Hypervalent iodine-catalyzed cycloaddition of nitrile oxides to alkenes

Article abstract of DOI:10.1080/00397911.2013.834364

A new and convenient method for preparation of isoxazolines was developed by a catalytic cycloaddition of nitrile oxides generated in situ from aldoximes to alkenes in the presence of a catalytic amount of iodobenzene. In this protocol, iodobenzene was fi

Full text of DOI:10.1080/00397911.2013.834364

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Hypervalent Iodine–Catalyzed
Cycloaddition of Nitrile Oxides to
Alkenes
a
a
a
Changbin Xiang , Tingting Li & Jie Yan
a
College of Chemical Engineering and Materials Science, Zhejiang
University of Technology , Hangzhou , Zhejiang , China
Accepted author version posted online: 28 Oct 2013.Published
online: 27 Dec 2013.
To cite this article: Changbin Xiang , Tingting Li & Jie Yan (2014) Hypervalent Iodine–Catalyzed
Cycloaddition of Nitrile Oxides to Alkenes, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:5, 682-688, DOI:
10.1080/00397911.2013.834364
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Synthetic Communications , 44: 682–688, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.834364
HYPERVALENT IODINE–CATALYZED CYCLOADDITION
OF NITRILE OXIDES TO ALKENES
Changbin Xiang, Tingting Li, and Jie Yan
College of Chemical Engineering and Materials Science, Zhejiang University
of Technology, Hangzhou, Zhejiang, China
GRAPHICAL ABSTRACT
Abstract A new and convenient method for preparation of isoxazolines was developed by a
catalytic cycloaddition of nitrile oxides generated in situ from aldoximes to alkenes in the
presence of a catalytic amount of iodobenzene. In this protocol, iodobenzene was first
oxidized into the hypervalent iodine intermediate by m-chloroperbenzoic acid, which then
transformed aldoximes into nitrile oxides, and a 1,3-dipolar cycloaddition of nitrile oxides
to alkenes to provide the isoxazolines in moderate to good yields.
[Supplementary materials are available for this article. Go to the publisher’s online
1
edition of Synthetic Communications for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Catalytic reaction; cycloaddition; hypervalent iodine intermediate;
iodobenzene; isoxazoline
INTRODUCTION
Isoxazolines are important pharmacophores in several pharmaceutical
[
1]
compounds. They are also useful intermediates for synthesis of natural products
[2]
and biologically active compounds. A variety of synthetic methods has been
developed for preparation of isoxazolines, of which the most convenient and attract-
[
3]
ive route is probably the 1,3-dipolar cycloaddition of nitrile oxides to alkenes.
Nitrile oxides are commonly generated from aldoximes via halogenation using differ-
ent reagents such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS),
[4]
NaOCl, t-BuOCl, t-BuOI, etc. All of these methods involve two steps and give
highly variable yields. Having low toxicity, ready availability, easy handling, and
reactivity similar to that of heavy-metal reagents or anodic oxidation, hypervalent
iodine compounds have found broad application in organic chemistry and are
Received May 29, 2013.
Address correspondence to Jie Yan, College of Chemical Engineering and Materials Science,
Zhejiang University of Technology, Hangzhou 310032, Zhejiang, China. E-mail: jieyan87@zjut.edu.cn
6
82

CYCLOADDITION OF NITRILE OXIDES TO ALKENES
683
[5]
frequently used in synthesis. The hypervalent iodine–induced 1,3-dipolar cyclo-
addition of nitrile oxides from aldoximes to alkenes is an improved process, in which
[
6]
the stoichiometric hypervalent iodine reagents usually are needed.
In recent years, the catalytic utilization of hypervalent iodine reagents has
increased in importance, with growing interest in the development of environmen-
[7]
tally benign synthetic transformations. In these catalytic reactions, a catalytic
amount of an iodine-containing molecule together with a stoichiometric oxidant
are used. The oxidant generates the hypervalent iodine reagent in situ, and after
the oxidative transformation, the reduced iodine-containing molecule is reoxidized.
Iodobenzene (PhI) is the most utilized iodoarene, and m-chloroperbenzoic acid
(
mCPBA) and oxone are usually used as the terminal oxidants.
DISCUSSION AND RESULTS
To extend the scope of catalytic use of hypervalent iodine reagents in organic
synthesis, we have investigated the catalytic cycloaddition of nitrile oxides generated
in situ from aldoximes to alkenes, in which a catalytic amount of PhI and a stoichio-
metric oxidant meta-chloroperbenzoic acid (mCPBA) were used. Now we report a
new and convenient procedure for preparation of isoxazolines, and to our knowledge
the catalytic cycloaddition of nitrile oxides from aldoximes to alkenes using a
catalytic amount of PhI has not been reported before.
At the onset of the research, benzaldoxime and styrene were chosen as the
model substrates. We first investigated the catalytic cycloaddition with 1.0 equiv.
of benzaldoxime, 1.5 equiv. of styrene, 0.2 equiv. of PhI, and 0.75 equiv. of mCPBA
in various solvents at room temperature for 24 h. It was shown from Table 1 that all
reactions gave the desired product of 3,5-diphenylisoxazoline, but the yield was vari-
able greatly: When 2,2,2-trifluoroethanol (TFE) was used as solvent, a good yield of
7
1
4% was reached; however, other solvents usually led to poor yields (Table 1, entries
–8). In the same conditions, when another oxidant, oxone, was used in place of
mCPBA, the reaction provided a moderate yield, so mCPBA was more suitable
for the reaction (entry 9). When the amount of mCPBA was increased from 0.75
equiv. to 1.0 equiv., the yield rose to 76%; however, when more mCPBA was added,
the yield decreased and some by-products, such as phenyl oxirane, were found
(
6
entries 10–13). The reaction was carried out rapidly, and only after 2 h a yield of
3% was recorded; to improve the yield, the reaction time was prolonged to 12 h,
which resulted in a good yield of 75% (entries 10, 14–17). The amount of styrene
was investigated and 2.0 equiv. of it was the best choice (entries 14, 18–20). The
amount of PhI was also checked and when 0.3 equiv. of it was added, the reaction
provided the best yield of 81%; however, in the absence of it, no desired product
was observed (entries 19, 21–24).
Having established the optimal conditions, the catalytic cycloaddition with 1.0
equiv. of aldoximes (1), 2.0 equiv. of alkenes (2), 0.3 equiv. of PhI, and 1.0 equiv. of
mCPBA in TFE at room temperature for 12 h was investigated, and a series of cor-
responding isoxazolines (3) were obtained (Scheme 1). The results are summarized in
Table 2.
As shown in Table 2, the reaction was compatible with most of alkenes except
cyclohexene 2g and provided the corresponding isoxazolines in moderate to good

684
C. XIANG, T. LI, AND J. YAN
Table 1. Optimization of the catalytic cycloaddition with benzaldoxime and styrene
a
Entry mCPBA (equiv.) PhI (equiv.) PhCH=CH
(equiv.)
Solvent
CH OH
Time (h) Yield (%)
2
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
Oxone (0.75)
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0
1.5
3
24
24
24
24
24
24
24
24
24
24
24
24
24
12
6
47
39
30
28
48
41
28
74
58
76
66
58
54
75
68
67
63
71
79
74
0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
2.0
3.0
2.0
2.0
2.0
2.0
EtOAc
THF
EtOH
MeCN
CH
2 2
Cl
DMF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
1.2
1.5
2.0
1.0
1.0
1.0
4
1.0
1.0
2
12
12
12
12
12
12
12
1.0
1.0
1.0
1.0
0.1
0.3
0.4
49
81
80
1.0
1.0
a
Isolated yield.
yields (entries 1–15). Compared with benzaldoxime 1a, 4-methylbenzaldoxime 1b or
-methoxybenzaldoxime 1c, which bear electron-donating groups on benzene rings,
usually afforded the corresponding products in somewhat poor yields (entries 1, 4, 5,
1–15). p-Nitro derivative 1d with an electron-withdrawing group was not active in
4
1
the reaction, and the desired isoxazoline was not obtained (entry 16). When pheny-
lacetaldoxime 1e, an aliphatic aldoxime, was used to treat with styrene in the same
conditions, no product was observed.
Scheme 1. Catalytic cycloaddition of nitrile oxides from aldoximes to alkenes.

CYCLOADDITION OF NITRILE OXIDES TO ALKENES
685
Table 2. Result of catalytic cycloaddition of nitrile oxides from aldoximes to alkenes
a
Entry
1
Aldoxime 1
Alkene 2
Isoxazoline 3
Yield (%)
81
2
1a
83
3
4
1a
1a
82
70
5
6
1a
1a
76
51
7
8
9
1a
1a
1a
40
81
68
1
1
1
1
0
1
2
3
1a
53
62
54
2a
2d
2e
1b
1b
53
(
Continued )

686
C. XIANG, T. LI, AND J. YAN
Table 2. Continued
Alkene 2
a
Entry
Aldoxime 1
Isoxazoline 3
Yield (%)
1
4
5
2a
2e
63
1
1c
65
—
—
1
6
7
2a
2a
—
—
1
a
Isolated yield.
Scheme 2. Reaction mechanism for the catalytic cycloaddition.
A plausible reaction pathway for the present reaction is shown in Scheme 2.
The iodobenzene is first oxidized into the hypervalent iodine intermediate by
mCPBA, which then transforms aldoximes into nitrile oxides, and finally a 1,3-
dipolar cycloaddition of nitrile oxides to alkenes is carried out and provides the
corresponding isoxazolines. The reduced by-product iodobenzene is reoxidized into
hypervalent iodine reagent by mCPBA in the recycling reaction.
CONCLUSIONS
In summary, we have developed a new and efficient method for preparation of
isoxazolines by the catalytic cycloaddition of nitrile oxides generated in situ from

CYCLOADDITION OF NITRILE OXIDES TO ALKENES
687
aldoximes to alkenes using a catalytic amount of iodobenzene, and a series of corre-
sponding isoxazolines was prepared in moderate to good yields. This method has
some advantages such as mild reaction conditions and simple procedure. Further-
more, the scope of hypervalent iodine reagents in organic synthesis could be
extended.
EXPERIMENTAL
Melting points were measured with an XT-4 melting-point apparatus and are
uncorrected. Infrared (IR) spectra were recorded on a Thermo-Nicolet 6700 instru-
1
13
ment, H NMR and C NMR spectra were measured on a Bruker Avance III
500 M) spectrometer, and mass spectra were determined on a Thermo-ITQ 1100 mass
(
spectrometer. Aldoximes, alkenes, mCPBA, and PhI were commercially available.
Aldoxime 1 (1.0 mmol), mCPBA (1.0 mmol), and PhI (0.3 mmol) were added to
a 2,2,2-trifluoroethanol (TFE) solvent (5 mL). The resulting mixture was stirred at rt
for about 25 min, alkene 2 (2.0 mmol) was added, and the mixture was continuously
stirred at rt for another 12 h. After the reaction, TFE was evaporated under reduced
pressure, and then H O (6 mL), saturated aqueous Na S O (4 mL), and saturated
2
2
2
3
aqueous Na CO (4 mL) were added. The mixture was extracted with CH Cl
2
2
3
2
(
3 Â 5 mL) and the combined organic layer was dried over anhydrous Na SO ,
2
4
filtered, and concentrated under reduced pressure. The residue was purified on a
silica-gel plate (3:1 petroleum ether–ethyl acetate) to provide the corresponding pure
isoxazoline 3.
ACKNOWLEDGMENT
Financial support from the Natural Science Foundation of China (Project
1072176) is greatly appreciated.
2
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