Construction of β‐Phenylalanine Derivatives through Pd‐Catalyzed, C(sp²)−H (ortho) Functionalization

Abstract

This paper describes the Pd(II)‐catalyzed, picolinamide‐directing‐group‐aided C(sp2)−H (ortho) functionalization of racemic and enantiopure β‐phenylalanines and 3‐amino‐3‐phenylpropanols (1,3‐amino alcohols). The C(sp2)−H (ortho) functionalizations including arylation, bromination, iodination, and alkoxylation were attempted. The C(sp2)−H (ortho) arylation reactions gave biaryl or terphenyl‐type β‐phenylalanine scaffolds, halogenation and methoxylation reactions gave ortho C−H halogenated or methoxylated β‐phenylalanines. Additionally, the C−H arylation of an ortho‐methyl substituted β‐phenylalanine containing both C(sp2)−H and remote C(sp3)−H bonds was investigated. β‐Phenylalanine is an arylated β‐amino acid motif present in various natural products, bioactive molecules, and β‐peptides and it is a precursor to medicinally active compounds. Accordingly, this work contributes to the expansion of the library of unnatural β‐phenylalanine (β‐amino acid) derivatives through site‐selective C−H functionalization.

Recent Advances in C–H Functionalization of Pyrenes

“…Miura et al revealed [81] two examples of copper-mediated dehydrogenative biaryl coupling of the pyrene core using the picolinamide bidentate directing group-assisted C-H functionalization strategy [81][82][83][84][85][86][87][88][89]. Substrate N-(pyren-1-yl)picolinamide 22a was treated with the azole derivatives 22aa and 22ab (2 equiv) in the presence of Cu(OAc) 2 (3 equiv) and PivOH (1 equiv) in mesitylene at 165 • C for 4 h under a nitrogen atmosphere (Scheme 15).…”