Facile Synthesis of New 6-Alkylamino-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile Derivatives

Article abstract of DOI:10.1002/jhet.3285

Some new derivatives of 6-alkylamino-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile have been prepared through a Knoevenagel condensation reaction of 5-chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde with malononitrile in ethanol containing a few d

Full text of DOI:10.1002/jhet.3285

Month 2018
Facile Synthesis of New 6-Alkylamino-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile Derivatives
a
a
Nadieh Dorostkar-Ahmadi, Abolghasem Davoodnia,
Niloofar Tavakoli-Hoseini,b and Hossein Behmadia
*
aDepartment of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, Iran
bYoung Researchers and Elite Club, Mashhad Branch, Islamic Azad University, Mashhad, Iran
*E-mail: adavoodnia@mshdiau.ac.ir; adavoodnia@yahoo.com
Received April 16, 2018
DOI 10.1002/jhet.3285
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Some new derivatives of 6-alkylamino-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile have
been prepared through a Knoevenagel condensation reaction of 5-chloro-1,3-diphenyl-1H-pyrazole-
4-carbaldehyde with malononitrile in ethanol containing a few drops of glacial acetic acid at reflux
temperature followed by cyclization with primary alkyl amines in the presence of 1,8-diazabicyclo[5.4.0]
undec-7-ene as catalyst in refluxing ethanol. The products were characterized on the basis of IR, 1H
NMR, and 13C NMR spectral and microanalytical data. The 1H NMR data ruled out the formation of the alter-
native cyclized isomers 6-imino-7-alkyl-1,3-diphenyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitriles.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
activities. Because of the importance of these
heterocycles, we became interested in the synthesis of
new compounds formed from a combination of both
pyrazole and pyridine scaffolds.
The presence of pyrazole and pyridine motifs, either
alone or as a fused ring with other heterocyclic moieties,
in a number of biological significant molecules has made
them prime targets for scientific research. It has been
known that certain pyrazoles possess important biological
activities such as analgesics [1], anti-inflammatory [1,2],
antimicrobial [3,4], antimalarial [4], antitumor [5,6], anti-
hepatitis C virus [6], antiproliferative [7], antioxidants
[8], antiangiogenic [9], and antiviral [10] properties. A
number of these compounds have been considered as
fungicides [11], and pesticides [12], and as the chelating
and extracting reagents for different metal ions [13].
Pyrazoles are also not only of interest as important
intermediates for the synthesis of fused heterocycles but
also as efficient analytical regents in the complexation of
transition-metal ions [14]. On the other hand, the pyridine
moiety is the base of many bioactive molecules having
important biological properties such as anticancer [15],
antioxidant [15], anti-inflammatory [16], antimicrobial
[17], antitubercular [18], antifungal [19], antileishmanial
[20], antiproliferative [21], and anticonvulsant [22]
There are various bicyclic pyrazolopyridine scaffolds
including pyrazolo[3,4-b] pyridine I, pyrazolo[4,3-b]
pyridine II, pyrazolo[3,4-c] pyridine III, and
pyrazolo[4,3-c] pyridine IV (Fig. 1), which are
constructed from two fused pyrazole and pyridine rings.
Among them, pyrazolo[3,4-b] pyridine core I has been
relatively of more interest because of reported interesting
biological properties such as antidiabetic [23],
antiproliferative [24], antifungal [25], anticancer [26,27],
antibacterial [28], anti-inflammatory [29], antiviral [30],
and antimalarial [31] activities. Some of them have also
inhibitory activities against fibroblast growth factor
receptor kinase [32], TNF-α [33], IL-6 [33], CDK1 [34],
and glycogen synthase kinase-3 [35]. A number of
methods have already been proposed for the synthesis
of pyrazolo[3,4-b] pyridines starting from pyrazole or
pyridine moiety [36–44].
Taking all these facts into consideration, and in
conjunction with our earlier studies of synthesis of
© 2018 Wiley Periodicals, Inc.

N. Dorostkar-Ahmadi, A. Davoodnia, N. Tavakoli-Hoseini, and H. Behmadi
Vol 000
from the reaction of benzyl amine with compound 3 in
CDCl3 showed a singlet at δ = 9.09 ppm belonging to the
CH in pyridine ring and the characteristic signals at
δ = 7.30–7.96 ppm for the aromatic protons. Surprisingly,
as shown in the expanded view of 1H NMR spectrum
(Fig. 2), an A2X splitting pattern for ─NH─CH2─ group
is seen which in the NH and CH2 have been appeared as a
broadened triplet at δ = 5.81 ppm and a doublet at
δ = 4.89 ppm, respectively, with coupling constant (J
value) of 5.8 Hz. Such splitting is in accord with structure
4a, and not 5a, which in the CH2 group can be split via
vicinal coupling with NH group. Such splitting is expected
when the proton exchange in NH group is slow. In the
Fourier transform infrared spectrum, the absorption bands
for NH and cyano groups appeared at 3352 and
2209 cmÀ1, respectively. Moreover, the characteristic
signals in 13C NMR spectrum at δ = 46.02, 69.14, 114.41,
114.87, 126.72, 127.56, 127.63, 127.79, 128.49, 128.76,
129.15, 129.45, 129.51, 131.34, 137.58, 138.65, 144.32,
148.01, 148.81, and 159.39 ppm are in accord with the
structure 4a. Finally, this compound gave satisfactory results
of elemental analysis corresponding to the molecular formula
C26H19N5. All the other reactions proceed very cleanly to
give the corresponding 6-alkylamino-1,3-diphenyl-1H-
pyrazolo[3,4-b]pyridine-5-carbonitrile in high yield, and
no undesirable side-products were observed. The splitting
between remained NH group with its vicinal protons rules
out the isolation of the alternative cyclized isomers 6-
imino-7-alkyl-1,3-diphenyl-6,7-dihydro-1H-pyrazolo[3,4-
b]pyridine-5-carbonitriles 5a–f (Experimental section and
Supplementary Information).
Figure 1. Structures of various pyrazolopyridines.
heterocyclic compounds [45–53], herein, we report the
synthesis of some new derivatives of 6-alkylamino-1,3-
diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 4a–f in
synthetically useful yields by Knoevenagel condensation
of 5-chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde
1
with malononitrile 2 in ethanol containing a few drops of
glacial acetic acid at reflux temperature, which afforded
compound 3, followed by cyclization with primary alkyl
amines in the presence of 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as catalyst in refluxing ethanol (Scheme 1). To
the authors’ knowledge, compounds 4a–f are new and
have not been reported in the literature.
RESULTS AND DISCUSSION
Our synthesis started from 5-chloro-1,3-diphenyl-1H-
pyrazole-4-carbaldehyde 1 [54] which was converted to
2-((5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)methylene)
malononitrile 3 [55] when heated with malononitrile 2 in
ethanol containing a few drops of glacial acetic acid at
reflux temperature. The compound 3 was then allowed to
interact with primary alkyl amines in the presence of DBU
as catalyst in ethanol under reflux. Monitoring of the
reactions with thin-layer chromatography (TLC) showed
the formation of a product in each case, which was isolated
from the reaction mixture as described in the Experimental
section. The structural elucidation of the isolated products
was based upon spectral and microanalytical data. For
As illustrated in Scheme 2, the final isolated products
4a–f can be formed through paths A, B, or C. It is
proposed that initial nucleophilic attack of the
deprotonated amino group onto the cyano moiety (paths
A and B) or 5-position of pyrazole (path C) in compound
3 afforded the intermediates I or II, respectively.
1
example, the H NMR spectrum of the compound isolated
Scheme 1. Synthesis of novel 6-alkylamino-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitriles 4a–f.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis of New 6-Alkylamino-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile Derivatives
Figure 2. The 1H NMR spectrum of compound 4a in CDCl3 and its expanded views. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 2. A plausible mechanism for the formation of compounds 4a–f.
Subsequent cyclization of the intermediate I, in path A,
affords the final products 4a–f, whereas in paths B and
C, the alternative cyclization of the intermediate I or II
produces compounds 5a–f, which finally undergoes 1,3-R
migration to give the final products 4a–f. Under the
reaction conditions, however, attempts to isolate
compounds 5a–f failed even after careful monitoring of
the reactions.
CONCLUSION
In summary, we have reported the synthesis of new
6-alkylamino-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitriles 4a–f in good yields by the Knoevenagel
condensation of 5-chloro-1,3-diphenyl-1H-pyrazole-4-
1 with malononitrile 2 in refluxing
ethanol containing a few drops of glacial acetic acid
carbaldehyde
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Dorostkar-Ahmadi, A. Davoodnia, N. Tavakoli-Hoseini, and H. Behmadi
Vol 000
followed by cyclization with primary alkyl amines in
the presence of DBU as catalyst. The splitting between
remaining NH group with its vicinal protons rules out
the formation of the alternative cyclized isomers 5a–f. A
plausible mechanism was also suggested. All new
Calcd for C26H19N5: C, 77.79; H, 4.77; N, 17.44. Found: C,
78.03; H, 4.91; N, 17.25.
6-(Phenethylamino)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-
5-carbonitrile (4b). 0.34 g (83%), mp 190–191°C; IR: NH
;
3352, C≡N 2208 cmÀ1 1H NMR: δ 2.99 (t, 2H,
1
J = 7.1 Hz, CH2), 3.90 (q, 2H, J = 6.8 Hz, NCH2), 5.54 (t
br., 1H, J = 5.6 Hz, NH), 7.23–7.65 (m, 13H, arom-H), 7.97
(dd, 2H, J = 8.1, 1.5 Hz, arom-H), 9.09 (s, 1H, pyridine
CH) ppm; 13C NMR: δ 36.09, 43.64, 69.02, 114.14, 114.83,
126.63, 126.70, 127.78, 128.74, 128.87, 129.12, 129.13,
129.43, 129.46, 131.38, 137.59, 138.80, 144.31, 147.97,
148.79, 159.49 ppm; Anal. Calcd for C27H21N5: C, 78.05;
products were characterized on the basis of IR, H NMR,
and 13C NMR spectra and microanalytical data.
EXPERIMENTAL
Melting points were recorded on a Stuart SMP3 melting
point apparatus (Staffordshire, UK). The IR spectra were
obtained with KBr disks using a Tensor 27 Bruker
spectrophotometer (Billerica, MA). The 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Bruker 300 FT spectrometer in CDCl3 as
solvent and using tetramethylsilane as internal standard.
Elemental analysis was performed on a Thermo Finnigan
Flash EA microanalyzer (Milan, Italy).
H, 5.09; N, 16.86. Found: C, 77.79; H, 5.20; N, 16.69.
6-(Methylamino)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (4c). 0.28 g (85%), mp 278–280°C; IR: NH
3363, C≡N 2207 cmÀ1 1H NMR: δ 3.20 (d, 3H,
;
J = 4.8 Hz, NCH3), 5.49 (q br., 1H, J = 4.5 Hz, NH),
7.49–7.66 (m, 8H, arom-H), 7.95 (dd, 2H, J = 8.0, 1.6 Hz,
arom-H), 9.09 (s, 1H, pyridine CH) ppm; 13C NMR: δ
29.24, 68.90, 114.12, 115.02, 126.67, 127.76, 129.10,
129.12, 129.40, 129.43, 131.38, 137.61, 144.32, 148.00,
148.72, 160.16 ppm; Anal. Calcd for C20H15N5: C, 73.83;
Synthesis of 2-((5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)
methylene) malononitrile 3. A mixture of 5-chloro-1,3-
H, 4.65; N, 21.52. Found: C, 73.62; H, 4.75; N, 21.70.
6-(Butylamino)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
diphenyl-1H-pyrazole-4-carbaldehyde 1 (1 mmol), and
malononitrile (1 mmol) in ethanol (5 mL) in the presence
of a few drops of glacial acetic acid as a catalyst was
heated under reflux for 5–6 h. The reaction was
monitored by TLC. After the completion of the reaction,
the mixture was cooled at room temperature, and the
precipitate was filtered off. The crude product was
recrystallized from ethanol to give the pure compound 3.
carbonitrile (4d).
0.28 g (75%), mp 183–185°C; IR:
NH 3351, C≡N 2206 cmÀ1 1H NMR: δ 0.99 (t, 3H,
;
J = 7.3 Hz, CH3), 1.46 (sex, 2H, J = 7.2 Hz, CH2), 1.67
(quin, 2H, J = 7.3 Hz, CH2), 3.65 (q, 2H, J = 6.3 Hz,
NCH2), 5.46 (t br., 1H, J = 5.1 Hz, NH), 7.49–7.65 (m,
8H, arom-H), 7.95 (d, 2H, J = 7.1, arom-H), 9.06 (s, 1H,
pyridine CH) ppm; 13C NMR: δ 13.86, 20.08, 31.95,
42.13, 68.63, 113.96, 115.08, 126.68, 127.76, 129.10,
129.12, 129.39, 129.43, 131.39, 137.62, 144.37, 147.98,
148.78, 159.72 ppm; Anal. Calcd for C23H21N5: C, 75.18;
1
0.31 g (95%), mp 182–184°C; IR: C≡N 2230 cmÀ1; H
NMR: δ 7.77 (s, 1H, CH═C (CN)2), 7.52–7.72 (m, 10H,
arom-H) ppm; Anal. Calcd for C19H11ClN4: C, 68.99; H,
3.35; N, 16.94. Found: C, 69.22; H, 3.17; N, 17.13.
H, 5.76; N, 19.06. Found: C, 75.43; H, 5.64; N, 19.22.
6-(Cyclohexylamino)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-
5-carbonitrile (4e). 0.30 g (75%), mp 179–181°C; IR: NH
General procedure for the synthesis of 6-alkylamino-1,3-
diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitriles 4a–
f. A mixture of 2-((5-chloro-1,3-diphenyl-1H-pyrazol-4-
1
3389, C≡N 2195 cmÀ1; H NMR: δ 1.20–2.15 (m, 10H,
5CH2 in cyclohexyl), 4.10–4.26 (m, 1H, CH in cyclohexyl),
5.31 (d br., 1H, J = 7.8 Hz, NH), 7.48–7.65 (m, 8H, arom-
H), 7.95 (dd, 2H, J = 7.9, 1.3 Hz, arom-H), 9.06 (s, 1H,
pyridine CH) ppm; 13C NMR: δ 25.03, 25.63, 33.45, 50.84,
68.56, 113.81, 115.07, 126.67, 127.75, 129.09, 129.10,
129.36, 129.40, 131.43, 137.65, 144.43, 147.93, 148.81,
158.99 ppm; Anal. Calcd for C25H23N5: C, 76.31; H, 5.89;
yl)methylene) malononitrile 3 (1 mmol) and a primary
alkyl amine (1 mmol) in ethanol (5 mL) in the
presence of a few drops of DBU as a catalyst was
heated under reflux for 2–3 h. Upon completion,
monitored by TLC, the mixture was cooled at room
temperature. The crude product was collected and
recrystallized from ethanol to afford the pure compounds
N, 17.80. Found: C, 76.58; H, 5.80; N, 17.61.
4a–f in high yields.
6-(Octylamino)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (4f). 0.30 g (70%), mp 116–118°C; IR: NH
6-(Benzylamino)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (4a). 0.32 g (80%), mp 194–196°C; IR: NH
1
3350, C≡N 2207 cmÀ1; H NMR: δ 0.70–1.90 (m, 15H,
3352, C≡N 2209 cmÀ1 1H NMR: δ 4.89 (d, 2H,
;
(CH2)6CH3), 3.50–3.80 (m, 2H, CH2), 5.48 (s br., 1H,
NH), 7.40–8.10 (m, 10H, arom-H), 9.06 (s, 1H, pyridine
CH) ppm; 13C NMR: δ 14.13, 22.68, 26.92, 29.25,
29.35, 29.87, 31.83, 42.44, 68.61, 113.95, 115.09,
126.68, 127.76, 129.10, 129.11, 129.39, 129.42, 131.41,
137.63, 144.36, 147.96, 148.78, 159.71 ppm; Anal. Calcd
J = 5.8 Hz, NCH2), 5.81 (t br., 1H, J = 5.8 Hz, NH), 7.30–
7.67 (m, 13H, arom-H), 7.96 (dd, 2H, J = 8.0, 1.4 Hz,
arom-H), 9.09 (s, 1H, pyridine CH) ppm; 13C NMR: δ
46.02, 69.14, 114.41, 114.87, 126.72, 127.56, 127.63,
127.79, 128.49, 128.76, 129.15, 129.45, 129.51, 131.34,
137.58, 138.65, 144.32, 148.01, 148.81, 159.39 ppm; Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis of New 6-Alkylamino-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile Derivatives
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Acknowledgments. This work was supported by Islamic Azad
University, Mashhad Branch, Iran.
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet