Nickel-Catalyzed Cross-Coupling of Acyl Chloride with Racemic α-Trifluoromethyl Bromide to Access Chiral α-Trifluoromethyl Ketones

Abstract

The nickel-catalyzed reductive cross-coupling reaction of acyl chloride with racemic secondary α-trifluoromethyl bromide has been developed. By this chemistry, a series of structurally interesting chiral α-CF3 carbonyl compounds could be accessed with great enantioselectivity and good functional group tolerance. The study of late-stage transformation indicated that this chemistry could be used as the robust method to prepare products that contain a bioactive motif. Furthermore, the importance of the α-trifluoromethyl group to this reaction has been illustrated by control experiments.

Radical-Polar Crossover Catalysis with a d0 Metal Enabled by a Redox-Active Ligand

“…While mechanism 1 is also unlikely, because catalyst 1 is known to induce radical mechanisms, further studies were needed to rule it out. 19,40 The importance of an anionic intermediate in the synthesis of gem-difluoroalkenes is supported by a Hammett analysis of this reaction which revealed an overall increase in reaction rate with increasingly electron-deficient substrates (Figure 5). A linear relationship is observed for the p-t Bu, p-Me, p-H, m-Br, p-CF3 and p-CN substrates.…”

Recent Advances in Nonprecious Metal Catalysis

“…Huang, Zhang and co-workers reported a method to prepare chiral α-trifluoromethyl ketones via Ni-catalyzed coupling between acyl chlorides and racemic α-trifluoromethyl bromides (Scheme 23). 44 Methods to prepare fluorinated compounds are highly sought in the pharmaceutical industry, 45 and many innovative methods have been reported over the past few years. 46 Newer, more practical methods to make fluorinated 47 the current work describes a reductive cross-coupling method to install a CF 3 group enantioselectively.…”

Radical-Polar Crossover Catalysis with a d0 Metal Enabled by a Redox-Active Ligand

“…Additionally, no competitive cross-coupling is observed between the organic fragments in the inner sphere mechanism of this coordinatively saturated complex further ruling out mechanism 3. While mechanism 1 is also unlikely, because catalyst 1 is known to induce radical mechanisms, further studies were needed to rule it out. , …”

“…While mechanism 1 is also unlikely, because catalyst 1 is known to induce radical mechanisms, further studies were needed to rule it out. 19,47 The experimental rate expression for the reaction in Figure 3a was determined by Variable Time Normalization Analysis. 48 The kinetic analysis shows that there is a first-order dependence on the concentrations of both 1 and 3b, but that there is a zero-order dependence on the concentration of benzyl zinc bromide (Figures S96−S98).…”