Peptide therapeutics have recently gained increased attention from the pharmaceutical industry due to their high potency and specificity. Compared to natural peptides and proteins, modified peptides or peptidomimetics with non-natural linkages and side chains often exhibit enhanced biological activities, which make them interesting targets as new drug candidates. During the past decades, Pd-catalysed selective C–H functionalisation has attracted considerable attention as a pathway to late-stage peptide modification.^[1]

Despite the considerable progress in directed C–H functionalisation of amino acids, late-stage C(sp³)–H functionalisation of peptides without an exogenous directing group remains to be developed. Moreover, existing methods are limited to the N-terminal primary C(sp³)–H bonds of peptides.^[2] Herein, we present the use of an amidoxime methyl ether, which can be incorporated into peptides at any amide bond, as a directing group for primary and secondary C(sp³)–H arylation of peptides including the unprecedented C(sp³)–H arylation of internal peptide residues. Under the optimised reaction conditions, β-arylated tri- and tetrapeptides were obtained in moderate to good yield (40–71%) and diastereoselectivity (3–20:1). Removal of amidoxime was also achieved to generate the parent amide.