Synthesis of trans-2,5-Disubstituted Tetrahydro-1-benzazepines via Nucleophilic Ring Opening of Selectively Quaternized N,N‑Acetals

A one-pot, two-step sequence involving a regiospecific quaternization of readily available aryl-fused N,N-acetals followed by a stereospecific nucleophilic ring opening has been developed. A wide range of nucleophiles have been shown to be compatible with this reaction sequence. This operationally simple methodology provides an effective route for the synthesis of a variety of trans-2,5-disubstituted tetrahydroarylazepines. In a demonstration of the utility of this reaction sequence, mozavaptan, a compound that is beneficial in the treatment of hyponatremia, has been efficiently prepared.