Iron-Catalyzed Late-Stage Radical C–H Alkylamination of Phenol-Containing Drugs and Biomolecules

A modular site-selective iron-catalyzed radical amination of a number of phenol-containing biomolecules such as tyrosine-containing peptides, estrogens and other phenol-based pharmaceuticals has been developed. The method features the use of the cost-efficient combination of FeBr3 as catalyst along with triflic acid as Brønsted acid, thereby enabling the predictable appendance of morpholine and related heterocycles at the ortho C–H bond of phenols in a late-stage fashion. This alkylamination technique leverages the electron-rich nature of phenols to undergo oxidation to the corresponding phenoxyl radicals and further coupling with in situ formed electrophilic aminium radical cation species.