Zn-mediated rhodium-catalyzed α-trifluoromethylation of ketones via silyl enol ethers

Article abstract of DOI:10.1016/j.tetlet.2008.04.030

The treatment of silyl enol ethers of ketones with CF₃-I and Et₂Zn in the presence of RhCl(PPh₃)₃ in DME gave α-trifluoromethyl ketones in good yields. The reaction can be widely applicable to silyl enol ethers

Full text of DOI:10.1016/j.tetlet.2008.04.030

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3558–3561
Zn-mediated rhodium-catalyzed a-trifluoromethylation
of ketones via silyl enol ethers
Kazuyuki Sato, 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 March 2008; revised 1 April 2008; accepted 7 April 2008
Available online 9 April 2008
Abstract
The treatment of silyl enol ethers of ketones with CF3–I and Et2Zn in the presence of RhCl(PPh3)3 in DME gave a-trifluoromethyl
ketones in good yields. The reaction can be widely applicable to silyl enol ethers derived from aliphatic or aromatic ketones. In the
absence of the rhodium catalyst, the reaction was very slow and the yields were quite poor.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fluorine; Trifluoromethyl; Rhodium; Silyl enol ether; a-Position
In the field of organofluorine chemistry, trifluoromethyl-
ation is one of the most fascinating reactions and it
has been reported by many authors.1 For example,
Kobayashi–Kumadaki’s trifluoromethylation,2 which uses
CF3Cu derived from CF3–X, and Burton’s trifluoromethyl-
ation,3 which uses CF2X2/Zn or Cd were applied to various
halides to give coupling products. CF3–TMS reacts with
carbonyl compounds in the presence of fluoride ion 4 or
CF3–I treated with tetrakis(dimethylamino)ethylene
(TDAE)5 to afford trifluoromethylated carbinols. In addi-
tion, a CF3 radical derived from CF3 –I with SmI2 or
Et3B was added to olefins.6
Although there are a number of methods for introduc-
ing a CF3 unit into an organic molecule, it is difficult to
introduce a CF3 group at the a-position of ketones. This
might be due to the fact that the polarization of
CFd3ꢀ–Idþ is opposite to that of CHd3þ–Idꢀ, which makes it
difficult to introduce CF3þ unit to enolates.7 Therefore,
there are very few reports for introducing the CF3 group
at the a-position of ketones. One of the most simple meth-
ods is the use of electrophilic trifluoromethylating reagents
such as trifluoromethyl chalcogenium salts,8 but their insol-
ubility in most organic solvents inhibits their common use
in organic synthesis. Another method is the use of radical
trifluoromethylation protocols, but these methods lead to
low yields and require special equipment or techniques in
some cases.9–11
Recently, Mikami and co-workers reported radical a-tri-
fluoromethylation of ketones using Li, Ti or Si enolates
assisted by Et3B/O2.12 Their reaction is very simple and
easily gives the a-CF3 ketones, but they have applied the
reaction only to aliphatic ketones. More recently, Cahard
et al. reported a radical a-trifluoromethylation of ammo-
nium enolates of 1,3-dicarbonyl compounds using
Na2S2O4,13 and Togni et al. reported an electrophilic
trifluoromethylation using a hypervalent iodine(III)–CF3
reagent.14 However, they did not apply their reaction to
simple ketones.
On the other hand, we recently reported a novel trifluo-
romethylation at the a-position of a,b-unsaturated ketones
(2) by treating it with CF3–I (1) and Et2Zn in the presence
of Wilkinson’s catalyst.15 This reaction proceeded
smoothly, and it could be applied to other halofluoroalkyl
compounds (Rf-X) in place of 1 to give a-R f ketones.16
*
Corresponding author. Tel.: +81 72 866 3140; fax: +81 72 866 3142.
E-mail address: aando@pharm.setsunan.ac.jp (A. Ando).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.030

K. Sato et al. / Tetrahedron Letters 49 (2008) 3558–3561
3559
Table 2
O
TMS
O
R2
R3
RhCl(PPh3)3
a-Trifluoromethylation of various silyl enol ethers of ketones
Rf
Rf
X
+
R1
1,4-dioxane
130 °C
R1
R2 R3
Rf = CF3, C10F21
C6F5-CF2, etc.
O
TMS O
R1
R2
R3
1) Et2Zn (1 equiv.), 0 ºC
4
CF3
R2 R3
R1
2) RhCl(PPh3)3 / CF3-I
DME, r.t.
4
5
Scheme 1. Rh-catalyzed a-fluoroalkylation via silyl enol ethers.
Entry
1
4
Time (h)
0.5
Yielda (%)
Ratiob
OTMS
4a
Furthermore, we recently reported a rhodium-catalyzed a-
fluoroalkylation of silyl enol ethers of ketones (4) as an
expansion of this reaction (Scheme 1).17
74 (81)c
OTMS
4b
In that work,17 we obtained the a-Rf ketones with large
Rf groups in moderate yields. However, the reaction of the
low-boiling Rf-X such as CF3–I or C4F9–I resulted in very
low yields, because the reaction only proceeded at 130 °C.
Herein, we would like to report that this Rh-catalyzed a-
trifluoromethylation of silyl enol ethers of ketones is accel-
erated tremendously by Et2Zn.
2
3
4
5
6
7
8
0.5
0.5
— (62)c,d,e
— (37)c
68d (70)c
84
[1:1]
OTMS
4c
OTMS
Thus, to solve this problem, we examined various reac-
tion conditions for a-trifluoromethylation, and found that
the addition of Et2Zn into the reaction mixture allowed the
reaction to proceed at or below room temperature and
improved the yields of a-CF3 ketones (5) tremendously
(Scheme 2). Then, we optimized the reaction conditions
extensively using 1-(trimethylsiloxy)cyclohexene (4a) as
the substrate (Table 1).18,19
0.5
0.5
0.5
0.5
0.5
0.5
[3:2]
4d
t-Bu
OTMS
4e
OTMS
4f
n-Pr
50
n-Pr
OTMS
4g
O
TMS O
R1
R2
R3
1) Et2Zn
— (84)f
[1:1]g
CF3
R2 R3
R1
2) Rh cat. / CF3-I
4
5
OTMS
4h
OTMS
Scheme 2. Zn-mediated Rh-catalyzed a-trifluoromethylation using 4.
53
Table 1
Optimization of reaction conditions
9
23
4i
TMS
O
O
1) Et2Zn (1 equiv.)
a
CF3
Isolated yield.
Diastereomeric ratio was calculated from 19F NMR.
19F NMR yield calculated from benzotrifluoride (BTF).
Total yield of diastereomeric mixture.
5c was obtained in 15% as a by-product.
The dimer (6g) was isolated in the yield in parentheses as the dia-
b
c
d
e
f
2) Rh cat. / CF3-I
4a
5a
Entry
Rh cat. (mol %)
Solv.
Time (h)
Yielda (%)
1
2
3
4
5
6
RhCl(PPh3)3 (4)
RhCl(PPh3)3 (4)
RhCl(PPh3)3 (4)
RhCl(PPh3)3 (4)
RhCl(PPh3)3 (4)
RhCl(PPh3)3 (4)
Toluene
CH2Cl2
Et2O
THF
DME
CH3CN
1
2
1
0.5
0.5
2
17
59
63
62
77
6
stereomeric mixture.
g
Diastereomeric ratio of 6g was calculated from 19F NMR.
In entries 1–8, the reaction proceeded smoothly to give
the desired a-CF3 ketone (5a) in good yields in ethereal
7
8
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (1)
DME
DME
0.5
1
81
72
TMS
9
10
11
12
13
a
None
DME
DME
DME
DME
DME
24
1
0.5
0.5
0.5
16
76
70
73
70
OTMS
O
O
Ph
Ph
[Rh(dppb)(cod)]BF4 (2)
Rh(acac)(CO)2 (2)
[RhCl(cod)]2 (1)
Rh4(CO)12 (0.5)
1) Et2Zn (1 equiv.)
CF3
CF3
OTMS
CF3
2) Rh cat. / CF3-I (1)
4g
5g
6g
19F NMR yield calculated from benzotrifluroide (BTF).
Scheme 3. Generation of the dimerization product (6g).

3560
K. Sato et al. / Tetrahedron Letters 49 (2008) 3558–3561
OTMS
R3
I
R1
I
(III)
R
Ln
O
R
Ln
R2
4
(III)
Rh
Et2Zn
CF3
CF3
Ln
Rh
R1
CF3-I
Rh(I) cat.
R3
R2
Ln
CF3
R2 R3
5
TMSO
R1
1
Ln
Scheme 4. Proposed reaction mechanism of a-trifluoromethylation.
solvents, especially, in DME. Furthermore, although other
Rh catalysts allowed the reaction to proceed in good yields
(entries 10–13), RhCl(PPh3)3 gave the best result as shown
in entry 7. On the other hand, without a rhodium catalyst,
the reaction gave the product in a very low yield as shown
in entry 9. It is clear that the Rh catalyst played an impor-
tant role in this reaction.
Next, we applied the reaction to the various substrates
(4) using the conditions of entry 7 in Table 1 and the results
are shown in Table 2.
As shown in entries 1–6, the reaction with aliphatic silyl
enol ethers proceeded smoothly to give the a-CF3 ketones
(5a–f) in moderate to good yields regardless of whether
cyclic or acyclic compounds were used. Furthermore, the
reaction could be applied to the silyl enol ethers derived
from aromatic ketones to give the desired products (5h
and 5i) (entries 8 and 9). The bulkier the substrates were,
the lower the yield became (compare entries 1 with 3, or
8 with 9). In our previous work using a,b-unsaturated
ketones,15 a product with a CF3-attached quaternary car-
bon was not obtained. This reaction overcame this prob-
lem, although the yields of products (5c and 5i) were not
so high (entries 3 and 9). On the other hand, the silyl enol
ether of acetophenone (4g) did not give product (5g), but
gave the dimerization product (6g) in a good yield as
shown in entry 7, although we do not know the reason at
this moment (Scheme 3).
Et2Zn played an important role, and we suggest that the
coordination of Rh complex to the silyl enol ether (4) gives
the a-CF3 ketones (Scheme 4).
In conclusion, we have developed a Zn-mediated rho-
dium-catalyzed a-trifluoromethylation reaction of ketones
by using silyl enol ethers. The reaction could be widely
applicable to silyl enol ethers of ketones, regardless of ali-
phatic or aromatic ketones. Furthermore, we could obtain
the products with a CF3-attached quaternary carbon easily.
Unfortunately, the reaction mechanism has not fully been
clarified. We are now carrying on a detailed examination
of the mechanism.
Acknowledgment
We gratefully acknowledge TOSOH F-TECH, Inc., for
the generous gift of CF3–I.
References and notes
1. (a) Fluorine-Containing Synthons; Soloshonok, V. A. Ed.; ACS
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We have not clarified the mechanism of the a-trifluo-
romethylation reaction yet, but we found that the forma-
tion of Zn enolate from 4 and Et2Zn has not been
formed in this a-trifluoromethylation. Because, when the
reaction was quenched by NaCl aq before the addition of
RhCl(PPh3)3 and CF3–I (1), the TMS enol ether (4a) was
detected on GLC. In addition, Mikami et al. reported that
a zinc enolate could not be observed upon the addition of
Me2Zn to a TMS enol ether by TLC or NMR analysis, and
they have explained the complexation of Me2Zn with the
TMS enol ether as d–p* complex or Lewis acid/base com-
plex.12d It might mean that a Rh enolate by transmetala-
tion does not concern in this reaction as we proposed
before. 17 Furthermore, the formation of CF3 radical by
Rh catalyst or Et2Zn also would not be a reasonable mech-
anism because of the generation of 5c from 4b as the by-
product. This result might suggests that the coordination
of Rh complex to p-bond of 4b leads the isomerization to
thermodynamically more stable 4c to give 5c.
4. For the nucleophilic trifluoromethylation by using CF3–TMS: (a)
Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.
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G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123–131.
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tetrakis(dimethylamino)ethylene (TDAE): (a) Aiet-Mohand, S.;
Takechi, N.; Medebielle, M.; Dolbier, W. R., Jr. Org. Lett. 2001, 3,
4271–4273; (b) Petrov, V. A. Tetrahedron Lett. 2001, 42, 3267–3269;
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and the reaction rate tremendously. So, it is clear that

K. Sato et al. / Tetrahedron Letters 49 (2008) 3558–3561
3561
9. For the trifluoromethylation of silyl and germyl enolates of esters and
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18. Typical procedure for 2-(trifluoromethyl)cyclohexanone (5a): To a
solution of 1-(trimethylsiloxy)cyclohexene (4a, 0.195 mL, 1 mmol) in
DME (3 mL) was added 1.0 M Et2Zn in hexane (1 mL, 1 mmol)
gradually at 0 °C and stirred for 1 h at this temperature. After the
reaction mixture was cooled to ꢀ30 °C, CF3–I (1, ca. 1 mL at ꢀ78 °C)
was introduced through a gas inlet tube, then the solution of
RhCl(PPh3)3 (18.5 mg, 2 mol %) in DME (2 mL) was added. The
reaction mixture was allowed to warm up to room temperature
and stirred for 0.5 h. The resulting mixture was quenched with 10%
HCl and extracted with Et2O. The Et2O layer was washed with sat.
NaCl and dried over MgSO4. The solvent was removed in vacuo and
the residue was purified by column chromatography (SiO2, Et2
`
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O–hexane
= 10:90) to give 2-(trifluoromethyl)cyclohexanone (5a,
123.7 mg, 74.5%).
19. Spectroscopic data of 5a: A colorless oil; 1H NMR (CDCl3) d: 1.66-
1.88 (3H, m), 1.96–2.15 (2H, m), 2.30–2.40 (2H, m), 2.46–2.54 (1H,
m), 3.02–3.14 (1H, m); 13C NMR (100 MHz, CDCl3) d: 23.80, 27.14,
27.59 (q, J = 2.5 Hz), 42.25 (q, J = 1.7 Hz), 53.66 (q, J = 25.4 Hz),
124.58 (q, J = 278.7 Hz), 202.88–202.95 (m); 19F NMR (90 MHz,
CDCl3)d: ꢀ6.01 (3F, d, J = 8.3 Hz); MS m/z: 166 (M+); HRMS calcd
for C7H9F3O: 166.061 (M+), found: 166.060; IR (neat) cmꢀ1: 2952,
2880, 1726, 1270, 1172, 1134.
15. (a) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org. Lett. 2004, 6,
4359–4361; (b) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org.
Synth. 2006, 83, 177–183.