Radical trifluoromethylation of ketone Li enolates

Article abstract of DOI:10.1016/j.tet.2006.03.115

It has generally been believed that highly basic Li enolates cannot be applied as substrates for radical trifluoromethylation due to defluorination of the α-CF₃ product. However, Li enolates can be in fact employed for radical trifluoromethylat

Full text of DOI:10.1016/j.tet.2006.03.115

Tetrahedron 62 (2006) 7199–7203
Radical trifluoromethylation of ketone Li enolates
*
Yoshimitsu Itoh and Koichi Mikami
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Received 1 December 2005; revised 28 March 2006; accepted 30 March 2006
Available online 9 May 2006
Abstract—It has generally been believed that highly basic Li enolates cannot be applied as substrates for radical trifluoromethylation due to
defluorination of the a-CF3 product. However, Li enolates can be in fact employed for radical trifluoromethylation. Moreover, the reaction is
extremely fast and the minimum reaction time is onlyw1 s.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(silyl-to-lithium method).8 The former method could gener-
ate kinetic Li enolate and the latter could afford both kinetic
and thermodynamic enolates depending on the parent silyl
enol ether. The effect of the preparation time of the Li eno-
late was first investigated (Table 1). In the case of LDA
method, 60 min of preparation time was necessary to give
sufficient yield of the a-CF3 product (entry 3). However, lon-
ger preparation time (120 min) was not necessary (entry 4).
Without radical initiator Et3B (entry 2), no product was de-
tected and a large amount of cyclohexanone was recovered,
indicating the radical reaction mechanism. On the other
hand, in the case of silyl-to-lithium transmetallation method,
CF3 units could make a significant functional modification
of an organic molecule as a new material and medicine.1
In recent years, we have been engaged in exploring the syn-
thetic potential of a-CF3 carbonyl compounds as a new
building block for CF3 containing organic compounds.2
The a-CF3 carbonyl compounds are sensitive to basic condi-
tions and facile defluorination is always a problem in the
synthesis (Scheme 1). Only several synthetic methodologies
for introducing CF3 unit to a-position of carbonyl group
have been developed.2d,e,3–7 We have already reported the
radical trifluoromethylation of Li2e enolates. Further explo-
ration of this reaction is herein reported.
Table 1. Preparation time of the Li enolate
O
Li
Li
O
F
O
O
CF
3
R
F
LDA (1.0 eq.)
R
R
Li
1a
CF I (ca. 5 eq.)
3
3
O
THF / -78 °C
O
Et B (1.0 eq.)
X min
Decomposition
CF
3
CF
3
-78 °C / 2 h
n
TMS
2a
BuLi (1.0 eq.)
THF / 0 °C
X min
O
O
O
CF
3
R
R
1a'
Scheme 1.
Entry
Substrate
X (min)
Yield (%)a
1
1a
30
30
60
120
63
0
73
72
2. Results and discussion
2b
3
There are two methods for the preparation of the Li enolate.
One is the reaction of ketone with LDA at ꢀ78 ꢁC and the
4
5
6
7
8
1a0
15
30
60
120
77
77
74
74
n
other is the reaction of silyl enol ether with BuLi at 0 ꢁC
Keywords: Trifluoromethylation; Li enolate; Radical addition.
* Corresponding author. Tel.: +81 3 5734 2142; fax: +81 3 5734 2776;
e-mail: kmikami@o.cc.titech.ac.jp
Determined by 19F NMR using BTF as an internal standard.
The reaction was carried out without Et3B.
a
b
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.115

7200
Y. Itoh, K. Mikami / Tetrahedron 62 (2006) 7199–7203
Table 3. Radical trifluoromethylation of Li enolates prepared by LDA
method
the yields of the a-CF3 product did not change over the prep-
aration time investigated (entries 5–8, 15–120 min). This
indicates that silyl-to-lithium transmetallation is completed
within 15 min. However, 30 min was adopted to ensure that
the transmetallation was completed.
Li
O
LDA (1.0 eq.)
O
R2
1
R2
R1
THF / -78 °C / 60 min
R1
O
CF3I (ca. 5 eq.) / Et3B (1.0 eq.)
-78 °C
CF3
R1
Next, radical reaction time was investigated (Table 2). In the
case of Li enolate prepared by the LDA method, 1 h of reac-
tion time gave the product in 80% yield (entry 3). The yield
decreased when the reaction was carried out for 13 h (entry
1, 62% yield), probably due to the decomposition of the
a-CF3 product when the product was exposed to basic con-
dition for prolonged time. However, shorter reaction time
did not affect the yield; found to be ‘long’w1 s is enough to
give the a-CF3 product in 81% yield (entry 5).9 On the other
hand, with Li enolate prepared by silyl-to-lithium transme-
tallation method, the maximum yield was given at 2 h reac-
tion time (entry 7, 77%). Shorter reaction time decreases the
yield and w1 s reaction time gave only 34% of the a-CF3
product (entry 9). In order to make the reaction condition al-
most the same as that for LDA method, the reaction was car-
ried out in the presence of LDA (entry 10). However, LDA
did not affect the reaction. The difference between these
two methods is not clear. However, it can be said that 2 h
of reaction time is required for silyl-to-lithium method.
R2
3
Entrya
Substrate
Product
Reaction Yield
time
(%)b
O
O
CF3
1
w1 s
81
1a
2a
O
O
CF3
71 (67)
[73:27]
2
w1 s
1b
2b
t
t
Bu
Bu
O
O
74
[57:43]
CF
3
3
4
5
6
w1 s
w1 s
5 min
5 min
2c
1c
O
O
43 (40)
[57:43]
Ph
Ph
CF3
1d
2d
O
O
A variety of ketonic substrates were investigated using LDA
to generate Li enolate (Table 3). In the case of cyclohexa-
none (entry 1) and 4-tBu- (entry 2), 2-Me- (entry 3), and
2-Ph- (entry 4) cyclohexanones, the reactions proceeded
with extremely fast reaction rates and provided the a-CF3
products in fair to good yields. The reaction rates of cyclo-
pentanone (entry 5) and cycloheptanone (entry 6) were rela-
tively slow (5 min). For acyclic substrates (entries 7–9), the
yields were poor. Ester and amide were also investigated but
did not give the a-CF3 product at all. From the results
CF3
40
48
1e
2e
O
O
CF
3
2f
1f
O
O
O
CF
7
8
5 min
5 min
25
17
3
Ph
Ph
1g
2g
O
CF
3
Ph
Ph
1h
2h
Table 2. Investigation of the trifluoromethylation time
O
O
O
3
( )
CF
9
1 min
35
( )
( ) ( )
4
4
4
1i
LDA (1.0 eq.)
THF / -78 °C
3
2i
Li
CF I (ca. 5 eq.)
1a
3
O
60 min
a
O
a
Et3B was added in flat 15 s.
Et B (1.0 eq.)
3
CF
Determined by 19F NMR using BTF as an internal standard. The values
in ( ) refer to the yields of isolated products. The values in [ ] are the
diastereomeric ratio.
b
3
-78 °C
Y [time]
n
TMS
2a
BuLi (1.0 eq.)
THF / 0 °C
30 min
O
described above, cyclohexanone derivatives are the most
suitable substrate for this reaction system.
1a'
Entry
Substrate
Reaction time Y
Yield (%)b
Li enolates prepared by silyl-to-lithium transmetallation
method were also investigated for the most suitable cyclo-
hexanone derivatives (Table 4). a-Me- and a-Ph-cyclohexa-
nones provided the products, which bear quaternary carbon
centers attached with CF3, in fair yields (entries 2 and 3).
1
2
3
4
5
1a
13 h
2 h
1 h
1 min
w1 s
62
73
80
83
81
6
7
8
1a0
13 h
2 h
30 min
w1 s
w1 s
52
77
67
34
36
In view of asymmetric radical trifluoromethylation, several
solvents and additives were examined (Table 5). a-Ph-cyclo-
hexanone was adopted as the substrate in order to prevent the
racemization of the product. The parent Li enolate was gen-
erated by silyl-to-lithium method in the presence of DME or
TMEDA. In THF, addition of DME (entry 2) and TMEDA
9
10c
a
Et3B was added in flat 15 s.
Determined by 19F NMR using BTF as an internal standard.
In the presence of LDA.
b
c

Y. Itoh, K. Mikami / Tetrahedron 62 (2006) 7199–7203
7201
Table 4. Radical trifluoromethylation of Li enolates prepared by silyl-
to-lithium method
of (S,S)-hydrobenzoin dimethyl ether in Et2O, the product
was obtained in 39% yield with 27% ee. In tBuOMe solution,
the reaction with (ꢀ)-sparteine gave the product in 13%
yield with ꢀ44% ee. These results show the possibility of
catalytic asymmetric radical trifluoromethylation of eno-
lates.
TMS
Li
O
n
O
BuLi (1.0 eq.)
3
3
R
R
1
1
THF / 0 °C / 30 min
R
4
R
2
2
R
R
O
CF I (ca. 5 eq.) / Et B (1.0 eq.)
3
3
CF
3
3
1
R
3
In summary, we have discovered that highly basic Li
enolates can be employed for radical trifluoromethylation.
The reaction rate is extremely fast compared to the previous
radical trifluoromethylation. The direct use of Li enolates is
simpler and faster than that of Ti ate enolates or any other
previous enolate equivalents.
-78 °C / 2 h
2
R
R
Entrya
Substrate
Product
Yield (%)b
TMS
O
O
CF3
1
77
2a
1a'
TMS
O
3. Experimental
3.1. General
O
CF
3
2c
58
2j
1j
1H NMR and 13C NMR were measured on Varian Gemini
2000 (300 MHz) spectrometer and 19F NMR was measured
on Varian UNITY INOVA (400 MHz) spectrometer.
Chemical shifts of 1H NMR were expressed in parts per mil-
lion downfield from tetramethylsilane as an internal standard
(d¼0) in CDCl3. Chemical shifts of 13C NMR were
expressed in parts per million downfield from CDCl3 as an
internal standard (d¼77.0) in CDCl3. Chemical shifts of
19F NMR were expressed in parts per million downfield
from BTF as an internal standard (d¼ꢀ63.24) in CDCl3.
IR spectra were measured on JASCO FT/IR-5000 spectro-
meter. EI mass spectra were measured on Shimadzu QP-
5000 spectrometer. Analytical thin layer chromatography
(TLC) was performed on glass plates and/or aluminum
sheets pre-coated with silica gel (Merck Kieselgal 60 F254,
layer thickness 0.25 and 0.2 mm). Visualization was accom-
plished by UV light (254 nm), anisaldehyde, KMnO4, and
phosphomolybdic acid. Column chromatography was per-
formed on Merck Kieselgel 60 and KANTO Silica Gel
60N (spherical, neutral), employing hexane ethyl acetate
mixture as an eluent unless otherwise noted. THF was
distilled from benzophenone-ketyl under Ar prior to use.
All experiments were carried out under argon atmosphere
unless otherwise noted.
TMS
Ph
O
O
CF
3
3d
44 (45)
Ph
2k
1k
a
Et3B was added in flat 15 s.
Determined by 19F NMR using BTF as an internal standard. The values in
( ) refer to the yields of isolated products.
b
c
d
Silyl enol ether of a-Me-cyclohexanone consists of thermodynamic and
kinetic enol ethers (87:13).
Silyl enol ether of a-Ph-cyclohexanone consists only thermodynamic enol
ether.
(entry 3) made no significant effect. When the reaction was
carried out in Et2O solution, the a-CF3 product was obtained
only in 11% (entry 4). The reaction was accelerated by DME
(entry 5, 34% yield) or TMEDA (entry 6, 26% yield) in Et2O
solution. The product was obtained only when the TMEDA
was added though in only 9% (entry 9) in iPr2O solution. The
reaction was also accelerated in tBuOMe solution. The yield
was 5% without additive. Addition of DME (entry 11) and
TMEDA (entry 12) increased the yield to 15 and 18%, re-
spectively. When the reaction was carried out with 1.0 equiv
Table 5. Effect of the bidentate additive
3.2. General procedure: starting from ketone
TMS
Li
n
O
O
O
BuLi (1.0 eq.)
CF I (ca. 5 eq.)
3
3
-78 °C / 2 h
CF
i
3
Ph additive (1.0 eq.)
Ph Et B (1.0 eq.)
To a solution of Pr2NH (28.0 ml, 0.20 mmol) in THF
*
Ph
n
solvent
(2.0 ml) was added BuLi (126.3 ml of 1.58 M solution in
0 °C / 30 min
hexane, 0.20 mmol) at ꢀ78 ꢁC. The reaction mixture was
stirred at 0 ꢁC for 30 min and then cooled to ꢀ78 ꢁC. To
the solution was added cyclohexanone (20.7 ml, 0.2 mmol)
and the solution was stirred for 60 min at the temperature.
Then, gaseous CF3I (ca. 200 mg, ca. 1.0 mmol) was added
with a cannula. Next, a syringe, which was filled with
0.12 ml of 5 M solution of acetic acid in THF, was set to
the reaction vessel and kept untouched till quenching the
reaction. Then Et3B (0.2 ml of 1.0 M solution in hexane,
0.2 mmol) was added in flat 15 s to start the radical addition
reaction. The reaction mixture was immediately quenched
(inw1 s) by acetic acid solution, which was set beforehand,
at ꢀ78 ꢁC. After warming to room temperature, BTF (10 ml,
0.082 mmol) was added as an internal standard. The yield
was determined by 19F NMR of the crude mixture (81%).
Entry
Solvent
THF
Additive
Yield (%)
1
2
3
4
5
6
7
8
—
45a
38a
34a
11b
34a
26a
—
DME
TMEDA
—
DME
TMEDA
—
DME
TMEDA
—
DME
TMEDA
Et2O
iPr2O
—
9
9b
10
11
12
tBuMeO
5b
15b
18b
a
Yield of the isolated products.
Determined by 19F NMR using BTF as an internal standard.
b

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Y. Itoh, K. Mikami / Tetrahedron 62 (2006) 7199–7203
3.3. General procedure: starting from silyl enol ether
128.4, 128.8, 137.0, 201.6. 19F NMR (CDCl3): d ꢀ69.6 (d,
J¼7.9 Hz). IR (KBr): 3036, 2946, 2872, 1722, 1605, 1452,
1385, 1270, 1168, 1133, 1045, 761, 704, 592 cmꢀ1. EI-MS
To a solution of 1-(trimethylsilyloxy)cyclohexene (38.9 ml,
ꢂ
n
1
0.2 mmol) in THF was added BuLi (128.2 ml of 1.56 M
m/z: 242 [M+ ]. Minor isomer: H NMR (CDCl3): d 1.86–
2.28 (m, 5H), 2.37–2.52 (m, 1H), 3.12–3.30 (dq, J¼6.0,
9.3 Hz, 1H), 3.82–3.92 (distorted t, J¼6.3 Hz, 1H), 7.17–
7.43 (m, 5H). 13C NMR (CDCl3): d 20.4, 27.4, 31.3, 52.0
(q, J¼26.9 Hz), 55.1, 125.1 (q, J¼280.8 Hz), 127.4, 127.6,
129.0, 136.7, 203.5. 19F NMR (CDCl3): d ꢀ67.9 (d,
J¼9.0 Hz). IR (neat): 3066, 3032, 2954, 2878, 2364, 1725,
1603, 1584, 1499, 1454, 1390, 1332, 1274, 1183, 1141,
solution in hexane, 0.20 mmol) at 0 ꢁC and stirred for 30 min
at the temperature. Then, the reaction mixture was cooled to
ꢀ78 ꢁC. To the mixture was added gaseous CF3I (ca.
200 mg, ca. 1.0 mmol) with a cannula followed by Et3B
(0.2 ml of 1.0 M solution in hexane, 0.2 mmol). The reaction
mixture was stirred for 2 h at ꢀ78 ꢁC and then quenched
by acetic acid (0.12 ml of 5 M solution in THF) at ꢀ78 ꢁC.
After warming to room temperature, BTF (10 ml,
0.082 mmol) was added as an internal standard. The yield
was determined by 19F NMR of the crude mixture (77%).
ꢂ
698 cmꢀ1. EI-MS m/z: 242 [M+ ].
3.8. 2-Trifluoromethyl-cyclopentanone (2e)
1H NMR (CDCl3): d 1.77–2.00 (m, 1H), 2.01–2.21 (m, 2H),
2.22–2.48 (m, 3H), 2.78–2.97 (qm, J¼9.6 Hz, 1H). 13C
NMR (CDCl3): d 20.0, 24.4, 38.5, 51.1 (q, J¼26.9 Hz),
124.6 (q, J¼278.3 Hz), 209.4. 19F NMR (CDCl3): d ꢀ67.9
(d, J¼10.5 Hz). IR (neat): 2986, 2896, 2366, 2344, 1758,
3.4. 2-Trifluoromethyl-cyclohexanone (2a)
1H NMR (CDCl3): d 1.62–1.88 (m, 3H), 1.92–2.14 (m, 2H),
2.24–2.39 (m, 2H), 2.42–2.53 (m, 1H), 2.98–3.13 (m, 1H).
13C NMR (CDCl3): d 23.7, 27.1, 27.5 (q, J¼2.4 Hz), 42.2,
53.6 (q, J¼25.7 Hz), 124.6 (q, J¼279.5 Hz), 203.0. 19F
NMR (CDCl3): d ꢀ69.3 (d, 7.9 Hz). IR (neat): 2954, 2876,
2364, 1729, 1272, 1170, 1125, 1060 cmꢀ1. EI-MS m/z:
1638, 1367, 1313, 1257, 1187, 1151, 1096, 1046 cmꢀ1
.
ꢂ
EI-MS m/z: 152 [M+ ].
3.9. 2-Trifluoromethyl-cycloheptanone (2f)
ꢂ
166 [M+ ].
1H NMR (CDCl3): d 1.22–1.48 (m, 2H), 1.48–1.75 (m, 2H),
1.86–2.05 (m, 3H), 2.09–2.20 (m, 1H), 2.54–2.61 (m, 2H),
3.16–3.31 (qdd, J¼4.1, 8.9, 11.1 Hz, 1H). 13C NMR
(CDCl3): d 24.4, 24.7 (q, J¼2.4 Hz), 27.5, 29.1, 43.1, 55.5
(q, J¼24.5 Hz), 124.9 (q, J¼280.8 Hz), 205.9. 19F NMR
(CDCl3): d ꢀ69.0 (d, 9.0 Hz). IR (neat): 2940, 2866, 1721,
3.5.4-Tertiarybutyl-2-trifluoromethyl-cyclohexanone(2b)
Major isomer: 1H NMR (CDCl3): d 0.94 (s, 9H), 1.42–1.68
(m, 3H), 2.18–2.20 (m, 1H), 2.26–2.42 (m, 2H), 2.44–2.56
(m, 1H), 3.00–3.16 (m, 1H). 13C NMR (CDCl3): d 27.5,
28.1, 28.6, 32.5, 41.7, 46.1, 53.0 (q, J¼25.7 Hz), 124.6 (q,
J¼279.6 Hz), 203.2. 19F NMR (CDCl3): d ꢀ69.7 (d,
J¼7.9 Hz). IR (KBr): 2970, 2878, 1734, 1392, 1369, 1274,
ꢂ
1178, 1151, 1096 cmꢀ1. EI-MS m/z: 180 [M+ ].
3.10. 1,1,1-Trifluoro-5-phenyl-3-pentanone (2g)
ꢂ
1170, 1120, 1067 cmꢀ1. EI-MS m/z: 222 [M+ ]. Minor
isomer (isomerization was observed during isolation.
Therefore, only 19F NMR data could be shown): 19F NMR
(CDCl3): d ꢀ66.1 (d, J¼10.5 Hz).
1H NMR (CDCl3): d 2.80–3.00 (m, 4H), 3.19 (q, J¼10.2 Hz,
2H), 7.14–7.35 (m, 5H). 13C NMR (CDCl3): d 29.2, 44.9,
46.5 (q, J¼28.1 Hz), 123.5 (q, J¼277.1 Hz), 126.4, 128.3,
128.6, 140.1, 199.1. 19F NMR (CDCl3): d ꢀ62.9 (t,
J¼10.2 Hz). IR (neat): 3068, 3032, 2922, 1734, 1605,
3.6. 2-Methyl-6-trifluoromethyl-cyclohexanone (2c)
1497, 1456, 1419, 1377, 1261, 1154, 1096, 750, 700 cmꢀ1
.
Major isomer: 1H NMR (CDCl3): d 1.03 (d, J¼6.3 Hz, 3H),
1.34–1.49 (m, 1H), 1.63–1.87 (m, 2H), 1.88–2.03 (m, 1H),
2.08–2.19 (m, 1H), 2.30–2.49 (m, 2H), 2.98–3.16 (m, 1H).
13C NMR (CDCl3): d 13.8, 24.0, 28.3, 36.3, 45.9, 53.7 (q,
J¼25.7 Hz), 124.8 (q, J¼279.5 Hz), 204.6. 19F NMR
(CDCl3): d ꢀ69.8 (d, J¼8.3 Hz). IR (neat): 2942, 2874,
2366, 1731, 1456, 1392, 1332, 1272, 1170, 1137, 1123,
ꢂ
EI-MS m/z: 216 [M+ ].
3.11. 1,1,1-Trifluoro-4,4-dimethyl-5-phenyl-3-penta-
none (2h)
1H NMR (CDCl3): d 1.16 (s, 6H), 2.81 (s, 2H), 3.17 (q,
J¼9.9 Hz, 2H), 7.07 (ddd, J¼1.7, 2.1, 6.3 Hz, 2H), 7.19–
7.32 (m, 3H). 13C NMR (CDCl3): d 23.8, 41.4 (q,
J¼28.1 Hz), 45.3, 48.9, 123.9 (q, J¼277.1 Hz), 126.8,
128.2, 130.2, 136.8, 205.2. 19F NMR (CDCl3): d ꢀ63.0 (t,
J¼9.8 Hz). IR (neat): 3034, 2976, 1721, 1369, 1282, 1133,
ꢂ
1038, 832, 688 cmꢀ1. EI-MS m/z: 180 [M+ ]. Minor isomer:
1H NMR (CDCl3): d 1.11 (d, J¼6.6 Hz, 3H), 1.46–2.21 (m,
6H), 2.57–2.71 (m, 1H), 3.07–3.22 (m, 1H). 13C NMR
(CDCl3): d 15.0, 20.2, 26.9, 29.6, 34.2, 44.5, 52.3 (q,
J¼25.7 Hz), 125.2 (q, J¼280.7 Hz), 206.3. 19F NMR
(CDCl3): d ꢀ66.7 (d, J¼10.2 Hz). IR (neat): 2928, 2858,
2364, 2344, 1725, 1458, 1265, 1143, 801 cmꢀ1. EI-MS
ꢂ
1100 cmꢀ1. EI-MS m/z: 244 [M+ ].
3.12. 7-Trifluoromethyl-6-undecanone (2i)
ꢂ
m/z: 180 [M+ ].
1H NMR (CDCl3): d 0.90 (t, J¼3.9 Hz, 6H), 1.18–1.41 (m,
8H), 1.53–1.65 (m, 2H), 1.65–1.79 (m, 1H), 1.81–1.97 (m,
1H), 2.47 (dt, J¼18.0, 7.2 Hz, 1H), 2.61 (dt, J¼7.4,
18.0 Hz, 1H), 3.11–3.26 (m, 1H). 13C NMR (CDCl3):
d 13.6, 13.8, 22.4, 22.7, 25.59, 25.62, 29.0, 31.1, 43.6,
55.6 (q, J¼24.4 Hz), 124.9 (q, J¼280.7 Hz), 204.5. 19F
NMR (CDCl3): d 67.4 (d, J¼9.0 Hz). IR (neat): 2966,
3.7. 2-Phenyl-6-trifluoromethyl-cyclohexanone (2d)
1
Major isomer: H NMR (CDCl3): d 1.83–2.21 (m, 4H),
2.28–2.40 (m, 1H), 2.40–2.56 (m, 1H), 3.16–3.35 (m, 1H),
3.56–3.68 (dd, J¼5.4, 12.6 Hz, 1H), 7.11–7.17 (m, 2H),
7.25–7.40 (m, 3H). 13C NMR (CDCl3): d 24.2, 28.3, 35.6,
54.1 (q, J¼25.6 Hz), 57.8, 124.6 (q, J¼280.8 Hz), 127.4,
ꢂ
2938, 2870, 1731, 1263, 1164 cmꢀ1. EI-MS m/z: 238 [M+ ].

Y. Itoh, K. Mikami / Tetrahedron 62 (2006) 7199–7203
7203
(l) Hudlicky, M. Chemistry of Organic Fluorine Compounds,
2nd ed. Ellis Horwood: Chichester, UK, 1976.
3.13. 2-Methyl-2-trifluoromethyl-cyclohexanone (2j)
1H NMR (CDCl3): d 1.36 (s, 3H), 1.70–2.00 (m, 5H), 2.06–
2.20 (m, 1H), 2.35–2.58 (m, 2H). 13C NMR (CDCl3): d 17.7
(q, J¼2.4 Hz), 20.5, 26.4, 33.5, 39.4, 53.7 (q, J¼23.2 Hz),
126.5 (q, J¼283.2 Hz), 206.2. 19F NMR (CDCl3): d ꢀ73.6
2. (a) Itoh, Y.; Yamanaka, M.; Mikami, K. Org. Lett. 2003, 5, 4803–
4806; (b) Itoh, Y.; Yamanaka, M.; Mikami, K. Org. Lett. 2003, 5,
4807–4809; (c) Itoh, Y.; Yamanaka, M.; Mikami, K. J. Am.
Chem. Soc. 2004, 126, 13174–13175; (d) Itoh, Y.; Mikami, K.
Org. Lett. 2005, 7, 649–651; (e) Our preliminary report on the
radical trifluoromethylation of Li enolates: Itoh, Y.; Mikami,
K. Org. Lett. 2005, 7, 4883–4885.
(s). IR (neat): 2936, 2874, 1725, 1274, 1170, 1137 cmꢀ1
.
ꢂ
EI-MS m/z: 180 [M+ ].
3. Trifluoromethylation of Li enolate of hindered imides (only
exception for the use of Li enolate): (a) Iseki, K.; Nagai, T.;
Kobayashi, Y. Tetrahedron Lett. 1993, 34, 2169–2170; (b)
Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron: Asymmetry
1994, 5, 961–974. They have succeeded in trifluoromethylation
by adopting Evans oxazolidinones with bulky substituent at
a-position to suppress defluorination.
4. Perfluoroalkylation of silyl and germyl enol ethers of esters and
ketones: (a) Miura, K.; Taniguchi, M.; Nozaki, K.; Oshima, K.;
Utimoto, K. Tetrahedron Lett. 1990, 31, 6391–6394; (b) Miura,
K.; Takeyama, Y.; Oshima, K.; Utimoto, K. Bull. Chem. Soc.
Jpn. 1991, 64, 1542–1553. Perfluoroalkylation of silyl enol
ethers provided the products in good yields except for trifluoro-
methylation. Trifluoromethylation of ketone germyl enol ethers
proceeds in good yield.
3.14. 2-Phenyl-2-trifluoromethyl-cyclohexanone (2k)
1H NMR (CDCl3): d 1.63–1.86 (m, 3H), 1.89–2.00 (m, 1H),
2.12–2.25 (m, 1H), 2.31–2.40 (m, 2H), 2.91 (qd, J¼3.0,
14.4 Hz, 1H), 7.29–7.35 (m, 2H), 7.35–7.47 (m, 3H). 13C
NMR (CDCl3): d 20.2, 27.4, 29.9 (q, J¼2.4 Hz), 39.8,
62.2 (q, J¼22.0 Hz), 125.1 (q, J¼283.2 Hz), 128.7, 128.8,
129.0, 131.8, 204.7. 19F NMR (CDCl3): d ꢀ72.9 (s). IR
(neat): 3066, 2954, 2874, 1725, 1282, 1255, 1176,
ꢂ
1152 cmꢀ1. EI-MS m/z: 242 [M+ ].
References and notes
1. (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146; (b)
Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev. 2004, 104,
1–16; (c) Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.;
Shimizu, M. Organofluorine Compounds; Springer: Berlin,
Heidelberg, 2000; (d) Enantiocontrolled Synthesis of Fluoro-
Organic Compounds; Soloshonok, V. A., Ed.; Wiley: Chichester,
UK, 1999; (e) Asymmetric Fluoroorganic Chemistry, Synthesis,
Applications, and Future Directions; Ramachandran, P. V., Ed.;
American Chemical Society: Washington, DC, 2000; (f) Orga-
nofluorine Chemistry; Chambers, R. D., Ed.; Springer: Berlin,
1997; (g) Iseki, K. Tetrahedron 1998, 54, 13887–13914; (h)
Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; American Chemical
Society: Washington, DC, 1996; (i) Smart, B. E., Ed.; Chem.
Rev. 1996, 96, 1555–1824 (Thematic issue of Fluorine
Chemistry); (j) Organofluorine Chemistry: Principles and Com-
mercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C.,
Eds.; Plenum: New York, NY, 1994; (k) McClinton, M. A.;
McClinton, D. A. Tetrahedron 1992, 48, 6555–6666;
`
5. Trifluoromethylation of enamines: (a) Cantacuzene, D.;
Wakselman, C.; Dorme, R. J. Chem. Soc., Perkin Trans. 1
1977, 1365–1371; (b) Kitazume, T.; Ishikawa, N. J. Am.
Chem. Soc. 1985, 107, 5186–5191.
6. Trifluoromethylation of enol acetates: Langlois, B. R.; Laurent,
E.; Roidot, N. Tetrahedron Lett. 1992, 33, 1291–1294.
7. There are some reports of trifluoromethylation using CF+3: (a)
Yagupol’skii, L. M.; Kondratenko, N. V.; Timofeeva, G. N.
J. Org. Chem. USSR 1984, 20, 115–118; (b) Umemoto, T.;
Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156–2164; (c)
Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59, 5692–5699.
8. (a) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462–
4464; (b) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90,
4464–4465.
9. For accuracy, Et3B was added in flat 15 s and the reaction time
was counted from the time when the addition of Et3B was
completed.