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.

Modular Access to Chiral α-(Hetero)aryl Amines via Ni/Photoredox-Catalyzed Enantioselective Cross-Coupling.

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.

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.

Electrophotocatalytic Decarboxylative C-H Functionalization of Heteroarenes.

Decarboxylative C-H functionalization reactions are highly attractive methods for forging carbon-carbon bonds considering their inherent step- and atom-economical features and the pervasiveness of carboxylic acids and C-H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon-carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C-H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late-stage functionalization of drug molecules.

Practical and stereoselective electrocatalytic 1,2-diamination of alkenes.

The 1,2-diamine motif is widely present in natural products, pharmaceutical compounds, and catalysts used in asymmetric synthesis. The simultaneous introduction of two amino groups across an alkene feedstock is an appealing yet challenging approach for the synthesis of 1,2-diamines, primarily due to the inhibitory effect of the diamine products to transition metal catalysts and the difficulty in controlling reaction diastereoselectivity and regioselectivity. Herein we report a scalable electrocatalytic 1,2-diamination reaction that can be used to convert stable, easily available aryl alkenes and sulfamides to 1,2-diamines with excellent diastereoselectivity. Monosubstituted sulfamides react in a regioselective manner to afford 1,2-diamines bearing different substituents on the two amino groups. The combination of an organic redox catalyst and electricity not only obviates the use of any transition metal catalyst and oxidizing reagent, but also ensures broad reaction compatibility with a variety of electronically and sterically diverse substrates.

An integrated immobilization strategy manipulates dual active centers to boost enantioselective tandem reactions.

Manipulation of dual active centers via an integrated immobilization strategy can overcome the restriction of homogeneous catalysis in a sequential organic transformation. Herein, by utilizing hollow-shell-structured silica, hydrogen-bonding immobilization via a ship-in-a-bottle synthesis locks a Pd(carbene) center in a nanocage and covalent-bonding immobilization tethers chiral Ru(diamine) centers within the nanochannels, constructing a hetero-bifunctional catalyst. The benefit of this dual center manipulation enables a challenging Suzuki coupling-asymmetric transfer hydrogenation tandem reaction, and the advantage of this process provides various chiral biarylols with enhanced reactivity and enantioselectivity.

A Cinchona Alkaloid-Functionalized Mesostructured Silica for Construction of Enriched Chiral ß-Trifluoromethyl-ß-Hydroxy Ketones over An Epoxidation-Relay Reduction Process.

A cinchona alkaloid-functionalized heterogeneous catalyst is prepared through a thiol-ene click reaction of chiral N-(3,5-ditrifluoromethylbenzyl)quininium bromide and a mesostructured silica, which is obtained by co-condensation of 1,2-bis(triethoxysilyl)ethane and 3-(triethoxysilyl)propane-1-thiol. Structural analyses and characterizations disclose its well-defined chiral single-site active center, and electron microscopy images reveal its monodisperse property. As a heterogenous catalyst, it enables an efficient asymmetric epoxidation of achiral ß-trifluoromethyl-ß,ß-disubstituted enones, the obtained chiral products can then be converted easily into enriched chiral ß-trifluoromethyl-ß-hydroxy ketones through a sequential epoxidation-relay reduction process. Furthermore, such a heterogeneous catalyst can be recovered conveniently and reused in asymmetric epoxidation of 4,4,4-trifluoro-1,3-diphenylbut-2-enone, showing an attractive feature in a practical construction of enriched chiral ß-CF3 -substituted molecules.