Regioselectivity of the trifluoroethanol-promoted intramolecular N-Boc-epoxide cyclization towards 1,3-oxazolidin-2-ones and 1,3-oxazinan-2-ones.

The intramolecular N-Boc-epoxide cyclization leading to the formation of 1,3-oxazolidin-2-one and 1,3-oxazinan-2-one derivatives has scarcely been reported in the literature. More specifically, the intramolecular cyclization of N-Boc aniline-tethered 2,3-disubstitued epoxides has never been disclosed. Herein, we demonstrate that this reaction could proceed in a diastereoselective fashion in refluxing trifluoroethanol, in the absence of any external promoter or catalyst. Substrates bearing an alkyl group at the C-3 position furnished 1,3-oxazolidin-2-ones in a completely regioselective fashion via 5-exo epoxide ring-opening cyclization, thereby paving the way to synthesize alkyl side chain-bearing analogs of the antidepressant drug toloxatone. On the other hand, replacing the alkyl group with an aryl group resulted in easily separable mixtures of 1,3-oxazolidin-2-ones and 1,3-oxazinan-2-ones, the former being obtained as the major products. Remarkably, a tetralin-bearing substrate underwent fully regioselective 6-endo ring closure to form the corresponding 1,3-oxazinan-2-one. Our present study on the intramolecular ring opening-cyclization of epoxides with a tethered N-Boc group is the most comprehensive to date and features broad substrate scope, mild transition metal-free conditions, excellent functional group tolerance, and scalability.

Switching of regioselectivity in base-mediated diastereoselective annulation of 2,3-epoxy tosylates and their N-tosylaziridine analogs with 2-mercaptobenzimidazole.

A base-mediated dinucleophilic cyclization of readily accessible 2,3-epoxy tosylates with 2-mercaptobenzimidazole has been developed for the one-pot diastereoselective synthesis of benzimidazole-based tricyclic compounds equipped with two stereogenic centres. With trans-substrates bearing an aryl or alkyl substituent at the C3 position, the reaction involves an initial S-C1 bond-forming intermolecular alkylation followed by an N-C3 bond-forming, endo-selective intramolecular epoxide ring-opening cyclization reaction. A spectacular regioselectivity switching (tandem S-C3 and N-C1 bond formation reactions) was observed with related trans-N-tosylaziridine substrates. Wide substrate scope, complete diastereoselectivity, high to complete regioselectivity and mild transition metal-free conditions render this protocol particularly efficient and practical.