Synthesis, Functionalization, and Reactivity of Vinyl Sulfondiimidamides
Katherine G Rodden1, Agamemnon E Crumpton1, Samuel E Dalton2
1Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK.
Angewandte Chemie (International Ed. in English)
|March 28, 2026
Summary
Vinyl sulfondiimidamides offer tunable electrophilicity for covalent inhibitors, reacting with biological nucleophiles. This new class of compounds expands options beyond acrylamides for drug design.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
Background:
- Acrylamides are key electrophilic warheads in covalent inhibitors.
- Modulating acrylamide electrophilicity is structurally limited, hindering drug design.
Purpose of the Study:
- Introduce vinyl sulfondiimidamides as a novel class of electrophilic motifs.
- Demonstrate tunable electrophilicity and reactivity with biological nucleophiles.
Main Methods:
- Synthesis of vinyl sulfondiimidamides via a short sequence.
- Utilizing Cope elimination as the key alkene-forming step.
- Exploring N-substituent variations to tune electrophilicity.
Main Results:
- Vinyl sulfondiimidamides react effectively with sulfur- and nitrogen-based nucleophiles.
- Electrophilicity is successfully tuned by altering imidic N-substituents.
- A diverse range of N-substituents can be incorporated.
Conclusions:
- Vinyl sulfondiimidamides represent a versatile platform for developing covalent inhibitors.
- Tunable reactivity offers advantages over traditional acrylamides in medicinal chemistry.
- The synthetic route allows for broad structural diversification.
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