Sequential Nucleophilic Arylation/Ring-Contractive Rearrangement of <i>N</i>-Alkoxylactams

3-(2H)-isoxazolone is an important skeletal structure in medicinal and agricultural chemistry. However, its synthetic methodology has limited substrate scope and requires unconventional substrate synthesis. Meanwhile, gold-catalyzed intramolecular oxidative cross-coupling involving the 5/6-endo-dig cyclization of substrates bearing an ynone structure has not been reported because of an undesirable protonation as a side-reaction. Thus, we hypothesized that the reactivity of cyclic N-alkoxypropiolamides would suppress protonation and allow dual functionalization. As a result, sequential gold-catalyzed 5-endo-dig cyclization, oxidative cross-coupling, and hydroxylation of N-alkoxypropiolamides was developed to synthesize 4-aryl-3-(2H)-isoxazolones with a hydroxy group. In an optimization study, dimethylformamide (DMF) and H 2 O were effective solvents for the sequential reaction. This method enabled 3-(2H)-isoxazolone backbone synthesis with the introduction of an aryl and hydroxy group in a single procedure. Moreover, a tolerance toward reactive functional groups, such as ketocarbonyl groups, was observed. Some chemical transformations of the synthesized 4-aryl-3-(2H)-isoxazolone were conducted to demonstrate the feasibility of functional group interconversion, CÀ C bond formation, and additional heterocycle synthesis. Notably, a fluorescent tetracyclic heterocycle was obtained by intramolecular oxidative cross-coupling. Control experiments indicated that the reactivity for protonation was suppressed by an alkoxyamide moiety. Therefore, the chemoselectivity of oxyarylation was improved. Finally, density functional theory (DFT) calculations were performed to estimate the reaction pathway, which suggested that ring-opening involving solvents (H 2 O or DMF) is important for these sequential reactions.

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Sequential Nucleophilic Arylation/Ring-Contractive Rearrangement of N-Alkoxylactams

Cited by 9 publications

References 71 publications

Dehomologation and Ring Contraction Strategies

Dehomologation and Ring Contraction Strategies

Transition‐Metal‐Free Reactions of Amides by Tetrahedral Intermediates

Gold‐Catalyzed Oxyarylation/Hydroxylation of N‐Alkoxypropiolamides for Chemoselective Synthesis of 4‐Aryl‐3‐(2H)‐isoxazolones

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