Deuterodehalogenation Under Net Reductive or Redox-Neutral Conditions Enabled by Paired Electrolysis

Area of Science:

• Organic Chemistry
• Electrochemistry
• Medicinal Chemistry

Background:

• Deuterated active pharmaceutical ingredients (APIs) are gaining interest for fine-tuning drug performance via kinetic isotope effects (KIE).
• Deuterium isotope labeling is crucial for studying reaction mechanisms and synthesizing complex molecules.
• Selective deuteration methods are highly sought after in organic synthesis.

Purpose of the Study:

• To introduce a novel electrochemical method for selective deuterodehalogenation of benzylic halides.
• To utilize inexpensive deuterium oxide (D2O) as the deuterium source.
• To explore the mechanism and scope of the developed deuteration reaction.

Main Methods:

• Electrochemical deuterodehalogenation of benzylic halides.
• Radical-polar crossover mechanism.
• Use of deuterium oxide (D2O) as the deuterium source.
• Sequential paired electrolysis with varying sacrificial reductants.

Main Results:

• Demonstrated broad functional group compatibility with various aryl and heteroaryl benzylic halides.
• Achieved selective deuteration of benzylic halides.
• Uncovered a sequential paired electrolysis regime enabling switchable redox-neutral or reductive reactions for sulfur-containing substrates.

Conclusions:

• The developed electrochemical method provides a selective and efficient route for deuterating benzylic halides.
• The method is compatible with a wide range of substrates and utilizes an inexpensive deuterium source.
• The sequential paired electrolysis offers tunable reactivity for complex synthetic challenges.