Copper-Catalyzed, Aminofunctionalization of Pi-Systems via O-benzoylhydroxylamines

Abstract

The design and development of novel transition-metal catalyzed amination strategies is a exceptionally important topic in the field of organic synthesis, due to their ubiquity in bioactive pharmaceuticals, agricultural, and industrially useful molecules. This importance is exemplified by the large body of work already accomplished in this field, which has built the foundation for the following work. Various methods have been reported in efforts to advance access to nitrogen-containing compounds, such as C-H activation, crossing-coupling, and simple substitution. While these methods are useful and allow for installation of the desired motif, it is common that useful nitrogen-containing molecules are of high molecular complexity. Due to this complexity, methods that allow for the installation of more than one functionality in one-step are needed. To realize this need, the field of pi-system difunctionalization offers a modular, step-economic approach to installation of aminofunctionalities in tandem with various coupling partners. Thus far, the field of amine difunctionalization has largely consisted of transition-metal catalyzed installation of electron-poor nitrogen motifs. To circumvent this limitation, use of an umpolung, electrophilic amination reagent allows for direct installation of electron rich amines, while avoiding classical issues in transition-metal catalysis, such as catalyst poisoning. Additionally, due to the electrophilic nature of such an amine precursor, a nucleophilic partner may be introduced to provide difunctionalization strategies that simultaneously install two electron-rich groups which would otherwise not be possible. Among umpolung nitrogen-precursors, O-acylhydroxylamines are especially attractive due to their facile synthesis, long-term stability, and ability to install a diverse set of cyclic and acyclic nitrogen moieties. Copper-catalyzed aminofunctionalization via O-acylhydroxylamines has been achieved with several nucleophilic coupling partners, such as phosphonates, amines, and carboxylic acids. Thus far, these methods have focused on the difunctionalization of simple alkene starting materials. To expand the available chemical space of nitrogen-containing compounds, a natural extension of this work would be the difunctionalization of dienes. Utilizing O-benzoylhydroxylamines in the presence of a copper-catalyst, the aminofunctionalization of alkenes and 1,3-dienes has been achieved. Examples include the first chiral construction of electron-rich aminolactones, the first regioselective synthesis of allylic 1,4-aminoethers, as well as aminocarbon skeletons. Beyond the novelty of such transformations, good functional group compatibility was observed, including acetals, esters, and halides.