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.