Facile palladium-catalysed synthesis of 1-aryl-1H-indazoles from 2-bromobenzaldehydes and arylhydrazines

Article abstract of DOI:10.1039/b312154m

2-Bromobenzaldehydes react with arylhydrazines in toluene at 100°C in the presence of a catalytic amount of a palladium catalyst and phosphorus chelating ligands such as 1,1′-bis(diphenylphosphino)ferrocene and 1,3-bis(diphenylphosphino)propane along with NaO-t-Bu to afford 1-aryl-1H-indazoles in good yields.

Full text of DOI:10.1039/b312154m

Facile palladium-catalysed synthesis of 1-aryl-1H-indazoles from
2-bromobenzaldehydes and arylhydrazines
Chan Sik Cho,*a Dong Kwon Lim,b Nam Ho Heo,b Tae-Jeong Kimb and Sang Chul Shim*b
a Research Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, Korea
b Department of Industrial Chemistry, College of Engineering, Kyungpook National University, Daegu
702-701, Korea. E-mail: scshim@knu.ac.kr
Received (in Cambridge, UK) 30th September 2003, Accepted 4th November 2003
First published as an Advance Article on the web 18th November 2003
2-Bromobenzaldehydes react with arylhydrazines in toluene at
100 °C in the presence of a catalytic amount of a palladium
catalyst and phosphorus chelating ligands such as 1,1A-bis(di-
phenylphosphino)ferrocene and 1,3-bis(diphenylphosphino)-
propane along with NaO-t-Bu to afford 1-aryl-1H-indazoles in
good yields.
with dppp (runs 2, 3). With other phosphorus chelating ligands such
as 1,1A-bis(di-i-propylphosphino)ferrocene (dipf) and (S)-
(2)-BINAP, the yield of 3a was lower than that when dppp and
dppf were employed (runs 4, 5), all combined with Pd(OAc)2.
However, catalytic systems such as Pd(OAc)2–PPh3, PdCl2(PPh3)2
and Pd(PPh3)4 were not effective at all for the present reaction;
hydrazone was mainly produced as an identifiable product (runs
6–8). As a result, among the various palladium precursors
examined the systems shown in runs 1, 2 and 3 are the choices of
preference for the effective formation of 3a.
Given these results, the reactions of various 2-bromobenzalde-
hydes 1 and arylhydrazines 2 were screened using three sets of
reaction conditions, Pd(OAc)2–dppp (condition A), Pd(OAc)2–
dppf (condition B) and PdCl2–dppp (condition C), and several
representative results are summarised in Table 2.† The reaction of
1b–1d with 2a under conditions A–C gave the corresponding
1-phenyl-1H-indazoles (3b–3d) in 47–79% yield with minimal
formation of hydrazones as identifiable side products (runs 1–5).
The product yield was not significantly affected by the electronic
Palladium-catalysed aromatic carbon–nitrogen bond forming reac-
tion by the cross-coupling of aryl halides (or triflates) and amines
has recently had an upsurge as a useful synthetic tool.1 Various
primary, secondary and tertiary amines can be prepared by this
protocol and its intramolecular version has been introduced to the
synthesis of nitrogen heterocycles as an elegant synthetic alter-
native.1 In connection with this report, Song et al. have reported a
palladium-catalysed intramolecular amination of N-aryl-NA-(o-
bromobenzyl)hydrazines leading to 1-aryl-1H-indazoles.2–4 How-
ever, the uneasy accessibility of the starting substrates in this
method, which are prepared via several steps from commercial
products,5 precludes a straightforward approach. This led us to
develop an efficient palladium-catalysed synthetic method for
1-aryl-1H-indazoles. Herein we report a successful palladium-
catalysed synthesis of 1-aryl-1H-indazoles from readily available
commercial substrates, 2-bromobenzaldehydes and arylhydrazines,
via an intrinsic intramolecular amination.6
The results of several attempted cyclisations of 2-bromo-
benzaldehyde (1a) with phenylhydrazine (2a) are listed in Table 1
(Scheme 1). Treatment of equimolar amounts of 1a and 2a in
toluene in the presence of a catalytic amount of Pd(OAc)2 (2 mol%)
and 1,3-bis(diphenylphosphino)propane (dppp) (3 mol%) along
with NaO-t-Bu at 100 °C for 15 h afforded 1-phenyl-1H-indazole
(3a) in 84% yield with concomitant formation of hydrazone ( <
5%) by condensation between the starting substrates (run 1). The
catalytic systems using Pd(OAc)2 combined with 1,1A-bis(diphe-
nylphosphino)ferrocene (dppf) and PdCl2 combined with dppp
were revealed to be as effective as that using Pd(OAc)2 combined
Scheme 1
Table 1 Palladium-catalysed reaction of 1a with 2a under several catalytic
systemsa
Table 2 Palladium-catalysed synthesis of 3 from 1 and 2a
Yield
(%)
Run
1
2
Conditionsb Products
1
2
3
4
5
6
7
8
9
10
11
12
13
1b
1b
1c
1d
1d
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
B
C
A
B
C
B
B
B
A
A
B
C
A
3b
3b
3c
3d
3d
3e
3f
3g
3h
3i
79
47
65
77
51
79
55
61
78
73
86
60
86
Palladium
catalysts
Isolated
yield (%)
Run
Ligands (mol%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
Pd(PPh3)4
dppp (3)
dppf (3)
dppp (3)
dipf (3)
(S)-(2)-BINAP (3)
PPh3 (6)
—
84
84
83
65
69
2g
2g
2h
3j
3j
3k
trace
trace
trace
—
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), palladium catalyst (2
mol%), chelating ligand (3 mol%), NaO-t-Bu (2 mmol), toluene (10 ml),
100 °C, for 15 h, under argon. b A: Pd(OAc)2–dppp; B: Pd(OAc)2–dppf; C:
PdCl2–dppp.
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), palladium catalyst (2
mol%), NaO-t-Bu (2 mmol), toluene (10 ml), 100 °C, for 15 h, under
argon.
104
C h e m . C o m m u n . , 2 0 0 4 , 1 0 4 – 1 0 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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nature of the substituent on 1. In contrast to the reaction between 1a
and 2a, the product yield varied according to the employed reaction
conditions (runs 1,2 and 4,5). From the reactions between 1a and
various arylhydrazines (2b–2h), the corresponding 1-aryl-1H-
indazoles (3e–3k) were also produced in good yields irrespective of
the examined functional groups on the aromatic ring of 2 (runs
6–13). Comparing the result of runs 11 and 12 with that of two sets
of reactions shown in runs (1 and 2) and (4 and 5), condition B was
generally superior to condition C for the formation of 1-aryl-1H-
indazoles.
A plausible reaction pathway is depicted in Scheme 2. Oxidative
addition of the carbon–bromide bond of hydrazone 4, initially
formed in situ between 1a and 2, to Pd(0) produces an ar-
ylpalladium(II) complex 5. This is followed by intramolecular
closure to give a palladacycle 6 which can reductively eliminate to
afford 1-aryl-1H-indazole 3.7,8
In summary, we have demonstrated that 2-bromobenzaldehydes
are cyclised with various arylhydrazines in the presence of a
catalytic amount of a palladium catalyst and a phosphorus chelating
ligand along with NaO-t-Bu to give 1-aryl-1H-indazoles in good
yields. The present reaction is a straightforward methodology for
the synthesis of 1-aryl-1H-indazoles from readily available 2-bro-
mobenzaldehydes and arylhydrazines. Similar reaction of alkyl
2-bromoaryl ketones with arylhydrazines leading to 1,3-dis-
ubstituted indazoles is currently under investigation.
This work was supported by the Brain Korea 21 Project in 2003
and a Korea Research Foundation Grant (KRF-2002-070-C00055).
C.S.C. gratefully acknowledges an MOE-KRF Research Professor
Program (2001-050-D00015).
Notes and references
† Typical experimental procedure: a mixture of 1a (1 mmol), 2a (1 mmol),
Pd(OAc)2 (0.02 mmol), dppp (0.03 mmol) and NaO-t-Bu (2 mmol) in dry
toluene (10 ml) was placed in a pressure vessel. The system was flushed
with argon and allowed to react at 100 °C for 15 h. The reaction mixture was
filtered through a short silica gel column (ethyl acetate) to eliminate
inorganic salts. Removal of the solvent left a crude mixture, which was
separated by column chromatography (silica gel, ethyl acetate–hexane = 1
: 5) to give 3a (84%).
1 J. P. Wolfe, S. Wagaw, J.-F. Marcoux and S. L. Buchwald, Acc. Chem.
Res., 1998, 31, 805; J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37,
2046; B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 1999, 576,
125.
2 J. J. Song and N. K. Yee, Tetrahedron Lett., 2001, 42, 2937.
3 The same authors have also reported on palladium-catalysed synthesis of
2-aryl-2H-indazoles from N-aryl-N-(o-bromobenzyl)hydrazines under
similar reaction conditions: J. J. Song and N. K. Yee, Org. Lett., 2000, 2,
519.
4 Conventional synthetic methods for indazoles: J. Elguero, Compre-
hensive Heterocyclic Chemistry; ed. A. R. Katritzky and C. W. Rees,
Pergamon, New York, 1984, vol. 5, pp. 167–303.
5 J. Barluenga, I. Merino, S. Vina and F. Palacios, Synthesis, 1990, 398.
6 Our recent report on palladium-catalysed synthesis of N-heterocycles
such as isoindolinones and b-lactams, see: C. S. Cho, J. W. Lee, D. Y.
Lee, S. C. Shim and T. J. Kim, Chem. Commun., 1996, 2115; C. S. Cho,
D. Y. Chu, D. Y. Lee, S. C. Shim, T. J. Kim, W. T. Lim and N. H. Heo,
Synth. Commun., 1997, 27, 4141; C. S. Cho, L. H. Jiang and S. C. Shim,
Synth. Commun., 1998, 28, 849; C. S. Cho, L. H. Jiang, D. Y. Lee, S. C.
Shim, H. S. Lee and S.-D. Cho, J. Heterocycl. Chem., 1997, 34, 1371; C.
S. Cho, X. Wu, L. H. Jiang, S. C. Shim, H.-J. Choi and T. J. Kim, J.
Heterocycl. Chem., 1998, 35, 265; C. S. Cho, X. Wu, L. H. Jiang, S. C.
Shim and H. R. Kim, J. Heterocycl. Chem., 1999, 36, 297; C. S. Cho, H.
S. Shim, H.-J. Choi, T.-J. Kim, S. C. Shim and M. C. Kim, Tetrahedron
Lett., 2000, 41, 3891; C. S. Cho, L. H. Jiang and S. C. Shim, Synth.
Commun., 1999, 29, 2695.
7 A. S. Guram, R. A. Rennels and S. L. Buchwald, Angew. Chem., Int. Ed.,
1995, 34, 1348.
8 Palladium-catalysed arylation of diphenylhydrazone with aryl halides is
known: J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2090.
Scheme 2
C h e m . C o m m u n . , 2 0 0 4 , 1 0 4 – 1 0 5
105