Electrochemically induced cascade reaction for the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives.
The scope and mechanism of an electrochemically induced cascade reaction, which leads to highly substituted 1,4-benzoxazine derivatives, have been explored through the variation of the structure of the o-azaquinone mediator. This reaction sequence, wherein both cycloaddition partners are generated in situ, at room temperature, under metal-free conditions, allows the regiospecific inverse-electron-demand Diels-Alder (IEDDA) reaction of an o-azaquinone heterodiene and a secondary alkylenamine dienophile, two chemically nonaccessible unstable entities. The cascade reaction was found to be general with electron-poor o-azaquinone entities generated from substituted 2-aminoresorcinol substrates. In the case of o-aminophenol derivatives which lack the 2-hydroxyl group, the generated o-azaquinone species failed to catalyze the oxidation of the amine to the corresponding imine, precursor of the enamine dienophile, because the absence of an intramolecular hydrogen bond at the origin of a highly reactive Schiff base cyclic transition state. To overcome this problem, a tandem oxidation-IEDDA reaction, in which the o-azaquinone is generated in the presence of a preformed enamine, has been developed as an alternative. These one-pot methodologies, which offer the opportunity to introduce variations in both cycloaddition partners, should be particularly useful for the development of libraries of biologically relevant 1,4-benzoxazine derivatives.
Xu
Daiwang
D
UMR 8638 CNRS-Université Paris 5, Synthèse et Structure de Molécules d'Intérêt Pharmacologique, Faculté des Sciences Pharmaceutiques et Biologiques, 75270 Paris Cedex 06, France.
Chiaroni
Angèle
A
Fleury
Maurice-Bernard
MB
Largeron
Martine
M
D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004563:Electrochemistry; D006900:Hydroxylation; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011336:Probability
D048588:Benzoxazines