Pd(II)-Catalyzed Intermolecular Arylation of Unactivated C(sp³)–H Bonds with Aryl Bromides Enabled by 8-Aminoquinoline Auxiliary

Abstract

An example of using readily available, less reactive aryl bromides as arylating reagents in the Pd(II)-catalyzed intermolecular arylation of unactivated C(sp(3))-H bonds is described. This reaction was promoted by a crucial 8-aminoquinolinyl directing group and a K2CO3 base, enabling regiospecific installation of an aryl scaffold at the β-position of carboxamides. A mechanistic study by DFT calculations reveals a C(sp(3))-H activation-led pathway featuring the oxidative addition as the highest energy transition state.

Auxiliary‐Directed C(sp3)−H Arylation by Synergistic Photoredox and Palladium Catalysis

“…The presence of ester and halogen functionalities was also well tolerated. Although aryl bromides have been reported to engage in Pd II ‐catalysed arylation of unactivated C(sp 3 )−H bonds at 120 °C, excellent chemoselectivity was noted for the brominated derivative 26 under our conditions (Table , entry 7).…”

“…Given the effectiveness of the 8‐aminoquinoline auxiliary in Pd‐catalyzed activation of C−H bonds, we hypothesized that palladacycle II would be a suitable intermediate for a one electron oxidative addition step (Figure ). The reaction design requires irradiation of a photocatalyst, PC n , to produce the excited state complex * PC n , which undergoes exergonic single electron transfer (SET) with aryl radical precursor.…”

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

“…However, the substrate scope was limited to aliphatic acids with a β-quaternary centre, due to the well-known Thorpe–Ingold effect in cyclopalladation17, and ratios of mono- to diarylated products in the range 2.5:1 to 5:1 were observed. Thus, the use of various directing groups to achieve regioselective β-C( sp 3 )–H bond functionalization of carboxylic acid derivatives18192021222324252627282930313233343536373839404142434445 has been extensively explored in the past decades (Fig. 1).…”

“…In the same year, Daugulis reported the well-known bidentate directing group 8-aminoquinoline, which has been demonstrated to have excellent ability in assisting β-C( sp 3 )-H arylation of carboxylic acids20. Since then, a number of β-C( sp 3 )-H functionalization reactions, such as arylation212223, alkenylation24, alkylation2526, alkynylation2728, alkoxylation29, amination30 and so on3132333435, employing various transition metal catalysts, have been developed. Inspired by the assisting ability of 8-aminoquinoline, researchers developed a series of N , N -bidentate directing groups for site-selective C( sp 3 )–H bond functionalization in aliphatic acids, which provided various approaches in the synthesis of important synthetic units (Fig.…”

8-Aminoquinoline

“…Key to this reaction is use of palladium(II) trifluoroacetate catalyst (Scheme 26). 28 Further application of directed β-sp 3 C-H bond functionalization of 8-aminoquinoline amides to cyclobutane containing natural product synthesis has been reported. Interestingly, all-ciscyclobutanes can be obtained selectively (Scheme 27).…”