Mapping Dual-Base-Enabled Nickel-Catalyzed Aryl Amidations: Application in the Synthesis of 4-Quinolones

Abstract

The C-N cross-coupling of (hetero)aryl (pseudo)halides with NH substrates employing nickel catalysts and organic amine bases represents an emergent strategy for the sustainable synthesis of (hetero)anilines. However, unlike protocols that rely on photoredox/electrochemical/reductant methods within Ni^I/III cycles, the reaction steps that comprise a putative Ni^0/II C-N cross-coupling cycle for a thermally promoted catalyst system using organic amine base have not been elucidated. Here we disclose an efficient new nickel-catalyzed protocol for the C-N cross-coupling of amides and 2'-(pseudo)halide-substituted acetophenones, for the first time where the (pseudo)halide is chloride or sulfonate, which makes use of the commercial bisphosphine ligand PAd2-DalPhos (L4) in combination with an organic amine base/halide scavenger, leading to 4-quinolones. Room-temperature stoichiometric experiments involving isolated Ni^{0, I, and II} species support a Ni^0/II pathway, where the combined action of DBU/NaTFA allows for room-temperature amide cross-couplings.

Keywords: 4-Quinolones; Amidation; Bisphosphine; Camps Cyclization; N-(ketoaryl)-amides.