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Accessing sulfonamides via formal SO2 insertion into C-N bonds
Myojeong Kim1, Carys E Obertone1, Christopher B Kelly2
1Department of Chemistry, University of Chicago, Chicago, IL, USA.
Nature Chemistry
|June 20, 2025
Summary
This study introduces a new method for synthesizing primary sulfonamides directly from primary amines via sulfur dioxide (SO2) insertion. This approach simplifies drug discovery by enabling rapid library diversification and modification of active pharmaceutical ingredients.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Chemical Synthesis
Background:
- Functional group interconversions are crucial for lead optimization and library diversification in medicinal chemistry.
- Direct synthesis of primary sulfonamides is challenging due to the need for preactivation of starting materials.
Purpose of the Study:
- To develop a novel method for the direct synthesis of primary sulfonamides from primary amines.
- To enable efficient library diversification and modification of active pharmaceutical ingredients.
Main Methods:
- Sulfur dioxide (SO2) insertion into the C-N bond of primary amines using a dual-function anomeric amide reagent.
- Mechanistic studies involving isodiazene radical chain mechanism.
- High-throughput library diversification and application to approved active pharmaceutical ingredients.
Main Results:
- Direct synthesis of primary sulfonamides from primary amines without preactivation.
- The developed protocol tolerates a wide range of functionalities.
- Successful application in high-throughput library diversification and modification of existing drugs.
Conclusions:
- The novel SO2 insertion method provides a facile route to primary sulfonamides, inverting nitrogen properties.
- This method facilitates drug discovery through efficient library synthesis and modification.
- The protocol enables isosteric replacement strategies, such as CO-to-SO2 replacement.
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