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.

本研究通过调控邻氮醌（o-azaquinone）介体的结构，对可生成高度取代1,4-苯并恶嗪衍生物的电化学诱导级联反应的适用范围与反应机理进行了系统探究。该反应序列可在室温、无金属条件下原位生成环加成反应的两个底物，实现邻氮醌杂二烯与二级烯胺亲双烯体之间的区域专一性反电子需求狄尔斯-阿尔德（inverse-electron-demand Diels−Alder, IEDDA）反应；而这两种底物均为常规化学方法难以获取的不稳定中间体。研究发现，由取代2-氨基间苯二酚底物生成的缺电子邻氮醌类中间体，可适配该级联反应，具有良好的普适性。而对于缺少2-羟基的邻氨基苯酚衍生物而言，所生成的邻氮醌物种无法催化胺氧化为相应的亚胺（即烯胺亲双烯体的前体），原因在于该类底物无法形成高反应性希夫碱环状过渡态所需的分子内氢键。为解决这一问题，本研究开发了一种氧化-反电子需求狄尔斯-阿尔德串联反应作为替代方案：该反应在预先制备的烯胺存在下原位生成邻氮醌中间体。这两种一锅法合成策略均可对环加成反应的两个底物进行结构修饰，有望为生物活性1,4-苯并恶嗪衍生物的化合物库构建提供有力支持。