Direct N-SF₅ and N-SF₄CF₃ Bond Formation through Strain-Release Functionalization of 3-Substituted...

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Fluorine Chemistry

Background:

• Direct heteroatom-SF5 bond formation is rare, limiting exploration of N-SF5 motifs.
• Existing methods for SF5 group introduction are primarily focused on carbon-SF5 bonds.

Purpose of the Study:

• To develop a method for direct N-SF5 bond formation.
• To explore the stability and synthetic utility of N-SF5 azetidines.
• To investigate the potential of N-SF5 as a sulfonamide bioisostere.

Main Methods:

• Strain-release pentafluorosulfanylation of 3-aryl [1.1.0]azabicyclobutanes using SF5Cl.
• Synthesis of N-SF4CF3 azetidines using trans-CF3SF4Cl.
• DFT calculations, Hammett analyses, and radical trapping experiments for mechanistic studies.
• Synthesis and ADME profiling of an N-SF5 derivative of a spleen tyrosine kinase inhibitor.

Main Results:

• Successful direct N-SF5 and N-SF4CF3 bond formation in azetidine scaffolds.
• N-SF5 azetidines exhibit remarkable chemical stability and undergo diverse synthetic modifications.
• Mechanistic studies support a radical chain propagation mechanism.
• N-SF5 azetidines show potential as bioisosteric replacements for sulfonamides, offering enhanced lipophilicity.

Conclusions:

• This work establishes a new synthetic route to previously inaccessible N-SF5 and N-SF4CF3 azetidines.
• The developed methodology provides foundational knowledge on the properties and reactivity of these novel motifs.
• N-SF5 azetidines represent a promising new class of compounds for medicinal chemistry applications.