Trifluoromethylated (CF₃) compounds are one of the most important classes of fluorine compounds, but the reactions for introducing a CF₃ group at the α-position of carbonyl compounds were rarely reported until recently. The reductive α-trifluoromethylation of α,β-unsaturated ketones using the combination of RhCl(PPh₃)₃-Et₂Zn, based on the Reformatsky-Honda reaction of non-fluorinated α-bromoacetate, became one of the breakthrough reactions in this field. The birth and advances of this α-trifluoromethylation and related reactions will be summarized here.

Formerly, we applied the so-called Reformatsky-Honda reaction, using RhCl(PPh₃)₃-Et₂Zn,² to the reaction of 2-cyclohexen-1-one with ethyl bromodifluoroacetate (BrCF₂COOEt), and found that the reaction afforded either the α-(ethoxycarbonyl)difluoromethyl ketone or the usual Reformatsky-type product selectively only by changing the solvent (Figure 1).³ The former was a new type of product; thus, we tried to expand this reaction to the synthesis of α-fluoroalkyl compounds, especially α-CF₃ compounds. After many efforts, we succeeded in the synthesis of α-CF₃ and other fluoroalkyl (R_f) ketones from α,β-unsaturated ketones,^4,5 and showed through the use of Et₂Zn-d₁₀ that a Rh-H complex played an important role (Figure 2).⁵ Furthermore, based on this mechanism, we developed a new methodology for synthesis of α-R_f ketones from silyl enol ethers of ketones in the absence of Et₂Zn, although this reaction required high temperature.⁶ The addition of Et₂Zn allowed the reaction to proceed at lower temperature, improved the yield⁷, and extended its application to various fluoroalkyl halides (Figure 3).⁸ Formation of the Rh(I)Et complex appears to promte the oxidative addition of CF₃I at lower temperature.

This Reformatsky-Honda reaction of BrCF₂COOEt has been applied to imines. Interestingly, we succeeded in selective syntheses of difluoro-β-lactams and 3-amino-2,2-difluorocarboxylic esters (Figure 4), depending upon the presence or absence of MgSO₄·7H₂O.⁹ MgSO₄·7H₂O serves as a convenient source of H₂O. Addition of H₂O also provided the ester, but the yield was lower. Furthermore, highly stereoselective syntheses of difluoro-β-lactams have also been accomplished using chiral auxiliaries.¹⁰

The mechanistic studies of α-fluoroalkylation of α,β-unsaturated ketone led to another new discovery. The most recent advance has been a synthesis of 1,3-diketones by reductive α-acylation of α,β-unsaturated ketones under the Reformatsky-Honda reaction conditions that easily generate a Rh-H complex (Figure 5).¹¹ α,β-Unsaturated esters can be utilized with various electrophiles besides acid chlorides to give reductive α-substitution products such as aldol-type and Mannich-type products.¹²