Copper powder-catalyzed C-N bond formation of arylhydrazones of 2-bromobenzaldehydes leading to 1-aryl-1 H-indazoles

Article abstract of DOI:10.1080/00397911.2011.614714

Arylhydrazones of 2-bromobenzaldehydes and its analogs are cyclized in PEG-400 at 110C in the presence of a catalytic amount of copper powder along with NaO^tBu to give 1-aryl-1H-indazole derivatives in good yields.

Full text of DOI:10.1080/00397911.2011.614714

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Copper Powder–Catalyzed C-N Bond
Formation of Arylhydrazones of 2-
Bromobenzaldehydes Leading to 1-
Aryl-1H-indazoles
Hye Kyung Lee a & Chan Sik Cho a
a Department of Applied Chemistry, Kyungpook National University,
Daegu, South Korea
Accepted author version posted online: 21 Feb 2012.Version of
record first published: 21 Dec 2012.
To cite this article: Hye Kyung Lee & Chan Sik Cho (2013): Copper Powder–Catalyzed C-N Bond
Formation of Arylhydrazones of 2-Bromobenzaldehydes Leading to 1-Aryl-1H-indazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:6, 915-921
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Synthetic Communications1, 43: 915–921, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.614714
COPPER POWDER–CATALYZED C-N BOND
FORMATION OF ARYLHYDRAZONES OF
2-BROMOBENZALDEHYDES LEADING TO 1-ARYL-1H-
INDAZOLES
Hye Kyung Lee and Chan Sik Cho
Department of Applied Chemistry, Kyungpook National University, Daegu,
South Korea
GRAPHICAL ABSTRACT
Abstract Arylhydrazones of 2-bromobenzaldehydes and its analogs are cyclized in PEG-400
at 110 ꢀC in the presence of a catalytic amount of copper powder along with NaOtBu to give
1-aryl-1H-indazole derivatives in good yields.
Keywords 1-Aryl-1H-indazoles; arylhydrazones; C-N bond formation; copper powder
INTRODUCTION
It is known that 1-aryl-1H-indazoles show a broad spectrum of pharmacologi-
cal and biological properties such as antidepressant, contraceptive, antitumors, anti-
inflammatory, and anti-HIV activities.[1] Thus, many conventional synthetic
methods have been used for the construction of 1-aryl-1H-indazoles.[1] 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. On the other hand, after the discovery of palladium-catalyzed
sp2-carbon-nitrogen bond-forming reaction by the cross-coupling of aryl halides (or
triflates) with primary and secondary amines,[2–4] several N-heterocycles could be
synthesized by such an amination protocol.[5–9] Among them, 1-aryl-1H-indazoles
can be formed by palladium-catalyzed intramolecular amination of arylhydrazones
of o-halo aromatic carbonyl compounds.[10–15] It is also worth noting that several cop-
per salts in combination with a ligand can be used to catalyze such an intramolecular
amination.[16–19] We also reported on the direct synthesis of 1-aryl-1H-indazoles from
2-bromobenzaldehydes and arylhydrazines in the presence of a palladium catalyst
Received July 5, 2011.
Address correspondence to Chan Sik Cho, Department of Applied Chemistry, Kyungpook
National University, Daegu 702-701, South Korea. E-mail: cscho@knu.ac.kr
915

916
H. K. LEE AND C. S. CHO
combined with a phosphorus chelating ligand.[20] Under these circumstances, the
amination protocol led us to seek a cheap catalyst alternative that exhibits a similar
catalytic activity.[21] Herein, this report describes a copper powder–catalyzed intra-
molecular amination of arylhydrazones of 2-bromobenzaldehydes and its analogs,
leading to 1-aryl-1H-indazole derivatives.
RESULTS AND DISCUSSION
Based on our report on palladium-catalyzed synthesis of 1-aryl-1H-indazoles
from 2-bromobenzaldehydes and arylhydrazines,[20] we initially attempted to synthe-
size 1-aryl-1H-indazoles directly from bromobenzaldehydes and arylhydrazines in
the presence of copper powder. Thus, treatment of equimolar amounts of 2-bromo-
benzaldehyde and phenylhydrazine in polyethylene glycol (PEG-400) in the presence
of a catalytic amount of copper powder (10 mol%) along with NaOtBu (2 equiv) at
110 ꢀC for 12 h afforded 1-phenyl-1H-indazole in 66% isolated yield. However, to
achieve a more satisfactory result, intramolecular C-N bond-forming reactions with
phenylhydazone of 2-bromobenzaldehyde 1a, which is readily prepared from 2-bro-
mobenzaldehyde and phenylhydrazine, were carried out under various conditions,
and the results of several attempted cyclizations of 1a for the optimization conditions
are listed in Table 1. Treatment of 1a under similar conditions [copper powder
(10 mol%), NaOtBu (2 equiv), PEG-400, at 110 ꢀC] for 1 h afforded 1-phenyl-1H-
indazole (2a) in 53% yield (entry 1). The yield of 2a increases with prolonging the
reaction time up to 5 h (entry 2). The reaction did not proceed at all without the
addition of copper powder (entry 3). Lower yield and conversion were observed in
solvents such as DMF and DMSO (entries 4 and 5). The reaction proceeded using
Table 1. Optimization of conditions for the cyclization of 1aa
Entry
Copper catalyst
Base
Solvent
Time (h)
Isolated yield (%)
1
2
Cu
Cu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
K3PO4
PEG-400
PEG-400
PEG-400
DMF
1
5
5
5
5
5
5
5
5
5
5
53
91
0
3
—
Cu
4
39
4
5
Cu
Cu
DMSO
PEG-400
PEG-400
PEG-400
DMF
6
76
72
21
68
58
59
7
Cu
Cs2CO3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
8
CuI
CuI
CuI=2PPh3
CuCl
9
10
11
DMF
DMF
aReaction conditions: 1a (0.5 mmol), copper catalyst (0.05 mmol), base (1 mmol), solvent (5 mL), 110 ꢀC,
under N2.

COPPER POWDER–CATALYZED C-N BONDS
917
Table 2. Cu powder–catalyzed intramolecular amination of 1 leading to 2a
Hydrazones 1
Time (h)
Indazole derivatives 2
Isolated yield (%)
1a Ar ¼ Ph
5
5
2a Ar ¼ Ph
91
65
95
85
40
79
43
76
53
80
1b Ar ¼ 4-MeC6H4
1c Ar ¼ 4-MeOC6H4
1d Ar ¼ 4-FC6H4
1e Ar ¼ 3-MeC6H4
1f Ar ¼ 3-ClC6H4
1g Ar ¼ 2-ClC6H4
1h Ar ¼ 2-FC6H4
1i Ar ¼ 2,5-Cl2C6H3
2b Ar ¼ 4-MeC6H4
2c Ar ¼ 4-MeOC6H4
2d Ar ¼ 4-FC6H4
2e Ar ¼ 3-MeC6H4
2f Ar ¼ 3-ClC6H4
2g Ar ¼ 2-ClC6H4
2h Ar ¼ 2-FC6H4
2i Ar ¼ 2,5-Cl2C6H3
20
20
20
12
20
20
20
5
5
5
73
81
90
20
20
20
10
0
aReaction conditions: 1 (0.5 mmol), Cu powder (0.05 mmol), NaOtBu (1 mmol), PEG-400 (3 mL),
110 ꢀC, under N2.

918
H. K. LEE AND C. S. CHO
other bases such as K3PO4 and Cs2CO3 in place of NaOtBu, but the yield of 2a was
generally lower than that by the use of NaOtBu (entries 6 and 7). Among copper salts
examined, CuI was found to be ineffective compared with copper powder in
PEG-400 (entries 2 and 8). However, with several copper salts such as CuI, CuI=
PPh3, and CuCl in DMF, the yield of 2a was generally higher than that when copper
powder in DMF was used (entries 4, 9–11). As a result, the best result in terms of
both yield and complete conversion of 1a is accomplished by the standard set of
reaction conditions shown in entry 2 of Table 1.
After the reaction conditions have been established, various hydrazones, which
are readily available from the corresponding halo carbonyl compounds and hydra-
zines, were screened in order to investigate the reaction scope and synthesize various
1-aryl-1H-indazole derivatives. Several representative results are summarized in
Table 2. An array of arylhydrazones of 2-bromobenzaldehyde (1a-i) having
electron-donating and –withdrawing substituents on the aromatic ring of arylhydra-
zine counterpart were readily cyclized to give the corresponding 1-aryl-1H-indazoles
(2a–i) in the range of 43–95% isolated yields. In almost all cases, a longer reaction
time was needed for the effective formation of 1-aryl-1H-indazoles. The cyclization
proceeds likewise with phenylhydrazones (1j and 1k), which were prepared from
fluoro- and methoxy group substituted 2-bromobenzaldehydes and phenylhydrazine,
to give the corresponding 1-aryl-1H-indazoles (2j and 2k) in similar yields.
Phenylhydrazone of 3-bromopyridine-4-carbaldehyde 1l was also cyclized under
the employed conditions to give 1-phenyl-1H-pyrazolo[3,4-c]pyridine (2l) in 81%
yield. In the reaction of phenylhydrazone of 20-bromoacetophenone (1 m) for
20 h, 3-methyl-1-phenyl-1H-indazole (2 m) was also obtained in 90% yield.
However, lower reaction rate and yield were observed with phenylhydrazone of
2-bromocyclohex-1-enecarbaldehyde (1n), with the cyclized product 1-phenyl-
4,5,6,7-tetrahydro-1H-indazole (2n) being obtained in only 10% yield for 20 h. In
the case of methylhydrazone of 2-bromobenzaldehyde 1o, the reaction did not
proceed at all toward cyclization and the starting hydrazone was recovered almost
completely.
CONCLUSION
In summary, it has been shown that arylhydrazones of 2-bromobenzaldehydes
and its analogs are intramolecularly cyclized in the presence of a catalytic amount of
copper powder along with NaOtBu in PEG-400 to give 1-aryl-1H-indazoles and its
analogs in good yields. The present reaction provides a cheaper catalytic system in
sp2-carbon–nitrogen bond-forming reactions and further study of synthetic applica-
tions using copper powder catalyst is in progress.
EXPERIMENTAL
1H and 13C NMR (400 and 100 MHz) spectra were recorded on a Bruker
Avance Digital 400 spectrometer using tetramethylsilane (TMS) as an internal stan-
dard. Melting points were determined on a Standford Research Inc. MPA100 auto-
mated melting-point apparatus. Gas–liquid chromatographic (GLC) analyses were
carried out with a Shimadzu GC-17A instrument equipped with a CBP10-S25-050

COPPER POWDER–CATALYZED C-N BONDS
919
column (Shimadzu, fused silica capillary column, 0.33 mm ꢁ 25 m, 0.25 mm film
thickness) using nitrogen as carrier gas. The isolation of pure products was carried
out via thin-layer (silica gel 60 GF254, Merck) chromatography. All hydrazones 1
were prepared by the reported method.[11] Copper powder (100 mesh, 99.5%) was
purchased from Strem. Commercially available organic and inorganic compounds
were used without further purification.
General Procedure for Copper Powder–Catalyzed Synthesis of
1-Aryl-1H-indazoles and Their Analogs
Hydrazone 1 (0.5 mmol), copper powder (0.05 mmol), NaOtBu (0.096 g,
1 mmol), and PEG-400 (3 mL) were added to an organic reactor (Radleys Discovery
Technologies). After the system was flushed with N2, the mixture was stirred at
110 ꢀC for an appropriate time. The reaction mixture was cooled down to room tem-
perature, poured into water, and extracted with ethyl acetate. The combined organic
layer was dried over Na2SO4 and concentrated under reduced pressure. The crude
mixture was purified by thin-layer chromatography (silica gel, ethyl acetate–hexane
mixture) to give 1-aryl-1H-indazoles and its analogs 2. All products prepared by this
procedure were characterized by GLC, melting point, and spectroscopic comparison
with authentic samples synthesized by the method of recent reports.[9,11,16,20] Spec-
troscopic data for new products are shown.
1-(3-Chlorophenyl)-1H-indazole (2f)
1
Oil. H NMR (400 MHz, CDCl3) d 7.24–7.28 (m, 1H), 7.32–7.35 (m, 1H),
7.45–7.49 (m, 2H), 7.65–7.67 (m, 1H), 7.76–7.83 (m, 3H), 8.22 (d, J ¼ 0.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) d 110.5, 120.6, 121.7, 122.1, 122.9, 125.7, 126.8,
127.8, 130.7, 135.4, 136.3, 138.8, 141.5. Anal calcd. for C13H9ClN2: C, 68.28; H,
3.97; N, 12.25. Found: C, 68.25; H, 4.14; N, 12.33.
1-(2-Fluorophenyl)-1H-indazole (2h)
1
Solid, mp 83–85 ꢀC (hexane–ethyl acetate). H NMR (400 MHz, CDCl3) d
7.22–7.26 (m, 1H), 7.30–7.35 (m, 2H), 7.39–7.46 (m, 3H), 7.61–7.65 (m, 1H), 7.81
(dt, J ¼ 8.1 and 1.0 Hz, 1H), 8.26 (d, J ¼ 0.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 110.7 (d, J ¼ 5.1 Hz), 117.2 (d, J ¼ 19.6 Hz), 121.3, 121.7, 124.9 (d, J ¼ 23.3 Hz),
125.1, 127.4, 127.8 (d, J ¼ 11.6 Hz), 128.1, 129.4 (d, J ¼ 8.0 Hz), 136.4, 140.3, 156.3
(d, J ¼ 251.0 Hz). Anal. calcd. for C13H9FN2: C, 73.57; H, 4.27; N, 13.20. Found:
C, 73.58; H, 4.34; N, 13.11.
1-(2,5-Dichlorophenyl)-1H-indazole (2i)
1
Oil. H NMR (400 MHz, CDCl3) d 7.24–7.29 (m, 2H), 7.40–7.46 (m, 2H),
7.53–7.55 (m, 2H), 7.82 (d, J ¼ 8.1 Hz, 1H), 8.25 (d, J ¼ 0.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 110.7, 121.5, 121.9, 124.6, 127.5, 129.7, 129.9, 130.0, 131.8,
133.4, 136.5, 138.2, 140.3. Anal. calcd. for C13H8Cl2N2: C, 59.34; H, 3.06; N,
10.65. Found: C, 59.48; H, 3.13; N, 10.40.

920
H. K. LEE AND C. S. CHO
ACKNOWLEDGMENT
This research was supported by Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the Ministry of Edu-
cation, Science, and Technology (2011-0005123).
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