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

Abstract

α-amino acids bearing aromatic side chains are important synthetic units in the synthesis of peptides and natural products. Although various β-C-H arylation methodologies for amino acid derivatives involving the assistance of directing groups have been extensively developed, syntheses that directly employ N-protected amino acids as starting materials remain rare. Herein, we report an N-acetylglycine-enabled Pd-catalysed carboxylate-directed β-C(sp3)-H arylation of aliphatic acids. In this way, various non-natural amino acids can be directly prepared from phthaloylalanine in one step in good to excellent yields. Furthermore, a series of aliphatic acids have been shown to be amenable to this transformation, affording β-arylated propionic acid derivatives in moderate to good yields. More importantly, this ligand-enabled direct β-C(sp3)-H arylation could be easily scaled-up to 10 g under reflux conditions, highlighting the potential utility of this synthetic method.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Zhao ( Scheme 17A ) focused on the arylation of N -phtaloyl alanines to synthesise non natural amino acids in a one-step procedure. 169 Generally, the scope of the transformation regarding aryl iodides was good, and the yields reported are in the 62–90% range. The reactions covered a wide range of para - and meta -substituted aryl iodides, one example of ortho substitution was also reported (1-fluoro-2-iodobenzene).…”

“…Advances have been made in the β-C(sp 3 )–H activation and arylation of propionic (also α-amino) acids. Zhao, 169 Yu 170 and van Gemmeren 171 all reported Pd catalysed protocols for this transformation ( Scheme 17A–C ).…”

“…Limitations were shown with acids substituted in β position as they gave only traces of the product. 169 …”

Nickel, Cobalt and Palladium Catalysed C−H Functionalization of Un‐Activated C(sp3)−H Bond

“…In 2017, Zhao et al . reported β‐C(sp 3 )−H arylation of aliphatic acids using Pd‐catalyzed and N ‐acetyl glycine carboxylate as directing group . Using 0.2 mmol of phthaloyl alanine with 0.2 mmol of 4‐iodoanisole in presence of 5 mol % of Pd(OAc) 2 as catalyst, 1 equiv.…”

Di-Palladium Complexes are Active Catalysts for Mono-N-Protected Amino Acid Accelerated Enantioselective C-H Functionalization

“…Mono-protected amino acid (MPAA) ligands have enabled remarkable advances in palladium-catalyzed C-H functionalization as a result of their ability to enhance reaction rates and to impart enantioselectivity to a range of transformations. [1][2][3][4][5][6][7][8][9][10][11] Pioneering efforts in enantioselective cyclopalladation (Fig. 1A) 12 and C-H functionalization (Fig.…”