Iron-Catalyzed CâH Bond Activation - Chemical Reviews (ACS

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Iron-Catalyzed C−H Bond Activation Rui Shang, Laurean Ilies,* and Eiichi Nakamura* Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan ABSTRACT: Catalytic C−H bond activation, which was an elusive subject of chemical research until the 1990s, has now become a standard synthetic method for the formation of new C−C and C−heteroatom bonds. The synthetic potential of C−H activation was first described for ruthenium catalysis and is now widely exploited by the use of various precious metals. Driven by the increasing interest in chemical utilization of ubiquitous metals that are abundant and nontoxic, iron catalysis has become a rapidly growing area of research, and iron-catalyzed C−H activation has been most actively explored in recent years. In this review, we summarize the development of stoichiometric C−H activation, which has a long history, and catalytic C−H functionalization, which emerged about 10 years ago. We focus in this review on reactions that take place via reactive organoiron intermediates, and we excluded those that use iron as a Lewis acid or radical initiator. The contents of this review are categorized by the type of C−H bond cleaved and the type of bond formed thereafter, and it covers the reactions of simple substrates and substrates possessing a directing group that anchors the catalyst to the substrate, providing an overview of iron-mediated and iron-catalyzed C−H activation reported in the literature by October 2016.

CONTENTS 1. Introduction 2. Stoichiometric C−H Activation by Iron Complexes and Examples of Isolated Ferracycles 2.1. Activation of C(sp 2 )−H Bonds by Iron Complexes 2.2. Activation of C(sp 3 )−H Bonds by Iron Complexes 3. Iron-Catalyzed C−H Activation/C−C Bond-Formation Reactions 3.1. Iron-Catalyzed C(sp2)−H Functionalization with Carbon Nucleophiles 3.1.1. Arylation and Heteroarylation of C(sp2)− H Bonds 3.1.2. Alkenylation of C(sp2)−H Bonds 3.1.3. Alkylation of C(sp2)−H Bonds 3.2. Iron-Catalyzed C(sp3)−H Functionalization with Carbon Nucleophiles 3.2.1. Arylation and Heteroarylation of C(sp3)− H Bonds 3.2.2. Alkenylation of C(sp3)−H Bonds 3.2.3. Alkylation of C(sp3)−H Bonds 3.3. Iron-Catalyzed C(sp2)−H Functionalization with Carbon Electrophiles 3.3.1. Alkylation of C(sp2)−H Bonds 3.3.2. Allylation of C(sp2)−H Bonds 3.3.3. Arylation of C(sp2)−H Bonds 3.4. Iron-Catalyzed Addition of C(sp2)−H to Alkenes and Alkynes 4. Iron-Catalyzed C−H Activation/C−X Bond-Formation Reactions 4.1. Amination of C−H Bonds 4.2. Borylation and Silylation of C−H Bonds 4.3. Tritiation of C−H Bonds © 2017 American Chemical Society

4.4. Oxygenation and Halogenation 5. Other Examples 6. Concluding Remarks Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments Abbreviations References

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1. INTRODUCTION Iron has the most tightly bound nucleus among elements created in supernova nucleosynthesis. The most abundant isotope of iron consists of 26 protons and 30 neutrons, and iron is the most

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Scheme 1. C−H Activation Reaction Catalyzed by Organoiron

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Special Issue: CH Activation Received: November 16, 2016 Published: April 5, 2017 9086

DOI: 10.1021/acs.chemrev.6b00772 Chem. Rev. 2017, 117, 9086−9139

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Scheme 2. Iron-Catalyzed (a) Carbometalation and (b) Cross-Coupling Reactions

Scheme 3. Discovery of Iron-Catalyzed C−H Arylation during Investigation of a Cross-Coupling Reaction

abundant heavy element in the universe and on the Earth.1 Such abundance accounts for the low biological toxicity2,3 as well as low cost, which stands in stark contrast to the rarity of precious metals (e.g., 0.0000015% abundance of palladium in the Earth’s crust). Thus, iron ideally conforms to the spirit of Element Strategy Initiative: systematic exploration of ubiquitous elements instead of rare and precious elements in the interest of sustainability and economy.4 Having 26 protons, iron has 26 electrons in an electron configuration of 1s2 2s2 2p6 3s2 3p6 3d6 4s2. It takes a variety of spin states and hence is chemically reactive. In fact, iron complexes are often chemically too reactive and too diverse in their reactivity compared with neighboring metals,5 and hence it is difficult to design catalytic cycles of synthetic organic significance. Kharasch and Fields6 in the 1940s and Tamura and Kochi7 in the 1970s were pioneers in the field of iron catalysis. Kochi explored the reactivity of iron in a modern sense and found a new field of metal-catalyzed cross-coupling chemistry8 before the reports on nickel-9 and palladiumcatalyzed10 cross-coupling reactions.11−14 As one of the authors (E.N.) recalls the situation of palladium catalysis being explored largely by Tsuji et al.15 in the late 1960s and early 1970s, the situation of iron catalysis now looks very similar to that of palladium catalysis then: good mechanistic understanding is lacking, and good ligands are yet to be discovered. While C−H activation reactions, and especially catalytic ones, have been the subject of considerable interest for many years16−23 and have even considered as a “Holy Grail” of chemistry24 for their step efficiency, atom economy, and potential as a method for late-stage functionalization of complex organic molecules,25−32 the directed C−H activation reaction catalyzed by organoiron reactive species is a newcomer in the field (Scheme 1), first reported by us in 2008.33 After working on iron-catalyzed asymmetric carbometalation34 and cross-coupling reactions35−41 (Scheme 2), we stumbled, in early 2006, over an interesting side product, 2-biphenylpyridine, formed in 8% yield during the synthesis of 2-phenylpyridine by cross-coupling between 2-bromopyridine and a phenylzinc reagent (Scheme 3).

It was apparent that, under the conditions specified in the scheme, the reaction would never produce this double phenylation side product. It soon became clear that the oxidant necessary to achieve this transformation was air that had leaked into the flask,42 and the reaction required 2,2′-bipyridine as a ligand, which formed by homocoupling of the 2-bromopyridine substrate. We spent some time before finding that 1,2dichloroisobutane (DCIB) is an optimum oxidant to carry out this reaction in quantitative yield (as will be discussed).33 The discovery of this mild oxidant allowed us to develop a series of iron-catalyzed C−H functionalization reactions that we describe in this review. After extensive investigations by us and others for 10 years, iron-catalyzed C−H functionalization reactions have found applications to introduce various organic groups to numerous substrates via C−H activation.43−45 Because of the high reactivity of iron catalytic species, the reactions often take place below or at room temperature and are generally much faster than the equivalent reactions catalyzed by precious metals such as palladium,46 ruthenium,47 and rhodium.48,49 Catalytic turnover as high as 6500 has been reported,50 while catalyst loading of 5% is still common. It is interesting to note that although rather large amounts of organometallic reagents are always required, the ironcatalyzed C−H bond-activation reactions are often more chemoselective than the equivalent cross-coupling reactions of organic halides because of the intrinsic inertness of a C−H bond compared with the high reactivity of a carbon−halogen bond.51 In light of the recent tendency of too liberal a use of the term C−H activation (e.g., base-catalyzed “activation” of a C−H bond α to a carbonyl group), we have focused this review, in accordance with the discussion by Godula and Sames,28 on the reactions25 where a C−H bond in the substrate first reacts with the iron catalyst to generate an organoiron species through coordination of the C−H bond to the inner-sphere of the iron complex. Thus, we did not include iron-mediated radical reactions such as iron-catalyzed C−H oxidation52−54 and halogenation.55,56 Similarly, we did not include iron-mediated 9087


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Scheme 4. Hydrogen Transfer between Ligand and Iron in a dppe-Coordinated Iron Complex

Scheme 5. Generation of Ortho-Metalated Triphenyl Phosphite Ligand in CpFe Complex

Friedel−Crafts-type electrophilic aromatic substitutions57−60 or cross-dehydrogenative-coupling (CDC) reactions,61,62 in which a variety of metals may also catalyze the reaction equally well, suggesting probable involvement of radicals rather than a discrete organoiron intermediate. This review does not cover C−H activation by iron carbenes63−67 and iron nitrenes68,69 because they do not generate an Fe−C bond after the initial C−H cleavage. In this review, we thus summarize the development during the past few decades of both stoichiometric C−H metalation and catalytic C−H functionalization reactions that involve the explicit participation of organoiron species in the C−H bondactivation step. The contents of this review are categorized by the type of C−H bond cleaved and the type of bond formed thereafter. Although there are a number of reviews on iron catalysis,70−74 systematic reviews entirely devoted to C−H activation via organoiron species are scarce.43,45 This review provides an overview of iron-catalyzed C−H functionalizations reported in the literature up to October 2016, which we hope will stimulate further research interest in this area.

the hydrogen atom as a proton. Several examples are discussed on the basis of this classification. 2.1. Activation of C(sp2)−H Bonds by Iron Complexes

Early in 1968, Hata et al.80 reported that irradiation of a 1,2bis(diphenylphosphino)ethane-ligated iron(0) ethylene complex [Fe(dppe)2·C2H4] results in the formation of an orthometalated iron(II) hydride complex accompanied by liberation of ethylene (Scheme 4). The ortho-C−H bond oxidatively added to the iron(0) directly to form a hydride ferracycle complex, and this complex converts back to initial iron(0) ethylene complex under ethylene pressure. The authors also discovered that the hydride ferracycle complex reacts with hydrogen gas at atmospheric pressure to generate H2Fe(dppe)2.80 In 1977, Corriu and co-workers81 reported that, under UV irradiation, (η5-C5H5)Fe(CO)2SiR3 reacted with triphenyl phosphite to give an ortho-metalated iron phosphite complex with elimination of CO and hydrosilane. When the silyl substituent is optically active, hydrosilane could be generated with full retention of configuration on the silicon center. The authors proposed a mechanism including oxidative addition of the ortho-C−H bond of triphenyl phosphite to iron center, followed by reductive elimination to deliver hydrosilane and ortho-metalated iron phosphite complex [Scheme 5 (1)]. In comparison to this mechanism, direct deprotonative metalation of the ortho-C−H bond by a silyl anion is also possible. In this study, the authors also revealed that the same ferracycle complex can be formed by direct reaction of [(η5-C5H5)Fe(CO)2]2 with triphenyl phosphite under UV irradiation in hexane, while the same reaction performed under thermal conditions gave only a CO-monosubstituted product, (η5-C5H5)2Fe2(CO)3P(OPh)3, without breaking the Fe−Fe bond [Scheme 5 (2)]. As early as the 1970s, Jesson and co-workers82−84 discovered that a bis(phosphine)-ligated iron(0) complex, Fe(dmpe)2, generated through the reductive elimination of naphthalene (NpH) from an iron(II) complex, HFeNp(dmpe)2, can

2. STOICHIOMETRIC C−H ACTIVATION BY IRON COMPLEXES AND EXAMPLES OF ISOLATED FERRACYCLES The literature from as early as the 1960s reports numerous examples of iron complexes that activate a variety of C−H bonds, including C(sp)−H, C(sp2)−H, and even C(sp3)−H bonds. These types of iron-mediated C−H activations generally lead to the formation of organoiron products possessing well-defined Fe−C bonds, including ferracycles,75 when a directing group is present on the substrate.76−79 Mechanistically, iron-mediated C−H activation can be categorized into two types: (1) oxidative addition of a C−H bond to a low-valent iron complex to form a C−Fe−H bond and (2) σ-bond metathesis or deprotonative metalation, in which the R group in the Fe−R complex removes 9088


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Scheme 6. Oxidative Insertion of Fe(dmpe)2 into the C−H Bond of Alkyne, Arene, Aldehyde, and Alkene

Scheme 7. Generation of Fe(dmpe)2 and Oxidative Addition to C(sp2)−H Bonds in Benzene, Cyclopentene, and 1-Pentene

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ortho-C−H of phenyl and to form a phosphine-ligated ferracycle after irradiation. Interestingly, when this ferracycle was heated in the presence of dihydrogen, H2Fe(dppe)2 could be regenerated (Scheme 8).87,88 This observation was similar to the early report by Hata et al.80 The half-sandwich-type iron(II) complex Cp*Fe(II)PhL2 [where L = P(OR)3] can activate the C−H bond of furans at the 2-position.89 This reaction proceeds through σ-bond metathesis, in which the phenyl group bound to the iron center acts as a base to deprotonate the C-2 hydrogen (Scheme 9). The half-sandwich iron(II) carbonyl complex Cp*Fe(II) (CO)Ph(MeCN) was also reported to cleave regioselectively the C−H bond of five-membered ring heteroaromatics, including furan, thiophene, and thiazole.90 These reactions took place at the most acidic C−H bond, and the phenyl group on the iron atom acted as a base to deprotonate the C−H bond (Scheme 10). Coordinative nitrogen atoms can direct various transition metals to cleave a C−H bond and to form metallacycles,91−94 In 2009, Camadanli et al.95 reported that an iron(0) trimethylphosphine complex reacts with an aromatic imine via oxidative addition of the ortho-C−H bond to the iron(0) center. The resulting iron(II) hydride complex was successfully crystallized and characterized by X-ray analysis (Scheme 11). The same group also reported that not only the iron(0) but also an iron(II) complex, FeMe2(PMe3)4, can react with benzophenone imine to generate an ortho-methylated iron(II) hydride complex.95 This reaction includes three steps. First, the benzophenone imine coordinates with FeMe2(PMe3)4 by ligand exchange, followed by ortho ferration via σ-bond metathesis, in which the C−H bond is deprotonated by the methyl group. Reductive elimination then takes place on the iron(II) ferracycle complex to generate a new C−Me bond and Fe(PMe3)3. Fe(PMe3)3 oxidatively adds to another available C−H bond to generate an ortho-methylated Fe(II) ferracycle (Scheme 12). Several aspects of this stoichiometric transformation are notable:

Scheme 8. Light-Promoted Intramolecular Ortho-C−H Cyclometalation of Fe(dppe)2H2

Scheme 9. Metalation of Furan with a Phosphite-Ligated Cp*Fe(II) Complex

oxidatively add to various unsaturated C−H bonds, including acetylene, (hetero)arene, aldehyde, and alkene (Scheme 6). The oxidative addition proceeds stereoselectively to produce the cis isomer, which then isomerizes to the thermodynamically stable trans isomer. Various functional groups, such as ester, ketone, ether, chlorine, and trifluoromethyl, were well tolerated. However, these complexes were characterized only by spectroscopic analysis and were not isolated. Field and co-workers85,86 reported that the same Fe(dmpe)2 complex can be generated by irradiation of H2Fe(dmpe)2 to release hydrogen. The formed Fe(dmpe)2 inserted into the C−H bond of benzene and cyclic or acyclic alkenes such as 1-pentene to generate a mixture of cis and trans products (Scheme 7). When the dmpe ligand was replaced by dppe, the complex H2Fe(dppe)2 reacted in an intramolecular fashion to activate the

Scheme 10. C−H Activation of Heteroaromatics by Cp*Fe(CO) (NCMe)Ph

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Scheme 11. Directed Oxidative Addition of Ortho-C−H Bond of Imine to Fe(PMe3)4

Scheme 12. Reaction of FeMe2(PMe3)4 with Diphenylmethanimine To Generate an Ortho-Methylated Ferracycle

arene C−H bond. However, the use of this reactivity to develop catalytic C−H bond methylation has not been achieved until recently.50 The same group reported that an aldimine can also react with FeMe2(PMe3)4 through σ-bond metathesis to generate an iron(II) ferracycle and methane in good yield without addition to the imine’s double bond (Scheme 13).95,96 Besides aldimine, thiobenzophenones also reacted with FeMe2(PMe3)4 in a similar fashion to generate an ortho-metalated iron(II) complex coordinated with the sulfur atom (Scheme 14).97 Cyclometalation of iron(0) carbonyls with imine and diazobenzene was reported in the 1960s.98−102 Thus, the nitrogen atom of the imine or diazobenzene guided the oxidative addition of ortho-C−H to iron(0) to form a dinuclear or mononuclear metallacycle, depending on the structure of the substrate (Scheme 15).103,104 The application of this reactivity of iron carbonyls for catalytic C−H functionalization has been achieved only recently (see Scheme 98).105 Wunderlich and Knochel106 reported in 2009 that an iron(II) amide, Fe(TMP)2·2MgCl2·4LiCl, can deprotonate an aromatic C−H bond to form an organoiron intermediate. The position of ferration depends on the acidity of the C−H bond and chelation assistance (Scheme 16). The authors used the resulting iron intermediates for nickel-catalyzed cross-coupling with functionalized alkyl halides. It is worthwhile to note that an amide (TMP) functions as a base to assist the ferration of the C−H bond, while typically a carbon anion acts as a base for σ-bond metathesis. Ferration of benzene was also reported to proceed via alkalimetal-mediated metalation. Klett and Mulvey and co-workers107 reported that an iron host−benzenediide guest inverse-crown complex was generated by treating benzene with Fe(TMEDA)-

Scheme 13. Directed Deprotonative C−H Activation of Aldimine with FeMe2(PMe3)4

Scheme 14. Directed Deprotonative Cyclometalation of Thiobenzophenones with FeMe2(PMe3)4

(1) Nitrogen-directed C(sp2)−H activation occurs either with iron(0) via oxidative addition or with methyliron(II) species via σ-bond metathesis. (2) The methyliron(II) complex reacts faster with the ortho-C(sp2)−H bond than with the N−H bond. (3) Reductive elimination to form the C−Me bond readily takes place on the phosphine-ligated iron(II) center to produce an iron(0) species, which then undergoes oxidative addition to an 9091


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Scheme 15. Cyclometalation of Iron(0) Carbonyl Compounds with Schiff Base and Azobenzene

Scheme 16. Ferration of Arenes by Use of Fe(TMP)2·2MgCl2· 4LiCl

When an alkylpolyphosphine-chelated iron hydride complex was irradiated with UV light, intramolecular cyclometalation took place on P−CH3 to form a three-membered C(sp3)−iron ferracycle,108 together with the release of hydrogen (Scheme 19).109 A similar intramolecular cyclometalation also proceeded on a methylene C−H bond. It was reported by Baker and Field110 that a coordinatively unsaturated iron(0) complex, Fe(depe)2, readily inserts into the ortho-methylene C−H bond to intramolecularly form a ferracycle. The formed phosphine ferracycle cleaves the C−H bond of benzene to generate an organoiron(II) complex (Scheme 20). An intermolecular reaction of Fe(dmpe)2 with alkanes was reported by Baker and Field.111 They reported that Fe(dmpe)2, generated by irradiation of H2Fe(dmpe)2, reacted with pentane to insert selectively into a terminal C−H bond and to form an organoiron hydride complex at −90 °C. This complex eliminated 1-pentene to regenerate H2Fe(dmpe)2 at very low temperature. This reaction produces alkene and hydrogen from alkane at low temperature and could be highly valuable if it could be rendered catalytic. However, the pentene generated in the reaction is far more reactive than pentane, traps the reactive iron complex, and prevents catalytic turnover (Scheme 21). This example illustrates that organoiron species possess enough reactivity to activate C− H bonds under mild conditions, but taming their reactivity to achieve an efficient catalytic cycle is a major problem for the realization of efficient iron catalysis. The same coordinatively unsaturated iron complex activated the C−H bond of methane at −100 °C (Scheme 22).112 This reactivity has not been successfully exploited for catalytic methane activation to date, although it is an extremely attractive reaction. There is one example of chelation-assisted, iron-mediated C− H activation of methylene C−H followed by C−Me bond formation, reported in 2009. Li and co-workers113 found that the methylene C−H bond in a substrate possessing two directing phosphorus atoms reacted with FeMe2(PMe3)4, resulting in methylation of the central methylene C−H bond, and subsequent oxidative addition of the tertiary C−H bond proceeded to form a tertiary C(sp3)−iron ferracycle, a rarely reported transformation (Scheme 23). This reaction proceeds

Scheme 17. Direct C−H Ferration by Formation of Host− Benzenediide Guest Crown Complexes

(CH2TMS)2 in the presence of HTMP and NaTMP (Scheme 17). 2.2. Activation of C(sp3)−H Bonds by Iron Complexes

Besides the activation of C(sp2)−H bonds, it has been known for a long time that an iron complex can activate a C(sp3)−H bond. The bis(phosphine)-ligated iron(0) complex already described in Scheme 4 adds oxidatively to various acidic C(sp3)−H bonds of α-carbonyl compounds and nitriles (Scheme 18).83 9092


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Scheme 18. Generation of Fe(dmpe)2 and Its Oxidative Addition into Acidic C(sp3)−H Bond

Scheme 19. Intramolecular Generation of PolyphosphineLigated C(sp3)−Iron Complex

Scheme 21. Intermolecular Terminal C−H Bond Activation of Alkanes with Fe(dmpe)2

Scheme 20. Ortho Cyclometalation with Methylene C−H Bond and Reaction with Benzene of depe-Ligated Iron Complex

Scheme 22. Activation of Methane by H2Fe(dmpe)2 at −100 °C

via several elementary steps involving deprotonative ferration, reductive elimination to form a C−C bond, and oxidative addition of the tertiary C−H bond with coordinatively unsaturated iron(0) complex. The final iron hydride complex possessing a tertiary C−Fe bond and a potentially eliminable βhydrogen atom was isolated and characterized by X-ray singlecrystal analysis. Similar chelation of phosphine could also facilitate cyclometalation of benzylic C−H to form ferracycles. Li and coworkers114 reported that Fe(PMe3)4 and FeMe2(PMe3)4 react with bis[2-(diphenylphosphanyl)phenyl]methane to produce two different types of ferracycles. Fe(PMe3)4 reacted with bis[2(diphenylphosphanyl)phenyl]methane through phosphine-assisted oxidative addition of iron(0) to a benzylic C−H bond to form an iron hydride complex, while reaction with Fe-

Me2(PMe3)4 generates a ferracycle through double C−H deprotonation, where both benzylic C−H and the ortho-C−H of phenyl are metalated (Scheme 24).114 A half-sandwich iron complex of N-heterocyclic carbene was reported to mediate intramolecular C−H cyclometalation with a carbanion base at 0 °C. The benzylic C−H bond in the mesityl group reacted to produce a six-membered ferracycle (Scheme 25).115 9093


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Scheme 23. Chelation-Assisted Activation of Secondary C−H Bond and Subsequent Oxidative Addition into a Tertiary C−H Bond

efficiency, this reactivity had not been exploited for synthetically useful, catalytic C−C bond formation until a serendipitous discovery in 2008. One of the authors (E.N.) noticed an unexpected ternary coupling product when optimizing the crosscoupling between diphenylzinc and 2-bromopyridine in the presence of adventitious atmospheric air (see Scheme 3).42 The discovery of the ternary coupling product switched the authors’ research interest from cross-coupling to C−H activation. After two years of optimization, this catalytic reaction was made synthetically useful. Discovery of a suitable dichloroalkane oxidant, DCIB, and identification of a bidentate nitrogen ligand to stabilize the iron intermediate were the two key findings that allowed the organoiron species to turn over to make a catalytic cycle. It is notable that most of the directed, transition-metalcatalyzed C−H activation reactions reported up to that time required elevated temperature,46,32,47,48 while the iron-catalyzed reaction proceeded even at 0 °C. The use of organozinc as a coupling partner for C−H functionalization was unprecedented at that time. Under the optimized reaction conditions, benzoquinoline, 2-phenylpyridine, 2-phenylpyrimidine, 4-phenylpyrimidine, and 1-phenyl-1H-pyrazole reacted well. The reaction is rather insensitive to the electronic effect of the substituents on the aryl group but rather sensitive to steric hindrance (e.g., o-tolyl Grignard reagent was completely unreactive). For aromatic substrates in which two ortho-C−H bonds are available, the reaction delivered a mixture of monoand diarylated products. In the presence of a meta substituent,

Scheme 24. Cyclometalation of Benzylic C−H Bonds Assisted by Phosphine Chelation

3. IRON-CATALYZED C−H ACTIVATION/C−C BOND-FORMATION REACTIONS 3.1. Iron-Catalyzed C(sp2)−H Functionalization with Carbon Nucleophiles

3.1.1. Arylation and Heteroarylation of C(sp2)−H Bonds. In section 2, we described how organoiron complexes can activate various types of C−H bonds. However, despite early attempts by Jones et al.116 to develop a catalytic reaction with low

Scheme 25. Intramolecular Cyclometalation of N-Heterocyclic Carbene-Coordinated Cp*Fe(II)

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Scheme 26. Iron-Catalyzed Arylation of C−H Bonds through Directed C−H Activation

Scheme 27. Iron-Catalyzed Ortho-C−H Arylation of Arylimines

presented a new class of homogeneous iron catalysis: ironcatalyzed C−C bond formation through C−H bond activation (Scheme 26). Subsequent studies showed that the same catalytic system can be used for ortho arylation of aromatic imines to deliver orthoarylated aromatic ketones and aldehydes upon hydrolysis (Scheme 27).117 The study demonstrated the orthogonal reactivity of iron and palladium catalysis. Halide and

the arylation on the sterically hindered C−H site can be totally suppressed, delivering the monoarylated product exclusively. Interestingly, Ph2Zn prepared from PhLi, magnesium-free Ph2Zn, and PhZnBr did not afford the phenylated product at all. Elevation of the reaction temperature was not preferred. It is assumed that phenanthroline coordinates to iron, TMEDA coordinates to zinc, and DCIB acts as a mild oxidant of a reduced iron intermediate back to iron(III) (see below). This report thus 9095


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Scheme 28. Iron-Catalyzed Direct Arylation of Arylpyridines and Aromatic Imines with Oxygen as Oxidant

Scheme 29. Iron-Catalyzed Stereospecific Arylation of Olefinic C−H Bonds with Grignard Reagents

Scheme 30. C−H Activation (1) versus Heck-type Mechanism (2) in Iron-Catalyzed Stereospecific Arylation of Olefinic C−H Bonds

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Scheme 31. Iron-Catalyzed Ortho-C−H Arylation of Arylpyridines and Arylimines with Grignard Reagents

Scheme 32. Reaction of Putative Ferracycle Intermediate with D2O

Scheme 33. Kinetic Isotope Effects in Iron-Catalyzed N-Directed C−H Arylation with Aryl Grignard Reagents

molecular oxygen effects iron-catalyzed arylation of imine and 2phenylpyridine, albeit less effectively than DCIB (Scheme 28). Iron-catalyzed C−H arylation of olefin substrates also takes place readily, allowing cyclic or acyclic olefins possessing a directing group to be arylated stereospecifically syn to the directing group (Scheme 29).118 The key discovery to achieve this syn selectivity was the effect of an aromatic cosolvent. When tetrahydrofuran (THF) was used as the solvent, reaction of 2(prop-1-en-2-yl)pyridine with phenylmagnesium bromide gave mainly the E product (E/Z = 95:5). However, when a mixture of chlorobenzene and diethyl ether was used, the same reaction delivered the arylated product with high Z selectivity (E/Z = 3:97). The reaction gave the C−H arylation product in a synselective manner via a putative ferracycle intermediate; the anti isomer forms through in situ isomerization catalyzed by lowvalent iron species. The cosolvent effect was explained by coordination of the aromatic solvent to a low-valent iron

pseudohalide substituents on the aromatic imine, which behave as a leaving group in palladium-catalyzed Negishi couplings, are compatible with iron-catalyzed activation of a C−H bond. The presence of DCIB is essential to achieve the observed preference for C−H arylation over C−X activation when using iron catalysis. Various aromatic aldimines and ketimines reacted well. For aromatic ketimines possessing two accessible ortho-C−H bonds, the reaction proceeds with high selectivity for the monosubstituted product, while for aromatic aldimines, the reaction generates a mixture of mono- and diarylated products. This selectivity is probably caused by the steric hindrance of the ortho substituent to disturb the formation of the ferracycle intermediate for the second step. It is worth noting that this reaction proceeded at 0 °C. The use of DCIB as an oxidant is a unique feature for ironcatalyzed C−H functionalizations, but oxygen could also be used as an inexpensive oxidant to turn over the organoiron catalyst. Nakamura and co-workers42 reported that slow diffusion of 9097


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ance of the iron catalyst. A remarkable feature is the reaction rate; thus, the reaction completes at 0 °C within 5 min of the slow addition time, demonstrating the high reactivity of organoiron for C−H bond activation. The authors also discussed the contrast of selectivity in olefinic C−H activation with a previous report, where an alkene was arylated with anti selectivity in the presence of an iron catalyst.122 Anti selectivity observed in the iron-catalyzed arylation of 2-[dimethyl(vinyl)silyl]pyridine was ascribed to a Mizoroki−Heck-type mechanism [Scheme 30 (2)], while syn selectivity observed in the reaction of alkenylpyridines [Scheme 30 (1)] rules out a Heck-type mechanism. The slow-addition method enabled the use of aryl Grignard reagents as a coupling partner in the reaction of aromatic substrates without preforming the zinc reagent. The use of a Grignard reagent enhanced the reaction rate significantly, and the reaction gave the arylation product in good yield at 0 °C after an addition time of 5 min. Both N-heteroaromatics and aromatic ketimines reacted well (Scheme 31).123 Nakamura and co-workers123 conducted studies relevant to the mechanism of the iron-catalyzed C−H substitution reaction with aryl Grignard reagent. First, the reaction with a stoichiometric amount of Fe(acac)3 and dtbpy ligand along with slow addition of PhMgBr generated a metal intermediate, as shown by quenching with D2O to obtain the deuterated product in 80% yield with D-incorporation of 80%. Without iron or dtbpy, neither D-incorporation nor phenylation occurred. The result of the stoichiometric experiment suggests the formation of a stable ferracycle intermediate, which undergoes reductive elimination upon interaction with DCIB (Scheme 32). In the

Scheme 34. Proposed Mechanism Based on Experimental Results

species119 to inhibit iron-catalyzed Z/E isomerization of the olefin. When 2-(3,3-dimethylbut-1-en-2-yl)pyridine was used as a substrate, the reaction gave the C−H phenylation product in 99% yield with Z/E selectivity higher than 99:1. It is worth mentioning that this reaction requires slow addition of the Grignard reagent to retard the otherwise fast iron-catalyzed homocoupling of PhMgBr120,121 and to enhance the perform-

Scheme 35. Proposed Fe(II)/Fe(III)/Fe(I) Mechanism Based on Density Functional Theory Studies

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Scheme 36. Proposed Fe(III)/Fe(I) Mechanism Based on Density Functional Theory Studies

Scheme 37. Iron-Catalyzed Monoselective Ortho Arylation of N-Methylbenzamide

catalytic reaction, both intramolecular and intermolecular kinetic isotope effects (KIE) were observed with similar magnitude, indicating that coordination of the pyridyl nitrogen to the iron catalyst is reversible, and the following C−H cleavage is the first irreversible step of the catalytic cycle (Scheme 33).123 On the basis of these mechanistic experiments and previous studies, the authors proposed a catalytic cycle that includes the following four steps (Scheme 34):123 (1) reversible coordination of the pyridyl group to the iron center of an aryliron species (A to B); (2) irreversible metalation of the ortho-C−H bond with concomitant elimination of an arene; (3) ortho-ferrated intermediate (C) undergoing reductive elimination to form the carbon−carbon bond upon interaction with DCIB to generate the desired coupling product, isobutene, and dichloroiron

species (D); and (4) transmetalation of dichloroiron species (D) with aryl Grignard reagent to regenerate the active species (A) to complete the catalytic cycle. The reaction of organoiron with DCIB may proceed after C−C bond-reductive elimination to regenerate the iron species, or it may proceed at the ferracycle (C) stage to accelerate C−C bond-forming reductive elimination. These considerations helped further development of efficient synthetic methods, to be discussed in more detail. Theoretical calculations to elucidate the detailed mechanism of nitrogen-directed iron-catalyzed C−H arylation were reported by Chen and co-workers.124 On the basis of results of mechanistic experiments reported by Nakamura et al., Chen’s calculation revealed a two-state reactivity (TSR) of organoiron to activate the C−H bond, in which control of both valence and 9099


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Scheme 38. Iron(III)-Catalyzed C−H Arylation of Arene and Alkene by Use of Arylboron Compounds Assisted by Bidentate Auxiliary with Broad Scope

Scheme 39. Experimental Evidence of C−H Bond Cleavage by Iron(III) Species

spin state is crucial for taming the reactivity of iron. On the basis of the calculation results, the authors proposed a spin acceleration effect during the key C−H activation step, in which high-spin ground-state Fe(II) and Fe(III) complexes were crossed over by excited low-spin states [singlet state of Fe(II) and doublet of Fe(III)] to cut through high energy barriers and to promote C−H cleavage. The spin acceleration effect was previously described by Holland125 for several fundamental organometallic reactions such as β-hydride elimination.

The authors also performed theoretical studies revealing that the ligand sphere of iron is crucial for stabilizing the reactive lowspin state that promotes C−H activation in the TSR mechanism to elucidate the unique ligand effect observed in experiments. The conclusions of Chen’s calculations further supported Nakamura’s mechanism proposed on the basis of experimental studies.126 The calculation results show that both organoiron(II) and organoiron(III), possibly present under different conditions, can efficiently promote C−H activation through deprotonation. 9100


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Scheme 40. Mechanistic Studies of Iron/Zinc Cocatalyzed Directed C−H Arylation with Arylborates: (a) 11B NMR Evidence of B−Zn Transmetalation; (b) Proposed Fe(III)/Fe(I) Mechanism

The reaction proceeded with high monoselectivity, which may be ascribed to steric hindrance of the ortho substituent disturbing the formation of the second ferracycle. One of the disadvantages of the reactions described above is that they require a preformed Grignard reagent or zinc reagent, which limits the scope and functional-group compatibility. Nitrogen-directed C−H functionalization of arenes and alkenes with aryl bromides promoted by metallic magnesium circumvented direct handling of an organometallic reagent,128 and the Grignard reagent was generated in situ with the assistance of the iron catalyst.129 In 2014, Nakamura and co-workers126 reported that readily available boronic acid pinacol ester can be used in iron-catalyzed C−H arylation reactions (Scheme 38). Butyllithium was used to preactivate the boronate as a lithium borate salt,130,131 which readily reacted with various (hetero)arenes and alkenes bearing an 8-quinolylamide directing group132,133 to form a C−C bond. The catalyst system for this reaction consisted of a catalytic amount of iron(III) salt, zinc(II) salt, and a diphosphine ligand bearing a conjugated backbone (dppen). In contrast to the magnesium- or zinc-based reactions discussed above, the boratebased reaction resulted in less than 5% homocoupling of the nucleophilic organic group. In this reaction, the borate acts as both coupling partner and base to deprotonate the amide N−H and the C−H bond. Because of the lower nucleophilicity and better functional-group compatibility of the borate than Grignard or zinc reagents, this reaction showed much broader substrate scope and good functional-group compatibility. Aryl fluoride, chloride, bromide, ether, amine, sulfide, trifluoromethyl, cyano, and ester were well tolerated. Heteroaromatics such as indole and thiophene could be used as substrates. Unlike previous reactions, steric hindrance was less problematic, and o-tolylboronate and otoluamide are suitable substrates. For arenecarboxamides possessing a meta substituent, monoarylation took place selectively, while for simple benzamide and para-substituted

Scheme 41. Iron-Catalyzed N-Directed C−H Arylation by Use of Arylborates

Organoiron(0) and organoiron(I) are less probable reactive intermediates to cleave the C−H bond via oxidative addition. Other important information revealed through the calculation is that DCIB can oxidize organoiron(II) to organoiron(III) via single-electron oxidation and thus accelerate the C−C coupling step to generate organoiron(I). DCIB can also oxidize organoiron(I) to organoiron(II) through single-electron oxidation, while the direct oxidative addition of DCIB to organoiron(I) to generate organoiron(III) is not favored. On the basis of this information, the authors proposed that, during the catalytic cycle, the oxidation state evolves in either Fe(II)/Fe(III)/Fe(I) or Fe(III)/Fe(I) cycles124,126 (Schemes 35 and 36). Besides N-arylpyridines and aromatic imines, N-methylbenzamides could also be used as a substrate for iron-catalyzed C−H arylation (Scheme 37).127 It is interesting to note that only Nmethylbenzamide functions as a suitable directing group for this reaction, while benzamide, N-isopropylbenzamide, N-phenylbenzamide, and N,N-dimethylbenzamide were all unreactive. 9101


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Scheme 42. Iron-Catalyzed Arylation of Benzamides Bearing a Triazole Directing Group

before C−H bond activation (Scheme 39). This mechanistic information supports the notion that an organoiron(III) species is responsible for C−H activation, and an Fe(III) intermediate likely formed before C−C reductive elimination to generate an Fe(I) intermediate. Thus, the stoichiometric experiment supports an Fe(III)/Fe(I) mechanism in which the Fe(I) intermediate interacts with 1,2-dichloroalkane to regenerate Fe(III). Single-electron oxidation of organoiron(I) by haloalkane was also supported by mechanistic studies in iron-catalyzed cross-coupling reactions between alkyl halides and an organometallic reagent.134−136 Two important additional features of this reaction are the zinc cocatalyst and the unique efficacy of a bis(phosphine) bearing a conjugated backbone (dppen). A 11B NMR experiment showed that transmetalation of the aryl group from borate to zinc took place in the absence of iron (Scheme 40a). Several lines of evidence suggest that, in the presence of the iron catalyst, either the gradual formation of an organozinc reagent from weakly reducing borate is distinct from directly using preformed zinc reagent or a discrete organozinc reagent is not formed at all and instead zinc simply assists the iron/boron transmetalation. The use of borate to generate zinc reagent in situ also provides a weakly reducing environment that retards the undesired

Scheme 43. Iron-Catalyzed Stereospecific C−H Arylation of Acrylamide Assisted by Triazole Directing Group

benzamides, the reaction delivered a mixture of mono- and diarylation products. Besides arenecarboxamides, alkenecarboxamides also reacted well. When tiglamide was used as a substrate, the arylation product was obtained in high yield with exclusive Z selectivity, but when acrylamide was used as a substrate, Z/E isomerization took place to give a mixture of diastereomers. In this study, important information on the valence of iron species that cleave the C−H bond was obtained through a stoichiometric experiment. Thus, in the presence of 1 equiv each of the substrate of an iron(III) salt, dppen, and a zinc(II) salt, the C−H arylation product was formed in 95% yield, accompanied by formation of a small amount of biphenyl. The mass balance of the reaction confirmed that no reduction of iron proceeded

Scheme 44. Iron-Catalyzed Arylation of Heteroarylimine with Grignard Reagent

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Scheme 45. Iron-Catalyzed Stereospecific Alkenylation of Alkene and Arene by Use of Alkenylborates

Scheme 46. Iron-Catalyzed Stereoselective Alkenylation of Alkene by Use of Alkenylzinc Reagent

assist iron-catalyzed C−H arylation of arene and alkene (Scheme 42). This system is similar to the system reported by Nakamura and co-workers, but a bis(phosphine) ligand without a conjugated backbone, dppe, was chosen as the ligand. The authors also showed that the TAM directing group was superior to 8-quinolylamine auxiliary when dppe was used as the ligand, probably because of better stabilization of a low-valent iron intermediate by TAM. The same catalyst system and directing group were applied to the syn-selective arylation of acrylamide. Under the reaction conditions, the cis product was obtained in 57% yield without Z/ E isomerization (Scheme 43).139 Deboef and co-workers140 modified the reaction conditions reported by Nakamura and co-workers for iron-catalyzed iminedirected C−H arylation and applied the reaction to the arylation of aromatic heterocycles. Furans, pyridines, and thiophenes could be arylated by Grignard reagents in 15 min at 0 °C. The slow-addition strategy developed previously was applied and found to be crucial for successful reaction (Scheme 44). 3.1.2. Alkenylation of C(sp2)−H Bonds. Besides arylation, iron catalysis is also capable of alkenylating a C(sp2)−H bond.

reduction of iron(III) reactive species. It is practically equivalent to slow addition of the Grignard reagent. On the basis of results from the stoichiometric reaction (see Scheme 39), the authors proposed an Fe(III)/Fe(I) mechanism.124,126 The authors also proposed that the efficiency of ligands possessing a conjugated backbone may indicate the redox-active nature of these ligands,137 which stabilize a low-valent iron(I) species through metal-to-ligand charge transfer (MLCT), such as A in Scheme 40b, as often observed for low-valent organoiron complexes.138 Butyllithium-activated boronates could also be utilized for monodentate nitrogen-directed C−H arylation of N-heteroaromatics. Benzoquinoline, phenylpyrazole, and 2-alkenylpyridine reacted well (Scheme 41).126 However, in contrast to the substrates possessing a bidentate directing group, these reactions generated a significant amount of homocoupling byproduct and must be carried out at lower reaction temperatures, presumably because of the lower stability of the corresponding ferracycle intermediates. Ackermann and co-workers139 reported that a 1,2,3-triazolebased bidentate auxiliary (TAM) that is easily accessible in a modular fashion could be used in place of 8-quinolylamine to 9103


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Scheme 47. Cobalt-Catalyzed Ortho Alkylation of Benzamide and N-Heterocycles

Scheme 48. Iron-Catalyzed Regio- and Stereoselective Alkylation of Alkenecarboxamide with Monoalkylzinc Reagents

Because of the lack of π−d interaction of an organoiron(III) species with an alkene, alkene isomerization reaction caused by low-valent iron118 may be avoided to achieve high stereospecificity, with the condition that low-valent iron species can be reoxidized to Fe(III) by DCIB. With this idea in mind, the reaction conditions developed for arylation of C(sp2)−H bonds with arylboronates were found to be effective also for the reaction of alkenylboronates.126 Various alkenylboronates are available with high E/Z selectivity by hydroboration141 and metathesis reactions,142,143 while the corresponding magnesium and zinc reagents are difficult to prepare. The boronate was first converted to a lithium borate in situ by activation with butyllithium and was allowed to couple with various arenes and alkenes bearing the 8quinolylamide directing group in high yield and with a high level of stereoselectivity. The stereochemistry of the alkene substrate was retained. Alkenylation of arene also proceeded smoothly with both aliphatic alkenylboronate and styrenylboronate. A highlight of this reaction is the stereoselective synthesis of trienes with high selectivity and good yields, a goal not yet achieved by precious-metal catalysts at that time (Scheme 45).

Later, Nakamura and co-workers144 also reported alkenylation of tiglamide with alkenylzinc reagents using the same directing group and iron catalyst (Scheme 46). 3.1.3. Alkylation of C(sp2)−H Bonds. Alkylation of a C(sp2)−H bond with an alkylmetal compound has generally been more challenging than that of arylation, often because of fast β-hydride elimination.145 Earlier studies by Nakamura and co-workers using cobalt catalysis146−148 demonstrated ortho alkylation of N-methylbenzamide and N-heterocyclic substrates with alkyl Grignard reagents,149 alkyl halides,150 and olefins151 (Scheme 47). However, attempts to perform an iron-catalyzed variant failed, probably because of the instability of alkyliron to generate iron black. One way to prevent premature reduction of an organoiron intermediate would be to make the iron intermediate coordinatively saturated, thus eliminating the vacant site required for alkene coordination. By using the 8-quinolylamide auxiliary132,133 in combination with a bis(phosphine) ligand to stabilize the putative alkyliron intermediate, alkylation of various alkenecarboxamides (Scheme 48) and (hetero)arenecarboxamides (Scheme 49) with alkylzinc 9104


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Scheme 49. Iron-Catalyzed Alkylation of (Hetero)arenecarboxamide with Monoalkylzinc Reagents

Scheme 50. Iron-Catalyzed Ortho Methylation of Ketimine

Scheme 51. Iron-Catalyzed Methylation of Picolinamide with Trimethylaluminum

reagents was achieved.144 Monoalkylzinc halides served as better alkyl donors than dialkylzinc or alkylmagnesium halides,

probably because their weaker reducing ability did not destroy the organoiron(III) active species. β-Hydride elimination and 9105


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Scheme 52. Iron-Catalyzed Methylation of 8-Quinolylamide with Trimethylaluminum

Scheme 53. Air-Stable DABCO·2AlMe3 as Methyl Source for Iron-Catalyzed C−H Methylation

50).117 In 2015, Nakamura and co-workers50 reported that commercially available trimethylaluminum can be used for ironcatalyzed C−H methylation. The reaction proceeded well for a wide variety of amide substrates bearing either a picolinoyl (Scheme 51) or 8-aminoquinolyl directing group (Scheme 52), enabling methylation of both (hetero)aryl and alkenyl amides. This reaction showed remarkably high efficiency, with a catalyst turnover number (TON) as high as 6500, which is rare in metalcatalyzed C−H functionalization. An air-stable trimethylaluminum derivative, bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (DABCO·2AlMe3), also acted as an effective methyl donor in this reaction (Scheme 53). An inexpensive haloalkane, 2,3-dichlorobutane, was used as the oxidant. The authors proposed that this reaction is mechanistically similar to the C−H activation reaction with boronates via an Fe(III) intermediate,126 and the weaker reducing ability of trimethylaluminum than zinc and magnesium reagent may partially account for the high TON. Unlike the reaction with zinc reagent, C−H functionalization with alkylaluminum is sensitive to the size of the aluminum reagent. Thus, triethylaluminum

Scheme 54. Iron-Catalyzed C−H Ethylation with Triethylaluminum

homocoupling of the alkyl organometallic reagent did not occur under these conditions. Primary alkyl and benzyl groups could be introduced smoothly. While cyclic secondary alkyl groups efficiently took part in the reaction, acyclic alkyl groups partially isomerized, resulting in a mixture of linear and branched alkyl products (e.g., for i-PrMgBr, branched:linear = 21:79). Notably, various alkene substrates were syn-alkylated with retention of stereochemistry. Conversion of a C−H bond to a new C−Me bond in a drug molecule can dramatically improve its binding to proteins and hence affect drug efficacy.152 However, earlier attempts at ironcatalyzed methylation−for example, reaction of an aromatic ketimine with dimethylzinc−proceeded in low yield (Scheme 9106


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Scheme 55. Ligand Effect in Iron-Catalyzed Direct Ortho Methylation of m-Toluic Acid

Scheme 56. Iron-Catalyzed Ortho Methylation of Arenecarboxylic Acids

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Scheme 57. Iron-Catalyzed Ortho Methylation of Aromatic Esters, Amides, and Ketones

Scheme 58. Iron-Catalyzed Methylation of C(sp2)−H Bonds with Triazole Assistance

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Scheme 59. Iron-Catalyzed Ethylation of C(sp2)−H Bond with Triazole Assistance

Scheme 60. Iron-Catalyzed Ortho-C−H Methylation of Aniline with Triazole Assistance

C−H activation without recourse to the use of a structurally complex directing group is obviously desirable, and this goal was recently achieved with a new tridentate phosphine ligand, 4{bis[2-(diphenylphosphanyl)phenyl]phosphanyl}-N,N-dimethylaniline (Me2N-TP). With this ligand, Nakamura and coworkers153 achieved iron-catalyzed ortho methylation of simple arenecarboxylic acids. Tridentate phosphine ligands were uniquely effective for this reaction, and among them, the electron-rich Me2N-TP performed the best. Other ligands such as monodentate phosphine, bidentate phosphine, and nitrogen ligands were ineffective (Scheme 55). The iron-catalyzed C−H methylation of arenecarboxylic acids showed several notable features compared with previous metal catalysts such as palladium. Chemoselectivity is unique, as illustrated, for example, by the preservation of arylboronate during the C−H activation (Scheme 56 , top). Coordinative heteroatoms such as nitrogen and sulfide did not poison the catalyst. For arylcarboxylic acids bearing a meta substituent, selective monomethylation took place at the less hindered C−H site. For 4-substituted benzoic acid and benzoic acid, a mixture of mono- and dimethylation products was obtained.153 The same iron/Me2N-TP catalyst could also methylate the ortho-C−H bond in aromatic ketones, esters, amides, and Nacetylindoles. Aromatic ketones possessing enolizable α-C−H reacted well. The catalyst was found to be powerful enough to methylate all of the accessible ortho-C−H bonds on benzophenone. Exclusive monomethylation of tert-butyl phenyl ketone is also remarkable. Xanthone, thioxanthone, and dibenzosuberenone gave the corresponding dimethylated products exclusively, while fluorenone gave none, probably because the small ionic size of iron does not permit the formation of a necessary ferracycle intermediate (Scheme 57).153 Ackermann and co-workers154 reported that by using TAM, the C−H bond of (hetero)arenes and alkenes could be methylated with dimethylzinc. FeCl3 was chosen as the catalyst and dppe as the ligand (Scheme 58). They also reported ethylation of an arene possessing the TAM directing group with diethylzinc (Scheme 59). Anilides were also ortho-methylated (Scheme 60).154

Scheme 61. Iron-Catalyzed Phenylation of Tetrahydrofuran with PhMgBr

Scheme 62. Iron-Catalyzed α-Functionalization of Aliphatic Amine with Grignard Reagents via 1,5-Hydrogen Transfer

3.2. Iron-Catalyzed C(sp3)−H Functionalization with Carbon Nucleophiles

3.2.1. Arylation and Heteroarylation of C(sp3)−H Bonds. An iron catalyst can also catalyze the functionalization of C(sp3)−H bonds,155,156 while the lack of a π-system for metal

smoothly took part in the reaction (Scheme 54), but larger alkylaluminum reagents (triisobutylaluminum and trioctylaluminum) did not.50 9109


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Scheme 63. Evidence for Intramolecular 1,5-Hydrogen Transfer and Kinetic Isotope Effect

Table 1. Iron-Catalyzed Allylic Arylation of Olefins with Grignard Reagents

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Scheme 64. Deuterium-Labeling Experiments for IronCatalyzed Allylic Arylation of Olefins

Scheme 66. Effect of Angle and Distance on Iron-Catalyzed βArylation of Aliphatic Carboxamides

coordination makes this process more difficult to achieve than C(sp2)−H bond activation. Nakamura and co-workers157 found one approach to addressing the problem during exploration of the cross-coupling of 4-iodotoluene with phenylzinc reagent in tetrahydrofuran as the solvent. Arylation of the α-C−H bond in

tetrahydrofuran shown in Scheme 61 requires an oxidant, and 4iodotoluene functioned as the oxidant to generate toluene. A similar reaction was also observed during the preparation of phenylmagnesium bromide from bromobenzene in the presence of a catalytic amount of Fe2O3.158 These reactions proceed through hydrogen abstraction from THF by an aryl radical generated through single-electron oxidation of low-valent organoiron by aryl halides, followed by the recombination of 2tetrahydrofuranyl radical to iron and reductive elimination to form the C−C bond. Nakamura and co-workers157 used the mechanistic hypothesis of THF arylation to design an iron-catalyzed α-arylation of aliphatic amines through 1,5-hydrogen transfer (Scheme 62).

Scheme 65. Iron-Catalyzed β-Arylation of Aliphatic Carboxamide: (a) Arylation of C(sp3)−H through a Putative Ferracycle Intermediate; (b) Effect of Directing Groups; and (c) Effect of Ligands

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Grignard reagent first reacts with the iron(III) species to generate a phenyliron species, which reacts with mesityl iodide to generate a coordinatively unsaturated iron species (A). This species coordinates with the olefin to generate intermediate B, and next the aryl groups abstract the allylic hydrogen to generate two allyliron species (C and D). Reductive elimination takes place selectively from intermediate C to form the arylation product, while intermediate D does not undergo reductive elimination. Mesityl iodide was an optimal oxidant because it does not undergo undesired cross-coupling with the Grignard reagent. The reactivity difference between trans- and cis-βmethylstyrene and the observed regioselectivity are consistent with the formation of an allyliron intermediate rather than a freeradical pathway (Table 1). The reaction took place at 0 °C, and a catalyst turnover up to 240 could be achieved. Under similar conditions, PhMgBr phenylates cyclohexane in 10% yield at 0 °C (Table 1, entry 12), indicating the potential for functionalization of simple hydrocarbons. Deuterium-labeling experiments supported the hydrogen-abstraction mechanism. Thus, deuterium incorporation into both butylbenzene and mesitylene occurred in the reaction of deuterated cyclohexene with 4-BuC6H4MgBr. A large intermolecular KIE suggested that hydrogen abstraction is the slow step (Scheme 64).159 In 2013, Nakamura and co-workers160 reported an ironcatalyzed directed C(sp3)−H activation, where various 2,2disubstituted propionamides bearing an 8-aminoquinolyl group were arylated with arylzinc reagents at the β-position in the presence of an Fe(III) salt, a bis(phosphine) ligand, and DCIB as an oxidant (Scheme 65). The sensitivity of the reaction to the structure of the directing group, ligand, and substrate, together with the observed propensity to react at the methyl rather than the benzylic position, suggests an organometallic mechanism that involves such an intermediate as ferracycle A (Scheme 65). The investigation of cyclic substrates revealed an interesting observation (Scheme 66): cyclohexane- and cyclopentanecarboxamide reacted well to give the arylation product in 75% and 69% yield, respectively, but the corresponding cyclobutane- and cyclopropanecarboxamides did not react at all. The authors explained this observation by the influence of the CH3−C−C(O) bond angle (θ) and distance (l) on formation of the putative ferracycle intermediate (Scheme 67). This angle and distance for the unreactive substrates are much larger than for the reactive substrates, making formation of the ferracycle intermediate less feasible. The KIE measured for two parallel reactions indicated that cleavage of the C(sp3)−H bond is the

Scheme 67. Deuterium-Labeling Experiment and Kinetic Isotope Effect of Iron-Catalyzed β-Arylation of Aliphatic Carboxamide

Thus, they discovered that an N-IBn (IBn, o-iodobenzyl) group in aliphatic amines serves as an internal trigger to generate an aryl radical (A) upon interaction with organoiron species through single electron transfer from iron. The aryl radical intramolecularly abstracts the α-hydrogen via 1,5-hydrogen transfer to generate an α-aminoalkyl radical (B). This alkyl radical recombines with the organoiron species (C), and subsequent reductive elimination delivers the α-arylamine product. The iron halide reacts with the organometallic reagent to regenerate the reactive organoiron species. This reaction proceeds within 15− 30 min, and the reaction rate is insensitive to the substituent on the aryl Grignard reagent. A broad range of aliphatic amines, including both cyclic and acyclic ones, could be used successfully. For an aniline substrate, the reaction was sluggish and gave the arylation product in low yield. A deuterium-labeling experiment confirmed that the 1,5hydrogen transfer takes place intramolecularly. The reaction of a 1:1 mixture of tetradeuterated N,N-diethylamine and piperidine substrates with 2.0 equiv of 4-fluorophenylmagnesium bromide gave the two arylation products quantitatively, where the deuterium was detected only in the ortho position of N,Ndiethylamine products in 100% incorporation without any H−D crossover. An intermolecular KIE experiment indicates that 1,5hydrogen transfer is not the turnover-limiting step (Scheme 63). This reaction reveals that organoiron species can exhibit both radical and organometallic behavior, and synthetic strategies used in radical chemistry, such as radical translocation, can be merged with iron catalysis to develop new reactions. Nakamura and co-workers159 further utilized this reactivity to arylate the allylic C−H bond of olefins, and even the C−H bond of unactivated alkanes. As hypothesized at the top of Table 1, a

Scheme 68. Iron-Catalyzed β-Arylation of Aliphatic Carboxamide Assisted by a Triazole Directing Group

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Scheme 69. Iron/Zinc Cocatalyzed β-Arylation of Aliphatic Carboxamide by Use of Arylborate Reagents

Scheme 70. Possible Reaction Pathway with Suggested Coordination Geometry

directing group, the reaction conditions and selectivity are the same as for reactions using the 8-quinolylamide directing group (Scheme 68). The borate reagents serve as much better donor reagents in the iron-catalyzed C(sp2)−H functionalization (section 3.1) than organozinc and Grignard reagents, and they show broader

turnover-limiting step. This study revealed that the organoiron species is capable of activating a saturated C−H bond via chelation-assisted cyclometalation.91 Ackermann and co-workers139 extended this chemistry to functionalization of aliphatic amides bearing a 1,2,3-triazolebased bidentate auxiliary (TAM). Apart from the different 9113


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Scheme 71. Iron-Catalyzed α-Alkenylation of Amines via 1,5Hydrogen Transfer

Scheme 74. Iron-Catalyzed β-Methylation of Carboxamide by Use of Trimethylaluminum

Scheme 72. Iron-Catalyzed Stereoselective β-Alkenylation of Carboxamides

in higher yield. Several amide substrates that reacted sluggishly with organozinc reagents (e.g., 2-phenyl-substituted propionamide)160 reacted well with borate. On the basis of previous studies on the reaction of arenecarboxamides with boronates,126 a stoichiometric reaction,126 and a density functional theory (DFT) study,124 the authors proposed a reaction mechanism (Scheme 70). A zinc amide is generated first by zinc-assisted deprotonation of the amide in the substrate to generate a zinc amide C (Scheme 70a). Amide deprotonation by lithium borate is very slow in the absence of the zinc salt. Next, boron/iron transmetalation gives organoiron(III) intermediate D. The lack of biphenyl suggests that the organoborate delivers only one organic group to generate monophenyliron complex D (X = OAc or acac). C−H activation of an iron(III) complex D through σ-bond metathesis94,124,162 via H to metalacycle I is a probable mechanism, while an oxidative addition mechanism [via F to produce an iron(V) species G] is highly unlikely. Ferracycle I will finally undergo reductive elimination in the presence of phenyl anion to create the C−C bond and to generate organoiron(I) intermediate J, which may be stabilized by electron delocalization over the ligand backbone of dppen.126 When a more nucleophilic base such as Ph2Zn is used, a large amount of biphenyl formed, probably suggesting the formation of a diphenyliron complex (D, X = Ph), which reductively eliminates to give biphenyl and a lowvalent organoiron E (Scheme 70b). 3.2.2. Alkenylation of C(sp3)−H Bonds. There have been few reported examples of alkenylation of a C(sp3)−H bond catalyzed by organoiron species until recently. There are two recent examples reported by Nakamura and co-workers157 of iron-catalyzed α-C−H functionalization of amine via 1,5hydrogen transfer (Scheme 71). When an alkenyl Grignard reagent was used, the alkenylation product was obtained in good yield. This reaction must be mechanistically similar to the corresponding arylation reaction discussed earlier (see Scheme 62).

reaction scope and better functional-group compatibility. Similarly, they are useful for the C(sp3)−H arylation of aliphatic carboxamides bearing an 8-quinolyl group (Scheme 69).161 A cocatalytic system consisting of 10 mol % iron(III) and 20 mol % zinc(II) was used, where a zinc(II) cocatalyst assists deprotonation of the amide and iron/boron transmetalation. Reactions at higher concentration proceeded faster and delivered the product

Scheme 73. Iron-Catalyzed α-Alkylation of Aliphatic Amine via 1,5-Hydrogen Transfer

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Scheme 75. Iron-Catalyzed β-Methylation of Carboxamide with Triazole Assistance

Scheme 76. Iron-Catalyzed C−H Alkylation of Tiglamide with Phenethyl Tosylate

Scheme 77. Selected Examples of Iron-Catalyzed Alkylation of Aryl- and Alkenylcarboxamides

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Scheme 78. Radical-Clock Experiment in Iron-Catalyzed Direct Ortho Alkylation of Carboxamides with (Pseudo)alkyl Halides

Scheme 79. Fe(acac)3/dppe-Catalyzed Ortho Benzylation of Arenecarboxamide with Benzyl Halides

Scheme 80. Fe(acac)3/dppe-Catalyzed Alkylation of Arenecarboxamides with Secondary Alkyl Halides

dppen ligand (MeO-dppen). This electron-rich ligand renders the reaction faster and higher-yielding than the parent dppen ligand. (E)-Alkenyl borate remained at 100%, while the (Z)alkenyl borate reacted with 83% stereoretention (Scheme 72).

Alkenyl pinacol boronate activated with butyllithium can be used as an alkenyl nucleophile to be coupled with a β-C−H bond in an aliphatic carboxamide bearing an 8-quinolyl auxiliary.161 The catalyst system developed for this process contains a catalytic amount of Fe(III), Zn(II), and a methoxy-substituted 9116


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Scheme 81. Fe(acac)3/dppe-Catalyzed Alkylation of Arenecarboxamide with Primary Alkyl Halides

Scheme 82. Iron-Catalyzed Direct Alkylation of Arenecarboxamide with Triazole Assistance

Scheme 83. Iron-Catalyzed Monoselective Ortho-C−H Allylation of Arenecarboxamides with Phenyl Allyl Ether

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Scheme 84. γ-Selectivity in Iron-Catalyzed Ortho Allylation of Arenecarboxamide

Scheme 85. Intermolecular Kinetic Isotope Effect in IronCatalyzed Ortho Allylation with Phenyl Allyl Ether

Scheme 87. Substrate Scope for Iron-Catalyzed C−H Allylation

3.2.3. Alkylation of C(sp3)−H Bonds. Creation of a C(sp3)−C(sp3) bond through iron-catalyzed C(sp3)−H activation still remains a challenging task in iron catalysis. This may be

attributed to the weak interaction of an iron catalyst with saturated C(sp3)−H bonds, and poor stability of both C(sp3)−

Scheme 86. Iron-Catalyzed Allylation of N-Arylpyrazole with Allyl Electrophiles

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Scheme 88. Iron-Catalyzed Ortho Allylation of (Hetero)arene- and Alkenecarboxamides with Allylic Chloride Assisted by Triazole Directing Group

Scheme 89. Iron-Catalyzed N-Directed Arylation of C(sp2)− H with Aryl Halides

before (see Scheme 62), and under the same reaction conditions, an alkylmagnesium halide can alkylate the amine at the αposition in moderate yield, together with a large amount of homocoupling byproduct generated from the dimerization of hexylmagnesium bromide (Scheme 73).157 Creation of a C(sp3)−C(sp3) bond via cyclometalation has been limited to methylation of propionamides. Nakamura and co-workers50 reported that trimethylaluminum can be used to methylate 2,2-disubstituted propionamides in the presence of Fe(acac)3/Ph-dppen as a catalyst and 2,3-dichlorobutane as an oxidant (Scheme 74). The selectivity observed in this reaction was similar to the analogous reaction using arylzinc160 and borate161 reagents, and may proceed through a similar mechanism. Ackermann and co-workers154 reported the methylation of the β-C−H bond of aliphatic carboxamide possessing a triazole auxiliary with dimethylzinc (Scheme 75). The scope and selectivity of this reaction are very similar to the report by Nakamura and co-workers.50 In this reaction, activation of a primary C−H bond is overwhelmingly preferred over a benzylic C−H bond, and further methylation on the secondary C−H bond of the product did not proceed. The observed selectivity suggests that the reaction proceeds through an organometallic mechanism, and radical cleavage of the C−H bond is unlikely.

ferracycle and the alkyliron species, as well as the high propensity of alkyliron to undergo β-hydride elimination. To date, there are only a few examples of iron-catalyzed C(sp3)−H activation, leading to the interaction of an alkyl group. Nakamura and coworkers157 reported one example during the study of ironcatalyzed α-functionalization of amines through 1,5-hydrogen transfer. This hydrogen-abstraction reaction was discussed 9119


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Scheme 90. Iron-Catalyzed [4 + 2] Benzannulation of Alkynes with Biaryl or 2-Alkenylphenyl Grignard Reagents

Scheme 91. Iron-Catalyzed [4 + 2] Benzannulation of 1,2-Diyne with Biaryl Grignard Reagent

3.3. Iron-Catalyzed C(sp2)−H Functionalization with Carbon Electrophiles

alkyl tosylates, mesylates, and halides (Scheme 76). A notable feature of this reaction is the use of alkanol derivatives such as tosylates and mesylates, largely ignored as an alkyl donor for C− H activation. The ligand played an important role in this reaction to facilitate C−H alkylation and to suppress undesired crosscoupling or C−H arylation, as shown at the bottom of Scheme 76. Bis(phosphine) ligands with a conjugated backbone were essential for this reaction, while monodentate phosphine and bipyridine ligands were totally inefficient, resulting in recovery of the starting amide. Another important feature of this reaction is the high stereospecificity, as the reaction cleanly delivered the syn-alkylated product. Another feature is the selective reaction of a secondary tosylate (e.g., 2-butyl tosylate), as isomerization through β-hydride elimination often occurs to deliver a mixture of linear and branched products. The stereochemistry of a chiral center connected to a tosyloxy group in a secondary alkyl tosylate was

The reactions described in section 3.2 utilized organometallics as the donor of the organic group to be transferred in the presence of an oxidant.163 Nakamura and co-workers164 reported in 2013 that electrophiles could be used as a coupling partner in ironcatalyzed C−H functionalization. These reactions require no oxidant, but to deprotonate the C−H bond, they need a base that does not react with the electrophile. Various types of bond formations have been achieved by this reaction protocol, including coupling with alkyl electrophiles,165 allylic electrophiles,164,171 or amine electrophiles.166 3.3.1. Alkylation of C(sp2)−H Bonds. Nakamura and coworkers165 reported that, in the presence of a catalytic amount of Fe(acac)3, dppen as a ligand, and ArZnBr as a base, alkenes, arenes, and heteroarenes bearing 8-quinolylamide as a directing group can be alkylated with a variety of primary and secondary 9120


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Scheme 92. Iron-Catalyzed [2 + 2 + 2] Annulation of Grignard Reagents with Alkynes

Scheme 93. Iron-Catalyzed Annulation of Arylindium with Alkynes

previous reports167 on the radical-like nature of alkyliron species. Tertiary alkyl halides did not react under these conditions. Cook and co-workers168 reported that a similar reaction proceeds in the presence of a catalytic amount of Fe(acac)3, dppe instead of the dppen that Nakamura found useful for the same type of reaction, and PhMgBr as base added slowly to the reaction mixture. Under these conditions, they achieved the

eroded during the reaction, which suggests a radical nature of the alkyliron intermediate (Scheme 77).38 Radical-clock experiments also confirmed the radical nature of the alkyliron intermediate. Thus, the reaction of 5-hexenyl tosylate delivered mainly a cyclized product without the olefin isomerization. Cyclopropylmethyl bromide reacted to give the ring-opened product (Scheme 78). These results are consistent with numerous 9121


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Scheme 94. A Possible Catalytic Cycle for the Iron-Catalyzed [2 + 2 + 2] Annulation Reaction of Arylindium with Alkyne

Scheme 95. Iron-Catalyzed Imine-Directed C2 Alkylation of Indole with Styrenes

KIE (kH/kD = 2.9) were observed. The authors rationalized these values with a mechanism involving turnover-limiting binding of the substrate to iron, followed by rapid and irreversible C−H cleavage. Similar to the oxidative reactions discussed in section 3.2, a triazole-based directing group can also be used for iron-catalyzed C−H coupling with alkyl electrophiles.170 Thus, various primary and secondary alkyl bromides, as well as methyl iodide, could alkylate amides under conditions similar to those reported by Cook et al. (Scheme 82). 3.3.2. Allylation of C(sp2)−H Bonds. Chronologically, the first report on iron-catalyzed C−H functionalization with electrophiles was the coupling of N-(quinolin-8-yl)benzamide with allyl phenyl ether (Scheme 83).164 The use of allyl phenyl ether as an electrophile for iron-catalyzed C−H functionalization, however, was serendipitously discovered earlier by Nakamura and co-workers33 in 2008, during optimization of oxidants for iron-catalyzed arylation of N-phenylpyrazole with diarylzinc (see Scheme 86). After five years of optimization, the authors found that by using 8-quinolylamide as a directing group

reaction of benzyl and secondary halides (Schemes 79 and 80). For coupling with secondary alkyl bromides, 1 equiv of 2,6-ditert-butyl-4-methylphenol (BHT), a radical scavenger, was used as an additive, presumably to suppress undesired overalkylation by trapping the transient secondary alkyl radicals. When secondary alkyl bromides were used under these reaction conditions, regioisomerization took place to deliver a mixture of linear and branched products (Scheme 80). The reaction time was typically short (5−8 min), which may reflect fast generation of highly reactive organoiron species generated by the slowly added Grignard reagent.123 Cook and co-workers169 subsequently reported on the same reaction for primary alkyl bromide as a separate report (Scheme 81). Coupling of primary alkyl bromides proceeds under similar conditions with the reaction of benzyl chloride, with slight tuning of the addition time and amounts of reagents. A radical-clock experiment similar to that of Nakamura gave the same results (see Scheme 78).165 The authors also measured the intramolecular and intermolecular KIE: a small intermolecular KIE (kH/kD = 1.5, up to 6% yield) and a significant intramolecular 9122


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Scheme 96. Iron-Catalyzed Imine-Directed C2 Alkenylation of Indole with Alkynes

Scheme 97. Evidence for C−H Bond Activation via Oxidative Addition to Fe/N-Heterocyclic Carbene Complex and Proposed Catalytic Cycle

stereoselectivity (E/Z = 59/41). The reaction of α-deuterated allyl phenyl ether proceeds with high γ-selectivity (Scheme 84). An intermolecular KIE was not observed (kH/kD = 1.1), suggesting that the reaction may proceed via fast iron-catalyzed C−H activation, followed by reaction of the organoiron intermediate with allyl phenyl ether (Scheme 85). The iron-catalyzed ortho allylation of N-arylpyrazole was further optimized by Nakamura and co-workers,171 and the desired allylation product was selectively obtained in the presence of iron/dtbpy catalyst and a phenylzinc reagent as a

and dppen as a supporting ligand, allylation with allyl phenyl ether proceeds smoothly in the presence of an iron catalyst and an organozinc base. Potential side reactions, such as coupling of organozinc with allyl phenyl ether or oxidative C−H functionalization with the organometallic reagent, did not occur. A variety of electron-rich and -deficient arenes were successfully allylated monoselectively. Iron-catalyzed isomerization of the double bond to styrene products was not observed (Scheme 83).164 Reaction with α-substituted allyl phenyl ether gave the allylation product in high yield but with little 9123


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3.3.3. Arylation of C(sp2)−H Bonds. The use of aryl electrophiles for iron-catalyzed C−H functionalization is challenging, probably because the Ar−X bond is stronger than the alkyl−X bond. Only one “formal” iron-catalyzed nitrogendirected C−H coupling with aryl bromides has been reported. This reaction probably proceeds through in situ formation of an aryl Grignard reagent, followed by participation of the Grignard reagent in the iron-catalyzed oxidative C−H arylation reaction discussed in section 3.2 (Scheme 89).128

Scheme 98. Iron−Carbonyl-Catalyzed Annulation of N−H Imines with Internal Alkynes via C−H Activation

3.4. Iron-Catalyzed Addition of C(sp2)−H to Alkenes and Alkynes

Alkenes and alkynes coordinate to low-valent iron to form alkene−iron or alkyne−iron complexes.39,172 Thus, it is reasonable to assume that a ferracycle intermediate generated via C−H activation can react with an alkene or alkyne to give alkylation, alkenylation, or cyclization products. In 2011, Nakamura and co-workers173 reported the synthesis of phenanthrene derivatives via iron-catalyzed [4 + 2] benzannulation of alkynes with 2-biaryl Grignard reagents. In the presence of Fe(acac)3/dtbpy as a catalyst and DCIB as an oxidant, cyclization of an alkyne with 2-biaryl Grignard reagent readily proceeded to give 9-substituted or 9,10-disubstituted phenanthrene derivatives (Scheme 90). This reaction may proceed through the formation of a five-membered ring ferracycle intermediate A followed by alkyne insertion and reductive elimination. On the basis of deuterium labeling, one can rule out another pathway that involves carbometalation of the alkyne (to generate alkenyliron species (B)) and intramolecular C−H activation/reductive elimination. The reaction proceeded well for a wide variety of alkynes, including alkenyl aryl alkyne, alkyl aryl alkyne, dialkyl alkyne, and even a terminal alkyne such as phenylacetylene. Highly electron-deficient alkynes and sterically hindered alkynes also reacted. 2-Heteroarylphenyl and 2alkenylphenyl Grignard reagents could also function as substrates. The reaction took place with remarkable chemoselectivity, as demonstrated by the tolerance of bromide, chloride, trimethylsilyl, trifluoromethyl, and olefin groups (Scheme 90). The reaction of 1,3-diyne with 2-biphenylmagnesium bromide resulted in 2-fold annulation to deliver a congested, twisted bis(phenanthrene) compound, of interest for materials science (Scheme 91).174 Nakamura and co-workers175 also reported an iron-catalyzed oxidative [2 + 2 + 2] annulation of aryl Grignard reagents with two molecules of an internal alkyne to form polysubstituted naphthalenes through C−H activation (Scheme 92). The reaction proceeds smoothly at 0 °C in the presence of an Fe(acac)3/1,10-phenanthroline catalyst. The reaction may proceed through iron-catalyzed carbometalation of the alkyne with an aryl Grignard to form an alkenyliron species (A), followed by intramolecular C−H activation to form a fivemembered ferracycle (B). Next, insertion of a second molecule of alkyne, followed by reductive elimination and oxidation by DCIB, delivers the cyclization product and regenerates the iron catalyst. Both diaryl alkynes and dialkyl alkynes could be used, although the yield was low for dialkyl alkynes. When the aryl group of the Grignard reagent and the aryl group of the diaryl alkyne are different, the reaction gives a mixture of regioisomers, probably because of the isomerization of intermediate A, leading to the generation of two different ferracycles (B). Adak and Yoshikai176 have developed a similar [2 + 2 + 2] annulation reaction of arylindium reagents (Scheme 93). An iron−bis(phosphine) complex was used as the catalyst, and no

Scheme 99. Pyridone Synthesis via Iron-Catalyzed Oxidative Annulation of Amide and Alkyne

base at 0 °C. The undesired C−H phenylation could be suppressed to less than 3%. Among various allyl electrophiles tested, phenyl allyl ether was the most suitable allyl source, while other allyl donors such as thioether and silyl ether were not as suitable (Scheme 86). The reaction of N-arylpyrazoles delivered allylated pyrazole derivatives with exclusive monoselectivity in a γ-selective fashion (Scheme 87). Other N-heterocycles, such as 2-phenylpyridine or benzoquinoline, were either unreactive or reacted poorly under the reaction conditions. Ackermann and co-workers170 later expanded the scope of iron-catalyzed ortho-C−H allylation to (hetero)arenes and alkenes bearing a triazole amide auxiliary. The authors used allyl chloride in the presence of Fe(acac)3/dppe as a catalyst and phenylmagnesium bromide as a base. Acyclic alkenes could be allylated with syn selectivity without E/Z isomerization. However, contrary to the high γ-regioselectivity reported by Nakamura and co-workers, Ackermann and co-workers reported that allyl chlorides possessing a substituent at the α- or γ-position gave a mixture of linear and branched products, and the branched isomer was the major product (Scheme 88). 9124


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Scheme 100. Steric Control in Iron-Catalyzed Annulation of Alkeneamide with Alkyne

Scheme 101. Isoquinolone Synthesis via Iron-Catalyzed Oxidative Annulation of Amide with Alkyne

phenylpropyne or 1-phenyl-1-butyne was used as the substrate, the reaction proceeded with high regioselectivity to produce 1,4dialkyl-2,3-diphenylnaphthalenes. This selectivity may suggest a mechanism that involves insertion of alkyne into the ferracycle (A) formed after carbometalation and C−H activation to form a bis(alkenyl)iron species (B), followed by reductive elimination to form naphthalene instead of forming aryl alkenyl-ligated iron intermediate (C). Unsymmetrical dialkyl alkenes showed no selectivity and produced an equimolar mixture of four regioisomers. In contrast to the reaction reported by Nakamura and co-workers using aryl Grignard reagents, the Yoshikai conditions using arylindium do not require an external oxidant. Yoshikai and co-workers177 also reported an iron/Nheterocyclic carbene system for alkylation and alkenylation reactions of indole with styrenes and alkynes at the C2-position through an imine-directed C−H activation (Schemes 95 and 96). The active iron catalyst was generated in situ from Fe(acac)3, an imidazolium salt, and a Grignard reagent. When β-methylstyrene was used as a substrate, the cis stereoisomer reacted well, while trans-β-methylstyrene reacted poorly, suggesting the importance of olefin coordination to the organoiron intermediate. The reaction was applied to various alkynes, including diaryl alkynes, dialkyl alkynes, and silyl alkyne. The reaction proceeded with

Scheme 102. Organometallic Base-Induced Selectivity between Oxidative Annulation and Alkenylation

additional oxidant was required. The authors proposed that an indium hydride species forms to regenerate the iron catalyst (Scheme 94). Arylindium reagents bearing electron-donating substituents reacted faster than those bearing electron-deficient substituents. Besides dialkyl alkynes, diaryl alkynes and aryl alkyl alkynes also reacted, albeit in moderate yield. When 19125


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Scheme 103. Mechanistic Pathways of C(sp3)−H Amination via Iron−Nitrene Intermediate

Scheme 104. Reaction of N-Chloromorpholine with Iron Intermediate Generated through C−H Bond Activation

Scheme 105. Iron-Catalyzed C−H Amination Enabled by Double Slow Addition and Choice of Ligand

good stereo- and regioselectivity: E-isomers were the major isomer, and E/Z selectivity higher than 99/1 was achieved (Scheme 96). When an unsymmetrical diaryl acetylene bearing a mesityl and a phenyl group was used as a substrate, the alkenylation product formed in 70% yield with exclusive regioselectivity, forming a C−C bond adjacent to the phenyl group. Similar high regioselectivity was also observed in the reaction of silyl alkynes and styrenes, where the C−C bond formed at the distal position to the silyl group. A deuteriumlabeling experiment revealed that the D atom at the C2 position of indole was completely incorporated (97% incorporation) into the vinylic position. This evidence points to a mechanism

involving oxidative addition of the C−H bond to a low-valent iron−carbene complex rather than a deprotonation mechanism. Hydrometalation of alkyne or alkene with the iron hydride species followed by reductive elimination delivers the product and regenerates the iron catalyst (Scheme 97).177 As discussed in section 2.1, iron(0) carbonyl complexes can insert into arene C−H bonds with the assistance of an imine directing group.98−100 On the basis of this stoichiometric reaction, Wang and co-workers105 designed an iron-catalyzed redox-neutral [4 + 2] cyclization reaction between aromatic imines and internal alkynes to produce cis-3,4-dihydroisoquinolines (Scheme 98). 9126


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Scheme 106. Scope of Iron-Catalyzed Ortho Amination of Arenecarboxamides

4. IRON-CATALYZED C−H ACTIVATION/C−X BOND-FORMATION REACTIONS

An iron/bis(phosphine) catalyst is also capable of catalyzing the cyclization reaction of alkene- and arenecarboxamides with alkynes to give pyridones and isoquinolones (Scheme 99).178 The C−N bond is created after C−H activation in the presence of an organoiron catalyst, an organometallic base, and a mild dichloroalkane oxidant. The reaction tolerated a broad range of internal alkynes, including diaryl alkyne, dialkyl alkyne, silyl alkyne, 1,3-diyne, and enyne. The regioselectivity of the reaction with unsymmetrical alkynes is controlled by the β-substituent on the alkeneamide substrate (Scheme 100). The authors ascribed the high regioselectivity to the sensitivity of the organoiron intermediate to steric effects. For isoquinolone synthesis, benzamides bearing N-8-quinolyl or picolinyl groups as a directing group could be used, and the latter is removable (Scheme 101). The authors also showed that the nature of the organometallic base plays an important role in dictating the selectivity between alkenylation and cyclization. When monoorganozinc halide was used as the base, the alkenylation product was observed as the major product regardless of the presence or absence of dichloroalkane oxidant. However, the cyclization product was exclusively formed when diorganozinc was used as the base in the presence of dichloroalkane. This selectivity was rationalized by the stronger nucleophilicity of diorganozinc, which may form a ferrate species that is readily oxidized to promote C−N bond formation (Scheme 102).

4.1. Amination of C−H Bonds

There have been several reports on iron-catalyzed amination or amidation of C−H bonds. However, most of these reactions include a nitrene mechanism involving the insertion of an iron nitrene intermediate into a C−H bond68,69,179−183or an electrophilic substitution pathway.184 C−H amination via ironimido/nitrene-mediated or -catalyzed N-group transfer has been proven an efficient way to synthesize various amino compounds, especially in the case of direct amination of a secondary or tertiary C−H bond, which is difficult to metalate by use of a transition metal complex. Representative examples in this field include the work of Che and co-workers,69 Paradine and White,182 and Betley and co-workers,181 who reported that iron−porphyrin, iron−phthalocyanine, and non-heme iron complex can be used as effective catalysts. The mechanism of C−H amination mediated by iron-imido species includes generation of an ironimido species through a nitrene precursor, followed by either radical H-atom abstraction/rebound or a direct nitrene insertion into the C−H bond to generate the amination product; both of these pathways do not involve the formation of an Fe−C bond (Scheme 103). Amination via iron-catalyzed C−H cleavage to form an organoiron species has scarcely been investigated. In 2014, Nakamura and co-workers166 found that a ferracycle intermediate stoichiometrically generated in situ reacts with 9127


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Scheme 107. Synthesis of Dihydrophenazines via Iron-Catalyzed Intramolecular Ring Closing C−H Amination

Scheme 108. Terminal C−H Borylation of Alkane by Use of Iron Boryl Complex

Scheme 110. Borylation of Furans and Thiophenes Catalyzed by Half-Sandwich Iron N-Heterocyclic Carbene Complex

Scheme 109. Borylation of Arene and Alkene Promoted by Iron Boryl Complexes

metallic base,185 and thus succeeded in making the reaction catalytic in iron (Scheme 105). The bis(phosphine) ligand was crucial for controlling the reactivity, and the reaction outcome was sensitive to the electronic nature of the ligand. For example, an electron-rich dppbz derivative (4-MeO-dppbz) slowed down the amination and instead accelerated the undesired phenylation. An electron-deficient dppbz derivative (4-F-dppbz) was found to be the best ligand, which suppressed the phenylation side reaction and delivered the amination product in quantitative yield. Further increase of fluorine atoms on the phosphine ligands decreased the yield of the amination product (Scheme 105). Bench-stable N-benzoyloxyamines could also be used for the reaction.

chloroamine to give the amination product (Scheme 104). Guided by this example, the authors developed a double slowaddition strategy, to suppress the undesired ortho phenylation of the amide and the reaction of chloroamine with the organo9128


Chemical Reviews

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Scheme 111. Stoichiometric Reactions and Catalytic Cycle for FeCp*(N-Heterocyclic Carbene)Me-Catalyzed Borylation of Furans and Thiophenes

4.2. Borylation and Silylation of C−H Bonds

Under the optimized conditions, a variety of chloroamines, including cyclic and acyclic chloroamines, could be used for ortho-C−H amination of arenes and heteroarenes bearing 8quinolylamide as the directing group. The reaction was sensitive to steric hindrance, and monoaminated products were obtained selectively (Scheme 106).166 An interesting example of iron-catalyzed intramolecular C−H amination for the synthesis of dihydrophenazines was reported by Nakamura and co-workers.186 The substrate scope is narrow, while the mechanism of this reaction is intriguing. Thus, a mechanism that involves C−H activation, followed by reductive elimination to form the C−N bond, may be operative, while an alternative electrophilic amination pathway was also proposed by the authors (Scheme 107).

Borylation of a C−H bond produces boronic acids or their esters, which are important intermediates in organic synthesis, in a straightforward manner.187,188 Hartwig and co-workers189−192 reported in the 1990s that a half-sandwich iron boryl complex reacts with alkanes (Scheme 108) and with arenes and alkenes (Scheme 109) to give borylated products. This stoichiometric reaction was recently made catalytic. For example, Tatsumi and co-workers193 reported that a half-sandwich iron N-heterocyclic carbene iron complex catalyzes borylation of furan and thiophene with pinacolborane in the presence of an alkene as hydrogen acceptor (Scheme 110). The authors also studied stoichiometric transformations, revealing that an alkyl half-sandwich iron−carbene complex 9129


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Scheme 112. Iron-Catalyzed C−H Borylation Enabled by Fe− Cu Cooperativity

Scheme 114. Irradiation-Promoted Iron-Catalyzed C−H Borylation of Arenes and Catalytic Cycle

Scheme 113. Proposed Mechanism for C−H Borylation Enabled by Fe−Cu Cooperativity

Scheme 115. Scope of Iron-Catalyzed C−H Borylation of Arenes

can react with an arene to form an aryl half-sandwich iron− carbene complex through a deprotonation/ferration mechanism (Scheme 111). The resulting aryl half-sandwich iron−carbene complex reacts with borane to deliver the borylation product, together with an iron borohydride complex. On the basis of these stoichiometric reactions, the authors proposed the catalytic cycle in Scheme 111: (1) The half-sandwich methyliron carbene complex (A) reacts with an arene to generate an aryliron complex (B). (2) Complex B reacts with HBpin to form an iron hydride intermediate (D) and to deliver the borylation product. (3) D reacts with tert-butylethylene to generate an alkyliron intermediate (C), which reacts with arene to regenerate the aryliron intermediate (B). Because the iron borohydride complex (E) does not react in the catalytic cycle and only leads to decomposition, its formation disturbs the catalytic cycle. As demonstrated by the stoichiometric reaction in Scheme 109, the half-sandwich iron carbonyl boryl complex can borylate the C−H bond of arenes and generate a half-sandwich iron carbonyl hydride complex under photochemical conditions.

However, this iron carbonyl hydride complex rapidly dimerizes into an inactive complex, together with the generation of hydrogen by a single-electron redox process. To suppress this reaction, Mankad and co-workers194,195 designed a metal−metal cooperative catalysis strategy. Thus, they reported that an IPrCuFeCp(CO)2 complex catalyzes borylation of arenes with pinacolborane. Arenes could be borylated at 5 mol % catalyst loading to afford products in synthetically useful yields. The reaction was sensitive to the steric bulk of the arene. However, borylation of a substituted benzene at the ortho position was inefficient (Scheme 112). A mechanism for Cu−Fe cooperativity was proposed that assumed involvement of a bimetallic oxidative addition for B−H bond activation and a bimetallic reductive elimination for generation of dihydrogen. A Cu−H species reacts rapidly with an Fe−H species to release hydrogen and to regenerate the bimetallic catalyst, which readily reacts with H-Bpin, which is 9130


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Scheme 116. Iron-Catalyzed C3-Selective C−H Silylation of N-Methylindole

Scheme 117. Iron-Catalyzed Tritiation of Arenes: (a) Selectivity between Ir and Fe Catalysts and (b) Selected Examples of IronCatalyzed H−D Exchange of Arene

inefficient, possibly because of directed ortho metalation on a phenyl group in dppe that kills the iron catalyst80,87 (Scheme 114). The authors successfully prepared and isolated an iron boryl complex (trans-D) from the active iron precatalyst and proved its involvement in the catalytic cycle. On the basis of information from the stoichiometric reaction, the authors proposed a catalytic cycle (Scheme 114). First, dmpe-ligated iron(0) complex (A)

the key for successful turnover of the bimetallic system (Scheme 113). We discussed in section 2.2 that a dmpe/iron(0) complex readily cleaves an arene C−H bond through oxidative addition.84 This reactivity was applied to the dehydrogenative borylation of simple (hetero)arenes with pinacolborane under UV irradiation.196 Both FeH2(dmpe)2 and FeMe2(dmpe)2 were good catalysts, but a similar complex using dppe was completely 9131


Chemical Reviews

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Scheme 118. Iron-Catalyzed Deuteration and Tritiation of Drug Molecules

candidates and hence important for drug discovery and development. The authors also demonstrated the use of this method for tritiation of commercialized drug molecules such as Cinacalcet (Scheme 118).

may react with an arene through reversible oxidative addition of the C−H bond to iron to form an iron hydride intermediate (B). This iron hydride complex reacts with HBpin to deliver the borylated arene and to generate an iron dihydride precatalyst (C), which reductively eliminates hydrogen to regenerate the dmpe-ligated iron(0) complex (A). The reaction may also proceed through other pathways involving an iron boryl hydride complex (D). In contrast to catalysis by metals other than iron,187,188 the scope of this iron/bis(phosphine)-catalyzed C−H borylation is relatively narrow and sensitive to steric effects. Interestingly, a dimethylamine group on the benzylic position does not act as a directing group but only exerts a steric effect to suppress orthoC−H borylation (Scheme 115). Recently, Ge and co-workers197 developed an E-selective C−H borylation of vinylarene with pinacolborane catalyzed by an iron(0) complex, Fe(PMe3)4, with norbornene as a hydrogen acceptor. According to a proposed mechanism, this reaction does not belong to C−H bond activation as defined in the beginning of the review. Silylation of a C−H bond catalyzed by organoiron species is rather rare.198 Nagashima and co-workers199 reported that an iron dicarbonyl complex containing a disilaferracycle moiety catalyzes the C3-silylation of N-methylindoles with phenyldimethylsilanes (Scheme 116). A similar reaction catalyzed by an NCN-pincer-type iron−carbonyl−silyl complex was reported by Ito et al.200

4.4. Oxygenation and Halogenation

Most of these transformations proceed through iron-mediated radical oxidation, such as the oxidation processes summarized as Gif chemistry52,53 and Fenton chemistry.54 Significant contributions to the development of iron-catalyzed C−H oxidation have been recently reported by Que and co-workers,202 Chen and White,203 and Talsi and Bryliakov.204 The (pseudo)halogenation of aliphatic C−H bonds in the presence of an iron catalyst also has seen significant progress recently.205 However, these transformations proceed through radical mechanisms rather than formation of an organoiron intermediate through C−H activation. Thus, these reactions are not discussed in this review.

5. OTHER EXAMPLES There have been several iron-catalyzed C−H transformations where the involvement of an organoiron species in the C−H Scheme 119. Iron-Catalyzed Insertion of Isonitrile into Aromatic C−H Bond

4.3. Tritiation of C−H Bonds

Low-valent iron complexes have long been known to react reversibly with the C−H bond of an arene and with dihydrogen via oxidative addition.82,84,85 This reactivity is potentially useful for isotopic labeling of the C−H bond of an arene, as explored by Chirik and co-workers,201 who reported that a well-defined bis(arylimdazol-2-ylidene)pyridine iron bis(dinitrogen) complex catalyzes deuterium and tritium exchange of arenes’ C−H bonds using deuterium and tritium gas, respectively. The authors also reported that the site selectivity of the iron catalyst is orthogonal to that of the commonly used iridium catalyst, enabling isotope labeling of complementary positions in a complex molecule (Scheme 117). Tritium labeling is a useful tool for pharmacokinetic and pharmacodynamic properties of drug

activation step is unclear. An early report in 1987 by Jones et al.116 described an iron isocyanide complex catalyzing insertion of the isocyanide group into the C−H bond of benzene under irradiation, where they proposed the generation of an electronrich low-valent iron species upon irradiation, which oxidatively adds the C−H bond. The reaction was catalytic in iron, but the TON was low (Scheme 119). Charette and co-workers206 reported that, in the presence of an iron(II) salt, bathophenanthroline as a ligand, and potassium tert-butoxide as the base, arenes reacted with aryl iodides to 9132


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Scheme 120. Iron-Catalyzed Arylation of Unactivated Arenes with Aryl Halides

Scheme 121. Iron-Catalyzed Oxidative Coupling of Arylboronic Acids with Pyrroles

pyrrol-2-yliron species214 followed by transmetalation with the arylboronic acid and subsequent reductive elimination to deliver the coupling product (Scheme 121). Hayashi and co-workers215 reported an iron-catalyzed oxidative coupling between arylboronic acids and excess (hetero)arenes in the presence of peroxide as oxidant. On the basis of mechanistic studies, the authors proposed that this reaction proceeds through iron-mediated homolytic aromatic substitution, where an aryl radical is generated by single-electron oxidation of the arylboronic acid with a tert-butoxide radical (Scheme 122).

produce biaryls (Scheme 120). One drawback was the need for a large excess of arene to achieve a synthetically useful yield. A similar reaction catalyzed by an iron(III) salt with DMEDA as the ligand and LiHMDS as the base was reported by Lei and coworkers.207 These reactions are formally nondirected ironcatalyzed C−H arylation reactions, but the involvement of organoiron species in C−H activation and formation of an Fe−C bond is unclear. A single-electron transfer initiated by the iron catalyst to mediate a radical attack on arene accounts for the observed reactivity and selectivity. Intriguingly, this reaction was later reported to proceed in the absence of a transition-metal catalyst through a single-electron transfer pathway.208−211 The iron-catalyzed reaction of arylboronic acids with excess arene or heteroarene produces biaryls. Yu and co-workers212,213 reported that a macrocyclic polyamine/iron complex catalyzes the reaction of arylboronic acids with excess pyrrole or pyridine under air. Pyrrole derivatives were arylated at the C2 position in good yield, while the arylation of pyridine proceeded with poor selectivity and yield. On the basis of DFT calculations, the authors considered that the reaction proceeds through deprotonative ferration by oxoiron complex to generate a

6. CONCLUDING REMARKS We have provided a comprehensive overview of the literature on stoichiometric and catalytic iron-catalyzed C−H bond-activation reactions that take place through organoiron catalytic intermediates. Thirty years passed after reports on stoichiometric C−H activation reactions in the 1970s before the significant development of synthetically useful catalytic reactions that occurred after 2008. After the period of “element hunt” in the 1970s and 1980s,4 research on iron catalysis has been driven by the interest in iron catalysis per se and by the merits of iron from sustainability, toxicity, and economic points of view. The stoichiometric reactions of iron complexes showed that an organoiron can activate a C−H bond through three types of mechanisms: deprotonative metalation (or σ-bond metathesis), oxidative addition, and radical abstraction. Many of the catalytic C−H activations developed so far involve deprotonative metalation for C(sp2)−H bonds and radical abstraction for C(sp3)−H bonds. Catalytic activation of methyl C(sp3)−H bonds through an organometallic mechanism is more difficult than that of C(sp2)−H bonds, and activation of methylene

Scheme 122. Iron-Catalyzed Oxidative Coupling of Arylboronic Acids with Arenes

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C(sp3)−H bonds under iron catalysis has not been achieved yet. Only the coupling of a C(sp2)−H bond with a neutral electrophile, but not a C(sp3)−H bond, has been reported. Iron-catalyzed C−H activation by use of organometallic donors and bases exhibits considerable versatility and efficiency rivaling precious-metal catalysis,126 while further development is necessary for C−X bond formation such as amination, alkoxylation, borylation, and silylation reactions. Future research needs to focus on more diverse substrates and C−H bond functionalization without the use of an explicit directing group216 and without reactive organometallic reagents. Rational design of the ligand might be the key enabler to achieve directing-groupfree iron-catalyzed C−H activation in the future. Further developments in this field will also require a thorough mechanistic understanding of the valence and spin state of the iron species involved in the catalytic cycle, together with the development of new types of ligands to tame the reactivity of organoiron catalytic intermediates. As is often observed for many of the catalytic reactions discussed in this review, ligands strongly affect the reactivity of organoiron intermediates and often present a key to the discovery of new catalytic reactivity.217,218 Uncovering new guidelines for ligand design will, therefore, play a vital role in iron-catalyzed C−H bond activation, as has been the case with precious metals such as palladium.219,220

Scientists’ Prize from MEXT (2015), and the Incentive Award in Synthetic Organic Chemistry, Japan (2016). Eiichi Nakamura was born in Tokyo, Japan, and obtained his Ph.D. in chemistry at Tokyo Institute of Technology. After postdoctoral work at Columbia University, he returned in 1980 to his alma mater as an assistant professor and was eventually promoted to full professor. In 1995, he was appointed as professor of physical organic chemistry in the Department of Chemistry, University of Tokyo, and was designated as Special Professor in January 2014. He is currently Molecular Technology Innovation Endowed Chair Professor in the Office of the President and the Department of Chemistry and a member of the Science Council of Japan. He works in a diverse field of synthetic and physical organic chemistry focusing on mechanism and functions, including organic solar cells. He recently introduced atomic-resolution transmission electron microscopy for the study of organic molecules, assemblies, and their reactions. His research activities have been recognized through awards and honors, including Young Chemists Award (Chemical Society of Japan, 1984), Japan IBM Science Prize (1993), Chemical Society of Japan Award (2003), Humboldt Research Award (2006), Medal of Honor with Purple Ribbon (2009), Arthur C. Cope Scholar Award of ACS (2010), 55th Fujiwara Award (2014), and Centenary Prize 2014, Royal Society of Chemistry (2014). Other honors include elected fellow of the American Association for the Advancement of Science (1998) and honorary foreign member of the American Academy of Arts and Sciences (2008).

AUTHOR INFORMATION Corresponding Authors

ACKNOWLEDGMENTS Dedicated to Professor Teruaki Mukaiyama in celebration of his 90th birthday (Sotsuju). We thank MEXT for financial support through Strategic Promotion of Innovative Research, JST (to E.N.) and KAKENHI Grant-in-Aid for Young Scientists (A) 26708011 (to L.I.).

*E-mail [email protected] (L.I.). *E-mail [email protected] (E.N.). ORCID

Eiichi Nakamura: 0000-0002-4192-1741 Notes

The authors declare no competing financial interest.

ABBREVIATIONS dmpe 1,2-bis(dimethylphosphanyl)ethane dppe 1,2-bis(diphenylphosphanyl)ethane TMEDA N1,N1,N2,N2-tetramethylethane-1,2-diamine DMEDA N1,N2-dimethylethane-1,2-diamine Cp* 1,2,3,4,5-pentamethylcyclopentadienyl HTMP 2,2,6,6-tetramethylpiperidine depe 1,2-bis(diethylphosphanyl)ethane dtbpy 4,4′-di-tert-butyl-2,2′-bipyridine dppbz 1,2-bis(diphenylphosphanyl)benzene dppen (Z)-1,2-bis(diphenylphosphanyl)ethene Ph-dppen ( Z ) - ( 1 - p h e n y l e t h e n e - 1 , 2 - d i y l ) b i s (diphenylphosphane) DABCO 1,4-diazabicyclo[2.2.2]octane BHT 2,6-di-tert-butyl-4-methylphenol DCIB 2,3-dichloroisobutane (1,2-dichloro-2-methylpropane) 2,3-DCB 2,3-dichlorobutane DBE 1,2-dibromoethane acac acetylacetonate

Biographies Rui Shang was born in Anhui Province, China, in 1987. He received his B.Sc. (2009) and Ph.D. (2014) from the University of Science and Technology of China (USTC). He worked with Professors Qing-Xiang Guo, Yao Fu, and Lei Liu during his undergraduate and masters work, focused on developing new catalytic decarboxylative coupling reactions. From 2012 to 2014, he worked as a joint-training Ph.D. in The University of Tokyo under the supervision of Professor Eiichi Nakamura, and then he served as a JSPS fellowship researcher hosted by Professor Nakamura at the same institute (2014−2016), focusing on iron catalysis. In 2017 he was promoted to project lecturer at the University of Tokyo. His research interests focus on development and mechanistic study of new catalytic reactions and organic photovoltaic materials. He received the Hundred Excellent Doctor Thesis of the Chinese Academy of Science from the Chinese Academy of Science in 2015, and the Springer Doctoral Thesis Prize in 2016. Laurean Ilies was born in Transylvania County, Romania, in 1978. He graduated from the University of Tokyo with a scholarship from the Ministry of Education of Japan (MEXT) and obtained his Master of Science in 2006 and Ph.D. in science in 2009 at the University of Tokyo under the supervision of Professor Eiichi Nakamura. During his doctoral program, he served as a JSPS fellow (2007−2009) and as a visiting researcher at the University of Chicago (2006). He became an assistant professor in 2009 at the University of Tokyo, and in 2014 he was promoted to associate professor. His current research interests include organic synthesis and organometallic chemistry. He has received several awards, including the Banyu Chemist Award (2014), the Young

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