Enantioselective Synthesis of Substituted Piperidines by Addition of Aryl Grignard Reagents to Pyridine N-Oxides

Abstract

The synthesis of optically active piperidines by enantioselective addition of aryl Grignard reagents to pyridine N-oxides and lithium binolate followed by reduction is reported for the first time. The reaction results in high yields (51-94%) in combination with good ee (54-80%). Some of these products were subsequently recrystallized, affording enhanced optical purities (>99% ee).

Sulfoxide-Directed Enantioselective Synthesis of Functionalized Tetrahydropyridines

“…Piperidines and 3-hydroxypiperidines are prevalent motifs within nature as well as in conformationally restricted peptidomimetics and synthetic drugs . Their presence in numerous bioactive compounds and their pronounced pharmacological properties have attracted considerable attention to the asymmetric syntheses of these targets . One of the most versatile routes to these nitrogen-containing frameworks is the aza-Diels–Alder reaction involving either aza-dienophiles or aza-dienes .…”

Organocatalytic Enantioselective Oxidative CH Alkenylation and Arylation of N‐Carbamoyl Tetrahydropyridines and Tetrahydro‐β‐carbolines

“…However, practical catalytic asymmetric methods that provide access to these structures have not been well established. Olsson and Almqvist disclosed an enantioselective addition of aryl Grignard reagents to 4‐phenylpyridine N ‐oxides with up to 80 % ee 3h. However, a stoichiometric amount of a chiral lithium binolate reagent was required.…”

Recent Developments in the Chemistry of Heteroaromatic N-Oxides

“…In addition to the dehydration, the initial adduct could be oxidized back to the pyridine Noxide, 54,55 or formed asymmetrically en route to chiral piperidines following reduction (Scheme 24). 56…”