Site-selective Photoredox-Catalyzed Late-stage Benzylic Hydrogen Isotope Exchange

Area of Science:

• Organic Chemistry
• Photocatalysis
• Isotope Chemistry

Background:

• Hydrogen isotope exchange (HIE) is crucial for synthesizing isotopically labeled compounds.
• Selective functionalization of benzylic positions remains a challenge in organic synthesis.

Purpose of the Study:

• To develop a regioselective visible light photoredox-catalyzed HIE method for benzylic positions.
• To enable late-stage functionalization of complex molecules with deuterium.

Main Methods:

• Dual catalytic system employing an acridinium photocatalyst and a thiol-based hydrogen atom transfer catalyst.
• Utilized D2O as a cost-effective and simple deuterium source.
• Investigated reaction mechanisms using experimental studies and DFT calculations.

Main Results:

• Achieved highly regioselective HIE at electron-rich benzylic positions.
• Demonstrated unprecedented selectivity for HIE between competing benzylic and alpha-heteroatom positions.
• Successfully applied the method for late-stage deuterium labeling of natural compounds and drug derivatives.

Conclusions:

• The developed method provides a powerful tool for selective deuterium incorporation into complex organic molecules.
• The dual catalytic system and visible light activation offer an efficient and practical approach to HIE.
• Understanding the reaction mechanism, including the role of halogenated solvents, is key to optimizing the process.