Annulation reactions provide an important and divergent approach to desirable ring systems by combining two fragments containing appropriate functionalities. Usually, these link matched nucleophilic and electrophilic sites on each component (e.g. Robinson Annulation) or proceed concertedly, such as the Diels–Alder reaction. However, examples that combine di-acceptor fragments with bis-nucleophiles, are scarce. This poster will describe the synthesis of 1,4-dioxanes from oxetan-3-ols and 1,2-diols using Brønsted acid catalysis. Importantly, this provides an overall annulation reaction and allows a divergent preparation of these heterocycles, which themselves are important motifs in medicinal chemistry. The one-pot process involves selective activation of the hydroxyl group on oxetane for generation of an oxetane carbocation, formation of a hydroxyl-containing oxetane ether intermediate and intra-molecular ring-opening of the oxetane ether. This reactivity makes oxetan-3-ols formal 1,2-bis-carbocation synthons that react with 1,2-bis-nucleophiles. The reaction was optimized and strong Brønsted acids such as Tf2NH were crucial for activation of the oxetanols in the presence of aliphatic diols. The usefulness of the reaction was showcased through the synthesis of 24 examples of 1,4-dioxanes including fused rings and spirocycles. The reactions proceeded in high yields, regio and diastereoselectivity. The protocol was extended towards the synthesis of further heterocycles such as dithianes, oxathianes, benzodioxanes and dioxanones. The utility of the methanol handle on the 1,4-dioxane products was shown through oxidation and alkylation reactions to incorporate further medicinally-relevant functionality.

Oxetan-3-ols as 1,2-bis-electrophiles in a Brønsted acid catalyzed synthesis of 1,4-dioxanes

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ACS Fall 2022

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