Efficient synthesis of 3-aryl-1H-indazol-5-amine by Pd-catalyzed Suzuki-Miyaura cross-coupling reaction under microwave-assisted conditions

Article abstract of DOI:10.1016/j.tetlet.2015.04.024

Various 3-aryl-1H-indazol-5-amine derivatives were synthesized by Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of (NH) free 3-bromo-indazol-5-amine with arylboronic acids under microwave-assisted conditions. The coupling reaction can be carried out under the conditions with dioxane/H₂O as solvent, Pd(OAc)₂ and RuPhos as catalyst system, and K₃PO₄ as a base in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2015.04.024

Tetrahedron Letters 56 (2015) 3750–3753
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Tetrahedron Letters
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Efficient synthesis of 3-aryl-1H-indazol-5-amine by Pd-catalyzed
Suzuki–Miyaura cross-coupling reaction under microwave-assisted
conditions
a,b,c,d,
Shengqiang Wang a,b,c, Ruiyun Guo b,c, Jingya Li b,c, Dapeng Zou a,b, Yangjie Wu a,b, , Yusheng Wu
⇑
⇑
a College of Chemistry and Molecular Engineering, Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University,
Zhengzhou, Henan 450052, PR China
b Collaborative Innovation Center of New Drug Research and Safty Evaluation, Henan Province, PR China
c Tetranov Biopharm, LLC. 75 Daxue Road, Zhengzhou, Henan 450052, PR China
d Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 February 2015
Revised 3 April 2015
Accepted 6 April 2015
Available online 11 April 2015
Various 3-aryl-1H-indazol-5-amine derivatives were synthesized by Pd-catalyzed Suzuki–Miyaura cross-
coupling reaction of (NH) free 3-bromo-indazol-5-amine with arylboronic acids under microwave-
assisted conditions. The coupling reaction can be carried out under the conditions with dioxane/H2O
as solvent, Pd(OAc)2 and RuPhos as catalyst system, and K3PO4 as a base in good to excellent yields.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
3-Aryl-1H-indazol-5-amine
Suzuki–Miyaura cross-coupling
Microwave-assisted conditions
Arylboronic acids
RuPhos
Introduction
processes have been developed for preparing 3-aryl-1H-indazole
derivatives through the Pd-catalyzed Suzuki–Miyaura cross-cou-
A variety of biological activities containing 3-aryl-1H-indazole
motifs, such as the inhibition of Mps1 kinase,1a inhibition of
JNK3,1b inhibition of potent cell cycle,1c and the EP1 receptor
antagonisms.1d Due to the usefulness of these types of
compounds, how to construct 3-aryl-1H-indazole motifs has
attracted much attention from the synthetic organic chemistry
community. Classical routes to 3-aryl-1H-indazole mainly focus
on the condensation of ortho-substituted arylaldehydes or
ketones with hydrazines,2 [3+2] cyclization of benzynes with diazo
compounds or hydrazones.3 Another attractive method is transi-
tion-metal-catalyzed intramolecular amination of ortho-halo aryl-
hydrazones4 or the direct C–H amination of arylhydrazones.5
However, these methods all suffer from requiring the need of pre-
functionalization of starting materials to get the diversity of substi-
tution on both the indazole and the aryl group.
pling reaction,7 usually the N-protecting group is required in order
to get a moderate yield in most of these processes including the
direct C3 C–H arylation of 1H-indazoles with aryl iodides or
bromides.8
So far, there are a few reports on Pd-catalyzed Suzuki–Miyaura
cross-coupling reactions of indazole containing free N–H groups. In
1999, the group of Rault first tried the Suzuki–Miyaura cross-cou-
pling reaction of (NH) free 3-iodo-indazole with 2-furyboronic acid,
but the yield was poor to 10%.7a In 2013, Guillaumet and co-
workers reported the Suzuki–Miyaura cross-coupling reaction of
(NH) free 3-bromo-indazole with arylboronic acids in moderate
yield under microwave-assisted conditions.9 In the same year,
Buchwald et al. prepared the c-Jun N-terminal kinase 3 inhibitor
in two steps through the Suzuki–Miyaura cross-coupling reaction
of (NH) free 3-chloro-1H-indazol-6-amine with phenylboronic acid
under their second generation precatalyst and a Pd-catalyzed C–N
bond-forming reaction on the NH2.10 Herein, we report a simple
and an economic synthetic method of 3-aryl-1H-indazol-5-amine
through Pd-catalyzed Suzuki–Miyaura cross-coupling reaction of
(NH) free 3-bromo-indazol-5-amine with arylboronic acids, aiming
at the synthesis of 3-aryl-1H-indazol-5-amine derivatives for
library biological active screening in our company’s projects.11
The Pd-catalyzed Suzuki–Miyaura cross-coupling reaction of
arylhalides with organoboron reagents is one of the most impor-
tant and powerful tools in the synthesis of library.6 Though some
⇑
Corresponding authors. Tel.: +1 732 253 7326; fax: +1 732 253 7327.
E-mail addresses: wyj@zzu.edu.cn (Y. Wu), yusheng.wu@tetranovglobal.com
(Y. Wu).
http://dx.doi.org/10.1016/j.tetlet.2015.04.024
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S. Wang et al. / Tetrahedron Letters 56 (2015) 3750–3753
3751
P
P
PCy2
OMe
PCy2
MeO
Me2N
PPh3
DavePhos
PCy3
SPhos
PCy2
iPr
PCy2
OiPr
N
iPr
Fe
Pd
iPrO
Cl
O
PCy3
PPh2
PPh2
iPr
XantPhos
XPhos
Ruphos
A Cyclopalladated catylst
Scheme 1. The structure of different ligands and catalyst.
To evaluate the activity of the combination of different catalysts
and ligands (Scheme 1), phenylboronic acid 1 and 3-bromo-1H-in-
Additionally, our laboratory once reported the Suzuki–Miyaura
cross-coupling catalyzed by cyclopalladated ferrocenylimine com-
plex A,12 at the present condition, the catalyst A was found to be
less active (entry 14).
dazol-5-amine
2
were chosen as
a
model reaction in
dioxane/H2O = 10/1 at 130 °C in the presence of K3PO4 as the base
for 30 min under microwave-assisted conditions (Table 1). The
combination of Pd(OAc)2 with PPh3, PCy3, SPhos, and DavePhos
was found to be much less active, giving desired products in poor
yields (entries 1–4). The trace product was detected when the
XantPhos was used as ligand. (entry 5). The ligands XPhos and
RuPhos gave 3 in moderate and good yields (entries 6, 7).
Changing the palladium source to PdCl2, Pd(PPh3)4, and Pd2(dba)3
all afforded the desired products in lower yields (entries 8–10).
Thus commercially cheaper Pd(OAc)2 was then chosen as palla-
dium source. It was noticed that employing a lower catalyst load-
ing (2 mol %) resulted in a sharp decrease in coupling efficiency.
(entry 11). Moreover, the yield was not improved evidently by
employing a more catalyst loading (entry 12). In the absence of
Pd source, no cross-coupling product was obtained (entry 13).
The cross-coupling reaction between phenylboronic acid 1 and
3-bromo-1H-indazol-5-amine 2 was further used to investigate the
effects of temperature and solvents by fixing 5 mol % Pd(OAc)2,
10 mol % RuPhos (Table 2). With the reaction temperature dropped
from 130 °C to 120 °C, the yield decreased and the starting materi-
als remained (entry 1). When the reaction temperature was
increased to 140 °C, the desired products were obtained in a good
yield (entry 2). However, a higher temperature does not benefit the
yield (entry 3). Several solvents such as dioxane/H2O, DMF,
toluene/H2O, and n-BuOH/H2O, were examined in the reaction. In
the case of DMF, toluene/H2O, only trace yields were observed
(entries 4, 5). The similar yield was obtained when n-BuOH/H2O
was used as the solvent instead of dioxane/H2O (entry 6). When
the ratio of dioxane/H2O reached to 1/1, the best result was
obtained. However, no desired product was found when the water
was used as the only solvent (entries 8–10).
Table 1
Finally, the effects of base, the amount of phenylboronic acid,
and the reaction time on the cross-coupling of 3-bromo-1H-inda-
zol-5-amine with phenylboronic acid were tested (Table 3). After
Effects of catalysts and ligands on the cross-coupling of 3-bromo-1H-indazol-5-amine
with phenylboronic acida
HO
OH
Br
N
B
H2N
Table 2
Catalyst, Ligant, K3PO4
+
H2N
Effects of temperature and solvents on the cross-coupling of 3-bromo-1H-indazol-5-
C
Dioxane/H2O, 130°
amine with phenylboronic acida
N
N
H
N
H
2
3
1
HO
OH
Br
N
B
H2N
Yieldb (%)
Pd(OAc)2, RuPhos
Solvent, K3PO4
Entry
Catalyst
Ligand
+
H2N
N
N
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
No catalyst
A
PPh3
PCy3
15
17
38
7
H
N
H
SPhos
DavePhos
XantPhos
XPhos
RuPhos
RuPhos
ꢀ
2
3
1
Trace
55
83
28
45
48
65c
85d
no
15
Entry
Temp (°C)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
120
140
150
140
140
140
140
140
140
140
Dioxane/H2O = 10/1
Dioxane/H2O = 10/1
Dioxane/H2O = 10/1
DMF
Toluene/H2O = 10/1
n-BuOH/H2O = 10/1
Dioxane/H2O = 5/1
Dioxane/H2O = 1/1
Dioxane/H2O = 1/2
H2O
65
85
80
9
10
11
12
13
14
RuPhos
RuPhos
RuPhos
ꢀ
Trace
Trace
78
86
90
75
ꢀ
ꢀ
a
Reaction conditions: 3-bromo-1H-indazol-5-amine (0.6 mmol), phenylboronic
acid (0.9 mmol), catalyst (5 mol %), ligand (10 mol %), K3PO4 (1.2 mmol), dioxane/
H2O = 10/1 (5.0 mL), 130 °C, 30 min, microwave-assisted conditions.
10
a
Reaction conditions: 3-bromo-1H-indazol-5-amine (0.6 mmol), phenylboronic
b
Detected by HPLC.
acid (0.9 mmol), Pd(OAc)2 (5 mol %), RuPhos (10 mol %), solvent (5.0 mL), 30 min,
microwave-assisted conditions.
c
2 mol % catalyst, 4 mol % ligand.
d
b
10 mol % catalyst, 20 mol % ligand.
Detected by HPLC.

3752
S. Wang et al. / Tetrahedron Letters 56 (2015) 3750–3753
Table 3
Table 4
Effects of base, the amount of phenylboronic acid, and the reaction time on the cross-
The cross-coupling reaction of 3-bromo-1H-indazol-5-amine with phenylboronic
coupling of 3-bromo-1H-indazol-5-amine with phenylboronic acida
acidsa,b
R
Br
N
HO
OH
R
HO
OH
Br
N
Pd(OAc)2 (5 mol%)
RuPhos (10 mol%)
B
1
H2N
B
H2N
H2N
Pd(OAc)2, RuPhos, Base
Dioxane/H2O, 140°C
+
H2N
N
+
N
Dioxane/H2O
K3PO4 140°C
N
H
H
N
N
H
N
H
2
3
2
1
3
O
O
Entry
Base
Phenylboronic acid (equiv)
Time (min)
Yieldb(%)
O
1
2
3
4
5
6
7
8
K3PO4
K2CO3
Na2CO3
LiOH
K3PO4
K3PO4
K3PO4
K3PO4
1.5
1.5
1.5
1.5
2.0
1.2
1.5
1.5
30
30
30
30
30
30
20
40
90
88
86
81
91
75
76
87
H2N
H2N
H2N
H2
N
N
N
N
N
N
N
N
H
N
N
H
N
H
N
H
3a, 91%
3b, 75%
3c, 98%
3d, 93%
Ph
H2N
H2N
H2
H2N
a
N
N
N
Reaction conditions: 3-bromo-1H-indazol-5-amine (0.6 mmol), phenylboronic
acid, Pd(OAc)2 (5 mol %), RuPhos (10 mol %), base (1.2 mmol), dioxane/H2O = 1/1
(5.0 mL), 140 °C, microwave-assisted condition.
N
N
N
N
N
H
N
H
H
H
3g, 97%
3e, 91%
3f, 98%
F
3h, 95%
b
Detected by HPLC.
Ph
F
F
H2N
H2N
H2N
H2
N
screening several inorganic bases, we found all the tested bases
could afford good yields and K3PO4 even better (entries 1–4).
When 1.5 equiv and 2.0 equiv of the phenylboronic acid were used
under the same catalytic system, similar results were obtained
(entry 1 vs 5). However, the yield of desired product was decreased
with the amount of phenylboronic acid dropped to 1.2 equiv (entry
6). When the reaction time was shortened to 20 min, the starting
material could not be transformed completely and the yield
decreased (entry 7). Too long reaction time will increase the occur-
rence of side reactions and result in a slight decrease of the yield
(entry 8). So, the combination of 5 mol % Pd(OAc)2, 10 mol %
RuPhos in dioxane/H2O = 1/1 in the presence of K3PO4 at 140 °C
under microwave-assisted conditions for 30 min was chosen as
the optimum condition.
Under the optimized reaction conditions, the scope of phenyl-
boronic acid derivatives was then examined (Table 4). It could be
noted that most reactions proceeded smoothly to provide the cor-
responding products in moderate to excellent yields (58–98%).
Moreover, a wide variety of functional groups including fluoro,
cyano, trifluoromethyl, amino, and methyl were tolerated in this
condition. However, the reactions were influenced by electron
effect of the substituent. Phenylboronic acid with electron-donat-
ing groups gave higher yields than those with electron-withdraw-
ing (3b–3g vs 3j–3q). Only trace desired coupling product was
detected, when substrate with electron-withdrawing group at
ortho-position (3j) was used. Meanwhile, substrates with groups
at ortho-position (3b, 3e) gave lower yields than those at meta-
position (3c, 3f,) or para-position (3d, 3g), indicating that the
steric hindrance likely has a negative effect on the reaction. A
moderate yield was gotten when 3-cyanophenylboronic acid or
4-cyanophenylboronic acid was employed under the optimized
reaction condition (3o, 3p). Under the same reaction condition,
phenylboronic acid with 3,4-disubstituents also gave good yields
(3q, 3r). Phenylboronic acid with amino substituent could also be
successfully converted into the desired product in good yield
(3s). Compared with phenylboronic acid, naphthalene-boronic acid
could also be successfully converted to the corresponding products
in excellent yields (3t, 3u).
N
N
N
H
N
H
N
H
N
H
3i, 83%
F3
3j, trace
3k, 85%
3l, 89%
CF3
CN
C
NC
H2N
H2N
H2N
H2N
N
N
N
N
H
N
H
N
N
H
H
3m, 84%
3n, 79%
3o, 72%
3p, 58%
O
NH2
F
O
F
H2N
H2N
H2N
H2N
N
N
N
N
H
N
N
N
N
H
H
H
3q, 88%
3r, 90%
3s, 76%
3t, 93%
H2
N
N
N
H
3u, 94%
a
Reaction conditions: 3-bromo-1H-indazol-5-amine (0.6 mmol), phenyl-boronic
acid (0.9 mmol), Pd(OAc)2 (5 mol %), RuPhos (10 mol %), K3PO4 (1.2 mmol), dioxane/
H2O = 1/1 (5 mL), 140 °C, 30 min, microwave-assisted conditions.
b
Isolated yields based on 2.
conditions, furan-2-ylboronic acid and thiophen-3-ylboronic acid
coupled with 3-bromo-1H-indazol-5-amine gave the desired prod-
ucts in excellent yields (5a, 5b).
Meanwhile, several substituted pyridinyl boronic acids were
successfully transformed to the desired products from moderate
to good yields. 5-Methoxypyridin-3-ylboronic acid and 6-ethoxy-
pyridin-3-ylboronic acid gave better yields (5c, 5d) than 5-ethyl-
pyridin-3-ylboronic acid and 5-phenylpyridin-3-ylboronic acid
(5e, 5f). Only the more excess loading of thiophen-2-ylboronic acid
and pyridin-3-ylboronic acid were used, the starting material could
be transformed completely, the desired products were isolated in
moderate yields (5g, 5h). Pyridin-4-ylboronic acid only provided
a poor yield in this system even though the loading of the boronic
acid was increased and the reaction time was prolonged (5i).
Encouraged by the results from phenylboronic acid we were
prompted to check whether the coupling of heteroarylboronic
acids with 3-bromo-1H-indazol-5-amine could work at the same
catalyst system. As shown in Table 5, under the optimized reaction

S. Wang et al. / Tetrahedron Letters 56 (2015) 3750–3753
3753
Table 5
References and notes
The cross-coupling reaction of 3-bromo-1H-indazol-5-amine with heteroarylboronic
acidsa,b
1. (a) Kusakabe, K.; Ide, N.; Daigo, Y.; Tachibana, Y.; Itoh, T.; Yamamoto, T.;
Hashizume, H.; Hato, Y.; Higashino, K.; Okano, Y.; Sato, Y.; Inoue, M.; Iguchi, M.;
Kanazawa, T.; Ishioka, Y.; Dohi, K.; Kido, Y.; Sakamoto, S.; Yasuo, K.; Maeda, M.;
Higaki, M.; Ueda, K.; Yoshizawa, H.; Baba, Y.; Shiota, T.; Murai, H.; Nakamura, Y.
J. Med. Chem. 2013, 56, 4343–4356; (b) Swahn, B. M.; Huerta, F.; Kallin, E.;
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Med. Chem. Lett. 2005, 15, 5095–5099; (c) Bouissane, L.; El Kazzouli, S.; Léonce,
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Lett. 2014, 24, 1327–1333.
Br
Pd(OAc)2 (5 mol%)
RuPhos (10 mol%)
Dioxane/H2O
Het
N
H2N
OH
B
OH
H2N
N
Het
+
N
H
N
K3PO4,
140°C
H
1
2
3
O
O
S
N
O
N
2. (a) Walser, A.; Zally, W. J.; Ian Fryer, R. J. Heterocycl. Chem. 1974, 11, 863–866;
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H2N
H2N
H2N
H2N
N
N
N
N
N
H
N
H
N
N
H
H
5b, 90%
Ph
5a, 91%
5c, 89%
5d, 91%
N
N
N
S
H2N
H2N
H2N
H2N
N
N
N
N
N
N
N
N
H
H
H
H
5h, 78%c
5g, 65%c
5f, 68%
5e, 75%
N
5. (a) Suleyman, S.; Rustem, A. Z. Synth. Commun. 2002, 32, 3399–3405; (b) Li, X.;
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H2N
N
N
H
5i, 32%c, d
a
Reaction conditions: 3-bromo-1H-indazol-5-amine (0.6 mmol), heteroaryl-
boronic acids (0.9 mmol), Pd(OAc)2 (5 mol %), RuPhos (10 mol %), K3PO4 (1.2 mmol),
dioxane/H2O = 1/1 (5 mL), 140 oC, 30 min, microwave-assisted conditions.
b
Isolated yields based on 2.
Heteroarylboronic acids (1.2 mmol).
H NMR contained 10% 4,40-bipyridine.
c
d
In summary, we have developed a more direct and efficient cat-
alytic system for the synthesis of 3-aryl-1H-indazol-5-amine from
3-bromo-1H-indazol-5-amine using Pd-catalyzed Suzuki–Miyaura
reactions under microwave-assisted conditions. The catalyst and
ligand are commercially available. The reaction system is applica-
ble to a wide range of substrates and produces a variety of densely
functionalized 3-aryl-1H-indazol-5-amine in good to excellent
yields within a very short time.
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Acknowledgments
We are grateful to the Natural Science Foundation of China
(20772114, 21172200), the Innovation Fund for Outstanding
Scholar of Henan Province (0621001100) and the Research
Program of Fundamental and Advanced Technology of Henan
Province (122300413203) for financial support.
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