Pd-Catalyzed N-Arylation of Secondary Acyclic Amides: Catalyst Development, Scope, and Computational Study

TLDR

The study develops an efficient N‑arylation of acyclic secondary amides using aryl nonaflates, triflates, and chlorides. The authors investigated ligand features through synthesis, mechanistic experiments, and computational analysis. The optimized biaryl phosphine ligand, featuring a methoxy‑substituted top ring and two electron‑withdrawing 3,5‑bis(trifluoromethyl)phenyl groups, enables efficient N‑arylation of acyclic secondary amides and facilitates amide binding to the Pd(II) intermediate.

Abstract

We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance of (1) a methoxy group on the aromatic carbon of the “top ring” ortho to the phosphorus and (2) two highly electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate.