It is textbook knowledge that carboxamides benefit from increased stabilisation of the electrophilic carbonyl carbon when compared to other carbonyl and carboxyl derivatives. This results in a considerably reduced reactivity towards nucleophiles. Accordingly, a perception has been developed of amides as significantly less useful functional handles than their ester and acid chloride counterparts. However, a significant body of research on the selective activation of amides to achieve powerful transformations under mild conditions has emerged over the past decades. This review article aims at placing electrophilic amide activation in both a historical context and in that of natural product synthesis, highlighting the synthetic applications and the potential of this approach.

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C–X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.

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A chemoselective and robust protocol for the γ‐oxidation of β,γ‐unsaturated amides is reported. In this method, electrophilic amide activation, in a rare application to unsaturated amides, enables a regioselective reaction with TEMPO resulting in the title products. Radical cyclisation reactions and oxidation of the synthesised products highlight the synthetic utility of the products obtained.

A direct C−C coupling process that merges Michael acceptors and Eschenmoser's salt is presented. Although reminiscent of the Morita–Baylis–Hillman reaction, this process requires no Lewis base catalyst. The underlying mechanism was unveiled by a combination of kinetic, isotopic labelling experiments as well as computational investigations, which showcased the critical role of HFIP as a superior mediator for proton‐transfer events as well as the decisive role of the halide counterion.

A regioselective synthesis of pyridines by the addition of malonate anions to pyridine N-oxide derivatives, which have been activated by trifluoromethanesulfonic anhydride, is reported. The reaction selectively affords either 2- or 4-substituted pyridines in good yields.Graphical abstract Electronic supplementary materialThe online version of this article (10.1007/s00706-017-2081-y) contains supplementary material, which is available to authorized users.

Herein we report a method for the synthesis of α-aryl acrylamides leveraging polar S-to-C aryl migrations induced by a Lewis basic organocatalyst. In contrast to previously reported radical aryl migrations of sulfonyl acrylimides, this polar process enables subsequent elimination, ultimately leading to a formal aryl/ hydrogen exchange including SO 2 extrusion. This reaction is selective for electron-deficient aromatic groups, while tolerating a variety of substituents on nitrogen and in the β-position, and it delivers useful building blocks for further transformations, including cycloaddition and cyclisation reactions. The mechanism was investigated in detail using quantum chemical calculations, which unexpectedly revealed the Lewis base to be involved in several decisive steps.

Ein chemoselektives und robustes Protokoll zur γ‐Oxidation von β,γ‐ungesättigten Amiden wird dargelegt. Bei dieser Methode ermöglicht elektrophile Amidaktivierung eine bei ungesättigten Amiden bisher selten angewendete regioselektive Reaktion mit TEMPO, die zu γ‐aminoxylierten α,β‐ungesättigten Amiden führt. Radikalische Zyklisierungen und Oxidationen der synthetisierten Produkte untermauern die Nützlichkeit der hergestellten Verbindungen.