Nickel-catalyzed Cross-coupling Reactions Research Articles

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.

A decarbonylative approach to alkylnickel intermediates and C(sp 3 )-C(sp 3 ) 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(sp 3 ) 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(sp 3 )-C(sp 3 ) 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.

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.

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.

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.

Electrochemical Synthesis of a Sitagliptin Precursor.

A novel synthesis of sitagliptin based on a redox-active ester derived from the chiral pool is reported. The key step is an electrochemical nickel-catalyzed sp2-sp3 cross-coupling reaction using inexpensive nickel foam in an undivided cell. It was successfully applied to 21 examples in up to 88% yield. These sitagliptin-analogue precursors could potentially interact with the DPP4 enzyme. A full synthesis based on our new reaction pathway provided sitagliptin in an overall yield of 33%.

Nickel-Catalyzed Reductive Cross-Coupling of Propargylic Acetates with Chloro(vinyl)silanes: Access to Silylallenes.

Because of their various reactivities, propargyl acetates are refined chemical intermediates that are extensively applied in pharmaceutical synthesis. Currently, reactions between propargyl acetates and chlorosilanes may be the most effective method for synthesizing silylallenes. Nevertheless, owing to the adaptability and selectivity of substrates, transition metal catalysis is difficult to achieve. Herein, nickel-catalyzed reductive cross-coupling reactions between propargyl acetates and substituted vinyl chlorosilanes for the synthesis of tetrasubstituted silylallenes are described. Therein, metallic zinc is a crucial reductant that effectively enables two electrophilic reagents to selectively construct C(sp2)-Si bonds. Additionally, a Ni-catalyzed reductive mechanism involving a radical process is proposed on the basis of deuteration-labeled experiments.

Enantioselective C(sp2)-C(sp3) Bond Construction by Ni Catalysis.

ConspectusAfter decades of palladium dominating the realm of transition-metal-catalyzed cross-coupling, recent years have witnessed exciting advances in the development of new nickel-catalyzed cross-coupling reactions to form C(sp3) centers. Nickel possesses distinct properties compared with palladium, such as facile single-electron transfer to C(sp3) electrophiles and rapid C-C reductive elimination from NiIII. These properties, among others, make nickel particularly well-suited for reductive cross-coupling (RCC) in which two electrophiles are coupled and an exogenous reductant is used to turn over the metal catalyst. Ni-catalyzed RCCs use readily available and stable electrophiles as starting materials and exhibit good functional group tolerance, which makes them appealing for applications in the synthesis of complex molecules. Building upon the foundational work in Ni-catalyzed RCCs by the groups of Kumada, Durandetti, Weix, and others, as well as the advancements in Ni-catalyzed enantioselective redox-neutral cross-couplings led by Fu and co-workers, we initiated a program to explore the feasibility of developing highly enantioselective Ni-catalyzed RCCs. Our research has also been driven by a keen interest in unraveling the factors contributing to enantioinduction and electrophile activation as we seek new avenues for advancing our understanding and further developing these reactions.In the first part of this Account, we organize our reported methods on the basis of the identity of the C(sp3) electrophiles, including benzylic chlorides, N-hydroxyphthalimide (NHP) esters, and α-chloro esters and nitriles. We highlight how the selection of specific chiral ligands plays a pivotal role in achieving high cross-selectivity and enantioselectivity. In addition, we show that reduction can be accomplished not only with heterogeneous reductants, such as Mn0, but also with the soluble organic reductant tetrakis(dimethylamino)ethylene (TDAE), as well as electrochemically. The use of homogeneous reductants, such as TDAE, is well suited for studying the mechanism of the transformation. Although this Account primarily focuses on RCCs, we also highlight our work using trifluoroborate (BF3K) salts as radical precursors for enantioselective dual-Ni/photoredox systems.At the end of this Account, we summarize the relevant mechanistic studies of two closely related asymmetric reductive alkenylation reactions developed in our laboratory and provide a context between our work and related mechanistic studies by others. We discuss how the ligand properties influence the rates and mechanisms of electrophile activation and how understanding the mode of C(sp3) radical generation can be used to optimize the yield of an RCC. Our research endeavors to offer insights on the intricate mechanisms at play in asymmetric Ni-catalyzed RCCs with the goal of using the rate of electrophile activation to improve the substrate scope of enantioselective RCCs. We anticipate that the insights we share in this Account can provide guidance for the development of new methods in this field.

Nickel-catalyzed selective disulfide formation by reductive cross-coupling of thiosulfonates.

Developing innovative methodologies for disulfide preparation is of importance in contemporary organic chemistry. Despite significant advancements in nickel-catalyzed reductive cross-coupling reactions for forming carbon-carbon and carbon-heteroatom bonds, the synthesis of S-S bonds remains a considerable challenge. In this context, we present a novel approach utilizing nickel catalysts for the reductive cross-coupling of thiosulfonates. This method operates under mild conditions, offering a convenient and efficient pathway to synthesize a wide range of both symmetrical and unsymmetrical disulfides from readily available, bench-stable thiosulfonates with exceptional selectivity. Notably, this approach is highly versatile, allowing for the late-stage modification of pharmaceuticals and the preparation of various targeted compounds. A comprehensive mechanistic investigation has been conducted to substantiate the proposed hypothesis.

A nickel-catalyzed carbon–sulfur cross-coupling reaction with disulfides enabled by mechanochemistry

A Ni-catalyzed C–S coupling has been proposed based on mechanochemistry. The mechanochemical synthesis of thioethers is realized with a wide range of disulfides and bromides. A multivalence Ni-catalytic cycle for C–S bond formation is proposed.

Electrochemical nickel-catalyzed cross-coupling of glycosyl thiols with preactivated phenols and ketones.

An efficient electrochemical nickel-catalyzed cross-coupling reaction has been reported here for the synthesis of S-glycosides from preactivated phenols and ketones under mild conditions. Various glycosyl thiols, including unprotected sugar, and a diverse range of aryl/alkenyl triflates, including some complex biorelevant phenols and ketones, were well tolerated in this method.

Nickel-Catalyzed Radical Mechanisms: Informing Cross-Coupling for Synthesizing Non-Canonical Biomolecules.

Nickel excels at facilitating selective radical chemistry, playing a pivotal role in metalloenzyme catalysis and modern cross-coupling reactions. Radicals, being nonpolar and neutral, exhibit orthogonal reactivity to nucleophilic and basic functional groups commonly present in biomolecules. Harnessing this compatibility, we delve into the application of nickel-catalyzed radical pathways in the synthesis of noncanonical peptides and carbohydrates, critical for chemical biology studies and drug discovery.We previously characterized a sequential reduction mechanism that accounts for chemoselectivity in cross-electrophile coupling reactions. This catalytic cycle begins with nickel(I)-mediated radical generation from alkyl halides, followed by carbon radical capture by nickel(II) complexes, and concludes with reductive elimination. These steps resonate with mechanistic proposals in nickel-catalyzed cross-coupling, photoredox, and electrocatalytic reactions. Herein, we present our insights into each step involving radicals, including initiation, propagation, termination, and the nuances of kinetics, origins of selectivity, and ligand effects.Radical generation from C(sp3) electrophiles via one-electron oxidative addition with low-valent nickel radical intermediates provides the basis for stereoconvergent and cross-electrophile couplings. Our electroanalytical studies elucidate a concerted halogen atom abstraction mechanism, where electron transfer is coupled with halide dissociation. Using this pathway, we have developed a nickel-catalyzed stereoselective radical addition to dehydroalanine, facilitating the synthesis of noncanonical peptides. In this application, chiral ligands modulate the stereochemical outcome through the asymmetric protonation of a nickel-enolate intermediate.The capture of the alkyl radical by nickel(II) expands the scope of cross-coupling, promotes reductive elimination through the formation of high-valent nickel(III) species, and governs chemo- and stereoselectivity. We discovered that nickel(II)-aryl efficiently traps radicals with a barrier ranging from 7 to 9 kcal/mol, followed by fast reductive elimination. In contrast, nickel(II)-alkyl captures radicals to form a nickel(III) species, which was characterized by EPR spectroscopy. However, the subsequent slow reductive elimination resulted in minimal product formation. The observed high diastereoselectivity of radical capture inspired investigations into C-aryl and C-acyl glycosylation reactions. We developed a redox auxiliary that readily couples with natural carbohydrates and produces glycosyl radicals upon photoredox activation. Nickel-catalyzed cross-coupling of the glycosyl radical with bromoarenes and carboxylic acids leads to diverse non-natural glycosides that can facilitate drug discovery.Stoichiometric studies on well-defined d8-nickel complexes have showcased means to promote reductive elimination, including ligand association, oxidation, and oxidative addition.In the final section, we address the influence of auxiliary ligands on the electronic structure and redox activity of organonickel intermediates. Synthesis of a series of low-valent nickel radical complexes and characterization of their electronic structures led us to a postulate that ligand redox activity correlates with coordination geometry. Our data reveal that a change in ligand redox activity can shift the redox potentials of reaction intermediates, potentially altering the mechanism of catalytic reactions. Moreover, coordinating additives and solvents may stabilize nickel radicals during catalysis by adjusting ligand redox activity, which is consistent with known catalytic conditions.

Nickel-Catalyzed Migratory Cross-Coupling Reactions: New Opportunities for Selective C-H Functionalization.

ConspectusMigratory cross-coupling via metal migration is a process of significant academic and industrial interest. It provides an attractive alternative for the selective installation of a functional group at remote C-H positions from simple precursors, thus enabling the direct synthesis of challenging structures not accessible with traditional cross-coupling. In particular, with the merger of 1,n-Ni/H shift and cross-coupling of nickel, the Ni-catalyzed migratory functionalization of simple precursors has undergone particularly intense development and emerged as a valuable field of research in the past few years. This Account will outline the recent progress made in this arena in terms of migration-functionalization modes, diverse functionalizations, and strategies for regio- and stereocontrol. Mechanistic studies and synthetic applications are also discussed.In detail, we systematically categorize our work into two parts based on the migration modes. In the first part, a platform is created for Ni-catalyzed migratory sp3 C-H functionalization of alkenes or alkyl halides via iterative 1,2-Ni/H shift-selective cross-coupling. The key reactive Ni(II)H species for chain-walking could be generated in situ either in a polarity-reversed fashion relying on stoichiometric reductants (X-Ni(II)-H) or in a redox-neutral fashion with the participation of nucleophilic coupling partners (FG-Ni(II)-H). One significant advantage associated with the polarity-reversed NiH system is the use of relatively stable, abundant, and safe olefin surrogates or alkyl halides instead of the sensitive organometallics required in traditional cross-coupling reactions. Another advantage is that diverse functionalizations, including carbonation and more challenging amination and thiolation could be smoothly achieved with suitable electrophiles or their precursors. Finally, to address the challenging multifaceted selectivity and reactivity issues in asymmetric migratory cross-coupling reactions, we have developed a feasible ligand relay catalytic strategy. In this dynamic ligand exchange process, one ligand promotes rapid migration while the other promotes highly regio- and stereoselective coupling. This innovative strategy overcomes the formidable challenge stemming from the difficulty of designing a single ligand to efficiently promote both steps of chain-walking and asymmetric coupling. In the second part, a new platform for Ni-catalyzed migratory sp2 C-H functionalization via 1,4-Ni/H shift-selective cross-coupling has been reported. Starting from readily available aryl or vinyl coupling partners, the in situ-generated aryl- or vinylnickel(II) species could undergo a rapid and reversible 1,4-Ni/H shift along an sp2 backbone, and subsequent selective coupling with various coupling partners would allow regio- and stereoselective access to diverse 1,4-migratory functionalization products. The key to success was the discovery of an appropriate ligand to efficiently promote both migration and subsequent selective cross-coupling. A vinyl-to-aryl 1,4-Ni/H shift successfully enables the modular ipso/ortho difunctionalization of aryl coupling partners, while an aryl-to-vinyl 1,4-Ni/H shift enables regio- and stereoselective access to functionalized trisubstituted alkenes.We hope that this Account will inspire broad interest and future development of migratory cross-coupling reactions. We strongly believe that continued efforts in this fascinating field will overcome many of the remaining challenges, including cutting-edge ligand/catalyst design to enhance reactivity and selectivity, conceptually new migration modes for additional transformations, and in-depth mechanistic studies for rational reaction design.

A Paradigm Shift in Catalysis: Electro- and Photomediated Nickel-Catalyzed Cross-Coupling Reactions.

ConspectusTransition-metal catalyzed cross-coupling reactions are fundamental reactions in organic chemistry, facilitating strategic bond formations for accessing natural products, organic materials, agrochemicals, and pharmaceuticals. Redox chemistry enables access to elusive cross-coupling mechanisms through single-electron processes as an alternative to classical two-electron strategies predominated by palladium catalysis. The seminal reports of Baran, MacMillan, Doyle, Molander, Weix, Lin, Fu, Reisman, and others in merging redox perturbation (photochemical, electrochemical, and purely chemical) with catalysis are pivotal to the current resurgence and mechanistic understanding of first-row transition metal-based catalysis. The hallmark of this redox platform is the systematic modulation of transition-metal oxidation states by a photoredox catalyst or at a heterogeneous electrode surface. Electrocatalysis and photocatalysis enhance transition metal catalysis' capacity for bond formation through electron- or energy-transfer processes that promote otherwise challenging elementary steps or elusive mechanisms. Cross-coupling conditions promoted by electrocatalysis and photocatalysis are mild, and bond formation proceeds with exceptionally high chemoselectivity and wide functional group tolerance. The interfacing of abundant first-row transition-metal catalysis with electrocatalysis and photocatalysis has brought about a paradigm shift in cross-coupling technology as practitioners are quickly applying these tools in synthesizing fine chemicals and pharmaceutically relevant motifs. In particular, the merger of Ni catalysis with electro- and photochemistry ushered in a new era for carbon-carbon and carbon-heteroatom cross-couplings with expanded generality compared to their thermally driven counterparts. Over the past decade, we have developed enabling photo- and electrochemical methods throughout our combined research experience in industry (BMS, AstraZeneca) and academia (Professor Baran, Scripps Research) in cross-disciplinary collaborative environments. In this Account, we will outline recent progress from our past and present laboratories in photo- and electrochemically mediated Ni-catalyzed cross-couplings. By highlighting these cross-coupling methodologies, we will also compare mechanistic features of both electro- and photochemical strategies for forging C(sp2)-C(sp3), C(sp3)-C(sp3), C-O, C-N, and C-S bonds. Through these side-by-side comparisons, we hope to demystify the subtle differences between the two complementary tools to enact redox control over transition metal catalysis. Finally, building off the collective experience of ourselves and the rest of the community, we propose a tactical user guide to photo- and electrochemically driven cross-coupling reactions to aid the practitioner in rapidly applying such tools in their synthetic designs.

Nickel-Catalyzed Cross-Coupling Reaction of Aryl Methyl Sulfides with Aryl Bromides.

A nickel-catalyzed cross-coupling reaction of aryl methyl sulfides with aryl bromides has been developed to access biaryls in yields of up to 86%. The reactions proceeded well using Ni(COD)2 as catalyst with the ligand BINAP (2,2'-bis(diphenylphosphanyl)-1,1'-binaphthalene) in the presence of magnesium. The method has a broad scope of substrates and is scalable. The wide availability of commercially available aryl bromides and the absence of preparation and preparation of organometallic reagents make the reaction of high application value.

Synthesis of Fluorinated Compounds by Nickel-Catalyzed Defluorinative Cross-Coupling Reactions

Synthesis of Fluorinated Compounds by Nickel-Catalyzed Defluorinative Cross-Coupling Reactions

Regioselective C-F Bond Transformations of Silyl Difluoroenolates.

Herein, we report the development of a nickel-catalyzed cross-coupling reaction of silyl difluoroenolates with aryl zinc reagents via C-F bond cleavage. Treatment of a stoichiometric amount of Ni(0)/N-heterocyclic carbene (NHC) with silyl difluoroenolates in the presence of a lithium salt resulted in C-F bond cleavage to selectively afford the corresponding (Z)-alkenyl Ni complexes. On the basis of the observations, we developed a catalytic cross-coupling reaction that selectively delivers a single geometric isomer of a fluoroenolate.

Nickel-Catalyzed Reductive Coupling of Chlorosilanes.

Organosilanes play essential roles in many important research areas. The use of readily available chlorosilanes to catalytically access these compounds is synthetically appealing but remains a long-standing challenge. Nickel-catalyzed reductive cross-coupling reaction has recently emerged as a promising protocol to arrive at this goal. This strategy allows the chlorosilanes to be coupled with various carbon electrophiles under mild conditions. These reactions afford organosilanes with improved molecular diversity, structural complexity, and functional group compatibility. This Concept article summarizes the recent advance on nickel-catalyzed reductive C-Si couplings of chlorosilanes.

Nickel-catalyzed desulfonative cross-coupling of benzylsulfonyl chlorides with arylsulfonyl chlorides for synthesis of asymmetric thioethers

C–S bond formation is of great interest and plays an important role in organic synthesis, material science, and medicinal chemistry. On the other hand, sulfonyl chlorides are inexpensive, readily available, and easily handled reagents. The use of two different types of sulfonyl chlorides to prepare unsymmetrical thioethers has been considered a challenge task. Here, a nickel-catalyzed desulfonative cross-coupling reaction for the synthesis of unsymmetrical thioethers is disclosed. In this reaction, benzylsulfonyl chlorides play a role as the electrophiles, and arylsulfonyl chlorides serve as the sulfur precursors. We demonstrate that arylsulfonyl chlorides reductively couple with electrophilic benzylsulfonyl chlorides through a desulfonylation process, giving a variety of asymmetric thioethers in moderate-to-excellent yields with good functional group tolerance. By employing readily available sulfonyl chlorides as both electrophiles and sulfur surrogates, we address a challenge in organic synthesis.

Mechanisms of nickel-catalyzed reductive cross-coupling reactions

Nickel-catalyzed reductive cross-coupling (RCC) reactions using two carbon electrophiles as coupling partners provide one of the most reliable and straightforward protocols for facile construction of valuable C-C bonds in the realm of organic chemistry. In recent years, significant progress has been made in the methodological developments and mechanistic studies of these reactions. This review summarizes four widely accepted mechanisms for RCC reactions that have been proposed by experiments or density functional theory calculations. The major difference between these four types of mechanisms lies in the oxidation state of the active catalyst, the change in the valence of nickel during the catalytic cycle, the involvement of carbon radicals, and the form in which the radicals are present. Herein, we focus on covering representative advancements in experimental and theoretical mechanistic studies, aiming to offer vital mechanistic insights into key intermediates, reaction rates, the activation modes of electrophiles, rate- or selectivity-determining steps, and the origin of the cross-selectivity.