Mechanism of Nickel(II)-Catalyzed C(2)–H Alkynylation of Indoles with Alkynyl Bromide

The
nickel system (THF)2NiBr2/phen has recently
been shown as an efficient catalyst for the C–H bond alkynylation
of diverse heteroarenes with (triisopropylsilyl)­alkynyl bromide via
monodentate chelation assistance. Herein, we report an extensive mechanistic
investigation for the direct alkynylation of indoles involving the
well-defined nickel catalyst, which features a coordinative insertion
pathway of alkynyl bromide with the Ni­(II) catalyst. Catalytic relevant
nickel complexes, (phen)­NiCl2 (5), (phen)2NiCl2 (6) and [(phen)3Ni]·NiCl4 (7) were isolated, and the complexes 6 and 7 were structurally characterized. Well-defined
complexes were as competent as the in situ generated catalyst system
(THF)2NiBr2/phen for the alkynylation of indoles.
Various controlled studies and reactivity experiments were performed
to understand the probable pathway for the alkynylation reaction.
Kinetics analysis highlights that the complex (phen)­NiX2 acts as a precatalyst, and the involvement of substrate indole and
LiOtBu are essential for the generation
of the active catalyst. Deuterium labeling and kinetic studies suggest
that the process involving C–H cleavage and carbo-nickelation
of indole is a crucial rate influencing step. Reactivity study of
various alkynyl compounds with nickel-species highlights a migratory
insertion route for the reaction. DFT calculations firmly support
the experimental findings and suggest the coordinative insertion pathway
of alkynyl bromide rather than oxidative addition toward the nickel­(II)
center.