C-metalated nitriles: electrophile-dependent alkylations and acylations

Sequential carbonyl addition-conjugate addition of Grignard reagents to 3-oxocyclohex-1-ene-1-carbonitrile generates C-magnesiated nitriles whose alkylation stereoselectivities intimately depend on the nature of the electrophile. The alkylation of these C-magnesiated nitriles with alkyl halides, sulfonates, and unstrained ketones occurs with the retention of the C-Mg configuration, whereas aldehyde and acyl cyanide acylations proceed with inversion of the stereochemistry. Mechanistic probes indicate that the stereoselectivity is controlled by stereoelectronic effects for most electrophiles, except allylic, benzylic, and cyclopropyl halides where single-electron-transfer processes intervene. Screening numerous alkylations of C-magnesiated nitriles with a diverse range of electrophiles reveals the reaction scope and delineates the fundamental stereoelectronic effects responsible for the highly unusual electrophile-dependent alkylations.