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Updated: May 12, 2025

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
Synthesis of α-Aryl and α-Heteroaryl 4-Silyloxy Piperidines via a One-Pot Negishi Cross-Coupling Approach
Matthew T Gill1, Lucy A Tomczyk1, Andres R Gomez-Angel1
1Department of Chemistry, University of York, York, YO10 5DD, U.K.
Abstract:
The direct α-arylation of a protected 4-hydroxy piperidine via a one-pot Negishi cross-coupling reaction is described. The methodology uses a single solvent, toluene, for the lithiation/transmetallation/Negishi sequence and 20 examples are presented. Of note, the high-yielding cross-coupling of a range of pharmaceutically relevant heteroaryl bromides is reported. The reactions show high levels of 2,4-cis-diastereoselectivity and further functionalizations are also described. Piperidine is the most common nitrogen heterocycle in approved drugs and our approach delivers such heterocycles via a direct diastereoselective α-functionalization of 4-substituted N-Boc piperidines; as such, the approach is ready to be utilized in the pharmaceutical industry.
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