Dynamic and static conformational analysis of acylated tetrahydrobenzazepines

A detailed high-field NMR analysis of several acylated tetrahydrobenzazepines, supported by molecular mechanics calculations, indicates that the heterocyclic ring in these compounds exists in a chair conformation, with the carbonyl oriented anti to the aryl moiety in the dominant rotamer. Surprisingly, ring methylenes are typically diastereotopic at room temperature, as the barriers for the process of enantiomerization of the seven-membered ring are much higher than expected. It is shown that ring inversion is correlated (but not concerted) with rotation of the amide moiety, as the carbonyl is forced out of conjugation with the nitrogen in the transition state.