The strain of 3- or 4-membered heterocycles can be harnessed for the generation of more complex or larger heterocyclic frameworks. While epoxides, aziridines and oxetanes have been extensively employed in ring expansion methodology, azetidines have been underutilised. This is despite the azetidine ring having comparable ring strain to aziridines. It has been shown that upon protonation azetidines are much less reactive towards ring opening than aziridines. Azetidines, therefore, present tractable building blocks because of this ring strain, predisposing them to ring opening, yet displaying relatively low reactivity. This presentation will demonstrate how Brønsted acids can be employed to ring expand 2,2-disubstituted azetidine carbamates to afford 6,6-disubstituted 1,3-oxazinan-2-ones. A reaction that was discovered for aziridine carbamates 20 years ago. Oxazinanones are six membered carbamates which have found wide use within drug discovery and organic synthesis. Yet, routes to 6,6-disubstituted examples are limited. We present methodology which can rapidly access a wide scope of 6,6-disubstituted 1,3-oxazinan-2-ones in one step from the azetidine carbamate or in one-pot from acyclic precursors. The ring expansion of azetidines derived from bioactive products is demonstrated to access highly complex final products. This methodology yields products with three orthogonal vectors, the carbamate, ester and aromatic group. The functionalization of these vectors demonstrates the utility of the 1,3-oxazinan-2-one core as a scaffold for the generation of medicinally relevant compounds. Evidence supports the formation of a benzylic carbocation which undergoes 6-exo-tet cyclization over 4-exo-tet cyclization and outcompeting deprotection of the azetidine carbamate.

Acid-mediated ring expansion of 2,2-disubstituted azetidine carbamates to 6,6-disubstituted 1,3-oxazinan-2-ones

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.