DOI: 10.1002/cssc.200900055

Coming of Age: Sustainable Iron-Catalyzed Cross-CouplingReactionsWaldemar Maximilian Czaplik,[a] Matthias Mayer,[a] J�n Cvengros,[b] and Axel Jacobivon Wangelin*[a]

Dedicated to Jay K. Kochi

396 � 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemSusChem 2009, 2, 396 – 417

Introduction

Over the past decades, transition-metal-catalyzed cross-cou-pling reactions have gained a strong foothold within the arsen-al of powerful carbon–carbon and carbon–heteroatom bondforming reactions.[1] Palladium, nickel, and copper catalystshave so far taken center stage when it comes to the synthesisof complex and functionalized organic molecules involvingcross-coupling reactions. Numerous applications documenttheir advantageous use with respect to generality and func-tional-group tolerance.[2] However, the stressing of modern effi-ciency criteria has prompted the search for alternative catalyststhat address the economic and ecological disadvantages asso-ciated with the use of palladium and nickel catalysts. With anaverage price of $300 per ounce,[3] palladium is the bull of anysynthesis it is employed in, especially in the context of manu-facturing on larger scales. Various toxicity aspects taint the useof nickel-catalyzed processes for consumer goods and health-care products.[4] Furthermore, both palladium and nickel cata-lyst systems usually require the addition of structurally com-plex and costly ligands of high molecular weight.

Iron catalysts have recently been introduced to addressthese economic and ecological challenges.[5] A multitude ofbiological systems and functions rely upon the rich chemistryof iron-containing enzymes. Iron is an essential metal for thelife cycle of all living things, and thus constitutes an attractivemetal for man-made synthetic transformations as no severetoxicity and side effects exist. Albeit the first iron-catalyzedhomo-coupling of aryl Grignard reagents was described byKharasch and Fields already in 1941,[6] the genuine era of iron-catalyzed cross-coupling reactions originated in the early1970s, predating its palladium and nickel relatives, when Kochicarefully studied reactions of alkenyl halides with Grignard re-agents.[7] Although limited with respect to catalytic activity andsubstrate scope, the first mechanistic rationale for such iron-catalyzed cross-coupling was put forward.[7] It invoked an anal-ogy to the Pd and Ni systems, where a coordinatively unsatu-rated reduced iron complex (of unspecified constitution) se-quentially undergoes oxidative addition of the organohalide,transmetallation from the organomagnesium species, and re-ductive elimination of the cross-coupling product. Some isolat-ed publications perpetuated the interest in this class of reac-tions through the 1990s, but it was not until the early 2000sthat the development of iron-catalyzed cross-coupling reac-tions really picked up momentum. F�rstner and Leitner then

reported on an optimized protocol for the highly selectiveiron-catalyzed reaction of aryl halides with alkyl magnesiumha-lides in the presence of NMP as co-solvent.[8] This work was thego-ahead signal for a series of forthcoming publications contri-buting to the development of ever-more-efficient and widelyapplicable protocols. Based upon the pioneering work byKochi[7] and spurred on by recent developments,[9] iron-cata-lyzed cross-coupling reactions have since matured to a multi-facetted class of effective C�C and C�X bond-forming reac-tions with a wide substrate scope and functional group toler-ance.

This Review summarizes the most significant milestones inthe quest for efficient carbon–carbon bond-forming cross-cou-pling reactions under iron catalysis, and highlights syntheticallyuseful protocols that constitute a serious competition for theestablished palladium and nickel catalyst systems. It is theclear intention of this Review to familiarize the reader with thehistory and state-of-the-art of iron-catalyzed carbon–carbonbond forming cross-coupling reactions. In order to reach awide perspective, all scientific contributions revolving aroundiron-catalyzed cross-coupling between an organic electrophilebearing a leaving group and an organometallic (or hydrocar-bon) nucleophile (i.e. , a formal substitution reaction) are cov-ered up to March 2009 (Scheme 1).[10] The Heck reaction wouldnot fall into such a definition, but as it involves a formal substi-

Iron-catalyzed carbon–carbon bond-forming reactions havematured to an indispensable class of reactions in organic syn-thesis. The advent of economically and ecologically attractiveiron catalysts in the past years has stepped up the competitionwith the established palladium and nickel catalyst systems thathave dominated the field for more than 30 years, but sufferfrom high costs, toxicity, and sometimes low reactivity. Iron-catalyzed protocols do not merely benefit from economic ad-vantages but entertain a rich manifold of reactivity patterns

and tolerate various functional groups. The past years havewitnessed a rapid development with ever-more-efficient proto-cols for the cross-coupling between alkyl, alkenyl, alkynyl, aryl,and acyl moieties becoming available to organic chemists. ThisReview intends to shed light onto the versatility that iron-cata-lyzed cross-coupling reactions offer, summarize major achieve-ments, and clear the way for further use of such superiormethodologies in the synthesis of fine chemicals, bioactivemolecules, and materials.

Scheme 1. Iron-catalyzed cross-coupling of an electrophile and an organo-metallic compound.

[a] W. M. Czaplik, M. Mayer, Dr. A. Jacobi von WangelinDepartment of ChemistryUniversity of CologneGreinstr. 4, 50939 Kçln (Germany)Fax: (+ 49) 221-470-5057E-mail : axel.jacobi@uni-koeln.de

[b] Dr. J. CvengrosDepartment of Chemistry and Applied BiosciencesSwiss Federal Institute of Technology ETH Z�richWolfgang-Pauli-Str. 10, 8093 Z�rich (Switzerland)

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Sustainable Iron-Catalyzed Cross-Coupling Reactions

tution of a hydride with an organic group it is often consid-ered a close relative and thus will be dealt with in this Review.However, iron-catalyzed additions and carbo-metallations arebeyond the scope of this Review. The definition of cross-cou-pling reactions has recently been expanded to also includecarbon–heteroatom bond-forming reactions, which have beenrecently reviewed.[9c] The Review is categorized by the natureof the electrophile, which most mechanistic models postulateto engage in the initiating step of the catalytic cycle. For rea-sons of clarity, the newly formed C�C bond is sketched bold inschemes.

Cross-Coupling with Alkenyl Electrophiles

The potential of iron catalysis for cross-coupling reactionswas first tapped by the seminal work of Kochi and his groupas early as 1971. The studies revealed that alken-1-yl halides, inmarked contrast to alkyl halides, readily reacted with Grignardreagents in the presence of catalytic amounts of FeCl3 to givecross-coupling products with high stereoselectivity(Scheme 2).[7] At ambient temperature and 0 8C, good yields of

the coupled product (up to 83 %) were obtained within a fewhours, although a large excess of the vinyl halide was required.The extension of this work allowed for the use of secondaryand tertiary alkyl and aryl Grignard reagents.[11] Various ironcomplexes and the effect of their aging on the catalytic activitywere evaluated by UV spectroscopy and conversion experi-ments. High rates of cross-coupling reactions were limited bydeactivation of the catalyst owing to an aging process attribut-ed to the aggregation of the active iron species (Figure 1). Itwas proposed that the active low-valent catalyst is generatedthrough the reduction of iron salts with alkyl Grignard re-agents.[12]

In Kochi’s studies, Fe ACHTUNGTRENNUNG(acac)3 and FeACHTUNGTRENNUNG(dbm)3 both provedequally active. The stereogenic information of 1-bromopro-pene was preserved during the transformation. Based on kinet-ic studies and electron paramagnetic resonance, a mechanismof the iron-catalyzed cross-coupling of vinyl bromides withGrignard reagents was proposed as depicted in Scheme 3.[13] In1978, Felkin and Meunier published a stereoselective cross-coupling reaction between alkenyl bromides and phenylGrignard reagents with iron–phosphine catalysts.[14] The cross-coupling product is formed in high yield and stereoselectivity

J�n Cvengros was born in Slovakia in

1980 and studied Chemistry at the Co-

menius University in Bratislava. He

completed his Ph.D. under the direc-

tion of Hans-G�nther Schmalz at the

University of Cologne (Germany) on

metal-based strategies in natural prod-

uct syntheses, for which he was award-

ed the Kurt Alder Prize in 2006. He

was a Marie-Curie post-doctoral fellow

with Cesare Gennari (University of

Milan, Italy) and moved to his current

position at the ETH Zurich (Switzerland) in 2008 to continue post-

doctoral research with Antonio Togni.

Waldemar M. Czaplik (center) was born in 1981 and studied

Chemistry at the University of Cologne (Germany). He was a visit-

ing scholar in the lab of Aaron Aponick (University of Florida, Gain-

esville, USA) and received a Max Buchner fellowship from the DE-

CHEMA in 2008. He is currently completing his graduate work in

the group of A.J.v.W., and will move to the UK to take up a post-

doctoral position.

Matthias Mayer (left) was born in 1983 and studied Chemistry at

the University of Cologne (Germany). He started his Ph.D. work

with A.J.v.W. in 2008. He is a fellow of the Deutsche Bundesstiftung

Umwelt (DBU) and currently working on C�H activation reactions.

Axel Jacobi von Wangelin (right) enjoyed his youth in Berlin and

studied Chemistry at the University of Erlangen-N�rnberg (Germa-

ny). He was a visiting scientist at the University of Utah (Salt Lake

City, USA) with John A. Gladysz before taking up graduate work in

the group of Matthias Beller (Leibniz Institute of Catalysis, Rostock,

Germany) on carbonylation and cycloaddition reactions. He was a

DAAD postdoctoral fellow with Barry M. Trost (Stanford University,

Stanford, USA). In 2005 he started his independent career at the

University of Cologne, where he has since been engaged in the de-

velopment of sustainable metal- and organo-catalyzed transforma-

tions. He is an Emmy-Noether fellow of the DFG and a 2007

Thieme Journal awardee.

When not drudging in the labs, they enjoy a diverting table foot-

ball match.

Scheme 2. First iron-catalyzed coupling of vinyl bromide with primaryGrignard reagents by Kochi et al.[7]

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A. Jacobi von Wangelin et al.

(84 % yield, E/Z = 90:10). Highly stereoselective FeACHTUNGTRENNUNG(dbm)3-cata-lyzed methylation of optically pure (+)-(S)-(4-methylcyclohexyl-ACHTUNGTRENNUNGidene)bromomethane with methyllithium was demonstratedby Walborsky and Banks to proceed with retention of configu-ration. Complete racemization was observed with catalyticAgBr.[15] Julia and coworkers later found that vinyl sulfones alsoundergo highly stereospecific coupling with Grignard reagents(Scheme 4). However, this reaction proved more sluggish com-pared to vinyl halides, resulting in longer reaction times.[16]

In 1983, Molander et al. performed a systematic study to de-termine optimal conditions for the iron-catalyzed coupling of

alkenyl halides with aryl Grignard reagents to provide aryl-ACHTUNGTRENNUNGethenes. It was found that DME as solvent consistently provid-ed the highest yields of the desired cross-coupling product.Furthermore, no excess of alkenyl halide was required, and alower initial reaction temperature (�20 8C) proved beneficial(Scheme 5).[17]

Naso and coworkers showed that various iron compoundssuch as Fe ACHTUNGTRENNUNG(dbm)3, FeACHTUNGTRENNUNG(dpm)3, Fe ACHTUNGTRENNUNG(acac)3, and FeCl3 catalyze thecross-coupling of (E)- or (Z)-1-bromo-2-phenylthioethenes withalkyl Grignard reagents in THF at �78 8C affording alkenyl sul-fides in good yields with high chemo- and stereoselectivity.[18]

The cross-coupling reaction between stoichiometric amountsof alkyl–FeII species (such as MeFeCl·2 LiCl, Me2Fe·3 LiCl, andMe3FeLi·3 LiCl) and vinylic bromides or acyl chlorides was de-scribed by Kauffmann et al.[19] The iron reagents also proved re-active towards aldehydes and ketones bearing a chelatinggroup. Cahiez and coworkers developed a general procedurefor the iron-catalyzed alkenylation of organomanganese com-pounds using mixtures of THF and NMP. As the reactivity wasgreatly enhanced in this solvent system, the amount of the or-ganomanganese reagent could be significantly reduced(Scheme 6).[20]

The same authors later reported on a highly stereoselectiveiron-catalyzed alkenylation of organomagnesium compounds.The chemoselectivity was demonstrated by the tolerance to-wards various functional groups (esters, nitriles, halides, andeven ketones). A screening of various cosolvents in model re-actions of alkenyl halides (X = I, Br, or Cl) with Grignard re-agents revealed that the use of NMP resulted in shorter reac-tion times, higher yields, and excellent stereoselectivity. Theauthors assumed that one of the roles of NMP might be theminimization of decomposition processes (i.e. , b-hydride elimi-nation) by stabilizing intermediate iron species. The loading ofthe catalyst could be lowered to 0.01 mol % in selected cases.This methodology was also applied to enol phosphates(Scheme 7).[21] The potential of organomanganese reagents forsuch reactions proved even more profound as F�rstner and

Figure 1. Effect of aging time on the conversion of 1-bromopropene andMeMgBr to 2-butene at 25 8C (black dots) and 1 8C (hollow dots) with cata-lytic FeACHTUNGTRENNUNG(acac)3.[12a]

Scheme 3. Proposed mechanism for the iron-catalyzed cross-coupling byKochi et al.[13]

Scheme 4. Coupling of vinyl sulfones with Grignard reagents by Juliaet al.[16a]

Scheme 5. FeACHTUNGTRENNUNG(acac)3-catalyzed coupling of vinyl bromides with aryl Grignardreagents by Molander et al.[17]

Scheme 6. Alkenylation of Grignard reagents by Cahiez et al.[20a]

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Sustainable Iron-Catalyzed Cross-Coupling Reactions

Brunner reported on a novel generation of various alkyl, alken-yl, aryl, and heteroaryl manganese reagents directly from alkylhalides and activated manganese. Highly active Mn–graphitewas formed upon reduction of MnBr2·nLiBr (n = 1, 2) with K–graphite (Scheme 8).[22]

Collaborative work by Cahiez and Knochel focused on theexploitation of functionalized arylmagnesium reagents bearingester, cyano, nonaflate, or trialkylsilyloxy groups generated byhalogen–metal exchange with iPrMgBr. Rapid reactions with al-kenyl iodides or bromides in the presence of catalytic amountsof FeACHTUNGTRENNUNG(acac)3 (5 mol %) at �20 8C resulted in the formation ofthe desired cross-coupling products as exclusively E isomerswith satisfactory yields (Scheme 9). Good results could also beachieved by performing the cross-coupling reaction on a solidphase by generating the Grignard reagent on Wang resin.[23]

The NMP protocol of Cahiez was later applied by Begtrupand coworkers in the synthesis of 3-substituted N-Boc-protect-

ed pyrrolidines. Primary and secondary alkylmagnesium halideswere reacted in THF/NMP at 0 8C. Aryl Grignard reagentsproved to be less reactive; tertiary Grignards did not react(Scheme 10).[24]

Hçlzer and Hoffmann reacted a chiral Grignard reagent, inwhich the magnesium-bearing carbon atom was the sole ste-reogenic center, with vinyl bromide under catalysis of varioustransition metals.[25] Whilst Pd0- and Ni0-catalyzed reactions pro-ceeded with full retention of configuration, considerable race-mization occurred in the presence of FeACHTUNGTRENNUNG(acac)3 and Co ACHTUNGTRENNUNG(acac)2

as catalysts (Scheme 11). This outcome established the trans-metallation of the Grignard reagent to PdII or NiII as a concert-ed SE2-ret process, while in the case of iron and cobalt, asingle electron transfer (SET) might be operative.

The group of Itami and Yoshida described an iron-catalyzedcross-coupling reaction of alkenyl sulfides with Grignard re-agents. While the cross-coupling proceeds efficiently at alken-yl�S bonds, almost no reaction takes place at aryl�S bonds, at-testing to a unique selectivity of iron catalysts (Scheme 12).[26]

The authors surmise that an addition–elimination mechanismmight be involved.

F�rstner and coworkers devised a protocol for the couplingreaction of a variety of alkenyl triflates derived from ketones,b-keto esters, or cyclic 1,3-diketones with functionalized orga-nomagnesium halides bearing ether, acetal, alkyne, or trime-

Scheme 7. Iron-catalyzed alkenylation of Grignard reagents by Cahiezet al.[21]

Scheme 8. Preparation of organomanganese reagents for iron-catalyzedcross-coupling by F�rstner and Brunner.[22]

Scheme 9. FeACHTUNGTRENNUNG(acac)3-catalyzed cross-coupling of functionalized aryl Grignardreagents with alkenyl halides.[23]

Scheme 10. Synthesis of 3-substituted pyrrolidines by Begtrup and cowork-ers.[24]

Scheme 11. Cross-coupling of chiral Grignard reagent with vinyl bromide byHçlzer and Hoffmann.[25]

Scheme 12. Cross-coupling reaction of alkenyl sulfides with Grignard re-agents by Itami et al.[26]

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A. Jacobi von Wangelin et al.

thylsilyl groups or aryl chloride entities in their backbones(Scheme 13).[27] This procedure was also applied by F�rstneret al. in syntheses of Latrunculin B,[28] (�)-a-cubene, and (�)-a-Cubebol.[29]

A modified protocol was used by Camacho-D�villa in thesynthesis of Combretastatin A-4 (Scheme 14).[30] Further appli-cations of the FeACHTUNGTRENNUNG(acac)3/THF/NMP protocol to coupling reac-

tions of enol triflates were realized in the synthesis of biologi-cally active compounds such as Ciguatoxin segments,[31] Agaro-spirol, Hinesol, a-Vetispirene,[32] and Cedrene and Cedrol.[33]

In the most detailed study to date, F�rstner’s venture intothe unexplored field of “low-valent” iron chemistry providedcompelling evidence that iron-catalyzed C�C bond formationsmay occur via different pathways (Scheme 15).[34] The interme-diacy of “iron-ate” complexes is likely in the case of speciesunable to undergo b-hydride elimination, such as MeLi, PhLi,or PhMgBr, which rapidly reduce Fe3 + to Fe2 + and then ex-haustively alkylate the metal center. Structures of homolepticorganoferrate complexes [(Me4Fe)ACHTUNGTRENNUNG(MeLi)][Li ACHTUNGTRENNUNG(OEt2)]2 and [Ph4Fe][Li ACHTUNGTRENNUNG(OEt2)2][Li(1,4-dioxane)] obtained from X-ray diffraction stud-ies were analyzed and the reactions with various electrophilesrevealed their only moderate nucleophilicity as they reactedsolely with activated electrophiles (Scheme 16).[34]

On the other hand, highly reduced metal clusters such as[FeACHTUNGTRENNUNG(MgX)2]n might be the active species when EtMgX or higheralkyl Grignard reagents are employed. Their behavior can bemimicked by structurally well-defined lithium ferrate com-plexes bearing only kinetically labile olefin ligands. Such elec-tron-rich and highly nucleophilic complexes cleanly react withprototype substrates amenable to catalytic cross-coupling. Itwas demonstrated that formal oxidation states of iron rangingfrom �2 to+3 are to be considered in cross-coupling reactionsand that different intertwined catalytic cycles might be popu-lated. In line with this notion, it is possible to prepare the ate-complex [Me4Fe]ACHTUNGTRENNUNG[Li2ACHTUNGTRENNUNG(OEt2)2] as a thermolabile and highly air-sensitive compound by reaction of MeLi with FeCl3. Treatmentof triflates with this defined reagent afforded the couplingproducts in similar yields as obtained under “in situ” conditions(Scheme 17).[27]

F�rstner et al. showed that strained cyclobutenyl iodidesprepared by ruthenium-catalyzed enyne cycloisomerization are

Scheme 13. Cross-coupling of vinyl triflates and alkyl Grignard reagents.[27]

Scheme 14. Iron-catalyzed (�)-a-cubene and Combretastatin A-4 synthe-ses.[29, 30]

Scheme 15. Mechanistic scenarios for iron-catalyzed cross-couplings.[34]

Scheme 16. Reactivity of homoleptic ferrate [(Me4Fe)ACHTUNGTRENNUNG(MeLi)][Li ACHTUNGTRENNUNG(OEt2)]2.[34]

Scheme 17. ACHTUNGTRENNUNG[Me4Fe]Li2-catalyzed cross-coupling reactions by F�rstner etal.[27]

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susceptible to further functionalization with Grignard reagentsunder iron catalysis.[35] The groups of Alami and Figad�re joint-ly investigated the iron-catalyzed cross-coupling reaction be-tween 1,1-dichloro-1-alkenes and Grignard reagents.[36] This re-action led mainly to double substitution in good to excellentyields and required mild conditions (�30 8C, THF). However,when 3 equivalents of c-hexylmagnesium bromide were used,the reaction stopped at the monoalkylation stage (Scheme 18).

Interestingly, analogous 2-aryl-1,1-dibromo-1-alkenes gave thehydrodebrominated products under almost identical reactionconditions (THF/NMP).[37] Hayashi and Berthon-Gelloz used theFeACHTUNGTRENNUNG(acac)3-catalyzed coupling of enol triflates with Grignard re-agents in the synthesis of C2-symmetric bicycloACHTUNGTRENNUNG[2.2.1]hepta-2,5-dienes (Scheme 19). In comparison to the palladium- or nickel-catalyzed alternatives, iron was found to be superior in termsof efficacy and selectivity.[38]

Tam and coworkers investigated the iron-catalyzed cross-coupling reaction of bicyclic alkenyl triflates derived from nor-bornenes with alkyl and aryl Grignard reagents.[39] Moderate togood selectivities toward 2-substituted norbornenes, thatcould not be prepared via palladium catalysis or lithium–halo-gen exchange, were obtained in good yields with catalyticFeACHTUNGTRENNUNG(acac)3 in a THF/NMP solvent mixture.

According to Dunet and Knochel, alkenyl or dienyl sulfo-nates reacted readily with functionalized arylcopper reagentsin the presence of 10 mol % Fe ACHTUNGTRENNUNG(acac)3 in DME at room temper-ature affording the anticipated cross-coupling products in

good yields (Scheme 20). Nitrile and ester functionalities weretolerated.[40]

Enol phosphates, synthesized from 4-piperidone, can be re-acted with Grignard reagents affording 4-substituted tetrahy-dropyridines as documented by Begtrup and coworkers(Scheme 21).[41]

In 2008 Cahiez et al. described an efficient stereoselectivecoupling of enol phosphates with alkyl Grignard reagents.[42]

Coupling of dienol phosphates led to terminal conjugateddienes. The synthetic utility is illustrated by the synthesis ofthe pheromone of Diparopsis castanea (Scheme 22).[43] A relat-ed iron-mediated methylation protocol (5 eqs. FeACHTUNGTRENNUNG(acac)3) wasrecently exploited by Hayashi and Nakada for the stereoselec-tive construction of a trisubstituted (Z)-alkene side chain ofMK8383, an inhibitor of microtubuline assembly.[44]

Olsson and coworkers developed a facile access to bioiso-steric analogues of Clozapine by iron-catalyzed cross-couplingreaction between Grignard reagents and imidoyl chlorides

Scheme 18. Cross-coupling of 1,1-dichloro-1-alkenes by Alami and cowork-ACHTUNGTRENNUNGers.[36a]

Scheme 19. Comparison of catalysts for the cross-coupling of enol tri-flates.[38]

Scheme 20. Coupling of alkenyl sulfonates with arylcuprates by Dunet andKnochel.[40]

Scheme 21. Access to 4-substituted tetrahydropyridines by Begtrup andcoworkers.[41]

Scheme 22. Vinyl phosphate cross-coupling according to Cahiez et al.[43]

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A. Jacobi von Wangelin et al.

(Scheme 23).[45] Functionalities such as aryl chloride, ester, orWeinreb amide were unaffected. However, when the iron cata-lyst was omitted, the reaction proceeded cleanly at the Wein-reb amide site. The mild reaction conditions make this protocolan efficient alternative for the synthesis of imines compared tothe forced conditions normally used in condensation reactions.

Unlike acylating cross-coupling reactions with acyl chlorides,sulfinyl chlorides are subject to SO2 extrusion. Rao Volla andVogel disclosed reaction conditions for the desulfinylative C�Ccross-coupling of alkenyl sulfonyl chlorides with aryl Grignardreagents to give substituted arenes with up to 82 % yield.[46]

Chloroenynes efficiently react with Grignard reagents underiron ACHTUNGTRENNUNG(III) catalysis as reported in a publication by the groups ofAlami and Figad�re.[47] Various functionalized unsaturated vinylchlorides were rapidly coupled at 0 8C in THF/NMP without anyinterference with several functional groups, for example, prop-argyl acetate, ethyl benzoate, aryl bromide or hydroxyl group(Scheme 24).

Similarly, Tan and Negishi efficiently reacted an alkenyl chlo-ride with octylmagnesium bromide affording a trisubstitutedolefin in 95 % yield in highly stereoselective fashion (>97 %Z).[48]

An efficient iron-catalyzed enyne cross-coupling reactionwas developed by Nakamura and coworkers for the reaction ofalkynyl magnesium reagents with alkenyl bromides or triflates.Good yields could be achieved using 0.5–1 mol % of FeCl3 and120 mol % of LiBr as a crucial additive (Scheme 25).[49]

Cross-Coupling with Acyl Electrophiles

Reaction of Grignard reagents and other organometallic spe-cies with acyl chlorides usually proceeds in the absence of anytransition-metal catalyst, but high reaction temperatures andformation of byproducts (mostly alcohols) limit a wider exploi-tation of this transformation. In an early report, Cook and co-ACHTUNGTRENNUNGworkers studied the acylation of alkyl Grignard reagents. Differ-ent catalysts and reaction conditions were tested; the best re-sults (47 % yield) were achieved with FeCl3 as catalyst.[50] Casonet al. investigated the use of FeCl3 as catalyst for the couplingreaction of succinyl chlorides with ethylmagnesium bromide atlow temperatures (0 to�40 8C). It was demonstrated that theuse of FeCl3 suppressed the formation of alcohol byprod-ucts.[51] A mechanism that seems to be consistent with the ex-perimental observations is shown in Scheme 26.

Marchese and coworkers showed that the use of catalyticFeACHTUNGTRENNUNG(acac)3 renders efficient acylations at ambient tempera-ture.[52] The conditions tolerated ester and nitrile functions andtwo different alkyl chains were successfully introduced ontocarbonochlorido-thioates (Scheme 27).[53] This procedure wasapplied by Ritter and Hanack in the facile synthesis of cyclo-heptatrienylketones.[54]

Cahiez et al. demonstrated that iron-catalyzed acylation oforganomanganese reagents can be efficiently employed forthe preparation of 2- and 3-acylfurans in high yields and ex-ploited such intermediates for the synthesis of Elsholtzione,Naginata ketone, and Perilla ketone (Scheme 28).[55] F�rstneret al. embarked on a related organomagnesium strategy for

Scheme 23. Synthesis of Clozapine analogues by Olsson and coworkers.[45]

Scheme 24. Fe ACHTUNGTRENNUNG(acac)3-catalyzed cross-coupling with chloroenynes by Alamiand Figad�re.[47]

Scheme 25. Enyne cross-coupling reaction by Nakamura and coworkers.[49]

Scheme 26. Proposed cross-coupling mechanism by Cason et al.[51a]

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the methylation of an acyl chloride in the total synthesis ofLantrunculin B (Scheme 29).[28]

In 1996 Reddy and Knochel discovered that diorganozinccompounds are another class of competent nucleophiles thatundergo facile acylation with acyl chlorides in the presence ofcatalytic FeCl3 (10 mol %) in THF/NMP at �10 8C.[56] F�rstnerand coworkers disclosed the rapid reaction of functionalizedacid chlorides with various alkyl and aryl magnesiumhalides togive ketones in good yields at �78 8C (<15 min). The iron-cat-alyzed reaction of acyl chloride is faster than the cross-cou-pling of aryl halides. Aryl chlorides and bromides thus do notinterfere (Scheme 30).[27]

Especially the “inverse addition” (the acyl chloride is addedto a cold solution containing Fe ACHTUNGTRENNUNG(acac)3 and the Grignard re-

agent) has attracted particular attention because the uncata-lyzed attack of the Grignard reagent onto the resulting ketoneis negligible.[29] Simultaneously, Knochel and coworkers deviseda strategy to build polyfunctionalized diarylketones by Fe-ACHTUNGTRENNUNG(acac)3-catalyzed arylation of aroyl cyanides. The procedure tol-erates aryl chlorides, esters, and ethers (Scheme 31).[57]

Cross-Coupling with Aryl Electrophiles

Alkyl Metal Nucleophiles

In 1989, Pridgen et al. revealed the superiority of FeACHTUNGTRENNUNG(acac)3 toNi ACHTUNGTRENNUNG(acac)2 in the cross-coupling reaction of ortho-halobenzaldi-mines with “reducing” Grignard reagents (i.e. , bearing b-hydro-gen atoms).[58] The iron-catalyzed reaction was not accompa-nied by the formation of reductive byproducts (Scheme 32).

F�rstner et al. developed general conditions for cross-cou-pling reactions of alkyl and aryl metal species (Mg, Zn, Mn)with aryl and heteroaryl chlorides, triflates, and tosylates(Scheme 33).[8, 59, 60] Unlike aryl chlorides, the corresponding bro-mides and iodides were prone to reduction of the C�X bonds.The wide substrate scope involved functionalized aromaticcompounds bearing ether, sulfonate, nitrile, or heterocyclesubstituents. Alkylmagnesium substrates containing alkene oralkyne moieties were also competent reactants. Both [Fe-ACHTUNGTRENNUNG(salen)Cl] and FeACHTUNGTRENNUNG(acac)3 proved equally active, while the formerexhibited superior activity with secondary Grignard reagents.

Scheme 27. Stepwise synthesis of ketones from carbonochloridothioate.[53a]

Scheme 28. Synthesis of Perilla ketone from 3-bromofuran by Cahiez et al.[55]

Scheme 29. Iron-catalyzed acylation in the synthesis of Lantrunculin B.[28]

Scheme 30. Iron-catalyzed acylations according to F�rstner et al.[27]

Scheme 31. Iron-catalyzed aroylation by Knochel and coworkers.[57]

Scheme 32. Coupling with halobenzylidene cyclohexylamine by Pridgenet al.[58]

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The versatility of this protocol was demonstrated by severaltotal syntheses, for example, macrocyclic spermidine alkaloidIsooncinotine,[59] cytotoxic marine natural product Montipyri-dine, and immunosuppressive FTY720 (Scheme 34).[60]

F�rstner and coworkers proposed a mechanism rationale foriron catalyzed cross-coupling reactions between aryl halidesand alkylmagnesium halides. In accordance with previous re-ports by Bogdanovic and Schwickardi,[61] a formal FeACHTUNGTRENNUNG(MgX)2

species was postulated to act as catalytically active low-valentcatalyst. This highly nucleophilic species, an “inorganicGrignard compound” with iron formally in oxidation state �2,is believed to undergo oxidative addition with aryl halides re-sulting in an aryliron intermediate, which is subject to alkylat-ing transmetallation from the Grignard reagent. Subsequent re-ductive elimination of the two organic moieties releases thecross-coupling product and regenerates the catalytically activeiron species (Scheme 35).[60a, 62] The exceptional efficiency ofthis aryl–alkyl cross-coupling methodology was demonstratedin the total synthesis of (R)-(+)-Muscopyridine by F�rstner andLeitner (Scheme 36).[63]

In similar fashion, Nagano and Hayashi exploited such meth-odology for the functionalization of aryl triflates.[64] The groupof Hocek studied the methylation of 2,6-dichloropurines and6,8-dichloropurines via iron-catalyzed cross-coupling reactionwith methylmagnesium halides and established a novel ap-proach toward 2-chloro-6-methylpurine and 6-chloro-8-methyl-purine (Scheme 37).[65, 66] Reactions with trichloro-substituted

purines revealed a rather unselective course of the coupling re-action as mixtures of mono-, di-, and trimethylated productswere obtained.[66] Schulz and coworkers synthesized a series ofsubstituted pyrazines, which have also been found in marinebacteria, from 2-chloropyrazines.[67]

Selective iron-catalyzed mono-substitutions of dichloro-sub-stituted arenes and heteroarenes in good yields were also re-ported by F�rstner and coworkers (Scheme 38). Reactions withortho-substituted substrates, however, were sluggish.[27]

Aryl Metal Nucleophiles

Scheme 33. Iron-catalyzed aryl-alkyl coupling reaction by F�rstner et al.[60a]

Scheme 34. Cross-coupling in the total synthesis of Montipyridine.[60a]

Scheme 35. Simplified Fe�II-based mechanism by F�rstner and cowork-ers.[34, 62]

Scheme 36. Consecutive coupling reactions toward (R)-(+)-Muscopyridine.[63]

Scheme 37. Selective iron-catalyzed methylation of 2,6-dichloropurine.[65a]

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Sustainable Iron-Catalyzed Cross-Coupling Reactions

The iron-catalyzed homo-coupling of aryl Grignard reagentswith bromobenzene as oxidant was described already by Khar-asch and Fields in 1941. Phenylmagnesium bromide was react-ed with bromobenzene in refluxing diethylether producing bi-phenyl within 1 h in 47 % yield (Scheme 39).[6] A related homo-

coupling procedure was described by Felkin and Meunierwhen phenyl magnesium bromide was treated with benzylchloride in the presence of iron catalysts. Minor formation ofthe cross-coupling product was also observed.[14]

In 2002, F�rstner and Leitner reported that cross-couplingproducts of heteroaromatic chlorides with aryl Grignard re-agents can be obtained in high yields by using catalytic Fe-ACHTUNGTRENNUNG(acac)3 in a solvent mixture of THF and NMP at 0 8C. Notewor-thy, electron-rich aryl halides tended to fail, giving merelyhomo-coupling of the arylmagnesium species.[8] With thissystem it is also possible to couple chlorides of various p-elec-tron-deficient heteroaromatic systems such as pyrimidine, pyr-azine, triazine, isoquinoline, quinoxaline, and quinazoline with3-pyridylmagnesiumbromide or 2-thienylmagnesium bromidein moderate yields without using NMP as co-solvent(Scheme 40). Sterically demanding Grignard reagents were un-reactive. Later, F�rstner et al. proved the inactivity of Fe-ACHTUNGTRENNUNG(salen)Cl catalysts for such protocols.[60a]

Figad�re and coworkers tested various solvents and addi-tives for the coupling of 3-bromoquinoline and 2-bromoquino-line with phenylmagnesium bromide in the presence of cata-lytic amounts of iron salts under various conditions(Scheme 41).[68] Highest yields were achieved with a simpleprotocol involving 10 mol % Fe ACHTUNGTRENNUNG(acac)3 in THF at �30 8C and 1 hreaction time.

Pl� and coworkers reported that iron-catalyzed cross-cou-pling reactions of pyridine or diazine chlorides with arylGrignard reagents allow the synthesis of various unsymmetricalpolyaryl or polyheteroaryl compounds with p-deficient rings(Scheme 42).[69]

Later Knochel and coworkers showed that iron powder alsoefficiently catalyzes this transformation. The cross-couplingproduct was obtained after 12 h at ambient temperature in86 % yield (Scheme 43). This result supports the considerationthat a reduced (ferrate) species might act as active catalyst.[70]

In 2004 Nagano and Hayashi reported on a novel methodol-ogy for the homo-coupling of various aryl Grignard reagentsusing FeCl3 as a catalyst precursor and 1,2-dichloroethane as

Scheme 38. Selective monofunctionalization via iron-catalyzed cross-cou-pling.[27]

Scheme 39. Iron-catalyzed biaryl coupling by Kharasch and Fields.[6]

Scheme 40. Iron-catalyzed coupling of heteroaryl chlorides with arylGrignard reagents by F�rstner et al.[60a]

Scheme 41. Coupling of haloquinolines with phenylmagnesium bromide byFigad�re and coworkers.[68]

Scheme 42. Iron-catalyzed synthesis of polyaryl compounds according to Pl�and coworkers.[69]

Scheme 43. Cross-coupling with catalytic iron powder by Knochel and co-ACHTUNGTRENNUNGworkers.[70]

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oxidant in refluxing diethylether.[71] This reaction system wasreadily amenable to a variety of aryl halides (aryl chlorideswere not reactive) and large-scale syntheses of the resultantbiaryl compounds. The best results were achieved with para-substituted compounds, whilst ortho-substitution led to loweryields and longer reaction times. According to the proposedmechanism, FeCl3 reacts with the Grignard reagent to form alow-valent iron complex A (Scheme 44). Oxidative addition of

1,2-dichloroethane to A gives alkyliron intermediate B whichupon b-halogen elimination and ethylene evolution gives diha-loiron species C. Subsequently, transmetalation of the arylgroup affords a diaryliron intermediate D which undergoes re-ductive elimination of the homo-coupling product and regen-erates catalyst A.

Cahiez et al. optimized this transformation and showed thatthe reaction can be performed with only 0.6 eqs. of 1,2-di-chloroethane. Reactions of ortho-substituted aryl Grignard re-agents were significantly accelerated when using 1,2-dibromo-or 1,2-diodoethane as reoxidants.[72] The authors extended theprocedure to also include highly functionalized substrates withester, nitrile, and nitro groups. Accordingly, the total synthesisof N-methylcrinasiadine was achieved via iron-catalyzed intra-molecular cross-coupling reaction (Scheme 45).[73]

Knochel and coworkers demonstrated that the homo-cou-pling reaction pathway can be suppressed if the Grignard re-agent is transmetalated to the corresponding organocopper

species.[74] This procedure allows for cross-coupling of aryl andheteroaryl compounds in high yields (Scheme 46). Some gener-al trends in the reactivity were observed: (a) electron-with-drawing groups at the aryl iodide accelerate the cross-cou-pling, (b) the reaction proceeds slower in the presence of elec-

tron-donating groups, (c) the rate of the reaction depends alsoon the leaving group: I>Br>Cl>OTf (tosylates were unreac-tive), and (d) 2- and 4-iodobenzoates react significantly fasterthan the 3-isomer. The mild reaction conditions tolerate esters,ketones, ethers, acetals, alkylsilanes, nitriles, and amides.[75]

Homo-coupling of arylbromides was reported by Pei andcoworkers to proceed with catalytic FeACHTUNGTRENNUNG(dbm)3 and 2 equiva-lents of magnesium with good yields.[76] In 2007, Hatakeyamaand Nakamura delivered a novel catalytic system for thehetero-biaryl coupling based on FeF3·3H2O and SIPrHCl (1,3-bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazolium chloride).The presence of NHC as ligand and fluoride counteranionproved critical for high selectivities and led to the suppressionof homo-coupling products (Scheme 47). The procedure is tol-erant of dimethylamino, methylthio, fluoro, and acetal func-tionalities. Various aryl Grignard reagents can be used, al-though sterically hindered ones reacted slower. A vast array ofaromatic and heteroaromatic halides were also tested, follow-ing the general trend Cl>OTf>Br = I.[77]

Scheme 44. Postulated mechanism of the homo-biaryl-coupling by Naganoand Hayashi.[71]

Scheme 45. Oxidative aryl-aryl coupling by Cahiez et al.[73]

Scheme 46. Organocopper reagents in aryl–aryl cross-coupling by Knocheland coworkers.[74, 75]

Scheme 47. Biaryl coupling with catalytic FeF3/NHC by Hatakeyama and Na-kamura.[77]

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Sustainable Iron-Catalyzed Cross-Coupling Reactions

A study by Young and coworkers disclosed a positive influ-ence of high pressure (15 kbar; 1 bar = 105 Pa) in the liquidphase on the Suzuki–Miyaura cross-coupling of aryl halidesand aryl boronic acids catalyzed by cheap metal salts (NiCl2,CoCl2, FeCl3) in the presence of dppy as ligand (Scheme 48).

Small amounts of biphenyl arising from boronic acid homo-coupling were formed along with the cross-coupling product.It was postulated that the primary effect of the pressure is theacceleration of the reduction of the metal to a catalyticallyactive oxidation state.[78]

Franz�n and coworkers have exploited a stable tetrakis-ACHTUNGTRENNUNG(pyridine)iron(II) catalyst for Suzuki-type biaryl forming reac-tions (Scheme 49). Functionalized aryl bromides (NO2, COMe,

OMe) can be reacted with phenylboronic acid in good yields inan aerobic atmosphere and aqueous ethanol (1:1) at low cata-lyst loadings (1 mol %). Addition of TBAB was found to increasethe yield of the biaryl.[79]

Iron-Catalyzed Sonogashira Reactions[80]

In 2008, the range of applications of iron catalysts to cross-coupling reactions was significantly broadened by a publica-tion from the group of Bolm, which developed a novel iron-catalyzed arylation of terminal alkynes. With catalytic amountsof FeCl3 and N,N’-dimethylethylenediamine (dmeda) as ligand,various electron-rich and -deficient aryl iodides furnished thedesired arylacetylenes in good yields. The scope of the reactionis limited to aryl iodides. Aryl tosylates and bromides turnedout to be significantly less reactive and gave only traces of orno coupling product (Scheme 50).[81]

A related ligand-free iron–copper-cocatalyzed cross-couplingreaction of aryl halides with terminal alkynes was recently re-ported by the group of Mao. While aryl iodides provided thecorresponding coupling products in good yields (up to 99 %,see Scheme 51), iodine (10 mol %) as additive was required in

the case of aryl bromides in order to achieve moderate yieldsof the alkynylation products. The same protocol was also ap-plied to C�O and C�S coupling reactions with good yields.[82]

A similar iron–copper-catalyzed procedure for the couplingof aryl iodides and aliphatic and aromatic alkynes in the pres-ence of Cs2CO3 as base was published by Rao Volla andVogel.[83]

Cross-Coupling with Alkyl Electrophiles

Alkenylmagnesium Nucleophiles

Reports on iron-catalyzed cross-coupling reaction betweenvinyl Grignard reagents and alkyl halides are scarce. Brinkerand Kçnig engaged iron catalysis in the synthesis of cyclobutyl-ACHTUNGTRENNUNGidene derivatives.[84] Vinylmagnesium bromide smoothly react-ed with a cyclobutyl bromide in the presence of anhydrousFeCl3 affording 61 % of the vinyl cyclobutane (Scheme 52).

Scheme 48. Suzuki–Miyaura cross-coupling at high pressure.[78]

Scheme 49. Suzuki–Miyaura coupling with tetrakis ACHTUNGTRENNUNG(pyridine)iron(II) cata-lyst.[79]

Scheme 50. Iron-catalyzed arylation of terminal alkynes by Bolm and co-ACHTUNGTRENNUNGworkers.[81]

Scheme 51. Ligand-free iron/copper-catalyzed alkynylations by Mao et al.[82]

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Cossy and coworkers carefully studied reaction conditionsfor the cross-coupling of vinyl Grignard reagents with primaryand secondary alkyl iodides and bromides.[85] While the stan-dard FeACHTUNGTRENNUNG(acac)3/THF/NMP protocol failed, the FeCl3/TMEDAsystem afforded the anticipated products in high yieldsACHTUNGTRENNUNG(>90 %). Slow addition of the Grignard reagent/TMEDA mixtureto the FeCl3/substrate solution was crucial for high conver-sions. These conditions were, however, not applicable to aro-matic halides and a- or b-bromo esters. The reactions of secon-dary halides were accompanied by the formation of elimina-tion products (Scheme 53). Simultaneously, Cahiez et al. also

realized an efficient coupling between alkenyl Grignard re-agents and primary or secondary alkyl halides using a Fe-ACHTUNGTRENNUNG(acac)3/TMEDA/HMTA (1:2:1) catalyst system in THF.[86] Whilethe reaction of alkyl iodides and bromides proceeded smooth-ly, the corresponding chlorides reacted only sluggishly, givinglow yields. The procedure is tolerant of ester and nitrile func-tions. The reaction was highly chemo- and stereoselective(E/Z~85:15). Selected examples of direct cross-coupling reac-tions between vinyl bromides and alkyl bromides were report-ed by Jacobi von Wangelin and coworkers as part of a studyon domino iron catalysis involving slow, in situ formation ofthe Grignard reagent (Scheme 54).[87]

Arylmetal Nucleophiles

Nakamura et al. discovered the beneficial effect of amines(such as TMEDA) on the selectivity of aryl–alkyl cross-couplingreactions in THF at �78 8C with FeCl3 as catalyst. Highly selec-tive cross-coupling reactions of primary and secondary alkylhalides with minimal competing elimination required slow ad-dition of the aryl Grignard reagent (Scheme 55).[88] Certain

trends in the reactivity of alkyl halides were observed (I>Br>Cl, electron-rich>electron-poor Grignard reagents). Mechanis-tic studies led to the assumption that a bulky “iron-bound radi-cal” intermediate acts as catalyst as it was suggested for theiron-catalyzed living radical polymerization.[89]

Nakamura et al. later expanded the scope of this procedureto arylzinc reagents.[90] The presence of a magnesium salt (asbyproduct of the Mg-to-Zn transmetalation) was shown to bemandatory for the successful course of the cross-coupling reac-tion (yields ca. 90 %, Scheme 56). With organozinc species, noslow addition of the organometallic was required.

F�rstner and coworkers investigated the competence of thewell-defined complex [Li ACHTUNGTRENNUNG(tmeda)2][Fe ACHTUNGTRENNUNG(C2H4)4] , a ferrate ACHTUNGTRENNUNG(�II) com-plex in which iron exhibits d10 configuration, as cross-couplingcatalyst.[62, 91] It could be prepared upon successive removal ofthe cyclopentadienyl rings from ferrocene under reducing con-

Scheme 52. Vinylation of a cyclobutyl bromide by Brinker and Kçnig.[84]

Scheme 53. Alkenylation of alkyl halides by Cossy and coworkers.[85]

Scheme 54. Direct cross-coupling by Jacobi von Wangelin and coworkers.[87]

Scheme 55. Reaction of secondary alkyl halides and aryl Grignard reagentsby Nakamura et al.[88]

Scheme 56. Coupling with arylzinc reagents by Nakamura et al.[90]

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Sustainable Iron-Catalyzed Cross-Coupling Reactions

ditions in the presence of pressurized ethylene and related tothe investigations into subvalent iron-olefin complexes pio-neered by Jonas et al.[34, 92] It was shown that primary alkyl io-dides, secondary alkyl bromides, and propargyl and allyl hal-ides reacted smoothly with aryl Grignard reagents, affordingthe desired arylated products in virtually quantitative yields inmost cases (Scheme 57). Tertiary halides and alkyl chlorides

were found to be inert. The obtained results suggest that Fe�II

species, such as the elusive [Fe ACHTUNGTRENNUNG(MgX)2] ,[60a, 61, 62] could be thecatalytically active species in iron-catalyzed cross-coupling re-actions between organohalides and organomagnesium com-pounds. A radical mechanism, however, cannot be ruled outbecause radical clock experiments with 6-bromo-hexene exhib-ited intramolecular ring closure rather than cross-coupling.[93]

Bedford et al. tested easily accessible iron ACHTUNGTRENNUNG(III)-salen com-plexes in reactions of primary and secondary alkyl halides bear-ing b-hydrogens with aryl Grignard reagents. The cross-cou-pling products were obtained in modest to good yields(Scheme 58).[94] Similarly, Nagano and Hayashi discovered thatprimary and secondary alkyl bromides efficiently react with aryl

Grignard reagents in the presence of catalytic FeACHTUNGTRENNUNG(acac)3 in re-fluxing diethylether.[64] Diethylether seemed to be more effi-cient than THF or THF/NMP mixtures, as competitive ß-hydrideelimination and reduction were minimized. The protocol is notsuitable for tertiary halides and triflates, allowing chemoselec-tive transformations (Scheme 59).

Bedford et al.[95] and Kozak and coworkers[96] proved thatmixtures of iron ACHTUNGTRENNUNG(III) chloride and appropriate amine ligands areactive catalysts for the coupling of aryl Grignard reagents with

primary and secondary alkyl halide substrates bearing b-hydro-gens (Scheme 60). FeCl3/triethylamine seemed to be optimalfor the consumption of sterically hindered alkyl halides under

mild conditions, while sterically hindered Grignard speciesfailed to react. The use of FeCl3/DABCO led to the highest E/Zselectivities and was most effective for less hindered halides. Incontrast to the aforementioned results by Nakamura et al. ,[88]

the FeCl3/TMEDA system fared least well in most reactions.In a concise study by Bedford et al. , alternative catalyst sys-

tems with phosphane, phosphite, arsine, or NHC ligands havealso been subjected to aryl–alkyl cross-coupling reactions andproved similarly active (Scheme 61).[93a] Better conversions tothe desired products were typically attained with alkyl bro-mides independent of the choice of catalyst. The general trendappeared to be Br> I>Cl. The same group also performedmechanistic studies on the model reaction of phenylmagnesi-um bromide with (bromomethyl)cyclopropane and postulateda plausible radical pathway (Scheme 62). The active low-valentiron species in oxidation state n is believed to react with thealkyl halide via a single-electron-transfer process to give analkyl radical/[Fe ACHTUNGTRENNUNG(n+1)X] pair. Transmetalation of the aryl moiety

Scheme 57. Ferrate ACHTUNGTRENNUNG(�II)-catalyzed cross-coupling according to F�rstner andcoworkers.[62]

Scheme 58. Iron ACHTUNGTRENNUNG(III)-salen-catalyzed cross-coupling by Bedford et al.[94]

Scheme 59. Chemoselective sequential cross-coupling by Nagano and Haya-shi.[64]

Scheme 60. Amine/iron catalysts in aryl-alkyl cross-coupling by Bedfordet al.[95]

Scheme 61. Mono- and bidentate ligands by Bedford et al.[93a]

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from the Grignard reagent generates an iron-aryl complex,which eliminates the coupling product. It was also shown thatthe active iron species might also include nanoparticles stabi-lized by additives such as poly(ethylene glycol).[93b]

Bedford et al. efficiently applied 1,2-bis(diphenylphosphino)-benzene as ligand for the iron-catalyzed Negishi-type couplingof arylzinc reagents with benzyl halides and phosphates. Theremarkable tolerance of halides on the benzyl ring allows se-lectivities that cannot be realized by analogous palladium cat-alysis.[97] Bica and Gaertner introduced a novel catalyst system.The ionic liquid n-butylmethylimidazolium tetrachloro-ferrate(bmim-FeCl4) was found to be a highly effective and complete-ly air-stable catalyst for the biphasic cross-coupling reaction ofprimary and secondary alkyl halides bearing b-hydrogens witharylmagnesium halides (Scheme 63).[98] Moreover, the iron cata-lyst was successfully recycled and reused multiple times. An in-creased reactivity of electron-poor Grignard reagents was ob-served. Attempts to use tertiary alkyl halides or aryllithium re-agents failed.

Cahiez et al. disclosed two efficient ecofriendly iron-cata-lyzed procedures to couple secondary and primary alkyl hal-ides (Br, I) with aromatic Grignard reagents using two novel

catalytic systems: [Fe ACHTUNGTRENNUNG(acac)3]/HMTA/TMEDA (1:1:2) and thecomplex [(FeCl3)2ACHTUNGTRENNUNG(tmeda)3] .[99] A large excess of TMEDA typicallyused under conventional conditions could be thus reduced tocatalytic amounts (Scheme 64). The authors suggested that theiron-catalyzed reaction commences with an oxidative addition

of the alkyl halide to a nucleophilic bisaryliron(0) complex via asingle-electron transfer (Scheme 65). Secondary and primaryalkyl bromides were used successfully in cross-coupling reac-tions, with the former giving higher yields.

Rao Volla and Vogel disclosed reaction conditions for the de-sulfinylative C�C cross-coupling of alkylsulfonyl chlorides withGrignard reagents using FeACHTUNGTRENNUNG(acac)3 as catalyst and NMP as co-solvent (Scheme 66).[46]

In 2009, Jacobi von Wangelin and coworkers reported onthe first direct cross-coupling reaction between aryl halidesand alkyl halides in the presence of metallic magnesium andiron/amine catalyst. The reaction involves in situ formation of

Scheme 62. Radical mechanism postulated by Bedford et al.[93a]

Scheme 63. Bica and Gaertner’s ionic-liquid-based iron catalyst.[98]

Scheme 64. Novel catalytic iron-based systems by Cahiez et al.[99]

Scheme 65. Radical mechanism proposed by Cahiez et al.[99]

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Sustainable Iron-Catalyzed Cross-Coupling Reactions

the Grignard reagent and subsequent rapid cross-coupling.The authors also elucidated a novel iron-catalyzed Grignardformation and demonstrated the concept of domino iron catal-ysis in cross-coupling reactions (Scheme 67). The reaction con-ditions of the underlying one-pot reaction are highly sustaina-

ble as they preclude the utilization of hazardous Grignard re-agents and limit the amount of reactive organomagnesium in-termediates to low quasi-stationary concentrations.[87]

Alkylmagnesium Nucleophiles

The seminal investigations into iron-catalyzed cross-couplingreactions between alkyl halides and alkyl Grignard reagents byKochi et al. revealed that significant amounts of coupled prod-ucts can only be obtained when the alkyl group is devoid ofany b-hydrogen atoms, as in methyl, neopentyl, phenyl, orbenzyl moieties.[12] In all other cases, disproportionation wasoperative and b-hydride elimination products were mainly ob-tained. Experiments with radical scavengers such as styreneled to inhibition of the cross-coupling reaction and suggestthe operation of a radical mechanism. Later, Kochi’s protocolwas optimized for the coupling of gem-dichlorocyclopropaneswith methyl magnesiumbromide by the group of Tanabe. Vari-ous iron precatalysts and additives were screened and thecombination of Fe ACHTUNGTRENNUNG(dmb)3 (5 mol %) with 4-methoxytoluene orp-xylene was identified to be most efficient (Scheme 68).[100]

Reaction conditions for the sp3–sp3 cross-coupling betweenalkyl Grignard reagents and unactivated primary or secondaryhalides were delivered by Chai and coworkers.[101] Based on theextensive screening of different ligands, iron sources, and sol-vents, FeACHTUNGTRENNUNG(OAc)2 in combination with bidentate phosphineligand Xantphos in DME at ambient temperature proved to bemost effective (Scheme 69). Yields up to 64 % were achieved

with primary bromides; secondary bromides afforded up to43 % of the long-chain alkanes. Mechanistic investigations re-vealed that the reaction of alkyl Grignard reagents with 6-bro-mohex-1-ene mostly led to cyclization, suggesting a radicalpathway.

Allyl and Propargyl Electrophiles

Allenes are versatile building blocks for advanced organicsynthesis because of the reactivity inherent to their axiallychiral backbone. They are usually prepared by SN2 reaction ofpropargylic systems with organocuprates. In 1976, Pasto et al.discovered that primary and secondary Grignard reagents canbe reacted with terminal and internal propargyl halides in thepresence of catalytic FeCl3 in a highly selective fashion, afford-ing allenes in yields up to 90 %. Reductive formation of onlysmall amounts of alkynes and conjugated dienes was observed(Scheme 70).[102] A mechanism for this tandem reaction of p-re-arrangement and cross-coupling was proposed.[103]

Hashmi and Szeimies studied related reactions with tricyclo-ACHTUNGTRENNUNG[4.1.0.0]hept-1-yl Grignard reagents and propargylic and allylichalides.[104] FeACHTUNGTRENNUNG(acac)3 is a competent catalyst for the formationof allyl, allenyl, and propargyl-substituted bicyclo-[1.1.0]bu-tanes in moderate yields and high purity while Ni ACHTUNGTRENNUNG(acac)2 and

Scheme 66. Desulfinylative cross-coupling of alkylsulfonyl chlorides by RaoVolla and Vogel.[46]

Scheme 67. Direct cross-coupling of aryl and alkyl halides by Jacobi vonWangelin and coworkers.[87]

Scheme 68. The sp3–sp3 cross-coupling reaction by Tanabe and cowork-ers.[100]

Scheme 69. Iron-catalyzed sp3–sp3 cross-coupling by Chai and coworkers.[101]

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CoCl2 appeared to be less effective. Stereo-electronic factorswere exploited to govern the course of the reaction for thepreparation of either propargylic or allenylic products(Scheme 71).

Similar reactions for the preparation of chiral allenes were in-vestigated by Mend�z and F�rstner. Enantiomerically enrichedpropargyl epoxides could be efficiently converted into the cor-responding 2,3-allenols upon iron-catalyzed reaction withGrignard reagents.[105] FeACHTUNGTRENNUNG(acac)3 (5 mol %) was used as catalystand the central chirality of the substrates was transferred tothe axial chirality of the products with high fidelity(Scheme 72). No additional ligands were required, the yieldswere good to excellent, and the substrate scope sufficientlybroad. Attempts with propargyl halides, however, resulted inlow yields and enantioselectivities. F�rstner et al. also appliedthis methodology in the total synthesis of Amphidinolides Xand Y.[106]

Yamamoto and coworkers showed that the treatment of pri-mary allylic phosphates with allyl, aryl, propargyl, or vinyl

Grignard reagents in the presence of 5 mol % FeACHTUNGTRENNUNG(acac)3 at�70 8C in THF resulted in the formation of cross-couplingproducts in a highly chemoselective manner (yields 70–90 %,selectivity <98:1, Scheme 73).[107]

Arylative and alkenylative iron-catalyzed ring-opening reac-tions of [2.2.1.]- and [3.2.1]-oxabicyclic alkenes with Grignardreagents were observed by Nakamura et al. to proceed withhigh regio- and stereocontrol (Scheme 74).[108]

Early studies by Roustan and coworkers, Ladoulis and Nicho-las, and Xu and Zhou documented the catalytic activity of ironcarbonyl complexes in allylic substitution reactions.[109] In 2006,Plietker published an efficient, salt-free, regioselective iron-cat-alyzed allylic alkylation of allyl carbonates.[110] Small amounts ofPPh3 led to a significant increase of the amount of substitutionproduct (Scheme 75). Reactions with enantiopure carbonatessuffered a slight decrease of the enantiomeric excess. LaterPlietker also proposed a mechanism for such iron-catalyzed al-

Scheme 70. Substituted allenes from propargyl halides by Pasto et al.[102, 103]

Scheme 71. Selective formation of allenes and alkynes according to Hashmiand Szeimies.[104]

Scheme 72. Stereoselective reaction of propargyl epoxides by Mend�z andF�rstner.[105]

Scheme 73. Reaction of allylic phosphates with Grignard reagents accordingto Yamamoto and coworkers.[107]

Scheme 74. Ring-opening substitutions by Nakamura et al.[108b]

Scheme 75. Plietker’s iron-catalyzed allylic alkylation of allyl carbonates.[110]

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Sustainable Iron-Catalyzed Cross-Coupling Reactions

lylic substitutions involving a ligand-dependent dichotomy.[111]

�kermark and Sjçgren disclosed a protocol for the substitutionof allylic acetate by diethyl methylmalonate with catalyticFe2(CO)9 and dimethylamine.[112]

C�H Functionalization

Transition-metal-catalyzed C�H activation has recentlygained considerable momentum and is now widely recognizedfor its potential to form a host of C�C and carbon–heteroatombonds in an inherently benign fashion. These challengingtransformations are currently dominated by expensive metalcatalysts based on palladium, rhodium, or ruthenium.[113] Thedevelopment of efficient iron catalysts for selective C�C bondforming reactions that involve C�H activation are still limitedto activated substrates (proximal heteroatom or directinggroup) while several methods exist for oxidations of C�Hbonds with iron catalysts.[114] Nakamura and coworkers devel-oped an iron-catalyzed C�C bond-forming reaction through in-itial C�H bond activation. Accordingly, a-benzoquinoline andrelated heterocyclic structures can be reacted with arylzinc re-agents at remarkably low temperatures (0 8C). The protocol re-quires a large excess of the Grignard reagent and theZnCl2·TMEDA complex (Scheme 76).[115] Li et al. demonstrated

that iron carbonyls are effective catalysts for the selective acti-vation of C�H bonds adjacent to heteroatoms for subsequentC�C bond formation (Scheme 77).[116]

A striking example of an efficient intermolecular iron-cata-lyzed 1,4-addition of a-olefins to 1,3-dienes was reported by

Ritter and coworkers in 2009 (Scheme 78). The catalyticallyactive species is formed upon reduction of FeCl2 with Mg inthe presence of an iminopyridine ligand. The resultant dieneswere found to be formed with high stereocontrol upon stereo-selective syn-b-HZ-elimination from an intermediate alkylironspecies.[117]

Heck-Type Reactions

An isolated example of an iron-catalyzed Heck reactions has sofar been reported by Vogel and coworkers. In the presence ofa rather large amount of FeCl2 (20 mol %), picolinic acid asligand (80 mol %), and KOtBu as base (4 eqs.) substituted styr-enes can be obtained from reaction of aryl and heteroaryl io-dides with styrenes in DMSO in moderate to good yields(Scheme 79).[118]

Summary and Outlook

Iron-catalyzed cross-coupling reactions have matured to an ad-vanced stage and provide synthetic organic chemists with aversatile arsenal of C�C and C�X bond-forming methods. Withhighly reactive iron catalysts, reactions of substrates usuallyconsidered cumbersome under palladium and nickel catalysis,such as secondary alkyl halides, become feasible. The high re-activity is inherited from the presence of organomagnesiumspecies that are (a) crucial for the in situ generation of highlyelectron-rich iron complexes by reduction of commercial

Scheme 76. C�H arylation of a-benzochinoline by Nakamura and cowork-ers.[115]

Scheme 77. C�H functionalization by Li et al.[116]

Scheme 78. Iron-catalyzed synthesis of (E,E)-1,4-dienes.[117]

Scheme 79. Iron-catalyzed Heck reactions by Vogel et al.[118]

414 www.chemsuschem.org � 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemSusChem 2009, 2, 396 – 417

A. Jacobi von Wangelin et al.

iron(II) or iron ACHTUNGTRENNUNG(III) salts, and (b) constitute a strong nucleophilefor the cross-coupling step.[5] Combinations of iron salts andamine ligands, which are the most prevalent type of catalystsystem, allow for mild reaction conditions and a large range ofapplications owing to their high reactivity towards variousclasses of electrophiles and organomagnesium compounds.General protocols for cross-coupling reactions with variousalkyl-, alkenyl-, and aryl-MgX nucleophiles have been devel-oped. However, the design of competent catalysts and reactionconditions for alkyl–alkyl cross-coupling is still at an early stageand remains a true challenge. Improvements with regard tofunctional group compatibility are clearly desirable. Anotheraspect that is closely linked to the use of Grignard reactants re-volves around the required operational safety arrangements.The hazard potential of organomagnesium halides (e.g. , flam-mable, corrosive, moisture- and air-sensitive) entails additionalcost-intensive measures that might limit industrial realizationson larger scales. The overall process simplicity would thushighly benefit from the employment of less-hazardous organo-metallic components or alternative safe or in situ Grignard-for-mation reactions as found under direct cross-coupling condi-tions. It is also important to note that the mechanistic detailsof iron-catalyzed cross-coupling reactions are not fully under-stood. This is largely due to the fact that structure and proper-ty data of low-valent iron or ferrate complexes are scarce. Thepostulated catalytically active iron species are highly reactiveand mostly too short-lived for classical direct analytical tech-niques. It will take extensive and elaborate synthetic efforts todesign ligand-stabilized iron complexes that lend themselvesto detailed investigations and allow monitoring catalytic inter-mediates.

Future research will certainly be aimed at the optimizationof reaction conditions to attain higher productivity (<1 mol %catalyst) and greater tolerance of sensitive functional groups.Further mechanistic studies are required to establish the iden-tity of catalyst species and intermediates as well as the oftenunpredictable effects of additives. With regard to efficiency cri-teria, improvements in atom economy are necessary, as mostprotocols require an excess of one substrate. The rapid prog-ress of iron-catalyzed cross-coupling reactions that the com-munity has witnessed over the past years encourages us toexpect more efficient catalyst systems and reaction conditionsto be developed in the near future. Furthermore, if selective(and stereospecific) reactions with sterically hindered secon-dary and tertiary alkyl halides become generally possible, thesemethods will undoubtedly become an indispensable part ofthe organic chemists’ toolbox for sustainable syntheses ofcomplex molecules.

Abbreviations

acac = acetylacetonateBOC = t-butyloxycarbonylc-hex = Cy = cyclohexylDABCO = 1,4-diazabicyclo ACHTUNGTRENNUNG[2.2.2]octanedbm = dibenzylmethideDME = dimethoxyethane

DMSO = dimethyl sulfoxidedpm = dipivaloylmethidedppe = 1,2-diphenylphosphinoethanedppf = 1,1’-bis(diphenylphosphino)ferrocenedppy = 2-(diphenylphosphino)pyridineHex = n-hexylHMTA = hexamethylenetetramineMOM = methoxymethylNHC = N-heterocyclic carbeneNMP = N-methyl-2-pyrrolidoneOct = n-octylONf = nonaflate, nonafluorobutanesulfonateOTf = triflate, trifluoromethanesulfonate1,10-phen = 1,10-phenanthrolinePMB = p-methoxybenzylpy = pyridineSIPrHCl = 1,3-bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazo-

lium chlorideTBAB = tetrabutylammonium bromideTBDPS = t-butyldiphenylsilylTBDMS = TBS = t-butyldimethylsilylTFA = trifluoroacetic acidTHF = tetrahydrofuranTIPS = triisopropylsilylTMEDA = N,N,N’N‘-tetramethylethylenediamineXantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxan-

thene

Acknowledgements

We gratefully acknowledge financial support from the DeutscheForschungsgemeinschaft (Emmy-Noether fellowship to A.J.v.W.),the Max-Buchner foundation of the DECHEMA (fellowship toW.M.C.), and the Deutsche Bundesstiftung Umwelt (fellowship toM.M.).

Keywords: homogeneous catalysis · cross-coupling · Grignardreaction · iron · transition metals

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Received: February 16, 2009Published online on May 7, 2009

ChemSusChem 2009, 2, 396 – 417 � 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemsuschem.org 417

Sustainable Iron-Catalyzed Cross-Coupling Reactions

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