Oxime-mediated oxychlorination and oxybromination of unactivated olefins

Article abstract of DOI:10.1002/ejoc.201403538

An oxime-mediated oxychlorination and oxybromination of unactivated olefins relying on palladium catalysis has been developed. A wide range of chlorinated and brominated isoxazolines has been synthesized in moderate to good yields. To demonstrate the value of the method, the brominated isoxazoline has been further converted to other useful synthetic feedstock.

Full text of DOI:10.1002/ejoc.201403538

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Date: 22-01-15 13:20:03
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403538
Oxime-Mediated Oxychlorination and Oxybromination of Unactivated Olefins
Kui-Yong Dong,[a] Hai-Tao Qin,[a] Feng Liu,*[a] and Chen Zhu*[b]
Keywords: Oximes / Halogenation / Oxybromination / Isoxazolines / Palladium / Homogeneous catalysis
An oxime-mediated oxychlorination and oxybromination of
unactivated olefins relying on palladium catalysis has been
developed. A wide range of chlorinated and brominated
isoxazolines has been synthesized in moderate to good
yields. To demonstrate the value of the method, the bromin-
ated isoxazoline has been further converted to other useful
synthetic feedstock.
formations. We have a long-term interest in the palladium-
catalyzed functionalization of unactivated olefins to con-
struct heterocycles.[8] Very recently, we developed the palla-
dium-catalyzed synthesis of 5-methylisoxazoles from ox-
imes.[9] A variety of 5-methylisoxazoles were obtained for
evaluation of their bioactivity. To enlarge the library of het-
erocycles for the purpose of medicinal chemistry, we need
to establish efficient access to a series of functionalized 3,5-
disubstituted isoxazolines. Herein, we wish to report the ox-
ime-mediated oxyhalogenation of unactivated olefins by
means of palladium catalysis in the presence of copper
salt.[10,11] The resulting halogenated isoxazolines can serve
as a versatile feedstock for diols, triols, and amino alcohols.
Introduction
Isoxazolines are extensively found in natural products
and molecules with biological activity.[1] They also fre-
quently serve as intermediates in organic synthesis, since
they can be easily transformed to β-hydroxy ketones and
other useful building blocks by virtue of the easy cleavage
of the N–O bond.[2] The conventional synthesis methods of
isoxazolines mainly rely on the 1,3-dipolar cycloaddition of
nitrile oxides and olefins, in which certain oxidants are gen-
erally required for the initial oxidation of aldoximes to
nitrile oxides.[3] However, these conversions sometimes pose
challenges in terms of the tolerance of sensitive functional
groups and the achievement of satisfactory regioselectivi-
ties. Recently, a variation was presented by which a variety
of functionalized isoxazolines were regioselectively fur-
nished by the palladium-catalyzed annulation of β,γ-unsat-
urated oximes.[4–7] Chen et al. firstly reported the palla-
dium-catalyzed oxyarylation of β,γ-unsaturated oximes
with aryl bromides. Intramolecular 5-exo-trig ring closure
occurred, giving rise to sole regioselectivities.[4] Later,
Mosher et al. and Loh et al. developed the regioselective
methoxycarbonylation and intramolecular dioxygenation of
β,γ-unsaturated oximes, respectively.[5,6]
Results and Discussion
We commenced by the oxychlorination of olefins. At the
outset, the reaction parameters were systematically sur-
veyed. It was found that by using palladium acetate as cata-
lyst, copper chloride did not only serve as chlorine source
but also as oxidant for the redox cycle. Among the solvents
examined, DMSO showed the best performance in terms of
chemical yield (Table 1, entries 1–8). The addition of inor-
ganic or organic base accelerated the reaction, but did not
improve the chemical yields (entries 9–11). Reducing the
catalyst loadings or replacing the catalyst compromised the
chemical yields (entries 12–15).
With the optimized reaction conditions on hand, we
turned to define the substrate scope of β,γ-unsaturated ox-
imes. As depicted in Figure 1, the broad generality was ob-
tained with a wide range of oximes regardless of their elec-
tronic and steric properties. Most of the reactions were
complete in a few hours, giving the corresponding isoxazol-
ines in moderate to good yields. Aryl substrates with elec-
tron-rich (2b–2f) or electron-deficient (2g–2k) substituents
did not have apparent impact on chemical yields and reac-
tion rates. Polyaryl (2l) and heteroaryl (2m) oximes were
also adaptable to the reaction conditions. Not only aryl but
Transition-metal-catalyzed vicinal difunctionalization of
unactivated olefins provides a powerful tool for olefin trans-
[a] Jiangsu Key Laboratory of Translational Research
and Therapy for Neuro-Psycho-Diseases and
Department of Medicinal Chemistry,
College of Pharmaceutical Sciences, Soochow University
199 Ren-Ai Road, Suzhou, Jiangsu 215123,
People’s Republic of China
E-mail: fliu2@suda.edu.cn
[b] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and
Materials Science, Soochow University
199 Ren-Ai Road, Suzhou, Jiangsu 215123,
People’s Republic of China
E-mail: chzhu@suda.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403538.
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K.-Y. Dong, H.-T. Qin, F. Liu, C. Zhu
SHORT COMMUNICATION
Table 1. Survey of reaction parameters.[a]
Entry Pd Cat.
Solvent
Additive Time[b] Yield[c]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
THF
–
–
–
–
–
–
–
–
3
13
7
5
9
3
2.5
3
1
1
2
4
12
6
10
24
74
71
35
63
80
42
82
74
80
69
69
42
65
58
acetonitrile
dioxane
DCE
toluene
chlorobenzene
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
K2CO3
NaOH
Et3N
–
–
–
–
10
11
12[d]
13
14
15
Pd(CH3CN)Cl2 DMSO
[a] Reaction conditions: 1a (0.15 mmol), CuCl2 (0.30 mmol), and
Pd catalyst (0.015 mmol) in solvent (5 mL). [b] Based on entire con-
version (hours). [c] Isolated yield (%). [d] 5 mol-% Pd(OAc)2.
alkyl oximes were suitable substrates (2n–2p). Compound
2q is noteworthy, as the olefin unit in cyclohexene did not
compete with the allyl group in Wacker-type oxypallad-
ation. Reactions with oximes that have substitutions on the
allyl group gave rise to fully functionalized isoxazolines (2r–
2u) in good yields. Compound 2t was obtained as a mixture
of two diastereomers (dr 3:2), but compound 2u was gener-
ated as a single 4,5-syn-isomer due to the stereocontrol of
the five-membered ring. In the case of oximes with internal
olefins (2v–2x), the transformation uniformly gave the cor-
responding oxychlorination products in anti-form which
was deduced from the conformation of the analogous 3j.
Inspired by these results, we considered whether the
strategy could be applied to the oxybromination of olefins
by simply replacing copper chloride with copper bromide
(Figure 2). Under similar reaction conditions, a variety of
oximes were readily converted into the desired oxybromin-
ation products in satisfactory yields. Both electron-rich and
electron-poor oximes (3a–3d) were compatible with the re-
action conditions. The chemical yield did not decrease when
thienyl oxime (3e) was employed. Polysubstituted oximes
furnished products 3f–3h in good yields in spite of their
more crowded chemical environment. Similarly to the
oxychlorination reaction, the transformation of oximes with
internal olefins also generated the sole anti product (3i, 3j),
Figure 1. Substrate scope for oxychlorination of olefins.
or amino alcohol structural motifs, respectively. Remarka-
bly, the treatment of 3f with Fe and aqueous NH4Cl ef-
ficiently led to β,γ-diol ketone 6, which could be further
converted into an important building block, 1,2,4-triol.
Conclusion
In summary, we have developed an oxime-mediated
which was unambiguously confirmed by the crystal struc- oxychlorination and oxybromination of unactivated olefins
ture of 3j.[12] It was in agreement with the conformation of relying on palladium catalysis. A vast array of chlorinated
adduct produced by Wacker-type reaction.
and brominated isoxazolines has been divergently synthe-
To demonstrate the utility of the method, brominated sized in moderate to good yields. The reaction has been
isoxazoline 3f was explored as a versatile precursor for diols achieved in good regio- and stereoselectivity and with high
and amino alcohols. As shown in Scheme 1, the nucleo- functional group tolerance. The halogenated isoxazolines
philic substitution of bromine in 3f with pyrrolidine or acet- can be further transformed into diols, triols, and amino
ate gave rise to the resulting isoxazolines 4 and 5 with diol alcohols, which demonstrates the value of the method.
2
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Oxime-Mediated Oxychlorination and Oxybromination
Figure 2. Representative substrates for oxybromination of olefins.
Scheme 1. Chemical transformations of brominated isoxazoline.
ganic extracts were washed with brine, dried with Na2SO4, filtered,
concentrated, and purified by flash chromatography on silica gel
(ethyl acetate/hexanes) to give product 2 (or 3).
Experimental Section
Synthesis Procedure: Oxime 1 (0.15 mmol, 1.0 equiv.), Pd(OAc)2
(0.015 mmol, 0.1 equiv.), and CuCl2 (or CuBr2, 0.3 mmol,
1.2 equiv.) were loaded into a flame-dried flask, which was sub-
jected to evacuation/flushing with dry argon three times. Anhy-
drous DMSO (5 mL) was added to the mixture by a syringe, and
the mixture was then stirred at room temp. until the starting mate-
rial had been consumed as determined by TLC. The mixture was
then extracted with ethyl acetate (3 ϫ 15 mL). The combined or-
Acknowledgments
F. L. is grateful for the financial support from the National Natural
Science Foundation of China (Grant no. 21302134), the Natural
Science Foundation of Jiangsu (Grant no. BK20130338), and the
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K.-Y. Dong, H.-T. Qin, F. Liu, C. Zhu
SHORT COMMUNICATION
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Received: November 26, 2014
Published Online: ᭿
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Oxime-Mediated Oxychlorination and Oxybromination
Synthesis of Isoxazolines
K.-Y. Dong, H.-T. Qin, F. Liu,*
C. Zhu* ............................................. 1–5
Oxime-Mediated Oxychlorination and
Oxybromination of Unactivated Olefins
One to two: An oxime-mediated oxychlor-
ination and oxybromination of unactivated
olefins relying on palladium catalysis has
been developed. A wide range of chlorin-
ated and brominated isoxazolines has been
synthesized in moderate to good
yields.
Keywords: Oximes / Halogenation / Oxy-
bromination / Isoxazolines / Palladium /
Homogeneous catalysis
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