Facile radical trifluoromethylation of lithium enolates

Article abstract of DOI:10.1021/ol0517574

(Chemical Equation Presented) Highly basic lithium enolates are shown to be applicable to radical trifluoromethylation. The reaction is extremely fast, and the minimum reaction time is ～1 s.

Full text of DOI:10.1021/ol0517574

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4883-4885
Facile Radical Trifluoromethylation of
Lithium Enolates
Yoshimitsu Itoh and Koichi Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology,
Tokyo 152-8552, Japan
kmikami@o.cc.titech.ac.jp
Received July 25, 2005 (Revised Manuscript Received September 23, 2005)
ABSTRACT
Highly basic lithium enolates are shown to be applicable to radical trifluoromethylation. The reaction is extremely fast, and the minimum
reaction time is 1 s.
∼
The synthesis of fluorine-containing compounds continues
to attract much attention because of their important applica-
tions in material and biological sciences. One of the most
important organofluorine functionalities is CF3, which ex-
hibits specific physical and biological properties.1 The R-CF3
carbonyl compounds are some of the most useful synthetic
intermediates for functionalization with CF3. However, deflu-
orination is problematic under basic conditions, in particular.2
This difficulty could also be encountered in radical trifluo-
romethylation of metal enolates, which is, in principle, the
most direct and efficient way to synthesize R-CF3 carbonyl
compounds. It has been widely recognized that highly basic
conditions with lithium enolates3 could not be applied to the
trifluoromethylation (Scheme 1);4 there are indeed only
Scheme 1
(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.
limited examples especially for ketones.4-7 To avoid deflu-
orination of R-CF3 ketone products, less reactive enolate
(3) Seebach, D. Angew. Chem,. Int. Ed. Engl. 1988, 27, 1624-1654.
(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
a bulky substitutent at the R position to suppress defluorination.
(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 proceeds in good yield.
(2) M-F interaction plays an important role in defluorination of R-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.
10.1021/ol0517574 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/07/2005

equivalents such as silyl or germyl enol ethers have been
used for radical trifluoromethylation.5 Therefore, it usually
requires a long reaction time (more than 40 h in the case of
ketone). During the course of our exploration of the radical
trifluoromethylation of titanium ate enolates,8 we discovered
that lithium enolate could be, in fact, employed for radical
trifluoromethylation and that the reaction proceeded ex-
tremely fast. We herein report the facile radical trifluorom-
ethylation of lithium enolates.
Table 2. Preparation Time of the Lithium Enolate
entry
X [min]
% yielda
1
2b
3
30
30
60
63
0
73
72
Radical trifluoromethylation of the titanium ate enolate
of cyclohexanone gave 81% yield of R-CF3 cyclohexanone
(Table 1, entry 1).8 The yield greatly decreased without
4
120
a Determined by 19F NMR using BTF as an internal standard. b The
reaction was carried out without Et3B.
Table 1. Radical Trifluoromethylation of Lithium Enolate
The radical reaction time was investigated using lithium
enolate prepared over 60 min (Table 3). When the radical
Table 3. Investigation of the Trifluoromethylation Time
entry
LDS [equiv]
Ti(OiPr)4 [equiv]
% yielda
1
2
3
1.6
1.6
1.0
1.6
0
0
81
41
63
entry
reaction time Y
% yieldb
1
2
3
4
5
13 h
2 h
1 h
1 min
∼1 s
62
73
80
83
81
a Determined by 19F NMR using BTF as an internal standard.
Ti(OiPr)4 (entry 2), presumably from decomposition of the
R-CF3 product due to an excess amount of LDA. Sur-
prisingly, the use of just 1.0 equiv of LDA gave 63% yield
of the R-CF3 product. Therefore, we decided to further inves-
tigate the radical trifluoromethylation of lithium enolates.
First, preparation time of the lithium enolate was inves-
tigated (Table 2). In the case of titanium ate enolate, the
preparation of the lithium enolate took only 30 min. It is
speculated that the titanium ate enolate is in equilibrium with
the parent ketone and ate complex (LDA/Ti(OiPr)4). There-
fore, even if the enolization by LDA was not completed in
30 min, enolization by titanium ate complex (LDA/Ti(OiPr)4)
would take place during the reaction.8 There is no such
equilibrium in the case of Li enolate. Therefore, 60 min of
the preparation time was necessary to give sufficient yield
of the R-CF3 product (entry 3). However, longer preparation
time was not necessary (entry 4). The reaction was carried
out without radical initiator Et3B (entry 2); no product was
detected and a large amount of cyclohexanone was recovered,
indicating that the reaction had proceeded by a radical
mechanism.
a Et3B was added in 15 s. b Determined by 19F NMR using BTF as an
inernal standard.
trifluoromethylation was carried out for 1 h, the yield was
80% (entry 3). Longer reaction times decreased the yields;
the R-CF3 product was obtained in 62% yield when the
reaction was quenched in 13 h (entry 1). This is probably
due to the decomposition of the R-CF3 product when exposed
to basic conditions for prolonged periods of time. Shorter
reaction times did not affect the yield. Finally, the ∼1 s
reaction gave the R-CF3 product in 81% yield (entry 5).9
Compared to the radical trifluoromethylation of titanium ate
enolate, which took 2 h to give 81% yield, the reaction of
lithium enolate is extremely fast.10
(9) For accuracy, Et3B was added in 15 s and the reaction time was
counted from the time when the addition of Et3B was completed.
(10) Typical Experimental Procedure. To a solution of Pr2NH (28.0
i
n
µL, 0.20 mmol) in THF (2.0 mL) was added BuLi (126.3 µL of 1.58 M
solution in 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 µL, 0.2 mmol), and the mixture 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 untouching till quenching the reaction. Then Et3B (0.2 mL of 1.0 M
solution in hexane, 0.2 mmol) was added in 15 s to start the radical addition
reaction. The reaction mixture was immediately quenched (in ∼1 s) by
acetic acid solution, which was set beforehand, at -78 °C. After warming
to room temperature, BTF (10 µL, 0.082 mmol) was added as an internal
standard. The yield was determined by 19F NMR of the crude mixture (81%).
(6) Trifluoromethylation of enamines: (a) Cantacuze`ne, 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.
+
(7) There are some reports of trifluoromethylation using CF3
: (a)
Yagupol’skii, L. M.; Kondratenko, N. V.; Timofeeva, G. N. J. Org. Chem.
U.S.S.R. 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) Itoh, Y.; Mikami, K. Org. Lett. 2005, 7, 649-651.
4884
Org. Lett., Vol. 7, No. 22, 2005

of nBuLi11 to give the regioisomeric R-CF3 product in
reasonable yield after a 2 h reaction time (entries 2, 5, 7).
The reaction rates of cyclopentanone (entry 8) and cyclo-
heptanone (entry 9) were relatively slow (5 min).
Table 4. Radical Trifluoromethylation of Various Carbonyl
Compounds
Considering the facts that the reaction did not proceed
without Et3B (Table 2, entry 2) and CF3I does not react in
an SN2-type trifluoromethylation,12 we propose a radical
reaction mechanism (Scheme 2).4b The CF3 radical is
Scheme 2
generated by Et3B and goes on to react with Li enolate. The
radical intermediate (A) then reacts with another CF3I to
reproduce the CF3 radial along with the R-CF3 product (B).13
In summary, we have discovered that highly basic lithium
enolates may be employed for radical trifluoromethylation.
The reaction rate is extremely fast compared to the previous
radical trifluoromethylation. The direct use of lithium enolate
as a substrate is simpler and faster than that of titanium ate
enolates or any other previous methods. The investigation
of the detailed reaction mechanism and further applications
of this methodology are now being pursued.
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a Et3B was added in 15 s. b Determined by 19F NMR using BTF as an
inernal standard. The values in ( ) refer to the yields of isolated products.
The values in square brackets are the diastereomeric ratio. c Silyl enol ether
of R-Me cyclohexanone consists of thermodynamic and kinetic enol ethers
(87:13). d Silyl enol ether of R-Ph cyclohexanone contains only thermo-
dynamic enol ether.
OL0517574
(11) (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.
Several substrates were investigated (Table 4). In the case
of 4-tBu (entry 3), 2-Me (entry 4), and 2-Ph (entry 6)
substrates, the reactions proceeded with extremely fast
reaction rates. By using LDA for the formation of lithium
enolate, only kinetic enolate could be formed. However,
thermodynamic lithium enolate could also be generated by
treatment of the corresponding silyl enol ether with 1.0 equiv
(12) In sharp contrast to normal alkyl halides, perfluoroalkyl halides
cannot undergo nucleophilic alkylation, because the electronegativities of
perfluoroalkyl groups are higher than those of halogens. Thus the polariza-
tion of perfluoroalkyl halides is as Rfδ--Iδ+ and treatment with nucleophile
could not produce Rf-Nu. (a) Yoshida, M.; Kamigata, N J. Fluorine Chem.
1990, 49, 1-20. (b) Huheey, J. E. J. Phys. Chem. 1965, 69, 3284-3291.
(13) When Et3B was used in 20 mol %, the product was obtained in
75% yield. This indicates the involvement of chain-propagation step.
Org. Lett., Vol. 7, No. 22, 2005
4885