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

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Abstract
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 π-bonds failed to give internal cycloadducts. However, placing a sp2 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 CO 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.

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