C2-selective direct alkynylation of indoles
Gergely L Tolnai1, Stephanie Ganss, Jonathan P Brand
1Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland.
Organic Letters
|December 20, 2012
Summary
Researchers developed a new method for C2-selective alkynylation of indoles using a hypervalent iodine reagent. This efficient process provides direct access to substituted alkynyl indoles, offering an alternative to traditional cross-coupling reactions.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Catalysis
Background:
- Indole derivatives are crucial in medicinal chemistry and materials science.
- Efficient methods for functionalizing indoles, particularly at the C2 position, are highly sought after.
- Classical cross-coupling reactions often face limitations with certain functional groups.
Purpose of the Study:
- To develop a novel and highly selective method for the C2-alkynylation of indoles.
- To introduce a convenient and robust synthetic route to substituted alkynyl indoles.
- To explore a Pd(II)-catalyzed reaction orthogonal to traditional Pd(0) cross-coupling.
Main Methods:
- Utilized the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX).
- Employed Palladium(II) as a catalyst for the alkynylation reaction.
- Investigated the reaction's tolerance to bromide and iodide substituents.
Main Results:
- Achieved the first C2-selective alkynylation of indoles using TIPS-EBX and Pd(II).
- Demonstrated a single-step synthesis of substituted alkynyl indoles with very high C2 selectivity.
- Showcased orthogonality to Pd(0) cross-coupling, tolerating bromide and iodide groups.
- Confirmed facile removal of the silyl protecting group to yield terminal acetylenes.
Conclusions:
- The developed Pd(II)-catalyzed method offers a highly selective and efficient route to C2-alkynylated indoles.
- This new reaction expands the synthetic toolkit for indole functionalization.
- The method's robustness and tolerance to halogens make it valuable for complex molecule synthesis.
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