Theoretical prediction of the synthesis of 2,3-dihydropyridines through Ir(III)-catalysed reaction of unsaturated oximes with alkenes

In spite of their widespread use as catalysts, 1,2,3,4,5-pentamethylcyclopentadienyl (Cp*) iridium complexes have been rarely employed in the synthesis of pyridine derivatives. Herein, we used density functional theory (DFT) calculations to predict the [Cp* Ir(OAc)](+)-catalysed synthesis of 2,3-dihydropyridines, which are important starting materials for pharmaceuticals, from alpha,beta-unsaturated oxime pivalates and alkenes. The corresponding Cp* Rh complex-catalysed processes were discussed in comparison. The simulated catalytic cycle consists of several elementary reactions, such as reversible acetate-assisted metalation-deprotonation, migratory insertion of the alkene, pivaloyl transfer, and reductive elimination. The migratory insertion of the alkene is identified as the rate-determining step, and the reductive elimination to furnish the product-ligated species makes the reaction irreversible (exergonic by about 48 kcal mol(-1)). The stabilities of the intermediates and the energy barrier of migratory insertion of the alkene can be affected by introducing substituent groups with different electronic characteristics into Cp* and the 2-position of a, b-unsaturated oxime pivalates, as well as by using polarised alkenes. The apparent activation energy of the reaction can be increased by increasing the electron-donating ability of the substituent group on Cp*, and by introducing electron-withdrawing groups into the terminus of alkenes. When a strong electrondonating group such as the amido group is introduced into the 2-position of alpha,beta-unsaturated oxime pivalates, the apparent activation energy is greatly reduced so that the reaction can occur at room temperature. In contrast, changing phenyl into the highly electron-deficient p-CF3-phenyl makes the reaction more difficult. Diastereoselectivity of the reaction was examined using cyclohexylethylene as a substrate, and a method for enhancing diastereocontrol was suggested.