Zincate-type enolate for radical α-trifluoromethylation

Article abstract of DOI:10.1016/j.tetlet.2007.10.041

Ketone zincate-type enolates can be applied to radical trifluoromethylation for the general synthesis of α-CF₃-ketones, cyclopentanones in particular. The addition of diethylzinc to lithium enolates is the key in the preparation of the zincate-

Full text of DOI:10.1016/j.tetlet.2007.10.041

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Tetrahedron Letters 48 (2007) 8922–8925
Zincate-type enolate for radical a-trifluoromethylation
Yuichi Tomita,a Yoshiyuki Ichikawa,a Yoshimitsu Itoh,a Kosuke Kawadab
and Koichi Mikamia,*
aDepartment of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552, Japan
bResearch Laboratory, TOSOH F-TECH Inc., 4988 Kaisei-cho, Shunan, Yamaguchi 746-0006, Japan
Received 12 May 2006; accepted 5 October 2007
Available online 11 October 2007
Abstract—Ketone zincate-type enolates can be applied to radical trifluoromethylation for the general synthesis of a-CF3-ketones,
cyclopentanones in particular. The addition of diethylzinc to lithium enolates is the key in the preparation of the zincate-type
enolates for efficient radical trifluoromethylation.
Ó 2007 Elsevier Ltd. All rights reserved.
OM
O
OM
Organofluorine compounds have attracted much inter-
est in view of their important applications in material
and biological sciences.1 One of the most important
organofluorine functionalities is trifluoromethyl (CF3)
one, which exhibits specific physical and biological
properties. a-CF3-carbonyl compounds are thus one of
the most useful synthetic building blocks for CF3-func-
tionalization. However, the defluorination of a-CF3-car-
bonyl compounds is problematic under basic conditions,
in particular.2 Defluorination is also encountered in
their preparation via radical trifluoromethylation of
metal enolates, because a-CF3-carbonyl products could
be easily deprotonated with the parent enolates and/or
bases (Scheme 1). Therefore, it had long been recognized
that highly basic conditions employing lithium enolates3
could not be applied to trifluoromethylation.4 Indeed
only few examples had been reported especially for
a-trifluoromethylation of ketones.4–8 Recently, we have
reported the radical trifluoromethylation of titanate
enolates9 with limited scope of ketonic substrates and
lithium enolates10 only applicable to cyclohexanone
derivatives; Cyclopentanone and acyclic ketones gave
only low-to-moderate yields.
CF3
CF3
CF3
R
R
R
Enolate
or
Base
M
F
O
O
R
F
Decomposition
M=Zn
R
F
F
F
M---F interaction
Scheme 1.
trifluoromethylation (Scheme 1). We report here that
the zincate-type enolates can be applied to radical tri-
fluoromethylation for the general synthesis of a-CF3-
ketones, particularly cyclopentanones.
First, several zinc enolates of cyclohexanone were exam-
ined for radical trifluoromethylation at ꢀ78 °C, using
CF3I (ca. 5 equiv), Et3B (1.0 equiv), and O2.11 The yields
were determined by 19F NMR analysis using BTF
(benzotrifluoride) as an internal standard (Fig. 1). In
the case of zinc enolate generated by Et2Zn and
a-bromo cyclohexanone,12 only a trace amount of
a-CF3-ketone was obtained (Eq. 1). The zincate-type
enolate13 could be easily formed just by adding Et2Zn
to the lithium enolate at low temperature. Upon treat-
ment of the zincate-type enolate with CF3 radical,
the a-CF3-ketone was obtained in an increased yield
(Eq. 2). To increase the reactivity of the zincate-type
enolate, the addition of 12-crown-4 was examined to
trap the lithium counter cation, giving further increased
yield up to 70% (Eq. 3).
On the basis of the longer bond length of soft late
transition metal Zn and hard F1d,2 in contrast to the
shorter bond length of hard early transition metals Ti
and F, we thought that zincate-type enolates might be
more effective than the titanate counterpart for radical
*
Corresponding author. Tel.: +81 3 5734 2142; fax: +81 3 5734
2776; e-mail: kmikami@o.cc.titech.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.041

Y. Tomita et al. / Tetrahedron Letters 48 (2007) 8922–8925
8923
ketone took place under the basic conditions for
prolonged reaction time. In stark contrast, trifluoro-
methylation of the zincate-type enolate took longer
reaction time to give the a-CF3-ketone in good yield.
O
OZnEt
Ph
O
CF3
Et2Zn (1.0 eq.)
THF
Ph
Br
Ph
(1)
(2)
CF3
-78 °C
5% (20 h)
Zinc Enolate
-
Li+
1) MeLi (1.0 eq.)
2) Et2Zn (1.0 eq.)
O
R
OZnEt2
On the basis of these results (Figs. 1 and 2), the zincate-
type enolate is likely to be the active species in the pres-
ent radical trifluoromethylation but not the lithium
enolate associated with dialkylzinc.
CF3
R
CF3
THF
OTMS
Zincate-Type Enolate
R=Ph 25% (20 h)
R=H 57% (20 h)
R
O
O
+O
Li
O
1) MeLi (1.0 eq.)
2) Et2Zn (1.0 eq.)
3)12-Cr-4 (1.0 eq.)
O
Therefore, radical trifluoromethylation of zincate-type
enolates was further studied by changing the dialkylzinc
species employed (Table 1). The use of Me2Zn was also
found to be effective in giving the good yield, after
longer period of reaction time though (58% yield, 20 h).
-
CF3
R
OZnEt2
R
(3)
CF3
THF
R=Ph 25% (20 h)
R=H 70% (20 h)
Zincate-Type Enolate
cf. Lithium Enolate: R=H
without 12-Cr-4 81% (~1 s)
with 12-Cr-4 30% (~1 s)
The scope of the ketonic substrates was then investi-
gated using silyl enol ethers as the enolate precursors,
to exclude the effects of amines observed in the titanate
case9 (Table 2). Acyclic as well as cyclic substrates
including cyclopentanone provided the a-CF3-ketones
in good yields. a-CF3-a0-C6H5-cyclohexanone was
obtained in an increased yield than that obtained by
the lithium enolate (entries 3 and 4 vs 5). Starting from
a-methylcyclohexanone,15 the a-CF3-ketone bearing all
carbon quaternary center16 was obtained in higher yields
than that obtained by the titanate enolate (entries 6 and
7 vs 8). a-CF3-cyclopentanone was also obtained in an
increased yield than those obtained by the lithium and
titanate enolates (entries 9 vs 10 and 11). An acyclic sub-
strate also provided the a-CF3-ketone in good yields
(entries 12 and 13 vs 14 and 15).
Figure 1. Trifluoromethylation of various zinc enolates.
Which is a reactive species, zincate-type enolate or sep-
arate lithium enolate associated with dialkylzinc? The
question has been the subject of excellent but controver-
sial mechanistic studies.3,13,14 The increased yield in our
case of the zincate-type enolate and 12-crown-4 is in
sharp contrast to the significantly decreased yield in
the case of lithium enolates with 12-crown-4. These
results imply the zincate-type enolate as the reactive
species at least in the radical trifluoromethylation of
ketone metal enolates (Fig. 1).
Time dependence of yields was also investigated with
zincate-type enolates in comparison with the lithium
enolate (Fig. 2). Trifluoromethylation of the lithium
enolate gave good yields of a-CF3-ketone in much short-
er reaction time because decomposition of the a-CF3-
These results show that a-trifluoromethylation of the
zincate-type enolates was particularly effective not only
for acyclic ketones but also for cyclic ketones including
cyclopentanone as compared with the titanate and lith-
ium enolates.
Li+
-
Et2Zn (1.0 eq.)
0 °C, 30 min
OTMS
MeLi (1.0 eq.)
OLi
OZnEt2
The synthesis of trifluoromethylated steroid D-ring
analogue was thus investigated to highlight the signifi-
cance of a-trifluoromethylation of carbonyl compounds,
cyclopentanones in particular (Fig. 3). General treat-
ment of zincate-type enolate of TMS-protected andros-
terone with CF3I/Et3B/O2 provided the a-CF3-
androsterone in 45% yield (a:b = 3:1).
THF / 0 °C
30 min
12-Cr-4 (1.0 eq.)
Lithium Enolate
Zincate-Type Enolate
CF3I (>5 eq.)
O
Et3B (1.0 eq.)
air
CF3
-78 °C, 20 h
57%
(70%)
Table 1. Trifluoromethylation of zincate-type enolates with diethyl-
100
Li Enolate
Zincate-Type Enolate
and dimethylzincs
CF3I (>5.0 eq.)
Et3B (1.0 eq.)
air
Zincate-Type Enolate + 12-Cr-4
80
60
40
20
R2Zn
(1.0 eq.)
12-Cr-4
(1.0 eq.)
MeLi
(1.0 eq.)
OTMS
O
CF3
0 °C
30 min
THF / 0 °C
30 min
0 °C
30 min
-78 °C
T h
T (h)
Yielda (%)
R = Et
R = Et
R = Me
R = Me
12-Cr-4
no 12-Cr-4
12-Cr-4
no 12-Cr-4
5
10
15
20
0
1
6
20
40
46
57
59
65
70
—
—
36
—
—
58
Time (h)
Figure 2. Time dependence of yields by zincate-type and lithium
enolates.
a Determined by 19F NMR using BTF as an internal standard.

8924
Y. Tomita et al. / Tetrahedron Letters 48 (2007) 8922–8925
Table 2. Trifluoromethylation of various substrates
104, 1–16; (f) Hiyama, T.; Kanie, K.; Kusumoto, T.;
Morizawa, Y.; Shimizu, M. Organofluorine Compounds;
Springer: Berlin, 2000; (g) Enantiocontrolled Synthesis of
Fluoro-Organic Compounds; Soloshonok, V. A., Ed.;
Wiley: Chichester, 1999; (h) Asymmetric Fluoroorganic
Chemistry, Synthesis, Applications, and Future Directions;
Ramachandran, P. V., Ed.; American Chemical Society:
Washington, DC, 2000; (i) Organofluorine Chemistry;
Chambers, R. D., Ed.; Springer: Berlin, 1997; (j) Iseki,
K. Tetrahedron 1998, 54, 13887–13914; (k) Biomedical
Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J.
R., Welch, J. T., Eds.; American Chemical Society:
Washington, DC, 1996; (l) Smart, B. E., Ed. Chem. Rev.
1996, 96, 1555–1824 (Thematic issue of fluorine chemis-
try); (m) Organofluorine Chemistry: Principles and Com-
mercial Applications; Banks, R. E., Smart, B. E., Tatlow, J.
C., Eds.; Plenum Press: New York, 1994; (n) Synthetic
Fluorine Chemistry; Olah, G. A., Prakash, G. K. S.,
Chambers, R. D., Eds.; Wiley: New York, 1992.
CF3I (>5 eq.)
Et3B (1.0 eq.)
air (0.5 ml)
Et2Zn (1.0 eq.)
0 °C
30 min
OTMS
R3
O
MeLi (1.0 eq.)
THF / 0
CF3
R2 R3
R1
R1
°
C
-78
20 h
°C
R2
12-Cr-4 (1.0 eq.)
30 min
Entry Si enol ether
Product
Yielda (%) deb (%)
1
2
57
(70)c
OTMS
O
CF3
OTMS
O
O
3
4
5
80
10
14
14
Ph
Ph
CF3
(86)c
43d
OTMS
6
7
8
56
(78)c
42e
CF3
CF3
2. M–F interaction plays an important role in defluorination
of a-CF3 carbonyl compounds (a) Schlosser, M. In
Organometallics in Synthesis—A Manual; Schlosser, M.,
Ed.; John Wiley & Sons: Chichester, 1994; pp 1–166; (b)
Murphy, E. F.; Murugavel, R.; Roesky, H. W. Chem. Rev.
1997, 97, 3425–3468; (c) Plenio, H. Chem. Rev. 1997, 97,
3363–3384, and references cited therein.
OTMS
O
O
9
10
11
50
40d
33e
12
13
14
15
74
OTMS
n
n
C4H9
CF3
(86)c
35d
64e
n
C4H9 C5H11
3. Seebach, D. Angew. Chem. Int., Ed. Engl. 1988, 27, 1624–
1654.
n
C5H11
4. Trifluoromethylation of lithium enolate of hindered
imides (only exception for the use of lithium 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 substitutent at a position to
suppress defluorination.
a Determined by 19F NMR analysis using BTF as an internal standard.
b Determined by 19F NMR analysis.
c With 12-crown-4 (1.0 equiv).
d With the lithium enolate.
e With the titanate enolate with Ti(OPri)4 (1.6 equiv).
5. 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 trifluoromethylation.
Trifluoromethylation of ketone germyl enol ethers pro-
ceeds in good yield; (c) Quite recently, we reported that the
addition of diethylzinc to the ketone silyl enol ethers led to
good yields even in the trifluoromethylation: Mikami, K.;
Tomita, Y.; Ichikawa, Y.; Amikura, K.; Itoh, Y. Org.
Lett. 2006, 8, 4671–4673.
O
Et2Zn (1.1 eq.)
LDA (1.1 eq.)
THF / -78 °C
-78 °C
30 min
1 h
TMSO
CF3I (3.7 eq.)
Et3B (1.0 eq.)
air
O
CF3
-40 °C (1 h) ~ 0 °C (3 h)
TMSO
45%, α:β=3:1
`
6. Trifluoromethylation of enamines: (a) Cantacuzene, D.;
Figure 3. Trifluoromethylation of TMS-protected androsterone.
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.
In conclusion, we have developed radical trifluoro-
methylation of zincate-type enolates, particularly cyclo-
pentanones; CF3 substituent can now be introduced into
various ketones in higher yields.
7. There are some reports on trifluoromethylation using
CF3þ: (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. Also see: Yoshida, M.; Ohkoshi, M.; Iyoda, M. Chem.
Lett. 2000, 804–805, However, they reported the addition
of perfluoroalkyl radical to a-chlorostyrenes giving even-
tually fluoroalkylated a,b-unsaturated ketones.
9. Titanate enolates: (a) Itoh, Y.; Mikami, K. Org. Lett.
2005, 7, 649–651; (b) Itoh, Y.; Mikami, K. J. Fluorine
Chem. 2006, 127, 539–544.
10. Lithium enolates: (a) Itoh, Y.; Mikami, K. Org. Lett.
2005, 7, 4883–4885; (b) Itoh, Y.; Mikami, K. Tetrahedron
2006, 62, 7199–7203.
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8925
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