Convenient synthesis of pyrazolo[3,4-b]pyridin-3-ones and pyrazolo[3,4-b]pyridine-5-carbaldehyde using vinamidinium salts

Article abstract of DOI:10.1016/j.tetlet.2011.05.024

An expedient method for the synthesis of 2-phenyl-5-aryl-2,3- dihydropyrazolo[3,4-b]pyridin-3-ones and 2-phenyl-3-oxo-2,3-dihydropyrazolo[3,4- b]pyridine-5-carbaldehyde in a single-step via condensation of vinamidinium salts with 3-amino-1-phenyl-2-pyrazo

Full text of DOI:10.1016/j.tetlet.2011.05.024

Tetrahedron Letters 52 (2011) 3648–3650
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Convenient synthesis of pyrazolo[3,4-b]pyridin-3-ones
and pyrazolo[3,4-b]pyridine-5-carbaldehyde using vinamidinium salts
⇑
Chtiba Samar, Jemmezi Fayçel, Khiari Jameleddine
Laboratoire de Chimie Organique et Analytique, Institut Supérieur de l’Education et de la, Formation Continue, Bardo, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient method for the synthesis of 2-phenyl-5-aryl-2,3-dihydropyrazolo[3,4-b]pyridin-3-ones and
2-phenyl-3-oxo-2,3-dihydropyrazolo[3,4-b]pyridine-5-carbaldehyde in a single-step via condensation of
vinamidinium salts with 3-amino-1-phenyl-2-pyrazolin-5-one is described.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 March 2011
Revised 13 April 2011
Accepted 6 May 2011
Available online 13 May 2011
Keywords:
2-Phenyl-5-aryl-2,3-dihydropyrazolo[3,4-
b]pyridin-3-ones
2-Phenyl-3-oxo-2,3-dihydropyrazolo[3,4-
b]pyridine-5-carbaldehyde
Heterocyclocondensation
Vinamidinium salts
Heterocyclic compounds can serve as scaffolds on which phar-
macophores can be arranged to yield potent and selective drugs.
Pyrazolopyridines, due to their analogy with purines, have been
the subject of many studies,1,2 particularly in the context of their
pharmacological properties; the four isomers [3,4-b], [3,4-c], [4,3-
c] and [1,5-a] all display high biological activity.3 Pyrazolo[3,4-
b]pyridine derivatives have been studied as antiviral,4 potential
antimalarial agents,5 compounds inhibiting cholesterol formation,6
for the treatment of Alzheimer’s disease, gastrointestinal diseases,
anorexia nervosa, drug and alcohol withdrawal symptoms, drug
addiction and infertility.7 They have also been reported as potent
and selective inhibitors of A1 adenosine receptors8 and phosphodi-
esterase 4 (PDE4) inhibitors in immune and inflammatory cells.9
Typically, pyrazolo[3,4-b]pyridines are synthesized via the copper-
and palladium-promoted cyclization reactions of 2-chloro-3-cya-
nopyridine with hydrazines,10 the reaction of 5-aminopyrazoles
In continuation of our interest in the development of synthetic
strategies to obtain functionalized heterocycles, we have concen-
trated our efforts on the preparation of such bioactive nitrogen-con-
taining heterocycles, and have already reported simple and efficient
procedures to synthesize interesting molecules, such as 2-pyri-
dones16–18 and pyrido[2,3-d]pyrimidines.19
Herein we report a novel synthetic approach for the prepa-
ration of pyrazolo[3,4-b]pyridine derivatives 3a–f via the one-
pot cyclocondensation of 3-amino-1-phenyl-2-pyrazolin-5-one
(1) with vinamidinium salts 2a–f under basic conditions
(Scheme 1).
The following mechanism may be proposed for the formation
of the substituted 2,3-dihydropyrazolo[3,4-b]pyridines 3 (Scheme
2). 3-Amino-1-phenyl-2-pyrazolin-5-one (1), on treatment with
sodium hydride in DMF, undergoes a Michael type addition to
vinamidinium salts 2 to give the intermediate enamine 4 after
elimination of dimethylamine. The next step involves aza-annu-
lation leading to the desired products 3 in good yields (Table 1).
Alternatively, when the reaction was carried out using the salt
2f20 followed by treatment with 1 N HCl in THF, aldehyde 3f
was obtained. The aldehyde group in 3f provides a synthetic
handle for subsequent functionalization to a variety of different
structures.
In conclusion, we have reported a simple and efficient method
for preparing 2-phenyl-5-aryl-2,3-dihydropyrazolo[3,4-b]pyridin-
3-ones 3a–e and 2-phenyl-3-oxo-2,3-dihydropyrazolo[3,4-b]pyri-
dine-5-carbaldehyde (3f) as precursors for new heterocyclic
systems.
with
a,b-unsaturated ketones or their precursors, such as b-di-
methyl-aminopropiophenones,11 condensation reactions of
5-aminopyrazoles, dimedone, and aldehydes,12 Friedländer-type
condensation of 5-aminopyrazole-4-carbaldehydes with reactive
a
-methylene ketones,13 cycloaddition reactions of pyrazolylimines
with aromatic and aliphatic nitroalkenes under microwave irradi-
ation,14 and the reaction of dialdehydes with pyrazole and active
methylene compounds under microwave irradiation.15
⇑
Corresponding author.
E-mail address: jamelkhiari@yahoo.fr (K. Jameleddine).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.024

C. Samar et al. / Tetrahedron Letters 52 (2011) 3648–3650
3649
R
O
O
ClO4
R
Me2N
NMe2
2a-e
Ph
Ph
N
Ph
N
N
NH2
NaH, DMF
N
N
N
H
1
3a-e
NMe2
NMe2
O
O
2ClO4
CHO
Me2N
2f
Ph
N
NH2
NaH, DMF,
then 1 N HCl, THF
N
N
N
H
1
3f
Scheme 1.
R
R
O
ClO4
NMe2
Me2N
NMe2
2
NH2
Ph
N
O
NaH, DMF
NH2
N
N
1
N
Ph
4
O
R
Ph
N
N
N
H
3
Scheme 2. A possible mechanism for the reaction shown in Scheme 1.
Table 1
Results of the reactions depicted in Scheme 1
5. Stein, R. G.; Biel, J. H.; Singh, T. J. Med. Chem. 1970, 13, 153–155.
6. Fujikama, Y.; Suzuki, M.; Iwasaki, H.; Sakashita, M.; Kitahara, M. Eur. Patent
Appl., EP 339358, 1989; Chem. Abstr. 1990, 113, 23903.
Producta
R
Yield (%)
7. Chen, Y. L. Int. Patent WO9534563 A1, 1995; Chem. Abstr. 1995, 124, 232447.
8. Manetti, F.; Schenone, S.; Bondavalli, F.; Brullo, C.; Bruno, O.; Ranise, A.; Mosti,
L.; Menozzi, G.; Fossa, P.; Trincavelli, M. L.; Martini, C.; Martinelli, A.; Tintori, C.;
Botta, M. J. Med. Chem. 2005, 48, 7172–7185.
9. Hamblin, J. N.; Angell, T. D. R.; Ballantine, S. P.; Cook, C. M.; Cooper, A. W. J.;
Dawson, J.; Delves, C. J.; Jones, P. S.; Lindvall, M.; Lucas, F. S.; Mitchell, C. J.; Neu,
M. Y.; Ranshaw, L. E.; Solanke, Y. E.; Somers, D. O.; Wiseman, J. O. Bioorg. Med.
Chem. Lett. 2008, 18, 4237–4241.
3a
3b
3c
3d
3e
3f
Ph
92
96
87
94
87
81
4-MeOC6H4
1-Naphthyl
4-MeC6H4
4-ClC6H4
CHO
All products were characterized from their 1H NMR, 13C NMR and mass spec-
a
10. (a) Sagitullina, G. P.; Lisitskaya, L. A.; Vorontsova, M. A.; Sagitullin, R. S.
Mendeleev Commun. 2007, 17, 192–193; (b) Lavecchia, G.; Berteina-Raboin, S.;
Guillaumet, G. Tetrahedron Lett. 2004, 45, 2389–2392.
troscopic data.20
11. Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonia, R.; Nogueras, M.; Cobo, J.
Tetrahedron Lett. 2008, 49, 2689–2691.
12. Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko, V. N.; Knyazeva, I. V.;
Groth, U.; Glasnov, T. N.; Kappe, C. O. J. Org. Chem. 2008, 73, 5110–5118.
13. Jachak, M. N.; Avhale, A. B.; Tantak, C. D.; Toche, R. B. J. Heterocycl. Chem. 2005,
42, 1311–1319.
14. Diaz-Ortiz, A.; Carrillo, J. R.; Cossio, F. P.; Gomez-Escalonilla, M. J.; de la Hoz, A.;
Moreno, A.; Prieto, P. Tetrahedron 2000, 56, 1569–1577.
References and notes
1. Green, J. V. Pyrazoles with Fused Six-Membered Heterocyclic Rings In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 5, p 305.
2. Townsend, L. B.; Wise, D. S. Bicyclic 5–6 Systems: Three Heteroatoms 2:1 In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Sciven, E.
F., Eds.; Pergamon: Oxford, 1996; Vol. 7, p 283.
3. Commeiras, L.; Woodcock, S. C.; Baldwin, J. E.; Adlington, R. M.; Cowley, A. R.;
Wilkinson, P. J. Tetrahedron 2004, 60, 933–938.
15. Tu, S.; Wang, Q.; Zhang, Y.; Xu, J.; Zhang, J.; Zhu, X.; Shi, F. J. Heterocycl. Chem.
2007, 44, 811–814.
16. Gmiza, T.; Khiari, J. E.; Hadj Ayed, M. A.; Ben Hassine, B. Synth. Commun. 2007,
37, 1053–1055.
17. Khiari, J. E.; Gmiza, T.; Hadj Ayed, M. A.; Ben Hassine, B. Synth. Commun. 2007,
37, 3939–3941.
4. Crenshaw, R. R.; Luke, G. M.; Smirnoff, P. J. Med. Chem. 1976, 19, 262–275.

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C. Samar et al. / Tetrahedron Letters 52 (2011) 3648–3650
18. Gmiza, T.; Hadj Ayed, M. A.; Khiari, J. E.; Ben Hassine, B. Tetrahedron Lett. 2011,
57, 764–766.
2-Phenyl-5-(4-methoxyphenyl)-2,3-dihydropyrazolo[3,4-b]pyridin-3-one
(3b).
Yield: 96%; yellow solid; mp = 141–143 °C; 1H NMR (300 MHz, CDCl3):
d = 3.76 (s, 3H), 6.87 (s, 1H), 7.10 (d, 2H, J = 8.7 Hz), 7.26 (m, 3H), 7.42 (d, 2H,
J = 8.7 Hz), 7.83 (m, 2H), 8.19 (d, 1H, J = 4.3 Hz), 8.42 (d, 1H, J = 4.3 Hz); 13C
NMR (75 MHz, CDCl3) d = 55.37, 114.65, 117.16, 125.72, 126.28, 126.30, 126.96,
129.53, 134.72, 136.13, 142.83, 151.49, 160.79, 162.51, 163.08. Anal. Calcd for
19. Hadj Ayed, M. A.; Khiari, J. E.; Ben Hassine, B. Mol. Divers. 2008, 12, 61–63.
20. General procedure for the heteroannulation: NaH (1 mmol) was suspended in
DMF (8 mL), then 3-amino-1-phenyl-2-pyrazolin-5-one (1) (0.48 mmol) was
dissolved in DMF (10 mL) and added slowly. The mixture was stirred for
30 min at 0 °C. Next vinamidinium salt 2 (0.48 mmol) was added and the
resulting mixture heated at 80 °C for 6 h and the residue partitioned between
CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 and the
combined organic layers dried over Na2SO4, filtered and the solvents removed
in vacuo. The crude residue was purified by column chromatography (10%
EtOAc in hexane) to give products 3a–e. For pyrazolo[3,4-b]pyridine 3f, after
evaporation of the solvent, THF (6 mL) and 1 N HCl (6 mL) were added. The
mixture was allowed to stir at room temperature for 2 h, then neutralized with
saturated aqueous NaHCO3 and extracted with CH2Cl2 (3 Â 15 mL). Work-up
and purification as above gave 3f.
C
19H15N3O2: C, 71.91; H, 4.76; N, 13.24. Found: C, 71.87; H, 4.74; N, 13.21. MS
(EI, 30 eV): m/z = 317 (M+).
2-Phenyl-5-(4-chlorophenyl)-2,3-dihydropyrazolo[3,4-b]pyridin-3-one
(3e).
Yield: 87%; yellow solid; mp = 130–132 °C; 1H NMR (300 MHz, CDCl3):
d = 7.15 (m, 3H), 7.35 (d, 2H, J = 8.7 Hz), 7.75 (m, 2H), 7.90 (d, 2H, J = 8.7 Hz),
8.20 (d, 1H, J = 4.3 Hz), 8.35 (s, 1H), 8.45 (d, 1H, J = 4.3 Hz); 13C NMR (75 MHz,
CDCl3) d = 117.16, 125.51, 125.72, 126.28, 126.30, 128.18, 129.53, 134.13,
134.60, 135.17, 140.30, 151.38, 162.51, 163.08. Anal. Calcd for C18H12N3ClO: C,
67.19; H, 3.76; N, 13.06. Found: C, 67.15; H, 3.72; N, 13.01%. MS (EI, 30 eV): m/
z = 321 (M+).
Representative spectral data of selected compounds
2-Phenyl-3-oxo-2,3-dihydropyrazolo[3,4-b]pyridin-5-carbaldehyde (3f). Yield:
81%; yellow solid; mp = 147–149 °C; 1H NMR (300 MHz, CDCl3): d = 7.24 (m,
3H), 7.75 (m, 2H), 8.20 (s, 1H), 8.45 (d, 1H, J = 4.3 Hz), 8.96 (d, 1H, J = 4.3 Hz),
10.65 (s, 1H); 13C NMR (75 MHz, CDCl3) d = 123.55, 125.33, 125.72, 126.28,
126.30, 128.89, 134.76, 152.59, 161.10, 162.35, 190.48.
2,5-Diphenyl-2,3-dihydropyrazolo[3,4-b]pyridin-3-one (3a). Yield: 92%; yellow
solid; mp = 135–137 °C; 1H NMR (300 MHz, CDCl3): d = 6.75 (s, 1H), 7.40–7.71
(m, 10H), 7.81 (d, 1H, J = 4.2 Hz), 8.1 (d, 1H, J = 4.2 Hz); 13C NMR (75 MHz,
CDCl3) d = 119.02, 125.99, 126.33, 127.43, 128.14, 129.13, 129.18, 129.30,
134.37, 135.38, 144.43, 150.09, 157.80, 166.06. Anal. Calcd for C18H13N3O: C,
75.25; H, 4.56; N, 14.62. Found: C, 75.22; H, 4.54; N, 14.58. MS (EI, 30 eV): m/
z = 287 (M+).
Anal. Calcd for C13H9N3O2: C, 65.27; H, 3.79; N, 17.56. Found: C, 65.24; H, 3.77;
N, 17.52. MS (EI, 30 eV): m/z = 239 (M+).