Structures of Highly Twisted Amides Relevant to Amide N−C Cross-Coupling: Evidence for Ground-State Amide Destabilization

• Published in: Chemistry : a European journal 2016-10, Vol.22 (41), p.14494-14498
• Main Authors: Pace, Vittorio, Holzer, Wolfgang, Meng, Guangrong, Shi, Shicheng, Lalancette, Roger, Szostak, Roman, Szostak, Michal
• Format: Article
• Language: English
• Subjects: Activation; Amides; Bonding; Bonding strength; Carbon; Chemical reactions; Chemistry; Cross coupling; Destabilization; N−C activation; rotation; steric hindrance; twisted amides
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201603543

Herein, we show that acyclic amides that have recently enabled a series of elusive transition‐metal‐catalyzed N−C activation/cross‐coupling reactions are highly twisted around the N−C(O) axis by a new destabilization mechanism of the amide bond. A unique effect of the N‐glutarimide substituent, leading to uniformly high twist (ca. 90°) irrespective of the steric effect at the carbon side of the amide bond has been found. This represents the first example of a twisted amide that does not bear significant steric hindrance at the α‐carbon atom. The 15N NMR data show linear correlations between electron density at nitrogen and amide bond twist. This study strongly supports the concept of amide bond ground‐state twist as a blueprint for activation of amides toward N−C bond cleavage. The new mechanism offers considerable opportunities for organic synthesis and biological processes involving non‐planar amide bonds. Let′s twist again! Acyclic amides that have recently been shown to be active in a series of elusive transition‐metal‐catalyzed N−C activation/cross‐coupling reactions are highly twisted around the N−C(O) axis by a new destabilization mechanism of the amide bond (see scheme).