Copper-catalyzed synthesis of trifluoromethyl-substituted isoxazolines

Article abstract of DOI:10.1039/c3cc42588f

A mild and efficient copper-catalyzed trifluoromethylation reaction which involves the cyclization of oximes has been developed. This method provides a convenient access to a variety of useful CF₃-containing 4,5-dihydroisoxazoles by constructing a C-CF₃ bond and a C-O bond in one step.

Full text of DOI:10.1039/c3cc42588f

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Copper-catalyzed synthesis of
trifluoromethyl-substituted isoxazolines†
Cite this: DOI: 10.1039/c3cc42588f
Yu-Tao He, Lian-Hua Li, Yan-Fang Yang, Yu-Qi Wang, Jian-Yi Luo, Xue-Yuan Liu
and Yong-Min Liang*
Received 9th April 2013,
Accepted 3rd May 2013
DOI: 10.1039/c3cc42588f
www.rsc.org/chemcomm
A mild and efficient copper-catalyzed trifluoromethylation reaction
which involves the cyclization of oximes has been developed.
This method provides a convenient access to a variety of useful
CF3-containing 4,5-dihydroisoxazoles by constructing a C–CF3 bond
and a C–O bond in one step.
Scheme 1 Synthesis of trifluoromethyl-substituted isoxazolines.
To begin, substrate 1a was chosen as a model substrate for
our investigation. We used Togni’s reagent 2a as the trifluoro-
methylation reagent under a catalytic amount of CuCl and KF
as the base in DMF. The reaction proceeded smoothly, which
gave the desired product 3a in 65% yield (Table 1, entry 1).
The trifluoromethyl group is considered to be a useful struc-
tural motif in pharmaceuticals, agrochemicals and functional
materials, mainly because of the excellent metabolic stability,
elevated electronegativity, and high lipophilicity.1,2 Therefore,
the development of new methods for the synthesis of CF3-
containing compounds is a research hotspot in the field of
organic synthesis. In recent years, a series of transition metal-
mediated or -catalyzed and photoredox catalyzed construction
of a C–CF3 bond has been reported.3–8 However, the synthesis
of CF3-containing heterocycles has been less explored,9 and
most of the construction methods in heterocycles are focused
on direct C–H trifluoromethylation. Thus, synthesis of trifluoro-
methyl-substituted heterocycles through a pattern of cyclization
is becoming a fascinating way for us to explore. Recently,
Buchwald et al. and Liu et al., independently, reported the
oxytrifluoromethylation of unactivated alkenes based on a
copper catalyst,10 and intramolecular oxidative aryltrifluoro-
methylation of activated alkenes using TMSCF3 (Ruppert–Prakash
reagent)11 in the presence of Pd(OAc)2.12
As we know, oximes are fascinating synthetic reagents since they
have both nitrogen and oxygen atoms as nucleophiles.13 In 2012,
the intramolecular addition of the oxime radical to a carbon–carbon
double bond to form isoxazolines was reported by Han et al.14
Inspired by this intriguing work and in connection with our interest
in the synthesis of heterocycles,15 we report an efficient procedure
for the preparation of a series of trifluoromethyl-substituted
4,5-dihydroisoxazoles by using Togni’s reagent16 (Scheme 1).
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Base
Solvent
Yieldb (%)
1
CuCl
CuCl
CuCl
—
Cu(OTf)2
Cu(OAc)2
[Cu(OTf)2]ÁC6H6
CuI
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
KF
KF
KF
KF
KF
KF
KF
KF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
THF
65
0
0
2c
3d
4e
5
0
18
40
10
62
61
73
70
59
79
42
30
70
69
67
6
7
8
9
10
11
12
13
14
15
16
17
18
KF
K3PO4
K2CO3
Cs2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NMP
DMSO
DMAC
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), copper catalyst
(0.04 mmol), base (0.24 mmol), solvent (3 mL), 50 1C, 0.5 h, under
b
c
d
argon. Isolated yield. TMSCF3 was used. Umemoto’s reagent 2b
was used. Without CuCl.
e
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China. E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. CCDC 932707(3a). For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3cc42588f
c
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Subsequently, we tested TMSCF3 and Umemoto’s reagent 2b17
as the trifluoromethylation reagents. Unfortunately, no desired
product was observed (Table 1, entries 2 and 3). The copper
catalyst was found to be essential to the reaction, since no desired
product was observed in the absence of the copper catalyst
(Table 1, entry 4). For comparison, other copper catalysts were
also studied, but using Cu(OTf)2, Cu(OAc)2, and [Cu(OTf)2]ÁC6H6
led to lower yields (Table 1, entries 5–7). The effect of inorganic
bases was also examined (Table 1, entries 10–13). The yield of 3a
was increased to 79% when NaOAc was used (Table 1, entry 13).
Other solvents, such as CH3CN and THF, were found to be less
effective for this reaction. Thus, 20 mol% CuCl, 1.2 equiv. NaOAc
and 1.5 equiv. Togni’s reagent 2a in DMF at 50 1C under an argon
atmosphere were considered as the optimal reaction conditions.18
With the optimized reaction conditions in hand, we further
explored the scope of trifluoromethylation with a variety of b,
g-unsaturated oximes (Table 2). In most cases, oximes 1a–q
proceeded smoothly to give the corresponding trifluoromethy-
lated products 3a–q in moderate to good yields under the
optimal conditions. The structures of the products were
Scheme 2 Copper-catalyzed trifluoromethylation of g,d-unsaturated oxime and
cyclohex-2-en-1-yl(phenyl)methanone oxime.
deduced from their IR, 1H NMR, 13C NMR, 19F NMR and HRMS
spectroscopic data. In addition, the NMR-based structures were
further confirmed by the X-ray crystal structure analysis of 3a
(see ESI†). Both electron-donating and electron-withdrawing
groups at the aromatic rings were found to be tolerated in this
reaction. Heterocycle-containing oximes were also transformed
into the desired product 3l–3n in 45–64% yield. Reaction of
substrates 1o and 1p gave a mixture of diastereoisomers 3o (d.r. =
3.3 : 1) and 3p (d.r. = 3.4 : 1), respectively. However, it is difficult to
obtain the 6-exo-trig cyclization products in this reaction and only
a trace amount of the trifluoromethylated product was detected
using GC-MS when 1r was used as the substrate (Scheme 2,
eqn (1)). We found that 1,2-disubstituted olefin 1s was not suitable
for the reaction and only dihydroisoxazole 3s was obtained in 45%
yield (Scheme 2, eqn (2)).
Table 2 Scope of copper-catalyzed trifluoromethylation of b,g-unsaturated
oximes with a hypervalent iodine(III) reagent 2aa
To gain some mechanistic insights into the current trifluoro-
methylation reaction, inhibition experiments were conducted.
We added TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) to the
reaction mixture, and the trifluoromethylation reaction was
found to be completely inhibited. Instead, the TEMPO-trapped
4,5-dihydroisoxazole 5 was obtained in 83% yield (Scheme 3,
eqn (1)). This result did not aid our understanding of the
reaction mechanism, which may be initiated by the oxime
radical.14 But, when BHT (2,6-di-tert-butyl-4-methyl-phenol)
was added to the optimal conditions, to our surprise, the desired
product was obtained with a low yield (36%) (Scheme 3, eqn (2)),
and a BHT–CF3 adduct was detected using GC-MS. These
experimental results provided evidence that the reaction mecha-
nism might involve the CF3 radical and the CF3 cation. Thus, two
plausible mechanisms19–21 for this transformation are proposed
in Scheme 4. In path A, in the presence of copper catalyst and
Togni’s reagent, a single-electron oxidation occurs resulting in
the formation of a radical intermediate, which could be further
trapped by the oxygen atom to generate the cyclization product.
In path B, first, reaction of Cu(I) with Togni’s reagent would
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), CuCl (0.04 mmol),
NaOAc (0.24 mmol), DMF (3 mL), 50 1C, 0.5 h, under argon, isolated
yield. The ratio of diastereomers was determined by crude 1H NMR
b
and 19F NMR. Structures of the major diastereomers are shown.
Scheme 3 Trapping experiments.
c
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+
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In summary, we have developed an efficient copper-catalyzed
trifluoromethylation reaction which involves the cyclization of
oximes to construct a C–CF3 bond and a C–O bond in one step.
This reaction provides a convenient and straightforward method to
prepare a variety of useful trifluoromethyl-substituted isoxazolines.
Further studies and application of this reaction are in progress.
We thank the National Science Foundation (NSF 21072080
and 21272101) and National Basic Research Program of China
(973 Program) 2010CB833203 and ‘‘111’’ program of MOE and
PCSIRT: IRT1138 for financial support.
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c
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