Synthesis of 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-5-carbonitrile via a one-pot, three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2010.03.109

A one-pot, three-component condensation reaction of an aldehyde, 3-amino-5-methylpyrazole and ethyl cyanoacetate in ethanol to give 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-5-carbonitriles, in high yields, at reflux, using a catalytic amount of p-toluenesulfonic acid, is described.

Full text of DOI:10.1016/j.tetlet.2010.03.109

Tetrahedron Letters 51 (2010) 2967–2970
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Synthesis of 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]-
pyridine-5-carbonitrile via a one-pot, three-component reaction
*
Abbas Rahmati
Department of Chemistry, University of Isfahan, PO Box 81746-73441, Isfahan, 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, three-component condensation reaction of an aldehyde, 3-amino-5-methylpyrazole and ethyl
cyanoacetate in ethanol to give 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-5-
carbonitriles, in high yields, at reflux, using a catalytic amount of p-toluenesulfonic acid, is described.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 9 October 2009
Revised 17 March 2010
Accepted 26 March 2010
Available online 31 March 2010
Multi-component condensation reactions (MCRs) occupy an
advantageous position because of high atom economy, their con-
vergent character and simple procedures. Therefore, the develop-
ment of novel MCRs are of interest for chemists.1
To explore the scope and limitations of this reaction, we ex-
tended it to various substituted benzaldehydes. As shown in Table
1, the reaction proceeds efficiently with electron-withdrawing and
electron-releasing substituted benzaldehydes.
Pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidine are
examples of condensed heterocycles, and are attractive com-
pounds for drug discovery since many of such scaffolds exhibit a
wide range of biological and pharmaceutical activities. These
include hypotensives, vasodilators, anti-inflammatories, analgesics
and antipyretics,2 inhibitors of xanthine oxidases,3 B-Raf kinase,4
cSRC kinase,5 cyclin dependent kinase6 and HIV reverse transcrip-
tase,7 anti-tumor and anti-proliferative agents,8 anxiolytics,9 as well
as compounds for the treatment of Alzheimer’s disease, gastrointes-
tinal diseases, anorexia nervosa, drug and alcohol withdrawal
symptoms, drug addiction and infertility.10 The development of
simple synthetic methods for these derivatives is therefore impor-
tant in organic synthesis.
A literature survey revealed that although a number of methods
have been reported for the synthesis of pyrazolo[3,4-b]pyridines,11
so far, none have dealt with the synthesis of 6-oxo-4,5,6,7-tetrahy-
dro-2H-pyrazolo[3,4-b]pyridines. In this Letter, a multi-component
procedure for the synthesis of these compounds is described.
Arising from our studies of syntheses based on aminoazole
MCRs,12 herein we report the synthesis of 4-aryl-6-oxo-4,5,6,7-tet-
rahydro-2H-pyrazolo[3,4-b]pyridine-5-carbonitriles13 4 via a one-
pot, three-component condensation reaction of an aldehyde 1
and 3-amino-5-methylpyrazole (2) in the presence of ethyl cya-
noacetate (3) under reflux conditions in ethanol using p-toluene-
sulfonic acid (p-TsOH) as the catalyst (Scheme 1).
The structures of products 4a–h were deduced from their IR, 1H
NMR, 13C NMR and mass spectra and by elemental analysis.
The 1H NMR spectra of the products indicated the formation of
two diastereoisomers (cis and trans) (Scheme 2). The 1H NMR spec-
trum of a mixture of cis- and trans-4b is presented in Figure 1.
Benzaldehydes with electron-releasing substituents tended to give
slightly better yields and to produce a slightly higher ratio of cis to
trans products (Table 1, entries 1–7). The trans isomer of 4h pre-
dominated probably due to increased steric hindrance (Table 1, en-
try 8).
Another interesting feature of this reaction was revealed when
ethyl acetoacetate and ethyl cyanoacetate were simultaneously
added to a reaction mixture of p-methylbenzaldehyde and amino-
pyrazole. It was found that only ethyl cyanoacetate participated in
the condensation reaction (Scheme 3). Using ethyl acetoacetate in-
stead of ethyl cyanoacetate resulted in the formation of three prod-
ucts as presented in Scheme 4.
There are no established mechanisms for the formation of 6-
oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridines; a reasonable
possibility is shown in Scheme 5. The reaction presumably pro-
ceeds via initial reaction between p-TsOH and the 3-aminopyrazole
(2) to give the 3-aminopyrazolium salt 8. Next, Michael addition of
this compound to benzylidene compound 9, itself produced by
Knoevenagel condensation of aldehyde 1 and ethyl cyanoacetate
(3) gives intermediate 10. Elimination of one proton from the imi-
num group results in compound 11. Subsequent cyclization of 11
results in condensed ring system 12. Finally, compound 12
undergoes tautomerism to produce the 6-oxo-4,5,6,7-tetrahydro-
2H-pyrazolo[3,4-b]pyridines 4 (Scheme 5).
Initial studies to optimize the reaction conditions indicated that
the best solvent for this reaction was ethanol with heating at reflux
temperature.
To sum up, a novel and efficient three-component condensation
reaction of an aldehyde, 3-amino-5-methylpyrazole and ethyl
cyanoacetate has been developed for the synthesis of
* Tel.: +98 311 7932730; fax: 98 311 6689732.
E-mail address: a.rahmati@sci.ui.ac.ir
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.109

2968
A. Rahmati / Tetrahedron Letters 51 (2010) 2967–2970
R1
CHO
NH2
CN
O
CN
p-TsOH
N
+
+
HN
N
H
COOEt
EtOH/reflux
24 h
R1
N
N
H
1
2
3
R1 =4-CH3, 4-OCH3, 4-Cl,
4a-h
4-Br, 4-NO2, 4-CN,
73-93%
2,4-di-OCH3, 2,4-di-Cl,
Scheme 1. Synthesis of 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-5-carbonitriles 4.
Table 1
Synthesis of 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-5-carbonitriles 4
Entry
Aldehyde
Product
Yield
84
trans:cis ratio
Mp (°C)
O
NC
CHO
NH
N
1
60/40
315–318
4a
N
H
O
NC
CHO
NH
N
H3CO
2
3
4
5
6
7
92
84
82
75
78
93
60/40
57/43
58/42
55/45
57/43
49/51
323–325
342–343
336–339
327–328
344–345
335–336
H3CO
4b
N
H
O
NC
CHO
NH
N
Cl
4c
N
H
Cl
O
NC
CHO
NH
N
Br
4d
N
H
Br
O
NC
CHO
NH
O2N
NC
N
4e
N
O2N
H
O
NC
CHO
NH
N
4f
N
NC
H
O
NC
CHO
OCH3
NH
H3CO
N
O
N
H
H3CO
Cl
H3C
4g
O
Cl
NC
CHO
Cl
NH
N
8
73
68/32
339–342
Cl
4h
N
H

A. Rahmati / Tetrahedron Letters 51 (2010) 2967–2970
2969
(60), 198 (90). Anal. Calcd for C15H14N4O: C, 67.65; H, 5.30; N,
21.04. Found: C, 68.01; H, 5.19; N, 21.53. (trans isomer) 1H NMR
(300 MHz, DMSO-d6) d: 1.45 (s, 3H, CH3), 2.31 (s, 3H, CH3), 4.39
(d, 3J = 11.6 Hz, 1H, CH), 4.64 (d, 3J = 11.7 Hz, 1H, CH), 7.21 (br s,
2H, 2CHarom), 7.25 (br s, 2H, 2CHarom), 10.95 (s, 1H, NHamide),
11.97 (br s, 1H, NHpyrazole) ppm. 13C NMR (75 MHz, DMSO-d6) d:
9.92, 21.18, 37.08, 44.00, 100.99, 117.69, 124.64, 129.78, 135.75,
136.41, 137.43, 147.62, 163.57 ppm. (cis isomer) 1H NMR
(300 MHz, DMSO-d6) d: 2.00 (s, 3H, CH3), 2.25 (s, 3H, CH3), 4.44
(d, 3J = 5.5 Hz, 1H, CH), 4.85 (d, 3J = 5.5 Hz, 1H, CH), 7.02 (d,
3J = 6.5 Hz, 2H, 2CHarom), 7.12 (d, 3J = 6.5 Hz, 2H, 2CHarom), 10.97
(s, 1H, NHamide), 12.06 (br s, 1H, NHpyrazole) ppm. 13C NMR
(75 MHz, DMSO-d6) d: 9.53, 21.05, 37.08, 42.85, 101.92, 117.23,
127.54, 129.78, 135.36, 137.18, 137.52, 147.60, 163.35 ppm.
4-(4-Methoxyphenyl)-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-
pyrazolo[3,4-b]pyridine-5-carbonitrile (4b): White powder (92%);
IR (KBr) cmÀ1: 3563, 3043, 2244, 1694, 1640, 1535; MS (EI,
Ar
Ar
CN
O
CN
O
HN
HN
N
N
N
H
N
H
trans isomer
cis isomer
Scheme 2. The cis and trans isomers of 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-
2H-pyrazolo[3,4-b]pyridine-5-carbonitriles 4.
4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyri-
dines. The simple one-pot nature of the reaction makes it an inter-
esting alternative to other multi-step approaches.
Representative data: 3-Methyl-6-oxo-4-p-tolyl-4,5,6,7-tetrahy-
dro-2H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4a): White pow-
der (84%); IR (KBr) cmÀ1: 3579, 3395, 2780, 2244, 1703, 1539;
MS (EI, 70 eV): m/z (%): 266 (M+, 100), 251 (90), 239 (45), 224
Figure 1. The 1H NMR signals of the cis and trans isomers of 4-(4-methoxyphenyl)-3-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4b).
CHO
NH2
CN
COCH3
COOEt
CN
N
HN
+
+
+
O
N
H
N
N
H
COOEt
1
2
3
5
4a
Scheme 3.
COOEt
COCH3
OH
N
OH
N
O
H
NH2
COCH3
+
+
+
N
COOCH3
N
H
NH
N
N
N
H
7
2
1
5
6
Scheme 4.

2970
A. Rahmati / Tetrahedron Letters 51 (2010) 2967–2970
NH2
NH2
NH2
p-TsO
p-TsO
p-TsOH
+
N
NH
N
N
H
H
2
N
H
N
H
8
NH2
CO2Et
CO2Et
H
O
H
NH2
O
H
N
H
NC
NC
NC
N
H
-H
H
6
OEt
N
N
3
9
10
1
O
O
O
OEt
NC
Ph
NH
NH
NC
Ph
NH
tautomerism
NC
H
-EtOH
H
N
N
N
N
NH
4
N
12
11
Scheme 5.
70 eV): m/z (%): 282 (M+, 100), 267 (15), 265 (17), 214 (20), 171
(15), 115 (25). Anal. Calcd for C15H14N4O2: C, 63.83; H, 5.00; N,
19.85. Found: C, 63.21; H, 4.73; N, 20.06. (trans isomer) 1H NMR
(300 MHz, DMSO-d6) d: 1.47 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.38
(d, 3J = 12.0 Hz, 1H, CH), 4.63 (d, 3J = 12.0 Hz, 1H, CH), 6.95 (d,
3J = 8.1 Hz, 2H, 2CHarom), 7.30 (d, 3J = 8.1 Hz, 2H, 2CHarom), 10.93
(s, 1H, NHamide), 11.97 (br s, 1H, NHpyrazole) ppm. 13C NMR
(75 MHz, DMSO-d6) d: 9.92, 36.68, 44.16, 55.52, 101.22, 114.51,
117.72, 129.86, 131.24, 135.75, 147.61, 159.18, 163.62 ppm. (cis
isomer) 1H NMR (300 MHz, DMSO-d6) d: 2.00 (s, 3H, CH3), 3.71
(s, 3H, CH3), 4.45 (d, 3J = 6.6 Hz, 1H, CH), 4.83 (d, 3J = 6.5 Hz, 1H,
CH), 6.88 (d, 3J = 8.1 Hz, 2H, 2CHarom), 7.05 (d, 3J = 8.1 Hz, 2H,
2CHarom), 10.97 (s, 1H, NHamide), 12.06 (br s, 1H, NHpyrazole) ppm.
13C NMR (75 MHz, DMSO-d6) d: 9.53, 36.68, 43.01, 55.47, 102.07,
114.51, 117.27, 128.82, 132.38, 135.27, 147.61, 159.00,
163.34 ppm.
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Acknowledgement
We gratefully acknowledge financial support from the Research
Council of the University of Isfahan.
Supplementary data
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13. General procedure for the synthesis of 4-aryl-3-methyl-6-oxo-4,5,6,7-tetrahydro-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.109.
References and notes
2H-pyrazolo[3,4-b]pyridine-5-carbonitriles 4a–h:
A solution of ethyl cyano-
acetate (1 mmol), aldehyde (1 mmol), 3-amino-5-methylpyrazole (1 mmol)
and p-TsOH (0.1 mmol) was heated at reflux in EtOH (10 ml) for 24 h. After
completion of the reaction as indicated by TLC (EtOAc/n-hexene, 1:2), the
reaction mixture was allowed to cool. The solvent was removed by evaporation
and the residue was washed with H2O (2 Â 20 ml). The solid product
recrystallized slowly from EtOH after 1–2 d.
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J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005.
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