Preparation of 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes by Vilsmeier-Haack reaction and its use in the synthesis of heterocyclic chalcones and dipyrazolopyridines

Article abstract of DOI:10.1016/j.tetlet.2010.03.117

Novel 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes 5 have been synthesized from the 4,5-dihydropyrazolo[3,4-b]pyridine-6-ones 4 via Vilsmeier-Haack reaction. Further treatment of carbaldehydes 5 with acetophenones 6 and hydrazine hydrate afforded chalc

Full text of DOI:10.1016/j.tetlet.2010.03.117

Tetrahedron Letters 51 (2010) 2928–2930
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Tetrahedron Letters
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Preparation of 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes by
Vilsmeier–Haack reaction and its use in the synthesis of heterocyclic
chalcones and dipyrazolopyridines
a
a
a
b,
b
Jairo Quiroga a, , Yurina Diaz , Braulio Insuasty , Rodrigo Abonıa , Manuel Nogueras , Justo Cobo
*
*
a Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360 Cali, Colombia
b Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes 5 have been synthesized from the 4,5-dihydro-
pyrazolo[3,4-b]pyridine-6-ones 4 via Vilsmeier–Haack reaction. Further treatment of carbaldehydes 5
with acetophenones 6 and hydrazine hydrate afforded chalcone analogues 7 and dipyrazolo[3,4-b:40,30-
e]pyridines 8, respectively.
Received 9 March 2010
Revised 25 March 2010
Accepted 29 March 2010
Available online 1 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Formylation
Vilsmeier–Haack reaction
Pyrazolo[3,4-b]pyridine
Chalcones
Dipyrazolo[3,4-b:40,30-e]pyridine
Pyrazolo[3,4-b]pyridine derivatives have been studied as antivi-
ral1 and potential antimalarial agents;2 and some exhibit parasiti-
cide properties3 and bactericidal activity;4 some others have been
used as vasodilators5 and evaluated for enzymatic inhibitory
activity.6
from 5-amino-3-methyl-1-phenylpyrazole 1, Meldrum’s acid 2,
and aromatic aldehydes 3a–f (Scheme 1).14
We describe here the preparation, 6-chloropyrazolo[3,4-b]pyri-
dine-5-carbaldehydes 5,15 which have been proved as interesting
precursors for new heterocyclic systems.
The use of formylation reaction as synthetic strategy to form
versatile carboxaldehyde intermediates is still of interest, due to
both their intrinsic pharmacological properties and chemical reac-
tivity.7 Formylation reactions have been described for pyrazoles,8
pyridines,9 and pyrimidines,10 as a key step to the introduction of
functionalities via the intermediate carboxaldehydes, and further
cyclization to fused heterocycles, such pyrido[2,3-d]pyrimidines,11
pyrazolo[3,4-b]pyridines,12 and pyrazolo[1,5-a]pyrimidines.12
Vilsmeier–Haack reaction carried out on methylene-active
compounds leads mainly to the formation of b-halo-carboxalde-
hyde derivatives, which are useful precursors in the construction
of different heterocyclic compounds by means of numerous
transformations.12,13
In this way, we have used as starting material the 4,5-dihydro-
pyrazolo[3,4-b]pyridin-6-ones 4 and employing classical Vilsme-
ier–Haack conditions, we were able to prepare the desired
6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes 5 in moderate
yields (Scheme 2).
These novel chloroformyl derivatives provide access to a great
number of structures for the introduction of functionalities via
the intermediate carbaldehydes. The Claisen–Schmidt condensa-
tion between heteroaromatic aldehydes and acetophenones is a
synthetic tool for the generation of C–C bonds permitting the
production of
a
,b-unsaturated ketones (chalcones).16
O
O
On the other hand, we have concentrated much of our recent
work on the preparation of bioactive nitrogen-containing hetero-
cycles, and have already described simple and efficient procedures
to prepare interesting molecules with biological properties as pyr-
azolo[3,4-b]pyridin-6-ones 4a–f in a three-component reaction
CH3
Ar
H3C
H3C
CH3
O
N
N
+
N
2
O
N
NH2
N
H
O
Ph
1
Ph
Ar
O
4a-f
* Corresponding authors. Fax: +57 2 33392440 (J.Q.); +34 618907111 (M.N.).
E-mail addresses: jaiquir@univalle.edu.co (J. Quiroga), mmontiel@ujaen.es (M.
Nogueras).
3a-f
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.117

J. Quiroga et al. / Tetrahedron Letters 51 (2010) 2928–2930
2929
Ar
Ar
Ar
4
Ar
H3C
N
H3C
3
H3C
N
H3C
N
5
CHO
Cl
CHO
Cl
DMF/POCl3
H2NNH2.H2O
N
N
2
N
N
N
7
N
N
N
1
N
N
H
4a-f
N
O
H
Ph
Ph
Ph
Ph
5a-f
8a-f
5a-f
Comp.
Ar
m.p. (oC)
Yield % m/z
Comp.
5a
Ar
m.p. (oC)
Yield %
55
m/z
8a
8b
8c
8d
8e
8f
C6H5
232-233
258-260
70
68
72
70
70
60
325
339
355
359
403
370
C6H5
165-167
173-175
159-161
153-154
189-190
217-219
347
361
477
381
425
392
4-CH3C6H4
5b
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
45
4-CH3OC6H4
4-ClC6H4
229-230
270-272
271-273
270-272
5c
45
5d
50
4-BrC6H4
5e
4-BrC6H4
50
4-O2NC6H4
5f
4-O2NC6H4
52
Scheme 4. Synthesis of dipyrazolopyridines.
Scheme 2. Chorine-formylation of pyrazolopyridinones.
In conclusion, we have described the preparation of novel
6-chloro-3-methyl-l-phenylpyrazolo[3,4-b]pyridine-5-carbaldehy-
des as versatile precursors for diverse pyrazolopyridine deriva-
tives. These new compounds present a privileged core from a
biological point of view. The chemical and biological interest of
the pyrazolopyridinecarbaldehydes and bis-pyrazolopyridines
mainly obtained in these experiments are under investigation.
The reaction of equimolar amounts of chloroaldehydes 5 with
acetophenones 6 in ethanol with 10 drops of NaOH (20%) was stir-
red for 48 h at room temperature yielding the novel chalcone ana-
logues 7a–l (Scheme 3).17
On the other hand, due to the highly electron-deficient nature of
the pyridine ring and the presence of the electron-withdrawing
formyl group, the nucleophilic substitution of the adjacent chlorine
atom can be favored; the nucleophilic heteroaromatic substitution
(SNAr) allows us to introduce the hydrazino group that further
cyclization leads to the formation of 1H,7H-dipyrazolo[3,4-b:40,30-
e]pyridines 8a–f. Accordingly, we carried out the reaction of equi-
molar amounts of aldehyde 5 with hydrazine hydrate in ethanol as
a solvent (Scheme 4).18 The synthesis of this kind of compounds
has previously been reported by heating at 220–260 °C,19a-d and
by microwave irradiation.19e,f Our approach allows to obtain
unsymmetrically substituted dipyrazolopyridines bearing a free
N–H bond which increases the possibility to introduce diversity
by further selective transformations.
Acknowledgements
The authors thank Universidad del Valle and COLCIENCIAS, the
Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía,
Spain), the Universidad de Jaén for financial support. The authors
also want to thank ‘Centro de Instrumentación Científico Técnica’
of Universidad de Jaén and the staff for data collection.
References and notes
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The structures of all new compounds were determined from
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Sci. 1989, 3, 90–94; Chem. Abstr. 1990, 112, 7420b.
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2005, 41, 492–495.
O
O
Ar
Ar
H3C
N
H3C
N
H3C
Ar'
CHO
Cl
6
Ar'
NaOH, 20%
N
N
N
N
Cl
Ph
Ph
5a-f
7a-f
8. (a) Quiroga, J.; Trilleras, J.; Cobo, J.; Glidewell, C. Acta Crystallogr., Sect. C 2010,
66, 47–49; (b) Trilleras, J.; Quiroga, J.; Cobo, J.; Low, J. N.; Glidewell, C. Acta
Crystallogr., Sect. E 2005, 61, 1055–1057.
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Martín, N.; Quintero, M.; Seoane, C.; Soto, J. L. J. Chem. Soc., Perkin Trans. 1 1996,
947–951.
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Torre, J. M. Arkivoc 2009, xiv, 9–27; (b) de la Torre, J. M.; Trilleras, J.; Cobo, J.;
Glidewell, C. Acta Crystallogr., Sect. C 2009, 65, 281–283.
11. Girreser, U.; Heber, D.; Schutt, M. Tetrahedron 2004, 60, 11511–11517.
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Tetrahedron Lett. 2008, 49, 2689–2691; (b) Low, J. N.; Cobo, J.; Trilleras, J.;
Glidewell, C. Acta Crystallogr., Sect. E 2006, 62, 4930–4932; (c) Trilleras, J.;
Quiroga, J.; Low, J. N.; Cobo, J.; Glidewell, C. Acta Crystallogr., Sect. C 2008, 64,
341–343.
13. (a) Brahma, S.; Ray, J. K. Tetrahedron 2008, 64, 2883–2896; (b) Paul, S.; Gupta,
M.; Gupta, R.; Loupy, A. Tetrahedron Lett. 2001, 42, 3827–3829; (c) Becher, J.;
Olesen, P. H.; Knudsen, N. A.; Toftlund, H. Sulfur Lett. 1986, 4, 175–183; (d) Zhu,
D.-G.; Gunawardana, I. W.; Boyd, S. A.; Melcher, L. M. J. Heterocycl. Chem. 2008,
45, 91–96; (e) Ivanov, I. C.; Glasnov, T. N.; Belaj, F. J. Heterocycl. Chem. 2008, 45,
177–180; (f) Choudhury, A.; Cheng, H.; Nilsen, C. N.; Sorgi, K. L. Tetrahedron
Lett. 2008, 49, 102–105; (g) Hegab, M. I.; Abdel-Fattah, A.-S. M.; Yousef, N. M.;
Nour, H. F.; Mostafa, A. M.; Ellithey, M. Arch. Pharm. 2007, 340, 396–403; (h)
Hegab, M. I.; Abdulla, M. M. Arch. Pharm. Chem. 2006, 339, 41–47; (i) Ortíz, A.;
Comp.
7a
7b
7c
Ar
Ar’
C6H6
m.p. (oC) Yield % m/z
C6H6
C6H6
C6H6
>300
>300 (d)
>300 (d)
250 (d)
300 (d)
>300
70
75
80
75
70
75
85
85
85
70
75
80
449
479
483
479
513
513
517
561
561
572
494
524
p-OCH3-Ph
p-Cl-Ph
C6H6
7d
7e
p-OCH3-Ph
p-OCH3-Ph
p-Cl-Ph
p-Cl-Ph
p-OCH3-Ph
p-Cl-Ph
p-Br-Ph
p-Cl-Ph
p-NO2-Ph
C6H6
7f
7g
7h
7i
p-Cl-Ph
280 (d)
>300
p-Cl-Ph
p-Br-Ph
>290 (d)
>300
7j
p-Br-Ph
7k
7l
p-NO2-Ph
p-NO2-Ph
>250 (d)
248 (d)
p-OCH3-Ph
Scheme 3. Synthesis of heterocyclic analogues of chalcones.

2930
J. Quiroga et al. / Tetrahedron Letters 51 (2010) 2928–2930
Insuasty, B.; Torres, M. R.; Herranz, M. A.; Martín, N.; Viruela, R.; Ortí, E. Eur. J.
Org. Chem. 2008, 99–108.
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35, 409–412; For a review on multi-component reactions with 1,3-dicarbonyl
compounds, see (b) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem.
2004, 4957–4980.
chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-(4-me-
thoxyphenyl)-2-propen-1-one 7f: Yellow solid, mp >300 °C (dec) (75%). 1H
NMR (400 MHz, CDCl3) d (ppm): 2.04 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 6.90 (d,
0 0
0
1H, H-9, J = 16 Hz), 6.91 (d, 2H, Hm , J = 8.6 Hz), 7.34 (m, 3H, Ho , Hp), 7.52 (d,
0
0 0
2H, Hm , J = 7.6 Hz), 7.57 (d, 2H, Hm NPh, J = 8.3 Hz), 7.63 (d, 2H, Ho , J = 8.6 Hz),
7.77 (d, 1H, H-8, J = 16 Hz), 8.22 (d, 2H, Ho NPh, J = 8.3 Hz). 13C NMR (100 MHz,
CDCl3) d (ppm): 14.5 (CH3), 55.4 (OCH3), 113.9 (Co –Cm ), 115.1 (C3a), 120.9
(Co), 122.5 (C5), 126.3 (Cp), 122.2 (Cm), 129.8 (C9), 120.46 (Cm ), 120.7 (Co ),
164.0 (Cp ), 135.4 (Ci ), 137.1 (C8), 138.7 (Ci), 143 (C6), 145.9 (C3), 148.1 (C4),
0
0
15. 4-Aryl-6-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehydes
5a–f. To a suspension of 4-aryl-4,5-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-
b]pyridin-6(7H)-one 4 (1 mmol) in DMF (2 mL) cooled into an ice/water bath,
POCl3 (0.2 mL, 2.1 mmol) was added dropwise, and afterwards the reaction
mixture was stirred for 30 min at ambient temperature, and finally heated at
100 °C for 5 h. After cooling down to ambient temperature, ice was added and
the mixture was neutralized with sodium bicarbonate with vigorous stirring.
The yellow precipitate was filtered, dried, and recrystallized from DMF. Data
for 6-chloro-4-(4-chlorophenyl)-3-methyl-l-phenylpyrazolo[3,4-b]pyridine-5-
carbaldehyde 5d: Yellow solid, mp 153–154 °C (50%). 1H NMR (400 MHz,
0
0
0
0
+
0
151.0 (C7a), 163.6 (Cp ), 187.8 (CHO). EI MS: m/z: 517/515/513 (M , 10), 480/
478 (35/100, M+ꢀCl), 77 (8). Anal. Calcd for C29H21Cl2N3O2: C, 67.71; H, 4.11; N,
8.17. Found: C, 67.60; H, 4.23; N, 8.09.
18. 4-Aryl-3methyl-1-phenyl-1H,7H-dipyrazolo[3,4-b:40,30-e]pyridines 8a–f. A solu-
tion of compound 5 (0.2 mmol) and an excess of hydrazine monohydrate
(0.5 mL) in ethanol (5 mL) was heated under reflux for 75 min, then allowed to
cool down to ambient temperature. The solid product was collected, washed
with ethanol, and recrystallized from ethanol. Data for 4-(4-chlorophenyl)-3-
methyl-l-phenyl-1H,7H-dipyrazolo[3,4-b:40,30-e]pyridine 8d: Yellow solid, mp
270–272 °C (70%). 1H NMR (400 MHz, CDCl3) d (ppm): 2.17 (CH3), 7.28 (t, 1H,
0
CDCl3) d (ppm): 2.00 (CH3), 7.27 (d, 2H, Ho J = 8.3 Hz), 7.36 (t, 1H, Hp J = 7.9 Hz,
0
NPh), 7.53 (m, 4H, Hm , Hm), 8.20 (d, 2H, Ho J = 7.9 Hz, NPh), 10.32 (s, 1H, CHO).
13C NMR (100 MHz, CDCl3) d (ppm): 14.4 (CH3), 115.4 (C3a), 121.2 (C5), 121.3
0
0
0
(Co NPh) 126.8 (Cp NPh), 128.7 (Cm NPh), 129.2 (Cm ), 128.6 (C7), 129.6 (Co ),
Hp NPh J = 7.5 Hz), 7.53 (t, 2H, Hm NPh J = 7.5 Hz), 7.56 (d, 2H, Ho J = 8.5 Hz),
0
0
0
132.2 (Cp ), 135.4 (Ci ), 138.2 (Ci NPh), 145.2 (C6), 148.8 (C3), 149.8 (C4), 152.1
(C7a), 188.9 (CHO). EI MS: m/z: 385/383/381 (M++4/M++2/M+, 12/69/100), 346
(14, M+ꢀCl), 241 (18), 77 (18). HR-MS (EI) calcd for C20H13Cl2N3O, 381.0436,
found 381.0449. Anal. Calcd for C20H13Cl2N3O: C, 62.84; H, 3.43; N, 10.99.
found: C, 63.00; H, 3.43; N, 10.91.
7.70 (d, 2H, Hm J = 8.5 Hz) 7.99 (s, 1H, H5), 8.26 (d, 2H, Ho NPh J = 7.6 Hz) 13.62
(s, 1H, NH). 13C NMR (100 MHz, CDCl3) d (ppm): 15.9 (CH3), 112.3 (C3a),
0
0
113.1(C4a), 120.5 (Co NPh), 125.6 (Cp NPh), 129.1 (Co ) 129.1 (Co ), 129.5 (Cm
0
0
0
NPh), 131.9 (Cm ), 133.2 (Ci ), 134.2 (C5), 134.8 (Cp ), 139.1 (C4), 139.6 (Ci), 143.9
(C3), 151.4 (C8a), 152.2(C7a). EI MS: m/z: 361/359 (M++2/M+, 36/100), 77 (7).
Anal. Calcd for C20H14ClN5: C, 65.13; H, 4.10; N, 18.99. Found: C, 65.08; H, 3.92;
N, 18.94.
16. (a) Trilleras, J.; Quiroga, J.; Cobo, J.; Low, J. N.; Glidewell, C. Acta Crystallogr.,
Sect. C 2005, 61, 414–416; (b) Trilleras, J.; Quiroga, J.; de la Torre, J. M.; Cobo, J.;
Low, J. N.; Glidewell, C. Acta Crystallogr., Sect. C 2006, 62, 518–520; (c) Trilleras,
J.; Quiroga, J.; Low, J. N.; Cobo, J.; Glidewell, C. Acta Crystallogr., Sect. C 2007, 63,
758–760.
19. (a) Gonzalez, E.; Sarlin, R.; Elguero, J. Tetrahedron 1978, 34, 1175–1178; (b)
Hennig, L.; Hofmann, J.; Astudillo, A.; Mann, G. J. Prakt. Chem. 1990, 332, 351–
358; (c) Abramov, M. A.; Ceulemans, E.; Jackers, C.; Van der Auweraer, M.;
Dehaen, W. Tetrahedron 2001, 57, 9123–9129; (d) Brack, A. Ann. Chem. 1965,
681, 105–110; (e) Esteves-Souza, A.; Echevarría, A.; Vecanto, I.; Jimeno, M. L.;
Elguero, J. Tetrahedron 2001, 57, 6147–6153; (f) Quiroga, J.; Portilla, J.; Insuasty,
B.; Abonía, R.; Nogueras, M.; Sortino, M.; Zacchino, S. J. Heterocycl. Chem. 2005,
42, 61–66.
17. 2(E)-3-[4-Aryl-6-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-
aryl-2-propen-1-ones 7a–l.
A solution of compound 5 (1 mmol) and the
corresponding acetophenones 6 (1 mmol) in ethanol with 10 drops of NaOH
(20%) was stirred for 48 h at rt. The solid product was collected, washed with
ethanol, and recrystallized from ethanol. Data for 2(E)-3-[6-chloro-4-(4-