Transformation of arenes into 3-arylpyrazoles and 3-arylisoxazolines with β-bromopropionyl chloride, hydrazine, and hydroxylamine

Article abstract of DOI:10.1016/j.tet.2019.130920

Successive treatment of arenes with β-bromopropionyl chloride and AlCl₃, followed by the reactions with hydrazines and Na₂CO₃, and then with MnO₂ gave the corresponding 3-arylpyrazoles in one pot in good to moderate yields. The same successive treatment of arenes with β-bromopropionyl chloride and AlCl₃, followed by the reactions with hydroxylamine and KF gave the corresponding 3-arylisoxazolines in one pot in good to moderate yields.

Full text of DOI:10.1016/j.tet.2019.130920

Journal Pre-proof
Transformation of arenes into 3-arylpyrazoles and 3-arylisoxazolines with β-
bromopropionyl chloride, hydrazine, and hydroxylamine
Takahiro Yamamoto, Hideo Togo
PII:
S0040-4020(19)31339-0
https://doi.org/10.1016/j.tet.2019.130920
TET 130920
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 December 2019
Revised Date: 24 December 2019
Accepted Date: 29 December 2019
Please cite this article as: Yamamoto T, Togo H, Transformation of arenes into 3-arylpyrazoles and 3-
arylisoxazolines with β-bromopropionyl chloride, hydrazine, and hydroxylamine, Tetrahedron (2020), doi:
https://doi.org/10.1016/j.tet.2019.130920.
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Transformation of Arenes into 3-Arylpyrazoles and
3-Arylisoxazolines with β-Bromopropionyl Chloride,
Hydrazine, and Hydroxylamine
Leave this area blank for abstract info.
Takahiro Yamamoto and Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522 Japan

Tetrahedron
1
TETRAHEDRON
Pergamon
Transformation of Arenes into 3-Arylpyrazoles and
3-Arylisoxazolines with β-Bromopropionyl Chloride, Hydrazine,
and Hydroxylamine
Takahiro Yamamoto and Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33,
Inage-ku, Chiba 263-8522 Japan
Abstract—Successive treatment of arenes with β-bromopropionyl chloride and AlCl3, followed by the reactions with hydrazines and
Na2CO3, and then with MnO2 gave the corresponding 3-arylpyrazoles in one pot in good to moderate yields. The same successive
treatment of arenes with β-bromopropionyl chloride and AlCl3, followed by the reactions with hydroxylamine and KF gave the
corresponding 3-arylisoxazolines in one pot in good to moderate yields.
© 2020 Elsevier Science. All rights reserved
1. Introduction
Extensive synthetic studies of the pyrazole unit1d, 1f and the
isoxazoline unit2 have been carried out. Recent synthetic
Nitrogen-containing heterocycles are very attractive in
view of medicinal chemistry because some of them show
potent biological activities. Among them, pyrazole and
isoxazolines are one of the most important
studies
of
pyrazoles
are
as
follows:3
the
Cu(NO3)2-catalyzed preparation of 1-arylpyrazoles with
arylhydrazines and 1,3-diketones using conventional
condensation;3a the CuBr-catalyzed preparation of
nitrogen-containing heterocycles.1,2
For example,
1,3,5-triaryl-4-(selenophenyl)pyrazoles
with
Celecoxib and Lonazolac which are 3-arylpyrazoles, are
anti-inflammatory drugs1a and dibenzo[b,f]azepine-tethered
isoxazoline is a potent anticancer agent,2 as shown in Fig.
1.
phenylhydrazines, chalcones, and PhSeSePh;3b the
I2-mediated preparation of 3,5-diarylpyrazoles with
p-toluenesulfonyl hydrazide and chalcones;3c the
microwave-irradiated
preparation
of
5-amino-1,3-diarylpyrazoles with arylhydrazines and
3-aminocrotonitrile;3d the AgOTf-catalyzed preparation of
1,5-diaryl-3-(trifluoromethyl)pyrazoles with arylhydrazines
and α,β-alkynyl trifluoromethyl ketones;3e the blue
LED-irradiated preparation of 3-arylpyrazoles with
ethynylarenes and hydrazine in the presence of CuI and
H2NO2S
(1)
(1)
(2)N
Ru(bpy)3Cl2;3f
the
4-iodo-3-trifluoromethyl-1,5-diarylpyrazoles
with −arylhydrazones of α,β-alkynyl trifluoromethyl
ketones;3g the PhSeSePh-mediated preparation of
I2-mediated
preparation
of
N
(2)
(3)
N
N
CF3
(3)
CO2H
Ν
Celecoxib
(anti-inflammatory Drug)
Cl
Lonazolac
(anti-inflammatory Drug)
1,3,5-triaryl-4-(selenophenyl)pyrazoles
α,β-alkynyl-N-arylhydrazones and
with
the
Oxone®;3h
(1)
(2)
N
Cu(OTf)2-catalyzed preparation of 4-aminoborated
O
3-aryl-1-tosylpyrazoles
with
α,β-alkynyl-N-tosyl-
(3)
hydrazones;3i the preparation of 2,5-di(alkoxycarbonyl)-
pyrazoles with acrylate esters, α-diazoesters, and Oxone®;3j
N
and
the
Et3N-promoted
preparation
of
Cl
4-(aminocarbonyl)-1,3-diarylpyrazoles with β-ketoamides
and hydrazonyl chlorides.3k As unique synthetic methods,
the Ag2CO3- and Mo(CO)6-catalyzed preparation of
Dibenzo[b,f]azepine-tethered isoxazoline
(anticancer agent)
3-arylpyrazoles
with
[N-(isocyano)imino]triphenyl-
Fig. 1 Typical Pharmaceuticals Bearing 3-Arylpyrazole unit
and 3-Arylisoxazoline Unit
phosphorane and ethynylarenes3l,3m and the CuCl-catalyzed
preparation of 3-arylpyrazoles bearing a CN or a CO2Et
group at 4 position with N,N-dialkylhydrazones and

2
Tetrahedron
trichloroacetonitrile or ethyl trichloroacetate3n were also
reported.
equiv.) in dichloromethane (2.0 mL) at 0 °C for 1 h gave
the corresponding ketone 1A-a in good yield. After
evaporation of the solvent, water (2.0 mL) was added to the
residue and then bases (5.0 equiv.), such as KF, K2CO3,
and Na2CO3, and methanol (6.0 mL) were added, and the
obtained mixture was refluxed for 5 min to neutralize
acidic species. Then, methylhydrazine (1.1 equiv.) was
added and the obtained mixture was refluxed for 22 h to
form methylhydrazone 1A-b first and then pyrazoline 1A-c.
After removal of the solvent, pyrazoline 1A-c was oxidized
by MnO2 (7.0 equiv.) in toluene (6.0 mL) under refluxing
On the other hand, isoxazolines are commonly prepared
from nitrile N-oxides and alkenes via a 1,3-dipolar
cycloaddition reaction. Recent synthetic studies of
isoxazolines are as follows:4 the preparation of
3-arylisoxazolines with aldoximes, terminal alkenes, and
Oxone® in the presence of KI,4a 3,5-Me2C6H3I,4b KCl,4c or
NaCl,4d and the Ru(bpy)3Cl2-catalyzed preparation of
3-phenylisoxazolines with phenyl α-N-(hydroxyl)imino
acid, terminal alkenes, and Oxone® under irradiation with
blue LED.4e As cyclization methods of allylic oximes, the
conditions
to
form
3-(4’-isopropylphenyl)-1-methylpyrazole (2A) in 62%,
73%, and 80% yields, respectively, as shown in Table 1
(entries 1~3).
t
oxidative cyclization of 2-arylphenylisonitriles, BuOOH,
and
nBu4NI
into
3-arylisoxazolines
bearing
(phenanthridine-6’-yl)methyl group at 5-position,4f the
TEMPO-mediated
cyclization
to
generate
3-arylisoxazolines,4g the Au(Ph3P)Cl-catalyzed cyclization
to produce 3-arylisoxazolines,4h the oxidative cyclization
into 3-arylisoxazolines using PhI(OAc)2,4i and the
Table 1. Optimization for Transformation of cumene into
3-(4'-Isopropylphenyl)-1-methylpyrazole 2A.
1) AlCl3 (1.6 equiv.)
O
fac-Ir(ppy)3-catalyzed
2-(difluoromethanesulfonyl)benzothiazole
cyclization
of
give
BrCH2CH2COCl
(1.0 equiv.)
H
to
Br
iPr
3-aryl-5-(2’,2’-difluoroethyl)isoxazolines under irradiation
with blue LED4j were reported. As unique methods for
the preparation of isoxazolines, the preparation of
5-aroyl-3-arylisoxazolines with aryl α-bromomethyl ketone
oximes, aroylmethyl(dimethyl)sulfonium salts, and
iPr
CH2Cl2 (2.0 mL)
0 °C, 1 h
1A
(1.0 mmol)
1A-a
2) evaporation,
H2O (2.0 mL)
Na2CO3;4k
the
preparation
of
3-aryl-
and
Me
NH
3-alkylisoxazolines with ketones, ethynylarenes, and
tBuOK, followed by the reaction with NH2OH, and then
KOH;4l the preparation of 5-arylisoxazolines with
methylarenes and t-butyl acrylate in the presence of
3) Base (5.0 equiv.)
3rd Solvent (6.0 mL)
Reflux, 5 min
N
Br
iPr
Pd(OAc)2
and
AgNO3;4m
the
preparation
of
H2NNHMe
(1.1 equiv.)
Reflux, 22 h
1A-b
5-arylisoxazolines bearing an ester group at 3-position with
t
vinylarenes, α-diazoacetate esters, and BuONO in the
presence
of
Cu(OAc)2;4n
the
preparation
of
3-aroyl-5-arylisoxazolines with vinylarenes and tBuONO in
the presence of Sc(OTf)3;4o and the preparation of
Me
Me
4) evaporation,
Oxidant (y equiv.)
N
N
N
N
3,5-diarylisoxazolines
with
vinylarenes,
4th Solvent (6.0 mL)
Reflux, 24 h
N-(hydroxy)arylmethanesulfonamides,
i
nBu4NIO4, and I24p were also reported.
iPr
Pr
1A-c
2A
However, to the best of our knowledge, the intermolecular
C-C bond constructing one-pot preparation of
3-arylpyrazoles and 3-arylisoxazolines from arenes has
3rd
4th
En Base
try
Oxidant
Yield
(%)
Solvent (y equiv.)
Solvent
been scarcely studied.
Here, as part of our synthetic
studies of the efficient preparation of heteroaromatics from
arenes,5 we would like to report a simple one-pot
preparation of 3-arylpyrazoles and 3-arylisoxazolines by
1
KF
MeOH
MeOH
MeOH
EtOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
MnO2 (7.0) Toluene 62
MnO2 (7.0) Toluene 73
MnO2 (7.0) Toluene 80
MnO2 (7.0) Toluene 73
MnO2 (7.0) Toluene 82
MnO2 (3.0) Toluene 42
2
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
3
the
Friedel-Crafts
acylation
of
arenes
with
β-bromopropionyl chloride and AlCl3, followed by the
reaction with hydrazine and hydroxylamine, and finally the
5-exo-tet cyclization with a base, respectively.
4
5
6
7
DDQ (7.0) DCE
35
0
8
DIB (7.0)
NIS (7.0)
DCE
DCE
2. Results and Discussion
9
0
First, treatment of cumene (1A, 1.0 mmol) with
β-bromopropionyl chloride (1.0 mmol) and AlCl3 (1.6
10
CrO3 (7.0) DCE
37

Tetrahedron
3
Product, Yield
N
Here, Na2CO3 showed the best result to form pyrazole 2A
Bn
Me
Ph
in good yield. The presence of water did not disturb the
formation of pyrazoline 1A-c in the 3rd reaction step.
When methanol was changed to ethanol and n-propanol in
the 3rd reaction step under the same procedure and
N
N
N
N
N
i
i
i
Pr
Pr
Pr
conditions,
3-(4’-isopropylphenyl)-1-methylpyrazole (2A) were 73%
and 82% yields, respectively (entries 4, 5). Thus,
n-propanol was the most effective solvent forming
3-(4’-isopropylphenyl)-1-methylpyrazole (2A) in 82%
yield (entry 5). The oxidation of pyrazoline 1A-c to
3-(4’-isopropylphenyl)-1-methylpyrazole (2A) by MnO2
did not proceed smoothly, and therefore, an excess amount
of MnO2 was required (entries 5, 6). When DDQ
the
yields
of
2A-1 86%
2A-2 83%
2A 82%
96%a
Me
Me
Me
Me
OH
N
N
N
N
N
N
i
Pr
Me
Me
tBu
2B 84%
2A-3 66%
2C 81%
Me
Me
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone),
DIB
N
N
N
N
N
N
[(diacetoxyiodo)benzene], and NIS (N-iodosuccinimide),
which are not transition-metal oxidants, were used instead
of MnO2 in 1,2-dichloroethane (DCE) in the 4th reaction
step, the yield of 3-(4’-isopropylphenyl)-1-methylpyrazole
(2A) was 35% in the former oxidant, and
3-(4’-isopropylphenyl)-1-methylpyrazole (2A) was not
formed at all in the latter two oxidants, respectively (entries
7~9). In addition, the oxidation ability of CrO3 was not
sufficiently high for the oxidation of pyrazoline 1A-c (entry
Me
Me
Ph
Me
Me
2D 89%b
2E 89%
2F 72%
Me
Me
N
N
N
Me
N
N
N
Me
Me
MeO
EtO
10).
Thus, the oxidation of pyrazoline 1A-c to
3-(4’-isopropylphenyl)-1-methylpyrazole (2A) with MnO2
was the most effective among these reactions. As a
gram-scale experiment, treatment of cumene (1A, 9.0
mmol) under the same procedure and conditions as those of
2G 53%
2H 82%
2I 66%
Me
Me
Me
N
N
N
OH N
N
OMeN
entry
5
in
Table
1
gave
O
3-(4’-isopropylphenyl)-1-methylpyrazole (2A) in 96%
Me
Me
yield, as shown in Scheme 1.
2J 75%c
2K
:
2K'
56%
0%
:
:
0%d
52%e
Based on those results, cumene (1A, 1.0 mmol) was treated
under the same procedure and conditions as those of entry 5
in Table 1, using phenylhydrazine, benzylhydrazine, and
(2-hydroxyethyl)hydrazine
3-(4’-isopropylphenyl)-1-phenylpyrazole
1-benzyl-3-(4’-isopropylphenyl)pyrazole
1-(2”-hydroxyethyl)-3-(4’-isopropylphenyl)pyrazole
(2A-3) in 86%, 83%, and 66% yields, respectively, as
shown in Scheme 1. Then, the same treatment of arenes
(1.0 mmol), such as toluene (1B), tert-butylbenzene (1C),
biphenyl (1D), p-xylene (1E), 1,2,3-trimethylbenzene (1F),
1,3,5-trimethylbenzene (1G), anisole (1H), phenetole (1I),
Me
Me
Me
Me
Me
N
N
N
N
N
N
N
to
give
(2A-1),
and
N
(2A-2),
F
Cl
Br
2N 55%
2M 66%
2L 75%
Me
N
N
N
N
Me
MeO
Scheme 1. Transformation of Arenes 1 into 3-Arylpyrazoles 2.
2Q 70%f
2O 84%
2P 76%f
1) AlCl3 (1.6 equiv.)
BrCH2CH2COCl
(1.0 equiv.)
3) Na2CO3 (5.0 equiv.)
nPrOH (6.0 mL)
Me
Me
H
Me
R1
N
Reflux, 5 min
N
N
N
Me
N
Me
N
S
H2NNHR2
(1.1 equiv.)
Reflux, 22 h
CH2Cl2 (2.0 mL)
0 °C, 1 h
1
Et
S
O
(1.0 mmol)
2) evaporation,
H2O (2.0 mL)
2S 60%c
2R 53%g
2T 57%h
a S.M (9.0 mmol) was used.
R2
b n-PrOH (12.0 mL) at 3rd step and Toluene (12.0 mL) at 4th step were used.
c 1st step reaction was carried out at -10 °C for 2 h .
d 1st step reaction was carried out at -55 °C for 22 h.
e 1st step reaction was carried out at r.t. for 22 h.
f 1st step reaction was carried out at r.t. for 3 h.
g 1st step reaction was carried out for 2 h.
N
N
4) evaporation,
MnO2 (7.0 equiv.)
R1
Toluene (6.0 mL)
Reflux, 24 h
h 1st step reaction was carried out for 3 h.
2

4
Tetrahedron
(1L),
2,3-dihydrobenzofuran
(1J),
fluorobenzene
Table 2. Optimization for Transformation of Cumene into
3-(4'-Isopropylphenyl)isoxazoline 3A.
chlorobenzene (1M), and bromobenzene (1N), with
β-bromopropionyl chloride (1.0 equiv.), AlCl3 (1.6 equiv.),
H2O (2.0 mL), Na2CO3 (5.0 equiv.), methylhydrazine (1.1
equiv.), and then MnO2 (7.0 equiv.) under the same
procedure and conditions as those of entry 5 in Table 1
gave the corresponding 3-aryl-1-methylpyrazoles 2B~2J
and 2L~2N in good to moderate yields, as shown in
Scheme 1. When the acylation of 4-methoxytoluene (1K)
with β-bromopropionyl chloride and AlCl3 was carried out
at -55 °C for 22 h and the subsequent reactions performed
under the same procedure and conditions as those of entry 5
1) AlCl3 (1.6 equiv.)
O
BrCH2CH2COCl
(1.0 equiv.)
H
Br
i
Pr
iPr
CH2Cl2 (2.0 mL)
0 °C, 1 h
1A
1A-a
(1.0 mmol)
2) H2O (2.0 mL),
evaporation
3) NH2OH•HCl
in
Table
1,
OH
(1.1 equiv)
Base (10.0 equiv.)
N
1-methyl-3-(2’-methoxy-5’-methylphenyl)pyrazole
(2K)
Br
O
was obtained in 56% yield. On the other hand, when the
acylation of 4-methoxytoluene (1K) was carried out at
room temperature for 22 h and the subsequent reactions
were conducted under the same procedure and conditions,
3-(2’-hydroxy-5’-methylphenyl)-1-methylpyrazole (2K’)
was obtained in 52% yield. Under the same procedure
and conditions, naphthalene (1O), 1-methylnaphthalene
(1P), 1-methoxynaphthalene (1Q), 2-ethylthiophene (1R),
3-methylbenzothiophene (1S), and 3-methylbenzofuran
(1T) were also successfully transformed into
MeOH (12.0 mL)
Reflux, Time
iPr
1A-d
N
iPr
3A
Entry
1a)
Base
K2CO3
Et3N
CsF
Time (h)
67
Yield (%)
1-methyl-3-(naphthalen-2’-yl)pyrazole
(2O),
(2P),
(2Q),
(2R),
0
1-methyl-3-(4’-methylnaphthalen-1’-yl)pyrazole
3-(4’-methoxynaphthalen-1’-yl)-1-methylpyrazole
3-(5’-ethylthiophen-2’-yl)-1-methylpyrazole
2
67
0
3
67
59
58
42
79
65
1-methyl-3-(3’-methylbenzothiophen-2’-yl)pyrazole (2S),
and 1-methyl-3-(3’-methylbenzofuran-2’-yl)pyrazole (2T)
in good to moderate yields, although their reaction times
and temperatures in 1st reaction step differed depending on
the electrophilicity of the aromatic rings.
4
K2CO3
Na2CO3
KF
67
5
67
6
67
7
KF
22
a) Aq. NH2OH was used instead of NH2OH•HCl.
Treatment
of
obtained
1-benzyl-3-(4’-isopropylphenyl)pyrazole (2A-2, 1.0 mmol)
with Pd on carbon under hydrogen gas in a mixture of 1M
HCl (0.5 mL) and methanol (4.0 mL) at room temperature
for 20 h gave 3-(4’-isopropylphenyl)-1H-pyrazole (2Aa) in
84% yield.
3~5). The key point in this reaction is the cyclization step
of formed oxime 1A-d to produce isoxazoline 3A via the
5-exo-tet cyclization mode. Finally, it was found that the
treatment of cumene (1A, 1.0 mmol) with
β-bromopropionyl chloride (1.0 equiv.) and AlCl3 (1.6
equiv.) in dichloromethane (2.0 mL) at 0 °C for 1 h,
followed by the addition of water (2.0 mL) and evaporation,
and warming treatment of the residue with NH2OH•HCl
(1.1 equiv.) and KF (10.0 equiv.) in MeOH (12.0 mL) for
67 h gave 3-(4’-isopropylphenyl)isoxazoline (3A) in 79%
Then, the transformation of arenes into 3-arylisoxazolines
was studied using the same procedure but with
hydroxylamine instead of hydrazines.
Treatment of
cumene (1A, 1.0 mmol) with β-bromopropionyl chloride
(1.0 equiv.) and AlCl3 (1.6 equiv.) in dichloromethane (2.0
mL) at 0 °C for 1 h gave the corresponding ketone 1A-a.
After the addition of water (2.0 mL) to decompose AlCl3,
the solvent was removed by evaporation. Then, aq. NH2OH
(1.1 equiv.), K2CO3 (10.0 equiv.), and MeOH (12.0 mL),
and NH2OH•HCl (1.1 equiv.), Et3N (10.0 equiv.), and
MeOH (12.0 mL) were added to the residue, respectively,
and the obtained mixtures were refluxed for 67 h.
However, 3-(4’-isopropylphenyl)isoxazoline (3A) was not
formed at all, as shown in Table 2 (entries 1, 2). On the
other hand, after the addition of water and evaporation,
treatment of the residue with NH2OH•HCl and bases, such
as CsF (10.0 equiv.), K2CO3 (10.0 equiv.), and Na2CO3
(10.0 equiv.), in MeOH (12.0 mL) under refluxing
conditions for 67 h gave 3-(4’-isopropylphenyl)isoxazoline
(3A) in 59%, 58%, and 42% yields, respectively (entries
yield
(entry
6).
The
oxidation
(3A)
of
to
3-(4’-isopropylphenyl)isoxazoline
3-(4’-isopropylphenyl)isoxazole with DDQ in toluene at
80 °C, with DIB in 1,2-dichloroethane at 80 °C, with MnO2
in toluene at 110 °C, and with CrO3 in 1,2-dichloroethane
at 80 °C did not proceed at all. As a gram-scale
experiment, treatment of cumene (1A, 9.0 mmol) under the
same procedure and conditions as those of entry 6 in Table
2 gave 3-(4’-isopropylphenyl)isoxazoline (3A) in 77%
yield, as shown in Scheme 2. Based on those results, the
successive treatment of arenes 1 (1.0 mmol), such as
toluene (1B), tert-butylbenzene (1C), biphenyl (1D),
1,2,3-trimethylbenzene (1F), anisole (1H), phenetole (1I),
2,3-dihydrobenzofuran (1J), fluorobenzene (1L), and
chlorobenzene (1M) with β-bromopropionyl chloride (1.0

Tetrahedron
5
mmol), AlCl3 (1.6 equiv.), H2O (2.0 mL), NH2OH•HCl (1.1
equiv.), and KF (10.0 equiv.) under the same procedure and
conditions as those of entry 6 in Table 2 gave the
corresponding 3-arylisoxazolines 3B~3D, 3F, 3H~3J, 3L,
and 3M in good to moderate yields, as shown in Scheme 2.
Under the same procedure and conditions, naphthalene
(1O) and 2-ethylthiophene (1R) could be also transformed
The possible reaction pathways for the preparation of
3-arylpyrazoles 2 and 3-arylisoxazolines 3 from arenes 1
are shown in Scheme 3. β-Bromopropiophenones 1-a
formed by the Friedel-Crafts acylation of arenes 1 with
β-bromopropionyl chloride and AlCl3, react with
hydrazines to form 3-arylpyrazolines 1-c via the 5-exo-tet
cyclization of hydrazones 1-b under basic conditions.
Formed 3-arylpyrazolines 1-c were smoothly oxidized to
3-arylpyrazoles 2 by MnO2 under warming conditions.
The formation of 3-arylpyrazolines 1-c from hydrazones
1-b is not affected by the presence of water. Similarly,
into
3-(naphthalen-2’-yl)isoxazoline
(3O)
and
3-(5’-ethylthiophen-2’-yl)isoxazoline (3R) in moderate
yields, respectively. However, when p-xylene (1E),
1,3,5-trimethylbenzene (1G), and 3-methylbenzothiophene
(1S) were used as substrates under the same procedure and
conditions, the corresponding 3-arylisoxazolines 3 were not
formed, because the 5-exo-tet cyclization of the formed
oximes failed to proceed smoothly due to steric hindrance.
formed
hydroxylamine•hydrogen
β-bromopropiophenones
1-a
react
to
with
form
chloride
3-arylisoxazolines 3 via the 5-exo-tet cyclization of oximes
1-d under basic conditions. The formation of
3-arylisoxazolines from formed oximes 1-d is
3
dramatically affected by water, and the complete removal
of water is important. On the other hand, the 5-exo-tet
cyclization is affected by the o-substituent of arenes 1 used.
Scheme 2. Transformation of Arenes 1 to 3-Arylisoxazolines 3.
1) AlCl3 (1.6 equiv.)
BrCH2CH2COCl
(1.0 equiv.)
R
H
Scheme 3. Reaction pathways
CH2Cl2 (2.0 mL)
1
0 °C, 1 h
2) H2O (2.0 mL),
evaporation
R'
(1.0 mmol)
NHR'
N
N
N
5-exo-tet
Br
R
R
- HBr
3) NH2OH•HCl
O
N
1-c
(1.1 equiv)
1-b
KF (10 equiv.)
MnO2
R'
R
MeOH (12.0 mL)
Reflux, 67 h
N
N
3
NH2NHR'
Na2CO3
- H2O
R
Product, Yield
iPr
O
O
N
O
N
N
2 3-Arylpyrazoles
tBu
Me
3A 79%
O
AlCl3
BrCH2CH2COCl
3C 62%
3B 73%
77%a
Br
R
R
O
O
O
O
O
N
N
N
1 Arenes
1-a
Me
Me
Ph
EtO
Cl
MeO
Me
3F 55%
3H 66%
3D 77%b
- H2O
NH2OH·HCl
KF
O
O
O
O
N
N
N
O
F
OH
O
N
3L 83%
N
3J 60%c
3I 58%
5-exo-tet
- HBr
Br
R
R
N
S
N
N
3 3-Arylisoxazolines
1-d
Et
3M 57%
3R 45%d
3O 58%
3. Conclusion
a Compound 1A (9.0 mmol) was used.
b MeOH (24 mL) was used.
Arenes
could
be
efficiently
transformed
into
c 1st reaction step was carried out at -10 °C for 2 h .
d 1st reaction step was carried out for 2 h.
3-arylpyrazoles by the successive treatment with
β-bromopropionyl chloride and AlCl3, with water, with
hydrazines and Na2CO3, and finally with MnO2. Arenes

6
Tetrahedron
MHz, CDCl3): δ = 1.28 (d, 2H, J = 6.9 Hz), 2.94 (septet, 1H, 6.9
Hz), 6.75 (d, 1H, J = 2.4 Hz), 7.26-7.30 (m, 3H), 7.47 (t, 2H, J =
7.6 Hz), 7.77 (d, 2H, J = 7.6 Hz), 7.84 (d, 2H, J = 8.3 Hz), 7.94 (d,
1H, J = 2.4 Hz); 13C-NMR (100 MHz, CDCl3): δ = 23.9, 33.9,
104.8, 118.9, 125.8, 126.1, 126.6, 127.8, 129.3, 130.6, 140.2,
could be also transformed into 3-arylisoxazolines by the
successive treatment with β-bromopropionyl chloride and
AlCl3, with water, and with hydroxylamine•hydrogen
chloride and CsF, although oxidative conversion into
3-arylisoxazoles could not be achieved. We believe that
the present methods would be useful for the preparation of
3-arylpyrazoles and 3-arylisoxazolines from arenes via
β-bromopropiophenones because those transformations
could be carried out in one pot with easily available
substrates and reagents.
148.7, 152.9; HRMS (ESI) Calcd for C18H19N2 [M+H]+
263.1543, Found = 263.1538.
=
4.2.3 1-Benzyl-3-(4’-isopropylphenyl)pyrazole (2A-2): Purified
by column chromatography on silica gel (eluent, hexane : ethyl
acetate = 10:1); Yield: 230.2mg (83%); white solid; Mp:
1
69-70 °C; IR (neat) 2959, 1606, 1455, 1229 cm-1; H-NMR (400
4. Experimental Section
MHz, CDCl3): δ = 1.26 (d, 6H, J = 6.8 Hz), 2.92 (septet, 1H, J =
6.8 Hz), 5.36 (s, 2H), 6.54 (d, 1H, J = 2.2 Hz), 7.22-7.26 (m, 4H),
7.31-7.36 (m, 4H), 7.74 (d, 2H, J = 8.6 Hz); 13C-NMR (100 MHz,
CDCl3): δ =23.9, 33.8, 55.9, 103.0, 125.5, 126.5, 127.5, 127.8,
128.6, 130.4, 131.1, 136.6, 148.2, 151.5; HRMS (ESI) Calcd for
C19H21N2 [M+H]+ = 277.1699, Found = 277.1695.
1
4.1 General: H NMR and 13C NMR spectra were obtained with
JEOL-JNM-ECX400 and JEOL-JNM-ECS400 spectrometers.
Chemical shifts were recorded as follows: chemical shift in ppm
from internal tetramethylsilane (TMS) on the
δ scale,
multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m =
multiplet; br = broad), coupling constant (Hz), integration, and
assignment. High-resolution mass spectra (HRMS) were recorded
4.2.4
1-(2”-Hydroxyethyl)-3-(4’-isopropylphenyl)pyrazole
(2A-3): Purified by column chromatography on silica gel (eluent,
hexane : ethyl acetate = 4:1); Yield: 152.4mg (66%); pale brown
solid; Mp: 78-80 °C; IR (neat) 3241, 2956, 1472, 1224 cm-1;
1H-NMR (400 MHz, DMSO-d6): δ = 1.20 (d, 6H, J = 6.9 Hz),
2.87 (septet, 1H, J = 6.9 Hz), 3.74 (q, 2H, J = 5.3 Hz), 4.15 (t, 2H,
J = 5.3 Hz), 4.90 (t, 1H, J = 5.3 Hz), 6.20 (d, 1H, J = 2.2 Hz), 7.23
(d, 2H, J = 8.3 Hz), 7.67 (d, 2H, J = 8.3 Hz), 7.70 (d, 1H, J = 2.2
Hz); 13C-NMR (100 MHz, CDCl3): δ = 23.9, 33.8, 53.6, 62.0,
102.4, 125.5, 126.6, 130.7, 131.3, 148.5, 152.0; HRMS (ESI)
Calcd for C14H19N2O[M+H]+ = 231.1492, Found = 231.1492.
by
a
Thermo Fisher Scientific Exactive Orbitrap mass
IR spectra were measured with JASCO
spectrometer.
a
FT/IR-4100 spectrometer. Melting points were determined with a
Yamato Melting Point Apparatus Model MP-21. Silica gel 60F254
(Merck) was used for TLC and Silica gel 60N (63~210 mesh,
Kanto Kagaku Co.) was used for short column chromatography.
4.2 Typical Procedure for One-pot Transformation of Arenes
1 into 3-Arylpyrazoles 2: To a solution of cumene (1a) (1.0
mmol, 120 mg) in CH2Cl2 (2.0 mL) was added β-bromopropionyl
chloride (1.0 mmol, 0.1 mL with a 250µL micro-syringe) at 0
under Ar atmosphere. The mixture was stirred for a few minutes.
Then, anhydrous AlCl3 (1.6 mmol, 213 mg) was added and the
mixture was stirred for 1 h at 0 . After removal of the solvent,
cooled water (2.0 mL) and then n-PrOH (6.0 mL) were added.
Na2CO3 (5.0 mmol, 523mg) was added and the obtained mixture
was stirred for a few minutes under air and refluxing conditions.
After that, NH2NHMe (1.1 mmol, 57ꢀl) was added and the
obtained mixture was stirred for 22 h under air and refluxing
conditions. After removal of the solvent, toluene (6.0 mL) and
MnO2 (7.0 mmol, 608 mg) were added. After being stirred for 24
h under air and refluxing conditions, the mixture was filtered
through celite, and then the filtrate was concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (eluent, hexane : ethyl acetate = 8:1)
to afford 3-(4’-isopropylphenyl)-1-methylpyrazole (2A) in 82%
yield (165 mg).
4.2.5 3-(4’-Isopropylphenyl)-1H-pyrazole (2Aa): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 4:1); Yield: 156.1mg (84%); white solid; Mp:
52-54 °C; IR (neat) 3177, 2958, 1455 cm-1; H-NMR (400 MHz,
1
CDCl3): δ = 1.27 (d, 6H, J = 7.0 Hz), 2.93 (septet, 1H, J = 7.0 Hz),
6.58 (d, 1H, J = 2.2 Hz), 7.27 (d, 2H, J = 8.1 Hz), 7.60 (d, 1H, J =
2.0 Hz), 7.66 (d, 2H, J = 8.1 Hz); 13C-NMR (100 MHz, CDCl3): δ
= 23.8, 33.8, 102.2, 125.8, 126.7, 129.5, 1337, 148.5, 148.7;
HRMS (ESI) Calcd for C12H15N2 [M+H]+ = 187.1230, Found =
187.1225.
4.2.6 3-(4’-Methylphenyl)-1-methylpyrazole (2B): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 8:1); Yield: 144.6mg (84%); pale yellow solid Mp:
42-44 °C; IR (neat) 2941, 1540, 1456 cm-1; H-NMR (400 MHz,
1
CDCl3): δ = 2.36 (s, 3H), 3.94 (s, 3H), 6.50 (d, 1H, J = 2.0 Hz),
7.19 (d, 2H, J = 8.1 Hz), 7.36 (d, 1H, J = 2.0 Hz), 7.68(d, 2H, J =
8.1 Hz); 13C-NMR (100 MHz, CDCl3): δ = 21.2, 38.9, 102.5,
125.3, 129.2, 130.6, 131.2, 137.1, 151.6; HRMS (ESI) Calcd for
C11H13N2 [M+H]+ = 173.1073, Found = 173.1074.
4.2.1 3-(4’-Isopropylphenyl)-1-methylpyrazole (2A): Purified
by column chromatography on silica gel (eluent, hexane : ethyl
acetate = 8:1); Yield: 165.2mg (82%); pale yellow oil; IR (neat)
2959, 1457, 1428 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.26 (d,
6H, J = 7.0 Hz), 2.92 (septet, 1H, J = 7.0 Hz), 3.95 (s, 3H), 6.50
(d, 1H, J = 2.0 Hz), 7.25 (d, 2H, J = 8.1 Hz), 7.35 (d, 1H, J = 2.0
Hz), 7.70 (d, 2H, J = 8.1 Hz); 13C-NMR (100 MHz, CDCl3): δ =
23.8, 33.7, 38.7, 102.4, 125.3, 126.4, 131.0, 131.1, 148.0, 151.4;
HRMS (ESI) Calcd for C13H17N2 [M+H]+ = 201.1386, Found =
201.1385.
4.2.7 3-(4’-tert-Butylphenyl)-1-methylpyrazole (2C): Purified
by column chromatography on silica gel (eluent, hexane : ethyl
acetate = 7:1); Yield: 173.8mg (81%); pale yellow oil; IR (neat)
2936, 1540, 1474, 1363 cm-1; H-NMR (400 MHz, CDCl3): δ =
1
1.33 (s, 9H), 3.93 (s, 3H), 6.50 (d, 1H, J = 1.8 Hz), 7.34 (d, 1H, J
= 1.8 Hz), 7.41 (d, 2H, J = 8.3 Hz), 7.72 (d, 2H, J = 8.3 Hz);
13C-NMR (100 MHz, CDCl3): δ = 31.2, 34.4, 38.7, 102.4, 125.0,
125.3, 130.6, 131.0, 150.2, 151.4; HRMS (ESI) Calcd for
C14H19N2 [M+H]+ = 215.1543, Found = 215.1541.
4.2.2 3-(4’-isopropylphenyl)-1-phenylpyrazole (2A-1): Purified
by column chromatography on silica gel (eluent, hexane : ethyl
acetate = 10:1); Yield: 224.5mg (86%); yellow solid; Mp:
4.2.8 3-[(1’,1”-Biphenyl)-4’-yl]-1-methylpyrazole (2D): Purified
by column chromatography on silica gel (eluent, hexane : ethyl
1
83-84 °C; IR (neat) 2971, 2360, 1597, 1448 cm-1; H-NMR (400
acetate
= 4:1); Yield: 181.1mg (89%); white solid; Mp:

Tetrahedron
7
115-116 °C; IR (neat) 2350, 1507, 1419 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 3.97 (s, 3H), 6.58 (d, 2H, J = 2.0 Hz), 7.34 (t, 1H, J =
7.2 Hz), 7.44 (t, 2H, J = 7.2 Hz), 7.63 (d, 2H, J = 8.1 Hz), 7.63 (d,
2H, J = 8.0 Hz), 7.86 (d, 2H, J = 8.6 Hz); 13C-NMR (100 MHz,
CDCl3): δ =38.9, 102.8, 125.8, 126.8, 127.1, 127.2, 128.6, 131.3,
132.4, 140.1, 140.7, 151.1; HRMS (ESI) Calcd for C16H15N2
[M+H]+ = 235.1230, Found = 235.1228.
8.1 Hz), 7.34 (d, 1H, J = 2.0 Hz), 7.51 (d, 1H, J = 8.1 Hz), 7.66 (s,
1H); 13C-NMR (100 MHz, CDCl3): δ = 29.4, 38.7, 71.2, 102.0,
109.0, 122.1, 125.4, 126.2, 127.2, 131.1, 151.6, 159.6; HRMS
(ESI) Calcd for C12H13ON2 [M+H]+ = 201.1022, Found =
201.1021.
4.2.15
3-(2’-Methoxy-5’-methylphenyl)-1-methylpyrazole
(2K): Purified by column chromatography on silica gel (eluent,
hexane : ethyl acetate = 4:1); Yield: 112.8mg (56%); colorless oil;
IR (neat) 2938, 2360, 1611, 1284 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 2.32 (s, 3H), 3.86 (s, 3H), 3.96 (s, 3H), 6.75 (d, 1H, J
= 2.2 Hz), 6.86 (d, 1H, J = 7.6 Hz), 7.07 (d, 1H, J = 7.6 Hz), 7.37
(d, 1H, J = 2.2 Hz), 7.71(s, 1H); 13C-NMR (100 MHz, CDCl3): δ
= 20.3, 38.7, 55.3, 106.7, 111.1, 121.8, 128.8, 129.7 (2C), 130.2,
4.2.9 3-(2’,5’-dimethylphenyl)-1-methylpyrazole (2E): Purified
by column chromatography on silica gel (eluent, hexane : ethyl
acetate = 8:1); Yield: 165.3mg (89%); pale yellow oil; IR (neat)
1
2946, 1615, 1456 cm-1; H-NMR (400 MHz, CDCl3): δ = 2.33 (s,
3H), 2.41 (s, 3H), 3.96 (s, 3H), 6.38 (d, 1H, J = 2.0 Hz), 7.04 (d,
1H, J = 7.6 Hz), 7.12 (d, 1H, J = 7.8 Hz), 7.38 (d, 1H, J = 2.0 Hz),
7.39 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ =20.5, 20.8, 38.9,
105.9, 128.2, 129.7, 130.2, 130.5, 132.6, 133.0, 135.1, 151.8;
HRMS (ESI) Calcd for C12H15N2 [M+H]+ = 187.1230, Found =
187.1225.
148.2, 154.2; HRMS (ESI) Calcd for C12H15ON2 [M+H]+
203.1179, Found = 203.1176.
=
4.2.16
3-(2’-Hydroxy-5’-methylphenyl)-1-methylpyrazole
(2K‘): Purified by column chromatography on silica gel (eluent,
hexane : ethyl acetate = 7:1); Yield: 96.9mg (52%); pale yellow
solid; Mp: 70-71 °C; IR (neat) 3648, 2943, 1518, 1284 cm-1;
1H-NMR (400 MHz, CDCl3): δ = 2.31 (s, 3H), 3.94 (s, 3H), 6.59
(d, 1H, J = 2.2 Hz), 6.91 (d, 1H, J = 8.1 Hz), 7.00 (dd, 1H , J =
8.1, 2.0 Hz), 7.35 (d, 1H, J = 2.0 Hz), 7.39 (d, 1H, J = 2.2 Hz),
10.61 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 20.5, 38.7, 101.9,
116.2, 116.6, 126.3, 128.0, 129.5, 130.8, 151.2, 153.4: HRMS
(ESI) Calcd for C11H13ON2 [M+H]+ = 189.1022, Found =
189.1022.
4.2.10 1-Methyl-3-(3’,4’,5’-trimethylphenyl)pyrazole (2F):
Purified by column chromatography on silica gel (eluent, hexane :
ethyl acetate = 8:1); Yield: 144.8mg (72%); pale yellow solid;
1
Mp: 43-45 °C; IR (neat) 2938, 1499, 1456 cm-1; H-NMR (400
MHz, CDCl3): δ = 2.18 (s, 3H), 2.32 (s, 6H), 3.94 (s, 3H) , 6.49 (d,
1H, J = 2.2 Hz), 7.35 (d, 1H, J = 2.2 Hz), 7.43 (s, 2H); 13C-NMR
(100 MHz, CDCl3): δ = 15.1, 20.5, 38.8, 102.4, 124.5, 130.2,
131.1, 134.4, 136.5, 151.7; HRMS (ESI) Calcd for C13H17N2
[M+H]+ = 201.1386, Found = 201.1385.
4.2.11 3-Mesityl-1-methylpyrazole (2G): Purified by column
chromatography on silica gel (eluent, hexane : ethyl acetate =
8:1); Yield: 107.1mg (53%); pale yellow oil; IR (neat) 2922, 1499,
1456 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.10 (s, 6H), 2.29 (s,
3H), 3.94 (s, 3H), 6.12 (d, 1H, J = 2.2 Hz), 6.89 (s, 2H), 7.40 (d,
1H, J = 2.2 Hz); 13C-NMR (100 MHz, CDCl3): δ = 20.4, 21.0,
38.7, 106.3, 127.9, 130.0, 131.0, 137.0, 137.4, 150.4; HRMS
(ESI) Calcd for C13H17N2 [M+H]+ = 201.1386, Found = 201.1385.
4.2.17 3-(4’-Fluorophenyl)-1-methylpyrazole (2L): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 6:1); Yield: 133.0mg (75%); pale yellow solid; Mp:
1
68-69 °C; IR (neat) 2971, 2360, 1507, 1065 cm-1; H-NMR (400
MHz, CDCl3): δ = 3.94 (s, 3H), 6.48 (d, 1H, J = 2.2 Hz), 7.08 (t,
2H, J = 8.8 Hz), 7.37 (d, 1H, J = 2.2 Hz), 7.72-7.78 (m, 2H);
13C-NMR (100 MHz, CDCl3): δ = 38.9, 102.5, 115.4 (d, JC-F
=
21.6 Hz), 127.0 (d, JC-F = 8.4 Hz), 129.7, 131.4, 150.6, 162.3 (d,
JC-F = 246.1 Hz); HRMS (ESI) Calcd for C10H10FN2 [M+H]+ =
177.0823, Found = 177.0822.
4.2.12 3-(4’-Methoxyphenyl)-1-methylpyrazole (2H): Purified
by column chromatography on silica gel (eluent, hexane : ethyl
acetate = 4:1); Yield: 155.3mg (82%); white solid; Mp: 73-74 °C;
4.2.18 3-(4’-Chlorophenyl)-1-methylpyrazole (2M): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 6:1); Yield: 127.9mg (66%); white solid; Mp: 68-69 °C;
IR (neat) 2970, 2361, 1455, 757 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 3.94 (s, 3H), 6.50 (d, 1H, J = 2.2 Hz), 7.35 (d, 2H, J
= 8.6 Hz), 7.37 (d, 1H, J = 2.2 Hz), 7.72 (d, 2H, J = 8.6 Hz);
13C-NMR (100 MHz, CDCl3): δ = 38.9, 102.7, 126.6, 128.6, 131.4,
132.0, 133.0, 150.3; HRMS (ESI) Calcd for C10H1035ClN2 [M+H]+
= 193.0527, Found = 193.0531.
1
IR (neat) 2966, 1615, 1507 cm-1; H-NMR (400 MHz, CDCl3): δ
= 3.83 (s, 3H), 3.93 (s, 3H), 6.46 (d, 1H, J = 2.0 Hz), 6.92 (d, 2H,
J = 8.7 Hz), 7.35 (d, 1H, J = 2.0 Hz), 7.71 (d, 2H, J = 8.7 Hz);
13C-NMR (100 MHz, CDCl3): δ =39.0, 55.3, 102.3, 114.0, 126.5,
126.8, 131.4, 151.4, 159.2; HRMS (ESI) Calcd for C11H13ON2
[M+H]+ = 189.1022, Found = 189.1022.
4.2.13 3-(4’-Ethoxyphenyl)-1-methylpyrazole (2I): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 4:1); Yield: 133.7mg (66%); white solid; Mp: 86-87 °C;
4.2.19 3-(4’-Bromophenyl)-1-methylpyrazole (2N): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 5:1); Yield: 129.9mg (55%); white solid; Mp: 76-77 °C;
IR (neat) 2341, 1498, 1456, 614 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 3.94 (s, 3H), 6.51 (d, 1H, J = 2.0 Hz), 7.37 (d, 1H, J
= 2.0 Hz), 7.50 (d, 2H, J = 8.1 Hz), 7.66 (d, 2H, J = 8.1 Hz);
13C-NMR (100 MHz, CDCl3): δ = 39.0, 102.7, 121.2, 126.9, 131.4,
131.6, 132.4, 150.3; HRMS (ESI) Calcd for C10H1079BrN2
[M+H]+ = 237.0022, Found = 237.0022.
1
IR (neat) 2360, 1507, 1240 cm-1; H-NMR (400 MHz, CDCl3): δ
= 1.42 (t, 3H, J = 6.9 Hz ), 3.93 (s, 3H), 4.06 (q, 2H, J = 6.9 Hz),
6.45 (d, 1H, J = 2.2 Hz), 6.91 (d, 2H, J = 8.7 Hz), 7.35 (d, 1H, J =
2.2 Hz), 7.70 (d, 2H, J = 8.7 Hz); 13C-NMR (100 MHz, CDCl3): δ
= 14.7, 38.8, 63.3, 102.1, 114.4, 126.1, 126.6, 131.2, 151.4, 158.4;
HRMS (ESI) Calcd for C12H15ON2 [M+H]+ = 203.1179 Found =
203.1177.
4.2.14
3-(2’,3’-Dihydrobenzofuran-5’-yl)-1-methylpyrazole
(2J): Purified by column chromatography on silica gel (eluent,
4.2.20 1-Methyl-3-(naphthalen-2’-yl)pyrazole (2O): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 7:1); Yield: 175.4mg (84%); pale yellow oil; IR (neat)
hexane : ethyl acetate = 4:1); Yield: 149.8mg (75%); white solid;
1
Mp: 74-75 °C; IR (neat) 2960, 2360, 1457, 1227 cm-1; H-NMR
1
(400 MHz, CDCl3): δ = 3.32 (t, 2H, J = 8.6 Hz ), 3.93 (s, 3H),
4.59 (t, 2H, J = 8.6 Hz), 6.43 (d, 1H, J = 2.0 Hz), 6.79 (d, 1H, J =
3046, 2360, 1592, 1508 cm-1; H-NMR (400 MHz, CDCl3): δ =
4.04 (s, 3H), 6.55 (d, 1H, J = 2.0 Hz), 7.47-7.52 (m, 4H), 7.67 (d,

8
Tetrahedron
1H, J = 7.0 Hz), 7.83-7.89 (m, 2H), 8.48-8.51 (m, 1H); 13C-NMR
(100 MHz, CDCl3): δ = 38.9, 106.6, 125.2, 125.6, 126.0, 126.1,
126.8, 128.0, 128.1, 130.5, 131.3, 131.6, 133.8, 151.0; HRMS
(ESI) Calcd for C14H13N2 [M+H]+ = 209.1073, Found = 209.1072.
under Ar atmosphere. The mixture was stirred for a few minutes.
Then, anhydrous AlCl3 (1.6 mmol, 213 mg) was added and the
mixture was stirred for 1 h at 0
.
After that, cooled water (2.0
mL) was added. After removal of the solvent under reduced
pressure, MeOH (12.0 mL), NH2OH・HCl (1.1 mmol, 76.4mg),
and KF (10.0 mmol, 581 mg) were added to the residue. After
being stirred for 67 h under air and refluxing conditions, the
mixture was quenched by water (30.0 mL) and extracted with
AcOEt (3 x 20 mL). The organic layer was dried over Na2SO4.
After removal of the solvent under reduced pressure, the residue
was purified by flash column chromatography on silica gel (eluent,
4.2.21 1-Methyl-3-(4’-methylnaphthalen-1’-yl)pyrazole (2P):
Purified by column chromatography on silica gel (eluent, hexane :
ethyl acetate = 7:1); Yield: 168.0 mg (76%); yellow oil; IR (neat)
1
2940, 2356, 1591 cm-1; H-NMR (400 MHz, CDCl3): δ = 2.72 (s,
3H), 4.03 (s, 3H), 6.51 (d, 1H, J = 2.2 Hz), 7.35 (d, 1H, J = 7.4
Hz), 7.47-7.57 (m, 4H), 8.04 (d, 1H, J = 9.6 Hz), 8.50 (d, 1H, J =
9.6 Hz); 13C-NMR (100 MHz, CDCl3): δ = 19.6, 39.0, 106.7,
124.2, 125.4, 125.7, 126.1, 126.6 (2C), 130.0, 130.4, 131.4, 132.8,
134.2, 151.3; HRMS (ESI) Calcd for C15H15N2 [M+H]+=223.1230,
Found = 223.1228.
hexane
:
ethyl
acetate
=
9:1)
to
afford
3-(4’-isopropylphenyl)isoxazoline (3A) in 79% yield (150 mg).
4.3.1 3-(4’-Isopropylphenyl)isoxazoline (3A): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 9:1); Yield: 150.1mg (79%); white solid; Mp: 46-48 °C;
4.2.22 3-(4’-Methoxynaphthalen-1’-yl)-1-methylpyrazole (2Q):
Purified by column chromatography on silica gel (eluent, hexane :
ethyl acetate = 4:1); Yield: 165.5 mg (70%); yellow oil; IR (neat)
1
IR (neat) 2961, 1607, 1187 cm-1; H-NMR (400 MHz, CDCl3): δ
= 1.26 (d, 6H, J = 6.7 Hz), 2.93 (septet, 1H, J = 6.7 Hz), 3.34 (t,
2H, J = 10.0 Hz), 4.47 (t, 2H, J = 10.0 Hz), 7.27 (d, 2H, J = 8.0
Hz), 7.62 (d, 2H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3): δ =
23.7, 34.0, 35.3, 68.9, 126.7 (2C), 126.9, 151.1, 156.7; HRMS
(ESI) Calcd for C12H16NO [M+H]+ = 190.1226, Found =
190.1226.
1
2938, 2350, 1417 cm-1; H-NMR (400 MHz, CDCl3): δ = 4.02 (s,
3H), 4.03 (s, 3H), 6.49 (d, 1H, J = 2.2 Hz), 6.89 (d, 1H, J = 8.1
Hz), 7.46-7.59 (m, 3H), 7.58 (d, 1H, J = 8.1 Hz), 8.31 (d, 1H, J =
7.0 Hz), 8.43 (d, 1H, J = 7.0 Hz) 13C-NMR (100 MHz, CDCl3): δ
= 38.7, 55.2, 103.2, 106.1, 121.8, 124.0, 124.8, 125.5, 125.6,
126.5, 126.9, 130.3, 132.1, 151.0, 155.0; HRMS (ESI) Calcd for
C15H15ON2 [M+H]+ = 239.1179, Found = 239.1177.
4.3.2 3-(4’-Methylphenyl)isoxazoline (3B): Purified by column
chromatography on silica gel (eluent, hexane : ethyl acetate =
9:1); Yield: 117.6mg (73%); white solid; Mp: 57-59 °C; IR (neat)
4.2.23
3-(5’-Ethylthiophen-2’-yl)-1-methylpyrazole
(2R):
1
2887, 1607, 1351 cm-1; H-NMR (400 MHz, CDCl3): δ = 2.38 (s,
Purified by column chromatography on silica gel (eluent, hexane :
ethyl acetate = 6:1); Yield: 101.6 mg (53%); brown oil; IR (neat)
3H), 3.32 (t, 2H, J = 10.1 Hz), 4.47 (t, 2H, J = 10.1 Hz), 7.17 (d,
2H, J = 7.8 Hz), 7.58 (d, 2H, J = 7.8 Hz): δ = 21.2, 35.1, 68.8,
126.5 (2C), 129.2, 140.1, 156.6; HRMS (ESI) Calcd for
C10H12NO [M+H]+ = 162.0913, Found = 162.0914.
1
2966, 1455, 1067 cm-1; H-NMR (400 MHz, CDCl3): δ = 1.32 (t,
3H, J = 7.4 Hz), 2.84 (q, 2H, J = 7.4 Hz), 3.90 (s, 3H), 6.38 (d, 1H,
J = 2.0 Hz), 6.71 (d, 1H, J = 3.4 Hz), 7.09 (d, 1H, J = 3.4 Hz),
7.31 (d, 1H, J = 2.0 Hz); 13C-NMR (100 MHz, CDCl3): δ = 15.8,
23.3, 38.7, 102.2, 122.8, 123.5, 131.1, 133.8, 146.3, 146.9; HRMS
(ESI) Calcd for C10H13SN2 [M+H]+ = 193.0794, Found =
193.0793.
4.3.3 3-(4’-tert-Butylphenyl)isoxazoline (3C): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 10:1); Yield: 126.7mg (62%); colorless oil; IR (neat)
1
2962, 1607, 1349 cm-1; H-NMR (400 MHz, CDCl3): δ = 1.33 (s,
4.2.24 1-Methyl-3-(3’-methylbenzo[b]thiophen-2’-yl)pyrazole
(2S): Purified by column chromatography on silica gel (eluent,
hexane : ethyl acetate = 5:1); Yield: 135.8 mg (60%); pale yellow
9H), 3.34 (t, 2H, J = 10.1 Hz), 4.47 (t, 2H, J = 10.1 Hz), 7.43 (d,
2H, J = 8.7 Hz), 7.62 (d, 2H, J = 8.7 Hz); 13C-NMR (100 MHz,
CDCl3): δ = 31.0, 34.6, 35.1, 68.8, 125.4, 126.4, 126.4, 153.2,
156.5; HRMS (ESI) Calcd for C13H18NO [M+H]+ = 204.1383,
Found = 204.1382.
1
oil; IR (neat) 2941, 1480, 1019, 654 cm-1; H-NMR (400 MHz,
CDCl3): δ = 2.64 (s, 3H), 4.01 (s, 3H), 6.43 (d, 1H, J = 2.0 Hz),
7.26-7.34 (m, 2H), 7.48 (d, 1H, J = 2.0 Hz), 7.75 (d, 1H, J = 7.0
Hz), 7.96 (d, 1H, J = 7.9 Hz); 13C-NMR (100 MHz, CDCl3): δ =
15.0, 39.0, 106.3, 121.6, 122.9, 123.5, 124.1, 125.9, 130.4, 137.8,
138.0, 139.8, 146.1; HRMS (ESI) Calcd for C13H13N2S [M+H]+ =
229.0794, Found = 229.0790.
4.3.4 3-[(1,1'-Biphenyl)-4’-yl]isoxazoline (3D): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate
= 7:1); Yield: 187.2mg (77%); white solid; Mp:
153-156 °C; IR (neat) 2359, 1681, 1602 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 3.38 (t, 2H, J = 9.9 Hz), 4.51 (t, 2H, J = 9.9 Hz), 7.38
(t, 1H, J = 7.7 Hz), 7.46 (t, 2H, J = 8.1 Hz), 7.61-7.66 (m, 4H),
7.77 (d, 2H, J = 7.7 Hz); 13C-NMR (100 MHz, CDCl3): δ = 35.1,
69.1, 126.9, 127.1, 127.2, 127.7, 128.2, 128.8, 140.0, 142.6,
156.4; HRMS (ESI) Calcd for C15H14NO [M+H]+ = 224.1070,
Found = 224.1069.
4.2.25 1-Methyl-3-(3’-methylbenzofuran-2’-yl)pyrazole (2T):
Purified by column chromatography on silica gel (eluent, hexane :
ethyl acetate = 7:1); Yield: 111.3 mg (57%); pale brown oil; IR
1
(neat) 2938, 1474, 1029, 791 cm-1; H-NMR (400 MHz, CDCl3):
δ = 2.49 (s, 3H), 3.99 (s, 3H), 6.64 (d, 1H, J = 2.2 Hz), 7.21-7.32
(m, 2H), 7.41 (d, 1H, J = 2.2 Hz), 7.49 (d, 1H, J = 7.4 Hz), 7.52 (d,
1H, J = 7.4 Hz); 13C-NMR (100 MHz, CDCl3): δ =8.70, 39.2,
104.4, 111.1, 111.5, 119.1, 122.2, 124.1, 130.7, 130.8, 143.9,
4.3.5 3-(3’,4’,5’-Trimethylphenyl)isoxazoline (3F): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 10:1); Yield: 110.0mg (55%); pale yellow solid; Mp:
145.8, 153.8; HRMS (ESI) Calcd for C13H13N2O [M+H]+
213.1022, Found = 213.1018.
=
1
77-79 °C; IR (neat) 2920, 1438, 1354 cm-1; H-NMR (400 MHz,
CDCl3): δ = 2.19 (s, 3H), 2.30 (s, 6H), 3.31 (d, 2H, J = 10.1 Hz),
4.45 (d, 2H, J = 10.1 Hz), 7.33 (s, 2H); 13C-NMR (100 MHz,
CDCl3): δ =15.4, 20.5, 35.3, 68.8, 125.8, 126.1, 136.7, 137.5,
156.9; HRMS (ESI) Calcd for C12H16NO [M+H]+ = 190.1226,
Found = 190.1225.
4.3 Typical Procedure for One-pot Transformation of Arenes
1 into 3-Arylisoxazolines 3: To a solution of cumene (1a) (1.0
mmol, 120 mg) in CH2Cl2 (2.0 mL) was added β-bromopropionyl
chloride (1.0 mmol, 0.1 mL with a 250µL micro-syringe) at 0

Tetrahedron
9
3H, J = 7.6 Hz), 2.85 (q, 2H, J = 7.6 Hz), 3.31 (t, 2H, J = 10.1 Hz),
4.46 (t, 2H, J = 10.1 Hz), 6.74 (d, 1H, J = 3.5 Hz), 7.02 (d, 1H, J
= 3.5 Hz); 13C-NMR (100 MHz, CDCl3): δ = 15.6, 23.5, 35.9, 69.1,
123.6, 128.5, 129.1, 151.1, 152.6; HRMS (ESI) Calcd for
C9H12NOS [M+H]+ = 182.0634, Found = 182.0633.
4.3.6 3-(4’-Methoxyphenyl)isoxazoline (3H): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 7:1); Yield: 116.1mg (66%); white solid; Mp: 78-79 °C;
1
IR (neat) 2965, 2360, 1604 cm-1; H-NMR (400 MHz, CDCl3): δ
= 3.31 (t, 2H, J = 10.1 Hz),3.84 (s, 3H), 4.46 (t, 2H, J = 10.1 Hz),
6.92 (d, 2H, J = 8.7 Hz), 7.63 (d, 2H, J = 8.7 Hz); 13C-NMR (100
MHz, CDCl3): δ = 35.4, 55.3, 68.9, 114.0, 122.0, 128.2, 156.3,
160.9; HRMS (ESI) Calcd for C10H12NO2 [M+H]+ = 178.0863,
Found = 178.0862.
Supporting Information: Copies of 1H NMR and 13C NMR
spectra of all 3-arylpyrazoles 2 and 3-arylisoxazolines 3.
Acknowledgments
4.2.7 3-(4’-Ethoxyphenyl)isoxazoline (3I): Purified by column
chromatography on silica gel (eluent, hexane : ethyl acetate =
7:1); Yield: 111.1 mg (58%); white solid; Mp: 58-59 °C; IR (neat)
This work was supported by JSPS KAKENHI Grant Number
JP15K05418 in Japan.
1
2890, 2360, 1607 cm-1; H-NMR (400 MHz, CDCl3): δ = 1.43 (t,
3H, J = 7.0 Hz), 3.31 (t, 2H, J = 9.9 Hz), 4.06 (q, 2H, J = 7.0 Hz),
4.45 (t, 2H, J = 9.9 Hz), 6.91 (d, 2H, J = 8.8 Hz), 7.62 (d, 2H, J =
8.8 Hz); 13C-NMR (100 MHz, CDCl3): δ = 14.7, 35.4, 63.4, 68.8,
114.5, 121.7, 128.1, 156.3, 160.3; HRMS (ESI) Calcd for
C11H14NO2 [M+H]+ = 192.1019, Found = 192.1017.
References
1.
Reviews for Pyrazoles: a) Xu, Z.; Gao, C.; Ren, Q.; Song,
X.; Feng, L.; Lv, Z. Eur. J. Med. Chem. 2017, 139, 429-440.
b) Faria, J. V.; Vegi, P. F.; Miguita, A. G. C.; dos Santos,
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Fustero, S.; Sánchez-Roselló, M.; Barrio, P.;
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Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocyclic
Chem. 1998, 35, 489-497. f) Yet, L. “Pyrazoles” in
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their Fused Carbocyclic Derivatives”, p.1-p.141, Chap.
4.01, Vol. 4, Eds. Katritzky, A. R.; Ramsden, C. A.;
Scriven, E. F. V.; Taylor, R. J. K. “Comprehensive
Heterocyclic Chemistry III”, Elsevier, 2008.
4.3.8
3-(2’,3’-dihydrobenzofuran-5’-yl)isoxazoline
(3J):
Purified by column chromatography on silica gel (eluent, hexane :
ethyl acetate = 7:1); Yield: 114.2mg (60%); white solid; Mp:
1
97-99 °C; IR (neat) 2922, 2359, 1615 cm-1; H-NMR (400 MHz,
CDCl3): δ = 3.24 (t, 2H, J = 8.6 Hz), 3.30 (t, 2H, J = 9.9 Hz), 4.45
(t, 2H, J = 9.9 Hz), 4.62 (t, 2H, J = 8.6 Hz), 6.79 (d, 1H, J = 8.0
Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.63 (s, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 29.3, 35.5, 68.8, 71.6, 109.2, 121.9, 123.3, 127.4,
127.8, 156.6, 161.7; HRMS (ESI) Calcd for C11H12NO2 [M+H]+ =
190.0863, Found = 190.0859.
4.3.9 3-(4’-Fluorophenyl)isoxazoline (3L): Purified by column
chromatography on silica gel (eluent, hexane : ethyl acetate =
6:1); Yield: 137.6mg (83%); white solid; Mp: 76-78°C; IR (neat)
2.
3.
Review for Isoxazolines: (a) Kaur, K.; Kumar, V.; Sharma,
A. K.; Gupta, G. K. Eur. J. Med. Chem. 2014, 77, 121-133.
Recent Reports for Pyrazoles: a) Wang, H.; Sun, X.; Zhang,
S.; Liu, G.; Wang, C.; Zhu, L.; Zhang, H. Synlett 2018, 29,
2689-2692. b) de Aquino, T. F. B.; Seidel, J. P.; de Oliveira,
D. H.; do Nascimento, J. E. R.; Alves, D.; Perin, G.;
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Q.; Zhu, G.; Qu, J.; Wang, B. Tetrahedron Lett. 2016, 57,
2633-2637. d) Everson, N.; Yniguez, K.; Loop, L.; Lazaro,
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Zharkova, D. A.; Asachenko, A. F.; Muzalevskiy, V. M.;
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Chem. 2018, 16, 7935-7946. h) Perin, G.; Nobre, P. C.;
Mailahn, D. H.; Silva, M. S.; Barcellos, T.; Jacob, R. G.;
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2293-2304. i) Tu, K. N.; Kim, S.; Blum, S. A. Org. Lett.
2019, 21, 1283-1286. j) Raj, J. P.; Gangaprasad, D.;
Karthikeyan, K.; Rengasamy, R.; Kesavan, M.;
Venkateswarulu, M.; Vajjiravel, M.; Elangovan, J.
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Bouyssi, D.; Monteiro, N. ACS Catal. 2016, 6, 7197-7201.
1
2895, 1596, 1159 cm-1; H-NMR (400 MHz, CDCl3): δ = 3.32 (t,
2H, J = 9.9Hz), 4.49 (t, 2H, J = 9.9 Hz), 7.10 (t, 2H, J = 8.6 Hz),
7.66-7.70 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ = 35.2, 69.2,
115.8 (d, JC-F = 21.9 Hz), 125.7, 128.6 (d, JC-F = 8.5 Hz), 155.8,
163.7(d, JC-F = 250.8 Hz); HRMS (ESI) Calcd for C9H9FNO
[M+H]+ = 166.0663, Found = 166.0661.
4.3.10 3-(4’-Chlorophenyl)isoxazoline (3M): Purified by column
chromatography on silica gel (eluent, hexane : ethyl acetate =
7:1); Yield: 103.4 mg (57%); white solid; Mp: 106-107 °C; IR
1
(neat) 2360, 2894, 1011 cm-1; H-NMR (400 MHz, CDCl3): δ =
3.33 (t, 2H, J = 10.1 Hz), 4.52 (t, 2H, J = 10.1 Hz), 7.38 (d, 2H, J
= 8.6 Hz), 7.62 (d, 2H, J = 8.6 Hz); 13C-NMR (100 MHz, CDCl3):
δ = 34.9, 69.3, 127.8 (2C), 128.8, 135.8, 155.8; HRMS (ESI)
Calcd for C9H935ClNO [M+H]+ = 182.0367, Found = 182.0365.
4.3.11 3-(Naphthalen-2’-yl)isoxazoline (3O): Purified by column
chromatography on silica gel (eluent, hexane : ethyl acetate =
9:1); Yield: 113.5 mg (58%); white solid; Mp: 78-80 °C; IR (neat)
1
2884, 1600, 1507 cm-1; H-NMR (400 MHz, CDCl3): δ = 3.47 (t,
2H, J = 10.1 Hz), 4.55 (t, 2H, J = 10.1 Hz), 7.51-7.53 (m, 2H),
7.84-7.87 (m, 3H), 7.93 (s, 1H), 7.99 (dd, 1H, J = 7.9, 1.8 Hz);
13C-NMR (100 MHz, CDCl3): δ = 35.1, 69.3, 123.6, 126.6, 126.9,
127.0 (2C), 127.8, 128.3, 128.5, 132.9, 133.9, 156.9; HRMS (ESI)
Calcd for C13H12NO [M+H]+ = 198.0913, Found = 198.0913.
4.
Recent Reports for Isoxazolines: a) Yoshimura, A.; Zhu, C.;
Middleton, K. R.; Todora, A. D.; Kastern, B. J.; Maskaev, A.
V.; Zhdankin, V. V. Chem. Commun. 2013, 49, 4800-4802.
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B. J.; Koski, S. R.; Maskaev, A. V.; Zhdankin, V. V. Org.
4.3.12 3-(5’-Ethylthiophen-2’-yl)isoxazoline (3R): Purified by
column chromatography on silica gel (eluent, hexane : ethyl
acetate = 7:1); Yield: 81.2 mg (45%); pale brown oil; IR (neat)
1
2967, 1260, 805 cm-1; H-NMR (400 MHz, CDCl3): δ = 1.32 (t,

10
Tetrahedron
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W.; Han, B. Org. Lett. 2014, 16, 6476-6479. g) Chen, F.;
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5.
4-Arylthiazoles and 4-Arylimidazoles from Arenes:
Yamamoto, T.; Togo, H. Eur. J. Org. Chem. 2018,
4187-4196.

Highlight
• One-pot operation.
• C(sp2)-C(sp2) construction.