Silver-catalyzed synthesis of disubstituted isoxazoles by cyclization of alkynyl oxime ethers

Article abstract of DOI:10.1016/j.tet.2011.04.083

A facile and practical synthesis of 3,5-disubstituted isoxazoles via a silver-catalyzed cyclization and subsequent protonation of alkynyl oxime ethers has been developed. The methodology was successfully applied to the synthesis of a biologically active i

Full text of DOI:10.1016/j.tet.2011.04.083

Tetrahedron 67 (2011) 4612e4615
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Tetrahedron
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Silver-catalyzed synthesis of disubstituted isoxazoles by cyclization of alkynyl
oxime ethers
Masafumi Ueda, Yuki Ikeda, Aoi Sato, Yuta Ito, Maiko Kakiuchi, Hiroko Shono, Tetsuya Miyoshi,
*
Takeaki Naito, Okiko Miyata
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and practical synthesis of 3,5-disubstituted isoxazoles via a silver-catalyzed cyclization and
subsequent protonation of alkynyl oxime ethers has been developed. The methodology was successfully
applied to the synthesis of a biologically active isoxazolecarboxylic acid.
Received 10 March 2011
Received in revised form 19 April 2011
Accepted 20 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 29 April 2011
Keywords:
Silver
Isoxazole synthesis
Oxime ether
Alkyne
O
N
R2
1. Introduction
R3=allyl
[M] = Au
R1
R3
O
OR3
Heterocycles are well known for their wide range of biological
properties.1 Among the various bioactive heterocycles, isoxazoles
attract great interest because of their wide reaching applications in
the medicinal chemistry2 and material science.3 The vast majority
of existing methodologies for the synthesis of isoxazoles4e9 rely on
either the condensation of a hydroxylamine with a 1,3-dicarbonyl
N
N
[M]
2
R2
R1
R1
H+
R2
O
[M]
N
R2
1
A
R1
H
compound or
a,
b
-unsaturated carbonyl compound,10 or the [3þ2]
3
cycloaddition reaction between an alkyne and a nitrile oxide.11
These methods usually require harsh conditions and result in
poor chemo- and regioselectivities. For this reason, research into
novel and efficient methods for the synthesis of isoxazoles is con-
tinuously being pursued.12
Scheme 1. Transition metal-catalyzed synthesis of isoxazoles.
disubstituted isoxazoles 3, via protonation of the vinyl metal in-
termediate A. Therefore, a switchable divergent synthesis of tri-
and disubstituted isoxazoles can be accomplished by tuning the
reaction conditions. Herein, we report an efficient and versatile
methodology for the synthesis of 3,5-disubstituted isoxazoles,
through the transition metal-catalyzed cyclization of alkynyl oxime
ethers in connection with our recent explorations of the chemistry
of conjugated imines.18
The transition metal-catalyzed intramolecular addition of
a heteroatom to an alkyne is one of the most powerful strategies for
the synthesis of heterocyclic compounds.13 This area has, however,
been less explored for isoxazoles.14e16 Recently, we have developed
a methodology for the synthesis of trisubstituted isoxazoles 2
through a gold-catalyzed domino reaction of an alkynyl oxime
ether, involving a 5-endo-dig cyclization and a subsequent Claisen-
type [3,3]-sigmatropic rearrangement (Scheme 1).17 We antici-
pated that the reaction in the presence of Brønsted acid would
suppress the migration of substituent R3 and produce the 3,5-
2. Results and discussion
Our studies commenced with a screening of catalysts (Table 1).
(Z)-O-Benzyl alkynyl oxime ether 1a, which was easily prepared by
the condensation of 1,3-diphenylprop-2-yn-1-one with O-benzyl-
hydroxylamine hydrochloride, was selected as a model substrate,
since the benzyl group would act as a good leaving group.19,20 The
* Corresponding author. Tel.: þ81 78 4417554; fax: þ81 78 4417556; e-mail
address: miyata@kobepharma-u.ac.jp (O. Miyata).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.083

M. Ueda et al. / Tetrahedron 67 (2011) 4612e4615
4613
cation would undergo polymerization, since the formation of any
benzyl phenyl ether was not observed in the reaction mixture. Fi-
nally, the aromatization of D affords isoxazole 3a and liberates the
catalytic silver species.
Table 1
Optimization of the cyclization reactiona
OBn
N
O
N
To examine the scope of the reaction, we treated various alkynyl
oxime ethers 1bej with AgBF4 and phenol, in refluxing THF, and
obtained the corresponding disubstituted isoxazoles 3bej in mod-
erate to good yield (Table 2). The cyclization reaction of 1b, which
had alkyl group on the triple bond terminus, proceeded to give 3b in
good yield (entry 1). Interestingly, substrates 1cee, bearing an
oxygen functionality at the propargylic position (R2) efficiently un-
derwent the cyclization within 1 h to yield 3cee (entry 2e4). We
propose that the chelation of the oxygen atom enhances the re-
activity of catalyst. It is noteworthy that the unprotected hydroxyl
group did not inhibit the course of the reaction (entry 4). Variation of
the substituent at R1 was then examined using a substrate bearing
the acetoxygroupat the propargylic position. Both electron-rich and
electron-poor aryl groups, and a hydrogen atom were readily
accommodated, producing the expected disubstituted isoxazoles
3feh and monosubstituted isoxazole 3i in good yield, respectively
(entries 5e8). A notably high chemical yield was observed in the
reaction of 1g, which has a p-trifluoromethylphenyl group at R1. An
imino ester 1j was also employed in this reaction, affording isoxazole
carboxylate 3j in high yield (entry 9).
catalyst
reflux
Ph
Ph
Ph
Ph
1a
3a
Entry
Catalyst
Proton source
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
AuCl3
AuCl(PPh3)
AgBF4
AgSbF6
Cu(OTf)2
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
PhOH
PhOH
PhOH
PhOH
PhOH
MeOH
AcOH
PhOH
PhOH
none
THF
THF
THF
THF
THF
THF
THF
benzene
toluene
THF
24
24
6
24
24
6
2
6
1
6
23
9
80
32
59
48 (50)c
71
14
9
10
11
39
NRd
NRd
none
PhOH
THF
6
a
Reaction conditions: 1a (0.16 mmol), 20 mol % of catalyst, 2.0 equiv of proton
source, solvent (5 mL).
b
Yield of isolated product after chromatography.
Yield in parentheses is for the recovered starting material 1a.
NR: no reaction.
c
d
screening of various metal catalysts (20 mol %), in the presence of
phenol as a proton source, in THF at reflux, revealed AgBF4 to be
optimal both for reaction time and yield (80%) (entries 1e5). We
then examined different proton sources. MeOH led to low conver-
sions into the corresponding 3,5-disubstituted isoxazole 3a (48%
yield) (entry 6). Although acetic acid could accelerate the silver-
catalyzed cyclization reaction, the yield was lower, due to the for-
mation of a decomposition product (entry 7). These results suggest
that weakly acidic conditions are required. The reaction was
strongly influenced by the choice of solvent, with benzene and
toluene leading to decreased chemical yields of 3a (entries 8 and 9).
A control reaction, in the absence catalyst or proton source, did not
lead to any conversion, confirming that these results are attributed
predominantly to the silver-catalyzed and phenol-promoted
reaction.
Table 2
Silver-catalyzed synthesis of disubstituted isoxazolesa
OBn
O
N
N
R2
AgBF4, PhOH
THF, reflux
R1
R1
R2
3b-j
1b-j
Entry Substrate R1
R2
Time (h) Product Yield (%)b
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
n-Bu
6
1
1
1
1
3b
3c
3d
3e
3f
3g
3h
3i
70
71
80
65
60
86
64
59
81
CH2OMe
CH2OAc
CH2OH
4-MeOC6H4 CH2OAc
1g
1h
1i
4-CF3C6H4
2-Furyl
H
CH2OAc
CH2OAc
CO2Et
Ph
1
1
7
12
On the basis of the above results, a proposed mechanism is
shown in Scheme 2. The addition of an oxygen atom to the Ag(I)-
activated CeC triple bond, in 5-endo-dig fashion, generates an
oxonium intermediate C. The protonation of C by phenol, and
subsequent elimination of the benzyl cation produces D. The benzyl
1j
CO2Me
3j
a
Reaction conditions: 1 (0.16 mmol), 20 mol % of catalyst, 2.0 equiv of phenol,
THF (5 mL).
b
Yield of isolated product after chromatography.
To illustrate the potential utility of this reaction, we have ex-
amined its application to synthesis of the biologically active iso-
xazolecarboxylic acid 6, which was synthesized by Ellman’s group
and found to be a strong Mycobacterium tuberculosis phosphatase
PtpB inhibitor (Scheme 3).21 Unfortunately, their synthetic strategy
for the synthesis of isoxazole ring, involving [3þ2] cycloaddition
reaction, was inefficient and resulted in a low yield. In contrast, our
method was highly effective, as shown in Scheme 3. The cyclization
OBn
O
N
N
Ph
Ag(I)
Ph
Ph
H
Ph
3a
1a
Bn
O
N
O
N
Ph
Ph
H
Ag(I)
Ph
Bn
Ph
Ag(I)
B
D
Bn
O
N
Ph
H
Ph
Ag(I)
C
Scheme 2. Proposed reaction pathway.
Scheme 3. Synthesis of phosphatase PtpB inhibitor.

4614
M. Ueda et al. / Tetrahedron 67 (2011) 4612e4615
of alkynyl oxime ether 5, which was readily prepared from alkyne 4,
afforded desired isoxazolecarboxylate in 75% yield. We finally
succeeded in the total synthesis of phosphatase PtpB inhibitor 6, by
hydrolyzing the ester with 1 M NaOH.
6.58 (1H, s), 4.84 (2H, s), 2.08 (1H, s). 13C NMR (CDCl3, 75 MHz)
d:
171.9, 162.5, 130.1, 128.9, 128.8, 126.8, 100.0, 56.6, 26.4. HRMS m/z:
calcd for C10H9NO2 (Mþ) 175.0633. Found: 175.0633.
4.2.5. Acetic acid [3-(4-Methoxyphenyl)-5-isoxazolyl]methyl ester
(3f). A colorless oil. IR (NaCl) cmꢀ1: 1744. 1H NMR (CDCl3, 300 MHz)
3. Conclusion
d
: 7.75e7.72 (2H, m), 6.99e6.96 (2H, m), 6.56 (1H, s), 5.21 (2H, s),
3.85 (3H, s), 2.14 (3H, s). 13C NMR (CDCl3, 75 MHz)
d
: 170.2, 166.9,
We have successfully developed a novel method for the syn-
thesis of disubstituted isoxazoles from alkynyl oxime ethers via
a silver-catalyzed cyclization and subsequent protonation with
phenol. This protocol was successfully applied to the synthesis of
a biologically active compound. The reaction is straightforward, and
allows for the efficient construction of substituted isoxazoles.
162.1, 161.1, 128.2, 121.2, 114.3, 102.0, 56.4, 35.3, 20.6. HRMS m/z:
calcd for C13H13NO4 (Mþ) 247.0844. Found: 247.0866.
4.2.6. Acetic acid [3-[4-(Trifluoromethyl)phenyl]-5-isoxazolyl]methyl
ester (3g). A colorless oil. IR (NaCl) cmꢀ1: 1745. 1H NMR (CDCl3,
300 MHz)
d
: 7.93 (2H, dd, J¼8.5, 0.5 Hz), 7.73 (2H, dd, J¼8.5, 0.5 Hz),
4. Experimental section
4.1. General
6.67 (1H, s), 5.25 (2H, d, J¼0.5 Hz), 2.16 (3H, s). 13C NMR (CDCl3,
125 MHz)
d
: 170.2, 167.9, 161.4, 132.0 (q, J¼33 Hz), 127.1, 125.9 (q,
J¼3.6 Hz), 123.8 (q, J¼271 Hz), 102.2, 56.3, 20.6. HRMS m/z: calcd for
C13H10F3NO3 (Mþ) 285.0612. Found: 285.0625.
NMR spectra were recorded at 300 MHz/75 MHz (1H NMR/13
C
NMR) or 500 MHz/125 MHz (1H NMR/13C NMR) using Varian
Gemini-300 (300 MHz), Varian MERCURY plus 300 (300 MHz), or
Varian NMR system AS 500 (500 MHz) spectrometers. Chemical
4.2.7. Acetic acid [3-(2-furanyl)-5-isoxazolyl]methyl ester (3h). A
colorless oil. IR (NaCl) cmꢀ1: 1748. 1H NMR (CDCl3, 300 MHz)
d: 7.56
(1H, dd, J¼2.0, 1.0 Hz), 6.92 (1H, dd, J¼3.5, 1.0 Hz), 6.58 (1H, s), 6.53
shifts (d) are reported as follows: chemical shift, multiplicity
(1H, dd, J¼3.5, 2.0 Hz), 5.21 (2H, s), 2.14 (3H, s). 13C NMR (CDCl3,
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, quint¼quintet,
sext¼sextet, m¼multiplet, br¼broad), coupling constants, and in-
tegration. IR spectra were obtained on a PerkineElmer Spec-
trumOne A spectrometer. Mass spectra were obtained by EI, CI or
ESI methods on a Hitachi M-4100 and Thermo Fisher Scientific
Exactive. Preparative TLC separations (PTLC) were carried out on
pre-coated silica gel plates (E. Merck 60F254). THF was freshly dis-
tilled from benzophenone ketyl radical anion prior to use.
125 MHz) d: 170.2, 167.9, 161.4, 127.1, 125.99, 125.96, 125.93, 125.90,
102.2, 56.3, 20.6. HRMS m/z: calcd for C13H10F3NO3 (Mþ) 285.0612.
Found: 285.0625.
4.2.8. 5-Isoxazolecarboxylic acid ethyl ester (3i). A colorless oil. IR
(NaCl) cmꢀ1: 1735. 1H NMR (CDCl3, 300 MHz)
d: 8.37 (1H, d,
J¼2.0 Hz), 6.96 (1H, d, J¼2.0 Hz), 4.45 (2H, q, J¼7.0 Hz), 1.43 (3H, t,
J¼7.0 Hz). 13C NMR (CDCl3, 125 MHz)
d: 160.1, 156.7, 150.6, 108.7,
4.2. General procedure for the silver-catalyzed synthesis of
disubstituted isoxazole 3
77.2, 62.3,14.1. HRMS m/z: calcd for C6H7NO3 (Mþ) 141.0425. Found:
141.0427.
To a solution of alkynyl oxime ether 1 (0.15 mmol) in THF (5 mL)
were added phenol (28 mg, 0.3 mmol) and AgBF4 (5.8 mg,
0.03 mmol), with a drying tube filled with silica gel at room tem-
perature. After being stirred at reflux for 1e12 h (TLC monitoring),
the reaction mixture was concentrated under reduced pressure. The
residue was purified by preparative TLC (hexane/AcOEt¼3e10:1) to
afford isoxazole 3. The physical and spectroscopic data of 3a5 and
3j12h were in accord with those reported in the literature.
4.3. Synthesis of isoxazolecarboxylic acid 6
4.3.1. 4-[3-Cyclohexyl-40-fluoro-30-(trifluoromethyl)[1,10-biphenyl]-
4-yl]-2-oxo-3-butynoic acid methyl ester. To a solution of CuI (14 mg,
0.072 mmol) in THF (5 mL) were added Et3N (0.4 mL, 2.89 mmol),
a solution of alkyne 421a (100 mg, 1.44 mmol) in THF (2 mL) and
methyl chloroglyoxalate (0.27 mL, 2.89 mmol), under an Ar atmo-
sphere at room temperature. After being stirred at the same tem-
perature for 15 h, the reaction mixture was diluted with H2O and
extracted with Et2O. The organic phase was dried over MgSO4 and
concentrated under reduced pressure. Purification by PTLC (hexane/
AcOEt¼8:1) afforded ketoester (76 mg, 61%) as a colorless solid. IR
4.2.1. 5-Butyl-3-phenylisoxazole (3b). A colorless oil. 1H NMR
(CDCl3, 300 MHz) d: 7.81e7.78 (2H, m), 7.46e7.41 (3H, m), 6.28 (1H,
d, J¼0.5 Hz), 2.85 (2H, t, J¼7.5 Hz), 1.73 (2H, quint, J¼7.5 Hz), 1.43
(2H, sext, J¼7.5 Hz), 0.96 (3H, t, J¼7.5 Hz). 13C NMR (CDCl3, 75 MHz)
(NaCl) cmꢀ1: 2191,1744,1674.1H NMR (CDCl3, 500 MHz)
d: 7.81e7.72
d
: 174.3, 162.3, 129.7, 129.4, 128.8, 126.7, 98.7, 29.6, 26.5, 22.2, 13.7.
(3H, m), 7.48 (1H, d, J¼2.0 Hz), 7.41 (1H, dd, J¼8.0, 2.0 Hz), 7.31 (1H, t,
HRMS m/z: calcd for C13H15NO (Mþ) 201.1153. Found: 201.1156.
J¼9.0 Hz), 3.99 (3H, s), 3.26e3.21 (1H, m), 1.97e1.81 (4H, m),
1.57e1.47 (4H, m), 1.33e1.25 (2H, m). 13C NMR (CDCl3, 125 MHz)
d:
4.2.2. 5-(Methoxymethyl)-3-phenylisoxazole (3c). A colorless oil. 1H
168.9,160.8, 159.7, 158.7, 154.1, 142.5, 136.73,136.70,135.7, 132.7, 132.6,
126.0,124.8,124.7,117.73,117.68,117.5, 97.0, 91.7, 53.7, 42.4, 33.8, 26.7,
26.0. HRMSm/z:calcdforC24H20O3F4 (Mþ)432.1347. Found:432.1371.
NMR (CDCl3, 300 MHz) d: 7.83e7.79 (2H, m), 7.47e7.44 (3H, m),
6.58 (1H, t, J¼0.5 Hz), 4.60 (2H, s), 3.48 (3H, s). 13C NMR (CDCl3,
75 MHz) d: 169.8, 162.4, 130.0, 128.9, 126.80, 126.76, 100.9, 65.4,
58.9. HRMS m/z: calcd for C11H11NO2 (Mþ) 189.0790. Found:
4.3.2. 4-[3-Cyclohexyl-40-fluoro-30-(trifluoromethyl)[1,10-biphenyl]-
4-yl]-2-[(phenylmethoxy)imino]-3-butynoic acid methyl ester (5). To
a solution of alkynyl ketone (47 mg, 0.11 mmol) in MeOH (2 mL)
were added O-benzylhydroxylamine hydrochloride (35 mg,
0.22 mmol), Na2SO4 (31 mg, 0.22 mmol), and pyridine (0.2 mL),
under an N2 atmosphere at room temperature. After being stirred at
the same temperature for 2 h, the reaction mixture was diluted
with H2O and extracted with Et2O. The organic phase was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. Purification by PTLC (benzene) afforded 5 (42 mg 71%) as
a colorless solid. IR (NaCl) cmꢀ1: 2202, 1736, 1622. 1H NMR (CDCl3,
189.0802.
4.2.3. Acetic acid (3-phenyl-5-isoxazolyl)methyl ester (3d). A color-
less oil. IR (NaCl) cmꢀ1: 1750. 1H NMR (CDCl3, 300 MHz)
d:
7.82e7.79 (2H, m), 7.47e7.45 (3H, m), 6.63 (1H, d, J¼0.5 Hz), 5.23
(2H, d, J¼0.5 Hz), 2.15 (3H, s). 13C NMR (CDCl3, 75 MHz)
d: 170.1,
167.1, 162.5, 130.1, 128.9, 128.6, 126.7, 102.1, 56.3, 20.5. HRMS m/z:
calcd for C12H11NO3 (Mþ) 217.0738. Found: 217.0752.
4.2.4. 3-Phenyl-5-isoxazolylmethanol (3e). A colorless solid. 1H
NMR (CDCl3, 300 MHz)
d
: 7.82e7.79 (2H, m), 7.47e7.45 (3H, m),
500 MHz)
d: 7.78e7.72 (2H, m), 7.61 (1H, d, J¼8.0 Hz), 7.45e7.28

M. Ueda et al. / Tetrahedron 67 (2011) 4612e4615
4615
(3H, m,), 5.47 (2H, s), 3.95 (3H, s), 3.15 (1H, tt, J¼12.0, 3.0 Hz),
1.92e1.89 (2H, m), 1.80e1.77 (2H, m), 1.71e1.69 (1H, m), 1.47e1.39
(2H, m), 1.35e1.20 (3H, m). 13C NMR (CDCl3, 125 MHz)
: 161.6,
160.5, 158.4, 151.8, 140.5, 137.15, 137.12, 136.1, 134.1, 133.9, 132.52,
132.45, 128.6, 128.43, 128.40, 125.81, 125.79, 124.4, 124.3, 120.2,
117.5, 117.3, 101.6, 82.5, 79.0, 53.2, 42.1, 33.6, 26.7, 26.1. HRMS m/z:
calcd for C31H27NO3F4 (Mþ) 537.1925. Found: 537.1941.
References and notes
1. Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K.; Joule, J. Com-
prehensive Heterocyclic Chemistry III; Elsevier: Oxford, 2008.
d
€
€
2. (a) Carlsen, L.; Dopp, D.; Dopp, H.; Duus, F.; Hartmann, H.; Lang-Fugmann, S.;
Schulze, B.; Smalley, R. K.; Wakefield, B. J. In Houben-weyl Methods in Organic
Chemistry; Schaumann, E., Ed.; Georg Thieme: Stuttgart, 1992; Vol. E8a, p 45;
(b) Sperry, J.; Wright, D. Curr. Opin. Drug Discovery Dev. 2005, 8, 723.
3. Lee, Y.; Koyama, Y.; Yonekawa, M.; Tanaka, T. Macromolecules 2009, 42, 7709.
4. For review, see: Wakefield, B. J. In Science of Synthesis: Houben-weyl Methods of
Molecular Transformations; Shaumann, E., Ed.; Georg Thieme: Stuttgart, 2001;
Vol. 11, p 229.
4.3.3. 5-[3-Cyclohexyl-40-fluoro-30-(trifluoromethyl)[1,10-biphenyl]-
4-yl]-3-isoxazolecarboxylic acid methyl ester. To
a solution of
5. Dang, T. T.; Albrecht, U.; Langer, P. Synthesis 2006, 2515.
alkynyl oxime ether 5 (42 mg, 0.078 mmol) in 1,4-dioxane (5 mL)
were added phenol (15 mg, 0.16 mmol) and AgBF4 (15 mg,
0.078 mmol), with a drying tube filled with silica gel at room
temperature. After being stirred at reflux for 7 days, the reaction
mixture was filtered with SiO2 and concentrated under reduced
pressure. Purification by PTLC (benzene) afforded isoxazole car-
boxylate (27 mg, 75%) as a colorless solid. IR (NaCl) cmꢀ1: 1741. 1H
6. Wang, K.; Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org. Lett. 2008, 10, 1691.
7. Li, X.; Du, Y.; Liang, Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, 2643.
8. Gaywood, A. P.; McNab, H. J. Org. Chem. 2009, 74, 4278.
9. Girardin, M.; Alsabeh, P. G.; Lauzon, S.; Dolman, S. J.; Ouellet, S. G.; Hughes, G.
Org. Lett. 2009, 11, 1159.
10. (a) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. Org. Lett. 2009, 11, 3982; (b) Ahmed, M.
S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487; (c) Ghosh, T.; Bandyo-
padhyay, C. Tetrahedron Lett. 2004, 45, 6169; (d) Cuadrado, P.; Gonzalez-Nogal,
A. M.; Valero, R. Tetrahedron 2002, 58, 4975.
€
11. For review, see: Jager, V.; Colinas, P. A. In Synthetic Applications of 1,3-Dipolar
NMR (CDCl3, 500 MHz)
d
: 7.82e7.76 (2H, m), 7.64 (1H, d, J¼8.0 Hz),
Cycloaddition Chemistry toward Heterocycles and Natural Products; Padwa, A.,
Ed.; Wiley: Hoboken, 2002; Vol. 59, p 361.
7.57 (1H, d, J¼2.0 Hz), 7.46 (1H, dd, J¼8.0, 2.0 Hz), 7.31 (1H, t,
J¼9.0 Hz), 6.80 (1H, s), 4.04 (3H, s), 2.90 (1H, tt, J¼11.5, 3.0 Hz),
12. For a recent study on the synthesis of disubstituted isoxazoles, see: (a) Debleds,
O.; Gayon, E.; Ostaszuk, E.; Vrancken, E.; Campagne, J.-M. Chem.dEur. J. 2010,
16, 12207; (b) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. J. Org. Chem. 2010, 75, 1961;
(c) Conti, P.; Pinto, A.; Tamborini, L.; Dunkel, P.; Gambaro, V.; Viscoti, G. L.;
Micheli, C. D. Synthesis 2009, 591; (d) Bhosale, S.; Kurhade, S.; Prasad, U. V.;
Palle, V. P.; Bhuniya, D. Tetrahedron Lett. 2009, 50, 3948; (e) McClendon, E.;
Omollo, A. O.; Valente, E. J.; Hamme, A. T., II. Tetrahedron Lett. 2009, 50, 533; (f)
Grecian, S.; Fokin, V. V. Angew. Chem., Int. Ed. 2008, 47, 8285; (g) Willy, B.;
Rominger, F.; Muller, T. J. J. Synthesis 2008, 293; (h) Hansen, T. V.; Wu, P.; Fokin,
V. V. J. Org. Chem. 2005, 70, 7761.
1.92e1.77 (5H, m), 1.58e1.26 (5H, m). 13C NMR (125 MHz)
d: 172.0,
160.5, 156.4, 147.6, 141.3, 136.97, 136.94, 132.6, 132.5, 130.4, 125.91,
125.88, 125.7, 125.2, 124.8, 117.6, 103.6, 53.0, 40.8, 34.4, 26.7, 26.0.
HRMS m/z: calcd for C24H21NO3F4 (Mþ) 447.1467. Found: 447.1475.
4.3.4. 5-[3-Cyclohexyl-40-fluoro-30-(trifluoromethyl)[1,10-biphenyl]-
4-yl]-3-isoxazolecarboxylic acid (6). To a solution of isoxazole car-
boxylate (27 mg, 0.06 mmol) in THF (1 mL) was added 1 M NaOH
(1 mL), under N2 at room temperature. After being stirred at the
same temperature for 1 h, the reaction mixture was concentrated
under reduced pressure, diluted with 2 M HCl and extracted with
AcOEt. The organic layer was washed with 2 M HCl, washed with
brine, dried over MgSO4, and concentrated under reduced pressure
to give 1 (26 mg, quant) as a colorless solid. IR (NaCl) cmꢀ1: 1719. 1H
13. (a) Lipshutz, B. H.; Yamamoto, Y. Chem. Rev. 2008, 108, 3239; (b) Kirsch, S. F.
Synthesis 2008, 3183.
14. Perumal’s group reported a gold-catalyzed synthesis of disubstituted isoxazoles
from
droxylamine with alkynyl ketones. Praveen, C.; Kalyanasundaram, A.; Perumal,
P. T. Synlett 2010, 777 However, the preparation of the -acetylenic oximes
suffer from poor reproducibility and the formation of undesired 4,5-dihy-
a,b-acetylenic oximes, which were prepared by the condensation of hy-
a,b
15
droisoxazol-5-ol, by a 1,4-addition of hydroxylamine and cyclization
.
15. (a) Marei, M. G.; Ghonaim, R. A. Indian J. Chem. 1993, 32B, 418; (b) Marei, M. G.;
El-Ghanam, M. Bull. Chem. Soc. Jpn. 1992, 65, 3509; (c) Linderman, R. J.; Kirollos,
K. S. Tetrahedron Lett. 1989, 30, 2049; (d) Linderman, R. J.; Lonikar, M. S. J. Org.
Chem. 1988, 53, 6013.
16. For the synthesis of dihydroisoxazoles, see: (a) Winter, C.; Krause, N. Angew.
Chem., Int. Ed. 2009, 48, 6339; (b) Debleds, O.; Zotto, C. D.; Vrancken, E.;
Campagne, J.-M.; Retailleau, P. Adv. Synth. Catal. 2009, 351, 1991.
17. Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.; Naito, T.; Miyata, O. Org. Lett. 2010, 12,
2594.
18. (a) Ueda, M.; Matsubara, H.; Yoshida, K.; Sato, A.; Naito, T.; Miyata, O. Chem.
dEur. J. 2011, 17, 1789; (b) Ueda, M.; Miyabe, H.; Torii, M.; Kimura, T.; Miyata, O.;
Naito, T. Synlett 2010, 1341; (c) Ueda, M.; Iwasada, E.; Miyabe, H.; Miyata, O.;
Naito, T. Synthesis 2010, 1999; (d) Ueda, M.; Miyabe, H.; Kimura, T.; Kondoh, E.;
Naito, T.; Miyata, O. Org. Lett. 2009, 11, 4632; (e) Rahaman, H.; Ueda, M.; Miyata,
O.; Naito, T. Org. Lett. 2009, 11, 2651; (f) Ueda, M.; Miyabe, H.; Shimizu, H.;
Sugino, H.; Miyata, O.; Naito, T. Angew. Chem., Int. Ed. 2008, 47, 5600; (g) Ueda,
M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem., Int. Ed. 2005, 44,
6190.
19. Larock recently reported the synthesis of 4-haloisoxazoles through the elec-
trophilic cyclization of O-methyl alkynyl oxime ethers, see: (a) Waldo, J. P.;
Mehta, S.; Neuenswander, B.; Lushington, G. H.; Larock, R. C. J. Comb. Chem.
2008, 10, 658; (b) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643; (c)
Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203.
NMR (CDCl3/CD3OD (1:1), 500 MHz) d: 7.83e7.80 (2H, m), 7.66 (1H,
d, J¼8.0 Hz), 7.59 (1H, s), 7.49 (1H, dd, J¼8.0, 1.5 Hz), 7.34 (1H, t,
J¼9.0 Hz), 6.82 (1H, s), 2.94e2.89 (1H, m), 1.89 (3H, t, J¼14.5 Hz),
1.79 (1H, d, J¼12.0 Hz), 1.56 (2H, q, J¼12.0 Hz), 1.45e1.25 (4H, m).
13C NMR (CDCl3/CD3OD (1:1), 125 MHz)
d: 171.6, 161.4, 157.1, 147.3,
141.0, 136.78, 136.75, 132.5, 132.4, 130.1, 125.6, 125.4, 125.1, 124.5,
117.3, 117.2, 103.6, 40.6, 34.1, 26.4, 25.7. HRMS m/z: calcd for
C23H20NO3F4 (Mþ) 434.1378. Found: 434.1387. The spectroscopic
data are consistent with those reported in the literature.21a
Acknowledgements
This work was supported by Grants-in Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan, and
the Research Foundation for Pharmaceutical Sciences.
Supplementary data
20. The silver-catalyzed cyclization also took place by using O-methyl alkynyl ox-
ime ether as a substrate.
21. (a) Soellner, M. B.; Rawls, K. A.; Grundner, C.; Alber, T.; Ellman, J. A. J. Am. Chem.
Soc. 2007, 129, 9613; (b) Rawls, K. A.; Grundner, C.; Ellman, J. A. Org. Biomol.
Chem. 2010, 8, 4066.
These data include experimental procedures for the synthesis of
alkynyl oxime ethers 1aeh and 1j. Supplementary data related to
this article can be found online at doi:10.1016/j.tet.2011.04.083.