A Facile One-Step Synthesis of 2-Arylindazoles via Reductive Cyclization of N-(2-nitroarylidene)amines

Article abstract of DOI:10.1002/jhet.2221

A mild and efficient synthesis of 2-arylindazole derivatives via the reductive cyclization of nitro-aryl substrates mediated by a low-valent titanium reagent (TiCl₄/Sm/Et₃N) has been developed. The attractive features of the current method include an N-N bond formation and the selective reduction of the =C-N bond and nitro group, both of which were easily achieved in one-pot by controlling the pH of the reaction mixture.

Full text of DOI:10.1002/jhet.2221

Month 2014 A Facile One-Step Synthesis of 2-Arylindazoles via Reductive Cyclization
of N-(2-nitroarylidene)amines
*
*
Wei Lin, Minghua Hu, Xian Feng, Chengpao Cao, Zhibin Huang, and Daqing Shi
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, People’s Republic of China
*
E-mail: zbhuang@suda.edu.cn
Received November 5, 2013
DOI 10.1002/jhet.2221
Published online in Wiley Online Library (wileyonlinelibrary.com).
A mild and efficient synthesis of 2-arylindazole derivatives via the reductive cyclization of nitro-aryl
substrates mediated by a low-valent titanium reagent (TiCl4/Sm/Et3N) has been developed. The
attractive features of the current method include an N–N bond formation and the selective reduction
of the C = N bond and nitro group, both of which were easily achieved in one-pot by controlling the
pH of the reaction mixture.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
associated with the use of each of these existing methods that
have severely limited their application, the use of expensive
catalysts (Pd, Rh) or reagents, and the requirement for forcing
reaction conditions or specialized equipment. Recently, we
reported the synthesis of 2-arylindazoles induced by a
low-valent titanium reagent [16], but this method requires
two steps: first, the N-(2-nitroarylidene)amines were reduced
by sodium borohydride to give N-(2-nitrobenzyl)aniline;
then N-(2-nitrobenzyl)anilines were cyclized to give 2-aryl-
indazoles induced by a low-valent titanium reagent. Herein
we report one-pot synthetic method to synthesis of 2-aryl-
indazoles using N-(2-nitroarylidene)amines as starting materials
mediated by low valent titanium reagent (e.q. 4, Scheme 1).
Low-valent Ti reagents have high reducing abilities and are
attracting increasing interest in organic synthesis [17].
Recently, we have focused on the synthesis of heterocyclic
compounds using low-valent Ti reagents [18]. In this paper,
we reported the novel and convenient synthesis of 2H-
indazoles via the reductive cyclization of nitro-aryl substrates
mediated by a low-valent titanium reagent (TiCl4/Sm/Et3N).
The attractive features of the current method include an N–N
bond forming reaction resulting from the reduction of the
C = N and nitro groups, both of which were easily achieved
without the need for multistep operations.
Indazole derivatives are an important class of heterocyclic
pharmaceuticals. Over the past decade, the chemistry of
indazole derivatives continues to be of interest because of
their industrial and agricultural applications and their biolog-
ical and analytical importance [1]. Indazole derivatives have
been reported for their antitumor potential [2], HIV protease
inhibition [3], antimicrobial activity [4], anti-inflammatory
[5], and contraceptive activities [6]. Recently, a number of
important biologically active compounds bearing and
2-substituted-indazole ring have been found, which can be
use as 5-HT1A receptors [7], estrogen receptor β [8], and high
affinity to the imidazoline I2 receptor [9]. A number of
synthetic access to the 1-substituted-indazoles have been
described, whereas much less attention has been paid to the
design of selective and efficient preparation of 2-
substituted-indazoles. Considering the potent bioactivities
of compounds 2-arylindazoles core have, significant efforts
have been devoted to the development of synthetic routes
toward 2-arylindazoles. Most existing methods give
mixtures of 1H- and 2H-indazoles [10], and it is difficult to
selective preparation of 2-arylindazoles, although recently,
several promising synthetic routes to 2-arylindazoles have
been reported [11]. Among them, reductive cyclization of
N-(2-nitroarylidene)amines attracts more attention because
diverse starting materials are readily available. Bose et al.
[12] and Zhao et al. [12,13] using triethyl phosphate as
reducing for the synthesis of indazoles (e.q. 1, Scheme 1).
Watanabe et al. [14] have reported PdCl2(PPh3)2)-SnCl2
catalyzed and initial CO pressure for the reductive
N-(2-nitrobenzy1idene)amine (e.q. 2 Scheme 1), and Alper
et al. [15] using Rh complex as catalyst to carry out this
reaction (e.q. 3 Scheme 1). There are several drawbacks
RESULTS AND DISCUSSION
For our preliminary evaluation of the transformation, the
reductive cyclization of 4-methoxy-N-(2-nitrobenzylidene)
aniline (1a), which was derived from the condensation of
2-nitrobenzaldehyde with 4-methoxyaniline was selected
as a model reaction. The reductive cyclization reaction of
1a was then evaluated under a variety of different conditions
© 2014 HeteroCorporation

W. Lin, M. Hu, X. Feng, C. Cao, Z. Huang, and D. Shi
Vol 000
Scheme 1. The synthesis of the 2-arylindazoles from N-(2-nitroarylidene)amines.
as triethylamine (TEA) [18b]. Pleasingly, when the
current reaction was conducted in the presence of TEA
(basic medium, pH = 8) using the TiCl4/Zn system as a
reducing reagent, the yield of the target compound 2a
was improved to 25% (Table 1, entry 2). The basic
conditions appeared to play a key role in the reaction by
hindering the reductive coupling of the C = N bond and
the complete reduction of the nitro group to the amine,
and therefore, effectively promoting the cyclization
reaction to produce the desired product 2a. To improve
the yield, different low-valent titanium systems were
evaluated. The results indicated that the TiCl4/Sm system
provided much better yields than the TiCl4/Zn and TiCl4/Fe
systems (Table 1, entries 2 and 3). To further optimize the
reaction conditions, the transformation was conducted over
a range of different pH values from pH 4 to 11 with an
increment of 1 each time. The results revealed that the yield
of product 2a increased with increasing pH from 4 to 8 -
(Table 1, entries 4–8). Further increases in the pH, however,
to pH values of 9 and 11 failed to provide any further
improvement in the yield of product 2a (Table 1, entries
9–11). Furthermore, several other bases were tested,
including piperidine and NaOH, but resulted only in lower
yields of the desired product (Table 1, entries 12–13). The
optimized conditions were therefore identified as including
the TiCl4/Sm system and TEA at a pH of 8. These conditions
were then used for all of the subsequent transformations.
in the presence of several different low-valent titanium
reagents. The results are summarized in Table 1.
Based on our previous experience of low-valent titanium
mediated reactions, we focused our efforts on the reduction
of 4-methoxy-N-(2-nitrobenzylidene)aniline (1a) by using
a low-valent titanium reagent (TiCl4/Zn), and the desired
reductive cyclization product 2a was obtained in 8% yield
together with the reduction product 3a (27%) and the
reductive coupling product 4a (27%) (Table 1, entry 1).
In this process, the nitro group was reduced to the corre-
sponding amine, whereas the C = N group was reduced
prior to being coupled. It is well known that the reduction
of an aryl nitro group proceeds through the corresponding
nitroso and hydroxylamine intermediates [19]. Based on
this understanding, it was envisaged that the mechanism
responsible for the formation of 2H-indazole 2a would in-
volve the reduction of the C = N bond to the corresponding
amine and the reduction of the nitro group to the nitroso
group [20]. In our previous work, we have been able to
control the reduction of the nitro by adding a base such
Table 1
Optimization of the reaction conditions for the synthesis of 2a.
Yielda (%)
Entry
Metal (M)
Base/pH
2a
3a
4a
1
2
3
4
5
6
7
8
Zn
Zn
Fe
No base/2
TEA/8
TEA/8
TEA/8
TEA/4
TEA/5
TEA/6
TEA/7
TEA/9
TEA/10
TEA/11
piperidine/8
NaOH/8
8
25
22
65
20
23
40
47
64
48
17
47
48
27
30
0
27
6
0
0
9
7
4
0
0
0
0
0
0
Sm
Sm
Sm
Sm
Sm
Sm
Sm
Sm
Sm
Sm
0
10
10
12
6
0
0
0
0
0
9
10
11
12
13
aYield was determined by HPLC-MS.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Facile One-Step Synthesis of 2-Arylindazoles
With the optimized conditions in hand, we proceeded to
investigate the substrate scope of the transformation. As
shown in Table 2, chloro and methoxy substituents on
the o-nitrophenyl ring, as well as N-phenyl groups bearing
either electron-withdrawing (i.e., chloro, bromo, and fluoro
groups) or electron-donating (i.e., methyl and methoxy
groups) groups, were all well tolerated under the reaction
conditions, providing the corresponding final products in
satisfactory yields (up to 80%).
The structures of the products were identified on the
basis of their spectroscopic data. The structure of 2 f was
further confirmed by X-ray diffraction analysis [23] (Fig. 1).
According to literature [16], we suppose the following
mechanism to explain this reaction. TiCl4 is reduced by
samarium dust to give low-valent titanium species. In the
initial step, N-(2-nitrobenzylidene)aniline 1 was reduced
by low-valent titanium species to N-(2-nitrosobenzyl)ani-
line A in the presence of TEA. 2-Nitrosobenzylamine A
then cyclized by the nucleophilic attack of the NH group
onto the nitroso group giving intermediate B. Finally, the
expected product 2 was produced by elimination of water
in the presence of TEA (Scheme 2).
formation mediated by low-valent titanium reagent (TiCl4/
Sm/Et3N). This method has several distinct advantages, in
that the starting materials are readily available, the handling
procedures required of the reaction are relatively straightfor-
ward, and the substrate scope is particularly broad.
EXPERIMENTAL
THF was distilled from sodium benzophene immediately prior to
use. All reactions were conducted under N2 atmosphere. Melting
points are uncorrected. IR spectra were recorded on Varian (Varian
Inc., Palo Alto, CA, USA) F-1000 spectrometer in KBr with absorp-
tions in per centimeter. 1H NMR was determined on Varian (Varian
Inc., Palo Alto, CA, USA) Inova-300 or Inova-400 MHz spectrometers
in CDCl3 or DMSO-d6 solution. J values are in hertz. Chemical
shifts are expressed in parts per million downfield from internal
standard TMS. HRMS data were obtained using Bruker (Bruker
Daltonics Inc., Billerica, MA, USA) micrOTOF-Q instrument.
General procedure for the synthesis of 1 is represented as
follows. A mixture of 2-nitrobenzaldehyde (10 mmol), aniline
(10 mmol), in EtOH (15 mL) was stirred at 85°C for 2–3 h. After
completion of the reaction confirmed by TLC (eluent acetone/
petroleum ether, 1:3), the reaction mixture was cooled to room
temperature (r.t.). Then, the precipitated product was filtered,
dried, and recrystallizated from ethanol to afford the pure 1 as a
yellow powder.
In conclusion, we have developed a procedure for the facile
synthesis of a variety of potentially biologically active 2-
aryl-2H-indazole derivatives based on a novel reductive
cyclization of nitro-aryl substrates through N–N bond
General procedure for the synthesis of compounds 2a–t.
TiCl4 (0.55 mL, 5 mmol) was added dropwise using a syringe to
a stirred suspension of samarium powder (0.75 g, 5 mmol) in
Table 2
Preparation of 2-aryl-indazoles 2.
Entry
Product
X
Y
Ar
Isolated yield (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-CH3OC6H4
4-ClC6H4
3-Cl-4-FC6H3
C6H5
4-CH3C6H4
3-CH3OC6H4
4-FC6H4
4-BrC6H4
3-Cl-4-CH3C6H3
4-ClC6H4
3-Cl-4-CH3C6H3
C6H5
3-CH3C6H4
4-FC6H4
65
60
55
65
63
80
52
64
78
65
61
57
55
55
62
80
60
55
75
60
9
10
11
12
13
14
15
16
17
18
19
20
4-BrC6H4
4-CH3OC6H4
3-ClC6H4
4-BrC6H4
4-FC6H4
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
2t
3-CH3C6H4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Lin, M. Hu, X. Feng, C. Cao, Z. Huang, and D. Shi
Vol 000
2-Phenyl-2H-indazole (2d). White solid; m.p. 84–85°C (Lit
[21] 84–85°C). IR (KBr) ν: 3055, 1591, 1505, 1382, 1199, 1045,
1
949, 757, 679 cmÀ1. H NMR (400 MHz, DMSO-d6) (δ, ppm):
7.11 (t, J = 7.6 Hz, 1H, ArH), 7.32 (t, J = 7.6 Hz, 1H, ArH), 7.44
(t, J = 7.2 Hz, 1H, ArH), 7.59 (t, J = 7.6 Hz, 2H, ArH), 7.72
(d, J = 8.8 Hz, 1H, ArH), 7.77 (d, J = 8.4 Hz, 1H, ArH), 8.10
(d, J = 8.0 Hz, 2H, ArH), 9.10 (s, 1H, ArH).
2-(4-Methylphenyl)-2H-indazole (2e). White solid; m.p. 97–
98°C (Lit [21] 96–98°C). IR (KBr) ν: 2946, 1909, 1618, 1515,
1377, 1193, 1110, 1035, 943, 798, 742 cmÀ1 1H NMR
.
Figure 1. Molecular structure of compound 2f.
(400 MHz, DMSO-d6) (δ, ppm): 2.37 (s, 3H, CH3), 7.09 (t,
J= 7.6 Hz, 1H, ArH), 7.30 (t, J= 7.6 Hz, 1H, ArH), 7.37 (d,
J= 7.6 Hz, 2H, ArH), 7.70 (d, J= 8.8 Hz, 1H, ArH), 7.75 (d,
J= 8.4 Hz, 1H, ArH), 7.96 (d, J= 6.8 Hz, 2H, ArH), 9.03 (s, 1H, ArH).
Scheme 2. Proposed mechanism for the synthesis of 2-aryl-indazoles.
2-(3-Methoxyphenyl)-2H-indazole (2f).
46–47°C (Lit [16] 46–47°C). IR (KBr) ν: 3051, 1628, 1497,
1379, 1200, 1053, 944, 817, 755 cmÀ1 1H NMR (400 MHz,
White solid; m.p.
TiCl + Sm
low-valent titanium species
4
3
.
low-valent titanium species
TEA
DMSO-d6) (δ, ppm): 3.75 (s, 3H, OCH3), 7.02–7.06 (m, 3H,
ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH), 7.67 (t, J = 8.4 Hz, 2H,
2
ArH), 7.94 (d, J = 8.4 Hz, 2H, ArH), 8.89 (s, 1H, ArH).
2-(4-Fluorophenyl)-2H-indazole (2g). White solid; m.p. 102–
103°C (Lit [21] 102–104°C). IR (KBr) ν: 3063, 1631, 1512, 1378,
1220, 1041, 947, 836, 749, 624 cmÀ1 1H NMR (400MHz,
.
DMSO) (δ, ppm): 7.05 (t, J= 7.2 Hz, 1H, ArH), 7.26 (t, J=7.2Hz,
1H, ArH), 7.38 (t, J= 8.4 Hz, 2H, ArH), 7.65 (d, J= 8.4 Hz, 1H,
ArH), 7.71 (d, J= 8.0 Hz, 1H, ArH), 8.06–8.07 (m, 2H, ArH), 9.01
(s, 1H, ArH).
2-(4-Bromophenyl)-2H-indazole (2h).
White solid; m.p.
freshly distilled anhydrous THF (10 mL) at r.t. under a dry N2
atmosphere. After completion of the addition, the mixture was
refluxed for 2 h. The suspension of the low-valent titanium
reagent formed was cooled to r.t., and then, TEA was added to
the mixture until the pH value is about 8 by pH indicator strips.
A solution of compound (1) (1 mmol) in THF (3 mL) was added
dropwise. The reaction mixture was then refluxed for 2 h under
N2. After this period, the TLC analysis of the mixture showed
the reaction to be complete. The reaction mixture was quenched
with 18% HCl (15 mL) and extracted with CHCl3 (3 × 40 mL).
The combined extracts were washed with water (3 × 40 mL) and
dried over anhydrous Na2SO4. After evaporation of the solvent
under reduced pressure, the crude products were purified by a
recrystallization from 95% ethanol.
148–149°C (Lit [21] 148–150°C). IR (KBr) ν: 3051, 1887,
1627, 1498, 1378, 1200, 1056, 943, 756 cmÀ1. 1H NMR (400 MHz,
CDCl3) (δ, ppm): 7.08 (t, J= 7.2 Hz, 1H, ArH), 7.30 (t, J=7.6
Hz, 1H, ArH), 7.56 (d, J= 8.4 Hz, 2H, ArH), 7.62 (d, J=8.4Hz,
1H, ArH), 7.72 (t, J= 7.6 Hz, 3H, ArH), 8.27 (s, 1H, ArH).
2-(3-Chloro-4-methylphenyl)-2H-indazole (2i).
White
solid; m.p. 133–135°C (Lit [16] 133–135°C). IR (KBr) ν: 3130,
3057, 2942, 1628, 1606, 1580, 1520, 1499, 1446, 1415, 1377,
1336, 1275, 1231, 1208, 1149, 1128, 1058, 963, 877, 842, 811,
778, 709, 690 cmÀ1. 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 2.34
(s, 3H, CH3), 7.09 (t, J= 7.2 Hz, 1H, ArH), 7.31 (t, J= 7.6 Hz, 1H,
ArH), 7.48 (d, J= 8.0 Hz, 1H, ArH), 7.68–7.75 (m, 2H, ArH), 7.94
(d, J= 8.0 Hz, 1H, ArH), 8.14 (s, 1H, ArH), 9.07 (s, 1H, ArH).
5-Chloro-2-(4-chlorophenyl)-2H-indazole (2j).
solid; m.p. 142–144°C. (Lit [21] 142–144°C). IR (KBr) ν: 3051,
1498, 1190, 1093, 1038, 938, 804, 611 cmÀ1 1H NMR
White
2-(4-Methoxyphenyl)-2H-indazole (2a).
123–124°C (Lit [21] 123–124°C). IR (KBr) ν: 2923, 1603, 1512,
1381, 1245, 1104, 1026, 946, 811, 754, 630 cmÀ1 1H NMR
White solid; m.p.
.
.
(400 MHz, DMSO-d6) (δ, ppm): 7.30 (d, J = 9.2 Hz, 1H, ArH),
7.66 (d, J = 8.8 Hz, 2H, ArH), 7.76 (d, J = 9.6 Hz, 1H, ArH), 7.86
(s, 1H, ArH), 8.11 (d, J = 8.4 Hz, 2H, ArH), 9.12 (s, 1H, ArH).
5-Chloro-2-(3-chloro-4-methylphenyl)-2H-indazole (2k).
White solid; m.p. 159–161°C (Lit [16] 159–161°C). IR (KBr)
ν: 3093, 1588, 1502, 1278, 1196, 1141, 1047, 927, 864, 802,
(400 MHz, DMSO-d6) (δ, ppm): 3.83 (s, 3H, OCH3), 7.09 (t,
J= 7.6 Hz, 1H, ArH), 7.13 (d, J= 9.2 Hz, 2H, ArH), 7.30 (t, J=7.6Hz,
1H, ArH), 7.69 (d, J= 8.4 Hz, 1H, ArH), 7.75 (d, J=8.8Hz, 1H,
ArH), 7.99 (d, J= 9.2 Hz, 2H, ArH), 8.99 (s, 1H, ArH).
2-(4-Chlorophenyl)-2H-indazole (2b).
140-141 °C. (Lit [22] 141–142°C). IR (KBr) ν: 3053, 1626,
1501, 1378, 1202, 1091, 944, 824, 753 cmÀ1 1H NMR
White solid; m.p.
698 cmÀ1 1H NMR (400 MHz, DMSO) (δ, ppm): 2.35 (s, 3H,
.
.
CH3), 7.26 (d, J = 8.8 Hz, 1H, ArH), 7.48 (d, J = 8.0 Hz, 1H,
ArH), 7.72 (d, J = 9.2 Hz, 1H, ArH), 7.79 (s, 1H, ArH), 7.91
(d, J = 8.0 Hz, 1H, ArH), 8.10 (s, 1H, ArH), 9.04 (s, 1H, ArH).
(400 MHz, DMSO-d6) (δ, ppm): 7.11 (t, J = 6.8 Hz, 1H,
ArH), 7.33 (t, J = 7.6 Hz, 1H, ArH), 7.65 (d, J = 8.8
Hz, 2H, ArH), 7.71 (d, J = 8.8 Hz, 1H, ArH), 7.77 (d, J = 8.4 Hz,
1H, ArH), 8.13 (d, J = 8.8 Hz, 2H, ArH), 9.12 (s, 1H, ArH).
5-Chloro-2-phenyl-2H-indazole (2l).
White solid; m.p. 143–
145°C (Lit [16] 143–144°C). IR (KBr) ν: 3047, 1591, 1502, 1191,
1
1047, 812, 752, 679 cmÀ1. H NMR (400 MHz, CDCl3) (δ, ppm):
2-(3-Chloro-4-fluorophenyl)-2H-indazole (2c).
White
solid; m.p. 130–132°C. (Lit [16] 130–132°C). IR (KBr) ν:
7.23 (dd, J1 =2.0Hz, J1 = 9.2 Hz, 1H, ArH), 7.40 (d, J = 7.2 Hz, 1H,
ArH), 7.53 (t, J = 8.0 Hz, 2H, ArH), 7.71 (d, J = 9.2 Hz, 1H, ArH),
7.79 (s, 1H, ArH), 8.01 (d, J = 7.6 Hz, 2H, ArH), 9.02 (s, 1H, ArH).
5-Chloro-2-(3-methylphenyl)-2H-indazole (2m). White solid;
m.p. 97–98°C (Lit [16] 97–99°C). IR (KBr) ν: 3031, 1599, 1494,
1047, 866, 777, 678 cmÀ1. 1H NMR (400MHz, DMSO-d6) (δ, ppm):
1
3051, 2921, 1621, 1506, 1373, 1252, 1060, 861, 756 cmÀ1. H
NMR (400 MHz, DMSO-d6) (δ, ppm): 7.12 (t, J = 7.6 Hz, 1H,
ArH), 7.33 (t, J = 7.6 Hz, 1H, ArH) , 7.64–7.72 (m, 2H, ArH),
7.77 (d, J = 8.4 Hz, 1H, ArH), 8.13–8.15 (m, 1H, ArH), 8.37
(dd, J1 = 2.0 Hz, J2 = 6.4 Hz,1H, ArH), 9.16 (s, 1H, ArH).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Facile One-Step Synthesis of 2-Arylindazoles
[2] (a) Keppler, B. K.; Hartmann, M. Met-Based Drugs 1994, 1, 145;
(b) Baraldi, P. G.; Balbonic, G.; Pavani, M. G.; Spalluto, G.; Tabrizi, M.
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[5] Picciola, G.; Ravenna, F.; Carenini, G.; Gentili, P.; Riva, M.
Farmaco Ed Sci 1981, 36, 1037.
2.40 (s, 3H, CH3), 7.24–7.29 (m, 2H, ArH), 7.45 (d, J= 8.0 Hz, 1H,
ArH), 7.75 (d, J= 9.2 Hz, 1H, ArH), 7.83 (d, J= 9.6 Hz, 1H, ArH),
7.91 (s, 1H, ArH), 9.03 (s, 1H, ArH).
5-Chloro-2-(4-fluorophenyl)-2H-indazole (2n).
White
solid; m.p. 133–135°C (Lit [16] 134–135°C). IR (KBr) ν:
1
3041, 1605, 1510, 1229, 1038, 930, 814, 630 cmÀ1. H NMR
(400 MHz, DMSO) (δ, ppm): 7.22 (d, J = 9.2 Hz, 1H, ArH),
7.37 (t, J = 8.0 Hz, 2H, ArH), 7.69 (d, J = 9.2 Hz, 1H, ArH),
7.77 (s, 1H, ArH), 8.03–8.06 (m, 2H, ArH), 8.98 (s, 1H, ArH).
2-(4-Bromophenyl)-5-chloro-2H-indazole (2o).
White
[6] Corsi, G.; Palazzo, G.; Germani, C.; Barcellona, P. S.;
Silvestrini, B. J Med Chem 1976, 19, 778.
[7] Andreonati, S.; Sava, V.; Makan, S.; Kolodeev, G. Pharmazie
1999, 54, 99.
solid; m.p. 150–152°C (Lit [21] 150–152°C). IR (KBr) ν: 3056,
1510, 1498, 1188, 1044, 925, 852, 827, 807, 691 cmÀ1. 1H NMR
(400MHz, CDCl3) (δ, ppm): 7.31 (d, J = 8.8 Hz, 1H, ArH), 7.
69–7.72 (m, 3H, ArH), 7.76 (d, J = 9.2 Hz, 1H, ArH), 7.82
(d, J = 8.4Hz, 2H, ArH), 8.37 (s, 1H, ArH).
[8] Angelis, M. D.; Stossi, F.; Carlson, K. A.; Karzenellenbogen,
B. S.; Katzenellenbogen, J. A. J Med Chem 2005, 48, 1132.
[9] Saczewski, F.; Saczewski, J.; Hudson, A. L.; Tyacke, R. J.;
Nutt, D. J.; Man, J.; Tabin, P. Eur J Pharm Sci 2003, 20, 201.
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Chem 1995, 60, 5678; (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Ad-
ams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett
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40, 2747; (d) Claramunt, R. M.; Elguero, J.; Garceran, R. Heterocycles
1985, 23, 2895; (e) Slade, D. J.; Pelz, N. F.; Bodnar, W.; Lampe, J. W.;
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Song, J. J.; Yee, N. K. Org Lett 2000, 2, 519; (c) Haag, B.; Peng, Z.;
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S. T.; Weaver, G. W. Tetrahedron Lett 2000, 41, 9893; (e) Varughese,
D. J.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett 2006, 47, 6795; (f)
Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett 2005, 46,
5387; (g) Moustafa, A. H.; Malakar, C. C.; Aljaar, N.; Merisor, E.;
Conrad, J.; Beifuss, U. Synlett 2013, 24, 1573; (h) Hwan, A. G.;
June, L. J.; Moo, J. Y.; Min, L. B.; Hyo, K. B. Org Bio Chem 2007, 5, 2472.
[12] Varughese, D. J.; Manhas, M. S.; Bose, A. K. Tetrahedron
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[14] Akazome, M.; Kondo, T.; Watanabé Y. J Org Chem 1994, 59,
3375.
[15] Okuro, K.; Gurnham, J.; Alper, H. Tetrahedron Lett 2012, 53, 620.
[16] Sun, F.; Feng, X.; Zhao, X.; Huang, Z. B.; Shi, D. Q. Tetrahedron
2012, 68, 3851.
[17] (a) McMurry, J. E. Acc Chem Res 1974, 7, 281; (b) McMurry,
J. E. Acc Chem Res 1983, 16, 405; (c) McMurry, J. E. Chem Rev 1989,
89, 1513; (d) Shohji, N.; Kawaji, T.; Okamoto, S. Org Lett 2011, 13,
2626; (e) Kumar, A.; Samuelson, A. G. Eur J Org Chem 2011, 951.
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B.; Shi, D. Q. Org Lett 2013, 15, 1238; (b) Lin, W.; Hu, M. H.;
Feng, X.; Cao, C. P.; Huang, Z. B.; Shi, D. Q. Tetrahedron 2013,
69, 6721; (c) Shi, D. Q.; Rong, R. C.; Wang, J. X.; Zhuang, Q.
Y.; Wang, X. S.; Hu, H. W. Tetrahedron Lett 2003, 44, 3199; (d)
Shi, D. Q.; Dou, G. L.; Shi, C. L.; Li, Z. Y.; Ji, S. J Synthesis
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Wang, X. S.; Wu, H.; Ji, S. J Tetrahedron 2007, 63, 9764; (g) Shi,
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5,6-Dimethoxy-2-(4-methoxyphenyl)-2H-indazole (2p). White
solid; m.p. 186–188°C (Lit [16] 186–188°C). IR (KBr) ν: 3407,
1
2947, 1640, 1517, 1343, 1230, 1155, 1014, 829, 626 cmÀ1. H
NMR (400 MHz, DMSO) (δ, ppm): 3.80 (s, 3H, OCH3), 3.81 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 6.98 (s, 1H, ArH), 7.03 (s, 1H,
ArH), 7.09 (d, J = 8.0 Hz, 2H, ArH), 7.89 (d, J = 8.4 Hz, 2H,
ArH), 8.67 (s, 1H, ArH).
2-(3-Chlorophenyl)-5,6-dimethoxy-2H-indazole (2q). White
solid; m.p. 143–144°C (Lit [16] 143–144°C). IR (KBr) ν: 3435,
2937, 1647, 1586, 1506, 1455, 1345, 1231, 1154, 1011, 882, 778,
671 cmÀ1 1H NMR (400 MHz, CDCl3) (δ, ppm): 3.92 (s, 3H,
.
OCH3), 3.97 (s, 3H, OCH3), 6.85 (s, 1H, ArH), 7.02 (s, 1H, ArH),
7.28 (d, J= 8.4 Hz, 1H, ArH), 7.40 (t, J= 8.0 Hz, 1H, ArH), 7.70
(d, J= 8.0 Hz, 1H, ArH), 7.89 (s, 1H, ArH), 8.17 (s, 1H, ArH).
2-(4-Bromophenyl)-5,6-dimethoxy-2H-indazole (2r). White
solid; m.p. 156–158°C (Lit [16] 156–158°C). IR (KBr) ν: 3424,
2943, 1507, 1343, 1230, 1007, 819, 737, 616 cmÀ1 1H NMR
.
(400MHz, DMSO) (δ, ppm): 3.79 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 6.93 (s, 1H, ArH), 7.01 (s, 1H, ArH), 7.69 (d, J = 8.4 Hz,
2H, ArH), 7.93 (d, J = 8.4 Hz, 2H, ArH), 8.73 (s, 1H, ArH).
2-(4-Fluorophenyl)-5,6-dimethoxy-2H-indazole (2s).
White
solid; m.p. 106–108°C (Lit [16] 106–108°C). IR (KBr) ν: 3413,
1
2921, 1641, 1516, 1345, 1231, 1006, 887, 817, 718, 617 cmÀ1. H
NMR (400 MHz, CDCl3) (δ, ppm): 3.92 (s, 3H, OCH3), 3.96 (s, 3H,
OCH3), 6.86 (s, 1H, ArH), 7.03 (s, 1H, ArH), 7.17 (t, J= 8.4 Hz, 2H,
ArH), 7.76–7.80 (m, 2H, ArH), 8.12 (s, 1H, ArH).
5,6-Dimethoxy-2-m-tolyl-2H-indazole (2t). White solid; m.p.
110–112°C (Lit [16] 110–112°C). IR (KBr) ν: 3425, 2931, 1599,
1507, 1345, 1245, 1154, 1011, 894, 788, 685 cmÀ1 1H NMR
.
(400MHz, CDCl3) (δ, ppm): 2.43 (s, 3H, CH3), 3.92 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.87 (s, 1H, ArH), 7.05 (s, 1H,
ArH), 7.13 (d, J = 7.2 Hz, 1H, ArH), 7.35 (t, J = 8.0 Hz, 1H, ArH),
7.58 (d, J = 8.0Hz, 1H, ArH), 7.70 (s, 1H, ArH), 8.18 (s, 1H, ArH).
Acknowledgment. We are grateful for financial support from the
National Natural Science Foundation of China (No. 21072144), the
Major Basic Research Project of the Natural Science Foundation of
the Jiangsu Higher Education Institution (No. 10KJA150049), and
a Project of the Natural Science Foundation of the Jiangsu Higher
Education Institution (No. 11KJB150014).
[19] Enwistle, I. D.; Gilkerson, T. Tetrahedron 1978, 34, 213.
[20] Frontana-Uribe, B. A.; Moinet, C. Tetrahedron 1998, 54, 3197.
[21] Shi, D. Q.; Dou, G. L.; Ni, S. N.; Shi, J. W.; Li, X. Y.; Wang,
X. S.; Wu, H.; Ji, S. J Synlett 2007, 2509.
[22] Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org Lett 2010, 12, 2234.
[23] Crystallographic data for the structure of compound 2 f has
been deposited at the Cambridge Crystallographic Data Centre, deposit
number is CCDC-985975. Copies of available material can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax:+44 1223 336 033; e-mail:deposit@ccdc.cam.ac.uk).
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet