An efficient synthesis of 2-isoxazolines from α-haloketone oximes and dimethyl sulfonium salts

Article abstract of DOI:10.1016/j.tetlet.2018.12.062

2-Isoxazolines were synthesized efficiently from a formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl sulfonium salts. This approach provides a new method to synthesize a rang

Full text of DOI:10.1016/j.tetlet.2018.12.062

Accepted Manuscript
An efficient synthesis of 2-isoxazolines from α-haloketone oximes and dimethyl
sulfonium salts
Sen Zhao, Hang Wang, Shaofa Sun, Haibing Guo, Zhiyu Chen, Jian Wang, Lu
Wang, Steven Liang, Gangqiang Wang
PII:
S0040-4039(18)31520-X
https://doi.org/10.1016/j.tetlet.2018.12.062
TETL 50525
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
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4 November 2018
23 December 2018
25 December 2018
Please cite this article as: Zhao, S., Wang, H., Sun, S., Guo, H., Chen, Z., Wang, J., Wang, L., Liang, S., Wang, G.,
An efficient synthesis of 2-isoxazolines from α-haloketone oximes and dimethyl sulfonium salts, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.062
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Graphical Abstract
2-Isoxazolines were synthesized efficiently at ambient temperature from a formal [4+1] cycloaddition of nitrosoalkenes and
sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl sulfonium salts. This approach provides a
new method to synthesize a range of 2-isoxazolines in high yields and high regioselectivity.
An efficient synthesis of 2-isoxazolines from
α-haloketone oximes and dimethyl sulfonium
salts
Leave this area blank for abstract info.
Sen Zhaoa, ‡, Hang Wanga, ‡, Shaofa Suna,*, Haibing Guoa, Zhiyu Chenb, Jian Wangb, Lu Wangc, Steven Liangc,
and Gangqiang Wanga,*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An efficient synthesis of 2-isoxazolines from α-haloketone oximes and dimethyl
sulfonium salts
Sen Zhaoa, ‡, Hang Wanga, ‡, Shaofa Suna,*, Haibing Guoa, Zhiyu Chenb, Jian Wangb, Lu Wangc, Steven
Liangc, Gangqiang Wanga,*
a. Non-power Nuclear Technology Collaborative Innovation Center, School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and
Technology, Xianning 437100, China; b. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China; c. Nuclear Medicine and Molecular
Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, USA.
‡. contributed equally to this paper
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2-Isoxazolines were synthesized efficiently from a formal [4+1] cycloaddition of nitrosoalkenes
and sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl
sulfonium salts. This approach provides a new method to synthesize a range of 2-isoxazolines in
high yields and high regioselectivity.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Isoxazoline
4,5-Dihydroisoxazole
[4+1] Cycloaddition
α-Haloketone oximes
Dimethyl sulfonium salt
regioisomers, a formal [4+1] cycloaddition would be a viable and
attractive strategy to synthesize 2-isoxazolines.14 Herein, we
report a formal [4+1] cycloaddition of nitrosoalkenes and sulfur
ylides to synthesize 2-isoxazolines from readily available α-
haloketone oximes and dimethyl sulfonium salts (Figure 1b).
2-Isoxazoline (also known as 4,5-dihydroisoxazole) represents an
important class of heterocyclic compounds and its derivatives are
frequently found in a wide range of natural products and
biologically active compounds.1 As significant pharmacophores,
2-isoxazolines exhibit important biological activities, such as
antiviral,2 antifungal,3 anticancer,4 and antitumor5 properties. 2-
Isoxazolines are also important synthetic intermediates in organic
chemistry and 2-isoxazolines can be converted to 1,3-diols, β-
amino alcohols, γ-amino alcohols, β-hydroxy ketones, β-hydroxy
oximes, β-hydroxy nitriles, α,β-unsaturated carbonyl compounds,
as well as some useful heterocyclic compounds, such as acyl
aziridines and isoxazoles.6 Therefore, the construction of 2-
isoxazolines have attracted much attention and continuous efforts
have been made to synthesis of 2-isoxazolines over past several
decades.7 The most common method to construct 2-isoxazoline
scaffold is the cycloaddition of nitrile oxides and alkenes.8 Nitrile
oxides are highly reactive and can be dimerized to form
furoxans.9 Several methods have been developed for in situ
generation of nitrile oxides (Figure 1a), such as oxidation of
aldoximes,10 dehydrodehalogenation of hydroximinoyl halides,11
dehydration of primary nitro compounds,12 and dehydration of O-
silylated hydroxamic acids.13 However, technical challenges
remain in the cycloaddition of nitrile oxides and alkenes,
especially in the control of regioselectivity. The [3+2]
cycloaddition of nitrile oxides with unsymmetrical alkenes, such
as 1,2-disubstituted alkenes usually lead to a mixture of
regioisomers. In order to avoid the formation of confounding
Figure 1. Representative methods for synthesis of 2-isoxazolines.

2
Tetrahedron
α-Haloketone oximes and dimethyl sulfonium salts are
the presence of NaOH as the base (Table 1, entry 1). We further
screened other inorganic and organic bases, such as Cs2CO3,
K2CO3, Na2CO3, NaOAc, Et3N, pyridine, and DMAP (4-
(dimethylamino)pyridine) (Table 1, entries 2-8). The yield of 3a
increased to 95% when Na2CO3 was used as the base (Table 1,
entry 4). After screening reaction solvents, such as CHCl3, THF,
PhCH3, MeOH and HFIP (1,1,1,3,3,3-Hexafluoro-2-propanol)
(Table 1, entries 9-14), CH2Cl2 was identified as optimal medium
for this type of reaction.
precursors of nitrosoalkenes and sulfur ylides, respectively. Since
it is unnecessary to isolate and use pure E- or Z-α-bromoketone
oxime as the precursors of nitrosoalkenes, E- and Z-oximes 1
were used directly in this formal [4+1] cycloaddition of
nitrosoalkenes and sulfur ylides to synthesize 2-isoxazolines.
Initially, α-bromoketone oxime 1a and dimethyl sulfonium salt
2a were used as model substrates for the optimization of reaction
conditions. To our delight, 2-isoxazoline 3a was afforded in 90%
isolated yield in dichloromethane at room temperature for 3 h in
Table 1. Optimization of reaction conditions
Entrya
1
Base
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
T/h
3
Yieldb
90%
93%
90%
95%
83%
89%
24%
19%
83%
62%
90%
<5%
83%
75%
NaOH
2
Cs2CO3
K2CO3
Na2CO3
NaOAc
Et3N
3
3
3
4
3
5
3
6
3
7
Pyridine
DMAP
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
3
8
3
9
3
10
11
12
13
14
3
PhCH3
CH3CN
MeOH
HFIP
3
3
3
3
aReaction conditions: a mixture of 1a (1.0 mmol), 2a (1.0 mmol), and base (2.0 mmol) in a solvent (2 mL) was stirred at room temperature for a certain period of
time.
bYield of isolated product.
Table 2. The formal [4+1] cycloaddition of nitrosoalkenes with various sulfur ylidesa, b
aReaction conditions: a mixture of 1a (1.0 mmol), 2 (1.0 mmol), and base (2.0 mmol) in solvent (2 mL) was stirred at room temperature for 3 h.
bYield of isolated product.
cThe reaction was stirred at room temperature for 4 h.

3
With the optimal reaction conditions in hand, we further
investigated the substrate scope of this formal [4+1]
cycloaddition of nitrosoalkenes and sulfur ylides. Firstly, diverse
dimethyl sulfonium salts 2 were used as precursors of sulfur
ylides. As shown in Table 2, both α-bromoketone oxime 1a and
α-chloroketone oxime 1a’ worked efficiently to generate 2-
isoxazoline 3a in high yields (95% and 96%). Various acyl
groups substituted dimethyl sulfonium salts 2, including electron-
donating groups (2b, 2c) and electron-withdrawing groups (2d,
2e, 2f, 2g and 2h) substituted benzoyl groups, are suitable for this
reaction. In addition, 2-naphthoyl, thiophene-2-carbonyl and
acetyl substituted dimethyl sulfonium salts 2 were compatible
and the corresponding 2-isoxazolines (3i, 3j and 3k) were
achieved in 86-90% yields. Furthermore, we also briefly
investigated the scope of α-haloketone oximes 1 (Table 3). Both
electron-donating groups (1b, 1c) and electron-withdrawing
groups (1d, 1e, 1f and 1g) as well as 2-naphthyl (1h) substituted
α-haloketone oximes, are suitable for this reaction. The 2-
isoxazolines were achieved in 80-98% yields. The reaction could
be also scaled up and performed in gram scale with high yield
(Figure 2).
can be achieved from 2-isoxazolines.6 As proof of concept, we
demonstrated an efficient post-cycloaddition transformation of 2-
isoxazoline 3a into isoxazole 5 in 98% yield via oxidation with
MnO2 in CH2Cl2 for 4 h at room temperature (Figure 3). The
formal [4+1] cycloaddition reaction of 1a and 2a and the
oxidation of 2-isoxazoline 3a to isoxazole 5 also could be
performed in a one-pot reaction, and yield was slightly low
(60%).
Figure 3. Further transformation of 2-isoxazoline to isoxazole.
On the basis of all the above results, a proposed reaction
mechanism is given in Figure 4. Firstly, α-haloketone oximes 1
are converted to nitrosoalkenes A and dimethyl sulfonium salts 2
are converted to sulfur ylides B in basic conditions. Then the
reaction between nitrosoalkenes and sulfur ylides generate 2-
isoxazolines 3 via a formal [4+1] cycloaddition.
Table 3. The formal [4+1] cycloaddition of various
nitrosoalkenes with sulfur ylidesa, b
Figure 4. Proposed reaction mechanism.
In conclusion, an efficient synthesis of 2-isoxazolines has been
achieved from the formal [4+1] cycloaddition of nitrosoalkenes
and sulfur ylides. Nitrosoalkenes and sulfur ylides were
generated in situ from α-haloketone oximes and dimethyl
sulfonium salts, respectively. A wide range of α-haloketone
oximes and dimethyl sulfonium salts have been shown to be
suitable in this reaction to afford 2-isoxazolines in high yields
and high regioselectivity. This new approach provides a new
method to synthesize 2-isoxazolines and may have translational
application in ‘click’-type and bioconjugate chemistry.15 Further
studies on the mechanism and application of 2-isoxazolines are
currently underway in our laboratory.
aReaction conditions: a mixture of 1 (1.0 mmol), 2a (1.0 mmol), and base (2.0
mmol) in solvent (2 mL) was stirred at room temperature for 3 h.
bYield of isolated product.
cThe reaction was stirred at room temperature for 4 h.
Acknowledgments
Figure 2. Reaction in gram scale.
This work was supported by the Hubei Provincial Natural
Science Foundation of China (2017CFC859) and the Non-power
Nuclear Technology Collaborative Innovation Center (Hubei
Province) are greatly appreciated.
2-Isoxazolines are also important intermediates in synthetic
chemistry and medicinal chemistry. Further functional group
transformations make 2-isoxazolines become an attractive
building block, and a variety of well-functionalized groups, such
as β- or γ-amino alcohols, β-hydroxy ketones, oximes, and
nitriles, α,β-unsaturated carbonyl compounds, and acyl aziridines

4
Tetrahedron
Supplementary Material
References and notes
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5
Highlights



a formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides
efficient synthesis of 2-isoxazolines
2-isoxazolines can be further converted to other well-functionalized building blocks