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 NiI/III cycles, the reaction steps that comprise a putative Ni0/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 Ni0, I, and II species support a Ni0/II pathway, where the combined action of DBU/NaTFA allows for room‐temperature amide cross‐couplings.

Mild Amide N-Arylation Enabled by Nickel-Photoredox Catalysis

“…In contrast, amide arylation cannot be achieved in the absence of organometallic reagents, and only a limited number of catalytic methods have been reported. Most of these strategies rely on Cu and Pd catalysis (Scheme a), although a few isolated examples have been mediated by Ni bisphosphine complexes (Scheme b) . While progress has been made in this area, the reduced nucleophilicity of amides still presents a challenge for promoting reductive elimination that has only been overcome by employing high reaction temperatures. − Thus, complementary methods that enable facile reductive elimination at moderate temperatures would be highly desirable to broaden the scope of this transformation.…”