Anthony Millet, O. Baudoin
2015
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Journal
Organic Syntheses
Abstract
3-Arylpiperidines are important building blocks in pharmaceutical research. They are usually synthesized through the construction of the piperidine ring or the reduction of a 3-arylpyridine precursor, because the inert character of the C–H bonds in β-position to the nitrogen atom is commonly thought to preclude direct β-functionalization. Palladium-catalyzed migrative Negishi coupling was developed to directly access 3-aryl-N-Boc-piperidines in good to excellent selectivity, and with yields between 43 and 76%. The design of a new flexible phenylpyrrole-based phosphine ligand proved to be a key element to induce both efficiency and β-selectivity. Keywords: n-Butyllithium; tert-Butyl 3-(3-methoxyphenyl)piperidine-1-carboxylate; Degassed methanol; 2-(Diisoproylphosphanyl)-1-phenylpyrrole; n-Hexane; Palladium-catalyzed β-selective C(sp3)-H arylation; N-Boc-Piperidines; Teflon-coated magnetic stirbar; Toluene