Stereochemistry of N-acyltetrahydro-1,5-benzodiazepines using NMR spectra, X-ray crystallography and semiempirical MO calculations

Abstract

The preferred conformations of N-acyl derivatives of 2,2,4-trimethyl-1<i style="">H</i>-tetrahydro-1,5-benzodiazepines <b style="">6-9</b> have been studied using NMR spectral techniques. In the case of N₁,N₅-diformyl derivative <b style="">9,</b> there is an equilibrium between the boat <b style="">BE</b> and chair <b style="">CE</b> conformations in which the two N-CO groups at N₁ and N₅ adopt <i style="">endo</i> and <i style="">exo</i> orientation, respectively. The average energy barrier for the interconversion between the <i style="">major</i> (<b style="">BE</b>) and <i style="">minor</i> (<b style="">CE</b>) conformers of <b style="">9</b> has been found to be 79.7 kJ/mol on the basis of the dynamic ¹H NMR spectral studies. The N₅-benzoyl- and N₅-phenylcarbamoyltetrahydrobenzodiazepines <b style="">6</b> and <b style="">7</b> prefer boat conformations <b style="">BE</b> with <i style="">exo</i> orientation of the N-CO groups. The X-ray crystal structure of <b style="">7</b> also shows the boat conformation <b style="">BE</b> with the <i style="">exo</i> orientation of the N-CO group. The diacetyl derivative <b style="">8</b> prefers a boat conformation <b style="">BE</b> in which the N-acetyl group at N₁ is predominantly at the <i style="">endo</i> position while that of N₅ is at <i style="">exo</i> orientation. The semiempirical molecular orbital calculations (<b style="">AM1</b> and <b style="">PM3</b>) support the conformational preferences derived from the NMR results.