Chiral 1,4-benzodiazepines—-XI: Kinetics of degenerate nucleophilic exchange of C(3)-hydroxy group

The rate for degenerate nucleophilic exchange (k_e) of the C(3)-OH group in the racemic compound 1 was determined in DMSO/H₂¹⁸O using mass spectrometry. Epimerization rates for diastereomers 15 and 16 were determined by polarimetry (k_ep) and NMR spectroscopy (k_r-c—for $\text{r}$ing-$\text{c}$hain tautomery). The ratio $\text{k}{}_{\mathrm{e}}\text{k}{}_{\mathrm{ep}}$ ~ 3.5 35° is close to that obtained for degenerate nucleophilic exchange of the C(3)-OMe group in the compound 1a ($\text{k}{}_{\mathrm{e}}\text{k}{}_{\mathrm{\alpha }}$ ~4, Refs. 3,4]). These data confirm the C(3)-OH substituted 1,4-benzodiazepin-2-ones lose the configurational identity of the C(3) chiral centre by both direct nucleophilic substitution of the OH group, and ring-chain tautomery processes.The synthesis of the diastereomeric compounds 15 and 16, and their chromatographic separation is described.