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

RSC Advances Pub Date: 2017-01-17 DOI: 10.1039/C6RA25501A

Abstract

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 α,β-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 α,β-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 electron-donating group such as the amido group is introduced into the 2-position of α,β-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.

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