Synthesis of trisubstituted isoxazoles by palladium(ii)-catalyzed cascade cyclization-alkenylation of 2-alkyn-1-one o -methyl oximes

Article abstract of DOI:10.1021/jo300090k

A palladium-catalyzed, cascade 5-endo-dig cyclization-alkenylation synthesis of isoxazoles has been developed. The addition of 1 equiv of n-Bu ₄NBr significantly increases the yield of the desired 4-alkenyl-3,4,5-trisubstituted isoxazoles. A va

Full text of DOI:10.1021/jo300090k

Note
pubs.acs.org/joc
Synthesis of Trisubstituted Isoxazoles by Palladium(II)-Catalyzed
Cascade Cyclization−Alkenylation of 2-Alkyn-1-one O-Methyl
Oximes
Zhigang She, Dongyue Niu, Lei Chen, Maria A. Gunawan, Xhesika Shanja, William H. Hersh,
and Yu Chen*
Department of Chemistry and Biochemistry, Queens College and the Graduate Center of the City University of New York, Flushing,
New York 11367, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed, cascade 5-endo-dig cyclization−alkenylation synthesis of isoxazoles has been developed.
The addition of 1 equiv of n-Bu4NBr significantly increases the yield of the desired 4-alkenyl-3,4,5-trisubstituted isoxazoles. A
variety of trisubstituted isoxazoles are prepared in moderate to excellent yields. One example of the synthesis of a
naphthoisoxazole is reported by a cascade cyclization−alkenylation-Heck reaction.
soxazoles exhibit a wide range of biological activities,
including analgesic,1 anti-inflammatory,1 antinociceptive,2
Scheme 1. Preparation of 2-Alkyn-1-one O-Methyl Oximes
I
and anticancer3 activity, and have been the focus of many
biological studies in recent years.4 A number of synthetic
methods have been developed to construct the isoxazole core
structure,5 including the [3 + 2] cycloaddition of alkynes/
alkenes and nitrile oxides,6 intramolecular cyclization of α,β-
unsaturated oximes,7 and intermolecular cyclization of oximes
with C−C double/triple bonds.8 Alkenyl-substituted hetero-
aromatic moieties are found in numerous natural products and
biologically active compounds.9 Their synthesis has attracted a
great degree of interest.10
Palladium-catalyzed cascade reactions have emerged as a
valuable component in the synthesis of complex molecular
scaffolds.11 In the presence of catalytic amounts of palladium,
sequential transformations can take place in one pot with the
formation of multiple chemical bonds. Our interest in 4-(1-
alkenyl)isoxazoles has prompted us to develop a convenient
new synthesis of these isoxazoles by a palladium(II)-catalyzed
cascade cyclization−alkenylation sequence from 2-alkyn-1-one
O-methyl oximes and alkenes.
(Scheme 2).13 However, when 2 equiv of tert-butyl acrylate
were added to the reaction mixture under the same conditions,
Scheme 2. Palladium-Catalyzed Cyclization of O-Methyl
Oxime 2a
Ynones 1 were prepared by the Sonogashira coupling of an
acid chloride and a terminal alkyne.12 The O-methyl oximes 2
were prepared by the reaction of ynones with methoxylamine
hydrochloride in the presence of pyridine and anhydrous
Na2SO4 (Scheme 1).
Our initial study focused on the cyclization of O-methyl
oxime 2a, which afforded the 3,5-disubstituted isoxazole 3a in a
67% yield in the presence of the PdCl2/CuCl2 catalyst system
Received: January 20, 2012
Published: February 29, 2012
© 2012 American Chemical Society
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Note
a
Table 1. Optimization of Reaction Conditions for the Palladium-Catalyzed Cascade Cyclization−Alkenylation
b
entry
catalyst
PdCl2
base
additive
solvent
4a yield (%)
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
DMF
DMF
DMF
DMSO
DMAc
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
52
62
73
60
62
70
72
73
81
89
95
80
37
86
58
2
Pd(OAc)2
3
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
4
5
6
7
8
9
10
11
n-Bu4NCl
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
c
12
d
13
e
14
f
15
g
16
(3)
a
Representative procedure: the palladium catalyst (0.05 mmol), CuCl2 (1.0 mmol), additive (0.5 mmol), base (1.0 mmol), O-methyl oxime (0.5
mmol), t-butyl acrylate (1.0 mmol), and solvent (3 mL) were mixed in a sealed 4-dram vial. The reaction was stirred at the indicated temperature for
b
c
d
e
2 h. Isolated yields after column chromatography. 5 mol % of Pd(O2CCF3)2 was added. 1 equiv of CuCl2 was added. The reaction was run at
120 °C. The reaction was run at 180 °C. The yield in parentheses was determined by H NMR.
f
g
1
the desired 3,4,5-trisubstituted isoxazole 4a was isolated in a
52% yield, alongside 10% of 3a (Table 1, entry 1). A similar
problem was encountered in the previously reported palladium-
catalyzed cascade cyclization−alkenylation synthesis of indole-
s10a and isoquinolines,10b where the direct cyclization products
were obtained together with the desired cyclization−
alkenylation products.
electron-donating substituent, such as a methoxy group (Table
2, entries 6 and 8), and an electron-withdrawing substituent,
such as a nitrile group (Table 2, entry 13), are compatible. A
variety of alkenes have been employed in this cascade, including
both electron-rich and electron-poor alkenes. Alkenes with an
electron-withdrawing substituent afford good to excellent yields
(Table 2, entries 1−8 and 13−14), while the electron-rich
alkene, ethyl vinyl ether, only produces a moderate yield (Table
2, entry 11). When vinyl acetate is used, the acetate group on
the alkene is eliminated instead of a β-hydrogen elimination,
leading to the 4-ethenylisoxazole 4j in a 52% yield (Table 2,
entry 10). A 42% yield is obtained when the sterically more
demanding (E)-methyl but-2-enoate is used (Table 2, entry
12). A wide variety of functional groups are tolerated under the
current reaction conditions, including ester, aldehyde, ketone,
amide, ether, nitrile, and chloro groups. High trans-selectivity is
observed in the alkenylation step since only a single isomer
with 3JHH > 15 Hz for the two alkene hydrogen atoms was seen
in all relevant cases (entries 1−9, 13, 14; see the Supporting
Information).
When the O-methyl oxime 2i was subjected to the current
reaction conditions, a cascade cyclization−alkenylation−Heck
reaction took place to afford naphthoisoxazole 5 in a 58% yield
(Scheme 3). Naphthoisoxazoles are known as estrogen receptor
agonist and antagonist compounds, useful in preventing or
treating estrogen receptor-mediated disorders such as osteopo-
rosis and breast cancer.17
This cyclization−alkenylation reaction presumably takes
place by Pd(II)-catalyzed 5-endo-dig cyclization to form the
heteroaryl palladium intermediate 6, which forms intermediate
7 after the loss of a methyl group. A Heck coupling then takes
place between 7 and the alkene to afford the trisubstituted
isoxazole 4 (Scheme 4). In the case of isoxazole 4o, where an
ortho-bromo group is present on the 3-aryl substituent, an
The yield of 4a was improved to 62 and 73%, respectively,
when Pd(OAc)2 and Pd(O2CCF3)2 were used (Table 1, entries
2 and 3). The amount of 3a was around 5% in both cases.
Different solvents and bases were also screened in the reaction
(Table 1, entries 4−9), and it was found that the combination
of NMP and Li2CO3 afforded superior yields of 4a (Table 1,
entry 9). The beneficial effect of quaternary ammonium salts in
the Heck reaction is known.14 The presence of n-Bu4NBr15 or
n-Bu4NCl16 can accelerate the reaction rate and increase the
chemical yields of the Heck reaction. To our delight, the yield
of 4a was increased to 89% with the addition of 1 equiv of n-
Bu4NCl (Table 1, entry 10). The addition of 1 equiv of n-
Bu4NBr further increased the yield to 95% with no 3a detected
(Table 1, entry 11). The yield of 4a dropped to 80% when
Pd(O2CCF3)2 was reduced to 5 mol % (Table 1, entry 12). A
significant drop in yield was observed when the amount of
CuCl2 was decreased to 1 equiv (Table 1, entry 13). Inferior
results were obtained when temperatures 30 degrees lower or
higher than 150 °C were used (Table 1, entries 14 and 15).
Only a trace amount of the desired product 4a was obtained
when the reaction was carried out in the absence of a palladium
catalyst (Table 1, entry 16).
This one-pot cyclization−alkenylation cascade reaction
protocol has proved to be a very general route to a variety of
isoxazoles (Table 2). A wide variety of O-methyl oxime
substrates have been studied in this cascade process, including
those bearing aryl, alkyl, and alkenyl substituents. Both an
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Note
a
Table 2. Preparation of 3,4,5-Trisubstituted Isoxazoles by a Palladium-Catalyzed Cascade Reaction
a
Representative procedure: the Pd(O2CCF3)2 (0.05 mmol), CuCl2 (1.0 mmol), n-Bu4NBr (0.5 mmol), Li2CO3 (1.0 mmol), O-methyl oxime (0.5
mmol), alkene (1.0 mmol), and NMP (3 mL) were mixed in a sealed 4-dram vial. The reaction mixture was stirred at 150 °C for the indicated time.
Isolated yields after column chromatography. The major product 3,5-diphenyl-4-vinylisoxazole (4j) was obtained in a 52% yield.
b
c
Scheme 3. Synthesis of Naphtho[1,2-c]isoxazole by a
Palladium-Catalyzed Cyclization−Alkenylation−Heck
Reaction
trisubstituted isoxazoles. The yields of the undesired direct
cyclization products, 3,5-disubstituted isoxazoles, are dimin-
ished by the addition of 1 equiv of n-Bu4NBr. A wide variety of
2-alkyn-1-one O-methyl oximes and olefins have been
successfully employed in this synthetic protocol. A number of
functional groups, including ester, amide, aldehyde, ether,
nitrile, and ketone groups, are compatible with the reaction
conditions. One example of the synthesis of a polycyclic
naphtho[1,2-c]isoxazole has been demonstrated by a palladium-
catalyzed cyclization−alkenylation−Heck cascade. Preparation
of the polycyclic naphtho[1,2-c]isoxazole derivatives using the
current protocol is underway.
intramolecular Heck coupling takes place subsequently to
afford naphthoisoxazole 5.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out in sealed 4-
dram oven-dried vials unless otherwise noted. All commercially
available chemicals were used as received without further purification
unless otherwise indicated. N-Methyl-2-pyrrolidone was dried by 4 Å
molecular sieves before use. All 1H and 13C NMR spectra were
recorded at 500 and 125 MHz, respectively, using CDCl3 as a solvent.
It is worth noting that although the majority of the studied
intramolecular Heck reactions proceed in the exo-trig mode,14
the intramolecular Heck coupling of 4o gives the 6-membered
ring exclusively via an endo-trig mode, rather than the 5-
membered ring that would have resulted from the exo-trig
reaction. Steric effects obviously play a significant role in the
high regioselectivity observed for the current 6-endo-trig
intramolecular Heck reaction, though the 6-endo-trig Heck
reaction is electronically disfavored. The regioselectivity was
unequivocally established by X-ray diffraction analysis of a
single crystal of compound 5 (see the Supporting Information).
In conclusion, we have developed a palladium-catalyzed
cascade cyclization−alkenylation for the synthesis of 3,4,5-
1
The chemical shifts of all H and 13C NMR spectra are referenced to
the residual signal of CDCl3 (δ 7.26 ppm for the 1H NMR spectra and
δ 77.23 ppm for the 13C NMR spectra). The high resolution mass
spectra were recorded on a double focusing magnetic sector mass
spectrometer using electrospray ionization. The melting points are
uncorrected.
General Procedure for the Preparation of Ynones (1). These
compounds were prepared according to a literature procedure.7d,12a
To a 50 mL round-bottom flask were added CuI (19 mg, 0.1 mmol),
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Note
Scheme 4. Plausible Mechanism for the One-Pot Synthesis of Trisubstituted Isoxazoles (4) and Naphtho[1,2-c]isoxazole (5)
1
PdCl2(PPh3)2 (14 mg, 0.02 mmol), and triethylamine (10 mL). The
flask was flushed with nitrogen, and the terminal acetylene (5.0 mmol)
was added to the stirred suspension, followed by immediate dropwise
addition of acyl chloride (6.5 mmol). If the acyl chloride was a solid, it
was added as a THF solution. The resulting mixture was allowed to stir
at room temperature overnight. Water (10 mL) was added to the
reaction mixture. The resulting solution was extracted with diethyl
ether (3 × 20 mL). The organic layers were combined and dried over
anhydrous MgSO4. The solvent was removed under a vacuum, and the
residue was purified by flash column chromatography on silica gel
using ethyl acetate/hexanes as the eluent.
The product was obtained as a yellow oil in a 72% yield: H NMR
(500 MHz, CDCl3) δ 7.51−7.54 (m, 2H), 6.87−6.90 (m, 2H), 3.83 (s,
3H), 1.26 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 194.6, 161.7,
135.2, 114.5, 112.2, 93.5, 86.0, 55.6, 44.9, 26.4; HRMS (EI) calcd for
C14H16O2, 216.1150, found 216.1151.
1-(4-Chlorophenyl)-3-(cyclohex-1-en-1-yl)prop-2-yn-1-one
(1e). Purification by flash column chromatography (5:1 hexanes/
EtOAc). This compound was obtained as a light yellow solid in a 68%
1
yield: mp 83−84 °C; H NMR (500 MHz, CDCl3) δ 8.06−8.09 (m,
2H), 7.44−7.47 (m, 2H), 6.59−6.61 (m, 1H), 2.26−2.30 (m, 2H),
2.20−2.24 (m, 2H), 1.70−1.74 (m, 2H), 1.63−1.67 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 177.1, 143.4, 140.6, 135.6, 131.0, 129.1,
119.2, 96.5, 85.1, 28.5, 26.4, 22.1, 21.3; HRMS (EI) calcd for
C15H13ClO, 244.0655, found 244.0657.
4,4-Dimethyl-1-phenylpent-1-yn-3-one (1a). Purification by
flash column chromatography (10:1 hexanes/EtOAc). This compound
1
was obtained as a yellow oil in an 81% yield: H NMR (500 MHz,
1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-one (1f). Purifica-
tion by flash column chromatography (10:1 hexanes/EtOAc). This
compound was obtained as a light yellow oil in a 90% yield: 1H NMR
(500 MHz, CDCl3) δ 8.19−8.22 (m, 2H), 7.67−7.69 (m, 2H), 7.46−
7.50 (m, 1H), 7.40−7.44 (m, 2 H), 6.98−7.01 (m, 2H), 3.91(s, 3H).
CDCl3) δ 7.57−7.58 (m, 2H), 7.43−7.46 (m, 1H), 7.36−7.40 (m,
1
2H), 1.28 (s, 9H). The H NMR spectral data are in good agreement
with the literature data.12b
1-Phenylhexadec-2-yn-1-one (1b). Purification by flash column
chromatography (20:1 hexanes/EtOAc). This compound was
1
1
The H NMR spectral data are in good agreement with the literature
obtained as a light yellow oil in an 83% yield: H NMR (500 MHz,
data.12b
CDCl3) δ 8.13−8.14 (m, 2H), 7.57−7.61 (m, 1H), 7.45−7.48 (m,
2H), 2.49 (t, J = 7.1 Hz, 2 H), 1.64−1.68 (m, 2 H), 1.45−1.48 (m,
2H), 1.22−1.34 (m, 18 H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 178.5, 137.1, 134.1, 129.7, 128.7, 97.2, 79.8, 32.1,
29.9, 29.83, 29.78, 29.7, 29.5, 29.24, 29.16, 28.0, 22.9, 19.4, 14.3;
HRMS (EI) calcd for C22H32O, 312.2453, found 312.2459.
1,3-Diphenylprop-2-yn-1-one (1g). Purification by flash column
chromatography (40:1 hexanes/EtOAc). This compound was
obtained as a yellow oil in a 96% yield: 1H NMR (500 MHz,
CDCl3) δ 8.23−8.24 (m, 2H), 7.69−7.71 (m, 2H), 7.63−7.66 (m,
1
1H), 7.48−7.55 (m, 3H), 7.42−7.45 (m, 2H). The H NMR spectral
data are in good agreement with the literature data.18
1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-one (1c). Purifica-
tion by flash column chromatography (20:1 hexanes/EtOAc). The
4-(3-Phenylpropioloyl)benzonitrile (1h). Purification by flash
column chromatography (10:1 hexanes/EtOAc). This compound was
1
product was obtained as a colorless oil in a 65% yield: H NMR (500
1
obtained as a yellow solid in a 92% yield: mp 51−52 °C; H NMR
MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 1H), 7.69(t, J = 7.6 Hz, 3H), 7.49
(t, J = 7.6 Hz, 1H), 7.41−7.44 (m, 3H), 7.18 (dd, J = 2.4 Hz, 1H), 3.88
(500 MHz, CDCl3) δ 8.31−8.32 (m, 2H), 7.82−7.84 (m, 2H), 7.69−
7.71 (m, 2H), 7.52−7.55 (m, 1H), 7.44−7.47 (m, 2H). The 1H NMR
spectral data are in good agreement with the literature data.18
1-(2-Bromophenyl)-3-phenylprop-2-yn-1-one (1i). Purifica-
tion by flash column chromatography (10:1 hexanes/EtOAc). This
1
(s, 3H). The H NMR spectral data are in good agreement with the
literature data.18
1-(4-Methoxyphenyl)-4,4-dimethylpent-1-yn-3-one (1d). Pu-
rification by flash column chromatography (10:1 hexanes/EtOAc).
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Note
compound was obtained as a light yellow oil in a 63% yield: 1H NMR
(500 MHz, CDCl3) δ 8.08 (dd, J = 7.7, 1.5 Hz, 1H), 7.70 (d, J = 7.9
Hz, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.44−7.50 (m, 2H), 7.37−7.43 (m,
2H), 7.38−7.42 (m, 6H), 4.15 (s, 3H). The 1H NMR spectral data are
in good agreement with the literature data.7c
(Z)-4-(1-(Methoxyimino)-3-phenylprop-2-yn-1-yl)-
benzonitrile (2h). Purification by flash column chromatography
(10:1 hexanes/EtOAc). This compound was obtained as a white solid
in a 42% yield: mp 55−56 °C; 1H NMR (500 MHz, CDCl3) δ 8.01−
8.03 (m, 2H), 7.67−7.69 (m, 2H), 7.61−7.63 (m, 2H), 7.38−7.45 (m,
3H), 4.17 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.5, 137.9,
132.4, 132.3, 130.1, 128.7, 127.1, 121.4, 118.8, 113.1, 102.5, 78.6, 63.8;
HRMS (EI) calcd for C17H12N2O, 260.0950, found 260.0950.
(E)-1-(2-Bromophenyl)-3-phenylprop-2-yn-1-one O-Methyl
Oxime (2i). Purification by flash column chromatography (10:1
hexanes/EtOAc). The product was obtained as a light yellow oil in an
18% yield: 1H NMR (500 MHz, CDCl3) δ 7.63−7.67 (m, 1H), 7.50−
7.59 (m, 3H), 7.34−7.40 (m, 5H), 4.15 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 140.4, 135.1, 133.7, 132.2, 131.2, 130.8, 129.7, 128.5, 127.6,
122.6, 121.8, 102.3, 80.1, 63.4; HRMS (EI) calcd for C16H12BrNO,
313.0102, found 313.0101.
General Procedure for the Preparation of 3,4,5-Trisubsti-
tuted Isoxazoles (4) and Naphtho[1,2-c]isoxazole (5). To an
oven-dried 4-dram vial were added Pd(O2CCF3)2 (16.6 mg, 0.05
mmol), CuCl2 (134.5 mg, 1.0 mmol), Li2CO3 (74 mg, 1.0 mmol), n-
Bu4NBr (161.2 mg, 0.5 mmol), O-methyl oxime (0.5 mmol), alkene
(1.0 mmol), and NMP (3 mL). The reaction mixture was stirred at
150 °C for the desired time. The reaction mixture was cooled to room
temperature and diluted with 5 mL of diethyl ether. The mixture was
then washed with 10 mL of a saturated NH4Cl aqueous solution. The
aqueous phase was extracted with diethyl ether (2 × 5 mL). The
combined organic layers were dried over anhydrous MgSO4 and
concentrated under a vacuum to yield the crude product, which was
purified by flash column chromatography on silica gel using ethyl
acetate/hexanes as the eluent.
1
3H). The H NMR spectral data are in good agreement with the
literature data.19
General Procedure for the Preparation of Ynone O-Methyl
Oximes (2). These compounds were prepared according to a
literature procedure.7d To a 50 mL round-bottom flask were added
the alkynone (3.5 mmol), methoxylamine hydrochloride (7.0 mmol,
579 mg), anhydrous Na2SO4 (7.0 mmol, 994 mg), pyridine (1 mL),
and anhydrous methanol (10 mL). The reaction mixture was stirred at
room temperature overnight. The mixture was diluted with water (25
mL) and extracted with EtOAc (3 × 25 mL). The organic layers were
combined, washed with brine, and dried over anhydrous MgSO4. The
solvent was removed under a vacuum, and the residue was purified by
flash column chromatography on silica gel using ethyl acetate/hexanes
as the eluent.
(Z)-4,4-Dimethyl-1-phenylpent-1-yn-3-one O-Methyl Oxime
(2a). Purification by flash column chromatography (10:1 hexanes/
EtOAc). This compound was obtained as a yellow oil in an 82% yield:
1H NMR (500 MHz, CDCl3) δ 7.52−7.55 (m, 2H), 7.32−7.37 (m,
1
3H), 3.97 (s, 3H), 1.26 (s, 9H). The H NMR spectral data are in
good agreement with the literature data.7c
(Z)-1-Phenylhexadec-2-yn-1-one O-Methyl Oxime (2b). Puri-
fication by flash column chromatography (10:1 hexanes/EtOAc). This
compound was obtained as a light yellow oil in a 74% yield: 1H NMR
(500 MHz, CDCl3) δ 7.84−7.86 (m, 2H), 7.37−7.39 (m, 3H), 4.09 (s,
3H), 2.55 (t, J = 7.1 Hz, 2H), 1.65−1.70 (m, 2H), 1.45−1.49 (m, 2H),
1.22−1.35 (m, 18H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 140.4, 134.1, 129.7, 128.5, 126.7, 104.2, 71.6, 63.1, 32.1,
29.88, 29.86, 29.8, 29.7, 29.6, 29.3, 29.1, 28.5, 22.9, 20.0, 14.3; HRMS
(EI) calcd for C23H35NO, 341.2719, found 341.2721.
(Z)-1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-one O-Meth-
yl Oxime (2c). Purification by flash column chromatography (10:1
hexanes/EtOAc). The product was obtained as a colorless oil in a 66%
yield: 1H NMR (500 MHz, CDCl3) δ 7.61−7.63 (m, 2H), 7.52 (d, J =
7.7 Hz, 1H), 7.47−7.48 (m, 1H), 7.36−7.41 (m, 3H), 7.32 (t, J = 7.9
Hz, 1H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 4.15 (s, 3H), 3.86 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 159.8, 140.0, 135.1, 132.4, 129.8, 129.6,
128.7, 121.9, 119.4, 115.9, 111.6, 101.3, 79.6, 63.4, 55.5; HRMS (EI)
calcd for C17H15NO2, 265.1103, found 265.1105.
(E)-tert-Butyl 3-(3-(tert-Butyl)-5-phenylisoxazol-4-yl)acrylate
(4a). Purification by flash column chromatography (10:1 hexanes/
EtOAc). This compound was obtained as a white solid in a 95% yield:
1
mp 81−83 °C; H NMR (500 MHz, CDCl3) δ 7.62−7.66 (m, 3H),
7.43−7.45 (m, 3H), 5.98 (d, J = 16.1 Hz, 1H), 1.47 (s, 9H), 1.42 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 169.7, 167.8, 165.8, 133.1,
130.5, 129.1, 128.03, 128.00, 125.2, 110.2, 81.0, 33.4, 29.1, 28.3;
HRMS (EI) calcd for C20H25NO3, 327.1834, found 327.1836.
(E)-Ethyl 3-(3-(tert-Butyl)-5-phenylisoxazol-4-yl)acrylate
(4b). Purification by flash column chromatography (10:1 hexanes/
EtOAc). The product was obtained as a light yellow oil in an 86%
yield: 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 16.1 Hz, 1H), 7.63−
7.65 (m, 2H), 7.42−7.45 (m, 3H), 6.04 (d, J = 16.1 Hz, 1H), 4.30 (q, J
= 7.1 Hz, 2H), 1.42 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 169.7, 168.0, 166.4, 134.2, 130.5, 129.1, 128.0, 127.9,
123.6, 110.1, 60.8, 33.4, 29.1, 14.3; HRMS (EI) calcd for C18H21NO3,
299.1521, found 299.1523.
(Z)-1-(4-Methoxyphenyl)-4,4-dimethylpent-1-yn-3-one O-
Methyl Oxime (2d). Purification by flash column chromatography
(10:1 hexanes/EtOAc). The product was obtained as a light yellow oil
1
in a 75% yield: H NMR (500 MHz, CDCl3) δ 7.45−7.48 (m, 2H),
6.84−6.87 (m, 2H), 3.96 (s, 3H), 3.80 (s, 3H), 1.25 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 160.5, 149.5, 133.8, 114.2, 114.1, 100.9, 78.5,
62.4, 55.4, 37.1, 28.4; HRMS (EI) calcd for C15H19NO2, 245.1416,
found 245.1414.
(Z)-1-(4-Chlorophenyl)-3-(cyclohex-1-en-1-yl)prop-2-yn-1-
one O-Methyl Oxime (2e). Purification by flash column
chromatography (10:1 hexanes/EtOAc). This compound was
(E)-3-(3-(tert-Butyl)-5-phenylisoxazol-4-yl)acrylaldehyde
(4c). Purification by flash column chromatography (10:1 hexanes/
EtOAc). The product was obtained as a light yellow oil in a 72% yield:
1H NMR (500 MHz, CDCl3) δ 9.61 (d, J = 7.6 Hz, 1H), 7.60−7.62
(m, 2H), 7.53 (d, J = 16.1 Hz, 1H), 7.47−7.49 (m, 3H), 6.36 (dd, J =
16.1, 7.6 Hz, 1H), 1.47 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
193.4, 169.4, 169.3, 142.1, 132.5, 131.0, 129.3, 128.3, 127.6, 110.1,
33.4, 29.2; HRMS (EI) calcd for C16H17NO2, 255.1259, found
255.1255.
1
obtained as a beige solid in a 37% yield: mp 47−48 °C; H NMR
(500 MHz, CDCl3) δ 7.76−7.79 (m, 2H), 7.32−7.35 (m, 2H), 6.39−
6.41 (m, 1H), 4.09 (s, 3H), 2.25−2.28 (m, 2H), 2.16−2.19 (m, 2H),
1.67−1.72 (m, 2H), 1.60−1.65 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 139.3, 139.1, 135.6, 132.5, 128.7, 127.9, 120.0, 104.0, 76.9,
63.3, 29.0, 26.1, 22.3, 21.5; HRMS (EI) calcd for C16H16ClNO,
273.0920, found 273.0920.
(E)-4-(3-Phenyl-5-tridecylisoxazol-4-yl)but-3-en-2-one (4d).
Purification by flash column chromatography (10:1 hexanes/EtOAc).
This compound was obtained as a yellow oil in an 81% yield: 1H NMR
(500 MHz, CDCl3) δ 7.53−7.55 (m, 2H), 7.47−7.50 (m, 3H), 7.31
(d, J = 16.4 Hz, 1H), 6.29 (d, J = 16.4 Hz, 1H), 2.91 (t, J = 7.7 Hz,
2H), 2.24 (s, 3H), 1.76−1.82 (m, 2H), 1.37−1.42 (m, 2H), 1.32−1.36
(m, 2H), 1.25−1.30 (m, 16H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 197.8, 173.9, 162.1, 131.4, 130.2, 129.1, 128.9,
128.7, 128.6, 110.4, 32.1, 29.83, 29.80, 29.76, 29.6, 29.5, 29.44, 29.39,
28.0, 27.4, 26.9, 22.9, 14.3; HRMS (EI) calcd for C26H37NO2,
395.2824, found 395.2826.
(Z)-1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-one O-Meth-
yl Oxime (2f). Purification by flash column chromatography (10:1
hexanes/EtOAc). This compound was obtained as a light yellow solid
in a 50% yield: mp 63−65 °C; 1H NMR (500 MHz, CDCl3) δ 7.88−
7.91 (m, 2H), 7.63−7.66 (m, 2H), 7.37−7.43 (m, 3H), 6.93−6.96 (m,
1
2H), 4.14 (s, 3H), 3.84 (s, 3H). The H NMR spectral data are in
good agreement with the literature data.20
(Z)-1,3-Diphenylprop-2-yn-1-one O-Methyl Oxime (2g).
Purification by flash column chromatography (10:1 hexanes/EtOAc).
1
This compound was obtained as a colorless oil in a 67% yield: H
NMR (500 MHz, CDCl3) δ 7.92−7.93 (m, 2H), 7.63(d, J = 7.6 Hz,
3631
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The Journal of Organic Chemistry
Note
(E)-3-(3-(3-Methoxyphenyl)-5-phenylisoxazol-4-yl)-
acrylaldehyde (4e). Purification by flash column chromatography
(10:1 hexanes/EtOAc). This compound was obtained as a beige solid
in an 80% yield: mp 108−110 °C; H NMR (500 MHz, CDCl3) δ
(d, J = 1.5 Hz, 3H), 1.39 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
168.9, 166.3, 164.3, 149.4, 130.1, 129.1, 127.8, 126.5, 124.3, 117.0,
51.6, 33.9, 29.7, 21.6; HRMS (EI) calcd for C18H21NO3, 299.1521,
found 299.1526.
1
9.53 (d, J = 7.7 Hz, 1H), 7.72−7.74 (m, 2H), 7.56−7.58 (m, 3H),
7.40−7.47 (m, 2H), 7.09−7.13 (m, 2H), 7.05−7.07 (m, 1H), 6.28 (q, J
= 16.3, 7.6 Hz, 1H), 3.84 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
193.6, 170.3, 162.4, 160.0, 140.4, 131.5, 131.2, 130.4, 129.49, 129.46,
128.4, 126.9, 121.2, 116.2, 114.4, 110.7, 55.5; HRMS (EI) calcd for
C19H15NO3, 305.1052, found 305.1053.
(E)-Methyl 3-(3-(tert-Butyl)-5-(4-methoxyphenyl)isoxazol-4-
yl)acrylate (4f). Purification by flash column chromatography (10:1
hexanes/EtOAc). This compound was obtained as a light yellow oil in
a 97% yield: 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 16.1 Hz, 1H),
7.57 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.07 (d, J = 16.3 Hz,
1H), 3.82 (s, 3H), 3.73 (s, 3H), 1.40 (s, 9 H); 13C NMR (125 MHz,
CDCl3) δ 169.6, 168.3, 167.0, 161.3, 134.8, 129.6, 122.5, 120.1, 114.5,
109.1, 55.5, 51.9, 33.3, 29.1; HRMS (EI) calcd for C18H21NO4,
315.1471, found 315.1473.
(E)-4-(3-(4-Chlorophenyl)-5-(cyclohex-1-en-1-yl)isoxazol-4-
yl)but-3-en-2-one (4g). Purification by flash column chromatog-
raphy (10:1 hexanes/EtOAc). This compound was obtained as a light
yellow oil in an 86% yield: 1H NMR (500 MHz, CDCl3) δ 7.47−7.48
(m, 4H), 7.44 (d, J = 16.4 Hz, 1H), 6.36−6.38 (m, 1H), 6.15 (d, J =
16.4 Hz, 1H), 2.46−2.49 (m, 2H), 2.29−2.33 (m, 2H), 2.21 (s, 3H),
1.78−1.83 (m, 2H), 1.70−1.75 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 197.7, 172.3, 161.0, 136.4, 136.2, 131.4, 130.4, 129.4, 129.2,
127.5, 126.7, 109.4, 28.5, 26.13, 26.12, 22.2, 21.6; HRMS (EI) calcd
for C19H18ClNO2, 327.1026, found 327.1029.
(E)-4-(3-(4-Methoxyphenyl)-5-phenylisoxazol-4-yl)but-3-en-
2-one (4h). Purification by flash column chromatography (5:1
hexanes/EtOAc). This compound was obtained as a light yellow
solid in a 77% yield: mp 120−121 °C; 1H NMR (500 MHz, CDCl3) δ
7.69−7.71 (m, 2H), 7.49−7.53 (m, 6H), 6.99−7.02 (m, 2H), 6.32 (d, J
= 16.4 Hz, 1H), 3.85 (s, 3H), 2.20 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 197.7, 169.6, 162.2, 161.1, 131.2, 131.0, 130.3, 129.9, 129.3,
128.2, 127.3, 120.7, 114.5, 110.5, 55.5, 28.2; HRMS (EI) calcd for
C20H17NO3, 319.1208, found 319.1210.
(E)-3-(3-(4-Cyanophenyl)-5-phenylisoxazol-4-yl)-N,N-dime-
thylacrylamide (4m). Purification by flash column chromatography
(10:1 hexanes/EtOAc). This product was obtained as a yellow solid in
a 90% yield: mp 146−148 °C; H NMR (500 MHz, CDCl3) δ 7.75−
1
7.81 (m, 6H), 7.66 (d, J = 15.4 Hz, 1H), 7.52−7.53 (m, 3H), 6.37 (d, J
= 15.4 Hz, 1H), 2.99 (s, 3H), 2.76 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.1, 165.7, 160.9, 133.9, 132.8, 131.2, 129.9, 129.44,
129.39, 128.1, 127.1, 122.7, 118.3, 113.9, 111.1, 37.1, 36.0; HRMS
(EI) calcd for C21H17N3O2, 343.1321, found 343.1323.
(E)-3-(3,5-Diphenylisoxazol-4-yl)-1-morpholinoprop-2-en-1-
one (4n). Purification by flash column chromatography (10:1
hexanes/EtOAc). This compound was obtained as a yellow solid in
an 81% yield: mp 135−136 °C; 1H NMR (500 MHz, CDCl3) δ 7.77−
7.79 (m, 2H), 7.71 (d, J = 15.6 Hz, 1H), 7.60−7.62 (m, 2H), 7.50−
7.54 (m, 6H), 6.28 (d, J = 15.6 Hz, 1H), 3.64−3.66 (m, 4H), 3.45−
3.52 (m, 2H), 3.03−3.07 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
168.6, 164.7, 162.4, 130.9, 130.5, 129.9, 129.3, 129.2, 129.1, 129.0,
128.1, 127.3, 120.7, 111.2, 66.8, 66.6, 45.8, 42.5; HRMS (EI) calcd for
C22H20N2O3, 360.1474, found 360.1480.
tert-Butyl 3-Phenylnaphtho[1,2-c]isoxazole-5-carboxylate
(5). Purification by flash column chromatography (10:1 hexanes/
EtOAc). This product was obtained as a yellow solid in a 58% yield:
mp 110−112 °C; 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 7.9 Hz,
1H), 8.59 (d, J = 7.9 Hz, 1H), 8.27 (s, 1H), 8.04 (d, J = 7.6 Hz, 2H),
7.69−7.72 (m, 1H), 7.59−7.66 (m, 3H), 7.53−7.56 (m, 1H), 1.70 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 166.7, 166.2, 157.1, 131.0,
130.9, 130.2, 129.62, 129.59, 128.2, 128.0, 127.4, 127.2, 124.4, 123.1,
122.7, 110.9, 82.5, 28.5; HRMS (EI) calcd for C22H19NO3, 345.1365,
found 345.1365.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra, ORTEP drawing of 5, and
X-ray data for 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
(E)-3-(tert-Butyl)-5-phenyl-4-styrylisoxazole (4i). Purification
by flash column chromatography (10:1 hexanes/EtOAc). This
compound was obtained as a white solid in a 72% yield: mp 125−
AUTHOR INFORMATION
Corresponding Author
*E-mail: yu.chen1@qc.cuny.edu.
1
127 °C; H NMR (500 MHz, CDCl3) δ 7.81−7.83 (m, 2H), 7.36−
■
7.43 (m, 7H), 7.29−7.33 (m, 1H), 6.99 (d, J = 16.4 Hz, 1H), 6.67 (d, J
= 16.4 Hz, 1H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 170.1,
165.5, 136.9, 135.8, 129.8, 129.0, 128.9, 128.7, 128.3, 127.6, 126.5,
117.7, 112.4, 33.5, 29.2; HRMS (EI) calcd for C21H21NO, 303.1623;
found 303.1625.
Notes
The authors declare no competing financial interest.
3,5-Diphenyl-4-vinylisoxazole (4j). Purification by flash column
ACKNOWLEDGMENTS
chromatography (10:1 hexanes/EtOAc). This compound was
■
1
obtained as a white solid in a 52% yield: mp 66−67 °C; H NMR
The work was supported by Queens College, City University of
New York. We thank Dr. Cliff Soll at Hunter College for
recording the mass spectra. We also thank Prof. Robert Bittman
for helpful discussions. This work is dedicated to Prof. Richard
Larock on the occasion of his retirement.
(500 MHz, CDCl3) δ 7.80−7.82 (m, 2H), 7.67−7.69 (m, 2H), 7.45−
7.52 (m, 6H), 6.65 (dd, J = 17.8, 6.5 Hz, 1H), 5.36 (dd, J = 7.8, 1.4 Hz,
1H), 5.33 (dd, J = 14.2, 1.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
166.0, 162.4, 130.2, 129.7, 129.5, 129.01, 129.00, 128.8, 128.2, 127.7,
124.8, 120.6, 112.8; HRMS (EI) calcd for C17H13NO, 247.0997, found
247.0998.
REFERENCES
4-(1-Ethoxyvinyl)-3,5-diphenylisoxazole (4k). Purification by
flash column chromatography (20:1 hexanes/EtOAc). This product
was obtained as a white solid in a 43% yield: mp 61−62 °C; 1H NMR
(500 MHz, CDCl3) δ 7.88−7.90 (m, 2H), 7.77−7.79 (m, 2H), 7.43−
7.48 (m, 6H), 4.46 (d, J = 2.4 Hz, 1H), 4.28 (d, J = 2.4 Hz, 1H), 3.92
(q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 167.1, 162.3, 151.9, 130.3, 129.8, 129.3, 128.8, 128.6, 128.3,
127.8, 127.2, 112.4, 90.3, 63.8, 14.5; HRMS (EI) calcd for C19H17NO2,
291.1259, found 291.1264.
■
(1) Daidone, G.; Raffa, D.; Maggio, B.; Plescia, F.; Cutuli, V. M. C.;
Mangano, N. G.; Caruso, A. Arch. Pharm. 1999, 332, 50.
(2) Giovannoni, M. P.; Vergelli, C.; Ghelardini, C.; Galeotti, N.;
Bartolini, A.; Dal Piaz, V. J. Med. Chem. 2003, 46, 1055.
(3) Li, W.-T.; Hwang, D.-R.; Chen, C.-P.; Shen, C.-W.; Huang, C.-L.;
Chen, T.-W.; Lin, C.-H.; Chang, Y.-L.; Chang, Y.-Y.; Lo, Y.-K.; Tseng,
H.-Y.; Lin, C.-C.; Song, J.-S.; Chen, H.-C.; Chen, S.-J.; Wu, S.-H.;
Chen, C.-T. J. Med. Chem. 2003, 46, 1706.
(4) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug Discovery Dev. 2005,
8, 723.
(5) For recent examples, see: (a) Gayon, E.; Quinonero, O.;
Lemouzy, S.; Vrancken, E.; Campagne, J.-M. Org. Lett. 2011, 13, 6418.
(b) Dissanayake, A. A.; Odom, A. L. Tetrahedron 2012, 68, 807.
(E)-Methyl 3-(3-(tert-Butyl)-5-phenylisoxazol-4-yl)but-2-
enoate (4l). Purification by flash column chromatography (10:1
hexanes/EtOAc). This product was obtained as a white solid in a 42%
1
yield: mp 78−79 °C; H NMR (500 MHz, CDCl3) δ 7.67−7.69 (m,
2H), 7.39−7.43 (m, 3H), 6.06 (q, J = 1.4 Hz, 1H), 3.77 (s, 3H), 2.42
3632
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Note
(6) For examples of alkynes, see: (a) Himo, F.; Lovell, T.; Hilgraf, R.;
Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am.
Chem. Soc. 2005, 127, 210. (b) Hansen, T. V.; Wu, P.; Fokin, V. V. J.
Org. Chem. 2005, 70, 7761. (c) Denmark, S. E.; Kallemeyn, J. M. J.
Org. Chem. 2005, 70, 2839. (d) Grecian, S.; Fokin, V. V. Angew. Chem.,
Int. Ed. 2008, 47, 8285. (e) Willy, B.; Rominger, F.; Mueller, T. J. J.
Synthesis 2008, 293. (f) Crossley, J. A.; Browne, D. L. J. Org. Chem.
2010, 75, 5414. For examples of alkenes, see: (g) Di Nunno, L.;
Vitale, P.; Scilimati, A.; Tacconelli, S.; Patrignani, P. J. Med. Chem.
2004, 47, 4881. (h) Di Nunno, L.; Scilimati, A.; Vitale, P. Tetrahedron
2005, 61, 11270. (i) Xu, J.; Hamme, A. T. Synlett 2008, 919.
(7) (a) Maeda, K.; Hosokawa, T.; Murahashi, S.; Moritani, I.
Tetrahedron Lett. 1973, 5075. (b) Hosokawa, T.; Shimo, N.; Maeda,
K.; Sonoda, A.; Murahashi, S. Tetrahedron Lett. 1976, 383. (c) Waldo,
J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203. (d) Waldo, J. P.; Larock, R.
C. J. Org. Chem. 2007, 72, 9643. (e) Wang, K.; Xiang, D.; Liu, J.; Pan,
W.; Dong, D. Org. Lett. 2008, 10, 1691. (f) Praveen, C.;
Kalyanasundaram, A.; Perumal, P. T. Synlett 2010, 777.
(8) (a) Linderman, R. J.; Kirollos, K. S. Tetrahedron Lett. 1989, 30,
2049. (b) Cuadrado, P.; Gonzalez-Nogal, A. M.; Valero, R. Tetrahedron
2002, 58, 4975. (c) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. Org. Lett.
2009, 11, 3982. (d) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. J. Org.
Chem. 2010, 75, 1961.
(9) (a) Rossi, R.; Bellina, F.; Lessi, M. Synthesis 2010, 4131.
(b) Bishara, A.; Rudi, A.; Aknin, M.; Neumann, D.; Ben-Califa, N.;
Kashman, Y. Org. Lett. 2008, 10, 4307. (c) Fakhfakh, M. A; Fournet,
A.; Prina, E.; Mouscadet, J.-F.; Franck, X.; Hocquemiller, R.; Figadere,
B. Bioorg. Med. Chem. 2003, 11, 5013.
(10) (a) Yasuhara, A.; Takeda, Y.; Suzuki, N.; Sakamoto, T. Chem.
Pharm. Bull. 2002, 50, 235. (b) Huang, Q.; Larock, R. C. J. Org. Chem.
2003, 68, 980. (c) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (d) Besselievre, F.;
Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett. 2008, 10,
4029. (e) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc.
2009, 131, 13888.
(11) Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth. Catal. 2011, 353,
809.
(12) (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977,
777. (b) Alonso, D. A.; Najera, C.; Pacheco, M. C. J. Org. Chem. 2004,
69, 1615.
(13) The following oxidants were investigated in our initial studies of
the cyclization of O-methyl oxime 2a, including CuCl2, FeCl3, and 1,4-
benzoquinone. A 67% yield of 3a was obtained in the presence of 10
mol % of PdCl2 and 2 equiv of CuCl2. A 56% yield of 3a was obtained
in the presence of 10 mol % of PdCl2 and 2 equiv of FeCl3. A 5% yield
of 3a was obtained in the presence of 10 mol % of PdCl2 and 2 equiv
of 1,4-benzoquinone.
(14) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(15) (a) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Synlett 2002, 439.
(b) Battistuzzi, G.; Cacchi, S.; De Salve, I.; Fabrizi, G.; Parisi, L. M.
Adv. Synth. Catal. 2005, 347, 308.
(16) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(17) Huebner, V. D.; Lin, X.; James, I.; Chen, L.; Desai, M.; Moore, J.
C.; Krywult, B.; Navaratnam, T.; Singh, R.; Trainor, R.; Wang, L. PCT
Int. Appl. 2000, WO 2000008001 A1 20000217.
(18) Park, A.; Park, K.; Kim, Y.; Lee, S. Org. Lett. 2011, 13, 944.
(19) Zhao, T.; Xu, B. Org. Lett. 2010, 12, 212.
(20) Tsuritani, T.; Yagi, K.; Shinokubo, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2003, 42, 5613.
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