Tandem radical cyclisation of enamides mediated by tin hydride; pyrrolizidinone or indolizidinone ring formation

Abstract

The tin hydride-mediated cyclisation of a variety of enamides under mild, neutral reaction conditions has been investigated. Enamides derived from pyruvate were reacted with R₃SnH–AIBN to generate α-carbamoylmethyl radicals which underwent 5-endo cyclisation to give cyclic α-amino ester radicals. Subsequent 6-endo or 5-exo cyclisation was observed leading to the formation of indolizidinone and pyrrolizidinone products respectively. The reaction pathway was governed by the alkene substitution. If an electron-rich double bond was used the cyclisation was under thermodynamic control and a 6-membered ring was observed. Five-membered rings were formed on reaction of the α-amino ester radical with unsaturated esters or ketones. The ester or ketone functional group can stabilise the radical produced on 5-exo cyclisation and pyrrolizidinones could be prepared in up to 66% yield. Stannane by-products were also isolated from some reactions. These were thought to be derived from a competitive Michael-type addition of the tin radical to the enamide double bond.