Enantioselective synthesis of 5-trifluoromethyl-2-isoxazolines and their N-oxides by [hydroxy(tosyloxy)iodo]benzene-mediated oxidative N-O coupling

Article abstract of DOI:10.1002/ejoc.201301096

Biologically attractive trifluoromethyl-2-isoxazoline N-oxides were synthesized in good yields for the first time by the [hydroxy(tosyloxy)iodo] benzene-mediated oxidative N-O coupling of β-trifluoromethyl β-hydroxy ketoximes generated from trifluoromethyl β-keto alcohols. The present method allows the synthesis of previously unknown 5-trifluoromethyl-2- isoxazoline N-oxides and also provides an alternative for the enantioselective synthesis of antiparasitic 5-trifluoromethyl-2-isoxazolines by sequential reduction. Biologically attractive trifluoromethyl-2-isoxazoline N-oxides were synthesized in good yields by the [hydroxy(tosyloxy)iodo]benzene-mediated oxidative N-O coupling of β-trifluoromethyl β-hydroxy ketoximes. This is the first synthesis of 5-trifluoromethyl-2-isoxazoline N-oxides, and this method provides an alternative for the enantioselective synthesis of antiparasitic 5-trifluoromethyl-2-isoxazolines. Copyright

Full text of DOI:10.1002/ejoc.201301096

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301096
Enantioselective Synthesis of 5-Trifluoromethyl-2-isoxazolines and Their N-
Oxides by [Hydroxy(tosyloxy)iodo]benzene-Mediated Oxidative N–O Coupling
Hiroyuki Kawai,[a] Satoshi Okusu,[a] Etsuko Tokunaga,[a] and Norio Shibata*[a]
Keywords: Fluorine / Iodine / Heterocycles / Hypervalent compounds / Organocatalysis / N–O coupling
Biologically attractive trifluoromethyl-2-isoxazoline N-oxides
were synthesized in good yields for the first time by the [hy-
droxy(tosyloxy)iodo]benzene-mediated oxidative N–O cou-
pling of β-trifluoromethyl β-hydroxy ketoximes generated
from trifluoromethyl β-keto alcohols. The present method al-
lows the synthesis of previously unknown 5-trifluoromethyl-
2-isoxazoline N-oxides and also provides an alternative for
the enantioselective synthesis of antiparasitic 5-trifluoro-
methyl-2-isoxazolines by sequential reduction.
Introduction
Since the discovery in 2004 that 3,5-diaryl-5-(trifluoro-
methyl)-2-isoxazoline derivatives 1 exhibit potent antipara-
sitic activity against cat fleas and dog ticks,[1] the explora-
tion for novel veterinary medicines and agrochemicals has
attracted much attention to this small five-membered tri-
fluoromethylated heterocycle.[2] More than 27000 com-
pounds having this skeleton are registered in SciFinder®,
and most of them are patented by several chemical compa-
nies.[3] Moreover, carbon and nitrogen variants of 1, that is,
trifluoromethylated pyrrolines 2 (about 7700 compounds)[4]
and pyrazolines 3 (about 7400 compounds),[3e,4d,5] have also
been designed and synthesized for the same purposes, and
their impressive biological activities have been revealed. On
the basis of this background, we were interested in tri-
fluoromethylated isoxazoline N-oxides 4 as future candi-
dates for pharmaceuticals and agrochemicals. Isoxazoline
N-oxides and their derivatives are structurally unique het-
erocycles, and they have been applied in the synthesis of
biologically active compounds.[6] However, there is no re-
port on the synthesis of trifluoromethylated 3,5-diarylisox-
azoline N-oxides 4, despite their potential as veterinary
drugs and agrochemicals (Figure 1).
Figure 1. Structures of agrochemically important 1, 2, and 3,[3–5]
and previously unknown 4.
preparation of trifluoromethylated isoxazoline and related
heterocycles,[8] we disclose herein the asymmetric synthesis
of 5-trifluoromethyl-2-isoxazoline N-oxides 4 mediated by
[hydroxy(tosyloxy)iodo]benzene (HTIB). The oxidatively
N–O-coupled β-trifluoromethylhydroxy β-ketoximes 5 are
derived from trifluoromethyl β-keto alcohols 6 and hydrox-
ylamine. This method provides the first synthesis of 4 and
also provides an alternative approach for the enantioselec-
tive synthesis of antiparasitic medicines 1 by successive re-
duction (Scheme 1).
In recent years, we reported the synthesis of 3,5-diaryl-
5-(trifluoromethyl)-2-isoxazolines 1 by means of direct tri-
fluoromethylation of aromatic isoxazoles as well as an
enantioselective hydroxylamine–enone cascade reaction
consisting of a conjugate addition/cyclization/dehydration
sequence.[7] As part of our ongoing research program di-
rected at the development of efficient methodologies for the
Scheme 1. Novel approaches to 5-trifluoromethyl-2-isoxazolines 1
and unknown N-oxides 4 by HTIB-mediated oxidative N–O cou-
pling; Ts = para-tolylsulfonyl.
[a] Department of Frontier Materials, Graduate School of
Engineering, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, Japan
Results and Discussion
E-mail: nozshiba@nitech.ac.jp
http://www.ach.nitech.ac.jp/~organic/shibata/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301096.
Inspired by the report of Yao and co-workers on the
HTIB-mediated oxidative N–O coupling of ketoximes bear-
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Synthesis of 5-Trifluoromethyl-2-isoxazolines and Their N-Oxides
ing a secondary alcohol at the β-position to provide isox- Table 1. Synthesis of 5-trifluoromethyl-2-isoxazoline N-oxides 4.
azoline N-oxides,[9] we envisioned the synthesis of 4 from
ketoximes 5 derived from readily available trifluoromethyl-
ated tertiary alcohols 6.[10] We initiated our investigation
with the oxime formation of 6 by using hydroxylamine
(H2NOH·HCl), followed by the HTIB-mediated oxidative
Entry
6
Ar1
Ar2
4
Yield [%][a]
N–O coupling of crude β-trifluoromethyl β-hydroxy ketox-
imes 5 in MeOH. We first attempted oxime formation of 6a
with H2NOH·HCl (2.0 equiv.) in EtOH under reflux condi-
tions, followed by N–O coupling (Scheme 2, conditions A:
H2NOH·HCl, EtOH, reflux). Gratifyingly, desired 5-tri-
fluoromethyl-2-isoxazoline N-oxide 4a was obtained in
moderate yield (59%). We next examined the same reaction
in pyridine in the presence of H2NOH·HCl (2.0 equiv.),
which afforded 4a in a better yield of 70% (Scheme 2, con-
ditions B: H2NOH·HCl, pyridine, 50 °C).
1
2
3
4
5
6
7
8
9
6a Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
70
60
60
63
50
63
64
61
51
57
6b 4-MeC6H4
6c 4-MeOC6H4
6d 4-ClC6H4
6e 2-naphthyl
6f Ph
Ph
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-naphthyl
6g Ph
4g
4h
4i
6h Ph
6i Ph
10
6j Ph
4j
[a] Yield of isolated product calculated on the basis of 6.
keto alcohols 6f–j were nicely converted into 5-trifluoro-
methyl-2-isoxazoline N-oxides 4f–j in 51–64% yield; the
yield was almost independent of the functional group (e.g.,
methyl, chloro, bromo, and nitro) on the aromatic ring of
Ar2, and a sterically demanding naphthyl substrate was also
tolerated (Table 1, entries 6–10).
Scheme 2. Synthesis of 4a under two different conditions. Condi-
tions A: NH2OH·H2O (2.0 equiv.), EtOH, reflux, 14 h, 59%; condi-
tions B: NH2OH·H2O (2.0 equiv.), pyridine, 50 °C, 6 h, 70%.
With suitable conditions in hand, the scope of the oxime
We finally attempted the asymmetric synthesis of N-ox-
formation of 6, followed by the HTIB-mediated oxidative ides 4. Enantioenriched tertiary alcohol 6a was easily pre-
N–O coupling, was explored with a variety of substrates 6, pared with 99%ee by methylhydrazine-induced non-met-
which were selected to establish the generality of the process allic aerobic catalytic enantioselective epoxidation of β-tri-
by using this strategy; all of the substrates afforded the fluoromethyl β,β-disubstituted enone 7 to afford epoxide
products in moderate to good yields (Table 1). Substrates 8[11] followed by chemoselective reduction in the presence
with substituents derived from trifluoromethyl ketone, such of zinc/ammonium chloride according to a reported meth-
as methyl, methoxy, and chloro, at the aromatic ring (Ar1) od.[10e,12] Alcohol (R)-6a was converted efficiently into (R)-
as well as a sterically demanding naphthyl substrate were 4a under the same reaction conditions without any loss of
nicely converted into 5-trifluoromethyl-2-isoxazoline N-ox- enantiomeric purity (55% yield, 99%ee). 5-Trifluoro-
ides 4b–e in good yields (50–63%; Table 1, entries 2–5). We methyl-2-isoxazoline N-oxides 4 would not only be promis-
next examined the substrate scope by changing the nature ing candidates as pharmaceuticals and agrochemicals, but
of the aryl substituents (Ar2) derived from ketones under they would also be useful precursors for remarkable biolo-
the same reaction conditions. A series of trifluoromethyl β- gically active compounds 1.[7b] Indeed, deoxygenation of
Scheme 3. Asymmetric synthesis of N-oxide 4a from epoxide 8 and access to 5-trifluoromethyl-2-isoxazoline 1a; MTBE = methyl tert-
butyl ether.
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H. Kawai, S. Okusu, E. Tokunaga, N. Shibata
SHORT COMMUNICATION
(R)-4a in P(OMe)3 provided (R)-1a[7b] in a good yield of
96% without any loss of enantiopurity (Scheme 3). The
series of enantioenriched tertiary alcohols 6 can also be ac-
cessed by a catalytic enantioselective decarboxylative aldol
reaction of β-keto acids with trifluoromethyl ketones by
employing the bis-cinchona alkaloid (DHQD)2AQN
(Scheme 4).[10d] Target 1a[7b] was synthesized according to
the same sequential procedure consisting of oxime forma-
tion, N–O coupling (68% yield, 78%ee), and reduction
(80% yield, 78%ee).
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[3]
Scheme 4. Asymmetric synthesis of N-oxide 4a from trifluoro-
methyl ketone 9 and β-keto acid 10.
Conclusions
[4]
We disclosed the first synthesis of 5-trifluoromethyl-2-
isoxazoline N-oxides 4 through the HTIB-mediated oxidat-
ive N–O coupling of β-trifluoromethyl β-hydroxy ketoximes
5 derived from trifluoromethyl β-keto alcohols 6 and hy-
droxylamine. Our protocol provides a wide range of 5-tri-
fluoromethyl-2-isoxazoline N-oxides 4, which are poten-
tially important and widely applicable for the syntheses of
pharmaceuticals and agrochemicals as well as important
precursors of veterinary medicines 1. The organocatalyzed
enantioselective synthesis of 4 and 1 was also achieved. The
use of HTIB for the synthesis of biologically active com-
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Acknowledgments
This study was financially supported in part by the Platform for
Drug Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), Japan, by Grant-in-Aid for Scientific Research from
MEXT (24105513, project number 2304: Advanced Molecular
Transformation by Organocatalysts), and Japan Science and Tech-
nology (JST) (ACT-C: Creation of Advanced Catalytic Transfor-
mation for the Sustainable Manufacturing at Low Energy, Low En-
vironmental Load).
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Received: July 23, 2013
Published Online: September 11, 2013
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