Direct synthesis of a trifluoromethyl copper reagent from trifluoromethyl ketones: Application to trifluoromethylation

Article abstract of DOI:10.1002/chem.201303828

Being economic with fluorine: The direct synthesis of CuCF₃ from a cuprate reagent and trifluoromethyl ketones, as one of the most economical and efficient trifluoromethyl sources, was accomplished. The advantages of this method are all of reagents employed are low-cost, operation is simple, and the yield of CuCF₃ is virtually quantitative (see scheme). Furthermore, three types of trifluoromethylations smoothly proceeded to provide the corresponding products in high yields. Copyright

Full text of DOI:10.1002/chem.201303828

DOI: 10.1002/chem.201303828
Direct Synthesis of a Trifluoromethyl Copper Reagent from Trifluoromethyl
Ketones: Application to Trifluoromethylation
[
a]
Hiroki Serizawa, Kohsuke Aikawa, and Koichi Mikami*
ꢀ
Trifluoromethyl compounds have attracted much atten-
tion in the pharmaceutical and agrochemical industries due
to the unique properties of the trifluoromethyl group.
a large-volume by-product of Teflon (DuPont) manufactur-
À
[9]
ing, as the cheapest and atom-economical CF3 source was
utilized with the aim of preparing CuCF reagents. Norm-
ant reported the preparation of CuCF by adding a Cu salt
to trifluoromethylated hemiaminolate [CF CH(O)NMe ] ,
which can be produced by the deprotonation of fluoroform
using a strong base followed by the addition to dimethylfor-
[1,2]
[10]
3
I
Various synthetic methods for such compounds have so far
been developed by the use of trifluoromethyl organometallic
3
À
3
2
[3]
(
MCF ) reagents. However, hard lithium and magnesium
3
cations cannot be employed for such reagents, because these
MCF reagents are unstable even at low temperature and
readily decompose to metal fluoride (MF) and singlet di-
mamide (DMF); however, the yield of CuCF was insuffi-
3
3
[10a]
cient.
Recently, Grushin succeeded in achieving a highly
fluoromethylene (:CF ) by means of a-fluoride elimina-
tion. In sharp contrast to hard metal cations, soft counter-
efficient preparation of CuCF by direct cupration of fluoro-
2
3
[3]
[10b]
form (Scheme 1b).
The fundamental drawback of these
parts are useful as MCF reagents for many types of trifluo-
methods is that fluoroform, a low boiling point gas (À838C)
3
[3,4]
Ar o
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
methylation.
Among the soft MCF reagents, CuCF re-
is hard to handle in many synthetic laboratories. Therefore,
3
3
agents are relatively stable, but maintain their high reactivi-
ty. Intensive studies have thus been focused on efficient
a more practical synthetic method for the preparation of
À
CuCF reagents using low-cost and operationally easy CF3
3
synthetic protocols for CuCF reagents and their application
sources in addition to fluoroform is strongly desired.
3
[5,6]
to various trifluoromethylations.
In particular, the Rup-
Herein, we describe the practical synthesis of a CuCF re-
3
[7]
À
pert–Prakash reagents (CF SiR ) are highly versatile as
agent from one of the most economical and efficient CF3
3
3
À
a stable CF3 source, and can readily generate CuCF re-
sources, that is, trifluoromethyl ketone derivatives, which
are low-cost liquid and easy to handle (Scheme 1c). More-
3
I
agents by treatment with a Cu salt and metal fluoride; how-
ever, this process is still cost-prohibitive for large scale oper-
over, the CuCF reagent thus prepared in excellent yield can
3
[6]
[8]
ations (Scheme 1a).
Therefore, fluoroform (CF H),
be utilized to a variety of trifluoromethylations with termi-
nal alkynes, arylbronic acids, and aryl iodides under mild re-
action conditions, and thus in late-stage functionalizations.
Two methods to employ trifluoromethyl ketone deriva-
3
À
tives as CF3 sources have been reported up to now. One is
[
11]
decarboxylation,
which is accomplished by heating with
I
catalytic or stoichiometric amounts of a Cu salt and alkali
metal trifluoroacetate and generates CuCF . The reaction,
3
however, occurs under harsh conditions (ca. 1608C), and
hence it is difficult to efficiently produce CuCF reagents
3
that are unstable under the high-temperature conditions.
The other method is via tetrahedral intermediates prepared
from trifluoromethyl ketone or trifluoroacetic acid deriva-
[12]
tives and appropriate nucleophiles.
Langlois and Billard
reported that trifluoromethyl ketone derivatives could be
À
employed as a CF3 source is such reactions—addition of
Scheme 1. Synthetic methods for the preparation of trifluoromethyl
copper reagents.
KOtBu, and trifluoromethylation to ketones without acidic
a-proton proceeded smoothly.
[12a]
However, CuCF reagents
3
[
a] H. Serizawa, Dr. K. Aikawa, Prof. Dr. K. Mikami
Department of Applied Chemistry
Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8552 (Japan)
Fax : (+81)3-5734-2776
have never been prepared successfully by this route. There-
fore, we envisioned a practical method for the preparation
of CuCF reagents through the formation of tetrahedral in-
3
termediates from trifluoromethyl ketone derivative and ap-
propriate nucleophiles.
E-mail: mikami.k.ab@m.titech.ac.jp
Initially, the preparation of the CuCF reagent by treat-
ment with 2,2,2-trifluoroacetophenone (1a) and CuOtBu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303828.
3
17692
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17692 – 17697

COMMUNICATION
generated from CuCl (1 equiv) and KOtBu (1 equiv) as a nu-
Table 1. Preparation of trifluoromethyl coper reagent using various tri-
fluoromethyl sources.
[
a]
cleophile was examined, but CuCF was not obtained. This
3
result implied that CuOtBu is not nucleophilic enough to
provide the tetrahedral intermediate, hence its cuprate was
used as a higher nucleophilic reagent. After K[Cu ACHTGNUTERNN(UNG OtBu) ]
2
was prepared from the reaction of CuCl (1 equiv) and
KOtBu (2 equiv) in DMF at room temperature for 1 h, the
addition of 1a to the resulting DMF solution led to the for-
Entry
R
x
t
[
Yield
[%]
[
b]
h]
1
2
3
4
5
6
7
8
9
p-MeOC
p-ClC
2,4,6,-Me
OMe (1e)
OMe (1e)
OEt (1 f)
OEt (1 f)
OtBu (1g)
6
H
H (1c)
4
(1b)
2
2
2
2
3
2
3
3
3
3
0.5
0.5
0.5
6
6
6
6
6
6
6
>95
>95
>95
33
66
29
64
2
21
0
mation of CuCF in >95% yield within 30 min (Scheme 2a).
3
6
4
3
6 2
C H (1d)
CO
OK (1i)
2
Et (1h)
1
0
[
a] Conditions: After treatment of CuCl (0.5 mmol) and KOtBu (0.5ꢂ
x mmol) in DMF (1.5 mL) at room temperature for 1 h, trifluoromethyl
sources 1 (0.5 mmol) were added to the DMF solution at the same tem-
1
9
perature. [b] Yield was determined by F NMR analysis using benzotri-
fluoride as an internal standard.
Scheme 2. Preparation of trifluoromethyl copper reagent from cuprate
and 2,2,2-trifluoroacetophenone. a) Conditions: After treatment of CuCl
(
0.5 mmol) and KOtBu (1.0 mmol) in DMF (1.5 mL) at room tempera-
ture for 1 h, 1a (0.5 mmol) was added to the DMF solution at the same
1
9
temperature. Yield was determined by F NMR analysis using benzotri-
1
9
fluoride as an internal standard. b) F NMR spectrum (282 MHz,
]DMF) of reaction mixture containing CuCF
species (À25.2 ppm) ob-
tained in >95% yield.
[
D
7
3
19
13
The F NMR and C NMR data of CuCF thus obtained
3
matched well with the data of CuCF reported by Grushin
3
[10b]
(
Scheme 2b).
In addition, the preparation of the CuCF reagent from
3
various trifluoromethyl ketones and esters was surveyed by
using the cuprate (Table 1). Even with ketones 1b–d bearing
not only electron-donating and -withdrawing groups (en-
tries 1–2), but also a sterically more demanding group
(
entry 3), excellent yields (>95% yield) were maintained
under the same reaction conditions. Unfortunately, the use
of trifluoroacetates 1e,f resulted in severely decreased
yields, probably because of the lower electrophilicity of 1e,f
and higher stability of the tetrahedral intermediate by chela-
tion between potassium and oxygen atoms (entries 4 and 6).
However, by employing three equivalents of KOtBu and
prolonged reaction times (6 h), it was found that CuCF3
could be obtained in more than 60% yield (entries 5 and 7).
tert-Butyl trifluoroacetate (1g) and ethyl trifluoropyruvate
Scheme 3. Top: Plausible structures of tetrahedral intermediates. Bottom:
19
F NMR spectra of
a reaction mixture containing CuCl (1 equiv),
KOtBu (2 equiv), and 4’-methoxy-2,2,2-trifluoroacetophenone (1b;
equiv) in [D
]DMF. The single peaks of À25.2 and À63.2 ppm are from
CuCF and benzotrifluoride (internal standard); the F NMR spectra
were obtained at a) À30, b) À10, and c) 208C; CuCF was obtained in
95% yield.
1
7
1
9
3
3
>
(
1h) gave low yields (entries 8 and 9), and the formation of
CuCF3 was not observed from potassium trifluoroacetate
1i) at all (entry 10).
gradually warmed up, the peaks began to broaden at À108C
(
(Scheme 3b), and the generation of the CuCF species was
3
19
Next, the F NMR analysis was performed to gain an in-
sight into tetrahedral intermediate A prepared with cuprate
subsequently observed at around room temperature (208C)
(Scheme 3c). It was proposed that the three peaks, which
are in equilibrium at À308C, correspond to those of tetrahe-
dral intermediates A of the potassium salt, the copper salt,
and the cuprate.
[10a]
and 1b as the CF source (Scheme 3).
At À308C, three
peaks (À84.2, À83.9, and À83.4 ppm) were observed in
F NMR spectrum (Scheme 3a). After the mixture was
3
19
Chem. Eur. J. 2013, 19, 17692 – 17697
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17693

K. Mikami et al.
maining KOtBu with appropriate acids (HX) to precipitate
potassium salt (KX) in the solution. Grushin has already
succeeded in minimizing the decomposition by neutraliza-
[10b]
tion with Et N·3HF (TREAT HF).
Therefore, various
3
acids, for example Et N·3HF, Et N·HCl, and HCl in Et O
3
3
2
(
1.0m solution) were used for the stabilization of the CuCF
3
[13]
19
reagent (Table 2). With all acids, the F NMR signal of
CuCF shifted upfield to À27.4 from À25.2 ppm due to ex-
3
change from tert-butoxide to tert-butanol, and the precipita-
tion of KF or KCl was observed. Even after one day,
Et N·3HF and Et N·HCl could retard the decomposition of
3
3
CuCF , compared with the conditions without acids. With
3
Scheme 4. Isolation of O-silylated tetrahedral intermediate 2 and tert-
butyl benzoate 3.
HCl in Et O, the stability was equal to that with Et N·3HF,
2
3
but CuCF decomposed up to 89% at an initial stage, likely
3
due to the heat of neutralization.
On the other hand, the addition of TMSCl to tetrahedral
intermediate A provided the O-silylated product 2 as the
tetrahedral intermediate trapped in 66% yield (Scheme 4).
tert-Butyl benzoate (3) was also isolated in 93% yield by
We then focused our attention to employ the CuCF re-
3
agent that can be directly prepared from 2,2,2-trifluoro
acetophenone (1a) for a variety of trifluoromethylation re-
actions. Initially, we attempted the oxidative trifluorometh-
warming up to room temperature. Significantly, the di
A
H
U
G
R
N
U
G
ACHTUNGTRENNUNyG lation of terminal alkynes as a coupling reaction at the sp-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ylformamide (DMF)-adduct B, formed by addition to DMF
carbon, because the products obtained are useful as CF -
3
À
[10a]
[6c,j]
solution of free CF3 ions as reported by Normant,
was
containing building blocks (Scheme 5).
zation of the reaction conditions, it was found to be effi-
cient to use tetramethylethylenediamine (TMEDA) and
After the optimi-
1
9
[13]
not totally observed in F NMR spectroscopy. Even in the
presence of electron-rich alkenes (2 equiv), such as a-meth-
ylstyrene, the reaction did not give the gem-difluorocyclo-
propane, which can be produced by difluoromethylene spe-
cies via the decomposition of free CF3 ion. These results
strongly indicate that CuCF is directly formed from the tet-
Et N·HCl as the ligand and acid, respectively, in the pres-
3
ence of the CuCF reagent (2 equiv) at room temperature in
3
À
air. The slow addition of alkynes 4 through a syringe pump
was also the key for enhancing the yield. The reaction with
not only electron-rich and -deficient aromatic but also ali-
phatic alkynes 4a–i proceeded in more than 88% yield
under much milder conditions, compared with previous re-
3
rahedral intermediate A.
The stability of CuCF in DMF at room temperature was
3
1
9
investigated by monitoring the F NMR spectrum (Table 2).
It was found that the yield of CuCF decreased from 97 to
[6c,j]
sults.
Aliphatic alkyne 4j, with a steroidal backbone, also
3
69% after 48 h, but further decomposition did not take
led to the corresponding product 5j in 91% yield.
place even after prolonged time. These results agreed with
Trifluoromethylation with boronic acids 6 was also scruti-
[10b]
2
the report by Grushin.
It was proposed that such decom-
nized as an oxidative coupling reaction at an sp -carbon
[3c]
position was caused by the potassium cation of remaining
(Scheme 6). The reaction by treatment of boronic acids 6
KOtBu, which would strongly interact with fluorine atom of
in the presence of the CuCF reagent (2 equiv) proceeded
3
the CuCF species prepared. To solve this problem, we tried
to suppress the decomposition through neutralization of re-
smoothly without any ligands to provide the corresponding
products 7 in good-to-excellent yields. In contrast to the oxi-
dative trifluoromethylation of
3
terminal alkynes, toluene was
Table 2. Stability of trifluoromethyl copper reagent.
the best solvent. Under the op-
[13]
timized reaction conditions,
aromatic boronic acids 6a–i
bearing both electron-with-
drawing and -donating substitu-
ents showed high yields. While
the reaction with 6 f and 6j re-
sulted in severely decreased
yields, which were improved by
using DMF instead of toluene
and extending the reaction time
up to 4 h. The pinacolboronate
ester, obtained by iridium-cata-
lyzed CÀH activation/boryla-
None
CuCF
[% yield
Et
3
N·3HF (1/3 equiv)
CuCF
[% yield
Et
3
N·HCl (1 equiv)
CuCF
[% yield
HCl in Et
t [h]
2
O (1 equiv)
CuCF
[% yield
t
[
3
t
3
t
3
3
[
a]
[a]
[a]
[a]
h]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
]
[h]
A
H
U
G
R
N
U
G
]
[h]
A
H
U
G
R
N
U
G
]
A
H
U
G
R
N
U
G
]
0
1
3
9
1
8
2
.1
97
95
89
83
74
69
69
0.1
1
3
97
95
91
91
89
85
83
0.1
1
3
93
89
89
88
84
79
74
0.1
1
3
6
20
89
87
86
85
83
81
79
6
6
2
4
7
27
42
72
24
45
72
42
72
tion of a-tocopherol nicotin-
1
9
[6h,i]
[
a] Yield was determined by F NMR analysis using benzotrifluoride as an internal standard.
A
H
U
G
E
N
N
ate,
was also examined to
17694
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17692 – 17697

Trifluoromethylation
COMMUNICATION
give the trifluoromethylated product 7k in an overall yield
for the two steps of 57%.
We ran a gram-scale reaction for oxidative trifluoro
ACHTUNGTRENNUNGm eth-
AHCTUNGTREGyNNNU lation with boronic acid (Scheme 7). Under the optimized
reaction conditions, the reaction with 6g (scale: 3.2 g,
Scheme 7. Large-scale operation for trifluoromethylation.
1
5 mmol) proceeded smoothly and we isolated the corre-
sponding product 7g in 87% yield (3.1 g, 13 mmol).
Finally, the CuCF reagent prepared by our new method
3
Scheme 5. Trifluoromethylation of terminal alkynes. Conditions;
4
was successfully applied to trifluoromethylation with aryl
iodide 8 (Scheme 8). After surveying a wide range of sol-
vents, oxidants, and ligands, we found that the reaction pro-
[3c]
(
0.1 mmol), CuCF
3
reagent (0.2 mmol), TMEDA (0.2 mmol), air (1 atm)
in DMF (1 mL) at room temperature. Alkynes 4 in DMF (0.5 mL) were
added over a period of 1 h by using a syringe pump. Yields were deter-
1
9
mined by F NMR analysis using benzotrifluoride as an internal stan-
dard. The CuCF reagent was neutralized by Et N·HCl (1 equiv) before
being used in the reaction. [a] Isolated yield. [b] 1,10-Phenanthroline
3
3
(
(
0.2 mmol) was used instead of TMEDA as
0.1 mmol) was added over 2 h by using a syringe pump under O
a ligand, and alkyne
2
.
Scheme 8. Trifluoromethylation of aryl iodides. Conditions; 8 (0.1 mmol),
CuCF
1 mL) at room temperature. Yields were determined by F NMR analy-
sis using benzotrifluoride as an internal standard. CuCF reagent neutral-
ized by Et N·HCl (1 equiv) before being used in the reaction. [a] Isolated
yield. [b] 1 equivalent of each of CuCF reagent and 1,10-phenanthroline
3
reagent (0.2 mmol), 1,10-phenanthroline (0.2 mmol) in DMF
1
9
(
3
3
3
were used. [c] Reaction temperature was 508C.
ceeded smoothly when conducted in DMF with 1,10-phe-
nanthroline, which was more efficient than TMEDA. With
Scheme 6. Trifluoromethylation of arylboronic acids. Conditions;
0.1 mmol), CuCF reagent (0.2 mmol), air (1 atm) in toluene (1 mL) at
room temperature. Yields were determined by F NMR analysis using
benzotrifluoride as an internal standard. The CuCF reagent was neutral-
ized by Et N·HCl (1 equiv) before being used in the reaction. [a] Isolated
yield. [b] DMF was used instead of toluene as a solvent, and reaction
time was 4 h. [c] Reaction time was 3 h. [d] CuCF reagent of 4 equiva-
6
(
3
[13]
1
9
the reaction conditions established,
the use of the elec-
3
tron-deficient aryl iodides 8a–e led to the corresponding
products 9a–e in good-to-excellent yields even at room tem-
perature. While decreased yields were found for 8 f, with
sterically more demanding ortho-substituent, uracil deriva-
tive 8g, and 8h–j, with increased electron density of aromat-
3
3
lents was used, and DMF was used instead of toluene as a solvent. [e] Pi-
nacolboronate ester (Bpin) was used instead of boronic acid.
Chem. Eur. J. 2013, 19, 17692 – 17697
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17695

K. Mikami et al.
ic ring; however, increasing the reaction temperature up to
Acknowledgements
508C improved the reactivity to give good yields.
This research was supported by Japan Science and Technology Agency
JST) (ACT-C: Creation of Advanced Catalytic Transformation for the
Sustainable Manufacturing at Low Energy, Low Environmental Load).
In summary, we have succeeded in the direct synthesis of
(
the CuCF reagent from cuprate and trifluoromethyl ketone
3
derivatives, as a useful trifluoromethyl source. It is notable
that all of the reagents are low-cost for large-scale opera-
tions, that the operation is simple, and that the yield of
Keywords: copper · fluorine · ketones · Ruppert–Prakash
reagents · trifluoromethylation
CuCF is virtually quantitative. Furthermore, it was demon-
3
strated that the CuCF reagent obtained from 2,2,2-trifluo-
3
ACHTUNGTRENNUNGr o ACHTUNGTRENNUNGa cetophenone (1a) can be successfully applied to three
types of trifluoromethylations with terminal alkynes, aryl-
bronic acids, and aryl iodides, to provide the corresponding
products in good-to-high yields. Development of novel reac-
[
1] a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity,
Applications, 2nd ed., Wiley-VCH, Weinheim, 2013; b) T. Hiyama,
Organofluorine Compounds: Chemistry and Applications, Springer,
Berlin, 2000; c) K. Uneyama, Organofluorine Chemistry, Blackwell,
Oxford (UK), 2006; d) I. Ojima, Fluorine in Medicinal Chemistry
and Chemical Biology, Wiley–Blackwell, Chichester (UK), 2009;
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f) K. Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 2004, 104, 1; g) J.-
A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119.
tions with the “ligandless” CuCF reagent prepared by our
3
method is now underway in our laboratory.
[
2] For recent excellent communications, see: a) E. J. Cho, T. D. Sene-
cal, T. Kinzel, Y. Zhang, D. A. Watson, S. L. Buchwald, Science
2010, 328, 1679; b) D. A. Nagib, D. W. C. MacMillan, Nature 2011,
Experimental Section
4
80, 224; c) Y. Fujiwara, J. A. Dixon, F. OꢃHara, E. D. Funder, D. D.
Dixon, R. A. Rodriguez, R. D. Baxter, B. Herlꢄ, N. Sach, M. R. Col-
lins, Y. Ishihara, P. S. Baran, Nature 2012, 492, 95.
3] For reviews, see: a) D. J. Burton, Z.-Y. Yang, Tetrahedron 1992, 48,
Synthetic procedure of CuCF
1a): A mixture of CuCl (50 mg, 0.50 mmol) and KOtBu (112 mg,
.0 mmol) in DMF or [D ]DMF (1 mL) was stirred for 1 h at room tem-
perature under argon atmosphere. 2,2,2-Trifluoroacetophenone (1a)
68 mL, 0.50 mmol) was added dropwise to the mixture at room tempera-
ture. After the reaction mixture was stirred for 30 min, CuCF species
3
reagent from 2,2,2-trifluoroacetophenone
(
1
[
7
189; b) M. A. McClinton, D. A. McClinton, Tetrahedron 1992, 48,
6555; c) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111,
4475.
(
3
1
9
[4] a) T. Kitazume, N. Ishikawa, Chem. Lett. 1982, 11, 137; b) M. M.
Kremlev, W. Tyrra, A. I. Mushta, D. Naumann, Y. L. Yagupolskii, J.
Fluorine Chem. 2010, 131, 212; c) N. D. Ball, J. W. Kampf, M. S. San-
ford, J. Am. Chem. Soc. 2010, 132, 2878; d) X. Wang, L. Truesdale,
J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 3648; e) Z. Weng, R. Lee, W.
Jia, Y. Yuan, W. Wang, X. Feng, K.-W. Huang, Organometallics
was observed by F NMR analysis using benzotrifluoride as an internal
standard (>95% yield).
Typical procedure for trifluoromethylation of terminal alkynes with the
CuCF
00 mL, 0.2 mmol) neutralized by Et
to a solution of TMEDA (30 mL, 0.2 mmol) or 1,10-phenanthroline
36 mg, 0.2 mmol) in DMF (1 mL) at room temperature. A solution of
3
reagent: The CuCF
3
reagent (DMF solution 0.40–0.50m, 400–
5
3
N·HCl (27 mg, 0.2 mmol) was added
2
011, 30, 3229; f) M. Fujiu, Y. Nakamura, H. Serizawa, K. Aikawa,
(
S. Ito, K. Mikami, Eur. J. Org. Chem. 2012, 7043; g) Y. Zeng, L.
Zhang, Y. Zhao, C. Ni, J. Zhao, J. Hu, J. Am. Chem. Soc. 2013, 135,
terminal alkyne 4 (0.1 mmol) in DMF (0.5 mL) was added to the mixture
over 1–2 h by using a syringe pump in air (1 atm). After stirring for
2
955.
1
5 min at room temperature, the reaction mixture was quenched by 1m
aqueous HCl (5 mL). The organic layer was separated, and the aqueous
layer was extracted with Et O (5 mLꢂ3). The organic layers were com-
bined and washed with brine (10 mL), dried over Na SO , and evaporat-
[
5] a) Y. Kobayashi, I. Kumadaki, Tetrahedron Lett. 1969, 10, 4095;
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2
2
4
ed. The resulting crude product was purified by silica-gel column chroma-
tography to give the trifluoromethylated products 5.
1
389; e) C.-P. Zhang, Z.-L. Wang, Q.-Y. Chen, C.-T. Zhang, Y.-C.
Gu, J.-C. Xiao, Angew. Chem. 2011, 123, 1936; Angew. Chem. Int.
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Typical procedure for trifluoromethylation of arylboronic acids with the
CuCF
3
reagent: The CuCF
3
reagent (DMF solution 0.40–0.50m, 400–
N·HCl (27 mg, 0.2 mmol) was added
5
00 mL, 0.2 mmol) neutralized by Et
3
to a solution of arylboronic acid 6 (0.1 mmol) in toluene or DMF (1 mL)
at room temperature in air. After stirring for 1–4 h, the reaction mixture
was quenched by 1m aqueous HCl (5 mL). The organic layer was separat-
[
6] For selected recent examples using Ruppert–Prakash reagents, see:
a) G. G. Dubinina, H. Furutachi, D. A. Vicic, J. Am. Chem. Soc.
ed, and the aqueous layer was extracted with Et
ic layers were combined and washed with brine (10 mL), dried over
Na SO , and evaporated. The resulting crude product was purified by
2
O (5 mLꢂ3). The organ-
2008, 130, 8600; b) M. Oishi, H. Kondo, H. Amii, Chem. Commun.
2009, 1909; c) L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2010, 132,
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2
4
silica-gel column chromatography to give the trifluoromethylated prod-
ucts 7.
cal, A. T. Parsons, S. L. Buchwald, J. Org. Chem. 2011, 76, 1174;
f) H. Morimoto, T. Tsubogo, N. D. Litvinas, J. F. Hartwig, Angew.
Chem. 2011, 123, 3877; Angew. Chem. Int. Ed. 2011, 50, 3793;
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Chem. 2012, 77, 1251; k) M. Hu, C. Ni, J. Hu, J. Am. Chem. Soc.
2012, 134, 15257.
Typical procedure for trifluoromethylation of aryl iodides with the
CuCF
00 mL, 0.2 mmol) neutralized by Et
to a solution of aryl iodide 8 (0.1 mmol) and 1,10-phenanthroline (36 mg,
.2 mmol) in DMF (1 mL) at room temperature under an argon atmos-
3
reagent: The CuCF
3
reagent (DMF solution 0.40–0.50m, 400–
5
3
N·HCl (27 mg, 0.2 mmol) was added
0
phere. After stirring for 12 h, the reaction mixture was quenched by 1m
aqueous HCl (5 mL). The organic layer was separated, and the aqueous
layer was extracted with Et
bined and washed with brine (10 mL), dried over Na
2
O (5 mLꢂ3). The organic layers were com-
SO , and evaporat-
2
4
ed. The resulting crude product was purified by silica-gel column chroma-
tography to give the trifluoromethylated products 9.
[7] a) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757;
b) G. K. S. Prakash, M. Mandal, J. Fluorine Chem. 2001, 112, 123.
17696
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17692 – 17697

Trifluoromethylation
COMMUNICATION
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[
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[13] For details, see the Supporting Information.
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Received: October 1, 2013
chynskyi, V. V. Grushin, J. Am. Chem. Soc. 2012, 134, 16167.
Published online: November 21, 2013
Chem. Eur. J. 2013, 19, 17692 – 17697
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17697