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