Facile synthesis of substituted 1H-pyrazolo[3,4-b]pyridines

Full text of DOI:10.1016/j.mencom.2007.05.022

Mendeleev
Communications
Mendeleev Commun., 2007, 17, 192–193
Facile synthesis of substituted 1H-pyrazolo[3,4-b]pyridines
Galina P. Sagitullina,* Ludmila A. Lisitskaya, Marina A. Vorontsova and Reva S. Sagitullin
Department of Organic Chemistry, Omsk State University, 644077 Omsk, Russian Federation.
Fax: +7 3812 642410; e-mail: Sagitullina@orgchem.univer.omsk.su
DOI: 10.1016/j.mencom.2007.05.022
Substituted 1H-pyrazolo[3,4-b]pyridines were synthesised by construction of pyrazole ring from 4-substituted 5-acetyl-2-methyl-
6-(methylamino)nicotinonitriles readily available via rearrangement of 3,5-dicyanopyridinium salts.
1H-Pyrazolo[3,4-b]pyridines and their derivatives possess wide-
occurred and resulted in pyrazole ring closure to form 3a–c.‡
ranging biological activity (antifungal, antibacterial, citotoxic,
analgesic, anxiolytic, hypotensive and other activities).1 The
usual synthetic approaches to the pyrazolo[3,4-b]pyridine core
are the annulation of a pyridine ring onto appropriately sub-
stituted pyrazoles or the annulation of a pyrazole ring onto
suitably substituted pyridines. The above substances were pre-
pared by the cyclocondensation of 5-aminopyrazole as a starting
All the reactions were performed under mild conditions and
–6
produced 2a–c and 3a–c in high yields. 1H-pyrazolo[3,4-b]-
§
pyridine-5-carboxamides 4a–c were prepared by the hydrolysis
of the cyano group in 3a–c.
Compounds 2a–c, 3a–c and 4a–c were purified by recrys-
tallization from ethanol.
The structures of all of the obtained compounds were con-
firmed by 1H NMR and IR spectroscopy, mass spectrometry
and elemental analysis.
7
–9
material with 1,3-dicarbonyl compounds
or their ethoxy-
in the first route. 1H-Pyrazolo-
3,4-b]pyridines were also prepared by the one-pot cyclocon-
densation of dihydropyrazolone, an aldehyde and ethyl aceto-
metylene derivatives5
,6,10–14
[
†
Synthesis of N-nitrosoamines 2a–c (general procedure). NaNO (3 mmol)
2
was added to a solution or suspension of 1a–c (2 mmol) in acetic acid
(8 ml). The mixture was stirred for 1 h at room temperature, diluted with
water and filtered to remove the precipitated crystals of 2a–c.
15
acetate. The promising Diels–Alder cycloaddition of pyrazolyl
imines as azadienes with nitroalkenes was reported recently.16
In the second approach, 1H-pyrazolo[3,4-b]pyridines were
obtained via the reaction of 2-halo-3-substituted pyridines
1
2a: yield 98%, mp 183–184 °C. H NMR (200 MHz, CDCl3) d: 2.35
(
s, 3H, Me), 2.55 (s, 3H, Me), 2.80 (s, 3H, COMe), 3.56 (s, 3H, N–Me).
–
1
1
7,18
IR (KBr, n/cm ): 1490 (N=O), 1700 (C=O), 2230 (CN). Found (%):
(
3-alkanoyl, aroyl, formyl and cyano) with hydrazines.
C, 56.92; H, 5.32. Calc. for C H N O (%): C, 56.89; H, 5.21.
1
1
12
4
2
1
2
b: yield 92%, mp 134–135 °C. H NMR (200 MHz, CDCl ) d: 1.90
3
R
R
(
s, 3H, Me), 2.87 (s, 3H, COMe), 3.56 (s, 3H, N–Me), 7.35 (m, 2H, Ph),
NC
Me
COMe
NC
Me
COMe
–
1
i
ii
7.53 (m, 3H, Ph). IR (KBr, n/cm ): 1500 (N=O), 1710 (C=O), 2225
(
CN). Found (%): C, 65.60; H, 4.73. Calc. for C H N O (%): C, 65.30;
16 14 4 2
N
NH
Me
N
NNO
Me
H, 4.79.
1
2
c: yield 96%, mp 198–199 °C. H NMR (200 MHz, CDCl ) d: 1.95
3
1
a–c
2a–c
(s, 3H, Me), 2.87 (s, 3H, COMe), 3.56 (s, 3H, N–Me), 7.30 (d, 2H, H-2',
–
1
H-6', J 8.5 Hz), 7.49 (d, 2H, H-3', H-5'). IR (KBr, n/cm ) d: 1495
N=O), 1700 (C=O), 2220 (CN). Found (%): C, 58.60, H, 4.01. Calc. for
C H ClN O (%): C, 58.45; H, 3.99.
R
N
R
Me
Me
N
(
NC
Me
H NOC
2
iii
1
6
13
4
2
N
‡
Synthesis of 1H-pyrazolo[3,4-b]pyridines 3a–c (general procedure).
10 mmol of zinc powder was added portionwise to a stirred solution of
mmol of 2a–c in 8 ml of acetic acid at a temperature below 10 °C. The
N
Me
N
N
2
Me
Me
3
a–c
4a–c
mixture was allowed to warm to room temperature, stirred for 1 h and
filtered; the filter was washed with acetic acid. The filtrate was diluted
with ice water and neutralised with aqueous ammonia; the precipitated
a R = Me
b R = Ph
6
c R = 4-ClC H4
crystals of 3a–c were separated.
1
3
a: yield 91%, mp 146–147 °C. H NMR (200 MHz, CDCl ) d: 2.67
3
Scheme 1 Reagents and conditions: i, NaNO , AcOH, room temperature,
2
(
(
s, 3H, Me), 2.80 (s, 3H, Me), 2.84 (s, 3H, Me), 4.02 (s, 3H, Me). IR
KBr, n/cm ): 2220 (CN). MS (EI, 70 eV), m/z (%): 200 (M , 100%),
6
0 min; ii, Zn, AcOH, room temperature, 60 min; iii, H SO , 100 °C, 60 min.
2 4
–1
+·
1
1
99 (95), 185 (25), 172 (9), 157 (5), 156 (6), 132 (29), 131 (6), 104 (5),
03 (5), 77 (8), 76 (7). Found (%): C, 65.91; H, 6.21. Calc. for C H N
4
Here, we report the synthesis of substituted 1H-pyrazolo-
3,4-b]pyridines from 4-substituted 5-acetyl-2-methyl-6-(methyl-
amino)nicotinonitriles as outlined in Scheme 1. Nicotinonitriles
1
1
12
[
(%): C, 65.98; H, 6.04.
1
3b: yield 75%, mp 165–166 °C. H NMR (200 MHz, CDCl ) d: 2.00
3
1
a–c were prepared by a rearrangement of 3,5-dicyano-
(s, 3H, Me), 2.84 (s, 3H, Me), 4.02 (s, 3H, Me), 7.42–7.55 (m, 5H, Ph).
–
1
+·
1
9,20
IR (KBr, n/cm ): 2230 (CN). MS (EI, 70 eV), m/z (%): 262 (M ,
00%), 261 (58), 247 (6), 234 (5), 220 (4), 131 (6), 77 (4). Found (%):
C, 73.38; H, 5.50. Calc. for C H N (%): C, 73.26; H, 5.38.
pyridinium salts upon treatment with sodium hydroxide.
1
The construction of a pyrazole ring in a fused ring system
was done upon N-nitrosation of a secondary amino group in
compounds 1a–c with sodium nitrite in acetic acid followed by
the reduction of resulting N-nitrosoamines 2a–c† with zinc
powder in acetic acid. During the reduction of the N-nitroso
group of 2a–c to a substituted hydrazino group, intramolecular
condensation onto acetyl group of pyridine ring simultaneously
1
6
14
4
1
3
c: yield 84%, mp 163–164 °C. H NMR (200 MHz, CDCl ) d: 2.09
3
(
s, 3H, Me), 2.89 (s, 3H, Me), 4.09 (s, 3H, Me), 7.42 (d, 2H, H-2', H-6',
–1
J 8.5 Hz), 7.55 (d, 2H, H-3', H-5'). IR (KBr, n/cm ): 2225 (CN).
+· 37
+· 35
MS (EI, 70 eV), m/z (%): 298 (M , Cl, 34), 296 (M , Cl, 100) 295
48), 281 (6), 261 (7), 245 (5), 164 (5), 130 (6), 76 (2). Found (%): C,
64.74; H, 4.64. Calc. for C H ClN (%): C, 64.76; H, 4.42.
(
1
6
13
4
–
192 –

Mendeleev Commun., 2007, 17, 192–193
This work was supported by the Russian Foundation for
Basic Research (grant no. 04-03-32652).
5
6
7
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1
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§
Synthethis of 1H-pyrazolo[3,4-b]pyridine-5-carboxamides 4a–c (general
procedure). A solution of 1 mmol of 3a–c in 2 ml of sulfuric acid was
heated in an oil bath (100 °C) for 1 h. After cooling, the mixture was
diluted with water, neutralised with aqeuous ammonia and filtered to
remove the precipitated solid of 4a–c.
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1
2
4
a: yield 76%, mp 242–244 °C. H NMR (200 MHz, [ H ]DMSO) d:
6
2
7
1
2
7
6
.53 (s, 3H, Me), 2.57 (s, 3H, Me), 2.58 (s, 3H, Me), 3.89 (s, 3H, Me),
–
1
.6 (s, 1H, anti-CONH ), 7.8 (s, 1H, sin-CONH ). IR (KBr, n/cm ):
2
2
+
·
670, 3400, 3525 (CONH ). MS (EI, 70 eV), m/z (%): 218 (M , 100),
2
17 (6), 203 (13), 202 (82), 201 (38), 174 (18), 158 (11), 100 (6), 92 (7),
7 (8). Found (%): C, 60.54; H, 6.30. Calc. for C H N O (%): C,
1
1
14
4
15 S. A. El-Assiery, G. H. Sayed and A. Fouda, Acta Pharm., 2004, 54,
0.53; H, 6.47.
b: yield 94%, mp 217–219 °C. H NMR (200 MHz, CDCl ) d: 1.90 (s,
1
43.
1
4
3
1
1
6 A. Diaz-Ortiz, A. Hoz and F. Langa, Green Chemistry, 2000, 2, 165.
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3
5
3
H, Me), 2.67 (s, 3H, Me), 4.00 (s, 3H, Me), 5.32 (s, 1H, anti-CONH ),
2
–1
.67 (s, 1H, sin-CONH ), 7.34–7.37 (m, 5H, Ph). IR (KBr, n/cm ): 1690,
2
+
·
400, 3525 (CONH ). MS (EI, 70 eV), m/z (%): 280 (M , 100), 279
2
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1995, 51, 8599.
(
42), 265 (16), 264 (72), 263 (22), 236 (6), 140 (14). Found (%): C,
6
8.39; H, 5.90. Calc. for C H N O (%): C, 68.55; H, 5.75.
16 16 4
1
2
4
c: yield 92%, mp 273–275 °C. H NMR (200 MHz, [ H ]DMSO) d:
6
1
.94 (s, 3H, Me), 2.71 (s, 3H, Me), 4.03 (s, 3H, Me), 7.42 (d, 2H, H-2',
H-6', J 8.6 Hz), 7.44 (d, 2H, H-3', H-5'), 7.1 (s, 1H, anti-CONH ), 7.5
20 G. P. Sagitullina, L. V. Glizdinskaya, S. I. Oleinikova, E. G. Atavin and
R. S. Sagitullin, Zh. Org. Khim., 2005, 41, 1395 (Russ. J. Org. Chem.,
2005, 41, 1367).
2
+
·
s, 1H, sin-CONH ). MS (EI, 70 eV), m/z (%): 316 (M , Cl, 36), 314
2
37
(
(
+
·
35
M , Cl, 100), 313 (39), 300 (27), 299 (22), 295 (81), 297 (20), 262
14), 235 (11), 234 (11), 190 (7), 140 (11), 139 (15), 138 (8), 89 (2), 76
3). Found (%): C, 60.82; H, 4.98. Calc. for C H ClN O (%): C, 61.05;
(
(
1
6
15
4
H, 4.80.
Received: 20th December 2006; Com. 06/2846
The English language edited by Valentin V. Makhlyarchuk, Moscow
Typeset by Sergei I. Ososkov, Moscow
Printed in the United Kingdom by Alden Press
–
193 –