The Diels-Alder cycloaddition has been demonstrated as one of the most useful reactions available to synthetic chemists, due to its ability to generate a great deal of molecular complexity in a single step. Through the highly chemoselective formation of two carbon-carbon s-bonds and up to four chiral centers, this reaction has enabled facile synthetic access to motifs common in bioactive molecules, drug leads, and natural products. The establishment of Lewis acid-catalyzed Diels-Alder reactions of alpha, beta-unsaturated carbonyl dienophiles via oxygen lone pair complexation has allowed for more efficient pursuit of desired structures. We demonstrate a similar Lewis acid-promoted Diels-Alder reaction, employing vinylpyridines and other vinyl <i>N</i>-heterocycles as dienophiles, and have undertaken the establishment of this method (Figure 1a). These reactions proceed at higher rates and lower temperatures, and with higher yields, diastereoselectivites, and regioselectivities than their thermal counterparts—thus enabling the facile production of cyclohexenyl aromatic <i>N-</i>heterocycles, a common moiety among natural products and small molecule pharmaceutical leads (Figure 1b). Reaction optimization, scope, and selected mechanistic studies will be presented.

Lewis acid-promoted Diels-Alder reactions of vinylheteroaromatics

ACS Fall 2021

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