Fenton reagent-catalyzed trifluoromethylation of enamines of 3-oxocarboxylates with CF3I

Article abstract of DOI:10.1016/j.jfluchem.2015.10.013

The trifluoromethylation of enamines of ethyl 3-oxocarboxylates catalyzed by Fenton reagent with CF₃I was investigated. Trifluoromethylation followed by acid hydrolysis provided 3-oxo-2-(trifluoromethyl)carboxylates in 64-94% yields, which were greater than those obtained by the trifluoromethylation of 3-oxocarboxylates as reported previously. Enamines trifluoromethylated at the 2-position were isolated as intermediates. Hydrolysis and successive decarboxylation of the obtained 3-oxo-2-(trifluoromethyl)carboxylates under acidic conditions provided (2,2,2-trifluoroethyl)ketones in satisfactory yields.

Full text of DOI:10.1016/j.jfluchem.2015.10.013

Journal of Fluorine Chemistry 181 (2016) 1–6
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Fenton reagent-catalyzed trifluoromethylation of enamines
of 3-oxocarboxylates with CF3I
Yuhki Ohtsuka a, Daisuke Uraguchi a, Kyoko Yamamoto a, Kenji Tokuhisa b,
Tetsu Yamakawa a,
*
a Sagami Chemical Research Institute, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
b Tosoh F-Tech Inc., Kaisei-cho 4988, Shunan, Yamaguchi 746-0006, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
The trifluoromethylation of enamines of ethyl 3-oxocarboxylates catalyzed by Fenton reagent with CF3I
was investigated. Trifluoromethylation followed by acid hydrolysis provided 3-oxo-2-(trifluoromethyl)-
carboxylates in 64–94% yields, which were greater than those obtained by the trifluoromethylation of 3-
oxocarboxylates as reported previously. Enamines trifluoromethylated at the 2-position were isolated as
intermediates. Hydrolysis and successive decarboxylation of the obtained 3-oxo-2-(trifluoromethyl)-
carboxylates under acidic conditions provided (2,2,2-trifluoroethyl)ketones in satisfactory yields.
ß 2015 Elsevier B.V. All rights reserved.
Received 5 October 2015
Received in revised form 20 October 2015
Accepted 23 October 2015
Available online 9 November 2015
Keywords:
Trifluoromethylation
Fenton reagent
3-Oxo-2-(trifluoromethyl)carboxylates
(2,2,2-Trifluoroethyl)ketones
1. Introduction
C55C double bond in the enol form. However, peaks corresponding
to the enol form were not observed in the 1H NMR of the reaction
Recently, we reported that Fenton reagent composed of FeSO4
or Cp2Fe and aqueous H2O2 catalyzes the trifluoromethylation of
olefinic C–H bonds in nucleobases and aromatic compounds by
generating trifluoromethyl radicals from CF3I in DMSO [1,2]. Based
on the observed reactivity and regioselectivity, the trifluoro-
methylation was concluded to proceed in a manner similar to the
electrophilic substitution of aromatic compounds. Furthermore,
the methylene carbon between the two carbonyl groups in 3-
oxocarboxylates was trifluoromethylated by CF3I in the presence of
Fenton reagent catalyst, giving 3-oxo-2-(trifluoromethyl)carbox-
ylates in 40–73% yield [3].
In solutions, 3-oxocarboxylates exist in equilibrium between
the enol and keto forms (Scheme 1). When the trifluoromethyla-
tion of ethyl 3-oxo-2-methylbutanoate (whose enol form has no H
at the C2 position) was attempted under the same conditions as
those of the trifluoromethylation of ethyl 3-oxocarboxylates [3],
ethyl 3-oxo-2-methylbutanoate was completely recovered, indi-
cating that the enol form was more reactive than the keto form and
that trifluoromethylation of 3-oxocarboxylates chiefly occurs the
solutions [3]. These results confirmed that the unsatisfactory
yields of 3-oxo-2-(trifluoromethyl)carboxylates were due to the
low concentration of the more reactive enol form than keto form.
3-Oxo-2-(trifluoromethyl)carboxylates produced by the tri-
fluoromethylation of 3-oxocarboxylates at the C2 carbon provided
5-fluoropyrazole-4-carboxylates via cyclization with hydrazines
[3], indicating that 3-oxo-2-(trifluoromethyl)carboxylates may
serve as building blocks for fluorinated heterocyclic compounds. In
addition, it is well known that 3-oxocarboxylic acids or their esters
provide corresponding the methylketones through acid hydroxyl-
ation and base decarboxylation [4]. Thus, they can potentially
furnish (2,2,2-trifluoroethyl)ketones, which have garnered signifi-
cant attention as precursors in the synthesis of various medicines
[5], drug candidates [6] and potential intermediates [7]. This
motivated us to develop a protocol that would result in improve
yields of 3-oxo-2-(trifluoromethyl)carboxylates.
The bond between C2 and C3 in the enamines of 3-
oxocarboxylates is a fixed C55C double bond, similar to the enol
form of 3-oxocarboxylates (Scheme 1). Therefore, these enamines
should exhibit greater reactivity than 3-oxocarboxylates in the
present trifluoromethylation.
Herein, we report that 3-oxo-2-(trifluoromethyl)carboxylates
can be obtained in high yields by the trifluoromethylation of the
*
Corresponding author.
E-mail address: t_yamakawa@sagami.or.jp (T. Yamakawa).
http://dx.doi.org/10.1016/j.jfluchem.2015.10.013
0022-1139/ß 2015 Elsevier B.V. All rights reserved.

2
Y. Ohtsuka et al. / Journal of Fluorine Chemistry 181 (2016) 1–6
was isolated in 64% yield after path (3) and its 1H, 13C and 19F NMR
data completely matched with those of ethyl 3-oxo-2-(trifluor-
omethyl)butanoate [3].
O
O
O
OH
R'O
R'O
R'O
C3 R
C3 R
C2
C2
keto
enol
These results strongly indicated that 1a was the intermediate in
the formation of 1b from the enamine. Therefore, we attempted to
isolate 1a from the reaction mixture. Half the amount of FeSO4 and
a shorter reaction time (0.5 h) (as compared to that used in path
(1)) provided only 1a in a low yield. 1H, 13C and 19F NMR revealed
that 1a is ethyl 3-amino-2-(trifluoromethyl)-2-butenoate, which
was converted to 1b (79% yield) upon addition of conc. HCl.
Therefore, trifluoromethylation of the enamine to 1a and conver-
sion of 1a to 1b occurred successively due to the acidity of H2O2 in
path (1). Furthermore, an extended reaction time (path (2)) and the
addition of HCl (path (3)) facilitated the conversion of 1a to 1b. The
conversion in path (2) contradicts the results of the H2O2 stability
experiment described above, suggesting that FeSO4 and/or the
presence of the trifluoromethyl group facilitated the conversion.
As expected, the total 19F NMR yield of 1a and 1b (78%) was
around twice the reported 19F NMR yield obtained in the
trifluoromethylation of ethyl 3-oxobutanoate (43%) [3]. This was
undoubtedly due to the exclusive existence of the reactive C55C
bond in the enamine.
O
NH2
C3 R
C2
enamine
Scheme 1. Keto–enol equilibrium of 3-oxocarboxylates.
corresponding enamines, followed by hydrolysis in the presence
of an acid. In addition, acid-catalyzed hydrolysis and decarboxyl-
ation by an acid of these products readily provided the (2,2,2-
trifluoroethyl)ketones in excellent yields.
2. Results and discussion
2.1. Trifluoromethylation of enamines
In the trifluoromethylation of 3-oxocarboxylates [3], FeSO4 was
more effective than Cp2Fe which provided the higher yield with
some substrates such as 2,6-dichloroaniline, 3-hydroxypyridine
and pyrazole [2]. Similarly, the trifluoromethylation of the
enamine with Cp2Fe afforded a lower yield of 1b, 41% 19F NMR
yield, than FeSO4.
Next the trifluoromethylation of various enamines of 3-
oxocarboxylates was examined. The substrates were synthesized
from the corresponding ethyl 3-oxocarboxylates via reaction with
AcONH4 [8]. Trifluoromethylation of the obtained enamines
proceeded readily and the successive HCl-catalyzed hydrolysis
gave the desired ethyl 3-oxo-2-(trifluoromethyl)carboxylates in
satisfactory yields (Table 1).
The yields for entries 2–5 (66–94%) were greater than the yields
obtained in the previous report, 32–63% [3]. This could also be
explained by the higher reactivity of the enamines than the 3-
oxocarboxylates.
As with 1a in Scheme 1, the intermediates were isolated from
the enamine substrates shown in Table 1. Notably, ethyl 3-amino-
3-phenyl-2-(trifluoromethyl)-2-propenoate (4a) was obtained in
an excellent yield (93%) from 3-amino-3-phenyl-2-propenoate
(Scheme 3). Hydrolysis of isolated intermediate 4a with conc. HCl
proceeded smoothly to give 4b in an excellent yield.
Trifluoromethylation is carried out using an aqueous solution of
H2O2. Therefore, the stability of enamines of 3-oxocarboxylates
under acidic conditions was examined. A mixture of ethyl 3-
amino-2-butenoate, the enamine synthesized form ethyl 3-
oxobutanoate, and 2.0 equivalents of H2O2 in DMSO were stirred
for 18 h at room temperature; the enamine was completely
recovered. Thus, ethyl 3-amino-2-butenoate was not hydrolyzed
to ethyl 3-oxobutanoate and the C55C double bond remained intact.
Scheme 2 depicted the results of the trifluoromethylation of
ethyl 3-amino-2-butenoate. After trifluoromethylation of the
enamine (path (1)), the 19F NMR spectrum indicated the formation
of two products, their corresponding peaks appeared at ꢀ48.6 ppm
and ꢀ63.8 ppm, and the yields calculated using an internal
standard were 71% and 7%, respectively, giving a total yield of
78%. The latter peak was assigned to the desired product, ethyl 3-
oxo-2-(trifluoromethyl)butanoate (1b), by comparison to the
reported 19F NMR chemical shift and coupling constant (d,
JFH = 9.0 Hz) [3].
After two days at room temperature, the yield of product 1a
decreased to 15% while the yield of 1b increased to 64% (path (2)).
Thus, the total yield of path (2) was 79%, which was essentially the
same as the total yield recorded for path (1) (78%). Furthermore,
the peak corresponding to 1a in the 19F NMR spectrum completely
disappeared upon addition of conc. HCl, increasing the yield of 1b
from 7% to 75% (path (3)). This yield (75%) was also virtually the
same as the total yield of 1a and 1b observed in path (1). Product 1b
2.2. Decarboxylation of (trifluoromethyl)enamines
Finally, we attempted to synthesize (2,2,2-trifluoroethyl)k-
etones from ethyl 3-oxo-2-(trifluoromethyl)carboxylates. The
synthesis of methylketones from 3-oxocarboxylic acids or their
esters is performed with an acid for hydroxylation and a base for
decarboxylation [4]. If the same procedure was applied to 3-oxo-2-
(trifluoromethyl)carboxylates, (2,2,2-trifluoroethyl)ketones could
likely be readily obtained. However, several reports have
suggested that the use of a base is unsuitable for the synthesis
(1)
3.0 eq. CF3I
0.6 eq. FeSO4
2.0 eq. H2O2
O
O
O
NH2
Me
CF3
O
NH2
Me
EtO
Me
+
EtO
DMSO, rt, 1 h
EtO
CF3
71%
1a
7%
1b
of (
For example, Ishihara and co-workers reported that the addition of
a base in the form of lithium enolates to -trifluoromethyl
carbonyls afforded -unsaturated- -difluoro ketones through
a-trifluoromethyl)ketones from a-trifluoromethyl carbonyls.
(2)
rt, 2 d
(3)
conc. HCl
rt, 2h
a
a
,
b
b,b
O
NH2
Me
O
O
O
O
defluorination [7c]. To avoid defluorination by a base, Shibata and
co-workers developed the palladium-catalyzed decarboxylative
EtO
EtO
Me
EtO
Me
+
CF3
CF3
64%
CF3
75%
allylation of allyl
a-trifluoromethyl-b-keto esters [9]. Therefore,
15%
we examined the stability of 3-oxo-2-(trifluoromethyl)carbox-
ylates under basic conditions using 4b. Following the addition of
3.0 mL of 2.0 mol/L NaOH aqueous solution to 4b in MeOH
1a
1b
1b
Scheme 2. Trifluoromethylation of ethyl 3-amino-2-butenoate.

Y. Ohtsuka et al. / Journal of Fluorine Chemistry 181 (2016) 1–6
3
Table 1
Table 2
Trifluoromethylationa and hydrolysisb of various enamines to 3-oxo-2-(trifluor-
omethyl)carboxylates
Synthesis of (2,2,2-trifluoroethyl)ketones via decarboxylation of 3-oxo-2-(trifluor-
omethyl)carboxylates.a
CF3I
O
O
O
H+
FeSO4
O
O
F3C
O
NH2
EtO
R
O
NH2
H+
R
.
H2O2
.
CF3
EtO
1c -10c
EtO
R
R
DMSO
EtO
R
1b - 10b
CF3
CF3
rt
1b 10b
-
1 h
Entry
-R
Yield/%b
Entry
-R
Yield/%c
1
2
3
4
5
6
-Me (1b)
-iPr (2b)
-nBu (3b)
-Ph (4b)
74c
83c
87c
88
1
2
3
4
5
6
-Me (1b)
-iPr (2b)
-nBu (3b)
-Ph (4b)
64
66
76
94
90
92
-tolyl (5b)
75
81
-tolyl (5b)
Cl
Cl
7
8
9
62
7
82
CF3
CF3
87
86
88
8
9
80
86
85
OMe
OMe
MeO
MeO
10
NO2
10
NO2
a
1b–10b: 0.18–2.0 mmol, conc. HCl: 2.9–3.0 mL, AcOH: 2.0–3.0 mL, 100 8C, 4–
8 h.
b
a
Enamines: 2.0 mmol, CF3I: 6.0 mmol, FeSO4: 0.6 mmol, H2O2: 4.0 mmol, DMSO:
Isolated yield.
19F NMR yield.
10 mL.
c
b
Conc. HCl: 2.0 mL, rt, 2 h.
Isolated yield.
c
(0.833 mol/L, 6.0 mL) and stirring for 2 h at room temperature,
peaks of 4b, desired product (phenyl(2,2,2-trifluoroethyl)ketone,
4c) and any other organofluorine compounds were not observed in
the 19F NMR spectrum at all. This indicated that defluorination of
yield in a similar manner to those shown in Scheme 2 and
Table 1. However, the hydrolysis of 11a did not result in ethyl
4,4,4-trifluoro-3-oxo-2-(trifluoromethyl)butanoate
11b,
but
yielded ethyl 4,4,4-trifluoro-3,3-dihydroxy-2-(trifluoromethyl)bu-
tanoate 11b0. Moreover, decarboxylation of 11a or 11b0 did not
afford 1,1,1,4,4,4-hexafluoro-2-butanone 11c, but generated
1,1,1,4,4,4-hexafluoro-2,2-butanediol 11c0 (Scheme 4). It is well
known that the addition of H2O to (perfluoroalkyl)ketones
provides gem-diols [11]. The trifluoromethyl groups in 11b and
11c are directly bound to the carbonyl carbons. Therefore, H2O
present in the reagents used in the trifluoromethylation and
decarboxylation, i.e., aqueous H2O2 and conc. HCl, caused the
hydration of 11b and 11c to the gem-diols.
4b by a base caused the decomposition of primary product of (b,b-
difluorovinyl)phenylketone to 3-oxo-3-phenylpropionic acid
[10]. Owing to the instability under basic conditions, we
investigated the use of an acid in the synthesis of (2,2,2-
trifluoroethyl)ketones. Screening of acids and other reaction
conditions revealed that decarboxylation proceeded smoothly
upon heating at 100 8C for 4–8 h in the presence of AcOH and conc.
HCl. As shown in Table 2, satisfactory yields of the (2,2,2-
trifluoroethyl)ketones were obtained from the corresponding 3-
oxo-2-(trifluoromethyl)carboxylates listed in Table 1 under the
optimized conditions.
The one-pot synthesis of 4c was examined using ethyl 3-amino-
3-phenyl-2-propenoate (4a). Conc. HCl and AcOH were added
directly to the reaction mixture, immediately after the trifluor-
omethylation of the enamine. However, the yield of 4c was poor
(28%), suggesting that DMSO was an unsuitable solvent for the
decarboxylation.
To date, a number of routes towards a-trifluoromethyl ketones,
including (2,2,2-trifluoroethyl)ketones, using various trifluoro-
methylating reagents have been reported [12]. Among them, two
radical mechanisms and an ionic mechanism have been reported
for the synthesis of (2,2,2-trifluoroethyl)ketones using CF3I. With
regard to the radical mechanisms, a trifluoromethyl radical is
generated via a photoredox reaction, either with a Ru catalyst [13]
or Et3B at ꢀ78 8C [14], which adds to silyl enol ethers or lithium
enolates, respectively. The ionic mechanism proceeds via the
oxidative addition of CF3I to Rh(I) [15]; the generated trifluor-
omethyl anion furnishes (2,2,2-trifluoroethyl)ketones upon reac-
In the reaction with ethyl 3-amino-4,4,4-trifluoro-2-butenoate,
trifluoromethylated enamine 11a was obtained in 63% isolated
tion with
a,b-unsaturated ketones. Because Fenton reagent is
inexpensive and the reaction conditions are very mild, the present
method is a promising candidate for the practical synthesis of
(2,2,2-trifluoroethyl)ketones with CF3I.
On the other hand, it is very difficult to synthesize
a-
trifluoromethyl ketones (1-substituted-(2,2,2-trifluoroethyl)ke-
tones) using this method. Thus, 3-oxocarboxylates that possess
Scheme 3. Trifluoromethylation of ethyl 3-amino-3-phenyl-2-propenoate.

4
Y. Ohtsuka et al. / Journal of Fluorine Chemistry 181 (2016) 1–6
Scheme 4. Trifluoromethylation of ethyl 3-amino-4,4,4-trifluoro-2-butenoate and decarboxylation of trifluoromethylated products (11a and 11b).
a trifluoromethyl group and another functional group such as an
alkyl moiety at the C2 position must be obtained. However, it is
impossible to obtain such 3-oxocarboxylates from enamines,
because the C2 position of an enamine must be substituted by a
functional group (Scheme 1); therefore, we could not introduce a
trifluoromethyl group at the C2 position. In addition, we were
unable to obtain C2-substituted 3-oxo-2-(trifluoromethyl)carbox-
ylates from the C2-substituted keto form of 3-oxocarboxylates via
the direct trifluoromethylation using Fenton reagent.
40 mL of EtOH and 4.81 g (25 mmol) of ethyl 3-phenylpropionate
were added, and the mixture was stirred for 2 days at 80 8C. After
the reaction was completed, MS3A was removed by filtration and
the resulting solution was concentrated in vacuo. After H2O was
added to the obtained crude mixture, the product was extracted
with ethyl acetate (70 mL ꢁ 3). The organic layer was washed with
brine and dried over anhydrous Na2SO4. Filtration of Na2SO4
followed by silica gel column chromatography (eluent hexane/
ethyl acetate = 8/1 v/v) provided ethyl 3-amino-3-phenyl-2-pro-
penoate as a pale yellow oil in 81% yield (3.88 g).
3. Conclusion
4.2.2. Synthesis of 3-oxo-2-(trifluoromethyl)carboxylates 1b–10b
The synthesis of ethyl 3-oxo-3-phenyl-2-(trifluoromethyl)pro-
pionate (4b) is described below as a representative example.
382 mg (2.0 mmol) of ethyl 3-amino-3-phenyl-2-propenoate,
2.0 mL of CF3I 3.0 mol/L DMSO solution (CF3I 6.0 mmol), 0.6 mL
of FeSO4 1.0 mol/L aqueous solution (FeSO4 0.60 mmol) and 8.0 mL
of DMSO were placed in a reaction vessel under an argon
atmosphere. Then, 0.4 mL of a 30% aqueous solution of H2O2
(H2O2 4.0 mmol) was added to the reaction mixture dropwise at a
rate of 0.040 mL/min for 10 min at room temperature. The mixture
was stirred for 1 h. Subsequently, 2.0 mL of conc. HCl was added
and the mixture was stirred for 2 h. H2O was added to the obtained
mixture and the product was extracted into diethyl ether
(70 mL ꢁ 3). The organic layer was washed with aqueous Na2S2O3
and then brine, and dried over anhydrous Na2SO4. Filtration of
Na2SO4 followed by silica gel column chromatography (eluent
hexane/ethyl acetate = 4/1 v/v) provided ethyl 3-oxo-3-phenyl-2-
(trifluoromethyl)propionate 4b as a colourless oil in 94% yield
(489 mg).
In conclusion, we demonstrated an efficient route towards 3-
oxo-2-(trifluoromethyl)carboxylates which are viable precursors
to synthetically important fluorinated compounds, by employing
enamines of 3-oxocarboxylates as substrates. The obtained 3-oxo-
2-(trifluoromethyl)carboxylates were readily converted to (2,2,2-
trifluoroethyl)ketones via decarboxylation in the presence of an
acid. The use of 3-oxo-2-(trifluoromethyl)carboxylates, 3-amino-
2-(trifluoromethyl)propenoates and (2,2,2-trifluoroethyl)ketones
as building blocks for fluorinated compounds is currently under
investigation in our laboratory.
4. Experimental
4.1. General techniques
1H, 13C and 19F NMR spectra were recorded in CDCl3 or (CD3)2SO
on a Bruker DRX-500 (13C 125 MHz) and DRX-250 (1H 250 MHz,
19F 235 MHz) using tetramethylsilane as an internal reference for
1H and 13C NMR, and fluorotrichloromethane as an external
reference for 19F NMR. The chemical shifts are expressed in ppm
4.2.3. Synthesis of trifluoromethylated enamines 1a and 4a
The synthesis of ethyl 3-amino-3-phenyl-2-(trifluoromethyl)-
2-propenoate (4a) is described below as
a representative
(d). The multiplicities are indicated by brs (broad singlet), d
example. 382 mg (2.0 mmol) of ethyl 3-amino-3-phenyl-2-
propenoate, 2.0 mL of CF3I 3.0 mol/L DMSO solution (CF3I
6.0 mmol), 0.6 mL of FeSO4 1.0 mol/L aqueous solution (FeSO4
0.6 mmol) and 8 mL of DMSO were placed in a reaction vessel
under an argon atmosphere. Then, 0.4 mL of a 30% aqueous
solution H2O2 (H2O2 0.4 mmol) was added to this reaction
mixture dropwise at a rate of 0.040 mL/min for 10 min at room
temperature. The mixture was stirred for 0.5 h. Aqueous Na2SO3
was added to the obtained mixture and the product was extracted
into diethyl ether (70 mL ꢁ 3). Then, the organic layer was
washed with brine and dried over anhydrous Na2SO4. Filtration of
Na2SO4 followed by silica gel column chromatography (eluent
hexane/ethyl acetate = 4/1 v/v) provided ethyl 3-amino-3-phe-
nyl-2-(trifluoromethyl)-2-propenoate 4a as a pale yellow solid in
93% yield (480 mg).
(doublet), t (triplet), q (quartet), quint (quintet) and m (multiplet).
The 19F NMR yields were calculated using 2,2,2-trifluoroethanol as
an internal standard. IR, high-resolution mass spectroscopy (HR–
MS) and melting point (Mp) were measured using a HORIBA FT-
720, a JMS-T100LP AccTOF LC-plus 4G and a METLLER TOLEDO
MP70 Melting Point System, respectively. IR spectra were obtained
in reflective mode. All the commercially available reagents were
used as received without purification.
4.2. Reaction procedures
4.2.1. Synthesis of 3-amino-2-propenoates
The synthesis of ethyl 3-amino-3-phenyl-2-propenoate is
described below as a representative example. 3.0 g of MS3A was
placed in a reaction vessel under an argon atmosphere. Then,

Y. Ohtsuka et al. / Journal of Fluorine Chemistry 181 (2016) 1–6
5
4a (259 mg, 1.0 mmol) was converted to 4b using 1.0 mL of
4.3.5. Ethyl 3-[3-(trifluoromethyl)phenyl]-2-(trifluoromethyl)
conc. HCl in DMSO (5.0 mL) at room temperature for 2 h in 93%
yield (243 mg).
propanoate (7b)
Pale yellow oil. 1H NMR (DMSO-d6)
d
1.07 (t, J = 7.1 Hz, 3H),
4.12–4.22 (m, 2H), 6.50 (q, JHF = 8.4 Hz, 1H), 7.83–7.90 (m, 1H),
4.2.4. Synthesis of (2,2,2-trifluoroethyl)ketones 1c–10c
8.11–8.16 (m, 1H), 8.31–8.37 (m, 1H), 8.38–8.43 (m, 1H). 13C NMR
The synthesis of phenyl(2,2,2-trifluoroethyl)ketone (4c) is
described below as a representative example. 520 mg (2.0 mmol)
of 4b was placed in a reaction vessel under an argon atmosphere.
Then, 2.0 mL of acetic acid and 2.0 mL of conc. HCl were
successively added, and the resulting mixture was stirred for 8 h
at 100 8C. After the reaction, H2O was added to the obtained
mixture and the product was extracted into diethyl ether
(70 mL ꢁ 3). Then, the organic layer was washed with brine and
dried over anhydrous Na2SO4. Filtration of Na2SO4 followed by
silica gel column chromatography (eluent hexane/ethyl ace-
tate = 8/1 v/v) provided phenyl(2,2,2-trifluoroethyl)ketone 4c as
a pale yellow solid in 88% yield (331 mg).
(DMSO-d6) d 13.6, 56.3 (q, JCF = 26.0 Hz), 62.7, 122.9 (q,
JCF = 280.0 Hz), 123.8 (q, JCF = 272.6 Hz), 125.7 (q, JCF = 3.8 Hz),
130.2 (q, JCF = 32.6 Hz), 130.7, 131.2 (q, JCF = 3.5 Hz), 132.9, 136.0
(q, JCF = 1.0 Hz), 162.6 (q, JCF = 2.9 Hz), 187.6. 19F NMR (DMSO-d6)
d
ꢀ61.4 (s, 3F), ꢀ63.1 (t, JFH = 8.4 Hz, 3F). IR (neat) 1751, 1705, 1614,
1331, 1234, 1124, 1074, 1024, 810, 692, 652 cmꢀ1. HR–MS: calcd
for C13H9O3F6 (M–H): 327.0461; found: 327.0503.
4.3.6. Ethyl 3-(3-methoxyphenyl)-2-(trifluoromethyl)propanoate
(8b)
Colorless oil. 1H NMR (DMSO-d6)
d 1.09 (t, J = 7.1 Hz, 3H), 3.83
(s, 3H), 4.17 (t, J = 7.1 Hz, 2H), 6.33 (q, JHF = 8.6 Hz, 1H), 7.29–7.34
(m, 1H), 7.48–7.58 (m, 2H), 7.64–7.69 (m, 1H). 13C NMR (DMSO-
4.3. Characterization of products
d6)
122.9 (q, JCF = 280.0 Hz), 130.5, 136.6, 159.9, 163.0 (q, JCF = 2.9 Hz),
188.2. 19F NMR (DMSO-d6)
1695, 1599, 1431, 1344, 1255, 1225, 1151, 1109, 1022, 787,
683 cmꢀ1. HR–MS: calcd for C13H14O3F3 (M+H): 291.0839; found:
291.0853.
d 13.8, 55.7, 56.1 (q, JCF = 25.8 Hz), 62.5, 113.6, 121.2, 121.7,
Following 11 compounds are new and Mp (in the case of solid),
NMR (1H, 13C and 19F), IR and HR–MS data of them are shown
below. The other compounds are known and the characterization
data of 1H, 13C and 19F NMR agreed with the reported data.
d
ꢀ63.1 (d, JFH = 8.6 Hz). IR (neat) 1747,
4.3.1. Ethyl 3-amino-2-(trifluoromethyl)-2-butenoate (1a)
4.3.7. Ethyl 3-(2-methoxyphenyl)-2-(trifluoromethyl)propanoate
White solid. Mp 8C 36.4–37.7 8C 1H NMR (DMSO-d6)
d
1.17 (t,
J = 7.1 Hz, 3H), 2.11 (q, JHF = 3.2 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 8.07
(brs, 1H), 9.12 (brs, 1H). 13C NMR (DMSO-d6)
14.4, 21.3
(q, JCF = 4.6 Hz), 59.1, 85.0 (q, JCF = 31.9 Hz), 127.1 (q,
JCF = 268.3 Hz), 165.3, 167.2. 19F NMR (DMSO-d6)
(9b)
Pale yellow oil. 1H NMR (DMSO-d6)
d
1.13 (t, J = 7.1 Hz, 3H), 3.86
(s, 3H), 4.13–4.23 (m, 2H), 5.66 (q, JHF = 8.9 Hz, 1H), 7.06–7.12 (m,
1H), 7.20–7.25 (m, 1H), 7.62–7.68 (m, 1H), 7.73–7.77 (m, 1H). 13
NMR (DMSO-d6) 13.8, 55.9, 60.5 (q, JCF = 24.7 Hz), 62.3, 113.0,
121.0, 123.1 (q, JCF = 280.7 Hz), 125.0 (q, JCF = 0.9 Hz), 130.5, 136.0,
159.0, 163.0 (q, JCF = 2.9 Hz), 187.2. 19F NMR (DMSO-d6)
d
C
d
ꢀ48.6 (q,
d
JFH = 3.2 Hz). IR (neat) 3392, 1628, 1508, 1321, 1261, 1086, 1055,
1011, 951, 796, 731 cmꢀ1. HR–MS: calcd for C7H11NO2F3 (M+H):
198.0736; found: 198.0772.
d
ꢀ62.8 (d,
JFH = 8.9 Hz). IR (neat) 1743, 1685, 1599, 1485, 1298, 1227, 1159,
1103, 1020, 868, 760, 619 cmꢀ1. HR–MS: calcd for C13H14O3F3
(M+H): 291.0839; found: 291.0853.
4.3.2. Ethyl 3-amino-3-phenyl-2-(trifluoromethyl)-2-propenoate
(4a)
Pale yellow solid. Mp 61.0–62.5 8C. 1H NMR (DMSO-d6)
d
1.22 (t,
J = 7.1 Hz, 3H), 4.17 (q, J = 7.1 Hz, 2H), 7.31–7.37 (m, 2H), 7.41–7.50
(m, 3H), 8.10 (brs, 1H), 9.13 (brs, 1H). 13C NMR (DMSO-d6)
14.4,
4.3.8. Ethyl 3-(4-nitrophenyl)-2-(trifluoromethyl)propanoate (10b)
Pale yellow solid. Mp 39.1–41.7 8C. 1H NMR (DMSO-d6)
d
1.08 (t,
J = 7.1 Hz, 3H), 4.14–4.21 (m, 2H), 6.46 (q, JHF = 8.4 Hz, 1H), 8.29 (d,
J = 9.0 Hz, 2H), 8.41 (d, J = 9.0 Hz, 2H). 13C NMR (DMSO-d6)
13.7,
56.7 (q, JCF = 26.1 Hz), 62.9, 122.8 (q, JCF = 280.1 Hz), 124.4, 130.5,
139.7, 151.0, 162.5 (q, JCF = 2.8 Hz), 187.8. 19F NMR (DMSO-d6)
d
59.6, 85.8 (q, JCF = 31.4 Hz), 126.0 (q, JCF = 268.5 Hz), 127.3 (q,
JCF = 1.2 Hz), 128.3, 129.8, 137.1, 160.0 (q, JCF = 1.8 Hz), 167.3. 19F
d
NMR (DMSO-d6)
d
ꢀ47.6. IR (neat) 3392, 1597, 1520, 1487, 1282,
d
1090, 1038, 889, 781, 702 cmꢀ1. HR–MS: calcd for C12H13NO2F3
(M+H): 260.0893; found: 260.0882.
ꢀ63.0 (d, JFH = 8.4 Hz). IR (neat) 1724, 1709, 1531, 1346, 1240,
1155, 1124, 1005, 849, 685 cmꢀ1. HR–MS: calcd for C12H9NO5F3
(M+H): 304.0438; found: 304.0479.
4.3.3. Ethyl 3-amino-4,4,4-trifluoro-2-(trifluoromethyl)-2-butenoate
(11a)
4.3.9. Ethyl 4,4,4-trifluoro-3,3-dihydroxy-2-
colorless oil. 1H NMR (DMSO-d6)
d
1.21 (t, J = 7.1 Hz, 3H), 4.21
(trifluoromethyl)butanoate (11b0)
(q, J = 7.1 Hz, 2H), 9.06 (brs, 2H). 13C NMR (DMSO-d6)
87.2 (q, JCF = 35.0 Hz), 120.0 (q, JCF = 279.0 Hz), 124.1 (q,
JCF = 268.2 Hz), 150.6 (q, JCF = 34.9 Hz), 166.8. 19F NMR (DMSO-
d
14.0, 60.9,
Colorless oil. 1H NMR (DMSO-d6)
d
1.19 (t, J = 7.1 Hz, 3H), 3.85
(q, JHF = 8.7 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 7.79 (brs, 2H). 13C NMR
(DMSO-d6) 13.9, 54.9 (q, JCF = 26.2 Hz), 61.8, 92.2 (qq, JCF = 1.1,
33.0 Hz), 122.7 (q, JCF = 289.9 Hz), 123.3 (q, JCF = 280.3 Hz), 163.4
(q, JCF = 3.2 Hz). 19F NMR (DMSO-d6)
d
d6)
d
ꢀ52.3 (q, JFF = 15.4 Hz, 3F), ꢀ64.3 (q, JFF = 15.4 Hz, 3F). IR
(neat) 1682, 1620, 1269, 1165, 1111, 1036, 897, 796, 733,
679 cmꢀ1. HR–MS: calcd for C7H8NO2F6 (M+H): 252.0459; found:
252.0488.
d
ꢀ61.0 (m, 3F), ꢀ82.5 (q,
JFF = 4.1 Hz, 3F). IR (neat) 1726, 1338, 1169, 1074, 1018, 897, 868,
719 cmꢀ1. HR–MS: calcd for C7H7O4F3 (M–H): 269.0254; found:
269.0254.
4.3.4. Ethyl 3-oxo-2-(trifuoromethyl)heptanoate (4b)
Pale yellow oil. 1H NMR (DMSO-d6)
(t, J = 7.1 Hz, 3H), 1.19–1.30 (m, 2H), 1.43–1.52 (m, 2H), 2.62–2.69
(m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 5.36 (q, JHF = 9.0 Hz, 1H). 13C NMR
d
0.84 (t, J = 7.3 Hz, 3H), 1.20
4.3.10. (2,2,2-trifluoroethyl)[3-(trifluoromethyl)phenyl]ketone (7c)
White solid. Mp 44.6–45.8 8C. 1H NMR (DMSO-d6)
d
4.53 (q,
JHF = 10.8 Hz, 2H), 7.78–7.85 (m, 1H), 8.04–8.10 (m, 1H), 8.24–8.30
(m, 2H). 13C NMR (DMSO-d6)
42.1 (q, JCF = 26.9 Hz), 123.9 (q,
(DMSO-d6)
d
13.6, 13.7, 21.4, 24.8, 42.4, 60.1 (q, JCF = 25.7 Hz), 62.4,
d
122.6 (q, JCF = 279.6 Hz), 162.7 (q, JCF = 3.0 Hz), 197.7. 19F NMR
JCF = 272.6 Hz), 125.0 (q, JCF = 3.8 Hz), 125.1 (q, JCF = 276.2 Hz),
129.8 (q, JCF = 32.5 Hz), 130.4, 130.5 (q, JCF = 3.6 Hz), 132.4, 136.5
(DMSO-d6)
d
ꢀ63.4 (d, JFH = 9.0 Hz). IR (neat) 1755, 1730, 1468,
1373, 1346, 1252, 1161, 1113, 1024, 843, 688 cmꢀ1. HR–MS: calcd
for C10H16O3F3 (M+H): 241.1046; found: 241.1071.
(q, JCF = 1.9 Hz), 190.5 (q, JCF = 2.7 Hz). 19F NMR (DMSO-d6)
(t, JFH = 10.8 Hz, 3F), ꢀ61.2 (s, 3F). IR (neat) 1707, 1371, 1329, 1275,
d
ꢀ61.1

6
Y. Ohtsuka et al. / Journal of Fluorine Chemistry 181 (2016) 1–6
1207, 1124, 1101, 930, 804, 692, 621 cmꢀ1. HR–MS: calcd for
10H5OF6 (M–H): 255.0245; found: 255.0235.
(b) T. Yokozawa, T. Nakai, N. Ishikawa, Tetrahedron Lett. 25 (1984) 3991–
3994;
(c) T. Ishihara, M. Kuroboshi, K. Yamaguchi, Y. Okada, J. Org. Chem. 55 (1990)
3107–3114;
C
4.3.11. 1,1,1,4,4,4-Hexafluoro-2,2-butanediol (11c0)
Colorless oil. 1H NMR (DMSO-d6)
2.69 (q, JHF = 11.0 Hz, 2H),
7.38 (s, 2H). 13C NMR (DMSO-d6)
39.3 (q, JCF = 27.6 Hz), 91.2
(qq, JCF = 2.9, 32.3 Hz), 123.6 (q, JCF = 289.0 Hz), 125.4 (q,
(d) M. Kuroboshi, T. Ishihara, Bull. Chem. Soc. Jpn. 63 (1990) 1191–1195;
(e) Y. Itoh, M. Yamanaka, K. Mikami, Org. Lett. 5 (2003) 4807–4809;
(f) Y. Itoh, M. Yamanaka, K. Mikami, J. Am. Chem. Soc. 126 (2004) 13174–
13175.
d
d
[8] T. Sasada, F. Kobayashi, N. Sakai, T. Konakahara, Org. Lett. 11 (2009) 2161–
2164.
[9] N. Shibata, S. Suzuki, T. Furukawa, H. Kawai, E. Tokunaga, Z. Yuan, D. Cahard,
Adv. Synth. Catal. 353 (2011) 2037–2041.
JCF = 276.8 Hz). 19F NMR (DMSO-d6)
d
ꢀ59.0 (m, 3F), ꢀ84.4 (q,
JFH = 3.4 Hz, 3F). IR (neat) 1265, 1182, 1147, 1080, 991 cmꢀ1. HR–
[10] (a) D.C. England, J. Org. Chem. 46 (1981) 147–153;
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2219.
MS: calcd for C4H3O2F6 (M–H): 197.0037; found: 197.0016.
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