The use of non-precious first row transition-metals for C‒C bond forming reactions continuous to be attractive.[122, 123] Their low price and earth abundance make them endearing catalysts for industrial transformations.[65, 124] Especially iron offers significant advantages compared to other metals, since it is the 4th most abundant metal in the earth crust. In the field of iron catalysis, a number of impressive examples demonstrate the potential of these cost-efficient and nontoxic iron complexes.[122, 125]
Besides, iron takes place in manifold essential biological processes. Facile interconversion of its oxidation states and Lewis acidity allows a broad range of versatile reactions, such as additions, reductions or oxidations. Respectable advances in traditional cross-coupling chemistry have been accomplished with iron complexes.[126]
Since Kharasch[127] studied the reaction of aryl Grignard reagents in the presence of metallic halides focusing on iron-catalyzed couplings with Grignard reagents, examples of iron-catalyzed cross-coupling reactions have been reported. Probably, the effect of iron catalysts upon cross-couplings was most significantly clarified by the investigations of reactions with alkenyl and aryl halides by Kochi et al.[128, 129] reactants in 1,2-dimethoxyethan as the solvent and by lowering the reaction temperature (Scheme 37).[131] Further development was accomplished by Cahiez, who used a mixture of polar solvents, such as THF and N-methylpyrrolidinone (NMP).[132] Especially NMP was important because of its stabilizing effect as a ligand for the catalytically active iron species, thus avoiding ß-hydride elimination.
Scheme 37: Iron-catalyzed cross-coupling by Molander et al.
Unfortunately, iron-catalyzed cross-coupling reactions suffer from major limitations. Thus, the methyl Grignard reagents were efficient in alkylations of alkenyl halides but not capable to methylate aryl chlorides 77 (Scheme 38).[133] In contrast, EtMgBr or higher alkyl Grignard reagents afforded the desired products, such as 78 and 79.
Scheme 38: Different behavior of MeMgBr and EtMgBr in iron-catalyzed coupling reactions.
The reaction was widely applicable for a variety of aryl chlorides and tosylates with alkyl or alkenyl Grignard reagents (Scheme 39).
Scheme 39: Iron-catalyzed cross-coupling with Grignard reagents.
These observations are in accordance with the findings of Bogdanović and coworkers.[134]
Iron(+II) can be reduced in situ by the Grignard reagent to form a highly nucleophilic species of the formal composition [Fe(MgX)2]n (Scheme 40), with a formal negative oxidation state and a d10 electron configuration. In this example the alkyl Grignard is able to undergo ß-hydride elimination.
Scheme 40: Formation of inorganic Grignard reagents.
In 2004, Nakamura discovered the influence of TMEDA as an additional Lewis-basic additive on suppressing the ß-hydride elimination (Scheme 41).[135] In the absence of TMEDA, the reaction of cycloheptyl bromide 80 with PhMgBr resulted in the formation of cycloheptene 82 as the major product.
Scheme 41: Effect of the additive TMEDA on the cross-coupling reaction of alkyl halide 80.
Additionally, iron complexes can be used for the introduction of branched alkyl chains. In the recently reported reactions by Cook[136] and Garg,[137] coupling of sulfamates 83 and tosylates 84 with several primary and secondary alkyl Grignard reagents in the presence of NHCs as ligands have successfully been utilized for the alkylation of arenes in the Kochi-type[130]couplings (Scheme 42).
Scheme 42: Iron-catalyzed alkylating cross-coupling.
In contrast, aryl-aryl bond formations were more sensible in iron-catalyzed cross-coupling reactions. The homo-coupling of the Grignard reagent was the primary problem. Moreover, these reactions appeared to be mostly limited to electron-deficient haloarenes 86.[138] The homo-coupling could be avoided by addition of KF or FeF3 in combination with NHC ligands (Scheme 43).[139]
Scheme 43: FeF3 catalyzed cross-coupling.
Mechanistic Insights in Iron-Catalyzed Cross-Coupling Chemistry
In spite of the rapid development of iron-catalyzed cross-coupling chemistry, the true nature of the catalytic cycle is thus far poorly understood due to the fact, that the active catalyst species is usually generated in situ. Depending on the ability of the Grignard reagent to reduce iron species, three oxidation states of the operating iron species will be presented, enclosing three different catalytic cycles with Fe(+I)/Fe(+III), Fe(0)/Fe(+II) or Fe(-II)/Fe(0).
The early studies by Kochi et al. reported on "a reduced form of soluble iron", that served as the active catalytic species presuming a Fe(+I)/Fe(+III) catalytic cycle, but did not exclude a Fe(0)/Fe(+II) manifold to be involved.[130] The canonic mechanism included an oxidative addition, transmetalation and reductive elimination, similar to the mechanism of the Kumada-Corriu coupling.[140] Several reports indicate a homoleptic nonstabilized alkyliron or organoferrat species of FeXn (n = 2,3).[141] Merely the reduction of FeCl3 to FeCl2 with one equivalent of MeLi has been proven.[142] In the reaction of FeCl3 with 5 portions of MeLi, the formation of Li2[FeMe4] has been postulated, but the latter was not isolated.[143] However, Fürstner and coworkers synthesized a similar tetrahedral homoleptic ferrate [(Me4Fe)(MeLi)][Li(OEt2)]2 (88) with an iron(+II) atom surrounded by four methyl groups (Figure 3).[144]
Figure 3: Structure of the "super ate" iron-complex [(Me4Fe)(MeLi)][Li(OEt2)]2.
The treatment of FeCl3 with a large excess of PhLi resulted in the thermally unstable planar-rectangular [Ph4Fe][Li(OEt2)]4 (89) with an iron(0) center (Figure 4).[145, 146]
The reaction of FeCl2 with four equivalents of PhLi led to the comparable tetraphenylferrate complex [Ph4Fe][Li(Et2O)2][Li(1,4-dioxane)] 90 with an iron(+II) center. Both complexes 89 and 90 can thermally decompose to generate biphenyl as the major product. The undesired homo-coupling, which was also observed in cross-coupling reactions with PhMgBr, indicated that decomposition was faster than the transfer of an aryl group to an electrophilic partner.[146]
Fürstner and coworkers proposed that the complexes are intermediates, which are formed through several catalytic cycles, thus explaining the formation of homocoupled byproducts.
Figure 4: Schematic presentation of planar-rectangular [Ph4Fe][Li(OEt2)]4.
As indicated above, MeMgBr and PhMgBr are unable to undergo ß-hydride elimination, whereas EtMgBr and higher homologues form inorganic Grignard reagents displaying low-valent iron bimetallic cluster species of the formal composition [Fe(MgX)2]n or [Fe(MgX2)2]n, first suggested by Bogdanović and coworkers.[134, 147] Four equivalents of RMgX reacted with FeX2 (X = Cl, Br) to produce complexes with a formally negative d10 electron configuration of iron (Scheme 44). The catalytic cycle involves an activation of the aryl halide by the low valent iron cluster species via σ-bond metathesis rather than oxidative insertion, following by additional alkylation with RMgX instead of transmetalation. The resulting bisorganoiron intermediate undergoes reductive elimination to form the alkylated product and regenerate the catalyst.
Scheme 44: Reduction of iron to "inorganic Grignard reagent".
These in situ generated low valent iron complexes have been used in alkyl-aryl and aryl-alkyl cross-coupling reactions with good results.[146, 148, 149]
Jonas and coworkers demonstrated the replacement of Cp*-ligands in ferrocene-type half-sandwich and sandwich complexes with ethylene[150] and TMEDA as substituted ligands, thus creating an iron(–II) center (Figure 5).[150] Examination of this structurally defined complex 91, resulted in similar effects on the yield, towards alkyl and aryl Grignard reagents to mimic cross-coupling reactions with the in situ generated low valent iron species.[146, 149]
Figure 5: Low-valent iron(–II) complex 91.
The spin state of iron strongly depends on the nature of the ligands and the ability of the Grignard reagents to reduce iron. Therefore, several oxidation states for iron catalysts are feasible, even allowing simultaneous operating of several mechanisms. These detailed investigations in the last decades demonstrate that iron-catalyzed cross-coupling reactions are able to pass through more than one catalytic pathway, indicating many conceivable events of potentially connected catalytic cycles (Figure 6).[146]
Figure 6: Interconnected catalytic cycles of iron-catalyzed cross-coupling reactions.