Annuloselectivity in cycloadditions of ketenes with imines: a DFT study

The annuloselectivity defined as the annulation selectivity between [2 + 2] cycloaddition and two kinds of novel cascade [2 + 2 + 2] cycloadditions (2 ketenes + imine and ketene + 2 imines) in a Staudinger reaction to afford three classes of annulation products has been studied in depth with the density functional theory (DFT) calculations. The computed results indicate that the cascade [2 + 2 + 2] reaction of ketene 4 and ketimine 5 initiates the dimerization of the ketene as the rate-determining step, affording a lactone that further converts to α-acetylketene, followed by the [4 + 2] cycloaddition with imine 5 to furnish a 2,3-dihydro-1,3-oxazin-4-one derivative. That is very competitive to the normal Staudinger reaction. The alternative [2 + 2 + 2] cycloaddition undergoes the hetero-Diels-Alder (HDA) cycloaddition of the zwitterionic intermediates generated from ketenes and conjugated imine 11 with less steric hindrance as a good dienophile to afford 2,3,4,5-tetrahydropyrimidin-6(1H)-ones, which is the most favorable pathway in the case of the Staudinger reaction system. The HDA process is supported and confirmed experimentally by X-ray crystallography via analysis of the stereochemistry of the cycloadducts. The further investigation into the nature of the frontier molecular orbitals accounts well for the origin of the annuloselectivity. The extensive studies on ketenes containing various representative substituents reveal that ketenes with electron-donor and conjugated monosubstituents are inclined to dimerization, preferring the [2 + 2 + 2] cycloaddition of two molecules of ketenes and one molecule of imines, while less steric bulky imines with ketenes are apt to the [2 + 2 + 2] cycloaddition of one molecule of ketenes and two molecules of imines.