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Complementary Site-Selective Sulfonylation of Aromatic Amines by Superacid Activation
Paul Bourbon1, Emeline Appert1,2, Agnès Martin-Mingot1
1Université de Poitiers, UMR-CNRS 7285, IC2MP, Superacid Lab - Organic Synthesis Team, 4 rue Michel Brunet, TSA 51106, 86073 Poitiers Cedex 9, France.
Organic Letters
|May 17, 2021
Summary
Superacids enable selective arene sulfonylation of aniline and indole derivatives at low temperatures. This novel method overcomes natural regioselectivity, allowing functionalization of complex molecules like pharmaceuticals.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
Background:
- Electrophilic aromatic substitution typically follows innate regioselectivity.
- Functionalizing complex molecules like alkaloids and APIs often requires multi-step protection/deprotection strategies.
Purpose of the Study:
- To develop a novel, site-selective sulfonylation method for arenes under superacidic conditions.
- To overcome inherent regioselectivity limitations in electrophilic aromatic substitution.
- To enable late-stage functionalization of complex organic molecules.
Main Methods:
- Sulfonylation of aniline and indole derivatives using arenesulfonic acids or arenesulfonyl hydrazides.
- Utilizing superacidic conditions at low temperatures.
- Employing protonation to modify functional-group directing effects.
Main Results:
- Achieved site-selective sulfonylation of aniline and indole derivatives.
- Demonstrated nonclassical site functionalization by overcoming innate regioselectivity.
- Successfully applied the method to late-stage functionalization of natural alkaloids and active pharmaceutical ingredients via protonation-based protection.
Conclusions:
- Superacid-mediated sulfonylation offers a complementary approach to existing methods.
- The developed technique allows for precise, late-stage functionalization of valuable organic compounds.
- Protonation-directed functionalization expands the synthetic toolkit for complex molecule synthesis.
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