New Strategies for the Functionalization of Carbonyl Derivatives via -Umpolung: From Enolates to Enolonium Ions

Conspectus Umpolung, a term describingthe reversal of innate polarity, hasbecome an indispensable tool to unlock new chemical space by overcomingthe limitations of natural polarity. Introduced by Dieter Seebachin 1979, this principle has had a tremendous impact on synthetic organicchemistry, offering previously inaccessible retrosynthetic disconnections.In contrast to the great progress made over the past decades for thegeneration of effective acyl anion synthons, the umpolung at the alpha-positionof carbonyls (converting enolates into enolonium ions) has long provedchallenging and only recently regained traction. Aiming to developsynthetic approaches to alpha-functionalization capable of complementingenolate chemistry, our group initiated, nearly 6 years ago, a programdevoted to the alpha-umpolung of carbonyl derivatives. In this Account,following an overview of established methods, we will summarize ourfindings in this rapidly developing field. We focus on two distinct,yet related, topics of two carbonyl classes: (1) amides, where umpolungis enabled by electrophilic activation, and (2) ketones, where umpolungis enabled using hypervalent iodine reagents. Our group has developedseveral protocols to allow amide umpolung and subsequent alpha-functionalization,relying on electrophilic activation. Over the course of our investigations,transformations that are particularly challenging using enolate-basedapproaches, such as the direct alpha-oxygenation, alpha-fluorination,and alpha-amination of amides as well as the synthesis of 1,4-dicarbonylsfrom amide substrates, have been unlocked. Based on some of our mostrecent studies, this method has been shown to be so general that almostany nucleophile can be added to the alpha-position of the amide.In this Account, special emphasis will be placed on the discussionof mechanistic aspects. It is important to note that recent progressin this area has involved a shift in focus, moving even further awayfrom the amide carbonyl, a development that shall also be detailedin a final subsection that highlights our latest investigations ofumpolung-based remote functionalization of the beta- and gamma-positionsof amides. The second section of this Account covers our more recentwork dedicated to the exploration of the enolonium chemistry of ketones,unlocked through the use of hypervalent iodine reagents. By placingour work in the context of previous pioneering achievements, whichmainly focused on the alpha-functionalization of carbonyls, we discussnew skeletal reorganizations of enolonium ions enabled by the uniqueproperties of incipient positive charges alpha to electron-deficientmoieties. Transformations such as intramolecular cyclopropanationsand aryl migrations are covered and supplemented by detailed insightinto the unusual nature of the intermediate species, including nonclassicalcarbocations.