SEARCH

SEARCH BY CITATION

Keywords:

  • Homogeneous catalysis;
  • Nickel;
  • C–C coupling;
  • C–H functionali­zation;
  • Arylation;
  • Biaryls

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Nickel catalysis for biaryl coupling reactions has received significant attention as a less expensive and less toxic alternative to “standard” palladium catalysis. Here we describe recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications. In particular we focus on nickel-catalyzed coupling reactions in which “unreactive” bonds such as C–H, C–O, and C–C bonds are converted into biaryl moieties.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Nickel-catalyzed cross-coupling reactions have recently been receiving significant attention from the synthetic community as a way to construct carbon–carbon bonds or carbon–heteroatom bonds, because nickel catalysts are less expensive and less toxic than palladium catalysts.1 An epoch-making discovery by the groups of Kumada, Tamao, and Corriu opened up the field of modern cross-coupling.2 In 1972, they independently found that nickel complexes or salts can catalyze cross-coupling of Grignard reagents and aryl halides (C–M/C–X coupling; M = metal, X = halogen). On the basis of this discovery, cross-coupling methodology for organometallic reagents and organohalides in the presence of various transition metal catalysts has been developed.3 So far, however, palladium still reigns as the most widely used transition metal for cross-coupling reactions, with nickel regarded as a “minor” metal.

Nickel and palladium, though, share common chemical features. Both metals, for example, belong to the d10 transition metal group, and can have oxidation numbers of 0 and +2 (in the case of nickel, oxidation numbers of +1 and +3 are also known). These features indicate that they should be amenable to general cross-coupling reactions, because these reactions proceed through sequences of oxidative addition (oxidation change from 0 to +2), transmetalation, and reductive elimination (oxidation change from +2 to 0). Nickel, however, is more nucleophilic and smaller in atomic radius than palladium, so “unreactive” bonds such as C–H, C–O, and even C–C bonds can often undergo oxidative addition to nickel. Furthermore, as an alternative to the use of organometallic reagents (C–M bonds) or organohalides (C–X bonds) as cross-coupling partners, the use of more convenient partners such as esters (C–C bonds) in nickel-catalyzed cross-coupling has recently been attracting much attention from the synthetic chemistry community.

Here we describe recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications. In particular we focus on nickel-catalyzed coupling reactions in which “unreactive” bonds such as C–H, C–O, and C–C bonds are converted into biaryl moieties.

Ar–M/Ar–O Coupling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Cross-coupling reactions using metalloarenes as nucleophiles and phenol derivatives as electrophiles (Ar–M/Ar–O coupling; Ar = arenes and heteroarenes) have been reported in many instances. Because arenes containing C–O bonds (such as phenols and naphthols) are readily available and less expensive than their aryl halide counterparts, nickel-catalyzed Ar–M/Ar–O couplings have been attracting interest. Although aryl triflates (Ar–OTf) are generally inferior to aryl halides (Ar–X) in terms of reactivity, they were first found to be useful as coupling partners in transition-metal-catalyzed reactions because they have relatively “reactive” C–O bonds.4 Later, biaryl couplings between metalloarenes and aryl sulfonates such as aryl tosylates (Ar–OTs)5 and aryl mesylates (Ar–OMs)6 were reported. Through extensive efforts, nickel-catalyzed cross-coupling reactions involving unconventional electrophilic coupling partners such as aryl carbonates and even aryl ethers have been made possible.

In 1979, Wenkert and co-workers reported nickel-catalyzed cross-coupling reactions involving Grignard reagents and aryl ethers rather than aryl halides (Ar–M/Ar–O coupling).7 This pioneering work indicated that oxidative addition of C–O bonds to nickel(0) species can occur readily. However, this 1979 discovery was not followed by others until several decades later, when nickel-catalyzed cross-coupling reactions began to attract renewed attention.

In 2004, Dankwardt developed a Ni/PCy3 (PCy3 = tricyclohexylphosphane) catalytic system for cross-coupling between aryl Grignard reagents and aryl methyl ethers.8 Several chemists later reported transformations of aromatic C–O bonds with the aid of the robust Ni/PCy3 catalyst. In 2008, for example, Chatani and co-workers demonstrated nickel-catalyzed cross-couplings between aryl methyl ethers and aryl boronates.9 Simultaneously, the groups of Garg and Shi also discovered similar types of coupling reactions.10 Subsequently, aryl carbamates,11 carbonates,11b,12 sulfamates,11c,13 and even phenolate salts14 were found to react with arylmetal reagents under similar conditions (Scheme 1).

thumbnail image

Scheme 1. Recently discovered modes of nickel-catalyzed cross-coupling between metalloarenes and aryl C–O electrophiles.

Download figure to PowerPoint

Aryl C–O bonds are stable under the general reaction conditions for cross-coupling between metalloarenes and aryl halides (Ar–M/Ar–X coupling), so orthogonal arylation strategies can lead to multiply arylated compounds (Scheme 2 and Schemes 3 and 4, below). Garg's group, for example, demonstrated the utility of nickel-catalyzed cross-coupling (Ar–B/Ar–O coupling) when combined with palladium-catalyzed Suzuki–Miyaura cross-coupling (Scheme 2).10a Treatment of 4-bromonaphthalen-1-yl pivalate (1) with indole-3-boronate 2 in the presence of a palladium catalyst afforded the corresponding coupling product 3 in 90 % yield without the loss of the pivalate group. Subsequently, cross-coupling of 3 with phenylboronic acid under nickel catalysis conditions was performed to give triaryl product 4 in 88 % yield.

thumbnail image

Scheme 2. Orthogonal arylation of 4-bromonaphthalen-1-yl pivalate (1).

Download figure to PowerPoint

Garg also achieved the concise synthesis of flurprofen (9), a well-known non-steroidal anti-inflammatory drug (NSAID), through nickel-catalyzed cross-coupling (Scheme 3).11b,11f Aryl iodide 6, readily prepared from arylboronic acid 5 by Ritter fluorination15 and para-selective iodination (48 % over two steps), was coupled with methyl 2-chloropropanoate in the presence of a NiBr2(bipy) (bipy = 2,2′-bipyridyl) catalyst and manganese metal to give sulfamate 7 in 70 % yield. Treatment of 7 with phenylboronic acid in the presence of catalytic NiCl2(PCy3)2, followed by hydrolysis of methyl ester 8, completed the synthesis of flurprofen (9) in 84 % yield over two steps. Although two types of nickel-catalyzed C–C bond formation are used in this synthesis, the sulfamate group did not disturb the nickel-catalyzed α-arylation step, but did react with phenylboronic acid when desired.

thumbnail image

Scheme 3. Concise synthesis of flurprofen (9).

Download figure to PowerPoint

Shi's group demonstrated the synthetic utility of their own nickel-catalyzed Ar–B/Ar–O coupling methodology in a triaryl synthesis (Scheme 4).10b Treatment of aryl pivalate 10 with (p-methoxyphenyl)boroxin in the presence of catalytic NiCl2(PCy3)2 furnished biphenyl 11 in 75 % yield. Baeyer–Villiger oxidation of 11, followed by hydrolysis of the acetyl group and pivalation of the resulting hydroxy group, afforded aryl pivalate 12 in 62 % yield over three steps. The synthesis of triaryl 13 was completed by Ar–B/Ar–O cross-coupling of 12 with p-tolylboroxin under nickel catalysis conditions (64 % yield).

thumbnail image

Scheme 4. Triaryl synthesis through nickel catalysis.

Download figure to PowerPoint

Direct C–H Coupling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Ar–H/Ar–X Coupling

Transition-metal-catalyzed direct C–H bond functionalization has been attracting increased attention in the context of streamlined chemical synthesis because carbon–carbon or carbon–heteroatom bonds can be derived from ubiquitous C–H bonds without the need for use of stoichiometric metal reagents.16,17 In 2009, Itami's and Miura's groups independently reported the first nickel-catalyzed C–H arylations of azoles with aryl halides (see Schemes 5, 6 and 7, below).18

thumbnail image

Scheme 5. Itami's nickel-catalyzed direct arylation of azoles with aryl halides and triflates.

Download figure to PowerPoint

Itami's group reported that 1,3-azoles can be cross-coupled with aryl iodides or bromides in the presence of Ni(OAc)2/bipy catalyst and stoichiometric LiOtBu in 1,4-dioxane at 85 °C (see Schemes 5 and 6).18a Benzothiazole (14, 1.5 equiv.), for example, can be coupled with iodobenzene or bromobenzene under nickel catalysis conditions [Ni(OAc)2/bipy] to afford 2-phenylbenzothiazole (15) in 80 % (X = I) and 62 % (X = Br) yields, respectively. On the other hand, 1,1′-bis(diphenylphosphanyl)ferrocene (dppf) is the most suitable ligand for the reactions using chlorobenzene and phenyl triflate, providing 15 in 74 % (X = Cl) and 48 % (X = OTf) yields, respectively (Scheme 5).

A number of structurally diverse 1,3-azoles and aryl halides are reactive under nickel catalysis conditions (Scheme 6). Benzothiazoles, benzoxazoles, benzimidazoles, oxazoles, and thiazoles can be arylated. Aryl halides substituted in their ortho-, meta-, and para-positions are viable substrates, as are both electron-rich and electron-deficient aryl halides. Additionally, heteroaryl halides such as thiophenes and pyridines can also be used.

thumbnail image

Scheme 6. Substrate scope of nickel-catalyzed C–H/C–X coupling.

Download figure to PowerPoint

At the same time, Miura also reported similar conditions for direct coupling between 1,3-(benzo)azoles and aryl bromides (Scheme 7).18b Various (benzo)azoles can be coupled with aryl bromides with the aid of NiBr2/phen (phen = 1,10-phenanthroline) or NiBr2/18 as the catalyst and LiOtBu as the base in diglyme or o-xylene at 150 °C. ortho-Substituted bromoarenes are particularly suitable coupling partners, giving products such as 16 and 19 in excellent yields. Additionally, when benzoxazole (17) is used as a substrate, the addition of Zn powder is effective in increasing the yield of product, presumably by functioning as a reductant to produce an active Ni0 species.

thumbnail image

Scheme 7. Miura's protocol for nickel-catalyzed heterobiaryl synthesis.

Download figure to PowerPoint

The studies discussed above clearly demonstrated the potential of nickel catalysis to allow rapid access to a range of 2-arylazoles. However, both nickel-catalyzed Ar–H/Ar–X coupling reactions require the use of LiOtBu; otherwise, the reaction does not proceed. In 2011, Itami's group reported a new protocol in which Mg(OtBu)2 (in DMF) is employed as the base (Scheme 8).19 As a result, two useful sets of coupling conditions based on the Ni(OAc)2/bipy catalytic system were established. Whereas the LiOtBu/1,4-dioxane system generally works well for robust substrates, the Mg(OtBu)2/DMF system is in many cases superior for substrates containing base-sensitive functional groups such as nitro and ester moieties. It is of note that Mg(OtBu)2 is milder and also less expensive than LiOtBu.

thumbnail image

Scheme 8. Selected examples of Ar–H/Ar–X coupling in which the Ni(OAc)2/bipy/Mg(OtBu)2/DMF system gives better results than the first-generation Ni(OAc)2/bipy/LiOtBu/1,4-dioxane system. The yields obtained with the first-generation catalytic systems are shown in parentheses.

Download figure to PowerPoint

Although the mechanisms of nickel-catalyzed arylations of azoles with aryl halides are not clear, a number of experiments are consistent with the proposed Ni0/NiII catalytic cycle shown in Scheme 9. The proposed Ni0/NiII redox catalysis consists of: 1) production of Ar–Ni–X (A) through oxidative addition of Ar–X to Ni0, 2) azole nickelation to produce Ar–Ni–Het (B), and 3) reductive elimination, generating heterobiaryl product Het–Ar (C) and Ni0. It is of note that LiOtBu and Mg(OtBu)2 most likely play a critical role in the azole nickelation step and are probably involved both in the product-generating catalytic cycle and in the generation of catalytically active Ni0 species from Ni(OAc)2.

thumbnail image

Scheme 9. Proposed mechanism for nickel-catalyzed heterobiaryl synthesis.

Download figure to PowerPoint

Nickel-catalyzed direct arylation can be applied to the synthesis of biologically active compounds (Scheme 10). With the Ni(OAc)2/bipy system, the rapid synthesis of febuxostat (Uloric®, 22), an inhibitor of xanthine oxidase developed by Teijin Pharma as a new drug for the treatment of gout and hyperuricemia, is possible. Thiazole 20 and iodoarene 21 undergo Ar–H/Ar–X coupling in 1,4-dioxane to furnish the corresponding coupling product. Subsequent treatment with CF3CO2H affords 22 in 62–67 % overall yield. This methodology has also been implemented in the synthesis of tafamidis (Vyndaqel®, 25, effective for the treatment of TTR amyloid polyneuropathy) and texaline (28, natural product with antitubercular activity).

thumbnail image

Scheme 10. Application to the synthesis of biologically active compounds.

Download figure to PowerPoint

Yamakawa and co-workers reported direct couplings of simple arenes and aryl halides in the presence of a nickel catalyst (Scheme 11).20 With Cp2Ni as a catalyst precursor and BEt3 or Ph3P as an additive, direct couplings of benzene, naphthalene, and pyridine (used as solvent) with haloarenes take place in moderate to good yields. Because these reactions produce regioisomers, however, their mechanisms are presumed to be a radical-type pathway.

thumbnail image

Scheme 11. Yamakawa's nickel-catalyzed biaryl coupling method.

Download figure to PowerPoint

Ar–H/Ar–O Coupling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Nickel-catalyzed Ar–H/Ar–X coupling reactions between (hetero)arenes and aryl halides have been reported, but the requirement for the use of aryl halides as aryl electrophiles is still a drawback. Coupling arenes with phenol derivatives (Ar–H/Ar–O coupling) would be more advantageous because numerous phenols and their derivatives are commercially available and inexpensive.

In 2012, Itami's group reported the first Ar–H/Ar–O coupling, with use of Ni(cod)2/dcype [31, 1,2-bis(dicyclohexylphosphanyl)ethane] as the catalyst (Scheme 12).21 In the presence of this catalyst and Cs2CO3 in 1,4-dioxane at 120 °C, benzoxazole (17) can be coupled with naphthalen-2-yl pivalate (29) to produce the coupling product 30 in excellent yield. Notably, the reaction displays dramatic ligand effects; the use of dcype (31) is essential. PCy3 and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr·HCl), which are known to be able to activate aryl C–O bonds, for example, are entirely ineffective in Ar–H/Ar–O coupling. Bipyridine, a standard ligand for Ar–H/Ar–X coupling as mentioned above, is also not effective.

thumbnail image

Scheme 12. Itami's nickel-catalyzed Ar–H/Ar–O coupling.

Download figure to PowerPoint

The Ni(cod)2/dcype catalyst is active for the coupling of other phenol derivatives such as carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates (80–99 % yields, Scheme 13). When naphthalene-1-yl, pyridin-3-yl, and quinolin-6-yl pivalates are used, coupling products are obtained in excellent yields, whereas phenyl derivatives react better when triflates are used instead of pivalates. This protocol is also effective for the direct arylation of oxazoles, benzothiazoles, and thiazoles (Scheme 13).

thumbnail image

Scheme 13. Nickel-catalyzed Ar–H/Ar–O coupling of azoles and phenol derivatives.

Download figure to PowerPoint

Syntheses based on more complex phenol derivatives such as estrone and quinine triflates are also possible with this catalyst (Scheme 14). Coupling between estrone triflate (32) and 5-phenyloxazole (33) proceeds smoothly in the presence of Ni(cod)2/dcype to afford heteroarylated estrone 34 in 52 % yield. The Ar–H/Ar–O coupling between quinine triflate (35) and benzoxazole (17) also occurs, to give the quinine-benzoxazole hybrid molecule 36, albeit with somewhat lower efficiency. Notably, the hydroxy, amino, and olefinic functionalities are tolerated under the coupling conditions.

thumbnail image

Scheme 14. Nickel-catalyzed arylation of complex steroid and alkaloid scaffolds.

Download figure to PowerPoint

Nickel-catalyzed Ar–H/Ar–O coupling thus has the potential to be extremely useful as an inexpensive coupling method for construction of heterobiaryls, despite having limitations in the scope of heteroarenes.

Ar–H/Ar–M Coupling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Nickel-catalyzed oxidative coupling reactions between arenes and metalloarenes (Ar–H/Ar–M; M = B, Si, Mg, Zn) have also been reported recently. In a first report describing Ar–H/Ar–M couplings of arenes, Miura's group disclosed that 1,3-azoles can be arylated at C2 with trimethoxyarylsilanes as the organometallic coupling partners (Scheme 15).22 In the presence of catalytic amounts of NiBr2·diglyme/bipy and stoichiometric amounts of CsF and CuF2, various 1,3-azoles such as benzoxazoles, oxazoles, benzothiazoles, benzimidazoles, and 1,3,4-oxadiazoles cross-couple with arylsilanes to afford 2-arylazoles. Classifying this C–H coupling into a reaction type is difficult, because oxidative C–H arylation with organosilanes is rare even with other transition metal catalysts.23

thumbnail image

Scheme 15. Miura's nickel-catalyzed Ar–H/Ar–Si couplings of azoles and trimethoxyarylsilanes.

Download figure to PowerPoint

A plausible mechanism for the Ar–H/Ar–Si coupling is illustrated in Scheme 16. Initial nickelation of the heteroarene substrate, through the action of basic CsF, could afford the Het–Ni–X intermediate D. Subsequent transmetalation with aryl or alkenyl silicate E (generated in situ with CsF), and an ensuing reductive elimination from intermediate F, could furnish the biaryl product and the Ni0 species. Reoxidation of Ni0 with CuF2 would regenerate the divalent NiX2 to complete the catalytic cycle.

thumbnail image

Scheme 16. A plausible mechanism for nickel-catalyzed Ar–H/Ar–Si coupling.

Download figure to PowerPoint

Oxidative C–H coupling requires a stoichiometric amount of oxidant, for which oxygen (air) is ideal. In 2010, Miura discovered nickel-catalyzed C–H arylations of azoles with arylboronic acids (Ar–H/Ar–B) that operate under air (Scheme 17).24 Treatment of benzoxazole (17) with m-tolylboronic acid in the presence of catalytic NiBr2/bipy and K3PO4 in DMAc at 120 °C affords the corresponding coupling product 37 in 76 % yield. With 5-phenyloxazole (33), a Ni/phen/NaOtBu catalytic system gives the coupling product 38 in a better yield.

thumbnail image

Scheme 17. Miura's nickel-catalyzed Ar–H/Ar–B couplings of azoles and arylboronic acids.

Download figure to PowerPoint

Additionally, a one-pot borylation/arylation sequence based on this nickel-catalyzed direct coupling has also been accomplished (Scheme 18). After conversion of hexafluoro-m-xylene into the corresponding arylboronate 39 by Hartwig–Miyaura borylation,25 39 can be directly coupled with oxadiazole 40 (Ar–H/Ar–M coupling) under nickel catalysis conditions to afford 2-arylated azole 41 in 73 % overall yield.

thumbnail image

Scheme 18. A one-pot sequence of C–H borylation and Ar–H/Ar–B coupling.

Download figure to PowerPoint

The stoichiometric reaction with isolated [PhNiCl(bipy)] complex 42 (Scheme 19) sheds light on the reaction mechanism. Upon exposure of 42 to a mixture of 5-phenyloxazole (33), NaOtBu, and phen in DMAc under nitrogen, product 43 is detected in 27 % GC yield. This result suggests that the active species in the catalytic cycle is [Ar–NiII–X] (X = bromide or alkoxide).

thumbnail image

Scheme 19. Stoichiometric reaction between an azole and the [PhNiCl(bipy)] complex.

Download figure to PowerPoint

Miura proposed a reaction mechanism for the Ar–H/Ar–B coupling that is in agreement with the above results (Scheme 20). Initial transmetalation of NiX2 with arylboronic acid, or its borate generated by the action of base (K3PO4 or NaOtBu), could afford arylnickel intermediate G, which is the equivalent of 42 in Scheme 19. Subsequent base-assisted nickelation of the azole partner followed by reductive elimination from intermediate H could lead to the desired biaryl product along with Ni0. Reoxidation with molecular oxygen would complete the catalytic cycle. However, other possibilities such as pathways involving alternative reaction orders (e.g., azole then boronic acid) cannot be ruled out at this stage.

thumbnail image

Scheme 20. A possible catalytic cycle for direct arylation of 1,3-azoles with arylboronic acids.

Download figure to PowerPoint

In 2011, nickel-catalyzed C–H arylations of azoles (purine) with aryl Grignard reagents (Ar–H/Ar–Mg coupling) were reported by Qu and Gao (Scheme 21).26 Various purine derivatives can be coupled with aryl Grignard reagents in the presence of NiCl2(dppp) at room temperature.

thumbnail image

Scheme 21. Ni-catalyzed Ar–H/Ar–Mg couplings.

Download figure to PowerPoint

Ar–H/Ar–M couplings of azoles, which are electron-rich heteroarenes, with organometallic reagents are described above. Electron-deficient heteroarenes such as azines can also be arylated directly with organometallic reagents. Although nickel-catalyzed C–H arylations of azines were reported by Yamakawa and co-workers as an early example in this field (see Scheme 11), they require excess amounts of azines and the regioselectivity is difficult to control.

In 2009, Chatani, Tobisu, and co-workers demonstrated nickel-catalyzed Ar–H/Ar–M couplings of azines and diarylzinc reagents (Scheme 22).27 With use of a diarylzinc reagent as an aryl nucleophile and Ni(cod)2/PCy3 as a catalyst, various azines such as pyridines, quinolines, phenanthridines, and pyrazines can be arylated regioselectively at C2 in good to excellent yields.

thumbnail image

Scheme 22. Chatani's nickel-catalyzed direct arylations of azines with diarylzinc reagents.

Download figure to PowerPoint

Chatani and Tobisu extensively investigated the substrate scope and mechanisms of these Ar–H/Ar–M coupling reactions (see Schemes 23, 24 and 25, below).28 To this end, various quinolines bearing functional groups at C6 were treated with diphenylzinc reagents under the standard conditions at elevated temperature (Scheme 23). Reactive functional groups such as chloro, methoxy, amine, and ester groups are tolerated, to afford the corresponding coupling products in good to excellent yields.

thumbnail image

Scheme 23. Functional group tolerance of nickel-catalyzed C–H arylations of quinolines.

Download figure to PowerPoint

The mechanisms of these coupling reactions are assumed to consist of addition of the aryl nucleophile under nickel catalysis conditions, followed by in situ rearomatization to form the coupling product. To support this hypothesis, the rearomatization reaction was specifically studied by Chatani's group (Scheme 24). Treatment of 2-phenyl-1,2-dihydroquinoline (44, prepared by nucleophilic addition of phenyllithium onto quinoline) with diphenylzinc at room temperature produces rearomatized product 46 without nickel catalyst in 75 % yield. According to this result, loss of the C2-hydrogen atom of 44 proceeds through the intermediacy of an organozinc species such as 45.

thumbnail image

Scheme 24. Rearomatization of dihydroquinoline with Ph2Zn.

Download figure to PowerPoint

On the basis of this investigation, a reaction mechanism for the nickel-catalyzed C–H arylation of azines with diarylzinc has been proposed (Scheme 25). Nickel(0) species I could initially react with diarylzinc–pyridine adduct J to form azanickelacyclopropane K. An intramolecular aryl transfer could afford a nickel species L, which could subsequently liberate Ni0 catalyst I along with zinc amide M by reductive elimination. The zinc amide species M should then undergo rapid oxidative rearomatization, leading to arylated product N.

thumbnail image

Scheme 25. A plausible reaction mechanism for nickel-catalyzed direct couplings of azines with diarylzinc reagents.

Download figure to PowerPoint

In 2011, Chatani and Tobisu also discovered regioselective C–H arylations of acridines at C4 (Scheme 26).29 In the presence of a catalytic amount of Ni(cod)2, SIPr·HCl [1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride], and a stoichiometric amount of NaOtBu, acridines cross-couple with excess amounts of diarylzinc reagents to afford C4-arylated products regioselectively.

thumbnail image

Scheme 26. Nickel-catalyzed C–H arylations of acridines with diarylzinc regents.

Download figure to PowerPoint

Decarbonylative C–H Coupling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Aroyl compounds such as aromatic carboxylic acids, acid chlorides, anhydrides, and esters have received significant attention as useful aryl sources in metal-catalyzed decarboxylative or decarbonylative biaryl coupling reactions.30 In comparison with typical cross-coupling partners such as metalloarenes or haloarenes, aroyl compounds are usually inexpensive, stable, and readily available. Typically, these types of coupling reactions are accomplished with palladium catalysts for decarboxylative coupling31 and rhodium catalysts for decarbonylative coupling;32 only a few reports of nickel-mediated (stoichiometric nickel) decarbonylative biaryl formation are known.33 Although decarboxylative and decarbonylative C–H couplings between (hetero)arenes and aroyl compounds have recently received much attention in the context of “green” methods, these reactions also require expensive palladium and rhodium catalysts.34,35

In 2012, Itami's group discovered the first nickel-catalyzed decarbonylative C–H biaryl couplings of azoles and aryl esters (Scheme 27).36 In the presence of a catalytic system similar to that used in the previously mentioned nickel-catalyzed Ar–H/Ar–O coupling (see Schemes 12 and 13), a decarbonylative C–H coupling between benzoxazole (17) and phenyl thiophenecarboxylate (47) proceeds smoothly to furnish the corresponding coupling product 48 in 96 % yield. Various esters, particularly heteroaromatic esters such as furans, thiophenes, thiazoles, pyridines, and quinolones, can be used in this reaction to give the corresponding coupling products.

thumbnail image

Scheme 27. Itami's nickel-catalyzed decarbonylative C–H coupling.

Download figure to PowerPoint

A plausible mechanism for these decarbonylative C–H arylation reactions is shown in Scheme 28. It is proposed that the reactions involve Ni0/NiII redox catalysis, consisting of: i) oxidative addition of the ester C–O bond in O to Ni0, ii) CO migration onto the nickel center to produce an Ar–NiII(CO)n+1–OPh species (P, n = 0 or 1), iii) C–H nickelation of azole (Het–H) with Ar–NiII(CO)n+1–OPh (Q) to generate Ar–NiII(CO)n+1–Het (R), and iv) reductive elimination to release the coupling product Het–Ar (S) and to generate a Ni0(CO)n+1 species (T). Although a seemingly inactive nickel dicarbonyl complex T would be produced after two turnovers, the active Ni0 catalyst could be regenerated by thermal extrusion of CO from T.

thumbnail image

Scheme 28. A plausible mechanism for the decarbonylative C–H arylation reaction.

Download figure to PowerPoint

The assumed intermediate Ni(dcype)(CO)2 (49) is indeed a competent catalyst: 48 can be obtained in 96 % yield from the reaction between 17 and 47 in the presence of a catalytic amount of 49 (Scheme 29). The use of the stable and less expensive NiCl2 in combination with zinc powder also promotes the decarbonylative C–H coupling (Scheme 29).

thumbnail image

Scheme 29. Alternative protocols for the decarbonylative C–H coupling.

Download figure to PowerPoint

This newly developed decarbonylative C–H arylation is useful in the synthesis of muscoride A (55), a natural product with antibacterial activity (Scheme 30).37 The two azole esters 51 and (–)-52 are coupled under Ni/dcype catalysis conditions to furnish the corresponding coupling product (–)-53 in 39 % yield. The conversion of (–)-53 into (–)-55 has been described previously, so a formal synthesis of (–)-muscoride A (55) has been completed. If the synthesis were instead planned and executed with typical cross-coupling substrates (aryl halides and organometallic reagents), it would become much less efficient, with many additional steps.

thumbnail image

Scheme 30. Formal synthesis of muscoride A through nickel-catalyzed decarbonylative C–H coupling.

Download figure to PowerPoint

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information

Forty years ago, nickel-catalyzed cross-coupling was an uncharted territory open to exploration by pioneering chemists. Now, in the 21st century, this catalytic reaction has been expanded to provide new types of cross-coupling methodology for the construction of biaryls, such as Ar–M (M = B, Mg)/Ar–O, Ar–H/Ar–X, Ar–H/Ar–O, Ar–M (M = B, Si, Mg, Zn)/Ar–H, and decarbonylative C–H coupling. These nickel-catalyzed coupling reactions not only turn traditional cross-coupling (Ar–M/Ar–X coupling) into a method that is less expensive, easily available, and less toxic, but also allow for new types of C–C bond connection yet to be achieved with palladium or other transition metal catalysts. Additionally, orthogonal strategies in cross-coupling and applications toward the synthesis of useful arene-assembled molecules have begun to appear. It is now an opportune moment to re-evaluate nickel-catalyzed biaryl coupling and to expand its chemistry further.

Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information
Thumbnail image of

Junichiro Yamaguchi was born in Tokyo, Japan (1979). He received his Ph.D. in 2007 from the Tokyo University of Science under the supervision of Prof. Yujiro Hayashi. From 2007 to 2008 he was a postdoctoral fellow in the group of Prof. Phil S. Baran at The Scripps Research Institute (JSPS postdoctoral fellowships for research abroad). In 2008 he became an Assistant Professor at Nagoya University working with Prof. Kenichiro Itami and was promoted to Associate Professor in 2012. His research interests include the total synthesis of natural products and the innovation of synthetic methods.

Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information
Thumbnail image of

Kei Muto was born in Aichi, Japan (1988). He received his B.Sc. degree from Nagoya University (Japan) in 2011 under the supervision of Prof. Kenichiro Itami. For three months in 2012 he was a visiting student in the group of Prof. Aiwen Lei at Wuhan University, China. He is currently a second-year graduate student in the group of Prof. Itami.

Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Ar–M/Ar–O Coupling
  5. Direct C–H Coupling
  6. Ar–H/Ar–O Coupling
  7. Ar–H/Ar–M Coupling
  8. Decarbonylative C–H Coupling
  9. Conclusions
  10. Biographical Information
  11. Biographical Information
  12. Biographical Information
Thumbnail image of

Kenichiro Itami was born in Pittsburgh, USA (1971) and raised in Tokyo. Educated in chemistry at Kyoto University, Japan, under the guidance of Prof. Yoshihiko Ito, he received his Ph.D. in 1998. From 1997 to 1998 he was a predoctoral researcher in the group of Prof. Jan-E. Bäckvall at Uppsala University, Sweden. In the fall of 1998 he began his academic career at Kyoto University as an Assistant Professor (with Prof. Jun-ichi Yoshida). He moved to Nagoya University to become an Associate Professor (with Prof. Ryoji Noyori) in 2005 and was promoted to Full Professor in 2008. Representative awards include the German Innovation Award (2012), the Novartis–MIT Lectureship Award (2012), the Nozoe Memorial Award for Young Organic Chemists (2011), the Merck–Banyu Lectureship Award (2008), the Minister Award for Distinguished Young Scientists (2006), the Mitsui Chemicals Catalysis Science Award of Encouragement (2005), and the Chemical Society of Japan Award for Young Chemists (2005).