Theoretical Insights into the Synthesis of 2,3-Dihydropyridines from Unsaturated Oximes by RhIII-Catalyzed C–H Activation – A DFT Study

A density functional theory study is performed on the reactions of ,-unsaturated oxime pivalates and alkenes through Cp*Rh-III-catalyzed (Cp* = pentamethylcyclopentadienyl) C-H activation. The catalytic cycle involves reversible metalation-deprotonation, migratory alkene insertion, pivaloyl transfer to the Rh center, and reductive elimination, among other steps. The results show that the migratory alkene insertion is rate-determining and that the reductive elimination to form the product-ligated species makes the reaction irreversible (exergonic by 60 kcal/mol). If the electron-donating ability of the substituents on the cyclopentadienyl (Cp) ligand is increased or an electron-withdrawing group is introduced into the terminus of the alkene, the apparent activation energy of the reaction increases. In contrast, if a stronger electron-donating group is introduced at the 2-position of the ,-unsaturated oxime pivalate, the apparent activation energy of the reaction decreases greatly, and the reaction can be performed at room temperature. On the other hand, for phenyl groups at the 2-position, the introduction of a more electron-deficient p-CF3-phenyl group increases the apparent activation energy. Finally, the diastereoselectivity of the reaction with cyclohexylethylene as the substrate is attributable to a clash between the cyclohexyl group and the ,alpha beta-unsaturated oxime pivalate.