Ligand-controlled sequential activation enables nickel-catalysed alkyl–alkynyl coupling

Cross-electrophile coupling between unactivated alkyl halides and alkynyl halides has long been challenged by reactivity mismatch and poor chemoselectivity. Here we report nickel-catalysed cross-electrophile coupling enabled by a tridentate ligand that controls the sequence of electrophile activation, allowing direct construction of alkynyl–alkyl bonds. This ligand-controlled strategy affords internal alkynes from unactivated primary, secondary, and tertiary alkyl halides with broad functional-group tolerance and enables reductive coupling of an unactivated tertiary alkyl electrophile with an alkynyl partner. Mechanistic studies reveal that the tridentate ligand enforces an unusual sequential activation pathway, in which the Ni(0) catalyst engages the alkyl halide prior to oxidative addition of the alkynyl partner. This alkyl-first activation mode ensures high chemoselectivity while suppressing homocoupling pathways, in contrast to conventional cross-electrophile coupling strategies that rely on rate-matching of electrophile reactivity. Overall, this study expands the scope of alkynyl–alkyl coupling and demonstrates how ligand control over activation sequence can enable challenging carbon–carbon bond-formation between mismatched electrophiles. Cross-electrophile coupling between unactivated alkyl halides and alkynyl halides has long been challenged by reactivity mismatch and poor chemoselectivity. Here the authors report nickel-catalysed crosselectrophile coupling enabled by a tridentate ligand that controls the sequence of electrophile activation, allowing direct construction of alkynyl–alkyl bonds.