Proximity effects in nucleophilic addition reactions to medium-bridged twisted lactams: remarkably stable tetrahedral intermediates.

The reactions of a series of strained bicyclic and tricyclic one-carbon bridged lactams with organometallic reagents have been investigated. These amides permit isolation of a number of remarkably stable hemiaminals upon nucleophilic addition to the twisted amide bonds present in the lactam precursors. The factors that affect the stability of the resulting bridged hemiaminals are presented. In some cases, the hemiaminals were found to collapse to the open-form amino ketones in a manner expected for traditional carboxylic acid derivatives. Transannular N...C=O interactions were also observed in some nine-membered amino ketones. Additionally, tricyclic bridged lactams were found to react with some nucleophiles that typically react with ketones but not with planar amides. The effect of geometry on the reactivity of amide bonds and the amide bond distortion range that marks the boundary of amide-like and ketone-like carbonyl reactivity of lactams are also discussed.