NiH-catalyzed C–N bond formation: insights and advancements in hydroamination of unsaturated hydrocarbons

The formation of C–N bonds is a fundamental aspect of organic synthesis, and hydroamination has emerged as a pivotal strategy for the synthesis of essential amine derivatives. In recent years, there has been a surge of interest in metal hydride-catalyzed hydroamination reactions of common alkenes and alkynes. This method avoids the need for stoichiometric organometallic reagents and overcomes problems associated with specific organometallic compounds that may impact functional group compatibility. Notably, recent developments have brought to the forefront olefinic hydroamination and hydroamidation reactions facilitated by nickel hydride (NiH) catalysis. The inclusion of suitable chiral ligands has paved the way for the realization of asymmetric hydroamination reactions in the realm of olefins. This review aims to provide an in-depth exploration of the latest achievements in C–N bond formation through intermolecular hydroamination catalyzed by nickel hydrides. Leveraging this innovative approach, a diverse range of alkene and alkyne substrates can be efficiently transformed into value-added compounds enriched with C–N bonds. The intricacies of C–N bond formation are succinctly elucidated, offering a concise overview of the underlying reaction mechanisms. It is our aspiration that this comprehensive review will stimulate further progress in NiH-catalytic techniques, fine-tune reaction systems, drive innovation in catalyst design, and foster a deeper understanding of the underlying mechanisms.


Introduction
3][34][35][36][37][38][39][40][41][42] Traditional approaches, which involve the nucleophilic reaction of amines with unsaturated substrates, oen require challenging conditions due to the electron-rich nature of both reactants.4][45] As an innovative alternative, the pioneering work of the Buchwald and Miura groups introduced CuH-catalyzed hydroamination. 46,47This method works through a mechanism where the polarity is reversed: the hydrogen atom is derived from a hydridic reagent, while the amino group comes from an electrophilic reagent.By separating the R 2 N and H components into distinct high-energy reagents, the conventional hydroamination process can be altered to become a notably exothermic reaction, providing a substantial driving force.
9][50][51][52][53][54][55][56][57][58][59] While nickel has historically been valued as a competitive alternative to precious metals like palladium and platinum due to its catalytic properties, recent applications have elevated its signicance beyond being merely costeffective.The comparative analysis of CuH and NiH in hydroamination and hydroamidation reactions reveals their unique chemical properties and reactivities.While both CuH and NiH nd applications in these reactions, their distinct properties oen dictate their suitability for specic substrates and reaction conditions.NiH, with its compatibility with sensitive functional groups and ability to perform chain-walking, emerges as a more adaptable candidate for complex organic syntheses.Specically, the three distinctive differences between CuH and NiH catalysis can be described as follows: (1) coordination with directing groups: nickel's propensity to easily coordinate with directing groups stands out as a notable advantage.This coordination ability allows for the regioselective functionalization of olens.Such precision is invaluable in the synthesis of complex molecules where regioselectivity is paramount.(2) Chain-walking ability: CuH species typically lack chain-walking capability, conning their reactivity to the immediate vicinity of the metal center.This limitation oen restricts the functionalization to positions adjacent to the metal.In contrast, NiH species, when combined with suitable chain-walking ligands, can engage in subsequent cross-coupling at distal positions.This chainwalking feature imparts the ability to perform regioselective functionalization of both remote and proximal olens, signicantly enhancing the versatility in organic molecule modication.(3) Compatibility with functional groups: CuH species are known for their strong reductive nature.While this reductive quality is a key feature, it can also restrict their compatibility with substrates containing sensitive functional groups such as ketones and aldehydes.Consequently, this may limit the variety of substrates suitable for hydroamination and hydroamidation reactions.On the other hand, NiH species show an enhanced compatibility with these sensitive groups, allowing for a wider range of substrates to be utilized in hydroamination and hydroamidation reactions.This review will spotlight the unique attributes of nickel in the realm of metal hydrides, including techniques such as rapid chain-walking for remote functionalization and the utilization of coordination to achieve specic outcomes.While many individual studies have offered valuable insights, a review paper is pivotal for consolidating the wealth of knowledge from these developments.It aims to provide researchers and practitioners with a comprehensive perspective on contemporary techniques, mechanisms, and applications in C-N bond formation through NiH catalysis.This review is structured into three sections, each shedding light on distinct aspects of NiH-catalyzed hydroamination chemistry (Scheme 1).( 1) Regioselective C-N bond formation of alkenes: in this section, we discuss the ways NiH catalysis facilitates the precise addition of amines to C-C double bonds.The discussion emphasizes the adaptability of this catalysis in handling diverse alkene substrates and its efficacy in optimizing the synthesis of vital nitrogen-based compounds.(2) Regioselective C-N bond formation of alkynes: turning our attention to alkynes, another class of unsaturated hydrocarbons, we elucidate how NiH catalysis plays a pivotal role in shaping alkynes, facilitating the synthesis of intricate molecules by the strategic integration of nitrogen atoms.(3) Asymmetric C-N bond formation: in this segment, we highlight the forefront of chiral molecule synthesis, showcasing advancements in NiH-catalyzed hydroamination.Specically, we discuss the incorporation of asymmetric induction, paving the way for enantioselective transformations.

NiH-catalyzed direct hydroamination/hydroamidation
At rst glance, the direct hydroamination and hydroamidation of alkenes may appear to be straightforward processes.However, upon closer examination, the inherent challenges and complexities of these reactions become apparent, particularly in the context of regioselectivity.When it comes to alkene hydroamination and hydroamidation, achieving precise control over which carbon atom in the alkene bond reacts with the amine or amide is critical for the synthesis of the desired compounds.While this challenge is pertinent to all alkenes, it becomes particularly pronounced in the case of 1,2-disubstituted internal alkenes.The close electronic and steric similarities of the carbons in a 1,2-disubstituted alkene necessitate the development of innovative strategies.These strategies oen entail the utilization of specic catalysts, ligands, or tailored reaction conditions designed to inuence the regioselectivity of the reaction in the desired direction.Ongoing research remains essential to the development of more predictable and efficient methods for achieving regioselectivity, especially in the challenging context of 1,2-disubstituted alkenes.
In 2020, Hong et al. reported a strategy involving the NiHcatalyzed proximal-selective hydroamination of unactivated alkenes using aminobenzoates and hydrosilane (Scheme 2). 60his innovative methodology achieved regioselective NiH insertion into alkenes, with its efficacy attributed to the robust chelation between the bidentate directing group and nickel.Consequently, the nickel complex interacted with the aminating agent, leading to the formation of aminated derivatives.Notably, this method demonstrated remarkable versatility, accommodating a diverse array of primary and secondary amines.It also exhibited exceptional regiocontrol for both internal and terminal unactivated alkenes under mild conditions.By strategically employing aminoquinoline and picolinamide as bidentate directing groups, the research accomplished selective b-, g-, and d-aminations.This pivotal work, supported by both experimental and computational data, provided comprehensive insights into the reaction mechanism.It particularly highlighted the signicance of migratory insertion steps as both the determinants of regioselectivity and turnover-limiting stages.
In 2021, Hu et al. reported a nickel-catalyzed hydroamination using anthranils as the electrophilic aminating agents (Scheme 3a). 61This method results in the synthesis of Nalkyl-2-aminobenzophenones, which serve as versatile intermediates.The process initiates with a migratory insertion during which a NiH complex, formed from the reaction of a bipyridine-type ligand-ligated nickel catalyst and hydrosilane, attaches at the benzylic position.Subsequently, this complex reacts with anthranils, giving rise to a nickel-nitrenoid complex.One distinctive aspect of this methodology is its unique reaction outcome compared to previous methods of copper hydride catalysis involving anthranils.While earlier processes led to a complete reduction resulting in benzyl alcohol, this method retains the carbonyl group, avoiding further reduction.Furthermore, the research emphasizes the adaptability of this method to different olens and anthranils, highlighting its utility in producing a diverse array of valuable amination products.The protocol stands out for its excellent benzylic selectivity, mild reaction conditions, and broad substrate range.It also proves highly effective in the late-stage modication of numerous pharmaceutical derivatives.
Subsequently, this research group developed a NiH-catalyzed hydroamination with proximal selectivity for unactivated alkenes bearing bidentate directing groups, employing anthranils as amination agents (Scheme 3b). 62This method builds upon the prior work of the Hong group in 2020, which also leveraged bidentate directing groups, highlighting the versatility of regioselective hydroamination techniques.The method effectively enables the incorporation of a wide range of primary arylamines with an ortho-carbonyl group into both terminal and internal unactivated alkenes.This results in the synthesis of invaluable band g-amino acid precursors, characterized by remarkable regiocontrol.Furthermore, the effectiveness and broad applicability of this method are evident in its capacity to convert multifunctionalized arylamines into N-heterocycles.
In 2023, Wang and Zheng et al. presented a method closely resembling the one described in the previous approach by Hu and Huo, which focuses on the hydroamination of unactivated alkenes using anthranils (Scheme 4). 63This approach distinguishes itself by categorizing the reaction conditions into two specic modes: one that preserves the carbonyl group and another that leads to alcohol formation through complete reduction, depending on the choice of bases.This method offered selective synthesis of a wide range of arylamino aldehydes and alcohols.In addition, it expands upon the prior work by examining alkenes in which the double bond is further distant from the carbonyl group.The authors observed favorable reactivity and appreciable regioselectivity for b,gand g,d-

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alkenes, as well as d,3-alkenes.However, 3,z-alkenes demonstrated only moderate reactivity with a near 1 : 1 regioselectivity.This method offers a useful framework for controlling the reaction outcome, allowing for the retention of the carbonyl group or the production of alcohols based on specic conditions and preferences.
In 2022, Yu and Lin et al. reported a NiH-catalyzed intermolecular hydroamidation using dioxazolones and pinacol borane that exhibits anti-Markovnikov selectivity (Scheme 5). 64his method employs 2,9-dibutylphenathroline (diBuphen) as a ligand, and the steric bulk of this ligand plays a pivotal role in facilitating the selective incorporation of nickel primarily at the terminal position.Subsequently, the nickel-alkyl intermediate reacts with dioxazolones to form a nickel-nitrenoid, ultimately leading to the formation of amidated products through C-N bond formation for the synthesis of various N-alkyl amides.A standout feature of this method is its versatility; it accommodates a diverse range of dioxazolones and is suitable for both terminal and internal alkenes, encompassing even natural products with multiple functional groups.Mechanistic insights, enriched through deuterium labeling studies and trapping reagent experiments, shed light on a reversible insertion/ elimination process of the NiH into the alkene, followed by an irreversible amidation step.Additional calculations suggest the involvement of the Curtin-Hammett selectivity model in this process.

NiH-catalyzed migratory hydroamination/ hydroamidation
NiH-catalyzed migratory hydrofunctionalization is a robust synthetic technique that selectively modies aliphatic C(sp 3 )-H bonds. 65This process unveils new horizons for transforming molecules at positions traditionally considered challenging to access.The intricacies of reaction conditions, ligand characteristics, and substrate specicities frequently require meticulous optimization.Despite the challenges, the undeniable potential of migratory hydroamination and hydroamidation places them at the forefront of contemporary synthetic research.In the following section, our focus is on recent advances in this eld using NiH catalysis.
In 2018, Zhu et al. developed a NiH-catalyzed remote relay hydroarylamination process (Scheme 6). 66This innovative approach allowed the introduction of arylamino groups at benzylic positions within alkyl chains, harnessing an intricate chain-walking mechanism.During the process, once the NiH was integrated into the alkene, it embarked on a meticulous chain-walking process.This involved a series of successive bhydride elimination and migratory insertion steps, eventually culminating at the benzylic position, where it forged a thermodynamically stable alkyl-nickel complex.This resultant complex was then primed to engage in the hydroarylamination reaction.It paired with the nitrosoarene, an intermediate derived from the efficient reduction of nitroarene by the NiH.This protocol provided an efficient route for the synthesis of valuable arylamines, directly from basic olens and nitro(hetero)arenes.The versatility of this method was highlighted by its ability to achieve regioconvergent arylamination of isomeric olen mixtures.
In 2020, building on their previous studies, the same group further advanced their methodology by unveiling a NiHcatalyzed migratory hydroamination procedure, employing aminobenzoate electrophiles (Scheme 7). 67This rened method facilitated the regiodivergent placement of a distal amino group at either the benzylic or terminal locations within alkyl chains.The choice between monophosphine-type ligands and bipyridine-type ligands determined the specic positioning.Impressively, this approach is both practical and efficient making use of easily accessible olens.Furthermore, the group showcased that an alkyl bromide could be converted into an olen when combined with Mn(0) as a reducing agent.The process exhibited remarkable compatibility with substrates containing a wide range of functional groups and achieved remote C(sp 3 )-H amination products with impressive yields and regioselectivity, maintaining these attributes even when scaled up to 10 mmol.Importantly, this technique was adeptly applied to the regioconvergent transformation of petroleumbased feedstocks.The efficient transformation of isomeric olen mixtures into a single, valuable amine compound variant further highlighted its potential.
In 2021, Hong et al. unveiled a groundbreaking NiHcatalyzed g-selective migratory hydroamination of alkenyl amides, leveraging both a bidentate directing group and phosphine ligand (Scheme 8). 68This innovative strategy represents the rst instance of g-C(sp 3 )-H functionalization via a chain-walking approach, distinguishing itself from previous methods that were conned to aand b-C(sp 3 )-H functionalizations.The process is facilitated by phosphine ligands, culminating in the formation of a 6-membered nickellacycle.This sequence is guided by an 8-aminoquinoline directing group and is eventually intercepted by an aminobenzoate.This method allows for the introduction of a diverse array of amines at the g-C(sp 3 )-H bond of unactivated alkenes, irrespective of their alkyl chain lengths, paving the way for the streamlined synthesis of valuable g-aminated derivatives.Moreover, the Scheme 7 NiH-catalyzed terminal-and benzylic selective migratory hydroamination using ligand effects.

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researchers extended the technique to d-selective amination, underscoring its adaptability with picolinamide-integrated alkene substrates.The intricate chain-walking mechanism and its selective pathways were elucidated using deuterium experiments and rigorous computational analysis.Yu and colleagues reported a NiH-catalyzed thioetherdirected cyclometalation strategy, enabling g-selective migratory hydroamidation of thioether-containing unactivated alkenes (Scheme 9). 69This innovative approach utilizes a phenanthroline derivative as a ligand and dioxazolones as amidating reagents to selectively target g-C(sp 3 )-H bonds, yielding amide products with remarkable regioselectivity and high yields.The preference for ve-membered nickelacycle formation effectively curtails chain-walking isomerization at a specic g-methylene site.Such selectivity ensures distinct regiodifferentiation amidst similar chemical environments present within the hydrocarbon sequence.Furthermore, this protocol demonstrated that a ligand bearing a single methyl group furnished the Markovnikov product for the terminal d,3-alkene substrates.Interestingly, the reaction proceeds even when the substratenickel complex, which features a sulde bond to the nickel center, is isolated and exposed to the standard reaction conditions.This catalytic hydroamidation protocol not only serves as a versatile tool for diverse amide synthesis but also provides insights into the development of regiocontrolled C-N bond formation in unactivated aliphatic alkanes.
In 2023, Zhang and Yuan et al. introduced an efficient nickelcatalyzed method for remote hydroamination and hydro-etherication of alkenes using amines and alcohols as coupling nucleophiles (Scheme 10). 70This method prociently synthesized gem-diamine and N,O-acetal derivatives, achieving commendable yields and exhibiting exclusive regioselectivity with the assistance of a phenanthroline-type ligand.This breakthrough overcomes previous challenges of modifying alkenes with traditionally unreactive amines and alcohols.The key to the success of this method was the incorporation of 2iodo-2-methylpropane ( t BuI), which functioned both as a hydride donor and a radical precursor.This study presents an innovative approach for the incorporation of diverse amino or alkoxyl functionalities onto C(sp 3 )-H sites distant from alkene's double bond.The methodology demonstrated its robustness with a broad substrate scope and the regioconvergent transformation of mixed alkenes into a single remote functionalized product.Additionally, DFT computational analyses shed light on the underlying mechanistic route, emphasizing the chainwalking process that ultimately results in a thermodynamically favorable ve-membered nickellacycle.

NiH-catalyzed regioselective C-N bond formation of alkynes
The hydroamination of alkynes has become a cornerstone in synthetic chemistry, allowing the introduction of an amine group across a carbon-carbon triple bond to produce enamines or imines.These intermediates are pivotal in organic synthesis because of their potential to be transformed into various functionalized compounds.Historically, achieving selective hydroamination of alkynes was challenging, especially under mild conditions with diverse substrates.However, NiH-catalyzed reactions stand out for their excellent regiocontrol in mild conditions.This method adeptly creates nitrogen-rich structures oen found in pharmaceuticals, agrochemicals, and natural products.Ongoing research hints at more rened methods, broader substrate applicability, and even more advanced and sustainable catalytic systems.
In 2021, the Hu group unveiled an efficient NiH-catalyzed hydroamination/cyclization cascade of alkynes and anthranils, offering a convenient route for synthesizing elaborately substituted quinolines (Scheme 11). 71This method stood out for its high regioselectivity, mild operating conditions, and extensive substrate compatibility, embracing a variety of alkynes ranging from terminal to internal and from aryl to alkyl, inclusive of both electron-decient and electron-rich types.Notably, the bipyridine-ligated NiH showed a Markovnikov-type migratory insertion with terminal alkynes, while favoring the aryl group with internal ones.The versatility of this approach also enabled the late-stage functionalization of natural products and the synthesis of crucial compounds, including the antitumor agent graveolinine and a potent triplex DNA intercalator.Such advancements in NiH catalysis hint at a promising future for transforming basic alkynes into a diverse array of high-value compounds.
In 2021, Chang, Seo, and colleagues introduced a groundbreaking NiH-catalyzed strategy for the formal hydroamidation of alkynes using dioxazolones, facilitating the synthesis of valuable secondary enamides.Selectivity between (E)-anti-Markovnikov or Markovnikov was determined by the choice of bipyridine ligands, being either disubstituted or monosubstituted (Scheme 12). 72This approach is versatile, accommodating both terminal and internal alkynes, and it exhibits tolerance toward various functional groups.Signicantly, it effectively overcame challenges related to semireduction pathways by employing a low-energy inner-sphere nitrenoid transfer.The method consistently achieved good to excellent regioselectivity, and the introduction of H 2 O proved essential for attaining high catalyst turnovers by facilitating transmetalation.This versatility extended to the construction of synthetically valuable alkylamide moieties, including enantioselective transformations through sequential asymmetric hydrogenation, highlighting its wide range of synthetic applications.Mechanistically, this work underscores a unique Ni-nitrenoid intermediacy, pointing to future C-N bond-forming methodologies.
In 2022, the same group introduced a NiH-catalyzed intramolecular hydroamidation of alkynyl dioxazolones, achieving precise endo-selective C-N bond formation, which produces various six-to eight-membered endocyclic enamides from a wide range of alkynes (Scheme 13). 73This novel process harnesses Ni(I) catalysis and progresses through a series of regioselective steps: syn-hydronickelation, alkenylnickel E/Z isomerization, oxidative activation of dioxazolone, and innersphere nitrenoid transfer.Mechanistic insights disclosed the Scheme 11 NiH-catalyzed quinoline synthesis using alkynes and anthranils.

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h 2 -vinyl-like transition state governing the key alkenylnickel isomerization, a previously unclaried step.Synthetically, this method shines by allowing the diastereoselective creation of rich d-lactams, emphasizing the enamide's adaptability for varied transformations.This research not only pioneers in endo-selective cyclizations but also sets the stage for NiHcatalyzed C-N bond formation, enriching the resources for craing valuable cyclic enamides.

Asymmetric hydroamination/hydroamidation at activated sites
The catalytic formation of enantiopure aliphatic amines and amides from abundant and readily accessible starting materials has persistently stood as a formidable challenge in synthetic chemistry.The success of such transformations largely hinges on the design of chiral ligands.In this section, we explore the latest advancements in asymmetric hydroamination and hydroamidation of activated systems.
In 2019, the Mazet group unveiled a Ni-catalyzed enantioselective hydroamination of branched 1,3-dienes, marking a signicant milestone in synthetic chemistry (Scheme 14). 74his method stands out due to its unparalleled regio-, chemo-, and enantioselectivity, providing an efficient avenue to produce high-value chiral allylic amines using both primary and secondary amines.In addition, this approach eliminates the dependency on oen complex amination reagents.To gain deeper insights into the intricate mechanisms, the group undertook comprehensive studies, including NMR tracking of the reaction, isotopic labeling using deuterium ( 2 H) to map reaction routes, and kinetic assessments to identify the crucial rate-determining step.Their ndings highlighted the catalytic resting state as a Ni−p-allyl complex and identied the pivotal step as an outer-sphere nucleophilic attack, made possible by Hbonded amine groupings, commonly seen as dimers.These insights not only optimized reaction conditions but also broadened the method's applicability to various functional groups.This research showcased a streamlined approach for the preparation of enantioenriched chiral primary allylamines.
In the same year, Yin and colleagues unveiled an innovative nickel/Brønsted acid-catalyzed asymmetric hydroamination . 75This method efficiently converts a broad spectrum of primary and secondary amines into highly enantioenriched allylic amines under mild conditions.Notably, it exhibits exceptional chemoselectivity for amines possessing multiple nucleophilic sites.Its success hinges on the pairing of chiral bisphosphine ligands with the right Brønsted acids, broadening the scope of accessible enantioenriched secondary and tertiary allylic amines and enabling late-stage modications of complex molecules.The method also demonstrates compatibility with a diverse array of functional groups and heterocycles.Mechanistic investigations showed the carbonnitrogen bond formation step to be reversible.Notably, racemization is observed in reactions using secondary amines over prolonged periods, while primary amines remain stable.This makes the approach exceptionally promising for yielding enantioenriched amines, holding signicant implications for medicinal chemistry and innovative reaction methodologies.
In 2021, the Zhu group advanced asymmetric catalysis by introducing a pioneering platform for regio-and enantioselective hydroarylamination, hydroalkylamination, and hydroamidation of styrenes (Scheme 16). 76Central to this breakthrough is the use of NiH catalysis combined with a straightforward bioxazoline ligand, functioning under mild conditions.Beyond furnishing enantioenriched benzylic arylamines, alkylamines, and amides, the methodology further demonstrates its adaptability by incorporating nitroarenes, hydroxylamines, and dioxazolones as versatile amination and amidation agents.Mechanistic insights suggest that chiral induction in these reactions stems from an enantiodifferentiating syn-hydronickellation step, adding further depth to this transformative approach.This cutting-edge approach holds immense promise for synthesizing enantioenriched compounds and offers potential applications across various domains of synthetic chemistry.
In 2022, the Zhu group achieved a signicant advancement in the eld of chiral a-aminoboronic acids and their derivatives, recognized for their role as bioactive compounds and approved therapeutic agents (Scheme 17). 77This study unveiled a NiHcatalyzed asymmetric hydroamidation process, facilitated by a straightforward and effective amino alcohol ligand.This method prociently produces a broad range of enantioenriched Scheme 16 NiH-catalyzed asymmetric hydroarylamination, hydroamination, and hydroamidation of vinylarenes.

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a-aminoboronates under benign conditions.The suggested reaction pathway commences with an enantioselective hydrometallation, evolving into a nely-tuned inner-sphere nitrenoid transfer, leading to C-N bond generation.The synthetic utility was further exemplied by a three-step synthesis of vaborbactam, a b-lactamase inhibitor, thereby streamlining the original six-step synthetic approach.This breakthrough has the potential to signicantly impact the production of chiral aminoboronic acids, with implications for the pharmaceutical industry.
In 2023, the Shu group embarked on a landmark project in synthetic chemistry, driven by the critical role of enantioenriched a-chiral-b-amino acid derivatives in both biological and pharmaceutical elds.This research led to the development of a unique enantioselective formal hydroamination method (Scheme 18). 78This method was specically tailored for N,Ndisubstituted acrylamides, making the synthesis of enantioenriched a-chiral-b-aminoamide derivatives more efficient.Impressively, this technique overcame challenges typically encountered with electronically disfavored hydroamination reactions.This success was achieved by harnessing a NiHcatalyzed anti-Markovnikov-selective formal hydroamination of alkenes, paving the way for producing the desired a-chiral-baminoamide derivatives.Showcasing impressive adaptability to a broad spectrum of functional groups, the procedure reliably yielded a diverse set of a-chiral-b-aminoamide derivatives.Furthermore, these compounds were craed with exceptional efficiency and unparalleled enantioselectivity, underscoring the method's transformative potential in synthetic chemistry.
In that same year, Ding and his colleagues made signicant breakthroughs by unveiling a Ni-catalyzed enantioselective hydroamination procedure tailored for vinylarenes (Scheme 19). 79This approach was instrumental in the streamlined synthesis of a vast array of a-branched chiral alkylamines.The method's standout feature was its unique Markovnikov regioselectivity paired with unparalleled enantioselectivity.Central to this technique's success was the SKP (spiroketal phosphine) ligand, which played a pivotal role.Its incorporation signicantly boosted the reaction's reactivity and netuned the enantiocontrol.Illustrating the broad versatility of their approach, the group successfully executed gram-scale reactions and showcased the technique's prowess in the precise modication of molecules with medicinal relevance.In pursuit of a deeper understanding of the process, deuterium-labeling experiments were undertaken, suggesting the irreversible hydronickelation of vinylarenes as the likely foundation for achieving such high enantioselectivity.

Asymmetric hydroamination/hydroamidation at unactivated sites
In this section, we explore the forefront of progress in asymmetric hydroamination and hydroamidation involving previously challenging unactivated alkenes.Central to our discussion is the enduring quest to synthesize enantiopure aliphatic amines and amides, utilizing commonly encountered starting materials.The intricate design and deployment of chiral ligands stand out as crucial elements, guiding the quest to realize this esteemed objective in synthetic chemistry.We cover a wide spectrum of both intermolecular and intramolecular reactions, highlighting the vast versatility and untapped potential of these contemporary approaches.
In 2022, the Hong group confronted a complex challenge in synthetic chemistry: the dual pursuit of enantio-and regioselective hydroamination of relatively uncharted, unactivated alkenes (Scheme 20). 80Their pioneering approach revolved around a Ni-catalyzed hydroamination, directed by expertly designed chiral ligands.This approach targeted readily accessible unactivated alkenes, especially those with weakly coordinating functionalities such as native amides or esters.Their methodology showcased impressive versatility, accommodating both terminal and internal unactivated alkenes while maintaining compatibility with a broad spectrum of amine coupling partners.The mildness of the reaction conditions positioned their technique as an ideal choice for the late-stage diversication of complex molecules.Such versatility enabled the efficient synthesis of enantioenriched bor g-amino acid derivatives, as well as 1,2-or 1,3-diamines in a modular fashion.Further investigation into the mechanism underscored the signicance of a chiral bisoxazoline-ligated Ni complex.Coupled with a carefully selected carbonyl directing group, this setup proved instrumental in guiding the sought-aer enantioand regioselective NiH insertion into the alkenes.
On a related note, the Shu group developed a Ni-catalyzed asymmetric hydroamination protocol employing weakly coordinating amide groups (Scheme 21). 81This method facilitated the efficient synthesis of enantioenriched amino acid derivatives and diamines featuring chiral a-branched aliphatic amine motifs.Demonstrating broad adaptability, their method embraced both terminal and internal unactivated alkenes, producing an assortment of enantioenriched amines characterized by varied substitution patterns.Furthermore, in-depth kinetic studies revealed that the nickel pre-catalyst and silane exhibited rst-order dependence, highlighting the potential involvement of NiH regeneration in the turnover-limiting step.This discovery not only deepens the understanding of the reaction mechanism of hydoramination but also sets the stage for pioneering advances in the design of new metal hydride chemistry.
In 2023, the Hong group marked a pivotal milestone in asymmetric hydroamination, employing kinetic resolution, which extracts enantioenriched compounds from racemic mixtures (Scheme 22). 82Their focus sharpened on a nickelcatalyzed kinetic resolution tailored for racemic a-substituted unconjugated carbonyl alkenes.This meticulously engineered method harmoniously combined enantioselectivity, diastereoselectivity, and regioselectivity in hydroamination.The result was the procient creation of chiral a-substituted butenamides and syn-b 2,3 -amino acid derivatives.The hallmark of their achievement lay in the remarkable enantiomeric purity, with an exemplary enantiomeric excess (ee) of up to 99%.Augmenting their accomplishment was a striking selectivity factor that eclipsed >684.At the heart of this kinetic resolution's success was the chiral nickel complex; its intricate design was essential for achieving excellent resolution and enantioselective formation of C-N bonds.
In 2023, the Wang group undertook a complex challenge, harnessing the combined potential of ligands and directing groups to advance transition-metal-catalyzed remote hydrofunctionalization of alkenes (Scheme 23). 83This research focused intently on optimizing the site-selective NiH-catalyzed hydroamination of unactivated alkenes, especially those bearing weakly coordinating amide groups.A cornerstone of their approach was the utilization of readily available bidentate nitrogen-containing ligands.This tactical choice enabled the streamlined synthesis of 1,1-, 1,2-, and 1,3-diamines from consistent substrates with outstanding regioselectivity.Additionally, their versatile methodology integrated a range of Obenzoyl hydroxylamine electrophiles, guiding them either via nickel chain-walking pathways or more straightforward techniques.By establishing these position-specic methods, the group set the foundation for the enantioselective craing of the sought-aer 1,2-diamines (through distant aliphatic C-H amination) and 1,3-diamines.This accomplishment underscores Scheme 20 NiH-catalyzed asymmetric hydroamination of unactivated alkenes.

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the profound implications of their technique in the evolving realm of chemical synthesis.
In 2023, the Chang group achieved a signicant breakthrough in developing synthetic techniques for the synthesis of enantioenriched b-lactams-compounds renowned for their prevalence in bioactive molecules. 84Confronting the longstanding issue of regioselectivity in the intramolecular hydroamidation of b,g-unsaturated amides, the group unveiled a pioneering NiH-catalyzed strategy that harnesses easily obtainable alkenyl dioxazolone derivatives.Breaking away from The lactam compound was prepared within a concise ninestep synthetic process, an improvement over the previously established 14-step procedure.This achievement marks a substantial advancement in synthetic methodology, demonstrating the effectiveness and efficiency of the novel approach adopted in this study (Scheme 24).

Conclusions and outlook
C-N bond formation stands as a cornerstone of organic synthesis, with hydroamination distinguishing itself as an incredibly versatile strategy for the synthesis of numerous essential amine molecules.The adoption of this approach has marked a transformative move towards greater efficiency and sustainability, turning the traditional thermoneutral approach into a more energetically favorable route.The rise of NiH catalysis in this domain is unequivocal, with its application in regio-and enantioselective hydroamination and hydroamidation reactions positioning it as a signicant and promising player for the future.This review illustrates recent advancements in NiH-catalyzed functionalization, categorizing them into distinct sections: regioselective C-N bond formation across alkenes and alkynes and asymmetric C-N bond synthesis involving alkenes.Current research emphasizes the adaptability of NiH-catalyzed hydroamination and hydroamidation, showcasing its capacity for the efficient synthesis of an array of amine or amide derivatives from readily available olenic feedstocks.Beyond cost considerations, where nickel presents an advantage over other precious metals, its inherent catalytic strengths are of notable signicance.Especially in the realm of metal hydrides, nickel's unique attributes become evident in its applications across alkenes and alkynes.Innovations like rapid chainwalking and meticulous coordination amplify its effectiveness to drive precise and desired outcomes.The pursuit of chiral molecule production via asymmetric induction exem-plies the vast potential in this domain.Despite signicant advancements in the eld, challenges in asymmetric hydroamination and hydroamidation of alkenes still remain.Innovations in ligand design, control of divergent pathways, and adherence to green chemistry principles are set to transform organic synthesis methodologies.The development of enhanced ligands and catalysts is anticipated to play a crucial role in driving innovative reactivity exploration.In addition, existing methods oen necessitate specic reaction conditions and rely heavily on expensive ligands and catalysts, posing scalability and environmental concerns.Therefore, a primary hurdle is the development of efficient chiral ligands and catalysts that are both cost-effective and versatile enough for intricate molecular syntheses and large-scale industrial applications.In this context, future catalysts must prioritize efficiency by using fewer reactants, achieving faster reaction rates, and providing exceptional regio-and enantioselectivities.

Chemical Science Review
Additionally, these next-generation catalysts should exhibit adaptability to various functional groups, enabling the handling of complex, late-stage modications while maintaining stability under ambient conditions through improved durability.There is a pressing need to broaden the spectrum of suitable alkenes and electrophiles developing nely tuned highly reactive amination reagents.In aiming high, the eld anticipates advancements that will generate multiple chiral centers, introduce heteroatoms, and facilitate the synthesis of quaternary amine structures, opening up new possibilities for chemical reactions.Moreover, the exploration of regiodivergent reactions, where catalyst systems yield different regioisomers from the same reactants, is particularly intriguing.This strategy transcends regioselective limitations, offering diverse product possibilities under controlled conditions.The potential for ligand-controlled regiodivergent reactions is substantial, as adjusting ligand structures could allow chemists to steer NiH-catalyzed reactions towards specic regioisomers, paving the way for the synthesis of complex molecules with varied structural frameworks.External factors like reaction temperature and time are also critical in determining regioselectivity and enantioselectivity in NiH-catalyzed reactions.Investigating these variables could lead to more adaptable and efficient synthetic methods, broadening the utility of NiH catalysis.
Finally, integrating green chemistry principles such as renewable resource utilization, waste minimization, energy efficiency, and cleaner production techniques, NiH catalysis can make a substantial contribution to more sustainable chemical processes.This involves moving away from traditional stoichiometric silanes towards greener reductants.The use of environmentally benign reductants not only diminishes the environmental impact of these reactions but also aligns with green chemistry ideals.Exploring bio-based reductants or harnessing renewable resources presents sustainable alternatives for NiH generation.A groundbreaking strategy is adopting photocatalysis in NiH generation.Leveraging light, an abundant and clean energy source, to facilitate NiH formation marks a signicant advancement in green methodologies.Photocatalysis could potentially reduce energy consumption and curb reliance on non-renewable energy sources.Implementing immobilized chiral catalysts in NiH catalysis also promotes greener chemistry.These catalysts, which enable easy separation and potential reusability, help to decrease the need for excessive reagents and thereby minimize waste.Developing durable, recyclable catalysts that retain high efficacy through multiple uses is essential.This method addresses reaction scalability and markedly reduces environmental impact by lowering waste and resource use.Moreover, employing realtime monitoring and ow chemistry techniques can optimize reaction conditions for maximum efficiency while reducing waste and harmful by-products.These methods not only bolster the sustainability of the process but also aid in rening catalytic systems for enhanced efficiency.
In conclusion, the collected insights within this review highlight the substantial advancements made in the eld of NiH-catalyzed hydroamination in organic chemistry.With these insights, our intention is to pave the path for researchers, emphasizing the opportunities in C-N bond formation and serving as inspiration for continued innovation and signicant milestones in the realm of organic synthesis.