Synthesis of various 4,6-diarylpyrazolo[3,4-b]pyridines, from aminopyrazoles and 1,3-dicarbonylcompounds or by a Doebner method are reported

Ain Khan, Misbahul

Ali Munawar, Munawar

Aslam, Samina

Bernadino, Alice

Maqbool, Tahir

Parveen, Najma

Revistes Catalanes amb Accés Obert

AFINIDAD LXXI, 566, Abril - Junio 2014152
RESUMEN 
Se presenta la síntesis de diversas 4,6-diarilpyrazolo[3,4-
b]piridinas, a partir de aminopirazoles y 1,3-dicarbonil de-
rivados o por un método de Doebner.
Palabras clave: aminopirazoles; diarilpyrazolo [3,4-b] piri-
dinas; método de Doebner.
ABSTRACT
Synthesis of various 4,6-diarylpyrazolo[3,4-b]pyridines, 
from aminopyrazoles and  1,3-dicarbonylcompounds or 
by a Doebner method are reported.
Keywords: Aminopyrazoles; diarylpyrazolo[3,4-b]
pyridines; Doebner’s method.
RESUM
Es presenta la síntesi de diverses 4,6-diarylpyrazolo [3,4-
b] piridines, a partir de aminopirazols i 1,3-dicarbonil deri-
vats o per un mètode de Doebner.
Paraules clau: aminopirazols; diarilpyrazolo [3,4-b] piridi-
nes, mètode de Doebner.
Synthesis and antibacterial activities of 
Diarylpyrazolo  [3,4-b]pyridines II1
Najma Parveen1, 2, Samina Aslam2*, Tahir Maqbool2, Alice M.R. 
Bernadino3, Munawar Ali Munawar4 and Misbahul Ain Khan2
1Department of Chemistry Government Degree College for Women Bahawalpur, Bahawalpur, Pakistan 2Department of 
Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan 3Instituto de Quimica, Universidade Federal 
Fluminense, Niteroi, RJ, Brasil 4Institute of Chemistry, University of the Punjab, Quaid-e-Azam Campus, Lahore Pakistan
Síntesis y actividad antibacteriana de Diarilpirazolo [3,4-b] piridinas II1
Síntesi i activitat antibacteriana de Diarilpyrazolo [3,4-b] piridines II1
Recibido: 4 de agosto de 2013; aceptado: 13 de noviembre de 2013
*Corresponding author: saminaaslam2009@gmail.com
AFINIDAD LXXI, 566, Abril - Junio 2014 153
INTRODUCTION
A number of substituted pyrazolo[3,4-b]pyridines have 
been reported and a variety of these have been synthe-
sized because of their potential biological activities such as 
xanthine-oxidase inhibitors, anti-microbial and anti-inflam-
matory agents 2. Some fluorinated tetraarylpyrazolo[3,4-b]
pyridines have been reported to act as nervous system 
depressants and anti-inflamatory agents3, Our continuous 
interest in the chemistry of this ring system1,4-6  led us to re-
port the synthesis of the parent  ring system by decarbox-
ylative rearrangement of 3-cyanopyrazolo[1,5-a]pyrimidine 
and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid5 and their 
electrophilic, nucleophlic and homolytic reactions were 
reported previously1. More recently reactions of some ami-
nopyrazoles with mono and diketo compounds leading to 
aryl and diarylpyrazolo[3,4-b]pyridines have appeared7-9 
and this prompts us to report our results on the synthe-
sis of various diaryl pyrazolo[3,4-b]pyridines. A general 
method of building a pyridine ring on to a pyrazole nucle-
us via reaction of 5-aminopyrazoles with 1, 3-dicarbonyl 
compounds in the presence of zinc chloride was earlier 
reported10. This method however failed when dibenzoyl-
methane was used as a 1,3-dicarbonyl component, a zinc 
complex11 being formed instead.
EXPERIMENTAL
The proton NMR spectra were recorded on a Hitachi-Per-
kin Elmer MODEL R-20-B(60MHz) and a Bruker AM 300 
spectrometer (Rheinstetten–Forchheim, Germany) operat-
ing at 300 MHz, respectively  using  CDCl3 solvent with 
tetramethylsilane(TMS) as an internal standard. The infra-
red spectra (IR) were taken on a Perkin-Elmer model 180. 
Samples were measured as potassium bromide disks. 
Melting points were obtained on Fisher Johns and Ga-
llenkamp apparatus and are uncorrected. Elemental analy-
ses were determined on a Perkin-Elmer model 2400. The 
5-aminopyrazole used in these reactions was prepared 
according to the literature method stated earlier1. All the 
reagents and solvents used in this work were of analytical 
grade and purity.
General Methods
Method A
A mixture of a 5-aminopyrazole (5mmoles) and 5mmoles 
of dibenzoylmethane in 5mL of acetic acid was heated un-
der reflux for a period of 16-48 hours. Excess of acetic 
acid was removed and after cooling, the reaction mixture 
was inverted over crushed ice, basified with ammonium 
hydroxide, filtered and recrystallized from a suitable sol-
vent to obtain the desired product. 
3-methyl-1-(4-nitrophenyl) 4, 6-diphenyl-1H-pyrazo-
lo[3, 4-b]pyridine (1), this compound was obtained in 60% 
yield; M.P. 210-212 oC; IR (KBr) (v, cm-1): 3060, 1600, 1595, 
1560, 1510, 1330 (NO2) , 840, 810, 760; 
1H NMR (CDCl3), δ 
ppm( J, Hz) : 2.28(3H,s,CH3); 7.34-8.22 (11H,m,H-5&ArH); 
8.24-8.44(2H,dd) N-aryl.H, 8.64-8.88 (2H,dd) N-aryl.H. 
Anal.Calcd.for C25H18N4O2 (Mw 406) C, 73.98; H, 4.46; N, 
13.78.Found C, 73.90; H, 4.35; N,13.81.
3-methyl-1, 4, 6-triphenyl-1H-pyrazolo[3,4-b]pyridine 
(2),  65% yield; M.P. 149-151 oC; IR (KBr) (v, cm-1): 3040
,2920,1600,1560,1500,930,840,750,690; 1H NMR (CDCl3), 
δ ppm( J, Hz) : 2.28(3H,s,CH3);7.18-7.66&8.06-8.58 
(16H,m,H-5& Ar-H) Anal.Calcd.for C25H19N3(Mw 361) C, 
83.08; H, 5.30; N,11.62.Found C, 82.83; H, 5.32; N,11.64.
1-(4-chlorophenyl) 4, 6-diphenyl-1H-pyrazolo[3,4-b]
pyridine (3), 78% yield; M.P. 174-75 oC; IR (KBr) (v cm-1): 
3100, 3060, 1590, 1560, 1500, 930, 820, 740,680 1H NMR 
(CDCl3), δ ppm( J, Hz) : 6.83(1H,s,H-3);7.32-8.56(15H,m, 
ArH&H-5)
Anal.Calcd.for C24H16ClN3 (Mw 381) C, 75.62; H, 4.23; N, 
11.02.Found C, 75.42; H, 4.42; N, 10.79
3-methyl-1-(2-chlorophenyl) 4, 6-diphenyl-1H-pyrazolo 
[3,4-b]pyridine (4), 64% yield; M.P. 153-54 oC; IR (KBr) (v 
cm-1): 3060, 3030, 2960, 2920, 1580, 1570, 1560, 1500, 
1480, 1380, 760, 750, 700, 690. 1H NMR (CDCl3), δ ppm( 
J, Hz) : 2.34(3H,s,CH3);7.30-8.24(15H,m, ArH&H-5) Anal.
Calcd.for C25H18ClN3 (Mw 395) C, 75.85; H, 4.58; N, 10.61.
Found C, 75.83; H, 4.57; N, 10.84
1-methyl-4, 6-diphenyl-1H-pyrazolo[3,4-b]pyridine (5), 
64% yield; M.P. 153-54 oC; IR (KBr) (v cm-1): 3060,3020,2
920,1590,1570,1480,1460,750,690,680. 1H NMR (CDCl3), 
δ ppm( J, Hz) : 4.15(3H,s,N-CH3);6.80(1H,s,H-3); 7.20-
8.20(11H,m, ArH&H-5) Anal.Calcd.for C19H15N3 (Mw 285) 
C, 79.97; H, 5.30; N, 14.72.Found C, 80.01; H, 5.32; N, 
14.84
Method B   
A mixture of 10mmoles of 5-amino-3-methyl-I-phen-
ylepyrazole, 10mmole of a benzaldehyde and a few drops 
of concentrated hydrochloric acid and 15-20 mL absolu-
te ethanol was held under reflux for three hours to give 
a Schiff’s base16, followed by addition of 10mmoles of 
acetophenone. The reaction mixture was heated under 
reflux for a further three hours period. On cooling the reac-
tion mixture was poured over crushed ice (100g) and the 
precipitates were filtered and crystallized from ethanol to 
give the desired products 6-11.
One pot reaction
An equimolar (5 mmoles) mixture of an arylaldehyde and 
acteophenone and a 5-aminopyrazole in 100mL acetic 
acid was heated under reflux for 6 hours. After cooling, 
the mixture was poured over excess water, the precipitates 
obtained were filtered and crystallized from ethanol to give 
the desired 4, 6-diarylpyrazolo [3, 4-b] pyridines in over 
80% yield. These were identical with the products of ste-
pwise reaction above.
3-methyl-6-(2-nitrophenyl)-1,4-diphenyl-1H-pyrazo-
lo [3, 4-b] pyridine (6) this compound was obtained in 
60% yield; M.P. 160 oC; IR (KBr) (v cm-1): 2920, 1570, 
1500,1560,1450,1340 (NO2),1020.
 1H NMR (CDCl3), δ ppm( 
J, Hz) : 1.25 (3H,s,CH3);7.80-9.85(15H,m,ArH&H-5) Anal.
Calcd.for C25H18N4O2 (Mw 406) C, 73.98; H, 4.43; N, 13.79.
Found C, 73.93; H, 4.35; N, 13.82
3-methyl-6-(2-methoxyphenyl)-1,4-diphenyl-1H-
pyrazolo[3,4-b]pyridine (7) this compound was obtai-
ned in 65% yield; M.P. 218 oC; IR (KBr) (v cm-1): 2800, 
1700, 1650, 1510, 1090,635. 1H NMR (CDCl3), δ ppm( J, 
Hz) : 1.20(3H,s,CH3);3.75 (3H,s,OCH3), 8.20-9.05 (15H,m, 
ArH,&H-5) Anal.Calcd.for C26H21N3O (Mw 391) C, 79.80; H, 
5.37; N, 10.74 Found C, 80.20; H, 5.40; N, 10.70
3-methyl-6-(2-bromophenyl)-1,4-diphenyl-1H-
pyrazolo[3,4-b]pyridine (8), 72% yield; M.P. 160 oC; 
IR (KBr) (v cm-1): 1750, 1630, 1570, 1520, 660, 470. 1H 
NMR (CDCl3), δ ppm( J, Hz) : 2.14 (3H,s,CH3); 7.87-9.80 
AFINIDAD LXXI, 566, Abril - Junio 2014154
(15H,m,ArH& H-5) Anal.Calcd.for C25H18BrN3 (Mw 439) C, 
68.18; H,4.05; N, 9.55 Found C, 68.08; H, 4.25; N, 9.05
3-methyl-6-(2-chlorophenyl)-1,4-diphenyl-1H-
pyrazolo[3,4-b]pyridine (9), 74% yield; M.P. 154 oC; IR 
(KBr) (v cm-1): 1640, 1570, 1530, 848, 630. Anal.Calcd.for 
C25H18ClN3 (Mw 395) C, 75.85; H, 4.58; N, 10.61 Found C, 
75.68; H, 4.51; N, 10.58
3-methyl-6-(2, 4-dichlorophenyl)-1,4-diphenyl-1H-
pyrazolo[3,4-b]pyridine (10), 70% yield; M.P. 130 oC; IR 
(KBr) (v cm-1): 1740, 1610, 1580, 1510, 850, 710. Anal.
Calcd.for C25H17Cl2N3 (Mw 429) C, 69.77; H, 3.95; N, 9.77 
Found C, 69.73; H, 3.91; N, 9.72
3-methyl-6-(2-hydroxyphenyl)-1,4-diphenyl-1H-
pyrazolo[3,4-b]pyridine (11), 73% yield; M.P. 260 oC; 
IR (KBr) (v cm-1): 3160, 2820, 2280, 1730, 1650, 1620, 
1515, 1070, 630. 1H NMR (CDCl3), δ ppm( J, Hz) : 1.20 
(3H,s,CH3);8.10-8.90 (15H,m,ArH& H-5) Anal.Calcd.for 
C25H19N3O (Mw 377) C, 79.58; H, 5.04; N, 11.14 Found C, 
79.52; H, 5.12; N, 11.17
RESULTS AND DISCUSSIONS 
During this work various  4,6-diarylpyrazolo[3,4-b]pyri-
dines were prepared from 5-aminopyrazoles’ reaction 
with  1,3-dicarbonyl compounds ( Combe’s  method12) 
or with aromatic aldehydes and ketones ( modified 
Doebner’s method13).As for the symmetrically substituted 
4,6-diarylpyrazolo[3,4-b]pyridines, 5-aminopyrazoles were 
condensed with a 1,3-dicarbonyl compound-dibenzoyl 
methane. Our earlier attempts employing zinc chloride ca-
talyst in this reaction had failed to give satisfactory results 
but now employing acetic acid as the solvent as well as 
the acid catalyst gave the desired products in excellent 
yields (upto 78%) (scheme I). The di-and triaryl substituted 
pyrazolo[3,4-b]pyridines thus obtained and their spectral 
data are given in the experimental section. 
3-methyl-6-(2-hydroxyphenyl)-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine (11), 73% yield; 
M.P. 260 oC; IR (KBr) (v cm-1): 3160, 2820, 2280, 1730, 1650, 1620, 1515, 1070, 630. 1H NMR 
(CDCl3), δ ppm( J, Hz) : 1.20 (3H,s,CH3);8.10-8.90 (15H,m,ArH& H-5) Anal.Calcd.for 
C25H19N3O (Mw 377) C, 79.58; H, 5.04; N, 11.14 Found C, 79.52; H, 5.12; N, 11.17
Results and Discussions 
During this work various  4,6-diarylpyrazolo[3,4-b]pyridines were prepared from 5-
aminopyrazoles’ reaction with  1,3-dicarbonyl compounds ( Combe’s  method12) or with 
aromatic aldehydes and ketones ( modifie  Doebner’s me hod13).As for the symmetrically
substituted 4,6-diarylpyrazolo[3,4-b]pyridines, 5-aminopyrazoles were condensed with a 1,3-
dicarbonyl c mpound-dibenzoyl methane. Our earlier attempts employing zinc chloride catalyst
in this reaction had failed to give satisfactory results but now employing acetic acid as the 
solvent as well as the acid catalyst gave the desired products in excellent yields (upto 78%)
(scheme I). The di-and triaryl substituted pyrazolo[3,4-b]pyridines thus obtained and their 
spectral data are given in the experimental section.
N
N NH2
R1
R2
+ C
O
CH2 C
O
C6H5C6H5 N
N N
R1
R2
C6H5
C6H5
AcOH
heat
1-5
Scheme 1
For the synthesis of 4,6-diarylpyrozolo  [3,4-b] pyridines bearing different  aryl rings at 4-
and 6- positions,  however ,  Doebner’s modified method  (method B) was used (scheme 2) and 
various arylated derivatives were obtained in good yields. Reaction of acetophenone with 
preformed schiff’s bases from 5-amino pyrazoles and arylaldehydes  or alternatively in a one pot 
reaction  of  5-amino pyrazoles with an aromatic aldehyde and acetophenone afforded the 
6 
 
Scheme 1
For the synthesis of 4,6-diarylpyrozolo  [3,4-b] pyridines 
bearing different  aryl rings at 4- and 6- positions,  howe-
ver ,  Doebner’s modified method  (method B) was used 
(scheme 2) and various arylated derivatives were obtained 
in good yields. Reaction of acetophenone with preformed 
schiff’s  bases from 5-amino pyrazoles and arylaldehydes 
or alternatively in a one pot reaction  of  5-amino pyrazo-
les with an aromatic aldehyde and acetophenone afforded 
the products 6-11(method B), their respective element 
analyses and spectral data are given in the experimental 
section. The products in both these reactions: stepwise or 
“one pot” were identical in all respects (TLC, MP, IR and 
NMR spectra).
                                                                                                                                          
products 6-11(method B), their respective element analyses and spectral data are given in the
experimental section. The products in both these reactions: stepwise or “one pot” were identical
in all respects (TLC, MP, IR and NMR spectra).
C
O
CH3C6H5
N
N N
R1
R2
Ar
C6H5
AcOH
N
N NH2
R1
R2
+ Ar C
O
H N
N N
R1
R2
CH Ar
H+
6-11
C
O
CH3C6H5
N
N N
R1
R2
Ar
C6H5
N
N NH2
R1
R2
Ar C
O
H+
heat, AcOH
6-11
Scheme 2
The Doebner’s method has the advantage of introducing the desired aryl groups at the 4-
and 6-position of pyrazolo [3, 4-b] pyridine ring by varying aromatic aldehydes and ketones. 
Further work on these syntheses is in progress.
The 1HNMR Spectra were helpful in characterizing the products. It was noted that the methyl 
protons at 3- position of some of the products demonstrated shielding effect of upto 1ppm due to 
the aryl group at 4- position. This shielding effect has also been observed earlier in other 
annealed pyrazole systems 9, 14, 15.
Antibacterial activity
Antibacterial activity of Diraylpyrazolo[3,4-b]pyridines (1-11) was tested by Agar plate disc 
diffusion method17 against six different bacterial strains; Staphylococcus aureus (gram +ve), 
7 
 
Sche e 2
The Doebner’s method has the advantage of introducing 
the desired aryl groups at the 4- and 6-position of pyrazolo 
[3, 4-b] pyridine ring by varying aromatic aldehydes and 
ketones. Further work on these syntheses is in progress.
The 1HNMR Spectra were helpful in characterizing the pro-
ducts. It was n ted that the methyl protons at 3- position 
of some f th  products demonstrated shielding effect of 
upto 1ppm due to the aryl group at 4- position. This shiel-
ding effect has also been observed earlier in other annea-
led pyrazole systems 9, 14, 15. 
Antibacterial activity
Antibacterial activity of Diraylpyrazolo[3,4-b]pyridines 
(1-11) was tested by Agar plate disc diffusion method17 
against six different bacterial strains; Staphylococcus au-
reus (gram +ve), Pseudomonas (gram –ve), Escherichia 
coli (gram –ve) and Klebsiella (gram –ve). The filter paper 
disc (6.00 mm in diameter) was soaked with the solution 
of 50 mg of compound in 1 mL of chloroform was placed 
in the centre of plate. The plates were incubated with the 
growing cultures of bacterial strains. 
The four different types of bacterial cultures were inocu-
lated and were further incubated at 37°C for 24-48 hours. 
Vibramycin and Cefizox were used as standards. The test 
organism S.aureus and E. coli showed an inhibition zone of 
(30 mm) for Vibramycin while Pseudomonas showed resis-
tance. Klebsiella showed an inhibition zone of (10 mm) for 
Vibramycin and (20 mm) for Cefizox, while in case of Cefi-
zox no antibacterial activity was observed in S. aureus and 
E. coli but klebsiella showed an inhibition zone of 20 mm. 
In case of antibacterial activity of synthesized compounds 
(1-11), only four compounds 2, 6, 7 and 8 showed mo-
derate activity against S.aureus, Klebsiella, Pseudomonas 
and E. coli. The results of antibacterial activity are given in 
Table-1. 
Table 1. Antibacterial Activity of 
Diraylpyrazolo[3,4-b]pyridines 1-11
Compound 
No.
S.aureus Klebsiella Pseudo-
monas
E. coli
1 - - - -
2 10 - 12 -
3 - - - -
4 - - - -
5 - - - -
6 10 10 - -
7 - - - 10
8 - - 15 -
9 - - - -
10 - - - -
11 - - - -
VIB 30 10 - 30
CEF - 20 - -
VIB: Vibramycin, CEF: Cefizox
AFINIDAD LXXI, 566, Abril - Junio 2014 155
CONCLUSIONS
The method used for the synthesis of Diraylpyrazolo[3,4-b]
pyridines is a mild and efficient one as it gives better yields 
(60-75%). Schiff’s bases being the reactive intermediate, 
their preformation or in situ formation both gave satisfac-
tory results. The synthesized compounds showed mode-
rate activity against some bacterial strains.  
ACKNOWLEDGMENTS
Samina Aslam and Tahir Maqbool would like to thank HEC, 
Government of Pakistan for the assistance in the form of 
indigenous Scholarships and Fellowships under the IRSIP 
Programme.
REFERENCES
1. Part 1. Lynch, B.M.; Khan, M.A, Teo, H.C.; Pedrotti, 
Can. J.Chem.1988, 66, 420,
2. Hardy, C.R., Adv.Heterocyclic Chem., 1984, 36, 343.
3. Joshi,K.C.; Pathak, V.N.; Sareen, V., Garg U., J. Ind. 
Chem. Soc.,1987,64,372.(Chem. Abs., 1988, 108, 
131665).
4. Bernadino, A.M.R.; Romeiro, G.A.; Mello, H., deSou-
za, M.C.B.V.; Ferrira,V.F., Heterocyclic Comd.1996, 2, 
415.
5. Khan, M.A; Lynch, B.M., J.Heterocyclic Chem., 1970, 
7, 247.
6. Maqbool,T.; Khan, M.A;, Khan, M.N;, Elliott, M.C;, 
Munawwar, M.A;, Nasrullah, M;, Bhatti, A.W;, Nazeer, 
A;. Lin, W.O, Asian J.Chem., In press.
7. Quiroga, J.; Insuasty, B.; Cruz, S.; Hernandez, P., 
Bolanos, A.; Moreno. R.; Hormaza, A.; de Almeidas, 
R.H., J. Heterocyclic Chem. 1998, 35, 333.
8. .Quiroga, J.; Hormaza,A..; Insuasty, B.;Marquez, M., 
J. Heterocyclic chem., 1998,35, 409.
9. Quiroga, J.; Insuasty, Bo, Hormaza, A.; Saitz, C.O.; 
Jullian, C., J. HeterocyclicChem, 1998, 35, 575,
10. Klemm, L.H.; Klopfenstein, C.E.; Zell, R., McCoy, 
D.R.; Klemm, R.A., J.Org. Chem.,  1969, 34, 347.
11. Shigramatsu, T.; Tabushi, M.; Tarumoto, T., Kurenai: 
Kyoto University Research Information Repository, 
1963,  388. 
12. Combes, A., compt.Rend. 1888, 106, 142.
13. Doebner, O., Ber., 1887,20, 277.
14. Khan, M.A.,Pedrotti,F.; Monatsh. Chem., 1982, 
113,123.
15. Khan, M.A.; Cosenza, A.G.; Ellis, G.P.; J.Heterocyclic 
Chem., 1982,19,1077.
16. Parveen,N.; Khan, M.A.; Moazzam, M.;J.Pure and 
Appl.Sci.1998,17, 39.
17. Bauer, A.W., Kirby, W.M.M., Serris, J.C. and Turck, M., 
J. Clin. Path., 45, 493 (1966).


Synthesis and antibacterial activities of Diarylpyrazolo [3,4-b]pyridines II1

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