Amide activation: an emerging tool for chemoselective synthesis

Abstract

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.

Synthesis of Benzazepinones via Intramolecular Cyclization Involving Ketene Iminium Intermediates

“…Since keteniminium salt intermediates were for the first time described in the late sixties, the field of application of this chemistry was constantly expanded to access new transformations. Among the plethora of accessible scaffolds, cyclobutanones stemming from a [2+2] cycloaddition with an alkene partner are undeniably the most often encountered and can be performed intermolecularly as well as intramolecularly . Besides that, other reactions involving keteniminium intermediates have been described more recently such as 6 π ‐electrocyclizations leading to 3‐aminobenzothiophenes, aminonaphthalenes, and more recently, 3‐aminothiophenes .…”

N-Acylphthalimides: Efficient Acyl Coupling Reagents in Suzuki–Miyaura Cross-Coupling by N–C Cleavage Catalyzed by Pd–PEPPSI Precatalysts

“…Furthermore, polyfluorinated substrates (3f), biaryl amides (3g), as well as heterocycles that are important from the medicinal chemistry standpoint (3h) were competent substrates for the coupling. Finally, the reaction conditions were even compatible with the challenging alkyl amides (3i), which often require extensive optimization of the reaction parameters due to less facile metal insertion [1][2][3][4][5][6][7][8]. With the catalyst system in hand, the scope of the reaction with respect to the N-acylphthalimide component was next investigated (Scheme 2).…”

“…The cross-coupling of amides by transition metal-catalyzed N-C acyl cleavage has emerged as a powerful method for the construction of C-C and C-X bonds, enabling the utilization of traditionally inert amide derivatives in cross-coupling reactions of broad synthetic importance [1][2][3][4][5][6][7][8]. The amide bond cross-coupling manifold hinges upon the availability of amide bond precursors to achieve facile metal insertion into the N-C bond under operationally simple and functional group-tolerant reaction conditions [9,10].…”

A Mild Synthesis of Bicyclic Alkoxyoxazolium Salts from Proline and Pipecolic Acid Derivatives

“…Pleasingly, an additional ester on the aliphatic chain does not interfere in the process. [2e] It is also noteworthy that a phenyl ring in proximity to the activated amide ( 2c ) does not trigger Friedel‐Crafts reactivity. The reaction was also found to be amenable to pipecolic acid derivatives ( 2f – 2j ).…”