Catalytic Asymmetric Synthesis of Tertiary Alkyl Fluorides: Negishi Cross-Couplings of Racemic α,α-Dihaloketones

Abstract

The development of new approaches to the construction of fluorine-containing target molecules is important for a variety of scientific disciplines, including medicinal chemistry. In this Article, we describe a method for the catalytic enantioselective synthesis of tertiary alkyl fluorides through Negishi reactions of racemic α-halo-α-fluoroketones, which represents the first catalytic asymmetric cross-coupling that employs geminal dihalides as electrophiles. Thus, selective reaction of a C–Br (or C–Cl) bond in the presence of a C–F bond can be achieved with the aid of a nickel/bis(oxazoline) catalyst. The products of the stereoconvergent cross-couplings, enantioenriched tertiary α-fluoroketones, can be converted into an array of interesting organofluorine compounds.

Direct Asymmetric Alkylation of Ketones: Still Unconquered

“…halogenated) α-position [10] will not be discussed here. Rather, we present a compilation of related transformations and efforts towards accomplishing the direct asymmetric α- alkylation of ketones.…”

Nickel‐Catalyzed Monofluoromethylation of Aryl Boronic Acids

“…Herein, we report the first example of a nickel-catalyzed monofluoromethylation of aryl boronic acids, wherein the fluoromethylating reagents bear either a phenylsulfone or an ethoxycarbonyl moiety. [9][10][11] We commenced our study with phenylboronic acid (1 a) as the pilot substrate and PhSO 2 CFHI [8] (2) as the coupling partner in the presence of a catalytic amount of [Ni(acac) 2 ] (5 mol %) in dichloromethane at 100 8C. To our delight, the desired fluoro(phenylsulfonyl)methylated product 3 a was obtained in 45 % yield when XantPhos (10 mol %) was used as the ligand (Table 1, entry 2).…”

Developments in the Chemistry of α‐Carbonyl Alkyl Bromides

“…In this transformation, both unfunctionalized organozincs and functionalized organozincs are useful coupling partners. In 2014, they also achieved similar asymmetric Negishi cross‐couplings of racemic α,α‐dihaloketones by using bis(oxazoline) as the ligand (Scheme (b)) …”