Syntheses and Reactions of Divinylhydroxylamine Intermediates And Copper-Catalyzed Vinylation of Oximes

Heterocyclic compounds are essential components of bioactive molecules and versatile building blocks in natural product synthesis. Specifically, the functionalized 5-membered nitrogen-containing heterocycles are ubiquitous in naturally occurring as well synthetic drug molecules. In the Anderson group, the modular syntheses of densely functionalized pyrrolines and pyrrolidines are leveraged by the weak N–O bond in hydroxylamine derivatives. These complex molecules are envisioned through rearrangement of transient intermediate N,O- divinylhydroxylamine, which is accessed by two different modular approaches: (1) by O- vinylation of N-vinylnitrones enabled by [3+2] cycloaddition reaction and (2) by N-vinylation of the 4-isoxazolines, an O-vinylhydroxylamine species, via nucleophilic addition. The pyrrolines prepared from the strain-promoted as well as the thermal [3+2]–[3,3’] cascade reactions not only open new chemical spaces by offering functional group compatibilities that are complimentary to literature methods, but also demonstrate potent abilities in derivatization, which is beneficial for drug discovery chemistry. The addition-rearrangement cascade reactions that produce 2- aminopyrrolines and 2-alkylidenepyrrolidines offer new and facile retrosynthetic disconnects, improving existing linear approaches. Meanwhile, the cycloaddition-rearrangement cascade reaction is one of the manifestations of the profound synthetic utility of electron-deficient N- vinylnitrones that are prepared by a copper-catalyzed amination of oximes in the Anderson group. To improve the reaction, the mechanism of the copper catalysis was investigated. The mechanistic investigation found intriguing characteristics that enable the unique N-vinylation reaction. Based on these characteristics, two alternative vinylation conditions were established.