Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier-Haack conditions

Article abstract of DOI:10.1016/j.tetlet.2008.02.166

Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier-Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4

Full text of DOI:10.1016/j.tetlet.2008.02.166

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2689–2691
Regioselective formylation of pyrazolo[3,4-b]pyridine and
pyrazolo[1,5-a]pyrimidine systems using Vilsmeier–Haack conditions
a,
a
a
a
*
´
Jairo Quiroga , Jorge Trilleras , Braulio Insuasty , Rodrigo Abonıa ,
Manuel Nogueras b, Justo Cobo b
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 Jae´n, 23071 Jae´n, Spain
Received 18 January 2008; revised 19 February 2008; accepted 29 February 2008
Available online 4 March 2008
Abstract
Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via
Vilsmeier–Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4,7-dihyd-
ropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbalde-
hyde only, and no reaction took place at the pyrazolopyridine derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 5-Aminopyrazole; Formylation; Dihydropyrazolo[3,4-b]pyridines; Dihydropyrazolo[1,5-a]pyrimidines; Vilsmeier–Haack reaction
Heterocyclic compounds provide scaffolds on which
pharmacophores can arrange to yield potent and selective
drugs. Pyrazole compounds can provide privileged scaf-
folds for the generation of target compounds for drug dis-
covery.1 Hence, the synthesis and study of pyrazolo-fused
compounds have been of interest due to their wide variety
of biological and pharmacological properties.1a,d–f
The structural diversity and biological importance of
pyridines and pyrimidines have made them attractive
targets for synthesis over many years.2 The 4,5-dihydro-
pyrazolo[3,4-b]pyridine and 6,7-dihydropyrazolo[1,5-a]-
carboxaldehydes, due to their intrinsic pharmacological
properties and chemical reactivity.3 Formylation reactions
have been described for pyrido[2,3-d]pyrimidines as a key
step to the introduction of functionalities via the intermedi-
ate carboxaldehydes.2
We have already reported some procedures for the syn-
thesis of aromatic and dihydro pyrazolo[3,4-b]pyridines
and pyrazolo[1,5-a]pyrimidines by the reaction of 5-amino-
pyrazoles 1 and 2 with a,b-unsaturated ketones 3 (chalcones)
or their precursors, such as b-dimethyl-aminopropio-
phenones 4 (Mannich bases)4,5 (Scheme 1). We report here
a specific formylation on the pyridine and pyrimidine rings,
which render pyrazolopyridine- and pyrazolopyrimidine-
carbaldehydes, respectively, only when starting from their
dihydro-derivatives 5 and 7.
pyrimidine systems are
a
convenient models for
investigating the reactivity, chemical stability, and tauto-
merism of partially hydrogenated azoloazines. As a result,
these compounds have become interesting targets for
further modifications aimed at preparing new fused or
substituted derivatives. There is a growing interest in
formylation as an interesting strategy to form intermediate
Both 4,5-dihydro- and aromatic pyrazolo[3,4-b]-
pyridines were synthesized according to the reported proce-
dure. The dihydro-derivatives were prepared and then
readily oxidized to their aromatic form with N-bromo-
succinimide in ethanol.4a
*
To functionalize the pyridine residue by inserting a one-
carbon fragment, the formylation via Vilsmeier–Haack
Corresponding author. Fax: +57 2 33392440.
E-mail address: jaiquir@univalle.edu.co (J. Quiroga).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.166

2690
J. Quiroga et al. / Tetrahedron Letters 49 (2008) 2689–2691
H3C
R
H3C
N
NH2
N
Ph
O
R'
N
N
1
N
R
Ph
(4,5-dihydro)
Ar
NBS
5
6
3
R'
Ar
(aromatic)
or
N
O
NH2
N
H
N
N
2
N(CH3)2.HCl
4
N
R'
R'
R
NBS
(6,7-dihydro)
7
8
(aromatic)
Scheme 1.
Table 1
conditions was attempted, affording the expected formyl-
ation along with the aromatization of the pyridinic ring
to yield 9 (Scheme 2 and Table 1).6
Formylation of pyrazolo[3,4-b]pyridines systems
Compound 9
In the case of the aromatic pyrazolopyridines 6, the
formation of any formylated product was not observed
and the starting material was always recovered unchanged.
Both 6,7-dihydro- and aromatic pyrazolo[1,5-a]pyrimi-
dines (7 and 8, respectively), synthesized according to a
previously reported procedure,5a were subjected to the
same formylation conditions described above for pyrazolo-
pyridines 5 and 7. Thus, when we started from the 6,7-di-
hydro-derivatives 7, a double formylation at positions 3
and 6 at the pyrazolopyrimidine system occurred to yield
pyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehyde 10 (Scheme
3 and Table 2).7
On the other hand, the formylation of pyrazolopyr-
imidines 8 (obtained by the oxidation of dihydroderivative
75a) under Vilsmeier conditions (DMF–POCl3) took place
only at position 3 of the pyrazole ring, leading to the
formation of the pyrazolopyrimidine-3-carbaldehyde 11
(Scheme 3 and Table 2).8 Reaction of electrophilic substitu-
tion on this position of the pyrazole ring is widely refer-
enced in the literature.9
R
H
H
65
H
H
H
H
C6H5 C6H5 C6H5
R0
OCH3 Cl Br NO2
67
H
66
Br
65
NO2
68
Yield (%)
65 75 78
H
Ar
R
Ar
O
N
N
H
i
N
N
N
N
R
CHO
7
R'
R'
10
ii
Ar
Ar
CHO
N
N
N
i
N
N
N
R
R
R'
R'
8
11
i) POCl3/DMF; ii) NBS/Ethanol;
Scheme 3.
The structure of all new compounds was determined on
the basis of their analytical and spectral data, 1D and 2D-
NMR mainly, MS and elemental analysis, which are in
agreement with their proposed structures. Single crystal
X-ray diffraction analysis of compound 10 (R = C6H5,
R0 = CH3, Ar = p-CH3-C6H4) was used to corroborate
the postulated structures.10 Based on X-ray findings, the
short intramolecular hydrogen bond interaction between
the oxygen of formyl group at C-3 and N(4)–H provides
Table 2
Formylation of dihydropyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]-
pyrimidines systems
R
R0
Ar
Yield (%)
Comp. 10
Comp. 11
H
H
H
H
NO2
OCH3
Cl
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-H3CC6H4
4-H3CC6H4
4-O2NC6H4
4-ClC6H4
65
60
70
81
65
65
70
54
60
63
50
60
60
70
Cl
R
R
CHO
C6H5
C6H5
4-ClC6H4
CH3
CH3
OCH3
H3C
H3C
i
R'
R'
N
N
N
5
N
9
N
Ph
N
Ph
a higher stability to compound 10 with respect to the di-
hydro analog of 9, and so precludes the further oxidation
step to the aromatic derivative.
i) POCl3/DMF; R = H, C6H5,
Scheme 2.

J. Quiroga et al. / Tetrahedron Letters 49 (2008) 2689–2691
2691
was filtered, dried, and recrystallized from DMF. Data for 6-(4-
chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carb-
aldehyde 9 (R = H, R0 = Cl): White solid, mp 210–212 °C (65%) 1H
NMR (400 MHz, CDCl3) d: 2.72 (s, 3H), 7.26–7.53 (m, 5H), 7.63–8.30
(dd, 4H, J = 8.81 Hz), 8.76 (s, 1H), 10.10 (s, 1H). 13C NMR
(100 MHz, CDCl3) d: 12.6 (CH3), 116.6 (C-3a), 124.5 (C-5), 132.0
(C-4), 145.2 (C-7a), 151.0 (C-3), 160.8 (C-6), 190.5 (C@O). EI MS:
m/z: 349/347 (M+, 37/100), 321/319 (M+ꢀCO, 6/18), 318 (19), 304
(6), 77 (5). HR-MS (EI): C20H14ClN3O calcd 347.0825, found
347.0815. Anal. Calcd for C20H14ClN3O: C, 69.07; H, 4.06; N,
12.08. Found: C, 69.24; H, 4.39; N, 12.26.
In conclusion, the formylation on the pyridine or pyr-
imidine rings only takes place when there is a dihydro-
derivative on the appropriate pyrazolo-fused systems.
The use of the Vilsmeier–Haack conditions has per-
mitted us to develop a fast and efficient method for the
formation of pyrazolo[3,4-b]pyridine-5-carbaldehydes, di-
hydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, and
pyrazolo[1,5-a]pyrimidine-3-carbaldehydes. These novel
formylderivatives provide access to a great number of
structures for the introduction of functionalities via the
intermediate carbaldehydes.
7. Preparation of 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbalde-
hydes 10: To a suspension of 1.0 mmol of 7 in 2.0 mL of DMF was
added dropwise 200 lL (0.33 g, 2.1 mmol) of POCl3 while cooling
with an ice/water bath. The reaction mixture was stirred for 30 min at
rt, then the reaction mixture was heated to 80 °C for 3 h. After
cooling, 15 g of ice was added and the mixture was stirred vigorously.
The precipitate was filtered, dried, and recrystallized from DMF.
Data for 2,5-di-(4-methylphenyl)-7-phenyl-4,7-dihydropyrazolo[1,5-a]-
pyrimidine-3,6-dicarbaldehyde 10 (Ar = p-CH3C6H4, R = C6H5,
R0 = CH3): Yellow solid, mp 271–273 °C (65%). 1H NMR
(400 MHz, DMSO) d: 2.33 (s, 3H, CH3, 2-aryl), 2.42 (s, 3H, CH3,
5-aryl), 6.36 (s, 1H, H-7), 7.23 (d, 2H, Hm, 2-aryl J = 7.85 Hz), 7.27
(t, 1H, Hp, 7-aryl), 7.36 (d, 4H, 7-aryl), 7.43 (d, 2H, Hm, 5-aryl,
J = 7.85 Hz), 7.56 (d, 2H, Ho, 5-aryl, J = 8.07 Hz), 7.64 (d, 2H, Ho,
2-aryl, J = 8.07 Hz), 9.16 (s, 1H, C6-CHO), 9.95 (s, 1H, C3-CHO),
10.95 (s, 1H, NH). 13C NMR (100 MHz, DMSO) d: 20.8 (CH3, 2-
aryl), 21.0 (CH3, 5-aryl), 57.1 (C-7), 104.6 (C-3), 110.6 (C-6), 126.8
(Co, 7-aryl), 127.7 (Ci, 5-aryl), 128.1 (Cp, 7-aryl), 128.3 (Co, 2-aryl),
128.6 (Cm, 2-aryl), 128.8 (Cm, 5-aryl), 129.2 (Cm, 7-aryl), 130.2 (Co,
5-aryl), 138.5 (Cp, 2-aryl), 141.1 (Cp, 5-aryl), 141.2 (Ci, 7-aryl), 141.5
(C-3a), 151,6 (C-2), 152.6 (C-5), 183.3 (3-C@O), 186.8 (6-C@O). EI
MS: m/z: 433 (M+, 92), 418 (23, M+ꢀCH3), 405 (M+ꢀCO, 14), 356
(100), 91 (44), 65 (25). HR-MS (EI): C28H23N3O2 calcd 433.1790,
found 433.1781. Anal. Calcd for C28H23N3O2: C, 77.58; H, 5.35; N,
9.69. found: C, 77.46; H, 5.28; N, 9.89.
8. Preparation of pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 11: Carbal-
dehydes 11 were obtained from compounds 8 in the reaction under the
same conditions as described above for 9. Data for 2,7-bis(4-
chlorophenyl)-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carb-
aldehyde 11 (Ar = R = p-ClC6H4, R0 = OCH3): Yellow solid, mp
>300 °C (dec) (60%). 1H NMR (400 MHz, DMSO, 100 °C) d: 3.90 (s,
3H, OCH3), 7.14 (d, 2H, Hm, 5-aryl, J = 8.53 Hz), 7.54 (d, 2H, Hm,
7-aryl, J = 8.03 Hz), 7.69 (d, 2H, Hm, 2-aryl, J = 8.28 Hz), 7.99 (s,
1H, 6-CH), 8.15 (d, 2H, Ho, 2-aryl, J = 8.28 Hz), 8.27 (d, 2H, Ho, 7-
aryl, J = 8.53 Hz), 8.38 (d, 2H, Ho, 5-aryl, J = 8.28 Hz), 10.48 (s, 1H,
CHO). 13C NMR (100 MHz, DMSO, 373 K) d: 54.9 (OCH3), 106.2
(C-3), 106.9 (C-6), 113.9 (Cm, 5-aryl), 127.6 (Cm, 7-aryl), 127.8 (Ci, 5-
aryl), 127.9 (Cm, 2-aryl), 129.0 (Co, 5-aryl), 129.7 (Ci, 2-aryl), 130.1
(Co, 7-aryl), 131.0 (Co, 2-aryl) 134.1 (Cp, 7-aryl), 135.7 (Cp, 2-aryl),
145.1 (C-7), 152.2 (C-2), 158.3 (C-5), 161.8 (Ci, 5-aryl), 181.6 (CHO).
EI MS: m/z: 477/475/473 (M+, 5/26/35), 449/447/445 (M+ꢀCO, 13/
70/100), 336 (79), 220(19), 219 (74), 111 (29), 77(25), 75 (47). HR-MS
(EI): C26H17Cl2N3O2 calcd 473.0698, found 473.0694.
Acknowledgments
The authors are grateful to COLCIENCIAS, to Uni-
´
versidad del Valle, to the Spanish ‘Consejerıa de Innova-
´
´
cion, Ciencia y Empresa, Junta de Andalucıa’, and
´
´
‘Servicios Tecnicos de Investigacion’ of ‘Universidad de
´
Jaen’ for financial support.
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6. Preparation of pyrazolo[3,4-b]pyridine-5-carbaldehydes 9: To
a
suspension of 1.0 mmol of 5 in 2 mL of DMF was added dropwise
200 lL (0.33 g, 2.1 mmol) of POCl3 while cooling with an ice/water
bath. The reaction mixture was stirred for 30 min at rt, then the
reaction mixture was heated to 80 °C for 3 h. After cooling, 15 g of
ice was added and the mixture was stirred vigorously. The precipitate