Radical trifluoromethylation of titanium ate enolate

Article abstract of DOI:10.1021/ol047565a

(Chemical Equation Presented) The radical trifluoromethylation of ketone titanium ate enolates gave α-CF₃ ketones in good yields. The use of excess amount of LDA and Ti(OⁱPr)₄ in the preparation of titanium ate enolates is

Full text of DOI:10.1021/ol047565a

ORGANIC
LETTERS
2005
Vol. 7, No. 4
649-651
Radical Trifluoromethylation of Titanium
Ate Enolate
Yoshimitsu Itoh and Koichi Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology,
Tokyo 152-8552, Japan
kmikami@o.cc.titech.ac.jp
Received November 27, 2004
ABSTRACT
The radical trifluoromethylation of ketone titanium ate enolates gave
r-CF3 ketones in good yields. The use of excess amount of LDA and
Ti(OiPr)4 in the preparation of titanium ate enolates is the key to the efficient radical trifluoromethylation.
Organofluorine compounds continue to attract much attention
because of their important applications as biological active
agents, liquid crystalline materials, and so on. One of the
most important fluorine-containing compounds is a CF3
compound, which exhibits specific physical and biological
properties.1 However, the synthesis of R-CF3 carbonyl
compounds has not been fully established. Radical trifluo-
romethylation of enolates is in principle one of the simplest
ways to introduce a CF3 unit at the R position of a carbonyl
group; however, there are only limited examples, especially
in the case of ketones.2-5 It has been reported that the
synthetic difficulty is due to the defluorination of the R-CF3
ketone product by the parent enolate or base during the
reaction (Scheme 1).3 Recently we have reported the efficient
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) Soloshonok, V. A., Ed.; Enantiocontrolled Synthesis of Fluoro-Organic
Compounds; Wiley: Chichester, 1999. (e) Ramachandran, P. V., Ed.;
Asymmetric Fluoroorganic Chemistry, Synthesis, Applications, and Future
Directions; American Chemical Society: Washington, DC, 2000. (f)
Chambers, R. D., Ed.; Organofluorine Chemistry; Springer: Berlin, 1997.
(g) Iseki, K. Tetrahedron 1998, 54, 13887-13914. (h) Ojima, I., McCarthy,
J. R., Welch, J. T., Eds.; Biomedical Frontiers of Fluorine Chemistry;
American Chemical Society: Washington, DC, 1996. (i) Smart, B. E., Ed.;
Chem. ReV. 1996, 96, 1555-1824 (thematic issue of fluorine chemistry).
(j) Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press: New
York, 1994. (k) Hudlicky, M. Chemistry of Organic Fluorine Compounds,
2nd ed; Ellis Horwood: Chichester, 1976.
(2) Perfluoroalkylation of silyl and germyl enolates 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
enolates proceeds in good yield.
generation of titanium enolates of R-CF3 ketones and high
yielding aldol reactions.6 The stability of the titanium enolates
of R-CF3 ketones stems from the linearity of Ti-O-C bonds
caused by the donation of the lone electron pair of the oxygen
to the empty d-orbital of titanium to suppress Ti-F interac-
(3) 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 oxazoli-
dinones with a bulky substitutent at the R position to suppress defluorination.
10.1021/ol047565a CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/22/2005

tion7 and successive defluorination. On the basis of the fact
that titanium enolates of R-CF3 ketones are stable to
defluorination, we report here that titanium ate enolates can
be applied to radical trifluoromethylation for the synthesis
of R-CF3 ketones.
LDA and Ti(OiPr)4 was found to be important in increasing
the yield (Table 1). When the enolate (2a) was formed by
Table 1. Trifluoromethylation of Titanium Ate Enolates
First, several titanium enolates of cyclohexanone were
reacted with CF3 radical, which was generated by CF3I (ca.
5 equiv) and Et3B (1.0 equiv).8 The reaction was carried out
at -78 °C for 2 h. The yields were determined by 19F NMR
using BTF as an internal standard (Figure 1). In the case of
entry
LDA (equiv)
Ti(OiPr)4 (equiv)
yield (%)a
1
2
3
4
5
1.0
1.3
1.6
2.0
1.0
1.0
1.3
1.6
2.0
1.6
56
72
81
80
52
a Determined by 19F NMR using BTF as an internal standard.
1.0 equiv of LDA and 1.0 equiv of Ti(OiPr)4, the product
(3a) was formed in 56% yield (entry 1). When 1.6 equiv of
LDA and 1.6 equiv of Ti(OiPr)4 were used, the yield
increased up to 81% (entry 3). Using 1.0 equiv of LDA and
1.6 equiv of Ti(OiPr)4 gave the R-CF3 ketone (3a) in almost
the same yield as in entry 1 (52%, entry 5). Therefore, both
LDA and Ti(OiPr)4 should be used in excess amounts.
The titanium ate enolate is prepared from the correspond-
ing lithium enolate. When LDA was used for the preparation
Figure 1. Trifluoromethylation of various titanium enolates.
TiCl3 enolate (formed by TiCl4 and Et3N in CH2Cl2 at -78
°C), no R-CF3 ketone (3a) was obtained. In the case of Ti-
(OiPr)3 enolate (formed by the addition of Ti(OiPr)3Cl to the
corresponding lithium enolate in THF at -78 °C), the R-CF3
ketone (3a) was formed, but in low yield (23%). To increase
the reactivity of the enolate, the titanium ate9,10 enolate was
examined. Titanium ate enolates could be easily formed just
by adding Ti(OiPr)4 to lithium enolate at low temperature.9
Upon treatment of titanium ate enolate (2a) with CF3 radical,
the R-CF3 ketone was obtained in an increased yield (56%).
Radical trifluoromethylation of titanium ate enolate (2a)
was further investigated and the use of excess amount of
i
of lithium enolate, 1 equiv of Pr2NH was formed simulta-
neously. To investigate the effect of iPr2NH, nBuLi was added
to silyl enol ether,11 to generate the lithium enolates without
i
i
formation of Pr2NH (Table 2) and the amount of Pr2NH
could be controlled at will). When the reaction was carried
(4) Trifluoromethylation of enamines: (a) Cantacuze`ne, D.; Wakselman,
C.; Dorme, R. J. Chem. Soc., Perkin Trans. 1 1977, 1365-1371. (b)
Table 2. Trifluoromethylation of Titanium Ate Enolates
Starting from the Silyl Enol Ether
Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186-5191.
+
(5) There are some reports of trifluoromethylation using CF3
: (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.
(6) Itoh, Y.; Yamanaka, M.; Mikami, K. J. Am. Chem. Soc. 2004, 126,
13174-13175.
nBuLi
entry (equiv)
R2NH
(equiv)
Ti(OiPr)4 yield
(equiv)
(7) (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.
(%)a
1
2
3
4
5
6
7
8
9
1.0
1.0
1.6
1.0
1.6
1.0
1.6
1.0
1.6
1.0
1.6
1.6
1.0
1.6
1.0
1.6
1.0
1.6
63
62
68
49
74
57
72
6
(8) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109,
2547-2549.
(9) Some reactions involving titanium ate enolates: (a) Siegel, C.;
Thornton, E. R. J. Am. Chem. Soc. 1989, 111, 5722-5728. (b) Bernardi,
A.; Cavicchioli, M.; Marchionni, C.; Potenza, D.; Scolastico, C. J. Org.
Chem. 1994, 59, 3690-3694. (c) Yachi, K.; Shinokubo, H.; Oshima, K. J.
Am. Chem. Soc. 1999, 121, 9465-9466. (d) Han, Z.; Yorimitsu, H.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 2000, 41, 4415-4418.
(10) Some reactions involving other titanium ate comlexes: (a) Reetz,
M. T.; Wenderoth, B. Tetrahedron Lett. 1982, 23, 5259-5262. (b) Reetz,
M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek,
R.; Maus, S. Chem. Ber. 1985, 118, 1421-1440. (c) Reetz, M. T.; Steinbach,
R.; Westermann, J.; Peter, R.; Wenderoth, B. Chem. Ber. 1985, 118, 1441-
1454. (d) Takahashi, H.; Kawabata, A.; Niwa, H.; Higashiyama, K. Chem.
Pharm. Bull. 1988, 36, 803-806. (e) Takahashi, H.; Tsubuki, T.; Higash-
iyama, K. Synthesis 1988, 238-240. (f) Takahashi, H.; Tsubuki, T.;
Higashiyama, K. Chem. Pharm. Bull. 1991, 39, 260-265. (g) Bernardi,
A.; Cavicchioli, M.; Scolastico, C. Tetrahedron 1993, 49, 10913-10916.
(h) Bernardi, A.; Marchionni, C.; Pilati, T.; Scolastico, C. Tetrahedron Lett.
1994, 35, 6357-6360. (i) Mahrwald, R. Tetrahedron 1995, 51, 9015-9022.
iPr2NH (1.0)
iPr2NH (1.6)
2,2,6,6-Me4-piperidine (1.0)
2,2,6,6-Me4-piperidine (1.6)
Et2NH (1.0)
Et2NH (1.6)
11
a Determined by 19F NMR using BTF as an internal standard.
i
out without addition of Pr2NH, the yields did not change
significantly even by increasing the amount of nBuLi and/or
Ti(OiPr)4 (Table 2, entry 1-3). On the contrary, when three
reagents (nBuLi, Pr2NH, Ti(OiPr)4) were used in 1.0 equiv
i
650
Org. Lett., Vol. 7, No. 4, 2005

each, the yield was decreased (entry 4 (vs entry 1)). In the
case that the three reagents were used in 1.6 equiv each, the
yield was increased (entry 5). Although the yield of entries
4 and 5 in Table 2 were slightly decreased compared to
entries 1 and 3 in Table 1, a similar tendency was observed
in the relationship of the yields and the amounts of the
reagents.
(Scheme 2) to ketone (1a). In fact, when Et2NH was used
in 1.0 equiv (entry 8) and 1.6 equiv (entry 9), the yield was
dramatically decreased. It should be noted that the LDA/Ti-
(OiPr)4 complex, which might act as a base, works not for
the decomposition of the R-CF3 ketone products but for
increasing the yield.
Several ketonic substrates were thus investigated (Figure
2). Acyclic substrates (3c,d) as well as cyclic substrates
From these results, the effect of iPr2NH could be proposed
i
as follows (Scheme 2). Pr2NH, which is formed by using
Scheme 2
Figure 2. Trifluoromethylation of various substrates: (a) yield
determined by 19F NMR, (b) isolated yield.
(3a,b) provided the R-CF3 ketones in good yields. Although
LDA could generate only kinetic lithium enolate, both kinetic
and thermodynamic enolate could easily be prepared from
silyl enol ethers. Therefore, thermodynamic titanium ate
enolate of R-substituted ketone could be generated by silyl-
to-lithium method to obtain quaternary carbon center attached
with CF3 substituent.13,14 In the case of R-Me15 and R-Ph16
substituted cyclohexanone, the products were obtained in
reasonable yields (3e,f).
In conclusion, we have developed radical trifluorometh-
ylation of titanium ate enolates. The key to the success is
the use of an excess amount of nBuLi, iPr2NH, and Ti(OiPr)4
to generate the titanium ate enolates. By this method, the
CF3 substituent can be introduced to give various ketones
even with R-CF3 quaternary carbon centers.
LDA in the preparation of titanium ate enolate (2a), would
i
i
exchange with -OiPr ligand to give PrOH. PrOH could
protonate the enolate to form ketone and titanium amide
complex (LDA/Ti(OiPr)4).12 This mechanism rationalizes not
i
only the decrease in yield upon addition of Pr2NH (Table
2, entry 4) (protonation of the enolate to reduce the amount
of the reactive enolate species) but also the increase in yield
using excess amount of LDA and Ti(OiPr)4 (the equilibrium
shifts to titanium ate enolate). To support the mechanism,
2,2,6,6-tetramethylpiperidine and Et2NH were investigated.
2,2,6,6-Tetramethylpiperidine is more bulky than iPr2NH and
i
its coordinating ability is lower than that of Pr2NH to shift
the proposed equilibrium (Scheme 2) to titanium ate enolate
(2a). In fact, when 2,2,6,6-tetramethylpiperidine was used
in 1.0 equiv (entry 6), the decrease in the yield was not
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data of the product. This
material is available free of charge via the Internet at
http://pubs.acs.org.
i
significant relative to Pr2NH (entry 4). When 2,2,6,6-
tetramethylpiperidine was used in 1.6 equiv (entry 7), the
i
OL047565A
yield was increased as in the case of Pr2NH (entry 5). On
the other hand, Et2NH is less bulky than iPr2NH and, hence,
its coordination ability is higher to shift the equilibrium
(13) Review of 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) Denissova, I.; Barriault, L. Tetrahedron 2003, 59,
10105-10146.
(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.
(14) Kimura, M.; Yamazaki, T.; Kitazume, T.; Kubota, T. Org. Lett.
2004, 6, 4651-4654.
(12) NMR study of a titanium ate enolate9b showed that the ketone was
formed in the generation of the titanium ate enolate (although this is only
mentioned in the foot note of Figure 2). This fact also supports the proposed
mechanism.
(15) Silyl enol ether of R-Me cyclohexanone consists of thermodynamic
enolate:kinetic enolate ) 87:13.
(16) Silyl enol ether of R-Ph cyclohexanone contains only thermodynamic
enolate.
Org. Lett., Vol. 7, No. 4, 2005
651