Palladium-catalyzed direct C7-arylation of substituted indazoles

Article abstract of DOI:10.1021/jo500876q

A novel direct C7-arylation of indazoles with iodoaryls is described using Pd(OAc)₂ as catalyst, 1,10-phenanthroline as ligand, and K ₂CO₃ as base in refluxing DMA. Direct C7-arylation of 3-substituted 1H-indazole containing an EWG on the arene ring gave the expected products in good isolated yields. In addition, a one-pot Suzuki-Miyaura/ arylation procedure leading to C3,C7-diarylated indazoles has been developed.

Full text of DOI:10.1021/jo500876q

Article
pubs.acs.org/joc
Palladium-Catalyzed Direct C7-Arylation of Substituted Indazoles
,§
‡
§,∥
Mohammed Naas,†,‡ Saıd El Kazzouli,* El Mokhtar Essassi, Mosto Bousmina,
̈
and Gerald Guillaumet*,†
́
†Institut de Chimie Organique et Analytique (ICOA), Universite
France
́ ́
d’Orleans UMR CNRS 7311, BP 6759, 45067 Orleans Cedex 2,
‡Faculte
§Euro-Mediterranean University of Fez, Fes
́ ́
des Sciences, Universite Mohammed V de Rabat, BP 1014, Avenue Ibn Batouta, Rabat, Morocco
̀
̀
-Shore, Route de Sidi Hrazem, 30070 Fes, Morocco
∥Hassan II Academy of Science and Technology, Avenue Mohammed VI, 10222 Rabat, Morocco
S
* Supporting Information
ABSTRACT: A novel direct C7-arylation of indazoles with iodoaryls is described
using Pd(OAc)2 as catalyst, 1,10-phenanthroline as ligand, and K2CO3 as base in
refluxing DMA. Direct C7-arylation of 3-substituted 1H-indazole containing an EWG
on the arene ring gave the expected products in good isolated yields. In addition, a
one-pot Suzuki−Miyaura/arylation procedure leading to C3,C7-diarylated indazoles
has been developed.
wish to present herein the results of the regioselective C7-
arylation of indazoles. To our knowledge, this is the first
example of direct arylation at the six-membered ring of 6,5-
bicyclic systems containing one or more heteroatoms on the
five-membered ring.
INTRODUCTION
■
The C−H activation of heteroarenes, a very useful reaction in
the field of organic synthesis, represents today a powerful
approach for the preparation of new and promising bioactive
aryl−heteroaryl systems.1 In addition, the arylation of six-
membered rings in 6,5-bicyclic systems containing no
heteroatom on the six-membered ring and at least one
heteroatom on the five-membered ring is quite rare. As far as
we know, only one example of the C−H arylation of the
benzene ring of quinolones has been reported.2 The reported
examples are usually related to the five-membered rings
(examples: indole,3 azaindole,4 imidazo[1,2-a]pyridine,5
imidazo[1,2-a]pyrimidine,6 benzimidazole,7 benzothiophene,8
benzofuran,8 and indazole,9,10 among others). Unluckily, the
arylation of the arene systems depends on directing groups
such as amides,11 carboxylic acids,12 phosphoramidates,13
cyano,14 aldehyde,15 purine,16 and nitro groups,17 among
others.18 In these cases, unfortunately, the reaction is limited
by regioselectivity because most of the directing groups act on
the ortho or meta position.19 It should also be noted that new
examples have been reported on the use of directing groups for
the arylation of heteroaenes.20
RESULTS AND DISCUSSION
■
Guided by our previous reaction conditions developed for the
C3-arylation of 1H-indazoles,9b we started our investigation
using 4-nitro-, 5-nitro-, 6-nitro-, and 7-nitroindazoles as starting
materials (1a−d)9b and iodobenzene as the coupling partner
(Table 1). After initial optimization, we found that the use of
K3PO4 as an additive to the previous reaction conditions
improved both reaction yields and times. Thus, using the
conditions 1 equiv of iodobenzene in the presence of 0.2 equiv
of Pd(OAc)2, 0.4 equiv of 1,10-phenanthroline, 3 equiv of
K2CO3, and 2 equiv of K3PO4 in refluxing DMA, both 5-nitro-
and 6-nitroindazoles (1a,b, respectively) gave mixtures of C3-
arylated products (2a,b, respectively) and C3/C7-double-
arylated products (3a,b, respectively). In both cases, when
the amount of iodobenzene was increased (2 or 6 equiv), the
ratios of C3-arylated products decreased while the ratios of C3/
C7-double-arylated products increased (entries 1 and 2, Table
1). Interestingly, the reaction using 4-nitroindazole gave
exclusively the C7-arylated product 4c; no trace of the C3-
Recently, we and others9 developed C3-arylation of low
reactive 1H-indazoles using Pd(OAc)2 as catalyst and 1,10-
phenanthroline as ligand. We and others have also reported that
nitroindazoles, which are commercially available materials, can
be transformed in a few steps into very interesting bioactive
molecules.21 Pursuing our effort to develop direct arylation, we
Received: April 21, 2014
© XXXX American Chemical Society
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and a very low amount of the C3/C7-double-arylated product
7d was obtained (5%, entry 4, Table 2). A similar result was
obtained when using 5e as starting material: in this case, only
the C3-arylated product 6e was isolated in 59% yield (entry 5.
Table 2). As expected, the reaction between 5f and
iodobenzene (2 equiv) led exclusively to the C3-arylated
product 6f in 65% yield (entry 6. Table 2). We noticed that, in
the cases of starting materials 5a−d, the same phenomenon was
observed when increasing the amount of iodobenzene (2
equiv): the ratios of C3-arylated products 6a−d dropped while
the ratios of C3/C7-double-arylated products 7a−d increased
(entries 1−4, Table 2).
Table 1. Results of C3-Arylation versus C3/C7-Arylation
In order to optimize the C7-arylation reaction, we decided to
use 1-methyl-5-nitroindazole 2a, containing a phenyl group at
the 3-position, as the starting material and 4-iodotoluene or 4-
bromotoluene as the coupling partner (Table 3). In addition,
Table 3. Optimization of C7-Arylation of Indazole 2a
arylated product was observed. This is probably due to the
steric demands of the nitro group in position 4 of compound
1c. Total conversion was obtained when 5 equiv of
iodobenzene was used (entry 3, Table 1). As expected, only
the C3-arylated product 2d was isolated in the case of 7-
nitroindazole 1d; here, the desired product was isolated in 71%
yield (entry 4, Table 1).
Pleased by our preliminary results, we decided to apply the
reaction conditions to indazoles 5a−e, containing various
substituents at either the 5- or 6-positions9b (Table 2). In the
case of 5a−c results similar to those obtained with 5-nitro- and
6-nitroindazoles were found. Explicitly, mixtures of the C3-
arylated products 6a−c and C3/C7-double-arylated products
7a−c were obtained. In the case of 5-fluoro-1-methyl-1H-
indazole (5d) as starting material, when 1 equiv of iodobenzene
was used, the C3-arylated product 6d was isolated in 69% yield,
amt of Pd
time
entry
X
(mol %) L (amt (mol %))
base
(h) yield (%)
a
1
I
20
20
20
20
20
20
20
20
20
20
20
20
Phen (40)
Phen (40)
Phen (40)
Phen (40)
Phen (40)
Phen (40)
Phen (40)
Ph3P (40)
Xantphos (40)
Phen (40)
none
K2CO3
K2CO3
none
48
24
48
48
24
24
24
24
24
24
24
24
61
2
I
I
I
I
I
I
I
I
I
I
I
64
b
3
48 (17)
57
4
Ag2CO3
Cs2CO3
K2CO3
Ag2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
5
58
c
6
62
c
7
59
b
8
0 (38)
b
9
0 (24)
Table 2. Results of C3-Arylation versus C3/C7-Arylation
d
10
11
12
49
e
41
Davephos (40)
traces
(34)
b
13
I
20
X-Phos (40)
K2CO3
24
traces
(26)
b
b
14
15
16
17
18
19
I
20
10
5
PCy3·HBF4 (40)
Phen (20)
K2CO3
K2CO3
K2CO3
Et3N
24
36
24
24
24
48
15 (23)
62
I
b
b
b
I
Phen (10)
16 (47)
12 (69)
42 (13)
I
20
20
20
Phen .(40)
Phen (40)
Br
Br
K2CO3
K2CO3
Phen (40)
47
a
b
In this case the reaction was carried out without K3PO4. The
c
amount of recovered starting material 2a is given in parentheses. In
this case PdCl2 was used instead of Pd(OAc)2. In this case 0.3 equiv
of PivOH as additive was added to the reaction mixture. In this case
d
e
the reaction was conducted without ligand in the presence of 0.3 equiv
of PivOH as additive.
various reaction conditions were investigated using different
bases (organic and inorganic), catalysts, ligands, amounts of
catalysts and ligands, and reaction times.
K3PO4 has a significant impact on the reaction time (entries
1 and 2, Table 3). Thus, when K3PO4 was added to the reaction
mixture, the reaction time was improved (24 h instead of 48 h).
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We also observed that the reaction yield was slightly enhanced
(64% instead of 61%). K2CO3 was found to be the best base in
comparison to Ag2CO3, Cs2CO3, and Et3N, (entries 2, 4, 5, and
17, Table 3). PdCl2 was also effective, giving the desired
arylated product 8 in similar yields in comparison to those
obtained when using Pd(OAc)2 (entries 6 and 7, Table 3).
Bromobenzene showed low reactivity in comparison to
iodobenzene (entries 18 and 19, Table 3), and 1,10-
phenanthroline proved to be the most effective ligand in
comparison to all the ligands investigated in this study (entries
8−14, Table 3).
and limitation demonstrated that the presence of strong
electron-withdrawing groups on positions 4, 5, and 6 is crucial
for the achievement of a C7-arylation reaction in good reaction
yields.
We then decided to introduce various aryls and heteroaryls at
the 7-position of 5-nitro-1-methylindazole 2a. To this end, we
used various iodo(hetero)aryls as coupling partners (Table 5).
Table 5. Results of C7-Arylation of 1H-Indazole 2a
In order to examine the scope and limitation of the C7-
arylation reaction, we decided to prepare a series of 7-
substituted indazoles using the optimized reaction conditions.
Various 3-phenyl-1-methylindazoles substituted with NO2, CN,
CF3, CO2Me, F, Cl, and H (2b,c and 6a−f) were prepared
starting from the substituted 1-methylindazoles 1b,c and 5a−f
under standard Suzuki−Miyaura conditions.22 Intermediates
2b,c and 6a−f were then used as starting materials, and 4-
iodotoluene was used as the coupling partner (Table 4). In the
Table 4. Results of C7-Arylation of 1H-Indazoles 2b,c and
6a−f by 4-Iodotoluene
a
A NOESY experiment for compound 10a confirmed the structure
b
(see the Supporting Information). The amounts of recovered 2a are
given in parentheses.
entry
starting material
product
yield (%)
a
1
2
3
4
5
6
7
8
2b
2c
6a
6b
6c
6d
6e
6f
9a
65
63
66
65
64
43
As desired, the arylation reactions between 2a and iodoaryls led
to the expected products 10a−f in yields ranging between 65
and 69%. Surprisingly, no reaction between 2a and
iodoheteroaryls was observed. In all cases only starting material
2a was recovered.
a
9b
9c
9d
9e
9f
For a mechanistic study, we decided to verify whether the
reaction is influenced by the nature of the substituent at N1.
For this reason we used 5-nitro-1,3-diphenyl-1H-indazole
(11)9b as the starting material instead of 2a. When 11 was
treated with 4-iodotoluene no C7-arylation reaction was
observed; only starting material 11 was recovered in 81%
yield (Scheme 1). On the basis of this result we assume that the
single lone pair of nitrogen (N1-methyl) plays the role of a
directing group for regioselective C7-arylation by coordination
with the palladium or by the inductive effect of the N1 nitrogen
b
c
b
9g
9h
8 (59), , 17 (31)
d
0 (74)
a
NOESY experiments for compounds 9a,b confirmed their structures
(see the Supporting Information). The amount of recovered starting
material 6e is given in parentheses. In this case 5 equiv of 4-
iodotoluene were used. The amount of recovered starting material 6f
b
c
d
is given in parentheses.
case of EWG-substituted indazoles, the desired compounds
9a−e were isolated in acceptable yields ranging between 63 and
66% (Table 4). In contrast, when 5-fluoro-3-phenyl-1-
methylindazole was used as the starting material, the yield of
the C7-arylated product 9f was relatively low (43%, Table 4).
The C7-arylation dropped when 5-chloro-1-methyl-3-phenyl-
1H-indazole (6e) was used as the starting material, and only
low yields were obtained when using either 2 or 5 equiv of 4-
iodotoluene: the yields of the isolated product 9g were 8 and
17%, respectively. In this case large amounts of starting material
6e were recovered (Table 4). As expected, the reaction between
3-phenyl-1-methylindazole (6f) and 4-iodotoluene gave no
trace of the desired product 9h; only starting material 6f was
recovered in 74% yield (Table 4). This first study of the scope
Scheme 1. Reaction between 1H-Indazole 11 and 4-
Iodotoluene
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atom to stabilize the C−Pd bond. When the single lone pair of
N1 is conjugated with a phenyl group, no coordination
occurred, resulting in no C7-arylation, which might be
attributed to the formation of an N2,C2′(phenyl ring)-
palladacycle that inhibits the catalytic activity of Pd. We also
think that the presence of an EWG at the 4-, 5-, or 6-position
significantly enhances the reactivity at the C7-position of the
six-membered ring.
Table 6. Results of One-Pot Suzuki/C7-Arylation
A plausible mechanism is proposed in Scheme 2. The N1-
indazole (starting material) coordinated to the catalyst
entry
starting material
product
one-pot yield (%)
Scheme 2. Plausible Mechanism of C7-Arylation Reaction
1
2
3
4
5
6
13a
13b
13c
13d
13e
13f
9a
8
55
58
53
56
50
51
9b
9c
9d
9e
1-methylindazole via the lone pair of N1-methyl acts as a
directing group and that the presence of electron-withdrawing
groups (EWG) on positions 4, 5, and 6 improves the C7-
arylation reaction yields. We think that this interesting reactivity
of substituted 1H-indazoles may open new avenues for the
development of direct arylation reactions of several hetero-
aromatic systems.
(complex 2) generated in situ from Pd(OAc)2 and 1,10-
phenanthroline (complex 1). Complex 2 led to complex 3
through C−H activation of the C7-position of indazole.
Oxidative addition of I-Ph led to complex 4. Reductive
elimination furnished the C7-arylated product and complex 5.
We then decided to develop a one-pot Suzuki/arylation
sequence for the synthesis of C3,C7-diarylated indazoles. For
this reason, we first developed new reaction conditions for
Suzuki−Miyaura coupling similar to those found for the C7-
arylation reaction. Accordingly, we found that adding Ph3P as
ligand to the reaction conditions previously developed for C7-
arylation (Pd(OAc)2 as catalyst, K2CO3 as base, and K3PO4 as
additive in refluxing DMA for 24 h) was crucial for the
achievement of total reaction conversions. Having optimized
reaction conditions for Suzuki−Miyaura coupling on the one
hand, we decided on the other hand to develop the one-pot
Suzuki/arylation sequence. To accomplish this goal, 3-
bromoindazoles 13a−f, used as starting materials, and phenyl-
boronic acid, used as coupling partner, were treated under
Suzuki−Miyaura conditions for 24 h (first cross-coupling
reactions) and then 1,10-phenanthroline and iodotoluene
were added and the reaction mixture was heated again for 24
h (second cross-coupling reactions). This sequence led to the
one-pot synthesis of C3,C7-diarylated products 8 and 9a−e in
yields ranging between 50 and 58% (Table 6).
EXPERIMENTAL SECTION
■
All reagents were purchased from commercial suppliers and were used
without further purification. Microwave-assisted reactions were carried
out with a microwave synthesis instrument, and temperatures were
measured by an IR sensor. The reactions were monitored by thin-layer
chromatography (TLC) analysis. Compounds were visualized by UV
irradiation, Flash column chromatography was performed on silica gel
60 (230−400 mesh, 0.040 0.063 mm). Melting points (mp, °C) were
1
taken on samples in open capillary tubes and are uncorrected. H and
13C NMR spectra were recorded on a spectrometer at 250 MHz (13C,
62.9 MHz) or 400 MHz (13C, 100 MHz). Chemical shifts are given in
parts per million from tetramethylsilane (TMS) as internal standard.
The following abbreviations are used for the proton spectra
multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; qt, quintuplet;
m, multiplet. Coupling constants (J) are reported in hertz (Hz). High-
resolution mass spectra (HRMS) were performed on a Q-TOF mass
spectrometer.
Synthesis of 1-Methyl-1H-indazole: 1a and 5f. In a 50 mL flask
was dissolved 1 g of indazole in 10 mL of acetone at 0 °C, and then 3
equiv of KOH was added and the contents of the flask, sealed with a
septum, were stirred for 60 min. Then, 1.5 equiv of CH3I was added
using a syringe and the reaction mixture was warmed to room
temperature and this temperature maintained for 18 h. The inorganic
base was removed by filtration, and the mixture was separated by flash
chromatography on silica gel.
Synthesis of 1-Methyl-1H-indazole: 1b−d and 5a−e. Sodium
hydride (55.0 mmol) was added to a solution of 1H-indazole (18.40
mmol) in N,N-dimethylformamide (50 mL), and the mixture was
maintained for 60 min at 0 °C. Then, methyl iodide (22.12 mmol) was
added and the reaction mixture. The reaction mixture was warmed to
room temperature and this temperature maintained for 18 h. The
reaction mixture was quenched with water (60 mL) and filtered
through Celite, and the filtrate was concentrated. Purification by flash
chromatography on silica gel led to the desired products 2a−d and
5a−e. This procedure gave exclusively N-methylation at the N1
position.
CONCLUSIONS
■
In conclusion, the first example of regioselective direct C7-
arylation of a 3-substituted 1H-indazole containing an EWG on
the arene ring was reported. The optimal reaction conditions
were found leading to the preparation of various C7-arylated
indazole derivatives. We have shown that direct arylation of 1-
methyl-4-nitroindazole gave exclusively the C7-arylated prod-
uct, while the direct arylation of 1-methyl-7-nitroindazole led to
the C3-arylated product. We then extended our study to the
synthesis of C3,C7-diarylated products using a new one-pot
Suzuki−Miyaura/arylation sequence. We believe that the N1 of
General Suzuki Procedure for the Preparation of 2b,c and
6a−f.22a A microwave vial containing a stirring bar was loaded with 3-
bromoindazoles in 1,4-dioxane/EtOH/H2O (3/1/0.5), phenylboronic
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acid (1.5 equiv) and cesium carbonate (1.3 equiv). The microwave vial
was evacuated and back-filled twice with dry argon. Tetrakis-
(triphenylphosphine)palladium (0.10 equiv) was then added, and
the mixture was submitted to microwave irradiation with stirring at
140 °C for 100 min. After it was cooled, the mixture was filtered and
the organic phase was extracted three times with ethyl acetate and
dried over magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel.
1-Methyl-4-nitro-3-phenyl-1H-indazole (2c). Yield: 0.35 g, 71%.
Yellow solid. Mp: 109−111 °C. IR (neat): νmax 32011.22, 2947.09,
1
1521.41, 1340.21, 978.82, 829.18, 729.19, 700.15, 666.52 cm−1. H
NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 8.5
Hz, 1H), 7.52−7.39 (m, 6H), 4.19 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 143.5, 143.0, 142.5, 133.1, 128.3 (2C), 128.0, 127.8 (2C),
125.2, 117.5, 112.6, 114.6, 35.8. HRMS (ESI): m/z calcd for
C14H11N3O2 [M + H]+ 254.0927, found 254.0924.
1-Methyl-7-nitro-3-phenyl-1H-indazole (2d). Yield: 0.34 g, 71%.
Yellow solid. Mp: 76−78 °C. IR (neat): νmax 3035.61, 2956.10,
1617.41, 1525.76, 1389.59, 1363.12, 1256.99, 985.90, 897.63, 728.19,
691.09 cm−1. 1H NMR (250 MHz, CDCl3): δ 8.27 (dd, J = 8.0, 1.0 Hz,
1H), 8.14 (dd, J = 7.8, 1.0 Hz, 1H), 7.89−7.85 (m, 1H), 7.58−7.43
(m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 4.29 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 145.6, 132.8, 132.2, 130.2, 129.3 (2C), 129.1, 128.4, 128.2
(2C), 127.0, 124.9, 120.3, 41.2. HRMS (ESI): m/z calcd for
C14H11N3O2 [M + H]+ 254.0927, found 254.0924.
Synthesis of 5-Nitro-1-phenyl-1H-indazole 11. In a microwave
tube, 1 g (0.0041 mol) of the 5-nitro-1H-indazole was dissolved with
stirring in 10 mL of N-methylpyrrolidine (NMP); then CuI (0.23 g,
0.0012 mol, 0.2 equiv), bipyridine (0.48 g, 0.003 mol, 0.5 equiv),
K2CO3 (2.54 g, 0.018 mol, 3 equiv), and iodophenyl (1.3 g, 0.0061
mol, 1.5 equiv) were added. The microwave tube was sealed with a
silicon septum and subjected to microwave irradiation at 200 °C with
stirring for 45 min. Then, the reaction mixture was diluted with ethyl
acetate and extracted (three times). The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (ether/CH2Cl2).
General Procedure of C7-Arylation. In a 10 mL flask, a solution
of phenanthroline (57 mg, 0.31 mmol, 0.4 equiv) in DMA (2 mL) was
degassed by bubbling argon, and then palladium acetate (0.14 mmol,
31 mg, 0.2 equiv) was added. The solution was stirred at room
temperature for 3 min, and then K2CO3 (2.1 mmol, 290 mg, 3 equiv),
K3PO4 (1.3 mmol, 297 mg, 2 equiv), 1-methylindazole (96 mg, 0.7
mmol), and 4-iodotoluene (0.9 mmol, 1 equiv) were successively
added. The reaction mixtures were refluxed under argon for 24 h. After
it was cooled, the mixture was filtered through Celite and the organic
phase was extracted three times with ethyl acetate, dried over
magnesium sulfate, and then concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel.
General Protocol of One-Pot Suzuki/Arylation. A flask
containing a stirring bar was charged with 3-bromoindazoles,
phenylboronic acid (1.5 equiv), K2CO3 (1.5 equiv), K3PO4 (1.5
equiv), and PPh3 (0.2 equiv) in DMA (2 mL). The flask was degassed
and back-filled with dry argon twice. Pd(OAc)2 (0.1 equiv) was added.
After the mixture was refluxed for 24 h, phenanthroline (0.4 equiv)
and 4-iodotoluene (1 equiv) were added, and then, the reaction
mixture was continuously refluxed under argon for 24 h. After it was
cooled, the mixture was filtered through Celite and the organic phase
was extracted three times with ethyl acetate, dried over magnesium
sulfate, and then concentrated under reduced pressure. The residue
was purified by flash chromatography to provide the desired products.
1-Methyl-5-nitro-1H-indazole (1a). Yield: 0.69 g, 70%. Beige solid.
Mp: 160−162 °C (lit.23 mp 161−162 °C).
1-Methyl-5-nitro-3,7-diphenyl-1H-indazole (3a). Yield: 20 mg,
21%. Yellow solid. Mp: 156 °C. IR (neat): νmax 3055.57, 2947.11,
1
1597.89, 1524.87, 1330.78, 1074.29, 780.22, 699.54, cm−1. H NMR
(400 MHz, CDCl3): δ 8.94 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 2.1 Hz,
1H), 7.95−7.91 (m, 2H), 7.58−7.47 (m, 8H), 3.70 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 146.9, 142.0, 140.9, 136.5, 131.8, 129.6 (2C),
129.1 (2C), 128.9, 128.75, 128.4 (2C), 127.6 (2C), 126.6, 122.7,
121.9, 118.0, 39.4. HRMS (ESI): m/z calcd for C20H15N3O2 [M + H]+
330.1239, found 330.1237.
1-Methyl-6-nitro-3,7-diphenyl-1H-indazole (3b). Yield: 18 mg,
19%. Yellow solid. Mp: 123−125 °C. IR (neat): νmax 3051.26, 2947.91,
1
1522.67, 1356.22, 1263.94, 1025.84, 758.96, 695.88 cm−1. H NMR
(400 MHz, CDCl3): δ 8.06 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 7.0 Hz,
2H), 7.67 (d, J = 8.8 Hz, 1H), 7.55−7.49 (m, 5H), 7.46−7.42 (m,
3H), 3.48 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 147.9, 144.1,
138.9, 132.5, 132.5, 130.0 (2C), 129.2, 129.1 (2C), 128.6, 128.4 (2C),
127.7 (2C), 123.9, 121.4, 120.7, 116.4, 39.3. HRMS (ESI): m/z calcd
for C20H15N3O2 [M + H]+ 330.1239, found 330.1237.
1-Methyl-4-nitro-7-phenyl-1H-indazole (4). Yield: 44 mg, 45%.
Yellow oil. IR (neat): νmax 2918.39, 2849.86, 1518.20, 1336.02, 963.25,
1
838.08, 699.42 cm−1. H NMR (250 MHz, CDCl3): δ 8.70 (s, 1H),
8.17 (d, J = 7.9 Hz, 1H), 7.54−7.51 (m, 3H), 7.45 (m, 2H), 7.33 (d, J
= 7.8 Hz, 1H), 3.67 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 139.8,
139.3, 136.9, 133.6, 132.8, 129.4 (2C), 129.0, 128.8, 128.5 (2C), 127.3,
118.3, 39.6. HRMS (ESI): m/z calcd for C14H11N3O2 [M + H]+
253.0859, found 253.0856.
1-Methyl-1H-indazole-6-carbonitrile (5a). Yield: 2.2 g, 73%.
Yellow solid. Mp: 261−263 °C. IR (neat): νmax 3072.28, 2942.20,
2222.74, 1475.11, 1380.95, 1293.27, 1229.00, 763.70, 875.58, 828.96,
1
763.70, 623.14 cm−1. H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H),
1-Methyl-6-nitro-1H-indazole (1b). Yield: 2.5 g, 85%. Yellow solid.
7.82 (dd, J = 8.3, 0.7 Hz, 1H), 7.79 (d, J = 0.7 Hz, 1H), 7.36 (dd, J =
8.3, 1.1 Hz, 1H), 4.14 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 138.5,
133.1, 125.9, 122.5, 122.3, 119.2, 114.3, 109.3, 35.8. HRMS (ESI): m/z
calcd for C9H7N3 [M + H]+ 158.0719, found 158.0712.
Mp: 124−126 °C. (lit.24 mp 125−126 °C).
1-Methyl-4-nitro-1H-indazole (1c). Yield: 2.3 g, 79%. Yellow solid.
Mp: 132−134 °C. (lit.21a mp 145 °C, lit.25 mp 123−125 °C).
1-Methyl-7-nitro-1H-indazole (1d). Yield: 2.6 g, 88%. Yellow solid.
Mp: 104−106 °C. (lit.26 mp 99−100 °C).
5-(Trifluoromethyl)-1-methyl-1H-indazole (5b). Yield: 2.5 g, 81%.
Yellow solid. Mp: 49−51 °C. IR (neat): νmax 2945.57, 1633.21,
1
1332.56, 1179.24, 1093.31, 933.97, 804.94, 716,92, 613.83 cm−1. H
1-Methyl-5-nitro-3-phenyl-1H-indazole (2a). Yield: 0.1 g, 61%.
Yellow solid. Mp: 123 °C. IR (neat): νmax 3093.83, 2945.67, 1614.36,
NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 8.05 (s, 1H), 7.60 (d, J =
1
1515.03, 1328.96, 1276,99, 1078.12, 746.17, 662.52 cm−1. H NMR
8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 4.11 (s, 3H). 13C NMR (101
MHz, CDCl3): δ 140.6, 133.8, 124.7 (qCq‑F, J1= 273 Hz), 123.3 (qCq‑CF
,
(400 MHz, CDCl3): δ 8.95 (s, 1H), 8.29 (d, J = 9.5 Hz, 1H), 7.92 (d, J
= 7.6 Hz, 2H), 7.50 (dt, J = 18.6, 8.2 Hz, 4H), 4.16 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 146.8, 142.9, 142.5, 131.8, 129.0 (2C), 128.8,
127.4 (2C), 121.4, 120.7, 119.3, 109.4, 35.9.HRMS (ESI): m/z calcd
J2= 32.3 Hz), 123.1, 122.7 (qCq‑CF, J2= 32.3 Hz), 122.8 (qCH‑F, J3= 3.8
Hz), 119.3 (qCH‑F, J3= 4 Hz), 109.5, 35.7. HRMS (ESI): m/z calcd for
C9H7F3N2 [M + H]+ 201.0638, found 201.0634.
+
for C14H11N3O2 [M + H] : 254.0926, found 254.0924.
Methyl 1-Methyl-1H-indazole-5-carboxylate (5c). Yield: 2.3 g,
75%. White solid. Mp: 117 °C. IR (neat): νmax 2957.87, 1697.76,
1618.19, 1423.55, 1250.71, 1192.44, 981.95, 825.08, 766.18, 630.16
1-Methyl-6-nitro-3-phenyl-1H-indazole (2b). Yield: 0.36 g, 73%.
Yellow solid. Mp: 109−111 °C. IR (neat): νmax 3085.94, 1514.65,
1339.64, 1286.48, 1116.32, 962.66, 781.42734.56, 689.96 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.39 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 8.9
Hz, 1H), 8.05 (dd, J = 8.9, 1.8 Hz, 1H), 7.93 (d, J = 8 Hz, 2H), 7.53 (t,
J = 7.5 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 4.23 (s, 3H). 13C NMR (101
MHz, CDCl3): δ 146.8, 144.8, 140.5, 132.6, 129.3 (2C), 128.9, 127.7
(2C), 124.9, 122.5, 115.9, 106.3, 36.46. HRMS (ESI): m/z calcd for
C14H11N3O2 [M + H]+ 254.0926, found 254.0924.
1
cm−1. H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 8.07 (d, J = 8.8
Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 4.10 (s, 3H), 3.95 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ 167.2, 141.5, 134.4, 127.0, 124.5, 123.6,
122.7, 108.5, 52.0, 35.6. HRMS (ESI): m/z calcd for C10H10N2O2 [M
+ H]+ 191.0820, found 191.0815.
5-Fluoro-1-methyl-1H-indazole (5d). Yield: 2.6 g, 83%. Yellow oil.
IR (neat): νmax 3068.19, 1500.41, 1249.55, 1143.29, 802.39, 761.04
E
dx.doi.org/10.1021/jo500876q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
cm−1. H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 0.6 Hz, 1H), 7.32
HRMS (ESI): m/z calcd for C21H15N3 [M + H]+ 310.1341, found
310.1338.
(dt, J = 7.8, 3.6 Hz, 2H), 7.16 (td, J = 9.0, 2.3 Hz, 1H), 4.06 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 158.9, 156.6, 136.9, 132.3 (d, J = 5
Hz), 123.8 (d, J = 10,1 Hz), 115.8 (d, J = 28.2 Hz), 109.9 (d, J = 9.1
Hz), 104.8 (d, J = 24.3 Hz), 35.7. HRMS (ESI): m/z calcd for
C8H7FN2 [M + H]+ 151.0671, found 151.0666.
5-(Trifluoromethyl)-1-methyl-3,7-diphenyl-1H-indazole (7b).
Yield: 52 mg, 30%. White solid. Mp: 102−104 °C. IR (neat): νmax
3062.00, 1617.76, 1316.13, 1302.48, 1260.16, 1107.32, 889.74, 758.43,
1
696.69, 649.33 cm−1. H NMR (400 MHz, CDCl3): δ 8.28 (s, 2H),
5-Chloro-1-methyl-1H-indazole (5e). Yield: 2.7 g, 86%. Orange
solid. Mp: 65−67 °C. IR (neat): νmax 3076.88, 2934.75, 1482.56,
1219.40, 880.81, 802.58, 746.66 cm−1. 1H NMR (400 MHz, CDCl3): δ
7.92 (s, 1H), 7.70 (d, J = 1.0 Hz, 1H), 7.33 (d, J = 1.6 Hz, 2H), 4.07
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 138.5, 132.2, 127.0, 126.3,
124.9, 120.3, 110.1, 35.8. HRMS (ESI): m/z calcd for C8H7ClN2 [M +
H]+ 167.0376, found 167.0371.
7.93 (d, J = 7.1 Hz, 4H), 7.52 (ddd, J = 11.4, 8.7, 4.8 Hz, 16H), 3.70
(s, 5H).13C NMR (101 MHz, CDCl3): δ 145.1, 140.1, 137.3, 132.5,
129.7 (2C), 128.9 (2C), 128.4, 128.3, 128.2 (2C), 127.6 (2C), 126.9,
124.6 (qCq‑F, J1 = 273 Hz), 124.4 (qCH‑F, J3 = 3.1 Hz), 123.2 (qCq‑CF, J2
= 32.7 Hz), 121.9, 118.7 (qCq‑CF, J2 = 32 Hz), 118.4 (qCH‑F, J3 = 4.04
Hz), 39.2. HRMS (ESI): m/z calcd for C21H15F3N2 [M + H]+
353.1262, found 353.1260.
1-Methyl-1H-indazole (5f). Yield: 0.78 g, 70%. White solid; mp
Methyl 1-Methyl-3,7-diphenyl-1H-indazole-5-carboxylate (7c).
Yield: 46 mg, 26%. White solid. Mp: 151−153 °C. IR (neat): νmax
3061.75, 2947.20, 2849.50, 1707.30, 1601.78, 1244.89, 1209.06,
58−59 °C (lit.9b mp 57−59 °C).
1-Methyl-3-phenyl-1H-indazole-6-carbonitrile (6a). Yield: 0.34 g,
70%. Yellow solid. Mp: 99−101 °C. IR (neat): νmax 3068.49, 2941.89,
2224.85, 1519.28, 1247.58, 965.81, 805.10, 699.02, 660.17, 628.62
1
761.64, 698.41 cm−1. H NMR (250 MHz, CDCl3): δ 8.74 (d, J =
1.5 Hz, 1H), 7.94 (d, J = 1.4 Hz, 2H), 7.59−7.43 (m, 9H), 3.95 (s,
3H), 3.69 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 167.4, 145.8,
141.1, 138.0, 132.8, 130.0 (2C), 129.1 (2C), 128.9, 128.5, 128.3 (2C),
128.3, 127.9 (2C), 126.1, 123.9, 123.2, 122.7, 52.2, 39.4. HRMS (ESI):
m/z calcd for C22H18N2O2 [M + H]+ 343.1442, found 343.1441.
5-Fluoro-1-methyl-3,7-diphenyl-1H-indazole (7d). Yield: 18 mg,
9%. White solid. Mp: 142−144 °C. IR (neat): νmax 3054.50, 2959.93,
1
cm−1. H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 7.91
(d, J = 7.1 Hz, 2H), 7.80 (s, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.47−7.39
(m, 2H), 4.18 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 144.4, 140.0,
132.4, 128.9 (2C), 128.4, 127.3 (2C), 123.5, 122.8, 122.6, 119.2, 114.5,
109.4, 35.8. HRMS (ESI): m/z calcd for C15H11N3 [M + H]+
234.1028, found 234.1025.
1
1961.95, 1491.48, 1385.79, 1140.44, 860.98, 756.66, 697.41 cm−1. H
5-(Trifluoromethyl)-1-methyl-3-phenyl-1H-indazole (6b). Yield:
0.33 g, 68%. Yellow solid. Mp: 74 °C. IR (neat): νmax 2929.32,
1622.99, 1316.89, 1277.91, 1138.40, 1097.23, 805.25, 685.74, 623.32
NMR (250 MHz, CDCl3): δ 8.05 (dd, J = 8.53, 2 Hz, 2H), 7.59−7.39
(m, 8H), 7.26 (dd, J = 8.9, 2.4 Hz, 1H), 7.15 (dd, J = 8.7, 2.4 Hz, 1H),
4.20 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 158.7, 156.3, 143.6 (d, J
= 6.06 Hz), 138.0, 136.5, 134.5, 133.1, 129.4 (2C), 128.8 (2C), 127.8
(2C), 127.5 (d, J = 9.09 Hz), 127.2 (2C), 122.4 (d, J = 10.1 Hz), 117.4
(d, J = 27.3 Hz), 104.0 (d, J = 24.2 Hz), 39.2. HRMS (ESI): m/z calcd
for C20H15FN2 [M + H]+ 303.1290, found 303.1292.
1
cm−1. H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.93 (d, J = 7.2
Hz, 2H), 7.64 (dd, J = 8.8, 1.2 Hz, 1H), 7.57−7.41 (m, 4H), 4.15 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 145.0, 142.1, 132.6, 128.9 (2C),
128.3, 127.4 (2C), 124.7 (qCq‑F, J1= 273 Hz), 123.6 (qCq‑CF, J2= 32.3
Hz),, 123.1, 122.8 (qCH‑F, J3= 3.6 Hz), 120.7, 119.5 (qCH‑F, J3= 4 Hz),
109.7, 35.7. HRMS (ESI): m/z calcd for C15H11F3N2 [M + H]+
277.0950, found 277.0947.
1-Methyl-5-nitro-3-phenyl-7-p-tolyl-1H-indazole (8). Yield: 86
mg, 64%. Yellow solid. Mp: 157 °C. IR (neat): νmax 2925.78,
Methyl 1-Methyl-3-phenyl-1H-indazole-5-carboxylate (6c). Yield:
0.37 g, 75%. White solid. Mp: 95−97 °C. IR (neat): νmax 2947.93,
1700.43, 1611.79, 1292.87, 1238.36, 1087.15, 780.02, 696,57, 669.26
1
1727.70, 1596.61, 1333.16, 1073.21, 820.24, 745.87, 695.10 cm−1. H
NMR (250 MHz, CDCl3): δ 8.92 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 2.1
Hz, 1H), 7.92 (d, J = 6.7 Hz, 2H), 7.59−7.29 (m, 7H), 3.71 (s, 3H),
2.47 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 144.2, 140.1, 135.1,
135.1, 128.5, 125.9 (2C), 125.3, 125.2 (2C), 125.1 (2C), 124.6, 123.7
(2C), 119.8, 117.2, 116.8, 112.4, 35.4, 17.5.HRMS (ESI): m/z calcd
for C21H17N3O2 [M + H]+ 344.1395, found 344.1393.
1-Methyl-4-nitro-3-phenyl-7-p-tolyl-1H-indazole (9a). Yield: 86
mg, 65%. Yellow oil. IR (neat): νmax 2918.66, 2850.12, 1519.07,
1337.16, 1036.77, 1020.35, 815.37, 698.90 cm−1. 1H NMR (250 MHz,
CDCl3): δ 7.87 (d, J = 7.5 Hz, 1H), 7.49−7.46 (m, 5H), 7.40−7.36
(m, 4H), 7.32 (d, J = 7.7 Hz, 1H), 3.74 (s, 3H), 2.51 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ 143.6, 142.3, 140.6, 138.8, 133.9, 133.4,
132.1, 129.3 (2C), 129.1 (2C), 128.4 (2C), 128.2, 128.0 (2C), 127.2,
117.7, 113.8, 39.7, 21.3. HRMS (ESI): m/z calcd for C21H17N3O2 [M
+ H]+ 344.1393, found 344.1393.
1
cm−1. H NMR (400 MHz, CDCl3): δ 8.75 (d, J = 0.6 Hz, 1H), 8.08
(dd, J = 8.9, 1.4 Hz, 1H), 7.96 (d, J = 7.1 Hz, 2H), 7.52 (t, J = 7.5 Hz,
2H), 7.41 (dd, J = 17.8, 8.1 Hz, 2H), 4.11 (s, 3H), 3.95 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ 167.2, 145.5, 143.0, 132.7, 128.8 (2C),
128.2, 127.4 (2C), 127.0, 124.8, 123.0, 121.3, 108.8, 52.0, 35.6. HRMS
(ESI): m/z calcd for C16H14N2O2 [M + H] +: 267.1132, found
267.1128.
5-Fluoro-1-methyl-3-phenyl-1H-indazole (6d). Yield: 0.37 g, 76%.
Yellow oil. IR (neat): νmax 3065.54, 2938.05, 1497.25, 1410.43,
1
1278.02, 1253.52, 1134.19, 878.02, 771.60, 696.29 cm−1. H NMR
(400 MHz, CDCl3): δ 7.67 (dd, J = 9.3, 4.6 Hz, 1H), 7.59−7.52 (m,
2H), 7.51−7.44 (m, 3H), 7.18−7.06 (m, 2H), 4.16 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 160.0, 157.6, 145.4, 136.3 (d, J = 8.1 Hz), 129.5,
129.2, 128.9, 120.5 (d, J = 12,1 Hz), 119.1 (d, J = 9.1 Hz), 117.6 (d, J
= 29.3 Hz), 102.7 (d, J = 24.2 Hz), 38.8. HRMS (ESI): m/z calcd for
C14H11FN2 [M + H]+ 227.0983, found 227.0979.
5-Chloro-1-methyl-3-phenyl-1H-indazole (6e). Yield: 0.36 g, 73%.
Colorless oil. IR (neat): νmax 3060.09, 2926.69, 2848.73, 1724.70,
1486.24, 1275.36, 821.35, 696.08 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.98 (d, J = 0.9 Hz, 1H), 7.91(d, J = 1.3 Hz, 2H), 7.51 (t, J = 7.5 Hz,
2H), 7.43−7.34 (m, 3H), 4.12 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ 143.4, 140.0, 133.2, 129.0 (2C), 128.2, 127.4 (2C), 127.1, 126.8,
122.5, 120.7, 110.4, 35.9. HRMS (ESI): m/z calcd for C14H11ClN2 [M
+ H]+ 243.0685, found 243.0683.
1-Methyl-6-nitro-3-phenyl-7-p-tolyl-1H-indazole (9b). Yield: 85
mg, 63%. Yellow solid. Mp: 177 °C. IR (neat): νmax 2922.64, 1525.30,
1
1357.28, 1264.34, 792.55, 818.30, 693.89 cm−1. H NMR (400 MHz,
CDCl3): δ 8.05 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 8.3, 1.2 Hz, 2H),
7.64 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 7.4 Hz, 2H), 7.45 (t, J = 7.4 Hz,
1H), 7.31 (s, 4H), 3.52 (s, 3H), 2.46 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 148.0, 143.9, 138.9, 138.91, 132.3, 129.7 (2C), 129.1, 129.0
(2C), 128.9 (2C), 128.4, 127.5 (2C), 123.6, 121.0, 120.6, 116.2, 39.2,
21.3. HRMS (ESI): m/z calcd for C21H17N3O2 [M + H]+ 344.1396,
found 344.1393.
1-Methyl-3-phenyl-7-p-tolyl-1H-indazole-6-carbonitrile (9c).
Yield: 91 mg, 66%. White solid. Mp: 149 °C. IR (neat): νmax
3027.82, 2921.54, 2225.34, 1463.28, 1262.181019.73, 817.62, 764.23,
697.81 cm−1. 1H NMR (250 MHz, CDCl3): δ 8.04 (d, J = 8.5 Hz, 1H),
7.89 (d, J = 7.0 Hz, 2H), 7.56−7.35 (m, 8H), 3.68−3.56 (s, 3H), 2.48
(s, 3H). 13C NMR (63 MHz, CDCl3): δ 144.3, 139.5, 132.6, 131.5,
131.4, 129.9 (2C), 129.4 (2C), 129.1 (2C), 128.5, 127.7 (2C), 127.5,
124.3, 123.7, 121.3, 118.7, 111.0, 39.4, 21.6. HRMS (ESI): m/z calcd
for C22H17N3 [M + H]+ 324.1498, found 324.1495.
1-Methyl-3-phenyl-1H-indazole (6f). Yield: 0.35 g, 72%. Yellow
solid. Mp: 72−73 °C (lit.9b mp 71−73 °C).
1-Methyl-3,7-diphenyl-1H-indazole-6-carbonitrile (7a). Yield: 66
mg, 34%. White solid. Mp: 119−121 °C. IR (neat): νmax 3064.22,
2949.53, 2225.07, 1727.07, 1463.69, 1444.89, 1267.46, 758.07, 698.64
1
cm−1. H NMR (250 MHz, CDCl3): δ 8.06 (d, J = 8.5 Hz, 1H), 7.90
(dd, J = 8.3, 1.4 Hz, 2H), 7.58−7.45 (m, 9H), 3.59 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 144.4, 138.7, 134.5, 132.6, 131.3, 130.0, 129.6,
129.1, 128.7, 128.6, 127.7, 124.4, 123.7, 121.5, 118.5, 110.9, 39.3.
F
dx.doi.org/10.1021/jo500876q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5-(Trifluoromethyl)-1-methyl-3-phenyl-7-p-tolyl-1H-indazole
(9d). Yield: 86 mg, 65%. White solid. Mp: 136 °C. IR (neat): νmax
2945.35, 1613.54, 1318.89, 1301.08, 1108.59, 888.50, 760.39, 699.69
(q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 165.9, 147.1, 142.0, 140.9, 140.6, 131.6, 130.9,
129.7 (2C), 129.6 (2C), 129.1 (2C), 129.0, 127.6 (2C), 125.4, 122.6,
122.2, 118.5, 61.3, 39.5, 14.3. HRMS (ESI): m/z calcd for C23H19N3O4
[M + H]+ 401.1376, found 401.1380.
1
cm−1. H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.94 (d, J = 7.1
Hz, 2H), 7.57 (t, J = 7.5 Hz, 2H), 7.51−7.45 (m, 2H), 7.41−7.32 (m,
4H), 3.74 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
146.0, 141.2, 139.2, 135.3, 133.6, 130.6 (2C), 129.9 (2C), 129.3 (2C),
128.6 (2C), 127.9, 125.6 (qCq‑F, J1 = 273 Hz), 125.4 (qCH‑F, J3 = 3.03
Hz), 124.2 (qCq‑CF, J2 = 32.3 Hz), 123.9 (qCq‑CF, J2 = 32 Hz), 122.9,
119.1 (qCH‑F, J3 = 4.04 Hz), 40.2, 22.2. HRMS (ESI): m/z calcd for
C22H17F3N2 [M + H]+ 367.1418, found 367.1416.
Methyl 1-Methyl-3-phenyl-7-p-tolyl-1H-indazole-5-carboxylate
(9e). Yield: 85 mg, 64% White solid. Mp: 138−140 °C. IR (neat):
νmax 2918.96, 2849.63, 1706.94, 1433.22, 1247.08, 1209.16, 762.91,
695.47 cm−1. 1H NMR (250 MHz, CDCl3): δ 8.72 (d, J = 1.8 Hz, 1H),
7.94 (m, 3H), 7.48−7.38 (m, 7H), 3.94 (s, 3H), 3.70 (s, 3H), 2.46 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 167.3, 145.6, 144.6, 137.9,
134.9, 132.7, 129.7 (2C), 128.9 (2C), 128.9 (2C), 128.8, 128.38,
127.7(2C), 126.0, 123.62, 123.06, 122.54, 52.12, 39.30, 21.30. HRMS
(ESI): m/z calcd for C23H20N2O2 [M + H]+ 357.1599, found
357.1597.
1-Methyl-5-nitro-3-phenyl-7-o-tolyl-1H-indazole (10e). Yield: 89
mg, 66%. Yellow oil. IR (neat): νmax 3065.97, 2945.32, 1597.87,
1527.01, 1330.10, 897.94, 694.02 cm−1. 1H NMR (400 MHz, CDCl3):
δ 8.94 (dd, J = 9.7, 2.2 Hz, 2H), 8.14 (dd, J = 8.7, 2.1 Hz, 1H), 8.10 (d,
J = 2.1 Hz, 1H), 7.95−7.92 (m, 2H), 7.59−7.28 (m, 5H), 3.71 (s, 3H),
3.58 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 147.1, 142.4, 141.2,
138.4, 136.9, 133.7, 130.5, 130.3, 129.74, 129.3 (2C), 129.1, 128.4,
127.8 (2C), 126.9, 126.1, 122.4, 118.3, 39.6, 20.3. HRMS (ESI): m/z
calcd for C21H17N3O2 [M + H]+ 344.1397, found 344.1393.
1-Methyl-5-nitro-3-phenyl-7-m-tolyl-1H-indazole (10f). Yield: 90
mg, 67%. Yellow oil. IR (neat): νmax 3055.47, 2918.88, 1598.36,
1525.29, 1330.58, 1077.53, 743.80, 680.61 cm−1. 1H NMR (250 MHz,
CDCl3): δ 8.89 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.89 (dd,
J = 8.4, 2.1 Hz, 2H), 7.59−7.43 (m, 1H), 7.42−7.23 (m, 1H), 3.68 (s,
3H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 147.1, 142.2,
141.1, 138.4, 136.6, 132.0, 130.5, 129.6, 129.2 (2C), 129.0, 128.4,
127.8 (2C), 127.0, 126.9, 122.8, 122.1, 118.0, 39.6, 21.6. HRMS (ESI):
m/z calcd for C21H17N3O2 [M + H]+ 344.1396, found 344.1393.
5-Nitro-1-phenyl-1H-indazole (11). Yield: 0.88 g, 88%. Yellow
solid. Mp: 180 °C (lit.27 mp 178−180 °C).
5-Fluoro-1-methyl-3-phenyl-7-p-tolyl-1H-indazole (9f). Yield: 60
mg, 43%. White solid. Mp: 135−137 °C. IR (neat): νmax 3066.64,
1
2921.78, 1489.14, 1262.94, 993.98, 823.45, 698.87 cm−1. H NMR
(400 MHz, CDCl3): δ 7.88 (d, J = 7.2 Hz, 2H), 7.60 (dd, J = 8.8, 2.3
Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.42−7.24 (m, 5H), 7.03 (dd, J =
9.3, 2.4 Hz, 1H), 3.66 (s, 3H), 2.45 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 158.5, 156.2, 143.5 (d, J = 6.06 Hz), 137.9, 137.7, 136.3,
134.3, 133.0, 130.1, 129.3 (2C), 128.6 (2C), 127.8, 127.7 (2C), 127.4
(d, J = 9.09 Hz), 127.1 (2C), 126.5, 122.4 (d, J = 10.1 Hz), 117.2 (d, J
= 27.2 Hz), 103.8 (d, J = 24.2 Hz), 39.1, 21.0. HRMS (ESI): m/z calcd
for C21H17FN2 [M + H]+ 317.1449, found 317.1448.
5-Chloro-1-methyl-3-phenyl-7-p-tolyl-1H-indazole (9g). Yield: 23
mg, 17%. Colorless oil. IR (neat): νmax 2922.10, 2851.19, 2388.26,
1728.20, 1482.53, 1261.03, 826.65, 698.95 cm−1. 1H NMR (250 MHz,
CDCl3): δ 7.94 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 8.3, 1.3 Hz, 2H),
7.55−7.49 (m, 3H), 7.43 (d, J = 7.1 Hz, 1H), 7.36−7.31 (m, 3H), 7.21
(d, J = 1.9 Hz, 1H), 3.66 (s, 3H), 2.46 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 143.5, 138.3, 138.2, 134.6, 133.1, 131.0, 129.7 (2C), 129.0
(2C), 128.6, 128.2 (2C), 127.6 (2C), 126.4, 125.2, 123.5, 119.4, 39.4,
21.4. HRMS (ESI): m/z calcd for C21H17ClN2 [M + H]+ 333.1451,
found 333.1453.
7-(4-Methoxyphenyl)-1-methyl-5-nitro-3-phenyl-1H-indazole
(10a). Yield: 95 mg, 67%. Yellow solid. Mp: 148−150 °C. IR (neat):
νmax 2960.90, 1596.52, 1507.82, 1284.87, 1704.93, 1024.50, 790.32,
692.85 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.92 (d, J = 2.1 Hz, 1H),
8.13 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 7.1 Hz, 2H), 7.56 (t, J = 7.4 Hz,
2H), 7.48 (t, J = 8 Hz,1H), 7.39 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7
Hz, 2H), 3.91 (s, 3H), 3.73 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
159.9, 146.9, 142.1, 141.3, 131.8, 130.8 (2C), 129.1 (2C), 128.8, 128.6,
127.6 (2C), 126.4, 122.8, 121.9, 117.7, 113.8 (2C), 55.3, 39.4. HRMS
(ESI): m/z calcd for C21H17N3O3 [M + H]+ 360.1342, found
360.1343.
5-Nitro-1,3-diphenyl-1H-indazole (12). Yield: 89 mg, 68%. Yellow
solid. Mp: 158 °C. IR (neat): νmax 3063.11, 2621.11, 2283.20, 2162.63,
1
2049.56, 1498.38, 1336.29, 1079.08, 749.97, 690.58 cm−1. H NMR
(250 MHz, CDCl3): δ 9.04 (dd, J = 2.2, 0.6 Hz, 1H), 8.32 (td, J = 9.3,
2.1 Hz, 1H), 8.03 (dd, J = 8.2, 1.6 Hz, 2H), 7.83−7.76 (m, 2H), 7.62−
7.44 (m, 5H), 7.09 (dd, J = 2.1, 4.6 Hz, 2H). 13C NMR (101 MHz,
CDCl3): δ 148.7, 143.2, 142.2, 139.1, 131.7, 129.9 (2C), 129.4, 129.3
(2C), 128.1, 127.9 (2C), 125.9, 123.5 (2C), 122.4, 119.6, 111.1.
HRMS (ESI): m/z calcd for C19H13N3O2 [M + H]+ 316.1081, found
316.1080.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures giving proton and carbon NMR spectra of the reported
compounds, NOESY NMR spectra of 9a,b and 10a, and IR
spectra of reported compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*S.E.K.: fax, (+)212 537716040; e-mail, s.elkazzouli@
ueuromed.org.
■
*G.G.: fax, (+) 33 238417281; e-mail, gerald.guillaumet@univ-
orleans.fr.
Notes
The authors declare no competing financial interest.
7-(4-(Trifluoromethyl)phenyl)-1-methyl-5-nitro-3-phenyl-1H-in-
dazole (10b). Yield: 100 mg, 65%. Green solid. Mp: 165−167 °C. IR
(neat): νmax 3093.02, 2946.32, 1596.14, 1323.76, 1121.81, 1065.12,
842.30, 780.83 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.98 (d, J = 2.1
Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.82 (d, J
= 8 Hz, 2H), 7.64 (d, J = 8 Hz, 2H), 7.58 (t, J = 7.2 Hz, 2H), 7.50 (t, J
= 7.4 Hz, 1H), 3.72 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 147.2,
142.0, 140.5, 140.2, 131.5, 131.3, 130.1 (2C), 129.1 (2C), 129.0 (2C),
127.6 (2C), 125.5 (qCH‑F, J3= 4.04 Hz), 125.0 (qCq‑CF, J2= 32 Hz),
123.8 (qCq‑F, J1= 273 Hz), 122.8, 122.2, 118.7, 39.6. HRMS (ESI): m/z
calcd for C21H14F3N3O2 [M + H]+ 398.1110, found 398.1111.
Ethyl 4-(1-Methyl-5-nitro-3-phenyl-1H-indazol-7-yl)benzoate
(10d). Yield: 100 mg, 65%. Yellow solid. Mp: 197 °C. IR (neat):
νmax 3054.39, 2979.68, 1702.27, 1458.69, 1289.58, 1098.04, 870.14,
774.78, 689.72 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.97 (d, J = 2.1
Hz, 1H), 8.22 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 2.1 Hz, 1H), 7.93 (d, J
= 7.1 Hz, 2H), 7.57 (dd, J = 7.8, 6.1 Hz, 4H), 7.53−7.47 (m, 1H), 4.46
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