Nickel-catalyzed Reaction Research Articles

Nickel-Catalyzed Reductive Alkenylation of Enol Derivatives: A Versatile Tool for Alkene Construction.

ConspectusKetone-to-alkene transformations are essential in organic synthesis, and transition-metal-catalyzed cross-coupling reactions involving enol derivatives have become powerful tools to achieve this goal. While substantial progress has been made in nucleophile-electrophile reactions, recent developments in nickel-catalyzed reductive alkenylation reactions have garnered increasing attention. These methods accommodate a broad range of functional groups such as aldehyde, ketone, amide, alcohol, alkyne, heterocycles, and organotin compounds, providing an efficient strategy to access structurally diverse alkenes. This Account primarily highlights the contributions from our laboratory to this growing field while also acknowledging key contributions from other researchers.Our early efforts in this area focused on coupling radical-active substrates, such as α-chloroboronates. This method follows the conventional radical chain mechanism, resulting in facile access to valuable allylboronates. Encouraged by these promising results, we subsequently expanded the substrate scope to encompass radical-inactive compounds. By developing new strategies for controlling cross-selectivity, we enabled the coupling of Csp3 electrophiles (e.g., alcohols and sulfonates), Csp2 electrophiles (e.g., bromoalkenylboronates and acyl fluorides), and heavier group-14 electrophiles like chlorosilanes and chlorogermanes with alkenyl triflates. These advances have provided efficient synthetic routes to a wide range of valuable products, including aliphatic alkenes, enones, dienylboronates, and silicon- and germanium-containing alkenes. Notably, these methods are particularly effective for synthesizing functionalized cycloalkenes, which are traditionally challenging to obtain through conventional methods involving alkenyl halide or organometallic couplings. We have also extended the scope of enol derivatives from triflates to acetates. These compounds are among the most accessible, stable, cost-effective, and environmentally friendly reagents, while their application in cross-coupling has been hampered by low reactivity and selectivity challenges. We showcased that by the use of a Ni(I) catalyst, alkenyl acetates could undergo reductive alkylation with a broad range of alkyl bromides, yielding diverse cyclic and acyclic aliphatic alkenes.Furthermore, our work has demonstrated that reductive coupling of enol derivatives with alkenes provides a highly appealing alternative for alkene synthesis. Particularly, this approach offers opportunity to address the regioselectivity challenges encountered in conventional alkene transformations. For instance, achieving regioselective hydrocarbonation of aliphatic 1,3-dienes has been a longstanding challenge in synthetic chemistry. By using a phosphine-nitrile ligand, we developed a nickel-catalyzed reductive alkenylation of 1,3-dienes with alkenyl triflates, delivering a diverse array of 1,4-dienes with high 1,2-branch selectivity (>20:1) while preserving the geometry of the C3-C4 double bond. Additionally, our investigations laid the foundation for enantioselective reductive alkenylation methodologies, offering new pathways for constructing enantioenriched diketones as well as complex carbo- and heterocyclic compounds. The introduced alkenyl functionality can be further diversified, enhancing molecular diversity and complexity.

Nickel-Catalyzed Cross-Coupling of Aziridines with Thioesters toward Atom-Economic Synthesis of β-Sulfanyl Amides.

Thioesters have been recognized as a class of powerful bifunctional reagents, namely, great donors of acyl and sulfide moieties. However, such application in value-added synthesis is still very limited to date. Herein, a nickel-catalyzed cross-coupling reaction system of aziridines with thioesters was developed under redox-neutral and mild conditions. This catalytic method provides an atom-economic route for the synthesis of diverse β-sulfanyl amide derivatives with wide substrate scope (43 examples), good functional group tolerance, and regioselectivity.

Nickel-Catalyzed Enantioconvergent Allenylic Amination of Allenols Activated by Hydrogen-Bonding Interaction with Methanol.

The ubiquitous nature of amines in drug compounds, bioactive molecules and natural products has fueled intense interest in their synthesis. Herein, we introduce a nickel-catalyzed enantioconvergent allenylic amination of methanol-activated allenols. This protocol affords a diverse array of functionalized allenylic amines in high yields and with excellent enantioselectivities. The synthetic potential of this method is demonstrated by employing bioactive amines as nucleophiles and conducting gram-scale reactions. Furthermore, mechanistic investigations and DFT calculations elucidate the role of methanol as an activator in the nickel-catalyzed reaction, facilitating the oxidative addition of the C-O bond of allenols through hydrogen-bonding interactions. The remarkable outcomes arise from a rapid racemization of allenols enabled by the nickel catalyst and from highly enantioselective dynamic kinetic asymmetric transformation of η3-alkadienylnickel intermediates.

A decarbonylative approach to alkylnickel intermediates and C(sp3)-C(sp3) bond formation.

The myriad nickel-catalyzed cross-coupling reactions rely on the formation of an organonickel intermediate, but limitations in forming monoalkylnickel species have limited options for C(sp3) cross-coupling. The formation of monoalkylnickel(II) species from abundant carboxylic acid esters would be valuable, but carboxylic acid derivatives are primarily decarboxylated to form alkyl radicals that lack the correct reactivity. In this work, we disclose a facile oxidative addition and decarbonylation sequence that forms monoalkylnickel(II) intermediates through a nonradical process. The key ligand, bis(4-methylpyrazole)pyridine, accelerates decarbonylation, stabilizes the alkylnickel(II) intermediate, and destabilizes off-cycle nickel(0) carbonyl species. The utility of this new reactivity in C(sp3)-C(sp3) bond formation is demonstrated in a reaction that is challenging by purely radical methods-the selective cross-coupling of primary carboxylic acid esters with primary alkyl iodides.

Nickel-catalyzed thiocarbonylation for the synthesis of thioesters-functionalized 2H-pyrones with sulfonyl chlorides as the sulfur sources

An efficient and straightforward protocol for the synthesis of thioesters-functionalized 2H-pyrones has been explored through a nickel-catalyzed thiocarbonylation reaction with sulfonyl chlorides as the sulfur sources. By using Mo(CO)6 as both CO source and reductant, a diverse set of thioesters-containing 2H-pyrones have been obtained in moderate to good yields. This reaction provides a good supplement for the carbonylative synthesis of thioesters-functionalized 2H-pyrones via a Ni/Mo(CO)6 catalytic system.

Redox Activity and Potentials of Bidentate N-Ligands Commonly Applied in Nickel-Catalyzed Cross-Coupling Reactions.

Bidentate N-ligands are paramount to recent advances in nickel-catalyzed cross-coupling reactions. Through comprehensive organometallic, spectroscopic, and computational studies on bi-oxazoline and imidazoline ligands, we reveal that a square planar geometry enables redox activity of these ligands in stabilizing nickel radical species. This finding contrasts with the prior assumption that bi-oxazoline lacks redox activity due to strong mesomeric donation. Moreover, we conducted systematic cyclic voltammetry (CV) analyses of bidentate pyridyl, oxazoline, and imidazoline nitrogen ligands, along with their corresponding nickel complexes. Complexation with nickel shifts the reduction potentials to a more positive region and narrows the differences in redox potentials among the ligands. Additionally, various ligands led to different degrees of bromide dissociation from singly reduced (L)Ni(Ar)(Br) complexes, reflecting varying reactivity in the subsequent activation of alkyl halides, a crucial step in cross-electrophile coupling. These insights highlight the significant electronic effects of ligands on the stability of metalloradical species and their redox potentials, which interplay with coordination geometry. Quantifying the electron-donating, p-accepting properties of these ligands, as well as their effect on catalyst speciation, provides crucial benchmarks for controlling catalytic activity and enhancing catalyst stability.

Recent Advances in Electrochemical Carboxylation with CO2.

ConspectusCarbon dioxide (CO2) is recognized as a greenhouse gas and a common waste product. Simultaneously, it serves as an advantageous and commercially available C1 building block to generate valuable chemicals. Particularly, carboxylation with CO2 is considered a significant method for the direct and sustainable production of important carboxylic acids. However, the utilization of CO2 is challenging owing to its thermodynamic stability and kinetic inertness. Recently, organic electrosynthesis has emerged as a promising approach that utilizes electrons or holes as environmentally friendly redox reagents to produce reactive intermediates in a controlled and selective manner. This technique holds great potential for the CO2 utilization.Since 2015, our group has been dedicated to exploring the utilization of CO2 in organic synthesis with a particular focus on electrochemical carboxylation. Despite the significant advancements made in this area, there are still many challenges, including the activation of inert substrates, regulation of selectivity, diversity in electrolysis modes, and activation strategies. Over the past 7 years, our team, with many great experts, has presented findings on electrochemical carboxylation with CO2 under mild conditions. In this context, we primarily highlight our contributions to selective electrocarboxylations, encompassing new reaction systems, selectivity control methods, and activation approaches.We commenced our research by establishing a Ni-catalyzed electrochemical carboxylation of unactivated aryl halides and alkyl bromides in conjunction with a useful paired anodic reaction. This approach eliminates the need for sacrificial anodes, rendering the carboxylation process sustainable. To further utilize the widely existing yet cost-effective alkyl chlorides, we have developed a deep electroreductive system to achieve carboxylation of unactivated alkyl chlorides and poly(vinyl chloride), allowing the direct modification and upgrading of waste polymers.Through precise adjustment of the electroreductive conditions, we successfully demonstrated the dicarboxylation of both strained carbocycles and acyclic polyarylethanes with CO2 via C-C bond cleavage. Furthermore, we have realized the dicarboxylative cyclization of unactivated skipped dienes to produce the valuable ring-tethered adipic acids through single-electron reduction of CO2 to the CO2 radical anion (CO2•-). In terms of the asymmetric carboxylation, Guo's and our groups have recently achieved the nickel-catalyzed enantioselective electroreductive carboxylation reaction using racemic propargylic carbonates and CO2, paving the way for the synthesis of enantioenriched propargylic carboxylic acids.In addition to the aforementioned advancements, Lin's and our groups have also developed new electrolysis modes to achieve regiodivergent C-H carboxylation of N-heteroarenes dictated by electrochemical reactors. The choice of reactors plays a crucial role in determining whether the hydrogen atom transfer (HAT) reagents are formed anodically, consequently influencing the carboxylation pathways of N-heteroarene radical anions in the distinct electrolyzed environments.

Nickel-Catalyzed Radical Hydroalkylative Dearomatization of Indoles with Alkyl Bromides

Dearomatization of indole derivatives offers a straightforward approach to accessing indoline framework. However, highly efficient dearomatization of indoles bearing electron-deficient groups remains underdeveloped. Herein, a nickel-catalyzed intermolecular hydroalkylative dearomatization reaction of indoles with simple alkyl bromides via single-electron-transfer process is reported. A wide variety of indole derivatives bearing versatile functional groups were compatible with this protocol, by reacting with primary, secondary, and tertiary bromides to afford a series of indolines in good yields (up to 82%) with excellent diastereoselectivity (up to >20:1). Notably, a nickel-mediated hydrogen atom transfer process was observed when terminal bromides were employed as the radical precursors, which resulted in the branched products.

Aliphatic Hydrosilanes via Nickel-Catalyzed Reductive Csp3-Si Coupling of Primary Alkyl Bromides and Chlorohydrosilanes.

The reductive C-Si coupling of chlorosilanes offers efficient access to organosilanes, but its potential for constructing aliphatic ones remains largely unexplored. This manuscript presents a nickel-catalyzed Csp3-Si coupling reaction of unactivated alkyl-Br and R2Si(H)Cl. This work establishes a new approach for synthesizing highly functionalized aliphatic hydrosilanes from readily available chemical feedstocks. The reaction is easily scalable and can accommodate various functional groups, including carboxylic acids, which are usually incompatible with basic conditions.

N-Alkoxyphthalimides as Nitrogen Electrophiles to Construct C-N Bonds via Reductive Cross-Coupling.

N-Alkoxyphthalimides, one kind of phthalimide derivative, have great importance in synthesis, mainly used as free radical precursors. While the phthalimide unit, for a long time, was treated as part of the waste stream. Construction of C-N bonds has always been a hot spot, especially in reductive cross-coupling. Herein, a nickel-catalyzed reductive cross-coupling reaction of N-methoxyphthalimides with alkyl halides is described, where N-methoxyphthalimides serve as nitrogen electrophiles. This tactic provides a new approach to construct C-N bonds under mild neutral conditions. Alkyl chlorides, bromides, iodides, and sulfonates are all fit to this transformation. Moreover, the reaction could tolerate a broad substrate scope, especially base-sensitive functional groups (boron or silicon groups), as well as competitive nucleophilic groups (phenols and amides), which are incompatible with traditional Gabriel synthesis under basic conditions, demonstrating a complementary role of this work to Gabriel synthesis.

Dual Nickel- and Photoredox-Catalyzed Asymmetric Reductive Cross-Couplings: Just a Change of the Reduction System?

ConspectusIn recent years, nickel-catalyzed asymmetric coupling reactions have emerged as efficient methods for constructing chiral C(sp3) carbon centers. Numerous novel approaches have been reported to rapidly construct chiral carbon-carbon bonds through nickel-catalyzed asymmetric couplings between electrophiles and nucleophiles or asymmetric reductive cross-couplings of two different electrophiles. Building upon these advances, our group has been devoted to interrogating dual nickel- and photoredox-catalyzed asymmetric reductive cross-coupling reactions.In our endeavors over the past few years, we have successfully developed several dual Ni-/photoredox-catalyzed asymmetric reductive cross-coupling reactions involving organohalides. While some probably think that this system is just a change of the reduction system from traditional metal reductants to a photocatalysis system, a question that we also pondered at the beginning of our studies, both the achievable reaction types and mechanisms suggest a different conclusion: that this dual catalysis system has its own advantages in the chiral carbon-carbon bond formation. Even in certain asymmetric reactions where the photocatalysis regime functions only as a reducing system, the robust reducing capability of photocatalysts can effectively accelerate the regeneration of low-valent nickel species, thus expanding the selectable scope of chiral ligands. More importantly, in many transformations, besides reducing nickel catalysts, the photocatalysis system can also undertake the responsibility of alkyl radical formation, thereby establishing two coordinated, yet independent catalytic cycles. This catalytic mode has been proven to play a crucial role in achieving diverse asymmetric coupling reactions with great challenges.In this Account, we elucidate our understanding of this system based on our experience and findings. In the Introduction, we provide an overview of the main distinctions between this system and traditional Ni-catalyzed asymmetric reductive cross-couplings with metal reductants and the potential opportunities arising from these differences. Subsequently, we outline various chiral carbon-carbon bond-forming types obtained by this dual Ni/photoredox catalysis system and their mechanisms. In terms of chiral C(sp3)-C(sp2) bond formation, extensive discussion focuses on the asymmetric arylations of α-chloroboronates, α-trifluoromethyl alkyl bromides, α-bromophosphonates, and so on. In the realm of chiral C(sp3)-C(sp) bond formation, asymmetric alkynylations of α-bromophosphonates and α-trifluoromethyl alkyl bromides have been presented herein. Regarding C(sp3)-C(sp3) bond formation, we take the asymmetric alkylation of α-chloroboronates as a compelling example to illustrate the great efficiency of this dual catalysis system. This summary would enable a better grasp of the advantages of this dual catalysis system and clarify how the photocatalysis regime facilitates enantioselective transformations. We anticipate that this Account will offer valuable insights and contribute to the development of new methodologies in this field.

Nickel-catalyzed defluorinative asymmetric cyclization of Trifluoromethyl-substituted 1,6-Enynes: Insights from DFT calculations on the reaction mechanism and selectivity

Density functional theory (DFT) calculations were employed to elucidate the mechanism and selectivity of nickel-catalyzed defluorinative asymmetric cyclization reactions of trifluoromethyl-substituted 1,6-enynes. The results indicate that the product is formed via a stepwise addition cyclization mechanism, including sequential steps of ligand coordination, transmetalation, ligand exchange, alkyne insertion, olefin insertion, β-F elimination, another transmetalation, and a final ligand exchange. The regioselectivity is primarily governed by the alkyne insertion step, where electrostatic interactions strongly favor 1,2-insertion of the carbon-carbon triple bond over 2,1-insertion. The enantioselectivity is largely determined during the insertion step of the olefin insertion step, with the (S)-product forming preferentially over the (R)-product due to stronger non-covalent interactions between the ligand and the substrate, minimal catalyst conformational distortion, and enhanced electronic interactions between the catalyst and the substrate.

Chemo-, regio- and stereoselective access to polysubstituted 1,3-dienes via Nickel-catalyzed four-component reactions

1,2-Difunctionalization of alkynes offers a straightforward approach to access polysubstituted alkenes. However, simultaneous multi-component cascade transformations including difunctionalization of two alkynes with both syn- and anti-selectivity in one catalyst system is undeveloped and proves to be a significant challenge. Herein, we report a Nickel-catalyzed four-component reaction to access polysubstituted 1,3-dienes using two terminal alkynes, aryl boroxines, and perfluoroalkyl iodides, wherein the reaction forms three new C-C bonds in a single vessel and serve as a modular strategy to access polysubstituted 1,3-dienes with excellent chemoselectivity, good regioselectivity and exclusive stereoselectivity. Control experiments reveal the plausible reaction mechanism and DFT calculations explain the cause for the formation of this unusual four-component reaction. Furthermore, we successfully incorporate two biologically active units into 1,2,3,4-tetrasubstituted 1,3-dienes, which greatly increases the diversity of molecular scaffolds and brings more potential values to medicinal chemistry, the synthetic utility of our protocol is further demonstrated by the late-stage transformations.

Nickel-Catalyzed Double Deoxygenative C-N Coupling of Acyloxyamines.

A double deoxygenative C-N coupling protocol has been developed by employing acyloxyamines through N-O bond activation. The C-N bond formation under mild reaction conditions, employing NiCl2 as the catalyst and cataCXiumA as a ligand, results in the production of a diverse array of alkylated secondary or tertiary amines, including heterocyclic amines. This method introduces a novel catalytic strategy that emphasizes the versatility of nickel-catalyzed reactions, extending beyond traditional synthetic boundaries.

A nickel-catalyzed Suzuki-Miyaura coupling reaction of aryl halides facilitated by pyridine derivatives

A nickel-catalyzed Suzuki-Miyaura coupling reaction facilitated by pyridine derivative ligands is reported. A wide range of (hetero) aryl halides and (hetero) aryl boronic acids were compatible, which led to the corresponding products in moderate to good yields. A gram-scale reaction proceeded well and afforded an efficient route to prepare methyl [1,1′-biphenyl]-4-carboxylate.

Enantioselective Nickel-Catalyzed Denitrogenative Transannulation En Route to N-N Atropisomers.

Nickel-catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, their use in asymmetric synthesis remains challenging because of the difficulty in controlling stereo- and regioselectivity. Herein, we report the first nickel-catalyzed asymmetric synthesis of N-N atropisomers by the denitrogenative transannulation of benzotriazones with alkynes. A broad range of N-N atropisomers was obtained with excellent regio- and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel-catalyzed reaction mechanism and enantioselectivity control.

Regioselective and Enantioselective Nickel-Catalyzed Intermolecular Reductive Coupling of Aliphatic Alkenes with Imines.

Unactivated aliphatic alkenes are particularly desirable as starting materials because they are readily accessible in large quantities, but the enantioselective intermolecular reductive coupling of unactivated alkenes with imines is challenging. In this paper, we report a method for nickel-catalyzed intermolecular reductive coupling reactions between aliphatic alkenes and imines to yield chiral amines with excellent enantioselectivities and good linear selectivities. The reaction conditions are compatible with a broad range of aliphatic alkenes, including those derived from bioactive molecules. The success of this method can be attributed to the use of newly developed monodentate chiral spiro phosphine ligands.

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.

Nickel-Catalyzed Atroposelective Cross-Electrophile Coupling of Aryl Halides: A General and Practical Route to Diverse MOP-Type Ligands.

We report a highly cross- and atroposelective coupling between ortho-(chloro)arylphosphine oxides and ortho-(bromo)aryl ethers. This previously unknown asymmetric nickel-catalyzed reaction offers a direct route to highly enantioenriched axially chiral biaryl monophosphine oxides that are difficult to access by other means. These products can be readily reduced to generate chiral MOP-type ligands bearing complex skeletal backbones. The utility of these chiral ligands in asymmetric catalysis is also demonstrated.

Nickel-Catalyzed Cross-Coupling Reaction of Aryl Bromides/Nitriles with Imidazolium Salts Involving Inert C-N Bond Cleavage.

We herein present a nickel-catalyzed cross-coupling reaction of aryl halides and nitriles with imidazolium salts. A series of 2-arylated imidazoles could be obtained in moderate to good yields through inert C-N bond cleavage. The imidazolium salt in this reaction acts as both a coupling partner and N-heterocyclic carbene (NHC) ligand precursor. Mechanistic studies reveal that consecutive steps of migratory insertion of the NHC into the aryl C-Ni bond and β-C elimination might be involved in the proposed reaction mechanism.