Synthesis of 3,5-difunctionalized 1-methyl-1H-pyrazolo[3,4-b]pyridines involving palladium-mediated coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2004.07.022

Indirect iodination of 2-chloro-nicotinonitrile gave 2-chloro-5- iodonicotinonitrile, which was cyclized with methylhydrazine to lead to 3-amino-5-iodopyrazolo[3,4-b]pyridine. Position 3 was then protected by pivaloyl group and the resulting 5-iodo-3-pivaloylaminopyrazolo[3,4-b]pyridine was engaged in palladium-promoted coupling reactions with various reagents to give 3-pivaloylamino-5-substituted compounds. Deprotection and iododediazoniation followed by cross-coupling reactions in position 3 afforded novel unsymmetrical 3,5-disubstituted pyrazolo[3,4-b]pyridine species.

Full text of DOI:10.1016/j.tetlet.2004.07.022

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6633–6636
Synthesis of 3,5-difunctionalized 1-methyl-1H-pyrazolo
[3,4-b]pyridines involving palladium-mediated coupling reactions
G. Lavecchia, S. Berteina-Raboin and G. Guillaumet*
´
´
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite d ÕOrleans, BP 6759, 45067 Orleans Cedex 2, France
Received 31 March 2004; revised 6 July 2004; accepted 6 July 2004
Available online 23 July 2004
Abstract—Indirect iodination of 2-chloro-nicotinonitrile gave 2-chloro-5-iodonicotinonitrile, which was cyclized with methylhydr-
azine to lead to 3-amino-5-iodopyrazolo[3,4-b]pyridine. Position 3 was then protected by pivaloyl group and the resulting 5-iodo-3-
pivaloylaminopyrazolo[3,4-b]pyridine was engaged in palladium-promoted coupling reactions with various reagents to give 3-piva-
loylamino-5-substituted compounds. Deprotection and iododediazoniation followed by cross-coupling reactions in position 3
afforded novel unsymmetrical 3,5-disubstituted pyrazolo[3,4-b]pyridine species.
Ó 2004 Elsevier Ltd. All rights reserved.
Indoles and aza-indoles are known to be natural or
not1–8 pharmacophoric moieties represented in many
active compounds.
oxychloride to lead 2-chloro-5-iodonicotinonitrile 4 in
fair yield (Scheme 1).
Efficient cyclization of 2-chloronicotinonitrile with vari-
ous hydrazines using copper iodide and ortho-phenantro-
line as catalyst in the presence of cesium carbonate in
DMF was reported earlier.17 Reaction of 2-chloro-5-
iodo nicotinonitrile 4 in these conditions only resulted
in degradation. However, cyclization to 3-amino-5-iodo-
pyrazolo[3,4-b]pyridine 5 occurred in the absence of
catalyst. Direct iodination of known 3-amino-pyrazolo-
[3,4-b]pyridine11,17 50 only granted dimer 60 (Scheme 2).
This kind of aromatic dimerization or coupling has been
already described when reagent like PIFA was used.18
Fused pyrazoles show a wide variety of biological prop-
erties.9–11 However, few publications are devoted to
chemistry of pyrazolo[3,4-b]pyridines12,13 as indole or
indazole isosteres. Particularly, functionalization of pyr-
azolo[3,4-b]pyridines in position 5 was only recently
investigated.14,15
Aiming to extend pyrazolo[3,4-b]pyridine libraries, we
report here a pathway leading to 3,5-disubstituted-pyr-
azolo[3,4-b]pyridines via successive palladium-catalyzed
coupling reactions.
The key intermediate 2-chloro-5-iodonicotinonitrile 4
was prepared by indirect iodination of 2-chloronicotino-
nitrile 1. Indeed, the latter was completely unreactive
toward electrophilic substitution with an ÔI+Õ equivalent
such as N-iodosuccinimide.
CN
Cl
CN
OH
CH3COOH
Reflux
N
N
1
2
100%
2-Chloronicotinonitrile 1 was transformed by nonanhy-
drous acetic acid16 into 2-hydroxynicotinonitrile 2. The
latter was halogenated in position 5 by iodine and potas-
sium carbonate in DMF. Resulting 2-hydroxy-5-iodo-
"I+"
I2, K2CO3
DMF 60°C
I
CN
Cl
I
CN
OH
POCl3
Reflux
nicotinonitrile
3
was refluxed with phosphorus
N
N
Keywords: Pyrazolo[3,4-b]pyridines.
*
4
80%
3
50%
Corresponding author. Tel.: +33-023-841-7073; fax: +33-023-841-
7078; e-mail: gerald.guillaumet@univ-orleans.fr
Scheme 1. Preparation of 2-chloro-5-iodonicotinonitrile.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.022

6634
G. Lavecchia et al. / Tetrahedron Letters 45 (2004) 6633–6636
NH2
N
MeNHNH2
Cs2CO3
I
CN
Cl
I
DMF
60°C
N
N
N
Me
5
90%
4
NIS
DMF
Me
N
N
NH2
N
NH2
N
N
NIS / DMF
or other positive
halogen source
NH2
N
N
N
N
Me
Me
6' 100%
5'
Scheme 2. Synthesis of 1-methyl-3-amino-5-iodopyrazolo[3,4-b]pyridine.
Prior to cross-coupling pivaloylation19 of 5 was compul-
sory to ensure cleaner reaction and easier isolation step
(Scheme 3).
conditions at 0°C led to the corresponding diazonium
salt, which was decomposed by potassium iodide26 into
1-methyl-3-iodo-5-substituted pyrazolo[3,4-b]pyridines
9a and 9b (Scheme 5) in moderate to satisfying yields.
Compounds 7a–d were prepared from 5-iodo-3-piva-
loylaminopyrazolo[3,4-b]pyridine 6 following Suzuki,20
Sonogashira,21 Heck,22 or Stille23 conditions. Deprotec-
tion was performed in anhydrous methanol/hydrogen
chloride solution24 to give 1-methyl-3-amino-5-substi-
tuted pyrazolo[3,4-b]pyridines 8a–d (Scheme 4).
3,5-Difunctionalized compounds 10a,b were prepared
from 1-methyl-3-iodo-5-substituted pyrazolo[3,4-b]pyr-
idines 9a,b according to Sonogashira27 and Heck28
methods (Scheme 6).
Cross-coupling reactions afforded unsymmetrical prod-
ucts in fair yields as shown in Table 2.
The transformations proceeded under quite mild condi-
tions and reaction times were often short. The experi-
ments led to the expected compounds in good to
excellent yields (Table 1).
In conclusion, we synthesized various pyrazolo[3,4-b]pyr-
idines by the mean of easy and clean reactions. The first
step consisted in introduction of iodine in position 5 fol-
lowed by palladium-mediated cross-coupling reactions.
A further derivatization using iododediazoniation in
position 3 was performed also by palladium-mediated
Treatment of 3-amino-5-substituted pyrazolo[3,4-b]pyr-
idines 8a and 8b by sodium nitrite25 in aqueous acidic
NHPiv
N
NH2
N
Pivaloyl
chloride
I
I
Table 1. Cross-coupling reactions in position 5 and deprotection of
position 3
Et3N
Dioxane
N
N
N
N
R1
Path
Coupling yield
Deprotection yield
Me
Me
1-Naphthyl
Phenylethynyl
(E)-Styryl
Phenyl
A
B
7a 90%
7b 75%
7c 65%
7d 50%
8a 93%
8b 99%
8c 92%
8d 94%
6
86%
5
C
D
Scheme 3. Pivaloylation of 1-methyl-3-amino-5-iodopyrazolo[3,4-
b]pyridine.
NHPiv
NHPiv
NH2
I
R1
R1
(E)
(A),(B),(C),(D)
N
N
N
N
Me
N
N
N
N
N
Me
Me
7a R1=1-naphthyl
7b R1=phenylethynyl
7c R1=(E)-styryl
7d R1=phenyl
8a R1=1-naphthyl
8b R1=phenylethynyl
8c R1=(E)-styryl
8d R1=phenyl
6
Scheme 4. Conditions and reagents: (A) (naphth-1-yl)-boronic acid, Pd(PPh3)4, Na2CO3, DME, 75°C, 1h 30 min; (B) phenylacetylene,
PdCl2(PPh3)2, CuI, DMF/TEA, rt overnight; (C) styrene, PdCl2(dppf)2, n-Bu4NI, DMF/TEA/H2O, 50°C, 2h; (D) Sn(Ph)4, Pd(PPh3)4, toluene, reflux
2h; (E) MeOH/HCl anhyd reflux overnight.

G. Lavecchia et al. / Tetrahedron Letters 45 (2004) 6633–6636
6635
NH2
N
N
Me
I
i) NaNO2 0°C
H2SO4 50%
R1
R1
N
N
N
N
ii) KI / H2O
Me
9a R1=1-naphthyl
9b R1=phenylethynyl 60%
49%
8a R1=1-naphthyl
8b R1=phenylethynyl
Scheme 5. Preparation of 1-methyl-3-iodo-5-substituted pyrazolo[3,4-b]pyridines.
´
7. Mazeas, D.; Guillaumet, G.; Viaud, M.-C. Heterocycles
1999, 50, 1065–1080.
I
R2
R1
R1
(A),(B)
´
8. Merour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 4,
471–506.
9. Elnagdi, M. H.; Al-Awadi, N.; Erian, A. W. In Compre-
hensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; 4,
pp 431.
10. Desenko, S. M.; Komykhov, S. A.; Orlov, V. D.; Meier,
H. J. Heterocycl. Chem. 1998, 35, 989–990.
11. 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.
12. Kuczynski, L.; Mrozikiewicz, A.; Banaszkiewicz, W.;
Poreba, K. Pol. J. Pharmacol. Pharm. 1997, 31, 217–
225.
13. Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti, F. Can.
J. Chem. 1988, 66, 420–428.
N
N
N
Me
N
N
N
Me
R1=1-naphthyl
9a R1=1-naphthyl
9b R1=phenylethynyl
10a
10b
NMe2
{
{
R2=
R1=phenylethynyl
COOMe
R2=
Scheme 6. Conditions and reagents: (A) 3-dimethylamino-prop-1-yne,
PdCl2(PPh3)2, CuI, DMF/TEA, rt overnight; (B) methyl acrylate,
PdCl2(dppf)2, n-Bu4NI, DMF/TEA/H2O, 50°C, 2h.
14. Witherington, J.; Bordas, V.; Garland, S. L.; Hickey, D.
M. B.; Ife, R. J.; Liddle, J.; Saunders, M.; Smith, D. G.;
Ward, R. W. Bioorg. Med. Chem. Lett. 2003, 13,
1577–1580.
15. Haigh, D.; Hickey, D. M. B.; Liddle, J.; Smith, D. G.;
Witherington, J.; Ward, R. W. 2002, PCT Int. Appl.
WO02/24694 A1.
Table
b]pyridines
2. Synthesis
of
1-methyl-3,5-disubstitutedpyrazolo[3,4-
R1
R2
Path
A
Coupling yield
10a 63%
NMe2
1-Naphthyl
Phenylethynyl
COOMe
B
10b 77%
16. Srivastava, R. P.; Seth, M.; Bhaduri, A. P. Indian J. Chem.
1989, 28, 65–66.
17. Lavecchia, G.; Berteina-Raboin, S.; Guillaumet, G. Tet-
rahedron Lett. 2004, 45, 2389–2392.
cross-coupling reactions, affording new dissymmetrical
species 10a and 10b.
18. Faul, M. M.; Sullivan, K. A. Tetrahedron Lett. 2001, 42,
3271–3273; Anakabe, E.; Carrillo, L.; Badia, D.; Vicario,
J. L.; Villegas, M. Synthesis 2004, 7, 1093–1101.
19. Turner, J. A. J. Org. Chem. 1983, 48, 3401–3408.
20. 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, Compound 7a:
1-methyl-3-(2,2-dimethyl-propionamido)-5-(naphth-1-yl)-
Acknowledgements
The authors gratefully acknowledge Laboratoires SER-
VIER (Courbevoie, France) for financial support.
1
1H-pyrazolo[3,4-b]pyridine: H NMR (CDCl3): dppm 1.34
(s, 9H, CCH3); 4.12 (s, 3H, NCH3); 7.40–7.57 (m, 4H,
References and notes
H
H
arom); 7.77–7.80 (m, 1H, Harom); 7.91–7.94 (m, 2H,
arom); 8.20 (sl, 1H, NH); 8.64 (d, 1H, H4, J = 1.9Hz);
8.68 (d, 1H, H6, J = 1.9Hz); 13C NMR (CDCl3): dppm 29.0
(CCH3); 35.1 (NCH3); 40.7 (CCH3); 109.6 (C3a); 126.8;
127.0; 127.4; 127.8; 129.5; 129.6; 129.8; 130.6; 133.6; 135.2;
136.1 (C4); 138.2; 140.1; 150.1 (C7a); 152.6 (C6); 177.8
(C@O); MS: m/z = 359 (M + H)+; IR (cmꢀ1): 1685 (C@O).
21. See experimental section for Sonogashira coupling: Ar-
nautu, A.; Collot, V.; Calvo Ros, J.; Alayrac, C.; Witulski,
B.; Rault, S. Tetrahedron Lett. 2002, 43, 2695–2697,
Compound 7b: 1-methyl-3-(2,2-dimethyl-propionamido)-5-
phenylethynyl-1H-pyrazolo[3,4-b]pyridine: 1H NMR
(CDCl3): dppm 1.38 (s, 9H, CCH3); 4.02 (s, 3H, NCH3);
7.33–7.38 (m, 3H, Harom); 7.53–7.57 (m, 2H, Harom); 8.16
(sl, 1H, NH); 8.62 (d, 1H, H4, J = 1.8Hz); 8.78 (d, 1H, H6,
J = 1.8Hz); 13C NMR (CDCl3): dppm 28.0 (CCH3); 33.9
(NCH3); 39.7 (CCH3); 87.3 (C„CPh); 90.9 (C„CPh);
108.0 (C3a); 113.0 (C5); 123.4 (Carom); 128.7 (Carom); 128.8
1. Moore, P. K.; Wallace, P.; Gaffen, Z.; Hart, S. L.;
Babbedge, R. C. Br. J. Pharmacol. 1993, 110, 219–225.
2. Patel, M.; Rodgers, J. D.; McHugh, R. J.; Johnson, B. L.;
Cordova, B. C.; Klabe, R. M.; Bacheler, L. T.; Erickson-
Viitanen, S.; Ko, S. S. Bioorg. Med. Chem. Lett. 1999, 9,
3217–3220.
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.

6636
G. Lavecchia et al. / Tetrahedron Letters 45 (2004) 6633–6636
(Carom); 131.9 (Carom); 137.4 (C4); 139.1 (C3); 149.7 (C7a);
152.6 (C6); 176.7 (C@O); MS: m/z = 333 (M + H)+; IR
1h then brought to pH = 7/8 using solid sodium carbonate
and extracted with dichloromethane. The organic phase
was washed with a saturated solution of sodium thiosul-
fate then dried on MgSO4 and finally evaporated under
reduced pressure. The crude was purified on silica gel
column chromatography.
(cmꢀ1): 1665 (C@O).
22. See experimental section for Heck coupling: Collot, V.;
Varlet, D.; Rault, S. Tetrahedron Lett. 2000, 41,
4363–4366, Compound 7c: (E)-1-methyl-3-(2,2-dimethyl-
propionamido)-5-styryl-1H-pyrazolo[3,4-b]pyridine: 1H
NMR (CDCl3): dppm 1.39 (s, 9H, CCH3); 3.99 (s, 3H,
NCH3); 7.11 (d, 1H, C@CH, Jtrans = 16.6Hz); 7.17 (d, 1H,
CH@C, Jtrans = 16.6Hz); 7.24–7.37 (m, 3H, Harom); 7.48–
7.51 (m, 2H, Harom); 8.35 (sl, 1H, NH); 8.60 (d, 1H, H4,
J = 2.2Hz); 8.66 (d, 1H, H6, J = 2.2Hz); 13C NMR
(CDCl3): dppm 27.6 (CCH3); 33.5 (NCH3); 39.3 (CCH3);
108.4 (C3a); 125.6 (C5); 126.1 (C@C); 126.4 (Carom); 127.6
(Carom); 128.6 (C@C); 128.7 (Carom); 130.8 (C4); 137.1
(Carom); 138.7 (C3); 148.9 (C6); 150.1 (C7a); 176.5 (C@O);
MS: m/z = 335 (M + H)+; IR (cmꢀ1): 1683 (C@O).
23. See experimental section for Stille coupling: Aboul-Fadl,
T.; Lo¨ber, S.; Gmeiner, P. Synthesis 2000, 10, 1727–1732,
Compound 7d: 1-methyl-3-(2,2-dimethyl-propionamido)-5-
phenyl-1H-pyrazolo[3,4-b]pyridine: 1H NMR (CDCl3):
dppm 1.36 (s, 9H, CCH3); 4.06 (s, 3H, NCH3); 7.37–7.50
(m, 3H, Harom); 7.61–7.65 (m, 2H, Harom); 8.19 (sl, 1H,
NH); 8.74 (s, 2H, H4 and H6); 13C NMR (CDCl3): dppm
27.7 (CCH3); 33.7 (NCH3); 39.4 (CCH3); 108.4 (C3a);
127.8; 128.0; 129.3; 130.4; 132.5 (C4); 138.9; 139.1; 149.8
(C6); 150.6 (C7a); 176.5 (C@O); MS: m/z = 309 (M + H)+;
IR (cmꢀ1): 1669 (C@O).
24. Kawana, M.; Nishikawa, M.; Yamasaki, N.; Kuzuhara,
H. J. Chem. Soc., Perkin Trans. 1 1989, 9, 1593–1596.
25. 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.
26. General procedure for the preparation of 1-methyl-3-iodo-5-
substitued pyrazolo[3,4-b]pyridines 9a,b: 3.4mmol of 1-
methyl-3-aminopyrazolo[3,4-b]pyridine in 10mL of sulf-
uric acid 16N were cooled to 0°C then 3.5mmol of sodium
nitrite in 3mL of water were added slowly at 0°C. The
medium was stirred 1h at 0°C then 13.5mmol of
potassium iodide in 10mL of water were poured all at
once. The mixture was heated to room temperature during
Compound 9b: 1-methyl-3-iodo-5-phenylethynyl-1H-pyr-
1
azolo[3,4-b]pyridine: H NMR (CDCl3): dppm 4.16 (s, 3H,
CH3); 7.35–7.38 (m, 3H, Harom); 7.54–7.58 (m, 2H, Harom);
7.93 (d, 1H, H4, J = 1.8Hz); 8.68 (d, 1H, H6, J = 1.8Hz);
13C NMR (CDCl3): dppm 35.8 (CH3); 86.3 (C„CPh); 89.5
(C3); 91.6 (C„CPh); 114.2 (C5); 120.0 (C3a); 122.7 (Carom);
128.6 (Carom); 128.8 (Carom); 131.7 (Carom); 133.0 (C4);
150.0 (C7a); 150.7 (C6); MS: m/z = 360 (M + H)+.
27. See experimental section of Ref. 20 for Sonogashira
coupling. Compound 10a: 1-methyl-3-(1-dimethylamino-
prop-2-ynyl)-5-(naphth-1-yl)-1H-pyrazolo[3,4-b]pyridine:
1H NMR (CDCl3): dppm 2.39 (s, 6H, N(CH3)2); 3.58
(s, 2H, CH2N); 4.24 (s, 3H, NNCH3); 7.45–7.94 (m, 7H,
H
arom); 8.21 (d, 1H, H4, J = 1.9Hz); 8.69 (d, 1H, H6,
J = 1.9Hz); 13C NMR (CDCl3): dppm 34.5 (N(CH3)2);
44.3 (NNCH3); 48.7 (CH2N); 89.1 (C„CCH2);
98.0 (C„CCH2); 117.0 (C3a); 125.4; 125.5; 126.2; 126.7;
127.2; 128.6; 128.7; 130.4; 130.5; 132.1; 132.2; 133.9;
136.5 (C4); 149.7 (C7a); 151.1 (C6); MS: m/z = 341
(M + H)+.
28. See experimental section of Ref. 21 for Heck coupling.
Compound 10b: methyl(E)-3-(1-methyl-5-phenylethynyl-
1H-pyrazolo[3,4-b]pyridin-3-yl)-acrylate:
1H
NMR
(CDCl3): dppm 3.85 (s, 3H, NCH3); 4.18 (s, 3H, OCH3);
6.73 (d, 1H, CH@CHCOOMe, Jtrans = 16.3Hz); 7.37–7.40
(m, 3H, Harom); 7.56–7.60 (m, 2H, Harom); 7.90 (d, 1H,
CH@CHCOOMe, Jtrans = 16.3Hz); 8.39 (d, 1H, H4,
J = 1.8Hz); 8.70 (d, 1H, H6, J = 1,8Hz); 13C NMR
(CDCl3): dppm 34.6 (NCH3); 52.0 (OCH3); 86.4 (C„CPh);
91.9 (C„CPh); 113.8 (C3a or C5); 114.7 (C3a or C5); 120.0
(C@CCOOMe); 122.7 (Carom); 128.6 (Carom); 128.8
(Carom); 131.7 (C4 or Carom); 132.4 (C4 or Carom); 135.5
(C@CCOOMe); 139.0 (C3); 140.5 (C6); 150.1 (C7a); 151.2
(C6); 167.2 (C@O); MS: m/z = 318 (M + H)+; IR (cmꢀ1):
1708 (C@O).