Trifluoromethylation, titanium enolates

Titanium enolates54 are widely used in aldol reactions and this research area has been reviewed until 2003.55 Thus, examples described in this chapter cover the literature since 2003. Recently, Mikami and co-workers reported the direct generation of titanium enolate 68 of an a-trifluoromethyl ketone56 for a high-yielding and zz /z -diastereose-lective aldol reaction (Scheme 25).57 The aldol reaction proceeded more smoothly if titanium(rv) isopropoxide was added as Lewis acid. On the other hand, low yield and moderate //-selectivity were obtained if HMPA was used instead of the titanium(rv) Lewis acid. 

C-Trifluoromethylation of titanium enolates by CF3I was recently compared to that of lithium enolates. Given that CF3 derivatives do not undergo substitution reactions by either Sn 1 or Sn2 reactions, a chain reaction involving CF3 and/or CF3U has been suggested. To understand this, thermochemical considerations include the strengths of Ti—I and Li—I bonds, and barriers for loss of Ti(III) and Li(0) from ketyl radicals. 

In a series of papers, Itoh and Mikami have reported the high yield, radical a-trifluoro-methylation of ketones using titanium euolates and Mefl/BEts as free radical generator and trifluoromethylating agent . The use of excess Ida and Ti(OPr-/)4 in the preparation of the titanium euolate represeuts the key to the success of the reaction (equation 41). Interest in this reaction stems from the fact that in general, the radical a-trifluoromethylation of ketones via lithium enolates is complicated by the easy defluorination of the a-CFs ketone by the parent enolate . For this reason, less reactive enolates such as silyl or germyl enolates have been initially used instead of lithium enolates" . 

More recently Ito and Mikami observed" that the titanium reagent is not indispensable in the case of highly basic lithium enolates derived from cyclic ketones or silyl enolates, for which the reactions are very fast (ending in ca Is to 5 min) and afford high yields of the a-trifluoromethylation products. A tentative radical mechanism has been proposed for these processes" involving reaction of the Mef free radical with the enolate to give a radical intermediate which reacts with another MefI molecule to afford Mef and the a-trifluoromethylation product (equation 42). 

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