Tandem Amination/Oxetane Ring Opening toward Benzomorpholines

Abstract

Herein, a tandem approach that allows rapid access to the benzomorpholine scaffold is reported. This operationally simple method allows for valuable heterocycles to be isolated in moderate to high yields. The overall transformation consists of an initial C−N coupling, demonstrated using traditional Ullmann or Buchwald−Hartwig conditions, followed by an in situ oxetane ring opening. A range of functionality is tolerated on the aryl ring, and the cyclization exposes a pendant hydroxymethyl substituent, providing opportunities for further functionalization.

Recent advances in the tandem copper-catalyzed Ullmann–GoldbergN-arylation–cyclization strategies

“…In 2021, DeRatt and co-workers disclosed the coupling reaction between 3-bromo-2-naphthol and oxetan-3-amine under copper catalysis to provide benzomorpholines. The reaction proceeds via ring opening of oxetane, which facilitates the C–N coupling; the nucleophilic NH undergoes N -arylation followed by O -alkylation to furnish the cyclized moiety 107 (Scheme 88).…”

Oxetan-3-ols as 1,2-bis-Electrophiles in a Brønsted-Acid-Catalyzed Synthesis of 1,4-Dioxanes

“… 15 Kuduk recently reported tandem amination and oxetane opening for the preparation of benzomorpholines. 16 …”

“…This has included the enantioselective synthesis of 1,4-dioxanes from preformed hydroxy-ether-containing oxetanes (Figure C) . Kuduk recently reported tandem amination and oxetane opening for the preparation of benzomorpholines …”

Unexpected Isomerization of Oxetane-Carboxylic Acids

“…Intended intramolecular isomerizations of oxetanes by nucleophiles have been reported in the literature (Scheme ). , In most cases, these reactions required additional activation of the oxetane ring by Lewis acid catalysts (In, Sc, Fe, BF 3 , Co, Pd, phosphoric acids, etc.). In our case, many oxetane-carboxylic acids easily isomerized while being stored or slightly heated, which required no external catalysis.…”