Palladium-catalyzed Suzuki–Miyaura coupling of amides by carbon–nitrogen cleavage: general strategy for amide N–C bond activation?

Organic & Biomolecular Chemistry Pub Date: 2016-02-11 DOI: 10.1039/C6OB00084C

Abstract

The first palladium-catalyzed Suzuki–Miyaura cross-coupling of amides with boronic acids for the synthesis of ketones by sterically-controlled N–C bond activation is reported. The transformation is characterized by operational simplicity using bench-stable, commercial reagents and catalysts, and a broad substrate scope, including substrates with electron-donating and withdrawing groups on both coupling partners, steric-hindrance, heterocycles, halides, esters and ketones. The scope and limitations are presented in the synthesis of >60 functionalized ketones. Mechanistic studies provide insight into the catalytic cycle of the cross-coupling, including the first experimental evidence for Pd insertion into the amide N–C bond. The synthetic utility is showcased by a gram-scale cross-coupling and cross-coupling at room temperature. Most importantly, this process provides a blueprint for the development of a plethora of metal catalyzed reactions of typically inert amide bonds via acyl-metal intermediates. A unified strategy for amide bond activation to enable metal insertion into N–C amide bond is outlined (Scheme 1).

Graphical abstract: Palladium-catalyzed Suzuki–Miyaura coupling of amides by carbon–nitrogen cleavage: general strategy for amide N–C bond activation
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