General Method for Ni-Catalyzed C–N Cross-Couplings of (Hetero)Aryl Chlorides with Anilines and Aliphatic Amines under Homogeneous Conditions Using a Dual-Base Strategy

Abstract

A general method for the Ni-catalyzed Buchwald–Hartwig amination of (hetero)­aryl chlorides using both anilines and aliphatic amines under homogeneous conditions has been developed. Key to the success of this method is the implementation of a dual-base strategy that utilizes an amine base combined with a soluble halide scavenger that allows for the use of a single air-stable, commercially available Ni­(II)-precatalyst and phosphine ligand [(R,S)-Josiphos] combination to promote aminations across a broad scope of (hetero)­aryl chlorides and pharmaceutically relevant amine nucleophiles at catalyst loadings as low as 1.0 mol %.

Ligand-Enabled Nickel Catalysis for the O-Arylation of Alcohols and Phenols with (Hetero)aryl Chlorides Using a Soluble Organic Base

“…Building on advances in Pd- and Cu-catalyzed C–N cross-coupling in which such bases spanning a broad p K BH + range (e.g., phosphazenes, guanidines, amidines, amines, and so on.) have been applied, Buchwald and co-workers in 2020 demonstrated the use of an organic base (NEt 3 ) in Ni-catalyzed C–N cross-coupling under thermal conditions . However, no reports documenting the successful use of organic bases in what are typically more challenging thermally promoted Ni-catalyzed O -arylations of aliphatic alcohols and phenols have appeared in the literature.…”

Thermal Nickel-Catalyzed N-Arylation of NH-Sulfoximines with (Hetero)aryl Chlorides Enabled by PhPAd-DalPhos Ligation

“…Substitution of Cs 2 CO 3 for either NaO t Bu (entry 3) or K 2 CO 3 (entry 4) afforded inferior results. Using so-called “dual-base” mixtures involving the putative halide scavenger sodium trifluoracetate (NaTFA) paired with either 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, entry 5) or 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, entry 6), in some cases proved effective but ultimately fell short of the performance achieved under the conditions in entry 1. While the use of tert -butylimino-tri(pyrrolidino)phosphorane (BTPP) in combination with NaTFA afforded excellent conversion to 3b – 3d (entry 7), given the relatively high cost and lack of wide commercial availability of BTPP, we opted to retain Cs 2 CO 3 as our preferred base in this chemistry.…”