CsF-Catalyzed Fluoroacylation of Tetrafluoroethylene Using Acyl Fluorides for the Synthesis of Pentafluoroethyl Ketones

Article abstract of DOI:10.1055/s-0040-1705962

A catalytic method for the synthesis of pentafluoroethyl ketones has been developed. The cesium fluoride catalyst can be used to convert acyl fluorides into the pentafluoroethyl ketones under tetrafluoroethylene pressure without generating stoichiometric

Full text of DOI:10.1055/s-0040-1705962

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–G
special topic
A
Bond Activation in Honor of Prof. Shinji
N. Ishida et al.
Special Topic
Synthesis
CsF-Catalyzed Fluoroacylation of Tetrafluoroethylene Using Acyl
Fluorides for the Synthesis of Pentafluoroethyl Ketones
Naoyoshi Ishida
thermally
controlled
F
O
F
F
O
O
Ar
cat. CsF
Hiroaki Iwamoto
Denise Eimi Sunagawa
Masato Ohashi1
C2F5
C2F5
F
F
R
+
F
R
F
O
R
F
F
F
pentafluoroethyl
ketone
transient
intermediate
TFE
Sensuke Ogoshi*
up to 79% isolated yield
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Suita, 565-0871, Japan
ogoshi@chem.eng.osaka-u.ac.jp
Published as part of the Special Topic
Bond Activation – in Honor of Prof. Shinji Murai
SDeMeenpasaiuClrkotomergroOeesnsghptoioo@snhfcdiAhipnepmgliA.eundtghC.oohsreamkais-tur.ya,cF.japculty of Engineering, Osaka University, Suita, 565-0871, Japan
Received: 08.09.2020
Accepted after revision: 30.09.2020
Published online: 28.10.2020
compared with other organofluorine compounds, negligi-
ble global warming potential and ozone depletion potential
values.11 Therefore, TFE has been employed in the synthesis
of organofluorine compounds to prepare building blocks
such as pentafluoroethyl iodide.12 The direct use of TFE for
fluoroalkylation reactions can potentially reduce both the
number of required reaction steps and the quantity of
chemical waste produced. Several organic reactions that in-
volve the conversion of TFE into various organofluorine
compounds have been reported.13,14 Furthermore, our
group has previously reported the copper(I)-catalyzed pen-
tafluoroethylation of aryl iodides using TFE.15 Herein, we
report a cesium fluoride (CsF)-catalyzed fluoroacylation of
TFE using acyl fluorides to furnish pentafluoroethyl ke-
tones. This reaction is highly atom-economical because the
amount of chemical waste produced by the reaction is sub-
stoichiometric. Mechanistic studies revealed that at low
temperature the reaction is in equilibrium between the
pentafluoroethyl ketone and an ester bearing two penta-
fluoroethyl units. Furthermore, these studies suggest that a
high temperature would furnish the thermodynamically
favored ketone as the main product (Scheme 1c).
To obtain the desired pentafluoroethyl ketone, we opti-
mized the reaction conditions for the fluoroacylation of TFE
with acyl fluoride 1a using a pressure-tight tube (12 mL to-
tal volume) as the reaction vessel (Table 1). In 1982,
Knunyants reported an example of the perfluoroisopro-
pylation of benzoyl fluoride (1a) by bubbling hexafluoro-
propylene (HFP) through the reaction mixture in the pres-
ence of a catalytic amount of CsF.16 Conversely, only a trace
amount (<1%) of the desired pentafluoroethyl ketone 2a
was obtained when TFE was employed under otherwise
identical reaction conditions (entry 1). These results indi-
cate that HFP reacts more readily with CsF than TFE. At high
temperature (120 °C) and high TFE pressure (5.0 atm; >4.0
equiv of TFE), 2a was obtained in moderate yield (55%) with
DOI: 10.1055/s-0040-1705962; Art ID: ss-2020-f0481-st
Abstract A catalytic method for the synthesis of pentafluoroethyl
ketones has been developed. The cesium fluoride catalyst can be used
to convert acyl fluorides into the pentafluoroethyl ketones under tetra-
fluoroethylene pressure without generating stoichiometric quantities of
chemical waste. Mechanistic studies suggest that high reaction tem-
perature is crucial for the ketone to be the major product.
Key words acyl fluoride, tetrafluoroethylene, pentafluoroethyl
ketone, pentafluoroethylation, cesium fluoride, DFT calculations
Organic molecules that contain fluorine atoms have at-
tracted much attention due to their unique physical proper-
ties and bioactivity, which originate from the electronega-
tivity and atomic size of fluorine.2 Therefore, a great deal of
research has been devoted to the development of synthetic
methods that can be used to introduce fluorine atom(s) into
organic compounds.3 The pentafluoroethyl carbonyl moiety
has recently been recognized as an effective functional
group for use in pharmaceuticals and other bioactive com-
pounds (Scheme 1a).4–7 Given the utility of pentafluoroeth-
yl ketones, several stoichiometric methods for their synthe-
sis have been developed (Scheme 1b).8,9 However, these re-
actions usually require highly reactive reagents or
extremely low temperatures to prevent the reagents from
decomposing or overreacting. Although the pentafluoroeth-
ylation of acyl chlorides with a stoichiometric amount of a
pentafluoroethyl copper(I) reagent has recently been re-
ported by Grushin and co-workers,10 catalytic reactions for
the pentafluoroethyl ketone synthesis remain elusive.
Tetrafluoroethylene (TFE) is one of the most important
feedstocks for the production of fluoropolymers. Although
some organofluorine compounds are recognized as being
environmentally hazardous substances, TFE exhibits, when
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
N. Ishida et al.
Special Topic
Synthesis
try 2). However, only a trace amount of ester 3a (3%) re-
mained after an additional three hours (entry 2) and the
yield of ketone 2a had increased. This observation indicated
that ester 3a was likely to be an intermediate in this reac-
tion. A lower TFE pressure (2.5 atm) improved the yield of
the desired product (2a: 71%, 3a: 2%; entry 3). When the
catalyst loading was lowered (5 mol%), the yield of 2a de-
creased slightly and the yield of 3a increased (2a: 65%, 3a:
11%; entry 4). Upon further lowering the TFE pressure (1.5
atm), the yield of 2a also further improved (2a: 74%, 3a: 3%;
entry 5). Increasing the reaction temperature (140 °C) also
increased the reaction efficiency (2a: 82%, 3a: 0%; entry 6).
Subsequently, various alkali metal fluorides were tested;
we found that reactions with LiF or NaF showed no conver-
sion of acyl fluoride 1a (entries 7 and 8), whereas the reac-
tion with KF furnished 3a in low yield (2a: 25%, 3a: 3%; en-
try 9). The results indicate that the reactivity is enhanced
when an alkali metal fluoride with a large ionic radius is
used as catalyst. The alkali earth metal fluoride CaF2 did not
work for this reaction system (entry 10). Accordingly, we
concluded that the reaction conditions listed in Table 1, en-
try 6 are the most suitable for this fluoroacylation reaction.
With the optimized reaction conditions in hand, the flu-
oroacylation of TFE was carried out using different aromatic
acyl fluorides (Scheme 2). The reaction using benzoyl fluo-
ride (1a) on 1.0 mmol scale furnished ketone 2a in excellent
yield (95% NMR yield). The reactions using acyl fluorides 1b
and 1c, which bear phenyl or tert-butyl groups at the para-
position, respectively, showed high reactivity (2b: 75%; 2c:
78%). The gram-scale synthesis of the ketone 2b was also
applicable (2b: 69%, 1.25 g). However, sterically hindered
acyl fluorides 1d and 1e, which bear substituents at the
ortho-positions, showed lower reactivity under these con-
ditions [2d: 9% (17% NMR yield); 2e: 13% NMR yield]. The
CsF-catalyzed fluoroacylation using substrates 1f and 1g,
which bear a naphthalene moiety, furnished the pentafluo-
roethyl ketones 2f and 2g in high to moderate yield [2f:
79%; 2g: 48% (67% NMR yield)]. The CsF-catalyzed fluoro-
acylation of TFE using acyl fluorides also showed good func-
tional-group tolerance. Pentafluoroethyl ketones 2h, 2i, and
2j, which bear an ether, ester, or iodide moiety, respectively,
were obtained in moderate yield [2h: 40% NMR yield; 2i:
52% (67% NMR yield); 2j: 54%]. In the case of the reaction of
an acyl fluoride bearing an iodine atom (1j), the aryl iodide
moiety remained intact after the reaction. This result
stands in contrast to the results obtained by Grushin, where
both the acyl chloride and aryl iodide moieties reacted with
the pentafluoroethyl copper(I) nucleophile.10 Benzofuran
derivative 1k furnished ketone 2k in good yield (56%),
while acyl fluoride 1l, which bears a benzothiophene moi-
ety, generated 2l in low yield (9% NMR yield). The reactions
using the ,-conjugated acyl fluorides 1m and 1n proceed-
ed, albeit with low yields of the ketones (2m: 21% NMR
yield; 2n: 7% NMR yield). The alkyl acyl fluoride 1o did not
react under the reaction conditions (2o: <1% NMR yield).
a) Representative bioactive pentafluoroethyl ketones
O
OH
O
O
O
H
N
C2F5
C2F5
N
R
N
H
C2F5
HO
O
O
anti-infective
agent
antitumor
agent
human neutrophil
elastase Inhibitor
b) Previous work: stoichiometric synthesis of pentafluoroethyl ketones
O
R
M
+
X
C2F5
O
F
F
X = OR, NR2
M = Li, Mg
R
F
F
F
O
pentafluoroethyl
ketone
M
C2F5
+
R
X
M = Li, Ti, Cu
X = OR, Cl
c) This work: catalytic fluoroacylation of TFE using acyl fluoride
O
F
F
F
O
R
C2F5
C2F5
overreaction
cat. CsF
O
F
R
+
F
F
O
R
R
F
F
F
decomposition
F
[disfavored at high temp.]
perfluoroalkyl ester
pentafluoroethyl
ketone
TFE
Scheme 1 Synthesis of pentafluoroethyl ketones
Table 1 Optimization of the Reaction Conditions
cat. MF
TFE (X atm)
O
O
O
C2F5
Ph
Ph
C2F5
C2F5
+
Ph
F
Ph
C2F5
2a
Ph
O
C2F5
DMF
temp, 4 h
HO
1a
3a
4a
0.50 mmol
Entry
MF
mol%
X (atm) Temp (°C) Yield (%)a
2a
3ab
1
2
CsF
CsF
CsF
CsF
CsF
CsF
LiF
8
1.5
5.0
2.5
2.5
1.5
1.5
1.5
1.5
1.5
1.5
rt
120
120
120
120
140
140
140
140
140
<1
<1
10
10
5
55 (31)c
3 (34)c
3
71
65
74
82
0
2
11
3
4
5
5
6
5
0
7
5
0
8
NaF
KF
5
0
0
9
5
25
0
3
10
CaF2
5
0
a Yields were determined by 19F NMR analysis using PhCF3 as internal stan-
dard.
b The yield of ester 3a was estimated based on the consumption of two
molecules of acyl fluoride 1a.
c The reaction was conducted for 1 h.
several side products according to the 19F NMR spectrum
(entry 2). A major side product was assigned to ester 3a
bearing two pentafluoroethyl groups. Tertiary alcohol 4a
was also identified as a minor side product. Furthermore,
monitoring the mixture during the course of the reaction
indicated that, after one hour, ester 3a was present in al-
most the same amount as ketone 2a (3a: 34%; 2a: 31%; en-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
N. Ishida et al.
Special Topic
Synthesis
F
a) Stoichiometric reaction
O
O
5 mol% CsF
F
O
O
+
O
C2F5
C2F5
1.0 eq. CsF
Ar
O
F
R
C2F5
R
F
DMF, 140 °C, 4 h
+
F
F
C2F5
Ar
Ar
DMF, 80 °C, 2 h
1
1.5 atm
(>1.1 eq)
2, yield
Ph
2b
3b
0.50 mmol
(NMR yield)
Ar: 4-Ph-C6H4
1b
13% (NMR)
47% (NMR)
O
O
O
Ph
O
b) Conversion of ester 3b under high temperature conditions
O
C2F5
C2F5
C2F5
O
O
C2F5
C2F5
C2F5
Ar
20 mol% CsF
+
tBu
C2F5
Ar
Ph
Ar
F
Ar
O
DMF, 140 °C, 4 h
2a (95%)a
2b 75% (69%)b
2c 78%
2d 9% (17%)
3b
2b
76% (NMR)
1b
14% (NMR)
Ar: 4-Ph-C6H4
O
O
O
O
C2F5
C2F5
Scheme 3 Isolation and reactivity of intermediate 3b
C2F5
C2F5
iPrO
2e (13%)
2f 79%
2g 48% (67%)
2h (40%)
favored at low temperature (<80 °C) [140 °C: ΔG = +4.4
kcal/mol; 80 °C: ΔG = –3.8 kcal/mol; 25 °C: ΔG = –11.3
kcal/mol]. Comparison of the thermodynamic stability of
ester 3a revealed that the formation of 3a is also favored at
lower temperatures [140 °C: ΔG = +8.6 kcal/mol; 80 °C: ΔG =
0.0 kcal/mol; 25 °C: ΔG = –7.9 kcal/mol]. The results of these
calculations are in good agreement with the experimental
results, in which the ester 3a was detected at lower tem-
perature (Table 1, entries 2–5).
O
O
O
O
C2F5
O
S
C2F5
C2F5
C2F5
MeO
I
O
2i 52%, (67%)
2j 54%
2k 56%
2l (9%)
O
O
O
C2F5
C2F5
C2F5
MeO
F3C
2m (21%)
2n (7%)
2o (<1%)
A detailed energetic analysis indicated that any differ-
ences in the relative free energy values are strictly con-
trolled by the relative entropy (ΔS) of formation (Table 2).
The product of the relative entropy and the temperature
(TΔS) is significantly higher for ketone 2a than for alkoxide
4a_Cs and ester 3a (2a: TΔS = –18.3 to –13.8 kcal/mol;
4a_Cs: TΔS = –55.8 to –40.9 kcal/mol; 3a: TΔS = –58.9 to
–43.2 kcal/mol). This trend is consistent with the observa-
tion that the pentafluoroethylation of ketone 2a by the pen-
tafluoroethyl cesium species B, generated from TFE and CsF
(A), is a process by which one product (4a_Cs) is generated
from three components [2a + CsF (A) + TFE]. Conversely, the
pentafluoroethylation of 1a to form 2a can be regarded as a
process through which two components [2a + CsF (A)] are
generated from three components [1a + CsF (A) + TFE]. The
relative entropy change ΔΔS between alkoxide 4a_Cs and
ester 3a is relatively small because the formation of ester 3a
is a process to give two components [3a + CsF (A)] from two
components [1a + 4a_Cs]. These results suggest that higher
temperatures are essential to thermodynamically destabi-
lize the side-product 3a.
Based on the experimental and computational studies,
we would like to propose a feasible catalytic cycle for the
CsF-catalyzed fluoroacylation of TFE with acyl fluorides
(Scheme 4). The proposed catalytic reaction consists of two
catalytic cycles. The first catalytic cycle is the formation of
ketone 2 (cycle 1). Initially, the pentafluoroethyl cesium
species B, a nucleophilic intermediate, would be generated
from the reaction with CsF (A) and TFE. The resulting inter-
mediate B would then react with acyl fluoride 1 to give the
desired pentafluoroethyl ketone 2 and regenerate CsF (A).
This catalytic cycle would be the main pathway for the for-
mation of ketone 2. The second catalytic cycle is the forma-
Scheme 2 Substrate scope of the reaction. NMR yields (given in paren-
theses) were determined by 19F NMR spectroscopy using PhCF3 as inter-
nal standard. a Reaction was conducted on 1.0 mmol scale. b Reaction
was conducted on 6.0 mmol scale.
To elucidate the reaction mechanism for this CsF-cata-
lyzed fluoroacylation of TFE with acyl fluorides, a mecha-
nistic study was conducted (Scheme 3). The stoichiometric
reaction of biphenyl-4-carboxylic acid fluoride (1b) with
CsF at 80 °C for 2 hours afforded ester 3b as the major prod-
uct (47% NMR yield) and the corresponding ketone 2b in
low yield (13% NMR yield; Scheme 3a). Subsequently, ester
3b, obtained from the stoichiometric reaction, was subject-
ed to the optimized reaction conditions (Scheme 3b). When
a DMF solution of ester 3b was treated at high temperature
(140 °C) with a catalytic amount of CsF, 3b was fully con-
sumed to give the ketone 2b in high yield (2b: 76% NMR
yield). However, acyl fluoride 1b was also obtained in a low-
er yield than ketone 2b (1b: 14% NMR yield). The result sug-
gests that ester 3b, generated from the acyl fluoride
(Scheme 3), can be decomposed by the CsF catalyst to give
the desired product 2b and acyl fluoride 1b.
As the experimental study had suggested that the equi-
librium between ketone 2 and ester 3 is affected by the re-
action temperature, we investigated the temperature de-
pendence of the product selectivity based on DFT calcula-
tions.17 Table 2 shows the proposed reaction pathway and
the energetic analysis of the fluoroacylation at various tem-
peratures. Although the generation of pentafluoroethyl ke-
tone 2a is an exothermic process at 25–140 °C, the Gibbs
free energy for the formation of cesium tert-alkoxide 4a_Cs
strongly depends on the temperature. Notably, the forma-
tion of 4a_Cs is disfavored at 140 °C and only becomes more
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
N. Ishida et al.
Special Topic
Synthesis
Table 2 Temperature-Dependent Relative Gibbs Free Energies of 2a, 4a_Cs, and 3aa
TFE + A
TFE + A
A: CsF
B: CsC2F5
B
A
A
B
A
A
1a
1a
OCs
O
O
Ph C2F5
O
C2F5
C2F5
4a_Cs
Ph
Ph
C2F5
Ph
O
Ph
F
C2F5
B
B
1a
2a
3a
TFE + A
TFE + A
Temp (°C)
ΔG (TΔS) (kcal/mol)
I (1a)
III (2a)
–6.7 (–18.3)
V (4a_Cs)
VI (3a)
140
80
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
+4.4 (–55.8)
–3.8 (–48.1)
–11.3 (–40.9)
+8.6 (–58.9)
0.0 (–50.7)
–7.9 (–43.2)
–9.4 (–15.8)
25
–11.6 (–13.8)
a All calculations were carried out at the B3LYP-D3/6-311++G(d,p), SDD for Cs/SMD (DMF,  = 37.219)//B3LYP-D3/6-31+G(d,p), LanL2DZ for Cs/SMD (DMF,  =
37.219), 413.15 K levels of theory.
tion of ester 3 (cycle 2). Ketone 2 would react with B to give
the cesium alkoxide 4_Cs due to the high electrophilicity of
ketone 2. Furthermore, the resulting cesium alkoxide 4_Cs
would react with acyl fluoride 1 to give A and ester 3 as a
side product. The catalytic cycle for the formation of ester3
(cycle 2) would operate as a minor reaction pathway at low
temperatures.
ketone and ester products. A simulation of the reaction at
various temperatures revealed that the temperature-
dependent thermodynamic stability of the products and
side products is the key to providing the ketone as the main
product in high yield.
All manipulations were conducted under a nitrogen atmosphere us-
ing dry-box techniques unless otherwise noted. 1H, 13C, and 19F NMR
spectra were recorded with a Bruker Avance III 400 spectrometer. The
chemical shifts were recorded relative to residual solvent peaks
(CDCl3:  = 7.26 ppm for 1H and  = 77.0 ppm for 13C, CD3CN:  = 1.94
ppm for 1H and  = 1.3 ppm for 13C) or to external standards (,,-
trifluorotoluene (PhCF3):  = –65.4 ppm for 19F). High-resolution mass
spectrometry (HRMS) and elemental analyses were performed at the
Instrumental Analysis Center, Faculty of Engineering, Osaka Universi-
ty. Gel permeation chromatography (GPC) was performed with a Ja-
pan Analytical Industry LC9225NEXT HPLC system equipped with
JAIGEL1H and JAIGEL-2H. Medium-pressure column chromatography
was carried out with a Biotage Flash Purification System Isolera,
equipped with a 250 nm UV detector. Gas chromatography–mass
spectrometry (GC-MS) was performed with a SHIMADZU GCMS-
QP2010 SE.
F
O
O
F
F
C2F5
C2F5
O
R
R
C2F5
R
F
F
TFE
R
O
1
2
CsF
A
3
CsF
A
CsC2F5
cycle 2
cycle 1
B
O
1
OCs
C2F5
C2F5
4_Cs
R
F
F
O
R
F
F
R
C2F5
F
TFE
2
Scheme 4 A plausible reaction mechanism for the CsF-catalyzed
fluoroacylation of TFE with acyl fluorides
The synthesis and characterization of acyl fluorides are described in
the Supporting Information.
In summary, we have developed a CsF-catalyzed fluoro-
acylation of TFE using aromatic acyl fluorides to furnish a
series of pentafluoroethyl ketones. This reaction proceeds
smoothly at low TFE pressure (1.5 atm). In addition, the
functional-group tolerance of this reaction allows the syn-
thesis of various pentafluoroethyl ketones (up to 95%). The
experimental results suggest that, at low temperature, an
ester bearing two pentafluoroethyl groups is generated as a
transient intermediate. Conducting the reaction at high
temperature is essential to ensure high reaction efficiency.
Computational studies indicated that the reaction mecha-
nism is complex and includes an equilibrium between the
All commercially available reagents and solvents were used as re-
ceived unless otherwise noted. Benzoyl fluoride (1a) was purchased
from Tokyo Chemical Industry Co., Ltd. (TCI). The degassed solvents
(CH2Cl2) used in this work were commercially available. DMF was
dried over CaH2. 2-Propanol was dried over K2CO3, then CaH2. CsF, LiF,
NaF, KF and CaF2 were dried by heating at 100 °C for 2 h under re-
duced pressure.
Caution: Tetrafluoroethylene (TFE) is suspected to be carcinogenic.
The reaction mixture must be handled in a well-ventilated fume
hood. TFE can deflagrate and explode upon instantaneous pressure
changes. The pressure in the reactor can reach ca. 3.4 atm during the
reaction.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

E
N. Ishida et al.
Special Topic
Synthesis
CsF-Catalyzed Fluoroacylation of TFE with Acyl Fluorides 1; Gen-
eral Procedure
HRMS (EI): m/z [M]+ calcd for C13H13F5O: 280.0887; found: 280.0889.
Under N2 atmosphere, acyl fluoride 1 (0.500 mmol) was dissolved in
DMF (2.50 mL) as a solvent. After addition of CsF (3.8 mg, 0.025
mmol) to a pressure-tight tube as a reactor (Wilmad-LabGlass, 513-
7PVM-9; 12 mL total volume), the solution was transferred to the
tube. TFE (1.5 atm, > ca. 1.1 equiv) was then charged into the reactor
and the reaction mixture was heated at 140 °C for 4 h. After remain-
ing TFE was purged from the reactor, the reaction was quenched with
water (10 mL) and the resulting mixture was extracted with Et2O (3 ×
10 mL). The combined organic phase was dried over Na2SO4, the sol-
vents were removed under reduced pressure, and the crude material
was purified by silica gel column chromatography (hexane/EtOAc =
97:3) to give the pentafluoroethyl ketone 2. For compounds 2a, 2e,
2h, and 2l–o, we present only NMR data in this section.
Pentafluoroethyl 2-Biphenyl Ketone (2d)
The reaction was performed with acyl fluoride 1d (100 mg, 0.499
mmol). The yield of the title compound 2d (17% NMR yield) was de-
termined by the 19F NMR measurement of the crude material using an
internal standard. The title compound 2d was isolated in 9% yield as a
colorless oil (14.2 mg, 0.0473 mmol).
1H NMR (CDCl3, 400 MHz):  = 7.65 (dd, J = 7.7 Hz, 2 H), 7.50 (dd, J =
7.1 Hz, 2 H), 7.45–7.38 (m, 3 H), 7.30–7.28 (m, 2 H).
19F NMR (CDCl3, 376 MHz):  = –84.2 (s, 3 F), –120.1 (s, 2 F).
13C{1H} NMR (CDCl3, 100 MHz):  = 189.7 (t, J = 27.5 Hz), 142.8 (s),
139.6 (s), 133.3 (s), 132.5 (s), 131.0 (s), 128.8 (s), 128.6 (s), 128.3 (t, J =
2.7 Hz), 128.1 (s), 127.3 (s), 118.0 (qt, J = 287.6, 34.5 Hz, CF3), 107.2
(tq, J = 269.0, 37.3 Hz, CF2).
HRMS (EI): m/z [M]+ calcd for C15H9F5O: 300.0574; found: 300.0570.
Pentafluoroethyl Phenyl Ketone (2a)
The reaction was performed with acyl fluoride 1a (124 mg, 0.999
mmol). The title compound 2a was detected in 95% yield. The yield
was determined by the 19F NMR measurement of the crude material
using an internal standard. The product 2a could not be isolated be-
cause the ketone was easily hydrated during purification by purifica-
tion process.
Pentafluoroethyl 2,4,6-Trimethylphenyl Ketone (2e)
The reaction was performed with acyl fluoride 1e (83.1 mg, 0.500
mmol). The yield of the title compound 2e (13% NMR yield) was
determined by 19F NMR measurement of the crude material using an
internal standard.
1H NMR (CDCl3, 400 MHz):  = 8.09 (dd, J = 8.4, 1.2 Hz, 2 H), 7.71 (t,
7.4 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 2 H).
19F NMR (DMF/CDCl3, 376 MHz):  = –83.7 (s, 3 F), –122.3 (s, 2 F).
19F NMR (DMF/CDCl3, 376 MHz):  = –84.3 (s, 3 F), –118.2 (s, 2 F).
GC-MS (EI): m/z [M]+ calcd for C9H5F5O: 224.0261; found: 224.
Pentafluoroethyl 1-Naphthyl Ketone (2f)
The reaction was performed with acyl fluoride 1f (87.1 mg, 0.500
mmol). The title compound 2f was isolated in 79% yield as a yellow oil
(109 mg, 0.398 mmol).
The analytical data are in agreement with those reported previous-
ly.18
1H NMR (CDCl3, 400 MHz):  = 8.56 (d, J = 8.7 Hz, 1 H), 8.17–8.13 (m, 2
H), 7.93 (d, J = 8.0 Hz, 1 H), 7.68 (ddd, J = 7.7, 7.0, 1.5 Hz, 1 H), 7.63–
7.55 (m, 2 H).
Pentafluoroethyl 4-Biphenyl Ketone (2b)
The reaction was performed with acyl fluoride 1b (100 mg, 0.499
mmol). The title compound 2b was isolated in 75% yield as a white
solid (112 mg, 0.373 mmol). A gram-scale reaction was also per-
formed with acyl fluoride 1b (1.20 g, 6.00 mmol). The ketone 2b was
isolated in 69% yield (1.25 g, 4.16 mmol).
19F NMR (CDCl3, 376 MHz):  = –83.9 (s, 3 F), –117.2 (s, 2 F).
13C{1H} NMR (CDCl3, 100 MHz):  = 185.8 (t, J = 25.8 Hz), 135.6 (s),
133.9 (s), 130.9 (s), 130.4 (t, J = 6.1 Hz), 129.3 (s), 128.9 (s), 128.1 (s),
127.1 (s), 124.9 (s), 124.1 (s), 118.3 (qt, J = 287.3, 34.1 Hz, CF3), 107.0
(tq, J = 270.7, 36.8 Hz, CF2).
1H NMR (CDCl3, 400 MHz):  = 8.18 (d, J = 8.4 Hz, 2 H), 7.78–7.76 (m, 2
H), 7.67–7.65 (m, 2 H), 7.54–7.44 (m, 3 H).
19F NMR (CDCl3, 376 MHz):  = –84.2 (s, 3 F), –118.1 (s, 2 F).
13C{1H} NMR (CDCl3, 100 MHz):  = 182.7 (t, J = 26.7 Hz), 148.2 (s),
139.1 (s), 130.7 (t, JC–F = 3.3 Hz), 129.6 (s), 129.1 (s), 128.9 (s), 127.6
(s), 127.3 (s), 118.1 (qt, J = 286.8, 33.7 Hz, CF3), 108.8 (tq, J = 268.8,
37.2 Hz, CF2).
HRMS (EI): m/z [M]+ calcd for C13H7F5O: 274.0417; found: 274.0418.
The analytical data are in agreement with those reported previous-
ly.20
Pentafluoroethyl 2-Naphthyl Ketone (2g)
The reaction was performed with acyl fluoride 1g (87.1 mg, 0.500
mmol). The yield of the title compound 2g (67% NMR yield) was de-
termined by 19F NMR measurement of the crude material using an in-
ternal standard. The title compound 2g was isolated in 48% yield as a
yellow oil (65.8 mg, 0.240 mmol).
HRMS (EI): m/z [M]+ calcd for C15H9F5O: 300.0574; found: 300.0576.
The analytical data are in agreement with those reported previous-
ly.19
Pentafluoroethyl 4-tert-Butylphenyl Ketone (2c)
1H NMR (CDCl3, 400 MHz):  = 8.66 (s, 1 H), 8.07 (d, J = 8.7 Hz, 1 H),
8.01 (d, J = 8.2 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H),
7.69 (ddd, J = 8.3, 6.9, 1.2 Hz, 1 H), 7.61 (ddd, J = 8.3, 6.9, 1.2 Hz, 1 H).
The reaction was performed with acyl fluoride 1c (87.1 mg, 0.483
mmol). The title compound 2c was isolated in 78% yield as a colorless
oil (105 mg, 0.375 mmol).
19F NMR (CDCl3, 376 MHz):  = –84.2 (s, 3 F), –117.5 (s, 2 F).
1H NMR (CDCl3, 400 MHz):  = 8.04 (d, J = 8.7 Hz, 2 H), 7.56 (d, J = 8.7
Hz, 2 H), 1.36 (s, 9 H).
19F NMR (CDCl3, 376 MHz):  = –84.3 (s, 1 F), –118.2 (s, 1 F).
13C{1H} NMR (CDCl3, 100 MHz):  = 182.7 (t, J = 26.5 Hz), 159.8 (s),
130.2 (t, J = 3.1 Hz), 128.4 (s), 126.1 (s), 118.1 (qt, J = 286.7, 33.8 Hz,
CF3), 108.8 (tq, J = 268.7, 37.1 Hz, CF2), 35.5 (s), 30.9 (s).
13C{1H} NMR (CDCl3, 100 MHz):  = 183.0 (t, J = 26.6 Hz), 136.4 (s),
133.2 (t, JC–F = 4.5 Hz), 132.1 (s), 130.3 (s), 130.1 (s), 129.0 (s), 128.2
(s), 127.9 (s), 127.4 (s), 124.2 (s), 118.1 (qt, J = 286.8, 33.8 Hz, CF3),
108.9 (tq, J = 268.9, 37.1 Hz, CF2).
HRMS (EI): m/z [M]+ calcd for C13H7F5O; 274.0417; found: 274.0413.
The analytical data are in agreement with those reported previous-
ly.21
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
N. Ishida et al.
Special Topic
Synthesis
Pentafluoroethyl 4-Isopropoxyphenyl Ketone (2h)
(E)-4-Methoxycinnamyl Pentafluoroethyl Ketone (2m)
The reaction was performed with acyl fluoride 1h (91.1 mg, 0.500
mmol). The yield of the title compound 2h (40% NMR yield) was de-
termined by 19F NMR measurement of the crude material using an in-
ternal standard. The product 2h could not be isolated because ketone
2h was easily hydrated during purification by purification process.
The reaction was performed with acyl fluoride 1m (90.1 mg, 0.500
mmol). The yield of the title compound 2m (21% NMR yield) was de-
termined by 19F NMR measurement of the crude material using an in-
ternal standard. The product 2m could not be isolated because ketone
2m was easily hydrated during purification by purification process.
19F NMR (DMF/CDCl3, 376 MHz):  = –84.5 (s, 3 F), –117.9 (s, 2 F).
19F NMR (DMF/CDCl3, 376 MHz):  = –85.0 (s, 3 F), –126.4 (s, 2 F).
Methyl 4-(Pentafluoropropanoyl)benzoate (2i)
(E)-4-Trifluoromethylphenyl Pentafluoroethyl Ketone (2n)
The reaction was performed with acyl fluoride 1i (90.3 mg, 0.496
mmol). The yield of the title compound 2i was determined by 19F
NMR measurement of the crude material using an internal standard
(67% NMR). The title compound 3i was isolated in 52% yield as a yel-
low oil (72.5 mg, 0.257 mmol).
The reaction was performed with acyl fluoride 1n (109 mg, 0.500
mmol). The yield of the title compound 2n (7% NMR yield) was deter-
mined by 19F NMR measurement of the crude material using an inter-
nal standard.
19F NMR (DMF/CDCl3, 376 MHz):  = –65.8 (s, 3 F), –85.0 (s, 3 F),
–126.4 (s, 2 F).
1H NMR (CDCl3, 400 MHz):  = 8.19 (d, J = 8.0 Hz, 2 H), 8.14 (d, J = 8.0
Hz, 2 H), 3.98 (s, 3 H).
19F NMR (CDCl3, 376 MHz):  = –84.2 (s, 3 F), –118.5 (s, 2 F).
Funding Information
13C{1H} NMR (CDCl3, 100 MHz):  = 182.9 (t, J = 27.3 Hz), 165.6 (s),
135.9 (s), 134.0 (s), 130.1 (s), 130.0 (t, J = 3.1 Hz), 117.9 (qt, J = 286.8,
33.1 Hz, CF3), 108.5 (tq, J = 269.1, 37.3 Hz, CF2), 52.7 (s).
This work was supported by Japan Society for the Promotion of Sci-
ence (JSPS KAKENHI) grants JP16H02276, JP17H03057, JP20K15278,
HRMS (EI): m/z [M]+ calcd for C11H7F5O3: 282.0315; found: 282.0315.
and JP19J10485.JapanSocietyforth
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Pentafluoroethyl 4-Iodophenyl Ketone (2j)
Acknowledgment
The reaction was performed with acyl fluoride 1j (125 mg, 0.500
mmol). The title compound 2j was isolated by preparative HPLC in
54% yield as an orange oil (94.5 mg, 0.270 mmol).
1H NMR (CDCl3, 400 MHz):  = 7.93 (d, J = 8.7 Hz, 2 H), 7.77 (d, J = 8.6
Calculations in this study were carried out using a PC cluster for
large-scale visualization (VCC) at the Cybermedia Center of Osaka
University (Japan).
Hz, 2 H).
19F NMR (CDCl3, 376 MHz):  = –84.8 (s, 3 F), –118.9 (s, 2 F).
Supporting Information
13C{1H} NMR (CDCl3, 100 MHz):  = 182.7 (t, J = 27.1 Hz), 138.6 (s),
131.2 (t, J = 3.2 Hz), 130.2 (s), 117.9 (qt, J = 286.7, 33.5 Hz, CF3), 108.5
(tq, J = 270.3, 36.7 Hz, CF2), 104. 7 (s).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705962. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
HRMS (EI): m/z [M]+ calcd for C9H4F5IO: 349.9227; found: 349.9224.
References
2-Benzofuranyl Pentafluoroethyl Ketone (2k)
The reaction was performed with acyl fluoride 1k (82.1 mg, 0.500
mmol). The title compound 2k was isolated in 56% yield as a yellow
oil (73.9 mg, 0.280 mmol).
1H NMR (CDCl3, 400 MHz):  = 7.88 (s, 1 H), 7.80 (d, JH–H = 8.0 Hz, 1 H),
7.65–7.58 (m, 2 H), 7.39 (ddd, JH–H = 8.0, 6.6, 1.2 Hz, 1 H).
(1) New address: Department of Chemistry, Faculty of Science,
Osaka Prefecture University, Sakai, 599-8531, Japan.
(2) (a) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell:
Oxford, 2004. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Kirsch, P.
Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applica-
tions, 2nd ed; Wiley-VCH: Weinheim, 2013. (d) Wang, J.;
Sánchez-Roselló, M.; Aceña, J. L.; Del Pozo, C.; Sorochinsky, A. E.;
Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
(e) Prchalová, E.; Štěpanek, O.; Smrček, S.; Kotora, M. Future
Med. Chem. 2014, 6, 1201. (f) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.;
Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem.
Rev. 2016, 116, 422.
19F NMR (CDCl3, 376 MHz):  = –84.4 (s, 3 F), –121.6 (s, 2 F).
13C{1H} NMR (CDCl3, 100 MHz):  = 172.7 (t, 2JC–F = 27.4 Hz), 156.7 (s),
147.2 (s), 130.8 (s), 126.4 (s), 124.8 (s), 124.3 (s), 120.6 (t, JC–F = 5.5
Hz), 117.8 (qt, 1JC–F = 287.2, 2JC–F = 34.1 Hz), 112.7 (s), 108.1 (tq, 1JC–F
266.4, 2JC–F = 38.3 Hz).
=
HRMS (EI): m/z [M]+ calcd for C11H5F5O2: 264.0210; found: 264.0211.
2-Benzothiophenyl Pentafluoroethyl Ketone (2l)
(3) (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
4475. (b) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int.
Ed. 2013, 52, 8214. (c) Barata-Vallejo, S.; Lantano, B.; Postigo, A.
Chem. Eur. J. 2014, 20, 16806. (d) Yerien, D. E.; Bonesi, S.;
Postigo, A. Org. Biomol. Chem. 2016, 14, 8398.
The reaction was performed with acyl fluoride 1l (90.1 mg, 0.500
mmol). The yield of the title compound 2l (9% NMR yield) was deter-
mined by 19F NMR measurement of the crude material using an inter-
nal standard.
(4) Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V. Chem. Rev.
2015, 115, 973.
19F NMR (DMF/CDCl3, 376 MHz):  = –84.3 (s, 3 F), –119.4 (s, 2 F).
(5) Brickl, R.; Eberhardt, H.; Appel, K.-R.; Lechner, U.; Merk, W. DE
2616479, 1977.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
N. Ishida et al.
Special Topic
Synthesis
(6) Tanaka, T.; Nishimura, Y.; Shimada, Y.; Ariyoshi, M.; Kamesawa,
M.; Kimura, T.; Tanaka, T. JP 2016204361, 2016.
(12) (a) Chambers, R. D.; Musgrave, W. K. R.; Savory, J. J. Chem. Soc.
1961, 3779. (b) Petrov, V. A.; Krespan, C. G. WO 9504020, 1995.
(c) Petrov, V. A.; Krespan, C. G. J. Org. Chem. 1996, 61, 9605.
(13) For selected examples of fluoroalkylation reactions of aromatic
compounds, see: (a) Barlow, M. G.; Haszeldine, R. N.; Kershaw,
M. J. Tetrahedron 1975, 31, 1649. (b) Saijo, H.; Ohashi, M.;
Ogoshi, S. J. Am. Chem. Soc. 2014, 136, 15158. (c) Li, L.; Ni, C.;
Xie, Q.; Hu, M.; Wang, F.; Hu, J. Angew. Chem. Int. Ed. 2017, 56,
9971. (d) Ohashi, M.; Adachi, T.; Ishida, N.; Kikushima, K.;
Ogoshi, S. Angew. Chem. Int. Ed. 2017, 56, 11911. (e) Xing, B.; Li,
L.; Ni, C.; Hu, J. Chin. J. Chem. 2019, 37, 1131. (f) Andrella, N. O.;
Xu, N.; Gabidullin, B. M.; Ehm, C.; Baker, R. T. J. Am. Chem. Soc.
2019, 141, 11506.
(14) For selected examples of fluoroakylation reactions of fluorofor-
mates or acyl fluorides bearing a perfluoroalkyl moiety, see:
(a) Galimberti, M.; Fontana, G.; Resnati, G.; Navarrini, W. J. Fluo-
rine Chem. 2005, 126, 1578. (b) Fenichev, I. M.; Berenblit, V. V.;
Bispen, T. A.; Lebedev, N. V.; Moldavskii, D. D. Russ. J. Appl.
Chem. 2013, 86, 1243.
(15) Ohashi, M.; Ishida, N.; Ando, K.; Hashimoto, Y.; Shigaki, A.;
Kikushima, K.; Ogoshi, S. Chem. Eur. J. 2018, 24, 9794.
(16) Knunyants, I. L.; Igumnov, S. M. Bull. Acad. Sci. USSR, Div. Chem.
Sci. (Engl. Transl.) 1982, 31, 192; Knunyants, I. L.; Igumnov, S. M.
Akad. Nauk SSSR, Ser. Khim. 1982, 204.
(17) For details of DFT calculations of the energies and structures in
the transition states, see the Supporting Information.
(18) Jiang, X.; Meyer, D.; Baran, D.; Cortés González, M. A.; Szabó, K. J.
J. Org. Chem. 2020, 85, 8311.
(7) (a) Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burkhart, J. P.; Chen, T.
M.; Durham, S. L.; Hare, C. M.; Huber, E. W.; Janusz, M. J.; Koehl,
J. R.; Marquart, A. L.; Mehdi, S.; Peet, N. P. J. Med. Chem. 1994, 37,
4538. (b) Ogilvie, W.; Bailey, M.; Poupart, M. A.; Abraham, A.;
Bhavsar, A.; Bonneau, P.; Bordeleau, J.; Bousquet, Y.; Chabot, C.;
Duceppe, J. S.; Fazal, G.; Goulet, S.; Grand-Maître, C.; Guse, I.;
Halmos, T.; Lavallée, P.; Leach, M.; Malenfant, E.; O’Meara, J.;
Plante, R.; Plouffe, C.; Poirier, M.; Soucy, F.; Yoakim, C.; Déziel, R.
J. Med. Chem. 1997, 40, 4113.
(8) For a review of fluorinated ketones, see: (a) Bégué, J. P.; Bonnet-
Delpon, D. Tetrahedron 1991, 47, 3207. For selected examples for
the synthesis of pentafluoroethyl ketones using pentafluoro-
ethyl electrophiles, see: (b) Burton, D. J.; Headley, J. A. J. Fluorine
Chem. 1981, 18, 323. (c) Jiang, X. D.; Kakuda, K. I.; Matsukawa,
S.; Yamamichi, H.; Kojima, S.; Yamamoto, Y. Chem. Asian J. 2007,
2, 314. (d) Yamazaki, T.; Terajima, T.; Kawasaki-Taskasuka, T.
Tetrahedron 2008, 64, 2419. (e) Kelly, C. B.; Mercadante, M. A.;
Carnaghan, E. R.; Doherty, M. J.; Fager, D. C.; Hauck, J. J.;
MacInnis, A. E.; Tilley, L. J.; Leadbeater, N. E. Eur. J. Org. Chem.
2015, 4071.
(9) For a review for fluorinated organometallics, see: (a) Burton, D.
J.; Yang, Z. Y. Tetrahedron 1992, 48, 189. For selected examples
for the synthesis of pentafluoroethyl ketones using pentafluoro-
ethyl nucleophiles, see: (b) Gassman, P. G.; O’Reilly, N. J. J. Org.
Chem. 1987, 52, 2481. (c) Fujiu, M.; Hashimoto, R.; Nakamura,
Y.; Aikawa, K.; Ito, S.; Mikami, K. Chem. Eur. J. 2014, 20, 2382.
(10) Panferova, L. I.; Miloserdov, F. M.; Lishchynskyi, A.; Martínez
Belmonte, M.; Benet-Buchholz, J.; Grushin, V. V. Angew. Chem.
Int. Ed. 2015, 54, 5218.
(19) Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS Catal. 2015, 5, 5947.
(20) Fujiu, M.; Negishi, K.; Guang, J.; Williard, P. G.; Kuroki, S.;
Mikami, K. Dalton Trans. 2015, 19464.
(11) (a) Acerboni, G.; Beukes, J. A.; Jensen, N. R.; Hjorth, J.; Myhre, G.;
Nielsen, C. J.; Sundet, J. K. Atmos. Environ. 2001, 35, 4113.
(b) UNEP, 1993 Report of the Technology and Economic Assess-
ment Panel.
(21) Ichitsuka, T.; Fujita, T.; Arita, T.; Ichikawa, J. Angew. Chem. Int.
Ed. 2014, 53, 7564.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G