Despite the exhaustive literature on enamines and enamides, tertiary enamides have only recently proved their enamidic reactivity toward several classes of electrophiles. Moreover, N-Acyliminium ions (NAIs) are highly reactive electrophiles that have been widely used in intramolecular cyclizations and intermolecular additions for accessing structurally diverse scaffolds of broad biological interest. In this context, we focused on enamides equipped with N-acyliminium ion precursors that were obtained through reduction of ynamides tethered to N-imides. Ynamides were reduced to enamides with NaBH4 when bearing an ester group and in a two-step process (NiP2 followed by NaBH4 reduction) when bearing an aryl group. Intramolecular Lewis acid-mediated trapping of N-acyliminium ions provided a variety of polyfunctionalized medium-sized diaza-heterocycles of pharmacological interest. The reaction tolerates several N-imides skeletons, various substituents on the ynamide function, as well as two- to four-carbon linker chains. In this way, 1,5-diazocanes and 1,5-diazonanes are accessible, allowing an expansion of routes to various diaza-heterocycles attractive in the field of drug design.

Trapping of N-acyliminium ions with enamides: Approach to medium-sized diaza-heterocycles

2019 Fall National Meeting

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