Modular Access to N-SF5 Azetidines
Renzhe Li1, Chao Hu1, Chang Liu1
1Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390, United States.
Journal of the American Chemical Society
|September 12, 2025
Summary
A new method synthesizes N-SF5 azetidines using SF5-transfer reagents and strained bicyclobutanes. These novel scaffolds offer potential in medicinal chemistry due to their stability and lipophilicity.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
Background:
- Development of novel heterocyclic scaffolds is crucial for drug discovery.
- Sulfur pentafluoride (SF5) functional groups can impart unique properties to molecules.
Purpose of the Study:
- To develop a general and modular strategy for synthesizing N-SF5 azetidines.
- To explore the utility of these new scaffolds in medicinal chemistry.
Main Methods:
- Utilized bench-stable and scalable SF5-transfer reagents.
- Employed strain-release difunctionalization reactions with azabicyclo[1.1.0]butanes.
- Investigated reactions with various substituents (ketone, ester, alkyl, aryl).
Main Results:
- Successfully synthesized a new class of N-SF5 azetidines.
- The method demonstrated mild reaction conditions and broad functional group tolerance.
- The resulting N-SF5 azetidines exhibited high aqueous stability and increased lipophilicity.
Conclusions:
- Established a versatile synthetic route to N-SF5 azetidines.
- N-SF5 azetidines represent a novel class of potential bioisosteres for medicinal chemistry.
- The unique properties of N-SF5 azetidines warrant further investigation in drug design.
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