Axially Chiral Enamides: Substituent Effects, Rotation Barriers, and Implications for their Cyclization Reactions

The barrier to rotation around the N-alkenyl bond
of 38 N-alkenyl-N-alkylacetamide
derivatives was measured (ΔG⧧ rotation varied between <8.0 and 31.0 kcal mol–1). The most important factor in controlling the rate of rotation
was the level of alkene substitution, followed by the size of the
nitrogen substituent and, finally, the size of the acyl substituent.
Tertiary enamides with four alkenyl substituents exhibited half-lives
for rotation between 5.5 days and 99 years at 298 K, sufficient to
isolate enantiomerically enriched atropisomers. The radical cyclizations
of a subset of N-alkenyl-N-benzyl-α-haloacetamides
exhibiting relatively high barriers to rotation round the N-alkenyl bond (ΔG⧧ rotation >20 kcal mol–1) were studied to determine
the regiochemistry of cyclization. Those with high barriers (>27
kcal
mol–1) did not lead to cyclization, but those with
lower values produced highly functionalized γ-lactams via a
5-endo-trig radical–polar crossover process
that was terminated by reduction, an unusual cyclopropanation sequence,
or trapping with H2O, depending upon the reaction conditions.
Because elevated temperatures were necessary for cyclization, this
precluded study of the asymmetric transfer in the reaction of individual
atropisomers. However, enantiomerically enriched atropsiomeric enamides
should be regarded as potential asymmetric building blocks for reactions
that can be accomplished at room temperature.