Reactivity Umpolung of Amides in Organic Synthesis

Abstract Amides are important carboxylic acid derivatives, having wide applications in chemistry, biochemistry, and material science. Due to the conjugation (n N ‐π* C=O ), the carbonyl group of amides is the least electrophilic and the C alpha −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.