Efficient synthesis of 1-aryl-1H-indazole derivatives via copper(I)-catalyzed intramolecular amination reaction

Article abstract of DOI:10.1080/00397910701750250

A copper(I)-catalyzed intramolecular amination reaction using CuI, KOH, and 1,4-dioxane at 105°C for the preparation of 1-aryl-1H-indazole derivatives was described. The method was applied to a wide scope of substrates and afforded indazole products in hi

Full text of DOI:10.1080/00397910701750250

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Efficient Synthesis of 1‐Aryl‐1H‐indazole
Derivatives via Copper(I)‐Catalyzed
Intramolecular Amination Reaction
Rui Liu a , Yongming Zhu a , Liena Qin a & Shunjun Ji a
a College of Pharmacy, Soochow University, Suzhou, China
Published online: 18 Jan 2008.
To cite this article: Rui Liu , Yongming Zhu , Liena Qin & Shunjun Ji (2008): Efficient Synthesis of
1‐Aryl‐1H‐indazole Derivatives via Copper(I)‐Catalyzed Intramolecular Amination Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:2,
249-254
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Synthetic Communicationsw, 38: 249–254, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701750250
Efficient Synthesis of 1-Aryl-1H-indazole
Derivatives via Copper(I)-Catalyzed
Intramolecular Amination Reaction
Rui Liu, Yongming Zhu, Liena Qin, and Shunjun Ji
College of Pharmacy, Soochow University, Suzhou, China
Abstract: A copper(I)-catalyzed intramolecular amination reaction using CuI, KOH,
and 1,4-dioxane at 1058C for the preparation of 1-aryl-1H-indazole derivatives was
described. The method was applied to a wide scope of substrates and afforded
indazole products in high yields.
Keywords: arylhydrazones, copper(I) iodide, indazole, intramolecular amination,
1,10-phenanthroline
The indazole is an important subunit in drugs with high biological activities such
as antitumor, anti-HIV, antidepressant, and contraceptive activities.[1–6] Varied
methods exist for their synthesis. Two strategies via palladium catalysts are (1)
synthesis of 1-aryl-1H-indazoles via the palladium-catalyzed cyclization of
N-aryl-N0-(o-bromobenzyl)hydrazines and [N-aryl-N0-(o-bromo benzyl)-hydra-
zinato-N0]-triphenylphoshponium bromides[7] and (2) palladium-catalyzed
cyclization of arylhydrazones of 2-bromoaldehydes and 2-bromoacetophenones
to give 1-aryl-1H-indazoles. Nevertheless, the high price of Pd renders commer-
cial processes based on Pd less attractive unless extremely active and/or recycl-
able catalysts are available. For these reasons, much recent attention has been
paid to employing less expensive transition-metal catalyst complexes, in particu-
lar, copper, to replace the palladium. Herein we describe a versatile method for
Received in Japan May 5, 2007
Address correspondence to Yongming Zhu, College of Pharmacy, Soochow
University, Suzhou 215123, China. E-mail: zhuyongming@suda.edu.cn
249

250
R. Liu et al.
Scheme 1.
the preparation of 1-aryl-1H-indazoles that is catalyzed by copper(I). Our
synthetic pathway is depicted in Scheme 1.
The starting material 1a (R1 ¼ R2 ¼ H) was readily prepared by a
modified literature procedure.[8] The following cyclization reaction was inves-
tigated using copper(I) iodide as catalyst. Based upon the Buchwald method,[9]
CuI was used for the intramolecular amination of 1a (R1 ¼ R2 ¼ H), but only
a trace amount of the target product 2a (R1 ¼ R2 ¼ H) was isolated. In our
investigation of the experimental processes, bases were found to have a
dramatic influence on the reaction outcomes. The conjunction with KOH as
base provided the product in 69% yield. Replacement of base with K2CO3,
Cs2CO3, or K3PO4 led to a sharp drop of yield. A strong base such as
tBuONa may induce side reactions with a poor yield. The dosages of the
bases and the optimal reaction time were also tested. 1,4-Dioxane was used
as solvent, affording better yield than toluene or THF for its good solubility.
Brief studies of the effect of ligand addition was also carried out. Employment
of 1,10-phenanthroline as a ligand in combination with KOH yielded a good
result, but replacement with ethylenediamine resulted in a decreased yield.
Reasonable results were not achieved using a ligandless catalytic system. It
was also noted that the use of CuBr for cyclization afforded a slightly lower
yield. Reaction without copper(I) catalyst presented no desired product. The
conditions for the intramolecular amination reaction are summarized in
Table 1. The best result with 82% yield was obtained by the reac-
tion condition with CuI (5 mol%)/1,10-phenanthroline (10 mol%)/KOH
(200 mol%) at 100–1058C for 5 h in anhydrous 1,4-dioxane.
With these results, we examined the scope and generality of this new
protocol. The results are summarized in Table 2. The standard reaction
condition is applicable to the synthesis of a wide variety of indazoles. The
hydrazone with nitro group need 12 h to finish the cyclization reaction (entry
4), because of the poor solubility in dioxane. Hydrazone, which was syn-
thesized from alkyl-aromatic ketone, provided the desired molecule in good
yield (entry 8). The hydrazone containing a pyridine ring was also going
through a cyclization reaction smoothly (entry 9). Methoxy, methyl, and
fluoro groups were all tolerated under this reaction condition. We found this
reaction condition provided access not only to electron-rich substrates but
also to derivatives bearing electron-withdrawing groups. We also examined

1-Aryl-1H-indazole Derivatives
251
Table 1. Optimization of reaction conditions in copper-catalyzed intramolecular
amination of 1aa
Time
(h)
Yield
(%)b
Base (mol%)
Solvent
Catalyst
Ligand
KOH (100)
KOH (150)
KOH (200)
KOH (250)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
K2CO3 (200)
K3PO4 (200)
Cs2CO3 (200)
Cs2CO3 (200)
tBuONa (200)
KOH (200)
KOH (200)
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
Ethylenediamine
5
5
,10
69
5
82
80
5
10
20
5
69
67
,10
55
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
5
5
,10
0
No ligand
5
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
5
,10
41
5
5
48
36
5
Dioxane
Dioxane
Dioxane
5
,10
45
5
No metal 1,10-Phenanthroline
5
0
aReaction was carried out in a pressure tube. A solution of 1a, CuI, ligand and base in
anhydrous solvent was heated at 100–1058C for 5 h; cyclization product 2a was
obtained.
bIsolated yields were obtained after chromatography.
the behaviors of substrates having chloride in the intramolecular amination
reaction, but only a trace amount of the target product was isolated (entry 10).
In summary, we developed a simple, economical, and efficient method for
the synthesis of 1-aryl-1H-indazoles derivatives from various arylhydrazones
using commercially available copper(I) iodide as an effective catalyst. The
reaction, which is finished in a short time and provides excellent product
yields, makes this methodology an alternative platform to the conventional
synthesis of indazoles processes. Further studies are currently under way to
expand the reaction in our laboratory.
EXPERIMENTAL
General Procedure for the Preparation of 2 from 1
The staring material 1 (1.0 mmol), anhydrous 1,4-dioxane (2.5 mL), CuI
(10 mg, 0.05 mmol), 1,10-phenanthroline (18 mg, 0.1 mmol), and KOH

252
R. Liu et al.
Table 2. Copper-catalyzed intramolecular amination reaction for synthesis of 1-aryl-
1H-indazoles
Entry
1
Substrate
Product
Yield (%)a
82
2
90
3
4
5
6
80
85
70
77
7
8
63
71
(continued)

1-Aryl-1H-indazole Derivatives
Table 2. Continued
253
Entry
9
Substrate
Product
Yield (%)a
71
10
10
aIsolated yields were obtained after chromatagraphy.
(112 mg, 2.0 mmol) were placed in a pressure tube, and the tube was sealed
after filling with N2. Reaction was initiated by heating, and temperature was
kept at 100–1058C for 5 h. The solution was filtered through a Celitew pad,
and the filtrate was evaporated. The residue was purified by flash-column
chromatography (silica gel, petroleum ether–ethyl acetate) to afford the
desired product 2 as white crystals.
Spectral Data for the New Compounds
2-Bromobenzaldehyde 4-nitrophenylhydrazone: white crystals, mp 255.8–
1
256.48C. H NMR (400 MHz, CDCl3): d 7.141 (d, J ¼ 8.8 Hz, 2H), 7.195–
7.245 (m, 3H), 7.355 (t, J ¼ 7.2 Hz, 1H), 7.562 (d, J ¼ 8.0 Hz, 1H), 8.057
(d, J ¼ 8.0 Hz, 1H), 8.188 (d, J ¼ 7.6 Hz, 2H). 13C NMR (400 MHz,
CDCl3): 109.613, 111.765, 117.484, 122.861, 126.414, 127.020, 128.305,
131.081, 133.359, 133.455, 139.058, 139.917, 150.255. HRMS: calcd. for
C13H10BrN3O2: 320.9936; found: 320.9941.
1-(4-Nitrophenyl)-1H-indazole: white crystals, mp 127.5–128.98C. 1H
NMR (400 MHz, CDCl3): d 7.329 (t, J ¼ 7.6 Hz, 1H), 7.546 (t, J ¼ 6.8 Hz,
1H), 7.864 (t, J ¼ 7.6 Hz, 2H), 7.997 (d, J ¼ 8.8 Hz, 2H), 8.291 (s, 1H),
8.431 (d, J ¼ 9.2 Hz, 2H). 13C NMR (400 MHz, CDCl3): 110.072, 111.032,
121.867, 122.409, 123.220, 125.817, 126.762, 128.780, 130.397, 138.168,
139.018, 145.487, 145.895. HRMS: calcd. for C13H9N3O2: 239.0695;
found: 239.0705.
2-Chlorobenzaldehyde phenylhydrazone: white crystals, mp 84.7–85.58C.
1H NMR (400 MHz, CDCl3): d 6.871 (t, J ¼ 7.2 Hz, 1H), 7.065–7.298
(m, 7H), 7.666 (s, 1H), 7.956 (s, 1H), 8.026 (d, J ¼ 9.6 Hz, 1H). 13C NMR
(400 MHz, CDCl3): 113.256, 120.828, 126.966, 127.302, 129.500, 129.744,

254
R. Liu et al.
130.080, 132.889, 133.072, 133.866, 144.706. HRMS: calcd. for C13H9N3O2:
230.0611; found: 230.0609.
ACKNOWLEDGMENT
This work was partially supported by the National Natural Science Foundation
of China (Grants 20472062 and 20672079) and the Natural Science Foun-
dation of Jiangsu Province (No. BK2006048).
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