Stereochemistry of benzodiazepinooxazoles: crystal structure and NMR spectroscopic investigations of new conformational variants of mexazolam analogues

Abstract

The varied stereochemistry of mexazolam analogues is described on the basis of six crystal-structure analyses of the 11b-hydro (2), methyl (3 and 4), phenyl (5) and 2′-chlorophenyl (6; mexazolam) derivatives of 3-methylbenzodiazepinooxazole and the benzodiazepinooxazole (1), all determined by X-ray diffraction techniques. Two new comformations for the benzodiazepinooxazole ring system have been found in these analyses, i.e., a flat conformation Y_II in the case of 2 and 3, and a skewed conformation Y_I in 1. The usual ‘boat-wing’ conformation X_I has been found in compounds 4–6. The solution-state ¹H NMR spectra of 1, 3 and 4 at room temperature have been examined by phenyl ring-current effects and support retention of the three types of solid-state conformation. In polar solvents, all these compounds (except for 1) show a diastereoisomeric equilibrium of trans↔cis interconversion through epimerization at the 11b position. The diastereoisomeric and conformational differences in these compounds are discussed along with the steric interaction of the substituents.