Direct Formation of 2-Substituted 2 H-Indazoles by a Pd-Catalyzed Reaction between 2-Halobenzyl Halides and Arylhydrazines

Article abstract of DOI:10.1021/acs.joc.0c01923

A direct and operationally simple method for the regioselective synthesis of 2-aryl-substituted 2H-indazoles is reported. The Pd-catalyzed reaction between easily available 2-bromobenzyl bromides and arylhydrazines employing Cs2CO3 as the base and t-Bu3PHBF4 as the ligand in DMSO at 120 °C in a sealed tube delivers the 2-substituted-2H-indazoles in a single synthetic step with yields up to 79%. The new method is based on a regioselective intermolecular N-benzylation followed by intramolecular N-arylation and oxidation.

Full text of DOI:10.1021/acs.joc.0c01923

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Direct Formation of 2‑Substituted 2H‑Indazoles by a Pd-Catalyzed
Reaction between 2‑Halobenzyl Halides and Arylhydrazines
̈
Nayyef Aljaar, Mousa Al-Noaimi, Jurgen Conrad, and Uwe Beifuss*
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ABSTRACT: A direct and operationally simple method for the regioselective
synthesis of 2-aryl-substituted 2H-indazoles is reported. The Pd-catalyzed
reaction between easily available 2-bromobenzyl bromides and arylhydrazines
employing Cs2CO3 as the base and t-Bu3PHBF4 as the ligand in DMSO at 120
°C in a sealed tube delivers the 2-substituted-2H-indazoles in a single synthetic
step with yields up to 79%. The new method is based on a regioselective
intermolecular N-benzylation followed by intramolecular N-arylation and
oxidation.
dehydes with primary amines and sodium azides.26 A closer
inspection reveals that some of these methods suffer from
certain drawbacks, such as the use of difficult accessible
substrates and catalysts, the need for an excess of reagents, or
poor atom economy. A number of methods mentioned have
the disadvantage that only one bond is formed during the key
step. This is why there is still a great need to develop simple to
perform and direct methods for the synthesis of 2H-indazoles
starting from readily available substrates.
During the last few years, we have contributed to the
synthesis of a number of carbo and heterocycles by developing
reactions between 2-halobenzyl halides/tosylates and bisnu-
cleophiles.27 In continuation of our work, we wondered
whether it is possible to synthesize 2-aryl-2H-indazoles 3 in a
regioselective manner in one step by direct reaction of easily
available 2-bromobenzyl bromides 1 and arylhydrazines 2
(Scheme 2). It was envisaged that the reaction starts with the
selective formation of a 1-o-bromobenzyl-1-arylhydrazine 4 by
regioselective N-benzylation, which in turn undergoes an
intramolecular N-arylation to 5. This is followed by oxidation
to finally yield the 2-aryl-2H-indazole 3. Of course, the main
challenge of this approach is to achieve the completely
regioselective formation of the 1-o-bromobenzyl-1-arylhydra-
zines 4 and to exclude the formation of the corresponding 1-o-
bromobenzyl-2-arylhydrazines 6, which would result in the
formation of the 1-aryl-1H-indazoles 7.
INTRODUCTION
■
Heterocycles play a very important role in organic synthesis
because they occur in countless natural products and other
biologically active compounds. 1H- and 2H-indazoles are
common heterocyclic motifs with interesting biological
properties.1 Typical examples include antiaggregation,1b
antihypertensive,2 HIV protease inhibiting,3 antitumor,4
antidepressant,5 anti-inflammatory and analgesic,6 antimicro-
bial,7 and antifungal8 activities. 2H-indazoles are known for
their wide range of pharmacological activities. They can act as
vascular endothelial growth factor receptor inhibitors (Pazo-
panib),9 poly(ADP-ribose)polymerase inhibitors (Nirapar-
ib),10 viral polymerase inhibitors,11 glucokinase activators,12
anti-inflammatory drugs,13 antinociceptives,14 antimicrobials,15
estrogen receptor β agonists,16 and farnesoid X receptor
antagonists.17 Because of the great importance of 1H-
indazoles, many routes for their preparation have been
established. In contrast to the synthesis of the thermodynami-
cally more stable 1H-indazoles, only a few methods have been
developed for the synthesis of 2H-indazoles. The most obvious
method, the direct synthesis by arylation/alkylation is not
suitable because usually mixtures of substituted 1H-indazoles
and 2H-indazoles are obtained. Among the selective methods
for 1H-indazoles are the Pd-catalyzed intramolecular amination
of 1-o-bromobenzyl-1-phenylhydrazines,18 the reductive cycli-
zation of 2-nitrobenzylamines with TiCl4/Zn,19 the reductive
cyclization of o-nitrobenzylidene amines,20 and the Fe-
catalyzed N-N bond formation of 2-azidophenylketoximes
(Scheme 1).21 Other examples include the Pd-catalyzed
domino reaction of 2-halophenylacetylenes with hydrazines,22
the reaction between 2-chloromethylarylzinc reagents and
aryldiazonium salts,23 the [3 + 2] cycloaddition of arynes and
sydnones,24 and the Co(III)-catalyzed C-H addition of
azobenzenes to aldehydes25a as well as the Rh(III)-catalyzed
C-H addition of azobenzenes to ethyl glyoxalate and aryl
glyoxals25b and the Cu-catalyzed reaction of 2-bromobenzal-
Song and Yee have circumvented this problem by perform-
ing the synthesis of the 2-aryl-2H-indazoles 3 in two separate
Received: August 9, 2020
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© XXXX American Chemical Society
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approach, a number of 1-o-bromobenzyl-1-arylhydrazines 4
have been synthesized and cyclized to the corresponding 2-
aryl-2H-indazoles 3 by Song and Yee. Without doubt, it would
be a considerable improvement if the isolation and chromato-
graphic purification of the 1-o-bromobenzyl-1-arylhydrazines 4
could be avoided. Here, we report on a method for the
synthesis of 2-aryl-2H-indazoles 3 that makes the isolation and
purification of the 1-o-bromobenzyl-1-arylhydrazines 4 super-
fluous. This makes the synthesis of the 2-aryl-2H-indazoles 3
from 2-bromobenzyl bromides 1 and arylhydrazines 2 more
efficient, and we will demonstrate that the yields are much
higher than those obtained by a two-step method.
Scheme 1. Different Approaches for the Synthesis of 2H-
Indazoles
RESULTS AND DISCUSSION
■
As a model reaction for our study, the reaction between 2-
bromobenzyl bromide (1a) and phenylhydrazine (2a) was
chosen. When 1 equiv 1a and 2.5 equiv 2a were reacted in the
presence of 10 mol % PdCl2, 10 mol % t-Bu3PHBF4, and 2
equiv Cs2CO3 in DMF in a sealed tube at 100 °C for 16 h, 2-
phenyl-2H-indazole (3a) could be isolated in only 12% along
with 5% of the undesired isomeric 1-phenyl-1H-indazole (7a)
(Table 1, entry 1). The yield of 3a could be slightly increased
by changing reaction time and temperature (Table 1, entries
2−7). The best result was achieved under the conditions of
Table 1, entry 5 with a yield of 31% for 3a and only traces of
7a.
To facilitate the reaction between 1a and 2a, the
transformations were run in a microwave oven at different
temperatures (Table 1, entries 8−12). Increasing the temper-
ature from 120 to 150 °C leads to a slight increase of the yield
of 3a from 31 to 35% (Table 1, entries 8−11). However, when
the reaction temperature was raised to 160 °C, the yield of 3a
dropped to 29% (Table 1, entry 12).
Then, the influence of solvents on the outcome of the model
reaction was examined (Table 1, entries 13−19). The
experiments clearly demonstrated that the reaction can not
only be performed in polar solvents (Table 1, entries 13, 14,
16, 17, and 19) but also in nonpolar solvents such as dioxane
and toluene (Table 1, entries 15 and 18). The best yields of 3a
were obtained with DMSO and H2O as solvents (Table 1,
entries 13 and 17).
synthetic steps.18 In the first step, the 1-o-bromobenzyl-1-
arylhydrazines 4 were synthesized and isolated in yields
between 60 and 70% by reaction of 2-bromobenzyl bromides
1 with the hydrochlorides of the arylhydrazines 2 under
strongly basic conditions (NaHMDS) based on the method of
28
̈
Lerch und Konig. In the second step, the so-formed 1-o-
bromobenzyl-1-arylhydrazines 4 were cyclized in a Pd-
catalyzed reaction to yield the corresponding 2-aryl-2H-
indazoles 3 in yields between 51 and 60%. Using this
After some experimentation, it was found that the yield of 3a
as well as the 3a: 7a ratio could be considerably improved
Scheme 2. Proposed Method for the Direct Synthesis of 2-Substituted-2H-Indazoles (3)
B
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Table 1. Initial Experiments and Optimization of the Reaction Conditions for the Selective Formation of 2-Phenyl-2H-
Indazole (3a)
entry
T (°C)
t
solvent
yield 3a (%)
yield 7a (%)
a
1
100
100
110
110
120
130
130
120
140
150
150
160
120
120
120
110
110
120
120
16 h
5 h
20 h
5 h
4 h
5 h
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
dioxane
CH3CN
H2O
12
18
21
28
31
26
15
31
30
34
35
29
33
31
18
21
34
15
23
5
6
a
2
a
3
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
2
10
8
11
trace
trace
11
a
4
a
5
a
6
a
7
4 h
b
8
10 min
10 min
10 min
15 min
10
4 h
4 h
4 h
4 h
b
9
b
10
11
12
13
14
15
16
17
b
b
a
a
a
a
a
4 h
4 h
4 h
a
18
19
toluene
DMF
c
a
b
1 Equiv 1a and 2.5 equiv 2a were heated in a sealed tube using an oil bath. 1 Equiv 1a and 2.5 equiv 2a were reacted in a sealed tube under
c
microwave conditions (50 W and 5 bar). 1 Equiv 1a and 2.5 equiv 2a were heated in a Schlenk tube.
a
Table 2. Influence of Mixed Solvents on the Outcome of the Model Reaction between 1a and 2a
entry
solvent 1
DMF
H2O
H2O
H2O
DMSO
DMSO/H2O
DMSO
solvent 2
DMF
DMF
DMSO
H2O
DMSO
DMSO/H2O
DMSO
yield 3a (%)
yield 7a (%)
b
1
45
27
52
40
57
53
50
4
1
3
2
2
11
7
b
2
b
3
b
4
b
5
b
6
c
7
a
In all cases, 1 equiv 1a was reacted with 2.5 equiv 2a. A solution of 1a, 2a, and Cs2CO3 in solvent 1 (solution A) and a solution of PdCl2, t-
b
Bu3PHBF4, and Cs2CO3 in solvent 2 (solution B) were prepared, and after 3 h at room temperature (rt), the two solutions were combined. The
reaction mixture was heated for 4 h in a sealed tube at 120 °C using an oil bath. The reaction was performed in a microwave oven (50 W) at 150
°C for 10 min.
c
using a different experimental approach (Table 2). We
prepared solutions of (a) reactants 1a, 2a, and Cs2CO3 in
solvent 1 (solution A) and (b) catalyst, ligand, and Cs2CO3 in
solvent 2 (solution B). Then, the two solutions A and B were
combined and reacted at 120 °C for 4 h. Using this approach,
the yield of 3a could be improved to 57% (Table 2, entry 5)
when DMSO was used as the solvent in both solutions A and
B. At least as important was the observation that under these
conditions the formation of 7a could be almost completely
suppressed (only 2% of the isomer 7a was formed).
For further optimization, the reaction between 1a and 2a
was conducted with different Pd catalysts, ligands, and bases
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(Table 3). It was found that the reaction can be run with 10
mol % of several Pd catalysts (Table 3, entries 1−3). However,
Table 4. Influence of the Molar Ratio 1a: 2a and the
Amounts of Catalyst and Ligands as well as the Reaction
a
Time on the Outcome of the Model Reaction
Table 3. Influence of Catalysts, Ligands, and Bases on the
a
Outcome of the Reaction 1a + 2a → 3a
molar
PdCl2
t-Bu3PHBF4
(mol %)
t
yield 3a yield 7a
entry ratio1a: 2a (mol %)
(h)
(%)
(%)
1
2
3
4
5
6
7
8
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:1
5
10
10
5
4
4
4
4
13
18
22
42
18
18
18
49
54
44
54
60
64
61
46
53
60
63
2
5
3
8
entry
catalyst
ligand
base
yield 3 (%) yield 7a (%)
15
10
10
10
10
10
10
10
10
10
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd2(dba)3
Pd(acac)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
t-Bu3PHBF4
t-Bu3PHBF4
t-Bu3PHBF4
PPh3
dppf
DIPHOS
t-Bu3PHBF4
t-Bu3PHBF4
t-Bu3PHBF4
t-Bu3PHBF4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
K2CO3
KOtBu
Cs2CO3
Cs2CO3
42
51
46
5
26
4
38
27
10
3
3
6
trace
5
15
10
10
10
10
10
10
10
< 1%
trace
3
9
10
11
4
1:2
1:3
9
trace
10
11
12
a
A solution of 1a, 2a, and Cs2CO3 in DMSO (solution A) and a
PdCl2
PdCl2
solution of PdCl2, t-Bu3PHBF4, and Cs2CO3 in DMSO (solution B)
were prepared. After 3 h at rt, the two solutions were combined, and
the reaction mixture was heated in a sealed tube at 120 °C using an oil
bath.
t-Bu3PHBF4
a
In all cases, 1 equiv 1a was reacted with 2.5 equiv 2a. A solution of
1a, 2a, and base in DMSO (solution A) and a solution of the catalyst,
ligand, and base in DMSO (solution B) were prepared. After 3 h at rt,
the two solutions were combined, and the reaction mixture was
heated for 4 h in a sealed tube at 120 °C using an oil bath.
Of course, we have also studied whether 2-bromobenzyl
bromide (1a) can be replaced with other 2-halobenzyl
bromides (Table 5). The experiments revealed that 1a can
easily be replaced by 2-iodobenzyl bromide (8a). 2-
Chlorobenzyl bromide (8b) can also be used as a substrate
for the Pd-catalyzed indazole synthesis. However, the yield of
3a was much lower (Table 5, entry 2). Because the yields with
2-bromobenzyl bromide (1a) and 2-iodobenzyl bromide (8a)
were comparable, all further reactions were conducted with 2-
bromobenzyl bromides 1 as substrates.
With optimized reaction conditions in hand, we focused on
the scope and limitations of the new method for the synthesis
of 2-aryl-2H-indazoles 3. For this purpose, selected 2-
bromobenzyl bromides 1 were reacted with several arylhy-
drazines 2 under the conditions given in Table 4, entry 6. First,
the substituted 2-bromobenzyl bromides 1b−e were reacted
with the unsubstituted 2a. In all cases, the 2-phenyl-2H-
indazoles 3b−e were formed exclusively with yields up to 76%
(Table 6, entries 2−5). Then, it was clearly demonstrated that
not only substituted 2-bromobenzyl bromides 1 but also a
considerable number of substituted arylhydrazines 2b−l,
including alkyl-, halogen-, and methoxy-substituted ones can
be employed as substrates for the selective preparation of 2-
aryl-2H-indazoles 3 (Table 6, entries 6−16). The yields were
in the range between 50 and 79%. Some preliminary
experiments with methylhydrazine and tert.-butyl hydrazine
as substrates did not yield the corresponding 2-alkyl-2H-
indazoles.
the yields were lower than those with PdCl2. The replacement
of t-Bu3PHBF4 with other ligands was also not met with
success (Table 3, entries 4−6). Furthermore, the replacement
of Cs2CO3 with other bases did not pay off (Table 3, entries
7−9). At this stage, we also took the opportunity to perform
some control experiments. For this purpose, the reaction
between 1a and 2a was conducted in the absence of a Pd
catalyst (Table 3, entry 10), a ligand (Table 3, entry 11), and a
base (Table 3, entry 12). In none of these control experiments,
the formation of 2-phenyl-2H-indazole (3a) could be observed.
Finally, the reaction was performed with different molar
ratios 1a: 2a, different amounts of PdCl2 and t-Bu3PHBF4, and
different reaction times (Table 4). With a molar ratio 1a: 2a =
1:2.5, 10 mol % PdCl2, 10 mol % t-Bu3PHBF4, and a reaction
time of 13 h, the yield of 3a could be raised to 60%, and the
formation of 7a could be almost suppressed (Table 4, entry 5).
An increase of the reaction time from 13 to 18 h delivered the
best result: Under these conditions, 3a could be isolated in
64%, and the side product formation could be effectively
suppressed (Table 4, entry 6). A further increase of the
reaction time from 18 to 22 h and 42 h, respectively, did not
pay off (Table 4, entries 7 and 8). Finally, the influence of the
molar ratio 1a: 2a was examined. It was found that the
exclusive formation of 3a could also be achieved when different
molar ratios 1a: 2a, such as 1:1, 1:2, and 1:3, were used (Table
4, entries 9−11). However, in no case, the yield of 3a exceeded
64%. In summary, the highest yield of 3a could be achieved
under the conditions presented in Table 4, entry 6.
With respect to the reaction mechanism, it is assumed that
the formation of 2-aryl-2H-indazole 3 proceeds by a domino
intermolecular N-benzylation/intramolecular N-arylation/oxi-
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a
Table 5. Reactions of Different 2-Halobenzyl Bromides 8 with Phenylhydrazine (2a)
entry
8
hal
yield 3a (%)
1
2
a
b
I
Cl
66
34
a
In all cases, 1 equiv 8 was reacted with 2.5 equiv 2a. A solution of 8, 2a, and Cs2CO3 in DMSO (solution A) and a solution of PdCl2, t-Bu3PHBF4,
and Cs2CO3 in DMSO (solution B) were prepared. After 3 h at rt, the two solutions were combined, and the reaction mixture was heated for 16 h
in a sealed tube at 120 °C using an oil bath.
dation reaction between a 2-bromobenzyl bromide 1 and an
arylhydrazine 2 (Scheme 3). The reaction starts with an
intermolecular N-benzylation of an arylhydrazine 2 with a 2-
bromobenzyl bromide 1, which proceeds completely regiose-
lective and produces exclusively the 1-o-bromobenzyl-1-
arylhydrazines 4. In the next step, the so-formed 1-o-
bromobenzyl-1-arylhydrazine 4 undergoes a Pd-catalyzed
intramolecular Buchwald−Hartwig N-arylation, which starts
with the oxidative addition of the C-Br bond of 4 to the Pd(0)
species by which the intermediate A is generated. A then
undergoes intramolecular nucleophilic attack by the terminal
amino group of the hydrazine, which is accompanied by
elimination of HBr and gives the six-membered palladacycle B.
Reductive elimination yields the dihydroindazole 5, which
undergoes spontaneous oxidation to the corresponding 2-aryl-
2H-indazole 3. It is assumed that the oxidation takes place
during product isolation with aerial oxygen as the terminal
oxidant.29 To support this mechanism, the proposed
intermediate, that is, 1-o-bromobenzyl-1-phenylhydrazine
(4a)18 was prepared according to Song and Yee in 53%
yield. Subsequently, 4a was cyclized under our reaction
conditions elaborated for the intramolecular N-arylation (1.5
equiv Cs2CO3, 10 mol % PdCl2, and 10 mol % t-Bu3PHBF4 in
DMSO at 120 °C for 18 h). Under these conditions, the
indazole 3a was formed with 72% yield. The outcome of this
control experiment strongly suggests that 4a is an intermediate
for the formation of indazole 3a. The outcome of the two
experiments also verifies that the total yield of 4a using a two-
step method amounts to only 38% and is therefore significantly
lower than the yield obtained employing the procedure
presented in this contribution (64%) (Table 6, entry 1).
To exclude a subsequent conversion of a 1-substituted 1H-
indazole 7 in a 2-substituted 2H-indazole 3, it was decided to
address the stability of the 1-aryl-1H-indazoles 7 under our
standard reaction conditions (Scheme 4). For this purpose, 1-
phenyl-1H-indazole (7a) was prepared in 75% yield by
reaction of phenylhydrazine (2a) with 2-bromobenzaldehyde
(9) according to the procedure of Cho and Shim.30 The 1-
phenyl-1H-indazole (7a) obtained was then mixed with 1.5
equiv Cs2CO3, 10 mol % PdCl2, and 10 mol % t-Bu3PHBF4 in
DMSO. After heating at 120 °C for 16 h in a sealed vial, work
up, and purification, the starting material 7a was recovered in
98% yield. This experiment clearly demonstrates that 7a is
stable under reaction conditions.
Because it is known that many Pd-catalyzed N-arylations can
also be performed under Cu-catalyzed reaction conditions, we
have tried to establish a Cu(I)-catalyzed method for the
formation of 2-substituted 2H-indazoles 3 using 2-bromoben-
zyl bromides 1 and arylhydrazines 2 as substrates. However, all
experiments between 2-bromobenzyl bromide (1a) and
phenylhydrazine (2a) in the presence of a Cu catalyst revealed
that instead of the expected 2-phenyl-2H-indazole (3a) the
noncyclized 1-o-bromobenzyl-1-phenylhydrazine (4a) was
formed as the major product. For example, when 1a and 2a
were reacted in the presence of 2 equiv Cs2CO3 and 10 mol %
CuI in water at 110 °C using an oil bath, only 9% of 3a and
58% of 4a were isolated (Scheme 5). Unfortunately, it was not
possible to increase the yield of 3a by variation of the Cu
catalysts, bases, solvents, and reaction conditions.
The structures of all compounds were unambiguously
1
elucidated by H and 13C NMR spectroscopy as well as mass
spectrometry.
CONCLUSIONS
■
In conclusion, we have developed an operational simple and
efficient method for the regioselective synthesis of 2-
substituted-2H-indazoles 3 relying on simple starting materials.
The 2-substituted-2H-indazoles 3 can be prepared in a single
preparative step between 2-bromobenzyl bromides 1 and
arylhydrazines 2. No traces of the 1-substituted-1H-indazoles 7
are formed. The selective preparation of 2-substituted-2H-
indazoles 3 is based on a regioselective intermolecular N-
benzylation followed by a Pd-catalyzed intramolecular N-
arylation and a final oxidation. Best results were achieved when
1 equiv of a 2-bromobenzyl bromide 1 and 2.5 equiv of an
arylhydrazine 2 were reacted with 2.5 equiv Cs2CO3, 10 mol %
PdCl2, and 10 mol % t-Bu3PHBF4 in DMF at 120 °C for 18 h.
Using this protocol, a range of substituted 2H-indazoles 3 was
made available in yields up to 79%. The advantage of our
method is that the completely regioselective intermolecular N-
benzylation of the arylhydrazines 2 with the 2-bromobenzyl
bromides 1 to the corresponding 1-o-bromobenzyl-1-arylhy-
drazines 4 can be linked with their Pd(0)-catalyzed intra-
molecular cyclization and the final oxidation to the 2-aryl-2H-
indazoles 3. This is why our method does not require the
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a
Table 6. Reaction of Different 2-Bromobenzyl Bromides 1 with Different Hydrazines 2
a
In all cases, 1 equiv 1 was reacted with 2.5 equiv 2. A solution of 1, 2, and Cs2CO3 in DMSO (solution A) and a solution of PdCl2, t-Bu3PHBF4,
and Cs2CO3 in DMSO (solution B) were prepared. After 3 h at rt, the two solutions were combined, and the reaction mixture was heated for 18 h
in a sealed tube at 120 °C using an oil bath.
agents prior to use. Solvents used for extraction and purification were
distilled prior to use. Reaction temperatures are reported as bath
temperatures. Thin-layer chromatography (TLC) was performed on
TLC silica gel 60 F254. Compounds were visualized with UV light (λ
= 254 nm) and/or by immersion in an ethanolic vanillin solution or
by immersion in KMnO4 solution followed by heating. Products were
purified by flash chromatography on silica gel, 0.04−0.063 mm.
Melting points were obtained on a melting point apparatus with open
capillary tubes and are uncorrected. Infrared spectra were recorded on
isolation and purification of the 1-o-bromobenzyl-1-arylhy-
drazines 4. As a result, the yields of the 2-aryl-2H-indazoles 3
are much better than those obtained by traditional two-step
methods.
EXPERIMENTAL SECTION
■
General Remarks. All commercially available reagents were used
without further purification. Glassware was dried overnight at 140 °C.
Solvents used in reactions were distilled over appropriate drying
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Scheme 3. Plausible Mechanism for the Formation of 2-Substituted-2H-Indazoles
under argon, and the reaction mixture was heated under the
conditions given in Table 1. After cooling to rt, the reaction mixture
was partitioned between EtOAc (20 mL) and sat. NH4Cl (20 mL).
The organic layer was isolated, and the aqueous layer was extracted
with EtOAc (3 × 20 mL). The combined organic layers were dried
over anhydrous MgSO4 and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel (cyclohexane/
EtOAc = 10:1) to yield 3a.
Scheme 4. Synthesis of 1-Phenyl-1H-indazole (7a) and
Treatment under Standard Reaction Conditions
General Procedure for the Preparation of Compounds 3a−
p. A dry vial was charged with Cs2CO3 (326 mg, 1 mmol), a 2-
bromobenzyl bromide 1 (1 mmol), and an arylhydrazine 2 (2.5
mmol) under argon. The vial was sealed, dry DMSO (1.5 mL) was
added under argon, and the mixture was stirred at rt for 3 h (solution
A). Another dry vial was charged with Cs2CO3 (488 mg, 1.5 mmol),
PdCl2 (18 mg, 0.1 mmol), and t-Bu3PHBF4 (29 mg, 0.1 mmol) under
argon. The vial was sealed, dry DMSO (1.5 mL) was added under
argon, and the mixture was stirred at rt for 3 h (solution B). Solution
A was added to solution B, and the resulting reaction mixture was
stirred at 120 °C using an oil bath for 18 h under argon. After cooling
to rt, the reaction mixture was partitioned between EtOAc (20 mL)
and sat. NH4Cl (20 mL). The organic layer was isolated, and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried over anhydrous MgSO4 and concentrated
under vacuum. The residue was purified by flash chromatography on
silica gel (cyclohexane/EtOAc = 10:1) to yield 3.
a Fourier transform infrared spectrometer. UV spectra were recorded
1
with a spectrophotometer. H (13C) NMR spectra were recorded at
300, (75), 500 (125), and 600 (150) MHz using CDCl3 as the
1
solvent. The H and 13C chemical shifts were referenced to residual
solvent signals at δ 7.26 H/77.0 C relative to TMS as the internal
standard. HSQC-, HMBC-, NOESY-, ROESY-, HSQMBC-, and
COSY spectra were recorded on a NMR spectrometer at 500 MHz.
Coupling constants J [Hz] were directly taken from the spectra and
are not averaged. Splitting patterns are designated as s (singlet), d
(doublet), t (triplet), q (quartet), quin (quintet), m (multiplet), and
br (broad). 1D and 2D homonuclear NMR spectra were measured
with standard pulse sequences. Low-resolution electron impact mass
spectra (MS) were obtained at 70 eV using a double-focusing sector
field mass spectrometer. Intensities are reported as percentages
relative to the base peak (I = 100%).
Procedure for the Preparation of Compound 3a. A dry vial was
flushed with argon and charged with Cs2CO3 (651 mg, 2 mmol), 2-
bromobenzyl bromide (1a) (250 mg, 1 mmol), phenylhydrazine (2a)
(270 mg, 2.5 mmol), PdCl2 (18 mg, 0.1 mmol), and t-Bu3PHBF4 (29
mg, 0.1 mmol). The vial was sealed, the solvent (1.5 mL) was added
2-Phenyl-2H-indazole (3a).18 According to the general procedure,
product 3a was isolated as a white solid in 64% yield (124 mg, 0.64
mmol): mp 81−82 °C (lit.18 mp 80−81.6 °C); Rf = 0.47 (PE/EtOAc
= 4:1; 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, 1H), 7.91 (dd, 2H, J =
7.5, 1.3 Hz), 7.80 (d, 1H, J = 8.2 Hz), 7.71 (d, 1H, J = 8.5 Hz), 7.48−
7.57 (m, 2H), 7.40 (ddd, 1H, J = 7.5, 7.4, 1.1 Hz), 7.33 (ddd, 1H, J =
7.6, 7.6, 1.0 Hz), 7.11 (ddd, 1H, J = 7.7, 7.6, 1.0 Hz); 13C{1H} NMR
(CDCl3, 125 MHz) δ 149.8, 140.5, 129.5, 127.9, 126.8, 122.7, 122.4,
121.0, 120.40, 120.37, 117.9; MS (EI, 70 eV) m/z 194 [M+], 180,
165, 152, 139.
Scheme 5. Reaction between 1a and 2a under Cu-Catalyzed Conditions
G
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Article
5-Methoxy-2-phenyl-2H-indazole (3b).18 According to the
general procedure, product 3b was isolated as a white solid in 76%
yield (170 mg, 0.76 mmol): mp 144−145 °C (lit.18 mp 143.1−143.9
yield (166 mg, 0.75 mmol): mp 118−119 °C; (lit.32 mp 117−119
1
°C); Rf = 0.47 (cyclohexane/EtOAc = 6:1); H NMR (CDCl3, 600
MHz) δ 8.38 (s, 1H), 7.79 (dd, 1H, J = 8.6, 1.1 Hz), 7.72 (d, 1H, J =
2.0 Hz), 7.70 (t-like, 1H, J = 8.5 Hz), 7.58 (dd, 1H, J = 8.1, 2.4 Hz),
7.32 (ddd, 1H, J = 7.8, 7.5, 2.1 Hz), 7.27 (d, 1H, J = 8.0 Hz), 7.11
(ddd, 1H, J = 7.7, 7.5, 2.1 Hz), 2.37 (s, 3H), 2.33 (s, 3H); 13C{1H}
NMR (CDCl3, 150 MHz) δ 149.6, 138.5, 138.1, 136.6, 130.5, 126.6,
122.6, 122.23, 122.19, 120.31, 120.29, 118.1, 117.8, 19.9, 19.4; MS
(EI, 70 eV) m/z 222 [M+], 207, 180.
1
°C); Rf = 0.41 (cyclohexane/EtOAc = 6:1); H NMR (CDCl3, 600
MHz) δ 8.28 (d, 1H, J = 2.3 Hz), 7.85−7.89 (m, 2H), 7.69 (t-like,
1H, J = 9.4 Hz), 7.49−7.54 (m, 2H), 7.37 (t-like, 1H, J = 7.4 Hz),
7.03 (dd, 1H, J = 9.2, 2.3 Hz), 6.90 (d, 1H, J = 2.3 Hz), 3.86 (s, 3H);
13C{1H} NMR (CDCl3, 150 MHz) δ 155.5, 146.8, 140.6, 129.5,
127.5, 122.8, 122.0, 120.6, 119.33, 119.25, 96.2, 55.3; MS (EI, 70 eV)
m/z 224 [M+], 209, 181, 147, 121.
2-(4-Isopropylphenyl)-2H-indazole (3j).35 According to the
general procedure, product 3j was isolated as a white solid in 71%
yield (167 mg, 0.71 mmol): mp 88−89 °C; Rf = 0.43 (cyclohexane/
2-Phenyl-2H-[1,3]dioxolo[4,5-f]indazole (3c).31 According to the
general procedure, product 3c was isolated as a white solid in 70%
yield (166 mg, 0.70 mmol): mp 174−175 °C (lit.31 mp 174−176 °C);
Rf = 0.53 (PE/EtOAc = 4:1); 1H NMR (CDCl3, 600 MHz) δ 8.19 (s,
1H), 7.82 (t-like, 2H, J = 8.1 Hz), 7.49 (t-like, 2H, J = 7.9 Hz), 7.34
(t-like, 1H, J = 7.5 Hz), 7.04 (s, 1H), 6.90 (s, 1H), 5.98 (s, 2H);
13C{1H} NMR (CDCl3, 150 MHz) δ 149.8, 147.3, 146.1, 140.4,
129.5, 127.2, 120.1, 119.7, 118.5, 101.0, 94.9, 94.1; MS (EI, 70 eV)
m/z 238 [M+], 208, 180, 161, 135.
1
EtOAc = 6:1); H NMR (CDCl3, 600 MHz) δ 8.39 (d, 1H, J = 1.1
Hz), 7.81−7.84 (m, 3H), 7.71 (d, 1H, J = 8.5 Hz), 7.39 (d, 2H, J =
8.5 Hz), 7.35 (ddd, 1H, J = 7.8, 7.7, 2.1 Hz), 7.11 (ddd, 1H, J = 7.3,
7.2, 1.2 Hz), 2.99 (sept, 1H, J = 6.9 Hz), 1.31 (d, 6H, J = 7.0 Hz);
13C{1H} NMR (CDCl3, 150 MHz) δ 149.4, 149.0, 138.3, 127.5,
126.9, 122.6, 122.4, 121.0, 120.5, 120.3, 117.7, 33.8, 23.9; MS (EI, 70
eV) m/z 236 [M+], 221, 194.
5-Fluoro-2-phenyl-2H-indazole (3d).32 According to the general
procedure, product 3d was isolated as a white solid in 52% yield (110
mg, 0.52 mmol): mp 136−137 °C (lit.32 mp 135.5−137.5 °C); Rf =
0.50 (PE/EtOAc = 4:1); 1H NMR (CDCl3, 600 MHz) δ 8.37 (s, 1H),
7.86−7.90 (m, 2H), 7.77 (dd, 1H, J = 9.9, 1.7 Hz), 7.51−7.56 (m,
2H), 7.41 (t-like, 1H, J = 8.12 Hz), 7.29 (dd, 1H, J = 9.2, 2.7 Hz),
7.13 (ddd, 1H, J = 9.3, 8.9, 2.4 Hz); 13C{1H} NMR (CDCl3, 150
MHz) δ 158.7 (d, J (19F, 13C) = 158 Hz), 147.2, 140.4, 129.6, 128.1,
122.1, 120.9, 120.5 (d, J (19F, 13C) = 9.9 Hz), 120.1 (d, J (19F, 13C) =
9.9 Hz), 118.6 (d, J (19F, 13C) = 28.6 Hz), 102.7 (d, J (19F, 13C) =
24.6 Hz); MS (EI, 70 eV) m/z 212 [M+], 195, 185, 165.
2-(4-Fluorophenyl)-2H-indazole (3k).32 According to the general
procedure, product 3k was isolated as a white solid in 68% yield (144
mg, 0.68 mmol): mp 104−105 °C (lit.32 mp 103−104 °C), Rf = 0.48
(cyclohexane/EtOAc = 6:1); 1H NMR (CDCl3, 600 MHz) δ 8.35 (s,
1H), 7.85−7.89 (m, 2H), 7.78 (dd, 1H, J = 8.7, 1.0 Hz), 7.71 (dd,
1H, J = 8.6, 2.1 Hz), 7.33 (ddd, 1H, J = 7.6, 7.6, 2.0 Hz), 7.19−7.25
(m, 2H), 7.13 (ddd, 1H, J = 7.8, 7.7, 2.2 Hz); 13C{1H} NMR (CDCl3,
150 MHz) δ 162.1 (d, J (19F, 13C) = 247.5 Hz), 149.7, 136.8 (d, J
(19F, 13C) = 3.3 Hz), 127.0, 122,9, 122.8 (d, J (19F, 13C) = 8.3 Hz),
122.6, 120.6, 120.3, 117.8, 116.5 (d, J (19F, 13C) = 23.3 Hz); MS (EI,
70 eV) m/z 212 [M+], 192, 165, 132, 117.
2-Phenyl-2H-benzo[g]indazole (3e).33 According to the general
procedure, product 3e was isolated as yellow oil in 61% yield (149
2-(3-Fluorophenyl)-2H-indazole (3l).20a According to the general
procedure, product 3l was isolated as a white solid in 50% yield (106
mg, 0.50 mmol): mp 89−90 °C; Rf = 0.37 (cyclohexane/EtOAc =
1
mg, 0.61 mmol): Rf = 0.42 (cyclohexane/EtOAc = 6:1); H NMR
(CDCl3, 600 MHz) δ 8.71 (t-like, 1H, J = 7.8 Hz), 8.38 (s, 1H),
7.94−7.97 (m, 2H), 7.82 (d, 1H, J = 8.2 Hz), 7.61 (ddd, 1H, J = 8.4,
7.8, 1.2 Hz), 7.52−7.59 (m, 4H), 7.41 (d, 1H, J = 8.2 Hz), 7.38 (t-
like, 1H, J = 7.4 Hz); 13C{1H} NMR (CDCl3, 150 MHz) δ 147.6,
140.6, 132.7, 129.6, 128.4, 127.3, 127.0, 126.7, 125.7, 124.6, 122.6,
121.1, 120.5, 120.0, 118.3; MS (EI, 70 eV) m/z 244 [M+], 216, 167,
141, 114.
1
6:1); H NMR (CDCl3, 600 MHz) δ 8.41 (s, 1H), 7.78 (d, 1H, J =
8.7 Hz), 7.68−7.73 (m, 3H), 7.46−7.53 (m, 1H), 7.34 (ddd, 1H, J =
7.8, 7.6, 2.1 Hz), 7.07−7.16 (m, 2H); 13C{1H} NMR (CDCl3, 150
MHz) δ 163.0 (d, J (19F, 13C) = 248.0 Hz), 149.8, 141.8 (d, J (19F,
13C) = 9.9 Hz), 130.9 (d, J (19F, 13C) = 9.8 Hz), 127.2, 122.86,
122.81, 120.48, 120.41, 118.0, 116.1 (d, J (19F, 13C) = 3.0 Hz), 114.7
(d, J (19F, 13C) = 21.1 Hz), 108.7 (d, J (19F, 13C) = 26.3 Hz); MS (EI,
70 eV) m/z 212 [M+], 192, 165, 117.
2-(4-Methylphenyl)-2H-indazole (3f).18 According to the general
procedure, product 3f was isolated as a white solid in 73% yield (152
mg, 0.73 mmol): mp 96−97 °C (lit.18 mp 96.5−97.6 °C); Rf = 0.39
(cyclohexane/EtOAc = 6:1); 1H NMR (CDCl3, 600 MHz) δ 8.38 (s,
1H), 7.76−7.81 (m, 3H), 7.71 (t-like, 1H, J = 8.7 Hz), 7.30−7.35 (m,
3H), 7.11 (ddd, 1H, J = 8.1, 7.1, 1.2 Hz), 2.42 (s, 3H); 13C{1H}
NMR (CDCl3, 150 MHz) δ 149.6, 138.3, 137.9, 130.1, 126.6, 122.7,
122.3, 120.9, 120.30, 120.28, 117.9, 21.0; MS (EI, 70 eV) m/z 208
[M+], 193, 181, 164.
2-(4-Chlorophenyl)-2H-indazole (3m).32 According to the general
procedure, product 3m was isolated as a white solid in 60% yield (137
mg, 0.71 mmol): mp 138−138 °C (lit.32 mp 137−139 °C); Rf = 0.54
(cyclohexane/EtOAc = 6:1); 1H NMR (CDCl3, 600 MHz) δ 8.39 (s,
1H), 7.86 (d-like, 2H, J = 8.9 Hz), 7.77 (dd, 1H, J = 8.7, 1.7 Hz), 7.71
(dd, 1H, J = 7.3, 1.3 Hz), 7.50 (t-like, 2H, J = 8.8 Hz), 7.33 (ddd, 1H,
J = 7.8, 7.6, 2.1 Hz), 7.12 (ddd, 1H, J = 7.3, 7.2, 1.7 Hz); 13C{1H}
NMR (CDCl3, 150 MHz) δ 149.9, 139.0, 133.6, 129.7, 127.1, 122.9,
122.7, 122.0, 120.4, 120.3, 117.9; MS (EI, 70 eV) m/z 228 [M+], 211,
193, 181.
2-(3-Methylphenyl)-2H-indazole (3g).34 According to the general
procedure, product 3g was isolated as yellow oil in 62% yield (129
1
mg, 0.62 mmol): Rf = 0.57 (cyclohexane/EtOAc = 6:1); H NMR
2-(4-Methoxyphenyl)-2H-indazole (3n).18 According to the
general procedure, product 3n was isolated as a white solid in 79%
yield (177 mg, 0.79 mmol): mp 130−131 °C (lit.18 mp 130.1−130.6
(CDCl3, 600 MHz) δ 8.40 (d, 1H, J = 1.0 Hz), 7.80 (dd, 1H, J = 8.1,
1.1 Hz), 7.77 (s, 1H), 7.71 (t-like, 1H, J = 8.5 Hz), 7.66 (t-like, 1H, J
= 8.5 Hz), 7.40 (dd, 1H, J = 7.8, 2.3 Hz), 7.35 (ddd, 1H, J = 7.6, 7.6,
2.1 Hz), 7.21 (t-like, 1H, J = 7.1 Hz), 7.15 (ddd, 1H, J = 7.8, 7.7, 2.0
Hz), 2.47 (s, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ 149.5, 140.3,
139.8, 129.3, 128.7, 126.8, 122.7, 122.4, 121.8, 120.6, 120.4, 118.0,
117.8, 21.4; MS (EI, 70 eV) m/z 208 [M+], 193, 181, 164.
1
°C); Rf = 0.40 (cyclohexane/EtOAc = 6:1); H NMR (CDCl3, 600
MHz) δ 8.32 (d, 1H, J = 1.1 Hz), 7.77−7.83 (m, 3H), 7.71 (d, 1H, J
= 8.5 Hz), 7.32 (ddd, 1H, J = 7.7, 7.7, 2.2 Hz), 7.11 (ddd, 1H, J = 7.6,
7.5, 2.1 Hz), 7.04 (t-like, 2H, J = 9.0 Hz), 3.87 (s, 3H); 13C{1H}
NMR (CDCl3, 150 MHz) δ 159.3, 149.6, 134.1, 126.5, 122.7, 122.4,
122.2, 120.3, 120.2, 117.8, 114.6, 55.6; MS (EI, 70 eV) m/z 224 [M+],
209, 181.
2-(3,5-Dimethylphenyl)-2H-indazole (3h).34 According to the
general procedure, product 3h was isolated as a white solid in 77%
yield (171 mg, 0.77 mmol): mp 98−99 °C; Rf = 0.43 (cyclohexane/
EtOAc = 6:1); 1H NMR (CDCl3, 600 MHz) δ 8.39 (s, 1H), 7.79 (dd,
1H, J = 7.6, 1.1 Hz), 7.70 (t-like, 1H, J = 8.3 Hz), 7.52 (s, 2H), 7.33
(ddd, 1H, J = 7.6, 7.6, 2.1 Hz), 7.11 (ddd, 1H, J = 9.1, 7.5, 1.6 Hz),
7.04 (s, 1H), 2.42 (s, 6H); 13C{1H} NMR (CDCl3, 150 MHz) δ
149.5, 140.3, 139.5, 129.6, 126.8, 122.6, 122.3, 120.5, 120.3, 118.8,
117.8, 21.3; MS (EI, 70 eV) m/z 222 [M+], 207, 180.
2-(3-Chloro-4-methylphenyl)-2H-indazole (3o).36 According to
the general procedure, product 3o was isolated as a white solid in 68%
yield (165 mg, 0.68 mmol): mp 130−131 °C; Rf = 0.47
1
(cyclohexane/EtOAc = 6:1); H NMR (CDCl3, 500 MHz) δ 8.38
(s, 1H), 7.96 (d, 1H, J = 2.3 Hz), 7.78 (t-like, 1H, J = 8.7 Hz), 7.70 (t-
like, 2H, J = 8.3 Hz), 7.37 (d, 1H, J = 8.4 Hz), 7.33 (ddd, 1H, J = 7.7,
7.6, 2.0 Hz), 7.12 (ddd, 1H, J = 7.8, 7.8, 2.2 Hz), 2.44 (s, 3H);
13C{1H} NMR (CDCl3, 125 MHz) δ 149.8, 139.3, 135.8, 135.2,
2-(3,4-Dimethylphenyl)-2H-indazole (3i).32 According to the
general procedure, product 3i was isolated as a white solid in 75%
H
https://dx.doi.org/10.1021/acs.joc.0c01923
J. Org. Chem. XXXX, XXX, XXX−XXX

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pubs.acs.org/joc
Article
131.6, 130.1, 127.0, 122.6, 121.5, 120.8, 120.3, 118.8, 117.9, 19.7; MS
(EI, 70 eV) m/z 242 [M+], 230, 208, 193.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01923.
■
sı
2-(Naphth-2-yl)-2H-indazole (3p).20b According to the general
procedure, product 3p was isolated as a white solid in 61% yield (149
mg, 0.61 mmol): mp 132−133 °C (lit.20b mp 131−132 °C); Rf = 0.36
(cyclohexane/EtOAc = 3:1); 1H NMR (CDCl3, 600 MHz) δ 8.55 (s,
1H), 8.38 (d, 1H, J = 2.1 Hz), 8.07 (dd, 1H, J = 8.7, 1.9 Hz), 8.00 (d,
1H, J = 8.6 Hz), 7.95 (d, 1H, J = 8.2 Hz), 7.91 (d, 1H, J = 8.0 Hz),
7.84 (dd, 1H, J = 8.8, 1.1 Hz), 7.75 (t-like, 1H, J = 8.4 Hz), 7.50−7.60
(m, 2H), 7.35 (ddd, 1H, J = 8.6, 6.6, 1.1 Hz), 7.14 (ddd, 1H, J = 7.7,
7.5, 1.9 Hz); 13C{1H} NMR (CDCl3, 150 MHz) δ 149.9, 137.9,
133.5, 132.6, 129.7, 128.3, 127.9, 127.2, 127.0, 126.6, 122.9, 122.5,
120.6, 120.4, 119.5, 118.8, 117.9; MS (EI, 70 eV) m/z 244 [M+], 167,
141, 114.
1H and 13C NMR spectra for all compounds(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Uwe Beifuss − Bioorganische Chemie, Institut für Chemie,
Universität Hohenheim, Stuttgart D-70599, Germany;
orcid.org/0000-0001-7085-6574; Email: ubeifuss@uni-
hohenheim.de; Fax: (+49)711-459-22951
1-Phenyl-1H-indazole (7a).37 In one of the optimization experi-
ments, 1-phenyl-1H-indazole (7a) was isolated as a side product in
6% (12 mg, 0.06 mmol) as a white solid (see Table 1, entry 2): mp
Authors
Nayyef Aljaar − Chemistry Department, Hashemite University,
Zarqa 13115, Jordan; orcid.org/0000-0002-3963-2238
Mousa Al-Noaimi − Chemistry Department, Hashemite
University, Zarqa 13115, Jordan
77−78 °C (lit.37 mp 76−78 °C); Rf = 0.49 (PE/EtOAc = 4:1); H
1
NMR (CDCl3, 300 MHz) δ 8.21 (d, 1H, J = 1.1 Hz), 7.81 (dt, 1H, J
= 1.1, 7.8 Hz), 7.72−7.77 (m, 3H), 7.51−7.59 (m, 2H), 7.40−7.47
(m, 1H), 7.33−7.39 (m, 1H), 7.21−7.23 (m, 1H); 13C{1H} NMR
(CDCl3, 75 MHz) δ 140.2, 138.7, 135.4, 129.4, 127.1, 126.6, 125.3,
122.7, 121.5, 121.3, 110.4; MS (EI, 70 eV) m/z 194 (100) [M+].
1-o-Bromobenzyl-1-phenylhydrazine (4a).18 Following the pro-
cedure of Song and Yee,18 phenylhydrazine (2a) (108 mg, 1 mmol)
was added to a stirred solution of NaHMDS (2 mL, 1.0 M THF, 2
mmol) at 0 °C under argon. After 20 min, the cooling bath was
removed, and the reaction mixture was stirred at rt for 1 h. The
reaction mixture was cooled to 0 °C, and 2-bromobenzyl bromide 1a
(250 mg, 1 mmol) was added. The reaction mixture was stirred at rt
for 1 h and quenched with water. The mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were dried over
anhydrous MgSO4 and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel (hexane/ether = 20:1)
to yield 4a as a pale yellow oil in 53% yield (147 mg, 0.53 mmol): Rf =
0.44 (PE/EtOAc = 4:1); 1H NMR (CDCl3, 300 MHz) δ 7.61 (d, 1H,
J = 7.4 Hz), 7.23−7.32 (m, 4H), 7.12−7.18 (m, 1H), 7.02 (d, 2H, J =
7.9 Hz), 6.82 (ddd, 1H, J = 7.3, 7.2, 1.1 Hz), 4.71 (s, 2H), 3.76 (brs,
2H); 13C{1H} NMR (CDCl3, 75 MHz) δ 151.3, 136.6, 133.0, 129.1,
128.8, 128.7, 127.6, 123.5, 118.4, 112.8, 60.7; MS (EI, 70 eV) m/z
(%) 277 (100) [M+].
Ju
̈
rgen Conrad − Bioorganische Chemie, Institut für Chemie,
Universität Hohenheim, Stuttgart D-70599, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01923
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Deutsche Forschungsgemeinschaft
(grant for the initiation of an international collaboration) is
gratefully acknowledged. We thank Mr. Mario Wolf (Institut
̈
fu
̈
r Chemie, Universitat Hohenheim) for recording of NMR
r Chemie,
Universitat Hohenheim), and Dipl.-Ing. (FH) J. Trinkner
spectra, Dr. Christina Braunberger (Institut fu
̈
̈
(Institut fur Organische Chemie, Universitat Stuttgart) for
̈
̈
recording of MS.
REFERENCES
Procedure for the Preparation of 2-Phenyl-2H-indazole (3a) by
Pd-Catalyzed Intramolecular Cyclization of 1-o-Bromobenzyl-1-
phenylhydrazine (4a). A dry vial was charged with Cs2CO3 (488 mg,
1.5 mmol), PdCl2 (18 mg, 0.1 mmol), and t-Bu3PHBF4 (29 mg, 0.1
mmol) under argon. The vial was sealed, dry DMSO (1.5 mL) was
added under argon, and the mixture was stirred at rt for 3 h. Then, 1-
o-bromobenzyl-1-phenylhydrazine (4a) (277 mg, 1 mmol) was added,
and the resulting reaction mixture was stirred at 120 °C for 18 h
under argon. After cooling to rt, the reaction mixture was partitioned
between EtOAc (20 mL) and sat. NH4Cl (20 mL). The organic layer
was isolated, and the aqueous layer was extracted with EtOAc (3 × 20
mL). The combined organic layers were dried over anhydrous MgSO4
and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (cyclohexane/EtOAc = 10:1) to yield 2-
phenyl-2H-indazole (3a) in 72% (140 mg, 0.72 mmol).
Preparation of 1-Phenyl-1H-indazole (7a) by the Pd-Catalyzed
Reaction between 2-Bromobenzaldehyde (9) and Phenylhydrazine
(2a).30 Following the procedure of Cho and Shim, a mixture of 2-
bromobenzaldehyde (9) (185 mg, 1 mmol), phenylhydrazine (2a)
(108 mg, 1 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), dppp (12.5 mg,
0.03 mmol), and NaOtBu (192 mg, 2 mmol) in dry toluene (10 mL)
was placed in a pressure vessel. The system was flushed with argon
and allowed to react at 100 °C for 15 h. After cooling to rt, the
reaction mixture was extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried over anhydrous MgSO4 and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate = 5:1) to yield 7a
as a white solid in 75% (146 mg, 0.75 mmol).
■
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