Piperidines are the most common nitrogen-containing heterocycle in FDA approved drugs, and these motifs are often substituted at the N-position. However, examples of N-(hetero)arylation of piperidines via C-N coupling methods are sparse when the the aryl electrophile is electron-rich, hindered, or a 5-membered heterocycle. We report an alternative approach that forms such products from a reductive amination/aza-Michael addition reaction sequence of an amino(hetero)arene and a bis-electrophile, forging both the piperidine ring and the desired N-aryl bond. The products of this sequence are formed in high diastereoselectivity, and this method allows for facile access to hindered N-(hetero)aryl piperidines containing electron-rich and 5-membered heteroaryl substituents on the piperidine nitrogen, which are challenging structures to form via Pd-catalyzed C-N coupling. The origins of the observed diastereoselectivity were investigated by DFT, and these studies suggest that a facially selective protonation of an enol intermediate leads to the often high observed diastereoselectivity.

Diastereoselective synthesis of N-(hetero)aryl-piperidines

ACS Fall 2020 Virtual Meeting

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