Disubstituted Meldrum's Acid: Another Scaffold with SuFEx-like Reactivity

Area of Science:

• Organic Chemistry
• Chemical Biology

Background:

• Sulfur Fluoride Exchange (SuFEx) chemistry is a powerful click reaction class with applications in drug discovery and materials science.
• Traditional SuFEx reactivity is limited to sulfur and fluorine-containing compounds, hindering the development of new scaffolds.

Purpose of the Study:

• To explore SuFEx-like reactivity in novel, non-sulfur/fluorine scaffolds.
• To identify and characterize a new carbon-based scaffold exhibiting SuFEx-like reactivity.

Main Methods:

• Modification of Meldrum's acid to enhance carbonyl electrophilicity and steric hindrance.
• Reactions with O-, S-, and N-nucleophiles using Barton's base or DBU.
• Development of a catalytic protocol for SuFEx-like reactions.

Main Results:

• Disubstituted Meldrum's acid identified as a novel carbon-based scaffold with SuFEx-like reactivity.
• Successful demonstration of exchange reactions with various nucleophiles.
• Development and application of a catalytic protocol for drug derivatization, including gram-scale acetaminophen modification.

Conclusions:

• Disubstituted Meldrum's acid offers a versatile platform for SuFEx-like click chemistry beyond traditional sulfur and fluorine compounds.
• The developed catalytic protocol enables efficient drug derivatization and modification.