Theoretical Insights Regarding the Cycloaddition Behavior of Push-Pull Stabilized Carbonyl Ylides

A series of diazoamido keto esters were prepared by the reaction of N-substituted 3-carbethoxy-2-piperidone with n-butylmagnesium chloride followed by the addition of ethyl 2-diazomalonyl chloride. Treatment of these diazo amides with rhodium(II) acetate afforded transient push-pull carbonyl ylide dipoles which could be readily trapped with electron deficient dipolarophiles. All attempts to induce the dipolar cycloaddition to occur across tethered alkenyl pi-bonds failed to give internal cycloadducts. However, placing a sp(2) center on the tethered side chain was found to result in the formation of a tricyclic adduct in 95% yield. The stereochemistry of the cycloadduct was firmly established by an X-ray crystallographic study and occurred endo with respect to the amido carbonyl ylide dipole. A detailed computational study was undertaken to provide better insight into the factors that influence the intramolecular cycloaddition process. The calculations indicate that a severe cross-ring 1,3-diaxial interaction caused by the bridgehead methyl group promotes a boat or twist-boat conformation in the piperidine ring fused to the newly forming one. The presence of a carbonyl group in the dipolarophile tether helps to relieve the steric congestion by virtue of favoring a second boat in the latter ring. Without the C=O group, both nascent and piperidine rings are in the chair conformation at lowest energy, and the reaction barrier is disadvantaged by 5.6 kcal/mol, allowing other competing processes to intervene.