Two-step synthesis of substituted 3-aminoindazoles from 2-bromobenzonitriles

Article abstract of DOI:10.1021/jo100243c

A general two-step synthesis of substituted 3-aminoindazoles from 2-bromobenzonitriles involving a palladium-catalyzed arylation of benzophenone hydrazone followed by an acidic deprotection/cyclization sequence is described. This procedure offers a general and efficient alternative to the typical S _NAr reaction of hydrazine with o-fluorobenzonitriles.

Full text of DOI:10.1021/jo100243c

pubs.acs.org/joc
HIV protease inhibitors,3 factor XIa inhibitors4 and CB1
Two-Step Synthesis of Substituted 3-Aminoindazoles
from 2-Bromobenzonitriles
receptor inhibitors.5 Moreover, the 3-aminoindazoles have
been shown to be able to mimic the adenine nucleus of ATP
for the design of ATP-competitive receptor tyrosine kinase
inhibitors with potent antitumor activities.1d
Valerie Lefebvre, Thomas Cailly, Frederic Fabis,* and
Sylvain Rault
Due to their potential as valuable templates for medicinal
chemistry, considerable effort has recently been devoted to
the synthesis of substituted indazoles.6 In this context, the
synthesis of 3-aminoindazoles has attracted much attention.
Their synthesis typically involved an aromatic nucleophilic
substitution between hydrazine and o-substituted benzoni-
triles. The leaving group used for the reaction to succeed is
mainly fluorine1,7 but also more rarely chlorine8 or a nitro
group.9 3-Aminoindazoles substituted on the amino group
were prepared as well by reaction of hydrazine with N-
substituted fluoroarylthioamides.10 The main drawback of
these methods is the low yields and harsh conditions when o-
fluorobenzonitriles are deactivated by an electron-donating
group. Some alternative methods have been described such
as the Buchwald-Hartwig amination of 3-haloindazoles2,5
or the Pd-catalyzed intramolecular cyclization of tosylhy-
drazines;11 however, these latter methods need the prepara-
tion of the required starting material in several steps.
ꢀ
Centre d’Etudes et de Recherche sur le Medicament de
Normandie, UPRES EA 4258, INC3M FR-CNRS 3038,
ꢀ
UFR des Sciences Pharmaceutiques, Universite de Caen
Basse-Normandie, boulevard Becquerel 14032 Caen Cedex,
France
frederic.fabis@unicaen.fr
Received February 10, 2010
Transition-metal-catalyzed C-N bond formation has be-
come in the past decades one of the most valuable tools for
the synthesis of arylamines.12,13 Arylation of hydrazine
derivatives can be performed as well using either copper14
A general two-step synthesis of substituted 3-aminoinda-
zoles from 2-bromobenzonitriles involving a palladium-
catalyzed arylation of benzophenone hydrazone followed
by anacidicdeprotection/cyclization sequenceisdescribed.
This procedure offers a general and efficient alternative to
the typical SNAr reaction of hydrazine with o-fluoroben-
zonitriles.
(5) Santhakumar, V.; Tomaszewski, M. WO 2006/052190, May 18, 2006.
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Published on Web 03/17/2010
DOI: 10.1021/jo100243c
r
2010 American Chemical Society

Lefebvre et al.
JOCNote
SCHEME 1. Two-Step Procedure for the Synthesis of Substi-
tuted 3-Aminoindazoles
TABLE 1. Arylation of Benzophenone Hydrazone with Substituted
2-Bromobenzonitriles
yielda (%)
or palladium15 catalysts. This methodology has permitted a
more general access to diverse aryl- or heteroarylhydrazine
derivatives avoiding the use of conventional methods such as
reduction of diazonium salts or SNAr reactions using hy-
drazine derivatives. Interestingly, the N-arylation of benzo-
phenone hydrazone and subsequent deprotection of the
arylhydrazone intermediate in the presence of enolizable
ketones or β-dicarbonyl derivatives, afforded respectively
substituted indoles15a,c and N-arylpyrazoles.16 The intramo-
lecular N-arylation of hydrazones has recently been de-
scribed as well for the synthesis of 3-arylindazoles.17
entry
R
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
99
80
86
84
92
86
87
91
87
3-Me
4-Me
5-Me
5-MeO
5-NO2
4-F
5-F
6-F
aIsolated yield.
results due to the equilibrated nature of the reaction and the
formation of aniline byproduct.15a,b We thought that the
presence of the carbonitrile group ortho to the hydrazone
would assist the deprotection by the irreversible formation of
the aminoindazole nucleus. Thus, by refluxing the arylhydra-
We thought that a two-step sequence involving the N-
arylation of benzophenone hydrazone with o-halobenzo-
nitriles followed by the deprotection of the hydrazone inter-
mediate would afford 3-aminoindazoles, thus circumventing
the limitations of the SNAr reaction (Scheme 1).
zones 2a-i with 2 equiv of p-TsOH H2O in methanol, we were
For the arylation of benzophenone hydrazone with 2-
bromobenzonitrile 1a, we tested different palladium cata-
lysts and ligands usually used in this reaction and found that
the combination of Pd(OAc)2 (5 mol %) and BINAP (5.5
mol %) in toluene at 100 °C with cesium carbonate as base
gave the arylhydrazone 2a in 99% yield (Table 1). It should
be noted that the use of cesium carbonate in place of NaO-t-
Bu conventionally used in this reaction avoids the Wolff-
Kischner-type reduction of benzophenone hydrazone.15c
We then applied these conditions to diversely substituted
2-bromobenzonitriles 1b-i. All the corresponding arylhy-
drazones 2b-i were obtained in 80-99% yield (Table 1). The
main advantage of this methodology over the SNAr reaction
with hydrazine is the possibility to use benzonitriles substi-
tuted with either strong electron-donating or strong electron-
withdrawing groups (2e and 2f). Moreover, fluorobromo-
benzonitriles 1g-i led to fluoroarylhydrazones 2g-i without
nucleophilic displacement of the fluorine atom.
3
pleased to isolate the corresponding 3-aminoindazoles 3a-i in
73-90% yields (Table 2).18 As in the arylation step, the nature
of the substituent did not influence the cyclization step.
Due to the nucleophilic nature of the N-1 and 3-amino
group, the N-alkylation of 3-aminoindazoles with alkyl
halides results in the competitive formation of the N-1-alkyl-
and 3-alkylamino derivatives.19 Therefore, the synthesis of
selectively N-1-alkylated 3-aminoindazoles generally re-
quires the protection of the 3-amino group before the
alkylation of the indazole nitrogen atom.1c,8 Moreover, the
direct access to N-1 substituted 3-aminoindazoles by the
SNAr reaction is limited by the low availability of N-sub-
stituted hydrazines and by the possible competitive nucleo-
philic displacement of the leaving group by the two nitrogen
atoms. The N-alkylation of the hydrazone intermediate
followed by the deprotection/cyclization step would pro-
vide selectively N-1-substituted-3-aminoindazoles. As an
example, hydrazone 2a was easily benzylated, and after a
typical extraction workup, the crude mixture was directly
engaged in the deprotection step affording free 3-amino-1-
benzylindazole 4 in 80% overall yield (Scheme 2).
The deprotection of stable benzophenone hydrazones
generally requires heating with strong acids such as concen-
trated HCl in ethyl alcohol. The formation of insoluble
hydrazine hydrochloride derivatives allows the reaction to
go to completion.15f Using p-toluenesulfonic acid monohy-
In summary, we have developed a new general route to
substituted 3-aminoindazoles in two steps from substituted
2-bromobenzonitriles using a simple and scalable procedure.
Moreover, the N-alkylation of the hydrazone intermedi-
ates allows the selective formation of N-1-substituted-3-
aminoindazoles, thus avoiding a protection-deprotection
sequence needed for the selective alkylation of 3-amino-
indazoles.
drate (p-TsOH H2O) in place of HCl gives only modest
3
(15) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 6621. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2090.
(c) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
10251. (d) Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett. 1999, 40,
3543. (e) Aeterburn, J. B.; Rao, K. V.; Ramdas, R.; Dible, B. R. Org. Lett.
2001, 3, 1351. (f) Mauger, C. C.; Mignani, G. A. Org. Proc. Res. Dev. 2004, 8,
1065. (g) Lim, Y. K.; Jung, J. W.; Lee, H.; Cho, C. G. J. Org. Chem. 2004, 69,
5778. (h) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2005, 44, 1371. (i) Kang, H. M.; Lim, Y. K.; Shin, I. J.; Kim, H. Y.;
Cho, C. G. Org. lett. 2006, 8, 2047. (j) Liu, X.; Barry, M.; Tsou, H. R.
Tetrahedron Lett. 2007, 48, 8409. (k) Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
Sgalla, S. Adv. Synth. Catal. 2007, 349, 453.
Experimental Section
General Procedure for the Synthesis of Hydrazones 2a-i.
A Schlenk tube was charged with benzophenone hydrazone
(16) (a) Haddad, N.; Baron, J. Tetrahedron Lett. 2002, 43, 2171.
(b) Haddad, N.; Salvagno, A.; Busacca, C. Tetrahedron Lett. 2004, 45, 5935.
(17) (a) Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.;
Sakamoto, T. Tetrahedron 2007, 63, 2695. (b) Inamoto, K.; Saito, T.;
Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931.
(18) The benzophenone released during the deprotection step was easily
removed by flash chromatography, see the Supporting Information.
(19) Kawakubo, H.; Fukuzaki, K.; Sone, T. Chem. Pharm. Bull. 1987, 35,
2292.
J. Org. Chem. Vol. 75, No. 8, 2010 2731

Lefebvre et al.
JOCNote
TABLE 2. Deprotection of Hydrazones and Subsequent Formation of
3-Aminoindazoles
SCHEME 2. Selective Formation of 3-Amino-1-benzylindazole
132.1, 131.6, 130.0, 129.9, 128.9, 128.5, 128.1, 127.0, 119.3,
116.5, 113.5, 94.7; MS-ESI [M þ H]þ 298; HRMS-EI m/z
[Mþ] calcd for C20H15N3 297.12659, found 297.12712.
entry
R
yielda (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
86
86
85
84
81
90
73
85
81
7-Me
6-Me
5-Me
5-MeO
5-NO2
6-F
General Procedure for the Synthesis of 3-Aminoindazoles
3a-i. Hydrazones 2a-i (1 equiv) and p-toluenesulfonic acid
monohydrate (2 equiv) were suspended in MeOH (2 mL/mmol
of hydrazone), and the reaction mixture was refluxed overnight.
The solution was diluted with a saturated solution of sodium
carbonate (5 mL/mmol of hydrazone) and extracted with ethyl
acetate (3ꢀ10 mL). The organic layer was then washed succes-
sively with brine (5 mL) and water (2 ꢀ 5 mL). After the layer
was dried with anhydrous sodium sulfate, the solvent was
removed under reduced pressure and the residue was purified
by flash chromatography on silica gel using cyclohexane/EtOAc
9:1 to remove the benzophenone and then EtOAc 100% to
afford the corresponding 3-aminoindazoles 3a-i.
3-Amino-1H-indazole (3a). According to general procedure:
194 mg (86%) obtained as an off-white solid from 2a (500 mg, 1.7
mmol); mp = 155-157 °C (lit.20 mp 154-155 °C); IR (KBr) ν
(cm-1) 3449 (NH), 3316 (NH2), 3192 (NH2); 1H NMR (DMSO-
d6, 400 MHz) δ 11.34 (s, 1H, NH), 7.66 (d, 1H, J = 7.8 Hz), 7.20
(m, 2H), 6.87 (m, 1H), 5.21 (s, 2H, NH2); 13C NMR (DMSO-d6,
100 MHz) δ 149.2, 141.4, 126.0, 120.2, 117.3, 114.0, 109.3; HRMS-
EI m/z [Mþ] calcd for C7H7N3 133.06399, found 133.06402.
5-F
4-F
aIsolated yield.
(1.1 equiv), palladium acetate (5 mol %), BINAP (5.5 mol %),
and toluene (1.5 mL per mmol of bromobenzonitrile), evac-
uated, and backfilled with argon. The mixture was heated at
100 °C for 3 min, and after it was cooled to room temperature,
bromobenzonitrile (1 equiv), cesium carbonate (1.4 equiv),
and toluene (0.5 mL per mmol of bromobenzonitrile) were
successively added. The Schlenk tube was then evacuated,
backfilled with argon, and heated at 100 °C for 7 h. After
cooling, the mixture was filtrated through a pad of Celite.
Celite was washed with methylene chloride, and the solvent
was removed under reduced pressure. The residue was purified
by flash chromatography on silica gel using cyclohexane/ethyl
acetate 9:1.
2-[2-(Diphenylmethylene)hydrazino]benzonitrile (2a). Accord-
ing to general procedure: 7.9 g (99%) obtained as pale yellow
crystals from 2-bromobenzonitrile 1a (5 g, 27 mmol); mp =
97-99 °C (EtOH); IR (KBr) ν (cm-1) 3323 (NH), 2213 (CN); 1H
NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H, NH), 7.73-6.83 (m,
14H); 13C NMR (CDCl3, 100 MHz) δ 148.2, 146.7, 137.5, 134.2,
Acknowledgment. Financial support (V.L.) came from the
ꢁ
Ministere de la Recherche et de l’Enseignement Superieur.
We thank Dr. Remi LEGAY for HRMS support.
ꢀ
ꢀ
Supporting Information Available: Detailed experimental
procedures and characterization data for the products included
in this paper. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Partridge, M. W. J. Chem. Soc 1964, 3663.
2732 J. Org. Chem. Vol. 75, No. 8, 2010