Trifluoromethylation of aromatic isoxazoles: Regio- and diastereoselective route to 5-trifluoromethyl-2-isoxazolines

Article abstract of DOI:10.1002/anie.201102442

It all adds up: The activation of aromatic isoxazoles with a nitro group at the 4-position has enabled the first regio- and diastereoselective trifluoromethylation at the 5-position of isoxazoles by nucleophilic addition using Me₃SiCF₃ (see scheme; DMF=N,N′- dimethylformamide). The process was demonstrated with a broad range of 3,5-aromatic, heteroaromatic and aliphatic substrates.

Full text of DOI:10.1002/anie.201102442

DOI: 10.1002/anie.201102442
Nucleophilic Addition
Trifluoromethylation of Aromatic Isoxazoles: Regio- and Diastereo-
selective Route to 5-Trifluoromethyl-2-isoxazolines**
Hiroyuki Kawai, Kentaro Tachi, Etsuko Tokunaga, Motoo Shiro, and Norio Shibata*
5-Trifluoromethyl-2-isoxazolines with a quaternary carbon
center bearing a CF3 group are part of an important class of
heterocyclic compounds with remarkable biological activities,
which make them promising synthetic targets in the fields of
medicinal chemistry and agrochemistry.[1] Particularly since
the discovery of the structurally unique 3,5-diaryl-5-(trifluor-
omethyl)-2-isoxazoline derivatives A (Scheme 1; R1 = R4 =
Scheme 2. Synthesis of 5-trifluoromethyl 2-isoxazolines 2, 4, and 7 by
regio- and diastereoselective trifluoromethylation of 4-nitroisoxazoles 1
and 3 by nucleophilic addition. Reaction conditions: a) Me3SiCF3
Scheme 1. Synthetic strategies for 5-trifluoromethyl 2-isoxazolines.
Ar) as pest-control agents in 2004,[2a] the search for new
(2.0 equiv), NaOAc (1.5 equiv), [CH3(CH2)15N(CH3)3]Br (30 mol%),
DMF, RT; b) nBu3SnH (1.5 equiv), AIBN (0.5 equiv).
agrochemicals and veterinary medicines has focused largely
on this skeleton.[2] Thus far, more than 20000 compounds
have been synthesized and patented over the past 6 years (the
result of a substructure search for A using the SciFinder
database), and many potential drug candidates have been
disclosed, including an antiparasitic. There are two principal
strategies for the construction of the 5-trifluoromethyl-2-
isoxazoline framework: 1) a building-block approach, which
includes the 1,3-dipolar cycloaddition of trifluoromethylated
styrenes and nitrile oxides,[2a–d] and a hydroxylamine/enone
cascade reaction consisting of the conjugated addition/
cyclization/dehydration reactions,[2e–h,3] and 2) the direct
nucleophilic addition of a CF3 group to an isoxazole
(Scheme 2).
However, only building-block methods have been
reported and no examples of the trifluoromethylation of
isoxazoles by direct nucleophilic addition have appeared,
despite the clear advantage of a direct method over the
building-block approach. This issue is apparently a conse-
quence of the fundamental aromatic character of isoxazoles,[4]
that is, the preference to retain the aromaticity rather than
become a nonconjugated system, particularly in the case of
the conjugated 3,5-diarylisoxazoles. Indeed, the addition of
nucleophiles at the 5-position of an isoxazole is a challenge.[5]
To realize the previously unknown trifluoromethylation of
aromatic 3,5-diarylisoxazoles by nucleophilic addition, we
came up with the idea of introducing a strong electron-
withdrawing nitro group at the 4-position of the isoxazole
ring; this group should alter the aromaticity of the isoxazoles
to activate the 5-position.[6] As part of our ongoing research
programs, which are directed towards the development of
novel methods of trifluoromethylation,[7] we disclose herein
an expeditious synthesis of biologically important 5-
(trifluoromethyl)-2-isoxazoline derivatives A in high yields
and with complete diastereoselectivity by a novel trifluoro-
methylation of 4-nitroisoxazoles using the Ruppert–Prakash
reagent (trifluoromethyltrimethylsilane) in the presence of
NaOAc and a phase-transfer catalyst. Regio- and diastereo-
selective trifluoromethylation by nucleophilic addition was
even also achieved in high to excellent yields without giving
any 1,6-adducts in the reaction of 1,6-conjugated styryl-4-
nitroisoxazoles 3 with Me3SiCF3 under the same reaction
conditions (Scheme 2). Despite the ever-increasing repertoire
of trifluoromethylation reactions of carbonyls,[8] imines,[9]
alkenes,[10] aromatic rings,[11] and other groups[8] with
Me3SiCF3, this is the first example of the trifluoromethylation
of an aromatic isoxazole by nucleophilic addition. Since the
nitro group in the products can be easily removed under
radical reaction conditions, the process not only constitutes a
[*] H. Kawai, K. Tachi, E. Tokunaga, Prof. N. Shibata
Department of Frontier Materials
Graduate School of Engineering, Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
Dr. M. Shiro
Rigaku Corporation
3-9-12 Mastubara-cho, Akishima, Tokyo 196-8666 (Japan)
[**] This study was financially supported in part by Kakenhi (21390030,
22106515). We also thank TOSOH F-TECH INC. for a gift of
Me3SiCF3.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102442.
Angew. Chem. Int. Ed. 2011, 50, 7803 –7806
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7803

Communications
Table 2: Stereoselective trifluoromethylation of 4-nitro-3,5-diarylisoxa-
zole 1a–f by nucleophilic addition.[a]
rare example of the trifluoromethylation of aromatic com-
pounds by nucleophilic addition, but also provides a new
synthetic route to the agrochemically important 5-trifluoro-
methyl-2-isoxazolines.
We first examined the reaction of 4-nitro-3,5-diphenyl-
isoxazole (1a), as a model substrate, with Me3SiCF3 in the
presence of a stoichiometric amount of tetrabutylammonium
fluoride (nBu4NF) in DMFat ambient temperature. Substrate
1a completely disappeared during the reaction, as monitored
by TLC analysis, but the trifluoromethylated adduct 2a was
not obtained (Table 1, entry 1). The reaction was next
Entry
1
R
Ar
2
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2 f
2g
2h
2i
95
85
90
90
99
92
90
97
72
67
4-MeC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
4-BrC6H4
Ph
3-MeC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
3-ClC6H4
Me
Table 1: Optimization of the reaction conditions.[a]
1j
Me
4-MeC6H4
2j
[a] Reaction conditions: a) Me3SiCF3 (2.0 equiv), NaOAc (1.5 equiv),
[CH3(CH2)15N(CH3)3]Br (30 mol%), DMF, RT; b) 1m HCl aq, RT. [b] The
yield of the isolated product.
Entry
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
nBu4NF·H2O
K2CO3
KOH
tBuOK
KF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH2Cl2
THF
–
28
44
57
59
57
67
80
78
–
arylisoxazoles 1i and 1j, which have enolizable protons, the
nucleophilic addition proceeded nicely to provide the corre-
sponding trifluoromethylated adducts 2i and 2j in good yields
(entries 9 and 10).
CsF
LiOAc
NaOAc
KOAc
NaOAc
NaOAc
NaOAc
NaOAc
9
We were next interested in the trifluoromethylation of 4-
nitro-5-styrylisoxazoles 3; these compounds are flexible
building blocks that bear a number of different functional-
ities.[12] Principally, 4-nitro-5-styrylisoxazoles 3 have two
electrophilic centers, both of which could be attacked by
nucleophiles. In a previous report, 3 selectively reacted with
nucleophiles by a 1,6-addition to yield conjugated Michael
adducts in good yields,[5e,f,12g–k,m,p] although the addition of
carbon nucleophiles at the 4-position of 3 is rare.[5e,f] To our
delight, the reaction of 3-methyl-4-nitro-5-styrylisoxazole
(3a) with Me3SiCF3 under the optimized reaction conditions
exclusively afforded the trifluoromethylation product 4a in
87% yield as a single isomer. Interestingly, when the reaction
of 3a was carried out under the same reaction conditions but
using Me3SiCN instead of Me3SiCF3, the 1,6-adduct 5 was
selectively furnished in 20% yield (Scheme 3). These results
indicated that addition at the 5-position of an aromatic
isoxazole ring is specific to the trifluoromethylation reaction.
Nucleophilic trifluoromethylation to conjugated alkenes
10
11
12
13[c]
–
–
95
toluene
DMF
[a] Reaction conditions: a )Me3SiCF3 (2.0 equiv), base (1.5 equiv),
solvent, RT, 6–10 h; b) 1m HCl aq, RT. [b] The yield of the isolated
product. [c] The reaction was performed in the presence of [CH3-
(CH2)15N(CH3)3]Br. DMF=N,N’-dimethylformamide.
attempted using K2CO3 instead of nBu4NF, which gave the
desired 2a in 28% yield as a single diastereoisomer (entry 2).
This preliminary result encouraged us to further investigate
the reaction conditions (entries 3–13). After screening several
bases (entries 3–9), the yield of 2a was increased to 80%
when the reaction was carried out using NaOAc (entry 8).
The choice of solvent is important to the conversion, as the
reaction did not proceed at all in CH2Cl2, THF, and toluene
(entries 10–12). The best result was obtained by treating 1a
with Me3SiCF3 (2.0 equiv) at room temperature in DMF in
the presence of cetyltrimethylammonium bromide ([CH3-
(CH2)15N(CH3)3]Br; 30 mol%) and NaOAc (1.5 equiv),
which led to the isolation of 2a in 95% yield (entry 13).
With the optimized conditions to hand, the scope of the
trifluoromethylation of 4-nitro-3,5-diarylisoxazole
1 by
nucleophilic addition was explored with a variety of sub-
strates, which were selected to establish the generality of the
process by using this strategy. A range of 4-nitro-3,5-diaryl-
isoxazoles (1a–h) were converted into the corresponding
trifluoromethylated adducts (2a–h), which were isolated as
single isomers in excellent yields of 85–99%; the yields were
not affected by the functional groups on the aromatic ring
(Table 2, entries 1–8). Interestingly, for 4-nitro-5-methyl-3-
Scheme 3. Addition of trimethylsilyl carbon nucleophiles to 3-methyl-4-
nitro-5-styrylisoxazole 3a. Reaction conditions: Me3SiX (2.0 equiv),
NaOAc (1.5 equiv), [CH3(CH2)15N(CH3)3]Br (30 mol%), DMF, RT; 1m
HCl aq.
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Angew. Chem. Int. Ed. 2011, 50, 7803 –7806

fundamentally occurs exclusively by a 1,2-addition, not a 1,4-
addition,[8] except for several specific examples in which the
1,4-addition of a CF3 anion has been reported.[10] Indeed, no
example of a 1,4-addition to nitroalkanes is known. In this
context, the phenomena could be explained by the nucleo-
philic 1,2-type addition of a CF3 anion to a reactive species B,
which is a tautomer of 3a and should be included in the
reaction mechanism, to provide 4a (Scheme 4). The same
mechanistic pathway is also suggested for the trifluorome-
thylation of 1 by nucleophilic addition to give 2 (Table 2).
The regio- and diastereoselective trifluoromethylation of
5-styrylisoxazoles 3 was found to be quite general in terms of
the substrates (Table 3). The 3-methyl-5-trifluoromethyl-5-
styrylisoxazoles 4a–l were obtained in high to excellent yields
and as single isomers, irrespective of the electronic nature of
the aryl groups, which included naphthyl and furanyl groups,
on substrates 3 (entries 1–12). 3-Aryl-4-nitro-5-styrylisox-
azoles 3m–p were also suitable substrates for the trifluoro-
methylation and gave the products in excellent yields of 90–
96% (entries 13—16). The relative stereochemistry of
(4S*,5S*)-4i was clearly determined by X-ray crystallo-
graphic analysis (Figure S1 in Supporting Information),[13]
and the stereochemistry of all the other products (2 and 4)
19F NMR spectra with those of 4i. The 4S*,5S* stereoselec-
tivity of 4 could result from a thermodynamically controlled
protonation of an intermediate, as shown in the last step in
Scheme 4. The (4S*,5S*)-4 might be more thermodynamically
favored than another isomer, (4R*,5S*)-4, although further
investigation is required to elucidate the mechanism.
In conclusion, the activation of aromatic isoxazoles with a
nitro group at the 4-position has resulted in the realization of
the first diastereoselective trifluoromethylation at the 5-
position of isoxazoles by nucleophilic addition using
Me3SiCF3. This method allows easy access to agrochemically
important 3,5-disubstituted-5-(trifluoromethyl)-2-isoxazoline
derivatives. Regio- and diastereoselective trifluoromethyla-
tion by nucleophilic addition was also achieved in the reaction
of the 1,6-conjugated styryl-4-nitroisoxazoles
3
with
Me3SiCF3 under the same reaction conditions. The process
can be applied to a broad range of 3,5-aromatic, heteroaro-
matic, and aliphatic substrates which contain diverse func-
tionality. Notably the nitro group at the 4-position is essential
for a successful transformation. No reaction was observed
between 3,5-diphenylisoxazole 6a, which is the non-nitro
analogue of 1a, and Me3SiCF3 under the same reaction
conditions. The nitro group of 2a was easily removed under
the radical reduction conditions to provide 7a in 62% yield
(Scheme 5). Hence, the process not only constitutes a rare
1
were tentatively assigned by the comparison of their H and
Scheme 4. A possible reaction pathway for the regioselective trifluoro-
methylation of 3a to 4a by nucleophilic addition.
Table 3: Regio- and diastereoselective trifluoromethylation of 4-nitro-5-
styrylisoxazoles 3a–p by nucleophilic addition.[a]
Scheme 5. The nitro group has an important role in these chemical
transformations. Reaction conditions: a) Me3SiCF3 (2.0 equiv), NaOAc
(1.5 equiv), [CH3(CH2)15N(CH3)3]Br (30 mol%), DMF, RT; b) nBu3SnH
(1.5 equiv), AIBN (0.5 equiv), benzene, reflux, 2 h.
Entry
3
Ar
R
4
Yield [%][b]
example of the trifluoromethylation of aromatic compounds
by nucleophilic addition but also provides a new synthetic
route to the agrochemically important 5-trifluoromethyl-2-
isoxazolines. The biological activities of selected 5-(trifluoro-
methyl)-2-isoxazoline derivatives are being investigated and
asymmetric variants of this method are now under consider-
ation.
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
87
84
82
87
89
96
80
90
67
86
85
93
90
95
90
96
4-MeC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-Cl-4-NO2C6H3
1-naphthyl
2-naphthyl
2-furyl
9
10
11
12[c]
13
14
15
16
Received: April 8, 2011
Published online: July 1, 2011
Ph
Ph
4-MeC6H4
4-ClC6H4
Keywords: agrochemicals · heterocycles · nucleophilic addition ·
.
4-MeC6H4
Ph
Ph
synthetic methods · trifluoromethylation
[a] Reaction conditions: a) Me3SiCF3 (2.0 equiv), NaOAc (1.5 equiv),
[CH3(CH2)15N(CH3)3]Br (30 mol%), DMF, RT, 3–8 h; b) 1m HCl aq, RT.
[b] The yield of the isolated product. [c] Me3SiCF3 (4.0 equiv), NaOAc
(3.0 equiv) and [CH3(CH2)15N(CH3)3]Br (50 mol%) were used.
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www.angewandte.org
7805

Communications
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7806 www.angewandte.org
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