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

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 <i>N</i>-deacylation of secondary amides to release amines. This method consists of <i>in situ</i> 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

Kinetic Resolution of Benzylamines via Palladium(II)-Catalyzed C–H Cross-Coupling

A Pd­(II)-catalyzed enantioselective C–H cross-coupling of benzylamines via kinetic resolution has been achieved using chiral mono-<i>N</i>-protected α-amino-<i>O</i>-methylhydroxamic acid (MPAHA) ligands. Both chiral benzylamines and <i>ortho</i>-arylated benzylamines are obtained in high enantiomeric purity. The use of a readily removable nosyl (Ns) protected amino group as the directing group is a crucial practical advantage. Moreover, the <i>ortho</i>-arylated benzylamine products could be further transformed into chiral 6-substituted 5,6-dihydro­phenanthridines as important structural motifs in natural products and bioactive molecules

A General Method for the One-Pot Reductive Functionalization of Secondary Amides

A one-pot reaction for the transformation of common secondary amides into amines with C–C bond formation is described. This method consists of <i>in situ</i> amide activation with Tf₂O–partial reduction–addition of <i>C</i>-nucleophiles. The method is general in scope, which allows employing both hard nucleophiles (RMgX, RLi) and soft nucleophiles, as well as enolates. With the use of soft nucleophiles, the reaction proceeded with high chemoselectivity at a secondary amide in the presence of ester, cyano, nitro, and tertiary amide groups

Palladium(II)-Catalyzed Enantioselective C(sp³)–H Activation Using a Chiral Hydroxamic Acid Ligand

An enantioselective method for Pd­(II)-catalyzed cross-coupling of methylene β-C­(sp³)–H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-<i>N</i>-protected α-amino-<i>O</i>-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd­(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective β-C­(sp³)–H activation of acyclic amides