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.