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.