Alternating Current-Driven Hydrogen Isotope Labeling of Aliphatic Amines Using 1,3-Propanedithiol as an Efficient...

Hydrogen isotope exchange (HIE) plays a pivotal role in the synthesis of isotopically labeled compounds, which are widely used in the pharmaceutical industry for drug pharmacokinetic and pharmacodynamic studies. While electrochemical HIE has emerged as a powerful strategy for site-selective labeling of C-H bonds, extending its application to alkyl amine-containing drugs has been hindered by the instability of α-amino radicals and their susceptibility to overoxidation. Here, we report the first electrochemical HIE protocol that enables efficient deuterium (D) labeling of both cyclic and acyclic alkyl amine substrates. The key innovation lies in using 1,3-propanedithiol as the hydrogen atom transfer (HAT) catalyst, which could in situ generate a potent HAT agent─a mercaptothiyl radical─via alternating current electrolysis. This radical benefits from a significantly weakened effective S-H bond dissociation energy of 34 kcal/mol compared to conventional monothiol HAT catalysts (∼80 kcal/mol), driven by exothermic disulfide ring formation. Mechanistic studies and computational analyses reveal a strong structure-activity relationship among dithiols, identifying 1,3-propanedithiol as the optimal catalyst, which is uniquely suited to balance fast HAT kinetics with efficient regeneration of the dithiol. The application of this method to over 30 pharmaceutically relevant compounds achieved up to 3.7 D per molecule. This work addresses a long-standing challenge in electrochemical HIE and introduces a new HAT platform with broad potential in synthetic and biological chemistry.