Synthesis of substituted 1 H-indazoles from arynes and hydrazones

Article abstract of DOI:10.1021/jo202598e

The 1H-indazole skeleton can be constructed by a [3 + 2] annulation approach from arynes and hydrazones. Under different reaction conditions, both N-tosylhydrazones and N-aryl/alkylhydrazones can be used to afford a variety of indazoles. The former reaction affords 3-substituted indazoles either via in situ generated diazo compounds or through an annulation/elimination process. The latter reaction leads to 1,3-disubstituted indazoles likely through an annulation/oxidation process. The reactions operate under mild conditions and can accommodate aryl, vinyl, and less satisfactorily, alkyl groups.

Full text of DOI:10.1021/jo202598e

Article
pubs.acs.org/joc
Synthesis of Substituted 1H-Indazoles from Arynes and Hydrazones
Pan Li,† Chunrui Wu,*,† Jingjing Zhao,† Donald C. Rogness,‡ and Feng Shi*,†
†Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng,
Henan 475004, PR China
‡Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: The 1H-indazole skeleton can be constructed
by a [3 + 2] annulation approach from arynes and hydrazones.
Under different reaction conditions, both N-tosylhydrazones
and N-aryl/alkylhydrazones can be used to afford a variety of
indazoles. The former reaction affords 3-substituted indazoles
either via in situ generated diazo compounds or through an
annulation/elimination process. The latter reaction leads to
1,3-disubstituted indazoles likely through an annulation/oxidation process. The reactions operate under mild conditions and can
accommodate aryl, vinyl, and less satisfactorily, alkyl groups.
To address these issues, we thought to introduce the easily
obtained hydrazone as an alternative substrate. Hydrazones can
be used as precursors for in situ generation of a number of 1,3-
dipoles for the subsequent aryne cycloaddition, including nitrile
imides (oxidation of N-monosubstituted hydrazones,15 path A,
Scheme 1), azomethine imines (thermal H-shift of N-
monosubstituted hydrazones,16 path B, Scheme 1), and diazo
compounds (base-promoted elimination of N-tosylhydrazones,
path C, Scheme 1).17,18 They can also independently react with
arynes in a nucleophilic attack−nucleophilic cyclization
fashion19,20 to afford indazolines (path D, Scheme 1),21
which can be readily transformed to indazoles under various
conditions depending on the exact substitution. These
possibilities inspired us to study the reactivity of hydrazones
in aryne chemistry, and herein we wish to disclose our full
results that extend the scope of our earlier communication.22
INTRODUCTION
■
The indazole unit is an important heterocyclic privileged
structure.1 Derivatives of indazoles exhibit a broad spectrum of
bioactivities including anti-inflammatory,2 anti-tumor,3 anti-
HIV,4 anti-cancer,5 anti-platelet,6 and serotonin 5-HT3
receptor antagonist activities.7 With the growing interest in
indazole derivatives, preparation of the indazole skeleton has
been pursued for a long time by synthetic organic chemists, and
recent developments have allowed for indazoles to be accessed
from easily obtained starting materials under milder conditions
in fewer steps.8−11
Among the different approaches, those involving arynes as a
starting material have gained increasing attention in the past
five years. Yamamoto, Larock, and their co-workers have
independently reported the [3 + 2] cycloaddition reaction of
arynes with diazo compounds (eq 1),12 and Moses and co-
RESULTS AND DISCUSSION
■
Reaction of N-Tosylhydrazones To Prepare 3-Sub-
stituted Indazoles. We first examined the possibility of path
C or path D1 using N-tosylhydrazones as a substrate. The
reaction of benzyne precursor 1a and anisaldehyde N-
tosylhydrazone (2a) was studied as a model (Table 1).
Through our survey of reaction conditions, a phase transfer
catalyst23 such as TEBAC (Et3NBn+Cl−) and a proper dilution
proved effective for a good yield (entries 1−4). THF was a
superior solvent compared to MeCN. Moreover, at least 2
equiv of CsF was needed (entry 5) since 1 equiv was used to
eliminate the Ts−.24 Gratifyingly, no further N-arylation of 3a
was observed under these reaction conditions.12
workers have disclosed a [3 + 2] cycloaddition with nitrile
imides (eq 2).13 Nonetheless, both routes have limitations in a
synthetic perspective. The diazo route is effective only for
indazoles with electron-withdrawing groups at the 3-position,
and the nitrile imide route is effective only for 1,3-diaryl
indazoles. Thus, developing a more general aryne approach that
accommodates a wider combination of aryl, alkyl, and vinyl
groups at the 1- and/or 3-positions is still needed.14
The scope of this reaction was then studied (Table 2).
Different arynes reacted smoothly (entries 1 and 2). N-
Received: December 17, 2011
Published: March 13, 2012
© 2012 American Chemical Society
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Scheme 1. Possible Reactivities of Hydrazones with Arynes To Afford Indazoles
Table 1. Optimization of the Reaction with N-
Tosylhydrazones
absorption at 2053 cm−1 when 2a and CsF were mixed in the
absence of 1, which is characteristic for diazo compounds.27
The latter pathway can be supported by the formation of the N-
arylation side product. The regioselectivity of the reaction
involving 3-methoxybenzyne (entry 2, Table 2) brought further
evidence. Path C, according to previous reports,12a should
afford the 7-methoxy isomer, but path D1, as a result of the
favorable distal attack of the nucleophile to the OMe
group,28−30 should lead to the 4-methoxy isomer (Scheme 2).
a
b
entry
CsF (equiv)
THF (mL)
TEBAC (mol %)
yield (%)
1
2
3
4
5
3
10
10
5
25
10
10
0
87
77
61
3
Scheme 2. Regioselectivity and Mechanistic Insights for the
Unsymmetrical Benzyne
3
c
3
5
38
1.5
10
25
40
a
All reactions were carried out on 0.4 mmol of 2a with 1.2 equiv of 1a.
Isolated yield. 59% of 2a was recovered.
b
c
Tosylhydrazones derived from aromatic (entries 3−8) and
heteroaromatic aldehydes (entries 9 and 10) were all
successfully transformed to the desired indazoles, despite the
lower yields for the latter. Hydrazones derived from primary or
secondary aliphatic aldehydes afforded only complex mixtures.
Nonetheless, 2j derived from a tertiary aldehyde allowed for a
marginal success (entry 11). Unsuccessful substrates also
include 2k with a vinylic R1 group (entry 12), which underwent
an apparent 1,5-dipolar cyclization to form 4 instead of reaction
with benzyne.23d,25 Ketone-derived hydrazones generally
resulted in complex mixtures, regardless of the type of ketone
(aliphatic, aromatic, acyclic, or cyclic),26 but 2l derived from an
α-dicarbonyl compound was reactive to afford 5 in a 63% yield
after an acyl migration12a (eq 3).
The resultant 4.8:1 ratio again suggested that the diazo route
(path C) was likely a major route for this specific benzyne.
Reaction of N-Aryl/Alkylhydrazones To Prepare 1,3-
Disubstituted Indazoles. Since the N-tosylhydrazone route
turned out to be effective only for 3-arylindazoles, our next
effort was to seek alternative substrates that could potentially
lead to indazoles with a more general substitution pattern,
especially to accommodate vinyl and alkyl groups. Thus, the
oxidative variant was sought using N-monosubstituted
hydrazones 6 as the substrate,31 in light of possible mechanistic
paths A, B, and D2 (see Scheme 1, vide supra). Air was chosen
as the oxidant.32 As such, the model reaction of hydrazone 6a
and benzyne precursor 1a was first attempted (Table 3).
The optimization endeavor revealed a set of best conditions
employing a less-soluble KF as the fluoride source at 100−120 °C
in MeCN (sealed-tube conditions,33 entries 1 and 2). Yields
As to the mechanism of this approach, we tend to consider
that both path C and path D1 (see Scheme 1, vide supra) were
involved. The former pathway can be supported by a strong IR
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a
Table 2. Scope of N-Tosylhydrazones
a
b
c
All reactions were carried out on approximately 0.4 mmol of 2 in 10 mL of THF. Isolated yield. A mixture of 4.8:1 regioisomers in favor of the
one shown, combined yield. The major isomer was assigned by NOESY experiment.
were lower when KF was replaced with CsF or with a decrease
in temperature (entries 3 and 4). THF proved ineffective as a
solvent, and DME was inferior to MeCN. We tend to consider
that this combination of fluoride source, temperature, and
solvent is associated with the desired kinetics of the aryne
generation to match the subsequent cycloaddition or
annulation steps. In addition, a Ce(IV) oxidant (entry 6) was
ineffective. The conditions described in entry 2 were chosen as
the standard conditions for subsequent studies.
9:1 mixture of regioisomers now favoring the 4-OMe isomer
(entry 2). This different regioselectivity (from the one depicted
in entry 2, Table 2) clearly suggests different mechanisms.
Hydrazones derived from aromatic aldehydes (entries 3−6)
showed a general success. Steric factors proved irrelevant in this
context (entries 5 and 6), while electron-negative R1 groups
tend to give higher yields (compare entries 3−6 with entry 2,
Table 3). Hydrazones derived from a heteroaromatic aldehyde
(entry 7) and an α,β-unsaturated aldehyde (entry 8) were
successfully employed, thus allowing for indazoles to bear
heteroaryl and vinyl groups at the 3-position. The hydrazine
moiety, namely, the R2 group of 6, can cover phenyl groups
We next examined the scope and limitations of this approach
(Table 4). Again, different arynes reacted smoothly (entries 1
and 2), and the unsymmetrical 3-methoxybenzyne resulted in a
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a
Table 3. Optimization of the Reaction with N-Phenylhydrazones
b
entry
fluoride
oxidant
air, sealed tube
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
KF
120
100
100
80
16
16
8
63
62
49
46
tr
c
KF
air, sealed tube
air, sealed tube
air, open flask
air, open flask
CsF
CsF
CsF
KF
8
rt
24
Ce(NO3)4·6H2O (2 equiv)
100
16
b
0
a
c
All reactions were carried out on a 0.3 mmol scale in 3 mL of solvent open to air. 1a:6a:fluoride =1.2:1:2. Isolated yield. See the Supporting
Information for the effects of the size of the tube.
with different electronic properties (entries 9 and 10), but a
nitro group was not tolerated (entry 11). Interestingly, N,N-
dibenzylhydrazone 6l′ worked smoothly to afford 7m in a
moderate yield (entry 12), where one of the benzyl groups was
presumably scavenged by the second equivalent of fluoride.21b
In contrast, N,N-dimethylhydrazone did not follow the same
path but instead afforded 2-dimethylaminophenyl ketone in a
moderate yield.21a
CONCLUSIONS
■
In summary, we have developed aryne reactions to prepare 3-
substituted and 1,3-disubstituted 1H-indazoles using hydra-
zones as inexpensive and readily available starting materials.
Specifically, N-tosylhydrazones can afford 3-substituted in-
dazoles, and N-monosubstituted hydrazones can lead to 1,3-
disubstituted indazoles. Compared with the early discoveries in
aryne reactions to indazoles, our methods allow for indazoles
bearing more diverse combination of substitutions at the 1- and
3-positions. Introduction of aryl and vinyl groups have been
successful, and the introduction of alkyl groups has been
partially resolved. With the rapid development of aryne
chemistry, construction of more heterocyclic scaffolds through
aryne processes can be expected in the future.
Other than N-arylhydrazones (R2 = Ar), reaction of N-
unsubstituted hydrazones (R2 = H) resulted in the incorpo-
ration of two molecules of benzyne to afford N-phenylindazole
instead of indazoles with free NH groups. Substrates with R2
being electron-withdrawing groups, including acyl, alkoxycar-
bonyl, and sulfonyl groups, were not compatible under the
oxidative conditions. Thus, hydrazones 2 could not be used to
afford 1-tosylindazoles. In addition, hydrazones derived from
aliphatic aldehydes (R1 = alkyl) were found to be much less
stable and quickly deteriorated upon standing. These
hydrazones could be prepared in situ by mixing the aldehyde
and the hydrazine in the flask 5 min before 1a and KF were
added (Scheme 3). Under these conditions, hydrazones with R1
being tertiary, secondary, or primary alkyl groups were all
welcome, albeit in lower yields.
EXPERIMENTAL SECTION
■
General Considerations. All reagents purchased from commercial
sources were used as received. The solvents THF and MeCN were
distilled from Na/benzophenone and CaH2, respectively. The silica gel
for column chromatography was supplied as 300−400 meshes.34
Powdered CsF was used as received and stored in a desiccator. All
melting points are uncorrected. The H and 13C NMR spectra are
1
1
referenced to the residual solvent signals (7.26 ppm for H and 77.0
ppm for 13C in CDCl3; 2.05 ppm for H and 29.8 ppm for 13C in
1
acetone-d6). All aryne reactions were carried out in oven-dried
glassware and were magnetically stirred.
It is difficult to differentiate the three mechanistic paths,
namely, A, B, and D2 (see Scheme 1, vide supra), in this
approach, since they share not only the same substrate and
reaction conditions but also the same regioselectivity with the
reaction of 1c. We tend to think that among the three
possibilities, path B was the most doubtful, as formation of
azomethine imines from 6 typically requires acidic or at least
neutral conditions, which are in contrast to our basic
conditions. To date, all efforts to trap intermediate A (see
Scheme 1, vide supra) in path D by external electrophiles such
as Ac2O or (MeO)2CO have been unsuccessful, even with
ketone-derived hydrazones. In addition, the reaction failed to
afford indazolines in the absence of any oxidant but resulted in
the recovery of 6. These two observations made us unable to
rule out path A, despite the dramatic difference in our reaction
conditions and Moses’ conditions.13 Whatever mechanism is
operative, use of hydrazones 6 clearly provides a wider scope of
indazoles where vinyl and, less satisfactorily, alkyl groups can be
accommodated.
General Procedure To Prepare N-Tosylhydrazones (2).27 To
a solution of p-toluenesulfonyl hydrazide (1.02 g, 5.5 mmol, 1.1 equiv)
in 5 mL of MeOH was added an aldehyde (5 mmol) slowly (liquid
aldehyde was added dropwise, and solid aldehyde was added in small
portions). The mixture was stirred at room temperature for 2 h.
MeOH was evaporated in vacuo, and the residue was recrystallized
from MeOH to afford the N-tosylhydrazones, which were used directly
to the aryne reactions.
Hydrazone 2a. The general procedure was applied to 680 mg of 4-
methoxybenzaldehyde to afford 1.37 g of 2a (90%) as white solid, mp
105−106 °C (lit.23d 110−111 °C); H NMR (400 MHz, CDCl3) δ
1
8.01 (s, 1 H), 7.87 (d, J = 8.3 Hz, 2 H), 7.73 (s, 1 H), 7.55−7.47 (m, 2
H), 7.30 (d, J = 8.1 Hz, 2 H), 6.87−6.85 (m, 2 H), 3.81 (s, 3 H), 2.40
(s, 3 H).
Hydrazone 2b. The general procedure was applied to 530 mg of
benzaldehyde to afford 0.70 g of 2b (51%) as white solid, mp 120−121
°C (lit.23d 127−128 °C); H NMR (400 MHz, CDCl3) δ 7.94 (s, 1
1
H), 7.88 (d, J = 8.3 Hz, 2 H), 7.75 (s, 1 H), 7.59−7.57 (m, 2 H),
7.38−7.34 (m, 3 H), 7.31 (d, J = 8.1 Hz, 2 H), 2.41 (s, 3 H).
Hydrazone 2c. The general procedure was applied to 925 mg of 4-
bromobenzaldehyde to afford 1.60 g of 2c (91%) as white solid, mp
171−171.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1 H), 7.86 (d,
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a
Table 4. Scope of N-Monosubstituted Hydrazones
a
b
c
All reactions were carried out on a 0.3 mmol scale in 3 mL of solvent in a 15 mL sealed tube. Isolated yield. A mixture of 9:1 regioisomers in favor
d
of the one shown, combined yield. Reaction was carried out using 1.6 equiv of 1a and 2.6 equiv of KF.
J = 8.3 Hz, 2 H), 7.69 (s, 1 H), 7.51−7.42 (m, 4 H), 7.32 (d, J = 8.1
Hz, 2 H), 2.41 (s, 3 H).
8.37 (t, J = 1.8 Hz, 1 H), 8.28 (s, 1 H), 8.21 (ddd, J = 8.2, 2.2, 1.0 Hz,
1 H), 7.93 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2 H), 7.82 (s, 1 H),
7.55 (t, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 2 H), 2.42 (s, 3 H).
Hydrazone 2e. The general procedure was applied to 700 mg of 2-
chlorobenzaldehyde to afford 1.30 g of 2e (84%) as white solid, mp
Hydrazone 2d. The general procedure was applied to 755 mg of 3-
nitrobenzaldehyde to afford 0.70 g of 2d (44%) as white solid, mp
153−154 °C (lit.23d 154−156 °C); H NMR (400 MHz, CDCl3) δ
1
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was stirred at 70 °C for 24 h, cooled to room temperature, poured into
brine, and extracted with EtOAc. The combined extracts were dried
over MgSO4, filtered, and evaporated. The residue was purified by
column chromatography (petroleum ether/EtOAc) to afford the
indazoles 3.
Scheme 3. Scope of the One-Pot Protocol with Hydrazones
Generated in Situ from Aliphatic Aldehydes
a
3-(4-Methoxyphenyl)-1H-indazole (3a). The general procedure
was applied to 122 mg of 2a and 143 mg of 1a to afford 78 mg of 3a
(87%) as slightly yellow solid, mp 85−86 °C (lit.40 88−90 °C); Rf =
1
0.30 (2:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3) δ 8.01 (d,
J = 8.2 Hz, 1 H), 7.95−7.89 (m, 2 H), 7.46−7.35 (m, 2 H), 7.22 (dt, J =
7.2, 1.6 Hz, 1 H), 7.10−7.01 (m, 2 H), 3.89 (s, 3 H), NH not
observed; 13C NMR (100 MHz, CDCl3) δ 159.6, 145.1, 141.4, 128.9,
126.8, 125.9, 121.13, 121.07, 120.7, 114.4, 110.4, 55.3; HRMS (ESI)
calcd for C14H13N2O (M + H) 225.1022, found 225.1020.
5,6-Dimethoxy-3-(4-methoxyphenyl)-1H-indazole (3b). The gen-
eral procedure was applied to 122 mg of 2a and 172 mg of 1b to afford
64 mg of 3b (56%) as white solid, mp 209−210 °C; Rf = 0.45
(EtOAc); 1H NMR (400 MHz, CDCl3) δ 11.66 (s, 1 H), 7.93 (d, J =
8.6 Hz, 2 H), 7.20 (s, 1 H), 7.08 (d, J = 8.7 Hz, 2 H), 6.38 (s, 1 H),
3.94 (s, 3 H), 3.87 (s, 3 H), 3.70 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 159.4, 150.8, 146.4, 144.4, 137.4, 128.9, 126.5, 114.5, 113.6,
99.8, 91.5, 55.1, 55.8, 55.3; HRMS (ESI) calcd for C16H17N2O3 (M +
H) 285.1234, found 285.1231.
a
All reactions were carried out on a 0.3 mmol scale in 3 mL of solvent
in a sealed tube.
137−138 °C (lit.35 154−156 °C); 1H NMR (400 MHz, CDCl3) δ 8.16
(s, 1 H), 7.95−7.90 (m, 2 H), 7.88 (d, J = 8.3 Hz, 2 H), 7.34−7.31 (m,
3 H), 7.30−7.24 (m, 2 H), 2.42 (s, 3 H).
7-Methoxy-3-(4-methoxyphenyl)-1H-indazole (3c). The general
procedure was applied to 122 mg of 2a and 158 mg of 1c to afford 61
mg of 3c (60%) as white solid. The major isomer can be separated: mp
Hydrazone 2f. The general procedure was applied to 875 mg of 2,6-
dichlorobenzaldehyde to afford 1.58 g of 2f (92%) as white solid, mp
182−182.5 °C; 1H NMR (400 MHz, acetone-d6) δ 10.7 (s, 1 H), 8.16
(s, 1 H), 7.84 (d, J = 8.3 Hz, 2 H), 7.46−7.36 (m, 5 H), 2.41 (s, 3 H).
Hydrazone 2g. The general procedure was applied to 830 mg of
3,4-dimethoxybenzaldehyde to afford 1.25 g of 2g (75%) as white
solid, mp 129−130 °C; 1H NMR (400 MHz, CDCl3) δ 7.87−7.85 (m,
2 H), 7.70 (s, 1 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.26 (s, 1 H), 7.24 (d,
J = 1.8 Hz, 1 H), 7.01 (dd, J = 8.2, 1.9 Hz, 1 H), 6.82 (d, J = 8.2 Hz, 1
H), 3.91 (s, 3 H), 3.89 (s, 3 H), 2.41 (s, 3 H)
Hydrazone 2h. The general procedure was applied to 535 mg of
nicotinaldehyde to afford 0.82 g of 2h (60%) as brown solid, mp 154−
155 °C (lit.36 155−156 °C); 1H NMR (400 MHz, acetone-d6) δ 10.48
(s, 1 H), 8.74 (d, J = 1.9 Hz, 1 H), 8.56 (dd, J = 4.8, 1.7 Hz, 1 H), 8.03
(s, 1 H), 8.01 (dt, J = 8.1, 1.9 Hz, 1 H), 7.87−7.81 (m, 2 H), 7.42−
7.38 (m, 3 H), 2.39 (s, 3 H).
1
149−151 °C; Rf = 0.35 (2:1 hexanes/EtOAc); H NMR (400 MHz,
CDCl3) δ 10.22 (s, 1 H), 7.92 (d, J = 8.7 Hz, 2 H), 7.58 (d, J = 8.1 Hz,
1 H), 7.14 (t, J = 7.8 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 2 H), 6.77 (d, J =
7.5 Hz, 1 H), 4.01 (s, 3 H), 3.88 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 159.6, 145.7, 145.3, 133.8, 128.7, 126.3, 122.4, 121.9, 114.3,
113.2, 105.0, 55.5, 55.3; HRMS (ESI) calcd for C15H15N2O2 (M + H)
255.1128, found 255.1126. The regiochemistry is assigned by the
NOESY experiment, where the H at the 4-position of the indazole
shows a correlation with the H’s at the 2′-position of the 3-aryl group.
3-Phenyl-1H-indazole (3d). The general procedure was applied to
110 mg of 2b and 143 mg of 1a to afford 64 mg of 3d (82%) as white
solid, mp 116−117 °C (lit.41 115−116 °C); Rf = 0.43 (2:1 hexanes/
1
EtOAc); H NMR (400 MHz, CDCl3) δ 12.53 (s, 1 H), 8.08 (d, J =
7.5 Hz, 2 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.59 (t, J = 7.4 Hz, 2 H), 7.50
(t, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H),
7.09 (d, J = 8.3 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 145.5,
141.6, 133.5, 129.0, 128.2, 127.8, 126.7, 121.2, 120.9, 120.8, 110.4;
HRMS (ESI) calcd for C13H11N2 (M + H) 195.0917, found 195.0915.
3-(4-Bromophenyl)-1H-indazole (3e). The general procedure was
applied to 142 mg of 2c and 143 mg of 1a to afford 92 mg of 3e (85%)
as slightly yellow solid, mp 135−137 °C; Rf = 0.42 (2:1 hexanes/
Hydrazone 2i. The general procedure was applied to 560 mg of
thiophene-2-carbaldehyde to afford 1.10 g of 2i (79%) as brown solid,
mp 134−135 °C (lit.37 140−141 °C); 1H NMR (400 MHz, CDCl3) δ
7.98 (s, 1 H), 7.85 (d, J = 8.3 Hz, 2 H), 7.77 (s, 1 H), 7.36 (d, J = 5.0
Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.20 (dd, J = 3.6, 0.7 Hz, 1 H),
7.01 (dd, J = 5.0, 3.7 Hz, 1 H), 2.41 (s, 3 H).
Hydrazone 2j. The general procedure was applied to 430 mg of
pivalaldehyde to afford 0.35 g of 2j (28%) as white solid, mp 107−108
1
°C (lit.38 110−112 °C); H NMR (400 MHz, CDCl3) δ 7.80 (d, J =
1
EtOAc); H NMR (400 MHz, CDCl3) δ 10.40 (s, 1 H), 8.00 (d, J =
8.2 Hz, 1 H), 7.91−7.82 (m, 2 H), 7.68−7.61 (m, 2 H), 7.50 (t, J = 8.4
Hz, 1 H), 7.44 (dd, J = 8.0, 7.1 Hz, 1 H), 7.29−7.22 (m, 1 H); 13C
NMR (100 MHz, CDCl3) δ 144.6, 141.6, 132.4, 132.1, 129.1, 127.0,
122.3, 121.7, 120.8, 120.7, 110.2; HRMS (ESI) calcd for C13H10BrN2
(M + H) 273.0022, found 273.0020.
8.3 Hz, 2 H), 7.34 (s, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.06 (s, 1 H),
2.43 (s, 3 H), 1.00 (s, 9 H).
Hydrazone 2k. The general procedure was applied to 660 mg of
cinnamaldehyde to afford 0.70 g of 2k (47%) as white solid, mp 156−
156.5 °C (lit.39 158−159 °C); H NMR (400 MHz, CDCl3) δ 7.86−
1
3-(3-Nitrophenyl)-1H-indazole (3f). The general procedure was
applied to 128 mg of 2d and 143 mg of 1a to afford 53 mg of 3f (55%)
as glassy yellow solid, mp 188−189 °C; Rf = 0.33 (2:1 hexanes/
7.84 (m, 2 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.41−7.39 (m, 2 H), 7.36−
7.30 (m, 5 H), 6.87−6.84 (m, 3 H), 2.41 (s, 3 H).
Hydrazone 2l. The general procedure was applied to 820 mg of
methyl 2-oxo-2-phenylacetate to afford 1.25 g of 2l as a mixture of two
geometric isomers in a 3.4:1 ratio (75% combined). Major isomer: 1H
NMR (400 MHz, CDCl3) δ 11.62 (s, 1 H), 7.88−7.86 (m, 2 H),
7.50−7.48 (m, 2 H), 7.41−7.30 (m, 5 H), 3.87 (s, 3 H), 2.42 (s, 3 H).
1
EtOAc); H NMR (400 MHz, acetone-d6) δ 12.78 (s, 1 H), 8.88 (t,
J = 1.9 Hz, 1 H), 8.54−8.51 (m, 1 H), 8.27 (ddd, J = 8.2, 2.3, 0.9 Hz, 1
H), 8.18 (d, J = 8.3 Hz, 1 H), 7.85 (t, J = 8.0 Hz, 1 H), 7.71 (d, J = 8.4
Hz, 1 H), 7.48 (dt, J = 7.5, 0.8 Hz, 1 H), 7.32 (dt, J = 7.6, 0.8 Hz, 1
H); 13C NMR (100 MHz, acetone-d6) δ 149.7, 143.1, 142.7, 136.8,
133.6, 131.1, 127.4, 122.9, 122.7, 122.0, 121.3, 121.1, 111.6; HRMS
(ESI) calcd for C13H10N3O2 (M + H) 240.0768, found 240.0764.
3-(2-Chlorophenyl)-1H-indazole (3g). The general procedure was
applied to 124 mg of 2e and 143 mg of 1a to afford 70 mg of 3g (77%)
1
Minor isomer: H NMR (400 MHz, CDCl3) δ 8.12 (s, 1 H), 7.86−
7.84 (m, 2 H), 7.20−7.18 (m, 2 H), 3.82 (s, 3 H), 2.45 (s, 3 H), other
signals are overlapping with the major isomer.
General Procedure To Prepare 3-Substituted Indazoles (3)
from N-Tosylhydrazones (2). To an oven-dried 25 mL round-
bottom flask equipped with a stirrer bar was added 0.4 mmol of N-
tosylhydrazone 2, followed by the aryne precursor (0.48 mmol, 1.2
equiv). THF (10 mL) was added, followed by TEBAC (23 mg, 0.1
mmol, 0.25 equiv) and CsF (ca. 180−185 mg, 1.2 mmol, 3 equiv). The
flask was topped with a refluxing condenser, and the reaction mixture
1
as white solid, mp 140−141 °C; Rf = 0.38 (2:1 hexanes/EtOAc); H
NMR (400 MHz, CDCl3) δ 10.71 (s, 1 H), 7.72 (d, J = 8.2 Hz, 1 H),
7.63−7.62 (m, 1 H), 7.60−7.56 (m, 1 H), 7.47−7.37 (m, 4 H), 7.21
(ddd, J = 7.9, 6.4, 1.3 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 143.8,
140.8, 133.8, 132.4, 132.2, 130.2, 129.7, 126.9, 126.7, 121.9, 121.4,
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121.0, 110.2; HRMS (ESI) calcd for C13H10ClN2 (M + H) 229.0527,
found 229.0524.
residue was recrystallized from MeOH to afford the N-alkyl/
arylhydrazones.
Hydrazone 6a. The general procedure was applied to 680 mg of 4-
methoxybenzaldehyde and 594 mg of phenylhydrazine to afford 0.75 g
of 6a (66%) as white solid, mp 119−120 °C (lit.44 121 °C); 1H NMR
(400 MHz, CDCl3) δ 7.64 (s, 1 H), 7.60 (d, J = 8.7 Hz, 2 H), 7.30−
7.26 (m, 2 H), 7.10 (d, J = 7.8 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 6.86
(t, J = 7.1 Hz, 1 H), 3.84 (s, 3 H), NH not observed.
3-(2,6-Dichlorophenyl)-1H-indazole (3h). The general procedure
was applied to 138 mg of 2f and 143 mg of 1a to afford 79 mg of 3h
(75%) as white solid, mp 160−161 °C; Rf = 0.47 (2:1 hexanes/
1
EtOAc); H NMR (400 MHz, CDCl3) δ 10.71 (s, 1 H), 7.53−7.47
(m, 4 H), 7.45−7.40 (m, 1 H), 7.37 (dd, J = 8.7, 7.4 Hz, 1 H), 7.20
(ddd, J = 7.9, 6.8, 0.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 141.4,
140.6, 136.7, 131.2, 130.5, 128.2, 126.9, 122.1, 121.2, 120.6, 110.2;
HRMS (ESI) calcd for C13H9Cl2N2 (M + H) 263.0137, found
263.0136.
Hydrazone 6b. The general procedure was applied to 925 mg of 4-
bromobenzaldehyde and 594 mg of phenylhydrazine to afford 1.02 g
1
of 6b (74%) as white solid, mp 123−124 °C; H NMR (400 MHz,
CDCl3) δ 7.65 (br, 1 H), 7.61 (s, 1 H), 7.53−7.48 (m, 4 H), 7.29 (t,
J = 7.9 Hz, 2 H), 7.11 (d, J = 7.9 Hz, 2 H), 6.90 (t, J = 7.3 Hz, 1 H).
Hydrazone 6c. The general procedure was applied to 530 mg of
benzaldehyde and 594 mg of phenylhydrazine to afford 0.80 g of 6c
(82%) as white solid, mp 161−162 °C (lit.44 158 °C); 1H NMR (400
MHz, CDCl3) δ 7.68−7.66 (m, 3 H), 7.59 (br, 1 H), 7.39 (t, J = 7.4
Hz, 2 H), 7.33−7.26 (m, 3 H), 7.13 (d, J = 7.9 Hz, 2 H), 6.90 (t, J =
7.3 Hz, 1 H).
3-(3,4-Dimethoxyphenyl)-1H-indazole (3i). The general procedure
was applied to 134 mg of 2g and 143 mg of 1a to afford 86 mg of 3i
(84%) as white solid, mp 147−149 °C; Rf = 0.13 (2:1 hexanes/
1
EtOAc); H NMR (400 MHz, CDCl3) δ 10.44 (s, 1 H), 8.03 (d, J =
8.2 Hz, 1 H), 7.57−7.53 (m, 2 H), 7.45−7.40 (m, 2 H), 7.26−7.22 (m,
1 H), 7.03 (d, J = 8.1 Hz, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 149.4, 149.2, 145.5, 141.7, 126.8, 126.4, 121.2,
121.1, 120.8, 120.2, 111.4, 110.7, 110.2, 56.0, 55.9; HRMS (ESI) calcd
for C15H15N2O2 (M + H) 255.1128, found 255.1125.
Hydrazone 6d. The general procedure was applied to 655 mg of 4-
formylbenzonitrile and 594 mg of phenylhydrazine to afford 0.70 g of
3-(Pyridin-3-yl)-1H-indazole (3j). The general procedure was
applied to 110 mg of 2h and 143 mg of 1a to afford 53 mg of 3j
(68%) as brown solid, mp 184−185 °C; Rf = 0.40 (10:1 CH2Cl2/
6d (63%) as bright yellow solid, mp 153−154 °C (lit.44 144 °C); H
1
NMR (400 MHz, CDCl3) δ 7.93 (s, 1 H), 7.73−7.71 (m, 2 H), 7.64−
7.62 (m, 3 H), 7.31 (t, J = 7.9 Hz, 2 H), 7.14 (d, J = 7.8 Hz, 2 H), 6.94
(t, J = 7.3 Hz, 1 H).
1
MeOH); H NMR (400 MHz, CDCl3) δ 10.55 (s, 1 H), 9.27 (d, J =
1.0 Hz, 1 H), 8.70−8.68 (m, 1 H), 8.29 (dt, J = 7.9, 1.7 Hz, 1 H), 8.03
(d, J = 8.2 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.48−7.45 (m, 2 H),
7.31−7.26 (m, 1 H); 13C NMR (100 MHz, acetone-d6) δ 149.6, 148.8,
142.9, 142.2, 134.7, 130.9, 127.3, 124.6, 122.3, 121.5, 121.3, 111.4;
HRMS (ESI) calcd for C12H10N3 (M + H) 196.0869, found 196.0866.
3-(Thiophen-2-yl)-1H-indazole (3k). The general procedure was
applied to 112 mg of 2i and 143 mg of 1a to afford 29 mg of 3k (36%)
as brown solid, mp 151−153 °C (lit.42 137 °C); Rf = 0.47 (2:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1 H), 8.07
(dt, J = 8.2, 0.9 Hz, 1 H), 7.68 (dd, J = 3.6, 1.1 Hz, 1 H), 7.51 (dt, J =
8.4, 0.9 Hz, 1 H), 7.46−7.42 (m, 1 H), 7.38 (dd, J = 5.1, 1.1 Hz, 1 H),
7.29−7.25 (m, 1 H), 7.19 (dd, J = 5.1, 3.6 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ 141.5, 140.7, 135.8, 127.7, 127.1, 125.2, 124.9, 121.6,
120.8, 120.4, 110.3; HRMS (ESI) calcd for C11H9N2S (M + H)
201.0481, found 201.0478.
Hydrazone 6e. The general procedure was applied to 925 mg of 2-
bromobenzaldehyde and 594 mg of phenylhydrazine to afford 0.71 g
of 6e (51%) as yellow solid, mp 70−71 °C (lit.8c 68−70 °C); 1H NMR
(400 MHz, CDCl3) δ 8.09−8.06 (m, 1 H), 7.85 (s, 1 H), 7.54 (d, J =
8.0 Hz, 1 H), 7.34−7.28 (m, 3 H), 7.17−7.13 (m, 3 H), 6.91 (t, J = 7.3
Hz, 1 H), NH not observed.
Hydrazone 6f. The general procedure was applied to 875 mg of 2,6-
dichlorobenzaldehyde and 594 mg of phenylhydrazine to afford 0.35 g
of 6f (26%) as sight yellow solid, mp 66−67 °C (lit.45 59−61 °C); 1H
NMR (400 MHz, CDCl3) δ 7.98 (s, 1 H), 7.91 (s, 1 H), 7.36 (d, J =
8.1 Hz, 2 H), 7.29 (t, J = 7.9 Hz, 2 H), 7.15−7.11 (m, 3 H), 6.91 (t, J =
7.3 Hz, 1 H).
Hydrazone 6g. The general procedure was applied to 560 mg
of thiophene-2-carbaldehyde and 594 mg of phenylhydrazine to
afford 0.35 g of 6g (35%) as yellow solid, mp 137−138 °C (lit.46
3-tert-Butyl-1H-indazole (3l). The general procedure was applied
to 102 mg of 2j and 143 mg of 1a to afford 23 mg of 3l (33%) as white
1
138−139 °C); H NMR (400 MHz, CDCl3) δ 7.87 (s, 1 H), 7.29−
7.25 (m, 4 H), 7.09−7.07 (m, 3 H), 7.02−7.00 (m, 1 H), 6.87
(t, J = 7.3 Hz, 1 H).
1
solid, mp 152−154 °C; Rf = 0.46 (2:1 hexanes/EtOAc); H NMR
(400 MHz, CDCl3) δ 9.72 (s, 1 H), 7.91 (d, J = 8.2 Hz, 1 H), 7.45 (d,
J = 8.4 Hz, 1 H), 7.36 (dt, J = 7.4, 0.9 Hz, 1 H), 7.13 (J = 7.6, 0.9 Hz, 1
H), 1.54 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 154.5, 141.8, 126.2,
122.1, 120.5, 119.8, 110.0, 33.7, 30.0; HRMS (ESI) calcd for C11H15N2
(M + H) 175.1230, found 175.1227.
Hydrazone 6h. The general procedure was applied to 660 mg
of cinnamaldehyde and 594 mg of phenylhydrazine to afford 0.65 g of
6h (59%) as bright yellow solid, mp 173−174 °C (lit.47 167−169 °C);
1H NMR (400 MHz, CDCl3) δ 7.56 (br, 1 H), 7.54 (d, J = 9.2 Hz, 1
H), 7.47−7.45 (m, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.30−7.26 (m, 3
H), 7.06−6.99 (m, 3 H), 6.88 (t, J = 7.3 Hz, 1 H), 6.69 (d, J = 16.0 Hz,
1 H).
5-Phenyl-1H-pyrazole (4). The general procedure was applied to
120 mg of 2k and 143 mg of 1a to afford 45 mg of 4 (99%) as white
solid, mp 75−76 °C (lit.43 76−77 °C); Rf = 0.24 (2:1 hexanes/
Hydrazone 6i. The general procedure was applied to 925 mg of 4-
1
EtOAc); H NMR (400 MHz, CDCl3) δ 11.09 (s, 1 H), 7.77 (d, J =
bromobenzaldehyde and 760 mg of (4-methoxyphenyl)hydrazine to
1
7.8 Hz, 2 H), 7.61 (d, J = 2.1 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 2 H), 7.34
(t, J = 7.3 Hz, 1 H), 6.62 (d, J = 2.1 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 149.1, 133.2, 132.1, 128.8, 128.0, 125.9, 102.6; HRMS (ESI)
calcd for C9H9N2 (M + H) 145.0760, found 145.0758.
afford 0.52 g of 6i (34%) as yellow solid, mp 132−133 °C; H NMR
(400 MHz, CDCl3) δ 7.60 (br, 2 H), 7.51−7.46 (m, 4 H), 7.06 (br, 2
H), 6.86 (d, J = 8.9 Hz, 2 H), 3.79 (s, 3 H).
Hydrazone 6j. The general procedure was applied to 925 mg of 4-
Methyl 3-Phenyl-1H-indazole-1-carboxylate (5). The general
procedure was applied to 133 mg of 2l and 143 mg of 1a to afford
63 mg of 5 (63%) as white solid, mp 112−114 °C; Rf = 0.48 (2:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.3 Hz,
1 H), 7.98−7.96 (m, 3 H), 7.60 (t, J = 7.7 Hz, 1 H), 7.56−7.45 (m, 3
H), 7.40 (t, J = 7.5 Hz, 1 H), 4.15 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 151.3, 150.8, 141.2, 131.4, 129.5, 129.2, 128.8, 128.3, 124.3,
124.2, 121.4, 114.7, 54.5; HRMS (ESI) calcd for C15H13N2O2 (M +
H) 253.0972, found 253.0969.
General Procedure To Prepare Hydrazones (6). To a solution
of a hydrazine (5.5 mmol, 1.1 equiv) in 5 mL of MeOH was added an
aldehyde (5 mmol) slowly (liquid aldehyde was added dropwise, and
solid aldehyde was added in small portions). The mixture was stirred
at room temperature for 2 h. MeOH was evaporated in vacuo, and the
bromobenzaldehyde and 1.16 g of (2,4,6-trichlorophenyl)hydrazine to
1
afford 1.04 g of 6j (55%) as pale-white solid, mp 126−127 °C; H
NMR (400 MHz, CDCl3) δ 7.72 (s, 1 H), 7.62 (s, 1 H), 7.49 (s, 4 H),
7.35 (s, 2 H).
Hydrazone 6k. The general procedure was applied to 925 mg of 4-
bromobenzaldehyde and 840 mg of (4-nitrophenyl)hydrazine to afford
0.38 g of 6k (24%) as yellow solid, mp 210−211 °C (lit.48 138−139
°C); 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 9.1 Hz, 2 H), 8.07 (s,
1 H), 7.75 (s, 1 H), 7.60−7.50 (m, 4 H), 7.13 (d, J = 9.1 Hz, 2 H).
Hydrazone 6l′. This compound was prepared using N,N-
dibenzylhydrazine as a starting material. N,N-Dibenzylhydrazine was
obtained as the exclusive product while we were attempting to prepare
N-benzylhydrazine by the reaction of 855 mg of benzyl bromide (5
mmol) with 300 mg of hydrazine monohydrate (6 mmol) under
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literature conditions49 (we obtained 400 mg of N,N-dibenzylhydrazine,
75%). The general procedure was applied to 505 mg of 4-
bromobenzaldehyde (2.7 mmol, 1.5 equiv) and 400 mg of N,N-
dibenzylhydrazine (1.9 mmol) to afford 0.38 g of 6l′ (53%) as white
solid, mp 134 °C; H NMR (400 MHz, CDCl3) δ 7.41−7.24 (m, 14
H), 7.08 (s, 1 H), 4.53 (s, 4 H).
General Procedure To Prepare 1,3-Disubstituted Indazoles
(7) from N-Aryl/Alkylhydrazones (6). To an oven-dried seal tube
equipped with a stirrer bar was added 0.3 mmol of hydrazone 6,
followed by the aryne precursor (0.36 mmol, 1.2 equiv). CH3CN
(3 mL) was added, followed by KF (ca. 34−37 mg, 0.6 mmol, 2 equiv).
The tube was sealed and heated to 100 °C for 16 h. Upon completion,
the reaction mixture was cooled to room temperature, poured into
brine, and extracted with EtOAc. The combined extracts were dried
over MgSO4, filtered, and evaporated. The residue was purified by
column chromatography (petroleum ether/DCM) to afford the
indazoles 7.
NMR (300 MHz, CDCl3) δ 7.87−7.82 (m, 3 H), 7.81−7.74 (m, 2 H),
7.66 (dd, J = 7.6, 1.7 Hz, 1 H), 7.62−7.53 (m, 2 H), 7.52−7.43 (m, 2
H), 7.42−7.38 (m, 1 H), 7.37−7.34 (m, 1 H), 7.28 (ddd, J = 7.9, 6.9,
0.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 146.2, 140.0, 139.4,
133.8, 133.3, 132.4, 130.0, 129.4, 127.3, 127.1, 126.6, 123.9, 123.4,
122.8, 122.1, 121.6, 110.5; HRMS (ESI) calcd for C19H14BrN2 (M +
H) 349.0335, found 349.0335.
1
3-(2,6-Dichlorophenyl)-1-phenyl-1H-indazole (7g). The general
procedure was applied to 80 mg of 6f and 108 mg of 1a to afford 96
mg of 7g (94%) as orange oil; Rf = 0.35 (2:1 petroleum ether/DCM);
1H NMR (300 MHz, CDCl3) δ 7.88−7.85 (m, 3 H), 7.60−7.55 (m, 3
H), 7.53−7.46 (m, 3 H), 7.43−7.32 (m, 2 H), 7.31−7.24 (m, 1 H);
13C NMR (75 MHz, CDCl3) δ 142.3, 140.0, 139.3, 136.6, 130.9, 130.4,
129.4, 128.2, 127.3, 126.7, 124.2, 122.9, 121.8, 121.1, 110.7; HRMS
(ESI) calcd for C19H13Cl2N2 (M + H) 339.0450, found 339.0452.
1-Phenyl-3-(thiophen-2-yl)-1H-indazole (7h). The general proce-
dure was applied to 61 mg of 6g and 108 mg of 1a to afford 58 mg of
7h (70%) as slightly yellow oil; Rf = 0.36 (2:1 petroleum ether/DCM);
1H NMR (300 MHz, CDCl3) δ 8.13 (dt, J = 8.2, 0.9 Hz, 1 H), 7.85−
7.74 (m, 4 H), 7.61−7.53 (m, 2 H), 7.47 (ddd, J = 8.5, 5.1, 1.1 Hz, 1
H), 7.44−7.36 (m, 2 H), 7.32 (ddd, J = 7.9, 6.9, 0.8 Hz, 1 H), 7.23
(dd, J = 5.1, 3.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 141.0, 140.1,
139.8, 135.4, 129.4, 127.6, 127.3, 126.7, 125.4, 125.1, 122.9, 122.5,
122.1, 121.3, 110.7; HRMS (ESI) calcd for C17H13N2S (M + H)
277.0794, found 277.0787.
1-Phenyl-3-styryl-1H-indazole (7i). The general procedure was
applied to 67 mg of 6h and 108 mg of 1a to afford 57 mg of 7i (64%)
as slightly yellow oil; Rf = 0.51 (1:1 petroleum ether/DCM); 1H NMR
(300 MHz, CDCl3) δ 8.11 (d, J = 8.1 Hz, 1 H), 7.80−7.75 (m, 3 H),
7.68−7.63 (m, 3 H), 7.60−7.54 (m, 3 H), 7.50−7.39 (m, 4 H), 7.37−
7.30 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 144.2, 140.1, 139.9,
137.2, 131.6, 129.4, 128.7, 127.9, 127.2, 126.7, 126.6, 123.4, 122.9,
121.9, 121.1, 119.6, 110.7; HRMS (ESI) calcd for C21H17N2 (M + H)
297.1386, found 297.1383.
3-(4-Methoxyphenyl)-1-phenyl-1H-indazole (7a). The general
procedure was applied to 68 mg of 6a and 108 mg of 1a to afford
56 mg of 7a (62%) as white solid, mp 121−122 °C (lit.13 128−129
1
°C); Rf = 0.45 (1:1 petroleum ether/DCM); H NMR (300 MHz,
CDCl3) δ 8.07 (d, J = 8.2 Hz, 1 H), 8.04−7.98 (m, 2 H), 7.84−7.78
(m, 3 H), 7.59−7.54 (m, 2 H), 7.49−7.43 (m, 1 H), 7.40−7.35 (m, 1
H), 7.31−7.26 (m, 1 H), 7.11−7.08 (m, 2 H), 3.90 (s, 3 H); 13C NMR
(75 MHz, CDCl3) δ 159.7, 145.9, 140.2, 140.1, 129.4, 128.9, 127.0,
126.5, 125.8, 123.0, 122.8, 121.7, 121.6, 114.2, 110.6, 55.3; HRMS
(ESI) calcd for C20H17N2O (M + H) 301.1335, found 301.1335.
3-(4-Bromophenyl)-5,6-dimethoxy-1-phenyl-1H-indazole (7b).
The general procedure was applied to 83 mg of 6b and 129 mg of
1b to afford 110 mg of 7b (89%) as slightly yellow solid, mp 146−147
1
°C; Rf = 0.30 (1:1 petroleum ether/DCM); H NMR (300 MHz,
CDCl3) δ 7.85 (d, J = 8.4 Hz, 2 H), 7.75 (d, J = 7.8 Hz, 2 H), 7.64 (d,
J = 8.4 Hz, 2 H), 7.56 (t, J = 7.8 Hz, 2 H), 7.38 (t, J = 7.4 Hz, 1 H),
7.28 (s, 1 H), 7.12 (s, 1 H), 3.98 (s, 3 H), 3.96 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 151.0, 146.9, 144.2, 140.0, 135.9, 132.3, 131.8, 129.4,
128.8, 126.6, 122.7, 121.9, 115.7, 100.3, 92.0, 56.2, 56.0; HRMS (ESI)
calcd for C21H18BrN2O2 (M + H) 409.0546, found 409.0552.
3-(4-Bromophenyl)-1-(4-methoxyphenyl)-1H-indazole (7j). The
general procedure was applied to 92 mg of 6i and 108 mg of 1a to
afford 64 mg of 7j (56%) as slightly yellow solid, mp 169−170 °C; Rf
1
4-Methoxy-1,3-diphenyl-1H-indazole (7c). The general procedure
was applied to 59 mg of 6c and 119 mg of 1c to afford 70 mg of 7c
(78%) as yellow oil; Rf = 0.41 (1:1 petroleum ether/DCM); 1H NMR
(major isomer, 300 MHz, CDCl3) δ 8.03−8.00 (m, 2 H), 7.82−7.78
(m, 2 H), 7.58−7.36 (m, 8 H), 6.64−6.57 (m, 1 H), 3.92 (s, 3 H); 13C
NMR (major isomer, 75 MHz, CDCl3) δ 154.6, 146.7, 142.3, 140.1,
133.7, 129.8, 129.3, 128.4, 127.9, 127.7, 126.7, 123.3, 114.1, 103.2,
100.9, 55.4; HRMS (ESI) calcd for C20H17N2O (M + H) 301.1335,
found 301.1337. This compound has been accessed before by Moses,13
and the spectroscopic data are identical with the reported regioisomer.
3-(4-Bromophenyl)-1-phenyl-1H-indazole (7d). The general pro-
cedure was applied to 83 mg of 6b and 108 mg of 1a to afford 86 mg
of 7d (82%) as white solid, mp 155−156 °C (lit.13 154−157 °C); Rf =
= 0.41 (1:1 petroleum ether/DCM); H NMR (300 MHz, CDCl3) δ
8.03 (d, J = 8.2 Hz, 1 H), 7.96−7.89 (m, 2 H), 7.70−7.62 (m, 5 H),
7.44 (ddd, J = 1.0, 6.9, 8.0 Hz, 1 H), 7.29 (ddd, J = 0.8, 7.0, 8.0 Hz, 1
H), 7.12−7.03 (m, 2 H), 3.89 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
158.6, 144.3, 140.5, 133.0, 132.3, 131.9, 129.1, 127.0, 124.8, 122.4,
122.1, 121.9, 121.1, 114.6, 110.6, 55.6; HRMS (ESI) calcd for
C20H16BrN2O (M + H) 379.0441, found 379.0430.
3-(4-Bromophenyl)-1-(2,4,6-trichlorophenyl)-1H-indazole (7k).
The general procedure was applied to 114 mg of 6j and 108 mg of
1a to afford 98 mg of 7k (72%) as slightly yellow oil; Rf = 0.49 (2:1
petroleum ether/DCM); 1H NMR (300 MHz, CDCl3) δ 8.07 (dt, J =
8.6, 0.8 Hz, 1 H), 7.94−7.91 (m, 2 H), 7.67−7.65 (m, 2 H), 7.57 (s, 2
H), 7.47 (ddd, J = 8.1, 7.0, 1.0 Hz, 1 H), 7.33 (ddd, J = 8.0, 7.0, 0.9 Hz,
1 H), 7.13 (dt, J = 8.4, 0.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ
146.0, 142.0, 136.3, 136.2, 133.4, 132.0, 131.9, 129.2, 128.9, 127.6,
122.7, 122.3, 121.7, 121.3, 109.9; HRMS (ESI) calcd for
C19H11BrCl3N2 (M + H) 450.9166, found 450.9159.
1
0.45 (2:1 petroleum ether/DCM); H NMR (300 MHz, CDCl3) δ
8.04 (d, J = 8.2 Hz, 1 H), 7.97−7.91 (m, 2 H), 7.83−7.75 (m, 3 H),
7.71−7.64 (m, 2 H), 7.63−7.53 (m, 2 H), 7.47 (dt, J = 1.0, 6.9 Hz, 1
H), 7.40 (tt, J = 1.1, 7.4 Hz, 1 H), 7.31 (dt, J = 0.7, 7.1 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 144.8, 140.3, 139.9, 132.2, 131.9, 129.5,
129.1, 127.2, 126.8, 123.0, 122.8, 122.3, 122.1, 121.2, 110.8; HRMS
(ESI) calcd for C19H14BrN2 (M + H) 349.0335, found 349.0334.
4-(1-Phenyl-1H-indazol-3-yl)benzonitrile (7e). The general proce-
dure was applied to 67 mg of 6d and 108 mg of 1a to afford 71 mg of
7e (80%) as yellow solid, mp 141−142 °C; Rf = 0.33 (1:1 petroleum
1-Benzyl-3-(4-bromophenyl)-1H-indazole (7m). The general
procedure was applied to 87 mg of 6l′ (0.23 mmol), 108 mg of 1a
(0.36 mmol, 1.57 equiv), and 35 mg of KF (0.6 mmol, 2.6 equiv) to
afford 45 mg of 7m (54%) as slightly yellow solid, mp 78−79 °C; Rf =
1
0.49 (1:1 petroleum ether/DCM); H NMR (300 MHz, CDCl3) δ
8.01−7.97 (m, 1 H), 7.94−7.85 (m, 2 H), 7.67−7.61 (m, 2 H), 7.38−
7.37 (m, 2 H), 7.32−7.20 (m, 6 H), 5.66 (s, 2 H); 13C NMR (75
MHz, CDCl3) δ 143.0, 141.1, 136.7, 132.6, 131.9, 128.9, 128.7, 127.8,
127.1, 126.5, 121.9, 121.4, 121.1, 109.8, 53.0 (1 overlapped signal);
HRMS (ESI) calcd for C20H16BrN2 (M + H) 363.0491, found
363.0492.
General Procedure To Prepare Indazoles 7n−7q from in Situ
Prepared Hydrazones. To an oven-dried seal tube equipped with a
stirrer bar were added 0.3 mmol of hydrazine and CH3CN (1 mL). A
solution of an aliphatic aldehyde (0.36 mmol, 1.2 equiv) in CH3CN
(2 mL) was added dropwise. The mixture was stirred at room
1
ether/DCM); H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 8.5 Hz, 2
H), 8.06 (d, J = 8.2 Hz, 1 H), 8.81−7.77 (m, 5 H), 7.61−7.55 (m, 2
H), 7.49 (dt, J = 0.9, 6.9 Hz, 1 H), 7.43 (tt, J = 1.0, 7.4 Hz, 1 H), 7.34
(dt, J = 0.6, 7.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 143.6, 140.4,
139.6, 137.7, 132.5, 129.5, 127.8, 127.4, 127.2, 123.0, 122. 7, 122.6,
120.9, 118.9, 111.3, 111.0; HRMS (ESI) calcd for C20H14N3 (M + H)
296.1182, found 296.1182.
3-(2-Bromophenyl)-1-phenyl-1H-indazole (7f). The general pro-
cedure was applied to 83 mg of 6e and 108 mg of 1a to afford 90 mg
1
of 7f (86%) as orange oil; Rf = 0.35 (2:1 petroleum ether/DCM); H
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The Journal of Organic Chemistry
Article
temperature for 5 min before being charged with the aryne precursor
1a (88 μL, 0.36 mmol, 1.2 equiv) and KF (ca. 34−37 mg, 0.6 mmol, 2
equiv). The tube was sealed and heated to 100 °C for 16 h. Upon
completion, the reaction mixture was cooled to room temperature,
poured into brine, and extracted with EtOAc. The combined extracts
were dried over MgSO4, filtered, and evaporated. The residue was
purified by column chromatography (petroleum ether/DCM) to
afford the indazole.
C.W.). We thank Mr. Lei Liu, Prof. Shrong-Shi Lin, Dr. Jiang
Zhou (all of Peking University), Mr. Huaiqiu Wang, Mr.
Weining Zhao, Prof. Zheng Duan (all of Zhengzhou
University), and Mr. Yong Wang and Dr. Li Yu (both of
Henan University) for their help in the spectroscopic analysis.
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■
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petroleum ether/DCM); H NMR (300 MHz, CDCl3) δ 7.97 (d, J =
8.2 Hz, 1 H), 7.76−7.74 (m, 3 H), 7.57−7.48 (m, 2 H), 7.40 (ddd, J =
8.2, 7.0, 0.9 Hz, 1 H), 7.32 (tt, J = 7.4, 1.0 Hz, 1 H), 7.23−7.15 (m, 1
H), 1.62 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 155.0, 140.4, 140.3,
129.3, 126.4, 126.0, 122.8, 122.7, 122.5, 120.3, 110.5, 33.9, 30.0;
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(2,4,6-trichlorophenyl)hydrazine to afford 34 mg of 7o (32%) as
slightly yellow solid, mp 133−134 °C; Rf = 0.26 (2:1 petroleum ether/
DCM); 1H NMR (300 MHz, CDCl3) δ 7.98 (dt, J = 8.2, 0.9 Hz, 1 H),
7.52 (s, 2 H), 7.37 (ddd, J = 8.2, 7.0, 1.0 Hz, 1 H), 7.20 (ddd, J = 8.0,
7.0, 0.9 Hz, 1 H), 7.03 (dt, J = 8.4, 0.8 Hz, 1 H), 1.59 (s, 9 H); 13C
NMR (75 MHz, CDCl3) δ 156.1, 141.9, 136.6, 135.6, 133.9, 128.9,
126.6, 122.5, 121.6, 120.5, 109.7, 34.0, 30.0; HRMS (ESI) calcd for
C17H16Cl3N2 (M + H) 353.03736, found 353.03658.
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general procedure was applied to 41 mg of cyclohexanecarbaldehyde
and 64 mg of (2,4,6-trichlorophenyl)hydrazine to afford 46 mg of 7p
(40%) as yellow oil; Rf = 0.23 (2:1 petroleum ether/DCM); 1H NMR
(400 MHz, CDCl3) δ 7.85 (d, J = 8.1 Hz, 1 H), 7.52 (s, 2 H), 7.39−
7.36 (m, 1 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 3.15
(tt, J = 11.8, 3.4 Hz, 1 H), 2.17−2.14 (m, 2 H), 1.93−1.89 (m, 2 H),
1.83−1.79 (m, 2 H), 1.54−1.32 (m, 4 H); 13C NMR (100 MHz,
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120.7, 109.5, 37.6, 32.5, 26.6, 26.2; HRMS (ESI) calcd for
C19H18Cl3N2 (M + H) 379.0530, found 379.0522.
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1
colorless oil; Rf = 0.43 (1:1 petroleum ether/DCM); H NMR (300
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(m, 1 H), 7.29−7.18 (m, 6 H), 7.04 (d, J = 8.4 Hz, 1 H), 3.43−3.33
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full 1H and 13C NMR spectra of the final products 3, 4, 5, and
7, including the NOESY spectrum for compound 3c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cwu@henu.edu.cn; fshi@henu.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project is financially supported by the National Natural
Science Foundation of China (No. 21002021 to F.S.), the Key
Project of the Chinese Ministry of Education (No. 210127 to
F.S.), and start-up funds from Henan University (to F.S. and
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