Metallaphotoredox-Catalyzed Enantioselective Cross-Electrophile Coupling Using Alcohols as Reducing Agents.

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.

Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis.

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.

Enantioselective ß-C(sp3)-H arylation of amides via synergistic nickel and photoredox catalysis.

An enantioselective benzylic ß-C(sp3)-H arylation of amides via synergistic nickel and photoredox catalysis is reported. The C-H bond is activated by a bromine-radical-mediated C-H cleavage. This mild yet straightforward protocol provides arylation products in up to 96% yield and with up to 95% ee.

Asymmetric benzylic C(sp3)-H acylation via dual nickel and photoredox catalysis.

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.

Direct Enantioselective C(sp3)-H Acylation for the Synthesis of α-Amino Ketones.

A direct enantioselective acylation of α-amino C(sp3)-H bonds with carboxylic acids has been achieved via the merger of transition metal and photoredox catalysis. This straightforward protocol enables cross-coupling of a wide range of carboxylic acids, one class of feedstock chemicals, with readily available N-alkyl benzamides to produce highly valuable α-amino ketones in high enantioselectivities under mild conditions. The synthetic utility of this method is further demonstrated by gram scale synthesis and application to late-stage functionalization. This method provides an unprecedented solution to address the challenging stereocontrol in metallaphotoredox catalysis and C(sp3)-H functionalization. Mechanistic studies suggest the α-C(sp3)-H bond of the benzamide coupling partner is cleavage by photocatalytically generated bromine radicals to form α-amino alkyl radicals, which subsequently engages in nickel-catalyzed asymmetric acylation.

Cyanohydrin-Mediated Cyanation of Remote Unactivated C(sp3)-H Bonds.

A new approach for generation of alkoxy radical from the O-H bond of cyanohydrin promoted by visible-light photoredox catalysis is reported. The alkoxy radical triggers the successive remote HAT and intramolecular cyano migration, leading to the regioselective cyanation of remote C(sp3)-H bonds. The reaction exhibits a broad functional group tolerance that allows many sensitive groups to remain intact under mild conditions. To demonstrate the utility of method, the ketonitrile products are converted to other synthetically valuable compounds.

Tertiary-Alcohol-Directed Functionalization of Remote C(sp3 )-H Bonds by Sequential Hydrogen Atom and Heteroaryl Migrations.

Reported for the first time is a tertiary-alcohol-guided heteroarylation of remote C(sp3 )-H bonds. The mild and direct generation of alkoxyl radicals from alcohols is enabled by visible-light photocatalysis. A remote hydrogen atom and heteroaryl migration sequence are involved in the reaction. Many sensitive groups remain intact in the reaction, thus illustrating wide functional-group compatibility. This protocol provides a practical strategy for the late-stage modification of alkyl ketones.

Chemo- and Regioselective Distal Heteroaryl ipso-Migration: A General Protocol for Heteroarylation of Unactivated Alkenes.

Herein we report a novel, general protocol for distal heteroaryl ipso-migration and its application to the elusive heteroarylation of unactivated alkenes. A set of nitrogen-containing heteroaryl groups showcase the migratory aptitude. This reaction provides a variety of fluoroalkyl functionalized heteroarenes under mild reaction conditions. This is the first report of a difunctionalization of unactivated alkenes with distal heteroaryl migration.

Manganese-Catalyzed Oxidative Azidation of Cyclobutanols: Regiospecific Synthesis of Alkyl Azides by C-C Bond Cleavage.

A novel, manganese-catalyzed oxidative azidation of cyclobutanols is described. A wide range of primary, secondary, and tertiary alkyl azides were generated in synthetically useful yields and exclusive regioselectivity. Aside from linear alkyl azides, otherwise elusive medium-sized cyclic azides were also readily prepared. Preliminary mechanistic studies reveal that the reaction likely proceeds by a radical-mediated C-C bond cleavage/C-N3 bond formation pathway.