Copper-catalyzed synthesis of trisubstituted isoxazoles via a cascade cyclization-migration process

Article abstract of DOI:10.1021/jo301358h

An atom-economical, catalytic, and regioselective synthesis of 3,4,5-trisubstituted isoxazoles has been successfully developed. Treatment of O-arylmethyl alkynyl oxime ethers with 5 mol % of Cu(OTf)₂ in chlorobenzene at reflux gave 4-arylmethylisoxazoles in good to excellent yields via the sequential intramolecular addition of the oxime moiety to the alkyne with subsequent 1,3-migration of the arylmethyl group.

Full text of DOI:10.1021/jo301358h

Note
pubs.acs.org/joc
Copper-Catalyzed Synthesis of Trisubstituted Isoxazoles via a
Cascade Cyclization−Migration Process
Masafumi Ueda, Shoichi Sugita, Aoi Sato, Tetsuya Miyoshi, and Okiko Miyata*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
S
* Supporting Information
ABSTRACT: An atom-economical, catalytic, and regioselective
synthesis of 3,4,5-trisubstituted isoxazoles has been successfully
developed. Treatment of O-arylmethyl alkynyl oxime ethers with
5 mol % of Cu(OTf)2 in chlorobenzene at reflux gave 4-
arylmethylisoxazoles in good to excellent yields via the sequential
intramolecular addition of the oxime moiety to the alkyne with
subsequent 1,3-migration of the arylmethyl group.
eterocycles are well-known for their wide range of
biological properties.1 Of the various bioactive hetero-
cycles, isoxazoles have attracted considerable interest because of
their wide reaching applications in medicinal chemistry2 and
material science.3 For this reason, considerable research efforts
have been focused on the development of novel and efficient
methods for the synthesis of isoxazoles 3.4
The π-acidic transition-metal-catalyzed intramolecular addi-
H
tion of a heteroatom to an alkyne with subsequent migration of
the substituent initially attached to the heteroatom is one of the
most powerful strategies for the synthesis of heterocyclic
compounds.15 Although the use of these transformations has
effectively provided well-precedented access to benzofurans,16
indoles,17 benzothiophenes,18 furans,19 pyrans,20 and pyrroli-
dine,21 less is known about the synthesis of isoxazoles using this
methodology.22 Our working hypothesis for the current
research is outlined in Scheme 1. We recently reported the
Although isoxazoles are generally synthesized according to an
intermolecular [3 + 2] cycloaddition reaction between an
alkyne and a nitrile oxide,5 the direct construction of
trisubstituted isoxazoles via a cycloaddition reaction with an
internal alkyne has not been reported as frequently in the
literature.6,7 Furthermore, these methods usually require harsh
conditions and result in poor chemo- and regioselectivities. An
alternative stepwise approach has also been reported for the
selective and efficient construction of trisubstituted isoxazoles.
This approach involves the preformation of an isoxazole ring
bearing a functional group at the 4-position, such as a halogen,8
silicon,9 boronic ester10 or aluminum,11 which can be
subsequently cross-coupled with an appropriate coupling
partner to provide the desired substituted product. Using a
more straightforward approach, Chen et al.12 and Campagne et
al.13 independently reported the one-pot synthesis of
trisubstituted isoxazoles using a domino sequence. This
involved the construction of the isoxazole ring system through
a palladium-catalyzed annulation of the corresponding acyclic
precursor with subsequent cross-coupling of the resulting 4-
isoxazolylpalladium intermediate.14 However, these reactions
were not atom-economical, as the loss of a functional group
would result in generation of chemical waste in the course of
the transformation.
Scheme 1. Synthesis of Di- and Trisubstituted Isoxazoles
development of a silver-catalyzed synthesis of disubstituted
isoxazoles via the generation of a vinyl metal intermediate A
which was subsequently protonated under acidic conditions to
give the desired disubstituted isoxazole 2.23 It was envisaged
that the benzyl group could migrate from the oxygen of the
oxonium ion in A to the 4-position of the isoxazole core,
leading to the formation of trisubstituted isoxazoles under
suitable conditions.
Alkynyl oxime ether 1a bearing a p-methoxybenzyl group on
the oxygen atom was selected as a model system for our initial
screening work because it would generate a highly stabilized
carbocation and enhance the migratory aptitude of the benzyl
group. A series of alkynophilic catalysts were screened for their
From the perspective of atom economy alone, the direct
synthesis of trisubstituted isoxazoles with high levels of chemo-
and regioselectivity in a one-pot sequence is both highly
desirable and challenging. Herein, we report the direct synthesis
of trisubstituted isoxazoles using a domino process involving
the transition metal catalyzed cyclization of an O-benzyl alkynyl
oxime ether with subsequent 1,3-migration of the benzyl
groups.
Received: July 8, 2012
© XXXX American Chemical Society
A
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Note
ability to catalyze the synthesis of the trisubstituted isoxazole 3a
(Table 1). When 1a was treated with AuCl3 in dichloroethane
the corresponding trisubstituted isoxazole 3b−i in good to high
yields (Table 2). Electron-rich and electron-poor aryl groups
and an alkyl group were well tolerated at the R1 position,
affording the corresponding trisubstituted isoxazoles 3b−d
(Table 2, entries 1−3) in good yields. Furthermore, the ester
moiety on oxime ether 1e was compatible with the reaction
conditions, providing isoxazole carboxylate 3e (Table 2, entry
4) in good yield and demonstrating the mild nature of the
current transformation. The substituent at the R2 position on
the triple bond terminus could also be varied without any
discernible issue under the optimized reaction conditions. For
example, substrates 1f and 1g bearing aliphatic substituents
performed well under the current reaction conditions providing
the desired trisubstituted isoxazoles in high yields (Table 2,
entries 5 and 6). It is noteworthy that the acidic proton of the
terminal alkyne in oxime 1h did not have an adverse impact on
the transformation and the desired product was obtained in
high chemical yield (Table 2, entry 7). Unfortunately, when the
silyl-protected substrate 1i was subjected to the current reaction
conditions, partial desilylation was observed. Consequently,
upon completion of the copper-catalyzed cyclization, the crude
product was treated with TBAF to afford 4-(hydroxymethyl)-
isoxazole 3i in 65% yield (Table 2, entry 8). Additionally, this
method for the synthesis of trisubstituted isoxazoles can be
applied to a gram scale synthesis; thus, the copper-catalyzed
reaction of 1b (1 g) afforded 3b in 63% yield (entry 9).
We then proceeded to investigate the scope for changing the
substituents on the migrating group (Table 3). The p-
silyloxybenzyl group in oxime ether 4a successfully migrated
to give the corresponding trisubstituted isoxazole 5a in high
yield (Table 3, entry 1). Remarkably, the introduction of a
dimethylamino group in oxime ether 4b enhanced the
efficiency of the domino reaction, which proceeded even at a
lower temperature in refluxing dichloroethane (Table 3, entry
2). The substrate 4c bearing an o-methoxy group gave 5c in
relatively lower yield, likely because of steric repulsion (Table 3,
entry 3). The introduction of an electron-withdrawing group
such as an ester moiety completely inhibited the cyclization
reaction and only the oxime ether 4d was recovered (Table 3,
entry 4). This result indicated that the rate-determining step
involved the generation of the benzyl cation by C−O bond
Table 1. Optimization of Cyclization−Migration Reaction
entry catalyst (mol %)
solvent
bp (°C) time (h) yield (%)
1
2
AuCl3 (5)
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
THF
83
83
10
8
29
23
AuCl3 (10)
3
AgBF4 (5)
83
6
43
4
CuCl2 (5)
83
10
2
NR
57
5
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
83
6
65
2
NR
47
7
toluene
110
137
132
116
2
8
xylenes
2
47
9
PhCl
2
70
a
10
n-BuOH
2
27
a
n-Butyl p-methoxybenzyl ether was obtained in 11% yield.
at reflux, the desired trisubstituted isoxazole 3a was obtained,
albeit in a low yield (Table 1, entries 1 and 2).24 A survey of
other catalysts revealed Cu(OTf)2 as the most effective catalyst
(Table 1, entries 3−5). This reaction was found to be strongly
temperature dependent (Table 1, entries 6−10). Solvent
polarity was also a significant factor for the efficiency of the
reaction (Table 1, entries 8 and 9). It should be noted that n-
butyl p-methoxybenzyl ether was obtained as a byproduct when
the reaction was carried out in n-BuOH (Table 1, entry 10).
This result indicated that the reaction proceeded via generation
of p-methoxybenzyl cation. Following the screening process,
the use of chlorobenzene at reflux was found to be optimal
(Table 1, entries 6−9).
The general scope of the reaction was then examined under
the optimized conditions (Table 1, entry 9). A variety of
different O-p-methoxybenzyl alkynyl oxime ethers 1b−i were
treated with Cu(OTf)2 in refluxing chlorobenzene, affording
Table 2. Copper-Catalyzed Synthesis of Trisubstituted Isoxazoles
a
entry
substrate
R1
R2
product
yield (%)
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
4-CF3C6H4
4-MeOC6H4
cyclohexyl
CO2Me
Ph
Ph
Ph
Ph
Ph
3b
3c
3d
3e
3f
85
78
73
70
66
93
80
65
63
n-Bu
1g
1h
1i
Ph
cyclohexyl
H
3g
3h
Ph
b
8
c
Ph
CH2OTBS
Ph
3i (R2= CH2OH)
9
1b
4-CF3C6H4
3b
a
b
c
Isolated yields. Reaction was carried out with Cu(OTf)2 (5 mol %) followed by treatment with TBAF (1 equiv). Reaction was carried out with 1
g of 1b.
B
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Note
Table 3. Substitution Effect of the Migrating Group
a
Reaction was carried out in (CH2Cl)2 at 83 °C.
Scheme 2. Crossover Reaction between 1b and 4a
cleavage. Pleasingly, the substituted benzyl groups and 2-
naphthylmethyl group in substrates 4e−g were well tolerated
under the current conditions, affording 5e−g (Table 3, entries
5−7) in moderate yields.
To investigate the migration step in the current reaction, a
crossover experiment was performed in which an equimolar
mixture of two different alkynyl oxime ethers, 1b and 4a,was
subjected to the domino reaction under the optimized
conditions (Scheme 2). As a result, the noncrossover products
3b and 5a were obtained in 76 and 58% yields, respectively,
together with small amounts of the crossover products 6 and
3a. This result demonstrated that the benzyl cation could
partially dissociate and exchange with the other cations
following the initial cyclization, as a consequence of the high
reaction temperature.
Although the precise mechanism of the reaction could not be
fully elucidated, a possible reaction pathway was proposed and
is depicted in Scheme 3. Initially, the oxygen atom of the oxime
ether adds to the Cu(II)-activated C−C triple bond in a 5-endo-
dig fashion, generating an oxonium intermediate B. The
irreversible generation and 1,3-migration of the benzyl cation
via the formation of ion-pair C would lead to the generation of
C
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Scheme 3. Possible Reaction Pathway
(3H, s). 13C NMR (75 MHz, CDCl3) δ: 159.5, 138.9, 137.1, 132.1,
131.4, 131.0, 130.0, 129.7, 129.3, 121.5, 113.8, 101.9, 79.1, 77.3, 55.2.
HRMS (Orbitrap-ESI): calcd for C24H19NO2F3 [M + H]+ 410.1362,
found 410.1362.
(1Z)-1-(4-Methoxyphenyl)-3-phenyl-2-propyn-1-one O-[(4-
Methoxyphenyl)methyl]oxime (1c). 1-(4-Methoxyphenyl)-3-phenyl-
2-propyn-1-one was used for ketone. Isolated yield 36% (0.87 g).
Colorless oil. IR (neat): 2934, 2213 cm−1. 1H NMR (300 MHz,
CDCl3) δ: 7.84 (2H, dt, J = 8.5, 2.0), 7.58−7.55 (2H, m), 7.41−7.32
(5H, m), 6.90 (2H, dt, J = 9.0, 2.0 Hz), 6.89 (2H, dt, J = 8.5, 2.0 Hz),
5.27 (2H, s), 3.81 (3H, s), 3.78 (3H, s). 13C NMR (75 MHz, CDCl3)
δ: 160.8, 159.3, 139.8, 132.1, 129.8, 129.3, 128.4, 127.9, 126.4, 122.0,
113.7, 113.7, 100.7, 79.8, 76.7, 55.3, 55.2. HRMS (Orbitrap-ESI): calcd
for C24H22NO3 [M + H]+ 372.1594, found 372.1591.
(1Z)-1-Cyclohexyl-3-phenyl-2-propyn-1-one O-[(4-Methoxy-
phenyl)methyl]oxime (1d). 1-Cyclohexyl-3-phenyl-2-propyn-1-one
was used for ketone. Isolated yield 72% (1.63 g). Colorless crystals.
Mp: 78−80 °C (Et2O−hexane). IR (neat): 2930, 2212 cm−1. 1H NMR
(300 MHz, CDCl3) δ: 7.51−7.47 (2H, m), 7.35−7.29 (5H, m), 6.87
(2H, dt, J = 8.5, 2.0 Hz), 5.12 (2H, s), 3.78 (3H, s), 2.41 (1H, tt, J =
11.5, 3.5 Hz), 1.89−1.17 (10H, m). 13C NMR (75 MHz, CDCl3) δ:
159.2, 146.6, 132.0, 131.9, 129.9, 129.7, 129.6, 129.1, 128.3, 122.1,
113.7, 113.6, 100.0, 79.9, 76.3, 75.9, 55.2, 42.9, 37.0, 30.7, 29.4, 25.8,
25.7. HRMS (Orbitrap-ESI): calcd for C23H26NO2 [M + H]+
348.1958, found 348.1958.
intermediate D. The interaction of benzyl cation and the π-
electron of the isoxazole core would lead to an intramolecular
1,3-migration, although partial separation of the ion-pair could
occur at high temperatures.18a However, an alternative pathway
for the formation of crossover product, in which the
intermediate B acted as an electrophile causing the
intermolecular benzylation without the generation of the cation
species, would not be excluded. In the final step, aromatization
of D would afford the trisubstituted isoxazole 3 and liberate the
copper catalyst.
In conclusion, we have successfully developed a copper-
catalyzed synthesis of trisubstituted isoxazoles from alkynyl
oxime ethers via the intermolecular addition of the oxime
oxygen atom to the alkyne group with subsequent 1,3-
migration of the substituted benzyl group. The current
synthetic method represents a typical atom-economical syn-
thesis in that all of the atoms in starting substrate were
incorporated in the final product without the loss of any atoms.
EXPERIMENTAL SECTION
■
General Procedure for Prepatarion of Alkynyl Oxime Ether
1a−g and 7. To a solution of alkynyl ketone (6.53 mmol) in EtOH
(65 mL) were added O-(p-methoxybenzyl)hydroxylamine (1.0 g, 6.53
mmol) and PPTS (163 mg, 0.65 mmol). The reaction mixture was
stirred at reflux for 12 h, then concentrated under reduced pressure,
diluted with H2O, and extracted with CHCl3. The combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. Purification by flash column chromatography on SiO2
(hexane/AcOEt = 30:1−10:1) afforded the corresponding oxime
ether 1a−g and 7. The geometry of CN was deduced by NOESY
experiments.
(2E)-2-[[(4-Methoxyphenyl)methyloxy]imino]-4-phenyl-3-buty-
noic Acid Methyl Ester (1e). Methyl 2-oxo-4-phenyl-3-butynoate was
used for ketone. Isolated yield 77% (1.62 g). Colorless oil. IR (neat):
1
2954, 2209, 1739 cm−1. H NMR (300 MHz, CDCl3) δ: 7.53−7.50
(2H, m), 7.39−7.28 (5H, m), 6.89 (2H, dt, J = 8.5, 2.0 Hz), 5.36 (2H,
s), 3.89 (3H, s), 3.78 (3H, s). 13C NMR (75 MHz, CDCl3) δ: 161.4,
159.7, 133.7, 132.1, 130.0, 129.7, 128.3, 128.1, 121.2, 113.8, 102.7,
78.5, 77.9, 77.2, 55.1, 53.0. HRMS (Orbitrap-ESI): calcd for
C19H18NO4 [M + H]+ 324.1230, found 324.1232.
(1Z)-1-Phenyl-2-heptyn-1-one O-[(4-Methoxyphenyl)methyl]-
(1Z)-1,3-Diphenyl-2-propyn-1-one O-[(4-Methoxyphenyl)-
methyl]oxime (1a). 1,3-Diphenyl-2-propyn-1-one was used for
ketone. Isolated yield 75% (1.67 g). Colorless oil. IR (neat): 2935,
2213 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.92−7.89 (2H, m),
7.60−7.57 (2H, m), 7.43−7.36 (8H, m), 6.91 (2H, dt, J = 8.5, 2.0 Hz),
5.30 (2H, s), 3.81 (3H, s). 13C NMR (75 MHz, CDCl3) δ: 159.3,
140.1, 133.7, 132.1, 129.9, 129.6, 129.6, 129.4, 128.4, 128.3, 126.5,
121.9, 113.7, 101.1, 79.7, 76.9, 55.2. HRMS (Orbitrap-ESI): calcd for
C23H20NO2 [M + H]+ 342.1489, found 342.1490.
oxime (1f). 1-Phenyl-2-heptyn-1-one was used for ketone. Isolated
1
yield 99% (2.07 g). Colorless oil. IR (neat): 2958, 2217 cm−1. H
NMR (300 MHz, CDCl3) δ: 7.84−7.81 (2H, m), 7.39−7.33 (5H, m),
6.89 (2H, dt, J = 8.5, 2.0 Hz), 5.24 (2H, s), 3.80 (3H, s), 2.52 (2H, t, J
= 7.0 Hz), 1.67−1.44 (4H, m,), 0.92 (3H, t, J = 7.0 Hz). 13C NMR (75
MHz, CDCl3) δ: 159.3, 140.4, 134.0, 129.9, 129.7, 129.3, 128.2, 126.4,
113.6, 103.8, 76.6, 71.7, 55.1, 30.3, 21.9, 19.4, 13.5. HRMS (Orbitrap-
ESI): calcd for C21H24NO2 [M + H]+ 322.1802, found 322.1804.
(1Z)-3-Cyclohexyl-1-phenyl-2-propyn-1-one O-[(4-Methoxy-
phenyl)methyl]oxime (1g). 3-Cyclohexyl-1-phenyl-2-propyn-1-one
was used for ketone. Isolated yield 50% (1.13 g). Colorless oil. IR
(1Z)-1-[4-(Trifluoromethyl)phenyl]-3-phenyl-2-propyn-1-one O-
[(4-Methoxyphenyl)methyl]oxime (1b). 3-Phenyl-1-[4-(trifluoro-
methyl)phenyl]-2-propyn-1-one was used for ketone. Isolated yield
41% (1.09 g). Colorless crystals. Mp: 69−71 °C (Et2O−hexane). IR
1
(neat): 2932, 2215 cm−1. H NMR (300 MHz, CDCl3) δ: 7.85−7.81
1
(neat): 2937, 2213 cm−1. H NMR (300 MHz, CDCl3) δ: 8.01 (2H,
(2H, m), 7.39−7.33 (5H, m), 6.89 (2H, dt, J = 8.5, 2.0 Hz), 5.24 (2H,
s), 3.81 (3H, s), 2.73 (1H, m), 1.89−1.33 (10H, m). 13C NMR (75
MHz, CDCl3) δ: 159.2, 140.5, 134.1, 129.7, 129.3, 128.1, 126.4, 113.6,
dd, J = 8.0, 0.5 Hz), 7.63 (2H, dd, J = 8.0, 0.5), 7.60−7.56 (2H, m),
7.42−7.37 (5H, m), 6.91 (2H, dt, J = 8.5, 2.0 Hz), 5.32 (2H, s), 3.81
D
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Note
1
107.5, 76.5, 71.7, 55.1, 32.0, 29.7, 25.7, 24.4. HRMS (Orbitrap-ESI):
calcd for C23H26NO2 [M + H]+ 348.1958, found 348.1948.
(neat): 2935, 1613 cm−1; H NMR (300 MHz, CDCl3) δ: 7.71−7.68
(2H, m), 7.64 (4H, s), 7.45−7.43 (3H, m), 7.08 (2H, d, J = 8.5 Hz),
6.87 (2H, dt, J = 8.5, 2.0 Hz), 4.04 (2H, s), 3.80 (3H, s). 13C NMR
(75 MHz, CDCl3) δ: 167.7, 163.0, 158.5, 132.9, 130.3, 130.1, 129.0,
128.8, 128.7, 127.8, 126.9, 125.7, 125.6, 114.4, 111.2, 55.3, 27.9.
HRMS (Orbitrap-ESI): calcd for C24H19NO2F3 [M + H]+ 410.1362,
found 410.1353.
(1Z)-3-(Trimethylsilyl)-1-phenyl-2-propyn-1-one O-[(4-Methoxy-
phenyl)methyl]oxime (7). 1-Phenyl-3-trimethylsilyl-2-propyn-1-one
was used for ketone. Isolated yield 68% (1.49 g). Colorless oil. IR
(neat): 2959, 2157, 1614. cm−1. 1H NMR (300 MHz, CDCl3) δ:
7.86−7.82 (2H, m), 7.42−7.36 (5H, m), 6.91 (2H, d, J = 8.5 Hz), 5.28
(2H, s), 3.82 (3H, s), 0.31 (9H, s). 13C NMR (75 MHz, CDCl3) δ:
159.5, 140.3, 133.6, 130.0, 129.85, 129.75, 128.6, 128.5, 126.7, 113.9,
108.4, 94.4, 77.7, 55.4, −0.1. HRMS (Orbitrap-ESI): calcd for
C20H24NO2Si [M + H]+ 338.1571, found 338.1571.
Prepatarion of Alkynyl Oxime Ether 1h,i. (1E)-1-Phenyl-2-
propyn-1-one O-[(4-Methoxyphenyl)methyl]oxime (1h). To a
solution of 7 (525 mg, 1.56 mmol) in THF (50 mL) was added
dropwise TBAF (3.1 mL, 3.11 mmol, 1.0 M in THF) under N2
atmosphere at 0 °C. After being stirred at the same temperature for 30
min, the reaction mixture was diluted with H2O and extracted with
CHCl3. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. Purification by FCC (hexane/
AcOEt = 30:1) afforded 1h (413 mg, 99%). Colorless crystals. Mp:
72−74 °C (Et2O-hexane). IR (neat): 2938, 2346, 1615 cm−1. 1H
NMR (300 MHz, CDCl3) δ: 7.85−7.82 (2H, m), 7.39−7.34 (5H, m),
6.88 (2H, d, J = 8.5 Hz), 5.26 (2H, s), 3.79 (3H, s), 3.73 (1H, s). 13C
NMR (75 MHz, CDCl3) δ: 159.4, 139.3, 133.0, 130.0, 129.7, 129.3,
128.3, 126.3, 113.7, 89.3, 77.1, 73.6, 55.2. HRMS (Orbitrap-ESI): calcd
for C17H16NO2 [M + H]+ 266.1176, found 266.1176.
3-(4-Methoxyphenyl)-4-[(4-methoxyphenyl)methyl]-5-phenyli-
soxazole (3c). Isolated yield 78% (23.4 mg). Colorless oil. IR (neat):
2935, 1612 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.69−7.65 (2H, m),
7.47 (2H, dt, J = 9.0, 2.5 Hz) 7.43−7.39 (3H, m), 7.10 (2H, dt, J = 9.0,
2.5 Hz) 6.89 (2H, dt, J = 9.0, 2.5 Hz), 6.86 (2H, dt, J = 9.0, 2.5 Hz),
4.02 (2H, s), 3.80 (3H, s), 3.79 (3H, s). 13C NMR (75 MHz, CDCl3)
δ: 166.9, 163.8, 160.6, 158.3, 130.8, 129.7, 129.6, 128.9, 128.8, 128.2,
126.8, 121.6, 114.3, 114.2, 111.0, 55.24, 55.21, 28.0. HRMS (Orbitrap-
ESI): calcd for C24H22NO3 [M + H]+ 372.1594, found 372.1591.
3-Cyclohexyl-4-[(4-methoxyphenyl)methyl]-5-phenylisoxazole
(3d). Isolated yield 73% (21.9 mg). Colorless crystals. Mp: 128−130
°C (EtOAc−hexane). IR (neat): 2927, 1615 cm−1. H NMR (300
1
MHz, CDCl3) δ: 7.64−7.60 (2H, m), 7.41−7.37 (3H, m), 7.05 (2H,
dt, J = 8.5, 2.0 Hz), 6.83 (2H, dt, J = 8.5, 2.0 Hz), 3.93 (2H, s), 3.78
(3H, s), 2.49 (1H, tt, J = 13.5, 3.0 Hz), 1.86−1.52 (7H, m), 1.29−1.21
(3H, m). 13C NMR (75 MHz, CDCl3) δ: 168.5, 165.5, 158.3, 130.7,
129.4, 128.8, 128.4, 126.8, 114.1, 111.2, 55.2, 35.6, 31.6, 27.5, 26.3,
25.9; HRMS (Orbitrap-ESI): calcd for C23H26NO2 [M + H]+
348.1958, found 348.1957.
4-[(4-Methoxyphenyl)methyl]-5-phenyl-3-isoxazolecarboxylic
Acid Methyl Ester (3e). Isolated yield 70% (21.0 mg). Colorless
crystals. Mp: 84−86 °C (Et2O−hexane). IR (neat): 2953, 1740, 1613
cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.69−7.66 (2H, m), 7.47−7.44
(3H, m), 7.05 (2H, d, J = 8.5 Hz), 6.83 (2H, dt, J = 8.5, 2.0 Hz), 4.21
(2H, s), 3.91 (3H, s), 3.77 (3H, s). 13C NMR (75 MHz, CDCl3) δ:
168.6, 160.8, 158.2, 155.4, 130.6, 130.3, 129.0, 128.8, 127.2, 127.1,
114.4, 114.0, 55.2, 52.6, 27.2. HRMS (Orbitrap-ESI): calcd for
C19H18NO4 [M + H]+ 324.1230, found 324.1227.
5-Butyl-4-[(4-methoxyphenyl)methyl]-3-phenylisoxazole (3f). Iso-
lated yield 66% (19.8 mg). Colorless oil. IR (neat): 2957, 1613 cm−1.
1H NMR (300 MHz, CDCl3) δ: 7.52−7.49 (2H, m), 7.38−7.36 (3H,
m), 6.98 (2H, dt, J = 8.5, 2.0 Hz), 6.80 (2H, dt, J = 8.5, 2.0 Hz), 3.79
(2H, s), 3.77 (3H, s), 2.67 (2H, t, J = 7.5 Hz), 1.65 (2H, quint, J = 7.5
Hz), 1.35 (2H, m), 0.90 (3H, t, J = 7.5 Hz). 13C NMR (75 MHz,
CDCl3) δ: 170.9, 162.8, 158.1, 131.2, 129.7, 129.2, 128.8, 128.6, 128.2,
114.0, 111.2, 55.2, 29.5, 27.2, 25.5, 22.3, 13.6. HRMS (Orbitrap-ESI):
calcd for C21H24NO2 [M + H]+ 322.1802, found 322.1800.
(1Z)-4-Hydroxy-1-phenyl-2-butyn-1-one O-[(4-Methoxyphenyl)-
methyl]oxime (8). To a solution of 1h (200 mg, 0.75 mmol) in
THF (11 mL) was added dropwise n-BuLi (0.71 mL, 1.13 mmol, 1.6
M in hexane) under Ar atmosphere at −40 °C. After the reaction
mixture was stirred for 5 min, paraformaldehyde (33 mg, 1.13 mmol)
was added. The reaction mixture was stirred for 15 min and then
allowed to warm to room temperature. The reaction was quenched
with satd NH4Cl and extracted with AcOEt. The combined organic
layers were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. Purification by PTLC (hexane/AcOEt = 5:1)
afforded 8 (194 mg, 88%).
(1Z)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-phenyl-2-butyn-
1-one O-[(4-Methoxyphenyl)methyl]oxime (1i). To a solution of 8
(50 mg, 0.17 mmol) in CH2Cl2 (2 mL) were added TBSCl (31 mg,
0.20 mmol) and imidazole (25 mg, 0.37 mmol) at room temperature.
After being stirred for 2 h under N2 atmosphere at room temperature,
the reaction mixture was diluted with H2O and extracted with CHCl3.
The organic layers dried over MgSO4 and concentrated in vacuo.
Purification by PTLC (hexane/AcOEt = 10:1) afforded 1i (62 mg,
89%). Colorless oil. IR (neat): 2931, 2215 1613 cm−1. 1H NMR (300
MHz, CDCl3) δ: 7.84−7.80 (2H, m), 7.38−7.33 (5H, m), 6.88 (2H,
dt, J = 8.5, 2.0 Hz), 5.23 (2H, s), 4.60 (2H, d, J = 1.0 Hz), 3.80 (3H,
s), 0.91 (9H, s), 0.12 (6H, s). 13C NMR (75 MHz, CDCl3) δ: 159.4,
139.6, 133.4, 130.1, 129.5, 128.2, 126.4, 113.7, 100.4 76.9, 75.4, 55.2,
52.1, 25.7, 18.2, −5.2. HRMS (Orbitrap-ESI): calcd for C24H32NO3Si
[M + H]+ 410.2146, found 410.2145.
General Procedure for Cu(OTf)2-Catalyzed Synthesis of
Trisubstituted Isoxazoles (3a−h). To a solution of alkynyl oxime
ether (30 mg) in chlorobenzene (15 mL) was added Cu(OTf)2 (5 mol
%) under an Ar atmosphere at room temperature. The reaction
mixture was stirred at reflux for 2.5 h and then concentrated under
reduced pressure. Purification by PTLC (hexane/EtOAc) afforded the
corresponding trisubstituted isoxazole 3a−h.
3,5-Diphenyl-4-[(4-methoxyphenyl)methyl]isoxazole (3a). Iso-
lated yield 70% (21.0 mg). Colorless solid. Mp: 98−101 °C (Et2O−
hexane). IR (neat): 2931, 1610 cm−1. 1H NMR (300 MHz, CDCl3) δ:
7.70−7.67 (2H, m), 7.55−7.52 (2H, m), 7.44−7.37 (6H, m), 7.09
(2H, dt, J = 8.5, 2.0 Hz), 6.86 (2H, dt, J = 8.5, 2.0 Hz), 4.04 (2H, s),
3.79 (3H, s). 13C NMR (75 MHz, CDCl3) δ: 167.0, 164.2, 158.3,
130.8, 129.8, 129.5, 129.3, 128.9, 128.8, 128.7, 128.3, 128.1, 126.8,
114.3, 111.2, 55.2, 27.9. HRMS (Orbitrap-ESI): calcd for C23H20NO2
[M + H]+ 342.1489, found 342.1489.
5-Cyclohexyl-4-[(4-methoxyphenyl)methyl]-3-phenylisoxazole
(3g). Isolated yield 93% (27.9 mg). Colorless crystals. Mp: 134−136
1
°C (EtOAc−hexane). IR (neat): 2926, 1615 cm−1. H NMR (300
MHz, CDCl3) δ 7.49−7.46 (2H, m), 7.38−7.34 (3H, m), 6.98 (2H, dt,
J = 8.5, 2.0 Hz), 6.80 (2H, dt, J = 8.5, 2.0 Hz,), 3.80 (2H, s), 3.77 (3H,
s), 2.71 (1H, tt, J = 11.5, 3.0 Hz), 1.83−1.64 (7H, m), 1.30−1.26 (3H,
m). 13C NMR (75 MHz, CDCl3) δ 174.2, 162.8, 158.1, 131.4, 129.7,
129.1, 128.8, 128.5, 128.2, 114.0, 109.8, 55.2, 36.2, 30.8, 27.1, 26.1,
25.6. HRMS (Orbitrap-ESI): calcd for C23H26NO2 [M + H]+
348.1958, found 348.1949.
4-[(4-Methoxyphenyl)methyl]-3-phenylisoxazole (3h). Isolated
1
yield 80% (24.0 mg). Colorless oil. IR (neat): 2935, 1611 cm−1. H
NMR (300 MHz, CDCl3) δ: 8.06 (1H, m), 7.63−7.60 (2H, m), 7.45−
7.42 (3H, m), 7.09 (2H, dt, J = 8.5, 2.0 Hz), 6.84 (2H, dt, J = 8.5, 2.0
Hz), 3.83 (2H, s), 3.79 (3H, s). 13C NMR (75 MHz, CDCl3) δ: 161.3,
158.3, 157.2, 130.7, 129.5, 129.4, 129.0, 128.7, 128.2, 118.2, 114.1,
55.2, 28.0. HRMS (Orbitrap-ESI): calcd for C17H16NO2 [M + H]+
266.1176, found 266.1176.
4-[(4-Methoxyphenyl)methyl]-3-phenyl-5-isoxazolemethanol
(3i). Cu(OTf)2 (4 mg, 0.01 mmol) was added to a solution of alkynyl
oxime ether 1i (100 mg, 0.24 mmol) in chlorobenzene (41 mL) under
an Ar atmosphere at room temperature. The reaction mixture was
stirred at reflux for 2 h and then filtered. The filter cake was then
washed with THF, and the filtrates were combined. A solution of
TBAF (0.24 mL, 0.24 mmol, 1 M in THF) was then added to the
mixture in a dropwise manner under a N2 atmosphere at 0 °C.
3-[4-(Trifluoromethyl)phenyl]-4-[(4-methoxyphenyl)methyl]-5-
phenylisoxazole (3b). Isolated yield 85% (25.5 mg). Colorless oil. IR
E
dx.doi.org/10.1021/jo301358h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Following a 30 min period of stirring at the same temperature, the
reaction mixture was diluted with H2O and extracted with CHCl3. The
combined organic extracts were dried over MgSO4 and concentrated
under reduced pressure. Purification by PTLC (toluene/EtOAc = 4:1)
to give 3i (46 mg, 65%). Colorless crystals. Mp: 73−75 °C (Et2O−
CDCl3) δ: 141.4, 141.0, 133.4, 132.1, 129.7, 129.5, 128.5, 128.3, 127.6,
127.3, 126.6, 122.0, 101.5, 87.7, 80.0, 77.2. HRMS (Orbitrap-ESI):
calcd for C28H22NO [M + H]+ 388.1696, found: 388.1692.
(1Z)-1,3-Diphenyl-2-propyn-1-one O-(2-naphthylmethyl)oxime
(4g). O-(2-Naphthalenylmethyl)hydroxylamine was used for alkoxy-
amine. Isolated yield 60% (1.05 g). Colorless solid. IR (neat): 3061,
2210, 1601 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.93−7.90 (3H, m),
7.87−7.82 (3H, m), 7.63−7.59 (3H, m), 7.49−7.46 (2H, m), 7.41−
7.37 (6H, m), 5.54 (2H, s). 13C NMR (75 MHz, CDCl3) δ: 140.6,
135.1, 133.7, 133.3, 133.0, 129.7, 129.5, 128.7, 128.42, 128.37, 128.1,
128.0, 127.7, 127.1, 127.0, 126.5, 126.03, 126.01, 125.9, 121.9, 101.4,
79.7, 77.2. HRMS (Orbitrap-ESI): calcd for C26H20NO [M + H]+
362.1539, found 362.1538.
Preparation of (1Z)-1,3-Diphenyl-2-propyn-1-one O-[[4-
(Dimethylamino)phenyl]methyl]oxime (4b). To a solution of O-
[(4-dimethylaminophenyl)methyl]hydroxylamine hydrochloride (0.84
mmol) in MeOH (6 mL) were added 1,3-diphenyl-2-propyn-1-one
(173 mg, 0.84 mmol), Na2SO4 (239 mg, 1.68 mmol), and pyridine
(0.6 mL) under N2 atmosphere at room temperature. After being
stirred at the same temperature for 6 h, the reaction mixture was
diluted with H2O and extracted with CHCl3. The organic phase was
washed with H2O, dried over MgSO4, and concentrated under reduced
pressure. Purification by flash column chromatography on SiO2
(hexane/AcOEt = 15:1) afforded 4b (98 mg, 34%). Colorless solid.
Mp: 83−87 °C (Et2O−hexane). IR (neat): 2927, 2211, 1615 cm−1. 1H
NMR (300 MHz, CDCl3) δ: 7.92−7.89 (2H, m), 7.60−7.56 (2H, m),
7.40−7.36 (8H, m), 6.74 (2H, dt, J = 9.0, 2.0 Hz), 5.27 (2H, s), 2.95
(6H, s). 13C NMR (75 MHz, CDCl3) δ: 150.4, 139.7, 133.9, 132.1,
129.9, 129.4, 129.3, 128.3, 128.3, 126.4, 125.1, 122.0, 112.2, 100.9,
79.9, 77.4, 40.5. HRMS (Orbitrap-ESI): calcd for C24H23N2O [M +
H]+ 355.1805, found 355.1806.
General Procedure for Cu(OTf)2-Catalyzed Synthesis of
Trisubstituted Isoxazoles (5a−c,e−g). To a solution of alkynyl
oxime ether (30 mg) in chlorobenzene or dichloroethane (15 mL) was
added Cu(OTf)2 (5 mol %) under an Ar atmosphere at room
temperature. The reaction mixture was stirred at reflux for 2−10 h and
then concentrated under reduced pressure. Purification by PTLC
(hexane/EtOAc) afforded the corresponding trisubstituted isoxazole
5a−c,e−g.
4-[4-[[(1,1-Dimethylethyl)dimethylsilyloxy]phenyl]methyl]-3,5-di-
phenylisoxazole (5a). Isolated yield 87% (26.1 mg). Colorless
crystals. Mp: 98−101 °C (Et2O−hexane). IR (neat) 2931, 1609
cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.70−7.67 (2H, m), 7.53−7.49
(2H, m), 7.44−7.33 (6H, m), 7.01 (2H, d, J = 8.0 Hz), 6.78 (2H, dt, J
= 8.0, 2.5 Hz), 4.02 (2H, s), 0.97 (9H, s), 0.19 (6H, s). 13C NMR (75
MHz, CDCl3) δ: 167.0, 164.2, 154.2, 131.5, 129.8, 129.5, 129.3, 128.9,
128.8, 128.6, 128.4, 128.1, 126.9, 120.4, 111.4, 28.1, 25.7, 18.2, −4.4.
HRMS (Orbitrap-ESI): calcd for C28H32NO2Si [M + H]+ 442.2197,
found 442.2194.
1
hexane). IR (neat): 3380, 2933, 1612 cm−1. H NMR (300 MHz,
CDCl3) δ: 7.50−7.47 (2H, m), 7.41−7.37 (3H, m), 6.99 (2H, dt, J =
8.5, 2.0 Hz), 6.78 (2H, dt, J = 8.5, 2.0 Hz), 4.62 (2H, s), 3.85 (2H, s),
3.75 (3H, s), 2.75 (1H, br s). 13C NMR (75 MHz, CDCl3) δ: 168.0,
163.1, 158.2, 130.8, 129.5, 129.0, 128.7, 128.3, 114.1, 113.8, 55.2, 54.9,
27.1; HRMS (Orbitrap-ESI): calcd for C18H18NO3 [M + H]+
296.1281, found 296.1275.
General Procedure for Preparation of Alkynyl Oxime Ethers
4a,c−g. To a solution of 1,3-diphenyl-2-propyn-1-one (1.0 g, 4.85
mmol) in EtOH (50 mL) were added alkoxyamine (4.85 mmol) and
PPTS (121 mg, 0.49 mmol). The reaction mixture was stirred at reflux
for 12 h, then concentrated under reduced pressure, diluted with H2O
and extracted with CHCl3. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. Purification by
flash column chromatography on SiO2 (hexane/AcOEt = 30:1−10:1)
afforded the corresponding oxime ethers 4a,c−g.
(1Z)-1,3-Diphenyl-2-propyn-1-one O-[[4-[[(1,1-Dimethylethyl)-
dimethylsilyl]oxy]phenyl]methyl]oxime (4a). O-[[4-[[(1,1-
Dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]hydroxylamine was
used for alkoxyamine. Isolated yield 71% (1.51 g). Colorless oil. IR
(neat): 2930, 2214, 1610 cm−1. 1H NMR (300 MHz, CDCl3) δ: 8.01−
7.98 (2H, m), 7.66−7.63 (2H, m), 7.47−7.39 (8H, m), 6.92 (2H, dt, J
= 8.5, 2.0 Hz), 5.38 (2H, s), 1.06 (9H, s), 0.28 (6H, s). 13C NMR (75
MHz, CDCl3) δ: 155.4, 140.1, 133.7, 132.1, 130.3, 129.7, 129.6, 129.4,
128.4, 128.3, 126.5, 121.9, 119.9, 101.1, 79.7, 76.9, 25.6, 18.1, −4.5.
HRMS (Orbitrap-ESI): calcd for C28H32NO2Si [M + H]+ 442.2197,
found 442.2198.
(1Z)-1,3-Diphenyl-2-propyn-1-one O-[(2-Methoxyphenyl)-
methyl]oxime (4c). O-[(2-Methoxyphenyl)methyl]hydroxylamine
was used for alkoxyamine. Isolated yield 7% (0.115 g). Colorless oil.
1
IR (neat): 2939, 2214, 1604 cm−1. H NMR (300 MHz, CDCl3) δ:
7.94−7.90 (2H, m), 7.62−7.59 (2H, m), 7.49 (1H, dd, J = 8.0, 2.0
Hz), 7.41−7.35 (6H, m), 7.28 (1H, td, J = 8.0, 2.0 Hz), 6.97 (1H, td, J
= 8.0, 2.0 Hz), 6.89 (1H, d, J = 8.0 Hz), 5.46 (2H, s), 3.86 (3H, s). 13C
NMR (75 MHz, CDCl3) δ: 157.0, 140.2, 133.7, 132.1, 129.5, 129.4,
128.9, 128.7, 128.4, 128.3, 126.5, 126.3, 122.0, 120.4, 110.3, 101.2,
79.8, 72.1, 55.4. HRMS (Orbitrap-ESI): calcd for C23H20NO2 [M +
H]+ 342.1489, found 342.1487.
4-[[(Z)-(1,3-Diphenyl-2-propyn-1-ylidene)amino]oxymethyl]-
benzoic Acid Methyl Ester (4d). Methyl 4-[(aminooxy)methyl]-
benzoate was used for alkoxyamine. Isolated yield 32% (0.572 g).
Colorless crystals. Mp: 64−68 °C (AcOEt−hexane). IR (neat): 2951,
2215, 1716, 1615 cm−1. 1H NMR (300 MHz, CDCl3) δ: 8.04 (2H, dt,
J = 8.5, 2.0 Hz) 7.91−7.88 (2H, m), 7.62−7.59 (2H, m), 7.52 (2H, d, J
= 8.5 Hz), 7.40−7.36 (6H, m), 5.41 (2H, s), 3.90 (3H, s). 13C NMR
(75 MHz, CDCl3) δ: 166.9, 142.9, 140.9, 133.3, 132.1, 129.8, 129.7,
129.6, 129.5, 128.5, 128.4, 127.5, 126.5, 121.7, 101.6, 79.4, 76.2, 52.0.
HRMS (Orbitrap-ESI): calcd for C24H20NO3 [M + H]+ 370.1438,
found 370.1437.
(1Z)-1,3-Diphenyl-2-propyn-1-one O-[1-(4-Methoxyphenyl)-
ethyl]oxime (4e). O-[1-(4-Methoxyphenyl)ethyl]hydroxylamine was
used for alkoxyamine. Isolated yield 39% (0.671 g). Colorless oil. IR
(neat): 2939, 2207, 1613 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.89−
7.86 (2H, m), 7.62−7.58 (2H, m), 7.40−7.35 (8H, m), 6.89 (2H, dt, J
= 8.5, 2.0 Hz), 5.44 (1H, q, J = 6.5 Hz), 3.79 (3H, s), 1.68 (3H, d, J =
6.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 159.0, 139.9, 135.2, 133.9,
132.1, 129.5, 129.4, 128.4, 128.3, 127.6, 126.5, 122.2, 113.7, 100.9,
82.0, 77.2, 55.2, 22.0. HRMS (Orbitrap-ESI): calcd for C24H22NO2 [M
+ H]+ 356.1645, found 356.1643.
4-[[4-(Dimethylamino)phenyl]methyl]-3,5-diphenylisoxazole
(5b). Isolated yield 83% (24.9 mg). Colorless crystals. Mp: 118−120
°C (Et2O−hexane). IR (neat): 3008, 1616 cm−1. 1H NMR (300 MHz,
CDCl3) δ 7.73−7.69 (2H, m), 7.58−7.55 (2H, m), 7.43−7.36 (6H,
m), 7.05 (2H, d, J = 8.5), 6.70 (2H, dt, J = 8.5, 2.0 Hz), 4.00 (2H, s),
2.93 (6H, s). 13C NMR (75 MHz, CDCl3) δ: 166.9, 164.2, 149.3,
129.6, 129.4, 129.3, 128.9, 128.6, 128.4, 128.3, 128.1, 126.8, 126.5,
113.0, 111.5, 40.6, 27.7. HRMS (Orbitrap-ESI): calcd for C24H23N2O
[M + H]+ 355.1805, found 355.1798.
4-[(2-Methoxyphenyl)methyl]-3,5-diphenylisoxazole (5c). Isolated
yield 57% (17.1 mg). Colorless crystals. Mp: 152−155 °C (EtOAc−
hexane). IR (neat) 3011, 1600 cm−1. 1H NMR (300 MHz, CDCl3) δ:
7.67−7.64 (2H, m), 7.54−7.52 (2H, m), 7.42−7.32 (6H, m), 7.27−
7.21 (1H, m), 6.99 (1H, d, J = 7.5 Hz), 6.91 (1H, d, J = 7.5 Hz), 6.85
(1H, t, J = 7.5 Hz), 4.02 (2H, s), 3.82 (3H, s). 13C NMR (75 MHz,
CDCl3) δ: 167.1, 164.3, 157.1, 129.6, 129.4, 128.8, 128.6, 128.4, 128.3,
127.7, 127.1, 126.8, 120.7, 110.8, 110.0, 55.2, 23.3. HRMS (Orbitrap-
ESI): calcd for C23H20NO2 [M + H]+ 342.1489, found 342.1504.
4-[1-(4-Methoxyphenyl)ethyl]-3,5-diphenylisoxazole (5e). Isolated
(1Z)-1,3-Diphenyl-2-propyn-1-one O-(Diphenylmethyl)oxime
(4f). O-(Diphenylmethyl)hydroxylamine was used for alkoxyamine.
Isolated yield 64% (1.20 g). Colorless crystals. Mp: 135−138 °C
1
(AcOEt/hexane). IR (neat): 3062, 2213, 1599 cm−1. H NMR (300
1
MHz, CDCl3) δ: 7.88−7.85 (2H, m), 7.62−7.59 (2H, m), 7.47 (4H, d,
yield 54% (16.2 mg). Colorless oil. IR (neat): 2973, 1612 cm−1. H
J = 8.0 Hz), 7.37−7.22 (12H, m), 6.46 (1H, s). 13C NMR (75 MHz,
NMR (300 MHz, CDCl3) δ: 7.60−7.57 (2H, m), 7.43−7.30 (8H, m),
F
dx.doi.org/10.1021/jo301358h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7.13 (2H, d, J = 8.5 Hz), 6.84 (2H, dt, J = 8.5 Hz), 4.35 (1H, q, J = 7.0
Hz), 3.81 (3H, s), 1.42 (3H, d, J = 7.0 Hz). 13C NMR (75 MHz,
CDCl3) δ: 166.5, 164.1, 158.0, 136.1, 129.9, 129.8, 129.2, 129.0, 128.6,
128.5, 128.3, 128.1, 128.0, 117.8, 113.8, 55.2, 32.1, 19.4. HRMS
(Orbitrap-ESI): calcd for C24H22NO2 [M + H]+ 356.1645, found
356.1641.
Georg Thieme Verlag: Stuttgart, 1992; Vol. E8a, p 45. (b) Sperry, J.;
Wright, D. Curr. Opin. Drug Discov. Devel. 2005, 8, 723.
(3) (a) Burrows, A. D.; Frost, C. G.; Mahon, M. F.; Raithby, P. R.;
Richardson, C.; Stevenson, A. J. Chem. Commun. 2010, 46, 5064.
(b) Lee, Y.; Koyama, Y.; Yonekawa, M.; Tanaka, T. Macromolecules
2009, 42, 7709.
3,5-Diphenyl-4-(diphenylmethyl)isoxazole (5f). Isolated yield 76%
(22.8 mg). Colorless solid. IR (neat): 3062, 1594 cm−1. 1H NMR (300
MHz, CDCl3) δ: 7.40−7.13 (16H, m), 7.03−7.00 (4H, m), 5.69 (1H,
s). 13C NMR (75 MHz, CDCl3) δ: 167.6, 164.6, 141.3, 129.6, 129.5,
129.2, 129.1, 128.3, 128.2, 128.1, 128.0, 126.6, 116.1, 45.7. HRMS
(Orbitrap-ESI): calcd for C28H22NO [M + H]+ 388.1696, found
388.1691.
3,5-Diphenyl-4-(2-naphthylmethyl)isoxazole (5g). Isolated yield
49% (14.7 mg). Colorless oil. IR (CHCl3): 3060, 1600 cm−1. 1H NMR
(300 MHz, CDCl3) δ: 7.85 (2H, d, J = 8.0 Hz), 7.74−7.68 (3H, m),
7.58−7.53 (3H, m), 7.50−7.44 (2H, m), 7.42−7.30 (7H, m), 4.26
(2H, s). 13C NMR (75 MHz, CDCl3) δ: 167.4, 164.3, 136.5, 133.7,
132.3, 129.9, 129.6, 129.2, 129.0, 128.8, 128.7, 128.3, 128.0, 127.8,
127.6, 126.8, 126.5, 126.3, 126.1, 125.7, 110.5, 29.1; HRMS (Orbitrap-
ESI): calcd for C26H20NO [M + H]+ 362.1539, found 362.1541.
Crossover Reaction. To a solution of alkynyl oxime ether 1b (45
mg, 0.11 mmol) and 4a (48.5 mg, 0.11 mmol) in chlorobenzene (38
mL) was added Cu(OTf)2 (4.1 mg, 0.01 mmol) under Ar atmosphere
at room temperature. The reaction mixture was stirred for 2 h at reflux
and then concentrated. Purification by PTLC hexane/EtOAc = 15/1)
afforded 3b (35 mg, 76%), 5a (30 mg, 58%), 3a (4 mg, 10%), and 6 (5
mg, 9%).
(4) Wakefield, B. J. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations; Shaumann, E., Ed.; Georg Thieme Verlag:
Stuttgart, 2001; Vol. 11, p 229.
(5) Jager, V.; Colinas, P. A. In Synthetic Applications of 1,3-Dipolar
̈
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Ed.; Wiley: Hoboken, 2002; Vol. 59, p 361.
(6) For recent examples, see: (a) Sanders, B. C.; Friscourt, F.; Ledin,
P. A.; Mbua, N. E.; Arumugam, S.; Guo, J.; Boltje, T. J.; Popik, V. V.;
Boons, G.-J. J. Am. Chem. Soc. 2011, 133, 949. (b) Budzik, B. W.;
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1363.
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(a) Wang, L.; Yu, X.; Feng, X.; Bao, M. Org. Lett. 2012, 14, 2418.
(b) Dadiboyena, S.; Nefzi, A. Tetrahedron Lett. 2012, 53, 2096.
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Goodenough, K. M.; Wybrow, R. A. J.; York, M.; Johnson, C. N.;
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W. H.; Chen, Y. J. Org. Chem. 2012, 77, 3627.
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Campagne, J.-M. Org. Lett. 2011, 13, 6418.
3-[4-(Trifluoromethyl)phenyl]-4-[4-[[(1,1-dimethylethyl)-
dimethylsilyloxy]phenyl]methyl]-5-phenylisoxazole (6). Color-
1
less solid. IR (neat): 2931, 1609 cm−1. H NMR (300 MHz, CDCl3)
δ: 7.71−7.68 (2H, m), 7.63 (4H, s), 7.46−7.44 (3H, m), 7.01 (2H, d, J
= 8.5 Hz), 6.79 (2H, dt, J = 8.5, 2.0 Hz), 4.02 (2H, s), 0.98 (9H, s),
0.19 (6H, s). 13C NMR (75 MHz, CDCl3) δ: 167.6, 163.1, 154.4,
131.0, 130.1, 129.0, 128.8, 128.7, 127.8, 126.9, 125.63, 125.58, 120.6,
111.3, 28.0, 25.6, 18.2, −4.4. HRMS (Orbitrap-ESI): calcd for
C29H31NO2F3Si [M + H]+ 510.2071, found 510.2069.
(14) For other recently reported methods for the synthesis of
trisubstituted isoxazoles, see: (a) Nishiwaki, N.; Kobiro, K.; Hirao, S.;
Sawayama, J.; Saigo, K.; Ise, Y.; Nishizawa, M.; Ariga, M. Org. Biomol.
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Shibata, N. Eur. J. Org. Chem. 2012, 1295. (c) Xiang, D.; Xin, X.; Liu,
X.; Zhang, R.; Yang, J.; Dong, D. Org. Lett. 2012, 14, 644.
(d) Hashimoto, Y.; Takada, A.; Takikawa, H.; Suzuki, K. Org. Biomol.
Chem. 2012, 10, 6003.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: miyata@kobepharma-u.ac.jp.
Notes
■
(15) (a) Lipshutz, B. H., Yamamoto, Y., Eds. Chem. Rev. 2008, 108,
3239. (b) Kirsch, S. F. Synthesis 2008, 3183. (c) Krause, N.; Winter, C.
Chem. Rev. 2011, 111, 1994. (d) Corma, C.; Leyva-Per
M. J. Chem. Rev. 2011, 111, 1657.
́
ez, A.; Sabater,
(16) (a) Manarin, F.; Roehr, J. A.; Gay, R. M.; Brandao, R.; Menezes,
P. H.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2009, 74, 2153.
The authors declare no competing financial interest.
(b) Furstner, A.; Heilmann, E. K.; Davies, P. W. Angew. Chem., Int. Ed.
2007, 46, 4760. (c) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am.
̈
ACKNOWLEDGMENTS
■
This work was supported by Grants-in Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
(MEXT), the MEXT-Supported Program for the Strategic
Research Foundation at Private Universities, and the Research
Foundation for Pharmaceutical Sciences. M.U. is grateful to the
Mitsubishi Chemical Award in Synthetic Organic Chemistry,
Japan.
Chem. Soc. 2005, 127, 15022. (d) Furstner, A.; Davies, P. W. J. Am.
̈
Chem. Soc. 2005, 127, 15024.
(17) (a) Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew.
Chem., Int. Ed. 2008, 47, 4906. (b) Li, G.; Huang, X.; Zhang, L. Angew.
Chem., Int. Ed. 2008, 47, 346. (c) Nakamura, I.; Yamagishi, U.; Song,
D.; Konta, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 2284.
(d) Cariou, K.; Ronan, B.; Mignani, S.; Fensterbank, L.; Malacria, M.
Angew. Chem., Int. Ed. 2007, 46, 1881. (e) Shimada, T.; Nakamura, I.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546.
(18) (a) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett.
2008, 10, 2649. (b) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2006, 45, 4473.
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H
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