A method for the regioselective synthesis of 1-alkyl-1H-indazoles

Article abstract of DOI:10.1016/j.tet.2013.03.042

A method for the regioselective synthesis of 3-unsubstituted 1-alkyl-1H-indazoles, starting with 2-halobenzonitriles and N-alkylhydrazines, is described. The two-step reaction pathway proceeds through the intermediacy of 1-alkyl-3-amino-1H-indazoles follo

Full text of DOI:10.1016/j.tet.2013.03.042

Tetrahedron 69 (2013) 3907e3912
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A method for the regioselective synthesis of 1-alkyl-1H-indazoles
,
Han-Jun Liu a, Shiang-Fu Hung a, Chuan-Lin Chen b, Mei-Huey Lin a
*
a Department of Chemistry, National Changhua University of Education, Changhua 50007, Taiwan
b Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the regioselective synthesis of 3-unsubstituted 1-alkyl-1H-indazoles, starting with 2-
halobenzonitriles and N-alkylhydrazines, is described. The two-step reaction pathway proceeds
through the intermediacy of 1-alkyl-3-amino-1H-indazoles followed by reductive deamination.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 2 January 2013
Received in revised form 6 March 2013
Accepted 9 March 2013
Available online 14 March 2013
Keywords:
Regioselective
Indazoles
2-Halobenzonitriles
N-Alkylhydrazines
Deamination
1. Introduction
applicable to the regioselective synthesis of 1-alkyl-1H-indazo-
les.13,14,15b,16,20 Thus, methods for the regioselective synthesis of 1-
The indazole ring system is recognized to be a highly effective
pharmacophore in medicinal chemistry as well as being the core of
important nitrogen-containing heterocycles that show a broad
range of biological activities, such as nitric oxide synthase1 and HIV
protease2 inhibitors, anti-inflammatory,3 antitumor,4 and anti-
cancer5 agents, and serotonin 5-HT3 receptor antagonists.6 A vari-
ety of methods for the preparation of indazoles have been re-
ported.7 The developed approaches include diazotization of 2-
alkylaniline derivatives followed by cyclization under basic condi-
tions,8 base promoted cyclization of (o-alkylaryl)azosulfides de-
rived from 2-alkylaniline derivatives,9 [3þ2] cycloadditions of
arynes with diazo compounds or hydrazones,10 condensation re-
actions of o-haloaryl carbonyls or salicylaldehydes with hydra-
zine,11 and cyclization reactions of o-aminobenzoximes in the
presence of bases.12 Although methods for regioselective synthesis
of indazoles have been described,12e20 only a few of these are
alkyl-1H-indazoles remain in demand.
2. Results and discussion
As a part of a recent research effort, we required 3-unsubstituted
1-alkyl-1H-indazoles as synthetic intermediates. The most
straightforward route to access these substances involves treat-
ment of 3-unsubstituted 1H-indazoles with alkylating agents.
However, the regiochemistry of these processes is highly de-
pendent on the nature of alkylating agent and, in general, mixtures
of N-1 and N-2 alkylated products are typically produced (Eq.1). For
example, methylation of 5-nitro-1H-indazole using iodomethane
(NaH, THF, 0 ꢀC, 2 h) results in formation of a mixture of 5-nitro-1-
methyl-1H- and 5-nitro-2-methyl-2H-indazoles in a 55:45 ratio.
Moreover, varying the solvent, temperature and base employed in
this reaction failed to improve the selectivity.
R+
R1
R1
R1
N
N
N R
+
N
N
H
N
R
Eq (1)
3
N-1
N-2
A common method for the preparation of 3-substituted 1-alkyl-
1H-indazoles involves cyclization of an arylhydrazone, derived
* Corresponding author. Tel.: þ886 4 7232105x3543; fax: þ886 4 7211190; e-mail
address: mhlin@cc.ncue.edu.tw (M.-H. Lin).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.042

3908
H.-J. Liu et al. / Tetrahedron 69 (2013) 3907e3912
from reaction of an arylketone possessing a leaving group in the
ortho-position with an alkylhydrazine.14,16 We envisioned that 3-
unsubstituted 1-alkyl-1H-indazoles could be generated utilizing
an analogous process in which an arylketone is replaced by an
arylaldehyde. However, treatment of methylhydrazine and
a mesylate, derived from reaction of 5-bromo-2-hydroxy-benzal-
dehyde with mesyl chloride, in refluxing xylene in the presence of
NH4OAc for 3 h gave only the corresponding hydrazone product,
and an increase in the time for this reaction to 14 h resulted in the
formation of multiple products.
4. Experimental section
4.1. General
All commercially available chemicals were used without further
purification. TLC analyses were run on a TLC glass plate (Silica gel 60
F254) and were visualized using UV and a solution of phosphomo-
lybdic acid in ethanol (5 wt %) or p-anisaldehyde stain. Flash
chromatography was performed using silica gel (70e230 mesh). 1H
and 13C NMR spectra were recorded on a 300 MHz spectrometer.
Owing to these observations, our attention turned to the use of
other substrates. 3-Aminoindazoles, obtained by using a variety of
methods,21e23 are known to have valuable biological activities in
several therapeutic areas.24 Wheeler et al. described a procedure
for the regioselective synthesis of 3-amino-1-methyl-1H-inda-
zoles utilizing reactions of 2-fluorobenzonitriles with methylhy-
drazine.20 We hypothesized that this process, when coupled with
the novel reductive deamination reaction of arylamines that
produces aromatic hydrocarbons described by Doyle and Piccio-
nello et al.,24,25 would serve as a regioselective two-step method
for the preparation of 3-unsubstituted 1-alkyl-1H-indazoles. The
viability of this proposal was demonstrated in the studies de-
scribed below.
As the results displayed in Scheme 1 and Table 1 show, reactions
of members of a series of 2-halobenzonitriles, containing either
electron-donating or -withdrawing groups, with methylhydrazine
in ethanol efficiently produce the corresponding 3-amino-1-
methyl-1H-indazoles 2. Reductive deamination reactions of the 3-
amino-1-methyl-1H-indazole products 2 with tert-butyl nitrite in
either CHCl3, DMF or THF generated 3-unsubstituted-1-methyl-1H-
indazoles 3 in high yields. It should be noted that the deamination
reaction of 3-amino-1-methyl-5-nitro-1H-indazole (2e) in THF or
CHCl3 gave a product that was expected to be 1-methyl-5-nitro-1H-
indazole (3e). In order to confirm its structure, this substance was
subjected to catalytic hydrogenation, which yielded 1-methyl-5-
amino-1H-indazole.
Chemical shifts are reported relative to CHCl3 [dH 7.24, dC (central
line) 77.0]. Mass spectra were recorded under fast atom bom-
bardment (FAB) or electron impact ionization (EI) conditions. High-
resolution mass spectra were recorded by electron impact ioniza-
tion with a magnetic sector analyzer.
4.2. Synthesis
4.2.1. General procedure for synthesis of 3-amino-1-methyl-1H-in-
dazole 2. A mixture of benzonitrile 1 (10.0 mmol) and methylhy-
drazine (2.8 mL, 50.0 mmol) in EtOH (10.0 mL) was heated to reflux
overnight. The mixture was cooled to rt and then concentrated. H2O
(10.0 mL) and EtOAc (20.0 mL) were added to the residue. The or-
ganic layer was washed with H2O (10.0 mL), brine (10.0 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
subjected to silica-gel chromatography by using EtOAc/hexanes
(1:1) as eluent to give the product 2.
4.2.1.1. 1-Methyl-1H-indazol-3-ylamine (2a). As described in the
general procedure, reaction of 2-fluorobenzonitrile 1a (1.21 g,
10.0 mmol) and methylhydrazine (2.8 mL, 50.0 mmol) in EtOH
(10.0 mL) afforded the title compound (1.35 g, 92%). Solid (EtOAc/
hexanes¼3:1), mp 94e95 ꢀC; TLC (EtOAc/hexanes (1:1)) Rf¼0.2; 1H
NMR (300 MHz, CDCl3)
d
3.79 (s, 3H), 4.13 (br s, 2H), 6.96 (dd, J¼8.6,
7.2 Hz, 1H), 7.15 (d, J¼8.6 Hz,1H), 7.30 (dd, J¼8.0, 7.2 Hz,1H), 7.47 (d,
J¼8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 34.6 (CH3), 108.5 (CH),
H
NH2
CN
X
MeNH-NH2
EtOH
t-BuONO
R
N
R
R
N
THF
N
N
1
2
3
Scheme 1. Regioselective synthesis of 1-methyl-1H-indazoles via 1-methyl-3-amino-1H-indazoles.
In order to determine if this methodology is suitable for the
preparation of other 1-alkyl-1H-indazoles, reactions of ethyl hy-
drazine and benzyl hydrazine with the respective benzonitriles
1b and 1e were examined. As the results displayed in Scheme 2
show, application of the two-step procedure gave the corre-
sponding 1-ethyl- (3j) and 1-benzyl- (3i) 1H-indazoles in high
yields. Other hydrazines, such as phenylhydrazine (PheNHeNH2)
and isopropylhydrazine (Me2CHeNHeNH2) were examined and
both reactions gave a mixture of multiple products. Based on
the results, a plausible mechanism is proposed and shown in
Scheme 3.
114.3 (C), 118.2 (CH), 119.4 (CH), 126.7 (CH), 141.3 (C), 146.9 (C); MS
m/z (rel intensity) 148 (MþþH, 100), 133 (5). These data are in
agreement with those reported in the literature.26
4.2.1.2. 4-Fluoro-1-methyl-1H-indazol-3-amine (2b). As described
in the general procedure, reaction of 2,6-difluorobenzonitrile 1b
(1.39 g, 10.0 mmol) and methylhydrazine (2.8 mL, 50.0 mmol) in
EtOH (10.0 mL) afforded the title compound (1.42 g, 86%). Solid
(EtOAc/hexanes¼1:1), mp 125e126 ꢀC; TLC (EtOAc/hexanes (1:1))
Rf¼0.2; IR (neat) 3438, 3308, 3206, 1634 cmꢁ1
;
1H NMR (300 MHz,
CDCl3)
d
3.77 (s, 3H), 4.12 (br s, 2H), 6.54 (dd, J¼9.0, 6.0 Hz, 1H), 6.88
(d, J¼6.0 Hz, 1H), 7.18 (m, 1H); 13C NMR (75 MHz, CD3OD)
d 35.0
3. Conclusion
(CH3),102.7 (CH),104.6 (CH),128.2 (CH),144.0 (C),145.5 (C),155.1 (C),
158.4 (C); MS m/z (rel intensity) 165 (Mþ, 100), 122 (28); HRMS [M]þ
for C8H8N3: 165.0702, found 165.0708.
In summary, the study described above has resulted in the de-
velopment of an alternative, two-step method for the regioselective
synthesis of 3-unsubstituted 1-alkyl-1H-indazoles starting with N-
alkylhydrazines and 2-halobenzonitriles.
4.2.1.3. 5-Fluoro-1-methyl-1H-indazol-3-amine
(2c). As
de-
scribed in the general procedure, reaction of 2,5-difluorobenzonitrile

H.-J. Liu et al. / Tetrahedron 69 (2013) 3907e3912
3909
Table 1
1c (1.39 g, 10.0 mmol) and methylhydrazine (2.8 mL, 50.0 mmol) in
EtOH (10.0 mL) afforded the title compound (1.32 g, 80%). Solid
(EtOAc), mp 76e77 ꢀC; TLC (EtOAc/hexanes (1:2)) Rf¼0.13; IR (neat)
Regioselective synthesis of 1-methyl-3-amino-1H-indazoles and 1-methyl-1H-
indazoles
3363, 3187, 1532, 1228 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 3.79 (s,
Entry
SM 1
Indazole 2
Yield
(%)a
Indazole 3
Yield
(%)a
3H), 3.85 (br s, 2H), 7.06e7.13 (m, 3H); 13C NMR (75 MHz, CD3OD)
d
34.9 (CH3), 103.5 (CH), 109.5 (CH), 113.7 (C), 116.1 (CH), 138.5 (C),
146.6 (C), 154.8 (C), 158.0 (C); MS m/z (rel intensity) 165 (Mþ, 100),
147 (16); HRMS [M]þ for C8H8FN3: 165.0702, found 165.0696.
1
92
86
91
91
4.2.1.4. 5-Iodo-1-methyl-1H-indazol-3-amine (2d). As described
in the general procedure, reaction of 2-fluoro-5-iodobenzonitrile
1d (2.47 g, 10.0 mmol) and methylhydrazine (2.8 mL, 50.0 mmol)
in EtOH (10.0 mL) afforded the title compound (2.52 g, 92%). Solid
(EtOAc), mp 151e152 ꢀC; TLC (EtOAc/hexanes (1:1)) Rf¼0.2; IR
(neat) 3418, 3280, 3178, 1648 cmꢁ1; 1H NMR (300 MHz, DMSO-d6)
2
d
3.74 (s, 3H), 5.58 (s, 2H), 7.21 (d, J¼8.7 Hz, 1H), 7.49 (dd, J¼8.7,
1.5 Hz, 1H), 8.16 (s, 1H); 13C NMR (75 MHz, CD3OD)
d
35.5 (CH3),
80.4 (C), 112.0 (CH), 117.7 (C), 130.1 (CH), 134.8 (CH), 140.8 (C), 148.4
(C); MS m/z (rel intensity) 273 (Mþ, 100), 258 (3); HRMS [M]þ for
C8H8IN3: 272.9763, found 272.9760.
3
4
5
80
92
94
84
85
83
4.2.1.5. 1-Methyl-5-nitro-1H-indazol-3-ylamine (2e). As described
in the general procedure, reaction of 2-fluoro-5-nitrobenzonitrile 1e
(1.66 g, 10.0 mmol) and methylhydrazine (2.8 mL, 50.0 mmol) in
EtOH (10.0 mL) afforded the title compound (1.81 g, 94%). Solid
(EtOH), mp 226e227 ꢀC; TLC (EtOAc/hexanes (1:1)) Rf¼0.2; IR (neat)
3336, 3194, 1616, 1329 cmꢁ1; 1H NMR (300 MHz, DMSO-d6)
d 3.83 (s,
3H), 6.14 (br s, 2H), 7.47 (d, J¼9.4 Hz, 1H), 8.11 (dd, J¼9.4, 2.1 Hz, 1H),
8.90 (d, J¼2.1 Hz,1H); 13C NMR (75 MHz, DMSO-d6)
d 35.9 (CH3),110.0
(CH), 114.5 (C), 120.7 (CH), 122.3 (CH), 139.6 (C), 143.0 (C), 152.4 (C);
MS m/z (rel intensity) 193 (Mþþ1, 100), 163 (60). These data are in
agreement with those reported in the literature.21i
4.2.1.6. 4-Methoxy-1-methyl-1H-indazol-3-ylamine (2f). As de-
scribed in the general procedure, reaction of 2-fluoro-6-
methoxybenzonitrile 1f (1.51 g, 10.0 mmol) and methylhydrazine
(2.8 mL, 50.0 mmol) in EtOH (10.0 mL) afforded the title compound
(1.61 g, 91%). Solid (EtOAc), mp 139e140 ꢀC; TLC (EtOAc/hexanes
6
7
91
88
(1:1)) Rf¼0.2; IR (neat) 3428, 3298, 3178, 1615 cmꢁ1
;
1H NMR
(300 MHz, CDCl3) d 3.75 (s, 3H), 3.90 (s, 3H), 4.38 (br s, 2H), 6.25 (d,
J¼7.5 Hz, 1H), 6.71 (d, J¼8.4 Hz, 1H), 7.17 (dd, J¼8.4, 7.5 Hz, 1H); 13C
90
94
82
85
NMR (75 MHz, CDCl3) d 34.8 (CH3), 55.2 (CH3), 97.3 (CH), 101.5 (CH),
105.2 (C), 128.4 (CH), 143.4 (C), 147.4 (C), 155.1 (C); MS m/z (rel in-
tensity) 177 (Mþ, 100), 162 (20); HRMS [M]þ for C9H11N3O:
177.0902, found 177.0896.
8
4.2.1.7. 1,5-Dimethyl-1H-indazol-3-ylamine (2g). As described in
the general procedure, reaction of 2-fluoro-5-methylbenzonitrile
1g (1.35 g, 10.0 mmol) and methylhydrazine (2.8 mL, 50.0 mmol)
in EtOH (10.0 mL) afforded the title compound (1.45 g, 90%). Solid
(EtOAc), mp 149e150 ꢀC; TLC (EtOAc/hexanes (1:1)) Rf¼0.2; IR
a
Isolated yield.
Scheme 2. Regioselective synthesis of 1-alkyl-1H-indazoles via 1-alkyl-3-amino-1H-indazoles.

3910
H.-J. Liu et al. / Tetrahedron 69 (2013) 3907e3912
Scheme 3. Plausible mechanism.
(neat) 3448, 3289, 3180, 2364 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
(1.0 mL, 8.1 mmol, 2.7 equiv) in THF (12.0 mL) was heated to reflux
d
2.39 (s, 3H), 3.72 (s, 2H), 3.78 (s, 3H), 7.07 (d, J¼8.4 Hz, 1H), 7.14 (d,
for 1 h. The mixture was cooled to rt and then concentrated. H2O
(10.0 mL) and EtOAc (20.0 mL) were added to the residue. The or-
ganic layer was washed with H2O (10.0 mL), brine (10.0 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
subjected to silica-gel chromatography by using Et2O/hexanes (1:4)
as eluent to give the product 3.
J¼8.4 Hz, 1H), 7.26 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 21.08 (CH3),
34.8 (CH3), 108.3 (CH), 114.6 (C), 118.5 (CH), 172.7 (C), 128.9 (CH),
140.33 (C), 146.3 (C); MS m/z (rel intensity) 161 (Mþ, 100), 160 (48);
HRMS [M]þ for C9H11N3: 161.0953, found 161.0961.
4.2.1.8. 4-Chloro-1-methyl-1H-indazol-3-amine (2h). As de-
scribed in the general procedure, reaction of 2-chloro-6-
fluorobenzonitrile 1h (1.55 g, 10.0 mmol) and methylhydrazine
(2.8 mL, 50.0 mmol) in EtOH (10.0 mL) afforded the title compound
(1.70 g, 94%). Solid (EtOAc/hexanes¼1:2), mp 131e132 ꢀC; TLC
4.2.2.1. 1-Methyl-1H-indazole (3a). As described in the general
procedure, reaction of 1-methyl-1H-indazol-3-amine 2a (0.44 g,
3.0 mmol) and tert-butyl nitrite (1.0 mL, 8.1 mmol, 2.7 equiv) in THF
(12.0 mL) afforded the title compound (0.34 g, 86%). Solid (EtOAc/
hexanes (1:3)), mp 49e50 ꢀC; TLC (EtOAc/hexane (1:4)) Rf¼0.2; IR
(EtOAc/hexanes (1:2)) Rf¼0.2; IR (neat) 3438, 3299, 1616,1542 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
3.76 (s, 3H), 4.49 (br s, 2H), 6.85 (d,
(neat) 2947,1597,1218, 746 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 4.05 (s,
J¼8.4 Hz, 1H), 7.00 (d, J¼8.4 Hz, 1H), 7.13 (t, J¼8.4 Hz, 1H); 13C NMR
3H), 7.11e7.15 (m,1H), 7.37 (br d, J¼4.1 Hz, 2H), 7.71 (dd, J¼8.0,1.0 Hz,
(75 MHz, CDCl3)
d
34.8 (CH3), 107.3 (CH), 111.5 (C), 118.3 (CH), 126.6
1H), 7.97 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
35.5 (CH3), 108.9 (CH),
(C), 127.4 (CH), 142.4 (C), 146.8 (C); MS m/z (rel intensity) 181 (Mþ,
120.3 (CH), 121.0 (CH), 123.9 (C), 126.1 (CH), 132.6 (CH), 139.7 (C).
These data are in agreement with those reported in the literature.20
100), 138 (25); HRMS [M]þ for C8H8ClN3: 181.0407, found 181.0400.
4.2.1.9. 1-Benzyl-5-nitro-1H-indazol-3-amine (2i). As described
in the general procedure, reaction of 2-chloro-5-nitrobenzonitrile
1e (0.91 g, 5.0 mmol), Et3N (5.06 g, 50.0 mmol) and benzyl hy-
drazine HCl (2.93 g, 15.0 mmol) in EtOH (20.0 mL) afforded the title
compound (1.07 g, 80%). Solid (EtOAc), mp 253e254 ꢀC; TLC (EtOAc/
4.2.2.2. 4-Fluoro-1-methyl-1H-indazole (3b). As described in
the general procedure, reaction of 4-fluoro-1-methyl-1H-indazol-
3-amine 2b (0.50 g, 3.0 mmol) and tert-butyl nitrite (1.0 mL,
8.1 mmol, 2.7 equiv) in THF (12.0 mL) afforded the title compound
(0.41 g, 91%). Solid (EtOAc), mp 36e37 ꢀC; TLC (EtOAc/hexanes
hexanes (1:2)) Rf¼0.18; IR (neat) 3428, 1597, 1468, 1329 cmꢁ1
;
1H
(1:1)) Rf¼0.2; IR (neat) 2919, 1634, 1584, 1506 cmꢁ1
;
1H NMR
NMR (300 MHz, DMSO-d6)
d
5.44 (s, 2H), 6.19 (s, 2H), 6.66 (d,
(300 MHz, CDCl3)
d
4.04 (s, 3H), 6.74 (dd, J¼10.2, 7.8 Hz, 1H), 7.13
J¼9.3 Hz, 1H), 7.24e7.37 (m, 5H), 8.14 (dd, J¼9.3, 2.1 Hz,1H), 8.94 (d,
(d, J¼8.4, 1.2 Hz, 1H), 7.26e7.30 (m, 1H), 8.02 (s, 1H); 13C NMR
J¼2.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d
52.3 (CH2), 110.1 (CH),
(75 MHz, CDCl3) d 35.8 (CH3), 104.8 (CH), 114.1 (C), 127.1 (CH),
114.9 (C), 120.7 (CH), 122.5 (CH), 128.3 (CH), 128.4 (CHꢂ2), 129.4
(CHꢂ2), 138.3 (C), 139.9 (C), 142.9 (C), 152.6 (C); MS m/z (rel in-
tensity) 268 (Mþ, 56), 91 (100); HRMS [M]þ for C14H12N4O2:
268.0960, found 268.0968.
129.1 (CH), 142.3 (C), 154.1 (C), 157.4 (C); MS m/z (rel intensity)
150 (Mþ, 100), 122 (15); HRMS [M]þ for C8H7FN2: 150.0593, found
150.0602.
4.2.2.3. 5-Fluoro-1-methyl-1H-indazole (3c). As described in the
general procedure, reaction of 5-fluoro-1-methyl-1H-indazol-3-
amine 2c (0.50 g, 3.0 mmol) and tert-butyl nitrite (1.0 mL,
8.1 mmol, 2.7 equiv) in THF (12.0 mL) afforded the title compound
(0.38 g, 84%). Oil; TLC (EtOAc/hexanes (1:2)) Rf¼0.5; IR (neat) 2947,
4.2.1.10. 1-Ethyl-4-fluoro-1H-indazol-3-amine (2j). As described
in the general procedure, reaction of 2,6-difluorobenzonitrile 1b
(0.70 g, 5.0 mmol), Et3N (5.06 g, 50.0 mmol) and ethyl hydrazine
oxalate (2.25 g, 15.0 mmol) in EtOH (20.0 mL) afforded the title
compound (0.75 g, 84%). Solid (EtOAc), mp 64e65 ꢀC; TLC (EtOAc/
1505, 1209, 839 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 4.04 (s, 3H),
hexanes (1:2)) Rf¼0.45; IR (neat) 3428, 3280, 3201, 1616 cmꢁ1
;
1H
7.10e7.17 (m,1H), 7.28e7.33 (m, 2H), 7.90 (s, 1H); 13C NMR (75 MHz,
NMR (300 MHz, CDCl3)
d
1.36 (t, J¼7.2 Hz, 3H), 4.11 (q, J¼7.2 Hz, 2H),
CDCl3) d 35.7 (CH3), 104.7 (CH), 109.9 (CH), 115.6 (CH), 123.7 (CH),
4.31 (br s, 2H), 6.52 (dd, J¼10.5, 7.8 Hz, 1H), 6.88 (d, J¼8.4 Hz, 1H),
132.6 (C), 136.9 (C), 156.1 (C); MS m/z (rel intensity) 150 (Mþ, 100),
7.10e7.17 (m,1H); 13C NMR (75 MHz, CDCl3)
d
14.6 (CH3), 43.1 (CH2),
122 (21); HRMS [M]þ for C8H7FN2: 150.0593, found 150.0599.
102.3 (CH), 104.5 (CH), 127.7 (CH), 143.1 (C), 145.5 (C), 155.2 (C),
158.5 (C); MS m/z (rel intensity) 179 (Mþ, 88), 164 (100); HRMS
[M]þ for C9H10FN3: 179.0859, found 179.0852.
4.2.2.4. 5-Iodo-1-methyl-1H-indazole (3d). As described in the
general procedure, reaction of 5-iodo-1-methyl-1H-indazol-3-amine
2d (0.82 g, 3.0 mmol) and tert-butyl nitrite (1.0 mL, 8.1 mmol,
2.7 equiv) in THF (12.0 mL) afforded the title compound (0.66 g, 85%).
Solid (EtOAc), mp 172e173 ꢀC; TLC (EtOAc/hexanes (1:2)) Rf¼0.4; IR
4.2.2. General procedure for synthesis of indazole 3. A mixture of 3-
amino-1-methyl-1H-indazole 2 (3.0 mmol) and tert-butyl nitrite

H.-J. Liu et al. / Tetrahedron 69 (2013) 3907e3912
3911
(neat) 2928, 1666, 1477, 802 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
4.02
4.2.2.10. 1-Ethyl-4-fluoro-1H-indazole (3j). As described in the
general procedure, reaction of 1-ethyl-4-fluoro-1H-indazol-3-
amine 2i (0.54 g, 3.0 mmol) and tert-butyl nitrite (0.84 g, 1.0 mL,
8.1 mmol, 2.7 equiv) in THF (12.0 mL) afforded the title compound
(0.40 g, 81%). Oil; TLC (EtOAc/hexanes (1:4)) Rf¼0.55; IR (neat)
(s, 3H), 7.14 (dd, J¼8.7 Hz,1H), 7.56 (dd, J¼8.7, 1.2 Hz,1H), 7.86 (s,1H),
8.04 (d, J¼1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 35.6 (CH3), 83.7
(C), 110.7 (CH), 126.3 (C), 129.9 (CH), 131.6 (CH), 134.4 (CH), 138.8 (C);
MS m/z (rel intensity) 258 (Mþ, 100), 131 (26); HRMS [M]þ for
C8H7IN2: 257.9654, found 257.9658.
2984, 2928, 1588, 1218 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 1.49 (t,
J¼7.2 Hz, 3H), 4.39 (q, J¼7.2 Hz, 2H), 6.73 (dd, J¼9.9, 7.5 Hz, 1H), 7.14
4.2.2.5. 1-Methyl-5-nitro-1H-indazole (3e). As described in the
general procedure, reaction of 1-methyl-5-nitro-1H-indazol-3-
amine 2e (0.58 g, 3.0 mmol) and tert-butyl nitrite (1.0 mL,
8.1 mmol, 2.7 equiv) in THF (12.0 mL) afforded the title compound
(0.44 g, 83%). Solid (MeOH), mp 161e162 ꢀC; TLC (EtOAc/hexanes
(d, J¼8.4 Hz, 1H), 7.22e7.29 (m, 1H), 8.03 (s, 1H); 13C NMR (75 MHz,
CDCl3)
d 14.8 (CH3), 44.0 (CH2), 104.4 (CH), 104.7 (CH), 126.9 (CH),
129.1 (CH), 141.6 (C), 154.2 (C), 157.6 (C); MS m/z (rel intensity) 164
(Mþ, 70), 149 (100); HRMS [M]þ for C9H9FN2: 164.0750, found
164.0755.
(1:4)) Rf¼0.2; IR (neat) 3030, 1634, 1496, 1329 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d
4.11 (s, 3H), 7.42 (d, J¼9.2 Hz, 1H), 8.16 (s, 1H),
Acknowledgements
8.24 (dd, J¼9.2, 2.1 Hz,1H), 8.68 (d, J¼2.1 Hz,1H); 13C NMR (75 MHz,
CDCl3)
d 36.0 (CH3), 109.2 (CH), 118.9 (CH), 121.4 (CH), 123.0 (C),
Financial support from the National Science Council of the Re-
public of China, Taiwan is gratefully acknowledged.
135.6 (CH), 141.5 (C), 142.3 (C). These data are in agreement with
those reported in the literature.27
Supplementary data
4.2.2.6. 4-Methoxy-1-methyl-1H-indazole (3f). As described in
the general procedure, reaction of 4-methoxy-1-methyl-1H-inda-
zol-3-amine 2f (0.53 g, 3.0 mmol) and tert-butyl nitrite (1.0 mL,
8.1 mmol, 2.7 equiv) in THF (12.0 mL) afforded the title compound
(0.43 g, 88%). An oil; TLC (EtOAc/hexanes (1:4)) Rf¼0.2; IR (neat)
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2013.03.042.
References and notes
2938, 1588, 1496, 1274 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 3.93 (s,
3H), 4.00 (s, 3H), 6.42 (d, J¼7.5 Hz,1H), 6.92 (d, J¼8.4 Hz,1H), 7.26 (t,
1. (a)Lohou, E.;Sopkova, J.; Schumann, P.;Boulouard, M.; Stiebing, S.;Rault, S.;Collot,
V. Bioorg. Med. Chem. 2012, 20, 5296 and references cited therein; (b) Salerno, L.;
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Giacomo, C.;Sorrenti, V. Eur. J. Med. Chem. 2012, 49,118;(c) Schumann, P.;Collot, V.;
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louard, M.; Rault, S. Bioorg. Med. Chem. Lett. 2001, 11, 1153.
J¼8.1 Hz, 1H), 8.02 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 35.5 (CH3),
55.3 (CH3), 99.2 (CH), 101.6 (CH), 115.8 (C), 127.4 (CH), 130.5 (CH),
141.6 (C), 153.7 (C); MS m/z (rel intensity) 162 (Mþ, 100), 147 (30);
HRMS [M]þ for C9H10N2O: 162.0793, found 162.0789.
2. (a) Kaltenbach, R. F.; Patel, M.; Waltermire, R. E.; Harris, G. D.; Stone, B. R. P.;
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Mazzei, A. Eur. J. Cancer 2001, 37, 364.
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Kato, S. Chem. Pharm. Bull. 1995, 43, 1912; (b) Robertson, D. W.; Bloomquist, W.;
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Stadlbauer, W.; Camp, N. In Science of Synthesis: Houben-Weyln Methods of
Molecular Transformations; Thieme: Stuttgart, Germany, 2002; Vol. 12, p 227.
8. (a) Porter, H. D.; Peterson, W. D. Organic Synthesis; 1955; Collect. Vol. III660; (b)
Huisgen, R.; Bast, K. Organic Synthesis; 1973; Collect. Vol. V650; (c) Foster, R. H.;
Leonard, N. J. J. Org. Chem. 1979, 44, 4609; (d) Bartsch, R. A.; Yang, I.-W. J.
Heterocycl. Chem. 1984, 21, 1063; (e) Arnautu, A.; Collot, V.; Ros, J. C.; Alayrac, C.;
Witulski, B.; Rault, S. Tetrahedron Lett. 2002, 43, 2695.
9. Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1994, 50, 3529.
10. (a) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323; (b) Liu, Z.; Shi, F.;
Martinze, P. D. G.; Raminelli, C.; Larock, R. C. J. Org. Chem. 2008, 73, 219; (c) Wu,
C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234; (d) Spiteri, C.; Keeling,
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Shi, F. Org. Lett. 2011, 13, 3340.
4.2.2.7. 1,5-Dimethyl-1H-indazole (3g). As described in the
general procedure, reaction of 1,5-dimethyl-1H-indazol-3-amine
2g (0.48 g, 3.0 mmol) and tert-butyl nitrite (1.0 mL, 8.1 mmol,
2.7 equiv) in THF (12.0 mL) afforded the title compound (0.36 g,
82%). Solid (EtOAc), mp 60e61 ꢀC; TLC (EtOAc/hexanes (1:4))
Rf¼0.2; IR (neat) 2920, 2374, 1565, 1218 cmꢁ1
;
1H NMR (300 MHz,
CDCl3)
d 2.44 (s, 3H), 4.03 (s, 3H), 7.18e7.28 (m, 2H), 7.47 (s, 1H),
7.86 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 21.2 (CH3), 35.5 (CH3), 108.5
(CH), 120.0 (CH), 124.4 (C), 128.3 (CH), 129.8 (C), 132.0 (CH), 138.6
(C); MS m/z (rel intensity) 146 (Mþ, 100), 131 (17); HRMS [M]þ for
C9H10N2: 146.0844, found 146.0840.
4.2.2.8. 4-Chloro-1-methyl-1H-indazole (3h). As described in
the general procedure, reaction of 4-chloro-1-methyl-1H-indazol-
3-amine 2h (0.54 g, 3.0 mmol) and tert-butyl nitrite (1.0 mL,
8.1 mmol, 2.7 equiv) in THF (12.0 mL) afforded the title compound
(0.42 g, 85%). oil; TLC (EtOAc/hexanes (1:2)) Rf¼0.5; IR (neat) 3086,
2928, 1616, 1487 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 4.02 (s, 3H),
7.06 (dd, J¼8.1, 3.0 Hz, 1H), 7.22e7.23 (m, 2H), 8.01 (s, 1H); 13C NMR
(75 MHz, CDCl3)
d 35.7 (CH3), 107.4 (CH), 119.9 (C), 123.1 (C), 126.4
(C), 126.6 (CH), 131.2 (CH), 140.6 (C). These data are in agreement
with those reported in the literature.11c
4.2.2.9. 1-Benzyl-5-nitro-1H-indazole (3i). As described in the
general procedure, reaction of 1-benzyl-5-nitro-1H-indazol-3-
amine 2h (0.48 g, 3.0 mmol) and tert-butyl nitrite (0.84 g, 1.0 mL,
8.1 mmol, 2.7 equiv) in THF (12.0 mL) afforded the title compound
(0.68 g, 90%). White solid (EtOAc), mp 125e126 ꢀC; TLC (EtOAc/
hexanes (1:2)) Rf¼0.45; IR (neat) 3122, 2956, 1514, 1329 cmꢁ1
;
1H
NMR (300 MHz, CDCl3)
d 5.62 (s, 2H), 7.18e7.39 (m, 6H), 8.16e8.22
(m, 2H), 8.70 (d, J¼2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 53.6
11. (a) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org. Chem. 2006, 71, 8166;
(b) Lokhande, P. D.; Raheem, A.; Sabale, S. T.; Chabukswar, A. R.; Jagdale, S. C.
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Lukin, K.; Hill, D. R. J. Org. Chem. 2009, 74, 9539.
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(CH2), 109.6 (CH), 118.9 (CH), 121.5 (CH), 123.5 (C), 127.2 (CHꢂ2),
128.3 (CH), 128.9 (CHꢂ2), 135.6 (C), 136.0 (CH), 141.2 (C), 142.4 (C);
MS m/z (rel intensity) 253 (Mþ, 61), 252 (25); HRMS [M]þ for
C14H11N3O2: 253.0851, found 253.0849.

3912
H.-J. Liu et al. / Tetrahedron 69 (2013) 3907e3912
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