Configurational stability of bis-ortho-methyl Tröger's base: methylene bridge substitution with retention of stereochemistry

Abstract

Racemic bis-ortho-methoxy-substituted Tröger's base (TB) was prepared by the lithiation of the corresponding bromo compound, and readily resolved via the preparation of a diastereomeric salt using dibenzoyl-L-tartaric acid (DBTA). Reactions of chiral bis-ortho-methyl Tröger's base with formamides afforded methylene bridge substitution products with up to 96% ee in the presence of POCl₃. However, chiral TB with para-methyl groups gave the target products as a racemic mixture. The results are discussed by considering a ring inversion of the cyclic iminium intermediates. The configurational stability of ortho-methyl Tröger's base was established by substituting the methylene bridge with the Vilsmeier reagent. This study also reveals that TB derivatives containing either bis-ortho-methoxy or bromo groups are configurationally less stable than the corresponding ortho-methyl derivative.