Direct Electrochemical Synthesis of Pentafluorophenyl Esters via Oxyl-Radical-Promoted Nucleophilic Aromatic Substitution

Abstract

An electrochemical coupling between carboxylic acids and pentafluorophenol (PFP–OH) to access synthetically versatile pentafluorophenyl (PFP) esters has been developed. Novel reactivity of PFP–OH was turned on by modulating its oxidation state, leveraging both its native O-nucleophilicity and its latent, oxidation-induced C-electrophilicity to promote a unique cascade of nucleophilic aromatic and acyl substitutions. Its esterification with acids was thus achieved for the first time without exogenous dehydrating agents. The acidity of PFP–OH and the oxidizability of its conjugate base enabled its mild and selective activation via deprotonation–oxidation, readily affording PFP esters that are useful in many applications (peptide synthesis, chemical biology, etc.) and that contain redox-sensitive functional groups. Finally, we verified in a unified forum that an amino-acid-derived PFP ester can be converted into a range of acyl-substitution products while retaining key stereochemical information, and we demonstrated that PFP esters have excellent stability to hydrolysis, comparing favorably even to N-hydroxysuccinimidyl (NHS) esters.