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

Abstract

The CÀ 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 CÀ N cross-coupling cycle for a thermally promoted catalyst system using organic amine base have not been elucidated. Here we disclose an efficient new nickelcatalyzed protocol for the CÀ 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 4quinolones. 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.

Ni‐Catalyzed Photochemical C−N Coupling of Amides with (Hetero)aryl Chlorides

“…Recently, Stradiotto [4c] proposed a Ni 0/II pathway in nickel catalyzed amidation under thermal catalytic conditions, and suggested that the reductive elimination of a putative (L)‐Ni(II)(2‐Ac−Ph)(amido) species bearing a bisphosphine ligand is facile. Bahamonde and co‐workers [8b] proposed a Ni 0/I/II/III pathway in Ni‐photoredox mediated amidation.…”

A Borane Lewis Acid in the Secondary Coordination Sphere of a Ni(II) Imido Imparts Distinct C–H Activation Selectivity

“…When 6a was treated with a combination of 9-azajulolidine and sodium t -pentoxide, we observed the reductive elimination product N -phenyl- N -adamantyl amine in 26% yield (Figure ). , These results represent a proof of principle that reductive elimination can be induced using a suitable set of reagents.…”

Comparative Screening of DalPhos/Ni Catalysts in C‐N Cross‐couplings of (Hetero)aryl Chlorides Enables Development of Aminopyrazole Cross‐couplings with Amine Base

“…Rather, we opted to conduct an alternative screening campaign using the inexpensive and soluble organic amine base DBU, paired with the presumptive chloride scavenger NaTFA (so‐called ‘dual‐base’ system [18] ). While we have successfully applied this approach in nickel‐catalyzed C−N cross‐couplings of fluoroalkylamines and amides, [17i–k] as well as in challenging α‐arylation chemistry, [27] the application of dual‐base systems remains unexplored in the context of nickel‐catalyzed C−N cross‐couplings involving nucleophiles a – d with (hetero)aryl chlorides. As with K 2 CO 3 , the catalytic performance achieved when using DBU/NaTFA was found to be inferior to that observed with NaO t Bu (Figure 3), with≥70 % conversion to the target complex being limited to following cases: 3 a ( C1 , C4 , and C5 ), 3 d ( C2 – C5 ), 4 a ( C1 , C4 , and C6 ), and 4 d ( C3 – C5 ).…”