Direct synthesis of 4-fluoroisoxazoles through gold-catalyzed cascade cyclization-fluorination of 2-alkynone O-methyl oximes

Article abstract of DOI:10.1021/jo5008702

A tandem protocol for the synthesis of fluorinated isoxazoles has been developed via catalytic intramolecular cyclizations of 2-alkynone O-methyl oximes and ensuing fluorination. The reactions proceed smoothly at room temperature in the presence of 5 mol

Full text of DOI:10.1021/jo5008702

Article
pubs.acs.org/joc
Direct Synthesis of 4‑Fluoroisoxazoles through Gold-Catalyzed
Cascade Cyclization−Fluorination of 2‑Alkynone O‑Methyl Oximes
Yunkyung Jeong,† Bom-I Kim,† Jae Kyun Lee,‡ and Jae-Sang Ryu*,†
†College of Pharmacy & Graduate School of Pharmaceutical Sciences, Global Top 5 Research Program, Ewha Womans University,
11-1 Daehyun-Dong, Seodaemun-Gu, Seoul 120-750, Republic of Korea
‡Center for Neuro-Medicine, Korea Institute of Science & Technology, Hwarangro 14-gil, Seongbuk-Gu, Seoul 136-791, Republic of
Korea
S
* Supporting Information
ABSTRACT: A tandem protocol for the synthesis of fluorinated
isoxazoles has been developed via catalytic intramolecular cycliza-
tions of 2-alkynone O-methyl oximes and ensuing fluorination. The
reactions proceed smoothly at room temperature in the presence of
5 mol % of (IPr)AuCl, 5 mol % of AgOTs, 2.5 equiv of Selectfluor,
and 2 equiv of NaHCO3. This process features an efficient one-pot
cascade route to fluoroisoxazoles with high yields and high selectivity
under mild reaction conditions.
for new, direct, and practical synthetic route for variously
substituted fluoroisoxazoles has continued to grow.
INTRODUCTION
■
Isoxazole1 is an important heteroaromatic scaffold exhibiting a
broad range of biological activities such as analgesic,2
antibiotic,3 antidepressant,4 and anticancer5 activities. In
particular, fluoroisoxazole6 has drawn medicinal chemists’
attention due to its pharmaceutical usefulness7 and the unique
role of fluorine in medicinal chemistry. Fluorine is the next
smallest substituent to hydrogen and is the most electro-
negative element in the periodic table. Moreover, replacement
of a C−H bond with a C−F bond entails only a modest steric
perturbation, effectively blocks metabolic sites, and increases
the lipophilicity of molecules. Therefore, fluorine can act as a
bioisostere of hydrogen and thereby enhance the metabolic
stability and cell-membrane permeability of therapeutic small
molecules, which can ultimately lead to the improvement of
pharmacokinetic and physicochemical properties.8 For this
reason, fluorine has been used as a remarkable tool for
medicinal chemists to create new medicines. Despite such
importance of organofluorine compounds, their synthetic
routes are limited because of the difficulty of fluorination. In
particular, the synthetic route for fluoroisoxazole has been very
rarely reported. The representative synthetic route for
fluoroisoxazole includes the condensation of 2-fluoro-1,3-
diketone and hydroxylamine·HCl in EtOH/H2SO4,9 which
suffers from poor chemical yield and requires strongly acidic
reaction conditions. Recently, a direct fluorination reaction of
the isoxazole ring using electrophilic fluorinating reagents has
been reported10 as an alternate synthetic route, but it is also
sluggish even in refluxing acetonitrile and requires harsher
conditions such as reflux in sulfolane, resulting in low chemical
yields (28−39%) and the formation of trifluorinated by-
products. In the past decade, the number of agrochemicals and
pharmaceuticals containing fluorine has increased, and the need
Although efficient C−F bond formation represents a major
challenge in organic and organometallic chemistry, homoge-
neous gold catalysis has made rapid progress in C−F bond-
forming reactions since Sadighi and co-workers reported the
direct gold-catalyzed hydrofluorination of alkynes with the
gold(I) fluoride complex and Et3N·3HF in 2007.11 While
seeking gold-catalyzed C−F bond-forming reactions to
construct fluoroisoxazole, we were particularly prompted to
explore the feasibility of a gold-catalyzed tandem cyclization−
fluorination sequence to give fluoroisoxazole. Tandem cycliza-
tion−fluorination of the C−C multiple bond allows an efficient
and atom-economic route to assemble fluorinated heterocycles
in one step. However, due to the scarcity of methods for the
fluorination of C−Au bonds, gold-catalyzed tandem cycliza-
tion−fluorination of C−C multiple bond has been less
investigated to date.12 In 2008, Gouverneur and co-workers
reported a gold-catalyzed alkoxyfluorination of β-hydroxy-α,α-
difluoroynones, which featured a sequential alkoxyauration and
oxidative fluorination of a transient vinyl gold species with
Selectfluor.13 Interestingly, α,α-difluorine substituents of the
carbonyl group were essential for successful fluorination. More
recently, Xu,14 Fensterbank,15 Wu,16 and Michelet17 independ-
ently developed gold-catalyzed intramolecular aminofluorina-
tions of alkynes to afford fluoropyrazole, fluoropyrrolidine,
fluoroimidazole, and fluoroindole, respectively. In these elegant
tandem transformations, the initially formed aminoauration
intermediates further reacted to afford the corresponding
fluorinated N-heterocycles. In the course of our studies on
gold-catalyzed tandem reactions to construct complex hetero-
Received: April 18, 2014
Published: June 30, 2014
© 2014 American Chemical Society
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cycles, we have developed an efficient synthetic method for
fluoroisoxazole. Herein, we report the first gold-catalyzed
cascade cyclization−fluorination of 2-alkynone O-methyl
oximes to give fluorinated isoxazoles at room temperature.
For the preliminary investigation, we chose (Z)-4-phenylbut-
3-yn-2-one O-methyl oxime (1a) as a model substrate to
optimize suitable conditions for the cascade reaction. First, we
carried out the tandem cyclization−fluorination reaction in the
presence of (PPh3)AuCl (5 mol %), Selectfluor (1.5 equiv), and
NaHCO3 (2 equiv) at room temperature. To our delight,
(PPh3)AuCl produced the cyclization−fluorination product 3a
in 54% yield as well as the cyclization−protodeauration product
4a in 3% yield after 120 h (Table 1, entry 1). When the amount
of Selectfluor was increased from 1.5 to 2.5 equiv, the
formation of 3a and 4a increased to 65% and 5%, respectively,
in a shorter time (96 h, Table 1, entry 2). In some gold-
catalyzed reactions, addition of H2O sometimes accelerates the
reaction progress by enhancing the solubility of reagents such
as base and Selectfluor, which are poorly soluble in CH3CN.18
However, when the reaction was carried out in the presence of
H2O (10 equiv), protodeaurated isoxazole 4a was obtained in
increased yield (14%), and the reaction was completed in a
much shorter time (68 h, Table 1, entry 3), suggesting that
H2O can accelerate protodeauration as well as the fluorination.
Notably, the yield of 3a and the selectivity of 3a/4a were
substantially reduced in the absence of base either with or
without H2O (Table 1, entries 4 and 5), indicating that the
addition of a base was essential for the reaction. With the above
RESULTS AND DISCUSSION
■
To develop a novel direct synthetic method for fluoroisox-
azoles, we envisioned that π-acidic gold could catalyze the
cyclization of 2-alkynone O-methyl oxime 1 leading to the
cationic gold intermediate 2 and that subsequent fluorination
might provide fluoroisoxazole 3 in a cascade manner (Scheme
1). This tandem transformation involves a gold-catalyzed
Scheme 1. Strategy for Cyclization−Fluorination
cyclization reaction combined with oxidative and/or electro-
philic fluorination in one pot, which allows direct access to
highly functionalized isoxazoles.
a
Table 1. Catalyst Screening and Optimization of Reaction Conditions for the Tandem Cyclization−Fluorination
b
yield (%)
entry
catalyst
additives (equiv)
NaHCO3 (2)
time (h)
3a
4a
c
1
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuNTf2
(PCy3)AuCl
(PEt3)AuCl
(PMe3)AuCl
(PhO)3PAuCl
AuCl
120
96
54
65
66
47
46
64
49
75
65
67
77
77
66
81
73
43
64
50
NR
NR
3
5
2
3
4
5
6
NaHCO3 (2)
NaHCO3 (2)/H2O (10)
H2O (10)
68
14
22
10
12
11
4
85
120
144
120
98
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
d
7
8
9
98
6
10
11
12
13
14
15
16
17
18
19
20
120
72
9
2
AuCl3
120
120
24
5
NaAuCl4·2H2O
(IPr)AuCl
5
10
0
117
120
105
92
6
6
16
5
7
8
22
e
e
96
NaHCO3 (2)
144
a
Reaction conditions: 1a (69.3 mg, 400 μmol), Au-catalyst (20.0 μmol), Selectfluor (354 mg, 1.00 mmol), NaHCO3 (800 μmol), CH3CN (4 mL).
Isolated yields. 1.5 equiv of Selectfluor was used. 16% of 1a was recovered. 26% of 1a was recovered. No reaction.
b
c
d
e
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preliminary data in hand, we began a survey of catalysts to
investigate various gold catalysts: (PPh3)AuNTf2, (PCy3)AuCl,
(PEt3)AuCl, (PMe3)AuCl, (PhO)3PAuCl, AuCl, AuCl3,
NaAuCl4·2H2O, (IPr)AuCl (IPr = N,N′-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene), and the gold(I) com-
plexes 5−8 bearing bulky biphenyl-based phosphine ligands.
After extensive optimization studies, (IPr)AuCl19 (5 mol %)
was identified as the best catalyst for the cascade cyclization−
fluorination reaction (Table 1, entry 14). In the presence of
(IPr)AuCl (5 mol %), fluoroisoxazole 3a was isolated in 81%
yield after 24 h at room temperature without the formation of
4a. The tandem reaction did not happen without a gold catalyst
(Table 1, entries 19 and 20) at room temperature under the
standard conditions.
it cannot be excluded that the apparent silver salt effect might
be originated from the anion effect. We are currently further
investigating the silver salt effect and the anion effect on the
cascade cyclization−fluorination reaction.
It was also found that base had a significant effect on the
outcome of the reaction. K2CO3, Li2CO3, Na3PO4, K3PO4, and
KOH gave comparable results to NaHCO3 (Table 3, entries 3,
Table 3. Base Effect and Fluorinating Reagent Effect on the
a
Tandem Cyclization−Fluorination Reaction
We further investigated the effect of silver cocatalysts on the
cascade cyclization−fluorination reaction as shown in Table 2.
b
yield (%)
Table 2. Silver Salt Effect on the Tandem Cyclization−
a
entry
base
fluorinating reagent
time (h)
3a
4a
Fluorination Reaction
1
2
3
Na2CO3
KHCO3
K2CO3
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
34
96
83
57
87
17
90
85
82
71
85
1
0
24
0
5
c
4
Cs2CO3
Li2CO3
Na3PO4
K3PO4
120
4.5
4.5
5.5
18.5
5.5
4.5
42
0
5
0
b
6
0
yield (%)
7
0
entry
catalyst
time (h)
3a
4a
8
NaOH
12
0
1
2
3
4
5
6
7
8
(IPr)AuCl/AgOTs
(IPr)AuCl/AgOTf
(IPr)AuCl/AgNTf2
(IPr)AuCl/AgSbF6
(IPr)AuCl/AgNO3
(IPr)AuCl/AgBF4
(IPr)AuCl/AgCl
AgOTs
4.5
5.5
4.5
5.5
4.5
4.5
28
92
91
88
87
88
85
88
NR
82
68
0
0
0
0
0
0
0
9
KOH
10
11
Et3N
86
34
0
2,6-lutidine
NaHCO3
NaHCO3
33
0
d
e
12
NFSI
48
f
g
13
NFPY-BF4
48
0
62
a
Reaction conditions: 1a (69.3 mg, 400 μmol), (IPr)AuCl (20.0
μmol), AgOTs (20.0 μmol), fluorinating reagent (1.00 mmol), base
c
96
b
c
(800 μmol), CH3CN (4 mL). Isolated yields. 79% of 1a was
recovered. 85% of 1a was recovered. NFSI = N-fluorobenzenesulfo-
nimide. 25% of 1a was recovered. NFPY-BF4 = N-fluoropyridinium
d
d
e
9
(IPr)AuCH3/TsOH
(IPr)AuCH3/TfOH
4.5
5.5
0
0
e
f
g
10
a
tetrafluoroborate.
Reaction conditions: 1a (69.3 mg, 400 μmol), Au-catalyst (20.0
μmol), Ag-salt (20.0 μmol), Selectfluor (354 mg, 1.00 mmol),
b
c
NaHCO3 (800 μmol), CH3CN (4 mL). Isolated yields. No reaction.
d
e
5, 6, 7 and 9). However, the reaction in the presence of
Na2CO3, KHCO3, Cs2CO3, or NaOH required a prolonged
reaction time (Table 3, entries 1, 2, 4, and 8), and Et3N
reversed the selectivity in favor of 4a (Table 3, entry 10).
Meanwhile, Selectfluor has been disclosed as the best
fluorinating reagent for gold-catalyzed tandem cyclization−
fluorination reaction. Other fluorinating reagent such as N-
fluorobenzenesulfonimide (NFSI) or N-fluoropyridinium tetra-
fluoroborate (NFPY-BF4) failed to give the desired product 3a
at room temperature after 48 h (Table 3, entries 12 and 13).
With the optimized reaction conditions in hand, we
investigated the scope of this tandem cyclization−fluorination
reaction with a variety of O-methyl oximes. As shown in
Scheme 2, 1,3-disubstituted propynone oximes displayed a
broad substrate scope and functional group compatibility.
Substrates 1c−f bearing electron-poor R1 groups at the 1
position of propynone oximes underwent the tandem reaction
very well and smoothly provided the corresponding fluoroisox-
azoles 3c−f at room temperature in good to excellent yields
(79−96%). Substrates 1g−i bearing electron-rich R1 groups at
the 1 position of propynone oximes also gave the desired
products 3g−i in slightly lower yields (62−96%). The
electronic effects of R2 group at the 3 position of propynone
oximes were also investigated. Both electron-poor and electron-
TsOH (20.0 μmol) was used instead of Ag-salt. TfOH (20.0 μmol)
was used instead of Ag-salt.
Addition of 5 mol % silver salts remarkably facilitated the
tandem process. The tandem reactions were completed in 4.5−
5.5 h in the presence of AgOTs, AgOTf, AgNTf2, AgSbF6,
AgNO3, or AgBF4 and afforded 3a as a sole product in 85−92%
yield (Table 2, entries 1−6). Interestingly, the addition of AgCl
did not speed up the tandem process at all (Table 2, entry 7).
This dramatic silver salt effect20 requires further mechanistic
investigation. A control experiment revealed that silver salt
alone did not provide the desired tandem product 3a at room
temperature after 96 h under the optimized reaction conditions
(Table 2, entry 8). In addition, we also carried out the cascade
cyclization−fluorination reaction with (IPr)AuOTs prepared by
premixing (IPr)AuCH3 and TsOH in the absence of silver salts,
which provided fluoroisoxazole 3a in 82% yield after 4.5 h
(Table 2, entry 9). It was comparable to the reaction of
(IPr)AuCl/AgOTs (92%, 4.5 h, Table 2, entry 1). Likewise,
(IPr)AuOTf prepared via protonolysis of (IPr)AuCH3 by
TfOH also provided fluoroisoxazole 3a in 68% yield after 5.5 h
(Table 2, entry 10). Obviously, anion had a significant effect on
the cascade cyclization−fluorination reaction as well. Therefore,
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Scheme 2. Gold-Catalyzed Cascade Cyclization−
Scheme 3. Gold-Catalyzed Cascade Cyclization−
Fluorination of (E)-O-Methyl Oximes
a
Fluorination of Various O-Methyl Oximes
Scheme 4. Gold-Catalyzed Direct Fluorination of 3,5-
Disubstituted Isoxazoles
reactions at room temperature under the standard conditions,
and the isoxazole fluorination did not happen even in the
presence of only Selectfluor. It has been also reported that the
direct fluorinations of isoxazoles with only Selectfluor in
refluxing acetonitrile were sluggish and gave only traces of the
4-fluoroisoxazoles.10 Therefore, unlike pyrazole,14 direct
fluorination of isoxazole 4 was excluded from the possible
mechanism. In addition, we carried out an in situ NMR
experiment using a stoichiometric amount of 1a, (IPr)AuCl,
and AgOTs (1:1:1) and monitored reaction progress from
intensity changes in substrate OMe resonance (Figure 1). In
this NMR experiment, we observed the generation of CH3OTs,
which suggests that −OTs can act as a demethylating agent.
After 24 h, the reaction produced an insoluble solid in the
NMR tube, and broad NMR peaks were observed (e, Figure 1).
The formed solid was isolated, crystallized, and characterized to
be the isoxazolyl-gold intermediate [(IPr)Au(C10H8NO)] (9)
by X-ray crystallography (Figure 2). The resulting structure
displays a nearly linear geometry at the gold(I) with C1−Au1−
C2 bond angle of 177.84° and nearly equal Au−C bond
distances (Au1−C1 = 2.026 Å, Au1−C2 = 2.020 Å). Further
efforts to investigate detailed mechanism are ongoing in our
laboratory.
a
Isolated yields are given. Reaction conditions: 1b−p (200 μmol),
(IPr)AuCl (6.2 mg, 10.0 μmol), AgOTs (2.8 mg, 10.0 μmol),
Selectfluor (177 mg, 500 μmol), NaHCO3 (33.6 mg, 400 μmol),
CH3CN (2 mL).
rich substrates 1j−m produced the desired products 3j−m in
good yields (65−100%). However, the electron-poor substrate
1j required a prolonged reaction time (96 h). Both
modifications to the R1 and R2 groups at 1 and 3 positions
did not change the reactivity (3n), while furan-substituted
propynone oxime 1o was rather unstable under the standard
conditions, decomposed rapidly, and afforded 3o in decreased
yield (26%). The tandem reaction could also be applied to the
synthesis of aliphatic fluoroisoxazole 3p.
In order to obtain mechanistic insight, we carried out several
experiments with (E)-O-methyl oximes (Scheme 3) and 3,5-
disubstituted isoxazoles (Scheme 4). First, when (E)-O-methyl
oximes were subjected to the standard reaction conditions, the
starting (E)-O-methyl oximes 1j′ and 1l′ were recovered
(Scheme 3) after 24 h, probably because (E)-O-methyl oximes
could not meet the geometric requirements for the cyclization−
fluorination reaction and the corresponding (E)- and (Z)-O-
methyl oximes were not interconvertible at room temperature.
Second, we also investigated direct fluorination of isoxazole
under the standard conditions (Scheme 4). 3,5-Disubstituted
isoxazoles 4a and 4b did not undergo direct fluorination
On the basis of previous studies14,15,21 and our own
observation, a plausible mechanistic pathway can be proposed
for the gold-catalyzed cyclization−fluorination of (Z)-2-
alkynone O-methyl oxime (Scheme 5). The initial coordination
of the gold(I) catalyst A to the alkyne of O-methyl oxime 1a
and subsequent cyclization would lead to the gold(I) complex
C. After this, demethylation and oxidation by Selectfluor would
afford the cationic gold(III) intermediate E bearing both
isoxazole and fluoride; E readily decomposes to yield cross-
coupled fluoroisoxazole 3a and the cationic gold(I) catalyst A
after reductive elimination. In the meanwhile, the protodeaura-
tion of D would generate isoxazole 4a. This proposed
mechanism involves a redox Au(I)/Au(III) catalytic cycle
mediated by the external oxidant Selectfluor. However, the
exact mechanistic pathway leading to 3a is still unclear and
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Figure 1. 1H NMR monitoring of the stoichiometric reaction of 1a, (IPr)AuCl, and AgOTs (1:1:1): (a) 0 h, (b) 2 h, (c) 4 h, (d) 6 h, (e) 24 h, (f)
MeOTs.
Scheme 5. Plausible Mechanism
CONCLUSIONS
■
We have successfully developed an efficient gold-catalyzed
tandem cyclization−fluorination of (Z)-2-alkynone O-methyl
oxime to furnish fluoroisoxazole under mild conditions (room
temperature). This is the first report of construction of
Figure 2. ORTEP drawing of the crystal structure for [(IPr)Au-
fluoroisoxazoles using one-pot gold(I)-catalyzed tandem
(C10H8NO)] (9). Selected bond lengths (Å) and angles (deg): Au1−
cyclization−fluorination. This methodology may be useful in
medicinal chemistry, and its application to the synthesis of
bioactive fluorinated isoxazoles is currently underway in our
laboratory.
C1 = 2.026(3), Au1−C2 = 2.020(3), C1−C4 = 1.363(4), C1−C3 =
1.432(4); C1−Au1−C2 = 177.84(10), Au1−C1−C4 = 132.8(2),
Au1−C2−N3 = 127.31(18).
requires further investigation. An alternative possible mecha-
nistic pathway is gold(III)-mediated cyclization. We carried out
a
Selectfluor = 1:1:2) and observed a small broad singlet peak
at −179.3 ppm, which is characteristic of Au(III)+XFL species.
Formation of Au(III) species in analogous 19F NMR experi-
ments was previously observed and described in the
literature.15,21b Additionally, AuCl3 has been reported to cyclize
acetylenic oximes.21d Thus, an alternative mechanism involving
gold(III)-mediated cyclization cannot be ruled out.
EXPERIMENTAL SECTION
■
19F NMR experiment in CD3CN ((IPr)AuCl/AgOTs/
General Methods. All reactions were performed in flame-dried
glassware fitted with a glass stopper under positive pressure of Ar with
magnetic stirring, unless otherwise noted. Air- and moisture-sensitive
liquids and solutions were transferred via syringe or stainless steel
cannula. TLC was performed on commercial 0.25 mm plates and
visualized under UV light (254 nm) or by staining with cerium
ammonium molybdenate (CAM), potassium permanganate (KMnO4),
or p-anisaldehyde. Flash chromatography was performed on
commercial 230−400 mesh silica gel 60. Reagents were purchased
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from commercial suppliers and used without further purification unless
otherwise noted. Solvents were distilled from proper drying agents
(CaH2 or Na wire) under Ar atmosphere at 760 mmHg. All moisture-
and/or oxygen-sensitive solids were handled and stored in a glovebox
under N2. NMR spectra were recorded at 24 °C. Chemical shifts are
expressed in ppm relative to TMS (1H, 0 ppm), CDCl3 (1H, 7.26 ppm;
13C, 77.2 ppm), acetone-d6 (1H, 2.05 ppm; 13C, 206.2, 29.9 ppm), and
C6H5F (19F, −113.15 ppm); coupling constants are expressed in Hz.
High resolution mass spectra electrospray ionization (HRMS-ESI) was
obtained on TOF LC−MS spectrometer. Infrared spectra were
recorded with peaks reported in cm−1.
hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz,
2H), 7.67 (d, J = 8.4 Hz, 2H), 7.47 (m, 2H), 7.36−7.32 (m, 3H), 5.76
(d, J = 6.0 Hz, 1H), 2.37 (d, J = 6.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 144.4, 131.8, 130.5 (q, JC−F = 32.2 Hz), 128.9, 128.4, 127.0.
125.6 (q, JC−F = 3.9 Hz), 124.1 (q, JC−F = 271 Hz), 122.0, 87.9, 87.3,
64.4. 19F NMR (376 MHz, CDCl3): δ −62.6 (s). LRMS (EI) m/z (rel
int): (pos) 276 ([M]+, 100), 259 ([M − OH]+,16), 207 ([M − CF3]+,
44). HRMS m/z calcd for C16H11F3O 276.0762, found 276.0768.
3-Phenyl-1-(p-tolyl)prop-2-yn-1-ol (S1g). Reaction time: 1 h. Pale
1
violet solid (1.12 g, 75%). TLC: Rf 0.30 (4:1 hexanes/EtOAc). H
NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.0 Hz, 2H), 7.47 (m, 2H),
7.33−7.31 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 5.66 (d, J = 6.4 Hz, 1H),
2.37 (s, 3H), 2.19 (d, J = 6.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 138.5, 138.0, 131.9, 129.6, 128.8, 128.5, 126.9, 122.7, 89.1, 86.7, 65.2,
21.4. LRMS (EI) m/z (rel int): (pos) 222 ([M]+, 72), 207 ([M −
CH3]+, 100). HRMS m/z calcd for C16H14O 222.1045, found
222.1046. IR (KBr film): 3346, 3054, 3023, 2921, 1597, 1489, 820,
757, 691 cm−1.
Synthesis of Substrates.
1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (S1h). Reaction
time: 1 h. Milky oil (1.06 g, 89%). TLC: Rf 0.26 (4:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 7.6, 1.6 Hz,
1H), 7.48 (m, 2H), 7.36−7.30 (m, 4H), 7.01 (td, J = 7.6, 0.8 Hz, 1H),
6.95 (dd, J = 7.6, 0.8 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 3.93 (s, 3H),
3.05 (d, J = 6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 156.9,
131.8, 129.8, 128.8, 128.4, 128.2, 128.1, 122.8, 120.9, 110.9, 88.3, 86.1,
61.7, 55.6. LRMS (EI) m/z (rel int): (pos) 238 ([M]+, 66), 223 ([M
− CH3]+, 100), 207 ([M − OCH3]+, 46). HRMS m/z calcd for
C16H14O2 238.0994, found 238.0995.
Representative Procedure for the Synthesis of Propargyl
Alcohols S1c−p. To a 50 mL two-neck round-bottom flask were
added phenylacetylene (625 mg, 6.00 mmol, 1.20 equiv) and
anhydrous THF (15 mL). The mixture was cooled to −78 °C, and
n-butyllithium (2.5 M in hexanes, 2.50 mL, 6.25 mmol, 1.25 equiv)
was added slowly via syringe. The mixture was stirred at −78 °C for 1
h, then warmed to 0 °C, stirred for 1 h, and then recooled to −78 °C.
p-Fluorobenzaldehyde (633 mg, 5.00 mmol) in THF (5 mL) was
added dropwise via syringe, and the reaction was stirred at −78 °C for
1 h, warmed to rt, and stirred for an additional 30 min. Upon the
completion of the reaction, the reaction was quenched with saturated
aqueous NH4Cl (30 mL) and extracted with Et2O (3 × 50 mL). The
combined organic extracts were washed with brine (50 mL), then
dried over anhydrous MgSO4, filtered, and concentrated by rotary
evaporation. The residue was purified by column chromatography
(10:1 hexanes/EtOAc) to afford S1d (947 mg, 84%) as a colorless
liquid.
1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (S1i). Reaction
time: 1 h. Milky oil (955 mg, 80%). TLC: Rf 0.08 (10:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.49−7.46 (m, 2H), 7.34−
7.31 (m, 4H), 7.21−7.18 (m, 2H), 6.89 (ddd, J = 8.4, 2.6, 1.0 Hz, 1H),
5.67 (d, J = 6.4 Hz, 1H), 3.84 (s, 3H), 2.26 (d, J = 6.4 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 159.9, 142.2, 131.8, 129.7, 128.6, 128.3,
122.4, 119.0, 114.1, 112.2, 88.6, 86.6, 65.0, 55.3. LRMS (EI) m/z (rel
int): (pos) 238 ([M]+, 100), 223 ([M − CH3]+, 25), 207 ([M −
OCH3]+, 33). HRMS m/z calcd for C16H14O2 238.0994, found
238.0994.
3-(3-Chlorophenyl)-1-phenylprop-2-yn-1-ol (S1j). Reaction time:
1 h. Pale yellow oil (1.21 g, 82%). TLC: Rf 0.20 (10:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 7.2 Hz, 2H),
7.50−7.28 (m, 7H), 5.72 (d, J = 6.0 Hz, 1H), 2.37 (d, J = 6.0 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 140.5, 134.4, 131.8, 130.1, 129.8,
129.1, 128.9, 128.8, 126.9, 124.3, 90.1, 85.4, 65.3. HRMS (EI) m/z
calcd for C15H11ClO 242.0498, found 242.0494.
1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (S1c). Reaction time:
1 h. White solid (983 mg, 52%). TLC: Rf 0.43 (4:1 hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.4 Hz, 2H), 7.47 (m,
2H), 7.38 (d, J = 8.4 Hz, 2H), 7.35−7.32 (m, 3H), 5.68 (d, J = 6.0 Hz,
1H), 2.27 (d, J = 6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 139.3,
134.5, 132.0, 129.0, 128.8, 128.6, 128.3, 122.4, 88.4, 87.2, 64.6. LRMS
(EI) m/z (rel int): (pos) 242 ([M]+, 46), 207 ([M − Cl]+, 100).
HRMS m/z calcd for C15H11ClO 242.0498, found 242.0496. IR (KBr
film): 3345, 1597, 1489, 837, 756, 691 cm−1.
1-Phenyl-3-(p-tolyl)prop-2-yn-1-ol (S1k). Reaction time: 1 h. Pale
yellow oil (1.08 g, 71%). TLC: Rf 0.13 (10:1 hexanes/EtOAc). H
1
NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.2 Hz, 2H), 7.45−7.35 (m,
5H), 7.15 (d, J = 8.0 Hz, 2H), 5.70 (d, J = 1.6 Hz, 1H), 2.73 (brs, 1H),
2.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 140.9, 138.9, 131.8,
129.2, 128.8, 128.5, 126.9, 119.5, 88.3, 86.9, 65.2, 21.6. HRMS (EI) m/
z calcd for C16H14O 222.1045, found 222.1049.
3-(4-Pentylphenyl)-1-phenylprop-2-yn-1-ol (S1l). Reaction time: 1
h. Pale yellow oil (1.13 g, 88%). TLC: Rf 0.20 (10:1 hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 6.8 Hz, 2H), 7.44−7.34
(m, 5H), 7.14 (d, J = 8.0 Hz, 2H), 5.70 (s, 1H), 2.61 (t, J = 7.6 Hz,
2H), 2.38 (brs, 1H), 1.62 (quintet, J = 7.6 Hz, 2H), 1.38−1.29 (m,
4H), 0.91 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.8,
140.8, 131.7, 128.6, 128.4, 128.3, 126.7, 119.5, 88.0, 86.9, 65.1, 35.8,
31.4, 30.9, 22.5, 14.0. HRMS (EI) m/z calcd for C20H22O 278.1671,
found 278.1673.
3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-ol (S1m). Reaction
time: 1 h. Pale yellow oil (1.11 g, 77%). TLC: Rf 0.15 (10:1
hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.2 Hz,
2H), 7.44−7.35 (m, 5H), 6.85 (d, J = 9.2 Hz, 2H), 5.68 (d, J = 2.4 Hz,
1H), 3.80 (s, 3H), 2.59 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ
160.0, 141.1, 133.4, 128.8, 128.5, 126.9, 114.7, 114.1, 87.6, 86.8, 65.3,
55.4. HRMS (ESI) m/z calcd for C16H14O2 238.0994, found 238.0991.
1-(4-Chlorophenyl)-3-(p-tolyl)prop-2-yn-1-ol (S1n). Reaction
time: 1 h. White solid (1.22 g, 95%). TLC: Rf 0.33 (5:1 hexanes/
1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-ol (S1d). Reaction time:
0.5 h. Colorless liquid (947 mg, 84%). TLC: Rf 0.25 (5:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.60 (dd, J = 8.4, 5.2 Hz,
2H), 7.47 (m, 2H), 7.35−7.32 (m, 3H), 7.09 (t, J = 8.4 Hz, 2H), 5.68
(d, J = 6.0 Hz, 1H), 2.27 (d, J = 6.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 162.7 (d, JC−F = 245.3 Hz), 136.5 (d, JC−F = 3.8 Hz), 131.8,
128.7, 128.6 (d, JC−F = 8.5 Hz), 128.4, 122.2, 115.5 (d, JC−F = 21.6
Hz), 88.5, 86.9, 64.4. 19F NMR (376 MHz, CDCl3): δ −113.8 (m).
HRMS (ESI) m/z calcd for C15H11FO 226.0794, found 226.0797.
1-(3-Nitrophenyl)-3-phenylprop-2-yn-1-ol (S1e). Reaction time: 1
h. Orange solid (1.08 g, 85%). TLC: Rf 0.23 (4:1 hexanes/EtOAc). 1H
NMR (400 MHz, CDCl3): δ 8.51 (t, J = 1.6 Hz, 1H), 8.22 (dm, J = 8.0
Hz, 1H), 7.96 (dm, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.48 (m,
2H), 7.39−7.32 (m, 3H), 5.81 (d, J = 5.6 Hz, 1H), 2.45 (d, J = 5.6 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 148.4, 142.7, 132.7, 131.8,
129.6, 129.1, 128.4, 123.3, 121.8, 121.7, 87.7, 87.4, 64.0. HRMS (ESI)
m/z calcd for C15H11NO3 253.0739, found 253.0743.
3-Phenyl-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-ol (S1f). Reac-
tion time: 0.5 h. Colorless liquid (1.19 g, 86%). TLC: Rf 0.48 (3:1
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1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.4 Hz, 2H),
3-Phenyl-1-(p-tolyl)prop-2-yn-1-one (S2g). Reaction time: 0.5 h.
Yellowish orange solid (796 mg, 80%). TLC: Rf 0.69 (10:1 hexanes/
EtOAc). H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.0 Hz, 2H),
7.69 (dm, J = 7.2 Hz, 2H), 7.49 (tm, J = 7.2 Hz, 1H), 7.42 (tm, J = 7.2
Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 177.7, 145.2, 134.6, 133.0, 130.7, 129.7, 129.3, 128.6, 120.3,
92.6, 87.0, 21.8. HRMS (ESI) m/z calcd for C16H12O 220.0888, found
220.0891. IR (KBr film): 3062, 3025, 2921, 2203, 1637, 1489, 833,
760, 690 cm−1.
7.37 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz,
2H), 5.66 (d, J = 6.0 Hz, 1H), 2.36 (s, 3H), 2.27 (d, J = 6.0 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 139.4, 139.2, 134.4, 131.8, 129.3,
128.9, 128.3, 119.2, 87.8, 87.3, 64.6, 21.7. LRMS (EI) m/z (rel int):
(pos) 256 ([M]+, 52), 241 ([M − CH3]+, 55), 221 ([M − Cl]+, 100).
HRMS m/z calcd for C16H13ClO 256.0655, found 256.0660.
1-(Furan-2-yl)-3-(4-methoxyphenyl)prop-2-yn-1-ol (S1o). Reac-
tion time: 0.33 h. White solid (1.04 g, 91%). TLC: Rf 0.22 (3:1
hexanes/EtOAc). Mp: 56−58 °C. H NMR (400 MHz, CDCl3): δ
7.44 (dd, J = 1.6, 0.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8
Hz, 2H), 6.52 (dt, J = 3.6, 0.8 Hz, 1H), 6.38 (dd, J = 3.6, 1.6 Hz, 1H),
5.68 (d, J = 7.2 Hz, 1H), 3.82 (s, 3H), 2.33 (d, J = 7.2 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 160.0, 153.2, 143.0, 133.3, 114.2, 114.0,
110.4, 107.8, 85.8, 84.9, 58.7, 55.3. LRMS (EI) m/z (rel int): (pos)
228 ([M]+, 100), 211 ([M − OH]+, 50). HRMS m/z calcd for
C14H12O3 228.0786, found 228.0787. IR (KBr film): 3404, 2839, 2232,
1606, 1510, 1464, 1249, 1032, 833 cm−1.
1
1
1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-one (S2h). Reaction
time: 0.5 h. Yellow oil (1.00 g, 97%). TLC: Rf 0.41 (4:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 8.08 (dd, J = 8.0, 2.0 Hz,
1H), 7.64 (dt, J = 6.8, 2.0 Hz, 2H), 7.53 (m, 1H), 7.44 (m, 1H), 7.38
(tm, J = 6.8, 2H), 7.07 (td, J = 8.0, 0.8 Hz, 1H), 7.01 (dm, J = 8.0 Hz,
1H), 3.95 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 176.7, 159.8,
135.0, 133.0, 132.6, 130.5, 128.6, 126.8, 120.7, 120.3, 112.2, 91.6, 89.2,
55.9. HRMS (ESI) m/z calcd for C16H12O2 236.0837, found 236.0839.
1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-one (S2i). Reaction
time: 0.5 h. Pale yellow solid (797 mg, 96%). TLC: Rf 0.52 (5:1
1-Phenylnon-2-yn-1-ol (S1p). Reaction time: 1 h. Pale yellow oil
(1.36 g, 87%). TLC: Rf 0.15 (10:1 hexanes/EtOAc). H NMR (400
1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.87 (ddd, J = 8.0,
1.6, 0.8 Hz, 1H), 7.22−7.68 (m, 3H), 7.50 (m, 1H), 7.46−7.41 (m,
3H), 7.19 (ddd, J = 8.0, 2.8, 0.8 Hz, 1H), 3.90 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 177.8, 159.8, 138.3, 133.1, 130.8, 129.7, 128.7, 122.9,
121.0, 120.1, 112.9, 93.0, 87.0, 55.5. HRMS (ESI) m/z calcd for
C16H12O2 236.0837, found 236.0838.
MHz, CDCl3): δ 7.47 (d, J = 7.2 Hz, 2H), 7.40−7.30 (m, 3H), 5.46
(dt, J = 6.4, 2.0 Hz, 1H), 2.27 (td, J = 7.2, 2.0 Hz, 2H), 2.10 (d, J = 6.4
Hz, 1H), 1.55 (quintet, J = 7.2 Hz, 2H), 1.44−1.37 (m, 2H), 1.35−
1.26 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 141.5, 128.7, 128.4, 126.8, 88.0, 80.1, 65.1, 31.5, 28.8, 28.7, 22.7,
19.0, 14.2. HRMS (EI) m/z calcd for C15H20O 216.1514, found
216.1509.
Representative Procedure for the Synthesis of Alkynones
S2c−p. In a 50 mL two-neck round-bottom flask, propargyl alcohol
S1c (850 mg, 3.50 mmol) was dissolved in acetone (25 mL). Activated
MnO2 (6.09 g, 70.0 mmol, 20 equiv) was added, and the mixture was
stirred at rt for 30 min. Upon the completion of the reaction, the
resulting suspension was filtered through a plug of Celite, and the
filtrate was concentrated by rotary evaporation. Purification of the
residue by column chromatography (10:1 hexanes/EtOAc) afforded
alkynone S2c (598 mg, 71%) as a white solid.
3-(3-Chlorophenyl)-1-phenylprop-2-yn-1-one (S2j). Reaction
time: 0.5 h. Yellow solid (954 mg, 95%). TLC: Rf 0.26 (10:1
hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.0 Hz,
2H), 7.67 (t, J = 1.6 Hz, 1H), 7.64 (dt, J = 7.6, 1.6 Hz, 1H), 7.57 (dt, J
= 7.6, 1.6 Hz, 1H), 7.53 (tm, J = 8.0 Hz, 2H), 7.47 (m, 1H), 7.37 (t, J
= 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 177.9, 136.9, 134.9,
134.6, 132.9, 131.3, 131.2, 130.2, 129.8, 128.9, 122.1, 91.1, 87.6.
HRMS (ESI) m/z calcd for C15H9ClO 240.0342, found 240.0344.
1-Phenyl-3-(p-tolyl)prop-2-yn-1-one (S2k). Reaction time: 0.5 h.
Yellow solid (930 mg, 95%). TLC: Rf 0.30 (10:1 hexanes/EtOAc). 1H
NMR (400 MHz, CDCl3): δ 8.23 (dd, J = 7.6, 1.2 Hz, 2H), 7.63 (tt, J
= 7.6, 1.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H),
7.23 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 178.3, 141.8, 137.2, 134.2, 133.3, 129.8, 129.7, 128.8, 117.2, 94.0,
87.0, 22.0. HRMS (ESI) m/z calcd for C16H12O 220.0888, found
220.0891.
1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-one (S2c). Reaction
time: 0.5 h. White solid (598 mg, 71%). TLC: Rf 0.65 (4:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8
Hz, 2H), 7.69 (dm, J = 7.2 Hz, 2H), 7.51 (m, 1H), 7.50 (d, J = 8.8 Hz,
2H), 7.44 (tm, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ
176.7, 140.7, 135.3, 133.1, 131.0, 130.9, 129.1, 128.7, 119.9, 93.6, 86.6.
HRMS (ESI) m/z calcd for C15H9ClO 240.0342, found 240.0343. IR
(KBr film): 2199, 1654, 847, 751, 681 cm−1.
3-(4-Pentylphenyl)-1-phenylprop-2-yn-1-one (S2l). Reaction time:
0.5 h. Yellow solid (1.01 g, 97%). TLC: Rf 0.39 (10:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 8.21 (dd, J = 7.6, 1.2 Hz,
2H), 7.63 (tt, J = 7.6, 1.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.52 (t, J =
7.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 1.64
(quintet, J = 7.6 Hz, 2H), 1.38−1.25 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 178.3, 146.8, 137.3, 134.2, 133.4,
129.8, 129.1, 128.8, 117.4, 94.1, 87.0, 36.3, 31.6, 31.0, 22.7, 14.2.
HRMS (ESI) m/z calcd for C20H20O 276.1514, found 276.1517. IR
(KBr film): 3030, 2929, 2195, 1644, 1598, 1449, 823, 700 cm−1
3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one (S2m). Reaction
time: 0.5 h. Yellow solid (1.21 g, 82%). TLC: Rf 0.27 (10:1 hexanes/
1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-one (S2d). Reaction
time: 0.5 h. White solid (761 mg, 95%). TLC: Rf 0.42 (5:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.25 (dd, J = 8.4,
5.2 Hz, 2H), 7.69 (m, 2H), 7.50 (m, 1H), 7.43 (m, 2H), 7.20 (t, J =
8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 176.4, 166.5 (d, JC−F
=
255.4 Hz), 133.4 (d, JC−F = 3.1 Hz), 133.1, 132.2 (d, JC−F = 10.1 Hz),
130.9, 128.7, 120.0, 115.8 (d, JC−F = 21.7 Hz), 93.4, 86.6. 19F NMR
(376 MHz, CDCl3): δ −103.3 (m). HRMS (ESI) m/z calcd for
C15H9FO 224.0637, found 224.0634.
1-(3-Nitrophenyl)-3-phenylprop-2-yn-1-one (S2e). Reaction time:
0.5 h. Lemon yellow solid (798 mg, 89%). TLC: Rf 0.44 (4:1 hexanes/
EtOAc). 1H NMR (400 MHz, CDCl3): δ 9.07 (t, J = 2.0 Hz, 1H), 8.53
(dt, J = 7.6, 1.2 Hz, 1H), 8.49 (ddd, J = 7.6, 2.0, 1.2 Hz, 1H), 7.77−
7.73 (m, 3H), 7.54 (m, 1H), 7.46 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 175.4, 148.5, 138.1, 134.6, 133.4, 131.5, 129.9, 128.9, 128.2,
124.6, 119.4, 95.4, 86.2. HRMS (ESI) m/z calcd for C15H9NO3
251.0582, found 251.0582.
1
EtOAc). H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.6 Hz, 2H),
7.65 (d, J = 8.8 Hz, 2H), 7.62 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 6.94
(d, J = 8.8 Hz, 2H), 3.86 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
178.3, 162.0, 137.3, 135.4, 134.1, 129.7, 128.8, 114.7, 112.2, 94.5, 87.1,
55.7. HRMS (ESI) m/z calcd for C16H12O2 236.0837, found 236.0839.
1-(4-Chlorophenyl)-3-(p-tolyl)prop-2-yn-1-one (S2n). Reaction
time: 0.5 h. White solid (848 mg, 81%). TLC: Rf 0.62 (5:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8
3-Phenyl-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one (S2f). Re-
action time: 0.5 h. White solid (780 mg, 91%). TLC: Rf 0.43 (10:1
hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 8.0 Hz,
2H), 7.80 (d, J = 8.0 Hz, 2H), 7.70 (m, 2H), 7.52 (m, 1H), 7.45 (m,
Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.25 (d, J
= 8.0 Hz, 2H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 176.7,
141.8, 140.6, 135.4, 133.2, 130.9, 129.6, 129.0, 116.8, 94.4, 86.5, 21.8.
HRMS (ESI) m/z calcd for C16H11ClO 254.0498, found 254.0495.
1-(Furan-2-yl)-3-(4-methoxyphenyl)prop-2-yn-1-one (S2o). Reac-
tion time: 0.5 h. Pale yellow solid (815 mg, 88%). TLC: Rf 0.36 (3:1
hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.68 (dd, J = 1.6,
0.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 3.6, 0.8 Hz, 1H),
6.93 (d, J = 8.8 Hz, 2H), 6.60 (dd, J = 3.6, 1.6 Hz, 1H), 3.86 (s, 3H).
2H). 13C NMR (100 MHz, CDCl3): δ 176.7, 139.4, 135.2 (q, JC−F
=
32.5 Hz), 133.2, 131.2, 129.8, 128.8, 125.7 (q, JC−F = 3.9 Hz), 123.6
(q, JC−F = 270.9 Hz), 119.7, 94.5, 86.6. 19F NMR (376 MHz, CDCl3):
δ −63.2 (s). HRMS (ESI) m/z calcd for C16H9F3O 274.0605, found
274.0606.
1
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EtOAc). Mp: 53−55 °C. (lit.22 52−54 °C). H NMR (400 MHz,
CDCl3): δ 7.85 (d, J = 8.8 Hz, 2H), 7.61 (m, 2H), 7.42−7.36 (m, 3H),
7.37 (d, J = 8.8 Hz, 2H), 4.14 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 138.9, 135.6, 132.2, 132.1, 129.7, 128.6, 128.5, 127.7, 121.6, 101.5,
79.0, 63.2. HRMS (ESI) m/z calcd for C16H12ClNO 269.0607, found
269.0610. IR (KBr film): 2935, 2212, 1597, 1489, 833, 756, 689 cm−1.
(Z)-1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-one O-Methyl
Oxime (1d) and (E)-1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-one
O-Methyl Oxime (1d′). The configurations of the E/Z-oximes were
determined by comparing NOE spectra. Reaction time: 24 h.
1
13C NMR (100 MHz, CDCl3): δ 165.0, 161.8, 153.4, 147.8, 135.1,
120.5, 114.5, 112.6, 111.7, 93.2, 86.2, 55.5. HRMS (ESI) m/z calcd for
C14H10O3 226.0630, found 226.0629.
1-Phenylnon-2-yn-1-one (S2p). Reaction time: 0.5 h. Pale yellow
oil (1.20 g, 92%). TLC: Rf 0.35 (10:1 hexanes/EtOAc). 1H NMR (400
MHz, CDCl3): δ 8.14 (dd, J = 7.6, 1.2 Hz, 2H), 7.59 (tt, J = 7.6, 1.2
Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 1.68
(quintet, J = 7.2 Hz, 2H), 1.50−1.44 (m, 2H), 1.34−1.31 (m, 4H),
0.91 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 178.4, 137.2,
134.0, 129.7, 128.7, 97.1, 79.9, 31.4, 28.8, 28.0, 22.7, 19.4, 14.2. HRMS
(ESI) m/z calcd for C15H18O 214.1358, found 214.1359.
1d. Colorless liquid (403 mg, 56%). TLC: Rf 0.27 (6:1 hexanes/
CHCl3). H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 8.8, 5.2 Hz,
1
(Z)-4-Phenylbut-3-yn-2-one O-Methyl Oxime (1a) and (E)-4-
Phenylbut-3-yn-2-one O-Methyl Oxime (1a′). In a 250 mL round-
bottom flask, 4-phenylbut-3-yn-2-one (S2a, 2.48 g, 16.5 mmol),
MeONH2·HCl (2.15 g, 25.8 mmol), and NaOAc (2.11 g, 25.8 mmol)
were dissolved in EtOH (69 mL), and the mixture was stirred at rt for
2 h. Upon the completion of the reaction, the reaction was quenched
with H2O (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were dried over anhydrous MgSO4, filtered,
and concentrated by rotary evaporation. The residue was purified by
column chromatography (100:1 hexanes/EtOAc) to afford (Z)-O-
methyl oxime 1a as a colorless liquid (1.74 g, 61%) and (E)-O-methyl
oxime 1a′ as a colorless liquid (1.12 g, 39%). The configurations of the
2H), 7.61 (m, 2H), 7.42−7.36 (m, 3H), 7.09 (t, J = 8.8 Hz, 2H), 4.13
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.7 (d, JC−F = 248.6 Hz),
138.9, 132.2, 129.8 (d, JC−F = 3.1 Hz), 129.6, 128.4 (d, JC−F = 6.9 Hz),
128.3, 121.6, 115.5 (d, JC−F = 21.7 Hz), 101.4, 79.2, 63.1. 19F NMR
(376 MHz, CDCl3): δ −111.4 (m). HRMS (ESI) m/z calcd for
C16H12FNO 253.0903, found 253.0903. IR (KBr film): 3064, 2937,
2214, 1509, 1489, 1233, 1157, 1053, 840, 756, 689 cm−1.
1d′. Milky oil (29.0 mg, 4%). TLC: Rf 0.18 (6:1 hexanes/CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.96 (dd, J = 8.8, 5.2 Hz, 2H), 7.56
(m, 2H), 7.40−7.33 (m, 3H), 7.11 (t, J = 8.8 Hz, 2H), 4.06 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 163.2 (d, JC−F = 250.0 Hz), 141.0,
132.0, 131.9 (d, JC−F = 7.7 Hz), 129.2, 128.4, 127.8 (d, JC−F = 3.1 Hz),
121.8, 115.2 (d, JC−F = 21.7 Hz), 90.7, 85.0, 63.3. 19F NMR (376 MHz,
CDCl3): δ −109.5 (m). HRMS (ESI) m/z calcd for C16H12FNO
253.0903, found 253.0903.
(Z)-1-(3-Nitrophenyl)-3-phenylprop-2-yn-1-one O-Methyl Oxime
(1e). The NOE spectra of the E/Z-oximes were not clear, and their
configurations were determined by Larock’s ICl reaction,22 which has
shown that only (Z)-O-methyl oximes afford iodoisoxazoles. Reaction
time: rt, 19 h; 40 °C, 3 h; 60 °C, 21 h. White solid (158 mg, 20%).
1
oximes were determined by comparing their H NMR spectra with
reported values.22
1a. TLC: Rf 0.42 (20:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3): δ 7.52 (m, 2H), 7.38−7.33 (m, 3H), 3.97 (s, 3H), 2.13 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 137.7, 132.3, 129.6, 128.6,
121.9, 99.3, 81.2, 62.5, 20.8. HRMS (ESI) m/z calcd for C11H11NO
173.0841, found 173.0840. IR (KBr film) 2936, 2223, 1599, 1490,
1375, 1313, 1170, 1061, 757, 690 cm−1.
1
1a′. TLC: Rf 0.48 (20:1 hexanes/EtOAc). H NMR (400 MHz,
1
TLC: Rf 0.38 (10:1 hexanes/EtOAc). Mp: 86−88 °C. H NMR (400
CDCl3): δ 7.51 (m, 2H), 7.36−7.31 (m, 3H), 3.98 (s, 3H), 2.09 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 142.4, 131.9, 129.0, 128.4,
122.0, 90.2, 85.5, 62.4, 16.6. HRMS (ESI) m/z calcd for C11H11NO
173.0841, found 173.0839.
MHz, CDCl3): δ 8.78 (m, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.25 (d, J =
8.0 Hz, 1H), 7.64 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.45−7.39 (m,
3H), 4.19 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 148.6, 138.0,
135.6, 132.5, 132.2, 130.2, 129.6, 128.8, 124.3, 121.6, 121.4, 102.6,
78.7, 63.8. LRMS (EI) m/z (rel int): (pos) 280 ([M]+, 100), 203 ([M
− C6H5]+, 14). HRMS m/z calcd for C16H12N2O3 280.0848, found
280.0846. IR (KBr film): 3083, 2937, 2204, 1532, 1489, 1050, 892,
757, 741, 719, 681 cm−1.
Representative Procedure for the Synthesis of O-Methyl
Oximes 1b−p. In a 50 mL round-bottom flask, 4-phenylbut-3-yn-2-
one (S2b, 206 mg, 1.00 mmol), MeONH2·HCl (167 mg, 2.00 mmol),
and Na2SO4 (284 mg, 2.00 mmol) were dissolved in anhydrous
MeOH (3 mL). Pyridine (0.3 mL) was added via syringe, and the
mixture was stirred at rt for 17 h. Upon the completion of the reaction,
the reaction was quenched with H2O (10 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed with
brine (10 mL), then dried over anhydrous MgSO4, filtered, and
concentrated by rotary evaporation. The residue was purified by
column chromatography (6:1 hexanes/CHCl3) to afford (Z)-O-methyl
oxime 1b as a pale yellow oil (181 mg, 77%) and (E)-O-methyl oxime
1b′ as a colorless oil (9.4 mg, 4%).
(Z)-3-Phenyl-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one O-
Methyl Oxime (1f). The configuration of the oxime was determined
22
1
by comparing its H NMR spectra with reported values. Reaction
time: 36 h. White solid (277 mg, 41%). TLC: Rf 0.56 (10:1 hexanes/
EtOAc). Mp: 44−46 °C. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J =
8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.62 (m, 2H), 7.43−7.37 (m,
3H), 4.17 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 138.7, 137.0 (q,
JC−F = 1.6 Hz), 132.2, 131.4 (q, JC−F = 32.5 Hz), 129.8, 128.5, 126.8,
125.4 (q, JC−F = 3.9 Hz), 124.0 (q, JC−F = 270.1 Hz), 121.5, 101.9,
78.9, 63.4. 19F NMR (376 MHz, CDCl3): δ −62.8 (s). HRMS (ESI)
m/z calcd for C17H12F3NO 303.0871, found 303.0872. IR (KBr film):
2938, 2899, 2213, 1619, 1599, 1489, 1324, 1127, 1053, 847, 756, 689
cm−1.
(Z)-1,3-Diphenylprop-2-yn-1-one O-Methyl Oxime (1b) and (E)-
1,3-Diphenylprop-2-yn-1-one O-Methyl Oxime (1b′). The config-
1
urations of the oximes were determined by comparing their H NMR
spectra with reported values.22
1b. TLC: Rf 0.29 (50:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3): δ 7.93−7.90 (m, 2H), 7.64−7.60 (m, 2H), 7.43−7.36 (m,
6H), 4.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 140.1, 133.8,
132.4, 129.9, 129.7, 128.7, 128.6, 126.7, 122.0, 101.4, 79.7, 63.3.
HRMS (ESI) m/z calcd for C16H13NO 235.0997, found 235.0996. IR
(KBr film): 3059, 2935, 2211, 1597, 1443, 755, 689 cm−1.
(Z)-3-Phenyl-1-(p-tolyl)prop-2-yn-1-one O-Methyl Oxime (1g).
The configuration of the oxime was determined by comparing its H
1
NMR spectra with reported values.23 Reaction time: rt, 19 h; 60 °C, 23
h. Yellow oil (579 mg, 75%). TLC: Rf 0.73 (10:1 hexanes/EtOAc). 1H
NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 2H), 7.61 (m, 2H),
7.40−7.35 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 4.12 (s, 3H), 2.38 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 140.1, 140.0, 132.3, 131.1,
129.7, 129.3, 128.6, 126.6, 122.1, 101.1, 79.8, 63.2, 21.6. HRMS (ESI)
m/z calcd for C17H15NO 249.1154, found 249.1156. IR (KBr film):
2935, 2897, 2212, 1611, 1489, 822, 756, 690 cm−1.
1
1b′. TLC: Rf 0.21 (50:1 hexanes/EtOAc). H NMR (400 MHz,
CDCl3): δ 7.92−7.90 (m, 2H), 7.57−7.55 (m, 2H), 7.45−7.39 (m,
3H), 7.37−7.32 (m, 3H), 4.06 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 142.4, 132.2, 131.9, 130.1, 129.7, 129.3, 128.5, 128.3, 122.2, 90.8,
85.4, 63.4. HRMS (ESI) m/z calcd for C16H13NO 235.0997, found
235.0997. IR (KBr film): 3055, 2936, 2210, 1597, 1444, 756, 690
cm−1.
(E)-1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-one O-Methyl
Oxime (1h). The NOE spectra of the E/Z-oximes were not clear,
and their configurations were determined by Larock’s ICl reaction,22
which has shown that only (Z)-O-methyl oximes afford iodoisoxazoles.
Reaction time: 14 h. White solid (950 mg, 99%). TLC: Rf 0.43 (10:1
(Z)-1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-one O-Methyl
Oxime (1c). The configuration of the oxime was determined by
comparing its 1H NMR spectra with reported values.22 Reaction time:
44 h. White solid (322 mg, 48%). TLC: Rf 0.61 (10:1 hexanes/
1
hexanes/EtOAc). Mp: 48−50 °C. H NMR (400 MHz, CDCl3): δ
6451
dx.doi.org/10.1021/jo5008702 | J. Org. Chem. 2014, 79, 6444−6455

The Journal of Organic Chemistry
Article
7.53 (m, 2H), 7.49 (dd, J = 7.6, 1.6 Hz, 1H), 7.38 (m, 1H), 7.35−7.31
(m, 3H), 7.00 (td, J = 7.6, 1.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.12
(s, 3H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 157.9, 139.0,
132.2, 131.0, 130.3, 129.4, 128.5, 123.7, 122.4, 120.8, 112.0, 100.3,
81.0, 63.1, 56.0. HRMS (ESI) m/z calcd for C17H15NO2 265.1103,
found 265.1102. IR (KBr film): 2936, 2211, 1599, 1488, 1251, 1047,
755, 691 cm−1.
(Z)-1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-one O-Methyl
Oxime (1i). The configuration of the oxime was determined by
comparing its 1H NMR spectra with reported values.24 Reaction time:
26 h. Colorless liquid (566 mg, 74%). TLC: Rf 0.32 (6:1 hexanes/
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.61 (m, 2H), 7.51 (dm, J =
8.0 Hz, 1H), 7.47 (dd, J = 2.4, 1.6 Hz, 1H), 7.41−7.36 (m, 3H), 7.32
(t, J = 8.0 Hz, 1H), 6.95 (ddd, J = 8.0, 2.4, 0.8 Hz, 1H), 4.14 (s, 3H),
3.86 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.6, 139.8, 134.9,
132.2, 129.5, 129.4, 128.4, 121.8, 119.3, 115.7, 111.5, 131.1, 79.4, 63.2,
55.3. HRMS (ESI) m/z calcd for C17H15NO2 265.1103, found
265.1104. IR (KBr film): 3057, 2936, 2201, 1600, 1486, 1255, 1048,
890, 790, 757, 690 cm−1.
δ 145.1, 140.2, 133.9, 132.3, 129.8, 128.8, 128.6, 126.7, 119.1, 101.8,
79.2, 63.3, 36.1, 31.6, 31.0, 22.7, 14.2. HRMS (ESI) m/z calcd for
C21H23NO 305.1780, found 305.1785. IR (KBr film): 3027, 2931,
2210, 1588, 1464, 834, 766, 692 cm−1.
1l′. Pale yellow oil (30.2 mg, 4%).TLC: Rf 0.46 (10:1 hexanes/
EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.91−7.89 (m, 2H), 7.46 (d,
J = 8.0 Hz, 2H), 7.44−7.40 (m, 3H), 7.15 (d, J = 8.0 Hz, 2H), 4.05 (s,
3H), 2.60 (t, J = 7.6 Hz, 2H), 1.61 (quintet, J = 7.6 Hz, 2H), 1.36−
1.29 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 144.6, 142.6, 132.2, 132.1, 130.1, 129.8, 128.7, 128.3, 119.3, 91.3,
84.9, 63.3, 36.1, 31.6, 31.0, 22.7, 14.2. HRMS (ESI) m/z calcd for
C21H23NO 305.1780, found 305.1778. IR (KBr film): 2927, 2208,
1509, 1461, 838, 816, 690 cm−1.
(Z)-3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one O-Methyl
Oxime (1m). The NOE spectra of the E/Z-oximes were not clear,
and their configurations were determined by Larock’s ICl reaction,22
which has shown that only (Z)-O-methyl oximes afford iodoisoxazoles.
Reaction time: 24 h. Pale yellow oil (926 mg, 80%). TLC: Rf 0.55
1
(10:1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.00−7.97
(m, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.46−7.42 (m, 3H), 6.92 (d, J = 8.8
Hz, 2H), 4.18 (s, 3H), 3.81 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
160.7, 140.2, 133.9, 133.8, 129.7, 128.5, 126.6, 114.2, 113.8, 101.8,
78.8, 63.1, 55.3. HRMS (ESI) m/z calcd for C17H15NO2 265.1103,
found 265.1104. IR (KBr film): 3003, 2935, 2208, 1584, 1463, 832,
766, 692 cm−1.
(Z)-3-(3-Chlorophenyl)-1-phenylprop-2-yn-1-one O-Methyl
Oxime (1j) and (E)-3-(3-Chlorophenyl)-1-phenylprop-2-yn-1-one
O-Methyl Oxime (1j′). The configurations of the E/Z-oximes were
determined by comparing NOE spectra. Reaction time: 25 h.
1j. Pale yellow oil (622 mg, 60%). TLC: Rf 0.37 (10:1 hexanes/
EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.90−7.87 (m, 2H), 7.60 (t,
J = 1.6 Hz, 1H), 7.49 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 7.42−7.36 (m, 4H),
7.32 (t, J = 7.6 Hz, 1H), 4.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
139.8, 134.6, 133.5, 132.1, 130.5, 130.0, 129.9, 128.7, 126.7, 123.7,
99.6, 80.6, 77.4, 63.4. HRMS (ESI) m/z calcd for C16H12ClNO
269.0607, found 269.0611. IR (KBr film): 3063, 2935, 2214, 1591,
1473, 1182, 767, 690 cm−1.
(Z)-1-(4-Chlorophenyl)-3-(p-tolyl)prop-2-yn-1-one O-Methyl
Oxime (1n). The NOE spectra of the E/Z-oximes were not clear,
and their configurations were determined by Larock’s ICl reaction,22
which has shown that only (Z)-O-methyl oximes afford iodoisoxazoles.
Reaction time: 52 h. White solid (183 mg, 57%). TLC: Rf 0.55 (10:1
1
hexanes/EtOAc). Mp: 46−48 °C. H NMR (400 MHz, CDCl3): δ
1j′. Yellow oil (28.2 mg, 3%). TLC: Rf 0.29 (10:1 hexanes/EtOAc).
7.85 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.8 Hz,
2H), 7.19 (d, J = 8.0 Hz, 2H), 4.13 (s, 3H), 2.39 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 140.3, 139.2, 135.8, 132.4, 132.3, 129.5, 128.8,
127.9, 118.7, 102.2, 78.8, 63.4, 21.8. HRMS (ESI) m/z calcd for
C17H14ClNO 283.0764, found 283.0767. IR (KBr film): 2935, 2210,
1594, 1490, 1049, 833, 815 cm−1.
1H NMR (400 MHz, CDCl3): δ 7.90−7.87 (m, 2H), 7.54 (t, J = 2.0
Hz, 1H), 7.45−7.41 (m, 4H), 7.35 (dm, J = 8.0 Hz,1H), 7.28 (t, J = 8.0
Hz, 1H), 4.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 142.1, 134.5,
132.0, 131.7, 130.3, 130.2, 129.9, 129.7, 129.6, 128.4, 123.9, 89.0, 86.5,
63.5. HRMS (ESI) m/z calcd for C16H12ClNO 269.0607, found
269.0607. IR (KBr film): 3023, 2930, 2208, 1609, 1465, 1192, 760, 699
cm−1.
(E)-1-(Furan-2-yl)-3-(4-methoxyphenyl)prop-2-yn-1-one O-Meth-
yl Oxime (1o). The NOE spectra of the E/Z-oximes were not clear,
and their configurations were determined by Larock’s ICl reaction,22
which has shown that only (Z)-O-methyl oximes afford iodoisoxazoles.
Reaction time: 22 h. Pale yellow oil (348 mg, 46%). TLC: Rf 0.24
(Z)-1-Phenyl-3-(p-tolyl)prop-2-yn-1-one O-Methyl Oxime (1k)
and (E)-1-Phenyl-3-(p-tolyl)prop-2-yn-1-one O-Methyl Oxime
(1k′). The NOE spectra of the E/Z-oximes were not clear and their
configurations were determined by Larock’s ICl reaction,22 which has
shown that only (Z)-O-methyl oximes afford iodoisoxazoles. Reaction
time: 24 h.
1
(10:1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.54 (d, J =
8.8 Hz, 2H), 7.50 (dd, J = 1.6, 0.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H),
6.82 (dd, J = 3.6, 0.8 Hz, 1H), 6.48 (dd, J = 3.6, 1.6 Hz, 1H), 4.13 (s,
3H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3): δ160.8, 148.3,
144.0, 133.9, 132.3, 144.2, 133.4, 112.2, 111.5, 99.8, 77.1, 63.3, 55.3.
HRMS (ESI) m/z calcd for C15H13NO3 255.0895, found 255.0896. IR
(KBr film): 2936, 2205, 1605, 1485, 1253, 1050, 832 cm−1.
1k. Pale yellow oil (690 mg, 71%). TLC: Rf 0.57 (10:1 hexanes/
EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.01(d, J = 7.2 Hz, 2H), 7.63
(d, J = 8.0 Hz, 2H), 7.53−7.48 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 4.26
(s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 140.2, 140.1,
133.9, 132.3, 129.8, 129.4, 128.6, 126.7, 118.9, 101.8, 79.2, 63.3, 21.8.
HRMS (ESI) m/z calcd for C17H15NO 249.1154, found 249.1156. IR
(KBr film): 3029, 2935, 2210, 1606, 1444, 816, 766, 692 cm−1.
1k′. Pale yellow oil (38.7 mg, 4%). TLC: Rf 0.49 (10:1 hexanes/
(Z)-1-Phenylnon-2-yn-1-one O-Methyl Oxime (1p) and (E)-1-
Phenylnon-2-yn-1-one O-Methyl Oxime (1p′). The NOE spectra of
the E/Z-oximes were not clear and their configurations were
determined by Larock’s ICl reaction,22 which has shown that only
(Z)-O-methyl oximes afford iodoisoxazoles. Reaction time: 23 h.
1p. Pale yellow oil (915 mg, 72%). TLC: Rf 0.37 (10:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.6 Hz, 2H),
7.45−7.40 (m, 5H), 7.15 (d, J = 7.6 Hz, 2H), 4.05 (s, 3H), 2.40 (s,
3H). 13C NMR (100 MHz, CDCl3): δ142.6, 139.6, 132.1, 132.0, 130.1,
129.8, 129.4, 128.3, 119.1, 91.2, 84.9, 63.4, 21.8. HRMS (ESI) m/z
calcd for C17H15NO 249.1154, found 249.1156. IR (KBr film): 3029,
2935, 2208, 1606, 1445, 816, 772, 692 cm−1.
(Z)-3-(4-Pentylphenyl)-1-phenylprop-2-yn-1-one O-Methyl
Oxime (1l) and (E)-3-(4-Pentylphenyl)-1-phenylprop-2-yn-1-one
O-Methyl Oxime (1l′). The NOE spectra of the E/Z-oximes were
not clear and their configurations were determined by Larock’s ICl
reaction,22 which has shown that only (Z)-O-methyl oximes afford
iodoisoxazoles. Reaction time: 26 h
1l. Pale yellow oil (676 mg, 80%). TLC: Rf 0.60 (10:1 hexanes/
EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.92−7.90 (m, 2H), 7.52 (d,
J = 8.0 Hz, 2H), 7.41−7.37 (m, 3H), 7.19 (d, J = 8.0 Hz, 2H), 4.13 (s,
3H), 2.62 (t, J = 7.6 Hz, 2H), 1.66 (quintet, J = 7.6 Hz, 2H), 1.36−
1.28 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.85−7.83 (m, 2H), 7.38−
7.35 (m, 3H), 4.01 (s, 3H), 2.54 (t, J = 7.2 Hz, 2H), 1.62 (quintet, J =
7.2 Hz, 2H), 1.51−1.47 (m, 2H), 1.35−1.31 (m, 4H), 0.91 (t, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 140.4, 134.1, 129.6, 128.4,
126.6, 104.1, 71.7, 63.1, 31.4, 28.8, 28.4, 22.7, 20.0, 14.2. HRMS (ESI)
m/z calcd for C16H21NO 243.1623, found 243.1623. IR (KBr film):
3061, 2933, 2217, 1585, 1444, 767, 692 cm−1.
1p′. Pale yellow oil (38.3 mg, 3%).TLC: Rf 0.32 (10:1 hexanes/
1
EtOAc). H NMR (400 MHz, CDCl3): δ 7.84−7.82 (m, 2H), 7.41−
7.37 (m, 3H), 3.99 (s, 3H), 2.40 (t, J = 7.2 Hz, 2H), 1.61 (quintet, J =
7.2 Hz, 2H), 1.54−1.41 (m, 2H), 1.33−1.29 (m, 4H), 0.89 (t, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 142.5, 132.3, 129.9, 129.7,
128.1, 93.0, 77.0, 63.1, 31.5, 28.9, 28.4, 22.7, 19.6, 14.2. HRMS (ESI)
m/z calcd for C16H21NO 243.1623, found 243.1626. IR (KBr film):
3061, 2931, 2217, 1632, 1465, 767, 692 cm−1.
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Representative Procedure for Direct Synthesis of 4-
Fluoroisoxazoles through Gold-Catalyzed Cascade Cycliza-
tion−Fluorination. In a 25 mL one-arm round-bottom flask, (Z)-4-
phenylbut-3-yn-2-one O-methyl oxime (1b, 47.0 mg, 200 μmol),
Selectfluor (177 mg, 500 μmol), NaHCO3 (33.6 mg, 400 μmol),
(IPr)AuCl (6.2 mg, 10.0 μmol), and AgOTs (2.8 mg, 10.0 μmol) were
dissolved in anhydrous CH3CN (2 mL) under Ar atmosphere. The
resulting suspension was stirred at rt for 24 h. Upon the completion of
the reaction, the reaction mixture was diluted with CH2Cl2 (20 mL),
filtered through a plug of Celite, and rinsed with CH2Cl2 (20 mL).
The filtrate was dried over anhydrous MgSO4, filtered, and
concentrated by rotary evaporation. The residue was purified by
column chromatography (10:1 hexanes/EtOAc) to afford 4-
fluoroisoxazole 3b as a white solid (47.2 mg, 98%).
148.7, 141.2 (d, JC−F = 257.7 Hz), 132.6 (d, JC−F = 3.1 Hz), 130.6,
130.2, 129.2, 128.5 (d, JC−F = 3.9 Hz), 125.5, 125.4 (d, JC−F = 4.7 Hz),
125.1, 122.0 (d, JC−F = 3.8 Hz). 19F NMR (376 MHz, CDCl3): δ
−177.7 (s). HRMS (ESI) m/z calcd for C15H9FN2O3 284.0597, found
284.0597. IR (neat): 1640, 1536, 1467, 1345, 1098, 947, 770, 752, 698,
689 cm−1.
4e. TLC: Rf 0.12 (10:1 hexanes/EtOAc (×2)). 1H NMR (400
MHz, CDCl3): δ 8.70 (t, J = 2.0 Hz, 1H), 8.34 (ddd, J = 8.0, 2.0, 1.2
Hz, 1H), 8.30 (dm, J = 8.0 Hz, 1H), 7.87 (m, 2H), 7.70 (t, J = 8.0 Hz,
1H), 7.56−7.48 (m, 3H), 6.93 (s, 1H). 13C NMR (100 MHz, CDCl3):
δ 171.5, 161.1, 148.7, 132.5, 131.0, 130.7, 130.1, 129.2, 127.0, 125.9,
124.6, 121.9, 97.3. HRMS (ESI) m/z calcd for C15H10N2O3 266.0691,
found 266.0691. IR (KBr film): 2917, 2849, 1737, 1533, 1462, 1349,
1242, 806, 765, 741, 686 cm−1.
4-Fluoro-3-methyl-5-phenylisoxazole (3a). This reaction was
carried out in 0.4 mmol scale. Purification by column chromatography
(40:1 hexanes/EtOAc) afforded 4-fluoroisoxazole 3a as a colorless
crystal (65.0 mg, 92%). TLC: Rf 0.51 (20:1 hexanes/EtOAc (×2)).
Mp: 31−33 °C. 1H NMR (400 MHz, CDCl3): δ 7.81 (dm, J = 7.2 Hz,
2H), 7.49 (tm, J = 7.2 Hz, 2H), 7.43 (tm, J = 7.2 Hz, 1H), 2.37 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 152.1 (d, JC−F = 10.0 Hz), 151.9
(d, JC−F = 6.9 Hz), 142.3 (d, JC−F = 254.7 Hz), 129.9 (d, JC−F = 1.5
Hz), 129.0, 126.0 (d, JC−F = 5.5 Hz), 125.2 (d, JC−F = 4.6 Hz), 8.7 (d,
JC−F = 3.1 Hz). 19F NMR (376 MHz, CDCl3): δ −180.6 (s). HRMS
(ESI) m/z calcd for C10H8FNO 177.0590, found 177.0590. IR (KBr
film): 3062, 2931, 1657, 1510, 1470, 1194, 766, 691 cm−1.
4-Fluoro-3,5-diphenylisoxazole (3b). Purification by column
chromatography (30:1 hexanes/EtOAc) afforded 3b (47.2 mg, 98%)
as a white solid. TLC: Rf10.25 (50:1 hexanes/EtOAc). Mp: 102−104
°C (lit.10 101−103 °C). H NMR (400 MHz, CDCl3): δ 7.96−7.94
(m, 2H), 7.89 (d, J = 7.2 Hz, 2H), 7.56−7.45 (m, 6H). 13C NMR (100
MHz, CDCl3): δ 153.8 (d, JC−F = 19.3 Hz), 153.4 (d, JC−F = 10.8 Hz),
4-Fluoro-5-phenyl-3-(4-(trifluoromethyl)phenyl)isoxazole (3f)
and 5-Phenyl-3-(4-(trifluoromethyl)phenyl)isoxazole (4f). Purifica-
tion by column chromatography (40:1 hexanes/EtOAc) afforded 3f
(59.2 mg, 96%) as a white solid and 4f (1.0 mg, 2%) as a white solid.
1
3f. TLC: Rf 0.47 (20:1 hexanes/EtOAc). Mp: 121−123 °C. H
NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.4 Hz, 2H), 7.90 (m, 2H),
7.79 (d, J = 8.4 Hz, 2H), 7.57−7.47 (m, 3H). 13C NMR (100 MHz,
CDCl3): δ 154.3 (d, JC−F = 18.6 Hz), 152.1 (d, JC−F = 10.8 Hz), 141.4
(d, JC−F = 257.7 Hz), 132.3 (q, JC−F = 32.5 Hz), 130.5 (d, JC−F = 1.5
Hz), 130.3 (dq, JC−F = 4.0, 1.0 Hz), 129.2, 127.4 (d, JC−F = 3.9 Hz),
126.0 (q, JC−F = 3.1 Hz), 125.6 (d, JC−F = 4.7 Hz), 125.3 (d, JC−F = 5.4
Hz), 123.8 (q, JC−F = 270.8 Hz). 19F NMR (376 MHz, CDCl3): δ
−177.7 (s), −63.1 (s). HRMS (ESI) m/z calcd for C16H9F4NO
307.0620, found 307.0620. IR (KBr film): 3055, 1644, 1450, 1327,
1265, 1115, 850, 740, 696 cm−1.
4f. TLC: Rf 0.29 (20:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3): δ 8.00 (d, J = 8.4 Hz, 2H), 7.86 (m, 2H), 7.76 (d, J = 8.4 Hz,
2H), 7.54−7.48 (m, 3H), 6.87 (s, 1H). 13C NMR (100 MHz, CDCl3):
δ 171.1, 161.9, 132.6 (q, JC−F = 1.1 Hz), 131.9 (q, JC−F = 32.5 Hz),
130.5, 129.1, 127.2, 127.1, 126.0 (q, JC−F = 3.1 Hz), 125.9, 123.9 (q,
JC−F = 270.9 Hz), 97.4. HRMS (ESI) m/z calcd for C16H10F3NO
289.0714, found 289.0713. IR (KBr film): 2923, 2852, 1736, 1450,
1258, 1113, 851, 769, 693 cm−1.
141.8 (d, JC−F = 258 Hz), 130.7, 130.4, 129.3, 129.2, 127.3 (d, JC−F
=
3.1 Hz), 127.0 (d, JC−F = 3.9 Hz), 126.1 (d, JC−F = 5.4 Hz), 125.5 (d,
JC−F = 5.4 Hz). 19F NMR (376 MHz, CDCl3): δ −177.7 (s). HRMS
(ESI) m/z calcd for C15H10FNO 239.0746, found 239.0746. IR (KBr
film): 3065, 1647, 1466, 1214, 772, 691 cm−1.
3-(4-Chlorophenyl)-4-fluoro-5-phenylisoxazole (3c). Purification
by column chromatography (40:1 hexanes/EtOAc) afforded 3c (50.8
mg, 93%) as a white solid. TLC: Rf 0.50 (20:1 hexanes/EtOAc). Mp:
4-Fluoro-5-phenyl-3-(p-tolyl)isoxazole (3g). Purification by col-
umn chromatography (40:1 hexanes/EtOAc) afforded 3g (48.7 mg,
96%) as a white solid. TLC: Rf 0.28 (40:1 hexanes/EtOAc). Mp: 119−
121 °C. 1H NMR (400 MHz, CDCl3): δ 7.89 (m, 2H), 7.84 (d, J = 8.0
Hz, 2H), 7.53 (m, 2H), 7.46 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 2.44
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.4 (d, JC−F = 19.3 Hz),
153.2 (d, JC−F = 10.8 Hz), 141.5 (d, JC−F = 256.9 Hz), 140.7, 130.1 (d,
1
133−134 °C. H NMR (400 MHz, CDCl3): δ 7.91−7.87 (m, 4H),
7.56−7.48 (m, 3H), 7.50 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 153.9 (d, JC−F = 19.3 Hz), 152.3 (d, JC−F = 10.0 Hz), 141.4
(d, JC−F = 257.7 Hz), 136.7, 130.3 (d, JC−F = 1.6 Hz), 129.4, 129.1,
128.3 (d, JC−F = 3.9 Hz), 125.7 (d, JC−F = 4.7 Hz), 125.3 (d, JC−F = 4.7
Hz), 125.2. 19F NMR (376 MHz, CDCl3): δ −177.7 (s). HRMS (ESI)
m/z calcd for C15H9ClFNO 273.0357, found 273.0356. IR (KBr film):
1447, 1265, 1093, 836, 739, 688 cm−1.
JC−F = 1.5 Hz), 129.7, 129.0, 126.9 (d, JC−F = 3.9 Hz), 126.0 (d, JC−F
=
4.7 Hz), 125.3 (d, JC−F = 4.7 Hz), 123.9 (d, JC−F = 3.9 Hz), 21.5. 19F
NMR (376 MHz, CDCl3): δ −177.7 (s). HRMS (ESI) m/z calcd for
C16H12FNO 253.0903, found 253.0905. IR (neat): 2923, 2854, 1649,
1446, 1218, 1116, 818, 761, 682 cm−1.
4-Fluoro-3-(4-fluorophenyl)-5-phenylisoxazole (3d). Purification
by column chromatography (40:1 hexanes/EtOAc) afforded 3d (46.6
mg, 91%) as a white solid. TLC: Rf 0.40 (15:1 hexanes/EtOAc). Mp:
4-Fluoro-3-(2-methoxyphenyl)-5-phenylisoxazole (3h). Purifica-
tion by column chromatography (40:1 hexanes/EtOAc) afforded 3h
(46.6 mg, 87%) as a white solid. TLC: Rf 0.39 (10:1 hexanes/EtOAc).
1
121−123 °C. H NMR (400 MHz, CDCl3): δ 7.95 (dd, J = 8.8, 5.2
1
Hz, 2H), 7.88 (m, 2H), 7.54 (m, 2H), 7.48 (m, 1H), 7.21 (t, J = 8.8
Mp: 92−93 °C. H NMR (400 MHz, CDCl3): δ 7.89 (m, 2H), 7.58
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 164.0 (d, JC−F = 250.0 Hz),
(dd, J = 7.6, 1.6 Hz, 1H), 7.54−7.45 (m, 4H), 7.10 (td, J = 7.6, 1.2 Hz,
1H), 7.06 (d, J = 7.6 Hz, 1H), 3.91 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 157.6, 153.0 (d, JC−F = 13.9 Hz), 152.6 (d, JC−F = 19.3 Hz),
142.0 (d, JC−F = 256.9 Hz), 131.9, 130.7 (d, JC−F = 1.6 Hz), 129.9,
129.0, 126.2 (d, JC−F = 5.4 Hz), 125.3 (d, JC−F = 4.7 Hz), 120.9, 115.7
(d, JC−F = 3.1 Hz), 111.4, 55.8. 19F NMR (376 MHz, CDCl3): δ
−173.9 (s). HRMS (ESI) m/z calcd for C16H12FNO2 269.0852, found
269.0854. IR (KBr film): 3065, 2939, 1477, 1273, 1252, 1118, 1027,
758, 757, 691 cm−1.
153.7 (d, JC−F = 19.3 Hz), 152.3 (d, JC−F = 10.9 Hz), 141.3 (d, JC−F
=
256.9 Hz), 130.3, 129.1 (dd, JC−F = 8.5, 3.8 Hz), 129.1, 125.8 (d, JC−F
= 5.4 Hz), 125.3 (d, JC−F = 5.5 Hz), 123.0 (dd, JC−F = 3.9, 3.1 Hz),
116.2 (d, JC−F = 21.6 Hz). 19F NMR (376 MHz, CDCl3): δ −178.0
(s), −109.3 (m). HRMS (ESI) m/z calcd for C15H9F2NO 257.0652,
found 257.0651. IR (KBr film): 1650, 1447, 1265, 1215, 1100, 848,
739, 689 cm−1.
4-Fluoro-3-(3-nitrophenyl)-5-phenylisoxazole (3e) and 3-(3-Ni-
trophenyl)-5-phenylisoxazole (4e). Purification by column chroma-
tography (100:1 hexanes/EtOAc) afforded 3e (44.8 mg, 79%) as a
white solid and 4e (5.6 mg, 11%) as a white solid.
4-Fluoro-3-(3-methoxyphenyl)-5-phenylisoxazole (3i) and 3-(3-
Methoxyphenyl)-5-phenylisoxazole (4i). Purification by column
chromatography (100:1 hexanes/EtOAc) afforded 3i (33.4 mg,
62%) as a white solid and 4i (2.9 mg, 6%) as a colorless oil.
3e. TLC: Rf 0.29 (10:1 hexanes/EtOAc (×2)). Mp: 144−146 °C.
1H NMR (400 MHz, CDCl3): δ 8.82 (t, J = 2.0 Hz, 1H), 8.37 (ddd, J
1
3i. TLC: Rf 0.28 (20:1 hexanes/EtOAc). Mp: 71−73 °C. H NMR
= 8.0, 2.0, 1.2 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.90 (dm, J = 7.2 Hz,
2H), 7.73 (t, J = 8.0 Hz, 1H), 7.58−7.48 (m, 3H). 13C NMR (100
MHz, CDCl3): δ 154.6 (d, JC−F = 19.3 Hz), 151.3 (d, JC−F = 10.1 Hz),
(400 MHz, CDCl3): δ 7.89 (dm, J = 6.8 Hz, 2H), 7.55−7.47 (m, 5H),
7.43 (t, J = 8.0 Hz, 1H), 7.06 (ddd, J = 8.0, 2.8, 1.2 Hz, 1H), 3.89 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 160.0, 153.6 (d, JC−F = 19.4
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Hz), 153.1 (d, JC−F = 10.1 Hz), 141.5 (d, JC−F = 257.0 Hz), 132.2,
130.1 (d, JC−F = 6.2 Hz), 129.1 (d, JC−F = 3.1 Hz), 127.9 (d, JC−F = 3.9
Hz), 125.9 (d, JC−F = 5.4 Hz), 125.3 (d, JC−F = 4.6 Hz), 119.6 (d, JC−F
= 4.7 Hz), 116.7, 111.9 (d, JC−F = 3.1 Hz), 55.4. 19F NMR (376 MHz,
CDCl3): δ −177.4 (s). HRMS (ESI) m/z calcd for C16H12FNO2
269.0852, found 269.0852. IR (KBr film): 1648, 1593, 1481, 1255,
1206, 1041, 862, 714, 688 cm−1.
calcd for C16H12FNO2 269.0852, found 269.0855. IR (KBr film): 2937,
1647, 1461, 1255, 832, 772, 692 cm−1.
3-(4-Chlorophenyl)-4-fluoro-5-(p-tolyl)isoxazole (3n). Purification
by column chromatography (40:1 hexanes/EtOAc) afforded 3n (53.6
mg, 93%) as a white solid. TLC: Rf 0.44 (20:1 hexanes/EtOAc (×2)).
Mp: 143−145 °C. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz,
2H), 7.76 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0
Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.1 (d, JC−F
= 19.3 Hz), 152.1 (d, JC−F = 10.9 Hz), 140.9 (d, JC−F = 256.2 Hz),
4i. TLC: Rf 0.13 (20:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3): δ 7.85 (dm, J = 6.4 Hz, 2H), 7.52−7.41 (m, 5H), 7. 39 (t, J =
7.6 Hz, 1H), 7.06 (ddd, J = 7.6, 2.4, 1.6 Hz, 1H), 6.82 (s, 1H), 3.89 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 170.4, 162.9, 160.0, 130.4,
130.3, 130.0, 129.0, 127.4, 125.8, 119.3, 116.2, 111.7, 97.6, 55.4.
HRMS (ESI) m/z calcd for C16H13NO2 251.0946, found 251.0946. IR
(KBr film): 2924, 2852, 1735, 1573, 1473, 1259, 1041, 839, 787, 764,
689 cm−1.
140.6, 136.6, 129.8, 129.3, 128.3 (d, JC−F = 3.1 Hz), 125.4 (d, JC−F
=
3.9 Hz), 125.2 (d, JC−F = 4.7 Hz), 123.0 (d, JC−F = 5.4 Hz), 21.6. 19F
NMR (376 MHz, CDCl3): δ −178.5 (s). HRMS (ESI) m/z calcd for
C16H11ClFNO 287.0513, found 287.0512. IR (KBr film): 1651, 1602,
1455, 1264, 1213, 1110, 1092, 1045, 836, 819 cm−1.
4-Fluoro-3-(furan-2-yl)-5-(4-methoxyphenyl)isoxazole (3o) and
3-(Furan-2-yl)-5-(4-methoxyphenyl)isoxazole (4o). Purification by
column chromatography (20:1 hexanes/EtOAc) afforded 3o (13.5 mg,
26%) as a white solid and 4o (2.8 mg, 6%) as a white solid.
5-(3-Chlorophenyl)-4-fluoro-3-phenylisoxazole (3j) and 5-(3-
Chlorophenyl)-3-phenylisoxazole (4j). Purification by column
chromatography (30:1 hexanes/EtOAc) afforded 3j (44.8 mg, 80%)
as a white solid and 4j (8.9 mg, 17%) as a white solid.
3o. TLC: Rf 0.44 (5:1 hexanes/EtOAc). Mp: 119−120 °C. 1H
NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 1.6
Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.02 (m, 1H), 6.59 (dd, J = 3.6, 1.6
Hz, 1H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.1 (d, JC−F
= 1.6 Hz), 153.3 (d, JC−F = 17.8 Hz), 146.2 (d, JC−F = 21.6 Hz), 144.5,
1
3j. TLC: Rf 0.27 (50:1 hexanes/EtOAc). Mp: 109−111 °C. H
NMR (400 MHz, CDCl3): δ 7.95−7.93 (m, 2H), 7.87 (m, 1H), 7.77
(dt, J = 7.2, 1.6 Hz, 1H), 7.54−7.51 (m, 3H), 7.49−7.43 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 153.6 (d, JC−F = 10.0 Hz), 152.4 (d, JC−F
= 19.4 Hz), 142.2 (d, JC−F = 258.8 Hz), 135.5, 130.9, 130.7, 130.4,
129.3, 127.6 (d, JC−F = 5.5 Hz), 127.3 (d, JC−F = 3.8 Hz), 126.7 (d,
141.4 (d, JC−F = 4.6 Hz), 138.9 (d, JC−F = 256.2 Hz), 127.0 (d, JC−F
=
JC−F = 3.8 Hz), 125.5 (d, JC−F = 5.5 Hz), 123.5 (d, JC−F = 5.4 Hz). 19
F
4.6 Hz), 118.4 (d, JC−F = 5.4 Hz), 114.6, 112.5 (d, JC−F = 1.8 Hz),
111.6, 55.4. 19F NMR (376 MHz, CDCl3): δ −179.9 (s). HRMS (ESI)
m/z calcd for C14H10FNO3 259.0645, found 259.0644. IR (KBr film):
1655, 1605, 1474, 1263, 1113, 1012, 828, 766 cm−1.
NMR (376 MHz, CDCl3): δ −176.2 (s). HRMS (ESI) m/z calcd for
C15H9ClFNO 273.0357, found 273.0360. IR (KBr film): 1650, 1463,
1165, 933, 792, 772, 701, 690 cm−1.
4o. TLC: Rf 0.35 (5:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H), 7.57 (dd, J = 1.8, 0.8 Hz, 1H),
7.00 (d, J = 8.8 Hz, 2H), 6.94 (dd, J = 3.2, 0.8 Hz, 1H), 6.66 (s, 1H),
6.54 (dd, J = 3.2, 1.8 Hz, 1H), 3.87 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.1, 161.3, 155.4, 144.5, 143.8, 127.5, 120.0, 114.4, 111.7,
110.0, 95.6, 55.4. HRMS (ESI) m/z calcd for C14H11NO3 241.0739,
found 241.0736. IR (KBr film): 1736, 1619, 1440, 1257, 1027, 837
cm−1.
4j. TLC: Rf 0.08 (50:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3): δ 7.88−7.83 (m, 3H), 7.74 (m, 1H), 7.52−7.47 (m, 3H),
7.44 (d, J = 5.2 Hz, 2H), 6.86 (s, 1H). 13C NMR (100 MHz, CDCl3):
δ 169.2, 163.3, 135.4, 130.6, 130.5, 130.4, 129.3, 129.2, 129.1, 127.0,
126.1, 124.1, 98.5. HRMS (ESI) m/z calcd for C15H10ClNO 255.0451,
found 255.0449. IR (KBr film): 3071, 1601, 1453, 934, 810, 708 cm−1.
4-Fluoro-3-phenyl-5-(p-tolyl)isoxazole (3k). Purification by col-
umn chromatography (30:1 hexanes/EtOAc) afforded 3k (50.0 mg,
100%) as a white solid. TLC: Rf 0.25 (50:1 hexanes/EtOAc). Mp: 89−
4-Fluoro-5-hexyl-3-phenylisoxazole (3p). Purification by column
chromatography (30:1 hexanes/EtOAc) afforded 3p (42.2 mg, 85%)
91 °C (lit.10 96−97 °C). H NMR (400 MHz, CDCl3): δ 7.95−7.93
1
1
(m, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.53−7.50 (m, 3H), 7.33 (d, J = 8.0
Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.0 (d, JC−F
= 19.3 Hz), 153.3 (d, JC−F = 10 Hz), 141.3 (d, J = 256.2 Hz), 140.7,
130.6, 130.0, 129.2, 127.3 (d, JC−F = 3.8 Hz), 127.1 (d, JC−F = 3.9 Hz),
125.4 (d, JC−F = 4.6 Hz), 123.4 (d, JC−F = 5.4 Hz), 21.8. 19F NMR
(376 MHz, CDCl3): δ −178.4 (s). HRMS (ESI) m/z calcd for
C16H12FNO 253.0903, found 253.0905. IR (KBr film): 2922, 1648,
1468, 819, 770, 691 cm−1.
as a pale yellow oil. TLC: Rf 0.50 (10:1 hexanes/EtOAc). H NMR
(400 MHz, CDCl3): δ 7.89−7.87 (m, 2H), 7.51−7.47 (m, 3H), 2.82
(td, J = 7.6, 1.2 Hz, 2H), 1.76 (quintet, J = 7.2 Hz, 2H), 1.42−1.30 (m,
6H), 0.9 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 157.8
(d, JC−F = 24.7 Hz), 152.5 (d, JC−F = 10.8 Hz), 142.0 (d, JC−F = 250.0
Hz), 130.4, 129.1, 127.3 (d, JC−F = 3.9 Hz), 127.2 (d, JC−F = 3.9 Hz),
31.5, 28.9, 26.7, 24.8, 22.7, 14.2. 19F NMR (376 MHz, CDCl3): δ
−184.5 (s). HRMS (ESI) m/z calcd for C15H18FNO 247.1372, found
247.1377. IR (KBr film): 3069, 2930, 1657, 1462, 1263, 771, 693
cm−1.
4-Fluoro-5-(4-pentylphenyl)-3-phenylisoxazole (3l). Purification
by column chromatography (30:1 hexanes/EtOAc) afforded 3l (62.2
mg, 99%) as a white solid. TLC: Rf 0.39 (50:1 hexanes/EtOAc). Mp:
Stoichiometric Reaction of 1a, (IPr)AuCl, and AgOTs. (IPr)AuCl
(46.6 mg, 75.0 μmol) and AgOTs (20.9 mg, 75.0 μmol) were placed in
a J. Young NMR tube under Ar atmosphere, and a solution of (Z)-4-
phenylbut-3-yn-2-one O-methyl oxime (1a) in acetonitrile-d3 (0.75
mL) was added. The ensuing formation of the gold intermediate was
1
56−58 °C. H NMR (400 MHz, CDCl3): δ 7.96−7.93 (m, 2H), 7.79
(d, J = 8.0 Hz, 2H), 7.54−7.50 (m, 3H), 7.33 (d, J = 8.0 Hz, 2H), 2.67
(t, J = 7.6 Hz, 2H), 1.66 (quintet, J = 7.6 Hz, 2H), 1.39−1.30 (m, 4H),
0.91 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 154.1 (d,
JC−F = 19.3 Hz), 153.3 (d, JC−F = 10.8 Hz), 145.7, 141.4 (d, JC−F
=
1
monitored at room temperature by H NMR spectroscopy. Upon the
256.2 Hz), 130.6, 129.3, 129.2, 127.3 (d, JC−F = 3.9 Hz), 127.1 (d, JC−F
= 3.9 Hz), 125.4 (d, JC−F = 4.7 Hz), 123.6 (d, JC−F = 4.7 Hz), 36.1,
31.7, 31.1, 22.7, 14.2. 19F NMR (376 MHz, CDCl3): δ −178.5 (s).
HRMS (ESI) m/z calcd for C20H20FNO 309.1529, found 309.1534. IR
(KBr film): 3055, 2951, 1645, 1462, 1212, 812, 769, 692 cm−1.
4-Fluoro-5-(4-methoxyphenyl)-3-phenylisoxazole (3m). Purifica-
tion by column chromatography (30:1 hexanes/EtOAc) afforded 3m
(34.9 mg, 65%) as a white solid. TLC: Rf 0.20 (50:1 hexanes/EtOAc).
completion of the reaction, the resulting suspension was filtered and
washed with anhydrous CH3CN (3 mL). Then, the solid was dissolved
in anhydrous CH2Cl2 (3 mL), and the insoluble powder was filtered
off. The filtrate was concentrated by rotary evaporation. Recrystalliza-
tion from CH3CN afforded 9 as a colorless crystal (32.0 mg, 57%).
TLC: Rf 0.18 (4:1 hexanes/EtOAc). 1H NMR (400 MHz, acetone-d6):
δ 7.80 (s, 2H), 7.73 (dm, J = 7.2 Hz, 2H), 7.64 (t, J = 8.0 Hz, 2H),
7.47 (d, J = 8.0 Hz, 4H), 7.14 (tm, J = 7.2 Hz, 1H), 7.08 (tm, J = 7.2
Hz, 2H), 2.76 (septet, J = 7.2 Hz, 4H), 1.57 (s, 3H), 1.34 (d, J = 7.2
Hz, 12H), 1.26 (d, J = 7.2 Hz, 12H). 13C NMR (100 MHz, acetone-
d6): δ 195.9, 173.2, 168.6, 147.0, 135.9, 134.4, 132.7, 131.3, 129.0,
128.1, 126.0, 125.0, 124.9, 29.7, 24.8, 24.3, 14.7. HRMS (ESI) m/z
calcd for C37H44AuN3O 743.3150, found 743.3144.
Mp: 97−99 °C (lit.10 103−104 °C). H NMR (400 MHz, CDCl3): δ
1
7.95−7.92 (m, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.53−7.50 (m, 3H), 7.04
(d, J = 8.8 Hz, 2H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
161.2, 154.0 (d, JC−F = 19.4 Hz), 153.3 (d, JC−F = 10.1 Hz), 140.8 (d,
JC−F = 255.4 Hz), 130.6, 129.2, 128.9, 127.2 (m, 2C), 119.0, 114.8,
55.6. 19F NMR (376 MHz, CDCl3): δ −179.7 (s). HRMS (ESI) m/z
6454
dx.doi.org/10.1021/jo5008702 | J. Org. Chem. 2014, 79, 6444−6455

The Journal of Organic Chemistry
Article
(18) (a) Zhang, G.; Luo, Y.; Wang, Y.; Zhang, L. Angew. Chem., Int.
Ed. 2011, 50, 4450−4454. (b) Hopkinson, M. N.; Ross, J. E.;
Giuffredi, G. T.; Gee, A. D.; Gouverneur, V. Org. Lett. 2010, 12, 4904−
4907.
ASSOCIATED CONTENT
■
S
* Supporting Information
The ORTEP structure and CIF file of compound 9 and copies
of NMR spectra of compounds S1c−p, S2c−p, 1a−p, 1a′, 1b′,
1d′, 1j′, 1k′, 1l′, 3a−p, 4e, 4f, 4i, 4j, 4o, and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) For a recent review on NHC ligands in gold catalysis, see:
Gatineau, D.; Goddard, J.-P.; Mouries
J. Chem. 2013, 53, 892−900.
(20) Wang, D.; Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli, S. K.;
Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen, J. L.; Shi, X. J. Am.
Chem. Soc. 2012, 134, 9012−9019.
̀
-Mansuy, V.; Fensterbank, L. Isr.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ryuj@ewha.ac.kr.
(21) (a) Mankad, N. P.; Toste, F. D. Chem. Sci. 2012, 3, 72−76.
(b) Wang, W.; Jasinski, J.; Hammond, G. B.; Xu, B. Angew. Chem., Int.
Ed. 2010, 49, 7247−7252. (c) Mankad, N. P.; Toste, F. D. J. Am.
Chem. Soc. 2010, 132, 12859−12861. (d) Praveen, C.;
Kalyanasundaram, A.; Perumal, P. T. Synlett 2010, 777−781.
(22) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643−9647.
(23) Dolliver, D. D.; Bhattarai, B. T.; Pandey, A.; Lanier, M. L.;
Bordelon, A. S.; Adhikari, S.; Dinser, J. A.; Flowers, P. F.; Wills, V. S.;
Schneider, C. L.; Shaughnessy, K. H.; Moore, J. N.; Raders, S. M.;
Snowden, T. S.; McKim, A. S.; Fronczek, F. R. J. Org. Chem. 2013, 78,
3676−3687.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (NRF-2012R1A2A2A01011831).
(24) She, Z.; Niu, D.; Chen, L.; Gunawan, M. A.; Shanja, X.; Hersh,
W. H.; Chen, Y. J. Org. Chem. 2012, 77, 3627−3633.
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