The union of photoredox and nickel catalysis has resulted in a renaissance in radical chemistry as well as in the use of nickel-catalyzed transformations, specifically for carbon-carbon bond formation. Collectively, these advances address the longstanding challenge of late-stage cross-coupling of functionalized alkyl fragments. Empowered by the notion that photocatalytically generated alkyl radicals readily undergo capture by Ni complexes, wholly new feedstocks for cross-coupling have been realized. Herein, we highlight recent developments in several types of alkyl cross-couplings that are accessible exclusively through this approach.

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Alkyl Carbon-Carbon Bond Formation by Nickel/Photoredox Cross-Coupling.

The distant and selective activation of unreactive C–H and C–C bonds remains one of the biggest challenges in organic chemistry. In recent years, the development of remote functionalization has received growing interest as it allows for the activation of rather challenging C–H and C–C bonds distant from the initiation point by means of a “metal-walk”. A “metal-walk” or “chain-walk” is defined by an iterative series of consecutive 1,2- or 1,3-hydride shifts of a metal complex along a single hydrocarbon chain. With this approach, simple building blocks or mixtures thereof can be transformed into complex scaffolds in a convergent and unified strategy. A variety of catalytic systems have been developed and refined over the past decade ranging from late-transition-metal complexes to more sustainable iron- and cobalt-based systems. As the possibilities of this field are slowly unfolding, this area of research will contribute considerably to provide solutions to yet unmet synthetic challenges.

Walking Metals for Remote Functionalization.

Cross-Coupling and Related Reactions: Connecting Past Success to the Development of New Reactions for the Future

Although carbon dioxide (CO2) is highly abundant, its low reactivity has limited its use in chemical synthesis. In particular, methods for carbon-carbon bond formation generally rely on two-electron mechanisms for CO2 activation and require highly activated reaction partners. Alternatively, radical pathways accessed via photoredox catalysis could provide new reactivity under milder conditions. Here we demonstrate the direct coupling of CO2 and amines via the single-electron reduction of CO2 for the photoredox-catalysed continuous flow synthesis of α-amino acids. By leveraging the advantages of utilizing gases and photochemistry in flow, a commercially available organic photoredox catalyst effects the selective α-carboxylation of amines that bear various functional groups and heterocycles. The preliminary mechanistic studies support CO2 activation and carbon-carbon bond formation via single-electron pathways, and we expect that this strategy will inspire new perspectives on using this feedstock chemical in organic synthesis.

Photoredox activation of carbon dioxide for amino acid synthesis in continuous flow

1,2-Dicarbofunctionalization of alkenes has emerged as an efficient synthetic strategy for preparing substituted molecules by coupling readily available alkenes with electrophiles and/or nucleophiles Nickel complexes serve as effective catalysts owing to their tendency to undergo facile oxidative addition and slow β-hydride elimination, and their capability to access both two-electron and radical pathways Two-component alkene functionalization reactions have achieved high chemo-, regio-, and stereoselectivities by tethering one of the coupling partners to the alkene substrate Three-component reactions, however, often incorporate directing groups to control the selectivity Only a few examples of directing-group-free difunctionalizations of unactivated alkenes have been reported Therefore, great opportunities exist for the development of three-component difunctionalization reactions with broad substrate scopes and tunable chemo-, regio-, and stereoselectivities

Nickel-Catalyzed Dicarbofunctionalization of Alkenes

The direct difunctionalization of alkenes, a cheap and abundant feedstock, represents one of the most attractive strategies for increasing molecular complexity in synthetic organic chemistry. In contrast with the 1,2-difunctionalization of alkenes, recent advances showcase alkene 1,n-difunctionalizations (n≠2) involving metal migration is an emerging and rapidly growing area of research. This promising strategy not only opens a novel avenue for future development of alkene transformations, but also significantly expands upon the bond disconnections available in modern organic synthesis. This Minireview summarizes recent progress in the migratory difunctionalization of alkenes, with an emphasis on the driving force for metal migration.

Difunctionalization of Alkenes Involving Metal Migration.

1,1-Diarylalkanes are important structural frameworks which are widespread in biologically active molecules. Herein, we report a reductive relay cross-coupling of alkyl bromides with aryl bromides by nickel catalysis with a simple nitrogen-containing ligand. This method selectively affords 1,1-diarylalkane derivatives with good to excellent yields and regioselectivity.

Ligand-Controlled Nickel-Catalyzed Reductive Relay Cross-Coupling of Alkyl Bromides and Aryl Bromides

An unprecedented arylboration of unactivated terminal alkenes, featuring 1,n-regioselectivity, has been achieved by nickel catalysis. The nitrogen-based ligand plays an essential role in the success of this three-component reaction. This transformation displays good regioselectivity and excellent functional-group tolerance. In addition, the incorporation of a boron group into the products provides substantial opportunities for further transformations. Also demonstrated is that the products can be readily transformed into pharmaceutically relevant molecules. Unexpectedly, preliminary mechanistic studies indicate that although the metal migration favors the α-position of boron, selective and decisive bond formation is favored at the benzylic position.

Migratory Arylboration of Unactivated Alkenes Enabled by Nickel Catalysis

Photochemical Nickel-Catalyzed Reductive Migratory Cross-Coupling of Alkyl Bromides with Aryl Bromides.

Cross-coupling reactions have developed into powerful approaches for carbon-carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki-Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process.

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Guoyin Yin

Papers

Difunctionalization of Alkenes Involving Metal Migration.

Ligand-Controlled Nickel-Catalyzed Reductive Relay Cross-Coupling of Alkyl Bromides and Aryl Bromides

Migratory Arylboration of Unactivated Alkenes Enabled by Nickel Catalysis

Photochemical Nickel-Catalyzed Reductive Migratory Cross-Coupling of Alkyl Bromides with Aryl Bromides.

Reaction scope and mechanistic insights of nickel-catalyzed migratory Suzuki-Miyaura cross-coupling.