Highly efficient synthesis of 5-benzyl-3-aminoindazoles

Article abstract of DOI:10.1016/j.tetlet.2009.04.024

A rapid and efficient procedure for the preparation of 5-benzyl-3-aminoindazoles 1 is reported. Key intermediates are fluoro-cyano diarylmethanes 2 which have been obtained by two different synthetic approaches. Benefits of these methods result from the u

Full text of DOI:10.1016/j.tetlet.2009.04.024

Tetrahedron Letters 50 (2009) 3098–3100
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Tetrahedron Letters
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Highly efficient synthesis of 5-benzyl-3-aminoindazoles
*
Paolo Orsini , Maria Menichincheri, Ermes Vanotti, Achille Panzeri
Nerviano Medical Sciences Srl, B.U. Oncology, Viale Pasteur 10, 20014, Nerviano (MI), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid and efficient procedure for the preparation of 5-benzyl-3-aminoindazoles 1 is reported. Key inter-
mediates are fluoro-cyano diarylmethanes 2 which have been obtained by two different synthetic
approaches. Benefits of these methods result from the use of commercially available starting materials
and practical experimental conditions that allow easy scale-up.
Received 16 March 2009
Revised 7 April 2009
Accepted 8 April 2009
Available online 12 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
3-Aminoindazoles
Diarylcarbinols
Diarylmethanes
Suzuki–Miyaura reaction
The indazole ring system represents the core skeleton of an
important class of heterocyclic compounds possessing a broad
range of biological activities.1 For this reason the development of
a wide array of synthetic approaches for their preparation has been
reported in the literature.2 In particular, 3-aminoindazole deriva-
tives have attracted great interest due to their activity against a
number of pharmacological targets, including kinases,3 central ner-
vous system,4 and inflammatory pathway.5
In the course of a drug discovery program, aimed at finding new
low molecular weight kinase inhibitors,6 we had to devise an effi-
cient synthesis of 5-benzyl-3-aminoindazoles 1 to be further elab-
orated at the amino moiety. We needed to prepare a series of such
compounds and were particularly interested in fluorinated 5-ben-
zyl derivatives. Methods for the preparation of 3-aminoindazoles
typically involve the reaction of a 2-haloaryl nitrile with hydra-
zine7 thus, according to our purpose, we required an efficient
and practical synthesis of unsymmetrical diarylmethanes 2, which
are important building blocks in organic synthesis.8
then allowed to react with 3-fluoro-4-cyanobenzaldehyde to pro-
vide diarylcarbinols 3 in excellent yields.11 Temperature control
seems to be a critical parameter, as keeping the reaction tempera-
ture between À5° and 0 °C prevents the oxidation to the correspond-
ing ketones.12 Initial attempts to reduce these diarylcarbinols to the
desired diarylmethanes 2 via reaction with triethylsilane under a
variety of conditions were unsuccessful. Remarkably, good results
were obtained by using iodotrimethylsilane, generated in situ from
chlorotrimethylsilane and sodium iodide in dry acetonitrile.13
Although substrates are electron-deficient benzylic alcohols, this
reagent provided high yields of deoxygenated products leaving a
reduction-sensitive functional group such as the nitrile unaf-
fected.14 Noteworthy, this reaction sequence has been successfully
To obtain the key intermediates 2, we pursued two possible alter-
native routes: (A) reduction of diarylcarbinols, in turn obtained by
addition of Grignard reagents to 3-cyano-4-fluorobenzaldehyde;
(B) palladium-catalyzed cross-coupling reaction of benzylbromides
with 3-cyano-4-fluorophenylboronic acid (Scheme 1). To possibly
extend the scope of this approach, a number of papers recently re-
ported the use of benzylic carbonates and phosphates in cross-cou-
pling reactions with aryl and heteroarylboronic acids.9
According to route A,10 bromoarenes 4 were treated with magne-
sium to generate the corresponding Grignard reagents that were
* Corresponding author. Tel.: +39 (0)331 581407; fax: +39 (0)331 581347.
E-mail address: paolo.orsini@nervianoms.com (P. Orsini).
Scheme 1. Retrosynthetic approaches to 5-benzyl-3-aminoindazoles.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.024

P. Orsini et al. / Tetrahedron Letters 50 (2009) 3098–3100
3099
Table 3
scaled up and applied to 50 g of starting material; no chromato-
graphic purifications are needed to obtain key intermediates 2a–b
(Table 1).
Preparation of 5-benzyl-3aminoindazoles 1a–f
Aiming at a shorter synthesis still amenable to be scaled up, we
then investigated the aforementioned route B, where the benzylic
carbon atom of the diarylmethane moiety could be directly ob-
tained in the right oxidation state, thus avoiding the reductive step.
The use of benzylic halides is not so common in the Suzuki–Miya-
ura cross-coupling, maybe because their use involves both the acti-
vation of a sp3-hybridized carbon atom, not so prone to the
oxidative insertion of a transition metal, and the slow reductive
elimination of the cross-coupled product from the catalyst. Not-
withstanding these drawbacks, Duchêne reports about the success-
Entry
X
R1
R2
1, Yield (%)
a
b
c
d
e
f
CH
CF
CH
CH
CH
N
H
F
F
F
F
H
H
F
CH3
H
77
92
88
88
76
85
ful regioselective cross-coupling of
a benzylic bromide with
H
H
respect to an arylic bromide, with aryl- and heteroaryl-boronic
acids.15,16 As 3-cyano-4-fluorophenylboronic acid is commercially
available,17 we synthesized compounds 2b–f using benzyl bro-
mides as electrophilic components of the Suzuki–Miyaura cross-
coupling reaction in the presence of 2% Pd(Ph3P)4 complex as a cat-
alyst and K3PO4 as a base. The reaction was carried out in fairly
good yields on a 10 mmol scale by refluxing in toluene for some
hours (1.5–8 h) (Table 2).18
According to a comparative analysis between the two reported
routes, method B results quite straightforward and allowed us to
avoid the synthesis and the use of a Grignard reagent, highly unde-
sirable in an industrial process. Furthermore, it fulfills the request
of a green chemistry process. As for the costs, the two methods
seemed to be comparable, but approach B is slightly better in
yields, as shown by the synthesis of compound 2b.
Having succeeded in developing a practical and efficient syn-
thesis of diarylmethanes 2a–f, these intermediates were treated
with 5 equiv of hydrazine hydrate in n-butanol to provide target
products 1a–f (Table 3).19 Interestingly, despite the presence of
several regiochemically different fluorine atoms on various sub-
strates (entries 2b–e), reaction conditions allow a good yield con-
version with a high degree of regioselectivity.
In conclusion we have presented simple and efficient synthetic
procedures of coupling reactions developed to obtain 5-benzyl-
substituted 3-aminoindazoles. Advantages of this method result
from the use of easily available starting materials and practical
experimental conditions. So obtained derivatives will be useful
for the preparation of functionalized structurally more elaborated
compounds.
Table 1
Preparation of diarylmethanes 2a–b
Acknowledgment
Authors would like to thank Dr. Ettore Perrone (Nerviano Med-
ical Sciences) for his fruitful discussions and suggestions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.024.
References and notes
Entry
R1
R2
3, Yield (%)
2, Yield (%)
1. Cerecetto, H.; Gerpe, A.; González, M.; Arán, V. J.; Ochoa de Ocáriz, C. Mini-Rev.
Med. Chem. 2005, 5, 869–878.
a
b
H
F
H
F
91
87
96
88
2. Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem. 2008, 24, 4073–4095.
3. (a) Stocks, M. J.; Barber, S.; Ford, R.; Leroux, F.; St-Galley, S.; Teague, S.; Xue, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 3459–3462; (b) Dai, Y.; Hartandi, K.; Ji, Z.;
Ahmed, A. A.; Albert, D. H.; Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G.
A.; Glaser, K. B.; Harris, C. M.; Hickman, D.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh,
K. C.; Moskey, M. D.; Martin, R. L.; Olson, A. M.; Osterling, D. J.; Pease, L. J.; Soni,
N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Reuter, D. R.; Michaelides, M. R.;
Davidsen, S. K. J. Med. Chem. 2007, 50, 1584–1597; (c) Lee, J.; Choi, H.; Kim, K.-
H.; Jeong, S.; Park, J.-W.; Baek, C.-S.; Lee, S.-H. Bioorg. Med. Chem. Lett. 2008, 18,
2292–2295.
Table 2
Preparation of diarylmethanes 2b–f
4. Vasudevan, A.; Souers, A. J.; Freeman, J. C.; Verzal, M. K.; Gao, J.; Mulhern, M.
M.; Wodka, D.; Lynch, J. K.; Engstrom, K. M.; Wagaw, S. H.; Brodjian, S.; Dayton,
B.; Falls, D. H.; Bush, E.; Brune, M.; Shapiro, R. D.; Marsh, K. C.; Hernandez, L. E.;
Collins, C. A.; Kym, P. R. Bioorg. Med. Chem. Lett. 2005, 15, 5293–5297.
5. Steffan, R. J.; Matelan, E.; Ashwell, M. A.; Moore, W. J.; Solvibile, W. R.;
Trybulski, E.; Chadwick, C. C.; Chippari, S.; Kenney, T.; Eckert, A.; Borges-
Marcucci, L.; Keith, J. C.; Xu, Z.; Mosyak, L.; Harnish, D. C. J. Med. Chem. 2004, 47,
6435–6438.
6. Lombardi Borgia, A.; Menichincheri, M.; Orsini, P.; Panzeri, A.; Perrone, E.;
Vanotti, E.; Nesi, M.; Marchionni, C. WO 2009/013126, 2009.
Entry
X
R1
R2
2, Yield (%)
b
c
d
e
f
CF
CH
CH
CH
N
F
F
F
F
H
H
F
CH3
H
H
85
66
75
90
57
7. (a) Antonysamy, S.; Hirst, G.; Park, F.; Sprengeler, P.; Stappenbech, F.;
Steensma, R.; Wilson, M.; Wong, M. Bioorg. Med. Chem. Lett. 2009, 19, 279–
282; (b) Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, H. D.; Bauch, L. J.;
Bouska, J. J.; Bousquet, F. P.; Cunha, A. G.; Glaser, B. K.; Harris, M. C.; Hickman,
D.; Guo, J.; Li, J.; Marcotte, A. P.; Marsh, C. K.; Moskey, D. M.; Martin, L. R.; Olson,
M. A.; Osterling, J. D.; Pease, J. L.; Soni, B. N.; Stewart, D. K.; Stoll, S. V.; Tapang,

3100
P. Orsini et al. / Tetrahedron Letters 50 (2009) 3098–3100
P.; Reuter, R. D.; Davidsen, K. S.; Michaelides, R. M. J. Med. Chem. 2007, 50,
13. General procedure for the preparation of diarylmethanes 2a–b: Diarylcarbinols
(1 equiv) and sodium iodide (10 equiv) were stirred in acetonitrile (4 mL/mmol
carbinol) under nitrogen at 60 °C in oil bath. To the reaction mixture TMSCl
(10 equiv) was gradually added over a period of 8 h. The mixture was diluted
with EtOAc and washed with water, saturated aqueous sodium bicarbonate,
10% aqueous sodium thiosulfate, and brine. Trituration with ethyl ether
afforded the title products in yields of 85–95%.
1584–1597; (c) Woods, W. K.; Fischer, P. J.; Claiborne, A.; Li, T.; Thomas, A. S.;
Zhu, G.-D.; Diebold, B. R.; Liu, X.; Shi, Y.; Klinghofer, V.; Han, K. E.; Guan, R.;
Magnone, R. S.; Johnson, F. E.; Bouska, J. J.; Olson, M. A.; de Jong, R.; Oltersdorf,
T.; Luo, Y.; Rosenberg, H. S.; Giranda, L. V.; Li, Q. Bioorg. Med. Chem. 2006, 14,
6832–6846; (d) Cui, J. J.; Araldi, G.-L.; Reiner, E. J.; Reddy, M. K.; Kemp, J. S.; Ho,
Z. J.; Siev, V. D.; Mamedova, L.; Gibson, S. T.; Gaudette, A. J.; Minami, K. N.;
Anderson, M. S.; Bradbury, E. A.; Nolan, G. T.; Semple, E. J. Bioorg. Med. Chem.
Lett. 2002, 12, 2925–2930.
14. Cain, G. A.; Holler, E. R. Chem. Commun. 2001, 1168–1169.
15. (a) Langle, S.; Abarbri, M.; Duchêne, A. Tetrahedron Lett. 2003, 44, 9255–9258;
(b) Nobre, S. M.; Monteiro, A. L. Tetrahedron Lett. 2004, 45, 8225–8228; (c)
Fairlamb, S. J. I.; Sehnal, P.; Taylor, J. K. R. Synthesis 2009, 3, 508–510; (d) Ines,
B.; Moreno, I.; SanMartin, R.; Dominguez, E. J. Org. Chem. 2008, 73, 8448–8451;
(e) Molander, A. G.; Elia, D. M. J. Org. Chem. 2006, 71, 9198–9202; (f) Chalen, L.;
Doucet, H.; Santelli, M. Synlett 2003, 1668–1672; (g) Chowdhury, S.;
Georghiou, E. P. Tetrahedron Lett. 1999, 40, 7599–7603.
8. (a) Nichele, T. Z.; Monteiro, A. L. Tetrahedron Lett. 2007, 48, 7472–7475; (b)
Yoshida, H.; Watanabe, M.; Morishita, T.; Ohshita, J.; Kunai, A. Chem. Commun.
2007, 1505–1507; (c) Chupak, L. S.; Wolkowski, J. P.; Chantigny, Y. A. J. Org.
Chem. 2009, 74, 1388–1390; (d) Sun, H.-B.; Li, B.; Chen, S.; Li, J.; Hua, R.
Tetrahedron 2007, 63, 10185–10188; (e) Dong, Z.; Manolikakes, G.; Li, J.;
Knochel, P. Synthesis 2009, 681–686.
9. (a) Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945–947; (b) McLaughlin, M. Org.
Lett. 2005, 7, 4875–4878; (c) Kuwano, R. Synthesis 2009, 7, 1049–1061.
10. Wai, J. S.; Egbertson, M. S.; Payne, L. S.; Fisher, T. E.; Embrey, M. W.; Tran, L. O.;
Melamed, J. Y.; Langford, H. M.; Guare, J. P.; Zhuang, L.; Gray, V. E.; Vacca, J. P.;
Holloway, M. K.; Naylor-Olsen, A. M.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.;
Stillmock, K. A.; Schleif, W. A.; Gabryelski, L. J.; Young, S. D. J. Med. Chem. 2000,
43, 4923–4926.
16. Monteiro15b showed that cross coupling reaction of benzyl halides is much less
sensitive to steric and electronic effects with respect to what observed for the
corresponding aryl halides; he found this order of reactivity with Pd(OAc)2 and
Ph3P: aryl iodide > benzyl bromide > benzyl chloride > aryl bromide.
17. From Small Molecules, Inc.
18. General procedure for the preparation of diarylmethanes 2b–f: 3-Cyano-4-
fluorophenylboronic acid (1 equiv), powdered K3PO4 (2 equiv), and Pd(PPh3)4
(2% mol) were charged in an oven-dried flask under argon atmosphere. The
flask was evacuated and back-filled with argon thrice. Toluene (3 mL/mmol
boronic acid) and benzyl bromide (1 equiv) were added under good stirring.
The reaction mixture was heated to 100 °C in half an hour and maintained at
that temperature for 1.5-8 h. The dark mixture was taken up with diethyl
ether, washed with saturated aqueous NH4Cl and brine. The organic phase was
dried over anhydrous Na2SO4 and evaporated to dryness. The residue was then
purified by flash chromatography (n-hexane/EtOAc) to provide the desired
diarylmethane in yields of 60–90%.
19. General procedure for the preparation of 3-aminoindazoles 1a–f: A mixture of 3-
cyano-4-fluoro-diarylmethane (1 equiv) and hydrazine hydrate (5 equiv) in n-
butanol (2.5 mL/mmol diarylmethane) was refluxed overnight. The reaction
mixture was diluted with water/EtOAc and the organic phase was washed
twice with brine, dried, and evaporated. The residue was purified by flash
chromatography (CH2Cl2/EtOH) to provide the desired 3-aminoindazole in
yields of 75–90%.
11. General procedure for the preparation of carbinols 3a–b: To
a stirred
suspension of Mg turnings (1.2 equiv) in dry THF under argon (0.1 mL/
mmol aldehyde), a solution of bromobenzene derivative (1.2 equiv) in dry
THF (1 mL/mmol aldehyde) was slowly added. The reaction mixture was
refluxed for 1 h. Thereafter, the reaction was cooled at À10 °C and
a
solution of aldehyde (1 equiv) in dry THF (1 mL/mmol aldehyde) was
added during 30 min. After 1 h, the reaction mixture was quenched by
adding dropwise 20% aqueous NH4Cl. EtOAc was added, the layers were
separated, and the aqueous phase was extracted twice with EtOAc.
Organic layers were collected, washed with brine, dried, and evaporated.
Trituration with i-propyl ether/n-hexane 1:1 afforded the title products in
yields of 85–90%.
12. Gemma, S.; Campiani, G.; Butini, S.; Kukreja, G.; Joshi, B. P.; Persico, M.;
Catalanotti, B.; Novellino, E.; Fattorusso, E.; Nacci, V.; Savini, L.; Taramelli, D.;
Basilico, N.; Morace, G.; Yardley, V.; Fattorusso, C. J. Med. Chem. 2007, 50,
595–598.