Radical trifluoromethylation of ketone silyl enol ethers by activation with dialkylzinc

Article abstract of DOI:10.1021/ol0611301

(Chemical Equation Presented) The radical trifluoromethylation of ketone silyl enol ethers gave α-CF₃ ketones in good yields with wide scope of the ketonic substrates including acyclic ketones and cyclopentanone. The use of dialkylzinc to activ

Full text of DOI:10.1021/ol0611301

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4671-4673
Radical Trifluoromethylation of Ketone
Silyl Enol Ethers by Activation with
Dialkylzinc
Koichi Mikami,* Yuichi Tomita, Yoshiyuki Ichikawa, Kazutoshi Amikura, and
Yoshimitsu Itoh
Department of Applied Chemistry, Tokyo Institute of Technology,
Tokyo 152-8552, Japan
kmikami@o.cc.titech.ac.jp
Received May 9, 2006 (Revised Manuscript Received September 12, 2006)
ABSTRACT
The radical trifluoromethylation of ketone silyl enol ethers gave
r-CF3 ketones in good yields with wide scope of the ketonic substrates
including acyclic ketones and cyclopentanone. The use of dialkylzinc to activate the silyl enol ethers is the key to the efficient radical
trifluoromethylation.
CF3 compounds have attracted much attention because of
their important applications as biologically active agents and
liquid crystalline materials, which exhibit specific biological
and physical properties.1 R-CF3 carbonyl compounds could
be promising building blocks for the construction of CF3
compounds. Radical trifluoromethylation of enolates is in
principle one of the simplest ways to introduce a CF3 unit
at the R position of a carbonyl group because polarization
of CF3δ--X
is in contrast to CH3δ+-Xδ- and because
δ+
the reaction of CF3I with enolates cannot give R-CF3
ketones.2 However, only limited examples are reported on
radical trifluoromethylation, especially in the case of
ketones.3-6
(2) (a) Huheey, J. E. J. Phys. Chem. 1965, 69, 3284-3291. (b) Yoshida,
M.; Kamigata, N. J. Fluorine Chem. 1990, 49, 1-20.
(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-Verlag: Berlin Heidelberg, 2000. (d)
Enantiocontrolled Synthesis of Fluoro-Organic Compounds; Soloshonok,
V. A., Ed.; Wiley: Chichester, 1999. (e) Asymmetric Fluoroorganic
Chemistry, Synthesis, Applications, and Future Directions; Ramachandran,
P. V., Ed.; American Chemical Society: Washington, DC, 2000. (f)
Organofluorine 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 Commercial Applications;
Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New York,
1994. (k) Hudlicky, M. Chemistry of Organic Fluorine Compounds, 2nd
ed.; Ellis Horwood: Chichester, 1976.
(3) Perfluoroalkylation of silyl and germyl enolates of esters and
ketones: (a) Miura, K.; Taniguchi, M.; Nozaki, K.; Oshima, K.; Utimto,
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
enolates proceeds in good yield.
(4) Trifluoromethylation of lithium enolate of imides: (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 R position to suppress defluori-
nation.
(5) Trifluoromethylation of enamines: (a) Cantacuze`ne, D.; Waksel-
man, 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.
10.1021/ol0611301 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/22/2006

The synthetic difficulty has been reported to be due to
defluorination of the R-CF3 ketone product by the parent
enolate or base during the reaction (Scheme 1).4 Recently,
Table 1. Trifluoromethylation of Silyl Enol Ether with
Dialkylzinc
Scheme 1
yield (%)
entry
time (h)
R ) Et
R ) Me
1
2
3
4
10 min
0.5
1
55
65
75
76
45
50
63
6
a Determined by 19F NMR analysis using BTF as an internal
standard.
we reported that the use of titanium ate enolates7 and lithium
enolates8 could avoid significant defluorination during radical
trifluoromethylation. However, these methods work with
limited scope of ketonic substrates. On the other hand, less
reactive enolate equivalents such as silyl enol ethers have
been used for radical trifluoromethylation to suppress de-
fluorination of the R-CF3 carbonyl compounds.3 Due to its
poor reactivity, this method could only be applied for ester
silyl enol ethers (ketene silyl acetals), which is more
nucleophilic than ketone silyl enol ethers. Thus, we focused
our attention to zinc enolate, on the basis of the fact that the
interaction between metals and the fluorine atom can be
widely changed by the nature of the metals: the longer bond
distance of soft late transition metal zinc with hard fluorine
implies the negligible associative interaction.1b,9 Therefore,
metal enolates with zinc countercation might be employed
for radical trifluoromethylation without decomposition of
R-CF3 ketonic products.
enol ethers as d-π* complex A or Lewis acid/base complex
B (Figure 1). The reactivity of the trimethylsilyl enol ether
is significantly increased with or without formation of the
zinc enolate under the reaction conditions. Quite recently,
lithium cation complexation with an alkene was reported to
accelerate radical addition reaction.11
Figure 1. Activation of silyl enol ethers with dialkylzinc.
First, the generation of the zinc enolate of cyclohexanone
was attempted starting from the silyl enol ether with
dialkylzinc for radical trifluoromethylation using CF3I
On the basis of these results, dialkylzinc can be reduced
in catalytic amounts (Table 2). As expected, even with a
10
(ca. 5 equiv), Et3B (1.0 equiv), and O2 at -78 °C. The
yields were determined by 19F NMR analysis using BTF
(benzotrifluoride) as an internal standard. R-CF3-cyclo-
hexanone was obtained in good yield (75%) only after 1 h
(Table 1).
Table 2. Trifluoromethylation with a Catalytic Amount of
Diethylzinc
The zinc enolate could not, however, be observed upon
addition of dimethylzinc to the trimethylsilyl enol ether of
cyclohexanone by TLC or NMR analyses. This observation
implies the simple complexation of dialkylzinc with the silyl
entry
Et2Zn (equiv)
time (h)
yielda (%)
+
(6) There are some reports of trifluoromethylation using CF3
: (a)
1
2
3
4
5
6
7
8
0
0
0
0.1
0.1
0.5
0.5
1.0
1
6
20
1
20
1
20
1
6
16
28
14
43
55
76
75
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.
(7) (a) Itoh, Y.; Mikami, K. Org. Lett. 2005, 7, 649-651. (b) Itoh, Y.;
Mikami, K. J. Fluorine Chem. 2006, 127, 539-544.
(8) (a) Itoh, Y.; Mikami, K. Org. Lett. 2005, 7, 4883-4885. (b) Itoh,
Y.; Mikami, K. Tetrahedron 2006, 62, 7199-7203.
(9) (a) Plenio, H. Chem. ReV. 1997, 97, 3363-3384. (b) Murphy, E. F.;
Murugavel, R.; Roesky, H. W. Chem. ReV. 1997, 97, 3425-3468 and
references therein.
a Determined by 19F NMR analysis using BTF as an internal
standard.
(10) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109,
2547-2549.
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Org. Lett., Vol. 8, No. 21, 2006

h; 76%, 20 h) (entries 6 and 7). Without diethylzinc, the
trifluoromethylation product was obtained in only low yields
(entries 1-3).3
Table 3. Trifluoromethylation of Various Silyl Enol Ethers of
Acyclic and Cyclic Ketones
Several ketonic substrates were then investigated (Table
3). The present radical trifluoromethylation was found to
give wide scope for the ketonic substrates applicable. The
wide scope of applicable substrates is in sharp contrast to
titanium ate enolate,7 which is not applicable to cyclopen-
tanone, and lithium enolate,8 which is limited to cyclohex-
anone derivatives. Acyclic substrates as well as cyclic
substrates including cyclopentanone provided the R-CF3
ketone products in good yields via the silyl enol ethers
activated with diethylzinc.
Since thermodynamic enolates could easily be prepared
from the silyl enol ethers, the quaternary carbon center12 with
a CF3 substituent could be produced from R-substituted
ketone.13 In the case of R-Me14-substituted cyclohexanone,
the product with a CF3-attached quaternary carbon was
obtained in 32% yield for 24 h (entry 3).
In conclusion, we have thus developed the radical tri-
fluoromethylation of ketone silyl enol ethers. Activation
with dialkylzinc leads to the R-CF3 ketones in increased
yields with wide scope of the ketonic substrates including
acyclic ketones and cyclopentanonone. The use of dialkyl-
zinc to activate the silyl enol ethers is the key to the effi-
cient radical trifluoromethylation, by which a CF3 sub-
stituent can be introduced to give various R-CF3 ketones,
with or without formation of the zinc enolate interme-
diates.
Supporting Information Available: Typical experimen-
tal procedure of trifluoromethylation and spectroscopic data
of all the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0611301
(11) (a) Vyakaranam, K.; Barbour, J. B.; Michl, J. J. Am. Chem. Soc.
2006, 128, 5610-5611. (b) Vyakaranam, K.; Korbe, S.; Michl, J. J. Am.
Chem. Soc. 2006, 128, 5680-5686. (c) Horn, A. H. C.; Clark, T. J. Am.
Chem. Soc. 2003, 125, 2809-2816. (d) Clark, T. J. Chem. Soc., Chem.
Commun. 1986, 1774-1776.
(12) Reviews on the construction of quaternary carbon centers: (a)
Martin, S. F. Tetrahedron 1980, 36, 419-460. (b) Fuji, K. Chem. ReV.
1993, 93, 2037-2066. (c) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388-401. (d) Christoffers, J.; Mann, A. Angew. Chem.,
Int. Ed. 2001, 40, 4591-4597. (e) Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105-10146. (f) Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5363-5367. (g) Christoffers, J.; Baro, A.
Quaternary Stereocenters. Challenges and Solutions for Organic Synthesis;
VCH: Weinheim, 2005. (h) Trost, B. M.; Jiang, C. Synthesis 2006, 369-
396.
a Determined by 19F NMR analysis using BTF as an internal standard.
b 16% de; trans major. c With lithium enolate. d Isolated yield. e 80% de.
f With titanium ate enolate.
(13) Kimura, M.; Yamazaki, T.; Kitazume, T.; Kubota, T. Org. Lett.
2004, 6, 4651-4654.
(14) Silyl enol ether of 2-methylcyclohexanone consists of thermody-
namic and kinetic enolates (87:13).
semicatalytic amount of diethylzinc (0.5 equiv), the trifluo-
romethylation product was obtained in good yield (55%, 1
Org. Lett., Vol. 8, No. 21, 2006
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