Despite the prevalence of the N-H aziridine motif in bioactive natural products and its clear advantages versus N-protected derivatives as synthetic building blocks, no practical methods have emerged for their direct synthesis from un-functionalized olefins until 2014 when the Kürti lab, in collaboration with the Falck and Ess labs, disclosed a direct and stereospecific N-H and N-Me aziridination method in the presence of di-rhodium complexes as homogenous catalysts. Prior to this publication, all reported methods for direct and stereospecific olefin aziridination invariably required a strong electron-withdrawing group to be attached to the N atom. The presence of the N-protecting/activating group greatly restricts the utility of the aziridine product as removal of this electron-withdrawing group necessitates the use of harsh reaction conditions that often result in the non-productive opening/destruction of the aziridine ring. Primary and N-alkyl arylamine motifs are key functional groups in pharmaceuticals, agrochemicals and functional materials as well as in bioactive natural products. However, there is a dearth of generally applicable methods for the direct replacement of aryl hydrogens with –NH2/-NHalkyl moieties. A mild dirhodium-catalyzed C-H amination method has been developed for the conversion of structurally diverse monocyclic and fused aromatics to the corresponding primary and N-alkyl arylamines using either N-unsubstituted- or N-alkyl-O-(p-toluenesulfonyl)hydroxylamines as aminating agents. The methodology is operationally simple, scalable, and fast at or below ambient temperature. Recently the Kürti lab developed a novel method for the direct electrophilic primary and secondary amination of aryl- metals in the presence of Cu(I)-salts. This transformation offers a practical solution for a long-standing synthetic problem of aminating heteroarylmetals directly and efficiently. In addition, the method does not rely on the presence of directing groups and requires only equimolar amounts of the aminating reagent. It is anticipated that this general and operationally simple amination approach will find wide utility in the synthesis of structurally complex molecules such as APIs and natural products.

Stereospecific N-H/N-alkyl aziridination of unactivated olefins, C-H amination of arenes and primary/secondary amination of (hetero)arylmetals

2019 Spring National Meeting

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