Titanium‐Mediated Synthesis of Spirocyclic NH‐Azetidines from Oxime Ethers

Abstract

The Ti IV -mediated synthesis of spirocyclic NHazetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through aproposed Kulinkovich-type mechanism, at itanacyclopropane intermediate forms and serves as a1 ,2aliphatic dianion equivalent, inserting into the 1,2-dielectrophilc oxime ether to ultimately give rise to the desired Nheterocyclic four-membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH-azetidines in as ingle step.

Constructing four-membered heterocycles by cycloisomerization

“…9 There are other synthetic methods to construct oxetane and/or azetidine such as ring-expansion using ylide, 10 -lactam reduction, 11 C−H bond amination, 12 and Ti VI -mediated spirocyclic azetidine synthesis. 13 Overall, the synthesis of less hindered oxetanes or azetidines is facile owing to classical intramolecular displacement reactions. However, new synthetic methods for sterically hindered and polysubstituted products are required.…”

Intermolecular 2+2 Imine-Olefin Photocycloadditions Enabled by Cu(I)-Alkene MLCT

“…itrogen heterocycles are prevalent motifs in small molecule pharmaceuticals and their rapid construction continues to drive new reaction development 1 . While 3-, 5and 6-membered N-heterocycles are exceptionally common, made possible by a variety of synthetically accessible routes for their construction, 4-membered heterocycles are scarce by comparison despite the promising biological activity displayed by many azetidine-containing compounds [2][3][4][5][6][7] . The 2 + 2 photocycloaddition of two π-components is a prototypical approach to 4-membered ring construction.…”