Copper(I) salt/PEG-400 catalysis in one-pot direct synthesis of 1-aryl-1H-indazoles from 2-bromobenzaldehydes and arylhydrazines

Article abstract of DOI:10.1002/aoc.2956

2-Bromobenzaldehydes are condensed and cyclized with arylhydrazines (or their hydrochlorides) in PEG-400 at 110 °C in the presence of a catalytic amount of a copper(I) salt along with a base to give 1-aryl-1H-indazoles in high yields. Copyright 2013 John Wiley & Sons, Ltd. Condensation of 2-bromobenzaldehydes with arylhydrazines (or their hydrochlorides) followed by C-N bond formation in PEG-400 in the presence of a copper(I) salt along with a base affords 1-aryl-1H-indazoles. Copyright

Full text of DOI:10.1002/aoc.2956

Full Paper
Received: 17 October 2012
Revised: 16 November 2012
Accepted: 30 November 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2956
Copper(I) salt/PEG-400 catalysis in one-pot
direct synthesis of 1-aryl-1H-indazoles from
2-bromobenzaldehydes and arylhydrazines
Yeon Kyu Bae and Chan Sik Cho*
2-Bromobenzaldehydes are condensed and cyclized with arylhydrazines (or their hydrochlorides) in PEG-400 at 110 ꢀC in
the presence of a catalytic amount of a copper(I) salt along with a base to give 1-aryl-1H-indazoles in high yields. Copyright
© 2013 John Wiley & Sons, Ltd.
Keywords: 1-aryl-1H-indazoles; arylhydrazines; CÀN bond formation; copper(I) salts; cyclization; PEG-400
equimolar amount of 2a in PEG-400 in the presence of a catalytic
Introduction
amount of CuI (10mol%) along with NaOtBu afforded 1-phenyl-
It is known that many indazole-containing compounds exhibit a
wide spectrum of pharmacological and biological activities such
as antidepressant, contraceptive, antitumor, anti-inflammatory,
and anti-HIV activities.[1] Thus, besides conventional methods,
transition metal-catalyzed synthetic approaches have been
attempted because of the facility and efficiency of reaction and
the wide availability of substrate. After the discovery of palla-
dium-catalyzed sp2-carbon–nitrogen bond-forming reaction by
the cross-coupling of aryl halides (or triflates) with primary and
secondary amines,[2–4] 1-aryl-1H-indazoles also could be formed
by such a palladium-catalyzed intramolecular amination of
arylhydrazones of o-halo aromatic carbonyl compounds.[5–10]
However, these precedents have some drawbacks requiring
cumbersome step-by-step procedure from easily available
commercial products, o-halo aromatic carbonyl compounds and
arylhydrazines (Scheme 1), as well as an expensive consumable
palladium catalyst combined with a ligand. To overcome these
drawbacks, several groups have disclosed convenient and
economical protocols. We reported on the one-pot direct procedure
for 1-aryl-1H-indazoles from 2-bromobenzaldehydes and arylhydra-
zines in the presence of a palladium catalyst combined with a phos-
phorus chelating ligand.[11] It was also disclosed that several copper
salts in combination with a ligand can be used to catalyze such an
intramolecular amination of arylhydrazones of o-halo aromatic
carbonyl compounds leading to 1-aryl-1H-indazoles.[12–15] Ding
et al. recently reported on a ligand-free CuI-catalyzed two-step synthe-
sis of 1-aryl-1H-indazoles from o-halo aromatic carbonyl compounds
and arylhydrazines.[16] Under these circumstances, this report
describes an efficient ligand-free copper salt-catalyzed one-pot
procedure in PEG-400 for the synthesis of 1-aryl-1H-indazoles from
2-bromobenzaldehydes and arylhydrazines (or their hydrochlorides).
1H-indazole (3a) in 85% isolated yield with complete conversion
of 1a, which was monitored until 1a had disappeared on thin-layer
chromatography (entry 1). In view of the availability of the
hydrazine counterpart, it is desirable to use arylhydrazine hydro-
chloride since most commercially available arylhydrazines are sold
as their hydrochloride salts. A similar yield of 3a was observed with
the use of phenylhydrazine hydrochloride in place of phenylhydra-
zine under the employed conditions (entry 2). Among bases
examined under the employment of CuI and PEG-400, Cs2CO3
and K3PO4 were shown to be as effective as that using NaOtBu,
whereas K2CO3 was not effective for the present amination (entries
3–5). Similar catalytic activity to CuI was observed with several cop-
per(I) salts such as CuCl and CuBr in combination with NaOtBu and
PEG-400 (entries 6–8). Here again, phenylhydrazine hydrochloride
also could be used in place of phenylhydrazine without any loss
of the yield of 3a under CuI/Cs2CO3 and CuBr/NaOtBu (entries 9
and 10). Among the solvents examined under the employment of
CuI and NaOtBu, PEG-400 in terms of product 3a yield and
complete conversion of 1a was shown to be the solvent of choice
(entries 11–13). This result indicates that PEG-400 plays a pivotal
role in the present reaction. It is reported by several groups that
poly(ethylene glycol) (PEG) is used as an efficient medium in
transition metal-catalyzed reactions.[17–27]
Based on optimized reaction conditions such as CuI/NaOtBu/
H2NNHAr (condition A), CuI/NaOtBu/HClÁH2NNHAr (condition B),
CuI/Cs2CO3/HClÁH2NNHAr (condition C) and CuBr/NaOtBu/
HClÁH2NNHAr (condition D), various 2-bromobenzaldehydes and
their analogues were subjected to the reaction with arylhydrazines
(or their hydrochloride salts) in order to investigate the reaction
scope, and several representative results are summarized in Table 2.
2-Bromobezaldehyde (1a) was readily cyclized with an array of
Results and Discussion
*
Correspondence to: Chan Sik Cho, Department of Applied Chemistry, Kyungpook
National University, Daegu 702–701, South Korea. E-mail: cscho@knu.ac.kr
The results of several attempted cyclizations of 2-bromobenzalde-
hyde (1a) with phenylhydrazine (2a) for the optimization of
reaction conditions are listed in Table 1. Treatment of 1a with an
Department of Applied Chemistry, Kyungpook National University,
Daegu 702-701, South Korea
Appl. Organometal. Chem. 2013, 27, 224–227
Copyright © 2013 John Wiley & Sons, Ltd.

Copper(I) salt/PEG-400 catalysis
Scheme 1. Synthesis of 1-aryl-1H-indazoles.
Table 1. Optimization of conditions for the reaction of 1a with 2aa
Entry
Copper catalyst
Bases
Solvents
Time (h)
Yield (%)
1
CuI
NaOtBu
NaOtBu
Cs2CO3
K3PO4
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
DMF
2
2
3
3
3
5
5
5
6
6
5
5
5
85
80
83
79
49
78
83
68
80
81
47
46
0
2b
CuI
3
CuI
4
CuI
5
CuI
K2CO3
6
CuCl
CuBr
CuOAc
CuI
NaOtBu
NaOtBu
NaOtBu
Cs2CO3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
7
8
9b
10b
11
12
13
CuBr
CuI
CuI
ethylene glycol
toluene
CuI
aReaction conditions: 1a (1 mmol), 2a (1 mmol), copper catalyst (0.1 mmol), base (2 mmol), solvent (3 ml), 110 ꢀC.
bPhenylhydrazine hydrochloride was used in place of phenylhydrazine.
arylhydrazines (or arylhydrazine hydrochloride salts) (2a–i) having
electron-donating and -withdrawing substituents on the aromatic
ring to give the corresponding 1-aryl-1H-indazoles (3a–i) in the range
of 40–89% isolated yields. Judging from the reaction of 1a with 2b–d
having electron-donating methyl substituent, the product yield had
relevance to the position of the substituent on the aromatic ring of
2b–d. With meta-methyl-substituted 2c, the product yield was
generally higher than that when para-methyl-substituted 2b and
ortho-methyl-substituted 2d were used. The reaction with 2d
proceeded invariably under the employed conditions B–D. However,
in the reaction with 2f–i having electron-withdrawing substituents,
the product yield was not significantly affected by the position of
the substituent. From the reactions between several 2-bromobenzal-
dehydes 1b–d and 2a, the corresponding 1-phenyl-1H-indazoles
(3j–l) were also produced in high yields irrespective of the examined
functional groups on the aromatic ring of 1b–d. Similar treatment of
2-bromonaphthalene-1-carbaldehyde (1e)[28,29] under condition D
also afforded the cyclized product 3m, however, the yield was lower
than when 2-bromobenzaldehydes (1a–d) were used. 2-Bromopyri-
dine-3-carbaldehyde (1f) and 3-bromopyridine-4-carbaldehyde
(1g)[30] were also cyclized under the employed condition B to give
1-phenyl-1H-pyrazolo[3,4-b]pyridine (3n) and 1-phenyl-1H-pyrazolo
[3,4-c]pyridine (3o) in 88% and 70% yields, respectively. However,
not shown in Table 2, similar treatment of 1a with methylhydazine
did not afford 1-methyl-1H-indazole at all. It is difficult to know
why arylhydazines are only available for the present system.
initially formed in situ from copper salt and PEG-400, produces
an arylcopper complex 6. This is followed by intramolecular clo-
sure to give a complex 7 which can reductively eliminate to
afford 1-aryl-1H-indazole 3.
Conclusion
In summary, we have demonstrated that 2-bromobenzaldehydes
react with arylhydrazines (or their hydrochlorides) in PEG-400 in
the presence of a copper(I) salt along with a base to give 1-aryl-
1H-indazoles in high yields. The present reaction provides an
efficient ligand-free copper(I) salt-catalyzed one-pot procedure
for the synthesis of 1-aryl-1H-indazoles from 2-bromobenzalde-
hydes and arylhydrazines. Further study of synthetic applications
using a ligand-free catalytic system of copper(I) salts/PEG-400 is
in progress.
Experimental
1H and 13C NMR (400 and 100 MHz) spectra were recorded on a
Bruker Avance Digital 400 spectrometer using tetramethylsilane
as an internal standard. Melting points were determined on a
Stanford Research Inc. MPA100 automated melting point
apparatus. The isolation of pure products was carried out via thin-
layer (silica gel 60 GF254, Merck) or column (silica gel 60, 70–230 mesh,
Merck) chromatography. 2-Bromonaphthalene-1-carbaldehyde
(1e) was synthesized in two steps: initial treatment of 2-tetralone
Although the details of the reaction scheme are not certain, a
plausible pathway is presented in Scheme 2. Oxidative addition
of the carbon–bromide bond of hydrazone 4 to a complex 5,
Appl. Organometal. Chem. 2013, 27, 224–227
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Table 2. Cul-calayzed synthesis of 1-aryl-1H-indazolesa
under bromination conditions of the Vilsmeier–Haack reaction
(PBr3/DMF/CHCl3) to produce 2-bromo-3,4-dihydro-1-naphthalde-
hyde and aromatization of 2-bromo-3,4-dihydro-1-naphthaldehyde
under 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.[28,29] 3-Bromo-
pyridine-4-carbaldehyde (1 g) was prepared by the treatment of
3-bromopyridine with lithium diisopropylamide and DMF.[30]
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Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 224–227

Copper(I) salt/PEG-400 catalysis
C14), 127.36 (C5), 127.75 (d, JCF = 11.6 Hz, C10), 128.13 (C6),
129.44 (d, JCF = 8.0 Hz, C13), 136.37 (C3), 140.32 (C9), 156.29
(d, JCF = 251.0 Hz, C11), assignments to C4–C7 are interchangeable.
Anal. Calcd for C13H9FN2: C, 73.57; H, 4.27; N, 13.20. Found: C, 73.58;
H, 4.34; N, 13.11.
1
Solid. m.p. 167–168 ꢀC (hexane–chloroform). H NMR (400 MHz,
CDCl3) d 7.42–7.44 (m, 1H, H17), 7.50–7.54 (m, 1H, H5), 7.56–
7.60 (m, 2H, H16), 7.64–7.68 (m, 1H, H6), 7.76–7.78 (m, 4H, H4,
H7 and H15), 7.94 (d, JHH = 8.0 Hz, 1H, H9), 8.29 (d, JHH = 8.0 Hz,
1H, H8), 8.62 (s, 1H, H3), assignments to H5, H6 and H17 are inter-
changeable. 13C NMR (100 MHz, CDCl3) d 111.42 (C9), 121.04
(C11), 123.21 (C8), 123.64 (C15), 125.06 (C17), 127.44 (C4),
127.53 (C12), 127.75 (C5), 128.87 (C6), 128.91 (C7), 129.74 (C16),
129.82 (C10), 134.31 (C3), 137.33 (C13), 140.17 (C14), assignments
to C4–C7 are interchangeable. Anal. Calcd for C17H12N2: C, 83.58;
H, 4.95; N, 11.47. Found: C, 83.50; H, 4.91; N, 11.45.
Scheme 2. A catalytic cycle.
Commercially available organic and inorganic compounds were
used without further purification.
Acknowledgments
General Procedure for Copper(I) Salt-Catalyzed Synthesis of
1-Aryl-1H-Indazoles from 2-Bromobenzaldehydes and Aryl-
hydrazines (or their Hydrochlorides)
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Tech-
nology (2012–0002856) and Kyungpook National University
Research Fund, 2012.
To an organic reactor (Radleys Discovery Technologies) were added
2-bromobenzaldehyde 1 (1mmol), arylhydrazine (or arylhydrazine
hydrochloride) 2 (1mmol), copper salt (0.05 mmol), base (2mmol)
and solvent (3ml). The system was stirred at 110ꢀC for an appropri-
ate time. The reaction mixture was cooled to room temperature,
poured into water and extracted with ethyl acetate twice. The
combined organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The crude mixture was purified by thin-
layer (silica gel 60 GF254, Merck) or column (silica gel 60, 70–230
mesh, Merck) chromatography (ethyl acetate–hexane mixture) to
give 1-aryl-1H-indazoles 2. Except for 3f, 3i and 3 m (Fig. 1), all pro-
ducts are known.[6,11,16,31,32]
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(m, 1H, H7), 7.45–7.49 (m, 2H, H5 and H6), 7.65–7.67 (m, 1H, H4),
7.76–7.83 (m, 3H, H11, H13 and H15), 8.22 (d, JHH = 0.8 Hz, 1H, H3).
13C NMR (100 MHz, CDCl3) d 110.51 (C7), 120.60 (C11), 121.72
(C15), 122.11 (C4), 122.89 (C5), 125.74 (C8), 126.76 (C13), 127.76
(C6), 130.66 (C14), 135.35 (C12), 136.26 (C3), 138.81 (C9), 141.47
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C12), 121.28 (C7), 121.74 (C4), 124.83 (C8), 125.08 (d, JCF = 3.6 Hz,
3f
3i
8
3m
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4
4
7
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N
2
12
N
9
3
9 N
1
1
7
11
10
10
F
11
12
N
15
2
8
15
11
Cl
N
13
1
9
14
14
14
12
15
16
15
16
13
13
17
Figure 1. Structures of products 3f, 3i and 3 m.
Appl. Organometal. Chem. 2013, 27, 224–227
Copyright © 2013 John Wiley & Sons, Ltd.
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