Regioselective Hydrocyanation of Internal Alkynes Enabled by a Transition‐Metal‐Free Dual‐Catalytic System

Abstract Since its discovery in 1954, the hydrocyanation of multiple carbon‐carbon bonds has emerged as a powerful strategy for the synthesis of nitriles. However, the elusive control of selectivity and typical reliance on expensive and toxic transition metal (TM) based catalysts significantly hinder the utility of this process. Here, we report an exclusively regioselective hydrocyanation of unbiased alkynes, driven by base‐catalyzed reversible alkyne‐allene isomerization and phosphine‐catalyzed HCN transfer to the allene. This TM‐free, dual‐catalytic approach introduces a novel mode of selectivity control via regioselective hydrocyanation of the allene intermediate. The methodology secures a cost‐effective access to a broad range of vinyl nitriles (40 examples) with yields up to 97% and Z/E stereoselectivity up to 20:1, including complex natural product derivatives. A comparison with TM‐based systems highlighted a 2500‐fold cost reduction, as well as the elimination of the troublesome separation of the regioisomers. Mechanistic studies elucidated the reaction pathway, shedding light on the achieved regioselectivity. By altering one catalyst in a dual‐catalytic system, we demonstrated the regioselectivity switch, thereby facilitating regiodivergent hydrocyanation (eight examples). In a broader context, this approach offers a foundation for developing the next generation of TM‐free strategies for the regioselective hydrofunctionalizations of unbiased alkynes.