Copper-catalyzed nucleophilic trifluoromethylation of allylic halides: A simple approach to allylic trifluoromethylation

Article abstract of DOI:10.1002/chem.201202853

Trifluoromethylation: The treatment of allylic halides with trifluoromethyltrimethylsilane in the presence of a catalytic amount of copper(I) thiophene-2-carboxylate (CuTC) gives the corresponding allylic trifluoromethylation products in good to high yields and with complete regioselectivity (see scheme). The use of THF as a solvent is crucial for obtaining good yields of product.

Full text of DOI:10.1002/chem.201202853

COMMUNICATION
DOI: 10.1002/chem.201202853
Copper-Catalyzed Nucleophilic Trifluoromethylation of Allylic Halides: A
Simple Approach to Allylic Trifluoromethylation
Yoshihiro Miyake, Shin-ichi Ota, and Yoshiaki Nishibayashi*[a]
Considerable attention has been paid to the development
of efficient methods for the introduction of a trifluoromethyl
(CF3) group into diverse molecular skeletons[1] because a
wide range of organic molecules bearing trifluoromethyl
groups has been applied in the field of pharmaceuticals and
materials.[2] In fact, the introduction of a trifluoromethyl
À
group into aromatic rings (the formation of Csp2 CF3 bonds)
À
through, for example, trifluoromethylation of aryl C H
bonds,[3,4] aryl halides,[5–7] and aryl boronic acids[8] has been
extensively developed.
In sharp contrast to methods for the formation of
À
À
Csp2 CF3 bonds, methods for the formation of Csp3 CF3
bonds are still limited.[1f] The development of allylic trifluo-
ACHTUNGTRENNUNGroACHTUNGTRENNUNGmethylation methods is important because compounds
containing allylic trifluoromethyl groups are versatile build-
ing blocks for the preparation of CF3-containing com-
pounds.[9] Recently, there have been some reports on
copper-catalyzed electrophilic allylic trifluoromethylation
reactions of terminal alkenes using Umemotoꢀs[10] and
Togniꢀs reagents[11] (Scheme 1a).[12,13] Although the precise
reaction mechanism has not been reported, the oxidation of
allyl groups to give either allylic cations or radicals and the
reaction of electrophilic CF3–copper species with alkenes
have been proposed as key steps for these trifluoromethyla-
tion reactions. The nucleophilic allylic trifluoromethylation
of allylic halides using transition-metal complexes is also a
promising method for the synthesis of compounds contain-
ing allylic trifluoromethyl groups, but has been considerably
less studied.[6b,14–16] Most of the reported reactions are
copper-mediated trifluoromethylation reactions of allylic
halides, where stoichiometric amounts of either copper
metal or a copper salt is required to obtain the products in
good yields (Scheme 1b).[14] Previously, Kitazume and
Scheme 1. Copper-catalyzed and copper-mediated allylic trifluorometh-
AHCTUNGTREGyNNNU lation reactions.
ited.[15,16] Moreover, in these reports, the generality of the
reactions was not explored. Herein, we report on the devel-
opment of an efficient catalytic allylic trifluoromethylation
reaction, specifically, a copper(I)-catalyzed allylic nucleo-
philic trifluoromethylation of allylic halides in the presence
of trifluoromethyltrimethylsilane (Ruppert–Prakash reagent;
CF3SiMe3).[17] In this reaction, the CF3 group was incorporat-
ed into the a position of the carbon–halogen bond with
complete regioselectivity. Herein, the scope and limitations
of the catalytic allylic nucleophilic substitution reaction with
CF3SiMe3 are described.
Treatment of (E)-cinnamyl bromide (1a) with 1.5 equiva-
lents of CF3SiMe3 in the presence of a catalytic amount of
A
copper(I) iodide (CuI, 5 mol%) and a stoichiometric
tion of allylic halides in the presence of a mixture of CF3I
and Zn under ultrasonic irradiation.[6b] However, examples
of catalytic nucleophilic substitution reactions are quite lim-
amount of potassium fluoride (KF, 1.5 equiv) in tetrahydro-
furan (THF) at 608C for 20 hours gave (E)-4,4,4-trifluoro-1-
phenylbut-1-ene (2a) in 67% yield with complete regiose-
lectivity for trifluoromethylation at the a position, that is,
the product derived from g trifluoromethylation (3) was not
observed (Table 1, entry 1). The choice of solvent is one of
the most important factors that affects the trifluoromethyla-
tion reaction. In fact, when N,N-dimethylformamide (DMF)
was used in place of THF, in the presence of 5 mol% of
CuI, 2a was obtained in 29% yield; even when using
1.5 equivalents of CuI in DMF, 2a was only obtained in
18% yield (Table 1, entries 2 and 3). These results indicate
[a] Dr. Y. Miyake, S.-i. Ota, Prof. Dr. Y. Nishibayashi
Institute of Engineering Innovation
School of Engineering, The University of Tokyo
Yayoi, Bunkyo-ku, Tokyo, 113-8656 (Japan)
Fax : (+81)3-5841-1175
E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202853.
Chem. Eur. J. 2012, 00, 0 – 0
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Table 1. Cu-catalyzed trifluoromethylation of cinnamyl bromide (1a).[a]
Table 2. Cu-catalyzed trifluoromethylation of cinnamyl halides (1).[a]
Entry
Allylic halide 1
Yield of 2 [%][b]
Entry [Cu] [mol%]
Solvent t [h] Recovery of Yield of
1a [%][b]
2a [%][b]
1
2
R1 =p-MeC6H4, X=Br (1b)
R1 =p-ClC6H4, X=Br (1c)
R1 =p-MeOC6H4, X=Br (1d)
R1 =p-MeOC6H4, X=Cl (1d’)
R1 =p-MeO(CO)C6H4, X=Br (1e)
R1 =o-MeC6H4, X=Br (1 f)
R1 =m-MeC6H4, X=Br (1g)
R1 =1-naphthyl, X=Br (1h)
R1 =2-naphthyl, X=Br (1i)
82 (2b)
74 (2c)
46 (2d)
58 (2d)
68 (2e)
79 (2 f)
78 (2g)
68 (2h)
65 (2i)
1
2
CuI (5)
CuI (5)
THF
DMF
DMF
NMP
DCE
toluene 20
hexane
THF
20
20
20
20
20
0
0
0
67
29
18
16
20
7
0
83
3[c]
4[c]
5[d]
6
3
4
CuI (150)
CuI (5)
0
5
CuI (5)
36
52
82
0
7
8
9
6
CuI (5)
7
CuI (5)
20
48
20
48
48
48
20
20
8
9
CuTC (5)
CuTC (5)
CuCl (5)
THF
THF
36
0
57
75
[a] All reactions of 1 (0.50 mmol) with CF3SiMe3 (1.5 mmol) were carried
out in the presence of 2 mol% of CuTc (0.010 mmol) in THF (3 mL) at
608C for 20 h. [b] Yield of isolated product. [c] At room temperature for
48 h. [d] At 408C.
10
11
12
13[c]
14[c,e]
CuOTf·0.5 C6H6 (5) THF
27
0
0
46
75
CuTC (2)
CuTC (2)
CuTC (2)
THF
THF
THF
79 (75)[d]
79
0
[a] All reactions of 1a (0.50 mmol) with CF3SiMe3 (0.75 mmol) were
ceeded smoothly to give the corresponding a-trifluoro
ylation products in good yields (Table 2). The use of cin
myl substrates bearing either a methyl or a chloro group, at
ACHTUNGTRENNUNG
ACHTUNGTRENNUNGcarried out in the presence of a catalytic amount of copper complex in
G
ACHTUNGTRENNUNG
solvent (3 mL) at 608C. [b] Determined by 1H NMR spectroscopy.
[c] CF3SiMe3 (1.5 mmol, 3 equiv) and KF (1.5 mmol, 3 equiv) were used.
[d] Yield of isolated product. [e] (E)-cinnamyl chloride (1a’) was used in
place of 1a. DCE=1,2-dichloroethane.
AHCTUNGTRENNUNG
the para position of the aromatic ring gave good yields of
the corresponding product 2 (Table 2, entries 1 and 2). Al-
though the yields of 2d and 2e were low when formed
under similar reaction conditions, the reactions of 1d, 1d’,
and 1e at lower temperatures (room temperature or 408C)
led to better yields (Table 2, entries 3–5). 3-Tolylallyl bro-
mides (1 f and 1g) and 3-naphthylallyl bromides (1h and 1i)
were also good substrates for this reaction, the correspond-
ing products (2 f–2i) being obtained in good yields (Table 2,
entries 6–9).
that the use of CuI in combination with DMF as a solvent is
not effective. The use of other solvents, such as N-methyl-
pyrrolidone (NMP), 1,2-dichloroethane, toluene, and
hexane, did not give better results (Table 1, entries 4–7).
Previously, when aprotic polar solvents, such as DMF, NMP,
hexamethylphosphoric triamide, and ionic liquids, were used
for copper-mediated allylic nucleophilic trifluoromethylation
reactions, the use of a stoichiometric amount of a copper(I)
salt was essential.[14] In sharp contrast to these previously re-
ported reactions, we found that less polar solvents, such as
THF, are more effective for the Cu-catalyzed allylic nucleo-
philic trifluoromethylation reaction described herein.
Other primary and secondary allylic halides were investi-
gated as substrates (Table 3). The reactions of b-substituted
and g,g-disubstituted bromides (1j and 1k) proceeded
smoothly to give the corresponding a-trifluoromethylation
Table 3. Cu-catalyzed trifluoromethylation of allylic halides 1.[a]
The use of copper(I) thiophene-2-carboxylate (CuTC) led
to an increase in the yield of 2a, although a longer reaction
time was necessary (Table 1, entries 8 and 9). When CuCl
and CuOTf·0.5C6H6 were used, 2a was obtained in 75%
and 46% yields, respectively (Table 1, entries 10 and 11). In-
terestingly, the use of only 2 mol% of CuTC was sufficient
for an efficient reaction (Table 1, entry 12); the use of
3 equivalents of CF3SiMe3, 2 mol% of CuTC, and 3 equiva-
lents of KF, together with a reaction time of 20 hours gave
2a in 79% yield (75% yield upon isolation; Table 1,
entry 13). In addition, the reaction of (E)-cinnamyl chloride
(1a’) also took place smoothly to give 2a in 79% yield
(Table 1, entry 14). When either cinnamyl acetate, cinnamyl
methyl ether, or cinnamyl tosylate were used as substrates,
no reaction occurred at all. In another experiment, we con-
firmed that 2a did not form in the absence of either CuTC
or KF.
Entry
1
Allylic halide (1)
Yield of 2 [%][b]
73 (2j)
(1j; E/Z=20:1)
(1k)
2
G
60 (2k)
3[c]
4[c]
X=Br (1l)
X=Cl (1lꢀ)
45 (2l)
59 (2l)
5[d]
A
81 (2m)
6[e]
7[e]
R1 =Ph (1n’)
44 (2n)
45 (2o)
R1 =p-MeC6H4 (1oꢀ)
[a] All reactions of 1 (0.50 mmol) with CF3SiMe3 (1.5 mmol) were carried
out in the presence of 2 mol% of CuTC (0.010 mmol) in THF (3 mL) at
608C for 20 h. [b] Yield of isolated product. [c] At room temperature for
48 h. [d] For 48 h. [e] In the presence of 10 mol% of CuTC (0.050 mmol)
at 408C.
Allylic trifluoromethylation of a variety of cinnamyl ha-
ACHTUNGTRENNUNGlides in the presence of a catalytic amount of CuTC pro-
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Copper-Catalyzed Nucleophilic Trifluoromethylation
COMMUNICATION
products (2j and 2k) in good yields (Table 3, entries 1 and
2). Allylic halides containing no conjugated aromatic rings
(1l, 1l’, and 1m) were also good substrates for this reaction,
the corresponding products (2l–2m) being isolated in good
yields (Table 3, entries 3–5). Interestingly, the reactions of
secondary allylic chlorides 1n’ and 1o’ gave 2n and 2o in 44
and 45% yield, respectively; however, the use of 10 mol%
of CuTC was necessary to obtain the products in these mod-
erate yields (Table 3, entries 6 and 7).
CuY. As described above, DMF was an ineffective solvent
for our reaction; we propose that the coordination of DMF
to the allylcopper
ACHTUNGTRENUN(NG III) species inhibits the regeneration of
CuY.[18]
In summary, we have developed a copper-catalyzed tri-
fluoromethylation reaction of allylic halides 1 that gives the
corresponding allylic trifluoromethylation products 2 in
good to high yields and with complete regioselectivity. We
believe that this methodology, which is an efficient way to
À
To obtain some information on the reaction pathway, we
investigated the reactions of 1p and 1q under similar reac-
tion conditions (Scheme 2). When the reaction of 3-phenyl-
introduce Csp3 CF3 bonds, can form part of useful strategies
for accessing CF3-containing compounds. The development
of an asymmetric variant of this reaction and clarification of
the precise reaction mechanism is currently in progress.
Experimental Section
Representative experimental procedure: CuTC (1.9 mg, 0.010 mmol) and
KF (87.2 mg, 1.5 mmol) were placed in a 20 mL Schlenk flask. Anhy-
drous and degassed THF (3.0 mL) was added, and then the mixture was
magnetically stirred at room temperature. After the addition of 1a
(98.5 mg, 0.50 mmol) and CF3SiMe3 (220 mL, 1.5 mmol), the reaction
flask was kept at 608C for 20 h. The solution was poured into water
(5 mL) and the resulting mixture was extracted with diethyl ether
(30 mLꢂ3). The combined extracts were washed with brine, and dried
over anhydrous MgSO4. After concentration under reduced pressure, the
resulting residue was purified by column chromatography (SiO2, eluent:
hexane) to give (E)-4,4,4-trifluoro-1-phenylbut-1-ene (2a) as a colorless
oil (69.5 mg, 0.373 mmol, 75% yield).
Scheme 2. Trifluoromethylation reactions of 1p and 1q.
1-bromopropane (1p) was carried out, no formation of the
corresponding trifluoromethylated product 2p was observed
at all (Scheme 2a). This result clearly indicates that the
presence of the double bond b to the halide group is neces-
sary for the copper-catalyzed trifluoromethylation reaction.
Furthermore, in the reaction of (Z)-cinnamyl bromide (1q),
the E-configured product 2a was obtained in 66% yield
without the formation of Z-configured product 2q (Sche-
me 2b). We monitored reactions of 1q in [D8]-THF at 608C
both in the presence and in the absence of CuTC.[18] The use
of 2 mol% of CuTC promoted the isomerization of the
alkene moiety of substrate 1q, thus converting it into 1a;
following reaction times of 2 hours and 20 hours, the ratio of
1q/1a was 25:75 and 1:99, respectively. On the other hand,
the isomerization was very slow in the absence of CuTC, the
ratio of 1q/1a being 83:17 even after a reaction time of
20 hours. In another experiment, we confirmed that no iso-
merization of 2q into 2a occurred at all under similar reac-
tion conditions.[18] These results indicate that CuTC medi-
ates the isomerization of 1q into 1a, which then undergoes
trifluoromethylation to give the product 2a (Scheme 2b); an
allylcopper species derived from complexation of copper
with 1 is probably a key intermediate.
Acknowledgements
This work was supported by the Funding Program for Next Generation
World-Leading Researchers (GR025) and a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from MEXT, Japan. We thank Dr. Koji Nakano, Dr.
Shingo Ito, and Prof. Dr. Kyoko Nozaki at The University of Tokyo for
the collection of 19F NMR spectra. We also thank the Research Hub for
Advanced Nano Characterization at The University of Tokyo for X-ray
analysis.
Keywords: allylic compounds
·
copper
·
fluorine
·
homogeneous catalysis · trifluoromethylation
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ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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Received: August 9, 2012
Published online: && &&, 0000
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Copper-Catalyzed Nucleophilic Trifluoromethylation
COMMUNICATION
Trifluoromethylation
Y. Miyake, S.-i. Ota,
Y. Nishibayashi* .............. &&&& — &&&&
Trifluoromethylation: The treatment
of allylic halides with trifluoromethyl-
trimethylsilane in the presence of a
catalytic amount of copper(I) thio-
phene-2-carboxylate (CuTC) gives the
corresponding allylic trifluoromethyla-
tion products in good to high yields
Copper-Catalyzed Nucleophilic
Trifluoromethylation of Allylic
Halides: A Simple Approach to Allylic
Trifluoromethylation
and with complete regioselectivity (see
scheme). The use of THF as a solvent
is crucial for obtaining good yields of
product.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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ÞÞ
These are not the final page numbers!