Synthesis of 6-aryl-1,6-dihydro-dipyrazolo[3,4-b:4,3-c]pyridines

Article abstract of DOI:10.1007/s10593-005-0014-x

6-Azido-1H-pyrazolo[3,4-b]pyridino-5-carbaldehydes react with aromatic amines to give the corresponding N-arylimines which cyclize on heating in boiling toluene to give 6-aryl-1,6-dihydrodipyrazolo[3,4-b:4,3-e]pyridines.

Full text of DOI:10.1007/s10593-005-0014-x

Chemistry of Heterocyclic Compounds, Vol. 40, No. 11, 2004
SYNTHESIS OF 6-ARYL-1,6-DIHYDRO-
DIPYRAZOLO[3,4-b:4,3-c]PYRIDINES
M. V. Vovk, N. V. Mel'nichenko, V. A. Sukach, and N. G. Chubaruk
6-Azido-1H-pyrazolo[3,4-b]pyridino-5-carbaldehydes react with aromatic amines to give the
corresponding N-arylimines which cyclize on heating in boiling toluene to give 6-aryl-1,6-
dihydrodipyrazolo[3,4-b:4,3-e]pyridines.
Keywords: N-aryl-6-azido-1H-pyrazolo[3,4-b]pyridine-5-carbaldimines, 6-aryl-1,6-dihydrodipyrazolo-
[3,4-b:4,3-e]pyridines, thermolysis.
Dipyrazolo[3,4-b:4,3-e]pyridines are examples of condensed heterocyclic compounds with notable
pharmacological activity, for example bactericidal [1], sedative [2], and antiasthmathic [3]. Substances with
electroluminescent properties are also found among them [4,5]. Only 1,7-disubstituted dipyrazolo[3,4-b:4,3-e]-
pyridines can be synthesized by the reported cyclization of 2,6-dichloro-3,5-diformylpyridine with hydrazines
[6], 5-aminopyrazoles with carbonyl compounds [7-10], and pyrazolin-5-ones with aldehydes and arylimines
[11]. The intramolecular cyclocondensation of the hydrazone of 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehyde
was used to prepare 3-methyl-1-phenyl-1,7-dihydrodipyrazolo[3,4-b:4,3-e]pyridine [12].
Me
Me
N
H
C
NNH2
, 18 h
EtOH, ∆
N
N
N
N
N
N
Cl
N
H
Ph
Ph
There are no reports of 1,6-dihydro analogs of these heterocyclic systems in the literature. It is for this
reason that we examine preparatively suitable routes to their synthesis in this paper.
6-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde
(1),
synthesized
from
5-acetylamino-3-methyl-1-phenylpyrazole by the Vilsmeier–Haack method [12] was proposed as the starting
material for the synthesis of the desired materials. Compound 1, like 5-chloropyrazole-4-carbaldehyde [13-15],
was converted in 85% yield to 6-azidopyrazolo[3,4-b]pyridine-5-carbaldehyde 2 by reaction with NaN3 in
DMSO in the presence of the phase transfer catalyst Bu4N+I-.
An investigation of the thermal properties of compound 2 showed that, in contrast to its close analog,
2-azido-7-methylquinoline-3-carbaldehyde, which is converted into the corresponding tetrazoloquinoline even at
40°C, it is quite stable and only underwent cyclization to pyrazolo[3,4-e][1,2,3,4]tetrazolo[1,5-a]pyridine 3 on
refluxing in toluene for 6 h. It was therefore suggested that when the condensation of the azidoaldehyde 2 with
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukraine National Academy of Sciences, Kiev 02094; e-mail:
mvovk@i.com.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1717-1722, November,
2004. Original article submitted July 5, 2002.
0009-3122/04/4011-1485©2004 Springer Science+Business Media, Inc.
1485

Me
N
H
C
O
N
N
N
Ph
N
N
3
110°C, 6 h
Me
N
Me
Me
N
H
C
H
H
C
ArNH2
4a–f
O
C
O
NAr
NaN3
N
DMSO
N
N
N
N
Cl
N
N3
N
N3
Ph
Ph
Ph
2
1
5a–f
110 oC
–N2
4c
Me
Me
H
C
NC H Me-
4
6
4
NaN3, DMSO
–N2
N
Ar
N
N
N
N
N
N
6a–f
N
Cl
Ph
Ph
7
4-6 a Ar = Ph, b Ar = 4-ClC6H4, c Ar = 4-MeC6H4, d Ar = 3-MeOC6H4,
e Ar = 4-MeOC6H4, f Ar = 3,4-Me2C6H3
arylamines was carried out under milder conditions the azido group would be retained in the reaction products.
In fact, heating compound 2 with the arylamines 4a-f in boiling ethanol for 4-5 h gave the N-arylamines 5a-f,
from which compounds 5c and f were isolated analytically pure and were characterized.
According to [17], 2-substituted indazoles were isolated in high yield from the thermolysis of
o-azidobenzylidene amines. From this it seemed expedient to use the thermolysis of the azido imines 5a-f for the
pyrazoloannelation of the pyridine ring. It was found that the 6-aryl-1,6-dihydrodipyrazolo[3,4-b:4,3-e]-
pyridines 6a-f were formed on refluxing compounds 5a-f in toluene for 5-6 h.
We note that to simplify the process compounds 5a-f were not subjected to additional purification and
were used for thermolysis after removal of the ethanol.
We also investigated the possibility of synthesizing compounds of type 6 by first converting the
aldehyde into an azomethine group with subsequent replacement of the chlorine atom by an azide group. As an
example imine 7 was obtained by reaction of aldehyde 1 with p-toluidine, and converting 7 into the
dipyrazolopyridine 6a by heating with sodium azide in DMSO at 70-72°C for 20 h. However the yield of
compound 6a under these conditions decreased by 19% in comparison with the first version of the reaction. The
deceleration of the process is evidently caused by a decrease in the mobility of the chlorine atom caused by the
lower acceptor power of the imino groups, and the requirement of a lower temperature regime.
The synthesized compounds 6a-f (Table 1) are high melting yellow crystalline compounds with a light
yellow fluorescence in 2:1 DMSO–CCl4 solution. Their structures are in agreement with their 1H NMR and mass
spectra (Table 2). The presence of molecular ion peaks with Imax 100% is characteristic for the mass spectra of all
the compounds.
1486

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
mp, °С
(solvent)
[M]+,
m/z
Yield, %
C
N
2
С14Н10N6O
C14H10N6O
C21H17N7
C22H19N7
C20H15N5
60.70
60.42
3.54
3.62
30.05
30.20
174-175
(MeCN)
85
76
78
74
73
66
74
65
72
68
67
3
60.69
60.42
3.54
3.62
29.62
30.20
245-246
(MeCN)
5c
5f
6a
6b
6c
6d
6e
6f
7
68.71
68.65
4.72
4.66
26.33
26.69
151-154
(EtOH–H2O)
68.94
69.27
5.18
5.02
25.91
25.71
161-163
(MeCN)
74.08
73.83
4.72
4.65
21.39
21.52
194-196
(MeCN)
325
360
339
355
355
353
C20H14ClN5 66.99
66.76
4.11
3.92
19.03
19.46
242-243
(MeCN)
223-224
(MeCN)
C21H17N5
C21H17N5O
C21H17N5O
C22H19N5
74.70
74.31
5.18
5.04
20.27
20.63
71.34
70.97
4.91
4.82
20.05
19.71
175-176
(MeCN)
70.72
70.97
4.89
4.82
19.56
19.71
227-229
(MeCN–dioxane)
74.46
74.76
5.43
5.42
20.03
19.82
230-231
(MeCN)
C21H17ClN4 70.93
70.71
4.48
4.62
15.30
15.11
200-201
(MeCN)
The structure of compounds 6 was also confirmed by the 13C NMR spectrum of compound 6c:
Me
4
3''
2''
5
3
3a
8a
4a
7a
6
N
4''
1''
2
Me
N
1
N
N
N
5''
6''
7
8
1'
6'
2'
3'
5'
4'
δ, ppm: 12.33 (СН3-3), 20.49 (CH3-4''), 112.77 (C-3a), 117.60 (C-4a), 118.84 (C-2', 6'), 120.19 (C-2'', 6''),
124.25 (C-4), 125.90 (C-5), 126.12 (C-4'), 128.92 (C-3'', 5''), 130.07 (C-3', 5'), 137.40 (C-1'), 138.17 (C-1''),
139.61 (C-4''), 144.68 (C-3), 152.06 (C-8a), 157.78 (C-7a)
EXPERIMENTAL
The course of reactions and the purity of the synthesized compounds was monitored by chromatography
on Silufol UV-254 strips with 20:1 chloroform–methanol as eluent. IR spectra of KBr disks were measured with
1
a UR-20 instrument. H and 13C NMR spectra of solutions in 2:1 DMSO-d6–CDCl3 with TMS as internal
standard were measured with a Varian-Gemini spectrometer (300 and 75 MHz respectively). Mass spectra were
recorded on an MX-121 mass spectrometer with direct injection into the ion source, energy of the ionizing
electrons 70 eV, temperature of the ionizing chamber 150°C.
1487

TABLE 2. 1H NMR Spectra of the Compounds Synthesized
Compound
Chemical shifts, δ, ppm (SSCC, J, Hz)
2
2.60 (3H, s, CH3-3); 7.32 (1H, t, J = 7.6, H-4'); 7.52 (2H, t, J = 7.8, H-3', 5');
8.18 (2H, d, J = 8.1, H-2', 6'); 8.65 (1H, s, H-4); 10.17 (1H, s, CH=O)
3
2.62 (3H, s, CH3-3); 7.26 (1H, t, J = 7.9, H-4'); 7.53 (2H, t, J = 8.1, H-3', 5');
8.31 (2H, d, J = 8.2, H-2', 6'); 8.94 (1H, s, H-4); 10.12 (1H, s, CH=O)
5c
2.36 (3H, s, CH3-4''); 2.58 (3H, s, CH3-3); 7.14-7.32 (5H, m, HAr); 7.50 (2H, t,
J = 7.8, H-3', 5'); 8.21 (2H, d, J = 7.8, H-2', 6'); 8.62 (1H, s, 5-CH=);
8,78 (1H, s, H-4)
5f
2.26 (3H, s, CH3-4''); 2.28 (3H, s, CH3-3''); 2.59 (3H, s, CH3-3);
6.94-7.30 (3H, m, HAr); 7.50 (2H, t, J = 7.8, H-3', 5'); 8.21 (2H, d, J = 7.5, H-2', 6');
8.62 (1H, s, 5-CH=); 8.77 (1H, s, H-4)
6a
6b
6c
6d
6e
2.64 (3H, s, CH3-3); 7.22 (1H, t, J = 7.8, H-4'); 7.46-7.62 (5H, m, HAr);
8.18 (2H, d, J = 7.8, H-2'', 6''); 8.45 (2H, d, J = 8.1, H-2', 6'); 8.80 (1H, s, H-4);
9.37 (1H, s, H-5)
2.63 (3H, s, CH3-3); 7.22 (1H, t, J = 7.6, H-4'); 7.52 (2H, t, J = 7.8, H-3', 5');
7.62 (2H, d, J = 8.7, H-3'', 5''); 8.20 (2H, d, J = 8.7, H-2'', 6'');
8.44 (2H, d, J = 7.8, H-2', 6'); 8.76 (1H, s, H-4); 9.36 (1H, s, H-5)
2.47 (3H, s, CH3-4''); 2.65 (3H, s, CH3-3); 7.21 (1H, t, J = 7.5, H-4');
7.39 (2H, d, J = 8.7, H-3'', 5''); 7.53 (2H, t, J = 7.8, H-3', 5'); 8.05 (2H, d,
J = 8.7, H-2'', 6''); 8.46 (2H, d, J = 8.1, H-2', 6'); 8.80 (1H, s, H-4); 9.31 (1H, s, H-5)
2.64 (3H, s, CH3-3); 3.92 (3H, s, OCH3-3''); 7.01 (2H, d, J = 8.1, H-4'');
7.22 (1H, t, J = 7.6, H-4'); 7.51-7.75 (5H, m, HAr); 8.47 (2H, d, J = 7.8, H-2', 6');
8.78 (1H, s, H-4); 9.38 (1H, s, H-5)
2.65 (3H, s, CH3-3); 3.87 (3H, s, OCH3-4''); 7.12 (2H, d, J = 9.0, H-3'', 5'');
7.22 (1H, t, J = 7.6, H-4'); 7.52 (2H, t, J = 7.8, H-3', 5');
8.08 (2H, d, J = 9.0, H-2'', 6''); 8.46 (2H, t, J = 8.4, H-2', 6'); 8.77 (1H, s, H-4);
9.24 (1H, s, H-5)
6f
7
2.31 (3H, s, CH3-4''); 2.36 (3H, s, CH3-3''); 2.64 (3H, s, CH3-3); 7.26 (1H, t, J = 7.8,
H-4'); 7.37 (1H, d, J = 8.4, H-5''); 7.56 (2H, d, J = 7.8, H-3', 5'); 7.89 (1H, d, J = 8.4,
H-6''); 7.99 (1H, s, H-2''); 8.43 (2H, d, J = 8.4, H-2', 6'); 8.89 (1H, s, H-4);
9.37 (1H, s, H-5)
2.37 (3H, s, CH3-4''); 2.67 (3H, s, CH3-3); 7.20-7.36 (5H, m, HAr); 7.54 (2H, t,
J = 7.9, H-3', 5'); 8.19 (2H, d, J = 8.1, H-2', 6'); 8.88 (1H, s, H-4); 8.96 (1H, s, 5-CH=)
6-Azido-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde (2). NaN3 (2.58 g, 40 mmol) and
Bu4N+I- (1.48 g, 4 mmol) were added to a solution of aldehyde 1 (9.0 g, 33 mmol) in DMSO (45 ml) and the
mixture was stirred at 50°C for 8 h. The reaction mixture was poured into ice water, the precipitate was filtered
off, dried, and crystallized. IR spectrum, ν, cm-1: 1700 (C=O), 2120 (N3).
3-Methyl-1-phenyl-1H-pyrazolo[3,4-e][1,2,3,4]tetrazolo[1,5-a]pyridine-5-carbaldehyde
(3).
A
suspension of the azidoaldehyde 2 (0.280 g, 1mmol) in toluene (15 ml) was refluxed for 6 h. After cooling the
reaction mixture the solid was filtered off and crystallized. IR spectrum, ν, cm-1: 1635 (C=C).
N-(p-Tolyl)-6-azido-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldimine (5c). p-Toluidine
(0.26 g, 2.4 mmol) was added to a suspension of azidoaldehyde 2 (0.56 g, 2 mmol) in ethanol (15 ml) and the
mixture was refluxed for 4 h. After cooling the reaction mixture the solid was filtered off and crystallized.
Compound 5f was prepared analogously.
6-Aryl-3-methyl-1-phenyl-1,6-dihydrodipyrazolo[3,4-b:4,3-e]pyridines, 6a-f. An arylamine (4a-f, 2.4
mmol) was added to a suspension of azidoaldehyde 2 (2 mmol) in ethanol (30 ml) and the mixture was refluxed
for 4 h. The ethanol was then evaporated , toluene (25 ml) was added to the residue, and the mixture was
refluxed again for 6 h. The reaction mixture was cooled, the solid was filtered off and crystallized.
N-(p-Tolyl)-6-chloro-3-methyl-1-phenyl[3,4-b]pyridine-5-carbaldimine (7). p-Toluidine (0.21 g,
2 mmol) was added to a suspension of the chloroaldehyde 1 (0.54 g, 2 mmol) in ethanol (25 ml) and the mixture
was refluxed for 4 h. The precipitate was filtered and crystallized.
1488

The Reaction of Compound 7 with NaN3. NaN3 (0.08 g, 1.2 mmol) and Bu4N+I-(0.44 g, 0.12 mmol)
were added to a solution of imine 7 (0.37 g, 1 mmol) in 20 ml DMSO and the mixture was stirred at 70-72°C for
20 h. The reaction mixture was poured into ice water (40 ml), the precipitate was filtered off, dried, and
crystallized to give compound 6c (55% yield).
We thank our senior scientific co-worker A. V. Mazene of the A. V. Bogatskii Physical Chemistry
Institute, Ukraine National Academy of Sciences, for recording the mass spectra.
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