Intermolecular Enantioselective Benzylic C(sp³)−H Amination by Cationic Copper Catalysis**

Abstract

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp3)−H functionalization by hydrogen‐atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp3)−H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp3)−H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen‐atom transfer.

Recent developments for intermolecular enantioselective amination of non-acidic C(sp3)–H bonds

“…Shortly afterwards, Zhou and co-workers reported a related intermolecular enantioselective benzylic C–H amidation by cationic copper catalysis using DTBP as an oxidant under thermal conditions (Scheme 14). 32,33 In this method, excess of the C–H substrate (4 equiv.) is required, and the amide is used as limiting reagent.…”

A General Photocatalytic Strategy for Nucleophilic Amination of Primary and Secondary Benzylic C–H Bonds

“…Despite these important advances, expansion of N -nucleophile identity beyond nitriles in solvent quantity has been comparatively less explored. Copper-catalyzed platforms, including variants of the original Karasch–Sosnocky reaction as well as more recent developments by Stahl, Liu, and others, have proven most versatile, enabling C–H (sulfonyl)­amidation, − azolation, and azidation. , Alternatively, transition-metal-free platforms for C­(sp 3 )–H (sulfonyl)­amidation − and C­(sp 3 )–H azolation − exist, but each method and set of reaction conditions is confined to a single nucleophile class (amides, sulfonamides, or azoles, but never all three within one protocol) (Figure B). Moreover, many still require stoichiometric oxidants such as Selectfluor, NFSI, or DDQ.…”

Atom Transfer Radical Coupling Enables Highly Enantioselective Carbo-Oxygenation of Alkenes with Hydrocarbons

“…Another widely employed strategy is controllable radical C–H functionalization via a hydrogen atom transfer (HAT) process, which finds extensive use in the functionalization of hydrocarbons . In this context, transition-metal-catalyzed radical relay, chiral Lewis acid catalysis, and organocatalyst-mediated radical coupling have enabled enantioselective transformations of aliphatic C–H bonds (Scheme A, middle and bottom). Despite these impressive advancements, there remains a pressing demand for new strategies that can facilitate straightforward conversion of hydrocarbon feedstocks into valuable chiral molecules.…”