Synthesis of 1-aryl-1H-indazoles via the palladium-catalyzed cyclization of N-aryl-N′-(o-bromobenzyl)hydrazines and [N-aryl-N′-(o-bromobenzyl)-hydrazinato-N′]-triphenylphosphonium bromides

Article abstract of DOI:10.1016/S0040-4039(01)00273-8

1-Aryl-1H-indazoles were synthesized by the palladium-catalyzed intramolecular amination [Pd(OAc)₂/dppf/tBuONa (150 mol%)/toluene/90°C] of the corresponding N-aryl-N′-(o-bromobenzyl)hydrazines. It was further demonstrated that cyclization of [N-aryl-N′-(o-bromobenzyl)-hydrazinato-N′]-triphenylphosphonium bromides under the conditions of [Pd(OAc)₂/dppf/tBuONa (250 mol%)/dioxane/90°C] also led to the formation of the corresponding 1-aryl-1H-indazoles. These methods were applied to a group of representative substrates to give indazole products in moderate to very good yields.

Full text of DOI:10.1016/S0040-4039(01)00273-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2937–2940
Synthesis of 1-aryl-1H-indazoles via the palladium-catalyzed
cyclization of N-aryl-N%-(o-bromobenzyl)hydrazines and
[N-aryl-N%-(o-bromobenzyl)-hydrazinato-N%]-
triphenylphosphonium bromides
Jinhua J. Song* and Nathan K. Yee
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, PO Box 368,
Ridgefield, CT 06877-0368, USA
Received 5 January 2001; accepted 13 February 2001
Abstract—1-Aryl-1H-indazoles were synthesized by the palladium-catalyzed intramolecular amination [Pd(OAc)2/dppf/tBuONa
(150 mol%)/toluene/90°C] of the corresponding N-aryl-N%-(o-bromobenzyl)hydrazines. It was further demonstrated that cycliza-
tion of [N-aryl-N%-(o-bromobenzyl)-hydrazinato-N%]-triphenylphosphonium bromides under the conditions of [Pd(OAc)2/dppf/
tBuONa (250 mol%)/dioxane/90°C] also led to the formation of the corresponding 1-aryl-1H-indazoles. These methods were
applied to a group of representative substrates to give indazole products in moderate to very good yields. © 2001 Elsevier Science
Ltd. All rights reserved.
The indazole subunit (Fig. 1) is a frequently found
motif in drug substances with important biological
activities such as anti-inflammatory,1 anti-tumor2 and
anti-HIV activities.3 Despite the importance of inda-
zoles in pharmaceutical development, the invention of
efficient and general methodologies for the synthesis of
N-substituted indazoles has met with limited success.
The existing methods often require the use of harsh
reaction conditions or special equipment, which signifi-
cantly limited their applications.4 We recently reported
a novel synthesis of 2-aryl-2H-indazoles from the corre-
sponding N-aryl-N-(o-bromobenzyl)hydrazines via the
palladium-catalyzed intramolecular CꢀN bond forma-
tion followed by spontaneous aromatization.5 It repre-
sents
the
first
general
method
by
which
2-aryl-2H-indazoles are constructed through the crea-
tion of the N(1)ꢀC(7a) bond. In this letter, we wish to
describe a complementary method for the synthesis of
1-aryl-1H-indazoles which involves the palladium-cata-
lyzed cyclization of N-aryl-N%-(o-bromobenzyl)-
hydrazines as well as [N-aryl-N%-(o-bromobenzyl)-
hydrazinato-N%]-triphenylphosphonium bromides.
Based on our experience with 2-aryl-2H-indazoles, the
initial efforts to synthesize 1-aryl-1H-indazoles focused
on the preparation of N-aryl-N%-(o-bromoben-
zyl)hydrazines (e.g. 3, Scheme 1) and their subsequent
cyclizations. Compound 3 was synthesized in two steps
4
3
4
3a
3
3a
5
2
5
2
N
R
N
R
R'
6
N
6
7a
1
N
1
7a
7
7
R' = aryl, alkyl
R'
2-R'-2H-indazoles
1-R'-1H-indazoles
Figure 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00273-8

2938
J. J. Song, N. K. Yee / Tetrahedron Letters 42 (2001) 2937–2940
+
+
R1
PPh3Br
R1
PPh3Br
H
N
N
HN
LHMDS
R1
NaOH, 60 o
C
NH
NH
NH
Br
Br
R2
Br
R2
R2
Br
3
1
R2 = H, or Me
2
Scheme 1.
Table 1. Optimization of solvent, ligand, and base in palladium-catalyzed intramolecular amination
+
Pd(OAc)2 (5 mol%)
ligand (7.5 mol%)
Pd(OAc)2 (5 mol%)
ligand (7.5 mol%)
PPh3Br
H
N
N
N
N
NH
NH
Br
Br
base/solvent, 90oC,
15 h
base/solvent, 90oC,
15 h
4
2a
3a
Substrate
Entry
Solvent
Ligand
Base (mol%)
Yield (%)
1
2
3
4
5
6
3a
2a
2a
2a
2a
2a
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
dppf
dppf
dppf
dppf
(R)-BINAP
No ligand
tBuONa (150)
tBuONa (250)
tBuONa (250)
Cs2CO3 (250)
tBuONa (250)
tBuONa (250)
81b
8a
53b
0a
38a
0a
a Yields were determined by 1H NMR of the crude products using 2-methoxynaphthalene as an internal standard.
b Isolated yield by chromatography.
(one pot) analogously to a literature procedure,6 as
shown in Scheme 1. Intermediate 2 can also be isolated
and deprotected in a separate step to give 3.
product to be formed. Presumably the extra equivalent
of the base is consumed to deprotect the triphenylphos-
phine. Cesium carbonate was found to be ineffective in
promoting the reaction. As was the case for the synthe-
sis of 2-aryl-2H-indazoles, the use of (R)-BINAP as the
supporting ligand7 resulted in a decrease in the yield.
Finally, it was shown that the cyclization did not
proceed without the presence of the ligand. Using the
above-described methods (A or B),8 a group of repre-
sentative substrates were cyclized to furnish indazole
products in moderate to very good yields, and the
results are presented in Table 2.9
When N-phenyl-N%-(o-bromobenzyl)hydrazine (3a,
Table 1) was subjected to the conditions of [Pd(OAc)2/
dppf/tBuONa (150 mol%)/toluene/90°C, method A],
the cyclization and the spontaneous aromatization
occurred smoothly to furnish 1-phenyl-1H-indazole (4)
in 81% isolated yield (Table 1, entry 1). Unlike the
synthesis
of
2-aryl-2H-indazoles,
very
little
debromonated by-product was observed. During the
course of this study, we also noticed that in some cases
the N-aryl-N%-(o-bromobenzyl)hydrazines are unstable
upon long-term storage. Therefore we investigated the
use of 2 as the reaction substrate, since this compound
proved to be stable under ambient conditions.
In summary, we have developed a new method for the
facile synthesis of 1-aryl-1H-indazoles from N-aryl-N%-
(o-bromobenzyl)hydrazines via the palladium-catalyzed
CꢀN bond formation followed by the spontaneous
aromatization. It was further demonstrated that [N-
aryl - N% - (o - bromobenzyl) - hydrazinato - N%] - triphenyl-
phosphonium bromides also underwent cyclizations
under suitable conditions to afford 1-aryl-1H-indazoles.
The present approach offers several advantages, includ-
ing mild reaction conditions and ease of operation.
Applications of this methodology to the synthesis of
novel biologically active compounds are under investi-
gation in these laboratories and will be reported in due
course.
Results from the investigation of different cyclization
conditions for 2a are summarized in Table 1 (entries
2–6). The 1-phenyl-1H-indazole was obtained in mod-
erate yield from compound 2a using the conditions of
[Pd(OAc)2/dppf/tBuONa (250 mol%)/dioxane/90°C,
method B]. The use of toluene as the solvent afforded
the product in only 8% yield due to the insolubility of
the starting material in toluene. It is also worth noting
that 250 mol% of the base was necessary for the desired

J. J. Song, N. K. Yee / Tetrahedron Letters 42 (2001) 2937–2940
2939
Table 2. Indazole synthesis via a palladium-catalyzed intramolecular CꢀN bond formation
yieldb
81%
substratea
method
product
entry
H
N
N
N
NH
1
A
A
Br
F
F
H
N
N
2
N
90%
NH
Br
MeO
MeO
H
N
N
3
N
NH
A
87%
58%
Br
N
+
PPh3Br
N
B
N
NH
4
5
Br
+
PPh3Br
N
N
NH
N
Br
40%
63%
B
B
CH3
CH3
N
+
F
F
PPh3Br
N
N
6
NH
Br
aAll substrates were prepared according to the modified literature procedure.
b Isolated yields by chromatography.
(e) Campi, E. M.; Habsuda, J.; Jackson, W. R.; Jonasson,
C. A. M.; McCubbin, Q. J. Aust. J. Chem. 1995, 48, 2023;
(f) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.;
Searle, R. J. G. J. Chem. Soc. 1965, 4831; (g) Armour, M.
A.; Cadogan, J. I. G.; Grace, D. S. B. J. Chem. Soc.,
Perkin Trans. 2 1975, 1185; (h) Cadogan, J. I. G.; Mackie,
R. K. Org. Synth. 1968, 48, 113; (i) Akazome, M.; Kondo,
T.; Watanabe, Y. J. Org. Chem. 1994, 59, 3375.
References
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F.; Carenini, G.; Gentili, P.; Riva, M. ibid. 1981, 36, 1037.
2. Keppler, B. K.; Hartmann, M. Met.-Based Drugs 1994, 1,
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Nugiel, D. A. J. Org. Chem. 1997, 62, 5627; (b) Rodgers,
J. D.; Johnson, B. L.; Wang, H.; Greenberg, R. A.;
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Chem. Lett. 1996, 6, 2919.
4. (a) Elguero, J. In Comprehensive Heterocyclic Chemistry;
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York, 1984; Vol. 5, p. 167; (b) Paal, C.; Krecke, Fr. Chem.
Ber. 1890, 23, 2640; (c) Paal, C. Chem. Ber. 1891, 24, 959;
(d) Busch, V.; Hartman, P. J. Prakt. Chem. 1895, 2, 404;
5. Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519.
6. Barluenga, J.; Merino, I.; Vina, S.; Palacios, F. Synthesis
1990, 5, 398–400.
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Soc. 1996, 118, 7215.
8. Method A: To a solution of the N-phenyl-N%-(o-bromo-
benzyl)hydrazine (84 mg, 0.3 mmol) in anhydrous toluene
(2.0 mL) in a pressure tube were added Pd(OAc)2 (3.5 mg,
0.015 mmol), dppf (13 mg, 0.0225 mmol) and tBuONa (43
mg, 0.45 mmol). Then the pressure tube was filled with Ar
and closed. The reaction was heated at 90°C for 15 h and

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J. J. Song, N. K. Yee / Tetrahedron Letters 42 (2001) 2937–2940
filtered through a pad of silica gel (50% ether/hexanes).
zyl)-hydrazinato-N%]-triphenylphosphonium bromide: 1H
NMR (CDCl3, 400 MHz) l 9.37 (s, 1H), 8.03 (dd, J=7.24,
8.58 Hz, 6H), 7.96 (d, J=3.04 Hz, 1H), 7.80 (m, 3H), 7.66
(m, 7H), 7.07 (d, J=8.79 Hz, 1H), 6.80 (m, 4H), 6.54 (m,
1H), 6.45 (dd, J=3.07, 8.78 Hz, 1H). [N-Phenyl-N%-(2-
bromo-5-fluorobenzyl)-hydrazinato-N%]-triphenylphospho-
nium bromide: 1H NMR (CDCl3, 400 MHz) l 9.32 (s, 1H),
7.99 (dd, J=7.21, 8.51 Hz, 7H), 7.80 (t, J=7.42 Hz, 3H),
7.67 (m, 7H), 7.19 (dd, J=5.13, 8.77 Hz, 1H), 6.83 (m,
4H), 6.60 (m, 2H). [N-(p-Tolyl)-N%-(o-bromobenzyl)-
After the removal of the volatiles, the residue was purified
by flash chromatography on silica (5–10% ether/hexanes)
to provide the desired product as white crystals (48 mg,
81%). For Method B the starting material was [N-phenyl-
N%-(o-bromobenzyl)-hydrazinato-N%]-triphenylphospho-
nium bromide, the solvent was dioxane and tBuONa was
used in 250 mol%.
9. Spectroscopic data for all new compounds: N-(2-Bro-
mobenzyl)-N%-phenylhydrazine: 1H NMR (CDCl3, 400
MHz) l 7.60 (d, J=7.64 Hz, 1H), 7.32 (m, 2H), 7.25–7.15
(m, 3H), 6.94 (d, J=8.60 Hz, 2H), 6.81 (t, J=7.24 Hz,
1H), 4.99 (br s, 1H), 4.09 (s, 3H). N-(2-Bromo-5-
fluorobenzyl)-N%-phenylhydrazine: 1H NMR (CDCl3, 400
MHz) l 7.54 (dd, J=5.21, 8.73 Hz, 1H), 7.23 (dd, J=7.43,
8.41 Hz, 2H), 7.14 (dd, J=3.08, 9.00 Hz, 1H), 6.92 (m,
3H), 6.82 (t, J=5.97 Hz, 1H), 5.04 (s, 1H), 4.07 (s, 3H).
1
hydrazinato-N%]-triphenylphosphonium bromide: H NM-
R (CDCl3, 400 MHz) l 8.87 (s, 1H), 8.09 (d, J=7.56 Hz,
1H), 7.97 (m, 6H), 7.78 (t, J=7.20 Hz, 3H), 7.65 (m, 6H),
7.24 (dd, J=1.24, 8.12 Hz, 1H), 7.03 (dt, J=1.20, 7.42 Hz,
1H), 6.93 (dt, J=1.73, 7.77 Hz, 1H), 6.65 (m, 4H), 2.06 (s,
3H). [N-(p-Tolyl)-hydrazinato-N%]-triphenylphosphonium
1
bromide: H NMR (CDCl3, 400 MHz) l 9.61 (d, J=24.1
N-(2-Bromo-5-methoxybenzyl)-N%-phenylhydrazine:
1H
Hz, 1H), 7.88 (m, 6H), 7.76 (t, J=7.58 Hz, 3H), 7.63 (m,
6H), 6.89 (d, J=8.00 Hz, 2H), 6.73 (d, J=8.44 Hz, 2H),
6.48 (br s, 1H), 2.20 (s, 3H). 5-Fluoro-1-phenyl-1H-inda-
NMR (CDCl3, 400 MHz) l 7.48 (d, J=8.71 Hz, 1H), 7.24
(m, 2H), 6.94 (m, 2H), 6.88 (d, J=3.06 Hz, 1H), 6.81 (t,
J=6.31 Hz, 1H), 6.76 (dd, J=3.65, 6.70 Hz, 1H), 5.07 (s,
1H), 4.04 (s, 2H), 3.77 (s, 3H). [N-Phenyl-N%-(o-bro-
mobenzyl)-hydrazinato-N%]-triphenylphosphonium bromide:
1H NMR (CDCl3, 400 MHz) l 9.17 (s, 1H), 8.24 (d,
J=7.54 Hz, 1H), 7.98 (m, 6H), 7.78 (t, J=6.05 Hz, 3H),
7.65 (m, 7H), 7.23 (d, J=7.91 Hz, 1H), 7.03 (t, J=6.62
Hz, 1H), 6.91 (t, J=7.74 Hz, 1H), 6.82 (m, 4H), 6.53 (t,
J=6.88 Hz, 1H). [N-Phenyl-N%-(2-bromo-5-methoxyben-
1
zole: H NMR (CDCl3, 400 MHz) l 8.16 (s, 1H), 7.70 (m,
3H), 7.55 (t, J=7.61 Hz, 2H), 7.40 (m, 2H), 7.21 (dt,
J=2.46, 9.00 Hz, 1H). 5-Methoxy-1-phenyl-1H-indazole:
1H NMR (CDCl3, 400 MHz) l 8.10 (s, 1H), 7.72 (d,
J=8.60 Hz, 2H), 7.65 (d, J=9.11 Hz, 1H), 7.53 (t, J=7.76
Hz, 2H), 7.35 (t, J=7.44 Hz, 1H), 7.14 (d, J=2.09 Hz,
1H), 7.10 (dd, J=2.42, 9.15 Hz, 1H), 3.89 (s, 3H).
.
.