Assembly of substituted 3-aminoindazoles from 2-bromobenzonitrile via a CuBr-catalyzed coupling/condensation cascade process

Article abstract of DOI:10.1021/jo400071h

CuBr-catalyzed coupling reaction of 2-halobenzonitriles with hydrazine carboxylic esters and CuBr/4-hydroxy-l-proline-catalyzed coupling reaction of 2-bromobenzonitriles with N′-arylbenzohydrazides proceed smoothly at 60-90 C to provide substituted 3-aminoindazoles through a cascade coupling/condensation (or coupling/deacylation/condensation) process. A wide range of 3-aminoindazoles with substituents at both the 1-position and the phenyl ring part can be prepared from the corresponding coupling partners.

Full text of DOI:10.1021/jo400071h

Note
pubs.acs.org/joc
Assembly of Substituted 3‑Aminoindazoles from
2‑Bromobenzonitrile via a CuBr-Catalyzed Coupling/Condensation
Cascade Process
Lanting Xu,† Yinsheng Peng,‡ Qiangbiao Pan,‡ Yongwen Jiang,§ and Dawei Ma*,§
†Department of Chemistry, Fudan University, Shanghai 200433, China
‡Lianhe Chemical Technology Co. Ltd., 41 Wangxi Road, Huangyan Dt., Taizhou, Zhejiang 318020, China
§State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: CuBr-catalyzed coupling reaction of 2-halobenzo-
nitriles with hydrazine carboxylic esters and CuBr/4-hydroxy-L-
proline-catalyzed coupling reaction of 2-bromobenzonitriles with
N′-arylbenzohydrazides proceed smoothly at 60−90 °C to
provide substituted 3-aminoindazoles through a cascade cou-
pling/condensation (or coupling/deacylation/condensation)
process. A wide range of 3-aminoindazoles with substituents at
both the 1-position and the phenyl ring part can be prepared from
the corresponding coupling partners.
3-Aminoindazole is a medicinally important heterocyclic moiety
that has been frequently applied for pharmaceutical design. The
compounds with this special skeleton have been demonstrated
to have significant biological activities, ranging from blocking
melanin-concentrating hormone (MCH) receptor-1 as dis-
played by compounds 1 and 2 (Figure 1)1 to inhibiting
multitargeted receptor tyrosine kinase (RTK), janus kinase 2
(JAK-2), and cyclin-dependent kinase as shown by ABT-869
(3),2 compounds 43 and 5,4 respectively.
The typical method for assembling 3-aminoindazoles has
relied on an aromatic nucleophilic substitution of o-
fluorobenzonitriles and o-chlorobenzonitriles with hydra-
zine.1−5 The major drawback for this approach is that when
electron-rich o-halobenzonitriles were used harsh reaction
conditions were required and the reactions normally gave the
desired products in low yields. This problem is believed to
result from the deactivation directed by the additional electron-
donating groups. Additionally, in order to obtain 1-substituted
3-aminoindazoles, further functionalization at the 1-position of
its products was required. Other notable synthetic methods
included condensation of N-substituted fluoroarythioamides
with hydrazine,6 Pd-catalyzed amination of 3-chloroindazoles,7
and Pd-catalyzed intramolecular C−N bond formation of
tosylhydrazines.8 These approaches suffer from requiring
several steps to obtain the starting materials. Recently, Fabis
and co-workers reported that 3-aminoindazoles could be
obtained by Pd-catalyzed arylation of benzophenone hydrazine
with substituted 2-bromobenzonitriles and subsequent depro-
tection and intramolecular condensation.9 Since this method
needs both basic and acidic operations at relatively high
Figure 1. Selected bioactive compounds with 3-aminoindazole moiety.
temperatures, its applications for diverse synthesis are
questionable.
During the past decade, arylation of hydrazine or its
derivatives under the catalysis of metal complexes has received
great attention.9−12 Based on our investigations on Cu-
Received: January 14, 2013
Published: February 28, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
catalyzed coupling of aryl halides with protected hydrazines,10
we speculated that Cu-catalyzed coupling of 2-halobenzonitriles
6 with protected hydrazines 7 might occur regioselectively to
afford aryl hydrazines 8 directly or after deacylation (Scheme
1). The resultant intermediates 8 could undergo spontaneous
We next examined the reaction scope by varying 2-
bromobenzonitriles and protected hydrazines. As summarized
in Table 2, three electron-rich and one electron-deficient 2-
Table 2. Synthesis of 3-Aminoindazoles via a CuBr-
Catalyzed Cascade Reaction Process from Hydrazine
a
Scheme 1
Carboxylic Esters and 2-Bromobenzonitriles
intramolecular condensation to afford cyclization products 9,
which would deliver 1-substituted 3-aminoindazoles 10 after
aromatization.
With this idea in mind, we conducted a coupling reaction of
2-iodobenzonitrile with N-Boc-hydrazine. It was found that
under the catalysis of 20 mol % of CuI and 20 mol % of L-
proline, the reaction proceeded smoothly in DMF at room
temperature to afford the desired tert-butyl 3-amino-1H-
indazole-1-carboxylate 10a in 68% yield (Table 1, entry 1).
Table 1. Condition Screening for Formation of tert-Butyl 3-
a
Amino-1H-indazole-1-carboxylate 10a
a
Reaction conditions: 2-bromobenzonitrile (0.5 mmol), hydrazine
carbamate (0.6 mmol), CuBr (0.1 mmol), K2CO3 (1 mmol), 80 °C, 12
b
c
h. Isolated yield. Reaction was carried out at 60 °C.
b
entry
X
[Cu]
solvent
DMF
temp (°C) time (h) yield (%)
bromobenzonitriles also worked well, affording the correspond-
ing 3-aminoindazoles 10b−e in good yields (entries 1−4).
These results indicated that the electronic nature of 2-
bromobenzonitriles has little influence to the present trans-
formation.
c
1
2
3
4
5
6
7
8
9
I
CuI
rt
rt
56
56
56
40
24
12
12
12
12
68
86
41
85
27
14
35
60
77
I
CuI
DMF
I
CuI
1,4-dioxane
DMSO
DMF
rt
I
CuI
rt
Br
Br
Br
Br
Br
CuI
80
80
80
80
80
Further investigations revealed that changing Boc to other
protecting groups was possible, evident because 3-amino-
indazoles 10f−k could be obtained from the corresponding 2-
bromobenzonitriles and hydrazine carboxylic esters (entries 5−
10). Obviously, compounds 10d, 10j, and 10k could be used
for preparing melanin-concentrating hormone (MCH) receptor
antagonist 1,1 cyclin-dependent kinase inhibitor 5,4 multi-
targeted receptor tyrosine kinase (RTK) inhibitor 3,2 and janus
kinase 2 (JAK-2) inhibitor 4,2 respectively.
We have recently found that N-acyl-N′-arylhydrazines could
couple with aryl iodides regioselectively to afford N-acyl-N′,N′-
diarylhydrazines under the catalysis of CuI and 4-hydroxy-L-
proline.10b We speculated that these nucleophiles could react
with 2-bromobenzonitriles to give the coupling products, which
would undergo deacylation and intramolecular condensation to
deliver aryl-substituted 3-aminoindazoles. Accordingly, CuBr/4-
hydroxy-L-proline-catalyzed coupling of 2-bromobenzonitrile
and N′-phenylbenzohydrazide was conducted. We were pleased
that the reaction took place at 90 °C to provide 1-phenyl-3-
aminoindazole 10l in 82% yield (Table 3, entry 1). Using N′-
phenylbenzohydrazide as a coupling partner, some substituted
2-bromobenzonitriles were checked and good yields were
observed for both electron-rich and electron-deficient sub-
CuCl
Cu2O
CuBr
CuBr
DMF
DMF
DMF
DMSO
a
Reaction conditions: 2-halobenzonitrile (0.5 mmol), hydrazine
carbamate (0.6 mmol), copper salt (0.1 mmol), K2CO3 (1 mmol).
Isolated yield.
b
cL-Proline as the additive.
In the absence of L-proline a better yield was observed (entry
2), indicating that the ligand is useless in this case. A similar
phenomenon has been observed in our studies on simple
arylation of N-Boc-hydrazine.10a For other solvents, 1,4-dioxane
gave a lower yield (entry 3), while DMSO led to complete
conversion in a shorter time (compare entries 2 and 4). When
less reactive 2-bromobenzonitrile was used, the cascade reaction
process worked in DMF at 80 °C, although the yield was poor
(entry 5). The condition screening by changing copper salts
revealed that CuBr is a more efficient catalyst (compare entries
5−8). The reaction yield could be further improved by using
DMSO as the solvent (entry 9). Taken together, we concluded
that using CuBr as the catalyst and DMSO as the solvent could
give the best results.
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Note
Table 3. Synthesis of 3-Aminoindazoles from 2-
EXPERIMENTAL SECTION
■
Bromobenzonitriles and N′-Arylbenzohydrazides under the
General Procedure for Synthesis of 3-Aminoindazoles. A
Schlenk tube was charged with 2-iodobenzonitrile (0.5 mmol),
hydrazines (0.6 mmol), CuBr (0.1 mmol), and K2CO3 (1.0 mmol).
The tube was evacuated and backfilled with argon before 1.0 mL of
DMSO was added. The reaction mixture was stirred at 80 °C (60 °C
for benzyl hydrazinecarboxylate) for 10−24 h. After the reaction
mixture was cooled, 10 mL of saturated NH4Cl was added. The
mixture was extracted with EtOAc, and then the organic layer was
washed with water and brine and dried over Na2SO4. After
concentration in vacuo, the residue was purified by column
chromatography on silica gel (eluting with Et3N/EtOAc/hexane) to
provide the desired product.
a
Catalysis of CuBr and trans-4-Hydroxy-L-proline
tert-Butyl 3-amino-1H-indazole-1-carboxylate (10a): white solid,
88 mg, 77% yield; mp 157−159 °C; 1H NMR (400 MHz, DMSO-d6)
δ 1.58 (s, 9H), 6.33 (br s, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.51 (dt, J =
0.8, 7.2 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H);
13C NMR (100 MHz, DMSO-d6) δ 152.4, 149.2, 139.9, 129.1, 122.5,
120.7, 119.3, 114.1, 82.4, 27.9; HRMS (ESI-FT) m/z (M + Na)+ calcd
for C12H15N3NaO2 256.1062, found 256.1063.
tert-Butyl 3-amino-6-methyl-1H-indazole-1-carboxylate (10b):
white solid, 95 mg, 78% yield; mp 140−142 °C; 1H NMR (400
MHz, DMSO-d6) δ 1.57 (s, 9H), 2.44 (s, 3H), 6.25 (br s, 2H), 7.10 (d,
J = 8.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δ 152.3, 149.2, 140.5, 139.1, 124.0, 120.3, 117.3,
114.1, 82.2, 27.9, 21.7; HRMS (ESI-FT) m/z (M + Na)+ calcd for
C13H17N3NaO2 270.1219, found 270.1215.
tert-Butyl 3-amino-5-methyl-1H-indazole-1-carboxylate (10c):
white solid, 88 mg, 72% yield; mp 164−166 °C; 1H NMR (400
MHz, DMSO-d6) δ 1.57 (s, 9H), 2.39 (s, 3H), 6.25 (br s, 2H), 7.33 (d,
J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ 152.2, 149.1, 138.3, 131.6, 130.4, 120.1, 119.5,
113.80, 82.1, 27.9, 20.7; HRMS (ESI-FT) m/z (M + Na)+ calcd for
C13H17N3NaO2 270.1219, found 270.1215.
tert-Butyl 3-amino-5-methoxy-1H-indazole-1-carboxylate (10d):
semisolid, 102 mg, 79% yield; 1H NMR (400 MHz, DMSO-d6) δ 1.57
(s, 9H), 3.80 (s, 3H), 6.24 (br s, 2H), 7.14 (dd, J = 2.0, 8.8 Hz, 1H),
7.40 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 9.6 Hz, 1H); 13C NMR (100
MHz, DMSO-d6) δ 155.3, 152.3, 149.1, 134.9, 119.9, 118.6, 115.0,
102.2, 82.1, 55.5, 27.9; HRMS (ESI-FT) m/z (M + Na)+ calcd for
C13H17N3NaO3 286.1168, found 286.1163.
a
Reaction conditions: 2-bromobenzonitrile (0.5 mmol), N′-arylbenzo-
hydrazide (0.6 mmol), CuBr (0.05 mmol), trans-4-hydroxy-L-proline
(0.1 mmol), K2CO3 (2 mmol), DMSO (1.5 mL), H2O (0.15 mL), 90
°C, 48 h. Isolated yield.
b
tert-Butyl 3-amino-5-fluoro-1H-indazole-1-carboxylate (10e):
white solid, 94 mg, 75% yield; mp 142−144 °C; 1H NMR (400
MHz, DMSO-d6) δ 1.57 (s, 9H), 6.34 (s, 2H), 7.38 (td, J = 9.1, 2.6 Hz,
1H), 7.66 (dd, J = 8.5, 2.5 Hz, 1H), 7.96−7.93 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 159.0 (J = 237.1 Hz), 152.1, 149.0, 136.7,
119.9 (J = 9.5 Hz), 117.5 (J = 25.5 Hz), 115.6 (J = 9.1 Hz), 106.1 (J =
24.3 Hz), 82.6, 27.9; HRMS (ESI-FT) m/z (M + Na)+ calcd for
C12H14FN3NaO2 274.0968, found 274.0975.
strates (entries 2−5). Further attempts indicated that a wide
range of aryl groups could be introduced to the 1-position of 3-
aminoindazoles by employing different N′-arylbenzohydrazides
as the coupling partners (entries 6−12). No regioisomers of
10l−w were determined from these reactions, indicating that
the first coupling step took place in a regioselective manner as
we observed before.10b Noteworthy is that without addition of
4-hydroxy-L-proline the reaction yield decreased greatly.
Benzyl 3-amino-1H-indazole-1-carboxylate (10f): white solid, 86
1
mg, 65% yield; mp 175−177 °C; H NMR (400 MHz, DMSO-d6) δ
It is notable that using N-acyl-N′-arylhydrazines as the
coupling partners is essential for this transformation because
coupling of phenyl hydrazine with 2-bromobenzonitrile under
similar conditions (CuBr/trans-4-hydroxy-L-proline, K2CO3,
DMSO, 100 °C) did not give any coupling products. These
results demonstrated that subtle change in pKa values of
nucleophiles could alter the coupling reaction process greatly.
In conclusion, we have developed a valuable method for
assembling pharmaceutically important substituted 3-amino-
indazoles. This method relies on a copper-catalyzed coupling
reaction of 2-halobenzonitriles with hydrazine carboxylic esters
and N′-arylbenzohydrazides. Its generality has been demon-
strated by synthesizing a number of 3-aminoindazoles with
substituents at both the 1-position and the phenyl ring part.
Our result gives another example for illustrating the usage of
copper-catalyzed coupling in heterocycles synthesis.13,14
5.39 (s, 2H), 6.41 (br s, 2H), 7.27−7.55 (m, 7H), 7.88 (d, J = 8.0 Hz,
1H), 8.01 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
152.9, 150.2, 139.9,135.8, 129.3, 128.5, 128.4, 128.3, 122.8, 120.8,
119.5, 113.9, 67.6; HRMS (ESI-FT) m/z (M + Na)+ calcd for
C15H13N3NaO2 290.0906, found 290.0895.
Benzyl 3-amino-1H-indazole-1-carboxylate (10g): white solid, 76
1
mg, 75% yield; mp 164−165 °C; H NMR (400 MHz, DMSO-d6) δ
1.34 (t, J = 6.8 Hz, 3H), 4.37 (q, J = 6.8 Hz, 2H), 6.39 (br s, 2H), 7.28
(t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H),
8.01 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 152.8,
150.4, 139.9, 129.2, 122.7, 120.8, 119.4, 113.9, 62.4, 14.3; HRMS (ESI-
FT) m/z (M + Na)+ calcd for C10H11N3NaO2 228.0749, found
228.0757.
Ethyl 3-amino-5-methoxy-1H-indazole-1-carboxylate (10h):
white solid, 89 mg, 76% yield; mp 176−178 °C; 1H NMR (400
MHz, DMSO-d6) δ 1.33 (t, J = 6.8 Hz, 3H), 3.80 (s, 3H), 4.34 (q, J =
6.8 Hz, 2H), 6.28 (br s, 2H), 7.15 (dd, J = 1.6, 8.4 Hz, 1H), 7.41 (s,
1H), 7.88 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
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Note
155.5, 152.6, 150.3, 134.9, 120.0, 118.7, 114.8, 102.3, 62.2, 55.5, 14.3;
HRMS (ESI-FT) m/z (M + Na)+ calcd for C11H13N3NaO3 258.0855,
found 258.0847.
(t, J = 8.0 Hz, 2H), 7.67 (d, J = 8.8 Hz, 3H), 7.76 (dd, J = 9.2, 4.0 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 157.3 (J = 233.6 Hz), 150.6
(J = 4.7 Hz), 140.4, 135.9, 129.4 (2C), 124.1, 119.8 (2C), 117.1 (J =
9.5 Hz), 116.7 (J = 26.4 Hz), 111.5 (J = 9.1 Hz), 105.6 (J = 23.6 Hz);
HRMS (ESI-FT) m/z (M + H)+ calcd for C13H11FN3 228.0937, found
228.0932.
1-(4-Methoxyphenyl)-1H-indazol-3-amine (10q): semisolid, 84
mg, 71% yield; 1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H),
5.80 (br s, 2H), 7.03−7.06 (m, 3H), 7.34−7.38 (m, 1H), 7.54−7.59
(m, 3H), 7.83−7.81 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 156.1, 150.3, 138.8, 133.9, 127.5, 121.9 (2C), 120.9,
118.8, 116.5, 114.5 (2C), 109.4, 55.3; HRMS (ESI-FT) m/z (M + H)+
calcd for C14H14N3O 240.1137, found 240.1131.
1-(4-Bromophenyl)-1H-indazol-3-amine (10r): semisolid, 99 mg,
69% yield; 1H NMR (400 MHz, CDCl3) δ 4.20 (br s, 2H), 7.15−7.11
(m, 1H), 7.25−7.23 (m, 1H), 7.38−7.43 (m, 1H),7.46−7.50 (m, 2H),
7.62 (d, J = 7.6 Hz, 1H), 7.69−7.66 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 149.1, 140.6, 139.9, 129.50 (2C), 128.1, 125.3, 121.6 (2C),
120.1, 119.8, 116.7, 110.5; HRMS (ESI-FT) m/z (M + H)+ calcd for
C13H11BrN3 288.0136, found 288.0131.
Ethyl 3-amino-5-methyl-1H-indazole-1-carboxylate (10i): white
solid, 86 mg, 79% yield; mp 143−145 °C; 1H NMR (400 MHz,
DMSO-d6) δ 1.33 (t, J = 6.8 Hz, 3H), 2.40 (s, 3H), 4.33 (q, J = 6.8 Hz,
2H), 6.29 (br s, 2H), 7.36 (dd, J = 1.2, 8.4 Hz, 1H), 7.63 (s, 1H), 7.87
(d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 152.5, 150.4,
138.4, 131.9, 130.6, 120.2, 119.6, 113.6, 62.2, 20.8, 14.3; HRMS (ESI-
FT) m/z (M + Na)+ calcd for C11H13N3NaO2 242.0906, found
242.0902.
Ethyl 3,5-diamino-1H-indazole-1-carboxylate (10j): yellow solid,
82 mg, 75% yield; mp 181−182 °C; 1H NMR (400 MHz, DMSO-d6)
δ 1.33 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 5.09 (br s, 2H),
6.07 (s, 2H), 6.82−6.84 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 152.5, 150.3, 144.8, 132.6, 120.5, 118.1,
114.4, 102.4, 61.8, 14.4; HRMS (ESI-FT) m/z (M + Na)+ calcd for
C10H12N4NaO2 243.0858, found 243.0852.
Ethyl 3-amino-5-bromo-1H-indazole-1-carboxylate (10k): yellow
solid, 59 mg, 42% yield; mp 136−138 °C; 1H NMR (400 MHz,
DMSO-d6) δ 1.36 (t, J = 7.2 Hz, 3H), 4.35 (q, J = 7.2 Hz, 2H), 6.45
(br s, 2H), 7.66−7.69 (m, 1H), 7.94 (d, J = 8.8 Hz, 1H), 8.14 (d, J =
2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 151.8, 150.2, 139.8,
131.8, 123.4, 121.1, 115.8, 114.6, 62.7, 14.2; HRMS (ESI-FT) m/z (M
+ Na)+ calcd for C10H10BrN3NaO2 305.9854, found 305.9850.
General Procedure for Preparing 1-Aryl-3-aminoindazoles.
A Schlenk tube was charged with 2-iodobenzonitrile (0.5 mmol), N′-
phenylbenzohydrazide (0.60 mmol), CuBr (0.05 mmol), trans-4-
hydroxy-L-proline (0.1 mmol), and K2CO3 (2.0 mmol). The tube was
evacuated and backfilled with argon before 1.5 mL of DMSO and 0.15
mL of H2O were added. After the reaction mixture was stirred at 90 °C
for 36−48 h, 10 mL of saturated NH4Cl solution was added at room
temperature to quench the reaction. The mixture was extracted with
EtOAc, and then the organic layer was washed with water and brine
and dried over Na2SO4. After concentration in vacuo, the residue was
purified by column chromatography (eluting with Et3N/EtOAc/
hexane) to provide the desired product.
1-p-Tolyl-1H-indazol-3-amine (10s): white solid, 82 mg, 74% yield;
1
mp 112−114 °C; H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 4.20
(br s, 2H), 7.12 (t, J = 7.6 Hz, 1H), 7.28−7.25 (m, 2H), 7.40−7.36 (m,
1H), 7.54−7.52 (m, 2H), 7.63−7.59 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 149.0, 139.8, 138.1, 134.9, 129.9 (2C), 127.8, 121.6 (2C),
119.8, 119.7, 116.4, 110.3, 21.0; HRMS (ESI-FT) m/z (M + H)+ calcd
for C14H14N3 224.1188, found 224.1182.
1-(4-Fluorophenyl)-1H-indazol-3-amine (10t): semisolid, 79 mg,
1
70% yield; H NMR (400 MHz, DMSO-d6) δ 6.05 (br s, 2H), 6.97−
7.01 (m, 1H), 7.12−7.16 (m, 1H), 7.42−7.58 (m, 4H), 7.82 (d, J = 8.8
Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
163.9 (J = 241.4 Hz), 151.2, 142.4 (J = 10.8 Hz), 138.8, 131.1 (J = 9.6
Hz), 128.3, 121.2, 120.0, 117.8, 115.0 (J = 2.6 Hz), 110.3, 110.2 (J =
21.0 Hz), 106.5 (J = 25.6 Hz); HRMS (ESI-FT) m/z (M + H)+ calcd
for C13H11FN3 228.0937, found 228.0932.
1-(3-Methoxyphenyl)-1H-indazol-3-amine (10u): semisolid, 78
1
mg, 66% yield; H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 4.16
(br s, 2H), 6.77−6.80 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.26−7.23 (m,
2H), 7.34−7.39 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 160.6, 149.2, 141.7, 139.8,
130.1, 127.9, 120.1, 119.8, 116.8, 113.6, 111.1, 110.6, 107.3, 55.5;
HRMS (ESI-FT) m/z (M + H)+ calcd for C14H14N3O 240.1137,
found 240.1131.
1-(3-Chlorophenyl)-1H-indazol-3-amine (10v): yellow solid, 80
mg, 66% yield; mp 102−105 °C; 1H NMR (400 MHz, CDCl3) δ 4.26
(br s, 2H), 7.20−7.14 (m, 2H), 7.46−7.37 (m, 2H), 7.62−7.57 (m,
2H), 7.71−7.67 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 149.7,
141.7, 139.6, 134.9, 130.3, 128.2, 124.7, 121.1, 120.4, 119.9, 118.8,
117.1, 110.3; HRMS (ESI-FT) m/z (M + H)+ calcd for C13H11ClN3
244.0642, found 244.0636.
1-o-Tolyl-1H-indazol-3-amine (10w): semisolid, 66 mg, 60% yield.
1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H), 4.19 (br s, 2H), 7.00−
7.04 (m, 2H), 7.22−7.33 (m, 5H), 7.56 (d, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 148.5, 141.7, 138.5, 135.7, 131.4, 128.1, 127.5,
127.5, 126.7, 119.6, 119.4, 115.3, 110.1, 18.2; HRMS (ESI-FT) m/z
(M + H)+ calcd for C14H14N3 224.1188, found 224.1182.
1-Phenyl-1H-indazol-3-amine (10l): yellow solid, 85 mg, 82%
yield; mp 87−89 °C; 1H NMR (400 MHz, DMSO-d6) δ 5.93 (s, 2H),
7.09 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz,
1H), 7.48 (t, J = 7.2 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.8
Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
150.8, 140.7, 138.7, 129.3 (2C), 127.9, 123.8, 119.8 (2C), 119.4, 117.3,
109.9; HRMS (ESI-FT) m/z (M + H)+ calcd for C13H12N3 210.1031,
found 210.1025.
6-Methyl-1-phenyl-1H-indazol-3-amine (10m): yellow solid, 81
1
mg, 73% yield; mp 121−123 °C; H NMR (400 MHz, DMSO-d6) δ
2.43 (s, 3H), 5.85 (s, 2H), 6.92 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.2 Hz,
1H), 7.49 (t, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H),
7.73 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 150.7,
140.8, 139.4, 137.8, 129.3 (2C), 123.7, 121.3, 120.7, 119.9 (2C), 115.5,
109.6, 21.7; HRMS (ESI-FT) m/z (M + H)+ calcd for C14H14N3
224.1188, found 224.1182.
5-Methyl-1-phenyl-1H-indazol-3-ylamine (10n): semisolid, 82 mg,
1
72% yield; H NMR (400 MHz, DMSO-d6) δ 2.39 (s, 2H), 5.81 (s,
1H), 7.15 (t, J = 7.3 Hz, 1H), 7.24 (d, J = 9.5 Hz, 1H), 7.46 (t, J = 7.9
Hz, 2H), 7.67−7.63 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ
150.4, 140.9, 137.4, 129.6, 129.3 (2C), 128.3, 123.5, 120.3, 119.4 (2C),
117.6, 109.9, 20.8; HRMS (ESI-FT) m/z (M + H)+ calcd for
C14H14N3 224.1188, found 224.1182.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
5-Methoxy-1-phenyl-1H-indazol-3-ylamine (10o): semisolid, 89
1
mg, 75% yield; H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 5.79
(br s, 2H), 7.06 (dd, J = 9.1, 2.5 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.39
(d, J = 2.6 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.69−7.63 (m, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 153.3, 150.4, 140.9, 134.5, 129.3 (2C),
123.4, 119.2 (2C), 118.5, 117.5, 111.2, 101.7, 55.5; HRMS (ESI-FT)
m/z (M + H)+ calcd for C14H14N3O 240.1137, found 240.1131.
5-Fluoro-1-phenyl-1H-indazol-3-amine (10p): yellow solid, 78 mg,
AUTHOR INFORMATION
Corresponding Author
*E-mail: madw@mail.sioc.ac.cn.
■
1
Notes
69% yield; mp 108−110 °C; H NMR (400 MHz, DMSO-d6) δ 5.93
(br s, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.28 (dt, J = 7.2, 2.4 Hz, 1H), 7.47
The authors declare no competing financial interest.
3403
dx.doi.org/10.1021/jo400071h | J. Org. Chem. 2013, 78, 3400−3404

The Journal of Organic Chemistry
Note
Chem., Int. Ed. 2009, 48, 348. (n) Ma, D.; Geng, Q.; Zhang, H.; Jiang,
Y. Angew. Chem., Int. Ed. 2010, 49, 1291. (o) Xu, W.; Fu, H. J. Org.
Chem. 2011, 76, 3846. (p) Wang, Z.; Yang, F.; Lv, X.; Bao, W. J. Org.
Chem. 2011, 76, 967. (q) Ma, D.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.;
Liu, X. Angew. Chem., Int. Ed. 2011, 50, 1118.
ACKNOWLEDGMENTS
■
We are grateful to the Ministry of Science and Technology
(Grant No. 2009ZX09501-00) and the Chinese Academy of
Sciences and National Natural Science Foundation of China
(Grant Nos. 20632050 and 20921091) for financial support.
REFERENCES
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