Nickel-Catalyzed Cross-Electrophile Coupling Research Articles

Cross-Electrophile Coupling of 2-Iodoglycals Enables Efficient Access to 2-C-Glycals

AbstractA general strategy was developed for synthesizing 2-C-glycals through a nickel-catalyzed cross-electrophile coupling reaction of 2-iodoglycals with (hetero)aryl iodides. Key to the success of this methodology is the use of an electron-deficient bipyridyl ligand. This innovative approach facilitates the efficient construction of 2-C-glycals, thereby broadening the synthetic repertoire available for glycochemistry.

Cross-selective Deoxygenative Coupling of Aliphatic Alcohols: Installation of Methyl Groups including Isotopic Labels by Nickel Catalysis.

Nickel-catalyzed cross-electrophile coupling reactions of two aliphatic alcohol derivatives remain a challenge. Herein, we report a nickel-catalyzed reductive methylation reaction of aliphatic mesylates with methyl tosylate. This reaction provides straightforward access to compounds bearing aliphatic methyl groups from alkyl alcohol derivatives. Isotopically labelled substrates and reagents can be employed in the reaction to provide perdeuterated and 13C-labelled products. This transformation can be achieved by employing stoichiometric Mn reductant or electrochemically. Additionally, mechanistic experiments show that alkyl iodides are key intermediates in the transformation which undergo a stereoablative reaction via radical intermediates.

Electrocatalytic Formal C(sp2)-H Alkylations via Nickel-Catalyzed Cross-Electrophile Coupling with Versatile Arylsulfonium Salts.

Producing sp3-hybridized carbon-enriched molecules is of particular interest due to their high success rate in clinical trials. The installation of aliphatic chains onto aromatic scaffolds was accomplished by nickel-catalyzed C(sp2)-C(sp3) cross-electrophile coupling with arylsulfonium salts. Thus, simple non-prefunctionalized arenes could be alkylated through the formation of aryldibenzothiophenium salts. The reaction employs an electrochemical approach to avoid potentially hazardous chemical redox agents, and importantly, the one-pot alkylation proved also viable, highlighting the robustness of our approach.

Nickel-catalyzed cross-electrophile coupling of unactivated (hetero)aryl sulfone with aryl bromide

A nickel-catalyzed cross-electrophile coupling of unactivated (hetero)aryl sulfones with aryl bromides via CS bond activation at ambient temperature is developed. By relying on the use of nickel as catalyst, 2,2′-bipyridine (bpy) as ligand, magnesium turnings as mediator, and THF as solvent, a myriad of biaryls could be facilely prepared in moderate to good yields with reasonable functionality compatibility. The present method potentially serves as an attractive alternative to conventional methods, for the use of unreadily available, relatively expensive, and sensitive organometallic reagents could be avoided.

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

Nickel-catalyzed γ-alkylation of cyclopropyl ketones with unactivated primary alkyl chlorides: balancing reactivity and selectivity via halide exchange.

A novel method was developed for synthesizing γ-alkyl ketones via nickel-catalyzed cross-electrophile coupling of cyclopropyl ketones and non-activated primary alkyl chlorides. High reactivity and selectivity can be achieved with sodium iodide as a crucial cocatalyst that generates a low concentration of alkyl iodide via halide exchange, thus avoiding the formation of alkyl dimers. This reaction possessed excellent regioselectivity and high step economy circumventing in situ or pregenerated organometallics.

Nickel-Catalyzed Reductive Arylation of α-Bromo Sulfoxide.

A nickel-catalyzed cross-electrophile coupling of aryl iodides with α-bromo sulfoxide to access a diverse array of aryl benzyl sulfoxides has been discovered. These reactions occurred under mild conditions with excellent functional group tolerance so that optically enriched sulfoxides could be coupled with aryl iodides, generating corresponding sulfoxides with excellent stereochemical integrity. Furthermore, the scalability of this transformation was demonstrated. Initial mechanistic studies revealed that the reaction undergoes a radical pathway.

Quinone-mediated hydrogen anode for non-aqueous reductive electrosynthesis.

Electrochemical synthesis can provide more sustainable routes to industrial chemicals1-3. Electrosynthetic oxidations may often be performed 'reagent-free', generating hydrogen (H2) derived from the substrate as the sole by-product at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications4, but more sustainable options are needed at larger scale. Anodic water oxidation is an especially appealing option1,5,6, but many reductions require anhydrous, air-free reaction conditions. In such cases, H2 represents an ideal alternative, motivating the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions7-12. Here we report a mediated H2 anode that achieves indirect electrochemical oxidation of H2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H2 anode is used to support nickel-catalysed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption in the pharmaceutical industry13-15. Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H2 anode technology disclosed here offers a general strategy to support H2-driven electrosynthetic reductions.

A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes.

Understanding mechanistic details of the nickel-catalyzed coupling reactions of Csp3 alcohol derivatives is key to developing selective reactions of this widely prevalent functional group. In this manuscript, we utilize a combination of experimental data and DFT studies to define the key intermediates, stereochemical outcome, and competing pathways of a nickel-catalyzed cross-electrophile coupling reaction of 1,3-dimesylates. Stereospecific formation of a 1,3-diiodide intermediate is achieved in situ by the Grignard reagent. The overall stereoablative stereochemical outcome is due to a nickel-catalyzed halogen atom abstraction with a radical rebound that is slower than epimerization of the alkyl radical. Finally, lifetimes of this alkyl radical intermediate are compared to radical clocks to enhance the understanding of the lifetime of the secondary alkyl radical.

Stereospecific Nickel-Catalyzed Cross-Electrophile Coupling Reaction of Alkyl Mesylates and Allylic Difluorides to Access Enantioenriched Vinyl Fluoride-Substituted Cyclopropanes.

Cross-electrophile coupling reactions involving direct C-O bond activation of unactivated alkyl sulfonates or C-F bond activation of allylic gem-difluorides remain challenging. Herein, we report a nickel-catalyzed cross-electrophile coupling reaction between alkyl mesylates and allylic gem-difluorides to synthesize enantioenriched vinyl fluoride-substituted cyclopropane products. These complex products are interesting building blocks with applications in medicinal chemistry. Density functional theory (DFT) calculations demonstrate that there are two competing pathways for this reaction, both of which initiate by coordination of the electron-deficient olefin to the low-valent nickel catalyst. Subsequently, the reaction can proceed by oxidative addition of the C-F bond of the allylic gem-difluoride moiety or by directed polar oxidative addition of the alkyl mesylate C-O bond.

Nickel-catalyzed cross-electrophile coupling of aryl thiols with aryl bromides via C–S bond activation

We report a cross-electrophile coupling of aryl thiols with aryl bromides via C–S bond activation instead of S–H bond cleavage. The reaction proceeded effectively in the presence of a nickel catalyst, magnesium, and lithium chloride to afford various biaryls in moderate to good yields.

Nickel-Catalyzed Cross-Electrophile Coupling of 1,2,3-Benzotriazin-4(3H)-ones with Aryl Bromides.

The nickel-catalyzed cross-electrophile coupling of 1,2,3-benzotriazin-4(3H)-ones with aryl bromides to generate a diverse array of ortho-arylated benzamide derivatives has been developed. The reaction displayed good functional group tolerance with Zn as the reductant. The key to this transformation is the ring opening of benzotriazinones, which undergo a denitrogenative process to obtain various benzamide derivatives (29 examples, 42-93% yield). The scalability of this transformation was demonstrated.

Mechanical Activation of Zero-Valent Metal Reductants for Nickel-Catalyzed Cross-Electrophile Coupling.

The cross-electrophile coupling of either twisted-amides or heteroaryl halides with alkyl halides, enabled by ball-milling, is herein described. The operationally simple nickel-catalyzed process has no requirement for inert atmosphere or dry solvents and delivers the corresponding acylated or heteroarylated products across a broad range of substrates. Key to negating the necessity of inert reaction conditions is the mechanical activation of the raw metal terminal reductant: manganese in the case of twisted amides and zinc for heteroaryl halides.

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Nickel-Catalyzed Cross-Electrophile Coupling of Heteroaryl Imines and Alkyl Halides

Nickel-Catalyzed Cross-Electrophile Coupling of Heteroaryl Imines and Alkyl Halides

The Merger of Benzophenone HAT Photocatalysis and Silyl Radical-Induced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins.

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

Efficient preparation of unsymmetrical disulfides by nickel-catalyzed reductive coupling strategy

Disulfides are widely found in natural products and find a wide range of applications in life sciences, materials chemistry and other fields. The preparation of disulfides mainly rely on oxidative couplings of two sulfur containing compounds. This strategy has many side reactions and other shortcomings. Herein, we describe the reductive nickel-catalyzed cross-electrophile coupling of unactivated alkyl bromides with symmetrical alkyl- and aryltetrasulfides to form alkyl-alkyl and aryl-alkyl unsymmetrical disulfides. This approach for disulfide synthesis is practical, relies on easily available, unfunctionalized substrates, and is scalable. We investigated the mechanism of this transformation and found that the tetrasulfide compound does not selectively break the central S–S bond, but regio-selectively generates trisulfide intermediates.

Nickel-Catalyzed Cross-Electrophile Coupling Reactions between Allylic Acetates and gem-Difluorovinyl Tosylate.

A nickel-catalyzed cross-electrophile coupling of allylic acetates and gem-difluorovinyl tosylate is presented, which first achieves allylic gem-difluoroolefins via C(sp3)-C(sp2) cross-electrophile coupling. In addition, this protocol was performed under mild reaction conditions, affording a variety of allylic gem-difluorovinyl arenes in moderate to good yields. Moreover, both linear and branched allylic acetate could produce a linear cross-coupling product exclusively. Mechanistic studies reveal that the reaction involves two different Ni(0)/Ni(II) catalytic cycles.

Nickel-Catalyzed C(sp3)-C(sp3) Cross-Electrophile Coupling of In Situ Generated NHP Esters with Unactivated Alkyl Bromides.

The formation of C(sp3)-C(sp3) bonds by cross-coupling remains a challenge in synthesis. Here, we demonstrate a two-step, one-pot protocol for the in situ generation of N-hydroxyphthalimide esters and their nickel-catalyzed cross-electrophile coupling with unactivated alkyl bromides for the construction of 1°/1 ° C(sp3)-C(sp3) bonds. The conditions tolerate an array of functional groups, and mechanistic studies indicate that both substrates are converted to alkyl radicals during the reaction.

Nickel-Catalyzed Cross-Electrophile Coupling of Vinyl Acetates and Alkyl Bromides

Nickel-Catalyzed Cross-Electrophile Coupling of Vinyl Acetates and Alkyl Bromides