Iminoxyl radical-promoted dichotomous cyclizations: Efficient oxyoximation and aminooximation of alkenes

Article abstract of DOI:10.1021/ol502258n

A novel iminoxyl radical-involved metal-free approach to vicinal oxyoximation and aminooximation of unactivated alkenes is developed. This method utilizes the dichotomous reactivity of the iminoxyl radical to furnish a general difunctionalization on alkenes using simple tert-butyl nitrite (TBN) as the iminoxyl radical initiator as well the carbon radical trap. By using this protocol, oxime featured 4,5-dihydroisoxazoles and cyclic nitrones were facilely prepared from β,γ- and γ,δ-unsaturated ketoximes, respectively.

Full text of DOI:10.1021/ol502258n

Letter
pubs.acs.org/OrgLett
Iminoxyl Radical-Promoted Dichotomous Cyclizations: Efficient
Oxyoximation and Aminooximation of Alkenes
Xie-Xue Peng, Yun-Jing Deng, Xiu-Long Yang, Lin Zhang, Wei Yu, and Bing Han*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
730000, P. R. China
S
* Supporting Information
ABSTRACT: A novel iminoxyl radical-involved metal-free
approach to vicinal oxyoximation and aminooximation of
unactivated alkenes is developed. This method utilizes the
dichotomous reactivity of the iminoxyl radical to furnish a
general difunctionalization on alkenes using simple tert-butyl
nitrite (TBN) as the iminoxyl radical initiator as well the
carbon radical trap. By using this protocol, oxime featured 4,5-
dihydroisoxazoles and cyclic nitrones were facilely prepared
from β,γ- and γ,δ-unsaturated ketoximes, respectively.
eteroatom-centered radical cyclizations have been
extensively studied, and they have wide applications in
Scheme 1. Iminoxyl Radical-Promoted Difunctionalization
of Alkenes
H
the synthesis of heterocyclic compounds.1 However, most of
those studies are focused on single-heteroatom-centered
radicals, whereas the cyclization involving heteroatom-centered
radicals with spin density located on two heteroatoms is rarely
reported. Different from the former, the cyclization of
heteroatom-centered radicals with spin density located on
two heteroatoms can not only provide a facile method for the
synthesis of double-heteroatom-containing heterocycles but
also take advantage of the dichotomous reactivity of both
heteroatoms depending on the position of the tethered
alkenes.2
Iminoxyl radicals are fascinating heteroatom-centered radi-
cals which possess the electronic structure where the single
electron spin is delocalized on both the O- and N-atom.3 Very
recently, we have demonstrated that the readily prepared β,γ-
and γ,δ-unsaturated ketoximes can be initiated to the
corresponding iminoxyl radicals which behave as the oxygen-
centered radicals as well as the N-centered radicals.
Consequently, both the O- and N-atom 5-exo-trig radical
cyclizations can take place to yield carbon-centered radicals
depending on the position of the carbon−carbon double bond.
The interception of the thus formed carbon centered radicals
by TEMPO delivers isoxazolines and cyclic nitrones in a way
that both the dioxygenation and aminooxygenation of alkenes
can be realized (Scheme 1).2a
To develop more efficient iminoxyl radical-promoted
dichotomous cyclizations for synthetic purposes, we hypothe-
sized that the commercially available tert-butyl nitrite (TBN)
could be used as an iminoxyl radical initiator as well as a nitric
oxide source.4 Previous studies have shown that TBN is an
effective reagent for the nitration5 and nitrosation (oximation)6
of alkenes. We hoped that by applying TBN to the cyclization
of β,γ- and γ,δ-unsaturated ketoximes, the nitroso incorporated
isoxazolines and cyclic nitrones would be obtained. The latter
would subsequently tautomerize to the corresponding stable
oxime incorporated isoxazolines and cyclic nitrones. Thus, both
the vicinal oxyoximation and aminooximation of the
unactivated alkenes could be realized as the novel types of
the oxyamination and diamination7 (Scheme 1).
These oxime attached isoxazolines and cyclic nitrones not
only are useful synthetic intermediates but also exhibit
attractive biochemical and pharmaceutical properties.8
We commenced our studies by stirring β,γ-unsaturated
ketoxime 1a to TBN in MeCN at room temperature under an
argon atmosphere. A colorless precipitate, which was confirmed
by a single-crystal X-ray diffraction study as 2a (Scheme 2), was
formed within 0.5 h in 96% yield. Apparently, the desired
reaction took place, generating NO trapped 4,5-dihydroisox-
azole 2a′ which immediately dimerized to the product 2a.
Heating compound 2a in MeCN at 80 °C in the presence of 1
Received: July 30, 2014
© XXXX American Chemical Society
A
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Scheme 2. Iminoxyl Radical-Promoted Oxyoximation of
Alkenes
Table 1. Iminoxyl Radical-Promoted Oxyoximation of
a
Alkenes for the Synthesis of Isoxazolines
equiv of triethylamine delivered isoxazoline carbaldehyde oxime
3a quantitatively (Scheme 2). In this way, a one-pot process for
the synthesis of isoxazoline carbaldehyde oximes was developed
by the reaction of 1a with TBN in MeCN following facile in
situ workup with N(Et)3 (eq 1).
To confirm that the reaction was initiated by the generation
of the iminoxyl radical rather than the radical addition of TBN
and/or NO to alkenes, TEMPO (2,2,6,6-tetramethylpiperidine-
1-oxyl) was used as the carbon-centered radical scavenger
under the same reaction conditions as those shown in eq 2. The
reaction gave TEMPO trapped isoxazoline 4 in 90% yield,
accompanied by less than 5% of 2a. This result demonstrated
clearly that the initiation step is the generation of the iminoxyl
radical because TEMPO is a more efficient scavenger than TBN
for the cyclized carbon radical.
To examine the scope of the present protocols, a variety of
β,γ-unsaturated ketoximes were subjected to the standard
reaction conditions outlined in eq 1. The results are
summarized in Table 1. Terminal alkenes participated in the
oxyoximation process very well, giving rise to isoxazoline
carbaldehyde oximes 3a−3h in good to excellent yields. Both
aromatic and aliphatic substituted ketoximes were tolerated
(Table 1, entries 1−6). Thiophen incorporated ketoxime 1g
was also transformed to the desired product 3g in excellent
yield (Table 1, entry 7). Oxyoximation involving 1,2-
disubstituted alkenes was also successful, as demonstrated in
the reaction of substrate 1h (Table 1, entry 8). When the
alkene moiety was incorporated in a ring, as in the cases of 1i
and 1j, the reactions afforded isoxazoline fused cyclopentanone
oxime 3i and cyclohexanone oxime 3j in 82% and 88% yield,
respectively (Table 1, entries 9 and 10). Notably, the reaction
can also be easily carried out in a gram scale without difficulty,
thereby delivering 3d in excellent yield.
a
All reactions run 0.1 M in MeCN using ketoximes 1 (0.5 mmol) and
b
TBN (1.5 mmol) at room temperature under Ar. Yields of isolated
c
product after N(Et)3 workup. Ratio in parentheses indicates the Z/E
isomers. The determination of the ratio of Z/E isomers is based on 1H
d
NMR (see Supporting Information for the detail). 10 mmol scale of
substrate was used.
oxime motif which is of great synthetic value in multi-
transformations for important organic intermediates. As in the
case of 3d, the aldoxime moiety can be transformed to the
cyano group after dehydration by treating with MsCl
(methanesulfonyl chloride) and pyridine at room temperature,
delivering 3-phenyl-4,5-dihydroisoxazole-5-carbo-nitrile 5 in
98% yield. In addition, 3d can be transformed to 3-phenyl-
4,5-dihydroisoxazole-5-carboxamide 6 in 67% yield through
Beckman rearrangement using a catalytic amount of In(NO3)3.
Moreover, 3d can also be converted to a 1,3-dipole by
treatment with NCS (N-chloro-succinimide) and N(Et)3,
which can further react with methyl propiolate to give
compound 7 in 96% yield (Scheme 3).
Having successfully achieved the O-atom 5-exo-trig radical
cyclization of β,γ-unsaturated ketoximes,9 we moved on to
extend the protocol to γ,δ-unsaturated counterparts to see if the
latter could also undergo the N-atom 5-exo-trig radical
cyclization to form cyclic nitrones, as we previously observed.2a
Indeed, as shown in Table 2, oxime incorporated cyclic nitrones
8 were obtained in high yields accompanied by the intra-
molecular aminooximation of alkenes in all cases. On the other
Besides the importance of the isoxazoline scaffold in
pharmacophores and organic synthesis,8a,b the formation of
compounds 3 involves oxyoximation of alkenes and features an
B
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hand, the O-atom-involved 1,5-H shift, which occurs under
other circumstances,10 was not observed in the present cases,
because it is much less favored than the N-atom-involved 5-exo-
trig cyclization. Unsaturated ketoxime incorporated terminal
olefins were transformed to cyclic nitrone carbaldehyde oximes
in good yields (Table 2, entries 1−6). When ketoximes 1o and
1p were utilized in the reaction, cyclic nitrones were formed as
spiro-compounds in excellent yields (Table 2, entries 5 and 6).
For compound 1q, which incorporates a styryl moiety, the
reaction afforded 8q in 91% yield (Table 2, entry 7). The
structures of Z-8q and E-8q were confirmed by single-crystal X-
ray diffraction studies. When the alkene moiety was
incorporated in a ring, as in the cases of 1r and 1s, the
reaction also afforded cyclic nitrone fused cyclopentanone
oxime 8r and cyclohexanone oxime 8s in 73% and 75% yield,
respectively. Reaction of 1t afforded the desired product 8t in
97% yield, demonstrating the compatibility of the mild,
efficient, radical-chain protocol with additional olefin groups
susceptible to nitration.
Scheme 3. Follow-up Transformation of Isoxazoline
Carbaldehyde Oximes
Table 2. Iminoxyl Radical-Promoted Aminooximation of
a
Alkenes for the Synthesis of Cyclic Nitrones
Cyclic nitrones have attracted great attention due to their
multiple uses in pharmacy8c,d and as 1,3-dipoles in organic
synthesis.11 In this context, the oxime incorporated cyclic
nitrones could also be used as 1,3-dipoles (Scheme 4). When
Scheme 4. Inter- and Intramolecular [3 + 2] Cycloadditions
of Oxime Attached Cyclic Nitrones
compound 8s was treated with methyl propiolate, it could give
formal [3 + 2] cycloaddition product 9 as a single
diastereoisomer in 61% yield. In addition, intramolecular [3 +
2] cycloaddition could also take place when compound 8t was
involved, delivering complex product 10 as a single
diastereomer in 80% yield.
In conclusion, we have developed a mild, convenient, and
efficient method for the synthesis of functionalized 4,5-
dihydroisoxazoles and cyclic nitrones from β,γ-unsaturated
and γ,δ-unsaturated ketoximes. This protocol employs the
simple TBN as the radical initiator, which can readily convert
the ketoximes to iminoxyl radicals. TBN also acts as a radical
trap in this reaction to capture the carbon radicals generated
from the C−O and C−N forming 5-exo-trig cyclizations of
unsaturated iminoxyl radicals, and thus the novel oxyoximation
and aminooximation of unactivated alkenes can be realized.12
To the best of our knowledge, the present study represents the
first example of using TBN to generate iminoxyl radicals as well
as the first example of vicinal oxyoximation and amino-
oximation of unactivated alkenes. Further studies on the
iminoxyl radical promoted reaction are in progress in our
laboratory.
a
All reactions run at 0.1 M in MeCN using ketoximes 1 (0.5 mmol)
b
and TBN (1.5 mmol) at room temperature under Ar. Yields of
isolated product after N(Et)3 workup. Ratio in parentheses indicates
the Z/E isomers. The determination of the ratio of Z/E isomers is
based on H NMR (see Supporting Information for the detail). Z/E
c
d
1
isomers were separated.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and spectral data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hanb@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NNSFC (21272106, J1103307), the Program for
New Century Excellent Talents in University (NCET-13-
0258), the Changjiang Scholars and Innovative Research Team
in University (IRT1138), the “111” project, and the
Fundamental Research Funds for the Central Universities
(lzujbky-2014-k03, lzujbky-2014-60, lzujbky-2013-ct02) for
financial support.
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