Oxidize Amines to Nitrile Oxides: One Type of Amine Oxidation and Its Application to Directly Construct Isoxazoles and Isoxazolines

Article abstract of DOI:10.1021/acs.joc.0c02281

A facile oxidative heterocyclization of commercially available amines and tert-butyl nitrite with alkynes or alkenes leading to isoxazoles or isoxazolines is described. The unprecedented strategy of the oxidation of an amine directly to a nitrile oxide was used in this cyclization process. This reaction is highly efficient, regiospecific, operationally simple, mild, and tolerant of a variety of functional groups. Control experiments support a nitrile oxide intermediate mechanism for this novel class of oxidative cyclization reactions. Moreover, synthetic applications toward bioactive molecular skeletons and the late-stage modification of drugs were realized.

Full text of DOI:10.1021/acs.joc.0c02281

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Oxidize Amines to Nitrile Oxides: One Type of Amine Oxidation and
Its Application to Directly Construct Isoxazoles and Isoxazolines
Xiao-Wei Zhang,* Xiao-Lin He, Nan Yan, Hong-Xing Zheng, and Xiang-Guo Hu*
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ABSTRACT: A facile oxidative heterocyclization of commercially
available amines and tert-butyl nitrite with alkynes or alkenes
leading to isoxazoles or isoxazolines is described. The unprece-
dented strategy of the oxidation of an amine directly to a nitrile
oxide was used in this cyclization process. This reaction is highly
efficient, regiospecific, operationally simple, mild, and tolerant of a
variety of functional groups. Control experiments support a nitrile
oxide intermediate mechanism for this novel class of oxidative cyclization reactions. Moreover, synthetic applications toward
bioactive molecular skeletons and the late-stage modification of drugs were realized.
Scheme 1. Synthesize Isoxazoles and Isoxazolines via a
Nitrile Oxide Intermediate
itrile oxides are valuable key intermediates that can
undergo [3 + 2] cycloaddition to allow the construction
N
of various heterocycles.1 Isoxazolines and isoxazoles are
privileged heterocyclic motifs found in various bioactive
compounds and natural products.1b,2 In addition, they can
also be employed as efficient ligands3 and eminent building
blocks in organic synthesis.4 The classic and well-established
1,3-dipolar cycloaddition of nitrile oxides with various alkenes
and alkynes is a powerful C−C or C−O bond-forming
transformation to deliver these five-membered heterocycles.1
Thus, the generation of the nitrile oxides are critical to this [3
+ 2] cycloaddition and is often achieved by one of the
following three strategies: transformation from hydroximinoyl
halides or aldoximes5 or the dehydration of nitroalkanes.6
Despite of their significance, most of the reported methods
suffer from a low efficiency, a limited substrate scope,
complicated operations, or harsh reaction conditions. More
seriously, the multistep fashion is a common roadblock for
accessing nitrile oxides. For example, such precursors always
need to be synthesized from aldehydes, alkyl halides, or amines
(Scheme 1a). Therefore, the development of practical and
efficient approaches to construct nitrile oxides from stable,
cheap, and readily accessible raw materials in one single step is
highly valuable.
Amines are widespread chemicals and industrial raw
materials because they are not only widely distributed but
also cheap and commercially available. It would undoubtedly
be a robust synthesis strategy if nitrile oxides could be
synthesized by a one-step oxidation reaction using an amine as
the starting material. Although there are many types of amines
oxidations reported in the literature,7 the direct transformation
of amines to nitrile oxides has not yet been reported. To
address the aforementioned limitations, we aim to develop a
novel method that selectively oxidizes amines to nitrile oxides,
which are in situ captured by alkenes or alkynes to construct
isoxazolines or isoxazoles (Scheme 1b). However, there are
two main challenges in this tandem oxidative/cyclization
hypothesis. The primary amine might poison the transition
Received: September 24, 2020
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© XXXX American Chemical Society
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metal catalysts because of its strong coordination ability, thus
blocking the catalytic process and leading to failure in the
synthesis of heterocycles. Additionally, a suitable oxidant is
required for this oxidative annulation strategy. Since amines are
easily oxidized to imines,8 nitriles,9 oximes,10 amides,11 etc.,
and dipolarphiles are susceptible under strong oxidation
conditions, a weak oxidant that does not cause the destruction
of unstable substrates but can enable the oxidative and
cyclization process should be found in this protocol. Herein, by
using the tert-butyl nitrite (TBN) as the oxidant, we report a
facile Rh-catalyzed oxidative heterocyclization of commercially
available amines, alkynes, or alkenes, leading to isoxazoles or
isoxazolines through a click reaction process.
slightly decreased to 85% (Table 1, entry 12). When 1 mol %
[Rh(OAc)2]2 was used in place of [Cp*RhCl2]2, the yield
sharply decreased to 27% (Table 1, entry 13).
With the optimum conditions in hand, we subsequently
proceeded to explore the substrate scope of this heterocycliza-
tion reaction. To our delight, various alkynes containing aryl,
heteroaryl, alkyl, amide, ester, ketone, and other functional
groups were compatible in this transformation, giving the
desired product in good to high yields (Scheme 2, 3a−z). A
a
Scheme 2. Synthesis of Isoxazoles
We selected commercially available 4-ethynyl-1,1′-biphenyl
1a with the ethyl glycinate hydrochloride salt 2a as the model
substrates for optimization. Extensive examinations (see the
Supporting Information) revealed that a combination of
[Cp*RhCl2]2/ZnBr2/TBN/NaHCO3 at room temperature
was optimal, with which the isoxazole product 3a was obtained
in a 97% yield (standard condition A, Table 1, entry 1). Very
a
Table 1. Evaluation of Reaction Conditions
1a
b
b
entry
variations from the standard conditions
none
other oxidant instead of TBN
NaNO2 instead of TBN
without the [Rh] catalyst
0.5 mol % [Rh] was used
without NaHCO3
1.5 equiv of NaHCO3 was used
without ZnBr2
1 equiv of ZnBr2 was used
(%)
3a (%)
c
1
2
3
4
5
6
7
8
0
97 (94)
d
0
19
0
84
26
45
0
40
75
77
85
27
64
88
0
44
5
80
23
15
0
9
a
10
11
12
13
2 equiv of TBN and 2 equiv of 2a were used
3 equiv of TBN and 2 equiv of 2a were used
under air instead of N2
The standard condition A was adopted from Table 1, entry 1.
b
Reaction yields refer to isolated yields. Gram-scale yield.
0
60
1 mol % of [Rh(OAc)2]2 was used
a
Standard conditions A are as follows: 1a (0.3 mmol), 2a (3 equiv),
gram scale reaction of 1a was also realized with no impact on
the yield or selectivity. Besides the simple ethyl glycinate
hydrochloride salt, glycine methyl, tert-butyl ester hydro-
chloride, aminoacetonitrile hydrochloride, and some complex
chiral amide containing hydrochlorides also gave the desired
products in good yields (3aa−gg). It is worth noting that
compound 3ff is an inducer of neurogenesis, which triggered
robust neuronal differentiation in adult neural stem cells that
rapidly signaled to the neuronal genome via a Ca2+ influx;2b
meanwhile, compound 3gg is a fatty acid amide hydrolase
(FAAH) inhibitor, which produced an anti-inflammatory effect
in a dextran sulfate sodium (DSS)-induced acute colitis model
in mice.2c Although an internal alkyne or compound 2 without
an electron withdrawing-group (EWG) remained retarded in
this condition, the late-stage modification of drugs was realized
successfully. For example, norethindrone and ethyl estradiol
were easily transformed to the corresponding isoxazoles
derivatives 3hh and 3ii in 55% and 66% yields, respectively.
Furthermore, we prepared ethyl glycinate from its hydro-
chloride salt 2a to test the scope of the free amine in our
reaction, and only a 7% yield of 3a was obtained in the
standard condition A. However, the desired product could be
[Cp*RhCl2]2 (1 mol %), TBN (3 equiv), ZnBr2 (2 equiv), and
NaHCO3 (3 equiv) in methyl tert-butyl ether (3 mL); stirred for 24 h
in a closed 10 mL vial at room temperature under a N2 atmosphere.
b
Yields were determined by 1H NMR spectroscopy with 1-bromo-3,5-
c
bis(trifluoromethyl)benzene as an external standard. Isolated yield.
d
In the place of TBN, 3 equiv of other oxidants was used; for details,
see Table S3.
interestingly, when other oxidants were applied, no product
could be detected except NaNO2 with a 19% yield (Table 1,
entries 2 and 3; see the Supporting Information for the
details). Decreasing the amount of the catalyst slightly lower
the yield, while no product was obtained without any catalyst
(Table 1, entries 4 and 5, respectively). Only a 26% yield was
obtained in the absence of a base, and a 45% yield was
achieved when 1.5 equiv of NaHCO3 was used (Table 1,
entries 6 and 7, respectively). Since the yield of 3a dropped
sharply when reducing the amounts of ZnBr2, 2 equiv of ZnBr2
was necessary (Table 1, entries 8 and 9, respectively).
Lowering the amounts of TBN or 2a slightly influenced the
yield (Table 1, entries 10 and 11, respectively). When the
reaction was conducted under an air atmosphere, the yield
B
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obtained in a comparable yield with the aid of p-
toluenesulfonic acid monohydrate (eq 1).
respectively). At last, this method was employed to synthesize
the herbicide safener isoxadifen-ethyl12 5x in a 67% yield from
the commercially available 1,1-diphenylethylene in a single
step.
To gain insight into the mechanism, several control
experiments were carried out (Scheme 4). A phenomenon of
Scheme 4. Control Experiments
To further demonstrate the potential utility of this reaction,
we employed this method to synthesize isoxazolines (Scheme
3). With slightly lower equivalents of compound 2, TBN, and
a
Scheme 3. Synthesis of Isoxazolines
slowly released nitrogen was observed,13 and the dimer
oxadiazole 6 was detected by HRMS in the model reaction.
Next, 2a was applied to the standard conditions in the absence
of alkenes or alkynes, and oxadiazole 6 was isolated in a 30%
yield (Scheme 4a). This result indicates that nitrile oxide could
be the key intermediate in this reaction system.14 In addition,
the heterocyclization reaction was completely shut down when
2 equiv of TEMPO was added, suggesting that a radical
intermediate may be involved in this transformation (Scheme
4b). Some possible intermediates were prepared and applied to
this reaction system, such as ethyl diazoacetate (7) and ethyl 2-
(hydroxyimino)acetate (8). Both of them afforded the desired
product 3a under the standard condition (Scheme 5c and d,
a
Standard conditions B are as follows: 4 (0.3 mmol), 2 (2 equiv),
[Cp*RhCl2]2 (1 mol %), TBN (2 equiv), ZnBr2 (2 equiv), and
NaHCO3 (2 equiv) in methyl tert-butyl ether (3 mL); stirred for 24 h
in a closed 10 mL vial at room temperature under a N2 atmosphere.
Reaction yields refer to isolated yields. Used 4 equiv of 2a, TBN, and
NaHCO3.
b
Scheme 5. Proposed Mechanism
NaHCO3 (standard condition B), the desired isoxazoline
products were still obtained with good to high yields. For
example, various alkenes containing aryl [(with electron-
withdrawing or electron-donoating functional groups (EWGs
or EDGs, respectively) in different positions) or alkyl groups
were compatible in this transformation (5a−o). When 2,3-
dimethylbuta-1,3-diene was used in this standard conditions,
compound 5p was obtained in a 73% yield with specificity;
meanwhile, the bisisoxazoline product 5q was achieved in a
65% yield, and no 5p was found when the equivalents of 2a,
TBN, and NaHCO3 were doubled. The enantiomerically pure
monoterpenes (1R)-(+)-α-pinene and (1S)-(−)-α-pinene
reacted with 2a to give 57% and 58% yields of thes isoxazoline
5r and 5s, respectively, as a single product. However, the
internal alkene with two EWGs, such as dimethyl fumarate,
only afforded product 5t in a 38% yield. Other amino-
acetonitrile, glycine methyl ester, or trifluoroethylamine
hydrochloride were compatible with these conditions and
gave the desired products in 60%−78% yields (5u−w,
respectively). Although the yield is relatively low, these
compounds may still be intermediates considering that the
reaction is sensitive to acid and alkali (Table 1, entries 6−9 and
eq 1].
Although the detailed reaction pathway remains to be
clarified, a plausible mechanism for this reaction was proposed
on the basis of the above results and previous literature reports
C
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(Scheme 5).15 The reaction is initiated by the formation of a
Rh-carbene B from the diazo-compound A,16 which was
generated in situ via the reaction of the amine with tert-butyl
nitrite. Meanwhile, the interaction of tert-butyl nitrite with
ZnBr2 gives rise to a nitroso radical, which is captured by the
Rh-carbene B to either afford the nitrile oxide D directly or go
preferentially through the intermediate C.5a Finally, inter-
mediate D undergoes 1,3-dipolar cycloaddition with the alkene
or alkyne to deliver the final product 3 or 5, respectively.
In summary, we have developed an unprecedented Rh-
catalyzed oxidative reaction of commercially available amines
and tert-butyl nitrite with alkynes or alkenes as an efficient
approach to the direct construction of isoxazoles or isoxazo-
lines, respectively, with multiple bonds formation in a “click”
manner. The salient features of this reaction include readily
available materials, mild reaction conditions, good functional
group tolerance, and the late-stage modification of drugs. In
addition, this is the first example of using a cheap and
commercially available amine as the nitrile oxide precursor. In
a broader context, our results demonstrate an unprecedented
control of the selectivity of amine oxidation to a nitrile oxide,
which was enabled by a mild Rh-catalyzed reaction. This
technology eliminates many problems inherent in the previous
multistep fashion of preparing the nitrile oxide intermediate. It
will create new opportunities to incorporate N−O heterocycles
in drugs and biologics. Further novel applications using an
amine as a safe and readily available nitrile oxide precursor can
be expected in the near future.
stirred at room temperature (during the reaction, the slowly generated
nitrogen needs to be released every few hours, otherwise the nitrogen
ballon may burst.) After 24 h, the reaction mixture was filtered over a
plug of Celite (EtOAc as the eluent), and the filtrate was washed with
saturated aqueous sodium thiosulfate (30 mL) and dried over
anhydrous magnesium sulfate. The organic phase was concentrated
under reduced pressure, and the resulting residue was purified by flash
column chromatography to afford the product 3a (1.58 g, 90%).
Ethyl 5-([1,1′-Biphenyl]-4-yl)isoxazole-3-carboxylate (3a).17a Pu-
rified by flash column chromatography (petroleum ether/AcOEt =
1
70:1), pale yellow solid (82.5 mg, 94% yield): H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 8.3 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.63 (d,
J = 7.5 Hz, 2 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.40 (t, J = 7.5 Hz, 1 H),
6.96 (s, 1 H), 4.48 (q, J = 7.1 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.8, 160.4, 157.3, 143.9,
140.1, 129.3, 128.4, 128.1, 127.4, 126.7, 125.7, 100.2, 62.6, 14.5;
HRMS (ESI) m/z calcd for C18H16O3N+ [M + H]+ 294.1125, found
294.1124.
Ethyl 5-Phenylisoxazole-3-carboxylate (3b).6f Purified by flash
column chromatography (petroleum ether/AcOEt = 70:1), pale
1
yellow solid (57.8 mg, 89% yield): H NMR (400 MHz, CDCl3) δ
7.80−7.77 (m, 2 H), 7.47−7.45 (m, 3 H), 6.91 (s, 1 H), 4.45 (t, J =
7.2 Hz, 1 H), 1.42 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 172.0, 160.3, 157.2, 131.1, 129.4, 126.9, 126.2, 100.2, 62.5,
14.4.
Ethyl 5-(3-Fluorophenyl)isoxazole-3-carboxylate (3c).15b Purified
by flash column chromatography (petroleum ether/AcOEt = 50:1),
colorless crystal (55.4 mg, 79% yield): 1H NMR (400 MHz, CDCl3) δ
7.58−7.56 (m, 1 H), 7.50−7.42 (m, 2 H), 7.18−7.13 (m, 1 H), 6.93
(s, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H); 13C{1H}
NMR (100 MHz, CDCl3) δ170.6 (C−F, 4JC−F = 2.9 Hz), 163.2 (C−
F, 1JC−F = 247.0 Hz), 160.1, 157.3, 131.3 (C−F, 3JC−F = 8.2 Hz),
128.7 (C−F, 3 JC−F = 8.4 Hz), 122.0 (C−F, 4 JC−F = 3.2 Hz), 118.1
(C−F, 2 JC−F = 21.3 Hz), 113.2 (C−F, 2 JC−F = 23.8 Hz), 101.0, 62.6,
14.4; 19F NMR (376 MHz, CDCl3) δ −111.13 to −111.19 (m, 1 F);
19F{1H} NMR (376 MHz, CDCl3) δ −111.16 (s, 1 F).
EXPERIMENTAL SECTION
■
General Information. tert-Butyl nitrite was purified by dis-
tillation. Other purchased reagents were used without further
purification unless otherwise noted. All solvents were dried over
activated 4 Å molecular sieves. Chromatographic purification of
products was carried out by flash column chromatography on silica gel
Ethyl 5-(4-Bromophenyl)isoxazole-3-carboxylate (3d).15b Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
50:1), white solid (73.7 mg, 83% yield): 1H NMR (400 MHz,
CDCl3) δ 7.67−7.60 (m, 4 H), 6.92 (s, 1 H), 4.46 (q, J = 7.2 Hz, 2
H), 1.43 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
170.9, 160.1, 157.4, 132.7, 127.6, 125.8, 125.6, 100.6, 62.6, 14.5.
Ethyl 5-(2-Chlorophenyl)isoxazole-3-carboxylate (3e).15b Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
50:1), colorless oil (66.6 mg, 88% yield): 1H NMR (400 MHz,
CDCl3) δ 7.97−7.95 (m, 1 H), 7.53−7.50 (m, 1 H), 7.41−7.39 (m, 2
H), 7.33 (s, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 1.44 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 168.3, 160.2, 157.2, 132.2,
1
(300−400 mesh). NMR spectra were measured in CDCl3 (TMS, H
1
δ 0; CDCl3, H δ 7.26, 13C δ 77.36), DMSO-d6, or CD3OD on a
Bruker AV 400 (1H at 400 MHz, 13C at 100 MHz, and 19F at 376
MHz) magnetic resonance spectrometer. High-resolution mass
spectra (HRMS) were recorded on a SYNAPT G2Si High Definition
MS system (ESI model).
General Procedure for the Synthesis of Isoxazoles. A
solution of alkyne 1 (0.3 mmol, 1.0 equiv) in methyl tert-butyl
ether (3 mL) and tert-butyl nitrite (0.9 mmol, 3.0 equiv) were added
successively to a 15 mL Schlenk tube charged with [Cp*RhCl2]2 (1
mol %), ammonium hydrochloride (0.9 mmol, 3.0 equiv), NaHCO3
(0.9 mmol, 3.0 equiv), ZnBr2 (0.6 mmol, 2.0 equiv), and a magnetic
stirring bar under a nitrogen atmosphere. The mixture was stirred at
room temperature for 24 h, concentrated under vacuum, and purified
by flash column chromatography.
General Procedure for the Synthesis of Isoxazolines. A
solution of alkene 4 (0.3 mmol, 1.0 equiv) in methyl tert-butyl ether
(3 mL) and tert-butyl nitrite (0.6 mmol, 2.0 equiv) were added
successively to a 15 mL Schlenk tube charged with [Cp*RhCl2]2 (1
mol %), ammonium hydrochloride (0.6 mmol, 2.0 equiv), NaHCO3
(0.6 mmol, 2.0 equiv), ZnBr2 (0.6 mmol, 2.0 equiv), and a magnetic
stirring bar under a nitrogen atmosphere. The mixture was stirred at
room temperature for 24 h, concentrated under vacuum, and purified
by flash column chromatography.
131.7, 131.3, 129.7, 127.6, 125.7, 105.1, 62.6, 14.5.
Ethyl 5-(4-(Trifluoromethyl)phenyl)isoxazole-3-carboxylate
(3f).17a Purified by flash column chromatography (petroleum ether/
AcOEt = 40:1), white crystalline solid (74.8 mg, 87% yield): 1H NMR
(400 MHz, CDCl3) δ 7.91 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 8.2 Hz, 2
H), 7.02 (s, 1 H), 4.46 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.3, 160.0, 157.4, 132.7 (C−
F, 2JC−F = 33.0 Hz), 130.0, 126.5, 126.5 (C−F, 3JC−F = 3.8 Hz), 123.9
(C−F, 1JC−F = 273.0 Hz), 101.7, 62.7, 14.4; 19F NMR (376 MHz,
CDCl3) δ −63.1 (s, 1 F); 19F{1H} NMR (376 MHz, CDCl3) δ −63.1
(s, 1 F).
Ethyl 5-(4-Nitrophenyl)isoxazole-3-carboxylate (3g).17b Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1),
light yellow solid (56.5 mg, 72% yield): 1H NMR (400 MHz, CDCl3)
δ 8.36 (d, J = 8.8 Hz, 2 H), 8.00 (d, J = 8.8 Hz, 2 H), 7.11 (s, 1 H),
4.49 (q, J = 7.2 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 169.4, 159.8, 157.6, 149.2, 132.3, 127.1, 124.9,
102.8, 62.9, 14.5; HRMS (ESI) m/z calcd for C12H10O5N2Na+ [M +
Na]+ 285.0482, found 285.0482.
Gram-Scale Synthesis of 3a. A solution of 4-ethynyl-1,1′-
biphenyl 1a (1.07 g, 6.0 mmol, 1.0 equiv) in tert-butyl ether (25 mL)
and tert-butyl nitrite (18.0 mmol, 3.0 equiv) were added successively
to a 150 mL Schlenk tube charged with [Cp*RhCl2]2 (1 mol %),
glycine ethyl ester hydrochloride 2a (2.51g, 18.0 mmol, 3.0 equiv),
NaHCO3 (18.0 mmol, 3.0 equiv), ZnBr2 (12.0 mmol, 2.0 equiv), and
a magnetic stirring bar under a nitrogen atmosphere. The mixture was
Ethyl 5-(3-Nitrophenyl)isoxazole-3-carboxylate (3h). Purified by
flash column chromatography (petroleum ether/AcOEt = 10:1, Rf =
0.28), colorless crystal (76.4 mg, 97% yield): IR (KBr, cm−1) ν 1728,
D
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1621, 1528, 1446, 1353, 1291, 1258, 1149, 1108, 1017, 942, 809, 781,
743, 687; H NMR (400 MHz, CDCl3) δ 8.62 (t, J = 1.8 Hz, 1 H),
H), 6.84−6.82 (m, 1 H), 6.71 (s, 1 H), 4.46 (q, J = 7.2 Hz, 2 H), 1.44
(t, J = 7.2 Hz, 3 H), 1.15 (s, 9 H); 13C{1H} NMR (100 MHz, CDCl3)
δ 171.8, 160.3, 157.1, 156.4, 135.8, 132.7, 130.5, 130.3, 128.2, 127.9,
122.5, 119.0, 117.5, 100.3, 62.4, 26.8, 19.8, 14.4.
1
8.32−8.30 (m, 1 H), 8.15−8.12 (m, 1 H), 7.71 (t, J = 8.0 Hz, 1 H),
7.09 (s, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 169.3, 159.8, 157.6, 149.0,
131.7, 130.8, 128.4, 125.5, 121.2, 102.0, 62.8, 14.4; HRMS (ESI) m/z
Ethyl 5-(3-Hydroxyphenyl)isoxazole-3-carboxylate (3p).2d Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
2:1), white powder (55.8 mg, 80% yield): 1H NMR (400 MHz,
CD3OD) δ 7.33−7.32 (m, 2 H), 7.27−7.26 (m, 1 H), 7.09 (s, 1 H),
6.94−6.91 (m, 1 H), 4.44 (q, J = 7.2 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3
H); 13C{1H} NMR (100 MHz, CD3OD) δ 173.3, 161.2, 159.4, 158.3,
131.5, 129.0, 119.1, 118.1, 113.4, 101.0, 63.2, 14.4.
calcd for C12H11O5N2 [M + H]+ 263.0662, found 263.0667.
+
Ethyl 5-(p-Tolyl)isoxazole-3-carboxylate (3i).15b Purified by flash
column chromatography (petroleum ether/AcOEt = 50:1), white
solid (59.1 mg, 85% yield): 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J
= 8.1 Hz, 2 H), 7.19 (d, J = 8.1 Hz, 2 H), 6.78 (s, 1 H), 4.38 (q, J =
7.2 Hz, 2 H), 2.31 (s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 172.1, 160.3, 157.1, 141.5, 130.0, 126.1, 124.2,
99.6, 62.4, 21.8, 14.4.
Ethyl 5-(1-(Ethoxycarbonyl)-1H-indol-3-yl)isoxazole-3-carboxy-
late (3q). Purified by flash column chromatography (petroleum
ether/AcOEt = 20:1, Rf = 0.30), white solid (83.7 mg, 85% yield): IR
(KBr, cm−1) ν 1734, 1619, 1599, 1546, 1451, 1380, 1324, 1236, 1100,
1022, 828, 780, 762; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.0
Hz, 1 H), 8.15 (s, 1 H), 7.90 (d, J = 7.7 Hz, 1 H), 7.45−7.36 (m, 2
H), 6.94 (s, 1 H), 4.54 (q, J = 7.2 Hz, 2 H), 4.49 (q, J = 7.2 Hz, 2 H),
1.50 (t, J = 7.2 Hz, 3 H), 1.45 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.9, 160.3, 157.1, 150.7, 135.8, 126.4, 126.1,
125.6, 124.5, 120.5, 115.9, 109.2, 100.5, 64.4, 62.6, 14.7, 14.5; HRMS
(ESI) m/z calcd for C17H16O5N2Na+ [M + Na]+ 351.0951, found
351.0950.
Ethyl 5-(2-Methoxyphenyl)isoxazole-3-carboxylate (3j). Purified
by flash column chromatography (petroleum ether/AcOEt = 30:1, Rf
= 0.30), white solid (55.4 mg, 75% yield): IR (KBr, cm−1) ν 1728,
1
1611, 1450, 1446, 1260, 1247, 1235, 1146, 1018, 779, 755, 750; H
NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 1.5, 7.8 Hz, 1 H), 7.46−
7.41 (m, 1 H), 7.17 (s, 1 H), 7.08 (t, J = 7.6 Hz, 1 H), 7.02 (d, J = 8.4
Hz, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 3.97 (s, 3 H), 1.44 (t, J = 7.2 Hz,
3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.1, 160.8, 157.3,
156.6, 132.2, 128.0, 121.2, 115.9, 111.6, 104.2, 62.4, 55.9, 14.5;
HRMS (ESI) m/z calcd for C13H14O4N+ [M + H]+ 248.0917, found
248.0925.
Ethyl 5-(Pyridin-3-yl)isoxazole-3-carboxylate (3r).17c Purified by
flash column chromatography (petroleum ether/AcOEt = 2:1),
colorless crystal (42.4 mg, 65% yield): 1H NMR (400 MHz,
CDCl3) δ 9.05 (d, J = 1.7 Hz, 1 H), 8.71 (dd, J = 1.6, 4.8 Hz, 1
H), 8.12 (dt, J = 2.0, 8.0 Hz, 1 H), 7.47−7.43 (m, 1 H), 7.03 (s, 1 H),
4.48 (q, J = 7.2 Hz, 2 H), 1.44 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 169.3, 160.0, 157.5, 151.9, 147.4, 133.4, 124.2,
123.3, 101.3, 62.8, 14.5; HRMS (ESI) m/z calcd for C11H11O3N2+ [M
+ H]+ 219.0764, found 219.0773.
Ethyl 5-(4-Methoxyphenyl)isoxazole-3-carboxylate (3k).15b Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
1
30:1), colorless crystal (52.7 mg, 71% yield): H NMR (400 MHz,
CDCl3) δ 7.73 (d, J = 8.9 Hz, 2 H), 6.98 (d, J = 8.9 Hz, 2 H), 6.78 (s,
1 H), 4.45 (q, J = 7.2 Hz, 2 H), 3.85 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3
H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 161.9, 160.5, 157.2,
127.9, 119.7, 114.9, 98.8, 62.4, 55.7, 14.5; HRMS (ESI) m/z calcd for
C13H14O4N+ [M + H]+ 248.0917, found 248.0923.
Ethyl 5-(4-(Methoxycarbonyl)phenyl)isoxazole-3-carboxylate
(3l). Purified by flash column chromatography (petroleum ether/
AcOEt = 20:1, Rf = 0.35), white solid (53.0 mg, 68% yield): IR (KBr,
cm−1) ν 1732, 1718, 1590, 1438, 1278, 1255, 1151, 1102, 1017, 949,
827, 784, 704; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2
H), 7.85 (d, J = 8.4 Hz, 2 H), 7.00 (s, 1 H), 4.45 (q, J = 7.2 Hz, 2 H),
3.92 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 170.7, 166.4, 160.0, 157.4, 132.3, 130.6, 130.6, 126.1, 101.7,
62.6, 52.7, 14.4; HRMS (ESI) m/z calcd for C14H14O5N+ [M + H]+
276.0866, found 276.0869.
Ethyl 5-(3-Acetamidophenyl)isoxazole-3-carboxylate (3m). Puri-
fied by flash column chromatography (petroleum ether/AcOEt = 1:1,
Rf = 0.40), white solid (60.7 mg, 74% yield): IR (KBr, cm−1) ν 3377,
1732, 1688, 1577, 1545, 1496, 1430, 1311, 1257, 1020, 939, 833, 782,
702; 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1 H), 8.17 (s, 1 H),
7.61 (dd, J = 7.9, 21.7 Hz, 2 H), 7.43 (t, J = 7.9 Hz, 1 H), 7.31 (s, 1
H), 4.35 (q, J = 7.1 Hz, 2 H), 2.05 (s, 3 H), 1.31 (t, J = 7.1 Hz, 3 H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 171.4, 169.2, 159.7, 157.3,
Ethyl 5-(Thiophen-2-yl)isoxazole-3-carboxylate (3s).15b Purified
by flash column chromatography (petroleum ether/AcOEt = 30:1),
pale yellow solid (51.5 mg, 77% yield): 1H NMR (400 MHz, CDCl3)
δ 7.53 (dd, J = 1.0, 3.7 Hz, 1 H), 7.47 (dd, J = 1.0, 5.0 Hz, 1 H), 7.11
(dd, J = 3.7, 5.0 Hz, 1 H), 6.75 (s, 1 H), 4.43 (q, J = 7.2 Hz, 2 H),
1.40 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.9,
160.0, 157.1, 129.1, 128.5, 128.4, 128.0, 99.8, 62.5, 14.4.
Ethyl 5-Hexylisoxazole-3-carboxylate (3t).17d Purified by flash
column chromatography (petroleum ether/AcOEt = 80:1), colorless
1
oil (55.6 mg, 82% yield): H NMR (400 MHz, CDCl3) δ 6.38 (s, 1
H), 4.41 (q, J = 7.2 Hz, 2 H), 2.77 (t, J = 7.6 Hz, 2 H), 1.72−1.65 (m,
2 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.37−1.23 (m, 6 H), 0.86 (t, J = 6.8
Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.1, 160.6, 156.7,
101.7, 62.3, 31.7, 28.9, 27.7, 27.0, 22.8, 14.5, 14.3; HRMS (ESI) m/z
calcd for C12H20O3N+ [M + H]+ 226.1438, found 226.1446.
Ethyl 5-(2-Hydroxyethyl)isoxazole-3-carboxylate (3u).17d Purified
by flash column chromatography (petroleum ether/AcOEt = 4:1),
1
colorless oil (38.7 mg, 70% yield): H NMR (400 MHz, CDCl3) δ
6.52 (s, 1 H), 4.39 (q, J = 7.2 Hz, 2 H), 3.94 (t, J = 6.2 Hz, 2 H), 3.04
(t, J = 6.2 Hz, 2 H), 2.54 (br s, 1 H), 1.37 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 173.1, 160.4, 156.7, 103.0, 62.5,
140.5, 130.3, 126.8, 121.7, 121.2, 116.0, 101.2, 62.4, 24.5, 14.4;
HRMS (ESI) m/z calcd for C14H15O4N2+ [M + H]+ 275.1026, found
275.1030.
60.0, 30.5, 14.4; HRMS (ESI) m/z calcd for C8H11O4NNa+ [M +
Na]+ 208.0580, found 208.0586.
Ethyl 5-(3-(((Benzyloxy)carbonyl)amino)phenyl)isoxazole-3-car-
boxylate (3n). Purified by flash column chromatography (petroleum
ether/AcOEt = 5:1, Rf = 0.30), colorless crystal (85.6 mg, 78% yield):
IR (KBr, cm−1) ν 3338, 1724, 1577, 1544, 1499, 1409, 1251, 1222,
Ethyl 5-(2-((4-Nitrobenzoyl)oxy)ethyl)isoxazole-3-carboxylate
(3v). Purified by flash column chromatography (petroleum ether/
AcOEt = 4:1, Rf = 0.42), colorless crystal (75.1 mg, 75% yield): IR
(KBr, cm−1) ν 1729, 1718, 1532, 1461, 1277, 1253, 1115, 1003, 935,
1
1068, 804, 775, 768, 695; H NMR (400 MHz, CDCl3) δ 7.91 (s, 1
1
882, 839, 787, 721; H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.9
H), 7.52−7.49 (m, 2 H), 7.43−7.34 (m, 6 H), 6.93 (s, 1 H), 6.91 (s, 1
H), 5.22 (s, 2 H), 4.46 (q, J = 7.2 Hz, 2 H), 1.43 (q, J = 7.2 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.6, 160.3, 157.3, 153.5,
139.1, 136.1, 130.3, 129.0, 128.8, 128.7, 127.8, 121.3, 121.1, 116.2,
100.7, 67.7, 62.6, 14.5; HRMS (ESI) m/z calcd for C20H19O5N2+ [M
+ H]+ 367.1288, found 367.1282.
Hz, 2 H), 8.14 (d, J = 8.9 Hz, 2 H), 6.56 (s, 1 H), 4.67 (t, J = 6.3 Hz,
2 H), 4.40 (q, J = 7.2 Hz, 2 H), 3.33 (t, J = 6.3 Hz, 2 H), 1.37 (t, J =
7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 164.7,
159.3 (t, J = 30.0 Hz), 151.1, 135.2, 131.1, 124.0, 109.3 (t, J = 237.0
Hz), 99.5, 62.6, 27.0; HRMS (ESI) m/z calcd for C15H15O7N2+ [M +
H]+ 335.0874, found 335.0862.
Ethyl 5-(3-((Tert-butyldiphenylsilyl)oxy)phenyl)isoxazole-3-car-
boxylate (3o).2d Purified by flash column chromatography (petro-
Ethyl 5-(Triisopropylsilyl)isoxazole-3-carboxylate (3w). Purified
by flash column chromatography (petroleum ether/AcOEt = 100:1, Rf
= 0.36), colorless oil (48.3 mg, 54% yield): IR (KBr, cm−1) ν 2947,
1
leum ether/AcOEt = 5:1), colorless oil (136.0 mg, 96% yield): H
NMR (400 MHz, CDCl3) δ 7.76−7.74 (m, 4 H), 7.47−7.38 (m, 6
H), 7.33−7.31 (m, 1 H), 7.23−7.22 (m, 1 H), 7.17 (t, J = 8.0 Hz, 1
1
2869, 1731, 1540, 1466, 1431, 1231, 1131, 1020, 883, 780, 686; H
E
https://dx.doi.org/10.1021/acs.joc.0c02281
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
NMR (400 MHz, CDCl3) δ 6.88 (s, 1 H), 4.43 (q, J = 7.2 Hz, 2 H),
1.41 (t, J = 7.2 Hz, 3 H), 1.38−1.33 (m, 3 H), 1.11 (s, 9 H), 1.09 (s, 9
H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.4, 160.9, 155.1, 114.9,
62.3, 18.6, 14.5, 11.2; HRMS (ESI) m/z calcd for C15H28O3N+ [M +
H]+ 298.1833, found 298.1833.
H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 170.5, 160.1, 159.4,
142.7, 139.4, 129.6, 128.7, 127.9, 127.3, 126.9, 125.7, 100.3, 26.4;
HRMS (ESI) m/z calcd for C17H14O2N2Na+ [M + Na]+ 301.0947,
found 301.0949.
Methyl (5-([1,1′-Biphenyl]-4-yl)isoxazole-3-carbonyl)-L-isoleuci-
nate (3ee). Purified by flash column chromatography (petroleum
ether/AcOEt = 8:1, Rf = 0.34), white solid (71.1 mg, 60% yield): IR
(KBr, cm−1) ν 3326, 2959, 2878, 1747, 1672, 1539, 1447, 1232, 1198,
1148, 843, 766, 723, 690; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J =
8.3 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.63 (d, J = 7.4 Hz, 2 H), 7.47
(t, J = 7.4 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.34 (d, J = 8.7 Hz, 1
H), 6.99 (s, 1 H), 4.80 (dd, J = 5.1, 8.8 Hz, 1 H), 3.79 (s, 3 H), 2.08−
2.01 (m, 1 H), 1.58−1.51(m, 1 H), 1.33−1.25 (m, 1 H), 1.01−0.95
(m, 6 H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 171.8, 159.1,
159.0, 143.8, 140.2, 129.3, 128.4, 128.1, 127.4, 126.7, 125.8, 99.5,
56.9, 52.6, 38.4, 25.5, 15.9, 11.9; HRMS (ESI) m/z calcd for
Ethyl 5-(Phenylcarbamoyl)isoxazole-3-carboxylate (3x). Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1, Rf
= 0.25), white solid (60.2 mg, 77% yield): IR (KBr, cm−1) ν 3342,
1
1744, 1679, 1539, 1443, 1323, 1248, 1224, 1028, 759, 750, 689; H
NMR (400 MHz, CDCl3) δ 8.42 (br s, 1 H), 7.67−7.65 (m, 2 H),
7.40−7.36 (m, 3 H), 7.20 (t, J = 7.4 Hz, 1 H), 4.46 (q, J = 7.2 Hz, 2
H), 1.42 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
165.2, 159.2, 157.8, 153.1, 136.6, 129.6, 126.0, 120.8, 108.4, 63.0,
+
14.4; HRMS (ESI) m/z calcd for C13H13O4N2 [M + H]+ 261.0870,
found 261.0876.
3-Ethyl 5-Methyl Isoxazole-3,5-dicarboxylate (3y). Purified by
flash column chromatography (petroleum ether/AcOEt = 20:1, Rf =
0.32), colorless crystal (53.9 mg, 90% yield): IR (KBr, cm−1) ν 1738,
+
C23H25O4N2 [M + H]+ 393.1809, found 393.1804.
N-Cyclopropyl-5-(thiophen-2-yl)isoxazole-3-carboxamide
(3ff).2b Purified by flash column chromatography (petroleum ether/
1
1724, 1586, 1434, 1253, 1085, 1019, 927, 879, 831, 773; H NMR
1
AcOEt = 10:1), white solid (51.2 mg, 73% yield): H NMR (400
(400 MHz, CDCl3) δ 7.30 (s, 1 H), 4.46 (q, J = 7.2 Hz, 2 H), 3.98 (s,
3 H), 1.42 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
161.9, 159.2, 157.3, 156.8, 110.1, 63.0, 53.5, 14.4; HRMS (ESI) m/z
calcd for C8H9O5NNa+ [M + Na]+ 222.0373, found 222.0379.
Ethyl 5-Benzoylisoxazole-3-carboxylate (3z). Purified by flash
column chromatography (petroleum ether/AcOEt = 15:1, Rf = 0.34),
colorless oil (50.6 mg, 69% yield): IR (KBr, cm−1) ν 1735, 1666,
MHz, CDCl3) δ 7.54 (dd, J = 1.0, 3.7 Hz, 1 H), 7.49 (dd, J = 1.0, 5.0
Hz, 1 H), 7.14 (dd, J = 3.7, 5.0 Hz, 1 H), 6.91 (br s, 1 H), 6.82 (s, 1
H), 2.93−2.87 (m, 1 H), 0.91−0.86 (m, 2 H), 0.69−0.65 (m, 2 H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 160.3, 159.3, 129.1,
128.8, 128.6, 128.0, 99.1, 22.9, 7.0; HRMS (ESI) m/z calcd for
C11H10O2N2SNa+ [M + Na]+ 257.0355, found 257.0356.
1
1599, 1448, 1242, 1186, 1019, 891, 798, 721, 681; H NMR (400
N-Adamantyl-5-(4-(pentyloxy)phenyl)isoxazole-3-carboxamide
(3gg).2c Purified by flash column chromatography (petroleum ether/
AcOEt = 30:1), colorless crystal (97.2 mg, 79% yield): 1H NMR (400
MHz, CDCl3) δ 7.70 (d, J = 8.6 Hz, 2 H), 6.96 (d, J = 8.6 Hz, 2 H),
6.77 (s, 1 H), 6.55 (br s, 1 H), 4.00 (t, J = 6.6 Hz, 2 H), 2.12 (s, 9 H),
1.82−1.69 (m, 8 H), 1.45−1.38 (m, 4 H), 0.94 (t, J = 7.0 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.8, 161.4, 160.4, 158.3,
MHz, CDCl3) δ 8.06−8.04 (m, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.51
(t, J = 7.8 Hz, 2 H), 7.33 (s, 1 H), 4.45 (q, J = 7.2 Hz, 2 H), 1.40 (t, J
= 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 180.8, 168.1,
159.3, 156.9, 135.3, 134.7, 130.1, 129.2, 110.6, 62.9, 14.3; HRMS
(ESI) m/z calcd for C13H12O4N+ [M + H]+ 246.0761, found
246.0765.
Methyl 5-([1,1′-Biphenyl]-4-yl)isoxazole-3-carboxylate (3aa).
Purified by flash column chromatography (petroleum ether/AcOEt
= 80:1, Rf = 0.48), pale yellow solid (75.6 mg, 90% yield): IR (KBr,
cm−1) ν 1755, 1741, 1612, 1461, 1418, 1241, 1148, 1016, 805, 768,
127.8, 119.8, 115.3, 98.0, 68.5, 52.9, 41.8, 36.6, 29.8, 29.2, 28.5, 22.8,
14.3; HRMS (ESI) m/z calcd for C25H32O3N2Na+ [M + Na]+
431.2305, found 431.2284.
Ethyl 5-((8R,9S,10R,13S,14S,17S)-17-Hydroxy-13-methyl-3-oxo-
2,3, 6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-17-yl)isoxazole-3-carboxylate (3hh).
Purified by flash column chromatography (petroleum ether/AcOEt
= 3:1, Rf = 0.22), white solid (67.9 mg, 55% yield): IR (KBr, cm−1) ν
3313, 2930, 2912, 1737, 1653, 1573, 1454, 1272, 1245, 1198, 1191,
1133, 1014, 916, 830, 817, 775; 1H NMR (400 MHz, CDCl3) δ 6.56
(s, 1 H), 5.80 (s, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 2.49−2.46 (m, 1 H),
2.38−2.34 (m, 2 H), 2.28−2.17 (m, 3 H), 2.12−2.05 (m, 2 H), 1.87−
1.73 (m, 4 H), 1.64−1.52 (m, 2 H), 1.43−1.39 (m, 5 H), 1.27−1.18
(m, 2 H), 1.06 (s, 3 H), 0.70−0.68 (m, 1 H), 0.59−0.53 (m, 1 H);
13C{1H} NMR (100 MHz, CDCl3) δ 200.0, 179.0, 166.3, 160.1,
1
726, 693; H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2 H),
7.69 (d, J = 8.3 Hz, 2 H), 7.61(d, J = 7.3 Hz, 2 H), 7.46 (t, J = 7.3 Hz,
2 H), 7.39 (t, J = 7.3 Hz, 1 H), 6.94 (s, 1 H), 4.00 (s, 3 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 171.8, 160.7, 156.9, 143.8, 140.0, 129.2,
128.4, 128.0, 127.3, 126.6, 125.6, 100.2, 53.1; HRMS (ESI) m/z calcd
for C17H13O3NNa+ [M + Na]+ 302.0788, found 302.0788.
tert-Butyl 5-([1,1′-biphenyl]-4-yl)isoxazole-3-carboxylate (3bb).
Purified by flash column chromatography (petroleum ether/AcOEt =
80:1, Rf = 0.50), white solid (84.7 mg, 88% yield): IR (KBr, cm−1) ν
2984, 1718, 1631, 1443, 1368, 1254, 1170, 1112, 995, 831, 769, 731,
1
699; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 2 H), 7.70
(d, J = 8.4 Hz, 2 H), 7.64−7.61 (m, 2 H), 7.49−7.45 (m, 2 H), 7.41−
7.37 (m, 1 H), 6.89 (s, 1 H), 1.65 (s, 9 H); 13C{1H} NMR (100
MHz, CDCl3) δ 171.5, 159.4, 158.5, 143.7, 140.2, 129.3, 128.4, 128.0,
127.4, 126.6, 125.9, 100.2, 84.0, 28.4; HRMS (ESI) m/z calcd for
C20H19O3NNa+ [M + Na]+ 344.1257, found 344.1248.
5-([1,1′-Biphenyl]-4-yl)isoxazole-3-carbonitrile (3cc). Purified by
flash column chromatography (petroleum ether/AcOEt = 70:1, Rf =
0.45), colorless crystal (49.4 mg, 67% yield): IR (KBr, cm−1) ν 1610,
1579, 1486, 1415, 1047, 1006, 949, 845, 802, 768, 722, 690; 1H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2 H), 7.75 (d, J = 8.5 Hz, 2
H), 7.64 (d, J = 7.5 Hz, 2 H), 7.50 (t, J = 7.3 Hz, 2 H), 7.43 (t, J = 7.3
Hz, 1 H), 6.84 (s, 1 H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.7,
144.7, 140.4, 139.8, 129.4, 128.7, 128.2, 127.4, 126.9, 124.5, 110.4,
101.7; HRMS (ESI) m/z calcd for C16H10ON2Na+ [M + Na]+
269.0685, found 269.0695.
5-([1,1′-Biphenyl]-4-yl)-N-methylisoxazole-3-carboxamide
(3dd). Purified by flash column chromatography (petroleum ether/
AcOEt = 20:1, Rf = 0.28), colorless crystal (54.1 mg, 65% yield): IR
(KBr, cm−1) ν 3329, 1668, 1564, 1447, 1263, 974, 948, 862, 812, 766,
728, 696; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (br s, 1 H), 8.02 (d,
J = 8.2 Hz, 2 H), 7.86 (d, J = 8.2 Hz, 2 H), 7.76 (d, J = 7.5 Hz, 2 H),
7.51 (t, J = 7.5 Hz, 1 H), 7.44−7.40 (m, 1 H), 7.39 (s, 1 H), 2.82 (s, 3
156.0, 124.7, 102.9, 83.5, 62.3, 48.8, 48.6, 48.2, 42.4, 40.9, 37.2, 36.5,
35.4, 32.8, 30.7, 26.5, 26.0, 23.6, 14.2, 14.0; HRMS (ESI) m/z calcd
for C24H32O5N+ [M + H]+ 414.2275, found 414.2258.
Ethyl 5-((8R,9S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,
12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-
yl)isoxazole-3-carboxylate (3ii). Purified by flash column chroma-
tography (petroleum ether/AcOEt = 1:1, Rf = 0.35), white solid,
(79.2 mg, 64% yield): IR (KBr, cm−1) ν 3251, 2927, 2855, 1729,
1619, 1586, 1500, 1451, 1287, 1251, 1223, 1205, 1018, 871, 821, 778;
1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1 H), 6.95 (d, J = 8.5 Hz,
1 H), 6.72 (s, 1 H), 6.49−6.46 (m, 1 H), 6.42 (s, 1 H), 5.86 (s, 1 H),
4.36 (q, J = 7.1 Hz, 2 H), 2.73−2.69 (m, 2 H), 2.30−2.23 (m, 1 H),
2.14−2.11 (m, 1 H), 2.03−1.97 (m, 1 H), 1.87−1.81 (m, 3 H), 1.69−
1.65 (m, 1 H), 1.48−1.36 (m, 3 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.26−
1.22 (m, 2 H), 0.94 (s, 3 H), 0.62−0.56 (m, 1 H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 181.1, 160.1, 155.8, 155.4, 137.5, 130.6,
126.4, 115.4, 113.2, 103.2, 82.7, 79.6, 62.2, 48.9, 48.4, 43.5, 39.6, 37.1,
33.4, 29.6, 27.6, 26.4, 23.6, 14.4; HRMS (ESI) m/z calcd for
C24H29O5NNa+ [M + Na]+ 434.1938, found 434.1920.
Ethyl 5-([1,1′-Biphenyl]-4-yl)-4,5-dihydroisoxazole-3-carboxylate
(5a).17e Purified by flash column chromatography (petroleum ether/
1
AcOEt = 20:1), pale yellow solid (80.8 mg, 91% yield): H NMR
F
https://dx.doi.org/10.1021/acs.joc.0c02281
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(400 MHz, CDCl3) δ 7.63−7.58 (m, 4 H), 7.47−7.35 (m, 5 H), 5.84
(dd, J = 8.9, 11.5 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 3.67 (dd, J =
11.5, 17.8 Hz, 1 H), 3.27 (dd, J = 8.9, 17.8 Hz, 1 H), 1.39 (t, J = 7.1
Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 151.5, 141.9,
140.7, 138.7, 129.1, 127.9, 127.9, 127.4, 126.7, 85.1, 62.5, 41.7, 14.4;
HRMS (ESI) m/z calcd for C18H18O3N+ [M + H]+ 296.1281, found
296.1287.
160.6, 151.6, 138.0, 131.4, 130.0, 129.8, 127.6, 126.7, 82.1, 62.5, 41.6,
14.4.
Ethyl 5-(m-Tolyl)-4,5-dihydroisoxazole-3-carboxylate (5i).17e Pu-
rified by flash column chromatography (petroleum ether/AcOEt =
20:1), colorless oil (58.9 mg, 84% yield): 1H NMR (400 MHz,
CDCl3) δ 7.28−7.24 (m, 1 H), 7.15−7.10 (m, 3 H), 5.75 (dd, J = 8.9,
11.5 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 3.62 (dd, J = 11.6, 17.8 Hz, 1
H), 3.21 (dd, J = 8.9, 17.8 Hz, 1 H), 2.36 (s, 3 H), 1.38 (t, J = 7.2 Hz,
3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 151.4, 139.8,
139.0, 129.7, 129.1, 126.8, 123.3, 85.3, 62.4, 41.7, 21.7, 14.4; HRMS
(ESI) m/z calcd for C13H16O3N+ [M + H]+ 234.1125, found
234.1128.
Ethyl 5-Phenyl-4,5-dihydroisoxazole-3-carboxylate (5b).17e Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
1
20:1), pale yellow oil (57.1 mg, 87% yield): H NMR (400 MHz,
CDCl3) δ 7.40−7.31 (m, 5 H), 5.79 (dd, J = 8.9, 11.6 Hz, 1 H), 4.36
(q, J = 7.2 Hz, 2 H), 3.64 (dd, J = 11.6, 17.8 Hz, 1 H), 3.22 (dd, J =
8.9, 17.8 Hz, 1 H), 1.38 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 160.9, 151.5, 139.9, 129.2, 129.0, 126.2, 85.3, 62.5,
41.8, 14.5.
Ethyl 5-Methyl-5-phenyl-4,5-dihydroisoxazole-3-carboxylate
(5j).17e Purified by flash column chromatography (petroleum ether/
1
AcOEt = 20:1), colorless oil (60.7 mg, 87% yield): H NMR (400
MHz, CDCl3) δ 7.41−7.35 (m, 4 H), 7.31−7.27 (m, 1 H), 4.33 (q, J
= 7.1 Hz, 2 H), 3.42−3.30 (m, 2 H), 1.77 (s, 3 H), 1.36 (t, J = 7.1 Hz,
3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.0, 151.3, 144.6,
128.9, 128.0, 124.7, 91.5, 62.3, 47.4, 28.4, 14.4.
Ethyl 5-(4-Bromophenyl)-4,5-dihydroisoxazole-3-carboxylate
(5c).17e Purified by flash column chromatography (petroleum ether/
1
AcOEt = 20:1), pale yellow oil (74.5 mg, 83% yield): H NMR (400
MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H),
5.73 (dd, J = 8.7, 11.6 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H), 3.64 (dd, J
= 11.6, 17.8 Hz, 1 H), 3.16 (dd, J = 8.7, 17.8 Hz, 1 H), 1.37 (t, J = 7.2
Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.7, 151.4, 138.9,
132.3, 127.8, 123.0, 84.4, 62.6, 41.8, 14.4.
Ethyl 5-Hexyl-4,5-dihydroisoxazole-3-carboxylate (5k).15a Puri-
fied by flash column chromatography (petroleum ether/AcOEt =
50:1), colorless oil (62.5 mg, 92% yield): 1H NMR (400 MHz,
CDCl3) δ 4.82−4.74 (m, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 3.23 (dd, J =
11.0, 17.5 Hz, 1 H), 2.82 (dd, J = 8.5, 17.5 Hz, 1 H), 1.78−1.70 (m, 1
H), 1.59−1.53 (m, 1 H), 1.43−1.39 (m, 1 H), 1.37−1.33 (m, 4 H),
1.31−1.27 (m, 6 H), 0.87 (t, J = 6.9 Hz, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 161.2, 151.7, 84.5, 62.3, 38.7, 35.4, 31.9, 29.3, 25.3,
22.8, 14.4, 14.3.
Ethyl 5-(4-Nitrophenyl)-4,5-dihydroisoxazole-3-carboxylate
(5d).17e Purified by flash column chromatography (petroleum
ether/AcOEt = 8:1), pale yellow oil (68.0 mg, 86% yield): 1H
NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.8 Hz, 2 H), 7.51 (d, J = 8.8
Hz, 2 H), 5.89 (dd, J = 8.2, 11.8 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H),
3.75 (dd, J = 11.7, 17.8 Hz, 1 H), 3.19 (dd, J = 8.2, 17.8 Hz, 1 H),
1.37 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.4,
151.4, 148.3, 147.0, 126.9, 124.5, 83.6, 62.8, 42.2, 14.4; HRMS (ESI)
m/z calcd for C12H12O5N2Na+ [M + Na]+ 287.0638, found 287.0640.
Ethyl 5-(4-Fluorophenyl)-4,5-dihydroisoxazole-3-carboxylate
(5e).17e Purified by flash column chromatography (petroleum
ether/AcOEt = 20:1), pale yellow oil (64.2 mg, 90% yield): 1H
NMR (400 MHz, CDCl3) δ 7.32−7.28 (m, 2 H), 7.08−7.04 (m, 2
H), 5.76 (dd, J = 8.9, 11.5 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 3.63
(dd, J = 11.5, 17.8 Hz, 1 H), 3.18 (dd, J = 8.9, 17.8 Hz, 1 H), 1.37 (t, J
= 7.1 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1 (C−F,
1JC−F = 247.7 Hz), 160.8, 151.5, 135.6 (C−F, 4JC−F = 3.2 Hz), 128.1
(C−F, 3JC−F = 8.3 Hz), 116.2 (C−F, 2 JC−F = 21.7 Hz), 84.6, 62.5,
41.8, 14.4; 19F NMR (376 MHz, CDCl3) δ −112.97 to −111.05 (m, 1
F); 19F{1H} NMR (376 MHz, CDCl3) δ −113.01 (s, 1 F).
Ethyl 5-(Trimethylsilyl)-4,5-dihydroisoxazole-3-carboxylate
(5l).17f Purified by flash column chromatography (petroleum ether/
AcOEt = 50:1), light yellow oil (49.2 mg, 76% yield): 1H NMR (400
MHz, CDCl3) δ 4.31 (q, J = 7.2 Hz, 2 H), 4.16 (dd, J = 12.4, 15.7 Hz,
1 H), 3.31 (dd, J = 12.4, 16.7 Hz, 1 H), 2.92 (dd, J = 15.7, 16.7 Hz, 1
H), 1.33 (t, J = 7.2 Hz, 3 H), 0.10 (s, 9 H); 13C{1H} NMR (100
MHz, CDCl3) δ 161.3, 151.6, 77.6, 62.2, 36.5, 14.4, −3.9; HRMS
(ESI) m/z calcd for C9H18O3NSi+ [M + H]+ 216.1050, found
216.1059.
Diethyl 4,5-Dihydroisoxazole-3,5-dicarboxylate (5m).17g Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1),
1
colorless oil (55.0 mg, 85% yield): H NMR (400 MHz, CDCl3) δ
5.14 (t, J = 10.0 Hz, 1 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.21 (q, J = 7.1
Hz, 2 H), 3.44 (d, J = 10.0 Hz, 2 H), 1.31 (t, J = 7.2 Hz, 3 H), 1.26 (t,
J = 7.1 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 160.0,
151.3, 80.1, 62.5, 62.4, 37.8, 14.3, 14.2.
Ethyl 5-(4-(Trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-car-
boxylate (5f).17e Purified by flash column chromatography (petro-
5-Benzyl 3-Ethyl 4,5-Dihydroisoxazole-3,5-dicarboxylate (5n).6d
Purified by flash column chromatography (petroleum ether/AcOEt =
1
leum ether/AcOEt = 15:1), white solid (73.8 mg, 86% yield): H
1
NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 2 H), 7.43 (d, J = 8.2
Hz, 2 H), 5.83 (dd, J = 8.5, 11.6 Hz, 1 H), 4.34 (q, J = 7.1 Hz, 2 H),
3.69 (dd, J = 11.7, 17.8 Hz, 1 H), 3.17 (dd, J = 8.4, 17.8 Hz, 1 H),
1.35 (t, J = 7.1 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5,
151.4, 143.9, 131.0 (C−F, 2JC−F = 32.6 Hz), 126.4, 126.1 (C−F,
3JC−F = 3.8 Hz), 124.1 (C−F, 1JC−F = 272.0 Hz), 84.1, 62.6, 42.0,
14.3; 19F NMR (376 MHz, CDCl3) δ −62.70 (s, 1 F); 19F{1H} NMR
10:1), pale yellow oil (68.1 mg, 82% yield): H NMR (400 MHz,
CDCl3) δ 7.38−7.31 (m, 5 H), 5.24−5.17 (m, 3 H), 4.32 (q, J = 7.1
Hz, 2 H), 3.50−3.43 (m, 2 H), 1.34 (t, J = 7.1 Hz, 3 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.9, 160.0, 151.3, 135.0, 128.9, 128.9,
128.6, 80.0, 67.9, 62.6, 37.8, 14.3.
5-Benzyl 3-Ethyl 5-Methyl-4,5-dihydroisoxazole-3,5-dicarboxy-
late (5o). Purified by flash column chromatography (petroleum
ether/AcOEt = 15:1, Rf = 0.38), pale yellow oil (84.8 mg, 97% yield):
IR (KBr, cm−1) ν 2984, 2941, 1719, 1595, 1381, 1342, 1269, 1130,
1018, 941, 859, 781, 747, 736; 1H NMR (400 MHz, CDCl3) δ 7.29−
7.23 (m, 5 H), 5.13 (s, 1 H), 4.24 (q, J = 7.2 Hz, 2 H), 3.62 (d, J =
18.0 Hz, 1 H), 2.99 (d, J = 18.0 Hz, 1 H), 1.58 (s, 3 H), 1.26 (t, J =
7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 160.2,
151.2, 135.2, 128.8, 128.7, 128.3, 88.7, 67.9, 62.4, 43.6, 23.5, 14.3;
HRMS (ESI) m/z calcd for C15H18O5N+ [M + H]+ 292.1179, found
292.1179.
Ethyl 5-Methyl-5-(prop-1-en-2-yl)-4,5-dihydroisoxazole-3-car-
boxylate (5p). Purified by flash column chromatography (petroleum
ether/AcOEt = 50:1, Rf = 0.40), colorless oil (43.3 mg, 73% yield): IR
(KBr, cm−1) ν 1719, 1588, 1446, 1340, 1261, 1127, 1018, 956, 810;
1H NMR (400 MHz, CDCl3) δ 5.07 (s, 1 H), 4.90 (s, 1 H), 4.33 (q, J
(376 MHz, CDCl3 ) δ −62.70 (s, 1 F); HRMS (ESI) m/z calcd for
+
C13H12O3NF Na+ [M + Na] 310.0661, found 310.0662.
3
Ethyl 5-(4-Methoxyphenyl)-4,5-dihydroisoxazole-3-carboxylate
(5g).15a Purified by flash column chromatography (petroleum
1
ether/AcOEt = 10:1), yellow oil (54.5 mg, 73% yield): H NMR
(400 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2
H), 5.73 (dd, J = 9.4, 11.3 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 3.81 (s,
1 H), 3.59 (dd, J = 11.5, 17.8 Hz, 1 H), 3.20 (dd, J = 9.2, 17.8 Hz, 1
H), 1.38 (t, J = 7.1 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
161.0, 160.2, 151.5, 131.6, 127.8, 114.5, 85.3, 62.4, 55.6, 41.4, 14.4.
Ethyl 5-(2-Chlorophenyl)-4,5-dihydroisoxazole-3-carboxylate
(5h).17e Purified by flash column chromatography (petroleum
1
ether/AcOEt = 30:1), colorless oil (57.2 mg, 75% yield): H NMR
(400 MHz, CDCl3) δ 7.47−7.45 (m, 1 H), 7.40−7.38 (m, 1 H),
7.32−7.25 (m, 2 H), 6.07 (dd, J = 7.8, 11.7 Hz, 1 H), 4.35 (q, J = 7.2
Hz, 2 H), 3.79 (dd, J = 11.7, 17.9 Hz, 1 H), 3.09 (dd, J = 7.8, 17.9 Hz,
1 H), 1.37 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
= 7.1 Hz, 2 H), 3.19 (d, J = 17.6 Hz, 1 H), 2.97 (d, J = 17.6 Hz, 1 H),
1.79 (s, 3 H), 1.54 (s, 3 H), 1.36 (t, J = 7.1 Hz, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.2, 151.0, 145.5, 111.9, 92.3, 62.3, 44.2, 25.5,
G
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Note
18.8, 14.5; HRMS (ESI) m/z calcd for C10H16O3N+ [M + H]+
198.1125, found 198.1126.
Ethyl 5,5-Diphenyl-4,5-dihydroisoxazole-3-carboxylate (5x).17j
Purified by flash column chromatography (petroleum ether/AcOEt
= 20:1), colorless solid (59.5 mg, 67% yield): H NMR (400 MHz,
1
Diethyl 5,5′-Dimethyl-4,4′,5,5′-tetrahydro-[5,5′-biisoxazole]-
3,3′-dicarboxylate (5q). Purified by flash column chromatography
(petroleum ether/AcOEt = 10:1, Rf = 0.52), light yellow oil (61.2 mg,
65% yield): IR (KBr, cm−1) ν 2959, 2941, 1740, 1596, 1455, 1381,
1267, 1132, 928, 748, 699; 1H NMR (400 MHz, CDCl3) δ 4.36−4.29
(m, 4 H), 3.48 (d, J = 17.8 Hz, 1 H), 3.17 (d, J = 17.8 Hz, 1 H), 2.92
(dd, J = 12.6, 18.0 Hz, 2 H), 1.50 (s, 3 H), 1.45 (s, 3 H), 1.37−1.33
(m, 6 H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.8, 160.7, 151.4,
151.2, 93.0, 93.0, 62.6, 62.4, 42.3, 41.1, 23.4, 22.3, 14.4, 14.4; HRMS
CDCl3) δ 7.40−7.28 (m, 10 H), 4.33 (q, J = 7.1 Hz, 2 H), 3.84 (s, 2
H), 1.35 (t, J = 7.1 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
160.9, 151.4, 143.3, 128.8, 128.3, 126.3, 95.1, 62.5, 47.1, 14.4; HRMS
(ESI) m/z calcd for C18H17O3NNa+ [M + Na]+ 318.1101, found
318.1104.
3,4-Bis(ethoxycarbonyl)-1,2,5-oxadiazole 2-Oxide (6).5g Purified
by flash column chromatography (petroleum ether/AcOEt = 50:1),
1
colorless oil (31.2 mg, 30% yield): H NMR (400 MHz, CDCl3) δ
+
(ESI) m/z calcd for C14H21O6N2 [M + H]+ 313.1394, found
4.49 (q, J = 7.1 Hz, 2 H), 4.44 (q, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.1 Hz,
3 H), 1.38 (t, J = 7.1 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
157.0, 155.5, 148.7, 107.1, 64.0 (2C), 14.3, 14.2; HRMS (ESI) m/z
calcd for C8H10O6N2Na+ [M + Na]+ 253.0431, found 253.0436.
313.1394.
Ethyl (3aS,5S,7S,7aS)-6,6,7a-Trimethyl-3a,4,5,6,7,7a-hexahydro-
5,7-methanobenzo[d]isoxazole-3-carboxylate (5r).5g Purified by
flash column chromatography (petroleum ether/AcOEt = 50:1),
light yellow oil (43.1 mg, 57% yield): 1H NMR (400 MHz, CDCl3) δ
4.38−4.30 (m, 2 H), 3.24 (dd, J = 4.0, 10.9 Hz, 1 H), 2.33−2.22 (m,
2 H), 2.18−2.15 (m, 1 H), 1.97−1.93 (m, 1 H), 1.75 (dt, J = 3.6, 14.0
Hz, 1 H), 1.38−1.35 (m, 6 H), 1.29 (s, 3 H), 1.01 (d, J = 10.9 Hz, 1
H), 0.92 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.4, 155.1,
95.6, 62.1, 49.9, 44.3, 39.4, 38.2, 30.7, 27.3, 27.2, 26.8, 23.4, 14.5.
Ethyl (3aR,5R,7R,7aS)-6,6,7a-Trimethyl-3a,4,5,6,7,7a-hexahydro-
5,7-methanobenzo[d]isoxazole-3-carboxylate (5s). Purified by flash
column chromatography (petroleum ether/AcOEt = 50:1, Rf = 0.44),
light yellow oil (43.3 mg, 58% yield): IR (KBr, cm−1) ν 2927, 2873,
1718, 1583, 1457, 1378, 1269, 1248, 1142, 1111, 1024, 955, 800, 771;
1H NMR (400 MHz, CDCl3) δ 4.38−4.30 (m, 2 H), 3.24 (dd, J = 4.0,
10.9 Hz, 1 H), 2.33−2.22 (m, 2 H), 2.18−2.15 (m, 1 H), 1.97−1.93
(m, 1 H), 1.75 (dt, J = 3.6, 14.0 Hz, 1 H), 1.38−1.35 (m, 6 H), 1.29
(s, 3 H), 1.01 (d, J = 10.9 Hz, 1 H), 0.92 (s, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.4, 155.1, 95.6, 62.1, 49.9, 44.3, 39.4, 38.2,
30.7, 27.3, 27.2, 26.8, 23.4, 14.5; HRMS (ESI) m/z calcd for
C14H22O3N+ [M + H]+ 252.1594, found 252.1598.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02281.
■
sı
1H, 13C, and 19F NMR spectra and HRMS spectra of
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Xiao-Wei Zhang − National Engineering Research Center for
Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China; School of Chemistry and
Chemical Engineering, Liaocheng University, Liaocheng,
Shandong 252059, China; orcid.org/0000-0002-2262-
4143; Email: xwzhang@jxnu.edu.cn
3-Ethyl 4,5-Dimethyl (4S,5S)-4,5-Dihydroisoxazole-3,4,5-tricar-
boxylate (5t).17h Purified by flash column chromatography
(petroleum ether/AcOEt = 6:1), pale yellow oil (29.7 mg, 38%
yield): 1H NMR (400 MHz, CDCl3) δ 5.36 (d, J = 6.2 Hz, 1 H), 4.64
(d, J = 6.2 Hz, 1 H), 4.37−4.30 (m, 2 H), 3.81 (s, 3 H), 3.77 (s, 3 H),
1.33 (t, J = 7.1 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.1,
168.0, 159.3, 149.4, 83.8, 63.0, 55.5, 53.8, 53.7, 14.3; HRMS (ESI) m/
z calcd for C10H13O7NNa+ [M + Na]+ 282.0584, found 282.0590.
Ethyl 3-Cyano-4,5-dihydroisoxazole-5-carboxylate (5u). Purified
by flash column chromatography (petroleum ether/AcOEt = 10:1, Rf
= 0.42), colorless oil (34.9 mg, 69% yield): IR (KBr, cm−1) ν 2245,
Xiang-Guo Hu − National Engineering Research Center for
Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China; School of Chemistry and
Chemical Engineering, Liaocheng University, Liaocheng,
Shandong 252059, China; orcid.org/0000-0002-5909-
2582; Email: huxianggg@iccas.ac.cn
Authors
Xiao-Lin He − National Engineering Research Center for
Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China; School of Chemistry and
Chemical Engineering, Liaocheng University, Liaocheng,
Shandong 252059, China
Nan Yan − National Engineering Research Center for
Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China; School of Chemistry and
Chemical Engineering, Liaocheng University, Liaocheng,
Shandong 252059, China
Hong-Xing Zheng − National Engineering Research Center
for Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China; School of Chemistry and
Chemical Engineering, Liaocheng University, Liaocheng,
Shandong 252059, China
1
1735, 1574, 1438, 1321, 1233, 937, 886, 806; H NMR (400 MHz,
CDCl3) δ 5.26 (dd, J = 7.6, 11.8 Hz, 1 H), 4.28 (q, J = 7.2 Hz, 2 H),
3.55−3.41 (m, 2 H), 1.33 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 168.0, 134.8, 110.3, 80.5, 63.1, 39.0, 14.3; HRMS
(ESI) m/z calcd for C7H9O3N2+ [M + H]+ 169.0608, found 169.0615.
cis-Methyl 3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazole-3-
carboxylate (5v).17i Purified by flash column chromatography
(petroleum ether/AcOEt = 20:1), colorless oil (30.5 mg, 60%
1
yield): H NMR (400 MHz, CDCl3) δ 5.20−5.17 (m, 1 H), 3.81−
3.76 (m, 4 H), 2.09−2.05 (m, 1 H), 1.96−1.91 (m, 1 H), 1.77−1.60
(m, 3 H), 1.38−1.29 (m, 1 H); 13C{1H} NMR (100 MHz, CDCl3) δ
161.4, 153.3, 90.5, 52.7, 51.0, 35.7, 31.6, 23.2.
5-([1,1′-Biphenyl]-4-yl)-3-(trifluoromethyl)-4,5-dihydroisoxazole
(5w). Purified by flash column chromatography (petroleum ether/
AcOEt = 50:1, Rf = 0.50), colorless oil (68.0 mg, 78% yield): IR (KBr,
cm−1) ν 1630, 1488, 1395, 1260, 1180, 1153, 1137, 1085, 925, 852,
832, 769, 730, 698; 1H NMR (400 MHz, CDCl3) δ 7.65−7.58 (m, 4
H), 7.48−7.44 (m, 2 H), 7.42−7.38 (m, 3 H), 5.89 (dd, J = 9.2, 11.2
Hz, 1 H), 3.64 (dd, J = 11.5, 17.5 Hz, 1 H), 3.23 (dd, J = 8.9, 17.5 Hz,
1 H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.8 (C−F, 2JC−F = 37.2
Hz), 142.4, 140.6, 138.0, 129.2, 128.1, 128.0, 127.5, 126.7, 120.0 (C−
F, 1JC−F = 272.0 Hz), 85.0, 40.2; 19F NMR (376 MHz, CDCl3) δ
−66.26 (s, 1 F); 19F{1H} NMR (376 MHz, CDCl3) δ −66.26 (s, 1
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02281
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (no. 21967011) and the Natural Science
■
+
F); HRMS (ESI) m/z calcd for C16H13ONF3 [M + H]+ 292.0944,
found 292.0950.
H
https://dx.doi.org/10.1021/acs.joc.0c02281
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
selective Access to Fused Isoxazoline Azetidines and Thietanes
through [3 + 2]-Cycloadditions. Org. Lett. 2018, 20, 6736.
(g) Kesornpun, C.; Aree, T.; Mahidol, C.; Ruchirawat, S.;
Kittakoop, P. Water-Assisted Nitrile Oxide Cycloadditions: Synthesis
of Isoxazoles and Stereoselective Synthesis of Isoxazolines and 1,2,4-
Oxadiazoles. Angew. Chem., Int. Ed. 2016, 55, 3997.
Foundation of Jiangxi Province (no. 2018BBE50004). We also
thank Dr. Yan-Biao Kang at USTC for proof reading.
REFERENCES
■
(1) (a) Feuer, H., Ed. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis: Novel Strategies in Synthesis, 2nd ed.; John Wiley &
Sons: Hoboken, NJ, 2008. (b) Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Chemistry of Heterocyclic
Compounds: A Series of Monographs, Vol. 59; John Wiley & Sons:
New York, NY, 2002. (c) Gothelf, K. V.; Jørgensen, K. A. Asymmetric
1,3-Dipolar Cycloadditions Reactions. Chem. Rev. 1998, 98, 863.
(d) Roscales, S.; Plumet, J. Metal-catalyzed 1,3-dipolar Cycloaddition
Reactions of Nitrile Oxides. Org. Biomol. Chem. 2018, 16, 8446.
(e) Kissane, M.; Maguire, A. R. Asymmetric 1,3-dipolar Cyclo-
additions of Acrylamides. Chem. Soc. Rev. 2010, 39, 845. (f) Hu, F.;
Szostak, M. Recent Developments in the Synthesis and Reactivity of
Isoxazoles: Metal Catalysis and Beyond. Adv. Synth. Catal. 2015, 357,
2583.
(6) For selected examples of the reaction of nitroalkanes, see:
(a) Basel, Y.; Hassner, A. An Improved Method for Preparation of
Nitrile Oxides from Nitroalkanes for In Situ Dipolar Cycloadditions.
Synthesis 1997, 1997, 309. (b) Kunetsky, R. A.; Dilman, A. D.; Ioffe, S.
L.; Struchkova, M. I.; Strelenko, Y. A.; Tartakovsky, V. A. New
Approach for the Synthesis of Isoxazoline-N-oxides. Org. Lett. 2003, 5,
4907. (c) Cecchi, L.; De Sarlo, F.; Machetti, F. Synthesis of 4,5-
Dihydroisoxazoles by Condensation of Primary Nitro Compounds
with Alkenes by Using a Copper/Base Catalytic System. Chem. - Eur.
J. 2008, 14, 7903. (d) Gangadhara Chary, R.; Rajeshwar Reddy, G.;
Ganesh, Y. S. S.; Vara Prasad, K.; Raghunadh, A.; Krishna, T.;
Mukherjee, S.; Pal, M. Effect of Aqueous Polyethylene Glycol on 1,3-
Dipolar Cycloaddition of Benzoylnitromethane/Ethyl 2-Nitroacetate
with Dipolarophiles: Green Synthesis of Isoxazoles and Isoxazolines.
Adv. Synth. Catal. 2014, 356, 160. (e) Enders, D.; Chow, S.
Organocatalytic Asymmetric Michael Addition of 2,2-Dimethyl-1,3-
dioxan-5-one to Nitro Alkenes Employing Proline-Based Catalysts.
Eur. J. Org. Chem. 2006, 2006 (20), 4578. (f) Vadivelu, M.; Sampath,
S.; Muthu, K.; Karthikeyan, K.; Praveen, C. Harnessing the TEMPO-
Catalyzed Aerobic Oxidation for Machetti−De Sarlo Reaction toward
Sustainable Synthesis of Isoxazole Libraries. J. Org. Chem. 2019, 84,
13636.
(2) (a) Tapadar, S.; He, R.; Luchini, D. N.; Billadeau, D. D.;
Kozikowski, A. P. Isoxazole Moiety in the Linker Region of HDAC
Inhibitors Adjacent to the Zn-chelating group; Effects on HDAC
Biology and Antiproliferative Activity. Bioorg. Med. Chem. Lett. 2009,
19, 3023. (b) Schneider, J. W.; Gao, Z.; Li, S.; Farooqi, M.; Tang, T.
S.; Bezprozvanny, I.; Frantz, D. E.; Hsieh, J. Small-Molecule
Activation of Neuronal Cell Fata. Nat. Chem. Biol. 2008, 4, 408.
(c) Tuo, W.; Leleu-Chavain, N.; Barczyk, A.; Renault, N.; Lemaire, L.;
Chavatte, P.; Millet, R. Design, Synthesis and Biological Evaluation of
Potent FAAH Inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 2701.
(d) Lilienkampf, A.; Pieroni, M.; Wan, B.; Wang, Y.; Franzblau, S. G.;
Kozikowski, A. P. Rational Design of 5-Phenyl-3-isoxazolecarboxylic
Acid Ethyl Esters as Growth Inhibitors of Mycobacterium tuber-
culosis. A Potent and Selective Series for Futher Drug Development. J.
Med. Chem. 2010, 53, 678.
(3) (a) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. A New
Asymmetric Wacker-Type Cyclization and Tandem Cyclization
Promoted by Pd(II)-Spiro Bis(isoxazoline) Catalyst. J. Am. Chem.
Soc. 2001, 123, 2907. (b) Tsujihara, T.; Shinohara, T.; Takenaka, K.;
Takizawa, S.; Onitsuka, K.; Hatanaka, M.; Sasai, H. Enantioselective
Intramolecular Oxidative Aminocarbonylation of Alkenylureas Cata-
lyzed by Palladium-Spiro Bis(isoxazoline) complexes. J. Org. Chem.
2009, 74, 9274. (c) Sen, A.; Takenaka, K.; Sasai, H. Enantioselective
Aza-Wacker Type Cyclization Promoted by Pd-SPRIX Catalyst. Org.
Lett. 2018, 20, 6827.
(4) (a) Kozikowski, A. P. The Isoxazoline Route to the Molecules of
Nature. Acc. Chem. Res. 1984, 17, 410. (b) Morita, T.; Fuse, S.;
Nakamura, H. Photochemical Conversion of Isoxazoles to 5-
Hydroxyimidazolines. Org. Lett. 2020, 22, 3460. (c) Zhu, X.-Q.;
Wang, Z.-S.; Hou, B.-S.; Zhang, H.-W.; Deng, C.; Ye, L.-W. Zinc-
Catalyzed Asymmetric Formal [4 + 3] Annulation of Isoazoles with
Enynol Ethers by 6π Electrocyclization: Stereoselective Access to 2H-
Azepines. Angew. Chem., Int. Ed. 2020, 59, 1666.
(5) For selected examples of the reaction of oxime halide or
aldoximes, see: (a) Zhao, G.; Liang, L.; Wen, C. H. E.; Tong, R. In
Situ Generation of Nitrile Oxides from NaCl-Oxone Oxidation of
Various Aldoximes and Their 1,3-Dipolar Cycloaddition. Org. Lett.
2019, 21, 315. (b) Grecian, S.; Fokin, V. V. Ruthenium-Catalyzed
Cycloaddition of Nitrile Oxides and Alkynes: Practical Synthesis of
Isoxazoles. Angew. Chem., Int. Ed. 2008, 47, 8285. (c) Mendelsohn, B.
A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A.
Oxidation of Oximes to Nitrile Oxides with Hypervalent Iodine
Reagents. Org. Lett. 2009, 11, 1539. (d) Minakata, S.; Okumura, S.;
Nagamachi, T.; Takeda, Y. Generation of Nitrile Oxides from Oximes
Using t-BuOI and Their Cycloaddition. Org. Lett. 2011, 13, 2966.
(e) Kesornpun, C.; Aree, T.; Mahidol, C.; Ruchirawat, S.; Kittakoop,
P. Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of
Isoxazoles and Stereoselective Synthesis of Isoxazolines and 1,2,4-
Oxadiazoles. Angew. Chem., Int. Ed. 2016, 55, 3997. (f) Baumann, A.
N.; Reiners, F.; Juli, T.; Didier, D. Chemodivergent and Stereo-
(7) For reviews, see: (a) Schumperli, M. T.; Hammond, C.;
̈
Hermans, I. Developments in the Aerobic Oxidation of Amines. ACS
Catal. 2012, 2, 1108. (b) Chen, B.; Wang, L.; Gao, S. Recent
Advances in Aerobic Oxidation of Alcohols and Amines to Imines.
ACS Catal. 2015, 5, 5851. (c) Bartelson, A.; Lambert, K.; Bobbitt, J.;
Bailey, W. Recent Developments in the Nitroxide-Catalyzed
Oxidation of Amines: Preparation of Imines and Nitriles.
ChemCatChem 2016, 8, 3421. (d) Largeron, M. Protocols for the
Catalytic Oxidation of Primary Amines to Imines. Eur. J. Org. Chem.
2013, 2013, 5225. (e) Wendlandt, A. E.; Stahl, S. S. Quinone-
Catalyzed Selective Oxidation of Organic Molecules. Angew. Chem.,
Int. Ed. 2015, 54, 14638.
(8) For selected examples of the oxidation of amines to imines, see:
(a) Largeron, M.; Fleury, M.-B. Bioinspired Oxidation Catalysts.
Science 2013, 339, 43. (b) Wendlandt, A. E.; Stahl, S. S. Bioinspired
Aerobic Oxidation of Secondary Amines and Nitrogen Heterocycles
with a Bifunctional Quinone Catalyst. J. Am. Chem. Soc. 2014, 136,
506. (c) Zhang, E.; Tian, H.; Xu, S.; Yu, X.; Xu, Q. Iron-Catalyzed
Direct Synthesis of Imines from Amines or Alcohols and Amines via
Aerobic Oxidative Reactions under Air. Org. Lett. 2013, 15, 2704.
(d) Mukherjee, A.; Nerush, A.; Leitus, G.; Shimon, L. J. W.; Ben
David, Y.; Espinosa Jalapa, N. A.; Milstein, D. Manganese-Catalyzed
Environmentally Benign Dehydrogenative Coupling of Alcohols and
Amines to Form Aldimines and H2: A Catalytic and Mechanistic
Study. J. Am. Chem. Soc. 2016, 138, 4298.
(9) For selected examples of the oxidation of amines to nitriles, see:
(a) Tseng, K-N. T.; Rizzi, A. M.; Szymczak, N. K. Oxidant-Free
Conversion of Primary Amines to Nitriles. J. Am. Chem. Soc. 2013,
135, 16352. (b) Kannan, M.; Muthaiah, S. Extending the Chemistry
of Hexamethylenetetramine in Ruthenium-Catalyzed Amine Oxida-
tion. Organometallics 2019, 38, 3560. (c) Dutta, I.; Yadav, S.;
̈
Sarbajna, A.; De, S.; Holscher, M.; Leitner, W.; Bera, J. K. Double
Dehydrogenation of Primary Amines to Nitriles by a Ruthenium
Complex Featuring Pyrazole Functionality. J. Am. Chem. Soc. 2018,
140, 8662. (d) Xu, B.; Hartigan, E. M.; Feula, G.; Huang, Z.; Lumb,
J.-P.; Arndtsen, B. A. Simple Copper Catalyst for the Aerobic Oxiation
of Amines: Selectivity Control by the Counterion. Angew. Chem., Int.
Ed. 2016, 55, 15802. (e) Kim, J.; Stahl, S. S. Cu/Nitroxyl Catalyzed
Aerobic Oxidation of Primary Amines into Nitriles at Room
Temperature. ACS Catal. 2013, 3, 1652.
I
https://dx.doi.org/10.1021/acs.joc.0c02281
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(10) For selected examples of the oxidation of amines to oximes, see:
(a) Suzuki, K.; Watanabe, T.; Murahashi, S.-I. Aerobic Oxidation of
Primary Amines to Oximes Catalyzed by DPPH and WO3/Al2O3.
Angew. Chem., Int. Ed. 2008, 47, 2079. (b) Patil, V. V.; Gayakwad, E.
M.; Shankarling, G. S. m-CPBA Mediated Metal Free, Rapid
Oxidation of Aliphatic Amines to Oximes. J. Org. Chem. 2016, 81,
781.
(11) For selected examples of the oxidation of amines to amides, see:
(a) Ray, R.; Hazari, A. S.; Chandra, S.; Maiti, D.; Lahiri, G. K. Highly
Selective Ruthenium-Catalyzed Direct Oxygenation of Amines to
Amides. Chem. - Eur. J. 2018, 24, 1067. (b) Legacy, C. J.; Wang, A.;
O’Day, B. J.; Emmert, M. H. Iron-Catalyzed Cα-H Oxidation of
Tertiary, Aliphatic Amines to Amides under Mild Conditions. Angew.
Chem., Int. Ed. 2015, 54, 14907. (c) Jin, X.; Kataoka, K.; Yatabe, T.;
Yamaguchi, K.; Mizuno, N. Supported Gold Nanoparticles for
Efficient α-Oxygenation of Secondary and Tertiary Amines into
Amides. Angew. Chem., Int. Ed. 2016, 55, 7212.
Intermolecular [2 + 1+n] Annulation: Diazo Compounds Act as
Radical Acceptors. Org. Lett. 2019, 21, 9300. (f) Guo, J.; Gaudette, J.;
Cheng, J.-F. Unprecedented Formation of Δ2-isoxazoline and/or 1-
nitroso-pyrazoline from α-bromoketone Oximes and Diazo Com-
pounds. Tetrahedron Lett. 2009, 50, 933. (g) Gao, M.; Gan, Y.; Xu, B.
From Alkenes to Isoxazolines via Copper-Mediated Alkene Cleavage
and Dipolar Cycloaddition. Org. Lett. 2019, 21, 7435. (h) Trogu, E.;
De-Sarlo, F.; Machetti, F. Michael Additions versus Cycloaddition
Condensations with Ethyl Nitroacetate and Electron Deficient
́
́
́
Olefins. Chem. - Eur. J. 2009, 15, 7940. (i) Romanski, J.; Jozik, J.;
Chapuis, C.; Asztemborska, M.; Jurczak, J. Asymmetric 1,3-dipolar
Cycloadditions of Chiral Carboxyloyl Nitrile Oxides to Cycloalkenes.
Tetrahedron: Asymmetry 2007, 18, 865. (j) Cremonesi, G.; Croce, P.
D.; Fontana, F.; Fiorelli, C.; La Rosa, C. Stereoselective Synthesis of
β, ε-dihydroxy-α-amino acids by Ring Opening of 4,5-dihydroisoox-
azolyl Derivatives. Tetrahedron: Asymmetry 2008, 19, 2850.
(12) Sun, L. L.; Xu, H. L.; Su, W. C.; Xue, F.; An, S. H.; Lu, C. T.;
Wu, R. H. The Expression of Detoxification Genes in Two Maize
Cultivars by Interaction of Isoxadifen-ethyl and Nicosulfuron. Plant
Physiol. Biochem. 2018, 129, 101.
(13) See the procedure for the gram-scale synthesis of 3a in the
Experimental Section.
(14) Nitrile oxides are highly unstable and readily undergo self-
dimerization, see: (a) Dondoni, A.; Mangini, A.; Ghersetti, S. Kinetics
of Dimerization of Benzonitrile N-oxides to Diphenylfuroxans.
Tetrahedron Lett. 1966, 7, 4789. (b) Yu, Z.-X.; Caramella, P.; Houk,
K. N. Dimerizations of Nitrile Oxides to Furoxans Are Stepwise via
Dinitrosoalkene Diradicals: A Density Functional Theory Study. J.
Am. Chem. Soc. 2003, 125, 15420.
(15) (a) Chen, R.; Zhao, Y.; Fang, S.; Long, W.; Sun, H.; Wan, X.
Coupling Reaction of Cu-Based Carbene and Nitroso Radical: A
Tandem Reaction To Construct Isoxazolines. Org. Lett. 2017, 19,
5896. (b) Wang, X.-D.; Zhu, L.-H.; Liu, P.; Wang, X.-Y.; Yuan, H.-Y.;
Zhao, Y.-L. Copper-Catalyzed Cascade Cyclization Reactions of
Diazo Compounds with tert-Butyl Nitrite and Alkynes: One-Pot
Synthesis of Isoxazoles. J. Org. Chem. 2019, 84, 16214. (c) Chen, R.;
Ogunlana, A. A.; Fang, S.; Long, W.; Sun, H.; Bao, X.; Wan, X. In Situ
Generation of Nitrile Oxides from Copper Carbene and tert-Butyl
Nitrite: Synthesis of Fully Substituted Isoxazoles. Org. Biomol. Chem.
2018, 16, 4683. (d) Mykhailiuk, P. K. In Situ Generation of
Difluoromethyl Diazomethane for [3 + 2] Cycloadditions with
Alkynes. Angew. Chem., Int. Ed. 2015, 54, 6558. (e) Zhang, X.-W.; Hu,
W.-L.; Chen, S.; Hu, X.-G. Cu-Catalyzed Synthesis of Fluoroalkylated
Isoxazoles from Commercially Available Amines and Alkynes. Org.
Lett. 2018, 20, 860.
(16) (a) Takamura, N.; Mizoguchi, T.; Koga, K.; Yamada, S. Amino
Acids and Peptides-XIV: A Simple and Convenient Method for
Preparation of α-Substituted α-Diazo Esters. Tetrahedron 1975, 31,
227. (b) Hock, K. J.; Koenigs, R. M. The Generation of Diazo
Compounds in Continuous-Flow. Chem. - Eur. J. 2018, 24, 10571.
(17) (a) Andrzejak, V.; Muccioli, G. G.; Body-Malapel, M.; El
Bakali, J.; Djouina, M.; Renault, N.; Chavatte, P.; Desreumaux, P.;
Lambert, D. M.; Millet, R. New FAAH Inhibitors Based on 3-
Carboxamido-5-aryl-isoxazole Scaffold that Protect Against Exper-
imental Colitis. Bioorg. Med. Chem. 2011, 19, 3777. (b) Zhao, J.; Tian,
W.; Qi, J.; Lv, D.; Liu, Y.; Jiang, Y.; Dong, G.; Chen, Q.; Zhou, Y.;
Zhu, J.; Wang, H.; Sheng, C.; Lv, J. Design and Synthesis of
Phenylisoxazole Derivatives as Novel Human Acrosin Inhibitors.
Bioorg. Med. Chem. Lett. 2014, 24, 2802. (c) Russell, J. L.; Goetsch, S.
C.; Aguilar, H. R.; Coe, H.; Luo, X.; Liu, N.; van Rooij, E.; Frantz, D.
E.; Schneider, J. W. Regulated Expression of pH Sensing G Protein-
Coupled Receptor-68 Identified through Chemical Biology Defines a
New Drug Target for Ischemic Heart Disease. ACS Chem. Biol. 2012,
7, 1077. (d) Baglieri, A.; Meschisi, L.; De Sarlo, F.; Machetti, F.
Competitive Copper Catalysis in the Condensation of Primary Nitro
Compounds with Terminal Alkynes: Synthesis of Isoxazoles. Eur. J.
Org. Chem. 2016, 2016, 4643. (e) Xiong, M.; Liang, X.; Gao, Z.; Lei,
A.; Pan, Y. Synthesis of Isoxazolines and Oxazines by Electrochemical
J
https://dx.doi.org/10.1021/acs.joc.0c02281
J. Org. Chem. XXXX, XXX, XXX−XXX