Chemoselective reduction of ketones: trifluoromethylketones versus methylketones

Expanding Mg–Zn Hybrid Chemistry: Inorganic Salt Effects in Addition Reactions of Organozinc Reagents to Trifluoroacetophenone and the Implications for a Synergistic Lithium–Magnesium–Zinc Activation

“…In general, the chemoselective alkylation of trifluoromethyl ketones by using polar organometallic reagents can be seriously compromised by their greater tendency to undergo b-hydride elimination reactions that yield unwanted reduction products (9). [20] Thus, the alkylation reaction of 7 with the homometallic reagents EtMgCl or [(tmeda)Zn(Et)Cl] were ineffective, yielding tertiary alcohol 8 in very low yields (4 % in both cases, Table 1, entries 1 and 2). Notably, illustrating the marked polarity difference between organomagnesium and organozinc reagents, when EtMgCl was employed a large amount of undesired reduction product 9 (90 %) was obtained, whereas the reaction with [(tmeda)Zn(Et)Cl] led to the recovery of the majority of starting material 7 and only 6 % secondary alcohol 9 was observed ( Table 1, entries 1 and 2).…”

“…The chemoselective alkylation of trifluoromethyl ketones is a powerful methodology for accessing trifluoromethyl‐substituted tertiary alcohols, which are important subunits in many natural products and pharmaceutical compounds 18. However, this approach is compromised by the tendency of these ketones to undergo reduction when reacted with polar organometallic reagents (even when soft organozinc reagents are employed),19 which results from a competing β‐hydride elimination reaction that is favoured by the presence of the highly electron‐withdrawing CF 3 group 20. We also report interesting findings after investigating the alkylation activity towards trifluoroacetophenone of several bi‐ and trimetallic mixtures that combine an organometallic reagent (EtMgCl or EtZnCl) with one or two inorganic additives (LiCl, MgCl 2 or ZnCl 2 ) and reveal that greater levels of chemoselectivity are obtained when trimetallic combinations are employed, which hints at the existence of a trilateral synergistic effect.…”

Direct Aldol Reaction of Trifluoromethyl Ketones with Ketones Catalyzed by Et2Zn and Secondary Amines

“…In our previous work, 3 we reported the chemoselective reduction of trifluoromethyl ketones (TFMKs) and an equimolar mixture of methyl ketones (Scheme 1). When we treated this mixture with Et 2 Zn, only TFMKs were reduced with good yields, leaving a small amount of aldoltype byproduct 3.…”

Catalytic asymmetric β-hydrogen transfer reduction of α-trifluoromethyl aromatic ketones with diethylzinc

“…36 However, due to the high reactivity of the diorganomagnesium reagent, a stoichiometric amount of chiral amide ligand and a low temperature (À78°C) were required to achieve high enantioselectivity. Diethylzinc is as a well-known b-hydrogen donor and was used in the reduction of trifluoromethyl ketones by Higashiyama et al 37 some other groups also found that trifluoromethyl ketones could be reduced by diethylzinc, [38][39][40][41] but the asymmetric version of the b-hydrogen transfer reduction of a-trifluoromethyl ketones with diethylzinc has never been reported.…”