4,5-Diamino-1-phenyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one in the synthesis of fused tricyclic systems

Article abstract of DOI:10.1007/s11172-007-0369-5

Starting from the substituted 4,5-diaminopyrazolo[3,4-b]pyridine, derivatives of a number of tricyclic systems, viz., imidazo[4,5-d]pyrazolo[3,4- b]pyridine, pyrazolo[3,4-b][1,2,5]thiadiazolo[3,4-d]pyridine, pyrazolo[3,4-b][1,2,3]triazolo[4,5-d]pyridine, and [1,3]oxazolo[5,4-b] pyrazolo[4,3-e]pyridine, were synthesized and reaction schemes for the processes were proposed.

Full text of DOI:10.1007/s11172-007-0369-5

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2337—2343, November, 2007
2337
4,5ꢀDiaminoꢀ1ꢀphenylꢀ1,7ꢀdihydroꢀ6Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone
in the synthesis of fused tricyclic systems
E. S. Komarova,a V. A. Makarov,b L. M. Alekseeva,b G. V. Avramenko,a and V. G. Granikb
aD. I. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation.
Eꢀmail: yes.komarova@mail.ru
bState Research Center for Antibiotics,
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Fax: +7 (495) 225 6104. Eꢀmail: makarꢀcl@ropnet.ru, vggranik@mail.ru
Starting from the substituted 4,5ꢀdiaminopyrazolo[3,4ꢀb]pyridine, derivatives of a number
of tricyclic systems, viz., imidazo[4,5ꢀd]pyrazolo[3,4ꢀb]pyridine, pyrazolo[3,4ꢀb][1,2,5]thiaꢀ
diazolo[3,4ꢀd]pyridine, pyrazolo[3,4ꢀb][1,2,3]triazolo[4,5ꢀd]pyridine, and [1,3]oxazoꢀ
lo[5,4ꢀb]pyrazolo[4,3ꢀe]pyridine, were synthesized and reaction schemes for the processes
were proposed.
Key words: pyrazolo[3,4ꢀb]pyridinꢀ6(7H )ꢀone, dihydroimidazo[4,5ꢀd]pyrazolo[3,4ꢀb]pyriꢀ
dinꢀ4(3H )ꢀone, diazepines, pyrazolo[3,4ꢀb][1,2,5]thiadiazolo[3,4ꢀd]pyridinꢀ4(3H )ꢀone,
[1,3]oxazolo[5,4ꢀb]pyrazolo[4,3ꢀe]pyridine, dimethylformamide diethyl acetal.
One of the most fruitful trends in the development of
chemistry of heterocyclic compounds is a creation of new
approaches to the synthesis of fused heterocycles, the
detailed analysis of properties of which has both the theoꢀ
retical and practical importance. Many compounds, conꢀ
taining pyrazole and pyridine rings (often the fused ones),
are of interest as the prospective biologically active subꢀ
stances. Thus, the new nonglycoside antiherpetic comꢀ
pounds,1,2 nonpeptide corticotropinꢀreleasing factor inꢀ
hibitors, active against depressions, anxiety, and other
stress pathologies,3—5 as well as selective GAMKꢀrecepꢀ
tor modulators, showing strong sedative effect and conꢀ
siderable analgesic activity, were discovered among
pyrazolopyridines.6
Earlier,7 we synthesized 4,5ꢀdiaminoꢀ1ꢀphenylꢀ1Hꢀ
pyrazolo[3,4ꢀb]pyridinꢀ6(7H )ꢀone hydrochloride (1). The
presence of two amino groups, located at the adjacent
positions of pyrazolopyridine (4 and 5), opens wide possiꢀ
bilities for the application of this compound in the
heterocyclization reaction for the synthesis of tricyclic
systems, including pyrazolo[3,4ꢀb]pyridine fragment.
We showed that the reflux of diamine 1 with acetylꢀ
acetone in ethanol for 2 h (Scheme 1) leads to the imidꢀ
azole ring closure, resulting in 69% isolated yield of
2ꢀmethylꢀ6ꢀphenylꢀ5,6ꢀdihydroimidazo[4,5ꢀd]pyrazoꢀ
lo[3,4ꢀb]pyridinꢀ4(3H )ꢀone hydrochloride (3). TLC
analysis of the reaction mixture showed the presence of
insignificant admixture of diazepine 2, which upon furꢀ
ther heating was completely converted to the final triꢀ
cyclic compound 4. Undoubtedly, the initial condensaꢀ
tion of diketone at one of the amino groups proceeds to
form azomethines А and (or) B. Further, the addition of
the free amino group at the azomethine double bond takes
place to form imidazoline ring, the aromatization of which
proceeds with elimination of acetone and formation of
tricycle 3.
Based on the data in papers,8—10 it can be assumed
that during the course of the reaction, an equilibrium
mixture of the starting compound 1, the intermediates
А—C, and diazepine 2 is formed, which further slowly
and irreversibly is converted to hydrochloride 3. Imidazoꢀ
pyrazolopyridine 4 can be further liberated from the latter.
In order to confirm our suggestions on the course of
cyclization under consideration, we carried out the reacꢀ
tion of the base of the starting diamine 1 with acetylacetone
in benzene with the removal of water by distillation. In
the reaction mixture, the formation of the product, the
structures of which, according to the mass spectrometry
data, corresponded to the structure of the diazepine deꢀ
rivative 2 was observed. We also showed that, when it
was kept or heated in water or aqueous ethanol for 2 days,
a mixture, consisting from imidazole derivative 4 and the
starting diamine 1, was formed according to the TLC data.
Of course, the possibilities for the creation of fused
fiveꢀmembered rings are not limited only to the imidazole
derivatives.
The presence of two orthoꢀamino groups in the startꢀ
ing molecule suggests a possibility for the thiadiazole
ring closure. Compounds with such structure are of inꢀ
terest due to the presence of the thiadiazole fragment in
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2258—2264, November, 2007.
1066ꢀ5285/07/5611ꢀ2337 © 2007 Springer Science+Business Media, Inc.

2338
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Komarova et al.
Scheme 1
a number of highly active compounds, showing, for
example, the ability to activate the cognitive funcꢀ
tions.11—13 Earlier,14—16 methods for the synthesis of
various thiadiazoles from aromatic diamines with the use
of thionyl chloride were described, where it was indicated
that inorganic acids increase the conversion. In accorꢀ
dance with this, it was shown that the reflux of diamine
hydrochloride 1 in thionyl chloride in the presence of
sulfuric acid for 2 days leads to 6ꢀphenylꢀ5,6ꢀdihydroꢀ
4Hꢀpyrazolo[3,4ꢀb][1,2,5]thiadiazolo[3,4ꢀd]pyridinꢀ
4(3H )ꢀone (5) in 78% yield (Scheme 2).
4(3H )ꢀone (6). During this, apparently, the diazotization
reaction of 5ꢀamino group initially takes place, the diazoꢀ
nium cation that formed undergoes cyclization with parꢀ
ticipation of the amino group in position 4, which leads to
triazole ring closure.
It is known17 that a variety of heterocyclic compounds
can be synthesized based on the use of amide acetals. In
this connection, the possibility of involvement of diamine
hydrochloride 1 into the reaction with amide acetals
was considered in this work.18 6ꢀMethylꢀ1ꢀphenylꢀ1Hꢀ
[1,3]oxazolo[5,4ꢀb]pyrazolo[4,3ꢀe]pyridinꢀ4ꢀamine (9)
was obtained by the reflux of compound 1 with excess
of dimethylacetamide dimethyl acetal in methanol
(Scheme 3).
Scheme 2
In accordance with Scheme 3, the ambident cation,19
presented in the solution of dimethylacetamide dimethyl
acetal in equilibrium with acetal and methoxide anion,20
undergoes condensation at the amino group of the pyriꢀ
dine ring in position 5 to form amidine 7, which is a key
intermediate in the synthesis of oxazole 9, forming, probꢀ
ably, through the intermediate compound 8.
The structure of compound 9 was confirmed also by
its conversion to 4ꢀ[(dimethylamino)methylidenamino]ꢀ
6ꢀmethylꢀ1ꢀphenylꢀ1Hꢀ[1,3]oxazolo[5,4ꢀb]pyrazoꢀ
lo[4,3ꢀe]pyridine (10) in 80% yield by heating with
dimethylformamide diethyl acetal for 30 min.
It turned out that the reaction of compound 1 with
dimethylformamide dimethyl acetal followed the other
direction than it was expected. The reflux of free diamine 1
or its hydrochloride with excess of dimethylformamide
dimethyl acetal in methanol for 1 h leads to 4,5ꢀbis[(diꢀ
methylamino)methylidenamino]ꢀ1ꢀphenylꢀ1,7ꢀdihydroꢀ
The reaction of diamine hydrochloride 1 with soꢀ
dium nitrite for 1 h smoothly afforded 6ꢀphenylꢀ5,6ꢀ
dihydropyrazolo[3,4ꢀb][1,2,3]triazolo[4,5ꢀd]pyridinꢀ

4,5ꢀDiaminoꢀ1ꢀphenylpyrazolo[3,4ꢀb]pyridine
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2339
Scheme 3
1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (11) (Scheme 4). This
compound can be obtained more smoothly by the reflux
in minimum dimethylformamide diethyl acetal due to the
higher activity of the latter comparing with dimethyl acꢀ
etal.18 The relatively higher reactivity of diethyl acetal can
be explained by the fact that the steric strain in its unꢀ
charged form, caused by the nonbonding interactions of
alkoxy groups, decreases by going to the ambident cation
(presented in equilibrium with acetal and responsible for
the high reactivity of amide acetal toward nucleophilic
reagents) to a greater extent than for dimethyl acetal.19
The further research showed that the reflux of bisamidine
11 in minimum aq. ethanol or in anhydrous Nꢀmethylꢀ
pyrrolidoneꢀ2 leads to compound, to which, based on the
spectral data, the structure of 6ꢀphenylꢀ5,6ꢀdihydroꢀ
imidazo[4,5ꢀd]pyrazolo[3,4ꢀb]pyridinꢀ4(3H )ꢀone (12)
was ascribed.
Scheme 4
This difference in the direction of the reaction of
diaminopyridine 1 with dimethylformamide or dimethylꢀ
acetamide acetal can be explained by the sterical factors.
Thus, as it follows from the experimental data, bisꢀ
amidine 11 is a key compound in the synthesis of imidꢀ
azole derivative 12, and the process of cyclization is deꢀ
termined by the correlation of the rates of formation of
this bisamidine and the closure of annulated fiveꢀmemꢀ
bered ring. When amidine 7 (containing methyl group in
the amidine mesoꢀposition) is formed, the steric hindrance
for the attack of the amino group in position 4 of the
pyridine ring by the ambident cation of dimethylacetamide
acetal arises, and the reaction changes its direction to the
cyclization at the oxo group of pyridine with the oxazole
ring closure. Obviously, the presence of free amino group
in position 4 of the pyridine ring makes the attack of
carbonyl group of pyridone fragment easier (below we

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Komarova et al.
show the resonance hybrid, in which a significant partial
negative charge is located on the oxygen atom, resulting
in acceleration of the oxazole cyclization). When diꢀ
methylformamide acetal is used, the situation changes:
the second amidine group in position 4 is considerably
less effective donor of electrons than unsubstituted amino
group, and the attack at the carbonyl group does not
occur. It seems likely that there is no need in the prelimiꢀ
nary hydrolysis of one of the amidine fragments in
bisamidine 11 for the imidazole cyclization to take place,
since, if the 4ꢀamino group (in the pyridine ring) would
have occurred during the hydrolysis, then the formation
of oxazole ring became possible for the reasons menꢀ
tioned above. However, this was not observed in the exꢀ
periment and the formation of compound 12 proceeded
in quite satisfactory yield. For the additional evidence,
imidazole 12 was also obtained in 71% yield by the reflux
of bisamidine 11 in minimum Nꢀmethylpyrrolidone.
The kinetics of the oxazole and imidazole cyclization,
without which it is hardly possible to reliably establish
their mechanism, was not studied in the frame of this
work. Nevertheless, the nontrivial results that obtained
are supposedly given in Scheme 5.
sulting in isolation from the reaction mixture of 6ꢀpheꢀ
nylꢀ3ꢀethylꢀ4ꢀethoxyꢀ3,6ꢀdihydroimidazo[4,5ꢀd]pyrazoꢀ
lo[3,4ꢀb]pyridine (13) in 39% yield. It is known that alkyꢀ
lation of 2ꢀpyridones can occur both at the oxygen21 and
at the nitrogen atoms of the pyridone ring of the molꢀ
ecule.22 The HMBC spectrum unambiguously proves that
the process of alkylation of compound 12 proceeds toꢀ
ward formation of 4ꢀethoxyimidazopyrazolopyridine 13:
the methylene group in position 3 (δ 4.45) has the correꢀ
lation peaks with С(2) and С(3а) atoms, whereas the
methylene group in position 4 (δ 4.60), with С(4) atom.
The full assignment of signals of carbon atoms, made on
the basis of HMBC and HSQC spectra, is given in the
Experimental.
A reflux of imidazole 12 in acetic anhydride for 2 h
leads to 4ꢀacetoxyꢀ3ꢀacetylꢀ6ꢀphenylꢀ3,6ꢀdihydroimidꢀ
azo[4,5ꢀd]pyrazolo[3,4ꢀb]pyridine (14), which is deꢀ
scribed23—25 for the similar compounds, containing a
pyridinꢀ2ꢀone fragment. The structure of compound 14
was established on the basis of NOEDIFF spectrum: durꢀ
ing saturation of the signal of the acetyl group (δ 2.86),
a response in only one singlet at δ 8.87 was observed; an
increase of the intensity of the signal due to the NOE was
18%. This result is in agreement with the selective
Nꢀacetylation at position 3 (if the acetylation occurs at
The structure of imidazole 12 was also confirmed by
its reaction with dimethylformamide diethyl acetal, reꢀ
Scheme 5
X– = EtO– or

4,5ꢀDiaminoꢀ1ꢀphenylpyrazolo[3,4ꢀb]pyridine
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2341
chloroform—methanol, 10 : 1; visualization, by the UV light).
Melting points were determined on a Electrothermal 9100 inꢀ
strument.
position 1, a response should be expected in the singlet of
the proton at δ 8.66, too).
In the IR spectrum of this compound, a strong abꢀ
sorption band at 1759 cm–1 is observed, characteristic of
the ester group (acetoxy group), which excludes the verꢀ
sions of the second acetylation at position 5.
In conclusion, we successfully accomplished a numꢀ
ber of transformations of 4,5ꢀdiaminoꢀ1ꢀphenylꢀ1Hꢀ
pyrazolo[3,4ꢀb]pyridinꢀ6(7H )ꢀone hydrochloride to obꢀ
tain a series of tricyclic systems, viz., the derivatives of
pyrazolo[3,4ꢀb][1,2,5]thiadiazolo[3,4ꢀd]pyridine, pyrazoꢀ
lo[3,4ꢀb][1,2,3]triazolo[4,5ꢀd]pyridine, [1,3]oxazoꢀ
lo[5,4ꢀb]pyrazolo[4,3ꢀe]pyridine, and imidazo[4,5ꢀd]pyrꢀ
azolo[3,4ꢀb]pyridine, and found out the unusual distincꢀ
tion in the direction of cyclizations of 4,5ꢀdiaminoꢀ
pyrazolo[3,4ꢀb]pyridine when dimethylformamide and
dimethylacetamide acetal were used.
Physical and chemical characteristics and elemental analyꢀ
sis data of the synthesized substances are given in Table 1.
2,4ꢀDimethylꢀ8ꢀphenylꢀ7,8ꢀdihydropyrazolo[4´,3´:5,6]pyriꢀ
do[3,4ꢀb]diazepinꢀ6(5H )ꢀone (2). A solution of sodium methꢀ
oxide (0.097 g, 1.8 mmol) in methanol (10 mL) was slowly
added dropwise to a vigorously stirred suspension of hydrochloꢀ
ride 1 (0.5 g, 1.8 mmol) to pH ~7. Pentanꢀ2,4ꢀdione (1.46 g,
14.6 mmol) was added to the reaction mixture obtained and this
was refluxed with stirring and simultaneous distillation off of
water for 4 days. The precipitate of compound 2 was filtered off
and washed with methanol.
2ꢀMethylꢀ6ꢀphenylꢀ5,6ꢀdihydroimidazo[4,5ꢀd]pyrazoꢀ
lo[3,4ꢀb]pyridinꢀ4(3H )ꢀone hydrochloride (3). Pentanꢀ2,4ꢀdione
(1.46 g, 14.6 mmol) was added to a suspension of hydrochloꢀ
ride 1 (1.0 g, 3.61 mmol) in ethanol (30 mL). The reaction
mixture was heated under stirring for 2 h, cooled, the precipitate
of compounds 3 formed was filtered off, washed with propanꢀ
2ꢀol, and recrystallized from EtOH. IR (Nujol), ν/cm–1: 3363
(N—H); 1660 (C=O). 1H NMR (DMSOꢀd6), δ: 2.79 (s, 3 H,
Me); 7.41 (t, 1 H, H(4´), Jo = 8.4 Hz); 7.55 (t, 2 H, H(3´),
Experimental
IR spectra of the compounds were recorded on
Perkin—Elmer 457 spectrometer in Nujol, mass spectra (EI)
were recorded on a Finnigan SSQꢀ710 massꢀspectrometer
with the direct inlet of the sample into the source of ions.
a
H(5´), Jo = 8.4 Hz); 7.88 (d, 2 H, H(2´), H(6´), Jo = 8.4 Hz);
8.27 (s, 1 H, H(8)); 12.80 (br.s, 2 NH).
2ꢀMethylꢀ6ꢀphenylꢀ5,6ꢀdihydroimidazo[4,5ꢀd]pyrazoꢀ
lo[3,4ꢀb]pyridinꢀ4(3H )ꢀone (4). Sodium hydroxide (0.13 g,
3.3 mmol) was added to a solution of imidazole hydrochloride 3
(1.0 g, 3.31 mmol) in water (30 mL). After 2 h, the precipitate of
compound 4 formed was filtered off, washed with cold methaꢀ
nol, and recrystallized from EtOH.
NMR spectra were recorded on
a Bruker АСꢀ300 and
DRXꢀ500 spectrometers. Monitoring of the products purity and
the reaction course was carried out by TLC on Merck
TLC Silicagel 60 F254 plates (eluents: hexane—acetone, 3 : 1;
Table 1. Yields, melting points, elemental analysis data, and mass spectrometry data for
compounds 3—6 and 9—14
Comꢀ Yield
M.p.
/°С
Found
Calculated
Molecular
formula
MS,
m/z (Irel (%))
(%)
N
poꢀ
(%)
und
С
H
3
69
33
78
67
36
80
84
69
39
85
>290
55.72 4.15 23.32
55.73 4.01 23.21
63.44 4.11 26.51
63.39 4.18 26.40
53.59 2.70 25.94
53.52 2.62 26.01
57.26 3.15 33.22
57.14 3.20 33.32
62.21 4.29 26.33
63.39 4.18 26.40
63.62 4.98 26.14
63.74 5.03 26.23
61.47 6.17 27.89
61.52 6.02 27.90
57.95 4.26 26.00
57.99 4.12 26.01
66.50 5.50 22.68
66.43 5.58 22.79
60.78 3.87 20.76
60.89 3.91 20.89
C14H12ClN5O
C14H11N5O
C12H7N5OS
C12H8N6O
265 [M]+ (98)
265 [M]+ (98)
269 [M]+ (80)
252 [M]+ (45)
265 [M]+ (100)
320 [M]+ (100)
351 [M]+ (55)
4
275—278
286—288
>300
5
6
9
235—237
225—6
C14H13N5O
C17H16N6O
C18H21N7O
10
11
12
13
14
202—203
>300
C13H9N5O•H2O 251 [M]+ (100)
135—137
238—240
C17H17N5O
C17H13N5O3
307 [M]+ (70)
251 [M]+ (45)

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Komarova et al.
6ꢀPhenylꢀ5,6ꢀdihydroꢀ4Hꢀpyrazolo[3,4ꢀb][1,2,5]thiadiazoꢀ
lo[3,4ꢀd]pyridinꢀ4(3H )ꢀone (5). Sulfuric acid (3 drops) was
added to a suspension of hydrochloride 1 (1.0 g, 3.61 mmol) in
thionyl chloride (10 mL) and this was refluxed with stirring
for 24 h. The reaction mixture was cooled and concentrated
dry in vacuo. The precipitate was treated with water, filtered off,
and after separation by column chromatography (SiO2, eluent:
chloroform—methanol, 10 : 1), pure product 5 was obtained.
1H NMR (DMSOꢀd6), δ: 7.47 (t, 1 H, H(4´), Jo = 8.4 Hz); 7.59
(t, 2 H, H(3´), H(5´), Jo = 8.4 Hz); 8.36 (s, 1 H, H(8)); 12.70
(br.s, 1 H, N(5)H).
6ꢀPhenylꢀ5,6ꢀdihydropyrazolo[3,4ꢀb][1,2,3]triazoꢀ
lo[4,5ꢀd]pyridinꢀ4(3H )ꢀone (6). Aqueous sodium nitrite (0.25 g,
3.62 mmol) was slowly added dropwise to a solution of diamine
hydrochloride 1 (1.0 g, 3.61 mmol) in water (20 mL) at 15 °C.
After 10 min, the precipitate yellow in color was formed. The
reaction mixture was stirred for 1 h at 20 °C. The precipitate of
compound 6 obtained was filtered off, washed with water, and
recrystallized twice from DMF. IR (Nujol), ν/cm–1: 3105
(N—H); 1638 (С=О). 1H NMR (DMSOꢀd6), δ: 7.47 (t, 1 H,
H(4´), Jo = 8.4 Hz); 7.58 (t, 2 H, H(3´), H(5´), Jo = 8.4 Hz);
8.19 (s, 1 H, H(8)); 12.30 (br.s, 1 H, N(5)H).
6ꢀMethylꢀ1ꢀphenylꢀ1Hꢀ[1,3]oxazolo[5,4ꢀb]pyrazoꢀ
lo[4,3ꢀe]pyridineꢀ4ꢀamine (9). A solution of diamine hydrochloꢀ
ride 1 (1.0 g, 3.61 mmol) and dimethylacetamide dimethyl acetal
(1.82 g, 13.67 mmol) in methanol (10 mL) was refluxed with
stirring for 6 h. After cooling in 30 min, a precipitate was formed.
Acetone was added to the suspension, and the solution obtained
was concentrated dry in vacuo. The precipitate was treated with
water, filtered off, and pure oxazole 9 was isolated by crystalliꢀ
zation from hexane—ethyl acetate. IR (Nujol), ν/cm–1: 3342,
3205 (NH2). 1H NMR (DMSOꢀd6), δ: 2.56 (s, 3 H, Me); 7.29
at +5 °C. The precipitate was filtered off, washed with water,
and recrystallized from aq. acetone.
C. A suspension of diamine hydrochloride 1 (1.5 g,
5.42 mmol) in dimethylformamide dimethyl acetal (5.4 g,
36.73 mmol) was refluxed with stirring for 4 h. The reaction
mixture was cooled and water (15 mL) was added. The precipiꢀ
tate formed was filtered off, washed with water, and recrystalꢀ
lized from aq. acetone. 1H NMR (DMSOꢀd6), δ: 3.01—3.14
(br.s and s, 12 H, 2 NMe2); 7.19 (t, 1 H, H(4´), Jo = 8.4 Hz);
7.46 (m, 2 H, H(3´), H(5´), Jo = 8.4 Hz); 8.20 (s, 1 H, H(3));
8.26 (d, 2 H, H(2″), H(5″), Jo = 8.4 Hz); 7.97, 8.62 (both s,
1 H each, N=CHNМe2).
6ꢀPhenylꢀ5,6ꢀdihydroimidazo[4,5ꢀd]pyrazolo[3,4ꢀb]pyridinꢀ
4(3H )ꢀone monohydrate (12). A. A suspension of bisamidine 11
(1.0 g, 2.85 mmol) in ethanol (5 mL) was refluxed with stirring
for 1 h. Water (10 mL) was added to the solution obtained and
this was triturated. The precipitate of monohydrate of comꢀ
pound 12 was filtered off, washed, and recrystallized from
aq. ethanol.
B. A suspension of bisamidine 11 (1.0 g, 2.85 mmol) in
Nꢀmethylpyrrolidone (5 mL) was refluxed with stirring for 4 h.
Water (10 mL) was added to the solution obtained and this was
triturated. The precipitate of monohydrate of compound 12 was
filtered off, washed, and recrystallized from propanꢀ2ꢀol.
IR (Nujol), ν/cm–1: 3105 (N—H); 1664 (С=О). 1H NMR
(DMSOꢀd6), δ: 7.37 (t, 1 H, H(4´), Jo = 8.4 Hz); 7.53 (t, 2 H,
H(3´), H(5´), Jo = 8.4 Hz); 7.90 (br.s, 2 H, H(2´), H(6´), Jo =
8.4 Hz); 8.11 (s, 2 H, H(2), H(8)). 1H NMR (pyridineꢀd5), δ:
7.07 (d, 2 H, H(2´), H(6´), Jo = 8.4 Hz); 7.18 (t, 1 H, H(4´),
Jo = 8.4 Hz); 7.32 (t, 2 H, H(3´), H(5´), Jo = 8.4 Hz); 8.47, 8.49
(both s, 1 H each, H(2), H(8)).
4ꢀEthoxyꢀ3ꢀethylꢀ6ꢀphenylꢀ5,6ꢀdihydroimidazo[4,5ꢀd]pyrꢀ
azolo[3,4ꢀb]pyridine (13). A suspension of monohydrate of imidꢀ
azole 12(1.0 g, 3.98 mmol) in dimethylformamide diethyl acetal
(4.3 g, 29.25 mmol) was refluxed with stirring for 4 h. The
solution obtained was cooled, water (10 mL) was added, and
this was triturated. The precipitate was filtered off and washed
with water. After separation by column chromatography (SiO2,
eluent: chloroform—methanol, 10 : 1), product 13 (0.42 g) was
obtained. 1H NMR (DMSOꢀd6), δ: 1.45, 1.47 (both t, 3 H each,
СH2СH3, J = 7.0 Hz); 4.45, 4.60 (both d, 2 H each, СH2СH3,
J = 7.0 Hz); 7.32 (t, 1 H, H(4´), Jo = 8.4 Hz); 7.55 (t, 2 H,
(t, 1 H, H(4´), Jo = 8.4 Hz); 7.53 (t, 2 H, H(3´), H(5´), Jo
=
8.4 Hz); 7.70 (br.s, 2 H, NH2); 8.24 (m, 2 H, H(2´), H(6´), Jo =
8.4 Hz); 8.49 (s, 1 H, H(3)).
4ꢀ[(Dimethylamino)methylidenamino]ꢀ6ꢀmethylꢀ1ꢀphenylꢀ
1Hꢀ[1,3]oxazolo[5,4ꢀb]pyrazolo[4,3ꢀe]pyridine (10). A suspenꢀ
sion of oxazole 9 (1.0 g, 3.77 mmol) in dimethylformamide
diethyl acetal (2.4 g, 16.33 mmol) was refluxed with stirring
for 1 h. The reaction mixture was cooled, water (10 mL) was
added, and this was triturated. The precipitate of compounds 10
was filtered off, washed with water, and recrystallized from acꢀ
etonitrile. 1H NMR (DMSOꢀd6), δ: 2.62 (s, 3 H, Me); 3.22,
3.26 (both s, 3 H each, NMe2); 7.27 (t, 1 H, H(4´), Jo = 8.4 Hz);
7.52 (t, 2 H, H(3´), H(5´), Jo = 8.4 Hz); 8.28 (d, 2 H, H(2´),
H(6´), Jo = 8.4 Hz); 8.31 (s, 1 H, H(3)); 9.05 (s, 1 H, H(1″)).
4,5ꢀBis[(dimethylamino)methylidenamino]ꢀ1ꢀphenylꢀ1,7ꢀ
dihydroꢀ1Нꢀpyrazolo[3,4ꢀb]pyridinꢀ6ꢀone (11). A. A solution of
sodium metal (0.083 g, 3.61 mmol) in methanol was added to a
stirred suspension of diamine hydrochloride 1 (1.0 g, 3.61 mmol)
in methanol (30 mL). After 15 min, the precipitate was disꢀ
solved. Dimethylformamide dimethyl acetal (2.97 g, 24.83 mmol)
was added to the solution obtained, and this was refluxed with
stirring for 1 h. The reaction mixture was cooled, water (20 mL)
was added, this was triturated and kept for 24 h at +5 °C. The
precipitate of bisamidine 11 was filtered off, washed with water,
and recrystallized from propanꢀ2ꢀol.
H(3´), H(5´), Jo = 8.4 Hz); 8.30 (d, 2 H, H(2´), H(6´), Jo
=
8.4 Hz); 8.37, 8.39 (both s, 1 H each, H(8), H(2)). 13C NMR
(DMSOꢀd6), δ: 14.1, 16.8, 41.8, 62.5 (3ꢀЕt, 4ꢀEtO); 105.5
(С(8а)); 114.8 (С(3а)); 120.2, 125.5, 129.0, 139.6 (СPh); 131.3
(С(8)); 144.1 (С(8b)); 144.8 (С(5а)); 145.4 (С(2)); 151.3 (С(4)).
4ꢀAcetoxyꢀ3ꢀacetylꢀ6ꢀphenylꢀ3,6ꢀdihydroimidazo[4,5ꢀd]pyrꢀ
azolo[3,4ꢀb]pyridine (14). A suspension of imidazole 12 (1.0 g,
3.98 mmol) in acetic anhydride (5 mL) was refluxed with stirꢀ
ring for 2 h. The precipitate was filtered off, washed with methaꢀ
nol, refluxed in water (10 mL), and filtered off to obtain pure
product 14. IR (Nujol), ν/cm–1: 1759 (О—COMe); 1751
(COMe). 1H NMR (DMSOꢀd6—СD3OD), δ: 2.45 (s, 3 H,
OCOMe); 2.86 (s, 3 H, NСОMe); 7.33 (t, 1 H, H(4´), Jo
=
8.4 Hz); 7.53 (t, 2 H, H(3´), H(5´), Jo = 8.4 Hz); 8.16 (d, 2 H,
H(2´), H(6´), Jo = 8.4 Hz); 8.66, 8.87 (both s, 1 H each,
H(8), H(2)).
B. A solution of diamine hydrochloride 1 (1.0 g, 3.61 mmol)
in methanol (20 mL) and dimethylformamide dimethyl acetal
(2.97 g, 24.83 mmol) was refluxed with stirring for 6 h. Water
was added to the solution, this was triturated and kept for 24 h
This work was financially supported by the CRDF
(Grant RUB2ꢀ2704ꢀМОꢀ05).

4,5ꢀDiaminoꢀ1ꢀphenylpyrazolo[3,4ꢀb]pyridine
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2343
Pike, P. Frank, B. D. Sawyer, and H. E. Shannon, J. Med.
Chem., 1992, 35, 2274.
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Received June 22, 2007;
in revised form September 7, 2007