Bottom-Up Construction of Ni(II)-Incorporated Covalent Organic Framework for Metallaphotoredox Catalysis.

The construction of an all-in-one catalyst, in which the photosensitizer and the transition metal site are close to each other, is important for improving the efficiency of metallaphotoredox catalysis. However, the development of convenient synthetic strategies for the precise construction of an all-in-one catalyst remains a challenging task due to the requirement of precise installation of the catalytic sites. Herein, we have successfully established a facile bottom-up strategy for the direct synthesis of Ni(II)-incorporated covalent organic framework (COF), named LZU-713@Ni, as a versatile all-in-one metallaphotoredox catalyst. LZU-713@Ni showed excellent activity and recyclability in the photoredox/nickel-catalyzed C-O, C-S, and C-P cross-coupling reactions. Notably, this catalyst displayed a better catalytic activity than its homogeneous analogues, physically mixed dual catalyst system, and, especially, LZU-713/Ni which was prepared through post-synthetic modification. The improved catalytic efficiency of LZU-713@Ni should be attributed to the implementation of bottom-up strategy, which incorporated the fixed, ordered, and abundant catalytic sites into its framework. This work sheds new light on the exploration of concise and effective strategies for the construction of multifunctional COF-based photocatalysts.

Stereoselective Vinylic C-H Addition via Metallaphotoredox Migration.

Geometrically defined allylic alcohols with SE, SZ, RE and RZ stereoisomers serve as valuable intermediates in synthetic chemistry, attributed to the stereoselective transformations enabled by the alkenyl and hydroxyl functionalities. When an ideal scenario presents itself with four distinct stereoisomers as potential products, the simultaneous control vicinal stereochemistry in a single step would offer a direct pathway to any desired stereoisomer. Here, we unveil a metallaphotoredox migration strategy to access stereodefined allylic alcohols through vinylic C-H activation with aldehydes. This method harnesses a chiral nickel catalyst in concert with a photocatalyst to enable a 1,4-Ni migration by using readily accessible 2-vinyl iodoarenes as starting materials. The efficacy of this methodology is highlighted by the precise construction of all stereoisomers of allylic alcohols bearing analogous substituents and the efficient synthesis of key intermediates en route to Myristinin family. Experimental and computational studies have shed light on pivotal aspects including the synergy of metal catalysis and photocatalysis, the driving forces behind the migration, and the determination of absolute configuration in the C-H addition process.

Direct Excitation Strategy for Deacylative Couplings of Ketones.

The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical-generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon-centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C-C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible-light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni-metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non-catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst-free approaches in cutting-edge research.

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp2)-C(sp3) Couplings via Nickel Catalysis.

The development of robust and reliable methods for the construction of C(sp2)-C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single-electron-transfer (SET) and energy-transfer (EnT) processes for the formation of C-X bonds, and in this manuscript we overcome previous limitations to furnish C-C over C-O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Synergistic Photoredox/Palladium Catalyzed Enantioconvergent Carboxylation of Racemic Heterobiaryl (Pseudo)Halides with CO2.

Herein, we report a synergistic photoredox/palladium catalytic system for the efficient enantioconvergent synthesis of axially chiral esters from racemic heterobiaryl (pseudo)halides (bromides/triflates) with CO2 and alkyl bromides under mild conditions. A wide range of axially chiral esters were obtained in good to high yields with excellent enantioselectivities. Detailed mechanistic studies unveiled that the ratio of photocatalyst and palladium catalyst exhibited significant impact on the chemo- and enantioselectivities of the reaction. Kinetic studies and control experiments supported the proposed mechanism involving cascade asymmetric carboxylation followed by SN2 substitution. The achievement of high enantioselectivity relies not only on the choice of synergistic metallaphotoredox catalysts but also on the utilization of alkyl bromides, which trap the generated chiral carboxylic anions in situ, thus preventing their immediate racemization.

Chromium- and Metal-Reductant-Free Asymmetric Nozaki-Hiyama-Kishi (NHK) Reaction Enabled by Metallaphotoredox Catalysis.

Chiral allylic alcohols are highly prized in synthetic chemistry due to their versatile reactivity stemming from both alkenyl and hydroxyl functionalities. While the Nozaki-Hiyama-Kishi (NHK) reaction is a widely used method for the synthesis of allylic alcohols, it suffers from drawbacks such as the use of toxic chromium salts, high amounts of metal reductants, and poor enantiocontrol. To address these limitations, we present a novel approach involving a metallaphotoredox-catalyzed asymmetric NHK reaction for the production of chiral allylic alcohols. This method marries alkenyl (pseudo)halides with aldehydes, leveraging a synergistic blend of a chiral nickel catalyst and a photocatalyst. This innovative technique enables both oxidative addition and insertion just using nickel, diverging significantly from the conventional NHK reaction pathway mediated by nickel and chromium salts. The adoption of this methodology holds immense promise for crafting a spectrum of intricate compounds, particularly those of significance in pharmaceuticals. Detailed experimental investigations have shed light on the metallaphotoredox process, further enhancing our understanding and enabling further advancements.

Enantioconvergent Reductive C(sp)-C(sp3 ) Cross-Coupling to Access Chiral α-Alkynyl Phosphonates Under Dual Nickel/Photoredox Catalysis.

Transition-metal-catalyzed asymmetric carbon-carbon bond formation to forge phosphonates with an α-chiral carbon center through C(sp3 )-C(sp3 ) and C(sp2 )-C(sp3 ) couplings has been successful. However, the enantioselective C(sp)-C(sp3 ) coupling has not yet been disclosed. Reported herein is an unprecedented enantioconvergent cross-coupling of alkynyl bromides and α-bromo phosphonates to deliver chiral α-alkynyl phosphonates.

Modular and Practical 1,2-Aryl(Alkenyl) Heteroatom Functionalization of Alkenes through Iron/Photoredox Dual Catalysis.

Efficient methods for synthesizing 1,2-aryl(alkenyl) heteroatomic cores, encompassing heteroatoms such as nitrogen, oxygen, sulfur, and halogens, are of significant importance in medicinal chemistry and pharmaceutical research. In this study, we present a mild, versatile and practical photoredox/iron dual catalytic system that enables access to highly privileged 1,2-aryl(alkenyl) heteroatomic pharmacophores with exceptional efficiency and site selectivity. Our approach exhibits an extensive scope, allowing for the direct utilization of a wide range of commodity or commercially available (hetero)arenes as well as activated and unactivated alkenes with diverse functional groups, drug scaffolds, and natural product motifs as substrates. By merging iron catalysis with the photoredox cycle, a vast array of alkene 1,2-aryl(alkenyl) functionalization products that incorporate a neighboring azido, amino, halo, thiocyano and nitrooxy group were secured. The scalability and ability to rapid synthesize numerous bioactive small molecules from readily available starting materials highlight the utility of this protocol.

Direct Aroylation of Olefins through a Cobalt/Photoredox-Catalyzed Decarboxylative and Dehydrogenative Coupling with α-Oxo Acids.

A photoredox/cobalt dual catalytic procedure has been developed that allows benzoylation of olefins. Here the photoredox catalyst effects the decarboxylation of α-ketoacids to form benzoyl radicals. After addition of this radical to styrenes, the cobalt catalyst abstracts a H-atom. Hydrogen evolution from the putative cobalt hydride intermediate allows a Heck-like aroylation without the need for a stoichiometric oxidant. Mechanistic studies reveal that electronically different styrenes lead to a curved Hammett plot, thus suggesting a change in product-determining step in the catalytic mechanism.

Modular and Fast Synthesis of Versatile Secondary α,α-Dialkyl Boronates via Deoxygenative Alkylboration of Aldehydes.

Secondary α,α-dialkyl boronates are widely used due to their great versatility. Herein we report an unprecedented deoxygenative alkylboration of aldehydes, a facile method to access this type of products. A sequence of difunctionalization can be obtained smoothly from the readily available aldehydes in only two steps. This difunctionalization of aldehydes rather than conventional alkenes also opens new possibilities within the field.

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor.

Metallaphotoredox catalysis is a powerful and versatile synthetic platform that enables cross-couplings under mild conditions without the need for noble metals. Its growing adoption in drug discovery has translated into an increased interest in sustainable and scalable reaction conditions. Here, we report a continuous-flow approach to metallaphotoredox catalysis using a heterogeneous catalyst that combines the function of a photo- and a nickel catalyst in a single material. The catalyst is embedded in a packed-bed reactor to combine reaction and (catalyst) separation in one step. The use of a packed bed simplifies the translation of optimized batch reaction conditions to continuous flow, as the only components present in the reaction mixture are the substrate and a base. The metallaphotoredox cross-coupling of sulfinates with aryl halides was used as a model system. The catalyst was shown to be stable, with a very low decrease of the yield (≈1% per day) during a continuous experiment over seven days, and to be effective for C-O arylations when carboxylic acids are used as nucleophile instead of sulfinates.

Dumbbell-Shaped 2,2'-Bipyridines: Controlled Metal Monochelation and Application to Ni-Catalyzed Cross-Couplings.

2,2'-Bipyridine ligands (dsbpys) with dumbbell-like shapes and differently substituted triarylmethyl groups at the C5 and C5' positions showed high ligand performance in the Ni-catalyzed cross-electrophile coupling and the Ni/photoredox-synergistically catalyzed decarboxylative coupling reactions. The superior ligand effects of dsbpys compared to the conventional bpy ligands were attributed to the monochelating nature of dsbpys.

Selective 1,2-Aryl-Aminoalkylation of Alkenes Enabled by Metallaphotoredox Catalysis.

A highly chemo- and regioselective intermolecular 1,2-aryl-aminoalkylation of alkenes by photoredox/nickel dual catalysis is described here. This three-component conjunctive cross-coupling is highlighted by its first application of primary alkyl radicals, which were not compatible in previous reports. The readily prepared α-silyl amines could be transferred to α-amino radicals by photo-induced single electron transfer step. The radical addition/cross-coupling cascade reaction proceeds under mild, base-free and redox-neutral conditions with good functional group tolerance, and importantly, provides an efficient and concise method for the synthesis of structurally valuable α-aryl substituted γ-amino acid derivatives motifs.

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis.

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.

The Dual Role of Benzophenone in Visible-Light/Nickel Photoredox-Catalyzed C-H Arylations: Hydrogen-Atom Transfer and Energy Transfer.

A dual catalytic protocol for the direct arylation of non-activated C(sp3 )-H bonds has been developed. Upon photochemical excitation, the excited triplet state of a diaryl ketone photosensitizer abstracts a hydrogen atom from an aliphatic C-H bond. This inherent reactivity was exploited for the generation of benzylic radicals which subsequently enter a nickel catalytic cycle, accomplishing the benzylic arylation.

Semi-heterogeneous Dual Nickel/Photocatalysis using Carbon Nitrides: Esterification of Carboxylic Acids with Aryl Halides.

Cross-coupling reactions mediated by dual nickel/photocatalysis are synthetically attractive but rely mainly on expensive, non-recyclable noble-metal complexes as photocatalysts. Heterogeneous semiconductors, which are commonly used for artificial photosynthesis and wastewater treatment, are a sustainable alternative. Graphitic carbon nitrides, a class of metal-free polymers that can be easily prepared from bulk chemicals, are heterogeneous semiconductors with high potential for photocatalytic organic transformations. Here, we demonstrate that graphitic carbon nitrides in combination with nickel catalysis can induce selective C-O cross-couplings of carboxylic acids with aryl halides, yielding the respective aryl esters in excellent yield and selectivity. The heterogeneous organic photocatalyst exhibits a broad substrate scope, is able to harvest green light, and can be recycled multiple times. In situ FTIR was used to track the reaction progress to study this transformation at different irradiation wavelengths and reaction scales.

Auxiliary-Directed C(sp3 )-H Arylation by Synergistic Photoredox and Palladium Catalysis.

Herein we describe the auxiliary-directed arylation of unactivated C(sp3 )-H bonds with aryldiazonium salts, which proceeds under synergistic photoredox and palladium catalysis. The site-selective arylation of aliphatic amides with α-quaternary centres is achieved with high selectivity for ß-methyl C(sp3 )-H bonds. This operationally simple method is compatible with carbocyclic amides, a range of aryldiazonium salts and proceeds at ambient conditions.

Pro-aromatic Dihydroquinazolinones - From Multigram Synthesis to Reagents for Gram-scale Metallaphotoredox Reactions.

Dihydroquinazolinone (DHQZ) has recently been harnessed as a ketone-derived pro-aromatic reagent extensively employed in (metalla)photoredox reactions as versatile group transfer agents. In this work, we outline a column chromatography-free protocol for the multigram-scale synthesis of pro-aromatic DHQZs as well as its use in a gram-scale nickel/photoredox dual-catalyzed cross-coupling in single-batch, photoflow, and simultaneous multiple smaller batches. While the single-batch approach leveraged moderate yields, a simple plug-flow photoreactor also exhibited amenable productivity (up to 45 % yield) despite the use of a heterogeneous base. Meanwhile, performing the metallaphotoredox-catalyzed reaction in multiple smaller batches in an improvised photoreactor facilitated high yields of up to 59 % and good reproducibility, implying a convenient alternative in the absence of photoflow setups.

Selective oxidation of ß-keto ester modulated by the d-band centers in D-A conjugated microporous metallaphotoredox catalysts containing M-salen (MZn, Cu and Co) and triazine monomers.

Photocatalytic selective oxidation plays an important role in developing green chemistry. However, it is challenging to design an efficient photocatalyst for controlling the selectivity of photocatalytic oxidation reaction and exploring its detailed mechanism. Here, we synthesized three conjugated microporous polymers (CMPs) with D-A structures, named M-SATE-CMPs (MZn, Cu and Co), with different d-band centers based on different metal centers, resulting in the discrepancy in adsorption and activation capacities for the reactants, which produces the selectivity of ß-keto esters being catalyzed into α-hydroperoxide ß-keto esters (ROOH) or to α-hydroxyl ß-keto esters (ROH). Density functional theory (DFT) calculations also demonstrate that the adsorption and activation capacities of the metal active centers in M-SATE-CMPs (MZn, Cu and Co) for ROOH are the key factors to influence the photocatalytic selective oxidation of ß-keto ester. This study provides a promising strategy for designing a metallaphotoredox catalyst whose photocatalytic selectivity depends on the d-band center of metal site in the catalyst.

Theoretical Mechanistic Study of C(sp3 )-C(sp2 ) Cross-Coupling by Photoredox-Mediated Iridium(III)/Nickel(II)/Quinuclidine Triple Catalysis.

The photoredox-mediated iridium(III)/nickel(II)/3-acetoxyquinuclidine triple-synergistic catalysis was comprehensively investigated by taking a C(sp3 )-C(sp2 ) bond cross-coupling as a reaction model using density functional theory (DFT) calculations. The synergistic mechanism of the triple catalytic system includes a reductive quenching cycle (IrIII -*IrIII -IrII -IrIII ), an organocatalytic cycle, and a nickel catalytic cycle (NiII -NiI -NiIII -[NiIII ]⊖ -NiII ). Electronic process analysis shows that 3-acetoxyquinuclidine acts as a hydrogen atom transfer (HAT) catalyst to regioselectively provide α-carbon centered radical. Due to more favorable oxidative addition of C-Br to Ni(I) than HAT to avoid the formation of stable Ni(II) species, the generated α-carbon centered radical prefers to be captured by oxidative addition product Ni(III) to form an unusual [NiIII ]⊖ C⊕ species when 3-acetoxyquinuclidine was employed. These theoretical insights not only provide deep electronic process understanding of the photoredox-mediated iridium(III)/nickel(II) synergistic catalysis, but also clarify the electron-withdrawing group effect of quinuclidine, which has a potential guiding role for further development of new cross-coupling reactions.