Complementary regioselective synthesis of 3,5-disubstituted isoxazoles from ynones

Article abstract of DOI:10.1016/j.tet.2018.09.043

Two regioselective synthetic routes towards 3,5-disubstituted isoxazoles from ynones are reported. One route takes place via first converting the ynones to ynone O-methyl oximes, followed by a palladium-catalyzed intramolecular cyclization. The other invo

Full text of DOI:10.1016/j.tet.2018.09.043

Accepted Manuscript
Complementary regioselective synthesis of 3,5-disubstituted isoxazoles from ynones
Xiaochen Liu, Dongsub Hong, Zhigang She, William H. Hersh, Barney Yoo, Yu Chen
PII:
S0040-4020(18)31139-6
10.1016/j.tet.2018.09.043
TET 29815
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 July 2018
Revised Date: 19 September 2018
Accepted Date: 21 September 2018
Please cite this article as: Liu X, Hong D, She Z, Hersh WH, Yoo B, Chen Y, Complementary
regioselective synthesis of 3,5-disubstituted isoxazoles from ynones, Tetrahedron (2018), doi: https://
doi.org/10.1016/j.tet.2018.09.043.
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Complementary regioselective synthesis of 3,5-
disubstituted isoxazoles from ynones
Xiaochen Liua, b, Dongsub Honga , Zhigang Shea , William H. Hersha, b , Barney Yooc and Yu Chen*a,b
aDepartment of Chemistry and Biochemistry, Queens College of the City University of New York, 65-30 Kissena Blvd.,
Queens, New York 11367, United States
bPh.D. Program in Chemistry, The Graduate Center of the City University of New York, 365 Fifth Ave., New York, New
York 10016, United States
cDepartment of Chemistry, Hunter College of the City University of New York, 695 Park Avenue, New York, New York
10065, United States

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Complementary regioselective synthesis of 3,5-disubstituted isoxazoles from ynones
Xiaochen Liua, b, Dongsub Honga , Zhigang Shea , William H. Hersha, b , Barney Yooc and Yu Chen*a,b
aDepartment of Chemistry and Biochemistry, Queens College of the City University of New York, 65-30 Kissena Blvd., Queens, New York 11367, United States
bPh.D. Program in Chemistry, The Graduate Center of the City University of New York, 365 Fifth Ave., New York, New York 10016, United States
cDepartment of Chemistry, Hunter College of the City University of New York, 695 Park Avenue, New York, New York 10065, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved
.
Two regioselective synthetic routes towards 3,5-disubstituted isoxazoles from ynones are
reported. One route takes place via first converting the ynones to ynone O-methyl oximes,
followed by a palladium-catalyzed intramolecular cyclization. The other involves the formation
Available online
of 5-hydroxy-4,5-dihydroisoxazoles by
a
cyclocondensation between ynones and
hydroxylamine, and subsequent acid mediated dehydration. The two routes are not only both
highly regioselective, but also complementary to each other as a pair of regioisomeric 3,5-
disubstituted isoxazoles are readily prepared from one single ynone substrate. The efficiency of
the two routes are further evaluated and demonstrated in the synthesis of three representative
3,5-disubstituted isoxazoles.
Keywords:
Keyword_1 isoxazoles
Keyword_2 complementary regioselectivity
Keyword_3 ynones
Keyword_4 5-hydroxy-4,5-dihydroisoxazoles
Keyword_5 intramolecular cyclization
Introduction
pair of regioisomeric 3,5-disubstituted isoxazoles from a single
ynone substrate when employing the following two
Isoxazoles are one of the most prominent classes of
heterocycles. They are key components of many pharmaceuticals
as well as biologically interesting compounds.1 In addition,
isoxazoles are known as masked 1,3-dicarbonyl synthons, and
their relatively labile N-O bond can be readily cleaved, forming
1,3-dicarbonyl equivalents such as β-amino enones.2 A variety of
protocols have been developed for the synthesis of isoxazoles,
including [3+2] cycloaddition reactions of alkenes/alkynes with
nitrile oxides and cyclocondensation between α,β-unsaturated
carbonyl compounds and hydroxylamine.2,3 These synthetic
methods all have their own advantages in terms of matters such
as catalyst cost, substrate scope, regioselectivity and operational
simplicity. Some of these methods are complementary to one
another, providing more options to chemists if their synthetic
target is restrained by the limitation of one particular method.
complementary synthetic protocols: 1) converting the ynone (1)
to ynone O-methyl oxime (2), followed by a palladium-catalyzed
cyclization (Scheme 1, path a); 2) treating ynone (1) with
hydroxylamine to form 5-hydroxy-4,5-dihydroisoxazole (4),
followed by an acid mediated dehydration (Scheme 1, path b).
We believe the current synthetic strategy is attractive, as
examples of synthesis of regioisomeric isoxazoles from a single
starting material via two mechanistically different synthetic
routes are still scarce. We herein report the details of the work,
including the synthetic protocol development, substrate scope
investigation and comparison of the efficiency of the two routes.
Results and discussion
We first chose palladium-catalyzed cyclization of ynone-O-
methyl oximes to construct isoxazole rings, based on the
following reasons: 1) operational simplicity, especially because
the starting material ynones were usually readily prepared by a
simple Sonogashira coupling between an acid chloride and
Our group has been interested in developing new synthetic
methods towards isoxazoles4 and employing isoxazoles as
synthetic intermediates in construction of more complex
heterocycles.5 During the course of synthesizing trisubstituted
isoxazoles by a palladium-catalyzed cascade reaction,4 we
noticed that we could selectively prepare either regioisomer of a

2
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 1. Regioselective Synthesis of 3,5-Disubstituted Isoxazoles from Ynones.
a terminal alkyne, and 2) the possibility of employing the direct
cyclization product, an isoxazolylpalladium species, straight into
a subsequent reaction step without terminating an on-going
cascade process. The latter is particularly useful in preparing
trisubstituted isoxazoles and more complex heterocycles. During
the course of exploring new synthetic protocols for trisubstituted
isoxazoles via palladium-catalyzed electrophilic cyclization of
ynone O-methyl oximes,4 we noticed that 3,5-disubstituted
isoxazoles formed as the major product in the presence of proton
sources such as a protic acid.
For example, in the presence of 10 mol% of PdCl2, 2
equivalents of CuCl2, and 2 equivalents of acetic acid, cyclization
of ynone O-methyl oxime 2a was completed in DMF at 150 °C
within 2 hours, yielding isoxazole 3a in 65% yield (Table 1,
entry 1). The yield of 3a was enhanced to 77%, when PdCl2 was
replaced by Pd(O2CCF3)2 (Table 1, entry 2). A quick solvent
screening showed that the chemical yield of the cyclized product
was further increased to 96% in DMSO (Table 1, entry 3). A
slight decrease of the yield to 92% was observed, when the
amount of CuCl2 was reduced to 1 equivalent (Table 1, entry 4).
On the other hand, in the absence of CuCl2, the chemical yield
dropped dramatically to 49%, and the starting material 2a was
recovered in 50% (Table 1, entry 5). Further study showed that
no 3a was obtained in the absence of any palladium catalyst, and
2a was fully recovered after 2 hours (Table 1, entry 6).
Table 1. Optimization of Reaction Conditions for the
Cyclization of Ynone O-Methyl Oxime 2a.a
We then examined the substrate scope of the palladium-
catalyzed cyclization reaction, using the conditions listed in
Entry 4 in Table 1. Both aliphatic (alkyl and alkenyl) and
aromatic (aryl and heteroaryl) substituents are well
accommodated at either the proximal (R1 group) or the distal (R2
group) position to the ynone O-methyl oxime (2) carbon. In
addition, both an electron-donating group such as methoxy
(MeO) and an electron-withdrawing group such as methyl ester
(CO2Me) are tolerated in the reaction (Table 2, 3b and 3c). Steric
effects, however, play a significant role in this cyclization
reaction. While the cyclization products formed in high yields
when a sterically hindered tertiary alkyl or phenyl group was
present proximal to the oxime carbon (as the R1 group) (3a-c, 3e,
Table 2), moderate yields were generally observed when a
sterically less hindered secondary alkyl or thienyl group was
present at the same position (3f, 3g, and 3q, Table 2). The lower
chemical yields obtained in the latter cases resulted from the
intrinsic nature of this electrophilic cyclization protocol. It only
takes place on the oxime substrates where the O-methyl group is
cis to the ynone triple bond6 (these isomers are usually in the Z
configuration7 according to IUPAC nomenclature). We found
that the configuration of the oximes that we prepared was
dependent on the difference in steric bulk of the two groups
flanking the ynone carbonyl, giving a preference for the oxime
O-methyl group anti to the sterically bulkier substituent. For
instance, both the tertiary-butyl and phenyl groups (as R1)
together with an alkynyl (as R2) gave exclusive formation of the
desired Z isomer. On the other hand, when sterically less
hindered secondary alkyl groups and a thienyl group were present
at the same position (as R1) in ynone 1, the stereoselectivity in
the oxime formation step dramatically decreased, leading to the
formation of a pair of inseparable E/Z isomers. The lower yields
observed in the palladium-catalyzed cyclization products 3f, 3g,
Entry
Pd Catalyst
(10 mol%)
PdCl2
CuCl2
Solvent
Yieldb
1
2eq
2eq
2eq
1eq
-
DMF
65%
77%
96%
92%
49%
-
2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
-
DMF
3
DMSO
DMSO
DMSO
DMSO
4
5c
6d
1eq
a
General procedure: The palladium catalyst (10 mol%),
CuCl2, substrate 2a (110.2 mg, 0.5 mmol), CH3CO2H (1.0 mmol,
2 equivalents), and solvent (4 mL) were added to a 20 mL glass
vial sealed with a pressure relief cap. The reaction mixture was
purged with argon, sealed, and stirred at 150 °C for 2 h. b Isolated
c
yields after column chromatography. Starting material 2a was
recovered in 50%. d Starting material 2a was fully recovered.

3
and 3q resulted from the contamination of the unreactive and
inseparable E-isomers generated together with the desired Z-
isomers in the oxime formation step.
The cyclocondensation protocol towards 3,5-disubstituted
ACCEPTED MANUSCRIPT
isoxazoles was first reported by Linderman’s group in the
preparation of trifluoromethyl substituted isoxazoles.8a It was
then employed by several other groups in syntheses of 3,5-
disubstituted isoxazoles and 5-hydroxy-4,5-dihydroisoxazoles.8b-f
The outcome of the cyclocondensation is often highly dependent
on the substrates and reaction conditions employed. For example,
Xie’s group reported that when the R1 group in ynone (1) is an
alkyl a complex mixture was obtained in the cyclocondensation.8c
Sydnes’s group found the cyclocondensation products of 1,1-
diethoxy-5-hydroxyalk-3-yn-2-ones were very stable and
resistant to dehydration to form isoxazoles even in acidic reaction
medium.8f Trofimov’s group observed an interesting
cyclocondensation with regioselectivity opposite to what was
reported by other groups.8d
Table 2. Palladium-Catalyzed Cyclization of Ynone O-Methyl
Oximes.a,b,c
Considering the aforementioned facts, we decided to
investigate the cyclocondensation with the ynone substrates
employed in our palladium-catalyzed cyclization protocol in
order to determine if we could develop a new complementary
synthetic route towards 3,5-disubstituted isoxazoles with the
same batch of ynones. We first treated ynone (1a) with NH2OH
(8 equivalents, 50 wt% aqueous solution) in several common
organic solvents such as DMSO, THF, CH3CN, NMP, MeOH,
and DMF (Table 3, Entries 1-6). The cyclocondensation took
place smoothly in these solvents at 50 °C, and the desired 5-
hydroxy-4,5-dihydroisoxazole 4a was obtained in good to
excellent yields. The highest yield was obtained in DMF (Table
3, Entry 6). When the reaction temperature was decreased to 25
°C, the reaction occurs at a slower rate with a slight decrease in
yield (Table 3, Entry 7). When the amount of NH2OH was
reduced to 4 equivalents, the yield dropped to 85% (Table 3,
Entry 8). We therefore chose the conditions listed in Entry 6 in
Table 3 as our optimal condition.
Table 3. Optimization of Reaction Conditions for
Cyclocondensation of Ynone (1a) and Hydroxylamine.a
a An oven dried 20 mL glass vial was charged with ynone O-
methyl oximes (0.50 mmol, 1.0 eq), Pd(CF3CO2)2 (16.6 mg, 0.05
mmol, 10 mol%), CuCl2 (67.2 mg, 0.50 mmol, 1.0 eq), acetic
acid (60.1 mg, 1.00 mmol, 2.0 eq) and dimethyl sulfoxide (4
b
mL). The reaction mixture was stirred at 150 °C for 2 h. The
chemical yields in the parentheses are isolated yields after
column chromatography. The chemical yields of products 3f,
3g, and 3q are calculated based on the weight of a mixture of the
E/Z isomers of the corresponding ynone O-methyl oximes.
Entry
Solvent
Time (h) Isolated
yieldb (%)
c
1
DMSO
THF
1 h
2 h
81
86
92
85
93
98
91
85
The disadvantage of the palladium-catalyzed ynone O-methyl
oxime cyclization protocol prompted us to explore alternative
synthetic methods for isoxazoles from ynone substrates. Previous
work showed that direct treatment of ynones with hydroxylamine
can lead to formation of 5-hydroxy-3,5-disubstituted-4,5-
dihydroisxazoles,8 which could be converted to isoxazoles upon
dehydration. It is worth noting this cyclocondensation reaction
can generate 3,5-disubstituted isoxazoles with the opposite
regioselectivity to what is observed in our palladium-catalyzed
cyclization protocol. Therefore, these two synthetic routes are
excellent complements to each other, as a pair of regioisomeric
3,5-disubstituted isoxazoles can be readily prepared from one
single ynone.
2
3
CH3CN
NMP
1 h
4
1.5 h
2 h
5
MeOH
DMF
6
1 h
7c
8d
DMF
2 h
DMF
1.5 h
a General procedure: A 20 mL glass vial was charged with ynone
(1a, 0.50 mmol), hydroxylamine (NH2OH, 50 wt% aqueous

4
Tetrahedron
ACCEPTED MANUSCRIPT
solution, 264.2 mg, 4.00 mmol), and solvent (4 mL). The
reaction mixture was stirred at 50 °C until the starting material 1a
Table 4. Preparation of 5-Hydroxy-4,5-dihydroisoxazoles (4)
is fully consumed. b Isolated yields after column chromatography.
from Ynones (1) and Hydroxylamine.a,b
c
d
Reaction was carried out at 25 °C. 4 equivalents of NH2OH
was added.
Under the optimized reaction condition, a variety of ynone
substrates were employed in the cyclocondensation (Table 3). A
broad range of substituents are compatible on the ynone (1)
substrates, including primary, secondary, and tertiary-alkyl,
alkenyl, aryl and heteroaryl groups. Both electron-donating and
electron-withdrawing groups are tolerated, though a lower yield
was observed in the presence of an electron-withdrawing methyl
ester group (CO2Me) (Table 4, 4c). We paid special attention to
those ynone substrates with a sterically less hindered primary-,
secondary-alkyl on the proximal side of the ynone carbonyl
group, as these substrates generally are considered challenging
since they form the E/Z isomers in the ynone O-methyl oxime
formation step. It turned out steric hindrance does not affect the
chemical yields and reaction rate, as both the sterically hindered
tertiary-alkyl (Table 4, 4a-e) and o-Br-phenyl (Table 4, 4r)
groups and sterically less hindered primary-, secondary-alkyl
(Table 4, 4f-h) and thienyl groups (Table 4, 4q) are all well
accommodated at the proximal position to the ynone carbonyl,
affording high yields of the cyclized products.
The regioselectivity outcome of the cyclocondensation has
been shown to depend on the acidity of the reaction medium. In
general, in either basic or neutral medium, 3,5-disubstituted 4,5-
dihydroisoxazoles form with the opposite regioselectivity to what
is observed in our palladium-catalyzed cyclization route. We
observed the same regioselectivity pattern in the
cyclocondensation as Linderman’s, Xie’s and Sydnes’s
groups.8a,c,f Our results showed the cyclocondensation between
ynones (1) and hydroxylamine is an excellent complementary
protocol to our palladium-catalyzed cyclization of ynone O-
methyl oximes (2) for the 3,5-disubstituted isoxazole synthesis.
N
O
MeO
HO
(97%)
4o
a
A 20 mL glass vial was charged with ynone (1, 0.50 mmol),
hydroxylamine (NH2OH, 50 wt% aq. Soln., 264.2 mg, 4.00
mmol), and DMF (4 mL). The reaction mixture was stirred at 50
b
°C for 2 h. The chemical yields in parentheses are isolated
c
yields after column chromatography. The reaction was carried
out at 100 °C for two hours.
Taking Sydnes’s results into account, we further examined the
dehydration reaction of our 5-hydroxy-4,5-dihydroisoxazoles. In
order to assess the efficiency of the two synthetic routes, we
selected to dehydrate the 4,5-dihydroisoxazoles 4j, 4k, and 4d, as
dehydration of these compounds will lead to the same isoxazole
products 3a, 3g, and 3q (listed in Table 2) synthesized by the

5
palladium-catalyzed cyclization protocol. In addition,
ACCEPTED MANUSCRIPT
dehydration of 4,5-dihydroisoxazoles 4f, 4h, 4r, 4s and 4t were
also carried out, as these substrates contain the representative
substituents such as primary- and secondary-alkyls, the sterically
hindered o-bromophenyl group, and an electron-deficient p-
nitrophenyl group. In the presence of 2 equivalents of H2SO4,
dehydration of the selected 5-hydroxy-4,5-dihydroisoxazoles all
took place smoothly at room temperature and afforded the
desired isoxazoles in moderate to excellent yields within 2 h,9
except 4t. No reaction occurred on 4t at room temperature, and
the dehydration product 3u was obtained only after 4t was heated
at 50 °C overnight.
a
A 20 mL glass vial was charged with 5-hydroxy-4,5-
Table 5. Preparation of 3,5-Disubstituted Isoxazoles (3) by
Acid Mediated Dehydration of 3,5-Disubstituted 5-Hydroxy-4,5-
dihydroisoxazoles (4).a,b
dihydroisoxazoles (4, 0.50 mmol), H2SO4 (98.0 mg, 1.00 mmol),
and DMF (4 mL). The reaction mixture was stirred at room
b
temperature for
2
h.
Isolated yields after column
chromatography. c The reaction was heated at 50 °C for 15 hours.
The efficiency of the two synthetic routes were briefly
evaluated based on the chemical yields obtained for isoxazoles
3a, 3g, and 3q via the two routes respectively (path a and path b,
Scheme 2). While 3a was prepared in similar overall chemical
yields via the two routes, isoxazoles 3g and 3q were synthesized
in much higher overall yields via the cyclocondensation-
dehydration route (path b, Scheme 2). The difference between the
two routes displayed in the synthesis of 3g and 3q mainly
resulted from the low stereoselectivity obtained for the ynone O-
methyl oximes 2g and 2q in the palladium-catalyzed cyclization
protocol.
Scheme 2. Efficiency Assessment of the Two Routes Based on the Synthesis of Isoxazoles 3a, 3g, and 3q.

6
Tetrahedron
hydroxyl group of HONH2 presumably plays a significant role in
ACCEPTED MANUSCRIPT
this step, so that the nucleophilic attack of HONH2 to the ynone
triple bond results in the formation of alkenes (7) with the
carbonyl and the hydroxyamino groups residing on the cis
position. An intramolecular cyclization of β-hydroxyamino
enone 7 leads to 2,5-dihydroisoxazole 8. Isomerization of 8 then
gives 2,5-dihydroisoxazole 4 (Scheme 4).
One selected isoxazole 3a was successfully converted to 4-
iodoisoxazole 5a in 94% yield in the presence of NIS and
trifluoroacetic acid (Eq 1).10 Since the iodo group readily
participates in transition metal catalyzed coupling reactions, the
success of iodination of 3,5-disubstituted isoxazoles will enhance
the possibility of further functionalizing the isoxazole framework
and enrich the chemistry.
Scheme 4. Proposed Mechanism of Cyclocondensation
between Ynones and Hydroxylamine
H
B
H
O
N
H
O
B
O
H
H
O
NH
R2
B
R1
R2
R1
1
H
7
B
H
N
N
O
O
R2
R2
R1
R1
HO
HO
8
4
B = H2O or NH2OH
The palladium-catalyzed protocol presumably takes place
from a 5-endo-dig cyclization of ynone oxime (2) to form the
isoxazolylpalladium intermediate 6, which forms isoxazole (3)
upon subsequent demethylation and depalladation-protonation
(Scheme 3). While CuCl2 does not directly participate in the Pd-
mediated catalytic cycle, it helps to maintain the concentration of
palladium (II) catalyst in the reaction mixture by oxidizing Pd(0)
species back to Pd(II) species upon any reduction occurring. In
the absence of CuCl2, the cyclization of ynone O-methyl oximes
stops after about 50% of substrate conversion, with a precipitate
of palladium black particles.
Conclusion
Synthesis of 3,5-disubstituted isoxazoles from simple ynones
by two complementary highly regioselective routes is reported.
The efficiency of the two synthetic routes has been assessed in
the course of preparing three 3,5-disubstituted isoxazoles. While
the palladium-catalyzed cyclization protocol is more
advantageous in the sophisticated cascade synthesis of complex
molecules, the cyclocondensation-dehydration protocol proves to
be more competitive in the synthesis of simple 3,5-disubstituted
isoxazoles. The two routes provide synthetic chemists with
convenient options towards 3,5-disubstituted isoxazoles from one
single ynone substrate. Upon the availability of starting materials
and the special needs for the target isoxazole products, synthetic
chemists can choose either protocol to prepare their desired
isoxazoles. The success of iodination at the 4-position of a
sample 3,5-disubstituted isoxazole shows further extension and
potential application of the current methodology is promising.
Further research on employing the isoxazole synthon in cascade
synthesis is currently underway in our group and will be reported
in due course.
Scheme 3. Proposed Mechanism for Pd-catalyzed Cyclization
of Ynone O-Methyl Oximes.
Experimental section
General Information: All reactions were carried out in
sealed 20 mL glass reaction vials with pressure relief caps, unless
otherwise indicated. All commercially available chemicals were
used as received without further purification, unless otherwise
noted. Triethylamine, tetrahydrofuran (THF) and methanol were
dried by 4Å molecular sieves over 48 hours before use.
Molecular sieves (4Å) were activated at 200 °C at 0.5 mmHg for
a week before use. All 1H and 13C NMR spectra were recorded at
400 or 500 MHz and 100 or 125 MHz, respectively, using CDCl3
The cyclocondensation between ynones and hydroxylamine
probably takes place from the conjugate addition of
hydroxylamine to ynone (1) forming β-hydroxyamino enone 7.
Hydrogen bonding between the ynone carbonyl oxygen and the
1
or acetone-d6 as solvent. The chemical shifts of all H and 13C
NMR spectra are referenced to the residual signal of CDCl3 (δ
1
7.26 ppm for the H NMR spectra and δ 77.16 ppm for the 13C
NMR spectra) or acetone-d6 (δ 2.09 ppm for the 1H NMR spectra

7
and δ 30.60 ppm for the 13C NMR spectra). The high-resolution
mass analysis was carried out on high resolution mass
spectrometers using electrospray ionization (ESI) or heated
electrospray ionization (HESI) method. Samples were dissolved
in methylene chloride and methanol and analyzed via flow
injection into the mass spectrometer at a flow rate of 200 µL/min.
The mobile phase was 90:10 methanol:water, with 0.1% formic
acid. The melting points of the solid compounds are uncorrected.
This compound was obtained as a brown oil (480.3 mg, 97%
1
ACCEPTED MANUSCRIPT
yield): H NMR (400 MHz, CDCl3) δ 7.41-7.36 (m, 5H), 7.35-
7.28 (m, 5H), 1.65 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 191.2,
143.3, 133.1, 130.6, 128.7, 128.6, 127.2, 126.7, 120.2, 93.5, 86.7,
52.9, 25.1; HRMS (ESI) calcd for (C18H16O+H)+ [M+H]+
249.1274, found 249.1279.
4-methyl-1-phenylpent-1-yn-3-one (1f)
This compound was obtained as a brown oil (289.3 mg, 84%
yield): H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.7 Hz, 2H),
Preparation of Ynones (1).
1
7.44 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 6.9 Hz, 2H), 2.70-2.82 (m,
1
1H), 1.26 (d, J = 7.0 Hz, 6H). The H NMR spectral data are in
good agreement with the literature data.13
1-cyclopropyl-3-phenylprop-2-yn-1-one (1g)
This compound was obtained as a yellow oil (275.4 mg, 81%
1
General Procedure:11 An oven dried 20 mL glass vial was
charged with PdCl2(PPh3)2 (28.1 mg, 0.04 mmol), CuI (7.6 mg,
0.04 mmol), acid chloride (2.60 mmol), terminal alkyne (2.00
mmol) and anhydrous triethylamine (10 mL). The vial was
flushed with nitrogen and sealed with a pressure relief cap. The
reaction mixture was stirred at room temperature, overnight, until
the disappearance of starting material was observed, as monitored
by thin layer chromatography. The reaction mixture was diluted
with diethyl ether (40 mL) and washed with brine (40 mL). The
aqueous phase was then extracted with diethyl ether (2 × 20 mL).
The combined organic layers were dried over anhydrous MgSO4,
and concentrated using a rotary evaporator under reduced
pressure (20 mmHg). The resulting residue was purified by flash
column chromatography on silica gel (eluent: hexanes/ethyl
acetate).
yield): H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.8 Hz, 2H),
7.43 (t, J = 7.3 Hz, 1H), 7.36 (t, J = 7.0 Hz, 2H), 2.12-2.21 (m,
1H), 1.29-1.36 (m, 2H), 1.06-1.13 (m, 2H). The 1H NMR spectral
data are in good agreement with the literature data.14
1,3-diphenylprop-2-yn-1-one (1i)
This compound was obtained as a yellow oil (396.0 mg, 96%
1
yield): H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 7.7 Hz, 2H),
7.70 (d, J = 7.4 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.55-7.48 (m,
1
3H), 7.43 (t, J = 7.5 Hz, 2H). The H NMR spectral data are in
good agreement with the literature data.15
4,4-dimethyl-1-phenylpent-2-yn-1-one (1j)
This compound was obtained as a yellow oil (349.9 mg, 94%
1
yield): H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.9 Hz, 2H),
7.58 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 1.39 (s, 9H).
The 1H NMR spectral data are in good agreement with the
literature data.16
4,4-dimethyl-1-phenylpent-1-yn-3-one (1a)
This compound was obtained as a yellow oil (350.2 mg, 94%
1
yield): H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 7.6 Hz, 2H),
3-cyclopropyl-1-phenylprop-2-yn-1-one (1k)
7.44 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 1.28 (s, 9H).
The 1H NMR spectral data are in good agreement with the
literature data.12
This compound was obtained as a yellow oil (333.6 mg, 98%
1
yield): H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 5.2, 3.3 Hz,
2H), 7.62–7.56 (m, 1H), 7.46 (dd, J = 10.5, 4.8 Hz, 2H), 1.58-
1
1-(4-methoxyphenyl)-4,4-dimethylpent-1-yn-3-one (1b)
1.49 (m, 1H), 1.09-0.99 (m, 4H). The H NMR spectral data are
in good agreement with the literature data.17
1-phenyloct-2-yn-1-one (1l)
This compound was obtained as a yellow oil (276.5 mg, 64%
1
yield): H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.7 Hz, 2H),
6.88 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 1.27 (s, 9H). The 1H NMR
spectral data are in good agreement with the literature data.4
This compound was obtained as a red oil (394.0 mg, 99%
1
yield): H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 2H),
methyl 4-(4,4-dimethyl-3-oxopent-1-yn-1-yl)benzoate (1c)
7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 2.48 (t, J = 7.1
Hz, 2H), 1.64-1.73 (m, 2H), 1.41-1.51 (m, 2H), 1.32-1.41 (m,
Note: Only one equivalent of triethylamine (relative to the
terminal alkyne) was used and the reaction was carried out in
anhydrous THF (10 mL). This compound was obtained as a
white solid (288.3 mg, 59% yield): m.p. 68.9-70.7 °C; 1H NMR
(500 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.5
Hz, 2H), 3.94 (s, 3H), 1.28 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 194.1, 166.2, 132.8, 131.2, 129.7, 124.8, 90.5, 87.8, 52.6, 45.1,
26.1; HRMS (ESI) calcd for (C15H16O3+H)+ [M+H]+ 245.1172,
found 245.1178.
1
2H), 0.91 (t, J = 7.3 Hz, 3H). The H NMR spectral data are in
good agreement with the literature data.18
1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-one (1m)
This compound was obtained as an orange solid (472.5 mg,
1
99% yield): m.p. 85.6-86.6 °C; H NMR (500 MHz, CDCl3) δ
8.19 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.4
Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 3.91
1
(s, 3H). The H NMR spectral data are in good agreement with
the literature data.15
4,4-dimethyl-1-(thiophen-3-yl)pent-1-yn-3-one (1d)
This compound was obtained as a brown oil (200.0 mg, 52%
3-(cyclohex-1-en-1-yl)-1-(4-methoxyphenyl)prop-2-yn-1-one
(1n)
1
yield): H NMR (500 MHz, CDCl3) δ 7.48 (t, J = 4.4 Hz, 2H),
7.07 (t, J = 4.4 Hz, 1H), 1.27 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 194.1, 136.5, 131.5, 127.8, 120.1, 90.8, 86.3, 44.9,
26.3; HRMS (ESI) calcd for (C11H12OS+H)+ [M+H]+ 193.0682,
found 193.0685.
This compound was obtained as a brown oil (297.7 mg, 62%
1
yield): H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.8 Hz, 2H),
6.93 (d, J = 8.8 Hz, 2H), 6.52-6.57 (m, 1H), 3.88 (s, 3H), 2.23-
2.30 (m, 2H), 2.16-2.23 (m, 2H), 1.60-1.74 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 177.1, 164.4, 142.2, 132.0, 130.6, 119.4,
4-methyl-1,4-diphenylpent-1-yn-3-one (1e)

8
Tetrahedron
ACCEPTED MANUSCRIPT
113.9, 95.1, 85.3, 55.7, 28.6, 26.3, 22.1, 21.3; HRMS (ESI)
calcd for (C16H16O2+H)+ [M+H]+ 241.1223, found 241.1228.
1-(3-methoxyphenyl)-3-phenylprop-2-yn-1-one (1o)
This compound was obtained as a yellow solid (462.1 mg,
To
a
100-mL round-bottomed flask was added
phenylacetylene (1326.0 mg, 13.00 mmol) and anhydrous THF
(30 mL). The solution was cooled to −78 °C. n-Butyllithium (1.6
M in hexanes, 10.6 mL, 16.90 mmol, 1.3 equivalents) was added
dropwise to the stirred solution over 20 minutes. After the
addition, the mixture was stirred at −78 °C for another 30 min. A
solution of propionaldehyde (1160.0 mg, 20.00 mmol, 1.5
equivalents) in THF (5 mL) was added dropwise at −78 °C. After
the addition, the reaction mixture was stirred and gradually
warmed to room temperature overnight. The reaction mixture
was quenched with saturated aqueous NH4Cl solution and
extracted with diethyl ether (3 × 50 mL). The organic phases
were combined and dried over anhydrous Mg2SO4, and
concentrated using a rotary evaporator under reduced pressure
(20 mmHg). The residue was purified by column
chromatography on silica gel (eluent: hexanes/ethyl acetate) to
afford 1-phenylpent-1-yn-3-ol in 71% yield (1476.8 mg). The
1
98% yield): m.p. 51.0-51.6 °C; H NMR (400 MHz, CDCl3) δ
7.86 (d, J = 7.7 Hz, 1H), 7.66-7.72 (m, 3H), 7.39-7.53 (m, 4H),
7.17 (dd, J = 8.2, 2.7 Hz, 1H), 3.89 (s, 3H). The 1H NMR spectral
data are in good agreement with the literature data.19
1-(4-chlorophenyl)-3-phenylprop-2-yn-1-one (1p)
This compound was obtained as a brown solid (481.4 mg,
1
99% yield): m.p. 98.6-99.6 °C; H NMR (500 MHz, CDCl3) δ
8.15 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.3
1
Hz, 3H), 7.42 (t, J = 7.3 Hz, 2H). The H NMR spectral data are
in good agreement with the literature data.19
4,4-dimethyl-1-(thiophen-2-yl)pent-2-yn-1-one (1q)
This compound was obtained as a brown solid (379.2 mg,
1
99% yield): m.p. 53.4-54.2 °C; H NMR (400 MHz, CDCl3) δ
1
product was obtained as a yellow oil: H NMR (400 MHz,
7.86 (d, J = 3.8 Hz, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.13 (t, J = 4.1
Hz, 1H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.4,
145.2, 134.9, 128.3, 102.7, 77.9, 30.2, 28.1 (fewer 13C signals
were observed due to signal overlapping); HRMS (ESI) calcd for
(C11H12OS+H)+ [M+H]+193.0682, found 193.0686.
CDCl3) δ 7.44-7.42 (m, 2H), 7.32-7.30 (m, 3H), 4.55 (d, J = 6.02
Hz, 1H), 1.93 (d, J = 5.63 Hz, 1H), 1.87-1.79 (m, 2H), 1.08 (t, J
= 7.58 Hz, 3H). The 1H NMR spectral data are in good agreement
with the literature data.22
To a stirred solution of 1-phenylpent-1-yn-3-ol (640.0 mg,
4.00 mmol) in DCM (10 mL) was added Dess–Martin
periodinane (DMP) (2544.0 mg, 6.00 mmol) and NaHCO3
(1008.0 mg, 12.00 mmol). The reaction mixture was stirred at
room temperature for 2 h, then quenched by saturated aqueous
Na2S2O3 solution (15 mL), and extracted with DCM (3 × 30 mL).
The combined organic phases were washed with brine (20 mL),
dried over anhydrous Mg2SO4, and concentrated using a rotary
evaporator under reduced pressure (20 mmHg). The residue was
purified by column chromatography on silica gel (eluent:
hexanes/ethyl acetate). The product 1-phenylpent-1-yn-3-one was
1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1r)
This compound was obtained as a yellow oil (467.6 mg, 82%
1
yield): H NMR (500 MHz, CDCl3) δ 8.08 (dd, J = 7.7, 1.8 Hz,
1H), 7.71 (dd, J = 7.9, 1.1 Hz, 1H), 7.64-7.66 (m, 2H), 7.37-7.50
1
(m, 5H). The H NMR spectral data are in good agreement with
the literature data.4
3-(2-bromophenyl)-1-phenylprop-2-yn-1-one (1s)
This compound was obtained a yellow solid (490.4 mg, 86%
yield): mp 86.0-88.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.32-8.34
(m, 2H), 7.72 (dd, J = 7.6, 1.8 Hz, 1H), 7.68 (dd, J = 7.9, 1.2 Hz,
1H), 7.63-7.66 (m, 1H), 7.51-7.55 (m, 2H), 7.38 (td, J = 7.6, 1.4
1
obtained as a yellow oil (625.0 mg, 99% yield): H NMR (400
MHz, CDCl3) δ 7.58-7.56 (m, 2H), 7.47-7.43 (m, 1H), 7.40-7.36
(m, 2H), 2.70 (q, J = 8.0 Hz, 2H), 1.21 (t, J = 8.0 Hz, 3H). The
1H NMR spectral data are in good agreement with the literature
data.23
1
Hz, 1H), 7.34 (td, J = 7.7, 2.0 Hz, 1H). The H NMR spectral
data are in good agreement with the literature data.5
1-(4-nitrophenyl)-3-phenylprop-2-yn-1-one (1t)
This compound was obtained as a yellow solid (196.0 mg,
o
1
39% yield): m.p. 155.2-156.1 C; H NMR (500 MHz, CDCl3) δ
8.38 (s, 4H), 7.72 (d, J = 6.9 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H),
Preparation of Ynone O-Methyl Oximes (2).
1
7.47 (t, J = 7.7Hz, 2H). The H NMR spectral data are in good
agreement with the literature data.20
Preparation of 1-phenylpent-1-yn-3-one (1h)21
General Procedure:24 An oven-dried 20 mL glass vial was
charged with O-methylhydroxylamine hydrochloride (167.0 mg,
2.00 mmol), anhydrous Na2SO4 (284.0 mg, 2.00 mmol), pyridine
(0.5 mL), alkynone (1, 1.00 mmol), and anhydrous methanol (5
mL). The reaction vial was sealed with a pressure relief cap and
the mixture was stirred at room temperature overnight. Methanol
was removed by using a rotary evaporator under reduced pressure
(20 mmHg). The residue was diluted with diethyl ether (30 mL)
and washed with brine (30 mL). The aqueous phase was
extracted with diethyl ether (2 × 20 mL), and the combined
organic layers were dried over anhydrous MgSO4 and
concentrated using a rotary evaporator under reduced pressure
(20 mmHg). The residue was then purified by flash column
chromatography on silica gel (eluent: hexanes/ethyl acetate).

9
1
(Z)-4,4-dimethyl-1-phenylpent-1-yn-3-one O-methyl oxime
(2a)
4.15 (s, 3H). The H NMR spectral data are in good agreement
ACCEPTED MANUSCRIPT
with the literature data.25
This compound was obtained as a yellow oil (206.7 mg, 96%
(Z)-4,4-dimethyl-1-phenylpent-2-yn-1-one O-methyl oxime
(2j)
1
yield): H NMR (400 MHz, CDCl3) δ 7.50-7.55 (m, 2H), 7.31-
1
7.38 (m, 3H), 3.97 (s, 3H), 1.26 (s, 9H). The H NMR spectral
This compound was obtained as a colorless oil (204.5 mg,
data are in good agreement with the literature data.25
1
95% yield): H NMR (500 MHz, CDCl3) δ 7.81-7.86 (m, 2H),
1
(Z)-1-(4-methoxyphenyl)-4,4-dimethylpent-1-yn-3-one
methyl oxime (2b)
O-
7.35-7.39 (m, 3H), 4.08 (s, 3H), 1.39 (s, 9H). The H NMR
spectral data are in good agreement with the literature data.25
(Z)-1-phenyloct-2-yn-1-one O-methyl oxime (2l)
This compound was obtained as a colorless oil (191.3 mg,
1
78% yield): H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.6 Hz,
This compound was obtained as a yellow oil (110.1 mg, 48%
2H), 6.86 (d, J = 8.6 Hz, 2H), 3.96 (s, 3H), 3.82 (s, 3H), 1.25 (s,
1
yield): H NMR (500 MHz, CDCl3) δ 7.82-7.87 (m, 2H), 7.34-
1
9H). The H NMR spectral data are in good agreement with the
7.40 (m, 3H), 4.09 (s, 3H), 2.53 (t, J = 7.2 Hz, 2H), 1.64-1.72 (m,
2H), 1.42-1.50 (m, 2H), 1.33-1.42 (m, 2H), 0.93 (t, J = 7.4 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 140.3, 134.0, 129.6, 128.4,
126.6, 104.2, 71.6, 63.1, 31.2, 28.1, 22.3, 19.9, 14.1; HRMS
(ESI) calcd for (C15H19NO+H)+ [M+H]+ 230.1539, found
230.1544.
literature data.4
methyl
(Z)-4-(3-(methoxyimino)-4,4-dimethylpent-1-yn-1-
yl)benzoate (2c)
This compound was obtained as a yellow oil (262.4 mg, 96%
1
yield): H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 2H),
7.57 (d, J = 8.2 Hz, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 1.26 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 166.5, 148.9, 132.1, 130.5, 129.6,
126.8, 99.3, 82.0, 62.6, 52.5, 37.1, 28.3; HRMS (ESI) calcd for
(C16H19NO3+H)+ [M+H]+ 274.1438, found 274.1440.
(Z)-1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-one O-methyl
oxime (2m)
Benzene (1 mL) was added as a co-solvent. This compound
was obtained as a yellow solid (138.0 mg, 52% yield): m.p. 57.7-
1
(E)-4-methyl-1,4-diphenylpent-1-yn-3-one O-methyl oxime
58.4°C; H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.9 Hz, 2H),
(2e)
7.56-7.66 (m, 2H), 7.34-7.44 (m, 3H), 6.92 (d, J = 8.9, 2H), 4.12
(s, 3H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.0,
139.7, 132.3, 129.6, 128.6, 128.0, 126.4, 121.9, 113.9, 101.0,
79.7, 63.1, 55.5; HRMS (ESI) calcd for (C17H15NO2+H)+ [M+H]+
267.1208, found 267.1212.
This compound was obtained as a brown oil (116.5 mg, 42%
yield): H NMR (500 MHz, CDCl3) δ 7.43 (dd, J = 8.5, 1.5 Hz,
1
2H), 7.36 (t, J = 7.5 Hz, 2H), 7.32-7.24 (m, 6H), 4.07 (s, 3H),
1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 148.0, 146.3, 132.1,
129.3, 128.3, 128.3, 126.5, 126.4, 122.0, 100.8, 80.1, 62.7, 44.8,
27.5; HRMS (ESI) calcd for (C19H19NO+H)+ [M+H]+ 278.1539,
found 278.1545.
(Z)-3-(cyclohex-1-en-1-yl)-1-(4-methoxyphenyl) prop-2-yn-1-
one O-methyl oxime (2n)
This compound was obtained as a colorless oil (169.7 mg,
1
4-methyl-1-phenylpent-1-yn-3-one O-methyl oxime (2f)
63% yield): H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 9.0 Hz,
2H), 6.88 (d, J = 8.9 Hz, 2H), 6.37-6.40 (m, 1H), 4.07 (s, 3H),
3.82 (s, 3H), 2.25-2.30 (m, 2H), 2.19-2.14 (m, 2H), 1.72-1.66 (m,
2H), 1.66-1.59 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 160.8,
139.9, 138.6, 128.0, 126.5, 120.0, 113.8, 103.2, 77.3, 63.0, 55.4,
28.9, 26.0, 22.2, 21.4; HRMS (ESI) calcd for (C17H19NO2+H)+
[M+H]+ 270.1494, found 270.1494.
The compounds were obtained as a yellow oil (173.1 mg, 86%
yield), ratio of two isomers (Z:E = 3:1): H NMR (400 MHz,
1
CDCl3) δ 7.55-7.51 [m, 2H (Z) and m, 2H (E)], 7.38-7.28 [m, 3H
(Z); and m, 3H (E)], 3.97 [s, 3H (Z); and s, 3H (E)], 3.45-3.35
[m, 1H (E)], 2.77-2.70 [m, 1H (Z)], 1.23 [d, J = 6.9 Hz, 6H (Z)],
1.16 [d, J = 6.9 Hz, 6H (E)]; 13C NMR (100 MHz, CDCl3) δ
152.7 (E), 147.0 (Z), 132.2 (Z), 132.0 (E), 129.4 (Z), 129.0 (E),
128.4 (Z/E), 122.2 (E), 122.0 (Z), 100.3 (Z), 92.2 (E), 82.6
(E),79.0 (Z), 62.5 (E), 62.3 (Z), 33.5 (Z), 27.0 (E), 20.6 (Z), 19.6
(E); HRMS (ESI) calcd for (C13H15NO+H)+ [M+H]+ 202.1226,
found 202.1231.
(Z)-1-(3-methoxyphenyl)-3-phenylprop-2-yn-1-one O-methyl
oxime (2o)
This compound was obtained as a colorless oil (148.6 mg,
1
56% yield): H NMR (500 MHz, CDCl3) δ 7.61 (dd, J = 7.5, 1.5
Hz, 2H), 7.52 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 2.2 Hz, 1H), 7.35-
7.44 (m, 3H), 7.31 (t, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.2, 2.2 Hz,
1H), 4.15 (s, 3H), 3.86 (s, 3H). The 1H NMR spectral data are in
good agreement with the literature data.4
1-cyclopropyl-3-phenylprop-2-yn-1-one O-methyl oxime (2g)
The compounds were obtained as a yellow oil (181.3 mg, 91%
1
yield), ratio of two isomers (Z:E = 2:1): H NMR (500 MHz,
CDCl3) δ 7.51-7.48 [m, 2H, (Z); and 2H, (E)], 7.48-7.44 (m, 1H,
(Z); and 1H, (E)], 7.39-7.29 [m, 2H, (Z); and 2H, (E)], 4.00 [s,
3H, (E)], 3.97 [s, 3H, (Z)], 2.42 (s, 1H, (E)], 1.86 [ddd, J = 8.3,
4.9, 3.3 Hz, 1H, (Z)], 1.04-0.97 [m, 2H, (E)], 0.96-0.87 [m, 2H,
(E); and 2H, (Z)], 0.89-0.80 [m, 2H, (Z)]; 13C NMR (125 MHz,
4,4-dimethyl-1-(thiophen-2-yl)pent-2-yn-1-one
oxime (2q)
O-methyl
This compound was obtained as an orange oil (225.5 mg, 51%
1
yield), ratio of two isomers (E:Z = 2:1): H NMR (400 MHz,
CDCl3) δ 7.75 [dd, J = 3.8, 1.1 Hz, 1H (Z)], 7.53 [dd, J = 5.1, 1.1
Hz, 1H (Z)], 7.41 [dd, J = 3.6, 1.1 Hz, 1H (E)], 7.28 [dd, J = 5.1,
1.0 Hz, 1H (E)], 7.11 [dd, J = 5.0, 3.9 Hz, 1H (Z)], 7.03 [dd, J =
5.0, 3.7 Hz, 1H (E)], 4.14 [s, 3H (Z)], 4.05 [s, 3H (E)], 1.39 [s,
9H (E/Z)]; 13C NMR (100 MHz, CDCl3) δ 138.4 (E), 136.7 (Z),
136.1 (E), 134.9 (Z), 132.7 (Z), 132.2 (Z), 131.0 (E), 128.3 (E),
128.1 (Z), 127.03 (E), 127.01 (E), 125.8 (Z), 110.2 (E) , 100.4
(Z), 69.5 (Z), 63.0 (E), 30.7 (Z), 30.6 (E), 30.2 (E), 28.5 (Z);
HRMS (ESI) calcd for (C12H15NOS+H)+ [M+H]+ 222.0947,
found 222.0952.
CDCl3)
δ 149.73 (E), 144.57(Z), 132.30(Z), 132.11(E),
129.64(Z), 129.27(E), 128.54(Z), 121.84(E), 121.62(Z),
99.63(Z), 91.06(E), 80.85(E), 62.64(E), 62.51, 31.12(E),
14.27(Z), 9.35(E), 6.83(Z), 5.75(Z and E); HRMS (ESI) calcd for
(C13H13NO+H)+ [M+H]+200.1070, found 200.1075.
(Z)-1,3-diphenylprop-2-yn-1-one O-methyl oxime (2i)
This compound was obtained as a white solid (157.6 mg, 67%
yield): m.p. 43.1-44.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.95-
7.87 (m, 2H), 7.65-7.58 (m, 2H), 7.40 (dd, J = 7.3, 5.0 Hz, 6H),

10
Tetrahedron
Preparation of 3,5-Disubstituted Isoxazoles (3) by
This compound was obtained as an orange solid (45.4 mg,
ACCEPTED MANUSCRIPT
Palladium-Catalyzed Cyclization of Ynone O-Methyl Oximes
(2)
49% yield, from starting material 2g [Z/E=2:1]): m.p. 60.9-61.7
1
oC; H NMR (400 MHz, CDCl3) δ 7.71-7.74 (m, 2H), 7.38-7.45
(m, 3H), 6.17 (s, 1H), 2.01-2.06 (m, 1H), 1.03-1.08 (m, 2H),
0.85-0.89 (m, 2H). The 1H NMR spectral data are in good
agreement with the literature data.27
Gen
eral
Proced
3,5-diphenylisoxazole (3i)
ure:
An
This compound was obtained as a white solid (91.8 mg, 83%
yield): m.p. 102.0-103.9 °C; H NMR (400 MHz, CDCl3) δ 7.87
1
oven dried 20 mL glass vial was charged with ynone O-methyl
oximes (0.50 mmol), Pd(CF3CO2)2 (16.6 mg, 0.05 mmol, 0.1 eq),
CuCl2 (67.2 mg, 0.50 mmol, 1.0 eq), acetic acid (60.1 mg, 1.00
mmol, 2.0 eq) and dimethyl sulfoxide (4 mL). The reaction vial
was sealed with a pressure relief cap and the mixture was stirred
at 150 °C for 2 h. The reaction mixture was diluted with 20 mL
of diethyl ether and washed with brine (20 mL). The aqueous
phase was extracted with diethyl ether (2 × 15 mL). The
combined organic layers were dried over anhydrous MgSO4, and
concentrated using a rotary evaporator under reduced pressure
(20 mmHg). The subsequent residue was purified by flash
column chromatography on silica gel (eluent: hexanes/ethyl
acetate) to afford the corresponding cyclization product.
(ddd, J = 9.8, 6.9, 1.9 Hz, 4H), 7.54-7.40 (m, 6H), 6.84 (s, 1H).
The 1H NMR spectral data are in good agreement with the
literature data.28
5-(tert-butyl)-3-phenylisoxazole (3j)
This compound was obtained as a colorless oil (89.6 mg, 89%
1
yield): H NMR (400 MHz, CDCl3) δ 7.76-7.82 (m, 2H), 7.39-
7.48 (m, 3H), 6.25 (s, 1H), 1.40 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 181.9, 162.3, 129.9, 129.6, 129.0, 126.9, 96.6, 33.0,
29.0; HRMS (ESI) calcd for (C13H15NO+H)+ [M+H]+ 202.1226,
found 202.1228.
5-pentyl-3-phenylisoxazole (3l)
This compound was obtained as a yellow oil (78.6 mg, 73%
yield): H NMR (400 MHz, CDCl3) δ 7.82-7.73 (m, 2H), 7.52-
3-(tert-butyl)-5-phenylisoxazole (3a)
1
This compound was obtained as a yellow oil (92.6 mg, 92%
7.37 (m, 3H), 6.29 (s, 1H), 2.79 (t, J = 7.6 Hz, 2H), 1.75 (dd, J =
1
1
yield): H NMR (400 MHz, CDCl3) δ 7.78-7.81 (m 2H), 7.43-
9.9, 5.0 Hz, 2H), 1.45-1.29 (m, 4H), 0.97-0.85 (m, 3H). The H
1
7.45 (m, 3H), 6.25 (s, 1H), 1.40 (s, 9H). The H NMR spectral
NMR spectral data are in good agreement with the literature
data are in good agreement with the literature data.26
3-(tert-butyl)-5-(4-methoxyphenyl) isoxazole (3b)
This compound was obtained as a yellow solid (112.2 mg,
data.29
3-(4-methoxyphenyl)-5-phenylisoxazole (3m)
This compound was obtained as a white solid (113.1mg, 90%
yield): m.p. 172.4-173.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.89-
7.74 (m, 4H), 7.56-7.39 (m, 3H), 7.07-6.94 (m, 2H), 6.78 (s, 1H),
o
1
97% yield): m.p. 60.3-61.7 C; H NMR (400 MHz, CDCl3) δ
7.68 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.30 (s, 1H),
3.84 (s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.8,
169.4, 160.9, 127.4, 120.7, 114.4, 96.2, 55.5, 32.2, 29.7; HRMS
(ESI) calcd for (C14H17NO2+H)+ [M+H]+ 232.1332, found
232.1333.
1
3.86 (d, J = 9.1 Hz, 3H). The H NMR spectral data are in good
agreement with the literature data.30
5-(cyclohex-1-en-1-yl)-3-(4-methoxyphenyl) isoxazole (3n)
This compound was obtained as a brown oil (102.1 mg, 80%
yield): H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.7 Hz, 2H),
methyl 4-(3-(tert-butyl) isoxazol-5-yl) benzoate (3c)
1
This compound was obtained as a yellow solid (112.8 mg,
87% yield): m.p. 113.4-114.8 °C; 1H NMR (400 MHz, CDCl3) δ
8.07(d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 6.52 (s, 1H),
3.90 (s, 3H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.0,
168.3, 166.5, 131.6, 131.2, 130.3, 125.7, 99.1, 52.4, 32.3, 29.7;
HRMS (ESI) calcd for (C15H17NO3+H)+ [M+H]+ 260.1281, found
260.1287.
6.95 (d, J = 8.7 Hz, 2H), 6.61-6.66 (m, 1H), 6.32 (s, 1H), 3.85 (s,
3H), 2.34-2.41 (m, 2H), 2.21-2.29 (m, 2H), 1.73-1.82 (m, 2H),
1.64-1.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.5, 162.1,
161.0, 130.2, 128.2, 125.5, 122.1, 114.4, 96.1, 55.5, 25.5, 25.3,
22.2, 21.9; HRMS (ESI) calcd for (C16H17NO2+H)+ [M+H]+
256.1332, found 256.1333.
3-(3-methoxyphenyl)-5-phenylisoxazole (3o)
5-phenyl-3-(2-phenylpropan-2-yl) isoxazole (3e)
This compound was obtained as a yellow oil (125.6 mg, 99%
yield): 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 8.0, 1.5 Hz,
2H), 7.56-7.35 (m, 6H), 7.07-6.96 (m, 1H), 6.82 (s, 1H), 3.89 (s,
This compound was obtained as a yellow solid (131.7 mg,
1
99% yield): m.p. 107.6-109.0 °C; H NMR (400 MHz, CDCl3) δ
1
7.71 (dd, J = 7.9, 1.5 Hz, 2H), 7.38-7.48 (m, 3H), 7.28-7.38 (m,
4H), 7.21-7.26 (m, 1H), 6.18 (s, 1H), 1.78 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 171.9, 169.6, 147.2, 130.1, 129.0, 128.5, 127.7,
126.6, 126.2, 125.9, 98.8, 39.9, 28.8; HRMS (ESI) calcd for
(C18H17NO+H)+ [M+H]+ 264.1383, found 264.1385.
3H). The H NMR spectral data are in good agreement with the
literature data.31
5-(tert-butyl)-3-(thiophen-2-yl)isoxazole (3q)
This compound was obtained as a yellow solid (63.2 mg, 61%
yield, from starting material 2q [Z/E=1:2]): m.p. 49.4-50.2 oC; 1H
NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 3.6, 0.7 Hz, 1H), 7.39
(dd, J = 5.1, 0.9 Hz, 1H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H), 6.18 (s,
1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 181.9, 157.4,
131.5, 127.7, 127.4, 127.1, 96.7, 33.0, 29.0; HRMS (ESI) calcd
for (C11H13NOS+H)+ [M+H]+ 208.0791, found 208.0796.
3-isopropyl-5-phenylisoxazole (3f)
This compound was obtained as a yellow oil (66.5 mg, 71%
yield, from starting material 2f [Z:E = 3:1]): 1H NMR (500 MHz,
CDCl3) δ 7.76 (dd, J = 8.4, 1.1 Hz, 2H), 7.39-7.47 (m, 3H), 6.40
1
(s, 1H), 3.06-3.17 (m, 1H), 1.33 (d, J = 7.0, 6H). The H NMR
spectral data are in good agreement with the literature data.26
3-cyclopropyl-5-phenylisoxazole (3g)

11
Preparation of 3,5-Disubstituted Isoxazolines (4) from
Ynones (1) and Hydroxylamine
J = 4.2, 2.4 Hz, 3H), 7.33 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.3
ACCEPTED MANUSCRIPT
Hz, 1H), 5.61 (s, 1H), 3.49, 3.05 (ABq, JAB = 18.1 Hz, 2H), 1.62
(s, 3H), 1.59 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 157.9,
146.9, 132.0, 131.3, 130.2, 129.7, 129.2, 127.9, 127.8, 113.9,
46.2, 44.3, 25.8, 25.3; HRMS (ESI) calcd for (C18H19NO2+H)+
[M+H]+ 282.1489, found 282.1493.
5-isopropyl-3-phenyl-4,5-dihydroisoxazol-5-ol (4f)
This compound was obtained as a yellow solid (89.3 mg, 87%
yield): m.p. 96.3-96.8 °C; H NMR (500 MHz, acetone-d6) δ
General Procedure: A 20 mL glass vial was charged with
ynone (1, 0.50 mmol), hydroxylamine (NH2OH, 50 wt% aq.
Soln., 264.2 mg, 4.00 mmol, 8.0 eq), and dimethylformamide (4
mL). The reaction vial was sealed with a pressure relief cap and
the mixture was stirred at 50 °C for 2 h, then diluted with 20 mL
of diethyl ether and washed with brine (20 mL). The aqueous
phase was extracted with diethyl ether (2 × 15 mL). The
combined organic layers were dried over anhydrous MgSO4, and
concentrated using a rotary evaporator under reduced pressure
(20 mmHg). The subsequent residue was purified by flash
column chromatography on silica gel (eluent: hexanes/ethyl
acetate) to afford the corresponding cyclization product.
1
7.79-7.69 (m, 2H), 7.53-7.42 (m, 3H), 5.61 (s, 1H), 3.45, 3.16
(ABq, JAB = 18.1 Hz, 2H), 2.27-2.13 (m, 1H), 1.14 (d, J = 6.8 Hz,
3H), 1.06 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, acetone-d6) δ
157.7, 132.3, 131.2, 130.2, 127.9, 113.1, 43.2, 37.2, 19.0, 18.5;
HRMS (ESI) calcd for (C12H15NO2+H)+ [M+H]+ 207.1208, found
207.1212.
5-cyclopropyl-3-phenyl-4,5-dihydroisoxazol-5-ol (4g)
This compound was obtained as a yellow solid (91.5 mg, 90%
1
yield): m.p. 96.7-97.7 °C; H NMR (500 MHz, acetone-d6) δ
7.75-7.68 (m, 2H), 7.51-7.42 (m, 3H), 5.72 (s, 1H), 3.46, 3.32
(ABq, JAB = 17.7 Hz, 2H), 1.48-1.39 (m, 1H), 0.69-0.59 (m, 2H),
0.59-0.49 (m, 2H); 13C NMR (125 MHz, acetone-d6) δ 158.2,
132.1, 131.3, 130.2, 127.9, 109.5, 46.8, 19.2, 2.9, 2.6; HRMS
(ESI) calcd for (C12H13NO2+H)+ [M+H]+ 204.1019, found
204.1024.
5-(tert-butyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (4a)
This compound was obtained as a yellow solid (109.6 mg,
1
99% yield): m.p. 141.8-142.7 °C; H NMR (500 MHz, acetone-
d6) δ 7.74 (dd, J = 6.5, 3.1 Hz, 2H), 7.47 (dd, J = 5.0, 1.8 Hz,
3H), 5.56 (s, 1H), 3.65, 3.15 (ABq, JAB = 18.1 Hz, 2H), 1.13 (s,
9H); 13C NMR (125 MHz, acetone-d6) δ 157.7, 132.3, 131.2,
130.2, 128.0, 114.4, 43.2, 39.0, 26.2; HRMS (ESI) calcd for
(C13H17NO2+H)+ [M+H]+ 220.1332, found 220.1336.
5-ethyl-3-phenyl-4,5-dihydroisoxazol-5-ol (4h)
This compound was obtained as a yellow oil (76.5 mg, 80%
yield): 1H NMR (500 MHz, CDCl3) δ 7.67-7.65 (m, 2H), 7.41-
7.38 (m, 3H), 3.27 (s, 2H), 2.90 (s, 1H), 2.07-1.96 (m, 2H), 1.09
5-(tert-butyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazol-5-ol
(4b)
1
(t, J = 7.53 Hz, 3H). The H NMR spectral data are in good
agreement with the literature data29
This compound was obtained as a white solid (122.2 mg, 98%
1
yield): m.p. 123.4-123.7 °C; H NMR (500 MHz, acetone-d6) δ
3,5-diphenyl-4,5-dihydroisoxazol-5-ol (4i)
7.70-7.64 (m, 2H), 7.04-6.99 (m, 2H), 5.45 (s, 1H), 3.87 (s, 3H),
3.61, 3.11 (ABq, JAB = 18.0 Hz, 2H), 1.12 (s, 9H); 13C NMR (125
MHz, acetone-d6) δ 162.6, 157.2, 129.5, 124.7, 115.6, 114.0,
56.4, 43.5, 38.9, 26.2; HRMS (ESI) calcd for (C14H19NO3+H)+
[M+H]+ 250.1438, found 250.1439.
This compound was obtained as a white solid (113.7 mg, 95%
yield): m.p. 97.8-99.9 °C; 1H NMR (500 MHz, acetone-d6) δ
7.79 (dd, J = 6.5, 2.9 Hz, 2H), 7.71 (d, J = 7.3 Hz, 2H), 7.51-7.47
(m, 3H), 7.45 (d, J = 7.7 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 6.43
1
(s, 1H), 3.70, 3.64 (ABq, JAB = 17.5 Hz, 2H). The H NMR
spectral data are in good agreement with the literature data.32
methyl 4-(5-(tert-butyl)-5-hydroxy-4,5-dihydroisoxazol-3-yl)
benzoate (4c)
3-(tert-butyl)-5-phenyl-4,5-dihydroisoxazol-5-ol (4j)
This compound was obtained as a white solid (73.5 mg, 53%
yield): m.p. 146.0-146.9 °C; H NMR (400 MHz, acetone-d6) δ
1
This compound was obtained as a white solid (106.4 mg, 97%
yield): m.p. 76.3-77.0 oC; 1H NMR (500 MHz, acetone-d6) δ 7.61
(dd, J = 7.0, 1.4 Hz, 2H), 7.41 (dd, J = 8.0, 6.5 Hz, 2H), 7.36 (d,
J = 6.9 Hz, 1H), 6.01 (s, 1H), 3.30, 3.18 (ABq, JAB = 18.1 Hz,
2H), 1.25 (s, 9H); 13C NMR (125 MHz, acetone-d6) δ 167.1,
144.3, 129.6, 129.5, 127.3, 108.3, 50.1, 34.5, 29.1; HRMS (ESI)
calcd for (C13H17NO2+H)+ [M+H]+ 220.1332, found 220.1335.
8.09 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 5.64 (s, 1H),
3.94 (s, 3H), 3.71, 3.20 (ABq, JAB = 17.9 Hz, 2H), 1.14 (s, 9H);
13C NMR (100MHz, acetone-d6) δ 167.5, 157.3, 136.5, 132.6,
131.2, 128.0, 115.2, 53.3, 42.9, 39.0, 26.1; HRMS (ESI) calcd for
(C15H19NO4+H)+ [M+H]+ 278.1387, found 278.1390.
5-(tert-butyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazol-5-ol (4d)
3-cyclopropyl-5-phenyl-4,5-dihydroisoxazol-5-ol (4k)
This compound was obtained as a yellow solid (84.5 mg, 75%
yield): m.p. 126.3-127.6 °C; H NMR (500 MHz, acetone-d6) δ
1
This compound was obtained as a light yellow oil (100.5 mg,
99% yield): H NMR (500 MHz, CDCl3) δ 7.57 (dd, J = 7.95,
1
7.59 (d, J = 4.7 Hz, 1H), 7.36 (d, J = 2.9 Hz, 1H), 7.15 (dd, J =
4.7, 3.9 Hz, 1H), 5.65 (s, 1H), 3.66, 3.16 (ABq, JAB = 18.1 Hz,
2H), 1.12 (s, 9H); 13C NMR (125 MHz, acetone-d6) δ 153.8,
134.5, 130.3, 129.3, 129.0, 114.6, 43.9, 38.9, 26.2; HRMS (ESI)
calcd for (C11H15NO2S+Na)+ [M+Na]+ 248.0716, found
248.0719.
1.49 Hz, 2H), 7.38-7.34 (m, 3H), 3.03, 2.96 (ABq, JAB = 17.1 Hz,
2H), 2.49 (s, 1H), 1.86-1.81 (m, 1H), 0.98-0.89 (m, 2H), 0.85-
0.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.4, 140.9,
128.9, 128.6, 125.7, 106.7, 49.2, 9.3, 6.9, 6.1; HRMS (HESI)
calcd for (C12H13NO2+H)+ [M+H]+ 204.1019, found 204.1018.
3-pentyl-5-phenyl-4,5-dihydroisoxazol-5-ol (4l)
3-phenyl-5-(2-phenylpropan-2-yl)-4,5-dihydroisoxazol-5-ol
(4e)
This compound was obtained as a yellow oil (106.2 mg, 91%
yield): 1H NMR (500 MHz, acetone-d6) δ 7.63-7.59 (m, 2H), 7.41
(ddd, J = 8.0, 5.0, 3.7 Hz, 2H), 7.38-7.34 (m, 1H), 6.04 (s, 1H),
3.20, 3.19 (ABq, JAB = 20.0 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H),
This compound was obtained as a yellow solid (128.0 mg,
o
91% yield): m.p. 101.4-102.4 C; 1H NMR (400 MHz, acetone-
d6) δ 7.75-7.67 (m, 2H), 7.65 (dd, J = 6.7, 3.0 Hz, 2H), 7.42 (dd,

12
Tetrahedron
ACCEPTED MANUSCRIPT
1.70-1.56 (m, 2H), 1.43-1.32 (m, 4H), 1.00-0.89 (m, 3H); 13
C
3-(2-bromophenyl)-5-phenyl-4,5-dihydroisoxazol-5-ol (4s)
NMR (125 MHz, acetone-d6) δ 160.4, 144.2, 129.6, 129.5, 127.4,
108.0, 52.6, 32.8, 29.1, 27.4, 23.7, 15.0; HRMS (ESI) calcd for
(C14H19NO2+H)+ [M+H]+ 234.1489, found 234.1489.
This compound was obtained as a yellow oil (147.9 mg, 93%
yield): H NMR (400 MHz, CDCl3) δ 7.63-7.69 (m, 4H), 7.36-
1
7.48 (m, 4H), 7.29 (td, J = 7.8, 1.9 Hz, 1H), 3.77, 3.72 (ABq, JAB
= 17.4 Hz, 2H), 3.23 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
158.5, 140.5, 133.9, 131.4, 131.2, 131.0, 129.2, 128.8, 127.7,
125.8, 122.0, 108.2, 51.4; HRMS (HESI) calcd for
(C15H12BrNO2+H)+ [M+H]+ 318.0124, found 318.0126.
5-(4-methoxyphenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (4m)
This compound was obtained as a yellow solid (116.6 mg,
o
1
87% yield): m.p. 142.1-142.6 C; H NMR (400 MHz, acetone-
d6) δ 7.78 (dd, J = 6.7, 3.0 Hz, 2H), 7.65-7.57 (m, 2H), 7.53-7.44
(m, 3H), 7.05-6.93 (m, 2H), 6.29 (s, 1H), 3.86 (s, 3H), 3.64, 3.62
(ABq, JAB = 18.0 Hz, 2H); 13C NMR (100 MHz, acetone-d6) δ
161.4, 158.2, 135.7, 132.0, 131.5, 130.3, 128.8, 128.2, 114.9,
109.4, 56.3, 50.3; HRMS (ESI) calcd for (C16H15NO3+H)+
[M+H]+ 270.1125, found 270.1129.
5-(4-nitrophenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (4t)
This compound was obtained as a yellow solid (129.0 mg,
o
1
91% yield): m.p. 151.0-152.0 C; H NMR (500 MHz, DMSO-
d6) δ 8.27 (d, J = 9.4 Hz, 2H), 7.90 (s, 1H), 7.84 (d, J = 9.4 Hz,
2H), 7.72-7.74 (m, 2H), 7.47-7.48 (m, 3H), 3.67(ABq J = 15.0
Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 156.9, 148.9, 147.4,
130.4, 129.4, 128.9, 127.5, 126.7, 123.4, 106.9, 48.6. The HRMS
data are in good agreement with the literature data.32
3-(cyclohex-1-en-1-yl)-5-(4-methoxyphenyl)-4,5-
dihydroisoxazol-5-ol (4n)
This compound was obtained as a yellow solid (125.7 mg,
92% yield): m.p. 116.7-117.5 °C; H NMR (500 MHz, acetone-
1
d6) δ 7.57-7.51 (m, 2H), 6.99-6.93 (m, 2H), 6.10-6.12 (m, 1H),
6.06 (s, 1H), 3.84 (s, 3H), 3.36, 3.23 (ABq, JAB = 17.2 Hz, 2H),
2.41 (td, J = 6.1, 1.8 Hz, 2H), 2.26-2.18 (m, 2H), 1.69 (ddt, J =
10.8, 5.3, 4.2 Hz, 4H); 13C NMR (125 MHz, acetone-d6) δ 161.2,
160.0, 136.0, 133.8, 131.4, 128.7, 114.8, 108.7, 56.3, 49.9, 27.1,
25.9, 23.6, 23.5; HRMS (ESI) calcd for (C16H19NO3+H)+ [M+H]+
274.1438, found 274.1438.
Preparation of 3,5-Disubstituted Isoxazoles (3) by Acid
Mediated
Dehydration
of
3,5-Disubstituted
4,5-
dihydroisoxazoles (4) 9
5-(3-methoxyphenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (4o)
This compound was obtained as a white solid (130.6 mg, 97%
o
1
yield): m.p. 120.9-121.2 C; H NMR (400 MHz, acetone-d6) δ
7.82-7.75 (m, 2H), 7.50 (dd, J = 4.1, 2.3 Hz, 3H), 7.36 (t, J = 8.1
Hz, 1H), 7.29-7.24 (m, 2H), 7.00-6.93 (m, 1H), 6.36 (s, 1H), 3.86
(s, 3H), 3.68, 3.65 (ABq, JAB = 18.0 Hz, 2H); 13C NMR (100
MHz, acetone-d6) δ 161.3, 158.2, 145.2, 131.9, 131.6, 130.8,
130.3, 128.2, 119.7, 115.3, 113.2, 109.3, 56.3, 50.5; HRMS (ESI)
calcd for (C16H15NO3+H)+ [M+H]+ 270.1125, found 270.1129.
General Procedure: A 20 mL glass vial was charged with
3,5-disubstituted 4,5-dihydroisoxazoles (4, 0.50 mmol), H2SO4
(98.0 mg, 1.00 mmol), and dimethylformamide (4.0 mL). The
reaction vial was sealed with a pressure relief cap and the mixture
was stirred at room temperature for 2 h, then diluted with 20 mL
of diethyl ether and washed with brine (20 mL). The aqueous
phase was extracted with diethyl ether (2 × 15 mL). The
combined organic layers were dried over anhydrous MgSO4, and
concentrated using a rotary evaporator under reduced pressure
(20 mmHg). The subsequent residue was purified by flash
column chromatography on silica gel (eluent: hexanes/ethyl
acetate) to afford the corresponding dehydration product.
5-(4-chlorophenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (4p)
This compound was obtained as a white solid (113.6 mg, 83%
o
1
yield): m.p. 193.0-193.3 C; H NMR (400 MHz, acetone-d6) δ
7.81-7.76 (m, 2H), 7.75-7.69 (m, 2H), 7.52-7.45 (m, 5H), 6.53 (s,
1H), 3.71, 3.67 (ABq, JAB = 16.0 Hz, 2H); 13C NMR (100 MHz,
acetone-d6) δ 158.3, 142.7, 135.3, 131.69, 131.65, 130.4, 129.8,
129.4, 128.2, 108.9, 50.4; HRMS (ESI) calcd for
(C15H12ClNO2+H)+ [M+H]+ 274.0629, found 274.0635.
3-(tert-butyl)-5-phenylisoxazole (3a)
This compound was prepared from 4j and obtained as a
yellow oil (95.0 mg, 95% yield).
3-(tert-butyl)-5-(thiophen-2-yl)-4,5-dihydroisoxazol-5-ol (4q)
This compound was obtained as a white solid (98.0 mg, 87%
yield): m.p. 93.2-93.7 oC; 1H NMR (500 MHz, acetone-d6) δ 7.45
(dd, J = 5.1, 1.2 Hz, 1H), 7.20 (dd, J = 3.6, 1.2 Hz, 1H), 7.03 (dd,
J = 5.1, 3.6 Hz, 1H), 6.37 (s, 1H), 3.36, 3.30 (ABq, JAB = 15.0
Hz, 2H), 1.25 (s, 9H); 13C NMR (125 MHz, acetone-d6) δ 167.5,
147.4, 128.2, 127.3, 126.5, 106.8, 50.3, 34.5, 29.0; HRMS (ESI)
calcd for (C11H15NO2S+H)+ [M+H]+ 226.0896, found 226.0901.
3-cyclopropyl-5-phenylisoxazole (3g)
This compound was prepared from 4k and obtained as an
orange solid (89.0 mg, 96 % yield).
5-ethyl-3-phenylisoxazole (3h)
This compound was prepared from 4h and obtained as a
yellow oil (70.2 mg, 81% yield): 1H NMR (500 MHz, CDCl3) δ
7.78-7.81 (m, 2H), 7.41-7.46 (m, 3H), 6.29 (s, 1H), 2.82 (q, J =
5-(2-bromophenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (4r)
1
This compound was obtained as a yellow solid (151.1 mg,
7.86 Hz, 2H), 1.35 (t, J = 7.47 Hz, 3H). The H NMR spectral
o
95% yield): m.p. 122.4-123.7 C; 1H NMR (400 MHz, CDCl3) δ
data are in good agreement with the literature data.29
7.97 (dd, J = 7.9, 1.8 Hz, 1H), 7.72-7.74 (m, 2H), 7.68 (dd, J =
8.0, 1.1 Hz, 1H), 7.43 (d, J = 2.3 Hz, 2H), 7.42 (d, J = 1.7 Hz,
1H), 7.37 (td, J = 7.5, 1.1 Hz, 1H), 7.22-7.25 (m, 1H), 3.91, 3.76
(ABq, JAB = 17.9 Hz, 2H), 3.16 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 157.8, 139.4, 134.8, 130.7, 130.6, 129.2, 128.9, 128.2,
127.6, 127.0, 121.5, 107.1, 47.6; HRMS (HESI) calcd for
(C15H12BrNO2+H)+ [M+H]+ 318.0124, found 318.0123.
5-(tert-butyl)-3-(thiophen-2-yl)isoxazole (3q)
This compound was prepared from 4d and obtained as a
yellow solid (87.1 mg, 84% yield).
5-(2-bromophenyl)-3-phenylisoxazole (3r)

13
This compound was obtained as a yellow solid (91.5 mg, 61%
3s, 4k, 4r and 4s were made in the Molecular Education,
ACCEPTED MANUSCRIPT
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1
yield): m.p. 54.6-55.7 C; H NMR (400 MHz, CDCl3) δ 7.86-
7.91 (m, 3H), 7.70 (dd, J = 8.0, 1.2 Hz, 1H), 7.42-7.47 (m, 4H),
7.23-7.29 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.1, 162.8,
134.3, 131.2, 130.23, 130.20, 129.2, 129.1, 128.5, 127.9, 127.0,
121.2, 102.4; HRMS (HESI) calcd for (C15H10BrNO+H)+
[M+H]+ 300.0019, found 300.0018.
Technology, and Research Innovation Center (METRIC) at
North Carolina State University.
References:
3-(2-bromophenyl)-5-phenylisoxazole (3s)
1) For recent reviews, see: (a) Agrawal, N.; Mishra, P. Med.
Chem. Res. 2018, 27, 1309-1344. (b) Sysak, A.; Obminska-
Mrukowicz, B. Eur. J. Med. Chem. 2017, 137, 292-309. (c)
Barmade, M. A.; Murumkar, P. R.; Sharma, M. K.; Yadav, M. R.
Curr. Top. Med. Chem. 2016, 16, 2863-2883. (d) Anand, P.;
Singh, B. Mini-Rev. Med. Chem. 2014, 14, 623-627.
This compound was obtained as a yellow solid (75.0 mg, 50%
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1
yield): m.p. 43.8-44.7 C; H NMR (400 MHz, CDCl3) δ 7.85-
7.87 (m, 2H), 7.69-7-73 (m, 2H), 7.41-7.52 (m, 4H), 7.33 (td, J =
7.8, 2.1 Hz, 1H), 6.96(s, 1H); 13C NMR (100 MHz, CDCl3) δ
169.7, 163.1, 133.8, 131.5, 131.2, 130.7, 130.4, 129.2, 127.8,
127.6, 126.0, 122.4, 101.0; HRMS (HESI) calcd for
(C15H10BrNO+H)+ [M+H]+ 300.0019, found 300.0018.
2) For reviews, see: (a) Pinho e Melo, T. M. V. D. Curr. Org.
Chem. 2005, 9, 925-958. (b) Pinho e Melo, T. M. V. D. Eur. J.
Org. Chem. 2010, 3363-3376. (c) Hamama, W. S.; Ibrahim, M.
E.; Zoorob, H. H. Synth. Commun. 2013, 43, 2393-2440. (d) Hu,
F.; Szostak, M. Adv. Synth. Catal. 2015, 357, 2583-2614.
5-isopropyl-3-phenylisoxazole (3t)
This compound was obtained as a yellow oil (54.3 mg, 58%
1
yield): H NMR (400 MHz, CDCl3) δ 7.79-7.81 (m, 2H), 7.42-
1
7.46 (m, 3H), 6.27 (s, 1H), 3.12 (sep, 1H). 1.36 (d, 6H). The H
3) For reviews on synthesis of isoxazoles, see: Reference (2),
and Morita, T.; Yugandar, S.; Fuse, S.; Nakamura, H.
Tetrahedron Lett. 2018, 59, 1159-1171.
NMR spectral data are in good agreement with the literature
data.33
5-(4-nitrophenyl)-3-phenylisoxazole (3u)
4) She, Z.; Niu, D.; Chen, L.; Gunawan, M. A.; Shanja, X.;
Hersh, W. H.; Chen, Y. J. Org. Chem. 2012, 77, 3627−3633.
The reaction was carried out at 50 oC for 15 hours. This
compound was obtained as a yellow solid (100.0 mg, 75% yield):
m.p. 226.0-227.0 C; H NMR (400 MHz, CDCl3) δ 8.37 (d, J =
8.5 Hz, 2H), 8.03 (d, J = 9.6 Hz, 2H), 7.86-7.89 (m, 2H), 7.50-
7.52 (m, 3H), 7.02 (s, 1H). The 1H NMR spectral data are in good
agreement with the literature data.34
5) Das, S.; Hong, D.; Chen, Z.; She, Z.; Hersh, W. H.;
Subramaniam, G.; Chen, Y. Org. Lett., 2015, 17, 5578-5581.
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1
6) A recent report showed that in the presence of a
stoichmetric amount of chlorotrimethylsilane (TMSCl), the trans
oxime isomer can fully or partially isomerize to the cis isomer
and undergo an NCS induced cyclization. For details, see:
Kaewsri, W.; Thongsornkleeb, C.; Tummatorn, J.; Ruchirawat, S.
RSC Adv. 2016, 6, 48666-48675.
Preparation of 3-(tert-Butyl)-4-iodo-5-phenylisoxazole (5a)
from 3-(tert-Butyl)-5-phenylisoxazole (3a)10
7) For convenience, in this manuscript we designate the oxime
configuration as Z if its O-methyl group is cis to the ynone triple
bond. This designation however conflicts with the IUPAC
nomenclature for a few of the ynone O-methyl oximes in this
report. The proper IUPAC names of all the ynone O-methyl
oximes mentioned can be found in the experimental section.
8) (a) Linderman, R. J.; Kirollos, K. S. Tetrahedron Lett.
1989, 30, 2049-2052. (b) Martins, M. A. P.; Emmerich, D. J.;
Pereira, C. M. P.; Cunico, W.; Rossato, M.; Zanatta, N.;
Bonacorso, H. G. Tetrahedron Lett. 2004, 45, 4935-4938. (c)
Xie, M.; Li, M.; Liu, C.; Zhang, J.; Feng, C. J. Heterocyclic
Chem. 2012, 49, 1462-1465. (d) Sobenina, L. N.; Tomilin, D. N.;
Gotsko, M. D.; Ushakov, I. A.; Mikhaleva, A. I.; Trofimov, B. A.
Tetrahedron 2014, 70, 5168-5174. (e) Harigae, R.; Moriyama,
K.; Togo, H. J. Org. Chem. 2014, 79, 2049-2058. (f) Nes, I.;
Sydnes, L. K. Synthesis 2015, 47, 89-94.
An oven dried 20 mL glass vial was charged with 3,5-
disubstituted isoxazoles (3a, 100.5 mg, 0.50 mmol), N-
iodosuccinimide (337.0 mg, 1.50 mmol, 3 equivalents), and
trifluoroacetic acid (TFA, 2.0 mL). The reaction vial was sealed
with a pressure relief cap and the mixture was stirred at 60 °C for
1 h. Saturated aq. NaHCO3 solution (15 mL) was added at room
temperature. The mixture was extracted by diethyl ether (3 × 20
mL). The combined organic phases were washed with 10% aq.
Na2S2O3 solution (20 mL) and brine (20 mL), respectively, then
dried over anhydrous MgSO4 and concentrated using a rotary
evaporator under reduced pressure (20 mmHg). The subsequent
residue was purified by flash column chromatography on silica
gel (eluent: hexanes/ethyl acetate) to afford the corresponding
cyclization product. The product was obtained as a white solid
9) A modified literature procedure was employed in the acid
mediated dehydration, see: Martins, M. A. P.; Siqueira, G. M.;
Bastos, G. P.; Bonacorso, H. G.; Zanatta, N. J. Heterocyclic
Chem. 1996, 33, 1619-1622.
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1
(154.0 mg, 94% yield): m.p. 80.0-82.0 C; H NMR (400 MHz,
CDCl3) δ 7.94-7.92 (m, 2H), 7.50-7.48 (m, 3H), 1.53 (s, 9H). The
1H NMR spectral data are in good agreement with the literature
data.25
10) A literature procedure was employed in the iodination
reaction, see: Day, R. A.; Blake, J. A.; Stephens, C. E. Synthesis
2003, 1586-1590.
11) These compounds were prepared using a modified
reaction condition reported in the following reference:
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467-4470.
Acknowledgments We thank Queens College and the City
University of New York for financial support. The high
resolution mass spectrometry measurements of compounds 3r,

14
Tetrahedron
ACCEPTED MANUSCRIPT
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