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