Convenient syntheses of pyrazolo[3,4-b]pyridin-6-ones using either microwave or ultrasound irradiation

Article abstract of DOI:10.1016/j.tetlet.2010.11.054

An efficient synthesis of 12 pyrazolo[3,4-b]pyridin-6-one derivatives was achieved using either microwave or ultrasound irradiation, resulting in yields of 40-60% and 60-95%, respectively. Under our conditions, these reactions occurred with notably reduced reaction times as compared to literature reports involving traditional heating. Furthermore, these reactions were highly regioselective and produced only one pyrazolo[3,4-b]pyridin-6-one isomer, whose identity was confirmed by NOESY spectroscopy.

Full text of DOI:10.1016/j.tetlet.2010.11.054

Tetrahedron Letters 52 (2011) 336–340
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient syntheses of pyrazolo[3,4-b]pyridin-6-ones using either microwave
or ultrasound irradiation
⇑
Cláudio E. Rodrigues-Santos, Aurea Echevarria
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, 23890-900 Seropédica, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 12 pyrazolo[3,4-b]pyridin-6-one derivatives was achieved using either micro-
wave or ultrasound irradiation, resulting in yields of 40–60% and 60–95%, respectively. Under our condi-
tions, these reactions occurred with notably reduced reaction times as compared to literature reports
involving traditional heating. Furthermore, these reactions were highly regioselective and produced only
one pyrazolo[3,4-b]pyridin-6-one isomer, whose identity was confirmed by NOESY spectroscopy.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 28 September 2010
Revised 7 November 2010
Accepted 10 November 2010
Available online 16 November 2010
Keywords:
Pyrazolo[3,4-b]pyridin-6-ones
Microwave
Ultrasound
Pyrazolo[3,4-b]pyridin-6-ones are a promising class of hetero-
cyclic compounds and have been shown to be inhibitors of cy-
clin-dependent protein kinase-2 (cdk-2), cyclin-dependent
protein kinase-5 (cdk-5), and phosphatidylinositol 3-kinase (PI3-
K).1,2 Thus, these compounds have potential in the treatment of
several diseases, including bipolar disorder, diabetes, dementia,
Alzheimer’s disease, schizophrenia, depression, and cancer.2
The synthesis of pyrazolo[3,4-b]pyridin-6-ones was first re-
ported by Hoehn three decades ago. These compounds were syn-
thesized by condensing ethylidene malonic acid diethyl ester and
1-ethyl-5-amino-methylpyrazole in refluxing dimethylformamide
and water for 94 h and resulted in a 53% yield.3 Later, Quiroga
et al. synthesized dihydropyrazolo[3,4-b]pyridin-6-ones by reflux-
ing equimolar amounts of aminopyrazole and the appropriate Mel-
drum’s acid benzylidene derivative in nitrobenzene for 30 min,
resulting in yields ranging from 42% to 72%.4
More recently, N-aminopyrazolo[4,3-c]pyridin-4-ones and N-
aminopyrazolo[3,4-c]pyridin-4-ones were prepared by Vasilevsky
et al. from vic-acetylenyl/hydrazido pyrazoles using the methyl es-
ters of acetylenyl-pyrazole carboxylic acids and hydrazine hydrate.
A cyclization reaction occurs upon heating the mixture to reflux in
butanol for 1–12 h and typically results in an 80% yield.5,6
Urban et al. prepared pyrazolo[3,4-c]pyridin-7-ones by treating
3-methoxy-pyridinone with cyclopentylhydrazine dihydrochloride
in THF at 95 °C for 12 h, which produced the desired product in 68%
yield. At nearly the same time, Mshvidobadze et al. reported an-
other interesting synthetic route to these compounds that relied
upon a heterocyclization reaction of vic-acetylenylpyrazol-
hydroxamic acids. These reactions were carried out in DMF using
copper(I) salts as a catalyst. These reactions afforded 5-hydroxypy-
razolo[4,3-c]pyridin-6-ones and pyrazolo[4,3-c]pyridin-4-ones in
50% and 90% yield, respectively, after a 12 h reaction time.7
Recently, Dress et al. obtained pyrazolo[3,4-b]pyridin-6-ones in
30–75% yield using condensation reactions that involved refluxing
aminopyrazole with the appropriate aldehyde and dimedone
derivatives in ethanol for 6–8 h.1 In addition, Martínez-Teipel
et al. developed a new synthetic route to this class of compound
involving an intermolecular cyclization of 2-methoxy-6-oxo-1,4,
5,6-tetrahydropyridine-3-carbonitriles with substituted hydra-
zines. Refluxing these materials between 3 and 48 h gave pyrazol-
o[3,4-b]pyridin-6-ones in 37–92% yield.8
Despite of the importance of the pyrazolo[3,4-b]pyridin-6-one
motif, there are still relatively few literature reports describing
the synthesis of these molecules, and those reports that do exist
generally employ synthetic methods that require long reaction
times. Thus, in this work we describe a new and efficient synthesis
of pyrazolo[3,4-b]pyridin-6-ones (6a–l). Of the 12 target struc-
tures, nine are new compounds that we synthesized using inter-
molecular cyclization reactions under solvent-free microwave
conditions and ultrasound irradiation conditions.
Our synthetic approach (Scheme 1) begins with substituted cin-
namic acids (1a–c), which were obtained from high yielding (83–
87%) Doebner–Knoevenagel condensation reactions between the
appropriate benzaldehydes and malonic acid in the presence of
pyridine and piperidine, as previously described.9 In the next step,
a solution of 1a–c and concentrated sulfuric acid in methanol was
heated to reflux for 12 h, furnishing the corresponding esters (2a–
c) in 90–93% yield, as reported in the literature.10,11
⇑
Corresponding author. Tel./fax: +55 21 2682 28 07.
E-mail address: echevarr@ufrrj.br (A. Echevarria).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.054

C. E. Rodrigues-Santos, A. Echevarria / Tetrahedron Letters 52 (2011) 336–340
337
Scheme 1.
Table 1
Next, the 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-car-
bonitrile intermediates (4a–c) were prepared from ,b-unsatu-
Reaction times and yields obtained for compounds 6a–l using the conventional
methodology, microwave irradiation, and ultrasound irradiation
a
rated esters (2a–c) and malononitrile (3) in a NaOMe/MeOH
solution that was heated at reflux for 4 h. This mixture was then
evaporated to dryness in vacuo, and the resulting residue was dis-
solved in a minimum amount of water and cooled in an ice bath.
The pH was then carefully adjusted to pH 8–9 with a 6 M HCl solu-
tion to prevent the rupture of the lactam group. Even so, com-
pounds 4a–c were only obtained in 25–60% yield, which is in
accord with previous literature data.8,12
The target compounds, the pyrazolo[3,4-b]pyridin-6-ones 6a–l,
were obtained both by the conventional method, which involves
refluxing in methanol, and by alternative methods, which involve
either microwave or ultrasound irradiation. In all cases, we began
with intermediates 4a–c and the appropriately substituted hydra-
zines 5a–f. The pyrazolo-pyridinones were obtained in moderate
to good yields (50–85%) using the conventional methanol reflux
method8 (see Table 1).
Compound
Conventional
Microwave
Ultrasound
Yield
Time
(h)
Yield
Time
(h)
Yield
Time
(h)
(%)
(%)
(%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
50
55
55
54
85
78
60
50
60
30
40
43
4
4
4
3
3
55
55
65
55
50
60
50
50
55
40
60
55
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
95
90
80
75
70
3
3
3
3
3
3
70
3
a
a
24
24
24
24
24
24
a
a
a
a
a
a
a
a
a
a
6j
6k
6l
a
No product observed.
To find the best microwave irradiation time, the reaction of
compounds 5b and 4b was used as a model and was monitored
by TLC and GC–MS. The results of these analyses indicated that
15 min was the optimal reaction total time. In the solvent-free
microwave irradiation conditions, the maximum continuous irra-
diation time was established to be 3 min and was followed by a
2 min cooling period between irradiations. This method was de-
signed to avoid overheating of the reactants, as unmodified domes-
tic microwave ovens lack the special attributes of commercial
reactors in terms of temperature control.13,14 Using this microwave
method, compounds 6a–l were obtained in moderate yield (50–
65%, see Table 1), however, it presented low yields when compared
to the conventional methodology (50–85%), but in notable time
conditions from 12 to 96 times faster than conventional method.
Compounds 6j–l were obtained using intermediates 4a–c and a
hydrazine hydrochloride.15 After conventional treatment with
NaOMe and refluxing methanol for 24 h, the desired products were
obtained in low yields (30–43%). However, when these derivatives
were prepared using solvent-free microwave irradiation condi-
tions, we observed a slight increase in the yields (40–60%, see
Table 1).
The ultrasound irradiation conditions were carried out in a sim-
ple way: compounds 5b and 4b were submitted to an ultrasound
bath as a solution in ethanol at room temperature. Reaction pro-
gress was monitored by TLC and GC–MS. After 30 min, the temper-
ature of the reaction mixture increased to 30–35 °C, and a yield of

338
C. E. Rodrigues-Santos, A. Echevarria / Tetrahedron Letters 52 (2011) 336–340
approximately 20% was detected. We also observed that at reaction
times of more than 3 h, no significant change in the yield occurred.
This method led to excellent results in the synthesis of compounds
6a–f (70–95% yield). However, compounds 6g–l were not observed
under the ultrasound conditions. Taken together, these results
show this methodology to be compatible with hydrazine moieties.
All three of the methodologies mentioned were ineffective when
the hydrazine in the reaction contained one or more nitro moieties
on the aromatic ring.
The reaction could develop into isomer A (pathway A) or B
(pathway B); however, the reaction was selective and afforded
only the isomer A (Scheme 1), independently of the applied
methodology.
We were able to differentiate between the possible product iso-
mers and confirm the structures of compounds 6d–l using NOESY
spectroscopy. For example, isomers 6h and 6h0 would represent N-
1 and N-2 atoms with different substituents. Our spectrum showed
a strong correlation between NH-7 with H-200, which indicates their
0
1
2
H-5a
H-5b
H-5a/H-5b
4'-OCH /H-3'
3
3
H-4
4'-OCH
H-4/H-5a
3
4
3-NH
2
3-NH /H-4
2
5
6
7
8
9
H-4''/H-3''
H-4''
H-3'/H-2''
H-3''
H-4/H-2'
H-2'
H-3-NH / H '
2
2
H-2'/H-3'
7-NH
7-NH/H-2''
9
8
7
6
5
4
3
2
1
0
ppm
Figure 1. Possible isomers 6h and 6h0 and the observed NOESY spectrum used to differentiate them.

C. E. Rodrigues-Santos, A. Echevarria / Tetrahedron Letters 52 (2011) 336–340
339
6-ones (6a–l) synthesis: Conventional methodology:8,15 The hydrazine (5a–f)
solution (120 mmol) and 4a–c (60 mmol) were refluxed for the time indicated
in Table 1. The solvent was concentrated in vacuo, and a small amount of
methanol was added. The mixture was then sonicated and the resulting solid
was filtered to afford the corresponding pyrazolo[3,4-b]pyridin-6-ones 6a–l.
Microwave irradiation: A mixture of 4a–c (0.60 mmol) and the hydrazine 5a–e
(0.60 mmol) was placed in the center of a microwave oven (Consul Pratice-
spatial proximity. Furthermore, no NOE correlation was observed
between the H-200 and NH2-3 amine hydrogen’s (Fig. 1). These data
were sufficient to reject the presence of isomer 6h0.
Based on these observations, the reaction was highly regioselec-
tive and produced only the pyrazolo[3,4-b]pyridin-6-one isomer.
All compounds were fully characterized by routine spectroscopic
methods, including IR, 1H and 13C NMR, and MS.16
In conclusion, we have demonstrated a very simple and highly
efficient method to prepare pyrazolo[3,4-b]pyridin-6-ones under
either microwave or ultrasound irradiation conditions, which have
shorter reaction times than those previously reported.
Brastemp S.A/Model MU31AO,
a domestic oven, 2450 MHz). The reaction
mixture was irradiated in 3 min intervals; each followed a 2 min cooling
interval. The total irradiation times are indicated in Table 1. Reaction progress
was monitored by TLC (EtOAc/hexane, 7:3). After irradiation, the reaction
mixture was washed with water (40 mL), and the product was extracted with
CHCl3 (4 ꢀ 15 mL). The material produced by this method did not require
subsequent purification. Ultrasound irradiation: A solution of 4a–c (0.60 mmol)
and the hydrazine 5a–b (0.60 mmol) in ethanol was ultrasound irradiated for
3 h (Ultra Cleaner 700-UNIQUE—55 kHz). Reaction progress was monitored by
TLC (EtOAc/hexane, 7:3). The work-up was performed using the procedure
described above for the microwave irradiation method and gave pyrazolo-
[3,4-b]pyridin-6-ones 6a–l. Compounds 6k–l were obtained after the addition
Acknowledgments
The authors gratefully acknowledge fellowships and financial
support from CNPq and Capes, the Brazilian Federal Government
Granting Agencies.
of
NaOMe
(20 mmol).
3-Amino-4-phenyl-1,4,5,7-tetrahydropyrazolo-
[3,4-b]pyridin-6-one (6a): yellow solid; mp 257–259 °C (lit.8 261–262 °C); IR
(KBr, cmꢁ1) 3345, 2879, 2927, 2838, 1656, 1614, 1492, 1452, 1H NMR (DMSO-
d6, 200 MHz) d 7.34 (m, J = 6, 10 Hz, 5H), 4.59 (s, 1H), 4.49 (s, 1H), 3.47 (dd,
J = 6, 12 Hz, 1H), 2.80 (dd, J = 4, 12 Hz, 1H), 2.52 (dd, J = 4, 12 Hz, 1H); 13C NMR
(DMSO-d6, 50 MHz) d 168.6, 144.7, 140.0, 138.6, 128.9, 127.6, 83.6, 37.4, 37.1.
3-Amino-4-p-methoxy-phenyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-
one (6b): yellow solid; mp 274–275 °C (lit.8 270–272 °C); IR (KBr, cmꢁ1) 3357,
2971, 2881, 2840, 1666, 1612, 1517, 1450; 1H NMR (DMSO-d6, 50 MHz) d 7.29
(d, 8 Hz, 2H), 6.92 (d, 8 Hz, 2H), 4.26 (s, 1H), 4.40 (s, 1H), 3.73 (s, 3H), 2.76 (dd,
J = 6, 12 Hz, 1H), 2.56 (d, J = 6 Hz, 1H); 13C NMR (DMSO-d6, 50 MHz) d 168.6,
158.7, 148.7, 143.9, 131.9, 128.6, 113.8, 86.1, 55.1, 38.4, 37.6. 3-Amino-4-p-
nitro-phenyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one (6c): yellow
solid; mp >300 °C (lit.8 >300 °C); IR (KBr, cmꢁ1) 3403, 2983, 2929, 2840,
1658, 1631, 1513, 1452; 1H NMR (DMSO-d6, 200 MHz) d 10.81 (s, 1H), 10.17 (s,
1H), 8.16 (d, J = 8 Hz, 2H), 7.39 (d, J = 8 Hz, 2H), 5.00 (s, 2H), 4.25 (d, J = 6 Hz,
1H), 2.94 (dd, J = 8, 16 Hz, 1H), 2.74 (dd, J = 4, 16 Hz, 1H); 13C NMR (DMSO-d6,
50 MHz) d 169.6, 153.2, 146.5, 145.5, 128.5, 124.1, 84.8, 39.4, 36.7. 3-Amino-1-
methyl-4-phenyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one (6d): yellow
oil; IR (KBr, cmꢁ1) 3347, 2971, 2929, 2827, 1666, 1612, 1492, 1452, 1351; 1H
NMR (DMSO-d6, 200 MHz) d 10.08 (s, 1H), 7.24 (m, J = 8 Hz, 5H), 7.11 (dd, J = 4
and 6 Hz, 2H), 5.07 (s, 1H), 4.05 (dd, J = 8 and 10 Hz, 1H), 3.35 (s, 3H), 2.83 (dd,
J = 8 and 18 Hz, 1H), 2.49 (m, J = 2 Hz, 1H); 13C NMR (DMSO-d6, 50 MHz) d
170.1, 146.7, 144.7, 143.2, 128.7, 126.9, 126.6, 86.3, 40.5, 34.1, 33.0; Calcd’ for
References and notes
1. Dress, B. E.; Chakravarty, L.; Prestwich, G. D.; Dorman, G.; Kavecz, M.; Lukacs,
A.; Urge, L.; Darvas, F.; Rzepecki, P. W.; Ferguson, C. G. W.O. Patent 016,245,
2005; Chem. Abstr. 2005, 142, 261534.
2. Kung, D. W. S.; Fuller, G. U.S. Patent 266,815, 2004; Chem. Abstr. 2005, 142,
266815.
3. Hoehn, H. U.S. Patent 3,935,222, 1976; Chem Abstr. 1976, 85, 21351.
4. Quiroga, J.; Hormanza, A.; Insuasty, B. J. Heterocycl. Chem. 1998, 35, 409–412.
5. Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. J. Heterocycl. Chem. 2002, 39,
1229–1233.
6. Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. Heterocycles 2002, 57, 2255–
2260.
7. Urban, F. J. E. P. Patent 1,380,585, 2004; Chem. Abstr. 2004, 140, 94049.
8. Martínez-Teipel, B.; Teixidó, J.; Pascual, R.; Mora, M.; Pujolà, J.; Fujimoto, T.;
Borrell, J. I.; Michelotti, E. L. J. Comb. Chem. 2005, 7, 436–448.
9. Santos, A. C. S.; Echevarria, A. Magn. Reson. Chem. 2001, 39, 182–186.
10. Peterson, J. R.; Russell, M. E.; Surjasasmita, I. B. J. Chem. Eng. Data 1988, 33, 534–
537.
11. Bernini, R.; Cacchi, S.; Fabrizi, G.; Forte, G.; Niembro, S.; Petrucci, F.; Pleixats, R.;
Prastaro, A.; Sebastián, R. M.; Soler, R.; Tristany, M.; Vallribera, A. Org. Lett.
2008, 10, 561–564.
C13H14N4O: C, 64.45; H, 5.82; N, 23.13. Found: C, 64.41; H, 5.88; N, 23.18.
3-Amino-1-methyl-4-p-methoxy-phenyl-1,4,5,7-tetrahydropyrazolo[3,4-b]-
pyridin-6-one (6e): yellow solid; mp 187–189 °C; IR (KBr, cmꢁ1) 3237, 2977,
2929, 2838, 1675, 1612, 1511, 1452, 1344; 1H NMR (DMSO-d6, 200 MHz) d
10.02 (s, 1H), 7.02 (d, J = 8 Hz, 2H), 6.80 (d, J = 8 Hz, 2H), 5.01 (s, 1H), 3.98 (dd,
J = 8 Hz, 1H), 3.67 (s, 3H), 2.78 (dd, J = 4 and 16 Hz, 1H), 2.38 (dd, J = 4 and
16 Hz, 1H); 13C NMR (DMSO-d6, 50 MHz) d 169.8, 157.8, 146.6, 142.9, 136.5,
127.8, 113.9, 86.5, 55.1, 40.7, 33.9, 32.2; Calcd’ for C14H16N4O2: C, 61.75; H,
5.92; N, 20.58. Found: C, 61.72; H, 5.89; N, 20.62. 3-Amino-1-methyl-4-p-
nitro-phenyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one (6f): orange
solid; mp >300 °C; IR (KBr, cmꢁ1) 3365, 2971, 2883, 1673, 1604, 1517, 1465,
1351; 1H NMR (DMSO-d6, 200 MHz) d 10.18 (s, 1H), 8.14 (d, J = 8 Hz, 2H), 7.36
(d, J = 8 Hz, 2H), 5.24 (s, 1H), 3.41 (s, 3H), 2.93 (dd, J = 8 and 16 Hz, 1H), 2.46
(dd, J = 2 Hz, 1H); 13C NMR (DMSO-d6, 50 MHz) d 169.1, 152.7, 146.5, 146.2,
128.1, 124.1, 123.4, 84.7, 39.8, 34.0, 32.9; Calcd’ for C13H13N5O3: C, 54.35; H,
4.56; N, 24.38. Found: C, 54.39; H, 4.42; N, 24.43. Amino-1-phenyl-4-phenyl-
1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one (6g): white solid; mp 211–
212 °C; IR (KBr, cmꢁ1) 3353, 2881, 2931, 1681, 1602, 1500; 1H NMR (DMSO-d6,
200 MHz) d 9.13 (s, 1H), 7.40 (m, J = 4 and 8 Hz, 5H), 7.17 (d, J = 6 Hz, 2H), 6.97
(d, J = 8 Hz, 2H), 6.72 (t, J = 6 and 8 Hz, 1H), 4.68 (s, 1H), 3.60 (m, J = 8 Hz, 1H),
2.87 (dd, J = 8 and 18 Hz, 1H), 2.63 (dd, J = 6 and 18 Hz, 1H); 13C NMR (DMSO-
d6, 50 MHz) d 168.7, 145.7, 144.3, 139.7, 132.3, 129.1, 128.9, 128.6, 127.8,
122.1, 118.8, 111.7, 38.1, 37.4; Calcd’ for C18H16N4O: C, 71.04; H, 5.30; N, 18.41.
Found: C, 70.98; H, 5.28; N, 18.47. Amino-1-phenyl-4-p-methoxy-phenyl-
1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one (6h): yellow solid; mp 208–
210 °C; IR (KBr, cmꢁ1) 3345, 2958, 2931, 2879, 2838, 1683, 1600, 1515, 1349;
1H NMR (DMSO-d6, 200 MHz) d 9.12 (s, 1H), 7.34 (d, J = 8 Hz, 2H), 7.19 (d,
J = 6 Hz, 2H), 6.97 (d, J = 8 Hz, 4H), 6.72 (t, J = 6 Hz, 1H), 4.61 (s, 1H), 3.75 (s,
3H), 3.55 (m, J = 8 Hz, 1H), 2.89 (dd, J = 6 and 18 Hz, 1H), 2.55 (d, J = 18 Hz, 1H);
13C NMR (DMSO-d6, 50 MHz) d 168.9, 158.8, 146.2, 131.7, 129.2, 128.7, 118.9,
117.2, 114.3, 111.8, 55.2, 38.8, 37.9; Calcd’ for C19H18N4O2: C, 68.25; H, 5.43; N,
16.76. Found: C, 68.32; H, 5.42; N, 16.82. Amino-1-phenyl-4-p-nitro-phenyl-
1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one (6i): yellow solid; mp 234–
235 °C; IR (KBr, cmꢁ1) 3345, 2925, 2879, 2854, 1691, 1598, 1517; 1H NMR
(DMSO-d6, 200 MHz) d 9.17 (s, 1H), 8.29 (d, J = 8 Hz, 2H), 7.73 (d, J = 8 Hz, 2H),
6.97 (d, J = 10 Hz, 2H), 6.73 (t, J = 8 Hz, 1H), 4.80 (s, 1H), 3.87 (m, J = 8 Hz, 1H),
2.92 (dd, J = 6 and 18 Hz, 1H), 2.69 (m, J = 8 Hz, 1H); 13C NMR (DMSO-d6,
50 MHz) d 168.2, 147.3, 147.2, 145.6, 138.2, 129.1, 128.1, 124.1, 116.8, 118.9,
111.8, 37.9, 36.94; Calcd’ for C18H15N5O3: C, 61.89; H, 4.33; N, 20.05. Found: C,
61.82; H, 4.29; N, 20.09. Amino-1-p-methoxy-phenyl-4-p-methoxy-phenyl-
12. Mont, N.; Fernández-Megido, L.; Teixidó, J.; Kappe, C. O.; Borrell, J. I. QSAR
Comb. Sci. 2004, 23, 836–849.
13. Sagrera, G. J.; Seoane, G. J. Braz. Chem. Soc. 2005, 16, 851–856.
14. Varma, R. S.; Dahiya, R. J. Org. Chem. 1998, 63, 8038–8041.
15. Falcó, J. L.; Lloveras, M.; Buira, I.; Teixidó, J.; Borrell, J. I.; Méndez, E.; Terencio,
J.; Palomer, A.; Guglietta, A. Eur. J. Med. Chem. 2005, 40, 1179–1187.
16. General procedure for the synthesis of 2-methoxy-6-oxo-1,4,5,6-tetrahydro-
pyridine-3-carbonitriles (4a–c)8: A solution of the
a,b-unsaturated ester (2a–
c) (170 mmol) in methanol (30 mL) was added dropwise to 30 mL of a 5.67 M
sodium methoxide solution. Following this, malononitrile (90 mmol) was
added dropwise as a solution in methanol (30 mL). This mixture was heated to
reflux for 4 h and, after cooling, was concentrated in vacuo. The resulting
residue was dissolved in the minimum amount of water required, cooled in an
ice bath, and carefully neutralized to pH 8–9 with a 6 M HCl solution. The
precipitate was filtered, washed with ice water, and extracted into CH2Cl2
(2 ꢀ 50 mL). The combined organic extracts were washed with water, dried
over MgSO4 and concentrated to give the intermediates 4a–c. 2-Methoxy-4-
phenyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carbonitriles (4a): orange solid,
mp 141–142 °C (lit.8 143–144 °C); IR (KBr, cmꢁ1): 3426, 3106, 2958, 2207,
1697, 1643, 1336, 1287; 1H NMR (DMSO-d6, 200 MHz) d 10.76 (s, 1H), 7.37 (dd,
J = 2, 10 Hz, 2H), 7.30 (dd, J = 2, 6 Hz, 2H), 7.23 (dd, J = 2, 6, 10 Hz, 2H), 3.95 (s,
3H), 3.89 (dd, J = 6, 8 Hz, 1H), 2.94 (dd, J = 6, 12 Hz, 1H), 2.56 (dd, J = 6, 16 Hz,
1H); 13C NMR (DMSO-d6, 50 MHz) d 169.8, 160.7, 141.2, 128.9, 127.4, 126.8,
118.4, 68.0, 58.9, 38.4, 36.7; MS m/z (% rel.) 228 (M+Å 100), 185 (60), 151 (40),
103 (20), 77 (24), 51 (20). 2-Methoxy-4-p-methoxy-phenyl-6-oxo-1,4,5,6-
tetrahydro-pyridine-3-carbonitriles (4b): orange solid, mp 173–175 °C (lit.8
174–176 °C); IR (KBr, cmꢁ1) 3443, 3095, 2959, 2197, 1691, 1691, 1626, 1363,
1294; 1H NMR (DMSO-d6, 200 MHz) d 7.13 (d, J = 8 Hz, 2H), 6.89 (d, J = 8 Hz,
2H), 3.93 (s, 3H), 3.80 (t, J = 6, 8 Hz, 1H), 3.71 (s, 3H), 2.87 (dd, J = 6, 16 Hz, 1H),
2.49 (dd, J = 6, 16 Hz, 1H); 13C NMR (DMSO-d6, 50 MHz) d 169.9, 160.5, 158.5,
132.9, 127.9, 118.5, 114.2, 68.4, 58.8, 55.1, 38.6, 36.0; MS m/z (% rel.) 258 (M+Å
100), 243 (27), 227 (40), 215 (73), 77 (7). 2-Methoxy-4-p-nitro-phenyl-6-oxo-
1,4,5,6-tetrahydro-pyridine-3-carbonitriles (4c): orange solid, mp 213–215
(lit.8 215); IR (KBr, cmꢁ1) 3428, 3093, 2950, 2193, 1696, 1627, 1554, 1297; 1H
NMR (DMSO-d6, 200 MHz) d 10.91 (s, 1H), 8.25 (d, J = 8 Hz, 2H), 7.56 (d,
J = 8 Hz, 2H), 4.15 (t, J = 6, 14 Hz, 1H), 3.00 (dd, J = 6, 16 Hz, 1H), 2.60 (dd,
J = 6 Hz, 1H); 13C NMR (DMSO-d6, 50 MHz) d 169.4, 161.2, 148.9, 146.9, 128.4,
124.4, 123.4, 118.1, 66.7, 58.9, 37.8, 36.5; MS m/z (% rel.) 273(M+Å 100), 256
(25), 232 (50), 151 (30), 63 (10). General procedure for pyrazolo[3,4-b]pyridin-
1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ne (6j): yellow oil; IR (KBr, cmꢁ1
)
3425, 2956, 2933, 2834, 1675, 1608, 1511, 1461, 1351; 1H NMR (DMSO-d6,
200 MHz) d 9.3 (s, 1H), 7.44 (d, J = 10 Hz, 2H), 7.23 (d, J = 8 Hz, 2H), 6.98 (d,

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C. E. Rodrigues-Santos, A. Echevarria / Tetrahedron Letters 52 (2011) 336–340
J = 10 Hz, 2H), 6.88 (d, J = 10 Hz, 2H), 4.48 (s, 1H), 4.19 (dd, J = 8 Hz, 1H), 3.82 (s,
NMR (DMSO-d6, 50 MHz) d 168.8, 158.8, 144.6, 144.6, 131.6, 129.5, 128.9,
128.6, 122.0, 114.2, 113.2, 55.1, 37.8, 37.0; Calcd’ for C19H17ClN4O2: C, 61.87; H,
4.65; N, 15.19. Found: C, 61.93; H, 4.61; N, 15.23. Amino-1-p-fluoro-phenyl-4-
p-methoxy-phenyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one (6l): pink
solid; mp 222–224 °C; IR (KBr, cmꢁ1) 3342, 2971, 2919, 2840, 1689, 1614,
1506, 1467, 1344; 1H NMR (DMSO-d6, 200 MHz) d 9.08 (s, 1H), 7.33 (d, J = 8 Hz,
2H), 7.07 (d, J = 8 Hz, 2H), 6.98 (d, J = 6 Hz, 2H), 6.93 (d, J = 8 Hz, 2H), 4.59 (s,
1H), 3.51 (dd, J = 6 Hz, 1H), 2.85 (dd, J = 4 and 18 Hz, 1H), 2.58 (dd, J = 2 Hz, 1H);
13C NMR (DMSO-d6, 50 MHz) d 168.8, 158.8, 153.5, 142.4, 131.6, 128.6, 117.1,
115.8, 115.4, 114.2, 112.8, 112.7, 55.1, 37.8, 37.3; Calcd’ for C19H17FN4O2: C,
64.76; H, 4.86; N, 15.90. Found: C, 64.71; H, 4.82; N, 15.94.
3H), 3.77 (s, 3H), 2.85 (dd, J = 8 Hz, 1H), 2.61 (dd, J = 10 and 12 Hz, 1H); 13C
NMR (DMSO-d6, 50 MHz) d 170.6, 159.8, 159.2, 145.1, 140.8, 135.6, 129.4,
129.1, 125.9, 124.5, 115.4, 115.2, 114.9, 56.0, 55.8, 42.3, 35.8; Calcd’ for
C20H20N4O3: C, 65.92; H, 5.53; N, 15.38. Found: C, 65.88; H, 5.49; N, 15.42.
Amino-1-p-chloro-phenyl-4-p-methoxy-phenyl-1,4,5,7-
tetrahydropyrazolo[3,4-b]pyridin-6-one (6k): pink solid; mp 226–228 °C; IR
(KBr, cmꢁ1) 3349, 2996, 2931, 2875, 2836, 1681, 1630, 1517, 1463, 1349; 1H
NMR (DMSO-d6, 200 MHz) d 8.59 (s, 1H), 7.40 (d, J = 8 Hz, 2H), 7.22 (d, J = 8 Hz,
2H), 7.09 (d, J = 8 Hz, 2H), 6.97 (d, J = 8 Hz, 2H), 4.44 (s, 1H), 3.80 (s, 3H), 3.63
(m, J = 6 Hz, 1H), 3.01 (dd, J = 6 and 14 Hz, 1H), 2.93 (dd, J = 16 Hz, 1H); 13C