Synthesis of pyrazolo[3,4-b]pyridine and pyrido[2p,3p:3,4]pyrazolo [1,5-a]pyrimidine derivatives

Article abstract of DOI:10.3184/030823410X12811125049438

The synthesis of two series of 1-phenyl and 1H-pyrazolo[3,4-b]pyridine is described. Thus, reacting 5-amino-1-phenylpyrazole with chalcone analogues gave 4,6-diarylpyrazolo[3,4-b]pyridine derivatives. While, reacting the same starting material with benzyl

Full text of DOI:10.3184/030823410X12811125049438

470 RESEARCH PAPER
JOURNAL OF CHEMICAL RESEARCH 2010
AUGUST, 470–474
Synthesis of pyrazolo[3,4-b]pyridine and pyrido[2p,3p:3,4]pyrazolo
[1,5-a]pyrimidine derivatives
Mervat M. El-Enany, Salwa E. M. El-Meligie, Nadia A. Abdou and Hala B. El-Nassan*
Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
The synthesis of two series of 1-phenyl and 1H-pyrazolo[3,4-b]pyridine is described. Thus, reacting 5-amino-1-
phenylpyrazole with chalcone analogues gave 4,6-diarylpyrazolo[3,4-b]pyridine derivatives. While, reacting the same
starting material with benzylidene derivatives of ethyl cyanoacetate and malononitrile resulted in 4-oxo and 4-
aminopyrazolo[3,4-b]pyridine derivatives, respectively. The synthesis of 3-amino-4,6-diarylpyrazolo[3,4-b]pyridines
starting from pyridine was also described. Thus, chlorination of 4,6-diarylpyridone derivatives and their subsequent
cyclisation with hydrazine hydrate afforded 3-amino-4,6-diarylpyrazolo[3,4-b]pyridines. Reaction of the latter com-
pounds with acetylacetone, ethyl ethoxymethylenecyanoacetate and chalcone analogue gave the tricyclic pyrido[2p,3p:
3,4]pyrazolo[1,5-a]pyrimidines. The structures of the products were confirmed by spectral data.
Keywords: pyrazolo[3,4-b]pyridine, pyrido[2p,3p: 3,4]pyrazolo[1,5-a]pyrimidine
Pyrazoles fused with pyridine and/or pyrimidine are associated
with a wide range of biological activities. Derivatives of pyr-
azolo[3,4-b]pyridines exhibited anxiolytic,1 antimicrobial2–5 as
well as cytotoxic6 effects. Recently, many pyrazolo[3,4-
b]pyridine derivatives were reported to have strong and
selective inhibitory effect on many kinase enzymes such as
glycogen synthase kinase GSK-3,7–9 cyclin dependent kinase
CDK10–12 and protein kinase enzyme.13 Whereas, pyrazolo[1,5-
a]pyrimidine derivatives exhibited CNS depressent activity14,15
and cytotoxic activity.16,17 The combination of pyridine, pyr-
azole and pyrimidine ring systems to give the tricyclic pyrido
[2p,3p:3,4]pyrazolo[1,5-a]pyrimidines and the subsequent
influence on biological activity is of current interest.18–20 Some
derivatives of pyrido[2p,3p:3,4]pyrazolo[1,5-a]pyrimidine were
reported to have cytotoxic activity.6
Reacting equimolar amounts of 5-amino-1-phenylpyrazole
(1) with ethyl substituted benzylidenecyanoacetate 4a,b in
ethanol and triethylamine afforded one of two possible
products, either 4-oxo-6-(substituted phenyl)pyrazolo
[3,4-b]pyridine-5-carbonitriles 5a,b or 6-oxo-4-(substituted
phenyl)pyrazolo[3,4-b]pyridine-5-carbonitriles5*.Theassign-
ment of the products as 5a and 5b rather than the isomeric 5*
depends on 13C NMR spectra study. Literature data indicated
that the carbonyl carbon appeared around δ 177 ppm in 13C
NMR spectrum of pyrazolo[3,4-b]pyridin-4-one; while, that of
the 6-one isomer appeared around δ 162 ppm.23–25 Since the
observed carbonyl carbon chemical shift of 5a and 5b appeared
at δ 177 ppm, then the product might be 5a,b and not 5*.
In the light of these findings, We aimed to synthesise new
pyrazolo[3,4-b]pyridine derivatives starting from pyrazole
or pyridine ring systems to be used as antimicrobial agents.
We report also the synthesis of new pyrido[2p,3p:3,4]pyrazolo
[1,5-a]pyrimidines starting from 3-amino-1H-pyrazolo[3,4-b]
pyridines to test them as antimicrobial agents as well.
Results and discussion
The synthesis of the new compounds is shown in Schemes 1
and 2. Scheme 1 describes the synthesis of 1-phenylpyrazolo
[3,4-b]pyridines starting from 5-amino-1-phenylpyrazole (1).
The reaction of 5-amino-1-arylpyrazoles with chalcone
analogues in acetic acid containing few drops of conc. H2SO4
was reported by Joshi et al.21 The products obtained were 4,6-
diarylpyrazolo[3,4-b]pyridines.Asimilarreactionwasreported
by Orlov and coworkers.22 The reaction was carried out in
DMF and the products obtained were noted as 4,5-dihydropyr-
azolo[3,4-b]pyridines which upon oxidation with NBS yielded
the corresponding pyrazolo[3,4-b]pyridines.
In this work, 5-amino-1-phenylpyrazole (1) was reacted
with chalcone analogues 2a and 2b in DMF for 10 h to give
4,6-diaryl-1-phenylpyrazolo[3,4-b]pyridines 3a,b. The possi-
bility of formation of 4,5-dihydropyrazolo[3,4-b]pyridines 3*
as was suggested by Orlov et al.22 was ruled out depending on
the elemental analyses and spectral data. The 1H NMR spectra
of 3a and 3b lacked any signal in the aliphatic proton region
and only aromatic protons appeared around δ 7.26–8.66 ppm.
Meanwhile, the mass spectrum of compound 3b displayed
molecular ion peaks M and M+2 at m/z 470 and 472 in the
ratio of 1:1 (Br pattern). The formation of 3a,b and not 3* may
be attributed to the longer time of reflux (10 h).
On the other hand, the synthesis of the 4-amino-6-(3-
nitrophenyl)-1-phenylpyrazolo[3,4-b]pyridine-5-carbonitrile
(7) was fulfilled by reacting 5-amino-1-phenylpyrazole (1)
with arylidenemalononitriles 6 in ethanol and triethylamine.
Scheme
2 describes the synthesis of 1-H-pyrazolo
[3,4-b]pyridines starting from 2-chloro-4,6-diarylpyridine-3-
carbonitrile 9a–c.
* Correspondent. E-mail: hala_bakr@hotmail.com

JOURNAL OF CHEMICAL RESEARCH 2010 471
Scheme 1
4-Aryl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitriles
8a–c were synthesised via the reaction of the respective
chalcone analogue with ethyl cyanoacetate and ammonium
acetate in n-butanol. Chlorination of compounds 8a–c was
achieved using a mixture of POCl3/N,N-dimethylaniline to
give the desired compounds in good yield (74–80%). Reacting
2-chloropyridines 9a,b with piperidine or morpholine in etha-
nol containing triethylamine resulted in 2-substituted pyridines
10a,b.
the mass spectrum of the product displayed molecular ion
peaks at m/z 620(M), 622(M+2) and 624(M+4) in the ratio
of 100:164.4:82.4 (as reported for compounds containing two
chlorine atoms and one bromine atom).26
Compounds 11c, 12c and 14c were tested for their antimi-
crobial activity against Staphylococcus aureus, Bacillus subti-
lis, Escherichia coli, Pseudomonas aeruginosa and Candida
albicans using Agar plate diffusion technique. None of the
tested compounds showed antimicrobial activity.
Cyclocondensation reaction of 2-chloropyridine-3-
carbonitriles 9a–c with hydrazine hydrate in ethanol was
applied to obtain 3-amino-1H-pyrazolo[3,4-b]pyridines 11a–c.
Cyclisation of 3-amino-1H-pyrazolo[3,4-b]pyridines 11a–c
with acetylacetone or ethyl ethoxymethylenecyanoacetate
(13) in acetic acid afforded the corresponding tricyclic pyrido
[2p,3p:3,4]pyrazolo[1,5-a]pyrimidines 12a–c and 14a–c,
respectively. Compounds 14a,b did not dissolve in the common
NMR solvents.
Experimental
Melting points were determined on a Griffin apparatus and were
uncorrected. IR spectra were determined as KBr discs on Shimadzu
IR 435 spectrophotometer and values were represented in cm−1. The
1H NMR and 13C NMR were carried out on Varian Gemini 200 MHz
spectrophotometer, Microanalytical Centre, Cairo University, Cairo,
Egypt, using TMS as an internal standard and chemical shifts were
recorded in ppm on δ scale. Mass spectra were run on Hewlett Packard
5988 spectrometer, Microanalytical Centre, Cairo University, Cairo,
Egypt. Elemental analyses were carried out at the Microanalytical
Centre, Cairo University, Cairo, Egypt, and at the Microanalytical
laboratory, National Research Center, Cairo, Egypt. Progress of the
reactions was monitored by TLC using TLC sheets precoated with UV
fluorescent silica gel Merck 60 F254 that were visualised using UV
Finally, compound 11a was reacted with chalcone analogue
2f in DMF to afford 2-(4-bromophenyl)-4-(4p-chlorophenyl)-
10-(2p-chlorophenyl)-8-phenylpyrido[2p,3p:3,4]pyrazolo[1,5-
1
a]pyrimidine (15). The H NMR spectrum of the product
demonstrated aromatic protons at δ 7.50–8.64 ppm. Moreover,

472 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
lamp and iodine vapour. The solvent system used in TLC was
benzene:methanol:chloroform [9:3:1.5].
arylidenecyanoacetate ester 4a,b or substituted benzylidenemalononi-
trile 6 (0.0015 mol) and triethylamine (1 mL) in absolute ethanol
(10 mL) was heated under reflux for 4 h. The reaction mixture was
cooled and acidified to litmus paper with drops of conc. HCl. The
obtained solid was filtered, dried and crystallised from the suitable
solvent.
5-Amino-1-phenylpyrazole (1)27, chalcone analogues 2a–f28–32
,
arylidenecyanoacetate ester 4a,b33, substituted benzylidenemalononi-
trile 633 and pyridone derivatives 8a–c34–36 were prepared according to
the literature.
6-(3-Nitrophenyl)-4-oxo-1-phenyl-7H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (5a): Crystallised from acetic acid; yield: 67%; m.p.
330–331 °C; IR (cm−1): 3300 (NH), 2200 (CN), 1650 (CO), 1530,
Synthesis of 4,6-diaryl-1-phenylpyrazolo[3,4-b]pyridines 3a,b
A mixture of 5-amino-1-phenylpyrazole (1) (0.0025 mol) and the
chalcone analogue (2a or 2b) (0.0025 mol) in DMF (3 mL) was heated
under reflux for 10 h. The solvent was evaporated under reduced
pressure, and the residue left was triturated with ethanol, filtered,
dried and crystallised from the suitable solvent.
1
1350 (NO2); H NMR (200 MHz, DMSO-d6) δ ppm 7.42–8.59 (m,
10 H, aromatic protons), 13.2 (br s, 1 H, NH, D2O exchangeable); 13
C
NMR (200 MHz, DMSO-d6) δ ppm 92.6 (C-5), 112.3 (C-3a), 117.4
(C-3), 123.4 (CN), 151.3 (C-6), 166.0 (C-7a), 177.3 (C-4), 125.7,
126.8, 128.7, 131.0, 132.6, 136.5, 137.0, 139.9, 149.8, 150.3
(aromatic carbons); MS m/z: 357 [M+, 100%]. Anal. Calcd for
C19H11N5O3: C, 63.86; H, 3.10; N, 19.60. Found: C, 63.58; H, 3.51; N,
19.68.
4-(4-Chlorophenyl)-1,6-diphenylpyrazolo[3,4-b]pyridine
(3a):
Crystallised from acetic acid; yield: 52%; m.p. 198–199 oC; IR (cm−1):
1
1600 (C=N); H NMR (200 MHz, CDCl3) δ ppm 7.26–8.46 (m,
aromatic protons). Anal. Calcd for C24H16ClN3: C, 75.49; H, 4.22; N,
11.00. Found: C, 75.03; H, 4.24; N, 11.41%.
6-(4-Chlorophenyl)-4-oxo-1-phenyl-7H-pyrazolo[3,4-b]pyridine-
5-carbonitrile (5b): Crystallised from ethanol; yield: 62%; m.p.
268–269 °C; IR (cm−1): 3417 (NH), 2200 (CN), 1645 (CO); 1H NMR
(200 MHz, DMSO-d6) δ ppm 7.35–8.27 (m, 10 H, aromatic protons),
13.2 (br s, 1 H, NH, D2O exchangeable); 13C NMR (200 MHz, DMSO-
d6) δ ppm 92.2 (C-5), 112.4 (C-3a), 118.0 (C-3), 123.4 (CN), 151.2
(C-6), 166.0 (C-7a), 179.0 (C-4), 128.6, 130.9, 132.7, 133.9, 137.1,
137.3, 139.9, 140.0, 150.0, 150.2 (aromatic carbons). Anal. Calcd for
C19H11ClN4O: C, 65.81; H, 3.19; N, 16.15. Found: C, 65.61; H, 3.49;
N, 16.35%.
6-(4-Bromophenyl)-4-(3-nitrophenyl)-1-phenylpyrazolo[3,4-b]
pyridine (3b): Crystallised from DMF; yield: 68%; m.p. 210–211 °C;
1
IR (cm−1): 1600 (C=N), 1530, 1350 (NO2); H NMR (200 MHz,
CDCl3) δ ppm 7.26–8.66 (m, aromatic protons); MS m/z: 472 [(M+2)+,
29.74%], 470 [M+, 31.03%]. Anal. Calcd for C24H15BrN4O2: C, 61.16;
H, 3.20; N, 11.88. Found: C, 61.20; H, 3.28; N, 11.97%.
Synthesis of 4-oxo-1-phenyl-6-(substituted phenyl)-7H-pyrazolo
[3,4-b]pyridine-5-carbonitriles 5a,b and 4-Amino-6-(3-nitrophenyl)-
1-phenylpyrazolo[3,4-b]pyridine-5-carbonitrile (7):
A
solution
of 5-amino-1-phenylpyrazole (1) (0.0015 mol), the appropriate

JOURNAL OF CHEMICAL RESEARCH 2010 473
4-Amino-6-(3-nitrophenyl)-1-phenylpyrazolo[3,4-b]pyridine-5-
carbonitrile (7): Crystallised from acetic acid; yield: 53%; m.p. 252–
253 °C; IR (cm−1): 3500, 3300 (NH2), 2200 (CN), 1530, 1350 (NO2);
1H NMR (200 MHz, DMSO-d6) δ ppm 7.37–8.56 (m, 10H, aromatic
protons), 8.57 (br s, 2 H, NH2, D2O exchangeable); MS m/z: 356 [M+,
100%]. Anal. Calcd for C19H12N6O2: C, 64.04; H, 3.39; N, 23.58.
Found: C, 63.97; H, 3.39; N, 23.22%.
Synthesis of 4-Aryl-2-chloro-6-phenylpyridine-3-carbonitriles
9a–c: A mixture of the respective 3,4,6-trisubstituted pyridones 8a–c
(0.0075 mol), N,N-dimethylaniline (10 mL) and phosphorus oxychlo-
ride (10 mL) was heated under reflux for 10 h. The reaction mixture
was cooled, poured gradually into crushed ice. The resulting product
was filtered, washed with water, and crystallised from the suitable
solvent.
(200MHz, DMSO-d6) δ ppm 5.41 (s, 2H, NH2, D2O exchangeable),
7.24–7.89 (m, 10H, aromatic protons), 12.35 (s, 1H, NH, D2O
exchangeable); MS m/z: 331 [M+, 100%]. Anal. Calcd for C18H13N5O2:
C, 65.25; H, 3.95; N, 21.13. Found: C, 65.16; H, 4.23; N, 20.81%.
Synthesis of 10-aryl-2,4-dimethyl-8-phenylpyrido[2p,3p:3,4]pyrazolo
[1,5-a]pyrimidines 12a–c and ethyl 4-amino-10-aryl-8-phenylpyrido
[2p,3p:3,4]pyrazolo[1,5-a] pyrimidine -3-carboxylates 14a–c
A mixture of 3-amino-4-aryl-6-phenyl-1H-pyrazolo[3,4-b]pyridines
11a–c (0.002 mol), acetylacetone or ethyl ethoxymethylenecyanoac-
etate (13) (0.002 mol) and glacial acetic acid (10 mL) was heated
under reflux for 12 h. The reaction mixture was cooled and poured
into an ice-water mixture. The solid separated was filtered, dried and
crystallised from the suitable solvent.
10-(2-Chlorophenyl)-2,4-dimethyl-8-phenylpyrido[2p,3p:3,4]pyra-
zolo[1,5-a]pyrimidine (12a): Crystallised from ethanol; yield: 75%;
m.p. 214–215 °C; IR (cm−1): 1610 (C=N); 1H NMR (200 MHz,
DMSO-d6) δ ppm 2.47 (s, 3H, 2-CH3), 2.90 (s, 3H, 4-CH3), 7.41–8.36
(m, 11H, aromatic protons). Anal. Calcd for C23H17ClN4: C, 71.77;
H, 4.45; N, 14.55. Found: C, 72.00; H, 4.20; N, 14.26%.
2-Chloro-4-(2-chlorophenyl)-6-phenylpyridine-3-carbonitrile (9a):
Crystallised from ethanol; yield: 78%; m.p. 194–195 °C; IR (cm−1):
1
2200 (CN); H NMR (200 MHz, DMSO-d6) δ ppm 7.05–7.89 (m,
10H, aromatic protons); MS m/z: 328 [(M+4)+, 11.88%], 326 [(M+2)+,
69.26%], 324 [M+, 100%]. Anal. Calcd for C18H10Cl2N2: C, 66.48; H,
3.09; Cl, 21.80. Found: C, 66.19; H, 2.95; Cl, 21.63%.
2,4-Dimethyl-10-(2-furyl)-8-phenylpyrido[2p,3p:3,4]pyrazolo[1,5-a]
2-Chloro-4-(2-furyl)-6-phenylpyridine-3-carbonitrile (9b): Cryst-
pyrimidine (12b): Crystallised from ethanol; yield: 76%; m.p. 226–
allised from ethanol; yield: 80%; m.p. 150–151 °C; IR (cm−1): 2200
1
227 °C; IR (cm−1): 1610 (C=N); H NMR (200 MHz, DMSO-d6)
1
(CN); H NMR (200 MHz, DMSO-d6) δ ppm 6.92 (m, 1H, 4-H of
δ ppm 2.68 (s, 3H, 2-CH3), 2.92 (s, 3H, 4-CH3), 6.65 (dd, 1H, 4-H of
furyl, JAX = 1.73 Hz, JMX = 3.51 Hz), 6.93–8.88 (m, 9H, aromatic
protons); MS m/z: 340 [M+, 10.49%]. Anal. Calcd for C21H16N4O:
C, 74.10; H, 4.73; N, 16.45. Found: C, 74.15; H, 4.53; N, 16.02%.
2,4-Dimethyl-10-(3-nitrophenyl)-8-phenylpyrido[2p,3p:3,4]pyrazolo
[1,5-a] pyrimidine (12c): Crystallised from ethanol; yield: 70%; m.p.
furyl, JAX=1.8 Hz, JMX=3.6 Hz), 7.62–8.43 (m, 8H, aromatic protons);
Anal. Calcd for C16H9ClN2O: C, 68.46; H, 3.23; Cl, 12.62. Found:
C, 68.13; H, 3.02; Cl, 12.50%.
2-Chloro-4-(3-nitrophenyl)-6-phenylpyridine-3-carbonitrile (9c):
Crystallised from toluene; yield: 74%; m.p. 182–183 °C; IR (cm−1):
2200 (CN), 1530, 1350 (NO2); 1H NMR (200 MHz, DMSO-d6) δ ppm
7.26–8.39 (m, 10H, aromatic protons); MS m/z: 337 [(M+2)+, 36.11%],
335 [M+, 100%]. Anal. Calcd for C18H10ClN3O2: C, 64.39; H, 3.00;
Cl, 10.56. Found: C, 64.86; H, 3.06; Cl, 10.97.
Synthesis of 4-Aryl-2-piperidino (or morpholino)-6-phenylpyridine-
3-carbonitriles 10a,b: A mixture of 4-aryl-2-chloro-6-phenylpyridine-
3-carbonitriles 9a,b (0.002 mol), the appropriate secondary amine
(0.002 mol) and triethylamine (0.002 mol) in 95% ethanol (10 mL)
was heated under reflux for 12 h. The solvent was evaporated under
vacuum, and the residue left was filtered, dried and crystallised from
ethanol.
1
202–203 °C; IR (cm−1): 1620 (C=N), 1530, 1350 (NO2); H NMR
(200 MHz, DMSO-d6) δ ppm 2.46 (s, 3H, 2-CH3), 2.94 (s, 3H, 4-CH3),
7.27–8.28 (m, 11H, aromatic protons); MS m/z: 395 [M+, 100%].
Anal. Calcd for C23H17N5O2: C, 69.86; H, 4.33; N, 17.71. Found:
C, 69.98; H, 4.30; N, 17.22%.
Ethyl 4-amino-10-(2-chlorophenyl)-8-phenylpyrido[2p,3p:3,4]pyra-
zolo[1,5-a] pyrimidine-3-carboxylate (14a): Crystallised from DMF;
yield: 62%; m.p. 326–327 °C; IR (cm−1): 3400, 3200 (NH2), 1700
(CO); MS m/z: 445 [(M+2)+, 38.26%], 443 [M+, 100%]. Anal. Calcd
for C24H18ClN5O2: C, 64.94; H, 4.08; N, 15.77. Found: C, 65.09;
H, 4.20; N, 16.09%.
Ethyl 4-amino-10-(2-furyl)-8-phenylpyrido[2p,3p:3,4]pyrazolo[1,5-a]
pyrimidine-3-carboxylate (14b): Crystallised from DMF; yield: 60%;
m.p. 340–341 °C; IR (cm−1): 3400, 3250 (NH2), 1700 (CO); MS m/z:
399 [M+, 100%]. Anal. Calcd for C22H17N5O3: C, 66.15; H, 4.29;
N, 17.53. Found: C, 66.50; H, 4.40; N, 17.13%.
Ethyl 4-amino-10-(3-nitrophenyl)-8-phenylpyrido[2p,3p:3,4]pyrazolo
[1,5-a] pyrimidine-3-carboxylate (14c): Crystallised from DMF;
yield: 75%; m.p. 338–339 °C; IR (cm−1): 3400, 3200 (NH2), 1700
(CO), 1530, 1350 (NO2); 1H NMR (200 MHz, DMSO-d6/CF3COOH)
δ ppm 0.75 (t, 3H, CH3), 3.84 (q, 2H, CH2), 7.04–8.55 (m, 10H,
aromatic protons), 7.72 (s, 1H, NH, D2O exchangeable), 8.1 (s, 1H,
NH, D2O exchangeable), 8.8 (s, 1H, N=CH); MS m/z: 454 [M+, 100%].
Anal. Calcd for C24H18N6O4: C, 63.43; H, 3.99; N, 18.49. Found:
C, 63.53; H, 4.08; N, 18.38%.
2-(4-Bromophenyl)-4-(4p-chlorophenyl)-10-(2p-chlorophenyl)-8-
phenylpyrido[2p,3p: 3,4]pyrazolo[1,5-a]pyrimidine (15): A mixture
of 3-amino-4-(2-chlorophenyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine
(11a) (0.64 g, 0.002 mol) and chalcone analogue 2f (0.64 g,
0.002 mol) in DMF (10 mL) was heated under reflux for 15 h. The
solvent was evaporated under vacuum, and the residue was triturated
with ethanol, filtered, dried and crystallised from toluene. Yield:
84%; m.p. 195–196 °C; IR (cm−1) :1655 (C=N); 1H NMR (200 MHz,
DMSO-d6) δ ppm 7.50–8.46 (m, aromatic protons); MS m/z: 624
[(M+4)+, 50.10%], 622 [(M+2)+, 100%], 620 [M+, 60.74%]. Anal.
Calcd for C33H19BrCl2N4: C, 63.68; H, 3.08; N, 9.00. Found: 63.45;
H, 3.37; N, 9.20%.
4-(2-Chlorophenyl)-2-piperidino-6-phenylpyridine-3-carbonitrile
(10a): Yield: 64%; m.p. 160–161 °C; IR (cm−1): 2200 (CN); 1H NMR
(200 MHz, DMSO-d6) δ ppm 1.69 (s, 6H, CH2), 3.73 (s, 4H, N-CH2),
7.48–8.22 (m, 10H, aromatic protons). Anal. Calcd for C23H20ClN3:
C, 73.88; H, 5.39; N, 11.23. Found: C, 73.77; H, 5.40; N, 10.78%.
4-(2-Furyl)-2-morpholino-6-phenylpyridine-3-carbonitrile (10b):
1
Yield: 67%; m.p. 118–119 °C; IR (cm−1): 2200 (CN); H NMR (200
MHz, DMSO-d6) δ ppm 3.67 (s, 4 H, CH2N), 3.81 (s, 4H, CH2O), 6.83
(d, 1H, 4-H of furyl), 7.54–8.21 (m, 8H, aromatic protons). Anal.
Calcd for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.39;
H, 5.20; N, 12.39%.
Synthesis of 3-amino-4-aryl-6-phenyl-1H-pyrazolo[3,4-b]pyridines
11a–c
A mixture of 4-aryl-2-chloro-6-phenylpyridine-3-carbonitriles 9a–c
(0.005 mol), hydrazine hydrate (99%, 2 mL, 0.04 mol) and absolute
ethanol (20 mL) was heated under reflux for 20 h. The solvent was
evaporated under vacuum, and the residue was filtered, dried and
crystallised from the suitable solvent.
3-Amino-4-(2-chlorophenyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine
(11a): Crystallised from ethanol; yield: 89%; m.p. 224–225 °C; IR
(cm−1): 3400, 3300, 3200 (NH/NH2); 1H NMR (200 MHz, DMSO-d6)
δ ppm 5.53 (s, 2H, NH2, D2O exchangeable), 7.06–7.80 (m, 10H,
aromatic protons), 12.23 (s, 1H, NH, D2O exchangeable); MS m/z:
322 [(M+2)+, 34.80%], 320 [M+, 100%]. Anal. Calcd for C18H13ClN4:
C, 67.39; H, 4.08; N, 17.46. Found: C, 67.29; H, 4.39; N, 17.62%.
3-Amino-4-(2-furyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine (11b):
Crystallised from dichloromethane; yield: 80%; m.p. 244–245 °C; IR
(cm−1): 3400, 3300, 3200 (NH/NH2); 1H NMR (200 MHz, DMSO-d6)
δ ppm 5.45 (s, 2H, NH2, D2O exchangeable ), 6.75 (dd, 1H ,4-H of
furyl, JAX=1.8 Hz, JMX=3.5 Hz), 7.48–8.23 (m, 8H, aromatic protons),
12.32 (s, 1H, NH, D2O exchangeable). Anal. Calcd for C16H12N4O:
C, 69.55; H, 4.37; N, 20.27. Found: C, 69.57; H, 4.80; N, 20.20%.
3-Amino-4-(3-nitrophenyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine
(11c): Crystallised from toluene; yield: 60%; m.p. 216–217 °C; IR
Received 30 May 2010; accepted 8 July 2010
Paper 1000164 doi: 10.3184/030823410X12811125049438
Published online: 30 August 2010
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