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.
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.
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