Microwave-assisted synthesis of 1-aryl-1H-indazoles via one-pot two-step Cu-catalyzed intramolecular N-arylation of arylhydrazones

Article abstract of DOI:10.1016/j.tetlet.2005.08.143

A highly efficient one-pot two-step microwave procedure was developed for the synthesis of 1-aryl-1H-indazoles. Microwave heating of 2-halobenzaldehydes or 2-haloacetophenones with phenylhydrazines at 160°C for 10 min quantitatively yielded the arylhydraz

Full text of DOI:10.1016/j.tetlet.2005.08.143

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7553–7557
Microwave-assisted synthesis of 1-aryl-1H-indazoles via
one-pot two-step Cu-catalyzed intramolecular N-arylation
of arylhydrazones
Chittari Pabba,* Hong-Jun Wang, Susan R. Mulligan, Zhen-Jia Chen,
Todd M. Stark and Brian T. Gregg
Department of Medicinal Chemistry, Albany Molecular Research, Inc., PO Box 15098, 21 Corporate Circle,
Albany, NY 12212-5098, USA
Received 28 July 2005; revised 25 August 2005; accepted 26 August 2005
Available online 16 September 2005
Abstract—A highly efficient one-pot two-step microwave procedure was developed for the synthesis of 1-aryl-1H-indazoles. Micro-
wave heating of 2-halobenzaldehydes or 2-haloacetophenones with phenylhydrazines at 160 °C for 10 min quantitatively yielded the
arylhydrazones, which were further cyclized to give 1-aryl-1H-indazoles via CuI/diamine-catalyzed N-arylation under microwave
heating (160 °C, 10 min). Good to excellent yields were observed for 2-iodo, 2-bromo, and 2-chloro benzaldehydes or
acetophenones.
Ó 2005 Elsevier Ltd. All rights reserved.
The indazole ring is an important pharmacophore in
medicinal chemistry. Indazole derivatives have shown
different levels of activity as MAPKAP kinase modula-
tors,1a PPARs agonists,1b potassium channel blockers,1c
5-HT4 receptor antagonists,1d CCK-A agonists,1e and
inhibitors of protein kinase C-b,1f SAH/MTA nucleo-
sidase,1g and DNA gyrase.1h Indazoles have been
synthesized in many ways.2 Several groups have recently
reported the synthesis of indazoles via palladium-
catalyzed intramolecular N-arylation of N-aryl-N-(o-
bromobenzyl)hydrazines,3a N-aryl-N0-(o-bromobenzyl)-
hydrazines,3b [N-aryl-N0-(o-bromobenzyl)-hydrazinato-
N0]-triphenylphosphonium bromides,3b or hydrazones
of 2-halobenzaldehydes or 2-haloacetophenones.3c–e
The developed conditions are limited with either 2-bro-
mo or activated 2-chloro substrates. A more efficient
and general N-arylation procedure for the synthesis of
indazoles remains desirable.
Cu-mediated systems have proven equally effective in
N-arylation of anilines,4 amides,5 hydrazides,6 alkyl-
amines,7 and nitrogen heterocycles.8 Mild conditions
have been developed using ligands such as diamines,8
diols,7a diethylsalicylamide,7b amino alcohols,9 and ami-
no acids.10 Fukuyama and co-workers have reported
mild intramolecular N-arylation using a stoichiometric
amount of CuI.11 The success of these studies prompted
us to examine the Cu-catalyzed N-arylation in the
indazole synthesis, especially for unactivated chloro
substrates. Herein, we report an efficient microwave-
assisted synthesis of 1-aryl-1H-indazole via CuI-cata-
lyzed N-arylation of hydrazones of 2-haloaldehydes or
2-haloacetophenones.
R2
R2
CuI, ligand
K2CO3, NMP
NHNH2
N
R1
O
N
+
R1
R3
X
microwave heating
R3
X = I, Br, Cl
Keywords: 1H-Indazole; Hydrazone; Copper; Cyclization; Arylation;
Microwave irradiation.
Microwave irradiation has been widely applied in
organic synthesis.12 Many organic transformations,
including N-arylation,13 have been accelerated by sub-
jecting them to microwave irradiation. As part of our
*
Corresponding author at present address: Innovation Research
Center, Medivas, LLC, 6275 Nancy Ridge Drive, San Diego, CA
92121, USA. Tel.: +1 858 622 2005x297; fax: +1 858 622 4850;
e-mail: cpabba@medivas.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.143

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C. Pabba et al. / Tetrahedron Letters 46 (2005) 7553–7557
continuing interest in the application of this technol-
ogy,14 microwave heating was used to speed up the reac-
tion optimization.
With an optimized procedure in hand, a list of 2-halo-
benzaldehydes or 2-haloacetophenones were examined
to explore the scope of the Cu-catalyzed one-pot two-
step transformation (Table 2).15 Good to excellent yields
were observed for 2-bromobezaldehydes bearing elec-
tron-donating or electron-withdrawing substituents (en-
tries a–d). For 2-bromo-5-nitrobenzaldehyde, heating at
lower temperature gave better yield (entry d). When 2-
bromonicotinic aldehyde was used, the observed yield
was 95% (entry e). While under Pd(dba)2/DPEphos
catalysis, no cyclization product was formed for the
same substrate due to possible catalyst inhibition.3e
The yield using 2-chlorophenylhydrazine was essentially
the same as using the nonsubstituted phenylhydrazine
(entries c and f). In comparison with 2-bromobenzalde-
hyde (entry a), 2-iodobenzaldehyde gave a slightly high-
er yield (94%) (entry g). It was reported that the reaction
of 2-chlorobenzaldehyde with phenylhydrazine using
palladium catalysis yielded less than 1% of indazole
product.3e In contrast, a remarkable yield of 87% was
achieved using the microwave conditions we described
(entry h). For the less reactive 2-bromo and 2-chloro
acetophenone substrates, the CuI/diamine microwave
condition was also effective with good yields achieved
(entries i–k). While using palladium catalysis, only
2-bromoacetophenone substrates were studied with
lower yields being reported.3e
As illustrated in Table 1, a Buchwald Cu–diamine system
was found effective in the cyclization of 2-bromobenz-
aldehyde and phenylhydrazine. After a few tests, we no-
ticed that better yields could be achieved by stepwise
cyclization. Thus, a one-pot two-step intramolecular
Cu-catalyzed N-arylation procedure was developed. In
a recent study on Pd-catalyzed indazole synthesis, pre-
formed hydrazones were similarly found to give better
yields.3e The hydrazone 3 was easily prepared in quanti-
tative yield by microwave heating a mixture of 2-bromo-
benzaldehyde and phenylhydrazine in NMP at 160 °C
for 10 min. Next, K2CO3, CuI and diamine ligand were
added, and the mixture was again microwave heated to
facilitate the cyclization. The best condition for the sec-
ond step N-arylation was 160 °C for 10 min with 2 equiv
of K2CO3, 5 mol % of CuI and 10 mol % of diamine 5
(entry 1). When diamine 6 was used as the ligand, the
conversion dropped to 82% (entry 2). Without a ligand,
only trace amount of product was formed and the con-
version was <5% (entry 3). As compared to K2CO3, no
difference was observed when Cs2CO3 was used as the
base (entry 4). Heating at 195 °C generated 5% of
uncharacterized side product, while heating at 100 and
140 °C caused incomplete conversion (entries 5–7).
Using other substrates, we also found that solvents such
as toluene, dioxane, and DMF were not as effective as
NMP. Notably, longer reaction time was required to
drive the reaction to completion when a regular heating
source was used. The microwave reactions were carried
out without nitrogen atmosphere.
In conclusion, a highly efficient one-pot two-step micro-
wave procedure was developed for the synthesis of
1-aryl-1H-indazoles. Microwave heating of 2-halobenz-
aldehydes or 2-haloacetophenones with phenylhydra-
zines at 160 °C for 10 min quantitatively yielded the
arylhydrazones, which were further cyclized to give
Table 1. Optimization of Cu-catalyzed one-pot two-step intramolecular cyclization
H
N
NHNH2
CHO
NMP
N
+
microwave
Br
Br
160 ˚C, 10 min
1a
2a
3a
NHMe
NHMe
K2CO3, CuI, ligand
N
5
6
N
microwave
160 ˚C, 10 min
NHMe
4a
NHMe
Entry
Liganda
Baseb
Microwave conditions
Conversion (%)
1
2
3
4
5
6
7
5
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
160 °C, 10 min
160 °C, 10 min
160 °C, 10 min
160 °C, 10 min
195 °C, 10 min
100 °C, 10 min
140 °C, 10 min
100c
82c
<5d
100c
94c,e
40c,d
83d
6
No ligand
5
5
5
5
a 5 mol % of CuI and 10 mol % of diamine ligand were used.
b 2 equiv of base was used.
c Based on 1H NMR analysis.
d Based on LC–MS analysis.
e 5% of uncharacterized side product was observed.

C. Pabba et al. / Tetrahedron Letters 46 (2005) 7553–7557
7555
Table 2. Synthesis of 1-aryl-1H-indazoles 4 via CuI/diamine-catalyzed intramolecular cyclization
R2
N
R2
NHNH2
1. microwave, 160 ˚C, 10 min
R1
NMP
N
O
+
R1
R3
X
2. microwave, 160 ˚C, 10 min
K2CO3 (2 equiv)
CuI (5 mol %), ligand 5 (10 mol %)
R3
X = I, Br, Cl
4
2
1
Entry
a
Substrate
Hydrazine
Producta
Isolated yield (%)
N
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
CHO
Br
N
91
MeO
MeO
N
MeO
MeO
CHO
Br
N
b
c
d
e
f
82
F
N
F
CHO
Br
N
84
O2N
N
O2N
CHO
Br
65, 95b
N
N
CHO
Br
N
N
95
N
F
NHNH2
Cl
N
F
CHO
Br
N
82
Cl
N
N
NHNH2
NHNH2
NHNH2
CHO
N
N
g
h
i
94
I
CHO
Cl
87
N
O
N
75
Br
(continued on next page)

7556
C. Pabba et al. / Tetrahedron Letters 46 (2005) 7553–7557
Table 2 (continued)
Entry
Substrate
Hydrazine
Producta
Isolated yield (%)
F3C
NHNH2
N
F3C
O
N
j
78
Cl
NHNH2
N
k
69
N
O
Cl
Cl
Cl
a Final compounds were characterized by MS, 1H NMR, and 13C NMR analyses.
b The second step N-arylation was carried out at 120 °C for 10 min.
Kuehne, H.; Luebbers, T.; Meunier-Keller, N.; Mueller, F.
J. Med. Chem. 2000, 43, 2664.
1-aryl-1H-indazoles via CuI/diamine-catalyzed N-aryla-
tion under microwave heating (160 °C, 10 min). Good to
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excellent yields were observed for hydrazones of 2-iodo,
2-bromo, and 2-chloro benzaldehydes. Notably, a yield
of 87% was achieved for a hydrazone of unactivated
2-chlorobezaldehyde, while using the reported palla-
dium catalysis, the yield was less than 1% for the same
substrate. Furthermore, for the less reactive hydrazones
of 2-bromo and 2-chloroacetophenones, good yields
were achieved using the same Cu-catalyzed microwave
procedure.
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15. Typical procedure for the microwave-assisted synthesis of
1-aryl-1H-indazole: A 0.5–2 mL Smith Process vial con-
taining a magnetic stir bar was charged with the 2-
halobenzaldehyde (or 2-haloacetophenone) (0.5 mmol,
1.0 equiv), phenylhydrazine (0.5 mmol, 1.0 equiv) and
NMP (0.5 mL). The vial was sealed without degassing,
and the solution was heated at 160 °C for 10 min (fixed
hold time) in the Smithcreator. Next, the reaction vial
was unsealed, and to the preformed hydrazone solution
was added base (1.0 mmol, 2.0 equiv), CuI (0.025 mmol,
0.05 equiv), and ligand (0.05 mmol, 0.1 equiv). The reac-
tion vial was again sealed without degassing, and the
suspension was heated at 160 °C for 10 min (fixed hold
time). The reaction mixture was filtered through Celite
and purified by flash chromatography (ethyl acetate/
hexanes). Characterization of compound 4e: 1H NMR
(300 MHz, CDCl3): d 8.64 (dd, J = 4.5, 1.5 Hz, 1H), 8.27
(d, J = 8.4 Hz, 2H), 8.20 (s, 1H), 8.13 (d, J = 8.4 Hz,
1H), 7.54 (t, J = 8.4 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H),
7.21 (dd, J = 8.1, 4.5 Hz, 1H) ppm; 13C NMR (75 MHz,
CDCl3): d 150.5, 149.5, 139.9, 134.3, 130.6, 129.5, 126.5,
121.7, 118.0, 117.6 ppm.