz); 7.18, 7.31,
and 7.51—7.69 (all m, 1 H each, 1 H, 3 H, H(7), H(3´)—H(6´));
8.22 (s, 1 H, H(2)); 11.69 (br.s, 1 H, N(6)H). IR, ν/cm–1: 3167
(NH); 1675, 1644 (CO). EI MS, m/z (Irel (%)): 269 [M]+•
(100), 241 [M – CO]+• (80), 213 [M – 2 CO]+• (78).
1ꢀ(2,5ꢀDimethoxyphenyl)ꢀ4,5ꢀdioxoꢀ1,4,5,6ꢀtetrahydroꢀ
pyrido[4,3ꢀd]pyrimidine (6b) was prepared analogously to comꢀ
pound 6a from pyrimidinone 4b. Acetic acid was evaporated,
the residue was triturated in water, and the crystalline precipiꢀ
tate that formed was filtered off and washed with water and ethyl
acetate. The yield was 78%, m.p. 162—165 °C (PriOH—DMF,
7 : 2). Found (%): C, 56.91; H, 4.59; N, 13.11. C16H9N5O•H2O.
Calculated (%): C, 56.78; H, 4.76; N, 13.24. 1H NMR
(DMSOꢀd6), δ: 3.88 and 3.90 (both s, 3 H each, 2 OMe); 5.55
Me); 3.73 and 3.77 (both s, 3 H each, 2 OMe); 6.80 (br.s, 2 H,
NH2); 6.82 (dd, 1 H, H(4), Jo = 8.4 Hz, Jm = 3.0 Hz); 6.88 (br.s,
1 H, H(6)); 7.05 (d, 1 H, H(3), Jo = 8.4 Hz); 12.37 (br.s, 1 H,
C(1)NH). EI MS, m/z (Irel (%)): 261 [M]+• (100), 229
[M – MeOH]+• (87), 201 [M – 2 MeO + 2 H]+• (45), 178
[M – NCCH=CONH2]+• (85), 153 [H2NC6H3(OMe)2]+• (37),
138 [C6H3(OMe)]+• (84).
5ꢀCyanoꢀ6ꢀ(2ꢀdimethylaminovinyl)ꢀ1ꢀ(2ꢀmethoxyphenyl)ꢀ4ꢀ
oxoꢀ1,4ꢀdihydropyrimidine (4a). A mixture of enaminoamide 2a
(0.2 g, 0.87 mol) and DMF acetal (4 mL) was refluxed for 5 h.
The reaction mixture was cooled to 5 °C, and the precipitate
that formed was filtered off and washed with ethanol. Comꢀ
pound 4a was obtained in a yield of 0.2 g (77%), m.p. 259—262 °C
(PriOH—DMF, 1 : 1). 1H NMR (DMSOꢀd6), δ: 2.78 (br.s, 6 H,
NMe2); 3.82 (s, 3 H, OMe); 4.09 (d, 1 H, Hα, Jo = 12.9 Hz);
7.15, 7.30, 7.46, and 7.59 (all m, 1 H each, H(3´)—H(6´)); 7.87
(br.s, 1 H, H(8)); 7.32 (dd, 1 H, H(4´), Jo = 9.2 Hz, Jm
=
2.8 Hz); 7.41 (d, 1 H, H(3´), Jo = 9.2 Hz); 7.43 (d, 1 H, H(6´),
Jm = 2.8 Hz); 7.65 (br.s, 1 H, H(7)); 8.40 (s, 1 H, H(2)); 11.85
(br.s, 1 H, N(6)H). IR, ν/cm–1: 3472 (OH); 3380 (NH); 1685,
1654 (CO). EI MS, m/z (Irel (%)): 299 [M]+• (100), 271
[M – CO]+• (28).
(d, 1 H, Hβ, Jo = 12.9 Hz); 8.07 (s, 1 H, H(2)). IR, ν/cm–1
:
3074 (NH); 2200 (CN); 1629 (CO); 1602 (C=C). EI MS,
m/z (Irel (%)): 296 [M]+• (63), 265 [M – MeO]+• (100), 238
[M – MeO – CN]+• (81), 223 [M – MeO – CN – Me]+• (52).
5ꢀCyanoꢀ1ꢀ(2,5ꢀdimethoxyphenyl)ꢀ6ꢀ(2ꢀdimethylaminoꢀ
vinyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydropyrimidine (4b) was prepared analoꢀ
gously to compound 4a from enaminoamide 2b and DMF acetal.
The yield was 80%, m.p. 194—196 °C (PriOH—DMF, 7 : 3).
1H NMR (DMSOꢀd6), δ: 2.81 (br.s, 6 H, NMe2); 3.76 (s, 6 H,
2 OMe); 4.14 (d, 1 H, Hα, Jo = 12.9 Hz); 7.20—7.60 (m, 3 H,
H(3´), H(4´), H(6´)); 7.90 (d, 1 H, Hβ, Jo = 12.9 Hz); 8.08 (s,
1 H, H(2)). IR, ν/cm–1: 3512, 3403, 3062 (NH); 2190 (CN);
1638 (CO). EI MS, m/z (Irel (%)): 326 [M]+• (45), 295
[M – MeO]+• (100), 268 [M – MeO – CN]+• (91), 253 [M –
MeO – CN – Me]+• (80).
NꢀFormylꢀ4ꢀ(2ꢀmethoxyphenyl)aminoꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyridineꢀ3ꢀcarboxamide (7a). A suspension of pyrimidinone 4a
(0.3 g, 1 mmol) in 1 M HCl (3 mL) was kept at 70 °C for 4 h. The
precipitate that formed was filtered off and washed with water.
Compound 8a was obtained in a yield of 0.06 g (80%, 1H NMR
spectroscopic data). The aqueous mother liquor was alkalized
with NaOH (sol.) to pH 8—9, and the precipitate that formed
was filtered off and washed with water. A mixture of compounds
1
7a and 8a was obtained in a yield of 0.15 g (65 : 35, H NMR
spectroscopic data). The precipitate that formed was recrystalꢀ
lized from a 2 : 1 PriOH—DMF mixture. Compound 7a
was obtained in a yield 0.06 g (21%), m.p. 208—211 °C
1
3ꢀCyanoꢀ4ꢀ(2ꢀmethoxyphenyl)aminoꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyridinꢀ2ꢀone (5a). A mixture of pyrimidinone 4a (0.3 g,
0.87 mol) and 1 M NaOH (7 mL) was refluxed for 1 h. The
solution was acidified with concentrated HCl to pH 3. The
precipitate that formed was filtered off and washed with water.
Compound 5a was obtained in a yield of 0.24 g (98%), m.p.
(PriOH—DMF, 2 : 1). H NMR (DMSOꢀd6), δ: 3.82 (s, 3 H,
OMe); 5.93 (d, 1 H, H(5), Jo = 7.4 Hz); 7.02, 7.17, and 7.31
(all m, 1 H each, 1 H, 2 H, H(3´)—H(6´)); 7.37 (d, 1 H, H(6),
Jo = 7.4 Hz); 9.25 (d, 1 H, CONHCHO, Jo = 9.8 Hz); 11.44
(br.s, 1 H, N(1)H); 11.57 (br.s, 1 H, C(4)NH); 13.09 (br.d, 1 H,
CONHCHO, Jo = 9.8 Hz). IR, ν/cm–1: 1700 (CONH2); 1650
(CONH); 1626 (C=C, C=N). EI MS, m/z (Irel (%)): 287 [M]+•
(96), 269 [M – H2O]+• (96), 259 [M – CO]+• (95), 242
[M – CO – OH]+• (97), 227 [M – CO – MeO]+• (62), 213
[M – 2 CO – H2O]+• (100).
1
241—242 °C (PriOH—DMF, 30 : 5). H NMR (DMSOꢀd6), δ:
3.79 (s, 3 H, OMe); 5.49 (d, 1 H, H(5), Jo = 7.4 Hz); 6.98,
7.11, 7.20, and 7.31 (all m, 1 H each, H(3´)—H(6´)); 7.24 (d,
1 H, H(6), Jo = 7.4 Hz); 8.60 (br.s, 1 H, C(4)NH); 11.04 (br.s,
1 H, N(1)H). EI MS, m/z (Irel (%)): 241 [M]+• (100),
226 [M – Me]+• (47), 198 [M – Me – CO]+• (45), 183
[M – MeOH – CN]+• (53), 108 [Ph(OMe)]+• (30).
NꢀFormylꢀ4ꢀ(2,5ꢀdimethoxyphenyl)aminoꢀ2ꢀoxoꢀ1,2ꢀdiꢀ
hydropyridineꢀ3ꢀcarboxamide (7b). A solution of pyrimidinone
4b (0.25 g, 0.77 mmol) in glacial AcOH (2 mL) was kept at 70 °C

1482
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
Tugusheva et al.
for 3 h and then at 40 °C for 6 h. The reaction mixture was
concentrated in vacuo, the residue was triturated in ethyl acꢀ
etate, and the precipitate that formed was filtered off and washed
with ethyl acetate. A mixture of compounds 6b, 7b, and 8b
(TLC) was obtained in a yield of 0.12 g. The precipitate was
recrystallized from a 6 : 5 PriOH—DMF mixture. Compound 7b
was obtained in a yield of 0.03 g (13%), m.p. 208—211 °C
precipitate that formed was filtered off and washed with EtOH.
Compound 10a was obtained in a yield of 2 g (82%), m.p.
229—230 °C (MeOH). IR, ν/cm–1: 3315 (NH); 2208 (CN);
1675 (CO); 1644, 1635 (C=C, C=N). EI MS, m/z (Irel (%)): 328
[M]+• (46), 222 [M – PhCH2NH]+• (79), 106 [PhCH2=NH]+•
(35), 106 [PhCH2=NH]+• (35), 91 [PhCH2]+• (100).
4ꢀ[(3ꢀCyanoꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀdihydropyridinꢀ5ꢀ
yl)methylenamino]butyric acid (10b). γꢀAminobutyric acid (1.29 g,
12.5 mmol) was added to a solution of NaOH (0.51 g) in EtOH
(25 mL), and the reaction mixture was stirred at 60 °C until
complete dissolution was achieved. Formylpyridone 9a (3 g,
12.6 mmol) was added to the resulting solution of the sodium
salt of γꢀaminobutyric acid in EtOH. The reaction mixture was
refluxed for 5 h and cooled to 0 °C. The precipitate was filtered
off and washed with EtOH. The sodium salt of compound 10b
was obtained in a yield of 1.74 g. The salt was dissolved in warm
water (20 mL) and the solution was filtered from the insoluble
impurity. The filtrate was acidified with concentrated HCl to
pH 2—3, and the precipitate that formed was filtered off and
washed with water. Compound 10b was obtained in a yield of
0.5 g (12%), m.p. 207—208 °C (MeOH). IR, ν/cm–1: 3180—3230
(NH associated); 2210 (CN); 1730, 1680 (CO); 1640, 1620,
1590 (C=C, C=N). EI MS, m/z (Irel (%)): 324 [M]+• (65), 222
[M – HOOC(CH2)3NH]+• (100).
3ꢀCyanoꢀ5ꢀ[2ꢀ(3,4ꢀdimethoxyphenyl)ethyliminomethyl]ꢀ2ꢀ
oxoꢀ4ꢀphenylaminoꢀ1,2ꢀdihydropyridine (10c) was prepared
analogously to 10a from formylpyridone 9a and homoveratrylꢀ
amine. The reaction time was 5.5 h. The yield was 50%, m.p.
202—204 °C (EtOH). IR, ν/cm–1: 3050 (NH); 2200 (CN); 1670
(CO); 1630, 1590 (C=C, C=N). EI MS, m/z (Irel (%)): 402
[M]+• (47), 222 [M – (MeO)2C6H4(CH2)2NH]+• (50), 193
[(MeO)2C6H3(CH2)2N=CH2]+• (43).
1
(PriOH—DMF, 6 : 5). H NMR (DMSOꢀd6), δ: 3.60 and 3.64
(both s, 3 H each, 2 OMe); 5.86 (d, 1 H, H(5), Jo = 7.4 Hz); 6.76
(m, 2 H, H(4´), H(6´)); 6.97 (d, 1 H, H(3´), Jo = 8.4 Hz); 7.26
(d, 1 H, H(6), Jo = 7.4 Hz); 9.11 (d, 1 H, CONHCHO, Jo =
9.8 Hz); 11.39 (br.s, 1 H, N(1)H); 11.43 (br.s, 1 H, C(4)NH);
12.98 (br.d, 1 H, CONHCHO, Jo = 9.8 Hz). EI MS,
m/z (Irel (%)): 317 [M]+• (48), 299 [M – H2O]+• (91), 289
[M – CO]+• (85), 271 [M – CO – H2O]+• (90), 257 [M –
CO – MeOH]+• (100).
4ꢀ(2ꢀMethoxyphenyl)aminoꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀ
carboxamide (8a). A solution of bicyclic compound 6a (0.1 g,
0.37 mmol) in 1 M KOH (1 mL) was kept at 20 °C for 3 h. The
precipitate that formed was filtered off and washed with water.
Compound 8a was obtained in a yield of 0.09 g (82%), m.p.
285—288 °C (PriOH—DMF, 2 : 1). Found (%): N, 15.86.
C13H13N3O3. Calculated (%): N, 16.21. 1H NMR (DMSOꢀd6),
δ: 3.80 (s, 3 H, OMe); 5.84 (d, 1 H, H(5), Jo = 7.4 Hz); 6.95—7.25
(m, 6 H, H(3´)—H(6´), H(6), C(3)CONH); 9.84 (br.s, 1 H,
C(3)CONH); 10.97 (br.s, 1 H, N(1)H); 12.31 (br.s, 1 H,
C(4)NH). EI MS, m/z (Irel (%)): 259 [M]+• (100), 242
[M – HO]+• (66), 213 [M – CO – H2O]+• (82).
4ꢀ(2,5ꢀDimethoxyphenyl)aminoꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ
3ꢀcarboxamide (8b). A suspension of pyrimidinone 4b (0.3 g,
0.9 mmol) in 1 M HCl (3 mL) was kept at 20 °C for 6 days or at
70 °C for 1 h. Then 1 M KOH (5 mL) was added to the reaction
mixture, and the mixture was kept at 20 °C for 1.5 h. The
precipitate that formed was filtered off and washed with water.
Compound 8b containing a small impurity of compound 7b
(formylcarboxamide) was obtained in a yield of 0.2 g. The preꢀ
cipitate was recrystallized from a 3 : 2 PriOH—DMF mixture.
Compound 8b was obtained in a yield of 0.07 g (27%), m.p.
3ꢀCyanoꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ5ꢀphenyliminomethylꢀ1,2ꢀ
dihydropyridine (10d) was prepared analogously to 10a from
formylpyridone 9a and aniline in ethylene glycol at 135 °C. The
reaction time was 2 h. The yield was 38%, m.p. 300 °C
(MeOH—DMF, 5 : 1). Found (%): N, 17.48. C19H14N4O. Calꢀ
culated (%): N, 17.83. 1H NMR (DMSOꢀd6), δ: 7.24—7.43 (m,
10 H, 2 Ph); 8.14 (s, 1 H, H(1´)); 8.67 (s, 1 H, H(6)); 12.11
1
208—210 °C (PriOH—DMF, 7 : 5). H NMR (DMSOꢀd6), δ:
3.71 and 3.75 (both s, 3 H each, 2 OMe); 6.08 (d, 1 H, H(5),
Jo = 7.4 Hz); 7.00 (m, 2 H, H(4´), H(6´)); 7.12 (d, 1 H, H(3´),
Jo = 8.4 Hz); 7.22 (br.d, 1 H, C(3)CONH, Jgem = 5.0 Hz); 7.31
(d, 1 H, H(6), Jo = 7.4 Hz); 10.00 (br.d, 1 H, C(3)CONH,
Jgem = 5.0 Hz); 11.00 (br.s, 1 H, N(1)H); 12.49 (br.s, 1 H,
C(4)NH). EI MS, m/z (Irel (%)): 289 [M]+• (100), 271
[M – H2O]+• (86), 257 [M – MeOH]+• (97).
4ꢀ(4ꢀChlorophenyl)aminoꢀ3ꢀcyanoꢀ5ꢀformylꢀ2ꢀoxoꢀ1,2ꢀdiꢀ
hydropyridine (9b). A solution of compound 3b (0.623 g,
1.8 mmol) in 90% AcOH (6 mL) was kept at 20 °C for 3 days.
The precipitate that formed was filtered off and washed with
ethyl acetate. Formylpyridone 9b was obtained in a yield of
0.437 g (89%), m.p. 290 °C (decomp., PriOH—DMF, 3 : 2).
1H NMR (DMSOꢀd6), δ: 7.41 (m, 4 H, C6H4Cl); 8.42 (s, 1 H,
H(6)); 9.59 (s, 1 H, CHO); 10.52 (br.s, 1 H, N(1)H); 12.40
(br.s, 1 H, C(4)NH). IR, ν/cm–1: 3198, 3130 (NH); 2219 (CN);
1691 (CO); 1646, 1586 (C=C, C=N). EI MS, m/z (Irel (%)): 273
[M]+• (100), 244 [M – CHO]+• (50).
(br.s, 1 H, N(1)H); 12.35 (br.s, 1 H, C(4)NH). IR, ν/cm–1
:
3080, 3020 (NH); 2200 (CN); 1670 (CO); 1630, 1590 (C=C,
C=N). EI MS, m/z (Irel (%)): 314 [M]+• (100), 222
[M – PhNH]+• (91).
3ꢀCyanoꢀ5ꢀhydrazinomethylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀdiꢀ
hydropyridine (11). A mixture of formylpyridone 9a (1.2 g,
5 mmol) and hydrazine hydrate (2.5 mL) in anhydrous EtOH
(5 mL) was kept at 20 °C for 1 h. The precipitate that formed
was filtered off and washed with EtOH. Hydrazone 11 was obꢀ
tained in a yield of 1.2 g (53%), m.p. 293—294 °C (DMF).
1H NMR (DMSOꢀd6), δ: 6.66 (br.s, 2 H, NH2); 7.25 and 7.39
(both m, 3 H and 2 H, Ph); 7.62 (s, 1 H, Hα); 7.75 (s, 1 H,
H(6)); 11.39 (br.s, 1 H, C(4)NH); 11.63 (br.s, 1 H, N(1)H). IR,
ν/cm–1: 3400, 3200 (NH); 2200 (CN); 1690 (CO); 1620, 1570
(C=C, C=N). ES MS, m/z: 254 [M + H]+•, 276 [M + Na]+•
,
529 [2 M + Na]+•. EI MS, m/z (Irel (%)): 253 [M]+• (50), 222
[M – NH2NH]+• (100).
5ꢀBenzylidenehydrazonomethylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀ
dihydropyridineꢀ3ꢀcarbonitrile (12a). A mixture of hydrazone 11
(0.5 g, 1.5 mmol) and benzaldehyde (3.68 g, 0.035 mol) in
anhydrous EtOH (20 mL) was kept at 20 °C for 2.5 h. The
precipitate that formed was filtered off and washed with EtOH.
5ꢀ(Benzylimino)methylꢀ3ꢀcyanoꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀ
dihydropyridine (10a). A mixture of formylpyridone 9a (2 g,
8 mmol), benzylamine (0.9 g, 8 mol), and a catalytic amount of
pꢀTsOH in anhydrous EtOH (40 mL) was refluxed for 1.5 h. The

Synthesis of 4ꢀarylaminoꢀ2ꢀpyridone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
1483
Compound 12a was obtained in a yield of 0.5 g (30%), m.p.
278—279 °C (EtOH). Found (%): N, 20.20. C20H15N5O. Calꢀ
culated (%): N, 20.53. 1H NMR (DMSOꢀd6), δ: 7.32—7.50 and
7.83 (both m, 8 H and 2 H, 2 Ph); 8.15 (s, 1 H, H(6)); 8.72 and
8.80 (both s, 1 H each, H(1´), H(4´)); 11.38 (br.s, 1 H, C(4)NH);
12.15 (br.s, 1 H, N(1)H). IR, ν/cm–1: 3525, 3500, 3180 (NH);
2200 (CN); 1620 (CO); 1575 (C=C, C=N). EI MS,
m/z (Irel (%)): 341 [M]+• (20), 222 [M – PhCHN=NH]+• (63),
120 [PhCH=NNH2]+• (100).
ν/cm–1: 3341 (OH); 3300 (NH); 2216 (CN); 1644, 1631
(CO). EI MS, m/z (Irel (%)): 240 [M – H]+• (14), 221 [M –
H2O – 2 H]+• (100), 193 [M – H2O – 2 H – CO] (17).
4ꢀ(4ꢀChlorophenylamino)ꢀ3ꢀcyanoꢀ5ꢀhydroxymethylꢀ2ꢀoxoꢀ
1,2ꢀdihydropyridine (13b) was prepared from formylpyridone 9b
(0.5 g, 1.8 mmol) and NaBH4 (0.069 g, 1.8 mmol) analogously
to compound 13a. The yield was 72%, m.p. 261—264 °C
1
(PriOH—DMF, 3 : 2). H NMR (DMSOꢀd6), δ: 4.34 (s, 2 H,
CH2OH); 5.25 (br.s, 1 H, CH2OH); 7.16—7.46 (m, 6 H, Ph,
H(6)); 8.62 (br.s, 1 H, C(4)NH); 11.35 (br.s, 1 H, N(1)H). IR,
ν/cm–1: 3405 (OH); 3273 (NH); 2208 (CN); 1646 (CO). ES MS,
m/z: 276 [M + H]+•, 298 [M + Na]+•, 551 [2 M + H]+•, 573
[2 M + Na]+.
5ꢀ[(4ꢀHydroxybenzylidene)hydrazonomethyl]ꢀ2ꢀoxoꢀ4ꢀpheꢀ
nylaminoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (12b) was prepared
analogously to 12a. The mixture was allowed to stand for 53 h.
The yield was 67%, m.p. 283—284 °C (DMF). IR, ν/cm–1
:
3400, 3200 (NH); 2200 (CN); 1690 (CO); 1620, 1570
3ꢀCyanoꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ5ꢀureidomethylꢀ1,2ꢀdihydroꢀ
pyridine (14). Urea (2.52 g, 0.042 mol) was added to a suspenꢀ
sion of formylpyridone 9a (0.4 g, 1.7 mmol) in AcOH (6 mL ).
The reaction mixture was heated with stirring at 90 °C until the
precipitate was completely dissolved. The solution was refluxed
for 13 h, cooled to 20 °C, and poured into water (20 mL). The
precipitate that formed was filtered off and successively washed
with water, a NaHCO3 solution, and water. Compound 14
was obtained in a yield of 3.54 g (89%), m.p. 247—250 °C
(MeCN—DMF, 6 : 1). 1H NMR (DMSOꢀd6), δ: 4.03 (d, 2 H, 2
HC(5), Jo = 6.4 Hz); 5.82 (br.s, 2 H, NH2); 6.55 (t, 1 H,
CH2NH, Jo = 6.4 Hz); 7.13 and 7.33 (both m, 3 H and 2 H each,
Ph); 7.33 (s, 1 H, H(6)); 10.26 (br.s, 1 H, C(4)NH); 11.18 (br.s,
1 H, N(1)H). IR, ν/cm–1: 3429 (OH); 3348, 3188 (NH); 2199
(CN); 1632 (CO). EI MS, m/z (Irel (%)): 283 [M]+• (1), 266
[M – NH3]+• (17), 222 [M – NH2CONH2 – H] + (100).
3ꢀCyanoꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ5ꢀpiperidinomethylꢀ1,2ꢀdiꢀ
hydropyridine (16). Thionyl chloride (0.4 mL) was added
dropwise to a suspension of pyridone 13a (0.4 g, 1.66 mmol) in
CH2Cl2 (4 mL). The reaction mixture was refluxed with stirring
for 10 h, and then CH2Cl2 (5 mL) was added. The precipitate
was triturated, filtered off, and washed with CH2Cl2. A chloro
derivative was obtained in a yield of 0.353 g. The resulting chloro
derivative (0.28 g) was stirred with Py (2 mL) at 90 °C for 6 h.
The reaction mixture was cooled to 20 °C, the solution was
removed by decantation, the residual oil was triturated with
acetonitrile, and the precipitate was filtered off and washed with
acetonitrile. Pyridinium salt 15 was obtained in a yield of 0.28 g
(C=C, C=N). EI MS, m/z (Irel (%)): 357 [M]+• (35),
222
[M
–
HOC6H4CHN=NH]+•
(67),
136
[HOC6H4CH=NNH2]+• (100).
5ꢀ[(4ꢀHydroxyꢀ3ꢀmethoxybenzylidene)hydrazonomethyl]ꢀ2ꢀ
oxoꢀ4ꢀphenylaminoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (12c) was
prepared analogously to 12a but with refluxing (5 h). The yield
1
was 53%, m.p. 292—293 °C (DMF). H NMR (DMSOꢀd6), δ:
3.80 (s, 3 H, OMe); 6.84 (d, 1 H, H(3´), Jo = 8.0 Hz); 7.24 (dd,
1 H, H(2´), Jo = 8.0 Hz, Jm = 2.0 Hz); 7.28—7.46 (m, 6 H, Ph,
H(6´)); 8.09 (s, 1 H, H(6)); 8.57 and 8.76 (both s, 1 H each,
H(1´), H(4´)); 9.80 (br.s, 1 H, OH); 11.45 (br.s, 1 H, C(4)NH);
12.10 (br.s, 1 H, N(1)H). IR, ν/cm–1: 3300, 3180 (NH); 2200
(CN); 1660 (CO); 1580 (C=C, C=N). EI MS, m/z (Irel (%)):
387 [M]+• (7), 222 [M – 3ꢀMeO,4ꢀOHC6H3CHN=NH]+•
(100).
5ꢀ[(4ꢀMethoxybenzylidene)hydrazonomethyl]ꢀ2ꢀoxoꢀ4ꢀpheꢀ
nylaminoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (12d) was prepared
analogously to 12a. The mixture was allowed to stand for 4 h.
The yield was 69%, m.p. 280—282 °C (DMF). Found (%):
C, 66.27; H, 4.57; N, 17.86; H2O, 3.43. C21H17N5O2•0.65H2O.
Calculated (%): C, 65.84; H, 4.81; N, 18.28; H2O, 3.06.
1H NMR (DMSOꢀd6), δ: 3.80 (s, 3 H, OMe); 7.02, 7.33—7.42,
and 7.77 (all m, 2 H each, 5 H, 2 H, Ph, C6H4OMe); 8.10 (s,
1 H, H(6)); 8.63 and 8.75 (both s, 1 H each, H(1´), H(4´));
11.41 (br.s, 1 H, C(4)NH); 12.10 (br.s, 1 H, N(1)H). IR, ν/cm–1
3560, 3350 (OH); 3180 (NH); 2216 (CN); 1651 (CO); 1635, 1616
(C=C, C=N). ES MS, m/z: 372 [M + H]+•, 393 [M + Na]+•
743 [2 M + H]+•, 765 [2 M + Na]+•
:
,
1
.
(63%), m.p. 320—322 °C (decomp.). H NMR (DMSOꢀd6), δ:
5ꢀCyclohexylidenehydrazonomethylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ
1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (12e) was prepared analoꢀ
gously to 12a but with refluxing (3 h). The yield was 91%, m.p.
290—291 °C (anhydrous EtOH). IR, ν/cm–1: 3190 (NH);
2200 (CN); 1690 (CO); 1620, 1580 (C=C, C=N). EI MS,
m/z (Irel (%)): 333 [M]+• (50), 222 [M – C6H10N=NH]+•
(100).
5.97 (s, 2 H, 2 HC(6)); 7.04, 7.12, and 7.26 (all m, 2 H each,
1 H, 2 H, Ph); 7.96 (s, 1 H, H(6)); 8.08, 8.55, and 9.10 (all m,
2 H each, 1 H, 2 H, Py); 9.51 (br.s, 1 H, C(4)NH); 11.93
(br.s, 1 H, N(1)H). ES MS, m/z: 224 [M – C5H5N]+, 80
[M – C5H5N + H]+. A mixture of pyridinium salt 15 (0.28 g,
0.83 mmol) and piperidine (0.19 g, 2.2 mmol) in benzene
(4 mL) was refluxed with stirring for 1 h. After cooling of the
reaction mixture to 20 °C, the precipitate that formed was filꢀ
tered off and triturated with petroleum ether. The precipitate
was filtered off and washed with water. Compound 16 was obꢀ
tained in a yield of 0.145 g (57%), m.p. 229—231 °C (MeCN).
Found (%): N, 18.38. C18H20N4O. Calculated (%): N, 18.17.
1H NMR (DMSOꢀd6), δ: 1.41—1.55 (m, 6 H, 2 H(3´)—H(5´));
2.39 (br.s, 4 H, 2 H(2´), 2 H(6´)); 3.42 (s, 2 H, 2 HC(5));
7.19—7.39 (m, 6 H, Ph, H(6)); 10.69 (br.s, 1 H, C(4)NH);
11.27 (br.s, 1 H, N(1)H). IR, ν/cm–1: 3250, 3150 (NH); 2210
(CN); 1630 (CO). ES MS, m/z: 309 [M + H]+, 331 [M + Na]+,
617 [2 M + H]+, 639 [2 M + Na]+, 224 [M – C5H5N]+•, 86
3ꢀCyanoꢀ5ꢀhydroxymethylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀdiꢀ
hydropyridine (13a). Sodium borohydride (0.726 g, 0.019 mol)
was added portionwise with stirring to a suspension of formylꢀ
pyridone 9a (3 g, 12.6 mmol) in PriOH (60 mL) at 50—55 °C for
3 h. The precipitate that formed was filtered off, washed with
PriOH, and dissolved in water (35 mL). The solution was acidiꢀ
fied to pH 6 and kept at 20 °C for 2 h. The precipitate that
formed was filtered off and washed with water. Compound 13a
was obtained in a yield of 2.15 g (70%), m.p. 222—223 °C
1
(PriOH—DMF, 50 : 1). H NMR (DMSOꢀd6), δ: 4.33 (s, 2 H,
CH2OH); 5.24 (br.s, 1 H, CH2OH); 7.13—7.39 (m, 6 H, Ph,
H(6)); 8.54 (br.s, 1 H, C(4)NH); 11.29 (br.s, 1 H, N(1)H). IR,
[C5H11N + H]+•
.

1484
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
Tugusheva et al.
3ꢀCyanoꢀ5ꢀhydroxyiminomethylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀ
dihydropyridine (17a). Formylpyridone 9a (2 g, 8.4 mmol) was
added to a solution of hydroxylamine hydrochloride (1.02 g,
14.7 mmol) in pyridine (8 mL). The reaction mixture was stirred
at 80 °C for 2 h, cooled, and poured into water (50 mL). The
precipitate that formed was filtered off and washed with water.
Compound 17a was obtained in a yield of 1.87 g (89%), m.p.
261—263 °C (MeOH). 1H NMR (DMSOꢀd6), δ: 7.23—7.50 (m,
5 H, Ph); 7.82 (s, 1 H, H(5´)); 8.21 (s, 1 H, H(6)); 10.37 (br.s,
1 H, C(4)NH); 11.29 (br.s, 1 H, OH); 11.86 (br.s, 1 H, N(1)H).
IR, ν/cm–1: 3660 (OH); 3420 (NH); 2220 (CN); 1680 (CO).
ES MS, m/z: 237 [M + H – H2O]+•, 255 [M + H]+•, 277
[M + Na]+•, 508 [2 M + H]+•, 531 [2 M + Na + H]+•. EI MS,
m/z (Irel (%)): 254 [M]+• (75), 237 [M – OH]+• (52),
236 [M – H2O]+• (89), 222 [M – HO – NH]+• (100), 77
[Ph]+•(60).
1660 (CO, ketone); 1630, 1570 (C=C, C=N). ES MS, m/z: 237
[M – CH3COOH + H]+•, 297 [M + H]+•, 319 [M + Na]+•
,
615 [2
M + . EI MS, m/z (Irel (%)): 236
Na]+•
[M – CH3COOH]+• (100), 209 [M – CH3COOH – HCN]+•
(13), 208 [M – CH3COOH – CO]+• (17).
B. Compound 17a (0.58 g, 0.002 mol) was refluxed in acetic
anhydride (4 mL) for 15 min. The precipitate was filtered off
and washed with water. Compound 18a was obtained in a yield
of 0.61 g (90%), m.p. 286—288 °C (DMF).
5ꢀAcetoxyiminomethylꢀ4ꢀ(4ꢀchlorophenyl)aminoꢀ3ꢀcyanoꢀ2ꢀ
oxoꢀ1,2ꢀdihydropyridine (18b) was prepared analogously to comꢀ
pound 18a by the method A or B in 90 or 75% yield, respectively,
1
m.p. 288 °C (decomp.). H NMR (DMSOꢀd6), δ: 2.15 (s, 3 H,
COMe); 7.32 and 7.47 (both m, 2 H each, C6H4Cl); 8.05 (s,
1 H, Hα); 8.66 (s, 1 H, H(6)); 10.06 (br.s, 1 H, C(4)NH); 12.28
(br.s, 1 H, N(1)H). IR, ν/cm–1: 3252, 3067 (NH); 2209 (CN);
1771 (CO); 1670 (CO, ketone); 1636, 1606 (C=C, C=N).
ES MS, m/z: 331 [M + H]+•, 353 [M + Na]+•, 683
4ꢀ(4ꢀChlorophenyl)aminoꢀ3ꢀcyanoꢀ5ꢀhydroxyiminomethylꢀ2ꢀ
oxoꢀ1,2ꢀdihydropyridine (17b). Formylpyridone 9b (0.5 g,
1.8 mmol) was added to a solution of hydroxylamine hydrochloꢀ
ride (0.21 g, 3 mmol) in pyridine (2 mL). The reaction mixture
was stirred at 115 °C for 10 min, cooled, and poured into water
(10 mL). The precipitate that formed was filtered off and washed
with water. Compound 17b was obtained in a yield of 0.52 g
[2 M + Na]+•, 271 [M + H – CH3COOH]+•
.
3,5ꢀDicyanoꢀ4ꢀphenylaminopyridine (19a). Formylpyridone
9a (0.5 g, 2 mmol) was added to a solution of hydroxylamine
hydrochloride (0.24 g, 4 mmol) in pyridine (3 mL) at 90—95 °C.
The reaction mixture was stirred for 0.5 h, and then acetic
anhydride (1.3 mL) was slowly added. After 8 min, pyridine
(2 mL) was added. The reaction mixture was stirred at 115 °C
for 2 h, cooled, and poured into water. The precipitate that
formed was filtered off, washed with water, and dried. Comꢀ
pound 19a was obtained in a yield of 0.44 g (90%), m.p.
1
(98%), m.p. 293—294 °C (PriOH). H NMR (DMSOꢀd6), δ:
7.25 and 7.40 (both m, 2 H each, C6H4Cl); 7.67 (s, 1 H, H(5´));
8.14 (s, 1 H, H(6)); 10.34 (br.s, 1 H, C(4)NH); 11.09 (br.s, 1 H,
OH); 11.80 (br.s, 1 H, N(1)H). IR, ν/cm–1: 3317 (OH);
2219 (CN); 1644 (CO). ES MS, m/z: 289 [M + H]+•, 311
[M + Na]+•, 599 [2 M + Na]+•. EI MS, m/z (Irel (%)): 270
[M – H2O]+•(100), 242 [M – CO]+• (27).
1
323—324 °C (MeOH). H NMR (DMSOꢀd6), δ: 7.25 and 7.37
(both m, 3 H and 2 H each, Ph); 8.34 (s, 1 H, H(6)); 9.62 (br.s,
1 H, C(4)NH); 12.41 (br.s, 1 H, N(1)H). IR, ν/cm–1: 3220
(NH); 2220 (CN); 1670 (CO); 1620, 1570 (C=C, C=N). ES MS,
3ꢀCyanoꢀ4ꢀdimethylaminoꢀ5ꢀhydroxyiminomethylꢀ2ꢀoxoꢀ
1,2ꢀdihydropyridine (17c). Formylpyridone 9c (0.2 g, 1 mmol)
was added to a solution of hydroxylamine hydrochloride (0.11 g,
1.7 mmol) in pyridine (0.9 mL). The reaction mixture was stirred
at 115 °C for 0.5 h, cooled, and poured into PriOH (7 mL). The
inorganic precipitate was filtered off, and the filtrate was conꢀ
centrated to dryness. The residue was triturated with diethyl
ether and heptane and decanted. Then PriOH was added to the
semicrystalline precipitate and the mixture was kept at 5 °C
for 12 h. The precipitate that crystallized out was filtered off,
washed with PriOH, and dried. Compound 17c was obtained in
m/z: 237 [M + H]+•, 259 [M + Na]+•, 495 [2 M + Na]+•
.
EI MS, m/z (Irel (%)): 236 [M]+• (100), 209 [M – HCN]+•
(13), 208 [M – CO]+• (17).
4ꢀ(4ꢀChlorophenyl)aminoꢀ3,5ꢀdicyanopyridine (19b) was preꢀ
pared analogously to 19a from compound 9b. The yield was 68%,
1
m.p. 335 °C (decomp., MeOH). H NMR (DMSOꢀd6), δ: 7.27
and 7.42 (both m, 2 H each, C6H4Cl); 8.31 (s, 1 H, H(6)); 9.58
(br.s, 1 H, C(4)NH); 12.40 (br.s, 1 H, N(1)H). IR, ν/cm–1
:
3300 (NH); 3084, 2243, 2212 (CN); 1651 (CO). ES MS, m/z:
1
a yield of 0.091 g (42%), m.p. 203—204 °C (PriOH). H NMR
271 [M + H]+•, 293 [M + Na]+•
.
(DMSOꢀd6), δ: 3.13 (s, 6 H, NMe2); 7.44 (s, 1 H, H(5´)); 7.87
(s, 1 H, H(6)); 10.85 (br.s, 1 H, OH); 11.65 (br.s, 1 H, N(1)H).
IR, ν/cm–1: 3169 (NH); 2216 (CN); 1635 (CO). ES MS, m/z:
207 [M + H]+•, 229 [M + Na]+•, 413 [2 M + H]+, 435
[2 M + Na]+. EI MS, m/z (Irel (%)): 206 [M]+• (5), 188
[M – H2O] (100), 173 [M – H2O – Me] (51).
2ꢀChloroꢀ3,5ꢀdicyanoꢀ4ꢀphenylaminopyridine (20a). A mixꢀ
ture of compound 19a (0.66 g, 2.8 mmol) and triethylamine
hydrochloride (0.35 g, 2.5 mmol) in phosphoryl chloride (5 mL)
was refluxed for 2 h, cooled, and poured into water. The precipiꢀ
tate that formed was filtered off and washed with water, ethanol,
and diethyl ether. Compound 20a was obtained in a yield of
0.62 g (87%), m.p. 192—194 °C (EtOH). 1H NMR (DMSOꢀd6),
δ: 7.34 (m, 5 H, Ph); 8.61 (s, 1 H, H(6)); 10.20 (br.s, 1 H,
C(4)NH). IR, ν/cm–1: 3270 (NH); 2200 (CN); 1590, 1570
(C=C, C=N).
2ꢀChloroꢀ4ꢀ(4ꢀchlorophenyl)aminoꢀ3,5ꢀdicyanopyridine (20b)
was prepared analogously to 20a from compound 19b. The yield
was 65%, m.p. 240—241 °C (MeOH). 1H NMR (DMSOꢀd6), δ:
7.36 and 7.47 (both m, 2 H each, C6H4Cl); 8.64 (s, 1 H, H(6));
10.16 (br.s, 1 H, C(4)NH). IR, ν/cm–1: 3280 (NH); 2226 (CN);
1568 (C=C, C=N).
5ꢀAcetoxyiminomethylꢀ3ꢀcyanoꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀ
dihydropyridine (18a). A. Formylpyridone 9a (0.5 g, 2 mmol)
was added to a solution of hydroxylamine hydrochloride (0.24 g,
4 mmol) in pyridine (3 mL) at 90—95 °C. The reaction mixture
was stirred for 0.5 h, and then acetic anhydride (1.3 mL) was
slowly added. The reaction mixture was allowed to stand for
8 min, cooled, and poured into water. The precipitate that formed
was filtered off, washed with water, and dried. Compound 18a
was obtained in a yield of 0.44 g (90%), m.p. 286—288 °C
1
(MeOH). H NMR (DMSOꢀd6), δ: 2.14 (s, 3 H, COMe); 7.28
and 7.40 (both m, 3 H and 2 H each, Ph); 8.04 (s, 1 H, H(5´));
8.66 (s, 1 H, H(6)); 10.09 (br.s, 1 H, C(4)NH); 12.20 (br.s, 1 H,
N(1)H). IR, ν/cm–1: 3200, 3030 (NH); 2200 (CN); 1780 (CO);
2ꢀAminoꢀ3,5ꢀdicyanoꢀ4ꢀphenylaminopyridine (21a). A mixꢀ
ture of pyridine 20a (3.35 g, 13 mmol) and a 14% ethanolic
solution of ammonia (35 mL) was heated in an autoclave at

Synthesis of 4ꢀarylaminoꢀ2ꢀpyridone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
1485
80 °C for 6 h. The precipitate was filtered off. Pyridine 21a was
obtained in a yield of 2.7 g (87%), m.p. 225—226 °C (EtOH).
1H NMR (DMSOꢀd6), δ: 7.20 (d, 2 H, H (2´), H(6´), J =
8.8 Hz); 7.35 (t, 3 H, H(3´)—H(5´), J = 8.8 Hz); 7.45 (br.s, 2 H,
NH2); 8.22 (s, 1 H, H(6)); 9.33 (br.s, 1 H, C(4)NH). IR,
ν/cm–1: 3360, 3300, 3280, 3125 (NH, NH2); 2220 (CN); 1660
(NH, NH2); 1590, 1550 (C=C, C=N). EI MS, m/z (Irel (%)):
235 [M]+• (100), 208 [M – HCN]+• (27), 208 [M – CO]+• (17).
2ꢀBenzylaminoꢀ3,5ꢀdicyanoꢀ4ꢀphenylaminopyridine (21b).
A mixture of compound 20a (1.8 g, 7.1 mmol) and benzylamine
(1.5 g, 0.014 mol) in anhydrous ethanol (60 mL) was stirred at
40—45 °C for 3 h. The precipitate was filtered off, washed with
ethanol and diethyl ether, and dried. Pyridine 21b was obtained
N(5)H). IR, ν/cm–1: 3084 (NH); 2218 (CN); 1654 (CO); 1631
(C=C, C=N). ES MS, m/z: 237 [M + H]+•, 259 [M + Na]+•
473 [2 M + H]+•, 495 [2 M + Na]+•
,
.
1ꢀ(4ꢀChlorophenyl)ꢀ7ꢀcyanoꢀ6ꢀoxoꢀ5,6ꢀdihydroꢀ1Hꢀpyrazoꢀ
lo[4,3ꢀc]pyridine (22b) was prepared analogously to 22a from
compound 18b. The yield was 79%, m.p. 332—335 °C (decomp.,
1
PriOH—DMF, 1 : 1). H NMR (DMSOꢀd6), δ: 7.62 (m, 4 H,
C6H4Cl); 8.41 (s, 1 H, H(3)); 8.73 (s, 1 H, H(4)); 13.00 (br.s,
1 H, N(5)H). 13C NMR (DMSOꢀd6), δ: 73.7 (C(7)); 112.1
(C(3a)); 114.5 (CN); 128.4, 128.8, 133.6, 135.8 (C(1´)—C(6´));
139.5 (C(3)); 140.8 (C(4)); 146.8 (C(7a)); 161.4 (C(6)). IR,
ν/cm–1: 3230 (NH); 2212 (CN); 1682 (CO); 1604 (C=C, C=N).
ES MS, m/z: 271 [M + H]+• 293 [M + Na]+•, 563 [2 M + Na]+•
.
in a yield of 2.1 g (91%), m.p. 219—220 °C (EtOH). IR, ν/cm–1
3360, 3280 (NH); 2200 (CN); 1590 (C=C, C=N, NH). ES MS,
m/z: 326 [M + H]+•, 348 [M + Na]+•
:
The threeꢀdimensional structure of molecule 22b was estabꢀ
lished by powder Xꢀray diffraction. Compound 22b crystallizes
in the orthorhombic space group P212121 with the unit cell paꢀ
rameters a = 3.879(1) Å, b = 7.633(2) Å, c = 38.83(1) Å and the
unit cell volume of 1168(1) Å3. The intensities of reflections
were measured on an XPert PRO powder diffractometer using
.
3,5ꢀDicyanoꢀ2,4ꢀdi(phenylamino)pyridine (21c) was prepared
analogously to 21b from compound 20a (0.3 g, 1.2 mmol) and
aniline (0.33 g, 3.6 mmol) in ethylene glycol (5 mL) at 100 °C.
The reaction mixture was allowed to stand for 1.5 h. The yield
was 91%, m.p. 234—236 °C (MeOH). IR, ν/cm–1: 3360, 3300
(NH); 2200 (CN); 1590 (C=C, C=N, NH). ES MS, m/z: 312
CuꢀKα radiation. The crystal structure of compound 22b was
1
solved by the systematic search method15 and refined by the
Rietveld method using the MRIA program.16 All structural data,
including the unit cell parameters, atomic coordinates, bond
angles, and bond lengths, were deposited with the Cambridge
Structural Database (CCDC604040).*
[M + H]+•, 645 [2 M + Na]+•
.
3,5ꢀDicyanoꢀ2ꢀ(4ꢀmethoxyphenyl)aminoꢀ4ꢀphenylaminoꢀ
pyridine (21d) was prepared analogously to 21b from comꢀ
pound 20a. The reaction mixture was allowed to stand for 2 h.
3ꢀFormylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀdihydropyridine (23).
A. A Ni—Al2 alloy (3 g) was added to a suspension of pyridone
5c (3 g, 0.014 mol) in 50% HCOOH (40 mL). The reaction
mixture was refluxed with stirring for 6 h and cooled to 20 °C.
The precipitate that formed was filtered off and washed with a
small amount of 50% HCOOH and water. The crude precipiꢀ
tate, which was a mixture of inorganic salts and the reaction
product, was extracted with DMF (4×20 mL), and the precipiꢀ
tate was filtered off. The filtrate was concentrated to dryness,
and the residue (the crystalline precipitate) was triturated with
petroleum ether, filtered off, and washed with petroleum ether.
Compound 23 was obtained in a yield of 1.62 g (53%), m.p.
The yield was 98%, m.p. 203—204 °C (MeOH). IR, ν/cm–1
:
3360, 3260 (NH); 2200 (CN); 1600, 1560 (C=C, C=N, NH).
ES MS, m/z: 342 [M + H]+•, 364 [M + Na]+•, 705
[2 M + Na]+•
.
2ꢀ(4ꢀChlorophenyl)aminoꢀ3,5ꢀdicyanoꢀ4ꢀphenylaminopyriꢀ
dine (21e) was prepared analogously to 21b from compound 20a
(0.35 g, 1.4 mmol) and 4ꢀchloroaniline (0.52 g, 4.1 mmol) in
ethylene glycol (5 mL) at 80 °C. The reaction mixture was
allowed to stand for 2.5 h. The yield was 91%, m.p. 218—219 °C
(EtOH). IR, ν/cm–1: 3310, 3280 (NH); 2200 (CN); 1600, 1580,
1560 (C=C, C=N, NH). ES MS, m/z: 346 [M + H]+•, 713
[2 M + Na]+•
.
251—254 °C (toluene). H NMR (DMSOꢀd6), δ: 5.88 (d, 1 H,
1
3,5ꢀDicyanoꢀ2ꢀ(4ꢀmethylphenyl)aminoꢀ4ꢀphenylaminopyriꢀ
dine (21f) was prepared analogously to 21b from compound 20a.
The reaction mixture was allowed to stand for 3 h. The yield was
42%, m.p. 224—226 °C (EtOH). IR, ν/cm–1: 3320, 3260 (NH);
2200 (CN); 1580, 1560 (C=C, C=N, NH). EI MS, m/z: 326
H(5), Jo = 7.4 Hz); 7.25—7.49 (m, 6 H, Ph, H(6)); 10.03 (s,
1 H, CHO); 11.07 (br.s, 1 H, N(1)H); 11.71 (br.s, 1 H, C(4)NH).
IR, ν/cm–1: 3142 (OH); 1630 (CO). ES MS, m/z: 237
[M + Na]+•, 451 [2 M + Na]+•, 665 [3 M + Na]+•. EI MS,
m/z (Irel (%)): 213 [M – H]+• (100), 185 [M – CHO]+• (100).
(Only a small amount of the starting compound was isolated
from the mother filtrate of the reaction mixture.)
[M + H]+•, 348 [M + Na]+•, 650 [2 M + H]+•
.
2,4ꢀDi[(4ꢀchlorophenyl)amino]ꢀ3,5ꢀdicyanopyridine (21g)
was prepared analogously to 21e from compound 20b. The yield
was 70%, m.p. 222—226 °C (EtOH). H NMR (DMSOꢀd6), δ:
B. A Ni—Al2 alloy (2 g) was added to a suspension of pyridone
5c (2 g, 9.5 mmol) in 85% HCOOH (30 mL). The reaction
mixture was refluxed with stirring for 20 h and cooled to 20 °C.
The precipitate that formed (inorganic salts) was filtered off and
washed with a small amount of 85% HCOOH. The filtrate was
diluted with water (150 mL) and kept at 20 °C for 1 h. The
precipitate that formed was filtered off and washed with water
and petroleum ether. Compound 23 was obtained in a yield of
0.538 g (26%) (a mixture of compound 23 and the sample preꢀ
pared by the method A showed no melting point depression).
1
7.24—7.55 (m, 8 H, 2 C6H4Cl); 8.37 (s, 1 H, H(6)); 9.49 and
9.58 (both br.s, 1 H each, 2 NH). IR, ν/cm–1: 3276 (NH);
2215 (CN); 1611, 1600 (C=C, C=N, NH). ES MS, m/z:
380 [M + H]+•
.
7ꢀCyanoꢀ6ꢀoxoꢀ1ꢀphenylꢀ5,6ꢀdihydroꢀ1Hꢀpyrazoꢀ
lo[4,3ꢀc]pyridine (22a). A solution of compound 18a (0.2 g,
0.68 mmol) in DMF (5 mL) was refluxed for 30 min, DMF was
evaporated to dryness, the residue (darkꢀcreamꢀcolored crysꢀ
tals) was triturated with ethyl acetate, and the precipitate was
filtered off and washed with ethyl acetate. Compound 22a was
obtained in a yield of 0.15 g (94%), m.p. 338—340 °C (decomp.,
PriOH—DMF, 1 : 1). Found (%): N, 23.49. C13H8N4O. Calcuꢀ
* These data can be obtained, free of charge, on application to
the Cambridge Crystallographic Data Centre (CCDC), 12 Union
Road, Cambridge CB2 1EZ, UK. Fax: +44 (0) 1223 336033.
Eꢀmail: deposit@ccdc.cam.ac.uk.
1
lated (%): N, 23.72. H NMR (DMSOꢀd6), δ: 7.55 (m, 5 H,
Ph); 8.40 (s, 1 H, H(4)); 8.74 (s, 1 H, H(3)); 13.00 (br.s, 1 H,

1486
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
Tugusheva et al.
1ꢀOxoꢀ1,2ꢀdihydrobenzo[b]ꢀ1,6ꢀnaphthyridine (24). A. A filꢀ
trate (HCOOH and washings) from the synthesis of compound
23 by the method B was concentrated to dryness, and the crysꢀ
talline residue was triturated with PriOH. Compound 24 was
obtained in a yield of 0.768 g (53%), m.p. 330—331 °C (MeOH).
1H NMR (DMSOꢀd6), δ: 6.63 (d, 1 H, H(3), Jo = 7.5 Hz); 7.38
(d, 1 H, H(2), Jo = 7.5 Hz); 7.57, 7.85, 8.02, and 8.14 (all m,
1 H each, H(5)—H(8)); 9.18 (s, 1 H, H(9)); 11.07 (br.s, 1 H,
N(1)H). IR, ν/cm–1: 3036 (NH); 1685, 1657, 1633 (CO).
ES MS, m/z: 197 [M + H]+•. EI MS, m/z (Irel (%)):
196 [M]+• (100), 168 [M – CO]+• (52), 140 [M – CO –
HCN – H]+• (27).
B. Piperidine (0.05 mL) was added to a solution of
3ꢀformylpyridone 23 (0.05 g, 0.23 mmol) in PriOH (2.5 mL).
The reaction mixture was refluxed for 7 h and then cooled
to 20 °C. The precipitate that formed was filtered off and washed
with PriOH. Compound 24 was obtained in a yield of 0.025 g
(56%). A mixture of compound 24 and the sample prepared by
the method A showed no melting point depression.
7.5 Hz); 6.91 and 8.09 (both m, 2 H each, C6H4NO2); 7.20—7.53
(m, 6 H, Ph, H(6)); 8.69 (s, 1 H, Hα); 10.68 (br.s, 1 H, C(4)NH);
10.94 (br.s, 1 H, NHC6H4NO2); 11.12 (br.s, 1 H, N(1)H).
IR, ν/cm–1: 3286, 3217, 3184 (NH); 1641 (CO). EI MS,
m/z (Irel (%)): 349 [M]+• (33), 212 [M – 4ꢀNHC6H4NO2]+•
(100), 197 [M – 4ꢀNH—NHC6H4NO2)]+• (64).
This study was financially supported by the Federal
Agency for Science and Innovations of the Russian Fedꢀ
eration (Contract No. 1/05).
References
1. L. V. Ershov and V. G. Granik, Khim. Geterotsikl. Soedin.,
1985, 646 [Chem. Heterocycl. Compd., 1985, 544 (Engl.
Transl.)].
2. V. A. Azimov, V. G. Granik, S. I. Grizik, L. V. Ershov, N. I.
Smetskaya, S. D. Yuzhakov, M. D. Mashkovskii, and L. N.
Yakhontov, Khim.ꢀfarm. Zh., 1985, 19, No. 8, 947 [Pharm.
Chem. J., 1985, 19, No. 8, 548 (Engl. Transl.)].
3. V. G. Granik and S. I. Kaimanakova, Khim. Geterotsikl.
Soedin., 1983, 816 [Chem. Heterocycl. Compd., 1983, 714
(Engl. Transl.)].
4. A. S. Ivanov, N. Z. Tugusheva, L. M. Alekseeva, and V. G.
Granik, Izv. Akad. Nauk, Ser. Khim., 2004, 837 [Russ. Chem.
Bull., Int. Ed., 2004, 53, 873].
5. M. D. Mashkovskii, Lekarstvennye sredstva [Drugs], Torgsin,
Kharkov, 1997, 1235 pp. (in Russian).
6. M. D. Mashkovskii, Lekarstva XX Veka [Drugs of the XX Cenꢀ
tury], Novaya Volna, Moscow, 1998, 319 pp. (in Russian).
7. V. G. Granik, Lekarstva. Farmakologicheskii, biokhimicheskii
i khimicheskii aspekty [Drugs. Pharmacological, Biochemical,
and Chemical Aspects], Vuzovskaya Kniga, Moscow, 2001,
407 pp. (in Russian).
8. V. G. Granik, S. I. Grizik, S. S. Kiselev, V. V. Chistyakov,
O. S. Anisimova, and N. P. Solov´eva, Khim. Geterotsikl.
Soedin., 1984, 532 [Chem. Heterocycl. Compd., 1984, 434
(Engl. Transl.)].
9. N. Z. Tugusheva, L. V. Ershov, V. G. Granik, G. Ya. Shvarts,
R. D. Syubaev, and M. D. Mashkovskii, Khim.ꢀfarm. Zh.,
1986, No. 7, 830 [Pharm. Chem. J., 1986, No. 7, 488 (Engl.
Transl.)].
10. A. A. Bakibaev, V. D. Filimonov, and L. G. Tignibidina,
Khim.ꢀfarm. Zh., 1993, No. 3, 28 [Pharm. Chem. J., 1993,
No. 3, 198 (Engl. Transl.)].
4ꢀ(2ꢀOxoꢀ1,2ꢀdihydropyridinꢀ4ꢀyl)aminobenzenesulfonic acid
(25). A 63% H2SO4 solution (2 mL) was added to pyridone 5c
(0.15 g, 0.7 mmol). The reaction mixture was refluxed for 1 h
and then cooled to 20 °C. The precipitate that formed was
filtered off, washed with water and PriOH, and triturated with a
NaHCO3 solution. The insoluble precipitate was filtered off.
The filtrate was acidified with 10% HCl to рH 4. The precipitate
that formed was filtered off and washed with water. Compound
25 was obtained in a yield of 0.084 g (52%), m.p. >350 °C
(MeOH). Found (%): C, 49.90; H, 3.73; N, 11.04; S, 11.63.
C11H10N21O4S. Calculated (%): C, 49.62; H, 3.79; N, 10.52;
S, 12.04. H NMR (DMSOꢀd6), δ: 6.22 (d, 1 H, H(3), Jm
=
2.0 Hz); 6.56 (dd, 1 H, H(5), Jo = 7.2 Hz, Jm = 2.0 Hz); 7.21 and
7.68 (both m, 2 H each, C6H5SO3H); 7.73 (d, 1 H, H(6), Jo =
7.2 Hz); 9.93 (br.s, 1 H, C(4)NH); 12.90 (br.s, 1 H, N(1)H).
IR, ν/cm–1: 3257 (OH); 3117 (NH); 1655, 1624 (CO). EI MS,
m/z (Irel (%)): 185 [M – HSO3]+• (100), 167 [M – HSO3 –
H2O]+• (13), 157 [M – HSO3 – CO]+• (20), 130 [M – HSO3 –
CO – HCN]+• (43), 64 [SO2] (48).
3ꢀHydroxyiminomethylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ1,2ꢀdihydroꢀ
pyridine (26a). Formylpyridone 23 (0.185 g, 0.86 mmol) was
added to a solution of hydroxylamine hydrochloride (0.06 g,
0.87 mmol) in pyridine (0.7 mL). The reaction mixture was
stirred at 60 °C for 1 h and concentrated to dryness. The residue
(oil) was triturated in water (7 mL) and kept at 20 °C for 40 min.
The precipitate that formed was filtered off and washed with
water. Compound 26a was obtained in a yield of 0.125 g (63%),
1
11. A. I. Bokanov, S. Yu. Kukushkin, V. A. Parshin,
L. M. Alekseeva, K. I. Kobrakov, and V. G. Granik,
Khim.ꢀfarm. Zh., 2004, No. 1, 11 [Pharm. Chem. J., 2004,
No. 1, 10 (Engl. Transl.)].
12. M. Yu. Yakovlev, A. V. Kadushkin, N. P. Solov´eva, O. S.
Anisimova, and V. G. Granik, Tetrahedron, 1998, 54, 5775.
13. C. H. Trabert, Arch. Pharm., 1961, 294, No. 4, 246.
14. T. van Es and B. Staskun, J. Chem. Soc., 1965, 5775.
15. V. V. Chernyshev and H. Schenk, Z. Krystallogr.,
1998, 213, 1.
m.p. 261—262 °C (acetonitrile). H NMR (DMSOꢀd6), δ: 5.97
(d, 1 H, H(5), Jo = 7.5 Hz); 7.15—7.44 (m, 6 H, Ph, H(6)); 8.50
(s, 1 H, Hα); 10.17 (br.s, 1 H, C(4)NH); 10.80 (br.s, 1 H, OH);
10.90 (br.s, 1 H, N(1)H). IR, ν/cm–1: 3254 (OH); 3246 (NH);
1624 (CO). ES MS, m/z: 230 [M + H]+•, 252 [M + Na]+•, 212
[M – OH] +•. EI MS, m/z (Irel (%)): 229 [M]+• (53), 212
[M – OH]+• (100), 197 [M – NH – OH]+• (36).
5ꢀ(4ꢀNitrophenyl)hydrazonomethylꢀ2ꢀoxoꢀ4ꢀphenylaminoꢀ
1,2ꢀdihydropyridine (26b). A mixture of 3ꢀformylpyridone 23
(0.16 g, 0.74 mmol) and pꢀnitrophenylhydrazone (0.11 g,
0.74 mmol) in EtOH (10 mL) was refluxed in the presence of a
catalytic amount of pꢀTsOH for 1.5 h. The precipitate that
formed was filtered off and washed with EtOH. Compound 26b
was obtained in a yield of 0.176 g (61%), m.p. 361—362 °C
16. V. B. Zlokazov and V. V. Chernyshev, J. Appl. Crystallogr.,
1992, 25, 447.
Received May 26, 2006;
in revised form July 12, 2006
(DMF). 1H NMR (DMSOꢀd6), δ: 6.10 (d, 1 H, H(5), Jo
=