Synthesis of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide derivatives via a one-pot four-component reaction

Article abstract of DOI:10.1016/j.tetlet.2009.03.200

A one-pot four-component reaction of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and 1,3-diphenyl-1H-pyrazol-5-amine in the presence of p-toluenesulfonic acid as a catalyst has been developed. In this reaction, a new class of fully subs

Full text of DOI:10.1016/j.tetlet.2009.03.200

Tetrahedron Letters 50 (2009) 2911–2913
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Tetrahedron Letters
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Synthesis of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide
derivatives via a one-pot four-component reaction
*
Ahmad Shaabani , Mozhdeh Seyyedhamzeh, Ali Maleki, Maryam Behnam, Fahimeh Rezazadeh
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot four-component reaction of an aliphatic or aromatic amine, diketene, an aromatic aldehyde
and 1,3-diphenyl-1H-pyrazol-5-amine in the presence of p-toluenesulfonic acid as a catalyst has been
developed. In this reaction, a new class of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide deriv-
atives is produced under mild reaction conditions and in good yields at ambient temperature.
Ó 2009 Published by Elsevier Ltd.
Received 31 December 2008
Revised 17 March 2009
Accepted 27 March 2009
Available online 2 April 2009
Keywords:
Pyrazolo[3,4-b]pyridine-5-carboxamide
Multicomponent reaction
One-pot
1,3-Diphenyl-1H-pyrazol-5-amine
Diketene
Multicomponent reactions (MCRs), are powerful synthetic tools
which have changed the landscape of organic and medicinal chem-
istry because of environmental concerns, atom economy and their
ability to generate large libraries of compounds in one synthetic
step or two synthetic steps.1,2
der-type condensation of 5-aminopyrazole-4-carbaldehydes with
reactive
-methylene ketones,16 cycloaddition reactions of pyra-
a
zolylimines with aromatic and aliphatic nitroalkenes under micro-
wave irradiation17 and the reaction of dialdehydes with pyrazole
and active methylene compounds under microwave irradiation.18
However, introduction of a simple protocol for the synthesis of a
novel class of substituted pyrazolo[3,4-b]pyridine derivatives is
important.
Keeping in mind the biological and pharmacological importance
of pyrazolo[3,4-b]pyridines and in continuation of our interest in
MCRs,19–23 we describe here the synthesis of novel substituted pyr-
azolo[3,4-b]pyridine-5-carboxamides 5. This one-pot process in-
volves a four-component condensation reaction of an aliphatic or
aromatic amine 1, diketene 2, an aromatic aldehyde 3 and 1,3-di-
phenyl-1H-pyrazol-5-amine 4 in the presence of p-toluenesulfonic
acid (p-TsOHÁH2O) as a catalyst, in good yields at ambient temper-
ature (Scheme 1).
Pyrazolo[3,4-b]pyridines have received considerable attention
and are of interest due to their wide variety of biological activities
such as anxiolytic,3,4 inhibitors of xanthine oxidases,5 cholesterol
formation-inhibiting compounds,6 treatment of Alzheimer’s dis-
ease, 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 adeno-
sine receptors,8 phosphodiesterase 4 (PDE4) inhibitors in immune
and inflammatory cells,9 glycogen synthase kinase-3 (GSK-3)
inhibitors,10 kinase inhibitors of p38
drugs11 as well as inhibitors of interleukin-6 (IL-6) and tumour
necrosis factor-alpha (TNF- ) which are two multifunctional pro-
a as anti-inflammatory
a
inflammatory cytokines involved in the pathogenesis of cardiovas-
In a pilot experiment, the reaction of N-alkyl-3-oxobutanamide
6, which was prepared by addition of benzylamine 1 to diketene 2,
with benzaldehyde and 1,3-diphenyl-1H-pyrazol-5-amine 4 in the
presence of p-TsOHÁH2O as a catalyst was performed in dry dichlo-
romethane at ambient temperature. The progress of the reaction
was monitored by TLC. After completion of the reaction (6 days),
the product, N-benzyl-6-methyl-1,3,4-triphenyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxamide 5a was obtained in 69% yield.24
We have shown that the use of a wide range of amines 1 and
aromatic aldehydes 3 in this four-component reaction makes pos-
sible the synthesis of libraries under similar circumstances. Two
substituents in the products can be varied independently of each
cular and neurodegenerative diseases and cancer.12
Several methods are available for the synthesis of pyrazolo[3,4-
b]pyridines. Some of the most efficient and commonly used meth-
ods are the copper- and palladium-promoted cyclization reactions
of 2-chloro-3-cyanopyridine with hydrazines,13 the reaction of 5-
aminopyrazoles with a,b-unsaturated ketones or their precursors,
such as b-dimethyl-aminopropiophenones,14 condensation reac-
tions of 5-aminopyrazoles, dimedone and aldehydes,15 Friedlän-
* Corresponding author. Tel.: +98 21 29902800; fax: +98 21 22431663.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.03.200

2912
A. Shaabani et al. / Tetrahedron Letters 50 (2009) 2911–2913
R2
O
Ph
O
CHO
Ph
N
N
Ph
R1
N
p-TsOH.H2O
CH2Cl2, r.t.
4-7 d
N
N
R1 NH2
O
NH2
H
N
Ph
R2
1
3
4
5
2
67-76%
R1 = benzyl, 4-Me-benzyl, n-propyl
R2 = H, 4-Cl, 4-Br, 4-F, 4-CH3, 3-Cl
Scheme 1.
other. The results are given in Table 1. As anticipated from our ini-
tial results, these reactions proceeded very cleanly under mild con-
ditions at room temperature and no undesirable side reactions
were observed. All the compounds described herein have been syn-
thesized for the first time.
3-oxobutanamide 6, derived from the addition of amine 1 to dike-
tene 2. Next, Michael-type addition of 1,3-diphenyl-1H-pyrazol-5-
amine 4 to 7 followed by an intramolecular condensation reaction
of intermediate 8 gives product 9. Finally, oxidation of 9 affords the
corresponding product 5 (Scheme 2).
Aromatic aldehydes possessing both electron-withdrawing and
electron-releasing substituents were converted into the corre-
sponding pyrazolo[3,4-b]pyridine-5-carboxamide derivatives in
good yields. It is noteworthy that the reactions of halo-substituted
benzaldehydes gave better yields. For example, 4-bromobenzalde-
hyde gave the best yield of 76%. We have also examined aliphatic
amines to survey the scope and generality of this reaction; thus
propylamine was successfully reacted under the same conditions
(entry 7).
In conclusion, we have demonstrated an effective one-pot four-
component approach for the synthesis of fully substituted pyrazol-
o[3,4-b]pyridine-5-carboxamide derivatives via cyclocondensation
of a primary aliphatic or aromatic amine, diketene, 1,3-diphenyl-
1H-pyrazol-5-amine and aromatic aldehydes in CH2Cl2 using p-
TsOHÁH2O as the catalyst at ambient temperature. All the products
were obtained with high purity and in good yields using very sim-
ple and accessible starting materials. We hope to assess this new
class of compounds for biological activity.
Compounds 5a–g were stable solids whose structures were
determined by IR, 1H and 13C NMR spectroscopy, mass spectrome-
try and elemental analysis. The mass spectra of products 5a–g dis-
played molecular ion peaks at appropriate values consistent with
the proposed products.
Acknowledgement
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
A possible mechanism for the formation of products 5a–g is
shown in Scheme 2. It is rational to assume that intermediate 7 re-
sults from initial condensation of the aldehyde 3 with N-alkylated-
References and notes
1. Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005.
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Botta, M. J. Med. Chem. 2005, 48, 7172–7185.
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M. Y.; Ranshaw, L. E.; Solanke, Y. E.; Somers, D. O.; Wiseman, J. O. Bioorg. Med.
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Table 1
Synthesis of pyrazolo[3,4-b]pyridine-5-carboxamides 5a–g
Entry
R1
R2
Product
Time (days)
Yielda (%)
1
2
3
4
5
6
7
C6H5CH2
C6H5CH2
H
5a
5b
5c
5d
5e
5f
6
5
4
5
5
7
6
69
71
76
71
74
67
73
4-Cl
4-Br
4-F
3-Cl
4-CH3
4-Cl
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
n-C3H7
5g
a
Isolated yield.
10. Witherington, J.; Bordas, V.; Gaiba, A.; Garton, N. S.; Naylor, A.; Rawlings, A. D.;
Slingsby, B. P.; Smith, D. G.; Takle, A. K.; Ward, R. W. Bioorg. Med. Chem. Lett.
2003, 13, 3055–3057.
11. Revesz, L.; Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel, R.; Gram, H.; Hiestand, P.;
Manning, U.; Neumann, U.; Rucklin, G. Bioorg. Med. Chem. Lett. 2006, 16, 262–
266.
12. Bharate, S. B.; Mahajan, T. R.; Gole, Y. R.; Nambiar, M.; Matan, T. T.; Kulkarni-
Almeida, A.; Balachandran, S.; Junjappa, H.; Balakrishnan, A.; Vishwakarma, R.
A. Bioorg. Med. Chem. 2008, 16, 7167–7176.
13. (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.
14. Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonia, R.; Nogueras, M.; Cobo, J.
Tetrahedron Lett. 2008, 49, 2689–2691.
O
O
O
O
R
3
4
R
1
2
N
N
H
H
Ar
6
7
O
R
HN
O
O
R
N
H
15. 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.
16. Jachak, M. N.; Avhale, A. B.; Tantak, C. D.; Toche, R. B. J. Heterocycl. Chem. 2005,
42, 1311–1319.
17. 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.
-H2O
-2H
5
Ar
Ph
NH
NH2
Ar
N
N
Ph
Ph
Ph
N
9
N
8
18. Tu, S.; Wang, Q.; Zhang, Y.; Xu, J.; Zhang, J.; Zhu, X.; Shi, F. J. Heterocycl. Chem.
2007, 44, 811–814.
19. Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem. 2007, 72, 6309–6311.
Scheme 2. A possible mechanism for the formation of 5a–g.

A. Shaabani et al. / Tetrahedron Letters 50 (2009) 2911–2913
2913
20. Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J. J. Org. Chem. 2008, 73,
3925–3927.
105 (58), 77 (100), 51 (45). Anal. Calcd for C34H27BrN4O: C, 69.51; H, 4.63; N,
9.54. Found: C, 69.41; H, 4.55; N, 9.67.
21. Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10,
323–326.
22. Shaabani, A.; Maleki, A.; Mofakham, H. J. Comb. Chem. 2008, 10, 595–598.
23. Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10,
883–885.
N-(4-Methylbenzyl)-4-(4-fluorophenyl)-6-methyl-1,3-diphenyl-1H-pyrazolo[3,4-b]
pyridine-5-carboxamide (5d): Yellow powder (0.37 g, 71%): mp = 240 °C (dec.).
IR (KBr) cmÀ1: 3451, 3270, 3058, 2927, 1635, 1599, 1560, 1504, 1410. 1H NMR
(300.13 MHz, DMSO-d6) d 2.06 (3H, s, CH3), 266 (3H, s, CH3), 4.19 (2H, br s,
CH2), 6.60–7.65 (16H, m, H-Ar), 8.30 (2H, br s, H-Ar), 8.72 (1H, br s, NHCO). 13
C
24. Typical procedure for the synthesis of N-benzyl-6-methyl-1,3,4-triphenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxamide (5a): A solution of benzylamine (0.107 g,
1.0 mmol) and diketene (0.084 g, 1.0 mmol) was magnetically stirred in 5 mL
of dry CH2Cl2 for 2 h. Then, benzaldehyde (0.106 g, 1.0 mmol), 1,3-diphenyl-
1H-pyrazol-5-amine (0.235 g, 1.0 mmol) and p-TsOHÁH2O (0.019 g, 0.1 mmol)
were added simultaneously. The reaction mixture was allowed to stir for
NMR (75.47 MHz, DMSO-d6) d 21.1, 23.6 (CH3), 42.4 (CH2), 111.9, 114.7, 115.0,
121.6, 126.7, 127.4, 127.9, 128.3, 129.0, 129.2, 129.3, 129.7, 131.7, 131.8, 132.5,
136.0, 139.3, 141.7, 146.5, 149.9, 156.1 (C-Ar and C@C), 167.4 (CO). MS m/z:
526 (M+, 32), 511 (60), 406 (85), 380 (36), 273 (12), 120 (70), 105 (50), 77 (100),
51 (43). Anal. Calcd for C34H27FN4O: C, 77.55; H, 5.17; N, 10.64. Found: C,
77.43; H, 5.01; N, 10.56.
6 days until
a
precipitate appeared. After completion of the reaction, as
N-(4-Methylbenzyl)-4-(3-chlorophenyl)-6-methyl-1,3-diphenyl-1H-pyrazolo[3,4-b]
pyridine-5-carboxamide (5e): Yellow powder (0.40 g, 74%): mp = 245 °C (dec.).
IR (KBr) cmÀ1: 3440, 3249, 3055, 2923, 1643, 1555, 1500, 1410. 1H NMR
(500.13 MHz, DMSO-d6) d 2.19 (3H, s, CH3), 2.64 (3H, s, CH3), 4.18 (2H, d,
J = 13.3 Hz, CH2), 6.47–7.87 (16H, m, H-Ar), 8.28 (2H, br s, H-Ar), 8.66 (1H, br s,
NHCO). 13C NMR (125.77 MHz, DMSO-d6) d 21.5 (CH3), 24.0 (CH3), 42.9 (CH2),
122.0, 127.2, 127.7, 128.3, 128.6, 128.8, 129.0, 129.2, 129.5, 130.1, 132.8, 136.3,
139.7, 146.8, 150.3, 156.7 (C-Ar and C@C), 167.7 (CO). MS m/z: 544 (M+, 37Cl, 6),
542 (M+, 35Cl, 14), 527 (25), 464 (14), 422 (50), 396 (45), 120 (80), 105 (50), 77
(100), 51 (48). Anal. Calcd for C34H27ClN4O: C, 75.20; H, 5.01; N, 10.32. Found:
C, 75.23; H, 5.06; N, 10.36.
N-(4-Methylbenzyl)-6-methyl-1,3-diphenyl-4-p-tolyl-1H-pyrazolo[3,4-b]pyridine-
5-carboxamide (5f): Yellow powder (0.35 g, 67%): mp = 250 °C (dec.). IR (KBr)
cmÀ1: 3243, 3062, 2920, 1635, 1560, 1499, 1441, 1413. 1H NMR (500.13 MHz,
DMSO-d6) d 2.20 (3H, s, CH3), 2.25 (3H, s, CH3), 2.62 (3H, s, CH3), 4.17 (2H, d,
J = 5.4 Hz, CH2), 6.67 (2H, d, J = 7.5 Hz, H-Ar), 6.82–7.05 (10H, m, H-Ar), 7.17
(1H, t, J = 6.7 Hz, H-Ar), 7.35 (1H, t, J = 7.2 Hz, H-Ar), 7.57 (2H, t, J = 7.6 Hz, H-
Ar), 8.30 (2H, d, J = 8.0 Hz, H-Ar), 8.63 (1H, t, J = 5.5 Hz, NHCO). 13C NMR
(125.77 MHz, DMSO-d6) d 21.5 (CH3), 21.7 (CH3), 24.0 (CH3), 42.9 (CH2), 112.4,
122.0, 126.4, 127.0, 127.9, 128.1, 128.4, 128.8, 129.4, 129.5, 129.6, 129.9, 130.1,
132.5, 133.0, 136.4, 136.5, 138.5, 139.9, 143.3, 147.0, 150.4, 156.5 (C-Ar and
C@C), 168.0 (CO). MS m/z: 522 (M+, 30), 507 (75), 402 (100), 374 (42), 299 (12),
255 (14), 120 (50), 105 (55), 77 (80), 51 (60). Anal. Calcd for C35H30N4O: C,
80.43; H, 5.79; N, 10.72. Found: C, 80.33; H, 5.71; N, 10.66.
4-(4-Chlorophenyl)-6-methyl-1,3-diphenyl-N-propyl-1H-pyrazolo[3,4-b]pyridine-
5-carboxamide (5g): Yellow powder (0.35 g, 73%): mp = 259–261 °C. IR (KBr)
cmÀ1: 3449, 3285, 3070, 2921, 1641, 1551, 1499, 1408. 1H NMR (300.13 MHz,
DMSO-d6) d 0.56 (3H, t, J = 7.0 Hz, CH3), 1.04–1.20 (2H, m, CH2), 2.64 (3H, s,
CH3), 2.83–2.97 (2H, m, CH2), 6.97–7.28 (9H, m, H-Ar), 7.36 (1H, t, J = 6.8 Hz, H-
Ar), 7.57 (2H, t, J = 7.1 Hz, H-Ar), 8.19–8.27 (2H, m, H-Ar), 8.28 (1H, d, J = 7.6 Hz,
NHCO). 13C NMR (75.47 MHz, DMSO-d6) d 12.0 (CH3), 22.7 (CH3), 24.0 (CH3),
41.4 (CH2), 112.1, 122.0, 127.1, 128.1, 128.3, 128.7, 129.7, 130.1, 131.7, 132.9,
134.1, 134.2, 139.8, 141.8, 146.8, 150.3, 156.6 (C-Ar and C@C), 167.6 (CO). MS
m/z: 482 (M+, 37Cl, 25), 480 (M+, 35Cl, 65), 465 (15), 438 (25), 422 (85), 386 (15),
344 (12), 255 (14), 211 (11), 179 (15), 77 (100), 51 (50). Anal. Calcd for
C29H25ClN4O: C, 72.42; H, 5.24; N, 11.65. Found: C, 72.53; H, 5.27; N, 11.36.
indicated by TLC (EtOAc/n-hexane, 1:2), the precipitate was filtered off, washed
with water and then with ethanol and dried in vacuo to give 5a as a yellow
powder (0.34 g, 69%): mp = 224 °C (dec.). IR (KBr) cmÀ1: 3438, 3260, 3060,
2924, 1634, 1597, 1561, 1497, 1452, 1412. 1H NMR (500.13 MHz, DMSO-d6) d:
2.64 (3H, s, CH3), 4.22 (2H, d, J = 5.5 Hz, CH2), 6.74 (2H, d, J = 4.8 Hz, H-Ar),
6.95–7.20 (12H, m, H-Ar), 7.27 (1H, t, J = 7.0 Hz, H-Ar), 7.36 (1H, t, J = 7.3 Hz, H-
Ar), 7.58 (2H, t, J = 7.8 Hz, H-Ar), 8.30 (2H, d, J = 7.9 Hz, H-Ar), 8.66–8.70 (1H, m,
NHCO). 13C NMR (125.77 MHz, DMSO-d6) d: 24.0 (CH3), 43.1 (CH2), 112.2,
122.0, 127.1, 127.4, 127.8, 128.2, 128.5, 129.0, 129.5, 129.6, 130.1, 133.0, 135.4,
139.5, 139.9, 143.1, 147.0, 150.4, 156.5 (C-Ar and C@C), 168.0 (CO). MS m/z:
495 (M++1, 40), 494 (M+, 18), 479 (65), 388 (100), 360 (35), 285 (15), 255 (15),
106 (27), 91 (54), 77 (85), 51 (40). Anal. Calcd for C33H26N4O: C, 80.14; H, 5.30;
N, 11.33. Found: C, 80.11; H, 5.47; N, 11.59.
Compounds Characterization Data. N-Benzyl-4-(4-chlorophenyl)-6-methyl-1,3-
diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (5b): White powder
(0.37 g, 71%): mp = 246–247 °C. IR (KBr) cmÀ1: 3443, 3265, 3064, 2924, 1640,
1598, 1558, 1454, 1418. 1H NMR (300.13 MHz, DMSO-d6) d: 2.68 (3H, s, CH3),
4.27 (2H, d, J = 5.1 Hz, CH2), 6.78 (2H, d, J = 4.0 Hz, H-Ar), 7.01–7.30 (12H, m, H-
Ar), 7.40 (1H, t, J = 7.3 Hz, H-Ar), 7.61 (2H, t, J = 7.8 Hz, H-Ar), 8.32 (2H, d,
J = 7.9 Hz, H-Ar), 8.78 (1H, t, J = 5.6 Hz, NHCO). 13C NMR (75.47 MHz, DMSO-d6)
d 23.6 (CH3), 42.7 (CH2), 111.8, 121.6, 126.8, 127.1, 127.4, 127.9, 128.3, 128.4,
128.9, 129.3, 129.7, 131.4, 132.4, 133.7, 133.8, 139.0, 139.3, 141.4, 146.4, 149.9,
156.2 (C-Ar and C@C), 167.4 (CO). MS m/z: 530 (M+, 37Cl, 10), 528 (M+, 35Cl, 13),
513 (72), 422 (100), 396 (37), 296 (50), 106 (70), 91 (70), 77 (78), 51 (40). Anal.
Calcd for C33H25ClN4O: C, 74.92; H, 4.76; N, 10.59. Found: C, 74.83; H, 4.87; N,
10.36.
N-(4-Methylbenzyl)-4-(4-bromophenyl)-6-methyl-1,3-diphenyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxamide (5c): Yellow powder (0.43 g, 76%): mp = 235 °C
(dec.). IR (KBr) cmÀ1: 3451, 3273, 3050, 2924, 1637, 1557, 1501. 1H NMR
(500.13 MHz, DMSO-d6) d 2.21 (3H, s, CH3), 2.63 (3H, s, CH3), 4.17 (2H, br s,
CH2), 6.53–7.63 (16H, m, H-Ar), 8.28 (2H, br s, H-Ar), 8.68 (1H, br s, NHCO). 13
C
NMR (125.77 MHz, DMSO-d6) d 21.6, 24.0 (CH3), 42.9 (CH2), 122.0, 122.9,
127.1, 127.8, 128.3, 128.6, 129.3, 129.7, 130.1, 131.2, 132.0, 132.8, 134.4, 136.4,
139.8, 146.8, 156.6 (C-Ar and C@C), 167.7 (CO). MS m/z: 588 (M+, 81Br, 10), 586
(M+ 79Br, 9), 573 (26), 460 (28), 440 (28), 387 (26), 255 (10), 214 (10), 120 (76),
,