Synthesis of hydroxy pyrrolidines and piperidines via free-radical cyclisations

Abstract

The tin hydride-mediated cyclisation of a variety of α- and β-amino aldehydes to form substituted pyrrolidines and piperidines under mild, neutral reaction conditions has been investigated. The amino aldehyde precursors, prepared from the corresponding amino ester or alcohol, are purified or immediately reacted with Bu₃SnH–AIBN in boiling benzene. The method is shown to be general and cyclisation of the intermediate O-stannyl ketyl is observed using a variety of (electron poor or rich) acceptor carbon–carbon double bonds to afford hydroxy-pyrrolidines or -piperidines after work-up. Related cyclisations using an alkyne or α,β-unsaturated amide radical acceptor are shown to be problematic and low-yielding. Radical cyclisation of allylic O-stannyl ketyls, generated from reaction of α,β-unsaturated ketones with tin hydride, are also shown to have application in pyrrolidine/piperidine synthesis. A dilution study suggests that the cyclisation onto a cinnamyl double bond is irreversible.

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