Pd^II-Catalyzed γ-C(sp³)–H (Hetero)arylation of Ketones Enabled by Transient Directing Groups

Abstract

Pd(II)-catalyzed γ-C(sp 3 )−H (hetero)arylation of aliphatic ketones is developed using α-amino acids as transient directing groups (TDG). A variety of aliphatic ketones were (hetero)arylated at the γ-position via a 5,6-membered fused cyclopalladation intermediate to afford the remotely arylated products in up to 88% yield. The crucial ligand effect of 2pyridone is further enhanced by reducing the loading of acid additives. Consequentially, the improved reactivity of this catalytic system has also made possible the cyclic γ-methylene C(sp 3 )−H arylation of ketones. Mechanistic investigation and comparison to the γ-C−H arylation of aldehydes revealed a structural insight for designing site-selective TDG.

Palladium-Catalyzed β-C(sp3)–H Bond Arylation of Tertiary Aldehydes Facilitated by 2-Pyridone Ligands

“…Based on the above results and previous reports [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ], a plausible catalytic cycle is proposed in Scheme 6 [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. The reversible imine formation of tertiary aliphatic aldehyde 1a with TDG1 generates imine intermediate A .…”

Ligand-Promoted Palladium-Catalyzed β-C(sp3)–H Arylation of Ketones Using Acetohydrazide as a Transient Directing Group

“…Methyl propyl ketone ( 1j ), which contains β-methylene and γ-methyl C–H bonds, gave a mixture of the β-arylation product 3j and the γ-arylation product 3j′ in a poor yield in a ratio of 2:1. 13 However, for ketones with β-methylene C–H bonds in a cyclobutyl or cyclohexyl ring ( 1k and 1l ), the reaction gave the monoarylation products 3k and 3l , respectively, in good yields. Furthermore, 1-adamantyl methyl ketone ( 1m ) could also be arylated to give 3m , albeit in a low yield.…”

C−H Functionalization of Aldehydes and Ketones with Transient Directing Groups: Recent Developments

“…[59] For his part, Yu's group reported a methyl γ-CÀ H arylation using glycine for the TDG and pyridine-2-ol L 5 as palladium ligand (Scheme 25.b). [60] Specific substrate scaffolds were used in such reactions. For instance, Sorensen's group developed an intramolecular arylation reaction of ketones 101 to synthesize benzocyclobutenes 102 (Scheme 26.a).…”

“…Similarly to aldehydes, palladium‐catalyzed methyl β‐C−H arylation of ketones 97 were described by Liao and Ji with an alkoxyamine (Scheme 25.a) [59] . For his part, Yu's group reported a methyl γ‐C−H arylation using glycine for the TDG and pyridine‐2‐ol L 5 as palladium ligand (Scheme 25.b) [60] …”