Chiral α-aryl N-heterocycles are commonly found in natural products, pharmaceutical agents, and chiral catalysts but remain challenging to access via asymmetric catalysis. Herein, we report a general and modular approach for the direct enantioselective α-arylation of saturated azacycles and acyclic N-alkyl benzamides via nickel/photoredox dual catalysis. This process exploits the hydrogen atom transfer ability of photoeliminated chlorine radicals to convert azacycles to the corresponding α-amino alkyl radicals that then are coupled with ubiquitous and inexpensive (hetero)­aryl chlorides. These coupling reactions require no oxidants or organometallic reagents, feature feedstock starting materials, a broad substrate scope, and high enantioselectivities, and are applicable to late-stage diversification of medicinally relevant complex molecules. Mechanistic studies suggest that the nickel catalyst uncommonly plays multiple roles, accomplishing chlorine radical generation, α-amino radical capture, cross-coupling, and asymmetric induction.

Asymmetric C(sp3)−H functionalization is a persistent challenge in organic synthesis. Here, we report an asymmetric benzylic C−H acylation of alkylarenes employing carboxylic acids as acyl surrogates for the synthesis of α-aryl ketones via nickel and photoredox dual catalysis. This mild yet straightforward protocol transforms a diverse array of feedstock carboxylic acids and simple alkyl benzenes into highly valuable α-aryl ketones with high enantioselectivities. The utility of this method is showcased in the gram-scale synthesis and late-stage modification of medicinally relevant molecules. Mechanistic studies suggest a photocatalytically generated bromine radical can perform benzylic C−H cleavage to activate alkylarenes as nucleophilic coupling partners which can then engage in a nickel-catalyzed asymmetric acyl cross-coupling reaction. This bromine-radical-mediated C−H activation strategy can be also applied to the enantioselective coupling of alkylarenes with chloroformate for the synthesis of chiral α-aryl esters.

Site- and enantioselective cross-coupling of saturated N-heterocycles and carboxylic acids—two of the most abundant and versatile functionalities—to form pharmaceutically relevant α-acylated amine derivatives remains a major challenge in organic synthesis. Here, we report a general strategy for the highly site- and enantioselective α-acylation of saturated N-heterocycles with in situ-activated carboxylic acids. This modular approach exploits the hydrogen-atom-transfer reactivity of photocatalytically generated chlorine radicals in combination with asymmetric nickel catalysis to selectively functionalize cyclic α-amino C−H bonds in the presence of benzylic, allylic, acyclic α-amino, and α-oxy methylene groups. The mild and scalable protocol requires no organometallic reagents, displays excellent chemo-, site- and enantioselectivity, and is amenable to late-stage diversification, including a modular synthesis of previously inaccessible Taxol derivatives. Mechanistic studies highlight the exceptional versatility of the chiral nickel catalyst in orchestrating (i) catalytic chlorine elimination, (ii) alkyl radical capture, (iii) cross-coupling, and (iv) asymmetric induction.

The cross‐electrophile coupling (XEC) represents a powerful strategy for C−C bond formation. However, controlling the enantioselectivity in these processes remains a challenge. Here, we report an unprecedented enantioselective XEC of α‐amino acid derivatives with aryl bromides, enabled by alcohols as reducing agents via Ni/photoredox catalysis. This mechanistically distinct approach exploits the ability of photocatalytically generated α‐hydroxyalkyl radicals to convert alkyl electrophiles to the corresponding alkyl radicals that are then enantioselectively coupled with aryl bromides. The readily scalable protocol allows modular access to valuable enantioenriched benzylic amines from abundant and inexpensive precursors, and is applicable to late‐stage diversification with broad functional group tolerance. Mechanistic studies rationalize the versatility of this alcohol‐based reactivity for radical generation and subsequent asymmetric cross‐coupling. We expect that this alcohol‐based cross‐coupling will render a general platform for the development of appealing yet challenging enantioselective XECs.