Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and N-Deacylation of Secondary Amides

Abstract

The direct transformation of common secondary amides into aromatic ketimines and aromatic ketones with C-C bond formation is described. The reaction can also be used for N-deacylation of secondary amides to release amines. This method consists of in situ amide activation with triflic anhydride and intermolecular capture of the resulting highly electrophilic nitrilium intermediate with an arene. The reaction is applicable to various kinds of secondary amides (electrophiles), but only electron-rich and moderately electron-rich arenes can be used as nucleophiles. Thanks to the use of bench stable arenes instead of reactive and basic organometallics as nucleophiles, the reaction proceeded with high chemoselectivity at the secondary amido group in the presence of a series of sensitive functional groups such as aldehyde, ketone, ester, cyano, nitro, and tertiary amido groups. The reaction can be viewed as a Friedel-Crafts-type reaction using secondary amides as acylating agents or as an intermolecular version of the Bischler-Napieralski reaction.

Enamines as Surrogates of Alkyl Carbanions for the Direct Conversion of Secondary Amides to α‐Branched Ketones

“…To avoid the limitation of using alkylmetallic nucleophiles, syntheses of ketones by addition of mild nucleophiles are intriguing alternatives. In this respect, we have recently demonstrated that both alkenes and arenes could serve as effective nucleophiles for the direct transformation of secondary amides into enones and aryl ketones …”

Asymmetric Transfer Hydrogenation of Aryl Heteroaryl Ketones using Noyori‐Ikariya Catalysts

“…This compound has been reported and fully characterized. [12] To a solution of furan-2-yl(phenyl) methanol 7 (424 mg, 2.44 mmol) in DCM (10 mL) at rt was added manganese dioxide (3.18 g, 36.6 mmol). The reaction mixture was left to stir under a nitrogen atmosphere overnight.…”

Water Phase, Room Temperature, Ligand‐Free Suzuki–Miyaura Cross‐Coupling: A Green Gateway to Aryl Ketones by C–N Bond Cleavage

“…Aryl ketones are commonly utilized in the synthesis of pharmaceuticals and functional materials, Over the past decades, palladium‐catalyzed Suzuki–Miyaura coupling reaction of electrophiles, including aryl halides, esters and amides with organoboron nucleophiles for synthesizing a series of aryl ketones has been developed. It has become one of the most powerful and important synthetic methods to construct aryl ketones via selective C–N bond transformations of activated amides.…”

“…It has become one of the most powerful and important synthetic methods to construct aryl ketones via selective C–N bond transformations of activated amides. Recently, transition metal‐catalyzed amides Suzuki–Miyaura coupling for synthesis of aryl ketones has been developed by Szostak, Zou, Huang, Garg and Yamaguchi (Scheme A1). However, most of these reactions need bulky or electron‐rich phosphine or N ‐heterocyclic carbenes as ligands, which are air, moisture‐sensitive and environmentally unfriendly (Scheme A2).…”