Synthesis of 1 H-indazoles and 1 H-pyrazoles via FeBr3/O 2 mediated intramolecular C-H amination

Article abstract of DOI:10.1021/jo3026862

A new synthesis of substituted 1H-indazoles and 1H-pyrazoles from arylhydrazones via FeBr₃/O₂ mediated C-H activation/C-N bond formation reactions is reported. The corresponding 1,3-diaryl-substituted indazoles and trisubstituted pyr

Full text of DOI:10.1021/jo3026862

Note
pubs.acs.org/joc
Synthesis of 1H‑Indazoles and 1H‑Pyrazoles via FeBr3/O2 Mediated
Intramolecular C−H Amination
Tianshui Zhang and Weiliang Bao*
Department of Chemistry, Xixi Campus, Zhejiang University, Hangzhou 310028, P. R. China
S
* Supporting Information
ABSTRACT: A new synthesis of substituted 1H-indazoles and 1H-
pyrazoles from arylhydrazones via FeBr3/O2 mediated C−H
activation/C−N bond formation reactions is reported. The
corresponding 1,3-diaryl-substituted indazoles and trisubstituted
pyrazoles were obtained in moderate to excellent yields under mild
conditions.
N-Heterocycles, because of their ubiquitous nature, are key
scaffolds of many biological molecules and pharmaceutical
products. Among them, 1H-indazoles1 and 1H-pyrazoles2 with
a broad spectrum of pharmacological activities are very
important. Presently many of their derivatives have been
reported with fantastic bioactivities, and some typical examples
are outlined in Figure 1. 5-Aminomethyl-1H-indazole (A) is an
independently reported the cycloaddition of arynes with
diazo compounds, and Moses10 has disclosed a 1,3-dipolar
cycloaddition of in situ generated nitrile imines with benzyne.
Later, a variety of N-aryl-1H-indazoles were synthesized via
intramolecular dehydration from common arylamino oximes,11
coupling reaction of N-acyl-N-substituted hydrazines with 2-
bromoarylcarbonylic compounds,12 and a [3 + 2] annulation
approach from arynes and hydrazones.13 At the same time, a
one-pot synthetic protocol for the synthesis of substituted
pyrazoles was achieved through cyclocondensation of ketones/
aldehydes with hydrazines.14 Early in 1965, Gladstone and
Norman15 had treated hydrazone with Pb(OAc)4 to give azo-
compounds that then cyclized to the indazole. Very recently,
Kou Hiroya and Yu Rao16 also obtained the corresponding N-
heterocycles from hydrazones via an orthometalation process.
As an abundant, cheap, and less toxic element, iron is an ideal
candidate to replace precious metals in organic synthesis,
especially for practical large scale preparation. The use of iron
as a catalyst for organic synthesis has recently been increasingly
attracting the interest of chemists from economical and
ecological points of view.17 Herein, we report a new cost-
effective synthesis of substituted 1H-indazoles and 1H-
pyrazoles from arylhydrazones catalyzed by cheap iron(III)
tribromide with oxygen as an ultimate oxidative agent under
mild conditions.
Figure 1. Structures of some pharmacologically important indazoles
and pyrazols.
extremely potent HIV protease inhibitor with excellent antiviral
activity;3 1H-indazole-3-carboxylic acid (B) has a selective and
potent antispermatogenic activity;4 1-(4-fluoro-phenyl)-1H-
indazole (C) has been used as the most effective treatment
of acute and chronic inflammatory conditions;5 1H-pyrazol-1-
benzenesulfonamide (D) is currently in phase III clinical trials
for treatment of rheumatoid arthritis and osteoarthritis;6 and so
on. As a class of privileged substructures, numerous efforts have
been devoted to pursue efficient methods for synthesis of the
above-mentioned frameworks.
The primal synthetic method of indazoles is the diazotization
of o-alkyl-substituted anilines followed by base-7 or acid-
promoted8 cyclization. Recently, a new approach of 1,3-dipolar
cycloaddition of arynes with different nitrogen sources was
developed. For instance, Yamamoto8c and Larock9 have
Benzophenone phenylhydrazone (1a) was chosen as the
substrate to investigate the reaction conditions (Table 1). First,
Pd(OAc)2 was used as a catalyst and the reaction was
conducted in 2 mL of toluene under O2 atmosphere at 110
°C; 24 h later, 41% yield of the desired product (2a) was
obtained (Table 1, entry 1). When Cu(OTf)2 or Cu(OAc)2
replaced the Pd(OAc)2, the yield declined to 10% or 22%
(Table 1, entries 2 and 4). The yield of 2a also decreased a little
when PhI(OAc)2, Ag2CO3, or DDQ was used as the oxidant
(Table 1, entries 3, 5, and 8). With addition of MS 4 Å or DIC
to the reaction mixture, no change was made in the yield (Table
Received: December 13, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo3026862 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
2g). As can be anticipated, the substrates singly substituted by
methyl or chloro group had isomers (Table 2, 2h and 2l).
Interestingly, when the phenylhydrazones substituted by
methoxy group were subjected to this procedure, the benzene
ring with methoxy group was preferentially activated, and the
reaction proceeded in high regioselectivity (Table 2, 2i−2k),
contrary to nitro group substituted substrate (Table 2, 2m). As
for substrates with substituents in the phenylhydrazines, the
yields were slightly reduced (Table 2, 2n−2p) and no distinct
electronic effect was observed.
Excitingly, this facile method can also be applied to the
construction of a pyrazole scaffold. A variety of substrates
derived from α,β-unsaturated ketones and phenylhydrazine
were surveyed to prepare different trisubstituted pyrazoles. As
shown in Table 3, the optimum reaction condition was also
successful in providing highly diversified trisubstituted
pyrazoles (compounds 3a−3h) with satisfactory yields.
Apparently, in terms of R2 substituents, the substrates with
alkyl group easily produced excellent yields of the correspond-
ing pyrazole products. It was found that both the electron-rich
and electron-deficient aryl groups were well tolerated and did
not show distinct electronic effect.
On the basis of these observations, a plausible mechanism is
proposed in Scheme 1. The reaction proceeded via one-
electron transfer from substrate 1 to FeBr3 to give the reduced
form (Fe2+) and a radical cationic species (A), which
underwent electrophilic attack to the electron-rich double
bond to form a C−N bond. At last, C lost one electron and
dehydrogenated to give the product 2 or 3. The reduced
catalyst reacted with O2 to regenerate the oxidized form (Fe3+)
with the formation of water.
In conclusion, we have developed a new synthetic method
for substituted 1H-indazoles and 1H-pyrazoles via FeBr3/O2
mediated oxidative C−N bond formation reactions. Using
molecular oxygen as an environmentally friendly oxidant and
the inexpensive and nontoxic iron(III) as the catalyst, this
protocol is an efficient method for the direct construction of N-
heterocycles and fits to be largely employed for industrial
applications.
Table 1. Reaction Conditions Optimization
entry
catalyst
oxidant
O2
time (h) temp (°C) yield (%)
1
2
3
4
5
Pd(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
FeCl3
24
24
24
24
24
24
24
18
18
18
18
18
18
18
16
16
16
16
16
16
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
41
10
tr
O2
PhI(OAc)2
O2
22
16
20
24
13
34
43
31
49
37
37
22
82
65
tr
Ag2CO3
O2
b
6
c
7
O2
8
DDQ
DDQ
BQ
9
10
11
12
FeCl3
FeBr3
DDQ
BQ
FeBr3
d
13
e
FeCl3
BQ
14
FeBr3
BQ
15
16
17
FeCl3
O2
FeBr3
O2
FeBr3
O2
f
18
FeBr3
O2
110
110
110
g
19
h
FeBr3
O2
25
75
20
FeBr3
O2
a
Reaction conditions: phenylhydrazone (0.25 mmol) and catalyst
(0.025 mmol), oxidant (0.3 mmol) or under an atmosphere of dry
oxygen, 2.0 mL toluene (reflux). MS 4 Å (200 mg) was added. 2
equiv of diisopropyl-carbodiimide (DIC) (126 mg) was added. 0.3
equiv of FeCl3 was used. 0.3 equiv of FeBr3 was used. 2 mL of DMF
b
c
d
e
f
g
h
as solvent. 2 mL of DMSO as solvent. 2 mL of PhCl as solvent.
1, entries 6 and 7). However, when iron(III) was used as
catalyst, moderate yield was obtained (Table 1, entries 9−12).
Increasing the amount of catalyst did not improve the yield
(Table 1, entries 13 and 14). Interestingly, oxidant had a
significant effect on product yield, and environmentally friendly
oxidant molecular O2 showed the best effect. Further
investigation found that FeBr3 was the best catalyst (Table 1,
entries 15 and 16). Reducing the temperature to 80 °C
decreased the yield slightly (Table 1, entry 17). Among the
solvents investigated, toluene was the best choice (Table 1,
entries 16, 18−20). Finally, the reaction was best promoted by
FeBr3 (10 mol %) /O2 in toluene (2 mL) at 110 °C for 16 h
(Table 1, entry 16).
With these optimized reaction conditions in hand, the
substrate scope was surveyed, and the results are summarized in
Table 2. Various substituted phenylhydrazones generated the
corresponding products in moderate to excellent yields. The
electronic properties of the phenylhydrazone substituents
affected the efficiency of the reaction. The phenylhydrazones
disubstituted by electron-donating groups gave the products in
good to excellent yields (Table 2, 2b−2d), while the reactions
of the phenylhydrazones disubstituted by electron-withdrawing
groups proceeded more slowly and afforded moderate yields
after 21 h (Table 2, 2e and 2f). Impressively, the substrate
disubstituted by chloro and methyl groups also had a
satisfactory yield of 78% and no isomer was found (Table 2,
EXPERIMENTAL SECTION
■
General Remarks. All reactions were carried out under oxygen
with oxygen balloon in oven-dried Schlenk tubes. All the reagents were
commercially available, and toluene was distilled from sodium. The
catalyst FeBr3 was anhydrous (>98%) from Alfa Aesar. The analytical
thin-layer chromatography (TLC) was performed on precoated silica
gel plates (GF 254), visualized with a UV254 lamp. Column
chromatography was performed on silica gel 60 (200−300 mesh)
with petroleum ether/dichloromethane (or petroleum ether/ethyl
acetate) as eluent. All products were confirmed by 1H NMR, 13C
NMR, MS, and IR. Unknown compounds were additionally confirmed
by high resolution mass spectrometry (HRMS). 1H NMR spectra were
recorded at 400 MHz and 13C NMR at 100 MHz. Chemical shifts (δ,
ppm) were determined with TMS as internal standard. Coupling
constants are reported in hertz (Hz). Mass spectra were obtained using
EI ionization. Melting points are uncorrected.
Synthesis of Benzophenone Phenylhydrazone. Benzophe-
none (5 mmol, 1.0 equiv) was added to a solution of phenylhydrazine
(6 mmol, 1.2 equiv) in EtOH, and then two or three drops of acetic
acid were added if necessary. It was stirred at 80 °C for about 10 h
equipped with a reflux condenser until most disappearance of the
benzophenone by TLC, purified by chromatography on a column of
silica gel with PE/DCM = 3:1 as eluent to give benzophenone
phenylhydrazone.
B
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Note
a
Table 2. Scope of C−H Activation/C−N Cyclization
a
Unless otherwise specified, the reactions were carried out with phenylhydrazone (0.25 mmol), FeBr3 (0.025 mmol), and toluene (2.0 mL) under an
b
atmosphere of dry oxygen. Temperature, 140 °C; solvent, p-xylene.
Synthesis of Phenylhydrazone of α,β-unsaturated ketones.
NaOAc (1.3 equiv) was added to a stirred solution of hydrazine
hydrochloride (1.2 equiv) in EtOH. After stirring at room temperature
for 15−20 min, ketones (1.0 equiv) were added to the upper solution
(warm to 40 °C or higher temp if necessary). If most of the ketone
disappeared from TLC, the reaction was quenched, purified by
chromatography on a column of silica gel with PE/EA = 20:1 as eluent
to give the phenylhydrazone. If a lot of solid precipitated from the
solution, the solid was collected by filtration and washed with cold
water and MeOH, followed by further purification by recrystallization
in EtOAc/MeOH cosolvent system.
General Procedure for the Synthesis of Substituted 1H-
Indazoles 2a−2p. An oven-dried Schlenk tube was charged with
FeBr3 (8 mg, 10 mol %) and phenylhydrazone (0.25 mmol), then 2
mL toluene was added as solvent, the reaction tube was sealed, and the
contents were stirred at 110 °C for 16 h under oxygen with oxygen
balloon. After the reaction was complete, the mixture was filtrated and
washed with EtOAc. Then the solvent was removed, and the crude
product was purified through column chromatography with PE/DCE
= 3:1 as eluent to give the pure product.
1,3-Diphenyl-1H-indazole (2a).8c,10 Compound 2a (55 mg,
82%) was obtained as a white solid; mp 96−98 °C ; 1H NMR (CDCl3,
400 MHz) δ 8.07 (d, J = 8 Hz, 1H), 8.04 (d, J = 8 Hz, 2H), 7.80−7.76
(m, 3H), 7.55−7.50 (m, 4H), 7.46−7.41 (m, 2H), 7.35 (t, J = 7.6 Hz,
1H), 7.27 (t, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 146.0,
140.2, 140.0, 133.1, 129.4, 128.8, 128.2, 127.8, 127.1, 126.6, 123.0,
122.9, 121.9, 121.5, 110.6; IR (neat, cm−1) 3052, 1613, 1595, 1498,
1392, 1228, 1110, 1071, 837, 772, 743, 694.
6-Methyl-1-phenyl-3-p-tolyl-1H-indazole (2b). Compound 2b
(56 mg, 75%) was obtained as a light yellow solid; mp 86−88 °C; 1H
NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 8 Hz, 3H), 7.83 (d, J = 7.6,
2H), 7.60−7.56 (m, 3H), 7.41−7.36 (m, 3H), 7.14 (d, J = 8 Hz, 1H),
2.54 (s, 3H), 2.47 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 145.9,
140.8, 140.2, 138.0, 137.4, 130.4, 129.5, 129.4, 127.5, 126.4, 123.9,
123.0, 121.3, 121.2, 110.1, 22.0, 21.3; IR (neat, cm−1) 3036, 2919,
2859, 1613, 1596, 1531, 1499, 1415, 1164, 850, 823, 759, 730; HRMS
(EI-TOF) [M]+ calculated for C21H18N2 298.1470, found 298.1470.
7-Methyl-1-phenyl-3-m-tolyl-1H-indazole (2c). Compound 2c
1
(33 mg, 44%) was obtained as a light yellow oil; H NMR (CDCl3,
400 MHz) δ 7.85−7.77 (m, 5H), 7.66 (d, J = 8.8 Hz, 1H), 7.53 (t, J =
C
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The Journal of Organic Chemistry
Note
3.876 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 159.8, 159.7, 145.8,
141.5, 140.2, 129.4, 128.8, 126.4, 125.8, 122.9, 122.3, 117.6, 114.2,
113.3, 91.8, 55.5, 55.3; IR (neat, cm−1) 3068, 3000, 2931, 2835, 1615,
1597, 1530, 1499, 1418, 1248, 1173, 1110, 1032, 860, 835, 814, 757,
698; HRMS (EI-TOF) [M]+ calculated for C21H18N2O2 330.1370,
found 330.1368.
a
Table 3. Synthesis of Trisubstituted Pyrazoles
6-Fluoro-3-(4-fluoro-phenyl)-1-phenyl-1H-indazole (2e).
Compound 2e (46 mg, 60%) was obtained as a light yellow solid;
mp 130−132 °C; 1H NMR (CDCl3, 400 MHz) δ 7.97−7.91 (m, 3H),
7.72 (d, J = 8 Hz, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.41−7.36 (m, 2H),
7.20 (t, J = 8.8 Hz, 2H), 7.03 (td, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 164.2, 163.8, 161.7, 161.3, 145.3, 140.6,
140.5, 139.6, 129.5, 129.4, 129.3, 128.82, 128.78, 127.0, 122.7, 122.6,
119.7, 115.9, 115.7, 111.8, 111.5, 96.7, 96.4; IR (neat, cm−1) 3064,
2956, 2924, 2853, 1621, 1599, 1528, 1501, 1417, 1224, 1177, 1157,
1106, 862, 839, 807, 758; HRMS (EI-TOF) [M]+ calculated for
C19H12F2N2 306.0966, found 306.0969.
6-Chloro-3-(4-chloro-phenyl)-1-phenyl-1H-indazole (2f).
Compound 2f (55 mg, 65%) was obtained as a white solid; mp
1
148−150 °C; H NMR (CDCl3, 400 MHz) δ 7.91−7.87 (m, 3H),
7.72−7.69 (m, 3H), 7.54 (t, J = 7.6 Hz, 2H), 7.47 (d, J = 8 Hz, 2H),
7.39 (t, J = 7.2 Hz,1H), 7.21 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 144.9, 140.6, 139.3, 134.4, 133.6, 131.1, 129.6, 129.0,
128.7, 127.2, 123.03, 129.96, 122.1, 121.3, 110.5; IR (neat, cm−1)
3063, 2923, 1650, 1601, 1499, 1413, 1164, 1117, 827, 805, 753, 717;
HRMS (EI-TOF) [M]+ calculated for C19H12Cl2N2 338.0378, found
338.0378.
3-(4-Chloro-phenyl)-6-methyl-1-phenyl-1H-indazole (2g).
Compound 2g (57 mg, 78%) was obtained as a light yellow solid;
mp 118−120 °C; 1H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 8.4 Hz,
2H), 7.86 (d, J = 8 Hz, 1H), 7.75 (d, J = 8 Hz, 2H), 7.55−7.51 (m,
3H), 7.46 (d, J = 8 Hz, 2H), 7.35 (t, J = 8 Hz, 1H), 7.09 (d, J = 8 Hz,
1H), 2.49 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 144.6, 140.9,
140.0, 137.6, 133.9, 131.8, 129.4, 128.9, 128.7, 126.7, 124.2, 123.0,
121.0, 120.8, 110.2, 22.0; IR (neat, cm−1) 3065, 2920, 2857, 1618,
1597, 1498, 1413, 1388, 1238, 1118, 1092, 832, 803, 758, 696; HRMS
(EI-TOF) [M]+ calculated for C20H15ClN2 318.0928, found 318.0924.
6-Methyl-1,3-diphenyl-1H-indazole (2h) and 1-Phenyl-3-p-
tolyl-1H-indazole (2h′). Compounds 2h and 2h′ (60 mg, 85%) were
a
Conditions: phenylhydrazone (0.3 mmol), FeBr3 (9 mg, 10 mol %,),
toluene (2.0 mL) under an atmosphere of dry oxygen.
Scheme 1. Tentative Mechanism
1
obtained as a light yellow oil, the regioisomer ratio was got from H
1
NMR spectrum about (3: 1). H NMR (CDCl3, 400 MHz) δ 8.06−
8.02 (m, 1.75 H), 7.93 (d, J = 8.4 Hz, 1.25H), 7.78−7.74 (m, 2.25H),
7.54−7.48 (m, 4.25H), 7.43−7.38 (m, 1H), 7.36−7.31 (m, 1.5H), 7.25
(t, J = 8 Hz, 0.25H, 2h′-isomer), 7.09 (d, J = 8.8 Hz, 0.75H, 2h-
isomer), 2.49 (s, 2.25H, 2h-isomer), 2.42 (s, 0.75H, 2h′-isomer); 13C
NMR (CDCl3, 100 MHz) δ 145.9, 140.9, 140.2, 137.4, 133.3, 129.4,
128.7, 128.1, 127.6, 126.5, 124.0, 123.0, 121.2, 121.1, 110.1, 22.0 (2h-
isomer); IR (neat, cm−1) 3057, 2958, 2921, 2859, 1615, 1598, 1561,
1500, 1417, 1260, 1237, 1164, 1115, 803, 753, 695; HRMS (EI-TOF)
[M]+ calculated for C20H16N2 284.1310, found 284.1313.
8 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (d, J
= 8.4, 1H), 7.24 (d, J = 4.4 Hz, 1H), 2.51 (s, 3H), 2.47 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 145.6, 140.2, 138.9, 138.4, 133.2, 131.3,
129.3, 129.0, 128.9, 128.6, 128.3, 126.3, 124.8, 123.5, 122.7, 120.6,
110.3, 21.5, 21.4; IR (neat, cm−1) 3043, 2920, 2857, 1653, 1596, 1498,
1455, 1306, 1209, 1116, 815, 792, 756, 694; HRMS (EI-TOF) [M]+
calculated for C21H18N2 298.1472, found 298.1470.
6-Methoxy-1,3-diphenyl-1H-indazole (2i). Compound 2i (62
1
mg, 82%) was obtained as a light yellow solid; mp 134−136 °C; H
NMR (CDCl3, 400 MHz) δ 8.00 (d, J = 7.2 Hz, 2H), 7.90 (d, J = 8.8
Hz, 1H), 7.76 (d, J = 8 Hz, 2H), 7.55−7.47 (m, 4H), 7.40 (t, J = 6.8
Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.08 (s, 1H), 6.91 (dd, J1 = 8.8 Hz,
J2 = 1.2 Hz, 1H), 3.83 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 159.9,
146.0, 141.6, 140.1, 133.2, 129.5, 128.8, 128.2, 127.6, 126.6, 123.0,
122.3, 117.7, 113.5, 91.9, 55.5; IR (neat, cm−1) 3058, 2956, 2926,
1615, 1597, 1500, 1455, 1276, 1207, 1169, 1111,860, 814, 763, 694;
HRMS (EI-TOF) [M]+ calculated for C20H16N2O 300.1266, found
300.1263.
5-Methyl-1-phenyl-3-m-tolyl-1H-indazole (2c′). Compound
2c′ (25 mg, 33%) was obtained as a light yellow solid, mp 86−88
°C; 1H NMR (CDCl3, 400 MHz) δ 7.93 (dd, J1 = 6.4 Hz, J2 = 2.8 Hz,
1H), 7.82 (s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.55−7.45 (m, 5H), 7.40 (t,
J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H),
7.16 (s, 1H), 2.44 (s, 3H), 2.13 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 145.8, 141.3, 141.0, 138.4, 133.1, 128.8, 128.7, 128.59, 128.56, 128.5,
128.4, 128.0, 125.0, 122.7, 121.6, 121.2, 119.2, 21.5, 19.4; IR (neat,
cm−1) 3044, 2921, 2858, 1654, 1597, 1501, 1453, 1210, 1125, 836,
796, 749, 697; HRMS (EI-TOF) [M]+ calculated for C21H18N2
298.1467, found 298.1470.
5-Methoxy-1,3-diphenyl-1H-indazole (2j).15,18 Compound 2j
(63 mg, 84%) was obtained as a light yellow solid; mp 86−88 °C; 1H
NMR (CDCl3, 400 MHz) (main isomer) δ 8.00 (d, J = 7.2 Hz, 2H),
7.78 (d, J = 8 Hz, 2H), 7.68 (d, J = 9.2 Hz, 1H), 7.53 (t, J = 7.6 Hz,
4H), 7.43 (t, J = 6.8 Hz, 1H), 7.39 (d, J = 2 Hz, 1H), 7.35 (t, J = 7.2
Hz, 1H), 7.12 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H); 3.90 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 155.5, 145.3, 140.1, 136.0, 133.4, 129.4,
128.8, 128.0, 127.5, 126.4, 123.4, 122.6, 118.8, 111.7, 100.9, 55.7; IR
6-Methoxy-3-(4-methoxy-phenyl)-1-phenyl-1H-indazole
(2d). Compound 2d (75 mg, 91%) was obtained as a light yellow
1
solid; mp 132−134 °C; H NMR (CDCl3, 400 MHz) δ 7.97 (d, J =
8.8 Hz, 2H), 7.90 (d, J = 9.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.57 (t,
J = 7.6 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.07
(d, J = 8.8 Hz, 2H), 6.93 (dd, J1 = 8.4 Hz, J2 = 1.6, 1H), 3.880 (s, 3H),
D
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Note
(neat, cm−1) 3060, 2926, 2863, 1613, 1596, 1497, 1455, 1416, 1261,
1115, 1071, 855, 835, 804, 754.
400 MHz) δ 7.31−7.19 (m, 10H), 6.30 (s, 1H), 2.38 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 149.4, 143.6, 140.1, 130.7, 128.8, 128.6,
128.3, 128.0, 127.0, 125.0, 107.7, 13.5; IR (neat, cm−1) 3059, 2925,
1597, 1551, 1502, 1456, 1417, 1364, 969, 912, 763.
4-Methoxy-1,3-diphenyl-1H-indazole (2k).13 Compound 2k
1
(57 mg, 76%) was obtained as a light yellow oil; H NMR (CDCl3,
3-Methyl-1-phenyl-5-(p-tolyl)-1H-pyrazole (3b).16b Com-
pound 3b (70 mg, 94%) was obtained as a light yellow oil; 1H
NMR (CDCl3, 400 MHz) δ 7.32−7.22 (m, 5H), 7.11−7.06 (m, 4H),
6.27 (s, 1H), 2.37 (s, 3H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 149.3, 143.7, 140.2, 137.9, 129.0, 128.7, 128.4, 127.7, 126.9, 125.1,
107.4, 21.2, 13.5; IR (neat, cm−1) 3057, 2922, 1598, 1504, 1456, 1428,
1366, 1316, 970, 762.
400 MHz) δ 7.81−7.75 (m, 4H), 7.71 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz,
1H), 7.53 (t, J = 8 Hz, 2H), 7.45−7.40 (m, 2H), 7.34 (t, J = 7.6 Hz,
1H), 7.21 (t, J = 7.2 Hz, 1H), 7.12−7.06 (m, 2H), 3.86 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 157.3, 144.7, 140.2, 139.7, 131.6, 129.9,
129.3, 126.8, 126.4, 124.5, 122.9, 122.0, 121.1, 120.8, 111.2, 110.3,
55.4; IR (neat, cm−1) 3056, 2927, 2864, 1595, 1499, 1461, 1245, 1098,
1071, 1023, 850, 799, 743, 695.
3-(4-Chloro-phenyl)-1-phenyl-1H-indazole (2l).19 Compound
2l (55 mg, 72%) was obtained as a light yellow solid; mp 120−122 °C;
1H NMR (DMSO, 400 MHz) (main isomer) δ 8.17 (d, J = 8.8 Hz,
1H), 8.08 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4
Hz, 2H), 7.65−7.61 (m, 4H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6
Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H); 13C NMR (DMSO, 100 MHz) δ
144.1, 140.1, 139.7, 133.5, 131.8, 130.0, 129.4, 129.2, 128.1, 127.2,
123.0, 122.9, 122.5, 121.6, 111.3; IR (neat, cm−1) 3050, 2961, 2925,
1652, 1597, 1499, 1414, 1389, 1164, 1111, 1093, 834, 807, 746, 695;
HRMS (EI-TOF) [M]+ calculated for C19H13ClN2 304.0763, found
304.0767.
5-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole
(3c).16b,20 Compound 3c (75 mg, 94%) was obtained as a light yellow
1
oil; H NMR (CDCl3, 400 MHz) δ 7.32−7.23 (m, 5H), 7.13 (d, J =
7.6 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.25 (s, 1H), 3.78 (s, 3H), 2.37
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 159.3, 149.3, 143.4, 140.2,
129.8, 128.7, 126.9, 125.0, 123.1, 113.7, 107.1, 55.1, 13.5; IR (neat,
cm−1) 3060, 2925, 1598, 1576, 1505, 1459, 1433, 1363, 969,762.
5-(4-Chloro-phenyl)-3-methyl-1-phenyl-1H-pyrazole
(3d).14a,21 Compound 3d (73 mg, 90%) was obtained as a light yellow
1
oil; H NMR (CDCl3, 400 MHz) δ 7.34−7.24 (m, 7H), 7.13 (d, J =
8.4 Hz, 2H), 6.30 (s, 1H), 2.38 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 149.5, 142.4, 139.8, 134.0, 129.7, 129.1, 128.9, 128.6, 127.3, 125.1,
107.8, 13.5; IR (neat, cm−1) 3055, 2924, 1598, 1499, 1460, 1428, 1397,
1364, 969, 794.
3-(4-Nitro-phenyl)-1-phenyl-1H-indazole (2m).15 Compound
2m (51 mg, 65%) was obtained as a yellow solid; mp 136−138 °C; 1H
NMR (CDCl3, 400 MHz) δ 8.36 (d, J = 8.4 Hz, 2H), 8.23 (d, J = 8.4
Hz, 2H), 8.08 (d, J = 8 Hz, 1H), 7.81−7.78 (m, 3H), 7.58 (t, J = 7.6
Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.36 (t, J =
7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ147.2, 143.3, 140.5,
139.7, 139.5, 129.5, 127.8, 127.4, 127.3, 124.1, 123.1, 122.82, 122.76,
120.9, 111.0; IR (neat, cm−1) 3076, 2925, 2852, 1653, 1595, 1501,
1342, 1228, 1166, 1105, 854, 747, 695.
5-(4-Bromo-phenyl)-3-methyl-1-phenyl-1H-pyrazole (3e).22
1
Compound 3e (85 mg, 90%) was obtained as a light yellow oil; H
NMR (CDCl3, 400 MHz) δ 7.40 (d, J = 8.4 Hz, 2H), 7.34−7.24 (m,
5H), 7.07 (d, J = 8.4 Hz, 2H), 6.30 (s, 1H), 2.38 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 149.5, 142.4, 139.8, 131.6, 130.0, 129.5, 128.9,
127.3, 125.1, 122.3, 107.8, 13.5; IR (neat, cm−1) 3053, 2923, 1596,
1501, 1460, 1427, 1393, 1364, 969, 765.
3-Phenyl-1-p-tolyl-1H-indazole (2n). Compound 2n (52 mg,
1,3,5-Triphenyl-1H-pyrazole (3f).14b,16b Compound 3f (56 mg,
63%) was obtained as a light yellow solid; mp 130−132 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.92 (d, J = 6.8 Hz, 2H), 7.42 (t, J = 7.2 Hz,
2H), 7.38−7.26 (m, 11H), 6.82 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 151.9, 144.3, 140.1, 133.0, 130.5, 128.8, 128.7, 128.6, 128.4,
128.2, 127.9, 127.3, 125.7, 125.2, 105.1; IR (neat, cm−1) 3060, 2930,
1596, 1550, 1498, 1458, 1411, 1363, 972, 763.
1
73%) was obtained as a light yellow solid; mp 88−90 °C; H NMR
(CDCl3, 400 MHz) δ 8.07−8.03 (m, 3H), 7.72 (d, J = 8.4 Hz, 1H),
7.65 (d, J = 8 Hz, 2H), 7.53−7.50 (m, 2H), 7.43−7.40 (m, 2H), 7.33
(d, J = 8 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 2.42 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 145.7, 140.3, 137.6, 136.5, 133.3, 129.3, 128.8,
128.1, 127.7, 126.9, 123.0, 122.9, 121.7, 121.5, 110.6, 21.1; IR (neat,
cm−1)3061, 2953, 2920, 2852, 1604, 1513, 1479, 1227, 1163, 1102,
1072, 844, 819, 800, 775, 746; HRMS (EI-TOF) [M]+ calculated for
C20H16N2 284.1312, found 284.1313.
1,3-Diphenyl-5-(p-tolyl)-1H-pyrazole (3g).14b Compound 3g
(60 mg, 65%) was obtained as a light yellow solid; mp 110−112 °C;
1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 7.6 Hz, 2H), 7.44−7.27
(m, 8H), 7.16 (d, J = 6.8 Hz, 2H), 7.11 (d, J = 8 Hz, 2H), 6.79 (s, 1H),
2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 151.8, 144.4, 140.2,
138.1, 133.1, 129.1, 128.8, 128.6, 127.8, 127.6, 127.3, 125.7, 125.2,
104.9, 21.2; IR (neat, cm−1) 3049, 2922, 1597, 1496, 1458, 1429, 1398,
1362, 972, 764.
1-(2-Fluoro-phenyl)-3-phenyl-1H-indazole (2o). Compound
2o (54 mg, 75%) was obtained as a light yellow solid; mp 76−78
°C; 1H NMR (CDCl3, 400 MHz) δ 8.07 (d, J = 8 Hz, 1H), 8.03 (d, J =
8 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 8 Hz, 2H), 7.47−7.39
(m, 4H), 7.33−7.27 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 157.4,
154.8, 146.9, 141.6, 133.0, 129.3, 129.2, 128.8, 128.3, 128.2, 127.8,
127.5, 127.4, 127.1, 124.90, 124.86, 122.5, 121.9, 121.3, 117.0, 116.8,
110.82, 110.77; IR (neat, cm−1) 3066, 2958, 2924, 2863, 1610, 1505,
1464, 1267, 1241, 1113, 844, 820, 747, 697; HRMS (EI-TOF) [M]+
calculated for C19H13FN2 288.1061, found 288.1063.
5-(4-Chloro-phenyl)-1,3-diphenyl-1H-pyrazole (3h).23 Com-
pound 3h (61 mg, 62%) was obtained as a light yellow solid; mp 100−
102 °C; 1H NMR (CDCl3, 400 MHz) δ 7.91 (d, J = 7.2 Hz, 2H), 7.43
(t, J = 7.2 Hz, 2H), 7.37−7.28 (m, 8H), 7.20 (d, J = 8 Hz, 2H), 6.81 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 152.0, 143.1, 139.8, 134.3,
132.8, 129.9, 129.0, 128.7, 128.6, 128.0, 127.6, 125.7, 125.2, 105.2; IR
(neat, cm−1) 3051, 2923, 1598, 1497, 1482, 1457, 1391, 1361, 971,761.
1-(4-Nitro-phenyl)-3-phenyl-1H-indazole (2p).15 Compound
2p (51 mg, 65%) was obtained as a yellow solid; mp 160−162 °C; 1H
NMR (CDCl3, 400 MHz) δ 8.38 (d, J = 9.6 Hz, 2H), 8.09 (d, J = 8 Hz,
1H), 8.01 (d, J = 8.4 Hz, 4H), 7.86 (d, J = 8.8 Hz, 1H), 7.57−7.52 (m,
3H), 7.47 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 148.2, 145.3, 144.8, 139.9, 132.2, 128.9, 128.1,
127.8, 125.2, 124.2, 123.0, 122.1, 121.3, 110.7; IR (neat, cm−1) 3059,
2924, 2853, 1653, 1592, 1502, 1326, 1108, 852, 818, 765, 745, 695.
General Procedure for the Synthesis of Substituted 1H-
Pyrazoles 3a−3h. An oven-dired Schlenk tube was charged with
FeBr3 (9 mg, 10 mol %) and phenylhydrazone (0.3 mmol), then 2 mL
toluene was added as solvent, the reaction tube was sealed, and the
contents were stirred at 110 °C for 4 h under oxygen with oxygen
balloon. After the reaction was complete, the mixture was filtrated and
washed with EtOAc. Then the solvent was removed, and the crude
product was purified through column chromatography with PE/EA =
20:1 as eluent to give the pure product.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of the H and 13C NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wlbao@css.zju.edu.cn.
3-Methyl-1,5-diphenyl-1H-pyrazole (3a).16b,20 Compound 3a
Notes
1
(67 mg, 95%) was obtained as a light yellow oil; H NMR (CDCl3,
The authors declare no competing financial interest.
E
dx.doi.org/10.1021/jo3026862 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(15) Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc. 1965,
3048−3052.
ACKNOWLEDGMENTS
■
This work was financially supported by the Natural Science
Foundation of China (No. 21072168).
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