Highly efficient Cu(I)-catalyzed trifluoromethylation of aryl(heteroaryl) enol acetates with CF3 radicals derived from CF3SO 2Na and TBHP at room temperature

Article abstract of DOI:10.1016/j.jfluchem.2014.01.020

An efficient method for the Cu(I)-catalyzed synthesis of α-trifluoromethyl ketones via the addition of CF₃ to aryl(heteroaryl) enol acetates by using the readily available CF ₃SO₂Na (Langlois reagent) has been developed. The reaction is experimentally simple and carried out at room temperature, providing good to excellent yields with wide functional group tolerance.

Full text of DOI:10.1016/j.jfluchem.2014.01.020

Accepted Manuscript
Title: Highly efficient Cu(I)-catalyzed trifluoromethylation of
aryl(heteroaryl) enol acetates with CF3 radicals derived from
CF3SO2Na and TBHP at room temperature
Author: Yang Lu Yaming Li Rong Zhang Kun Jin Chunying
Duan
PII:
S0022-1139(14)00039-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.01.020
FLUOR 8267
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Revised date:
Accepted date:
7-1-2014
24-1-2014
29-1-2014
Please cite this article as: Y. Lu, Y. Li, R. Zhang, K. Jin, C. Duan, Highly efficient
Cu(I)-catalyzed trifluoromethylation of aryl(heteroaryl) enol acetates with CF3 radicals
derived from CF3SO2Na and TBHP at room temperature, Journal of Fluorine Chemistry
(2014), http://dx.doi.org/10.1016/j.jfluchem.2014.01.020
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Highly efficient Cu(I)-catalyzed trifluoromethylation of aryl(heteroaryl) enol acetates
with CF3 radicals derived from CF3SO2Na and TBHP at room temperature
Yang Lu, Yaming Li*, Rong Zhang, Kun Jin, Chunying Duan*
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian
University of Technology, Dalian 116024, China
Tel./fax: +86 411 84986295; E-mail address: ymli@dlut.edu.cn (Y. Li)
O
15 mol% CuI
OAc
R2
5 equiv TBHP
CF
R1
3SO2Na
R2
R1
CH3CN, RT, 2 h
CF3
R1 = aryl, heteroaryl
R2 = H, Me, Ph
14 examples
61-96% yields
ABSTRACT: An efficient method for the Cu(I)-catalyzed synthesis of α-trifluoromethyl
ketones via the addition of CF3 to aryl(heteroaryl) enol acetates by using the readily
available CF3SO2Na (Langlois reagent) has been developed. The reaction is experimentally
simple and carried out at room temperature, providing good to excellent yields with wide
functional group tolerance.
Keywords: Trifluoromethylation; Enol acetates; Synthetic methods; α-CF3 ketone; Radical
addition
1. Introduction
Trifluoromethylated compounds have been widely utilized as the important building
blocks for the synthesis of pharmaceuticals, agrochemicals and specialty materials due to
the stereoelectronic property of the CF3 moiety and the increased bioavailability [1].
Therefore, it has been of great interest to develop more efficient, operationally simple and
1
Page 1 of 29

versatile methods for the incorporation of CF3 group into organic molecules [2].
α-CF3-substituted ketones are some of useful synthetic precursors [3] since ketones are
easily converted into other functional groups. Consequently, there have been three different
approaches reported and new routes to α-trifluoromethyl ketones have been recently drawn
significant attention (Scheme 1) [4].
Electrophilic T rifluoromethylation
Hu, 2013
F3C I
O
O
O
O
CF3
R
COOH
R
Togni's reagent
Nucleophilic Trif luoromethylation
Grushin, 2012
O
X
CF3H
CuCF3
CF3
R
R
(X = Br, Cl)
Radical T rifluoromethylation
Mikami, 2005
OM
O
R3
CF3I / Et3B
-78 °C
CF3
R3
R1
R1
R2
R2
(M = Li, Ti, Zn)
MacMillan, 2011
OSiR3
O
O
CF3I
CF3
CF3
R1
R1
Ar
cat. hv
R2
R2
R
Ph2SCF3OTf
H
Xiao, 2011
Ar
CF3SO2Na
Maiti, 2013
R
Langlois reagent
Zhang, 2013
O
OAc
CF3SO2Cl
CF3
R
Ar
cat. hv
Ar
R
Langlois, 1992
OAc
O
OAc
CF3SO2Na / TBHP
R1
CF3
R1
R2
R1
CF3
Cu(OTf)
cat.
2
R2
R2
H
H
α-deprotonation
22-60%
side-reaction
This work
OAc
cheaper catalyst
O
CF3SO2Na / TBHP
CF3
R
without α-deprotonation
Ar
Ar
cat. CuI
good to excellent yields
R
Scheme 1. Synthesis of α-CF3-substituted ketones.
2
Page 2 of 29

Recently, Hu reported that Cu(II)-mediated electrophilic trifluoromethylation of the
+
substituted propiolic acids by using electrophilic CF3 source (CF3 ), the 1-trifluoromethyl-1,
2-benziodoxol-3(1H)-one (Togni reagent) in the presence of water. However, the yields of
alkyl-substituted α-trifluoromethyl ketones were much lower than those of aryl-substituted
(Scheme 1) [4a]. In 2012, Grushin and co-workers developed the nucleophilic
trifluoromethylation of the C−X (X = Br, Cl) bond of α-haloketones [4b], employed CuCF3
which was produced directly from fluoroform. In addition, nearly quantitative yields were
obtained and the problem of 1,2-addition of the CF3 group across the C=O bond was
circumvented.
Radical trifluoromethylation is the most common methods for the synthesis of
α-CF3-substituted ketones and provides versatile protocols for the construction of C-CF3
bond. In the past several years, the trifluoromethylation of metal enolates Li [4c,5] and Ti
ate [4d,6] enolates or ketone silyl enol ethers by activation with dialkylzinc [4e,7] was
extensively developed by Mikami and co-workers using CF3I [4f,8]. In most instances,
these methods were not operationally simple and a strong base, such as LDA, had to be
premade, which limits the scope of the substrates. MacMillan and co-workers successfully
explored a new photoredox-based method to generate α-CF3-substituted carbonyl
compounds from aldehydes, ketones, esters, and amides [4f,8g]. Moreover, the synthesis of
α-CF3-substituted ketones by using costly [Ph2SCF3]+OTf− or the cheaper Langlois reagent
(CF3SO2Na) with styrenes directly has been reported by Xiao [4g] and Maiti [4h],
respectively.
3
Page 3 of 29

Enol acetates are metal-free, stable nucleophiles and easily synthesized (see
Experimental Section), which makes them potential reagents. More recently, Zhang and
co-workers reported the visible-light photoredox catalyzed trifluoromethylation of aryl enol
acetates with CF3SO2Cl and gave the desired products in satisfactory to excellent yields [4i].
In 1992, Langlois and co-workers reported the synthesis of α-CF3-substituted ketones by
direct use of the alkyl-substituted enol acetates [9], however, the yields of the
α-CF3-substituted ketones were unsatisfied (22–60%) due to the α-deprotonation
side-reaction of the R1 side chain at the enol acetates (Scheme 1). If R1 side chain was
replaced by an aromatic group, this side-reaction would be avoided. Furthermore,
considering the importance of α-trifluoromethyl aryl ketones, herein we explored the
Cu(I)-catalyzed CF3 radical addition reaction of aryl enol acetates bearing various functional
groups or certain heteroaromatics. In addition, a radical scavenger experiment was carried
out to confirm the reaction mechanism.
2. Results and discussion
Initially, we chose the reaction between 1-phenylvinyl acetate 1a and CF3SO2Na as a
model reaction to survey the reaction conditions. As shown in Table 1, the corresponding
product 2a was obtained in moderate yield when a mixture of 1-phenylvinyl acetate (1a, 1.0
equiv.), CF3SO2Na (4.0 equiv.) and TBHP (tert-butylhydroperoxide, 5.0 equiv.) was
performed in CH3CN at room temperature under air for 4 h (Table 1, entry 1). Screening a
series of copper catalysts revealed that the catalysts could promote the yield effectively
(Table 1, entry 2-10). It was found that either Cu(II) salts, such as Cu(OTf)2, Cu(OAc)2,
4
Page 4 of 29

Cu(acac)2 or Cu(I) salts, such as CuCl, CuBr afforded 2a in almost similar yields. Addition
of 10 mol% Cu(CO2CF3)2 or CuI gives the product in 95% and 96% yields, respectively
(Table 1, entries 9 and 10). Considering the lower cost of CuI, it was employed as the
preferred catalyst. Further optimization of the reaction condition showed that the highest
yield of 99% (Table 1, entry 17) could be obtained by adding 15 mol% CuI, 4.0 equivalents
CF3SO2Na and 5.0 equivalents TBHP in the reaction for 2 h (Table 1, entry 10-17).
Decreasing the temperature and prolonging the reaction time lowered the yield slightly
(Table 1, entry 18).
Table 1. Optimization of reaction conditions.a
OAc
O
TBHP (aq.)
Cu salt
CF3
CF3SO2Na
MeCN, RT
1a
2a
Entry Catalyst (mol%)
CF3SO2Na
TBHP
Time
(h)
GC Yield
(%)b
57
(eq.)
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
3.5
3.0
4.5
4.0
4.0
4.0
4.0
4.0
(eq.)
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
4.0
5.0
5.0
5.0
5.0
1
2
—
Cu (10)
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
10.0
71
3
Cu(OTf)2 (10)
CuSO4•5H2O (10)
Cu(OAc)2 (10)
Cu(acac)2 (10)
CuCl (10)
CuBr (10)
Cu(CO2CF3)2 (10)
CuI (10)
88
4
68
5
83
6
85
7
85
8
86
9
95
10
11
12
13
14
15
16
17
18c
96
CuI (10)
85
CuI (10)
83
CuI (10)
92
CuI (10)
90
CuI (15)
99
CuI (20)
96
CuI (15)
99 (93)
91
CuI (15)
5
Page 5 of 29

a
Reaction conditions: 1-phenylvinyl acetate (1a, 1.0 equiv.), Cu salt as the catalyst, TBHP:
tert-butyl hydroperoxide 70% in water, MeCN (1.0 mL) at room temperature under air.
b Yields are determined by GC analysis using n-dodecane as an internal standard. Yields of isolated
product are given within parentheses.
c The reaction was conducted at 0 °C.
Having optimized the reaction conditions in hand, we next investigated the substrate
scope of the method. As shown in Table 2, all reactions were completed within 2 h at room
temperature, and afforded the corresponding α-CF3-substituted ketones in moderate to good
yields. The electronic properties of the enol acetates did not significantly affect this
transformation. Electron-rich, -neutral and -deficient 4-substituted aryl enol acetates were
all smoothly trifluoromethylated to give the desired products (2b-e). Excellent yields can be
obtained with aromatic enol acetates (2a-d), these results indicate that a well stabilized
benzylic radical is formed upon addition of the CF3 radical (see Scheme 3, intermediate II).
The aryl enol acetates bearing ortho–substitutents also worked well to generate 2f and 2g,
respectively. The presence of strongly electronwithdrawing -NO2 group at the meta-position
afforded the desired products (2h) in 79% yield. However, in the case of with a weak
electron-withdrawing NHAc group at the meta-position, the target product (2i) was isolated
in 61% yield. The lower yields observed may be due to the contemporary formation of
by-products. Branched enol acetates also give α-trifluoromethyl ketones (2j-k) in
satisfactory yields. The scope of this trifluoromethylation method was then tested on
heteroaromatic substrates. We found that these reactions are not sensitive to the electronic
6
Page 6 of 29

nature of the heteroaryl enol acetates, that is, both electron-rich and electron-poor heteroaryl
enol acetates could react to give products (2l-n) in satisfactory to good yields.
Table 2. Scope of the trifluoromethylation reaction.a
O
15 mol% CuI
OAc
R2
5 equiv TBHP
CF3SO2Na
R1
R2
R1
CH3CN, RT, 2 h
CF3
2a-n
1a-n
O
O
O
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
MeO
Cl
2a
2c
, 93%
2b, 94%
, 92%
O
O
O
CF3
Br
O2N
2e
, 75%
2d, 96%
2f, 94%
O
O
O
CF3
F
NO2
NHAc
b
2g
2h
2i
, 61%
, 83%
O
, 79%
O
O
CF3
N
Ph
2j, 89%
2k, 64%
2l, 85%
O
O
O
S
CF3
CF3
2n, 74%b
b
2m
, 64%
a
Reaction conditions: 0.20 mmol of enol acetates, 0.80 mmol of CF3SO2Na, 0.03 mmol copper
iodide, 70% aq TBHP (1.0 mmol), 1.0 mL of MeCN, 2 h.
b 0.40 mmol of enol acetates.
7
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For understanding the reaction mechanism of this trifluoromethylation, it is reasonable
to conceive a pathway involving radical species according to the previous reports [9,10].
Therefore a radical scavenger 2,2,6,6-tetramethyl-1-piperdinyloxy (TEMPO) was added
under the standard reaction conditions to conceive a pathway involving radical species
(Scheme 2). The yield of 2a was diminished to 58% and TEMPO-CF3 (detected by GC/MS
and 19F NMR spectroscopy) was formed in 27% yield when 1.0 equiv of TEMPO was
added. In the presence of 4.0 equivalents of TEMPO, only trace amount of 2a was formed,
while the yield of TEMPO-CF3 adduct increased to 64%. However, no TEMPO-enol acetate
adduct was detected in these experiments, as judged by GC-MS analysis of the crude
product.
15 mol % CuI
CF
(4 equiv)
3SO2Na
5 equiv TBHP
N
O
1a
2a
CH3CN (1 mL)
RT, 2 h
TEMPO
CF3
-CF
TEMPO
3
2a
TEMPO = 1.0 equiv, , 58%, TEMPO-CF3, 27%
TEMPO = 4.0 equiv, 2a, 0.1%, TEMPO-CF3, 64%
(Yield determined by 19F NMR based on 1a)
Scheme 2. Capture of CF3 radical by TEMPO.
Above experimental results indicated that the CF3 radical is involved in the
transformation (Scheme 3). Initially, the trifluoromethyl radical is generated in situ by the
reaction of tert-butyl hydroperoxide with CF3SO2Na in the presence of catalytic amounts of
CuI [9,10]. Next, addition of the CF3 radical to the electron-rich α-position of I results in the
radical species II. Then the intermediate II is oxidized by Cu(II) ( produced from Cu(I)
8
Page 8 of 29

oxidated by tert-butyl hydroperoxide) to produce cationic intermediate III via single
electron transfer (SET) [11]. Finally, cationic intermediate III loses an acetyl cation to
generate the desired product IV. However, the low yields in Langlois’s report [9] for alkyl
substrates is partly due to the competitive α-deprotonation on the R1 side in intermediate III
leading to CF3-substitued enol acetates, as compared to deacetylation pathway to
CF3-substitued ketones. Aryl(heteroaryl) substrates are expected to have improved yields
since no competitive α-deprotonation occurs.
OAc
OAc
CF3
R2
R2
R1
R1
CF3
II
I
OH
CF3SO2
t-BuO
CuII
SET
SO2 t-BuO
t-BuOOH
CuI
OAc
O
R2
R2
- Ac
R1
R1
CF3
IV
CF3
III
Scheme 3. Possible mechanism.
3. Conclusions
In conclusion, we have developed an efficient conversion of aryl(heteroaryl) enol
acetates to α-CF3-substituted ketones. The reactions are easy to set up at room temperature
under ambient conditions, and use a stable and cheap CF3SO2Na as the trifluoromethylating
reagent. In addition, this reaction is high-yielding and wide functional group tolerance. We
expect this method to find broad application in both academic and industry.
9
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4. Experimental
4.1. General
All reagents unless otherwise noted were obtained from commercial sources and used
without further purification. CH3CN (≥98.0%) and CF3SO2Na (>95.0%) were used without
any purification. All these reactions were monitored by TLC with silica gel GF254 precoated
plates. The products were isolated by column chromatography on silica gel (200–300 mesh
1
13
19
size). H NMR, C NMR and F NMR spectra were recorded on INOVA 400 instrument
1
with operating frequency of 400, 100 and 376 MHz, respectively. Chemical shifts for H
13
NMR were reported in ppm relative to TMS. All C NMR spectra were reported in ppm
relative to deuterated chloroform (77.00 ppm). The following abbreviations are used to set
multiplicities: s=singlet, d=doublet, t=triplet, dd=doublet of doublets, ddd=doublet of
doublet of doublets, m=multiplet. Coupling constants (J) were reported in Hertz (Hz). Gas
chromatography analyses were performed with an FID detector. GC-MS data were also
performed. High-resolution mass data were recorded on a high–resolution mass
spectrometer in the ESI mode.
4.2. General procedure for preparation of aryl(heteroaryl) enol acetates
Compounds were prepared according to literature [12]. To a mixture of the ketone (5
mmol) and isopropenyl acetate (25 mmol) was added TsOH•H2O (0.5 mmol). The resulting
mixture was refluxed overnight. The acetone formed was continuously distilled off. The
reaction mixture was cooled to room temperature and diluted with Et2O (20 mL) and water
(30 mL). The aqueous layer was extracted with Et2O (2×20 mL). The combined organic
10
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layers were dried over Na2SO4 and the solvent was evaporated in vacuo. The resulting crude
mixture was purified by column chromatography using silica gel (200-300 mesh size) and
petroleum ether/EtOAc (30:1 to 2:1) as the eluent.
4.3. General procedure for trifluoromethylation of aryl(heteroaryl) enol acetates
A flame-dried reaction vessel with a magnetic stirring bar was charged with
CF3SO2Na (124.8 mg, 0.8 mmol, 4.0 equiv), CuI (5.7 mg, 0.03 mmol, 0.15 equiv), enol
acetates (0.2 mmol, 1.0 equiv) and MeCN (1.0 mL) in sequence. After the reaction mixture
was cooled to 0 °C using an ice bath, an aqueous solution of TBHP (70% solution in water,
145 µL, 1.0 mmol, 5.0 equiv) was slowly added dropwise with stirring. The mixture was
stirred at room temperature under air for 2 h. The resulting mixture was concentrated under
reduced pressure. After evaporation, the residue was purified by column chromatography
using silica gel (200-300 mesh size) and n-hexane/CH2Cl2 as the eluent.
4.3.1. 3,3,3-trifluoro-1-phenylpropan-1-one (2a) [4b]. White solid (35 mg, 93% yield), mp:
34–35 °C (lit [8j] 37-38 °C). Column chromatography (n-hexane/CH2Cl2=1:1, Rf = 0.43).
1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J =
13
7.4 Hz, 2H), 3.80 (q, J = 10.0 Hz, 2H) ppm; C NMR (100 MHz, CDCl3): δ 189.7 (q, J =
1.3 Hz), 135.7, 134.2, 128.9, 128.3, 124.0 (q, J = 275.1 Hz), 42.0 (q, J = 27.8 Hz) ppm; 19F
NMR (376 MHz, CDCl3): δ -62.5 (t, J = 9.8 Hz, 3F) ppm; GC-MS (EI, m/z): 188 (M+ ,
21.08), 105 (100.00), 77 (68.03), 51 (18.48), 106 (9.20).
11
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4.3.2. 3,3,3-trifluoro-1-(4-methoxyphenyl)propan-1-one (2b) [4b]. Colourless oil (41 mg,
1
94% yield), Column chromatography (n-hexane/CH2Cl2=1:1, Rf = 0.38). H NMR (400
MHz, CDCl3): δ 7.91 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 3.88 (s, 3H), 3.74 (q, J =
13
10.1 Hz, 2H) ppm; C NMR (100 MHz, CDCl3) δ 188.1, 164.3, 130.8, 128.9, 124.1 (q, J
=275.2 Hz), 114.1, 55.5, 41.8 (d, J = 27.8 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -62.4 (t,
J = 10.2 Hz, 3F) ppm; GC-MS (EI, m/z): 218 (M+, 15.19), 135 (100.00), 107 (21.50), 92
(18.15), 77 (27.80).
4.3.3. 1-(4-chlorophenyl)-3,3,3-trifluoropropan-1-one (2c) [4b]. White solid (41 mg, 92%
yield), mp: 49-50 °C. Column chromatography (n-hexane/CH2Cl2=1:1, Rf = 0.58). 1H NMR
(400 MHz, CDCl3): δ 7.88 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 3.77 (q, J = 9.9 Hz,
13
2H) ppm; C NMR (100 MHz, CDCl3): δ 188.5, 140.9, 134.1, 129.7, 129.3, 123.8 (q, J =
275.2 Hz), 42.1 (q, J = 28.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -62.5 (t, J = 9.8 Hz,
3F) ppm; GC-MS (EI, m/z): 222 (M+, 11.73), 139 (100.00), 111 (56.94), 75 (32.41).
4.3.4. 1-(4-bromophenyl)-3,3,3-trifluoropropan-1-one (2d) [4i]. White solid (51 mg, 96%
yield), mp: 70-71 °C (lit [13] 74-75 °C). Column chromatography (n-hexane/CH2Cl2=1:1,
Rf = 0.62). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H),
13
3.77 (q, J = 9.9 Hz, 2H) ppm; C NMR (100 MHz, CDCl3): δ 188.7, 134.5, 132.3, 129.8,
19
129.7, 123.8 (q, J = 275.3 Hz), 42.1 (t, J = 28.2 Hz) ppm; F NMR (376 MHz, CDCl3): δ
-62.4 (t, J = 10.0Hz, 3F) ppm; GC-MS (EI, m/z): 266 (M+, 9.74), 183 (100.00), 155 (54.56).
12
Page 12 of 29

4.3.5. 3,3,3-trifluoro-1-(4-nitrophenyl)propan-1-one (2e)[4i]. White solid (35 mg, 75%
yield), mp: 104-105 °C (lit [14] 103°C). Column chromatography (n-hexane/CH2Cl2=1:1,
Rf = 0.37). 1H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 7.8 Hz, 2H), 8.12 (d, J = 7.8 Hz, 2H),
13
3.88 (q, J = 9.8 Hz, 2H) ppm; C NMR (100 MHz, CDCl3): δ 188.3, 150.9, 139.9, 129.4,
19
124.1, 123.5 (q, J = 275.2 Hz), 42.7 (q, J =28.7 Hz) ppm; F NMR (376 MHz, CDCl3): δ
-62.4 (t, J = 9.6 Hz, 3F) ppm; GC-MS (EI, m/z): 233 (M+, 3.67), 150 (100.00), 120 (18.42),
104 (29.94), 92 (18.38).
4.3.6. 3,3,3-trifluoro-1-o-tolylpropan-1-one (2f) [4h]. Colourless oil (38 mg, 94% yield).
1
Column chromatography (n-hexane/CH2Cl2=2:1, Rf = 0.52). H NMR (400 MHz, CDCl3):
δ7.61 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 3.74 (q, J = 10.0
Hz, 2H), 2.54 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 192.7, 139.6, 135.9, 132.5,
19
132.4, 128.9, 125.9, 124.0 (q, J = 275.1 Hz), 44.4 (d, J = 27.8 Hz), 21.5 ppm; F NMR
(376 MHz, CDCl3): δ -62.5 (t, J = 10.2 Hz, 3F) ppm; GC-MS (EI, m/z): 202 (M+, 32.34),
119 (100.00), 91 (77.69), 65 (18.69).
4.3.7. 3,3,3-trifluoro-1-(2-fluorophenyl)propan-1-one (2g) [4a]. White solid (34 mg, 83%
yield), mp: 66-67 °C (lit [4a] 68-70 °C). Column chromatography (n-hexane/CH2Cl2=2:1,
Rf = 0.48). 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.29 (d, J
= 8.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 3.89 (q, J = 9.8 Hz, 2H) ppm; 13C NMR (100 MHz,
CDCl3): δ187.60 (d, J = 6.1 Hz), 162.0 (d, J = 252.6 Hz), 135.9 (d, J = 9.3 Hz), 130.9,
13
Page 13 of 29

124.9 (d, J = 2.8 Hz), 124.3 (d, J = 12.4 Hz), 123.8 (d, J = 274.7 Hz), 116.8 (d, J = 23.7 Hz),
19
46.6 (q, J = 28.3 Hz) ppm; F NMR (376 MHz, CDCl3): δ -63.1 (td, J = 9.9, 2.2 Hz, 3F),
-110.2 (m, 1F) ppm; GC-MS (EI, m/z): 206 (M+, 7.02), 123 (100.00), 95 (42.44), 75
(16.86).
4.3.8. 3,3,3-trifluoro-1-(3-nitrophenyl)propan-1-one (2h) [4h]. White solid (37 mg, 79%
yield), mp: 87-88 °C (lit [13] 89-90 °C). Column chromatography (n-hexane/CH2Cl2=1:2,
Rf = 0.73). 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.50 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H),
8.30 (ddd, J = 8.0, 1.6 , 0.8 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 3.90 (q, J = 9.8 Hz, 2H) ppm;
13C NMR (100 MHz, CDCl3): δ 187.8 (d, J = 1.9 Hz), 148.5, 136.8, 133.8, 130.4, 128.4,
123.6 (q, J = 275.4 Hz), 123.2, 42.4 (d, J = 28.7 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ
-62.4 (t, J = 9.8 Hz, 3F) ppm; GC-MS (EI, m/z): 233 (M+, 2.01), 150 (100.00), 111 (10.41),
104 (36.87), 76 (25.55).
4.3.9. N-(3-(3,3,3-trifluoropropanoyl)phenyl)acetamide (2i). White solid (60 mg, 61%
yield), mp: 98-100 °C. Column chromatography (petroleum ether/EtOAc=1:1, Rf = 0.52).
1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 8.00-7.89 (m, 2H), 7.63 (d, J = 7.6 Hz, 1H),
13
7.44 (t, J = 7.6 Hz, 1H), 3.79 (q, J = 9.9 Hz, 2H), 2.22 (s, 3H) ppm; C NMR (100 MHz,
CDCl3): δ 189.7, 169.1, 138.9, 136.4, 129.6, 125.5, 124.0, 123.9 (q, J = 90.2 Hz), 119.3,
19
42.1 (q, J = 28.2 Hz), 24.4 ppm; F NMR (376 MHz, CDCl3): δ -62.1 ppm; GC-MS (EI,
m/z): 245 (M+, 8.70), 203 (35.29), 120 (100.00), 92 (46.58), 43 (50.59); HRMS (ESI) m/z:
14
Page 14 of 29

[M+H]+ Calcd for C11H11F3NO2 246.0742; Found 246.0734.
4.3.10. 3,3,3-trifluoro-2-methyl-1-phenylpropan-1-one (2j) [4i]. Colourless oil (36 mg, 89%
1
yield). Column chromatography (n-hexane/CH2Cl2=1:1, Rf = 0.70). H NMR (400 MHz,
CDCl3): δ 7.96 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 4.25
13
(heptet, J = 7.4 Hz, 1H), 1.48 (d, J = 7.4 Hz, 3H) ppm; C NMR (100 MHz, CDCl3): δ
194.4, 135.6, 134.0, 128.9, 128.6, 125.3 (q, J = 278.3 Hz), 44.28 (q, J = 26.4 Hz), 11.7 ppm;
19F NMR (376 MHz, CDCl3): δ -68.7 (d, J = 8.3 Hz, 3F) ppm; GC-MS (EI, m/z): 202 (M+,
0.69), 105 (100.00), 77 (68.03), 51 (15.67).
4.3.11. 3,3,3-trifluoro-1,2-diphenylpropan-1-one (2k) [4i]. Colorless oil (34 mg, 64% yield).
Column chromatography (n-hexane/CH2Cl2=4:1, Rf = 0.42). 1H NMR (400 MHz, CDCl3): δ
7.90 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.46-7.36 (m, 7H), 5.28 (q, J = 8.2 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3): δ 191.1, 135.4, 133.8, 129.8, 129.6, 129.3, 129.2, 128.8,
128.7, 124.3 (q, J = 278.5 Hz), 56.5 (q, J = 26.3 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ
-67.0 (d, J = 8.3 Hz, 3F) ppm; GC-MS (EI, m/z): 264 (M+, 0.50), 105 (100.00), 77 (50.01),
51 (9.22).
4.3.12. 3,3,3-trifluoro-1-(pyridin-2-yl)propan-1-one (2l) [4b]. Colorless oil (32 mg, 85%
1
yield), Column chromatography (petroleum ether/EtOAc=5:1, Rf = 0.56). H NMR (400
MHz, CDCl3) δ 8.69 (d, J = 4.8 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.89 (td, J = 7.6, 1.6 Hz,
15
Page 15 of 29

13
1H), 7.54 (td, J = 6.0, 1.2 Hz, 1H), 4.15 (q, J = 10.4 Hz, 2H) ppm; C NMR (100 MHz,
CDCl3): δ 191.8, 152.0, 149.1, 137.2, 128.0, 124.4 (q, J = 275.0 Hz), 122.1, 40.8 (q, J =
28.2 Hz ) ppm; 19F NMR (376 MHz, CDCl3): δ -62.8 (t, J = 10.3 Hz, 3F) ppm; GC-MS (EI,
m/z): 189 (M+, 22.63), 79 (74.48), 78 (100.00), 51 (35.94), 52 (19.79).
4.3.13. 3,3,3-trifluoro-1-(thiophen-2-yl)propan-1-one (2m) [4b]. Colorless oil (50 mg, 64%
1
yield), Column chromatography (n-hexane/CH2Cl2=2:1, Rf = 0.42). H NMR (400 MHz,
13
CDCl3): δ 7.76-7.73 (m, 2H), 7.16 (t, J = 4.4 Hz 1H), 3.72 (q, J = 10.0 Hz, 2H) ppm; C
NMR (100 MHz, CDCl3): δ 182.1, 143.1, 135.7, 133.4, 128.5, 123.6 (q, J = 275.4 Hz), 43.0
(q, J = 28.6 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -62.4 (t, J = 10.2 Hz, 3F) ppm;
GC-MS (EI, m/z): 194 (M+, 21.95), 111 (100.00), 83 (18.62), 39 (14.53).
4.3.14. 3,3,3-trifluoro-1-(5-methylfuran-2-yl)propan-1-one (2n) [4a]. White solid (57 mg,
74% yield), mp: 47-48 °C (lit [4a] 57-59 °C). Column chromatography
(n-hexane/CH2Cl2=1:1, Rf = 0.62). 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 3.2 Hz, 1H),
6.23 (d, J = 3.2 Hz, 1H), 3.60 (q, J = 10.4 Hz, 2H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 177.2, 159.3, 150.7, 123.8 (q, J = 275.4 Hz), 121.0, 109.8, 41.9 (t, J = 28.5 Hz),
14.1 ppm; 19F NMR (376 MHz, CDCl3): δ -62.4 (t, J = 10.3 Hz, 3F) ppm; GC-MS (EI, m/z):
192 (M+, 15.08), 109 (100.00), 53 (20.77).
16
Page 16 of 29

Acknowledgments
This work was supported by the National Natural Science Foundation of China (NSFC)
(Project No 21176039 and 20923006)
Appendix A. Supplementary data
1
13
19
Supplementary data (mechanistic experimental details and H NMR, C NMR and F
NMR spectra of all products) associated with this article can be found, in the online version,
at http:// http://dx.doi.org/
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20
Page 20 of 29

Electrophilic T rifluoromethylation
Hu, 2013
F3C I
O
O
O
O
CF3
R
COOH
R
Togni's reagent
Nucleophilic Tr if luor omethylation
Grushin, 2012
O
X
CF3H
CuCF3
CF3
R
R
(X = Br, Cl)
Radical T rifluoromethylation
Mikami, 2005
OM
O
R3
CF3I / Et3B
-78 °C
CF3
R3
R1
R1
R2
R2
(M = Li, Ti, Zn)
MacMillan, 2011
OSiR3
O
O
CF3I
CF3
CF3
R1
R1
Ar
cat. hv
R2
R2
R
Ph2SCF3OTf
H
Xiao, 2011
Ar
CF3SO2Na
Maiti, 2013
R
Langlois reagent
Zhang, 2013
O
OAc
CF3SO2Cl
CF3
R
Ar
cat. hv
Ar
R
Langlois, 1992
OAc
O
OAc
CF3SO2Na / TBHP
R1
CF3
R1
R2
R1
CF3
Cu(OTf)
cat.
2
R2
R2
H
H
α-deprotonation
22-60%
side-reaction
This work
OAc
cheaper catalyst
O
CF3SO2Na / TBHP
CF3
R
without α-deprotonation
Ar
Ar
cat. CuI
good to excellent yields
R
Scheme 1.
21
Page 21 of 29

OAc
O
TBHP (aq.)
Cu salt
CF3
CF3SO2Na
MeCN, RT
1a
2a
Entry Catalyst (mol%)
CF3SO2Na
TBHP
Time
(h)
GC Yield
(eq.)
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
3.5
3.0
4.5
4.0
4.0
4.0
4.0
4.0
(eq.)
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
4.0
5.0
5.0
5.0
5.0
(%)b
1
2
—
Cu (10)
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
10.0
57
71
3
Cu(OTf)2 (10)
CuSO4•5H2O (10)
Cu(OAc)2 (10)
Cu(acac)2 (10)
CuCl (10)
CuBr (10)
Cu(CO2CF3)2 (10)
CuI (10)
88
4
68
5
83
6
85
7
85
8
86
9
95
10
11
12
13
14
15
16
17
18c
96
CuI (10)
85
CuI (10)
83
CuI (10)
92
CuI (10)
90
CuI (15)
99
CuI (20)
96
CuI (15)
99 (93)
91
CuI (15)
Table 1.
22
Page 22 of 29

O
15 mol% CuI
5 equiv TBHP
OAc
R2
CF3
CF3SO2Na
R1
R2
R1
CH3CN, RT, 2 h
1a-n
2a-n
O
O
O
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
MeO
Cl
2a
2c
, 93%
2b, 94%
, 92%
O
O
O
CF3
Br
O2N
2e
2d, 96%
, 75%
2f, 94%
O
O
O
CF3
F
NO2
NHAc
b
2g
2h
2i
, 61%
, 83%
O
, 79%
O
O
CF3
N
Ph
2j, 89%
2k, 64%
2l, 85%
O
O
O
S
CF3
CF3
b
2m
2n, 74%b
, 64%
Table 2.
23
Page 23 of 29

15 mol % CuI
5 equiv TBHP
CF
(4 equiv)
3SO2Na
N
O
1a
2a
CH3CN (1 mL)
RT, 2 h
TEMPO
CF3
-CF
TEMPO
3
2a
TEMPO = 1.0 equiv, , 58%, TEMPO-CF3, 27%
TEMPO = 4.0 equiv, 2a, 0.1%, TEMPO-CF3, 64%
(Yield determined by 19F NMR based on 1a)
Scheme 2.
24
Page 24 of 29

OAc
I
OAc
CF3
R2
R2
R1
R1
CF3
II
OH
CF3SO2
t-BuO
CuII
SET
SO2 t-BuO
t-BuOOH
CuI
OAc
O
R2
R2
- Ac
R1
R1
CF3
IV
CF3
III
Scheme 3.
25
Page 25 of 29

Scheme 1. Synthesis of α-CF3-substituted ketones.
Table 1. Optimization of reaction conditions.a
a
Reaction conditions: 1-phenylvinyl acetate (1a, 1.0 equiv.), Cu salt as the catalyst, TBHP:
tert-butyl hydroperoxide 70% in water, MeCN (1.0 mL) at room temperature under air.
b Yields are determined by GC analysis using n-dodecane as an internal standard. Yields of isolated
product are given within parentheses.
c The reaction was conducted at 0 °C.
Table 2. Scope of the trifluoromethylation reaction.a
a
Reaction conditions: 0.20 mmol of enol acetates, 0.80 mmol of CF3SO2Na, 0.03 mmol copper
iodide, 70% aq TBHP (1.0 mmol), 1.0 mL of MeCN, 2 h.
b 0.40 mmol of enol acetates.
Scheme 2. Capture of CF3 radical by TEMPO.
Scheme 3. Possible mechanism.
26
Page 26 of 29

Highlights
•This reaction is high‐yielding and wide functional group tolerance.
•A variety of α‐trifluoromethyl aryl ketones can be prepared by this practical method.
•The reaction is experimentally simple and carried out at room temperature.
27
Page 27 of 29

*Graphical Abstract - Pictogram
Page 28 of 29

*Graphical Abstract - Synopsis
CuI-catalyzed trifluoromethylation of aryl(heteroaryl) enol acetates using CF3SO2Na provided the
corresponding α-trifluoromethyl ketones. The reaction is carried out at at room temperature, providing
good to excellent yields with broad substrate scope.
Page 29 of 29