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

Area of Science:

• Organic Chemistry
• Electrochemistry
• Isotope Labeling

Background:

• Hydrogen isotope exchange (HIE) is crucial for synthesizing labeled compounds used in pharmaceutical studies.
• Electrochemical HIE is effective for C-H bond labeling but limited for alkyl amines due to radical instability.

Purpose of the Study:

• To develop a novel electrochemical HIE protocol for efficient deuterium labeling of cyclic and acyclic alkyl amines.
• To overcome limitations in labeling alkyl amine-containing drugs.

Main Methods:

• Utilized alternating current electrolysis with 1,3-propanedithiol as a hydrogen atom transfer (HAT) catalyst.
• Generated a mercaptothiyl radical with a significantly weakened S-H bond dissociation energy (34 kcal/mol).
• Investigated structure-activity relationships of dithiols to identify optimal catalysts.

Main Results:

• Achieved efficient deuterium labeling for a diverse range of cyclic and acyclic alkyl amine substrates.
• Successfully applied the method to over 30 pharmaceutically relevant compounds, achieving up to 3.7 deuterium atoms per molecule.
• Identified 1,3-propanedithiol as the optimal catalyst balancing HAT kinetics and dithiol regeneration.

Conclusions:

• Presents the first electrochemical HIE protocol for deuterium labeling of alkyl amines.
• Introduces a novel HAT platform based on dithiols with broad applications in synthetic and biological chemistry.
• Addresses a significant challenge in electrochemical HIE for drug development.