Rhodium-catalyzed α-fluoroalkylation reaction of ketones using silyl enol ethers

Article abstract of DOI:10.1016/j.jfluchem.2007.08.013

The treatment of silyl enol ethers with fluoroalkyl halides (R_f-X) in the presence of RhCl(PPh₃)₃ gave α-fluoroalkylated ketones. It seems that a rhodium complex derived from the silyl enol ether and RhCl(PPh₃)<

Full text of DOI:10.1016/j.jfluchem.2007.08.013

Journal of Fluorine Chemistry 129 (2008) 51–55
www.elsevier.com/locate/fluor
Rhodium-catalyzed a-fluoroalkylation reaction of ketones
using silyl enol ethers
Kazuyuki Sato, Makoto Higashinagata, Takashi Yuki, Atsushi Tarui,
*
Masaaki Omote, Itsumaro Kumadaki, Akira Ando
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Received 10 August 2007; received in revised form 29 August 2007; accepted 29 August 2007
Available online 1 September 2007
Abstract
The treatment of silyl enol ethers with fluoroalkyl halides (Rf–X) in the presence of RhCl(PPh3)3 gave a-fluoroalkylated ketones. It seems that a
rhodium complex derived from the silyl enol ether and RhCl(PPh3)3 played an important role for the oxidative addition of fluoroalkyl halides and
the reductive elimination of the product.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Fluorine; Rhodium; Silyl enol ethers; a-Fluoroalkylation
1. Introduction
We recently tried to apply this methodology to fluoroalk-
ylzinc reagents and found a novel a-trifluoromethylation [5] or
a-fluoroalkylation [6] of a, b-unsaturated ketones (1) by using
Et2Zn and RhCl(PPh3)3 (Wilkinson’s catalyst) (Scheme 1). In
general, the treatment of ketones and alkylhalides (R–X) with a
base lead to the corresponding a-alkylated ketones. However, it
is difficult to synthesize a-fluoroalkylated ketones by treating
ketones with fluoroalkyl halides (Rf–X: 2) in the presence of a
base because the halogen of 2 has a partial positive charge due
to the strong electron negativity of fluorine, and it cannot work
as a leaving group [7] So, our a-fluoroalkylation reactions are
valuable reactions.
Fluorinatedcompoundshave significantly interestingfeatures
in the field of bioactive materials as medicine or agricultural
chemicals and functional materials as polymers or liquid crystals
[1]. However, it is difficult to synthesize the fluorinated
compounds for the reason that they have unusual features
compared with typical organic compounds. Although many
reports have been published on the syntheses of fluorinated
compounds, the development of a more efficient methodology is
still desired to satisfy the increasing demands [2].
On the other hand, transition metal catalyzed transforma-
tions are playing an important role in organic synthesis. Among
them, there are a lot of reactions using a rhodium catalyst, such
as catalytic reduction, carbonylation and metathesis [3].
Furthermore, recently, rhodium-catalyzed 1,4-addition reaction
of organoboronic acids, organostannanes or organosilanes to a,
b-unsaturated carbonyl compounds has also been reported [4].
The mechanism of these reactions was illustrated that the
transmetalation with rhodium catalyst and organometallics is
followed by 1,4-addition of the rhodium compounds to enones
to form rhodium enolates.
As an expansion of our a-fluoroalkylation reaction, we
attempted to use silyl enol ethers (4) instead of a, b-unsaturated
ketones expecting the formation of similar a-fluoroalkylated
ketones (5) (Scheme 2). Herein, we would like to report the
reaction of silyl enol ethers (4) with 2 in the presence of a Rh
catalyst.
2. Discussion
Recently, we have reported that the reaction of various a, b-
unsaturated ketones (1) with Rf–X (2) in the presence of Et2Zn
and Wilkinson’s catalyst gives a-fluoroalkylated ketones (3)
[5,6]. In this reaction, it seems that a rhodium enolate (6)
derived from 1 and Rh hydride complex played an important
* Corresponding author. Tel.: +81 72 866 3140; fax: +81 72 850 7020.
E-mail address: aando@pharm.setsunan.ac.jp (A. Ando).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.08.013

52
K. Sato et al. / Journal of Fluorine Chemistry 129 (2008) 51–55
Scheme 1.
Fig. 2. Expected mechanism of Rh-catalyzed a-fluoroalkylation of ketone silyl
enol ethers.
Scheme 2.
found that the best yield of a product was obtained under the
reflux with 10 mol% of RhCl(PPh3)3 in the 1,4-
dioxane.(Table 1) However, further investigations showed that
the product was not the objective product (5a) but a
dehydrofluorinated product (8a).
Next, we examined the reaction with various silyl enol ethers
as shown in Table 2. The reaction proceeded with aliphatic,
aromatic, cyclic or acyclic substrates, although the yield was
decreased with crowded substrates (entries 1–7). In this
reaction, most substrates gave the dehydrofluorinated product
(8). We thought that the acidity of the hydrogen atom was
increased by the electronic effects of the neibouring carbonyl
and Rf groups, and that HF was easily eliminated from 5.
Furthermore, it was found that the dehydrofluorination
occurred during the purification with silica gel column
Fig. 1. Reaction mechanism of Rh-catalyzed a-fluoroalkylation of a,b-unsa-
turated ketones.
role for the oxidative addition and the reductive elimination of 2
(Fig. 1).
So, we expected that a-fluoroalkylated ketones (5) could be
obtained via a similar rhodium enolate (7), if silyl enol ethers
(4) were used for the reaction instead of 1. In other words, we
expected the generation of 7 by using transmetalation of 4 with
a Rh catalyst (Fig. 2).
1
chromatography. Namely the H NMR of the crude mixture
didn’t show the peak of the olefinic proton before purification in
entry 7. In order to prove this speculation, the crude 5g was
stirred with the silica gel in the same elution solvent
(Et2O:hexane = 5:95), then formation of the dehydrofluori-
First, we examined the reaction condition by using the
trimethylsilyl enol ether (4a) derived from cyclohexanone with
C10F21–I (2a). From the examination of various conditions, we
1
nated product (8g) was soon confirmed on GLC and H NMR
measurement.
Table 1
Examination of reaction conditions
Entry
Rh Catalyst
Ammount of
Rh (mol%)
Time (h)
Solvent
Yielda of 8a (%)
1
2
3
4
5
6
RhCl(PPh3)3
Rh(acac)(CO)2
Rh4(CO)12
[RhCl(cod)]2
[RhCl(nbd)]2
None
2
15
17
24
23
23
15
THF
THF
THF
THF
THF
THF
10
2
12
2
12
2
No reaction
No reaction
No reaction
2
None
7
8
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
2
24
24
18
21
22
20
21
24
CH3CN
13
10
16
6
2
CH2Cl2
9
2
Toluene
10
11
12
13
14
2
Et2O
2
DME
Trace
25
39
42
2
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
10
20
a
Isolated yield.

K. Sato et al. / Journal of Fluorine Chemistry 129 (2008) 51–55
53
Table 2
Application to the various silyl enol ethers
Entry
4
Product
8a
Yield (%)a
1
2
39
8b
28b
3
8c
37c
4
5
5d
5e
32
46
6
7
5f
13
8g
53c
8
9
8g
8g
8g
44c
43c
14c
10
11
8g
20c
a
Isolated yield.
b
2:1 mixture of E/Z products.
c
Z-form was only obtained.
Table 3
Application to the several perfluoroalkyl iodides
On the other hand, the dehydrofluorination was not found in
entries 4–6. This might mean that the methyl group on the a-
carbon decreased the acidity of a-hydrogen by the electronic
effect or the steric effect. Next, we examined the effect of silyl
group as shown in entries 7–11. Also in these cases, the steric
hindrance affected the yields.
Entry
Rf–I
Product
Yield (%)a
1
CF3(CF2)9–I 2a
CF3(CF2)3–I 2b
CF3–I 2c
8g
10b
9c
53
37c
32
70
Finally, we examined the reaction with several fluoroalkyl
halides (2) (Table 3). The reaction proceeded with all
fluoroalkyl halides examined. Interestingly, perfluoroisopropyl
iodide (2d) and perfluorobenzyl iodide (2e) gave the
corresponding products in good yields as shown in entries 4
and 5. These results might suggest that the oxidative addition
onto rhodium enolate (7) and/or the reductive elimination from
rhodium complex occurs more easily by the longer carbon–
iodine bond owing to the strong electron negativity of the large
fluoroalkyl chains. On the other hand, the reaction of
perfluorobutyl iodide (2b) and trifluoroiodomethane (2c)
resulted in poor yields (entries 2 and 3). We thought that 2b
or 2c might be gradually lost from the reaction system ahead of
the oxidative addition to the rhodium enolate (7) under the
reflux condition of 1,4-dioxane, even if a sealed tube was used.
2b
3b
4b
11dd
5
10e
65c
a
Isolated yield.
b
c
In sealed tube.
Z-form was only obtained.
d
was obtained.

54
K. Sato et al. / Journal of Fluorine Chemistry 129 (2008) 51–55
3. Conclusion
4.3.1.2. 4-tert-Butyl-2-(perfluorodecylidene)cyclohexan-1-one
(8b) (minor). Colorless crystals; M.p. 45.0–46.0 8C; 1H NMR
(CDCl3) d: 0.97 (9H, s), 1.56–1.70 (2H m), 2.00–2.10 (1H, m),
2.12–2.21 (1H, m), 2.45–2.56 (1H, m), 2.60–2.67 (1H, m),
3.13–3.20 (1H, m); 19F NMR (600 MHz, CDCl3) d: À64.17 (1F,
m), À63.30 (2F, t, J = 12.9 Hz), À59.89 (2F, m), À59.70 to
À58.25 (10F, m), À51.75 to À51.10 (1F, m), À50.60 to À49.95
(1F, m), À17.99 (3F, t, J = 10.3 Hz); MS m/z: 652 (M+); HRMS
Calcd. for C20H16F20O: 652.088 (M+), Found: 652.089; IR
(KBr) cmÀ1: 2980, 1724, 1678, 1216, 1156.
We could obtain a-perfluoroalkylated ketones or their
dehydrofluorination products by the reaction of silyl enol
ethers with perfluoroalkyl halides in moderate yields. We
unfortunately have not clarified the mechanism yet, because
the possible mechanisms were remained. However, it is no
wonder that the rhodium catalyst played an important role, the
reason why this reaction did not proceed without the Rh
catalyst at all.
4. Experimental
4.3.1.3. 4-tert-Butyl-2-(perfluorodecylidene)cyclohexan-1-one
(8b) (major). Colorless crystals; M.p. 43.0–44.0 8C; 1H NMR
(CDCl3) d: 0.940 (9H, s), 1.52–1.65 (2H, m), 2.00–2.20 (2H,
m), 2.41–2.54 (1H, m), 2,64–2.71 (1H, m), 2.98–3.06 (1H, m);
19F NMR (600 MHz, CDCl3) d: À63.35 to À63.20 (2F, m),
À60.49 (2F, m), À59.88 (2F, m), À59.15 to À58.75 (8F, m),
À57.74 (1F, m), À51.75 to À51.15 (1F, m), À50.85 to À50.25
(1F, m), À17.97 (3F, m); MS m/z: 652 (M+); HRMS Calcd. for
4.1. General
1
NMR and 13C NMR spectra were recorded on JNM-
GX400 spectrometers. Tetramethylsilane (TMS) was used as
an internal standard. 19F NMR spectra were recorded on
Hitachi FT-NMR R-1500 and JEOL-ECA-600SN spectro-
meters. Benzotrifluoride (BTF) was used as an internal
standard. Mass spectra were obtained on JEOL JMS-700T
spectrometers. IR spectra were recorded on Hitachi 270–30
Infrared spectrophotometer. Gas–liquid chromatography
(GLC) was carried out on a Hitachi 263-50 gas chromatograph
(column; 5% SE-30 3 mm  2 m, carrier; N2 at 30 ml/min).
Peak areas were calculated on a Shimadzu C-R5A Chroma-
topac. Melting points were measured on Yanagimoto micro-
melting point apparatus MP-S3. All the solvents were purified
by standard procedure under Ar atmosphere, and other
commercially available reagents were used without further
purification.
C20H16F20O: 652.088 (M+); Found: 652.087; IR (KBr) cmÀ1
2972, 1722, 1218, 1152.
:
4.3.1.4. (Z)-5-Fluoro-5-perfluorononyl-2,2-dimethylpent-4-
en-3-one (8c). Colorless crystals; M.p. 61.5–62.5 8C; 1H
NMR (CDCl3) d: 1.19 (9H, s), 6.46 (1H, d, J = 30.4 Hz); 19F
NMR (600 MHz, CDCl3) d: À63.34 to À63.24 (2F, m), À59.88
(4F, m), À59.15 to À58.85 (8F, m), À55.63 (2F, m), À50.45 to
À50.29 (1F, m), À17.97 (3F, t, J = 10.2 Hz); MS m/z: 598 (M+);
HRMS Calcd. for C16H10F20O: 598.041 (M+), Found: 598.040;
IR (KBr) cmÀ1: 1714, 1654, 1212, 1154.
4.3.1.5. 2-Perfluorodecylpentan-3-one (5d). Colorless crys-
tals; M.p. 60.5–61.5 8C; 1H NMR (CDCl3) d: 1.09 (3H, t,
J = 7.3 Hz), 1.36 (3H, d, J = 7.2 Hz), 2.55 (1H, dq, J = 18.8,
4.2. Typical procedure
Under an Ar atmosphere, to a solution of RhCl(PPh3)3
(92.5 mg, 0.1 mmol) and 1-iodoperfluorodecane (2a, 969.0 mg,
1.5 mmol) in 1,4-dioxane (4 mL) was added 1-phenyl-1-
trimethylsiloxyethene (4g, 0.02 mL, 1.0 mmol), then the
mixture was refluxed for 24 h. The solution was quenched
with 10% HCl, and extracted with Et2O. The Et2O layer was
washed with sat. NaCl and dried with MgSO4. The solvent was
removed in vacuo and purified by column chromatography
(SiO2, Et2O:hexane = 5:95) to give 3-fluoro-3-perfluorononyl-
1-phenylprop-2-en-1-one (8g, 330.3 mg, 53%).
7.3 Hz), 2.63 (1H, dq, J = 18.8, 7.3 Hz), 3.32–3.47 (1H, m); 19
F
NMR (600 MHz, CDCl3) d: À63.35 to À63.25 (2F, m), À59.89
(2F, m), À59.20 to À58.70 (10F, m), À57.77 (2F, m), À51.96 to
À51.82 (2F, m), À18.01 to À17.95 (3F, m); MS m/z: 604 (M+);
HRMS Calcd. for C15H9F21O: 604.032 (M+), Found: 604.032;
IR (KBr) cmÀ1: 1684, 1208, 1152.
4.3.1.6. 2-Perfluorodecyl-1-phenylpropan-1-one (5e). Color-
less crystals; M.p. 78.0–79.0 8C; 1H NMR (CDCl3) d: 1.49 (3H,
d, J = 6.8 Hz), 4.31–4.46 (1H, m), 7.49–7.98 (5H, m); 19F NMR
(600 MHz, CDCl3) d: À63.32 (2F, t, J = 14.1 Hz), À59.90 (2F,
m), À59.18 to À58.68 (10F, m), À57.83 (1F, d, J = 295.3 Hz),
À56.92 (1F, d, J = 295.3 Hz), À18.04 to À17.97 (3F, m); MS m/
z: 652 (M+); HRMS Calcd. for C19H9F21O: 652.032 (M+),
Found: 652.033; IR (KBr) cmÀ1: 1694, 1228, 1154.
4.3. Spectral data
4.3.1. Examination of various silyl enol ethers
4.3.1.1. 2-(Perfluorodecylidene)cyclohexan-1-one (8a). Col-
orless crystals; M.p. 69.5–70.5 8C; 1H NMR (CDCl3) d: 1.83–
1.92 (2H, m), 1.92–2.03 (2H, m), 2.54–2.61 (2H, m), 2.62–2.70
(2H, m); 19F NMR (600 MHz, CDCl3) d: À63.35 to À63.24 (2F,
m), À60.61 (2F, m), À59.88 (2F, m), À59.15 to À58.80 (8F, m),
À57.77 (1F, m), À51.13 to À51.03 (2F, m), À17.97 (3F, t,
J = 9.9 Hz); MS m/z: 596 (M+); HRMS Calcd. for C16H8F20O:
596.026 (M+), Found: 596.026; IR (KBr) cmÀ1: 1712, 1216,
1154.
4.3.1.7. 2-Methyl-2-perfluorodecyl-1-phenylpropan-1-one
(5f). Colorless crystals; M.p. 78.5–79.5 8C; 1H NMR (CDCl3)
d: 1.59 (6H, s), 7.39–7.63 (5H, m); 19F NMR (600 MHz,
CDCl3) d: À63.38 to À63.24 (2F, m), À59.90 (2F, m), À59.20
to À58.72 (10F, m), À53.76 (2F, m), À17.98 (3F, m); MS m/z:
666 (M+); HRMS Calcd. for C20H11F21O: 666.047 (M+),
Found: 666.047; IR (KBr) cmÀ1: 1684, 1216, 1154.

K. Sato et al. / Journal of Fluorine Chemistry 129 (2008) 51–55
55
4.3.1.8. (Z)-3-Fluoro-3-perfluorononyl-1-phenylprop-2-en-1-
one (8g). Colorless crystals; M.p. 68.0–69.0 8C; 1H NMR
(CDCl3) d: 6.76 (1H, d, J = 32.0 Hz), 7.50–7.96 (5H, m); 19F
NMR (600 MHz, CDCl3) d: À63.29 (2F, m), À59.88 (2F, m),
À59.65 (2F, m), À59.20 to À58.7 (9F, m), À55.48 to À55.36
(2F, m), À17.97 (3F, m); MS m/z: 618 (M+); HRMS Calcd. for
NMR (CDCl3) d: 6.60 (1H, d, J = 32.8 Hz), 7.49–7.99 (5H, m);
19F NMR (90 MHz, CDCl3) d: À97.43 to À96.66 (2F, m),
À85.67 (1F, tt, J = 20.7, 4.1 Hz), À75.21 to À74.44 (2F, m),
À25.18 (1F, dt, J = 32.8, 19.4 Hz); MS m/z: 316 (M+); HRMS
Calcd. for C15H6F6O: 316.032 (M+), Found: 316.033; IR (KBr)
cmÀ1: 1688, 1646, 1522, 1502, 1234, 1018, 994.
C18H6F20O: 618.010 (M+), Found: 618.009; IR (KBr) cmÀ1
1702, 1654, 1210, 1152.
:
Acknowledgments
4.3.2. Examination of some perfluoroalkyl iodides
This work was partially supported by Pfizer Award in
Synthetic Organic Chemistry, Japan. We gratefully acknowl-
edge to TOSOH F-TECH, Inc. for generous gift of CF3I.
4.3.2.1. (Z)-3-Fluoro-3-perfluoropropyl-1-phenylprop-2-en-
1-one (10b). Colorless oil; 1H NMR (CDCl3) d: 6.75 (1H, d,
J = 31.6 Hz), 7.50–7.94 (5H, m); 19F NMR (90 MHz, CDCl3)
d: À64.20 to À63.85 (2F, m), À56.62 to À56.10 (2F, m),
À50.00 to À49.05 (1F, m), À17.80 (3F, td, J = 9.1, 2.4 Hz);
MS m/z: 318 (M+); HRMS Calcd. for C12H6F8O: 318.029
(M+), Found: 318.030; IR (neat) cmÀ1: 1706, 1674, 1274,
1240, 1192, 1126.
References
´
[1] (a) M. Hudlicky, A.E. Pavlath (Eds.), Chemistry of Organic Fluorine
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4.3.2.2. 3,3,3-Trifluoro-1-phenylpropan-1-one (9c). Color-
1
less crystals; M.p. 37.0–38.0 8C; H NMR (CDCl3) d: 3.81
(2H, q, J = 10.0 Hz), 7.48–7.97 (5H, m); 13C NMR (100 MHz,
CDCl3) d: 42.04 (q, J = 28.3 Hz), 123.96 (q, J = 276.8 Hz),
128.26, 128.87, 134.15, 135.67 (q, J = 1.7 Hz), 189.63 (q,
J = 2.5 Hz); 19F NMR (60 MHz, CDCl3) d: 0.78 (3F, t,
J = 9.6 Hz); MS m/z: 188 (M+); HRMS Calcd. for C9H7F3O:
188.045 (M+), Found: 188.045; IR (KBr) cmÀ1: 1690, 1422,
1378, 1286, 1230, 1132, 1104, 758, 688, 624.
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4.3.2.3. 4,4,4-Trifluoro-3-trifluoromethyl-1-phenylbut-2-en-1-
one (11d). Colorless oil; 1H NMR (CDCl3) d: 7.41–7.43 (1H,
m), 7.53–7.90 (5H, m); 13C NMR (100 MHz, CDCl3) d: 119.94
(qq, J = 275.1, 0.9 Hz), 120.22 (qq, J = 273.9, 2.1 Hz), 124.85–
126.25 (m), 128.99, 129.12, 134.11 (q, J = 9.0 Hz), 135.07,
139.88–140.12 (m), 189.18; 19F NMR (90 MHz, CDCl3) d:
À1.79 (3F, qd, J = 6.7, 1.3 Hz), 2.73 (3F, q, J = 6.7 Hz); MS m/
z: 268 (M+); HRMS Calcd. for C11H6F6O: 268.032 (M+),
Found: 268.033; IR (neat) cmÀ1: 1688, 1386, 1286, 1222, 1172.
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4.3.2.4. (Z)-3-Fluoro-3-(pentafluorophenyl)-1-phenylprop-2-
1
en-1-one (10e). Pale yellow crystals; M.p. 98.5–99.5 8C; H