Rotational Isomers of N‑Methyl‑N‑arylacetamides and Their Derived Enolates: Implications for Asymmetric Hartwig Oxindole Cyclizations

The rotational preferences of N-(2-bromo-4,6-dimethylphenyl)-N-methyl 2-phenylpropanamide were studied as a model of precursors for Hartwig asymmetric oxindole cyclizations. The atropisomers of this compound were separated by flash chromatography, and then the enantiomers were resolved and the interconversions of the stereocenter and the N–Ar axis were studied. Under thermal conditions, the axis is very stable. Under the basic conditions of the Hartwig cyclization, both the stereocenter and the chiral axis equilibrate via enolate formation. The N–Ar rotation barrier of a 2-phenylacetamide analogue was reduced from 31 kcal mol–1 in the precursor to 17 kcal mol–1 in the enolate. Reasons for this dramatic barrier reduction and implications of both N–Ar and amide C–N rotations for Hartwig cyclizations are discussed.