Mechanism and Selectivity in Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl Halides

Abstract

The direct cross-coupling of two different electrophiles, such as an aryl halide with an alkyl halide, offers many advantages over conventional cross-coupling methods that require a carbon nucleophile. Despite its promise as a versatile synthetic strategy, a limited understanding of the mechanism and origin of cross selectivity has hindered progress in reaction development and design. Herein, we shed light on the mechanism for the nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides and demonstrate that the selectivity arises from an unusual catalytic cycle that combines both polar and radical steps to form the new C-C bond.

Nickel-Catalyzed Reductive Couplings

“…Ni-catalyzed radical-chain mechanism, see [16][17][18][19][20]). It may also bind to the catalytic species in a cage upon its generation via one-electron reduction or halide abstraction by low-valent Ni (cage-rebound, Scheme 2) [21][22][23].…”

“…A radical chain process is proposed for the formation of the Ni III species through addition of alkyl radical to Ar-Ni II complex (Scheme 16, left) [16]. Alkyl radical can be generated via halide abstraction from the alkyl halides by Ni I , which results from the reductive elimination of the Ar-Ni III -alkyl intermediate.…”

Bimetallic Oxidative Addition in Nickel-Catalyzed Alkyl–Aryl Kumada Coupling Reactions

“…While the study was specific to the reactions catalyzed by 1, the groups of Weix, Mirica, and Tilley subsequently showed evidence for organometallic Ni(III) intermediates and the involvement of two Ni(III) species in related C-C coupling reactions. [21][22][23] The Nickamine catalyst is versatile. In addition to alkyl-alkyl Kumada coupling, it also catalyzes alkyl-aryl and alkyl-alkynyl Kumada coupling as well as alkyl-alkyl and alkyl-aryl Suzuki coupling.…”

Nickel-Catalyzed Enantioselective Cross-Coupling of N-Hydroxyphthalimide Esters with Vinyl Bromides

“…This Ni-dependent behavior suggests that the mechanism proceeds through a cage-escaped radical, which at higher concentrations of 4b , can competitively recombine with nickel before undergoing ring scission. 23 Further studies of the mechanism are ongoing; it is unclear at this time whether the absolute stereochemistry is set during the oxidative addition or reductive elimination steps. 24 We do note, however, that the products are formed in similar ee when using either the NHP esters under the conditions reported here or the benzylic chloride using the conditions reported previously, 8b which suggests that the reactions proceed through the same stereochemistry-determining step.…”