Triflic acid-promoted post-Ugi condensation for the assembly of 2,6-diarylmorpholin-3-ones

Abstract

We report a two-step one-pot synthesis of the 2,6-diarylmorpholin-3-one core based on the Ugi reaction of 2-oxoaldehyde with 2-hydroxycarboxylic acid, a primary amine and tert-butyl isocyanide followed by a triflic acid-promoted intramolecular condensation accompanied by the loss of the isocyanide-originated amide moiety. The overall transformation proceeds with complete retention of stereoconfiguration at the 2-hydroxycarboxylic acid-derived chiral center, allowing the target morpholin-3-ones to be obtained in an enantiopure form. Subsequent double bond hydrogenation and amide reduction allow the degree of unsaturation to be reduced, providing a convenient entry to the cis-2,6-diphenylmorpholine motif.