Efficient tin hydride-mediated radical cyclisation of secondary amides. Part 1. Synthesis of a variety of substituted pyrrolidinones

Abstract

The tin hydride-mediated 5-exo-trig cyclisation of a variety of secondary haloamides under mild, neutral reaction conditions has been investigated. Cyclisation was found to produce substituted pyrrolidinones in good to reasonable yield when the reaction was carried out in boiling toluene; lower yields were observed when using boiling benzene. The predominant formation of the trans-(C-3–C-4) isomers is consistent with a reversible cyclisation leading to the thermodynamically more stable product. The nature of the acceptor carbon–carbon double bond and substituents at the radical centre were found to influence the stereoselectivity of the cyclisation: more of the cis-isomer was isolated from precursors bearing a radical stabilising group on the alkene. This can be explained by a slower radical ring opening (or fragmentation) reaction leading to more of the kinetic (cis) product. The introduction of substituents alpha to nitrogen (which can influence the amide conformer population) improved the yield of cyclisation and substituted pyrrolidinones could be isolated in up to 76% yield.