Reactivity Umpolung of Amides in Organic Synthesis

Amides are important carboxylic acid derivatives, having wide applications in chemistry, biochemistry, and material science. Due to the conjugation (nN-pi*C=O), the carbonyl group of amides is the least electrophilic and the Calpha-H bond of amides is the least acidic among the carbonyl derivatives, thereby making it challenging to develop highly efficient and selective transformations based on amides. Reactivity umpolung refers to the reversion of polarity of a functional group. The idea of inverting the innate polarity of organic functional groups, initially introduced by Wittig and later popularized by Seebach, marks a pivotal conceptual breakthrough in organic synthesis. In contrast to the progress for the umpolung of aldehyde, the umpolung of amides has proved challenging and only recently made notable progress. Following the elegant design, the C1 of the amide can become nucleophilic, and the C2 can be electrophilic. In this review, we attempt to summarize the reported examples that are broadly categorized as reactivity umpolung of amides. This review is structured around the umpolung of C1 through radical or carbanion reactions, as well as the umpolung of C2 through electrophilic amide activation or the unique properties of Weinreb amide. Amides are important carboxylic acid derivatives. It is widely accepted that the C1 of amide is electrophilic and the C2 is nucleophilic after the deprotonation. Following the elegant design, the C1 of the amide can become nucleophilic, and the C2 can be electrophilic. Recent examples in the context of amide umpolung are summarized and discussed.image

Automated summary

Amides are important carboxylic acid derivatives widely used in chemistry, biochemistry, and material science. Reactivity umpolung allows for the inversion of the innate polarity of functional groups. Developing efficient and selective transformations based on amides is challenging due to their low electrophilicity and weak acidity. Recent progress has been made in the umpolung of amides, with C1 becoming nucleophilic and C2 becoming electrophilic.