Rationalizing Ring-Size Selectivity in Intramolecular Pd-Catalyzed Allylations of Resonance-Stabilized Carbanions

Abstract

Computational methods were applied to the Pd-catalyzed intramolecular allylations of resonance-stabilized carbanions obtained from amide and ketone substrates, with the aim of rationalizing the endo vs exo selectivity in the cyclizations. In addition, ester substrates were prepared and subjected to the Pd-catalyzed cyclization conditions, and were found to form lactones via exo attack. DFT calculations with the BP 8 6 /LACVP*+ level of theory with a CH 2 Cl 2 solvation correction reproduce the relative transition state energies. The preference for exo-cyclization of the nitrogen-containing starting material appears to result from the preference for near-planarity of the amide N. Both the oxygen and nitrogen tethers are too short to allow efficient endo cyclization, whereas the carbon tether is long enough to allow favorable endo cyclization. The carbon tether also disfavors the exo cyclization transition states slightly from eclipsing interaction, leading to almost isoenergetic exo and endo transition states, and thus accounting for the experimentally observed mixture of five- and seven-membered-ring products.