The Terphenyl Phosphines as Effective and Affordable Ligands for Pd-Catalyzed Arylation of Secondary Aliphatic Amines

This study investigates the performance of terphenyl phosphine palladium catalyst precursors in C-N coupling reactions of secondary aliphatic amines. The TRuPhos-based palladium catalyst precursor has been found to be highly efficient, combined with NaOTMS as base, especially for the C─N coupling of five-membered heteroaryl halides with cyclic secondary aliphatic amines (including α-branched, sterically hindered amines) as well as acyclic aliphatic amines. Replacing the 2,6‑isopropyl groups on the non‑phosphorus‑containing phenyl ring with sterically less demanding isopropoxy groups is a key reason why TRuPhos is highly efficient for the C─N coupling of bulky secondary aliphatic amines, whereas the presence or absence of an isopropyl group at the 4‑position of this phenyl ring has little effect on the catalytic performance. Mechanistic studies reveal that with NaOTMS as the base, the transmetalation pathway most likely proceeds via the intermediate [(TRuPhos)(Ar)Pd^II(OTMS)], formed from the oxidative addition product and the base, which then reacts with the amine to yield the amido complex [(TRuPhos)(Ar)Pd^II(NR¹R²)], although a direct metalation pathway between the oxidative addition product and the amide anion as strong base NaOtBu used, and a pathway through the adduct [(TRuPhos)(Ar)Pd^IIX(HNR¹R²)] of the oxidative addition product to amine having less sterically hindered cyclic amines cannot be ruled out.