Decoupling Cyanide Activation from C-C Bond Formation in Ni-Catalyzed Cyanation of Strained Ketones Using Benzonitriles.

We have developed a Ni-catalyzed approach that generates silyl cyanides in situ to enable C-CN bond formation from readily available, low-toxicity benzonitriles. This strategy decouples cyanide activation from subsequent bond-forming reactions within distinct catalytic cycles to facilitate the ring-opening cyanation of cyclopropyl and cyclobutyl ketones. By separating C-CN activation from coupling, the chemistry is not limited by the intrinsic reactivity of the specific intermediate generated from activating the cyanide precursor. Indeed, we demonstrate that the separation of both cycles allows us to expand Ni-catalyzed cyanation chemistry using nontoxic precursors beyond hydrocyanation of π-systems and benzonitrile synthesis. Specifically, we report the synthesis of γ- and δ-cyanated ketones with broad functional group tolerance. Mechanistic investigations, including kinetic studies, stoichiometric reactions, and the isolation of a rare bimetallic Ni species featuring a bridging cyano ligand, collectively support a pathway in which Ni-catalyzed formation of TMSCN occurs concurrently with Ni-mediated activation of the cyclopropyl and cyclobutyl ketones. This work provides a safer and more sustainable alternative to conventional toxic cyanation reagents and presents a complementary reactivity scope to other nontoxic cyanide protocols where cyanide activation and coupling occur within the same cycle.