Base-Promoted Double-Bond-Migration/Hydrolysis/Isomerization of 4-Aryl-1,1,1-trifluorobut-2-en-2-yl Trifluoromethanesulfonates: A Metal-Free Approach to β-Trifluoromethyl Ketones

Article abstract of DOI:10.1002/ejoc.201801025

A method for the synthesis of β-trifluoromethyl ketones promoted by a base is described. In the presence of DBU, 1-aryl-4,4,4-trifluoromethylbutanones with various functional groups were obtained through the reaction of 4-aryl-1,1,1-trifluorobut-2-en-2-yl

Full text of DOI:10.1002/ejoc.201801025

A Journal of
Accepted Article
Title: Base-promoted double-bond-migration/hydrolysis/isomerization
of 4-aryl-1,1,1-trifluorobut-2-en-2-yl trifluoromethanesulfonates: a
metal-free approach to β-trifluoromethyl ketones
Authors: Yuhan Zhou, Chunxia Zhang, Yilong Zhao, Dong Li, Jinfeng
Zhao, Zhaotian Wang, and Jingping Qu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801025
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801025
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10.1002/ejoc.201801025
European Journal of Organic Chemistry
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Base-promoted double-bond-migration/hydrolysis/isomerization
of 4-aryl-1,1,1-trifluorobut-2-en-2-yl trifluoromethanesulfonates: a
metal-free approach to β-trifluoromethyl ketones
Yuhan Zhou,*[a] Chunxia Zhang,[a] Yilong Zhao,[a] Dong Li,[a] Jinfeng Zhao,[a] Zhaotian Wang,[a] and
Jingping Qu[a]
Abstract: A method for the synthesis of β-trifluoromethyl ketones
promoted by a base is described. In the presence of DBU, 1-aryl-
4,4,4-trifluoromethylbutanones with various functional groups were
obtained through the reaction of 4-aryl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonates with water in moderate to excellent yields.
The reaction underwent
a
double-bond-migration/hydrolysis/
isomerization pathway, and 1-aryl-4,4,4-trifluorobut-2-en-1-ols were
determined as the key intermediates. Both electron-withdrawing and
electron-donating groups, such as fluoro, chloro, bromo, ester,
cyano, trifluoromethyl, alkyl, and alkoxy, were tolerated well in this
reaction.
Introduction
Trifluoromethyl-containing compounds are widely used in
pharmaceuticals, agrochemicals, and functional materials owing
to the strong electron-withdrawing nature, superior lipophilicity
and metabolic stability of trifluoromethyl group.[1] Among them,
β-trifluoromethyl ketones constitute an important structural motif
of many biologically active molecules and are intermediates for
the preparation of trifluoromethylated compounds (Figure 1).[2]
Thus, the synthetic approaches to β-trifluoromethyl ketones
have drawn much attention.
Figure 1. Applications of β-trifluoromethyl ketones
Figure 2. Synthesis of β-trifluoromethyl ketones
The first and foremost, β-trifluoromethyl ketones have been
prepared successfully through the transition-metal-mediated
trifluoromethylation of various substrates (Figure 2, a), such as
copper-catalyzed
cyclopropanols,[3]
ring-opening
copper-catalyzed
trifluoromethylation
of
[a]
State Key Laboratory of Fine Chemicals, School of Pharmaceutical
Science and Technology
Dalian University of Technology
Linggong road 2, Dalian 116024, PR China
E-mail: zhouyh@dl.cn
or
photoredox
trifluoromethylation of propargylic alcohols,[4] copper or iron
catalyzed trifluoromethylation/semipinacol rearrangement of
allylic alcohols,[5] copper-catalyzed trifluoromethylation of α,β-
unsaturated ketones.[6] Additionally, the transformations of the
fluorine-containing building blocks can afford β-trifluoromethyl
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801025
European Journal of Organic Chemistry
FULL PAPER
ketones (Figure 2, b), for example the Wacker-type oxidation of
allylic trifluoromethyl-substituted alkenes,[7] hydrogenation or
nucleophilic addition of β-trifluoromethyl-substituted enones,[8]
isomerization of trifluoromethylated allylic alcohols,[9] boron
trifluoride promoted ring-opening of gem-difluorocyclopropyl
ketones,[10] AgF-mediated fluorination with concomitant cross-
coupling/hydrolysis between gem-difluoroolefins and α-
Table 1. Optimization of the formation of 2a based on temperature [a]
Yield (%)[b]
T (oC)
methoxyalkenes.[11] Furthermore, the oxidative coupling of
Entry
2a
0
0
3a
85
78
20
0
0
0
0
0
0
0
0
0
0
0
0
[12]
vinylarenes with ICH2CF3
enol ethers (Figure 2, c)
substituted ketones.
and the trifluoroethylation of silyl
also leaded to β-trifluoromethyl-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15c
-40 °C 7 h
-20 °C 7 h
0 °C 7 h
25 °C 7 h
[13]
61
68
61
80
81
84
84
82
79
67
85
80
84
Recently, our group also committed to the preparation of organic
fluorides.[14] It is worth mentioning that the useful fluorinated
building blocks, (Z)-trifluoromethyl alkenyl triflates, were
prepared and utilized successfully for the synthesis of various
trifluoromethyl derivatives such as alkynes, diarylethylenes,
enynes, benzofurans, allyl azides, and azirines. During the
exploration of the reaction of 4-aryl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonates in the presence of a base and water,
1-aryl-4,4,4-trifluorobutanones were detected. That offered us a
practical method to β-trifluoromethyl ketones (Figure 2). And this
metal-free reaction shows its merit for the strict restriction on the
residual amount of heavy metals in pharmaceuticals and some
functional materials. In this context, we describe the base-
promoted synthesis of β-trifluoromethyl ketones from (Z)-
trifluoromethyl alkenyl triflates.
80 °C 7 h
-40 °C 5 h, 40 °C 7 h
-40 °C 5 h, 60 °C 7 h
-40 °C 5 h, 80 °C 7 h
-40 °C 5 h, 90 °C 7 h
-40 °C 5 h, 100 °C 7 h
-40 °C 5 h, 120 °C 7 h
-40 °C 5 h, 80 °C 2 h
-40 °C 5 h, 80 °C 3 h
-40 °C 5 h, 80 °C 12 h
-40 °C 5 h, 80 °C 7 h
[a] Reaction conditions: 1a (0.2 mmol), DBU (4.0 eq.), and H2O (1.0 eq.)
in DMF (1 mL). [b] The yield was determined by 1H NMR with dimethyl
terephthalate as an internal standard. [c] H2O (2.0 eq.).
Results and Discussion
4-Phenyl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonate
Table 2. Optimization of the formation of 2a based on base [a]
(1a) was selected as the model substrate for optimization of the
reaction conditions. 1-Phenyl-4,4,4-trifluorobutan-1-one (2a) and
1-phenyl-4,4,4-trifluorobut-2-en-1-ol (3a) were formed in the
reaction of 1a with water promoted by DBU in DMF. The
Yield (%)[b]
preliminary results indicated that the temperature has
a
Entry
Base
Conv. (%) [b]
significant effect on the selectivity of 2a to 3a. Thus, the effect of
the temperature was investigated initially (Table 1). When the
reaction was carried out at a low temperature, 3a was
determined as the major product without the generation of 2a
(Table 1, entries 1 and 2). Raising the temperature, the ratio of
2a to 3a was increased (Table 1, entry 3). When the reaction
was performed at room temperature, 2a was obtained in 68%
yield without 3a (Table 1, entry 4).
We proposed that 3a is an intermediate in the formation of 2a
(see Scheme 1), and lower temperature is in favor of the
transformation of 1a to 3a, while higher temperature is in favor of
the transformation of 3a to 2a. Gratifyingly, a two-step procedure
was found to give better result. In other words, initiate the
reaction at a low temperature (-40 °C ), after the starting
materials is consumed, raise it to a higher temperature. The
disappearance of 3a and the generation of 2a at higher
temperature support our suggestion. And in the second step,
reacting at 80 °C for 3 h gave the best result (Table 1, entry 13).
Increasing the amount of water to 2 equivalents has no effect on
the reaction (Table 1, entry 15). In most of the reactions, a small
amount of unknown tarry byproduct was formed.
2a
68
43
49
<10
43
17
0
85
<10
80
79
3a
0
DBN (4 eq.)
Et3N (4 eq.)
100
100
100
88
100
100
100
100
56
1
2
3
4
5
6
7
8
9
42
40
70
15
39
0
0
0
0
0
EtN(i-Pr)2 (4 eq.)
Pyridine (4 eq.)
K2CO3 (4 eq.)
KHCO3 (4 eq.)
NaOH (4 eq.)
DBU (4 eq.)
DBU (0.5 eq.)
DBU (3 eq.)
DBU (5 eq.)
100
100
10
11
[a] Reaction conditions: 1a (0.2 mmol), base, and H2O (1.0 eq.) in DMF (1
mL) was stirred at -40 °C for 5 h, then at 80 °C for 3 h. [b] The yield was
determined by 1H NMR with dimethyl terephthalate as an internal
standard.
Considering the significant role of the base in this transformation,
different bases were examined (Table 2). If a weak base, such
as Et3N, K2CO3 or KHCO3, was used, 3a was found in the
reaction mixture (Table 2, entries 2-6). When NaOH was used,
the reaction gave complicated mixture (Table 3, entry 7). The
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10.1002/ejoc.201801025
European Journal of Organic Chemistry
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Table 4. Preparation of 1-aryl-4,4,4-trifluorobutan-1-one derivatives [a]
results suggested that a stronger base was beneficial to the
generation of 2a, and 4 equivalent of DBU gave the best results
(Table 2, entry 8). Raising or reducing the amount of DBU
resulted in a decreased yield of 2a (Table 2, entries 9-11).
Then, the effect of the solvent was also explored (Table 3).
Although the reaction proceeded smoothly in most solvents,
polar solvents were more favorable. When THF or Et2O were
used as solvents, the reaction gave complicated mixture (Table
3, entries 2 and 3). DMF was shown to be a better choice (Table
3, entry 8).
Table 3. Optimization of the formation of 2a based on solvent [a]
Yield (%)[b]
Entry
Solvent
Conv. (%) [b]
2a
53
<10
<10
56
68
82
69
85
3a
0
0
0
0
0
0
0
0
toluene
THF
Et2O
CH2Cl2
CHCl3
CH3CN
DMSO
DMF
100
100
86
100
100
100
100
100
1
2
3
4
5
6
7
8
[a] Reaction conditions: 1a (0.2 mmol), DBU (4.0 eq.), and H2O (1.0 eq.)
in solvent (1 mL) was stirred at -40 °C for 5 h, then at 80 °C for 3 h. [b]
The yield was determined by 1H NMR with dimethyl terephthalate as an
internal standard.
[a] Reaction conditions: 1 (0.4 mmol), DBU (4.0 eq.), and H2O (1.0 eq.) in
DMF (2 mL) was stirred at -40 °C for 5 h, then at 80 °C for 3 h. Isolated
yield.
With the optimum reaction conditions in hand, the scope in
terms
of
4-aryl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonates (1) was explored (Table 4). A series
of 4-aryl-1,1,1-trifluorobut-2-en-2-yl trifluoromethanesulfonates
bearing either electron-withdrawing or electron-donating groups
on the aromatic ring underwent this transformation, and the
desired products were obtained in moderate to excellent yields.
Halo substituted molecules gave good yields in this reaction (2b-
2f). And 2-chlorophenyl substrate gave similar result with 3- and
4-chloro ones (2b-2d). Trifluoromethyl, ester and cyano groups
were also tolerated well (2h-2j). In addition, naphthyl and
biphenyl substitutes (2k and 2m) also showed efficiency as well
as multi-substituted substrate (2n). It is noteworthy that methyl-
substituted
4-phenyl-1,1,1-trifluorobut-2-en-2-yl
Scheme 1. Plausible reaction mechanism.
trifluoromethanesulfonate gave an excellent yield (2o) while
thienyl substitute gave moderate yield (2p). 4-Alkyl-1,1,1-
trifluorobut-2-en-2-yl trifluoromethanesulfonates, for example
(Z)-1,1,1-trifluoroundec-2-en-2-yl trifluoromethanesulfonate, was
also examined. Unfortunately, the conversion and the yield were
very low.
According to the fact that 3a is an intermediate in the formation
of 2a, the possible mechanism for the synthesis of 1-aryl-4,4,4-
trifluoromethylbutanones from 4-aryl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonates was shown in Scheme 1. Firstly,
through the double bond isomerization, the intermediate A was
generated in the presence of DBU. Secondly, the intermediate A
could be transformed into 3 in two possible pathways. One way
was SN2' substitution, OH- anion took a conjugate addition over
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2b was prepared according to the general procedure using 1b as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2b was obtained as a light yellow
liquid. Yield: 69% (66 mg); IR (KBr): ṽ = 2965, 1637, 1261, 1098, 803
cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.56 - 7.49 (m, 1H), 7.45 - 7.41 (m,
2H), 7.35 (m, 1H), 3.33 - 3.19 (m, 2H), 2.73 - 2.52 (m, 2H). 13C NMR (101
MHz, CDCl3) δ = 199.3, 138.3, 132.3, 131.1, 130.7, 129.1, 127.1, 126.9
(q, J = 272.7 Hz), 35.4 (q, J = 2.7 Hz), 28.43 (q, J = 30.0 Hz). 19F NMR
(470 MHz, CDCl3) δ = -66.47 (t, J = 10.8 Hz). HRMS (EI) m/z: calcd for
C10H8ClF3O [M+.] 236.0216, found: 236.0206.
the double bond, and –OTf group left to afford 3 (path I). And the
other way was that the leaving of –TfO in intermediate A
resulted in the formation of CF3-allyl cations.[14d,15] Having two
resonances, the relative stable CF3-allyl cations could be
captured by OH- to afford 3 (path II). Finally, the product 2 was
formed from 3 after double bond migration under DBU action.[9a]
Conclusions
1-(3’-Chlorophenyl)-4,4,4-trifluorobutan-1-one (2c):[10]
In summary,
trifluoromethylbutanones has been developed. Promoted by
DBU, 4-aryl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonates were converted into 1-aryl-4,4,4-
trifluoromethylbutanones smoothly in moderate to excellent
yields. Both electron-withdrawing and electron-donating groups,
such as fluoro, chloro, bromo, ester, cyano, trifluoromethyl, alkyl,
and alkoxy, were tolerated well in this reaction.
a
metal-free synthesis of 1-aryl-4,4,4-
2c was prepared according to the general procedure using 1c as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2c was obtained as a light yellow
liquid. Yield: 73% (69 mg); IR (KBr): ṽ = 2964, 1697, 1260, 1101, 802,
681 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.93 (t, J = 1.6 Hz, 1H), 7.84 (d,
J = 7.8 Hz, 1H), 7.58 - 7.56 (m, 1H), 7.45 -7.41 (m, 1H), 3.36 - 3.17 (m,
2H), 2.72 - 2.49 (m, 2H). 13C NMR (101 MHz, CDCl3) δ = 195.0, 137.6,
135.2, 133.5, 130.1, 128.1, 127.0 (q, J = 276.8 Hz), 126.1, 31.3 (q, J =
2.7 Hz), 28.2 (q, J = 29.9 Hz). 19F NMR (470 MHz, CDCl3) δ = -66.49 (t, J
= 10.8 Hz). HRMS (EI) m/z: calcd for C10H8ClF3O [M+.] 236.0216, found:
236.0215.
Experimental Section
1
All H NMR (400 MHz), 13C NMR (101 MHz) and 19F NMR (377 MHz or
1-(4’-Chlorophenyl)-4,4,4-trifluorobutan-1-one (2d):[10]
470 MHz) were recorded on Bruker AVANCE II-400 or Bruker AVANCE
III-500 spectrometer with chemical shifts reported as ppm. High
resolution mass spectra (HRMS) (ESI) were recorded on a Micromass
Waters Q-TOF Microspectrometer. IR spectra were determined by a
Thermo Fisher FT-IR spectrometer. Column chromatography was
performed on silica gel (200~300 mesh). 4-Aryl-1,1,1-trifluorobut-2-en-2-
yl trifluoromethanesulfonates (1) were prepared following our previous
methods.[14a,14d] Other reagents and the substrates were purchased and
used as received.
2d was prepared according to the general procedure using 1d as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2d was obtained as a light yellow
liquid. Yield: 74% (70 mg); IR (KBr): ṽ = 2987, 1680, 1308, 1096, 825,
691 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.99 - 7.87 (m, 2H), 7.57 - 7.40
(m, 2H), 3.31 - 3.20 (m, 2H), 2.67 - 2.52 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ = 195.0, 140.1, 134.4, 129.4, 129.1, 127.1 (q, J = 275.7 Hz),
31.2 (q, J = 5.0 Hz), 28.2 (q, J = 29.8 Hz). 19F NMR (470 MHz, CDCl3) δ
= -66.49 (t, J = 10.8 Hz). HRMS (EI) m/z: calcd for C10H8ClF3O [M+.]
236.0216, found: 236.0210.
General
procedure
for
the
synthesis
of
1-aryl-4,4,4-
trifluoromethylbutanones (2):
1-(4’-Bromophenyl)-4,4,4-trifluorobutan-1-one (2e):[10]
To a solution of (Z)-trifluoromethyl alkenyl triflates 1 (0.4 mmol) in DMF (5
mL) was added DBU (1.6 mmol) and H2O (0.4 mmol) at -40 oC. After the
reaction was complete (monitored by TLC), the reaction solution was
moved to 80 °C with stirring for 3 h. After the reaction was complete
(monitored by TLC), the reaction solvent was poured into water (15 mL)
and extracted with EtOAc (3 × 15 mL). The combined organic extracts
were washed with brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure. The crude product was
purified by column chromatography on silica gel to afford the product 2.
2e was prepared according to the general procedure using 1e as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2e was obtained as a white solid.
Yield: 81% (91 mg); mp. 84.5 - 84.7 °C ; IR (KBr): ṽ = 2937, 1688, 1334,
1136, 781, 626 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.91 - 7.77 (m, 2H),
7.67 - 7.57 (m, 2H), 3.24 - 3.20 (m, 2H), 2.68 - 2.50 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ = 195.1, 134.8, 132.1, 129.5, 128.8, 127.1 (q, J =
275.7 Hz), 31.2 (q, J = 2.6 Hz), 28.2 (q, J = 29.9 Hz). 19F NMR (470 MHz,
CDCl3) δ = -66.46 (t, J = 10.8 Hz). HRMS (EI) m/z: calcd for C10H8BrF3O
[M+.] 279.9711, found: 279.9708.
1-Phenyl-4,4,4-trifluorobutan-1-one (2a):[12a]
2a was prepared according to the general procedure using 1a as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2a was obtained as a white solid.
Yield: 82% (66 mg); mp. 65.3 - 65.6 °C ; IR (KBr): ṽ = 3442, 1686, 1335,
1128, 750, 691 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.97 (d, J = 7.3 Hz,
2H), 7.60 (t, J = 7.4 Hz, 1H), 7.51 - 7.47 (m, 2H), 3.29 - 3.25 (m, 2H),
2.69 - 2.50 (m, 2H). 13C NMR (101 MHz, CDCl3) δ = 196.3, 136.1, 133.6,
128.8, 128.0, 127.2 (q, J = 276.9 Hz), 31.2 (q, J = 2.3 Hz), 28.3 (q, J =
29.5 Hz). 19F NMR (470 MHz, CDCl3) δ = -66.47 (t, J = 10.8 Hz). HRMS
(EI) m/z: calcd for C10H9F3O [M+.] 202.0605, found: 202.0603.
1-(4’-Fluorophenyl)-4,4,4-trifluorobutan-1-one (2f):[10]
2f was prepared according to the general procedure using 1f as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2f was obtained as a white solid.
Yield: 84% (74 mg); mp. 54.0 - 54.2 °C ; IR (KBr): ṽ = 2910, 1686, 1332,
1157, 852, 642 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.13 - 7.94 (m, 2H),
7.22 - 7.11 (m, 2H), 3.35 - 3.13 (m, 2H), 2.73 - 2.48 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 194.7, 166.0 (d, J = 255.6 Hz), 132.6 (d, J = 3.0 Hz),
130.7 (d, J = 9.4 Hz), 127.1 (q, J = 275.7 Hz), 115.9 (d, J = 22.0 Hz),
31.1 (q, J = 2.7 Hz), 28.3 (q, J = 29.8 Hz). 19F NMR (470 MHz, CDCl3) δ -
1-(2’-Chlorophenyl)-4,4,4-trifluorobutan-1-one (2b):[12a]
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10.1002/ejoc.201801025
European Journal of Organic Chemistry
FULL PAPER
66.52 (t, J = 10.8 Hz, 3F), δ -104.35(s, 1F). HRMS (EI) m/z: calcd for
solid. Yield: 81% (82 mg); mp. 59.1 - 59.3 °C ; IR (KBr): ṽ = 2995, 1686,
1320, 1256, 1139, 976, 774 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.71 (d,
J = 8.5 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.72 (s, 1H),7.67 -
7.63 (m, 1H), 7.61 - 7.56 (m, 1H), 7.52 (t, J = 7.7 Hz, 1H), 3.38 - 3.34 (m,
2H), 2.86 - 2.61 (m, 2H). 13C NMR (101 MHz, CDCl3) δ = 199.9, 134.6,
134.0, 133.4, 130.2, 128.6, 128.3, 128.1, 127.3 (q, J = 276.9 Hz), 126.7,
125.7, 124.3, 34.2 (q, J = 2.2 Hz), 28.7 (q, J = 29.6 Hz). 19F NMR (470
MHz, CDCl3) δ = -66.24 (t, J = 10.9 Hz). HRMS (EI) m/z: calcd for
C14H11F3O [M+.] 252.0762, found: 252.0758.
C10H8F4O [M+.] 220.0511, found: 220.0518.
1-(4’-Methoxylphenyl)-4,4,4-trifluorobutan-1-one (2g):[10]
2g was prepared according to the general procedure using 1g as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/5), 2g was obtained as a white solid;
Yield: 77% (72 mg); mp. 63.5 - 64.3 °C ; IR (KBr): ṽ = 2933, 1678, 1340,
1140, 835, 642 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.87 - 7.84 (m, 2H),
6.99 - 6.89 (m, 2H), 3.85 (s, 3H), 3.26 - 3.14 (m, 2H), 2.65 - 2.47 (m, 2H).
13C NMR (101 MHz, CDCl3) δ = 194.8, 163.9, 130.3, 129.2, 127.3 (q, J =
275.7 Hz), 113.9, 55.4, 30.7 (q, J = 2.5 Hz), 28.4 (q, J = 29.6 Hz). 19F
NMR (470 MHz, CDCl3) δ = -66.45 (t, J = 10.9 Hz). HRMS (EI) m/z: calcd
for C11H11F3O2 [M+.] 232.0711, found: 232.0713.
1-(4’-Isopropylphenyl) -4,4,4-trifluorobutan-1-one (2l):[4b]
2l was prepared according to the general procedure using 1l as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2l was obtained as a white solid.
Yield: 84% (82 mg); mp. 48.8 - 49.8 °C ; IR (KBr): ṽ = 2965, 1686, 1140,
1
978, 854 cm-1; H NMR (400 MHz, CDCl3) δ = 7.90 (d, J = 8.4 Hz, 2H),
1-(3’-Trifluoromethylphenyl)-4,4,4-trifluorobutan-1-one (2h):[3b]
7.33 (d, J = 8.4 Hz, 2H), 3.35 - 3.15 (m, 2H), 2.94 (dt, J = 6.9 Hz, 1H),
2.72 - 2.45 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3)
δ = 195.9, 155.2, 134.0, 128.3, 127.2 (q, J = 275.6 Hz), 126.8, 34.3, 31.0
(q, J = 2.5 Hz), 28.4 (q, J = 29.7 Hz), 23.6. 19F NMR (470 MHz, CDCl3) δ
= -66.47 (t, J = 10.9 Hz). HRMS (EI) m/z: calcd for C13H15F3O [M+.]
244.1075, found: 244.1074.
2h was prepared according to the general procedure using 1h as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2h was obtained as a colorless
liquid. Yield: 88% (95 mg); IR (KBr): ṽ = 2920, 1636, 1261, 1023, 803
cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.26 (s, 1H), 8.24 (d, J = 7.8 Hz,
1H), 7.92 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 3.42 - 3.35 (m, 2H),
2.74 – 2.52 (m, 2H). 13C NMR (101 MHz, CDCl3) δ = 194.9, 136.6,
131.50 (q, J = 33.2 Hz), 131.1, 129.9 (q, J = 3.3 Hz), 129.5, 127.0 (q, J =
275.7 Hz), 124.8 (q, J = 7.6 Hz), 123.6 (q, J = 273.7 Hz), 31.4 (q, J = 2.7
Hz), 28.2 (q, J = 30.0 Hz). 19F NMR (470 MHz, CDCl3) δ = -62.96 (s, 3F),
-66.53 (t, J = 10.7 Hz, 3F). HRMS (EI) m/z: calcd for C11H8F6O [M+.]
270.0479, found: 270.0476.
1-(4’-Phenylphenyl)-4,4,4-trifluorobutan-1-one (2m):[3b]
2m was prepared according to the general procedure using 1m as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2m was obtained as a white solid.
Yield: 72% (80 mg); mp. 127.1 - 127.6 °C ; IR (KBr): ṽ = 2977, 1683, 1337,
1140, 977, 759 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.04 (d, J = 8.4 Hz,
2H), 7.71 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 7.1 Hz, 2H), 7.51 - 7.47 (m, 2H),
7.46 - 7.40 (m, 1H), 3.35 - 3.23 (m, 2H), 2.73 - 2.54 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ = 195.9, 146.3, 139.7, 134.8, 129.0, 128.6, 128.4,
127.4, 127.3, 127.0 (q, J = 215.6 Hz), 31.2 (q, J = 5.1 Hz), 28.4 (q, J =
29.7 Hz). 19F NMR (470 MHz, CDCl3) δ = -66.49 (t, J = 10.8 Hz). HRMS
(EI) m/z: calcd for C16H13F3O [M+.] 278.0918, found: 278.0915.
Ethyl 4-(4’,4’,4’-trifluorobutyryl)benzoate (2i):
2i was prepared according to the general procedure using 1i as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/5), 2i was obtained as a white solid.
Yield: 75% (82 mg); mp. 86.8 - 87.0 °C ; IR (KBr): ṽ = 2997, 1710, 1687,
1286, 1150, 760 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.14 (d, J = 8.2 Hz,
2H), 8.02 (d, J = 8.2 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.38 - 3.18 (m, 2H),
2.75 - 2.47 (m, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ = 195.8, 165.5, 139.1, 134.7, 129.8, 127.8, 126.7 (q, J = 275.8 Hz),
61.5, 31.5 (q, J = 2.6 Hz), 28.2 (q, J = 29.9 Hz), 14.1. 19F NMR (470 MHz,
CDCl3) δ = -66.51 (t, J = 10.6 Hz). HRMS (EI) m/z: calcd for C13H13F3O3
[M+.] 274.0817, found: 274.0807.
1-(3’,4’,5’-Trimethoxylphenyl)-4,4,4-trifluorobutan-1-one (2n):
2n was prepared according to the general procedure using 1n as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/3), 2n was obtained as a light yellow
solid. Yield: 67% (78 mg); mp. 63.1 - 63.4 °C; IR (KBr): ṽ = 2951, 1682,
1
1349, 1137, 865 cm-1; H NMR (400 MHz, CDCl3) δ = 7.12 (s, 2H), 3.84
(s, 9H), 3.25 - 3.04 (m, 2H), 2.56 - 2.44 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ = 195.0, 153.2, 143.1, 131.3, 127.2 (q, J = 275.8 Hz), 105.5,
60.9, 56.3, 30.9 (q, J = 5.0 Hz), 28.4 (q, J = 29.7 Hz). 19F NMR (470 MHz,
CDCl3) δ = -66.40 (t, J = 10.9 Hz). HRMS (EI) m/z: calcd for C13H15F3O4
[M+.] 292.0922, found: 292.0926.
1-(4’- Cyanophenyl)-4,4,4-trifluorobutan-1-one (2j):
2j was prepared according to the general procedure using 1j as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/5), 2j was obtained as a white solid.
Yield: 66% (60 mg); mp. 79.8 - 80.6 °C ; IR (KBr): ṽ = 3240, 2234, 1697,
1138, 983, 851 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.07 (d, J = 8.4 Hz,
2H), 7.81 (d, J = 8.4 Hz, 2H), 3.37 - 3.24 (m, 2H), 2.80 - 2.49 (m, 2H). 13
NMR (101 MHz, CDCl3) δ = 195.0, 138.9, 132.7, 128.5, 126.9 (q, J =
278.1 Hz), 117.7, 116.9, 31.6 (q, J = 2.7 Hz), 28.2 (q, J = 30.0 Hz). 19
4,4,4-Trifluoro-1-p-tolylbutan-1-one (2o):[12a]
C
2o was prepared according to the general procedure using 1o as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2o was obtained as a white solid.
Yield: 98% (85 mg); mp. 68.8 - 69.4 °C ; IR (KBr): ṽ = 3281, 1637, 1227,
F
NMR (470 MHz, CDCl3) δ = -66.34 (t, J = 10.9 Hz). HRMS (EI) m/z: calcd
for C11H8F3NO [M+.] 227.0558, found: 227.0552.
1
1009, 976 cm-1; H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 8.1 Hz, 2H),
7.19 (d, J = 8.1 Hz, 2H), 3.16 - 3.10 (m, 2H), 2.56 - 2.41 (m, 2H), 2.33 (s,
3H). 13C NMR (101 MHz, CDCl3) δ = 196.0, 144.4, 133.7, 129.4, 128.1,
127.3 (q, J = 276.7 Hz), 31.0 (q, J = 5.3 Hz), 28.3 (q, J = 30.3 Hz), 21.6.
19F NMR (470 MHz, CDCl3) δ = -66.48 (t, J = 10.9 Hz). HRMS (EI) m/z:
calcd for C11H11F3O [M+.] 216.0762, found: 216.0760.
1-(1’-Naphthyl)-4,4,4-trifluorobutan-1-one (2k):
2k was prepared according to the general procedure using 1k as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2k was obtained as a yellow
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801025
European Journal of Organic Chemistry
FULL PAPER
1-(1’-Thienyl)-4,4,4-trifluorobutan-1-one (2p):
2012, 22, 2693–2697; b) B. A. Czeskis, D. K. Satonin, J. Label. Compd.
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2p was prepared according to the general procedure using 1p as the
starting material. After purification by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether = 1/10), 2p was obtained as a white solid.
Yield: 58% (60 mg); mp. 69.4 - 69.9 °C ; IR (KBr) ṽ = 3070, 1652, 1385,
1
1143, 760 cm-1; H NMR (400 MHz, CDCl3) δ = 7.8 (dd, J = 3.7, 0.5 Hz,
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1H), 7.67 (d, J = 4.9 Hz, 1H), 7.18 - 7.12 (m, 1H), 3.19 (t, J = 9.9 Hz, 2H),
2.68 - 2.47 (m, 2H). 13C NMR (101 MHz, CDCl3) δ = 187.4, 141.4, 132.5,
130.4, 126.5, 125.2 (q, J = 276.7 Hz), 29.9 (q, J = 2.7 Hz), 26.6 (q, J =
30.0 Hz). 19F NMR (470 MHz, CDCl3) δ = -66.47 (t, J = 10.8 Hz). HRMS
(EI) m/z: calcd for C7H7F3S [M+.] 180.0221, found: 180.0161.
Procedure for the synthesis of 1-phenyl-4,4,4-trifluorobut-2-en-1-ol
(3a):[16]
To
a
solution
of
4-phenyl-1,1,1-trifluorobut-2-en-2-yl
[6]
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trifluoromethanesulfonate (1a) (0.4 mmol) in DMF (5 mL) was added
DBU (1.6 mmol) and H2O (0.4 mmol) at -40 oC. After the reaction was
complete (monitored by TLC), the reaction solvent was poured into water
(15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic
extracts were washed with brine and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure. The crude
product was purified by column chromatography on silica gel (eluent:
EtOAc/petroleum ether = 1/5) to afford the product 3a as a colorless oil.
Yield: 78% (63 mg); IR (KBr) ṽ = 3566, 1724, 1251, 1142, 973, 767 cm-1;
1H NMR (400 MHz, CDCl3) δ = 7.39 - 7.35 (m, 3H), 7.32 - 7.28 (m, 2H),
6.51 - 6.45 (m, 1H), 6.03 - 5.94 (m, 1H), 5.25 - 5.23 (m, 1H), 2.52 (br, 1H).
13C NMR (100 MHz, CDCl3) δ 141.1 (q, J = 6.1 Hz), 140.5, 129.0, 128.7,
126.6, 123.3 (q, J = 269.3 Hz), 117.9 (q, J = 34.1 Hz), 72.7.19F NMR (377
MHz, CDCl3) δ -64.38 (d, J = 6.3 Hz, 3F).
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Acknowledgements
The authors gratefully acknowledge the financial support of the
National Natural Science Foundation of China (Nos. 21878037
and 21576041). We also thank Prof. Baomin Wang, Dr. Yuming
Song, and Dr. Ying Peng (Dalian University of Technology,
China) for valuable discussions.
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Keywords: fluorine • ketones • Domino reactions • β-
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10.1002/ejoc.201801025
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Entry for the Table of Contents (Please choose one layout)
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β-trifluoromethyl ketones
Yuhan Zhou,* Chunxia Zhang, Yilong
Zhao, Dong Li, Jinfeng Zhao, Zhaotian
Wang, and Jingping Qu
Page No. – Page No.
A metal-free synthesis of 1-aryl-4,4,4-trifluoromethylbutanones has been
developed. Promoted by DBU, 4-aryl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonates were converted into 1-aryl-4,4,4-
trifluoromethylbutanones smoothly in moderate to excellent yields.
Base-promoted double-bond-
migration/hydrolysis/isomerization of
4-aryl-1,1,1-trifluorobut-2-en-2-yl
trifluoromethanesulfonates: a metal-
free approach to β-trifluoromethyl
ketones
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