Synthesis and functionalisation of 1H-pyrazolo[3,4-b]pyridines involving copper and palladium-promoted coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2004.01.067

A convenient route to novel 3-iodo-1H-pyrazolo[3,4-b]pyridines via iododediazonation of 3-amino-1H-pyrazolo[3,4-b]pyridines, which are obtained by copper-catalysed cyclisation of 2-chloro-3-cyanopyridine with hydrazines. We describe also efficient couplin

Full text of DOI:10.1016/j.tetlet.2004.01.067

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2389–2392
Synthesis and functionalisation of 1H-pyrazolo[3,4-b]pyridines
involving copper and palladium-promoted coupling reactions
G. Lavecchia, S. Berteina-Raboin and G. Guillaumet*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universitꢀe d’Orlꢀeans, BP6759, 45067 Orleans Cedex 2, France
Received 8 December 2003; revised 16 January 2004; accepted 16 January 2004
Abstract—A convenient route to novel 3-iodo-1H-pyrazolo[3,4-b]pyridines via iododediazonation of 3-amino-1H-pyrazolo[3,4-
b]pyridines, which are obtained by copper-catalysed cyclisation of 2-chloro-3-cyanopyridine with hydrazines. We describe also
efficient coupling reactions from 3-iodo derivatives with various reagents according to Suzuki, Heck, Stille, and Sonogashira
conditions.
Ó 2004 Elsevier Ltd. All rights reserved.
NH2
Indoles and indazoles are known to be pharmacophoric
elements in numerous active compounds, natural or
not.1–6
CN
Cl
RNHNH2
N
Xylene or ethanol
10-15h reflux
K2CO3 or not
N
R
N
N
Interest in the synthesis of condensed pyrazoles has
recently revived because of the wide variety of their
biological properties.7–9
R=Ph 66% (30% effective)10
R=Me 30-46% 11
R=H yield not specified 11
Scheme 1. Previous synthesis of 3-aminopyrazolo[3,4-b]pyridines.
However, few publications are devoted to chemistry of
pyrazolo[3,4-b]pyridines10;11 as indole or indazole iso-
steres. We report here the synthesis of 3-aminopyraz-
olo[3,4-b]pyridines by copper-mediated cyclisation of
2-chloronicotinonitrile with hydrazines.
We present here a modified procedure using copper
catalyst based on Buchwald and co-workerÕs12 work.
They have reported efficient amination of aryl iodides
with acylhydrazides using copper(I) iodide/ortho-phe-
nanthroline as catalyst in DMF. However two regio-
isomers (A and B) may be obtained depending on the
substitution on the benzene ring (Scheme 2).
Aiming to extend pyrazolo[3,4-b]pyridine libraries, we
also describe a versatile pathway leading to 3-alkylated
pyrazolo[3,4-b]pyridines via palladium-catalysed cou-
pling reactions involving 3-iodopyrazolo[3,4-b]pyr-
idines, which are obtained by iododediazonation of
3-aminopyrazolo[3,4-b]pyridines.
We found that reaction of 2-chloro-3-cyanopyridine 1
with hydrazines using the above method gave only A
The unique way to prepare 3-aminopyrazolo[3,4-
b]pyridines10;11 starts with 2-chloronicotinonitrile and
hydrazines but requires harsh conditions and proceeds
in poor yield (66% yield with phenylhydrazine in xylene
according to Kuczynski,10 in our hands we have
obtained only 30%). Chemical variation in position 1is
also weakly representated because only three substitu-
ents were investigated (Scheme 1).
path. A
R
R
O
O
A
N
CuI / o-phen
R'
NH2
R
HN
NH2
R'
+
or
Cs2CO3
DMF
I
80°C
H
path. B
N
R'
N
H
Keywords: 1H-pyrazolo[3,4-b]pyridines.
* Corresponding author. Tel.: +33-023-841-7073; fax: +33-023-841-
7078; e-mail: gerald.guillaumet@univ-orleans.fr
B
O
Scheme 2. Copper-catalysed amination of aryl iodides.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.067

2390
G. Lavecchia et al. / Tetrahedron Letters 45 (2004) 2389–2392
isomer (Scheme 3). Structures were confirmed by com-
parison of the 1H NMR spectra with literature11 for
described compounds. Note that B isomer type is not
known, except for R ¼ Me, which was reported in a
Japanese patent13 application.
NH2
I
i) H2SO4 16N
NaNO2 0°C
N
N
N
N
ii) KI 4 éq. / H2O
N
N
R
R
2a R=Ph
2b R=Me
2c R=H
3a R=Ph 60%
3b R=Me 70%
3c R=H never observed
Reaction of 2-chloro-3-cyanopyridine 1 with excess
hydrazines, 5/10 mol % of CuI/o-phenanthroline and
cesium carbonate in DMF overnight afforded 1-sub-
stitued-3-amino-pyrazolo[3,4-b]pyridines in fair yields14
(Table 1).
Electrophilic
Substitution
i) CH3COOH/NaNO2
or
Me
N
N
H
N
N
NH2
i) HBF4/NaNO2
ii) 18 crown 6/AcOK
chloroforme
3'
2'
Strongly nucleophilic hydrazines such as aliphatic
derivatives gave higher yields and cleaner reactions than
aromatic ones. Particularly deactivated hydrazines such
as p-cyanophenylhydrazine and 2,4-dinitrophenylhydr-
azine have, respectively, shown no reaction or degra-
dation.
Scheme 4. Preparation of 3-iodo-pyrazolo[3,4-b]pyridines.
I
R'
(A),(B),(C),(D)
N
N
N
N
N
N
Treatment of 3-amino-pyrazolo[3,4-b]pyridines (2a,b)
with sodium nitrite15 in aqueous acidic conditions at 0 °C
lead to the diazonium salt (not isolated), which was
decomposed by potassium iodide to give 3-iodo-pyraz-
olo[3,4-b]pyridines16 (3a,b). If R ¼ H (3c) complete de-
gradation of the starting material occurred. To prepare
missing product 3c we applied RaultÕs method,17 used
in the benzopyrazole series, to our pyridinic system.
Unfortunately diazotization of 2-aminopicoline 20 failed
to give pyrazolo[3,4-b]pyridine 30. No trace of 30 was
isolated and 20 was recovered unchanged (Scheme 4).
R
R
4a,b-7a,b
3a,b
Scheme 5. Reagents and conditions: (A) (1-ethoxyvinyl)-tributyltin,
Pd(PPh3)4, toluene, reflux 2 h; (B) methyl acrylate, PdCl2(dppf)2,
n-Bu4NI, DMF/TEA/H2O, 50 °C, 2 h; (C) phenylacetylene, PdCl2
(PPh3)2, CuI, DMF/TEA, rt, overnight; (D) PhB(OH)2, Pd(PPh3)4,
Na2CO3, DME, 75 °C, 1h 30.
The transformations proceeded under quite mild con-
ditions and reaction times were often short. The experi-
ments lead to the expected compounds with excellent
yields (Table 2) even for ethoxyvinyl products (4a,b),
which are usually sensitive derivatives.
Compounds (4a–7a and 4b–7b) were prepared from 3-
iodopyrazolo[3,4-b]pyridines (3a,b) following Stille,18
Heck,19 Sonogashira20 or Suzuki21 conditions (Scheme 5).
NH2
Table 2. Coupling yields
A
R
R0
Path
Compound % Yield
N
N
N
Me
(A)
4a
80
R
path. A
EtO
2a R=Ph
CN
Cl
2b R=Me
2c R=H
2d R=Et
2e R=p-tolyl
2f R=p-methoxyphenyl
2g R=benzyl
H
CuI / o-phen
Cs2CO3
N
+
OMe
R
NH2
N
Me
Me
(B)
(C)
5a
6a
82
92
DMF
60°C 12h
1
O
path. B
NH2
B
N
R
N
N
Me
Ph
(D)
(A)
7a
4b
80
78
never observed
Scheme 3. Synthesis of pyrazolo[3,4-b]pyridines.
EtO
Table 1. Cyclisation yields
OMe
Ph
(B)
5b
86
Product
% Yield
O
2a
2b
2c
2d
2e
2f
R ¼ Ph
50
93
70
86
53
61
72
R ¼ Me
R ¼ H
Ph
Ph
(C)
(D)
6b
7b
78
73
R ¼ Et
R ¼ p-tolyl
R ¼ p-methoxyphenyl
R ¼ benzyl
2g

G. Lavecchia et al. / Tetrahedron Letters 45 (2004) 2389–2392
2391
NH2); 6.92 (dd, 1H, H5, J ¼ 4:4, 8.1Hz); 7.85 (dd, 1H, H ,
In conclusion, we have improved the formation of pyr-
azolo[3,4-b]pyridine ring from 2-chloro-3-cyanopyridine
and hydrazines using catalytic amounts of CuI/o-phe-
nanthroline. We have also obtained new 3-iodopyraz-
olo[3,4-b]pyridines, extending the possibilities in this
heterocycle chemistry. In this way, four classic types of
cross-coupling palladium-mediated reactions were
investigated successfully from the 3-iodo compounds.
4
J ¼ 1:5, 8.1Hz); 8.43 (dd, 1H, H , J ¼ 1:5, 4.4 Hz). 13C
6
NMR (CDCl3) dppm 32.9 (CH3); 106.6 (C3a), 114.2 (C5);
128.7 (C4), 145.5 (C3); 149.1 (C6); 150.8 (C7a). MS
m=z ¼ 148 (M+H)þ.
15. Wright, J. L.; Gregory, T. F.; Kesten, S. R.; Boxer, P. A.;
Serpa, K. A.; Meltzer, L. T.; Wise, D. L. J. Med. Chem.
2000, 43, 3408–3419.
16. General procedure for the preparation of 3-iodo-pyraz-
olo[3,4-b]pyridines (3a,b): 3-Amino-pyrazolo[3,4-b]pyri-
dine (3.4 mmol) in 10 mL of sulfuric acid 16 N were
cooled to 0 °C then 3.5 mmol of sodium nitrite in 3 mL of
water was added slowly at 0 °C. The medium was stirred
1 h at 0°C then 13.5 mmol of potassium iodide in 10 mL of
water was poured all at once. The mixture was heated to
room temperature for 1h then brought to pH ¼ 7/8 using
solid sodium carbonate and extracted with dichlorome-
thane. The organic phase was washed with a saturated
solution of sodium thiosulfate then dried over MgSO4 and
finally evaporated under reduced pressure. The crude
residue was purified on silica gel column chromatography.
Compound 3b: 3-Iodo-1-methyl-1H-pyrazolo[3,4-b]pyri-
dine: 1H NMR (CDCl3) dppm: 4.19 (s, 3H, CH3); 7.17
(dd, 1H, H5, J ¼ 4:4, 8.2 Hz); 7.81(dd, 1H, H 4, J ¼ 1:6,
8.2 Hz); 8.58 (dd, 1H, H6, J ¼ 1:6, 4.4 Hz). 13C NMR
(CDCl3) dppm 34.4 (CH3), 89.2 (C3); 117.4 (C5); 120.5
(C3a); 130.5 (C4); 150.0 (C6); 150.7 (C7a). MS m=z ¼ 260
(M+H)þ.
Acknowledgements
The authors gratefully acknowledge Laboratoires SER-
VIER (Courbevoie FRANCE) for financial support.
References and notes
1. Moore, P. K.; Wallace, P.; Gaffen, Z.; Hart, S. L.;
Babbedge, R. C. Br. J. Pharmacol. 1993, 110, 219–225.
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3217–3220.
17. Arnautu, A.; Collot, V.; Calvo Ros, J.; Alayrac, C.;
Witulski, B.; Rault, S. Tetrahedron Lett. 2002, 43, 2695–
2697.
3. Kharitonov, V. G.; Sharma, V. S.; Magde, D.; Koesling,
D. Biochemistry 1999, 38, 10699–10706.
4. Schumman, P.; Collot, V.; Hommet, Y.; Gsell, W.;
Dauphin, F.; Sopkova, J.; MacKenzie, E.; Duval, D.;
Boulouard, M.; Rault, S. Bioorg. Med. Chem. Lett. 2001,
11, 1153–1156.
5. Sanger, G. J.; Nelson, G. R. Eur. J. Pharmacol. 1989, 159,
113–124.
6. Villa, R.; Orlandi, L.; Berruti, A.; Dogliotti, L.; Zaffaroni,
N. Int. J. Oncol. 1999, 14, 133–138.
7. Elnagdi, M. H.; Al-Awadi, N.; Erian, A. W. In Compre-
hensive Heterocyclic Chem II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol.
4, p 431.
8. Desenko, S. M.; Komykhov, S. A.; Orlov, V. D.; Meier,
H. J. Heterocycl. Chem. 1998, 35, 989–990.
9. Quiroga, J.; Insuashy, B.; Craz, S.; Hernandez, P.;
Bolafios, A.; Moreno, R.; Homoza, A.; de Almedias, R.
H. J. Heterocycl. Chem. 1998, 35, 333–338.
10. Kuczynski, L.; Mrozikiewicz, A.; Banaszkiewicz, W.;
Poreba, K. Pol. J. Pharmacol. Pharm. 1997, 31, 217–225.
11. Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti, F. Can.
J. Chem. 1988, 66, 420–428.
18. See experimental section for Stille coupling: Aboul-Fadl,
€
T.; Lober, S.; Gmeiner, P. Synthesis 2000, 1727–1732.
Compound 4a: 3-(1-Ethoxyvinyl)-1-methyl-1H-pyraz-
olo[3,4-b]pyridine: 1H NMR (CDCl3) dppm: 1.47 (t, 3H,
CH2CH3, J ¼ 7:2 Hz); 4.01(q, 2H, OC H2, J ¼ 6:9 Hz);
4.13 (s, 3H, NCH3); 4.32 (d, 1H, C@CH, J ¼ 2:5 Hz); 5.01
(d, 1H, C@CH, J ¼ 2:5 Hz); 7.08 (dd, 1H, H5, J ¼ 4:4,
8.1Hz); 8.29 (dd, 1H, H , J ¼ 1:5, 8.1Hz); 8.48 (dd, 1H,
4
H6, J ¼ 1:5, 4.4 Hz). 13C NMR (CDCl3) dppm 14.6
(CH2CH3), 34.1(N CH3); 63.3 (OCH2); 83.4 (C@CH);
113.5 (C3a); 117.0 (C5); 131.5 (C4); 139.5 (C3); 148.8 (C6);
151.0 (C@CH); 155.1 (C7a). MS m=z ¼ 204 (M+H)þ.
19. See experimental section for Heck coupling: Collot, V.;
Varlet, D.; Rault, S. Tetrahedron Lett. 2000, 41, 4363–
4366.
Compound 5a: Methyl-3-(E)-(1-methyl-1H-pyrazolo[3,4-
b]pyridin-3-yl)-acrylate: 1H NMR (CDCl3) dppm: 3.83 (s,
3H, NCH3); 4.17 (s, 3H, OCH3); 6.71(d, H1 , N @C–
CH@C; J ¼ 16:0 Hz); 7.21(dd, 1H, H 5, J ¼ 4:4, 8.1Hz);
7.91(d, 1H, @CH–COO, J ¼ 16:0 Hz); 8.23 (dd, 1H, H4,
J ¼ 1:5, 8.1Hz); 8.57 (dd, 1H, H , J ¼ 1:5, 4.4 Hz). 13C
12. Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001,
3, 3803–3805.
13. Takayuki, I.; Nobutaka, F. Jpn. Kokai Tokkyo Koho JP
2003082251, 2003.
14. General procedure for the preparation of 3-amino-pyraz-
6
NMR (CDCl3) dppm 34.4 (NCH3); 51.9 (OCH3); 114.4
(C3a); 117.9 (C5); 119.5 (C@C–C@O); 129.8 (C@C–C@O);
135.9 (C4); 138.7 (C3); 149.2 (C6); 151.4 (C7a); 167.3
(C@O). MS m=z ¼ 218 (M+H)þ.
20. See experimental section of Ref. 17 for Sonogashira
coupling. Compound 6a: 1-Methyl-3-phenylethynyl-1H-
pyrazolo[3,4-b]pyridine: 1H NMR (CDCl3) dppm: 4.11 (s,
3H, NCH3); 7.11 (dd, 1H, H5, J ¼ 4:4, 8.2 Hz); 7.10–7.39
(m, 3H, Harom); 7.48–7.60 (m, 2H, Harom); 8.10 (dd, 1H,
H4, J ¼ 1:6, 8.2 Hz); 8.50 (dd, 1H, H6, J ¼ 1:6, 4.4 Hz).
13C NMR (CDCl3) dppm 34.4 (NCH3); 80.4 (CBCPh) 93.3
(CBCPh); 117.2 (C3a); 117.5 (C5); 122.5 (Carom); 127.2
(C3); 128.5 (Carom); 128.9 (Carom); 129.9 (Carom); 131.9 (C4);
149.4 (C6); 150.3 (C7a). MS m=z ¼ 234 (M+H)þ.
olo[3,4-b]pyridines (2a–c): 2-Chloronicotinonitrile
1
(1.4 mmol) was introduced into a 25 cm3 flask then
0.07 mmol (5 mol %) of copper(I) iodide, 2.1mmol of
caesium carbonate and finally 0.16 mmol (10 mol %) of
1,10-phenanthroline. DMF (5 mL) was poured followed
by 8.7 mmol of suitable hydrazine. The mixture was heated
to 60 °C overnight. Water (10 mL) was introduced after
cooling and the aqueous phase was extracted with
dichloromethane. The organic layer was dried over
MgSO4 and evaporated in vacuo. The crude residue was
purified on silica gel column chromatography. Compound
2b: 3-Amino-1-methyl-1H-pyrazolo[3,4-b]pyridine: 1H
NMR (CDCl3) dppm 3.91(s, 3H, C H3); 4.21(sl, 2H,
21. See experimental section for Suzuki coupling: Enguehard,
C.; Renou, J. L.; Allouchi, H.; Leger, J. M.; Gueiffier, A.
Chem. Pharm. Bull. 2000, 48, 935–940.

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G. Lavecchia et al. / Tetrahedron Letters 45 (2004) 2389–2392
Compound 7a: 1-Methyl-3-phenyl-1H-pyrazolo[3,4-b]pyri-
8.56 (dd, 1H, H6, J ¼ 1:2, 4.4 Hz). 13C NMR (CDCl3) dppm
34.1(N CH3); 113.6 (C3a); 117.0 (C5); 127.1 (Carom); 128.4
(Carom); 129.0 (Carom); 130.5 (C4); 133.3 (Carom); 142.6 (C3);
148.8 (C6); 151.5 (C7a). MS m=z ¼ 210 (M+H)þ.
dine: 1H NMR (CDCl3) dppm 4.21(s, 3H, NCH 3); 7.15 (dd,
1H, H5, J ¼ 4:7, 8.2 Hz); 7.38–7.53 (m, 3H, Harom); 7.87–
8.02 (m, 2H, Harom); 8.31(dd, 1H, H 4, J ¼ 1:2, 7.8 Hz);