ACS Publications. Most Trusted. Most Cited. Most Read
Regiodivergent sp3 C–H Functionalization via Ni-Catalyzed Chain-Walking Reactions
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:JACS Au 2023, 3, 12, 3270-3282
  • Open Access
Perspective

Regiodivergent sp3 C–H Functionalization via Ni-Catalyzed Chain-Walking Reactions
Click to copy article linkArticle link copied!

  • Jesus Rodrigalvarez
    Jesus Rodrigalvarez
    The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain
    More by Jesus Rodrigalvarez
  • Franz-Lucas Haut
    Franz-Lucas Haut
    The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain
    More by Franz-Lucas Haut
  • Ruben Martin*
    Ruben Martin
    The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain
    ICREA, Passeig Lluís Companys, 23, 08010 Barcelona, Spain
    *Email: [email protected]
    More by Ruben Martin
    Orcidhttps://orcid.org/0000-0002-2543-0221
Open PDF

JACS Au

Cite this: JACS Au 2023, 3, 12, 3270–3282
Click to copy citationCitation copied!
https://doi.org/10.1021/jacsau.3c00617
Published November 28, 2023

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY-NC-ND 4.0 .

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

The catalytic translocation of a metal catalyst along a saturated hydrocarbon side chain constitutes a powerful strategy for enabling bond-forming reactions at remote, yet previously unfunctionalized, sp3 C–H sites. In recent years, Ni-catalyzed chain-walking reactions have offered counterintuitive strategies for forging sp3 architectures that would be difficult to accomplish otherwise. Although these strategies have evolved into mature tools for advanced organic synthesis, it was only recently that chemists showed the ability to control the motion at which the catalyst “walks” throughout the alkyl chain. Specialized ligand backbones, additives and a judicious choice of noninnocent functional groups on the side chain have allowed the design of “a la carte” protocols that enable regiodivergent bond-forming scenarios at different sp3 C–H sites with distinct topological surface areas. Given the inherent interest in increasing the fraction of sp3 hybridized carbons in medicinal chemistry, Ni-catalyzed regiodivergent chain-walking reactions might expedite the access to target leads in drug discovery campaigns.

This publication is licensed under

CC-BY-NC-ND 4.0 .
  • cc licence
  • by licence
  • nc licence
  • nd licence
Copyright © 2023 The Authors. Published by American Chemical Society

Subjects

what are subjects

Keywords

what are keywords

Introduction

Click to copy section linkSection link copied!
Saturated hydrocarbons are the major constituents of natural gas and crude oil. In addition, these compounds constitute the main skeleton of a myriad of natural products and compounds that display important biological activities. Indeed, compounds with increased number of saturated sp3 hybridized carbons have showed recently to improve several molecular attributes that contribute to clinical success, including molecular shape (3D-structure), enhanced solubility or bioavailability, among others. (1) Driven by these observations, chemists have been challenged to design de novo catalytic techniques that harness the potential of C(sp3)–H linkages as molecular handles for enabling further bond-forming reactions, including late-stage functionalization of advanced synthetic intermediates. (2−4) However, the catalytic functionalization of C(sp3)–H bonds is not particularly straightforward compared to their parent C(sp2)–H analogues. Indeed, the former are considerably less acidic than their corresponding C(sp2)–H congeners, and they lack empty low-energy or filled high energy orbitals that interact with the d electrons of the transition metal. In addition, multiple, yet similar, C(sp3)–H bonds are present in an alkyl side chain, thus raising a reasonable doubt on whether a metal catalyst might be able to discriminate between C(sp3)–H bonds with similar steric or electronic considerations (Scheme 1). (5) If successful, however, the ability to enable a mild and site-selective functionalization of C(sp3)–H bonds might offer the advantage of carrying orthogonally reactive motifs through a chemical synthesis while providing access to chemical libraries of utmost significance in medicinal chemistry settings.

Scheme 1

Scheme 1. Metal-Catalyzed C(sp3)–H Functionalization
High Resolution Image
Download MS PowerPoint Slide
As judged by the wealth of literature data, recent years have witnessed considerable advances in the C(sp3)–H functionalization arena. At present, the majority of these processes rely primarily on the utilization of proximal directing groups that allow exquisite control of both chemical reactivity and site-selectivity via the intermediacy of cyclometalated structures (Scheme 2). (6−9) Despite the advances realized with transient, hemilabile and native directing groups, these approaches tend to favor five-membered metallacycles, hence limiting the number of C(sp3)–H sites amenable for functionalization (Scheme 2, left). (10) Although other elegant alternatives have been designed, particularly in the context of metallacarbene-mediated strategies, (11,12) open-shell species (13,14) or enzymatic C(sp3)–H functionalization (Scheme 2, right), (15,16) reactivity and selectivity are typically dictated by bond-dissociation energies or by the presence of specific substituents, thus reinforcing the need for more flexible approaches for functionalizing remote C(sp3)–H linkages.

Scheme 2

Scheme 2. Site-Selectivity in C(sp3)–H Functionalization
High Resolution Image
Download MS PowerPoint Slide
While originally designed to control the topology of polymers, chain walking reactions have recently offered new vistas for the functionalization of remote C(sp3)–H sites. (17−19) Although a variety of transition metals have been shown to be competent for promoting such processes, nickel catalysts have gained considerable momentum as an enabling new technique for C(sp3)–H functionalization. Its popularity is likely ascribed to the versatility of nickel to forge a variety of sp3 architectures with exceptional ease and its redox promiscuity that allows operation via either one- or two-electron manifolds. Ni-catalyzed chain walking is typically orchestrated by a dynamic and reversible series of β-hydride elimination and migratory insertion events, thus allowing formal translocation of the nickel center ranging from one carbon to distal positions along the saturated backbone (Figure 1). Given that site-selectivity in chain walking is formally controlled by the motion at which the nickel center is displaced throughout the alkyl side-chain, it comes as no surprise that recent years have witnessed impressive developments on the ability to promote regiodivergent C(sp3)–H functionalization events by means of chain walking scenarios, with proposed mechanisms operating via either Ni(I) or Ni(II) centers. This perspective aims at summarizing the recent efforts toward this goal by utilizing different strategies, with bond-formation occurring (a) adjacent to a stabilizing functional group, (b) at terminal C(sp3)–H sites on steric grounds or (c) at methylene C(sp3)–H linkages via “interrupted” chain-walking events aided by proximal directing groups. The regiodivergent chain-walking strategies delineated in this perspective have been classified as either ligand- or substrate-controlled. These techniques appear in chronological order, and can selectively target multiple C(sp3)–H sites by changing the reaction parameters from the same precursor.

Figure 1

Figure 1. Regiodivergent Ni-catalyzed chain-walking C(sp3)–H functionalizations by utilizing alkyl halides or olefins.

High Resolution Image
Download MS PowerPoint Slide

Ligand-Controlled Ni-Catalyzed Chain-Walking

Click to copy section linkSection link copied!
In 2013, Ong described an intriguing Ni-catalyzed regiodivergent scenario by reacting allyl benzene derivatives with a variety of heteroarene architectures, resulting in compounds arising from either benzyl C(sp3)–H functionalization or with a canonical anti-Markovnikov selectivity across the double bond (Scheme 3). (20) While the majority of chain walking reactions with olefins typically rely on external hydride sources, this technique relied on the utilization of particularly acidic C(sp2)–H sites at the heteroarene to form the propagating Ni–H species.

Scheme 3

Scheme 3. Site-Selective Heteroarylation of Allyl Benzene
High Resolution Image
Download MS PowerPoint Slide
While the utilization of 2,2′-bipyridines and 1,10-phenanthrolines as ligands proved to be inefficient, regiodivergency could be effected by the nature of the N-heterocyclic carbene utilized. Specifically, anti-Markovnikov selectivity was illustrated by the combination of IPr and AlMe3 with benzimidazole as substrates (2a–d) whereas benzylic C(sp3)–H functionalization was found to be competent with otherwise related IMes instead (3a–d). The crucial role of AlMe3 dictating linear selectivity could be rationalized in the context of cooperative Lewis-acid/transition metal catalysis, whereas Lewis-acid coordination to the N-heteroaromatic likely outcompetes chain walking due to steric repulsion, thus guiding the Ni-complex at terminal positions. (21) Subsequently, Ong described an otherwise similar behavior with differently substituted pyridines at coupling partner, resulting in functionalization at C4 by an intriguing combination of aluminum Lewis acids and low-valent Ni(0) complexes supported by N-heterocyclic carbene ligands (Scheme 4). (22) As shown, the utilization of MAD [methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide] or AlMe3, respectively, led to the para-selective C(sp2)–H functionalization of pyridines. Although regioselectivity was not altered regardless of the Lewis acid utilized, its nature was critical to achieve a high para-selectivity. However, site-selectivity could be controlled by subtle ligand modulation; indeed, IMes delivered 4 with anti-Markovnikov selectivity whereas the inclusion of sterically less encumbered L1 resulted in benzylic C(sp3)–H functionalization 5. Even 3-substituted pyridines could be utilized as coupling partners, delivering the corresponding linear (4c,d) or branched (5c,d) products with excellent regioselectivities.

Scheme 4

Scheme 4. Hydroarylation of Allyl Benzene with Pyridine
High Resolution Image
Download MS PowerPoint Slide
Recently, Sun showed that regiodivergency can be enabled beyond allyl benzene derivatives (Scheme 5), (23) with substrates possessing distal unsaturation from the appendant arene being competent as precursors, albeit in lower regioselectivity patterns (6b vs 6c). In addition, the reaction could be applied to heteroarenes other than benzimidazole, such as pyrazoles (6d, 7c) or furans (6e, 7d) with similar selectivity. Regiodivergency could be rationalized by steric considerations; IMes triggered rapid reversible alkene isomerization leading to functionalization of benzylic C(sp3)–H bonds whereas the utilization of bulky IPr*OMe prevented the isomerization process, thus resulting in anti-Markovnikov selectivity across the double bond.

Scheme 5

Scheme 5. Hydroarylation of Arene-Containing Olefins
High Resolution Image
Download MS PowerPoint Slide
In 2017, Martin described a regiodivergent Ni-catalyzed chain walking strategy of unactivated alkyl bromides with CO2 as coupling partner, resulting in either linear or α-branched carboxylic acids (Scheme 6). (24) 1,10-Phenanthroline ligands bearing substituents adjacent to the nitrogen atom (L2) were found to be critical for reactivity whereas site-selectivity could be easily modulated and controlled by a subtle modulation of the reaction temperature and the nature of the substituents on the alkyl side chain. Indeed, linear carboxylic acids could be obtained at 10 °C whereas branched-selectivity, likely the thermodynamic C–H site, was observed at 42 °C if carbonyl derivatives were utilized as coupling partners (9a vs 9e). It is worth noting that CO2 insertion was not observed in any case at the internal methylene positions of the alkyl-side chain. Notably, chain walking could be utilized for forging all-carbon quaternary centers (10d). Interestingly, control experiments with enantioenriched 8a indicated a significant preservation of the chiral stereogenic center, thus arguing against a dissociative-type mechanism in which the nickel is disengaged from the olefin backbone prior to migratory insertion. The ability of Ni/L2 to promote chain-walking can tentatively be ascribed to the intermediacy of cationic alkyl-Ni(II) species that result from a bromide dissociation at the nickel center imposed by the steric bulk around the 1,10-phenanthroline backbone, thus facilitating the agostic interaction required for enabling β–H elimination events. Moreover, the authors showed that regioconvergent carboxylation of statistical mixtures of olefins with CO2 could be realized via a tandem hydrobromination/carboxylation event. Later on, the authors described a related chain walking scenario by combining olefins feedstocks, CO2 and water, with the latter being formally employed as a hydride source, thus representing a bonus from a synthetic standpoint (bottom). (25)

Scheme 6

Scheme 6. Regiodivergent Carboxylation of Alkyl-Br
High Resolution Image
Download MS PowerPoint Slide
The reactivity shown in Scheme 6 could be expanded beyond carboxylation events, as illustrated by the development of a regiodivergent amidation with isocyanates as coupling partners (Scheme 7). (26) Exquisite site-selectivity was achieved by a subtle modulation of the substituents at the 2,2′-bipyridine backbone; while a Ni/L4 regime resulted in linear selectivity, the utilization of a protocol based on otherwise related L5 prevented the metal translocation throughout the alkyl side-chain, resulting in α-branched amide backbones instead. The authors showed that differently substituted isocyanates could participate in the regiodivergent scenario, even in the presence of different functional groups that might a priori compromise the selectivity of the process. In addition, the utilization of tert-butyl isocyanate allowed the authors to prepare a series of mono-, di-, and trisubstituted amides by simple homologation procedures. Although speculative, the higher steric bulk around the nickel center with L4 as the ligand might facilitate the access to cationic intermediates that would facilitate the key β-hydride elimination event.

Scheme 7

Scheme 7. Site-Selective Amidation of Alkyl Bromides
High Resolution Image
Download MS PowerPoint Slide
In 2020, Zhu and Wang reported an elegant site-selective hydroamination of alkenes utilizing hydroxylamine esters as coupling partners (Scheme 8). (27) The choice of the ligand backbone was critical for site-selectivity, with monodentate phosphine ligands such as SPhos leading to α-branched amines 16 whereas linear selectivity (17) was accomplished with L6 instead. Careful optimization revealed 2-methylpyridine as a key additive for boosting yield and chemoselectivity, probably due to its beneficial role as an ancillary ligand in the oxidative addition step. Unfortunately, however, a single substrate was described to undergo regiodivergent chain-walking en route to either 16a or 17a. Regioisomeric furans of types 16b and 17b could be obtained in high regioselectivities by utilizing different olefins; while 16b was prepared from a terminal alkene, the utilization of an internal olefin resulted in 17b in high regioselectivity. Unfortunately, no explanation or mechanistic experiments were given to understand the difference in reactivity between phosphine and bipyridine ligands.

Scheme 8

Scheme 8. Regiodivergent Hydroamination of Alkenes
High Resolution Image
Download MS PowerPoint Slide
In addition, Zhu showed the viability for enabling a Ni-catalyzed regiodivergent hydrothiolation of alkenes (Scheme 9). (28) The authors observed an intriguing dichotomy exerted by the nature of the ligand backbone. While the utilization of bathocuproine (L3) resulted in benzyl sulfides (18a–c) when combined with HBpin in THF/MeCN, the utilization of a protocol based on 2,2′-bipyridine L6 and (MeO)2MeSiH in DMSO resulted in anti-Markovnikov products 19a–c in high yields and selectivities. While a single example demonstrated the viability for enabling such a regiodivergent scenario starting from the same precursor (18a–19a), it is worth noting that the benzylic C(sp3)–H functionalization could accommodate a broad range of functional groups, including unprotected alcohols, amines, and N-heterocycles, among others. Unfortunately, however, it is not yet clear how the ligand backbone exerts influence on site-selectivity.

Scheme 9

Scheme 9. Regiodivergent Hydrothiolation of Alkenes
High Resolution Image
Download MS PowerPoint Slide
Later on, Fang showed that a Ni-catalyzed hydrocyanation of internal alkenes could be within reach with phosphite ligands (Scheme 10). (29) Intriguingly, regioselectivity was controlled by the utilization of different diastereomers of BINOL-derived ligand L7, differing in the axial chirality of the biaryl backbone (S-enantiomer illustrated). DFT calculations indicated that chain-walking was facile and reversible (ΔΔG# < 13 kcal/mol), whereas reductive elimination was found to be irreversible. Site-selectivity could be interpreted on the differences in the coordination sphere of the two Ni-complexes; while Ni/(S)-L7 features a large pocket, allowing for rapid chain-waking en route to the thermodynamic benzylic C(sp3)–H bond, Ni/(R)-L7 experiences steric repulsions between the substrate and the ligand, disrupting the otherwise beneficial coordination of the aryl group with Ni. Consequently, the less sterically encumbered transition state leads to cyanation at the terminal C(sp3)–H bond. As shown in Scheme 11, regiodivergent hydrocyanation occurred with a broad scope and high regioselectivities. In line with other disclosures in the area of chain-walking, regioselectivity can also be accomplished with statistical mixtures of olefins, leading to either branched (21c) or linear nitriles (22c). It is worth noting that the utilization of (S)-L7 resulted in 21b with a rather promising 77% ee, thus representing a significant step forward for the development of highly enantioselective chain-walking events.

Scheme 10

Scheme 10. Regiodivergent Hydrocyanation of Alkenes
High Resolution Image
Download MS PowerPoint Slide

Scheme 11

Scheme 11. Coupling of Allyl Benzenes, BnCl and B2pin2
High Resolution Image
Download MS PowerPoint Slide
Recently, Yin described an interesting three-component Ni-catalyzed chain-walking aided by Co(II) porphyrin Co-1 (Scheme 11). (30) Specifically, the authors showed that allyl benzenes underwent carboboration with B2pin2 and benzyl chlorides. In line with Weix (31) and Reisman’s reports, (32) the use of cobalt additives was believed to stabilize the transient radical species. Strikingly, the nature of the solvent exerted a profound influence on site-selectivity; 1,4-dioxane was found to be suited for benzylic C(sp3)–H functionalization, whereas DMA or NMP resulted in a 1,1-difunctionalization event. While lower yields and regioselectivities were found for the former protocol (23a–c), excellent yields and site-selectivities were obtained in the latter (24a–c).
Recently, Yin demonstrated the crucial role of lithium bases such as MeOLi for chain-walking scenarios with cyclic alkenes; interestingly, the corresponding sodium counterparts predominantly led to the formation of 1,2-difunctionalization products. (33) Subsequent studies by Yin extended this regiodivergent method to alkenyl bromides, delivering 1,1- or 1,3-difuncitonalized products with excellent regioselectivities, even without cobalt porphyrin additives (Scheme 12). (34) Neither the arene electron-density of the substrate (25a–c, 26a–c) nor the presence of ortho-substituents (25d, 26d) altered the regioselectivity, evidencing the robustness of this nickel chain-walking regime.

Scheme 12

Scheme 12. Site-Selective Carboboration of Allyl Benzenes
High Resolution Image
Download MS PowerPoint Slide
The authors conducted DFT studies to elucidate the striking differences in the reactivity exerted by two similar ligand backbones. Theoretical calculations on β–H elimination enabled by Ni(II) intermediates concluded that the α-boronate products (26) are thermodynamically favored, while benzylic C(sp3)–H functionalization is kinetically driven (25). The authors claimed that a kinetic equilibrium is established during Ni-chain-walking. However, deuterium experiments elucidated little deuterium scrambling along the hydrocarbon fragment, but rather a very selective 1,2-Ni shift for benzylic alkylation (27, Scheme 13).

Scheme 13

Scheme 13. Deuterium-Labeling Studies on the Regiodivergent Ni-Catalyzed Carboboration with Alkenyl Bromides
High Resolution Image
Download MS PowerPoint Slide
Recently, photoredox-catalysis has offered an entry point to enable regiodivergent alkylation of alkyl bromides with α-silyl amines counterparts (Scheme 14). (35) Specifically, the utilization of 1,10-phenantroline L11 under a dual Ir/Ni metallaphotoredox scenario led to retentive functionalization. Such a protocol tolerated a wide number of functional groups, including esters, amides or nitriles (30a–c) or cyclic backbones (30d) in excellent site-selectivities (>20:1). Intriguingly, the utilization of L3 in combination with 4-CzIPN resulted in a chain walking adjacent to stabilizing functional groups (31a–c). Notably, cyclobutane 30d was within reach, and the method could be extended beyond cyclic amines with similar ease and site-selectivities. Experimental and theoretical studies supported a mechanistic scenario initiated by single-electron transfer oxidation of the α-silyl amine followed by reduction of Ni(II) to Ni(0). Oxidative addition of the alkyl bromide to the latter followed by chain walking and interception of the α-amino radical sets the stage for a reductive elimination, leading to the targeted product while recovering back the propagating Ni species.

Scheme 14

Scheme 14. Regiodivergent Ni-Catalyzed Alkylation with α-Silyl Amines under Photoredox-Catalytic Conditions
High Resolution Image
Download MS PowerPoint Slide

Chelation-Controlled Ni-Catalyzed Chain-Walking

Click to copy section linkSection link copied!
Prompted by an example described by Martin on the coupling of N-Boc 2,5-dihydropyrrole with haloboranes, (36) Hu described a regiodivergent hydroalkylation of similar substrates aided by carbamate protecting groups (Scheme 15). (37) Interestingly, subtle differences at the pyrox backbone led to either olefin functionalization (34) or nickel translocation at C2 (33). In line with recent developments in chain-walking reactions, the inclusion of substituents adjacent to the nitrogen atom at the pyridine core was found to be critical for enabling the nickel translocation. Secondary (33a,b, 34a,b) and primary alkyl iodides (33c, 34c) could be used as electrophiles for forging sp3 C–C linkages. Unfortunately, no mechanistic investigations were conducted to shed light on the role of the N-protecting group, thus questioning whether C2 stabilization arises from chelation of the carbamate fragment or from electronic considerations of the α-C–Ni bond to nitrogen.

Scheme 15

Scheme 15. Hydroalkylation of N-Protected Pyrrolines
High Resolution Image
Download MS PowerPoint Slide
Despite the existing precedents from Martin and Hu on chain-walking events at internal C(sp3)–H bonds in cyclic, N-protected heteroarenes, the means to promote nickel translocation in aliphatic side-chains at internal C(sp3)–H bonds was an unmet synthetic challenge. In 2021, Yu described a Ni-catalyzed interrupted chain-walking by utilizing thioethers as chelating groups (Scheme 16). (38) As anticipated, subtle differences at the 1,10-phenanthroline backbone were critical for dictating the regioselectivity. The utilization of L14 facilitated a C(sp3)–N bond-formation at the γ-position, whereas less-sterically encumbered ligand L15 resulted in a 1,2-hydroamination across the olefin backbone. The authors argued that site-selectivity might arise by forming five- or six-membered nickelacycles facilitated by the different steric environments at L14 and L15. Regiodivergency proved to be compatible with a range of protected thioether scaffolds (36d, 37b). However, a significant loss in regioselectivity was observed when placing the reactive alkene at long-range (36a vs 36b-c), which was rationalized due to diminished chelation in the hydrometalation step.

Scheme 16

Scheme 16. Hydroamidation of Thioethers
High Resolution Image
Download MS PowerPoint Slide
Driven by seminal contributions from Koh (39) and Hong (40) on β- and γ-selective chain-walking events, Lu and Fu reported in 2022 an alternative strategy for interrupted nickel chain-walking using 8-aminoquinolinamides as directing groups (38, Scheme 17). (41) While Markovnikov hydroalkylation (40) occurred in the presence of ethanolamine, a Ni translocation occurred with the Ni(PPh3)2Cl2 precatalyst to obtain β-functionalized products (39), albeit in lower yields. Alkyl iodides bearing esters, nitriles, protected amines, indoles, aryl bromides, and free alcohols could be tolerated without affecting the γ-regioselectivity (40a–c). However, only n-butyl iodide was used to show the potential of a regiodivergent β-alkylation (39a–c). Interestingly, the utilization of ethylenediamine, butylamine, or aniline in lieu of ethanolamine delivered the targeted products in good yields but moderate regioselectivities. Further ligand optimization revealed that 80% ee could be achieved with L16, which is a significant achievement in the area of asymmetric hydroalkylation events.

Scheme 17

Scheme 17. Hydroalkylation of 8-Aminoquinolinamides
High Resolution Image
Download MS PowerPoint Slide
While the previous examples constituted a proof-of-concept for enabling Ni-catalyzed interrupted chain-walking at internal C(sp3)–H bonds, the utilization of protected thiols and engineered amides as chelating moieties might hamper the applicability of these strategies. Indeed, chemists have been challenged to design alternatives with native directing groups for enabling interrupted chain-walking scenarios. For example, Lu described a temperature-controlled regiodivergent hydroalkylation using bisoxazoline ligand L17 (Scheme 18). (42) Thus, nickel translocation could be promoted either at the α or β-position by promoting the reaction at 10 or 100 °C, with site-selectivity arising from the formation of five- or six-membered nickelacycle intermediates. Notably, good reactivity could be accomplished when the olefin was located at distal positions from the amine moiety (42a,b). Note, however, that selectivity was highly dependent on the protecting group utilized at the amine backbone; while a 12:1 ratio was observed for N-pivalates (43a,b), otherwise related benzoates eroded the targeted β-selectivity (40c). In addition, N-Boc, N-acetate, or N-phthalimide derivatives resulted in an α-functionalization. Good reactivity was achieved with geminal and internal olefins, even in the presence of benzylic C(sp3)–H sites (42e, 43e). In addition, high enantioselectivities, regioselectivities, and yields were obtained when utilizing chiral ligands (45a,b). Note, however, that these results could only be obtained for a Markovnikov alkylation rather than a chain-walking scenario.

Scheme 18

Scheme 18. Lu’s Hydroalkylation of N-Protected Amines
High Resolution Image
Download MS PowerPoint Slide
Wang independently reported an otherwise identical transformation using a ligand-controlled approach at room temperature (Scheme 19). (43) With very similar regioisomeric ratios obtained for α- and β-alkylated products, the reported substrate scope proved to tolerate a wide range of functional groups in the electrophile backbone and included the successful reactivity of secondary alkyl iodides. Nevertheless, the selectivity for β-alkylation was only demonstrated in a discrete chain-walking regime using homoallylic amine substrates with L18.

Scheme 19

Scheme 19. Wang’s Hydroalkylation of N-Protected Amines
High Resolution Image
Download MS PowerPoint Slide
Mechanistic experiments with L18 showed that alkene isomerization occurred en route to protected enamines (41a′), thus setting the basis for promoting α-alkylation (Scheme 20). On the contrary, L19 delivered a slower kinetic rate of Ni-migration comparable to the overall cross-coupling, with low amounts (<10%) of other alkene regioisomers detected, thus leading to β-alkylation, likely via the six-membered ring nickelacycles. In line with the initial results reported by Hu and Martin, (33,34) α-alkylation was obtained with pyrroline 41b.

Scheme 20

Scheme 20. Mechanistic Studies for the Ni-Catalyzed Hydroalkylation of N-Protected Amines
High Resolution Image
Download MS PowerPoint Slide
Shortly after, Shu described the α- and β-alkylation of protected allyl amines by utilizing alkyl iodides as electrophiles (45 and 46, Scheme 21). (44) Interestingly, α- and β-selectivity was dictated by subtle differences at the bis-oxazoline backbone, whereas the inclusion of cobalt catalysts enabled an anti-Markovnikov hydroalkylation of the pending olefin (47a–c). The observed site-selectivity was computationally investigated, revealing the preferred formation of a five-membered nickelacycle when using L20 (ΔG# = −3.2 kcal/mol compared to its six-membered analogue). As for L21, the six-membered metallacycle is thermodynamically favored by ΔG# = +1.3 kcal/mol, preventing further chain walking and affording the β-alkylated product.

Scheme 21

Scheme 21. Shu’s Hydroalkylation of N-Protected Amines
High Resolution Image
Download MS PowerPoint Slide
More recently, Shu described that a similar methodology could be applicable to functionalize amides containing an appendant C–Br bond (Scheme 22). (45) Importantly, the reaction allowed for dictating ipso-, γ-, or β-functionalization by subtle control of the reaction conditions and the ligand backbone. Box-type ligands proved to be suited for β-alkylation (49), whereas bipyridine ligands were particularly efficient for γ-functionalization (50). Furthermore, tridentate pybox ligands delivered ipso-functionalized products (51), likely due to the absence of vacant sites in the nickel complex that are amenable to β-hydride elimination. Notably, the directing amide can be mono- or disubstituted with either aromatic rings or alkyl fragments without affecting the regioselectivity of the process. It is worth noting that all amide substrates displayed an internal C(sp2)–Br bond. Therefore, it remains uncertain whether the ligands employed might be capable of overcoming the facile ipso-reactivity of nickel complexes when utilizing terminal, primary C(sp2)–Br bonds. As judged by the data provided by the authors, both primary and secondary alkyl bromides could be utilized for the other counterpart, resulting in some regioselectivity issues only when targeting γ-functionalization (50c-d).

Scheme 22

Scheme 22. Regiodivergent Cross-Electrophile Coupling of Bromine-Containing Amides
High Resolution Image
Download MS PowerPoint Slide
In parallel, Martin leveraged unsaturated amides as directing groups to promote a regiodivergent hydroalkylation of olefins with redox-active pyridinium salts as electrophiles, resulting in the formation of three different products arising from functionalization at the β-, γ-, and terminal position (Scheme 23). (46) As shown, subtle differences at the pyrox-type ligand were critical for success. While β-alkylation (49) was found with L26 possessing a methyl substituent adjacent to the pyridyl ring, a γ-alkylation (50) was found instead for 2-oxazoquinoline L27. It is worth noting that a wide variety of native amides could participate in the targeted reaction, including compounds possessing N-aryl substituents, ring-strained heterocycles, or Weinreb amides. Similarly, terminal, internal, or geminal alkenes all delivered the targeted products with similar site-selectivities, even at long-range. The reaction could be extended beyond pyridiniums as alkyl iodides could also be employed as electrophilic partners (49h). It is worth noting that compounds possessing a free NH group such as natural capsaicin could be selectively functionalized at the β- or γ-positions by selecting the adequate ligand (49i, 50i).

Scheme 23

Scheme 23. Martin’s Hydroalkylation of Unsaturated Amides
High Resolution Image
Download MS PowerPoint Slide
While β-selectivity might a priori be achieved via the intermediacy of α,β-unsaturated amides arising from olefin isomerization followed by 1,4-addition of in situ generated alkyl radicals, the lack of deuterium scrambling observed for 49e-d2 indicates otherwise (Scheme 24). In line with this observation, enantioenriched amide 52b (85% ee) possessing a α-methyl substituent could be coupled with primary alkyl iodides to furnish compound 49j with preservation of the chiral integrity. Careful monitoring of the reaction revealed no evidence for acrylamide derivatives or intermediate olefins, an observation that is in contrast to previously developed chain-walking scenarios (Scheme 20). Taking these results into consideration, the authors argued that site-selectivity arises from the intermediacy of five- or six-membered nickelacycle intermediates by coordination of the native amide backbone to the nickel center.

Scheme 24

Scheme 24. Mechanistic Experiments
High Resolution Image
Download MS PowerPoint Slide
A recent example by Cao and Wang described the development of a regiodivergent nickel-catalyzed chain-walking hydroamination reaction with protected amines and N–O electrophiles (Scheme 25). (47) Interestingly, two a priori similar ligands L3 and L6 were responsible for dictating the site-selectivity switch. With N-benzoyl protected amines affording better regioisomeric control (53a,b, 54a,b), the reaction was compatible with both acyclic and N-heterocycles. However, a direct comparison was elusive as only dibenzyl amines delivered excellent regioselectivities for β-amination, whereas α-amination predominantly used morpholine as the N–O electrophile.

Scheme 25

Scheme 25. Hydroamination with N–O Electrophiles
High Resolution Image
Download MS PowerPoint Slide
Interestingly, mechanistic experiments showed that exposure of 41a to the standard reaction conditions without electrophile delivered 1-carbon olefin isomerization for ligand L6, whereas a 1:1 ratio of protected enamine 41c and allylamine 41d was observed with L3, likely suggesting the intervention of nickelacycles, respectively (Scheme 26). This was further evidenced by reacting enamine 41c under both catalytic regimes; L6 delivered a 3:1 rr favoring β-amination, whereas L3 afforded α-functionalization almost exclusively.

Scheme 26

Scheme 26. Ligand Effects in Regiodivergent Hydroamination
High Resolution Image
Download MS PowerPoint Slide
In addition, the authors reported the asymmetric β-functionalization of protected amines (55) and directed Markovnikov olefin hydroamination (56) (Scheme 27). Importantly, seemingly similar hindered box-type ligands were responsible for dictating the selectivity of these reactions, with the inclusion of PMe3 being essential for obtaining β-aminated products in high enantiomeric excesses. While poor yields were obtained with internal olefins (55c), it is worth noting that the development of asymmetric transformations within the context of nickel chain-walking is extremely rare. Therefore, the ability to obtain products 55a-c stands as a testament to the impact that chiral ligands might have when controlling olefin isomerization in asymmetric Ni-catalyzed chain-walking reactions.

Scheme 27

Scheme 27. Regiodivergent Asymmetric Hydroamination
High Resolution Image
Download MS PowerPoint Slide

Conclusion

Click to copy section linkSection link copied!
Ni-catalyzed chain walking reactions have recently offered new vistas for enabling functionalization at remote C(sp3)–H sites prior to carbon-carbon or carbon-heteroatom bond-formation. The dynamic and reversible metal translocation throughout the alkyl side chain enables functionalization (i) adjacent to a stabilizing functional group, (ii) at the terminal site of an alkyl chain based on steric grounds, or (iii) at internal C(sp3)–H sites via an interrupted chain-walking event. Site-selectivity can be modulated by the ligand backbone or by the fine-tuning of the reaction conditions, including the utilization of additives or a subtle temperature control. While it is evident that remarkable advances have been realized in the context of Ni-catalyzed chain-walking reactions, these technologies are in the midst of a transition that might impact the practice of organic synthesis. Indeed, a number of daunting challenges remain in these scenarios: (i) chain-walking regimes with polyolefin backbones still constitutes “terra incognita”; (ii) the majority of chain-walking reactions with olefin counterparts are initiated by nickel hydride intermediates. Therefore, the potential applicability of these reactions beyond olefin hydrofunctionalization has not yet been fully assessed; (iii) the inclusion of branched substituents typically hinders the nickel translocation, whereas the utilization of densely substituted olefins still remains particularly problematic; (iv) despite the enormous potential that catalytic asymmetric chain-walking has for forging enantioenriched sp3 architectures, a limited number of these methods have been described in the literature.
There is ample consensus, however, that the major challenge that chain-walking techniques should overcome lies in the existing ambiguity behind the nature of the nickel species that enable the dynamic displacement throughout the alkyl side-chain. Indeed, speculation remains on whether Ni(I), Ni(II), or even Ni(III) might be responsible for the motion that ultimately results in bond-formation at remote C(sp3)–H sites. This is largely due to the fleeting nature of short-lived, yet exceptionally sensitive, nickel entities, the presence of low-coordinate species, and the redox promiscuity of nickel complexes supported by nitrogen-containing ligands, thus constituting serious barriers for studying the intricacies of these processes. In addition, a non-negligible number of chain-walking reactions require specific substitution patterns at the ligand backbone and enigmatic additives for these processes to occur efficiently. Taking into consideration the recent efforts made at the molecular level for understanding the nickel speciation in a myriad of catalytic processes, it is fair to assume that these challenges will be eventually met in the not so distant future, thus setting the basis to design even more powerful techniques that might forge exceedingly complex sp3 architectures via remote functionalization.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Author
  • Authors
    • Jesus Rodrigalvarez - The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain
    • Franz-Lucas Haut - The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain
  • Author Contributions

    J.R. and F.-L.H. contributed equally to this work.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

Click to copy section linkSection link copied!

We thank ICIQ, FEDER/MCI PID2021-123801NB-I00 and European Research Council (ERC) under European Union’s Horizon 2020 research and innovation program (grant agreement 883756) for financial support. J.R. and F.-L.H. thank the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 101105032 and Alexander von Humboldt Foundation for a Feodor Lynen Research Fellowship.

References

Click to copy section linkSection link copied!

This article references 47 other publications.

  1. 1
    Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752– 6756,  DOI: 10.1021/jm901241e
    Google Scholar
    1
    Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success
    Lovering, Frank; Bikker, Jack; Humblet, Christine
    Journal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvN&md5=4ca92c30c17c53d77ad376719bad951e
  2. 2
    Guillemard, L.; Kaplaneris, N.; Ackermann, L.; Johansson, M. J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 2021, 5, 522– 545,  DOI: 10.1038/s41570-021-00300-6
    Google Scholar
    2
    Late-stage C-H functionalization offers new opportunities in drug discovery
    Guillemard, Lucas; Kaplaneris, Nikolaos; Ackermann, Lutz; Johansson, Magnus J.
    Nature Reviews Chemistry (2021), 5 (8), 522-545CODEN: NRCAF7; ISSN:2397-3358. (Nature Portfolio)
    A review. Over the past decade, the landscape of mol. synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C-H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C-H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programs. This Review highlights the significant advances achieved in the late-stage C-H functionalization of drugs and drug-like compds., and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examd. and classified by mechanistic patterns involving directed or innate C-H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small mols. are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new mols. of interest.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvVGgsbbL&md5=9c9314ac4bb84e8affc1a1b347447e05
  3. 3
    Docherty, J. H.; Lister, T. M.; Mcarthur, G.; Findlay, M. T.; Domingo-Legarda; Kenyon, J.; Choudhary, S.; Larrosa, I. Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules. Chem. Rev. 2023, 123, 7692– 7760,  DOI: 10.1021/acs.chemrev.2c00888
    Google Scholar
    3
    Transition-Metal Catalyzed C-H Bond Activation for the Formation of C-C Bonds in Complex Molecules
    Docherty, Jamie H.; Lister, Thomas M.; Mcarthur, Gillian; Findlay, Michael T.; Domingo-Legarda, Pablo; Kenyon, Jacob; Choudhary, Shweta; Larrosa, Igor
    Chemical Reviews (Washington, DC, United States) (2023), 123 (12), 7692-7760CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Site-predictable and chemoselective C-H bond functionalization reactions offer synthetically powerful strategies for the step-economic diversification of both feedstock and fine chems. Many transition-metal catalyzed methods have emerged for the selective activation and functionalization of C-H bonds. However, challenges of regio- and chemoselectivity have emerged with application to highly complex mols. bearing significant functional group d. and diversity. As mol. complexity increases within mol. structures the risks of catalyst intolerance and limited applicability grow with the no. of functional groups and potentially Lewis basic heteroatoms. Given the abundance of C-H bonds within highly complex and already diversified mols. such as pharmaceuticals, natural products and materials, design and selection of reaction conditions and tolerant catalysts has proved crit. for successful direct functionalization. As such, innovations within transition-metal catalyzed C-H bond functionalization for the direct formation of carbon-carbon bonds have been discovered and developed to overcome these challenges and limitations. This review highlights progress made for the direct metal-catalyzed C-C bond forming reactions including alkylation, methylation, arylation and olefination of C-H bonds within complex targets.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXps1Wjsbo%253D&md5=ea36a32e3d03270aa5e8c9fa15ef8ec6
  4. 4
    Bellotti, P.; Huang, H.-M.; Faber, T.; Glorius, F. Photocatalytic Late-Stage C–H Functionalization. Chem. Rev. 2023, 123, 4237– 4352,  DOI: 10.1021/acs.chemrev.2c00478
    Google Scholar
    4
    Photocatalytic Late-Stage C-H Functionalization
    Bellotti, Peter; Huang, Huan-Ming; Faber, Teresa; Glorius, Frank
    Chemical Reviews (Washington, DC, United States) (2023), 123 (8), 4237-4352CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. This review highlights the photocatalytic late-stage C-H functionalization strategies of small-mol. drugs, agrochems., and natural products, classified according to the targeted C-H bond and the newly formed one. Emphasis is devoted at identifying, describing and comparing the main mechanistic scenarios. The review draws a crit. comparison between established ionic chem. and photocatalyzed radical-based manifolds. The review aims at establishing the current state-of-the-art and at illustrating the key unsolved challenges to be addressed in the future. The authors aim at introducing the general readership to the main approaches toward the photocatalytic late-stage C-H functionalization, and the specialist practitioners to the crit. evaluation of the current methodologies, potential for improvement and future, uncharted directions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhs1Sktrs%253D&md5=68758b9b6fa0a03f66b0b499e321de2c
  5. 5
    Bergman, R. G. C–H Activation. Nature 2007, 446, 391– 393,  DOI: 10.1038/446391a
    Google Scholar
    5
    Organometallic chemistry: C-H activation
    Bergman, Robert G.
    Nature (London, United Kingdom) (2007), 446 (7134), 391-393CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The stability of the chem. bonds in satd. hydrocarbons makes them generally unreactive. But the invention of processes in which carbon-hydrogen (C-H) bonds in hydrocarbons can be activated is allowing chemists to exploit org. compds. in previously unimaginable ways.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjt1Wqs7w%253D&md5=65c9a1b108168f5d6d8a17009437c6e5
  6. 6
    Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Transition Metal-Catalyzed Ketone-Directed or Mediated C–H Functionalization. Chem. Soc. Rev. 2015, 44, 7764– 7786,  DOI: 10.1039/C5CS00272A
    Google Scholar
    6
    Transition metal-catalyzed ketone-directed or mediated C-H functionalization
    Huang, Zhongxing; Lim, Hee Nam; Mo, Fanyang; Young, Michael C.; Dong, Guangbin
    Chemical Society Reviews (2015), 44 (21), 7764-7786CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Advancements in use of ketone carbonyls as directing groups, direct β-functionalization, and α-alkylation/alkenylation with unactivated olefins and alkynes has been reviewed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyktr7O&md5=f62241e8054c3a12584b016339000d41
  7. 7
    He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-Catalyzed Transformations of Alkyl C–H Bonds. Chem. Rev. 2017, 117, 8754– 8786,  DOI: 10.1021/acs.chemrev.6b00622
    Google Scholar
    7
    Palladium-Catalyzed Transformations of Alkyl C-H Bonds
    He, Jian; Wasa, Masayuki; Chan, Kelvin S. L.; Shao, Qian; Yu, Jin-Quan
    Chemical Reviews (Washington, DC, United States) (2017), 117 (13), 8754-8786CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. This Review summarizes the advancements in Pd-catalyzed C(sp3)-H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C-H bonds, many C(sp3)-H activation/C-C and C-heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chem. A no. of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)-H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C-H functionalization reactions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFOltbnF&md5=1eb3ce0a36a301ef8374722c96a4a050
  8. 8
    Xu, Y.; Dong, G. Sp3 C–H Activation via Exo-Type Directing Groups. Chem. Sci. 2018, 9, 1424– 1432,  DOI: 10.1039/C7SC04768A
    Google Scholar
    8
    sp3 C-H activation via exo-type directing groups
    Xu, Yan; Dong, Guangbin
    Chemical Science (2018), 9 (6), 1424-1432CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A review. In this mini-review article the challenges in sp3 C-H activation via exo-type directing groups and the achievements, including directing group designs, reaction discoveries and mechanistic studies were discussed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVeltb0%253D&md5=1975f056fb68aa8fef8c2e82cd9ff37c
  9. 9
    Rej, S.; Ano, Y.; Chatani, N. Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds. Chem. Rev. 2020, 120, 1788– 1887,  DOI: 10.1021/acs.chemrev.9b00495
    Google Scholar
    9
    Bidentate Directing Groups: An Efficient Tool in C-H Bond Functionalization Chemistry for the Expedient Construction of C-C Bonds
    Rej, Supriya; Ano, Yusuke; Chatani, Naoto
    Chemical Reviews (Washington, DC, United States) (2020), 120 (3), 1788-1887CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Broadly discussed various C-H functionalization reactions for the formation of C-C bonds with the aid of bidentate directing groups are reviewed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXislWjug%253D%253D&md5=c89f782e69952af391a23ac9575fa3cd
  10. 10
    Mingo, M. M.; Rodríguez, N.; Gómez Arrayás, R.; Carretero, J. C. Remote C(sp3)–H functionalization via catalytic cyclometallation: beyond five-membered ring metallacycle intermediates. Org. Chem. Front. 2021, 8, 4914– 4946,  DOI: 10.1039/D1QO00389E
    Google Scholar
    10
    Remote C(sp3)-H functionalization via catalytic cyclometallation: beyond five-membered ring metallacycle intermediates
    Mingo, Mario Martinez; Rodriguez, Nuria; Arrayas, Ramon Gomez; Carretero, Juan C.
    Organic Chemistry Frontiers (2021), 8 (17), 4914-4946CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
    Despite impressive recent momentum gained in C(sp3)-H activation, achieving high regioselectivity in mols. contg. different C-H bonds with similar high energy without abusing tailored substitution remains as one of the biggest challenges. The use of directing groups, esp. those featuring bidentate coordination, typically in combination with palladium catalysis, has fueled the development of a no. of direct C(sp3)-H bond functionalizations via cyclometallation. In most of the reported examples, the regioselectivity is detd. by the strong propensity of PdII to form square planar five-membered metalacycles. In contrast, targetting C-H bonds that are farther than three bonds away from the coordinating heteroatom through the intermediacy of less favorable six-membered (or higher) metalacycles is far more difficult. In fact, achieving high selectivity via six-membered metalacycles without blocking the competitive functionalization via a five-membered metalacycle represents an even more difficult challenge. This review provides an overview of methods enabling catalytic C(sp3)-H activation via six-membered metalacycle intermediates, with an emphasis on mechanistic aspects regarding the control of regioselectivity and strategies towards disfavoring the formation of the five-membered palladacycle in preference for the six-membered analog.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtFSgsLjO&md5=35f3f6c4d72f6ef751727789d03c7ecd
  11. 11
    Davies, H. M. L.; Morton, D. Recent Advances in C–H Functionalization. J. Org. Chem. 2016, 81, 343– 350,  DOI: 10.1021/acs.joc.5b02818
    Google Scholar
    11
    Recent Advances in C-H Functionalization
    Davies, Huw M. L.; Morton, Daniel
    Journal of Organic Chemistry (2016), 81 (2), 343-350CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    A review. This review highlights 24 recent papers and illustrates their significance to the C-H functionalization endeavor. Some of the current trends are covered. E.g., design of new directing groups that are readily removed or converted into useful functionality, broadening the scope from the more traditional functionalization of sp2 C-H bonds to sp3 C-H bonds, application of the methodol. to a broader range of functionality, and modification of the directing influence away from just ortho-functionalization.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks12jtQ%253D%253D&md5=e8d7906606252f770b50d28fd4e4dc2f
  12. 12
    He, Y.; Huang, Z.; Wu, K.; Ma, J.; Zhou, Y.-G.; Yu, Z. Recent Advances in Transition-Metal-Catalyzed Carbene Insertion to C–H Bonds. Chem. Soc. Rev. 2022, 51, 2759– 2852,  DOI: 10.1039/D1CS00895A
    Google Scholar
    12
    Recent advances in transition-metal-catalyzed carbene insertion to C-H bonds
    He, Yuan; Huang, Zilong; Wu, Kaikai; Ma, Juan; Zhou, Yong-Gui; Yu, Zhengkun
    Chemical Society Reviews (2022), 51 (7), 2759-2852CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. This crit. review will summarize the advance in transition-metal-catalyzed carbene insertion to C-H bonds dated up to July 2021, by the categories of C-H bonds from aliph. C(sp3)-H, aryl (arom.) C(sp2)-H, heteroaryl (heteroarom.) C(sp2)-H bonds, alkenyl C(sp2)-H, and alkynyl C(sp)-H, as well as asym. carbene insertion to C-H bonds, and more coverage will be given to the recent work. Due to the rapid development of the C-H functionalization area, future directions in this topic are also discussed. This review will give the authors an overview of carbene insertion chem. in C-H functionalization with focus on the catalytic systems and synthetic applications in C-C bond formation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XnsFClsLg%253D&md5=42fa9cae1d5657ca3b1462ef8e878699
  13. 13
    Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Recent Advances in Radical C–H Activation/Radical Cross-Coupling. Chem. Rev. 2017, 117, 9016– 9085,  DOI: 10.1021/acs.chemrev.6b00620
    Google Scholar
    13
    Recent Advances in Radical C-H Activation/Radical Cross-Coupling
    Yi, Hong; Zhang, Guoting; Wang, Huamin; Huang, Zhiyuan; Wang, Jue; Singh, Atul K.; Lei, Aiwen
    Chemical Reviews (Washington, DC, United States) (2017), 117 (13), 9016-9085CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Research and industrial interest in radical C-H activation/radical cross-coupling chem. has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting mol. fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C-H activation. This review includes radical addn., radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M-R groups, and coupling of radical cations with nucleophiles (Nu).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVamu7fM&md5=d9f5525fbdfacb26f1cec1d00d95e5ed
  14. 14
    Sarkar, S.; Cheung, K. P. S.; Gevorgyan, V. C–H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals. Chem. Sci. 2020, 11, 12974– 12993,  DOI: 10.1039/D0SC04881J
    Google Scholar
    14
    C-H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals
    Sarkar, Sumon; Cheung, Kelvin Pak Shing; Gevorgyan, Vladimir
    Chemical Science (2020), 11 (48), 12974-12993CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A review. Recent developments of mild methodologies for generation of various carbon-centered radical species enabled their utilization in the HAT process, which, in turn, led to the development of remote C(sp3)-H functionalization reactions of alcs., amines, amides and related compds. This review covers mostly recent advances in C-H functionalization reactions involving the HAT step to carbon-centered radicals.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitlCksbfF&md5=95f8a74b3b31147efec6f3ff32d41a51
  15. 15
    Lewis, J. C.; Coelho, P. S.; Arnold, F. H. Enzymatic Functionalization of Carbon–Hydrogen Bonds. Chem. Soc. Rev. 2011, 40, 2003– 2021,  DOI: 10.1039/C0CS00067A
    Google Scholar
    15
    Enzymatic functionalization of carbon-hydrogen bonds
    Lewis, Jared C.; Coelho, Pedro S.; Arnold, Frances H.
    Chemical Society Reviews (2011), 40 (4), 2003-2021CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. The development of new catalytic methods to functionalize carbon-hydrogen (C-H) bonds continues to progress at a rapid pace due to the significant economic and environmental benefits of these transformations over traditional synthetic methods. In nature, enzymes catalyze regio- and stereoselective C-H bond functionalization using transformations ranging from hydroxylation to hydroalkylation under ambient reaction conditions. The efficiency of these enzymes relative to analogous chem. processes has led to their increased use as biocatalysts in preparative and industrial applications. Furthermore, unlike small mol. catalysts, enzymes can be systematically optimized via directed evolution for a particular application and can be expressed in vivo to augment the biosynthetic capability of living organisms. While a variety of tech. challenges must still be overcome for practical application of many enzymes for C-H bond functionalization, continued research on natural enzymes and on novel artificial metalloenzymes will lead to improved synthetic processes for efficient synthesis of complex mols. In this crit. review, we discuss the most prevalent mechanistic strategies used by enzymes to functionalize non-acidic C-H bonds, the application and evolution of these enzymes for chem. synthesis, and a no. of potential biosynthetic capabilities uniquely enabled by these powerful catalysts (110 refs.).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsFegsLs%253D&md5=208b878c36d75557758eed7b39ee9e6f
  16. 16
    Dunham, N. P.; Arnold, F. H. Nature’s Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases. ACS Catal. 2020, 10, 12239– 12255,  DOI: 10.1021/acscatal.0c03606
    Google Scholar
    16
    Nature's machinery, repurposed: Expanding the repertoire of iron-dependent oxygenases
    Dunham, Noah P.; Arnold, Frances H.
    ACS Catalysis (2020), 10 (20), 12239-12255CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    A review. Iron is an esp. important redox-active cofactor in biol. because of its ability to mediate reactions with atm. O2. Iron-dependent oxygenases exploit this earth-abundant transition metal for the insertion of oxygen atoms into org. compds. Throughout the astounding diversity of transformations catalyzed by these enzymes, the protein framework directs reactive intermediates toward the precise formation of products, which, in many cases, necessitates the cleavage of strong C-H bonds. In recent years, members of several iron-dependent oxygenase families have been engineered for new-to-nature transformations that offer advantages over conventional synthetic methods. In this Perspective, we first explore what is known about the reactivity of heme-dependent cytochrome P 450 oxygenases and nonheme iron-dependent oxygenases bearing the 2-His-1-carboxylate facial triad by reviewing mechanistic studies with an emphasis on how the protein scaffold maximizes the catalytic potential of the iron-heme and iron cofactors. We then review how these cofactors have been repurposed for abiol. transformations by engineering the protein frameworks of these enzymes. Finally, we discuss contemporary challenges assocd. with engineering these platforms and comment on their roles in biocatalysis moving forward.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFaqs7fL&md5=007b291f3cab1ae5ddce677e44d64861
  17. 17
    Vasseur, A.; Bruffaerts, J.; Marek, I. Remote Functionalization through Alkene Isomerization. Nat. Chem. 2016, 8, 209– 219,  DOI: 10.1038/nchem.2445
    Google Scholar
    17
    Remote functionalization through alkene isomerization
    Vasseur, Alexandre; Bruffaerts, Jeffrey; Marek, Ilan
    Nature Chemistry (2016), 8 (3), 209-219CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    A review discusses the use of metal-catalyzed alkene isomerization to remotely functionalize alkenes and its potential use in org. synthesis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVCnurw%253D&md5=d564ccf0a48bf37eedf74056b116f750
  18. 18
    Sommer, H.; Juliá-Hernández, F.; Martin, R.; Marek, I. Walking Metals for Remote Functionalization. ACS Cent. Sci. 2018, 4, 153– 165,  DOI: 10.1021/acscentsci.8b00005
    Google Scholar
    18
    Walking Metals for Remote Functionalization
    Sommer, Heiko; Julia-Hernandez, Francisco; Martin, Ruben; Marek, Ilan
    ACS Central Science (2018), 4 (2), 153-165CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    A review. The distant and selective activation of unreactive C-H and C-C bonds remains one of the biggest challenges in org. chem. In recent years, the development of remote functionalization has received growing interest as it allows for the activation of rather challenging C-H and C-C bonds distant from the initiation point by means of a "metal-walk". A "metal-walk" or "chain-walk" is defined by an iterative series of consecutive 1,2- or 1,3-hydride shifts of a metal complex along a single hydrocarbon chain. With this approach, simple building blocks or mixts. thereof can be transformed into complex scaffolds in a convergent and unified strategy. A variety of catalytic systems have been developed and refined over the past decade ranging from late-transition-metal complexes to more sustainable iron- and cobalt-based systems. As the possibilities of this field are slowly unfolding, this area of research will contribute considerably to provide solns. to yet unmet synthetic challenges.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlarsrs%253D&md5=d35dc67867297ea182ba63d767a3651e
  19. 19
    Ghosh, S.; Patel, S.; Chatterjee, I. Chain-walking reactions of transition metals for remote C–H bond functionalization of olefinic substrates. Chem. Commun 2021, 57, 11110– 11130,  DOI: 10.1039/D1CC04370F
    Google Scholar
    19
    Chain-walking reactions of transition metals for remote C-H bond functionalization of olefinic substrates
    Ghosh, Soumen; Patel, Sandeep; Chatterjee, Indranil
    Chemical Communications (Cambridge, United Kingdom) (2021), 57 (85), 11110-11130CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A review. Herein, authors have provided a comprehensive overview of the chain-walking reactions involving a variety of catalytic systems ranging from the first-row transition metal catalysts to the third-row transition metal catalysts for C-H activation in a concise fashion with the hope for further developments in this area through the appropriate application of the chain-walking reactions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitVegt7%252FI&md5=0e47af9569a16c75b9bd396383789b5b
  20. 20
    Lee, W.-C.; Wang, C.-H.; Lin, Y.-H.; Shih, W.-C.; Ong, T.-G. Tandem Isomerization and C–H Activation: Regioselective Hydroheteroarylation of Allylarenes. Org. Lett. 2013, 15, 5358– 5361,  DOI: 10.1021/ol402644y
    Google Scholar
    20
    Tandem Isomerization and C-H Activation: Regioselective Hydroheteroarylation of Allylarenes
    Lee, Wei-Chih; Wang, Chun-Han; Lin, Yung-Huei; Shih, Wei-Chun; Ong, Tiow-Gan
    Organic Letters (2013), 15 (20), 5358-5361CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Heterocycles such as 1-methylbenzimidazole underwent regioselective hydroarylation reactions with allylbenzenes in the presence of bis(1,5-cyclooctadiene)nickel and N-heterocyclic carbenes to give aralkylheterocycles such as I and II [R = Ph, 4-MeC6H4, 2-MeC6H4, 3-MeC6H4, 4-MeOC6H4, 2-MeOC6H4, 3,4-(MeO)2C6H3, 4-F3CC6H4, 4-FC6H4, 1,3-benzodioxole-5-yl] in 33-95% yields and in 58:42->99:1 regioselectivities. In the presence of Me3Al, linear hydroarylation products such as I were isolated in 92:8->99:1 regioselectivities, while in its absence, the α-arylpropyl heterocycles such as II were isolated in 42:58->99:1 regioselectivities (all but one with selectivities >83:17).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFKksrfI&md5=d62aa287cf1cb413b962f741b90cca05
  21. 21

    For a selected example of pyridine functionalization aided by Lewis acids:

    Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. Selective C-4 Alkylation of Pyridine by Nickel/Lewis Acid Catalysis. J. Am. Chem. Soc. 2010, 132, 13666– 13668,  DOI: 10.1021/ja106514b
    Google Scholar
    21
    Selective C-4 Alkylation of Pyridine by Nickel/Lewis Acid Catalysis
    Nakao, Yoshiaki; Yamada, Yuuya; Kashihara, Natsuko; Hiyama, Tamejiro
    Journal of the American Chemical Society (2010), 132 (39), 13666-13668CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Direct C-4-selective addn. of pyridine across alkenes and alkynes is achieved for the first time by nickel/Lewis acid cooperative catalysis with an N-heterocyclic carbene ligand. A variety of substituents on both alkenes and pyridine are tolerated to give linear 4-alkylpyridines, e.g., I in modest to good yields. The addn. across styrene gives branched 4-alkylpyridines. A single example of C-4-selective alkenylation is also described.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWru7zK&md5=5d3b911b3a8ab27421566e8d35d8ecb0
  22. 22
    Lee, W.-C.; Chen, C.-H.; Liu, C.-Y.; Yu, M.-S.; Lin, Y.-H.; Ong, T.-G. Nickel-Catalysed Para C-H Activation of Pyridine with Switchable Regioselective Hydroheteroarylation of Allylarenes. Chem. Commun. 2015, 51, 17104– 17107,  DOI: 10.1039/C5CC07455J
    Google Scholar
    22
    Nickel-catalyzed para-CH activation of pyridine with switchable regioselective hydroheteroarylation of allylarenes
    Lee, Wei-Chih; Chen, Chien-Hung; Liu, Cheng-Yuan; Yu, Ming-Shiuan; Lin, Yung-Huei; Ong, Tiow-Gan
    Chemical Communications (Cambridge, United Kingdom) (2015), 51 (96), 17104-17107CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Para-CH activation of pyridine with allylbenzene is described by Ni/Al cooperative catalysis in combination with a bulkier NHC ligand and a Lewis acid, leading to linear hydroheteroarylation products. Interestingly, branch selectivity can be achieved by using a combination of a less sterically hindered amino-NHC ligand and AlMe3 through tandem reaction of facile alkene isomerization followed by a slow CH bond activation process. Under optimized conditions the synthesis of the target compds. was achieved using bis[(1,2,5,6-η)-1,5-cyclooctadiene]nickel and 1,3-dihydro-1,3-bis(2,4,6-trimethylphenyl)-2H-imidazol-2-ylidene carbene, 1-[2-(dimethylamino)ethyl]-1,3-dihydro-3-(2,4,6-trimethylphenyl)-2H-imidazol-2-ylidene carbene (NHC) as catalyst and ligand combinations. Starting materials included pyridine, quinoline, 5,6,7,8-tetrahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine and (propenyl)benzene derivs., (butenyl)benzene, (ethenyl)benzene, 5-(2-propen-1-yl)-1,3-benzodioxole. The title compds. thus formed included 4-(3-phenylpropyl)pyridine (linear product) and 4-(1-phenylpropyl)pyridine (branched product).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsF2htr3K&md5=c8fcba43c682c4c3e88148b9a3dfacbf
  23. 23
    Imran, S.; Jin, W.-H.; Li, R.-P.; Ismaeel, N.; Sun, H.-M. Ligand-Controlled Nickel-Catalyzed Tandem Isomerization/Regiodivergent Hydroheteroarylation of α-Alkenes with Heteroarenes. Org. Lett. 2022, 24, 8875– 8879,  DOI: 10.1021/acs.orglett.2c03689
    Google Scholar
    23
    Ligand-Controlled Nickel-Catalyzed Tandem Isomerization/Regiodivergent Hydroheteroarylation of α-Alkenes with Heteroarenes
    Imran, Sajid; Jin, Wen-Hui; Li, Rui-Peng; Ismaeel, Nadia; Sun, Hong-Mei
    Organic Letters (2022), 24 (48), 8875-8879CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    The authors herein describe an accessible ligand-controlled Ni-catalyzed tandem isomerization/regiodivergent hydroheteroarylation of α-alkenes with heteroarenes, wherein the NHC ligand of heteroleptic Ni(II) complexes Ni(NHC)[P(OEt)3]Br2 displayed significant effects on regulation. In the presence of NaOtBu, Ni(IMes)[P(OEt)3]Br2 enables C:C bond isomerization of α-alkenes over up to four sp3 C atoms to afford branched products, while Ni(IPr*OMe)[P(OEt)3]Br2 greatly deactivates α-alkene isomerization and favors the formation of linear products.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XivF2isLfJ&md5=26ba118a39454e63840564b46647eb5e
  24. 24
    Juliá-Hernández, F.; Moragas, T.; Cornella, J.; Martin, R. Remote Carboxylation of Halogenated Aliphatic Hydrocarbons with Carbon Dioxide. Nature 2017, 545, 84– 88,  DOI: 10.1038/nature22316
    Google Scholar
    24
    Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide
    Julia-Hernandez, Francisco; Moragas, Toni; Cornella, Josep; Martin, Ruben
    Nature (London, United Kingdom) (2017), 545 (7652), 84-88CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Catalytic carbon-carbon bond formation has enabled the streamlining of synthetic routes when assembling complex mols. It is particularly important when incorporating satd. hydrocarbons, which are common motifs in petrochems. and biol. relevant mols. However, cross-coupling methods that involve alkyl electrophiles result in catalytic bond formation only at specific and previously functionalized sites. Here we describe a catalytic method that is capable of promoting carboxylation reactions at remote and unfunctionalized aliph. sites with carbon dioxide at atm. pressure. The reaction occurs via selective migration of the catalyst along the hydrocarbon side-chain with excellent regio- and chemoselectivity, representing a remarkable reactivity relay when compared with classical cross-coupling reactions. Our results demonstrate that site-selectivity can be switched and controlled, enabling the functionalization of less-reactive positions in the presence of a priori more reactive ones. Furthermore, we show that raw materials obtained in bulk from petroleum processing, such as alkanes and unrefined mixts. of olefins, can be used as substrates. This offers an opportunity to integrate a catalytic platform en route to valuable fatty acids by transforming petroleum-derived feedstocks directly.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVOrsrY%253D&md5=f4ee3908fea3b62fe46e6ab8fe274ab9
  25. 25
    Gaydou, M.; Moragas, T.; Juliá-Hernández, F.; Martin, R. Site-Selective Catalytic Carboxylation of Unsaturated Hydrocarbons with CO2 and Water. J. Am. Chem. Soc. 2017, 139, 12161– 12164,  DOI: 10.1021/jacs.7b07637
    Google Scholar
    25
    Site-Selective Catalytic Carboxylation of Unsaturated Hydrocarbons with CO2 and Water
    Gaydou, Morgane; Moragas, Toni; Julia-Hernandez, Francisco; Martin, Ruben
    Journal of the American Chemical Society (2017), 139 (35), 12161-12164CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A catalytic protocol that reliably predicts and controls the site-selective incorporation of CO2 to a wide range of unsatd. hydrocarbons utilizing water as formal hydride source is described. This platform unlocks an opportunity to catalytically repurpose three abundant, orthogonal feedstocks under mild conditions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlCgu7bP&md5=97655bfb25a0ddc35f6672fafa7ce7c8
  26. 26
    Tortajada, A.; Menezes Correia, J. T.; Serrano, E.; Monleón, A.; Tampieri, A.; Day, C. S.; Juliá-Hernández, F.; Martin, R. Ligand-Controlled Regiodivergent Catalytic Amidation of Unactivated Secondary Alkyl Bromides. ACS Catal. 2021, 11, 10223– 10227,  DOI: 10.1021/acscatal.1c02913
    Google Scholar
    26
    Ligand-Controlled Regiodivergent Catalytic Amidation of Unactivated Secondary Alkyl Bromides
    Tortajada, Andreu; Menezes Correia, Jose Tiago; Serrano, Eloisa; Monleon, Alicia; Tampieri, Alberto; Day, Craig S.; Julia-Hernandez, Francisco; Martin, Ruben
    ACS Catalysis (2021), 11 (16), 10223-10227CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    A regiodivergent Ni-catalyzed amidation of unactivated secondary alkyl bromides is described. The site-selectivity of the amidation event is dictated by subtle differences on the ligand backbone, allowing introduction of the amide function at either the original sp3 carbon-halide bond or at distal sp3 C-H sites within an alkyl side-chain via chain-walking scenarios.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1OlsbrJ&md5=257c66f095abc23fa6421c55c2d7a10a
  27. 27
    Zhang, Y.; He, J.; Song, P.; Wang, Y.; Zhu, S. Ligand-Enabled NiH-Catalyzed Migratory Hydroamination: Chain Walking as a Strategy for Regiodivergent/Regioconvergent Remote sp3 C–H Amination. CCS Chem. 2021, 3, 2259– 2268,  DOI: 10.31635/ccschem.020.202000490
    Google Scholar
    27
    Ligand-enabled NiH-catalyzed migratory hydroamination: chain walking as a strategy for regiodivergent/regioconvergent remote sp3C-H amination
    Zhang, Yulong; He, Jun; Song, Peihong; Wang, You; Zhu, Shaolin
    CCS Chemistry (2021), 3 (9), 2259-2268CODEN: CCCHB2 ISSN:. (Chinese Chemical Society)
    A nondirected, remote sp3C-H amination process with predictable and switchable regioselectivity was reported. This reaction used a nickel hydride-catalyzed remote relay hydroamination strategy in which an aliph. amino group was installed at a position far from the original C=C bond present in all unsatd. hydrocarbon substrates. Depending on the choice of ligand, either terminal or benzylic functionalization products were obtained with excellent levels of regioselectivity. It was shown that an alkyl bromide could also be used as an olefin precursor when using Mn0 as a reductant. The utility of this transformation was further highlighted by the regioconvergent migratory hydroamination of isomeric mixts. of olefins forming single isomers of value-added benzylic or linear amines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisFantbbL&md5=f507228aab2dd87bdf79bc349b65b89d
  28. 28
    Zhang, Y.; Xu, X.; Zhu, S. Nickel-Catalysed Selective Migratory Hydrothiolation of Alkenes and Alkynes with Thiols. Nat. Commun. 2019, 10, 1752,  DOI: 10.1038/s41467-019-09783-w
    Google Scholar
    28
    Nickel-catalysed selective migratory hydrothiolation of alkenes and alkynes with thiols
    Zhang Yulong; Xu Xianfeng; Zhu Shaolin; Zhu Shaolin
    Nature communications (2019), 10 (1), 1752 ISSN:.
    Direct (utilize easily available and abundant precursors) and selective (both chemo- and regio-) aliphatic C-H functionalization is an attractive mean with which to streamline chemical synthesis. With many possible sites of reaction, traditional methods often need an adjacent polar directing group nearby to achieve high regio- and chemoselectivity and are often restricted to a single site of functionalization. Here we report a remote aliphatic C-H thiolation process with predictable and switchable regioselectivity through NiH-catalysed migratory hydrothiolation of two feedstock chemicals (alkenes/alkynes and thiols). This mild reaction avoids the preparation of electrophilic thiolation reagents and is highly selective to thiols over other nucleophilic groups, such as alcohols, acids, amines, and amides. Mechanistic studies show that the reaction occurs through the formation of an RS-Bpin intermediate, and THF as the solvent plays an important role in the regeneration of NiH species.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FlslKksg%253D%253D&md5=33f6a3b20a2f248b87e6cef1dd42d7b7
  29. 29
    Gao, J.; Jiao, M.; Ni, J.; Yu, R.; Cheng, G.-J.; Fang, X. Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric-Ligand-Controlled Regiodivergence. Angew. Chem., Int. Ed. 2021, 60, 1883– 1890,  DOI: 10.1002/anie.202011231
    Google Scholar
    29
    Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric-Ligand-Controlled Regiodivergence
    Gao, Jihui; Jiao, Mingdong; Ni, Jie; Yu, Rongrong; Cheng, Gui-Juan; Fang, Xianjie
    Angewandte Chemie, International Edition (2021), 60 (4), 1883-1890CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A regiodivergent nickel-catalyzed hydrocyanation of a broad range of internal alkenes involving a chain-walking process is reported. When appropriate diastereomeric biaryl diphosphite ligands are applied, the same starting materials can be converted to either linear or branched nitriles with good yields and high regioselectivities. DFT calcns. suggested that the catalyst architecture dets. the regioselectivity by modulating electronic and steric interactions. In addn., moderate enantioselectivities were obsd. when branched nitriles were produced.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisVGltb7E&md5=2e5cb32855000617c2fbee46f1ea1d3e
  30. 30
    Li, Y.; Wei, H.; Yin, G. Nickel-Catalyzed Migratory Benzylboration of Allylbenzenes. Tetrahedron Lett. 2022, 100, 153889  DOI: 10.1016/j.tetlet.2022.153889
    Google Scholar
    30
    Nickel-Catalyzed Migratory Benzylboration of Allylbenzenes
    Li, Yangyang; Wei, Hong; Yin, Guoyin
    Tetrahedron Letters (2022), 100 (), 153889CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    While 1,2-regioselective difunctionalizations of alkenes are well developed, their migratory difunctionalization of alkenes remains comparatively under-researched. Herein, we report a nickel-catalyzed, divergent, solvent-controlled 1,1- or 1,3-regioselective benzylboration of allylbenzenes, that provides efficient access to primary and secondary alkyl boronates. The mild reaction conditions of these transformations allow good regioselectivity and wide functional group tolerance.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsVCltLnE&md5=06366da1b92a728ee889a32404228be0
  31. 31
    Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt Co-Catalysis for Cross-Electrophile Coupling: Diarylmethanes from Benzyl Mesylates and Aryl Halides. Chem. Sci. 2015, 6, 1115– 1119,  DOI: 10.1039/C4SC03106G
    Google Scholar
    31
    Cobalt co-catalysis for cross-electrophile coupling: diarylmethanes from benzyl mesylates and aryl halides
    Ackerman, Laura K. G.; Anka-Lufford, Lukiana L.; Naodovic, Marina; Weix, Daniel J.
    Chemical Science (2015), 6 (2), 1115-1119CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    In this study, a new co-catalyst, cobalt phthalocyanine (Co(Pc)), was introduced and demonstrated to be effective for coupling substrates not prone to homolysis. This was because Co(Pc) reacted with electrophiles by an SN2 mechanism instead of by the electron-transfer or halogen abstraction mechanisms previously explored. Studies demonstrating the orthogonal reactivity of (bpy)Ni and Co(Pc), applying this selectivity to the coupling of benzyl mesylates with aryl halides, and the adaptation of these conditions to the less reactive benzyl phosphate ester and an enantioconvergent reaction were presented.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyqtb7F&md5=cbd3652857e0c46b6ee9db7ddc6988ec
  32. 32
    Hofstra, J. L.; Cherney, A. H.; Ordner, C. M.; Reisman, S. E. Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 139– 142,  DOI: 10.1021/jacs.7b11707
    Google Scholar
    32
    Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling
    Hofstra, Julie L.; Cherney, Alan H.; Ordner, Ciara M.; Reisman, Sarah E.
    Journal of the American Chemical Society (2018), 140 (1), 139-142CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An asym. Ni-catalyzed reductive cross-coupling has been developed to prep. enantioenriched allylic silanes. This enantioselective reductive alkenylation proceeds under mild conditions and exhibits good functional group tolerance. The chiral allylic silanes prepd. here undergo a variety of stereospecific transformations, including intramol. Hosomi-Sakurai reactions, to set vicinal stereogenic centers with excellent transfer of chirality.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWhsr3N&md5=d06247e88d916085793efaf7f21a0aaf
  33. 33
    Kong, W.; Bao, Y.; Lu, L.; Han, Z.; Zhong, Y.; Zhang, R.; Li, Y.; Yin, G. Base-Modulated 1,3-Regio- and Stereoselective Carboboration of Cyclohexenes. Angew. Chem., Int. Ed. 2023, 62, e202308041  DOI: 10.1002/anie.202308041
    Google Scholar
    33
    Base-Modulated 1,3-Regio- and Stereoselective Carboboration of Cyclohexenes
    Kong, Weiyu; Bao, Yang; Lu, Liguo; Han, Zhipeng; Zhong, Yifan; Zhang, Ran; Li, Yuqiang; Yin, Guoyin
    Angewandte Chemie, International Edition (2023), 62 (35), e202308041CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    While chain-walking stimulates wide interest in both polymn. and org. synthesis, site- and stereoselective control of chain-walking on rings is still a challenging task in the realm of organometallic catalysis. Inspired by a controllable chain-walking on cyclohexane rings in olefin polymn., we have developed a set of chain-walking carboborations of cyclohexenes based on nickel catalysis. Different from the 1,4-trans-selectivity disclosed in polymer science, a high level of 1,3-regio- and cis-stereoselectivity is obtained in our reactions. Mechanistically, we discovery that the base affects the redn. ability of B2pin2 and different bases lead to different catalytic cycles and different regioselective products (1,2- Vs 1,3-addn.). This study provides a concise and modular method for the synthesis of 1,3-disubstituted cyclohexylboron compds. The incorporation of a readily modifiable boronate group greatly enhances the value of this method, the synthetic potential of which was highlighted by the synthesis of a series of high-valued com. chems. and pharmaceutically interesting mols.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhsFahsr3L&md5=5405825e9ddf5d413228664d59d2a160
  34. 34
    Sun, C.; Ding, C.; Yu, Y.; Li, Y.; Yin, G. Ligand-Modulated Regiodivergent Alkenylboration of Allylarenes: Reaction Development and Mechanistic Study. Fundamental Research 2023,  DOI: 10.1016/j.fmre.2023.03.016
    Google Scholar
    There is no corresponding record for this reference.
  35. 35
    Wang, W.; Yan, X.; Ye, F.; Zheng, S.; Huang, G.; Yuan, W. Nickel/Photoredox Dual-Catalyzed Regiodivergent Aminoalkylation of Unactivated Alkyl Halides. J. Am. Chem. Soc. 2023, 145, 23385– 23394,  DOI: 10.1021/jacs.3c09705
    Google Scholar
    35
    Nickel/photoredox Dual-Catalyzed Regiodivergent Aminoalkylation of Unactivated Alkyl Halides
    Wang, Wenlong; Yan, Xueyuan; Ye, Fu; Zheng, Songlin; Huang, Genping; Yuan, Weiming
    Journal of the American Chemical Society (2023), 145 (42), 23385-23394CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A mild and regiodivergent aminoalkylation of unactivated alkyl halides is disclosed via dual photoredox/nickel catalysis. Bipyridyl type ligands without ortho-substituent control the site-selective coupling at original position, while ortho-disubstituted ligands tune the site-selectivity at remote, unprefunctionalized position. Mechanistic studies combined with DFT calcns. give insight into the mechanism and the origins of the ligand-controlled regioselectivity. Notably, this redox-neutral, regiodivergent alkyl-alkyl coupling features mild conditions, broad substrate scope for both alkyl coupling partners, excellent site-selectivity, and offers a straightforward way for α-alkylation of tertiary amines to synthesize structurally diverse alkylamines and value-added amino acid derivs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXitV2qu7bJ&md5=69950065baf4edc6606268f791319a31
  36. 36
    Sun, S-Z.; Börjesson, M.; Martin-Montero, R.; Martin, R. Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins. J. Am. Chem. Soc. 2018, 140, 12765– 12769,  DOI: 10.1021/jacs.8b09425
    Google Scholar
    36
    Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins
    Sun, Shang-Zheng; Borjesson, Marino; Martin-Montero, Raul; Martin, Ruben
    Journal of the American Chemical Society (2018), 140 (40), 12765-12769CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A mild, chemo- and site-selective catalytic protocol that allows for incorporating an alkylboron fragment into unactivated olefins is described. The use of internal olefins enables C-C bond-formation at remote sp3 C-H sites, constituting a complementary and conceptually different approach to existing borylation techniques that are currently available at sp3 centers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKqt7fN&md5=61a75b25fcd19b58f08554391df37c27
  37. 37
    Qian, D.; Hu, X. Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines. Angew. Chem., Int. Ed. 2019, 58, 18519– 18523,  DOI: 10.1002/anie.201912629
    Google Scholar
    37
    Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines
    Qian, Deyun; Hu, Xile
    Angewandte Chemie, International Edition (2019), 58 (51), 18519-18523CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Two series of C-alkylated pyrrolidines I [R = Boc, Cbz; R1 = i-Pr, cyclopentyl, indol-1-yl, etc.] and II [R2 = CO2Ph, Boc, Cbz; R3 = cyclohexyl, (CH2)3Ph, 2-thienyl, etc.] were synthesized via ligand controlled nickel-catalyzed regiodivergent hydroalkylation of 3-pyrrolines with alkyl/aryl halides. This method demonstrated broad scope and high functional-group tolerance and could be applied in late-stage functionalizations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGqtrjJ&md5=b0d3de22f6800e5b425e895d666c1dba
  38. 38
    Du, B.; Ouyang, Y.; Chen, Q.; Yu, W.-Y. Thioether-Directed NiH-Catalyzed Remote γ-C(sp3)–H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-Ones. J. Am. Chem. Soc. 2021, 143, 14962– 14968,  DOI: 10.1021/jacs.1c05834
    Google Scholar
    38
    Thioether-Directed NiH-Catalyzed Remote γ-C(sp3)-H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-ones
    Du, Bingnan; Ouyang, Yuxin; Chen, Qishu; Yu, Wing-Yiu
    Journal of the American Chemical Society (2021), 143 (37), 14962-14968CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A NiH-catalyzed thioether-directed cyclometalation strategy was developed to enable remote methylene C-H bond amidation of unactivated alkenes. Due to the preference for five-membered nickelacycle formation, the chain-walking isomerization initiated by the NiH insertion to an alkene could be terminated at the γ-methylene site remote from the alkene moiety. By employing 2,9-dibutyl-1,10-phenanthroline as the ligand and dioxazolones as the reagent, the amidation occurs at the γ-C(sp3)-H bonds to afford the amide products in up to 90% yield (<40 examples) with remarkable regioselectivity (up to 24:1 rr).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFykt73M&md5=658e27ff1daa2f9f0cb01c40529ea3be
  39. 39
    Chen, X.; Rao, W.; Yang, T.; Koh, M. J. Alkyl halides as both hydride and alkyl sources in catalytic regioselective reductive olefin hydroalkylation. Nat. Commun. 2020, 11, 5857,  DOI: 10.1038/s41467-020-19717-6
    Google Scholar
    39
    Alkyl halides as both hydride and alkyl sources in catalytic regioselective reductive olefin hydroalkylation
    Chen, Xianxiao; Rao, Weidong; Yang, Tao; Koh, Ming Joo
    Nature Communications (2020), 11 (1), 5857CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    An Ni-based catalyst in conjunction with a stoichiometric reducing agent promotes Markovnikov-selective hydroalkylation of unactivated alkenes I (R = H, Me, Et, Ph, Bn) tethered to a recyclable 8-aminoquinaldine directing auxiliary. These mild reductive processes employ readily available primary and secondary haloalkanes R1X (R1 = Et, n-Bu, cyclopentyl, etc.; X = Br, I) as both the hydride and alkyl donor. Reactions of alkenyl amides I with ≥ five-carbon chain length regioselectively afforded β-alkylated products II through remote hydroalkylation, underscoring the fidelity of the catalytic process and the directing group's capability in stabilizing five-membered nickelacycle intermediates. The operationally simple protocol exhibits exceptional functional group tolerance and is amenable to the synthesis of bioactive mols. as well as regioconvergent transformations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitl2ns7jK&md5=c500c83b64bd56a4391b1e53049559be
  40. 40
    Lee, C.; Seo, H.; Jeon, J.; Hong, S. γ-Selective C(sp3)–H amination via controlled migratory hydroamination. Nat. Commun. 2021, 12, 5657,  DOI: 10.1038/s41467-021-25696-z
    Google Scholar
    40
    γ-Selective C(sp3)-H amination via controlled migratory hydroamination
    Lee, Changseok; Seo, Huiyeong; Jeon, Jinwon; Hong, Sungwoo
    Nature Communications (2021), 12 (1), 5657CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: Remote functionalization of alkenes via chain walking has generally been limited to C(sp3)-H bonds α and β to polar-functional units, while γ-C(sp3)-H functionalization through controlled alkene transposition is a longstanding challenge. Herein, authors describe NiH-catalyzed migratory formal hydroamination of alkenyl amides achieved via chelation-assisted control, whereby various amino groups are installed at the γ-position of aliph. chains. By tuning olefin isomerization and migratory hydroamination through ligand and directing group optimization, γ-selective amination can be achieved via stabilization of a 6-membered nickellacycle by an 8-aminoquinoline directing group and subsequent interception by an aminating reagent. A range of amines can be installed at the γ-C(sp3)-H bond of unactivated alkenes with varying alkyl chain lengths, enabling late-stage access to value-added γ-aminated products. Moreover, by employing picolinamide-coupled alkene substrates, this approach is further extended to δ-selective amination. The chain-walking mechanism and pathway selectivity are investigated by exptl. and computational methods.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitFWisr%252FF&md5=a694fce5976803104fdf1966eb6f68a5
  41. 41
    Wang, X.-X.; Xu, Y.-T.; Zhang, Z.-L.; Lu, X.; Fu, Y. NiH-Catalysed Proximal-Selective Hydroalkylation of Unactivated Alkenes and the Ligand Effects on Regioselectivity. Nat. Commun. 2022, 13, 1890,  DOI: 10.1038/s41467-022-29554-4
    Google Scholar
    41
    NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes and the ligand effects on regioselectivity
    Wang, Xiao-Xu; Xu, Yuan-Tai; Zhang, Zhi-Lin; Lu, Xi; Fu, Yao
    Nature Communications (2022), 13 (1), 1890CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
    Herein, a NiH-catalyzed proximal-selective hydroalkylation of unactivated alkenes e.g., N-(quinoline-8-yl)pent-4-enamide to access β- or γ-branched alkyl carboxylic acids and β-, γ- or δ-branched alkyl amines e.g., 4-methyl-N-(quinolin-8-yl)octanamide was reported. A broad range of alkyl iodides and bromides e.g., 1-iodobutane with different functional groups can be installed with excellent regiocontrol and availability for site-selective late-stage functionalization of biorelevant mols. Under modified reaction conditions with NiCl2(PPh3)2 as the catalyst, migratory hydroalkylation takes place to provide β- (rather than γ-) branched products. The keys to success are the use of aminoquinoline and picolinamide as suitable directing groups and combined exptl. and computational studies of ligand effects on the regioselectivity and detailed reaction mechanisms.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpsV2gsrk%253D&md5=8c341a912b8afc251599bbb21762a42f
  42. 42
    Wang, J.-W.; Liu, D.-G.; Chang, Z.; Li, Z.; Fu, Y.; Lu, X. Nickel-Catalyzed Switchable Site-Selective Alkene Hydroalkylation by Temperature Regulation. Angew. Chem., Int. Ed. 2022, 61, e202205537  DOI: 10.1002/anie.202205537
    Google Scholar
    42
    Nickel-Catalyzed Switchable Site-Selective Alkene Hydroalkylation by Temperature Regulation
    Wang, Jia-Wang; Liu, De-Guang; Chang, Zhe; Li, Zhen; Fu, Yao; Lu, Xi
    Angewandte Chemie, International Edition (2022), 61 (31), e202205537CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A nickel-catalyzed switchable site-selective alkene hydroalkylation was reported. The selection of reaction temps. led to protocols that provide regiodivergent hydroalkylated products starting from a single alkene substrate. This protocol allowed the convenient synthesis of α- and β-branched protected amines, both of which are important to the fields of pharmaceutical chem. and biochem. In addn., enantioenriched β-branched alkylamines can be accessed in a catalytic asym. variant. Preliminary mechanistic studies indicate that the formation of a more stable nickelacycle provides the driving force of migration. The thermodn. and kinetic properties of different redn. elimination intermediates are responsible for the switchable site-selectivity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsFCisbbL&md5=c74f49806159147d8f894c1823b48f18
  43. 43
    Zhao, L.; Zhu, Y.; Liu, M.; Xie, L.; Liang, J.; Shi, H.; Meng, X.; Chen, Z.; Han, J.; Wang, C. Ligand-Controlled NiH-Catalyzed Regiodivergent Chain-Walking Hydroalkylation of Alkenes. Angew. Chem., Int. Ed. 2022, 61, e202204716  DOI: 10.1002/anie.202204716
    Google Scholar
    43
    Ligand-Controlled NiH-Catalyzed Regiodivergent Chain-Walking Hydroalkylation of Alkenes
    Zhao, Lei; Zhu, Yuqin; Liu, Mengyuan; Xie, Leipeng; Liang, Jimin; Shi, Haoran; Meng, Xiao; Chen, Zhengyang; Han, Jian; Wang, Chao
    Angewandte Chemie, International Edition (2022), 61 (30), e202204716CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A NiH-catalyzed migratory hydroalkylation of alkenyl amines with predictable and switchable regioselectivity is reported. By utilizing a ligand-controlled, directing group-assisted strategy, various alkyl units are site-selectively installed at inert sp3 C-H sites far away from the original C=C bonds. A range of structurally diverse α- and β-branched protected amines are conveniently synthesized via stabilization of 5- and 6-membered nickelacycles resp. This method exhibits broad scope and high functional group tolerance, and can be applied to late-stage modification of medicinally relevant mols.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvFWgtLfP&md5=b79b9c614e30ff4eb8516b26ad493fab
  44. 44
    Yang, P.-F.; Shu, W. Orthogonal Access to α-/β-Branched/Linear Aliphatic Amines by Catalyst-Tuned Regiodivergent Hydroalkylations. Angew. Chem., Int. Ed. 2022, 61, e202208018  DOI: 10.1002/anie.202208018
    Google Scholar
    44
    Orthogonal Access to α-/β-Branched/Linear Aliphatic Amines by Catalyst-Tuned Regiodivergent Hydroalkylations
    Yang, Peng-Fei; Shu, Wei
    Angewandte Chemie, International Edition (2022), 61 (34), e202208018CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Herein, a catalyst-controlled synthesis of α-branched e.g., N-(1-phenylpentan-3-yl)benzamide, β-branched e.g., N-(2-methyl-4-phenylbutyl)benzamide and linear aliph. amines e.g., N-(5-phenylpentyl)benzamide from Ni/Co-catalyzed regio- and site-selective hydroalkylations of alkenyl amines e.g., N-(prop-2-en-1-yl)benzamide with alkyl halides RX (R = butan-2-yl, Bn, 2-phenylethyl, 2-(1,3-dioxolan-2-yl)ethyl, etc.; X = I, Br) is developed. This catalytic protocol features the reliable prediction and control of the coupling position of alkylation to provide orthogonal access to α-branched, β-branched and linear alkyl amines from identical starting materials. This platform unlocks orthogonal reactivity and selectivity of nickel hydride and cobalt hydride chem. to catalytically repurpose three types of alkyl amines under mild conditions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvVCms7jI&md5=da36f594ce297dd1a495d636c3c57552
  45. 45
    Zhao, W-T.; Meng, H.; Lin, J-N.; Shu, W. Ligand-Controlled Nickel-Catalyzed Regiodivergent Cross-Electrophile Alkyl-Alkyl Couplings of Alkyl Halides. Angew. Chem., Int. Ed. 2023, 62, e202215779  DOI: 10.1002/anie.202215779
    Google Scholar
    45
    Ligand-Controlled Nickel-Catalyzed Regiodivergent Cross-Electrophile Alkyl-Alkyl Couplings of Alkyl Halides
    Zhao, Wen-Tao; Meng, Huan; Lin, Jia-Ni; Shu, Wei
    Angewandte Chemie, International Edition (2023), 62 (7), e202215779CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Functionalizing specific positions on a satd. alkyl mol. is a key challenge in synthetic chem. Herein, a ligand-controlled regiodivergent alkylations of alkyl bromides at different positions by Ni-catalyzed alkyl-alkyl cross-electrophile coupling with the second alkyl bromides has been developed. The reaction undergoes site-selective isomerization on one alkyl bromides in a controlled manner, providing switchable access to diverse alkylated structures at different sites of alkyl bromides. The reaction occurs at three similar positions with excellent chemo- and regioselectivity, representing a remarkable ligand tuned reactivity between alkyl-alkyl cross-coupling and nickel migration along the hydrocarbon side chain. This reaction offers a catalytic platform to diverse satd. architectures by alkyl-alkyl bond-formation from identical starting materials.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhtFGis7o%253D&md5=0710389231b25bd3e95c2205ae6d9d1d
  46. 46
    Rodrigalvarez, J.; Wang, H.; Martin, R. Native Amides as Enabling Vehicles for Forging sp3-sp3 Architectures via Interrupted Deaminative Ni-Catalyzed Chain-Walking. J. Am. Chem. Soc. 2023, 145, 3869– 3874,  DOI: 10.1021/jacs.2c12915
    Google Scholar
    46
    Native Amides as Enabling Vehicles for Forging sp3-sp3 Architectures via Interrupted Deaminative Ni-Catalyzed Chain-Walking
    Rodrigalvarez, Jesus; Wang, Hao; Martin, Ruben
    Journal of the American Chemical Society (2023), 145 (7), 3869-3874CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Herein, authors disclose an interrupted deaminative Ni-catalyzed chain-walking strategy that forges sp3-sp3 architectures at remote, yet previously unfunctionalized, methylene sp3 C-H sites enabled by the presence of native amides. This protocol is characterized by its mild conditions and wide scope, including challenging substrate combinations. Site-selectivity can be dictated by a judicious choice of the ligand, thus offering an opportunity to enable sp3-sp3 bond formations that are otherwise inaccessible in conventional chain-walking events.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXislemtrw%253D&md5=ef39435bc0c7ad119e5852beb49d4a20
  47. 47
    Xie, L.; Liang, J.; Bai, H.; Liu, X.; Meng, X.; Xu, Y-Q.; Cao, Z-Y.; Wang, C. Ligand-Controlled NiH–Catalyzed Regiodivergent and Enantioselective Hydroamination of Alkenyl Amides. ACS Catal. 2023, 13, 10041– 10047,  DOI: 10.1021/acscatal.3c01845
    Google Scholar
    47
    Ligand-Controlled NiH-Catalyzed Regiodivergent and Enantioselective Hydroamination of Alkenyl Amides
    Xie, Leipeng; Liang, Jimin; Bai, Haohao; Liu, Xuanyu; Meng, Xiao; Xu, Yuan-Qing; Cao, Zhong-Yan; Wang, Chao
    ACS Catalysis (2023), 13 (15), 10041-10047CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Herein, a ligand-controlled, directing-group-assisted strategy to promote NiH-catalyzed site-selective (α, β, or γ) hydroamination of unactivated alkenes with weakly coordinating amide groups was reported. The key to success lies in the employment of proper yet com. available bidentate nitrogen-contg. ligands, which enabled delivery of 1,1-, 1,2-, and 1,3-diamines with good-to-excellent regioselectivity starting from the same substrates. A broad range of O-benzoylhydroxylamine electrophiles with different functional groups can be installed via Ni migration or nonmigration. Moreover, these predicable and positionally selective protocols provided a method for the enantioselective synthesis of highly valued 1,2-diamines (via remote aliph. C-H amination) and 1,3-diamines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhsVymsrzM&md5=fe3ff60d584fc8ffb1dc36a367b748a5

Cited By

Click to copy section linkSection link copied!

This article is cited by 16 publications.

  1. Chong Liu, Ling Wang, Haibo Ge. Multifunctionalization of Alkenyl Alcohols via a Sequential Relay Process. Journal of the American Chemical Society 2024, 146 (45) , 30733-30740. https://doi.org/10.1021/jacs.4c09522
  2. Seungdae Park, Baeho Yang, Dohyun Lee, Hyunwoo Kim, Kwangmin Shin. Electrooxidative Pd-Catalyzed Remote Hydrofunctionalization of Alkenes with Nucleophiles. ACS Catalysis 2024, 14 (21) , 15858-15868. https://doi.org/10.1021/acscatal.4c04279
  3. Zhong Liu, Francesco D’Amico, Ruben Martin. Regiodivergent Radical-Relay Alkene Dicarbofunctionalization. Journal of the American Chemical Society 2024, 146 (42) , 28624-28629. https://doi.org/10.1021/jacs.4c10204
  4. Chong Liu, Robbie Ge, Jun Chen, Hongmei Guo, Tyler A. Bartholome, Debabrata Maiti, Haibo Ge. Facile construction of distal and diversified tertiary and quaternary stereocenters. Proceedings of the National Academy of Sciences 2024, 121 (51) https://doi.org/10.1073/pnas.2408541121
  5. Yao-Xin Wang, Zhen Wang, Xiao-Hui Yang. Palladium-catalyzed remote internal C(sp3)−H bond chlorination of alkenes. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-54896-6
  6. Yan Li, Xi Lu. Cobalt-Catalyzed Regio- and Enantioselective Hydroalkylation of 1,1-Disubstituted Styrenes. Synlett 2024, 31 https://doi.org/10.1055/a-2408-0043
  7. Shuang Yang, Qi Zhang, Hui Chen, Da Zhao, Yang Wang. Nickel-hydrogen-bonding-enabled, phosphine-ligand-tuned regiodivergent isomerization of olefins. Chem Catalysis 2024, 4 (8) , 101043. https://doi.org/10.1016/j.checat.2024.101043
  8. Chao Fan, Uttam Dhawa, Deyun Qian, Davor Sakic, Jennifer Morel, Xile Hu. Regiodivergent and Enantioselective Synthesis of Cyclic Sulfones via Ligand‐Controlled Nickel‐Catalyzed Hydroalkylation. Angewandte Chemie International Edition 2024, 63 (29) https://doi.org/10.1002/anie.202406767
  9. Chao Fan, Uttam Dhawa, Deyun Qian, Davor Sakic, Jennifer Morel, Xile Hu. Regiodivergent and Enantioselective Synthesis of Cyclic Sulfones via Ligand‐Controlled Nickel‐Catalyzed Hydroalkylation. Angewandte Chemie 2024, 136 (29) https://doi.org/10.1002/ange.202406767
  10. Pooja Patel, Srinivasarao Arulananda Babu, Radha Tomar. Construction of C5‐Indole Unnatural Amino Acid Motifs via Diastereoselective Pd(II)‐Catalyzed β ‐C(sp 3 )‐H Functionalization. European Journal of Organic Chemistry 2024, 27 (25) https://doi.org/10.1002/ejoc.202400190
  11. Xian‐Jin Zou, Zhao‐Xing Jin, Hui‐Yi Yang, Fei Wu, Zhi‐Hui Ren, Zheng‐Hui Guan. Palladium‐Catalyzed Inward Isomerization Hydroaminocarbonylation of Alkenes. Angewandte Chemie 2024, 136 (26) https://doi.org/10.1002/ange.202406226
  12. Xian‐Jin Zou, Zhao‐Xing Jin, Hui‐Yi Yang, Fei Wu, Zhi‐Hui Ren, Zheng‐Hui Guan. Palladium‐Catalyzed Inward Isomerization Hydroaminocarbonylation of Alkenes. Angewandte Chemie International Edition 2024, 63 (26) https://doi.org/10.1002/anie.202406226
  13. Shefali Banga, Srinivasarao Arulananda Babu. Fluorene and Fluorenone Unnatural Amino Acid Motifs via Diastereoselective Pd(II)‐Catalyzed sp 3 C−H Functionalization. European Journal of Organic Chemistry 2024, 27 (23) https://doi.org/10.1002/ejoc.202400272
  14. Ya-Ping Shao, Zhuo-Min Chi, Yong-Min Liang. Ligand-controlled NiH-catalyzed regiodivergent hydroalkylation of 2-alkenylazaarenes. Science China Chemistry 2024, 67 (6) , 1935-1940. https://doi.org/10.1007/s11426-024-1949-1
  15. Soumen Biswas, William B. Hughes, Luca De Angelis, Graham C. Haug, Ramon Trevino, Seth O. Fremin, Hadi D. Arman, Oleg V. Larionov, Michael P. Doyle. The “cesium effect” magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions. Chemical Science 2024, 15 (14) , 5277-5283. https://doi.org/10.1039/D4SC00316K
  16. Laura Talavera, Carlota Odena, Ruben Martin. Recent advances in Ni-catalyzed functionalization of strong C−O and C−H bonds. 2024, 133-179. https://doi.org/10.1016/bs.acat.2024.05.002
Download PDF
Go to JACS Au
Get e-Alerts
Get e-Alerts

JACS Au

Cite this: JACS Au 2023, 3, 12, 3270–3282
Click to copy citationCitation copied!
https://doi.org/10.1021/jacsau.3c00617
Published November 28, 2023

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY-NC-ND 4.0 .

Article Views

5095

Altmetric

-

Citations

16
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 1

    Scheme 1. Metal-Catalyzed C(sp3)–H Functionalization
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 2

    Scheme 2. Site-Selectivity in C(sp3)–H Functionalization
    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Regiodivergent Ni-catalyzed chain-walking C(sp3)–H functionalizations by utilizing alkyl halides or olefins.

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 3

    Scheme 3. Site-Selective Heteroarylation of Allyl Benzene
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 4

    Scheme 4. Hydroarylation of Allyl Benzene with Pyridine
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 5

    Scheme 5. Hydroarylation of Arene-Containing Olefins
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 6

    Scheme 6. Regiodivergent Carboxylation of Alkyl-Br
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 7

    Scheme 7. Site-Selective Amidation of Alkyl Bromides
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 8

    Scheme 8. Regiodivergent Hydroamination of Alkenes
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 9

    Scheme 9. Regiodivergent Hydrothiolation of Alkenes
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 10

    Scheme 10. Regiodivergent Hydrocyanation of Alkenes
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 11

    Scheme 11. Coupling of Allyl Benzenes, BnCl and B2pin2
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 12

    Scheme 12. Site-Selective Carboboration of Allyl Benzenes
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 13

    Scheme 13. Deuterium-Labeling Studies on the Regiodivergent Ni-Catalyzed Carboboration with Alkenyl Bromides
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 14

    Scheme 14. Regiodivergent Ni-Catalyzed Alkylation with α-Silyl Amines under Photoredox-Catalytic Conditions
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 15

    Scheme 15. Hydroalkylation of N-Protected Pyrrolines
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 16

    Scheme 16. Hydroamidation of Thioethers
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 17

    Scheme 17. Hydroalkylation of 8-Aminoquinolinamides
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 18

    Scheme 18. Lu’s Hydroalkylation of N-Protected Amines
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 19

    Scheme 19. Wang’s Hydroalkylation of N-Protected Amines
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 20

    Scheme 20. Mechanistic Studies for the Ni-Catalyzed Hydroalkylation of N-Protected Amines
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 21

    Scheme 21. Shu’s Hydroalkylation of N-Protected Amines
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 22

    Scheme 22. Regiodivergent Cross-Electrophile Coupling of Bromine-Containing Amides
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 23

    Scheme 23. Martin’s Hydroalkylation of Unsaturated Amides
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 24

    Scheme 24. Mechanistic Experiments
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 25

    Scheme 25. Hydroamination with N–O Electrophiles
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 26

    Scheme 26. Ligand Effects in Regiodivergent Hydroamination
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 27

    Scheme 27. Regiodivergent Asymmetric Hydroamination
    High Resolution Image
    Download MS PowerPoint Slide

  • References

    This article references 47 other publications.

    1. 1
      Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752– 6756,  DOI: 10.1021/jm901241e
      1
      Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success
      Lovering, Frank; Bikker, Jack; Humblet, Christine
      Journal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvN&md5=4ca92c30c17c53d77ad376719bad951e
    2. 2
      Guillemard, L.; Kaplaneris, N.; Ackermann, L.; Johansson, M. J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 2021, 5, 522– 545,  DOI: 10.1038/s41570-021-00300-6
      2
      Late-stage C-H functionalization offers new opportunities in drug discovery
      Guillemard, Lucas; Kaplaneris, Nikolaos; Ackermann, Lutz; Johansson, Magnus J.
      Nature Reviews Chemistry (2021), 5 (8), 522-545CODEN: NRCAF7; ISSN:2397-3358. (Nature Portfolio)
      A review. Over the past decade, the landscape of mol. synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C-H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C-H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programs. This Review highlights the significant advances achieved in the late-stage C-H functionalization of drugs and drug-like compds., and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examd. and classified by mechanistic patterns involving directed or innate C-H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small mols. are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new mols. of interest.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvVGgsbbL&md5=9c9314ac4bb84e8affc1a1b347447e05
    3. 3
      Docherty, J. H.; Lister, T. M.; Mcarthur, G.; Findlay, M. T.; Domingo-Legarda; Kenyon, J.; Choudhary, S.; Larrosa, I. Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules. Chem. Rev. 2023, 123, 7692– 7760,  DOI: 10.1021/acs.chemrev.2c00888
      3
      Transition-Metal Catalyzed C-H Bond Activation for the Formation of C-C Bonds in Complex Molecules
      Docherty, Jamie H.; Lister, Thomas M.; Mcarthur, Gillian; Findlay, Michael T.; Domingo-Legarda, Pablo; Kenyon, Jacob; Choudhary, Shweta; Larrosa, Igor
      Chemical Reviews (Washington, DC, United States) (2023), 123 (12), 7692-7760CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Site-predictable and chemoselective C-H bond functionalization reactions offer synthetically powerful strategies for the step-economic diversification of both feedstock and fine chems. Many transition-metal catalyzed methods have emerged for the selective activation and functionalization of C-H bonds. However, challenges of regio- and chemoselectivity have emerged with application to highly complex mols. bearing significant functional group d. and diversity. As mol. complexity increases within mol. structures the risks of catalyst intolerance and limited applicability grow with the no. of functional groups and potentially Lewis basic heteroatoms. Given the abundance of C-H bonds within highly complex and already diversified mols. such as pharmaceuticals, natural products and materials, design and selection of reaction conditions and tolerant catalysts has proved crit. for successful direct functionalization. As such, innovations within transition-metal catalyzed C-H bond functionalization for the direct formation of carbon-carbon bonds have been discovered and developed to overcome these challenges and limitations. This review highlights progress made for the direct metal-catalyzed C-C bond forming reactions including alkylation, methylation, arylation and olefination of C-H bonds within complex targets.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXps1Wjsbo%253D&md5=ea36a32e3d03270aa5e8c9fa15ef8ec6
    4. 4
      Bellotti, P.; Huang, H.-M.; Faber, T.; Glorius, F. Photocatalytic Late-Stage C–H Functionalization. Chem. Rev. 2023, 123, 4237– 4352,  DOI: 10.1021/acs.chemrev.2c00478
      4
      Photocatalytic Late-Stage C-H Functionalization
      Bellotti, Peter; Huang, Huan-Ming; Faber, Teresa; Glorius, Frank
      Chemical Reviews (Washington, DC, United States) (2023), 123 (8), 4237-4352CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This review highlights the photocatalytic late-stage C-H functionalization strategies of small-mol. drugs, agrochems., and natural products, classified according to the targeted C-H bond and the newly formed one. Emphasis is devoted at identifying, describing and comparing the main mechanistic scenarios. The review draws a crit. comparison between established ionic chem. and photocatalyzed radical-based manifolds. The review aims at establishing the current state-of-the-art and at illustrating the key unsolved challenges to be addressed in the future. The authors aim at introducing the general readership to the main approaches toward the photocatalytic late-stage C-H functionalization, and the specialist practitioners to the crit. evaluation of the current methodologies, potential for improvement and future, uncharted directions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhs1Sktrs%253D&md5=68758b9b6fa0a03f66b0b499e321de2c
    5. 5
      Bergman, R. G. C–H Activation. Nature 2007, 446, 391– 393,  DOI: 10.1038/446391a
      5
      Organometallic chemistry: C-H activation
      Bergman, Robert G.
      Nature (London, United Kingdom) (2007), 446 (7134), 391-393CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The stability of the chem. bonds in satd. hydrocarbons makes them generally unreactive. But the invention of processes in which carbon-hydrogen (C-H) bonds in hydrocarbons can be activated is allowing chemists to exploit org. compds. in previously unimaginable ways.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjt1Wqs7w%253D&md5=65c9a1b108168f5d6d8a17009437c6e5
    6. 6
      Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Transition Metal-Catalyzed Ketone-Directed or Mediated C–H Functionalization. Chem. Soc. Rev. 2015, 44, 7764– 7786,  DOI: 10.1039/C5CS00272A
      6
      Transition metal-catalyzed ketone-directed or mediated C-H functionalization
      Huang, Zhongxing; Lim, Hee Nam; Mo, Fanyang; Young, Michael C.; Dong, Guangbin
      Chemical Society Reviews (2015), 44 (21), 7764-7786CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Advancements in use of ketone carbonyls as directing groups, direct β-functionalization, and α-alkylation/alkenylation with unactivated olefins and alkynes has been reviewed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFyktr7O&md5=f62241e8054c3a12584b016339000d41
    7. 7
      He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-Catalyzed Transformations of Alkyl C–H Bonds. Chem. Rev. 2017, 117, 8754– 8786,  DOI: 10.1021/acs.chemrev.6b00622
      7
      Palladium-Catalyzed Transformations of Alkyl C-H Bonds
      He, Jian; Wasa, Masayuki; Chan, Kelvin S. L.; Shao, Qian; Yu, Jin-Quan
      Chemical Reviews (Washington, DC, United States) (2017), 117 (13), 8754-8786CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This Review summarizes the advancements in Pd-catalyzed C(sp3)-H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C-H bonds, many C(sp3)-H activation/C-C and C-heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chem. A no. of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)-H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C-H functionalization reactions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFOltbnF&md5=1eb3ce0a36a301ef8374722c96a4a050
    8. 8
      Xu, Y.; Dong, G. Sp3 C–H Activation via Exo-Type Directing Groups. Chem. Sci. 2018, 9, 1424– 1432,  DOI: 10.1039/C7SC04768A
      8
      sp3 C-H activation via exo-type directing groups
      Xu, Yan; Dong, Guangbin
      Chemical Science (2018), 9 (6), 1424-1432CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A review. In this mini-review article the challenges in sp3 C-H activation via exo-type directing groups and the achievements, including directing group designs, reaction discoveries and mechanistic studies were discussed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVeltb0%253D&md5=1975f056fb68aa8fef8c2e82cd9ff37c
    9. 9
      Rej, S.; Ano, Y.; Chatani, N. Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds. Chem. Rev. 2020, 120, 1788– 1887,  DOI: 10.1021/acs.chemrev.9b00495
      9
      Bidentate Directing Groups: An Efficient Tool in C-H Bond Functionalization Chemistry for the Expedient Construction of C-C Bonds
      Rej, Supriya; Ano, Yusuke; Chatani, Naoto
      Chemical Reviews (Washington, DC, United States) (2020), 120 (3), 1788-1887CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Broadly discussed various C-H functionalization reactions for the formation of C-C bonds with the aid of bidentate directing groups are reviewed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXislWjug%253D%253D&md5=c89f782e69952af391a23ac9575fa3cd
    10. 10
      Mingo, M. M.; Rodríguez, N.; Gómez Arrayás, R.; Carretero, J. C. Remote C(sp3)–H functionalization via catalytic cyclometallation: beyond five-membered ring metallacycle intermediates. Org. Chem. Front. 2021, 8, 4914– 4946,  DOI: 10.1039/D1QO00389E
      10
      Remote C(sp3)-H functionalization via catalytic cyclometallation: beyond five-membered ring metallacycle intermediates
      Mingo, Mario Martinez; Rodriguez, Nuria; Arrayas, Ramon Gomez; Carretero, Juan C.
      Organic Chemistry Frontiers (2021), 8 (17), 4914-4946CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
      Despite impressive recent momentum gained in C(sp3)-H activation, achieving high regioselectivity in mols. contg. different C-H bonds with similar high energy without abusing tailored substitution remains as one of the biggest challenges. The use of directing groups, esp. those featuring bidentate coordination, typically in combination with palladium catalysis, has fueled the development of a no. of direct C(sp3)-H bond functionalizations via cyclometallation. In most of the reported examples, the regioselectivity is detd. by the strong propensity of PdII to form square planar five-membered metalacycles. In contrast, targetting C-H bonds that are farther than three bonds away from the coordinating heteroatom through the intermediacy of less favorable six-membered (or higher) metalacycles is far more difficult. In fact, achieving high selectivity via six-membered metalacycles without blocking the competitive functionalization via a five-membered metalacycle represents an even more difficult challenge. This review provides an overview of methods enabling catalytic C(sp3)-H activation via six-membered metalacycle intermediates, with an emphasis on mechanistic aspects regarding the control of regioselectivity and strategies towards disfavoring the formation of the five-membered palladacycle in preference for the six-membered analog.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtFSgsLjO&md5=35f3f6c4d72f6ef751727789d03c7ecd
    11. 11
      Davies, H. M. L.; Morton, D. Recent Advances in C–H Functionalization. J. Org. Chem. 2016, 81, 343– 350,  DOI: 10.1021/acs.joc.5b02818
      11
      Recent Advances in C-H Functionalization
      Davies, Huw M. L.; Morton, Daniel
      Journal of Organic Chemistry (2016), 81 (2), 343-350CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      A review. This review highlights 24 recent papers and illustrates their significance to the C-H functionalization endeavor. Some of the current trends are covered. E.g., design of new directing groups that are readily removed or converted into useful functionality, broadening the scope from the more traditional functionalization of sp2 C-H bonds to sp3 C-H bonds, application of the methodol. to a broader range of functionality, and modification of the directing influence away from just ortho-functionalization.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks12jtQ%253D%253D&md5=e8d7906606252f770b50d28fd4e4dc2f
    12. 12
      He, Y.; Huang, Z.; Wu, K.; Ma, J.; Zhou, Y.-G.; Yu, Z. Recent Advances in Transition-Metal-Catalyzed Carbene Insertion to C–H Bonds. Chem. Soc. Rev. 2022, 51, 2759– 2852,  DOI: 10.1039/D1CS00895A
      12
      Recent advances in transition-metal-catalyzed carbene insertion to C-H bonds
      He, Yuan; Huang, Zilong; Wu, Kaikai; Ma, Juan; Zhou, Yong-Gui; Yu, Zhengkun
      Chemical Society Reviews (2022), 51 (7), 2759-2852CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. This crit. review will summarize the advance in transition-metal-catalyzed carbene insertion to C-H bonds dated up to July 2021, by the categories of C-H bonds from aliph. C(sp3)-H, aryl (arom.) C(sp2)-H, heteroaryl (heteroarom.) C(sp2)-H bonds, alkenyl C(sp2)-H, and alkynyl C(sp)-H, as well as asym. carbene insertion to C-H bonds, and more coverage will be given to the recent work. Due to the rapid development of the C-H functionalization area, future directions in this topic are also discussed. This review will give the authors an overview of carbene insertion chem. in C-H functionalization with focus on the catalytic systems and synthetic applications in C-C bond formation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XnsFClsLg%253D&md5=42fa9cae1d5657ca3b1462ef8e878699
    13. 13
      Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Recent Advances in Radical C–H Activation/Radical Cross-Coupling. Chem. Rev. 2017, 117, 9016– 9085,  DOI: 10.1021/acs.chemrev.6b00620
      13
      Recent Advances in Radical C-H Activation/Radical Cross-Coupling
      Yi, Hong; Zhang, Guoting; Wang, Huamin; Huang, Zhiyuan; Wang, Jue; Singh, Atul K.; Lei, Aiwen
      Chemical Reviews (Washington, DC, United States) (2017), 117 (13), 9016-9085CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Research and industrial interest in radical C-H activation/radical cross-coupling chem. has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting mol. fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C-H activation. This review includes radical addn., radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M-R groups, and coupling of radical cations with nucleophiles (Nu).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVamu7fM&md5=d9f5525fbdfacb26f1cec1d00d95e5ed
    14. 14
      Sarkar, S.; Cheung, K. P. S.; Gevorgyan, V. C–H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals. Chem. Sci. 2020, 11, 12974– 12993,  DOI: 10.1039/D0SC04881J
      14
      C-H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals
      Sarkar, Sumon; Cheung, Kelvin Pak Shing; Gevorgyan, Vladimir
      Chemical Science (2020), 11 (48), 12974-12993CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A review. Recent developments of mild methodologies for generation of various carbon-centered radical species enabled their utilization in the HAT process, which, in turn, led to the development of remote C(sp3)-H functionalization reactions of alcs., amines, amides and related compds. This review covers mostly recent advances in C-H functionalization reactions involving the HAT step to carbon-centered radicals.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitlCksbfF&md5=95f8a74b3b31147efec6f3ff32d41a51
    15. 15
      Lewis, J. C.; Coelho, P. S.; Arnold, F. H. Enzymatic Functionalization of Carbon–Hydrogen Bonds. Chem. Soc. Rev. 2011, 40, 2003– 2021,  DOI: 10.1039/C0CS00067A
      15
      Enzymatic functionalization of carbon-hydrogen bonds
      Lewis, Jared C.; Coelho, Pedro S.; Arnold, Frances H.
      Chemical Society Reviews (2011), 40 (4), 2003-2021CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. The development of new catalytic methods to functionalize carbon-hydrogen (C-H) bonds continues to progress at a rapid pace due to the significant economic and environmental benefits of these transformations over traditional synthetic methods. In nature, enzymes catalyze regio- and stereoselective C-H bond functionalization using transformations ranging from hydroxylation to hydroalkylation under ambient reaction conditions. The efficiency of these enzymes relative to analogous chem. processes has led to their increased use as biocatalysts in preparative and industrial applications. Furthermore, unlike small mol. catalysts, enzymes can be systematically optimized via directed evolution for a particular application and can be expressed in vivo to augment the biosynthetic capability of living organisms. While a variety of tech. challenges must still be overcome for practical application of many enzymes for C-H bond functionalization, continued research on natural enzymes and on novel artificial metalloenzymes will lead to improved synthetic processes for efficient synthesis of complex mols. In this crit. review, we discuss the most prevalent mechanistic strategies used by enzymes to functionalize non-acidic C-H bonds, the application and evolution of these enzymes for chem. synthesis, and a no. of potential biosynthetic capabilities uniquely enabled by these powerful catalysts (110 refs.).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsFegsLs%253D&md5=208b878c36d75557758eed7b39ee9e6f
    16. 16
      Dunham, N. P.; Arnold, F. H. Nature’s Machinery, Repurposed: Expanding the Repertoire of Iron-Dependent Oxygenases. ACS Catal. 2020, 10, 12239– 12255,  DOI: 10.1021/acscatal.0c03606
      16
      Nature's machinery, repurposed: Expanding the repertoire of iron-dependent oxygenases
      Dunham, Noah P.; Arnold, Frances H.
      ACS Catalysis (2020), 10 (20), 12239-12255CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      A review. Iron is an esp. important redox-active cofactor in biol. because of its ability to mediate reactions with atm. O2. Iron-dependent oxygenases exploit this earth-abundant transition metal for the insertion of oxygen atoms into org. compds. Throughout the astounding diversity of transformations catalyzed by these enzymes, the protein framework directs reactive intermediates toward the precise formation of products, which, in many cases, necessitates the cleavage of strong C-H bonds. In recent years, members of several iron-dependent oxygenase families have been engineered for new-to-nature transformations that offer advantages over conventional synthetic methods. In this Perspective, we first explore what is known about the reactivity of heme-dependent cytochrome P 450 oxygenases and nonheme iron-dependent oxygenases bearing the 2-His-1-carboxylate facial triad by reviewing mechanistic studies with an emphasis on how the protein scaffold maximizes the catalytic potential of the iron-heme and iron cofactors. We then review how these cofactors have been repurposed for abiol. transformations by engineering the protein frameworks of these enzymes. Finally, we discuss contemporary challenges assocd. with engineering these platforms and comment on their roles in biocatalysis moving forward.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFaqs7fL&md5=007b291f3cab1ae5ddce677e44d64861
    17. 17
      Vasseur, A.; Bruffaerts, J.; Marek, I. Remote Functionalization through Alkene Isomerization. Nat. Chem. 2016, 8, 209– 219,  DOI: 10.1038/nchem.2445
      17
      Remote functionalization through alkene isomerization
      Vasseur, Alexandre; Bruffaerts, Jeffrey; Marek, Ilan
      Nature Chemistry (2016), 8 (3), 209-219CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      A review discusses the use of metal-catalyzed alkene isomerization to remotely functionalize alkenes and its potential use in org. synthesis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVCnurw%253D&md5=d564ccf0a48bf37eedf74056b116f750
    18. 18
      Sommer, H.; Juliá-Hernández, F.; Martin, R.; Marek, I. Walking Metals for Remote Functionalization. ACS Cent. Sci. 2018, 4, 153– 165,  DOI: 10.1021/acscentsci.8b00005
      18
      Walking Metals for Remote Functionalization
      Sommer, Heiko; Julia-Hernandez, Francisco; Martin, Ruben; Marek, Ilan
      ACS Central Science (2018), 4 (2), 153-165CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      A review. The distant and selective activation of unreactive C-H and C-C bonds remains one of the biggest challenges in org. chem. In recent years, the development of remote functionalization has received growing interest as it allows for the activation of rather challenging C-H and C-C bonds distant from the initiation point by means of a "metal-walk". A "metal-walk" or "chain-walk" is defined by an iterative series of consecutive 1,2- or 1,3-hydride shifts of a metal complex along a single hydrocarbon chain. With this approach, simple building blocks or mixts. thereof can be transformed into complex scaffolds in a convergent and unified strategy. A variety of catalytic systems have been developed and refined over the past decade ranging from late-transition-metal complexes to more sustainable iron- and cobalt-based systems. As the possibilities of this field are slowly unfolding, this area of research will contribute considerably to provide solns. to yet unmet synthetic challenges.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlarsrs%253D&md5=d35dc67867297ea182ba63d767a3651e
    19. 19
      Ghosh, S.; Patel, S.; Chatterjee, I. Chain-walking reactions of transition metals for remote C–H bond functionalization of olefinic substrates. Chem. Commun 2021, 57, 11110– 11130,  DOI: 10.1039/D1CC04370F
      19
      Chain-walking reactions of transition metals for remote C-H bond functionalization of olefinic substrates
      Ghosh, Soumen; Patel, Sandeep; Chatterjee, Indranil
      Chemical Communications (Cambridge, United Kingdom) (2021), 57 (85), 11110-11130CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A review. Herein, authors have provided a comprehensive overview of the chain-walking reactions involving a variety of catalytic systems ranging from the first-row transition metal catalysts to the third-row transition metal catalysts for C-H activation in a concise fashion with the hope for further developments in this area through the appropriate application of the chain-walking reactions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitVegt7%252FI&md5=0e47af9569a16c75b9bd396383789b5b
    20. 20
      Lee, W.-C.; Wang, C.-H.; Lin, Y.-H.; Shih, W.-C.; Ong, T.-G. Tandem Isomerization and C–H Activation: Regioselective Hydroheteroarylation of Allylarenes. Org. Lett. 2013, 15, 5358– 5361,  DOI: 10.1021/ol402644y
      20
      Tandem Isomerization and C-H Activation: Regioselective Hydroheteroarylation of Allylarenes
      Lee, Wei-Chih; Wang, Chun-Han; Lin, Yung-Huei; Shih, Wei-Chun; Ong, Tiow-Gan
      Organic Letters (2013), 15 (20), 5358-5361CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Heterocycles such as 1-methylbenzimidazole underwent regioselective hydroarylation reactions with allylbenzenes in the presence of bis(1,5-cyclooctadiene)nickel and N-heterocyclic carbenes to give aralkylheterocycles such as I and II [R = Ph, 4-MeC6H4, 2-MeC6H4, 3-MeC6H4, 4-MeOC6H4, 2-MeOC6H4, 3,4-(MeO)2C6H3, 4-F3CC6H4, 4-FC6H4, 1,3-benzodioxole-5-yl] in 33-95% yields and in 58:42->99:1 regioselectivities. In the presence of Me3Al, linear hydroarylation products such as I were isolated in 92:8->99:1 regioselectivities, while in its absence, the α-arylpropyl heterocycles such as II were isolated in 42:58->99:1 regioselectivities (all but one with selectivities >83:17).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFKksrfI&md5=d62aa287cf1cb413b962f741b90cca05
    21. 21

      For a selected example of pyridine functionalization aided by Lewis acids:

      Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. Selective C-4 Alkylation of Pyridine by Nickel/Lewis Acid Catalysis. J. Am. Chem. Soc. 2010, 132, 13666– 13668,  DOI: 10.1021/ja106514b
      21
      Selective C-4 Alkylation of Pyridine by Nickel/Lewis Acid Catalysis
      Nakao, Yoshiaki; Yamada, Yuuya; Kashihara, Natsuko; Hiyama, Tamejiro
      Journal of the American Chemical Society (2010), 132 (39), 13666-13668CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Direct C-4-selective addn. of pyridine across alkenes and alkynes is achieved for the first time by nickel/Lewis acid cooperative catalysis with an N-heterocyclic carbene ligand. A variety of substituents on both alkenes and pyridine are tolerated to give linear 4-alkylpyridines, e.g., I in modest to good yields. The addn. across styrene gives branched 4-alkylpyridines. A single example of C-4-selective alkenylation is also described.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWru7zK&md5=5d3b911b3a8ab27421566e8d35d8ecb0
    22. 22
      Lee, W.-C.; Chen, C.-H.; Liu, C.-Y.; Yu, M.-S.; Lin, Y.-H.; Ong, T.-G. Nickel-Catalysed Para C-H Activation of Pyridine with Switchable Regioselective Hydroheteroarylation of Allylarenes. Chem. Commun. 2015, 51, 17104– 17107,  DOI: 10.1039/C5CC07455J
      22
      Nickel-catalyzed para-CH activation of pyridine with switchable regioselective hydroheteroarylation of allylarenes
      Lee, Wei-Chih; Chen, Chien-Hung; Liu, Cheng-Yuan; Yu, Ming-Shiuan; Lin, Yung-Huei; Ong, Tiow-Gan
      Chemical Communications (Cambridge, United Kingdom) (2015), 51 (96), 17104-17107CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Para-CH activation of pyridine with allylbenzene is described by Ni/Al cooperative catalysis in combination with a bulkier NHC ligand and a Lewis acid, leading to linear hydroheteroarylation products. Interestingly, branch selectivity can be achieved by using a combination of a less sterically hindered amino-NHC ligand and AlMe3 through tandem reaction of facile alkene isomerization followed by a slow CH bond activation process. Under optimized conditions the synthesis of the target compds. was achieved using bis[(1,2,5,6-η)-1,5-cyclooctadiene]nickel and 1,3-dihydro-1,3-bis(2,4,6-trimethylphenyl)-2H-imidazol-2-ylidene carbene, 1-[2-(dimethylamino)ethyl]-1,3-dihydro-3-(2,4,6-trimethylphenyl)-2H-imidazol-2-ylidene carbene (NHC) as catalyst and ligand combinations. Starting materials included pyridine, quinoline, 5,6,7,8-tetrahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine and (propenyl)benzene derivs., (butenyl)benzene, (ethenyl)benzene, 5-(2-propen-1-yl)-1,3-benzodioxole. The title compds. thus formed included 4-(3-phenylpropyl)pyridine (linear product) and 4-(1-phenylpropyl)pyridine (branched product).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsF2htr3K&md5=c8fcba43c682c4c3e88148b9a3dfacbf
    23. 23
      Imran, S.; Jin, W.-H.; Li, R.-P.; Ismaeel, N.; Sun, H.-M. Ligand-Controlled Nickel-Catalyzed Tandem Isomerization/Regiodivergent Hydroheteroarylation of α-Alkenes with Heteroarenes. Org. Lett. 2022, 24, 8875– 8879,  DOI: 10.1021/acs.orglett.2c03689
      23
      Ligand-Controlled Nickel-Catalyzed Tandem Isomerization/Regiodivergent Hydroheteroarylation of α-Alkenes with Heteroarenes
      Imran, Sajid; Jin, Wen-Hui; Li, Rui-Peng; Ismaeel, Nadia; Sun, Hong-Mei
      Organic Letters (2022), 24 (48), 8875-8879CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      The authors herein describe an accessible ligand-controlled Ni-catalyzed tandem isomerization/regiodivergent hydroheteroarylation of α-alkenes with heteroarenes, wherein the NHC ligand of heteroleptic Ni(II) complexes Ni(NHC)[P(OEt)3]Br2 displayed significant effects on regulation. In the presence of NaOtBu, Ni(IMes)[P(OEt)3]Br2 enables C:C bond isomerization of α-alkenes over up to four sp3 C atoms to afford branched products, while Ni(IPr*OMe)[P(OEt)3]Br2 greatly deactivates α-alkene isomerization and favors the formation of linear products.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XivF2isLfJ&md5=26ba118a39454e63840564b46647eb5e
    24. 24
      Juliá-Hernández, F.; Moragas, T.; Cornella, J.; Martin, R. Remote Carboxylation of Halogenated Aliphatic Hydrocarbons with Carbon Dioxide. Nature 2017, 545, 84– 88,  DOI: 10.1038/nature22316
      24
      Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide
      Julia-Hernandez, Francisco; Moragas, Toni; Cornella, Josep; Martin, Ruben
      Nature (London, United Kingdom) (2017), 545 (7652), 84-88CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Catalytic carbon-carbon bond formation has enabled the streamlining of synthetic routes when assembling complex mols. It is particularly important when incorporating satd. hydrocarbons, which are common motifs in petrochems. and biol. relevant mols. However, cross-coupling methods that involve alkyl electrophiles result in catalytic bond formation only at specific and previously functionalized sites. Here we describe a catalytic method that is capable of promoting carboxylation reactions at remote and unfunctionalized aliph. sites with carbon dioxide at atm. pressure. The reaction occurs via selective migration of the catalyst along the hydrocarbon side-chain with excellent regio- and chemoselectivity, representing a remarkable reactivity relay when compared with classical cross-coupling reactions. Our results demonstrate that site-selectivity can be switched and controlled, enabling the functionalization of less-reactive positions in the presence of a priori more reactive ones. Furthermore, we show that raw materials obtained in bulk from petroleum processing, such as alkanes and unrefined mixts. of olefins, can be used as substrates. This offers an opportunity to integrate a catalytic platform en route to valuable fatty acids by transforming petroleum-derived feedstocks directly.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVOrsrY%253D&md5=f4ee3908fea3b62fe46e6ab8fe274ab9
    25. 25
      Gaydou, M.; Moragas, T.; Juliá-Hernández, F.; Martin, R. Site-Selective Catalytic Carboxylation of Unsaturated Hydrocarbons with CO2 and Water. J. Am. Chem. Soc. 2017, 139, 12161– 12164,  DOI: 10.1021/jacs.7b07637
      25
      Site-Selective Catalytic Carboxylation of Unsaturated Hydrocarbons with CO2 and Water
      Gaydou, Morgane; Moragas, Toni; Julia-Hernandez, Francisco; Martin, Ruben
      Journal of the American Chemical Society (2017), 139 (35), 12161-12164CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A catalytic protocol that reliably predicts and controls the site-selective incorporation of CO2 to a wide range of unsatd. hydrocarbons utilizing water as formal hydride source is described. This platform unlocks an opportunity to catalytically repurpose three abundant, orthogonal feedstocks under mild conditions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlCgu7bP&md5=97655bfb25a0ddc35f6672fafa7ce7c8
    26. 26
      Tortajada, A.; Menezes Correia, J. T.; Serrano, E.; Monleón, A.; Tampieri, A.; Day, C. S.; Juliá-Hernández, F.; Martin, R. Ligand-Controlled Regiodivergent Catalytic Amidation of Unactivated Secondary Alkyl Bromides. ACS Catal. 2021, 11, 10223– 10227,  DOI: 10.1021/acscatal.1c02913
      26
      Ligand-Controlled Regiodivergent Catalytic Amidation of Unactivated Secondary Alkyl Bromides
      Tortajada, Andreu; Menezes Correia, Jose Tiago; Serrano, Eloisa; Monleon, Alicia; Tampieri, Alberto; Day, Craig S.; Julia-Hernandez, Francisco; Martin, Ruben
      ACS Catalysis (2021), 11 (16), 10223-10227CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      A regiodivergent Ni-catalyzed amidation of unactivated secondary alkyl bromides is described. The site-selectivity of the amidation event is dictated by subtle differences on the ligand backbone, allowing introduction of the amide function at either the original sp3 carbon-halide bond or at distal sp3 C-H sites within an alkyl side-chain via chain-walking scenarios.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1OlsbrJ&md5=257c66f095abc23fa6421c55c2d7a10a
    27. 27
      Zhang, Y.; He, J.; Song, P.; Wang, Y.; Zhu, S. Ligand-Enabled NiH-Catalyzed Migratory Hydroamination: Chain Walking as a Strategy for Regiodivergent/Regioconvergent Remote sp3 C–H Amination. CCS Chem. 2021, 3, 2259– 2268,  DOI: 10.31635/ccschem.020.202000490
      27
      Ligand-enabled NiH-catalyzed migratory hydroamination: chain walking as a strategy for regiodivergent/regioconvergent remote sp3C-H amination
      Zhang, Yulong; He, Jun; Song, Peihong; Wang, You; Zhu, Shaolin
      CCS Chemistry (2021), 3 (9), 2259-2268CODEN: CCCHB2 ISSN:. (Chinese Chemical Society)
      A nondirected, remote sp3C-H amination process with predictable and switchable regioselectivity was reported. This reaction used a nickel hydride-catalyzed remote relay hydroamination strategy in which an aliph. amino group was installed at a position far from the original C=C bond present in all unsatd. hydrocarbon substrates. Depending on the choice of ligand, either terminal or benzylic functionalization products were obtained with excellent levels of regioselectivity. It was shown that an alkyl bromide could also be used as an olefin precursor when using Mn0 as a reductant. The utility of this transformation was further highlighted by the regioconvergent migratory hydroamination of isomeric mixts. of olefins forming single isomers of value-added benzylic or linear amines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisFantbbL&md5=f507228aab2dd87bdf79bc349b65b89d
    28. 28
      Zhang, Y.; Xu, X.; Zhu, S. Nickel-Catalysed Selective Migratory Hydrothiolation of Alkenes and Alkynes with Thiols. Nat. Commun. 2019, 10, 1752,  DOI: 10.1038/s41467-019-09783-w
      28
      Nickel-catalysed selective migratory hydrothiolation of alkenes and alkynes with thiols
      Zhang Yulong; Xu Xianfeng; Zhu Shaolin; Zhu Shaolin
      Nature communications (2019), 10 (1), 1752 ISSN:.
      Direct (utilize easily available and abundant precursors) and selective (both chemo- and regio-) aliphatic C-H functionalization is an attractive mean with which to streamline chemical synthesis. With many possible sites of reaction, traditional methods often need an adjacent polar directing group nearby to achieve high regio- and chemoselectivity and are often restricted to a single site of functionalization. Here we report a remote aliphatic C-H thiolation process with predictable and switchable regioselectivity through NiH-catalysed migratory hydrothiolation of two feedstock chemicals (alkenes/alkynes and thiols). This mild reaction avoids the preparation of electrophilic thiolation reagents and is highly selective to thiols over other nucleophilic groups, such as alcohols, acids, amines, and amides. Mechanistic studies show that the reaction occurs through the formation of an RS-Bpin intermediate, and THF as the solvent plays an important role in the regeneration of NiH species.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FlslKksg%253D%253D&md5=33f6a3b20a2f248b87e6cef1dd42d7b7
    29. 29
      Gao, J.; Jiao, M.; Ni, J.; Yu, R.; Cheng, G.-J.; Fang, X. Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric-Ligand-Controlled Regiodivergence. Angew. Chem., Int. Ed. 2021, 60, 1883– 1890,  DOI: 10.1002/anie.202011231
      29
      Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric-Ligand-Controlled Regiodivergence
      Gao, Jihui; Jiao, Mingdong; Ni, Jie; Yu, Rongrong; Cheng, Gui-Juan; Fang, Xianjie
      Angewandte Chemie, International Edition (2021), 60 (4), 1883-1890CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A regiodivergent nickel-catalyzed hydrocyanation of a broad range of internal alkenes involving a chain-walking process is reported. When appropriate diastereomeric biaryl diphosphite ligands are applied, the same starting materials can be converted to either linear or branched nitriles with good yields and high regioselectivities. DFT calcns. suggested that the catalyst architecture dets. the regioselectivity by modulating electronic and steric interactions. In addn., moderate enantioselectivities were obsd. when branched nitriles were produced.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisVGltb7E&md5=2e5cb32855000617c2fbee46f1ea1d3e
    30. 30
      Li, Y.; Wei, H.; Yin, G. Nickel-Catalyzed Migratory Benzylboration of Allylbenzenes. Tetrahedron Lett. 2022, 100, 153889  DOI: 10.1016/j.tetlet.2022.153889
      30
      Nickel-Catalyzed Migratory Benzylboration of Allylbenzenes
      Li, Yangyang; Wei, Hong; Yin, Guoyin
      Tetrahedron Letters (2022), 100 (), 153889CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      While 1,2-regioselective difunctionalizations of alkenes are well developed, their migratory difunctionalization of alkenes remains comparatively under-researched. Herein, we report a nickel-catalyzed, divergent, solvent-controlled 1,1- or 1,3-regioselective benzylboration of allylbenzenes, that provides efficient access to primary and secondary alkyl boronates. The mild reaction conditions of these transformations allow good regioselectivity and wide functional group tolerance.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsVCltLnE&md5=06366da1b92a728ee889a32404228be0
    31. 31
      Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt Co-Catalysis for Cross-Electrophile Coupling: Diarylmethanes from Benzyl Mesylates and Aryl Halides. Chem. Sci. 2015, 6, 1115– 1119,  DOI: 10.1039/C4SC03106G
      31
      Cobalt co-catalysis for cross-electrophile coupling: diarylmethanes from benzyl mesylates and aryl halides
      Ackerman, Laura K. G.; Anka-Lufford, Lukiana L.; Naodovic, Marina; Weix, Daniel J.
      Chemical Science (2015), 6 (2), 1115-1119CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      In this study, a new co-catalyst, cobalt phthalocyanine (Co(Pc)), was introduced and demonstrated to be effective for coupling substrates not prone to homolysis. This was because Co(Pc) reacted with electrophiles by an SN2 mechanism instead of by the electron-transfer or halogen abstraction mechanisms previously explored. Studies demonstrating the orthogonal reactivity of (bpy)Ni and Co(Pc), applying this selectivity to the coupling of benzyl mesylates with aryl halides, and the adaptation of these conditions to the less reactive benzyl phosphate ester and an enantioconvergent reaction were presented.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyqtb7F&md5=cbd3652857e0c46b6ee9db7ddc6988ec
    32. 32
      Hofstra, J. L.; Cherney, A. H.; Ordner, C. M.; Reisman, S. E. Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 139– 142,  DOI: 10.1021/jacs.7b11707
      32
      Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling
      Hofstra, Julie L.; Cherney, Alan H.; Ordner, Ciara M.; Reisman, Sarah E.
      Journal of the American Chemical Society (2018), 140 (1), 139-142CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An asym. Ni-catalyzed reductive cross-coupling has been developed to prep. enantioenriched allylic silanes. This enantioselective reductive alkenylation proceeds under mild conditions and exhibits good functional group tolerance. The chiral allylic silanes prepd. here undergo a variety of stereospecific transformations, including intramol. Hosomi-Sakurai reactions, to set vicinal stereogenic centers with excellent transfer of chirality.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWhsr3N&md5=d06247e88d916085793efaf7f21a0aaf
    33. 33
      Kong, W.; Bao, Y.; Lu, L.; Han, Z.; Zhong, Y.; Zhang, R.; Li, Y.; Yin, G. Base-Modulated 1,3-Regio- and Stereoselective Carboboration of Cyclohexenes. Angew. Chem., Int. Ed. 2023, 62, e202308041  DOI: 10.1002/anie.202308041
      33
      Base-Modulated 1,3-Regio- and Stereoselective Carboboration of Cyclohexenes
      Kong, Weiyu; Bao, Yang; Lu, Liguo; Han, Zhipeng; Zhong, Yifan; Zhang, Ran; Li, Yuqiang; Yin, Guoyin
      Angewandte Chemie, International Edition (2023), 62 (35), e202308041CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      While chain-walking stimulates wide interest in both polymn. and org. synthesis, site- and stereoselective control of chain-walking on rings is still a challenging task in the realm of organometallic catalysis. Inspired by a controllable chain-walking on cyclohexane rings in olefin polymn., we have developed a set of chain-walking carboborations of cyclohexenes based on nickel catalysis. Different from the 1,4-trans-selectivity disclosed in polymer science, a high level of 1,3-regio- and cis-stereoselectivity is obtained in our reactions. Mechanistically, we discovery that the base affects the redn. ability of B2pin2 and different bases lead to different catalytic cycles and different regioselective products (1,2- Vs 1,3-addn.). This study provides a concise and modular method for the synthesis of 1,3-disubstituted cyclohexylboron compds. The incorporation of a readily modifiable boronate group greatly enhances the value of this method, the synthetic potential of which was highlighted by the synthesis of a series of high-valued com. chems. and pharmaceutically interesting mols.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhsFahsr3L&md5=5405825e9ddf5d413228664d59d2a160
    34. 34
      Sun, C.; Ding, C.; Yu, Y.; Li, Y.; Yin, G. Ligand-Modulated Regiodivergent Alkenylboration of Allylarenes: Reaction Development and Mechanistic Study. Fundamental Research 2023,  DOI: 10.1016/j.fmre.2023.03.016
      There is no corresponding record for this reference.
    35. 35
      Wang, W.; Yan, X.; Ye, F.; Zheng, S.; Huang, G.; Yuan, W. Nickel/Photoredox Dual-Catalyzed Regiodivergent Aminoalkylation of Unactivated Alkyl Halides. J. Am. Chem. Soc. 2023, 145, 23385– 23394,  DOI: 10.1021/jacs.3c09705
      35
      Nickel/photoredox Dual-Catalyzed Regiodivergent Aminoalkylation of Unactivated Alkyl Halides
      Wang, Wenlong; Yan, Xueyuan; Ye, Fu; Zheng, Songlin; Huang, Genping; Yuan, Weiming
      Journal of the American Chemical Society (2023), 145 (42), 23385-23394CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A mild and regiodivergent aminoalkylation of unactivated alkyl halides is disclosed via dual photoredox/nickel catalysis. Bipyridyl type ligands without ortho-substituent control the site-selective coupling at original position, while ortho-disubstituted ligands tune the site-selectivity at remote, unprefunctionalized position. Mechanistic studies combined with DFT calcns. give insight into the mechanism and the origins of the ligand-controlled regioselectivity. Notably, this redox-neutral, regiodivergent alkyl-alkyl coupling features mild conditions, broad substrate scope for both alkyl coupling partners, excellent site-selectivity, and offers a straightforward way for α-alkylation of tertiary amines to synthesize structurally diverse alkylamines and value-added amino acid derivs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXitV2qu7bJ&md5=69950065baf4edc6606268f791319a31
    36. 36
      Sun, S-Z.; Börjesson, M.; Martin-Montero, R.; Martin, R. Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins. J. Am. Chem. Soc. 2018, 140, 12765– 12769,  DOI: 10.1021/jacs.8b09425
      36
      Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins
      Sun, Shang-Zheng; Borjesson, Marino; Martin-Montero, Raul; Martin, Ruben
      Journal of the American Chemical Society (2018), 140 (40), 12765-12769CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A mild, chemo- and site-selective catalytic protocol that allows for incorporating an alkylboron fragment into unactivated olefins is described. The use of internal olefins enables C-C bond-formation at remote sp3 C-H sites, constituting a complementary and conceptually different approach to existing borylation techniques that are currently available at sp3 centers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKqt7fN&md5=61a75b25fcd19b58f08554391df37c27
    37. 37
      Qian, D.; Hu, X. Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines. Angew. Chem., Int. Ed. 2019, 58, 18519– 18523,  DOI: 10.1002/anie.201912629
      37
      Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines
      Qian, Deyun; Hu, Xile
      Angewandte Chemie, International Edition (2019), 58 (51), 18519-18523CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Two series of C-alkylated pyrrolidines I [R = Boc, Cbz; R1 = i-Pr, cyclopentyl, indol-1-yl, etc.] and II [R2 = CO2Ph, Boc, Cbz; R3 = cyclohexyl, (CH2)3Ph, 2-thienyl, etc.] were synthesized via ligand controlled nickel-catalyzed regiodivergent hydroalkylation of 3-pyrrolines with alkyl/aryl halides. This method demonstrated broad scope and high functional-group tolerance and could be applied in late-stage functionalizations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGqtrjJ&md5=b0d3de22f6800e5b425e895d666c1dba
    38. 38
      Du, B.; Ouyang, Y.; Chen, Q.; Yu, W.-Y. Thioether-Directed NiH-Catalyzed Remote γ-C(sp3)–H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-Ones. J. Am. Chem. Soc. 2021, 143, 14962– 14968,  DOI: 10.1021/jacs.1c05834
      38
      Thioether-Directed NiH-Catalyzed Remote γ-C(sp3)-H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-ones
      Du, Bingnan; Ouyang, Yuxin; Chen, Qishu; Yu, Wing-Yiu
      Journal of the American Chemical Society (2021), 143 (37), 14962-14968CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A NiH-catalyzed thioether-directed cyclometalation strategy was developed to enable remote methylene C-H bond amidation of unactivated alkenes. Due to the preference for five-membered nickelacycle formation, the chain-walking isomerization initiated by the NiH insertion to an alkene could be terminated at the γ-methylene site remote from the alkene moiety. By employing 2,9-dibutyl-1,10-phenanthroline as the ligand and dioxazolones as the reagent, the amidation occurs at the γ-C(sp3)-H bonds to afford the amide products in up to 90% yield (<40 examples) with remarkable regioselectivity (up to 24:1 rr).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFykt73M&md5=658e27ff1daa2f9f0cb01c40529ea3be
    39. 39
      Chen, X.; Rao, W.; Yang, T.; Koh, M. J. Alkyl halides as both hydride and alkyl sources in catalytic regioselective reductive olefin hydroalkylation. Nat. Commun. 2020, 11, 5857,  DOI: 10.1038/s41467-020-19717-6
      39
      Alkyl halides as both hydride and alkyl sources in catalytic regioselective reductive olefin hydroalkylation
      Chen, Xianxiao; Rao, Weidong; Yang, Tao; Koh, Ming Joo
      Nature Communications (2020), 11 (1), 5857CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      An Ni-based catalyst in conjunction with a stoichiometric reducing agent promotes Markovnikov-selective hydroalkylation of unactivated alkenes I (R = H, Me, Et, Ph, Bn) tethered to a recyclable 8-aminoquinaldine directing auxiliary. These mild reductive processes employ readily available primary and secondary haloalkanes R1X (R1 = Et, n-Bu, cyclopentyl, etc.; X = Br, I) as both the hydride and alkyl donor. Reactions of alkenyl amides I with ≥ five-carbon chain length regioselectively afforded β-alkylated products II through remote hydroalkylation, underscoring the fidelity of the catalytic process and the directing group's capability in stabilizing five-membered nickelacycle intermediates. The operationally simple protocol exhibits exceptional functional group tolerance and is amenable to the synthesis of bioactive mols. as well as regioconvergent transformations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitl2ns7jK&md5=c500c83b64bd56a4391b1e53049559be
    40. 40
      Lee, C.; Seo, H.; Jeon, J.; Hong, S. γ-Selective C(sp3)–H amination via controlled migratory hydroamination. Nat. Commun. 2021, 12, 5657,  DOI: 10.1038/s41467-021-25696-z
      40
      γ-Selective C(sp3)-H amination via controlled migratory hydroamination
      Lee, Changseok; Seo, Huiyeong; Jeon, Jinwon; Hong, Sungwoo
      Nature Communications (2021), 12 (1), 5657CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: Remote functionalization of alkenes via chain walking has generally been limited to C(sp3)-H bonds α and β to polar-functional units, while γ-C(sp3)-H functionalization through controlled alkene transposition is a longstanding challenge. Herein, authors describe NiH-catalyzed migratory formal hydroamination of alkenyl amides achieved via chelation-assisted control, whereby various amino groups are installed at the γ-position of aliph. chains. By tuning olefin isomerization and migratory hydroamination through ligand and directing group optimization, γ-selective amination can be achieved via stabilization of a 6-membered nickellacycle by an 8-aminoquinoline directing group and subsequent interception by an aminating reagent. A range of amines can be installed at the γ-C(sp3)-H bond of unactivated alkenes with varying alkyl chain lengths, enabling late-stage access to value-added γ-aminated products. Moreover, by employing picolinamide-coupled alkene substrates, this approach is further extended to δ-selective amination. The chain-walking mechanism and pathway selectivity are investigated by exptl. and computational methods.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitFWisr%252FF&md5=a694fce5976803104fdf1966eb6f68a5
    41. 41
      Wang, X.-X.; Xu, Y.-T.; Zhang, Z.-L.; Lu, X.; Fu, Y. NiH-Catalysed Proximal-Selective Hydroalkylation of Unactivated Alkenes and the Ligand Effects on Regioselectivity. Nat. Commun. 2022, 13, 1890,  DOI: 10.1038/s41467-022-29554-4
      41
      NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes and the ligand effects on regioselectivity
      Wang, Xiao-Xu; Xu, Yuan-Tai; Zhang, Zhi-Lin; Lu, Xi; Fu, Yao
      Nature Communications (2022), 13 (1), 1890CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
      Herein, a NiH-catalyzed proximal-selective hydroalkylation of unactivated alkenes e.g., N-(quinoline-8-yl)pent-4-enamide to access β- or γ-branched alkyl carboxylic acids and β-, γ- or δ-branched alkyl amines e.g., 4-methyl-N-(quinolin-8-yl)octanamide was reported. A broad range of alkyl iodides and bromides e.g., 1-iodobutane with different functional groups can be installed with excellent regiocontrol and availability for site-selective late-stage functionalization of biorelevant mols. Under modified reaction conditions with NiCl2(PPh3)2 as the catalyst, migratory hydroalkylation takes place to provide β- (rather than γ-) branched products. The keys to success are the use of aminoquinoline and picolinamide as suitable directing groups and combined exptl. and computational studies of ligand effects on the regioselectivity and detailed reaction mechanisms.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpsV2gsrk%253D&md5=8c341a912b8afc251599bbb21762a42f
    42. 42
      Wang, J.-W.; Liu, D.-G.; Chang, Z.; Li, Z.; Fu, Y.; Lu, X. Nickel-Catalyzed Switchable Site-Selective Alkene Hydroalkylation by Temperature Regulation. Angew. Chem., Int. Ed. 2022, 61, e202205537  DOI: 10.1002/anie.202205537
      42
      Nickel-Catalyzed Switchable Site-Selective Alkene Hydroalkylation by Temperature Regulation
      Wang, Jia-Wang; Liu, De-Guang; Chang, Zhe; Li, Zhen; Fu, Yao; Lu, Xi
      Angewandte Chemie, International Edition (2022), 61 (31), e202205537CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A nickel-catalyzed switchable site-selective alkene hydroalkylation was reported. The selection of reaction temps. led to protocols that provide regiodivergent hydroalkylated products starting from a single alkene substrate. This protocol allowed the convenient synthesis of α- and β-branched protected amines, both of which are important to the fields of pharmaceutical chem. and biochem. In addn., enantioenriched β-branched alkylamines can be accessed in a catalytic asym. variant. Preliminary mechanistic studies indicate that the formation of a more stable nickelacycle provides the driving force of migration. The thermodn. and kinetic properties of different redn. elimination intermediates are responsible for the switchable site-selectivity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsFCisbbL&md5=c74f49806159147d8f894c1823b48f18
    43. 43
      Zhao, L.; Zhu, Y.; Liu, M.; Xie, L.; Liang, J.; Shi, H.; Meng, X.; Chen, Z.; Han, J.; Wang, C. Ligand-Controlled NiH-Catalyzed Regiodivergent Chain-Walking Hydroalkylation of Alkenes. Angew. Chem., Int. Ed. 2022, 61, e202204716  DOI: 10.1002/anie.202204716
      43
      Ligand-Controlled NiH-Catalyzed Regiodivergent Chain-Walking Hydroalkylation of Alkenes
      Zhao, Lei; Zhu, Yuqin; Liu, Mengyuan; Xie, Leipeng; Liang, Jimin; Shi, Haoran; Meng, Xiao; Chen, Zhengyang; Han, Jian; Wang, Chao
      Angewandte Chemie, International Edition (2022), 61 (30), e202204716CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A NiH-catalyzed migratory hydroalkylation of alkenyl amines with predictable and switchable regioselectivity is reported. By utilizing a ligand-controlled, directing group-assisted strategy, various alkyl units are site-selectively installed at inert sp3 C-H sites far away from the original C=C bonds. A range of structurally diverse α- and β-branched protected amines are conveniently synthesized via stabilization of 5- and 6-membered nickelacycles resp. This method exhibits broad scope and high functional group tolerance, and can be applied to late-stage modification of medicinally relevant mols.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvFWgtLfP&md5=b79b9c614e30ff4eb8516b26ad493fab
    44. 44
      Yang, P.-F.; Shu, W. Orthogonal Access to α-/β-Branched/Linear Aliphatic Amines by Catalyst-Tuned Regiodivergent Hydroalkylations. Angew. Chem., Int. Ed. 2022, 61, e202208018  DOI: 10.1002/anie.202208018
      44
      Orthogonal Access to α-/β-Branched/Linear Aliphatic Amines by Catalyst-Tuned Regiodivergent Hydroalkylations
      Yang, Peng-Fei; Shu, Wei
      Angewandte Chemie, International Edition (2022), 61 (34), e202208018CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Herein, a catalyst-controlled synthesis of α-branched e.g., N-(1-phenylpentan-3-yl)benzamide, β-branched e.g., N-(2-methyl-4-phenylbutyl)benzamide and linear aliph. amines e.g., N-(5-phenylpentyl)benzamide from Ni/Co-catalyzed regio- and site-selective hydroalkylations of alkenyl amines e.g., N-(prop-2-en-1-yl)benzamide with alkyl halides RX (R = butan-2-yl, Bn, 2-phenylethyl, 2-(1,3-dioxolan-2-yl)ethyl, etc.; X = I, Br) is developed. This catalytic protocol features the reliable prediction and control of the coupling position of alkylation to provide orthogonal access to α-branched, β-branched and linear alkyl amines from identical starting materials. This platform unlocks orthogonal reactivity and selectivity of nickel hydride and cobalt hydride chem. to catalytically repurpose three types of alkyl amines under mild conditions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvVCms7jI&md5=da36f594ce297dd1a495d636c3c57552
    45. 45
      Zhao, W-T.; Meng, H.; Lin, J-N.; Shu, W. Ligand-Controlled Nickel-Catalyzed Regiodivergent Cross-Electrophile Alkyl-Alkyl Couplings of Alkyl Halides. Angew. Chem., Int. Ed. 2023, 62, e202215779  DOI: 10.1002/anie.202215779
      45
      Ligand-Controlled Nickel-Catalyzed Regiodivergent Cross-Electrophile Alkyl-Alkyl Couplings of Alkyl Halides
      Zhao, Wen-Tao; Meng, Huan; Lin, Jia-Ni; Shu, Wei
      Angewandte Chemie, International Edition (2023), 62 (7), e202215779CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Functionalizing specific positions on a satd. alkyl mol. is a key challenge in synthetic chem. Herein, a ligand-controlled regiodivergent alkylations of alkyl bromides at different positions by Ni-catalyzed alkyl-alkyl cross-electrophile coupling with the second alkyl bromides has been developed. The reaction undergoes site-selective isomerization on one alkyl bromides in a controlled manner, providing switchable access to diverse alkylated structures at different sites of alkyl bromides. The reaction occurs at three similar positions with excellent chemo- and regioselectivity, representing a remarkable ligand tuned reactivity between alkyl-alkyl cross-coupling and nickel migration along the hydrocarbon side chain. This reaction offers a catalytic platform to diverse satd. architectures by alkyl-alkyl bond-formation from identical starting materials.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhtFGis7o%253D&md5=0710389231b25bd3e95c2205ae6d9d1d
    46. 46
      Rodrigalvarez, J.; Wang, H.; Martin, R. Native Amides as Enabling Vehicles for Forging sp3-sp3 Architectures via Interrupted Deaminative Ni-Catalyzed Chain-Walking. J. Am. Chem. Soc. 2023, 145, 3869– 3874,  DOI: 10.1021/jacs.2c12915
      46
      Native Amides as Enabling Vehicles for Forging sp3-sp3 Architectures via Interrupted Deaminative Ni-Catalyzed Chain-Walking
      Rodrigalvarez, Jesus; Wang, Hao; Martin, Ruben
      Journal of the American Chemical Society (2023), 145 (7), 3869-3874CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Herein, authors disclose an interrupted deaminative Ni-catalyzed chain-walking strategy that forges sp3-sp3 architectures at remote, yet previously unfunctionalized, methylene sp3 C-H sites enabled by the presence of native amides. This protocol is characterized by its mild conditions and wide scope, including challenging substrate combinations. Site-selectivity can be dictated by a judicious choice of the ligand, thus offering an opportunity to enable sp3-sp3 bond formations that are otherwise inaccessible in conventional chain-walking events.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXislemtrw%253D&md5=ef39435bc0c7ad119e5852beb49d4a20
    47. 47
      Xie, L.; Liang, J.; Bai, H.; Liu, X.; Meng, X.; Xu, Y-Q.; Cao, Z-Y.; Wang, C. Ligand-Controlled NiH–Catalyzed Regiodivergent and Enantioselective Hydroamination of Alkenyl Amides. ACS Catal. 2023, 13, 10041– 10047,  DOI: 10.1021/acscatal.3c01845
      47
      Ligand-Controlled NiH-Catalyzed Regiodivergent and Enantioselective Hydroamination of Alkenyl Amides
      Xie, Leipeng; Liang, Jimin; Bai, Haohao; Liu, Xuanyu; Meng, Xiao; Xu, Yuan-Qing; Cao, Zhong-Yan; Wang, Chao
      ACS Catalysis (2023), 13 (15), 10041-10047CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Herein, a ligand-controlled, directing-group-assisted strategy to promote NiH-catalyzed site-selective (α, β, or γ) hydroamination of unactivated alkenes with weakly coordinating amide groups was reported. The key to success lies in the employment of proper yet com. available bidentate nitrogen-contg. ligands, which enabled delivery of 1,1-, 1,2-, and 1,3-diamines with good-to-excellent regioselectivity starting from the same substrates. A broad range of O-benzoylhydroxylamine electrophiles with different functional groups can be installed via Ni migration or nonmigration. Moreover, these predicable and positionally selective protocols provided a method for the enantioselective synthesis of highly valued 1,2-diamines (via remote aliph. C-H amination) and 1,3-diamines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhsVymsrzM&md5=fe3ff60d584fc8ffb1dc36a367b748a5