Sequential Regioselective C-H Functionalization of Thiophenes.
Matthew H Daniels1, Jeremy R Armand2, Kian L Tan1
1Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Organic Letters
|July 9, 2016
Summary
This study introduces a new method for functionalizing five-membered heterocycles, enabling diverse substitutions on thiophene rings using C-H activation in water.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
Background:
- Sequential functionalization of heterocycles is crucial for drug discovery.
- C-H activation offers efficient synthetic routes but often requires harsh conditions.
Purpose of the Study:
- To develop a versatile method for sequential C-H functionalization of five-membered heterocycles.
- To achieve regioselective synthesis of substituted thiophenes.
- To explore environmentally friendly reaction conditions.
Main Methods:
- Utilized a pH-sensitive directing group for C-H activation.
- Performed C-H arylation reactions in aqueous media.
- Employed a surfactant to enhance reaction efficiency and product recovery.
Main Results:
- Achieved both directed and non-directed C-H activation pathways.
- Synthesized 2,3,4- and 2,4,5-substituted thiophenes.
- Demonstrated improved yields and mass recovery in water using a surfactant.
Conclusions:
- The developed method provides access to diverse thiophene derivatives.
- The pH-sensitive directing group acts as an 'on/off' switch for regiocontrol.
- This approach offers a powerful strategy for generating molecular diversity in medicinally relevant scaffolds.
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