康 · 学术 | Reaction of the Day No. 1747

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

Lixue Zhang, Guoyu Cheng, Fabin Zhou, Xin Yang, Huicheng Cheng, Mei Yu*, Dahong Jiang, Peng Zhou, FukYee Kwong*, Wenjun Tang*, and Ji-cheng Shi*

College of Chemistry, Maoming Technology Center of Organic Materials, Guangdong University of Petrochemical Technology, Maoming, Guangdong, China;

Department of Chemistry, The Chinese University of Hong Kong Shatin, Hong Kong, China;

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

—Chem. Eur. J.,2026. DOI: org/10.1002/chem.71356.

Recommended by Shi Li _ MOC

KEYWORDS: Pd catalysis, arylation, C-N coupling (反应类型), aryl halides, five-membered heteroaryl halides, secondary aliphatic amines (原料), aryl amies, arylation products (产物), C(sp2)-N (成键类型),TRuPhos,NaOTMS(其他)

ABSTRACT: 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)PdII(OTMS)], formed from the oxidative addition product and the base, which then reacts with the amine to yield the amido complex [(TRuPhos)(Ar)PdII(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)PdIIX(HNR1R2)] of the oxidative addition product to amine having less sterically hindered cyclic amines cannot be ruled out.

Evolving Ligand Design from Phenylphosphines to Terphenyl Phosphines for Palladium-Catalyzed C-N Cross-Coupling

Synthesis of Terphenyl Phosphines Ligands

Matching Bases and Comparing the Precatalyst for Aminations of 4-Bromothiazole with Morpholine

Performance Comparison of Terphenyl Phosphines with Other Ligands on Five?Membered Heteroaryl Substrates

Substrate Scope (selected examples) 

Proposed Mechanism

Summary and Comments

Prof. Ji-cheng Shi et al. designed and synthesized the terphenyl phosphine ligand TRuPhos, when used as a catalyst precursor, is highly efficient for the C-N coupling of secondary aliphatic amines. It is particularly effective for the coupling of five-membered heteroaryl halides with cyclic secondary aliphatic amines (including α-branched, sterically hindered ones) as well as acyclic aliphatic amines. NaOTMS, KOTMS, Cs2CO3, and NaOtBu are all effective bases. 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 suggest that when NaOTMS or KOTMS is used as the base, the transmetalation most likely proceeds via the [(TRuPhos)(Ar)Pd‖(OTMS)] intermediate formed fromthe oxidative addition product and the base, which subsequently reacts with the amine to afford [(TRuPhos)(Ar)Pd‖(NR1R2)]. When the strong base NaOtBu is employed, the direct formation of [(TRuPhos)(Ar)Pd‖(NR1R2)] from the oxidative addition product and the amide anion cannot be ruled out. For sterically unhindered cyclic amines, even a pathway involving the formation of the adduct intermediate [(TRuPhos)(Ar)Pd‖Br(HNR1R2)] from the oxidative addition product and the amine cannot be excluded.