Preparation of Resin-Bound N-(α-Methoxyalkyl)amides: An Advantageous Use of Solid-Phase Chemistry for the Handling of Unstable Precursors of the Versatile N-Acyliminium Ions

The development of a new and efficient synthesis of resin‐bound N‐(α‐methoxyalkyl)amides is described. The condensation of aldehydes on a supported amide in the presence of trimethyl orthoformate afforded, in acidic media, the resin‐bound N‐acyliminium ion precursors. Repeating the reaction a second time led to a great improvement in yields, demonstrating one advantage of the solid‐phase chemistry for the handling of sensitive intermediates difficult to isolate. An efficient preparation of a masked resin‐bound N‐acyliminium ion is described. The condensation of aldehydes on a supported amide in the presence of trimethyl orthoformate affords, in acidic media, the resin‐bound N‐(α‐methoxyalkyl)amides (see scheme). Treated under Lewis acid conditions, this sensitive precursor gives a transient N‐acyliminium ion which can be trapped by reaction with nucleophiles.