Iron-Catalyzed Cross-Coupling Reactions Research Articles

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

A TMEDA-Iron Adduct Reaction Manifold in Iron-Catalyzed C(sp2 )-C(sp3 ) Cross-Coupling Reactions.

Herein, we expand the current molecular-level understanding of one of the most important and effective additives in iron-catalyzed cross-coupling reactions, N,N,N',N'-tetramethylethylenediamine (TMEDA). Focusing on relevant phenyl and ethyl Grignard reagents and slow nucleophile addition protocols commonly used in effective catalytic systems, TMEDA-iron(II)-aryl intermediates are identified via in situ spectroscopy, X-ray crystallography, and detailed reaction studies to be a part of an iron(II)/(III)/(I) reaction cycle where radical recombination with FePhBr(TMEDA) (2Ph ) results in selective product formation in high yield. These results differ from prior studies with mesityl Grignard reagent, where poor product selectivity and low catalytic performance can be attributed to homoleptic iron-ate species. Overall, this study represents a critical advance in how amine additives such as TMEDA can modulate selectivity and reactivity of organoiron species in cross-coupling.

Iron-Catalyzed Oxidative Cross-Coupling of Phenols and Tyrosine Derivatives with 3-Alkyloxindoles.

In this study, a novel iron-catalyzed oxidative cross-coupling reaction between phenols and 3-alkyloxindole derivatives is reported. The efficient method, which is based on the FeCl3 catalyst and the t-BuOOt-Bu oxidant in 1,2-dichloroethane at 70 °C, affords 3-alkyl-3-(hydroxyaryl)oxindole compounds with a high degree of selectivity. The generality of the conditions was proven by reacting various substituted phenols, naphthols, and tyrosine derivatives with 3-alkyloxindoles. To apply the chemistry for the conjugation of tyrosine-containing short peptides with oxindolylalanine (Oia) derivatives, the reaction conditions were modified [Fe(O2CCF3)3 catalyst, t-BuOOt-Bu, HFIP, 70 °C], and amino acids with acid-stable N-protecting groups were used.

Iron-catalyzed oxidative amidation of acylhydrazines with amines

A new approach for amide bond formation via a mild and efficient Iron-catalyzed cross-coupling reaction of acylhydrazines and amines using TBHP as oxidant is described. This protocol is compatible with a wide range of amines and acylhydrazines. In addition, the synthetic application of the reaction is presented.

Iron-Catalyzed Cross-Coupling Reactions Tuned by Bulky Ortho-Phenylene Bisphosphine Ligands

Abstract The significant progress made in the context of iron-catalyzed cross-coupling reactions in the past several years has boosted competition with well-known nickel and palladium catalyst systems. Iron-catalyzed protocols not only benefit from economic and toxicology standpoints, but also exhibit a range of reactivities and tolerate many functional groups. To date several iron catalyst systems have been developed, ranging from the use of simple iron salts to more complex stoichiometric/catalytic modifiers. Effective N-heterocyclic carbenes and bisphosphine ligands have also been developed for the cross-coupling reactions of organic electrophiles using diverse organometallic reagents. Indeed, the use of bisphosphine ligands in the field of iron-catalyzed cross-coupling reactions is important for new applications in modern synthetic organic chemistry. This account summarizes the recent developments in practical and novel iron-catalyzed cross-coupling reactions employing bulky o-phenylene bisphosphine ligands and their mechanistic views.

Stereocomplementary and Parallel Syntheses of Multi-Substituted (E)-, (Z)-Stereodefined α,β-Unsaturated Esters: Application to Drug Syntheses.

Ubiquitous α,β-unsaturated esters are well recognized as key structural olefin scaffolds in organic chemistry. (E)- and (Z)-steroselectivity is the most critical issue in their synthesis, however, (E)- and (Z)- stereocomplementary synthetic methods remain quite limited. The present account discloses general (E)-, (Z)-stereocomplementary syntheses of a variety of α,β-unsaturated esters from highly accessible (E)-, (Z)-stereodefined enol tosylates derived from β-ketoesters and α-formyl esters. Step 1 toward the stereocomplementary preparation of (E)-, (Z)-stereodefined enol tosylates is implemented by using inexpensive reagents under mild reaction conditions. Step 2 toward the highly stereoretentive synthesis of (E)- and (Z)-stereodefined α,β-unsaturated esters involves Suzuki-Miyaura, Negishi, Sonogashira, Iron-catalyzed, Mizoroki-Heck, and Buchwald-Hartwig cross-coupling reactions. Notably, this strategy was successfully applied for parallel drug syntheses of (E)- and (Z)-zimelidine, (E)- and (Z)-tamoxifen, and Merck's cyclopropane pharmacophore. Representative successful utilizations by other groups are also introduced.

A facile iron catalyzed cross-coupling reaction under micro-flow conditions

The iron-catalyzed cross-coupling reaction between an aromatic Grignard reagent and a haloalkane was investigated under micro-flow conditions. The reaction proceeded smoothly by the separate feeding of the substrate solutions to give the desired cross-coupling product. Compared to the previously reported batch reaction, the effect of additives was more predominant in the micro-flow reaction. The flow reactor system appears to contribute to the stabilization and rapid trapping of the unstable catalytic species.

Iron-Catalyzed Cleavage Reaction of Keto Acids with Aliphatic Aldehydes for the Synthesis of Ketones and Ketone Esters.

The radical-radical coupling reaction is an important synthetic strategy. In this study, the iron-catalyzed radical-radical cross-coupling reaction based on the decarboxylation of keto acids and decarbonylation of aliphatic aldehydes to obtain valuable aryl ketones is reported for the first time. Remarkably, when tertiary aldehydes were used as carbonyl sources, ketone esters were selectively obtained instead of ketones. The gram-scale preparation of aryl ketone through this strategy was easily achieved by using only 3 mol % of the iron catalyst. As a proof-of-concept, the bioactive molecule flurprimidol was synthesized in two steps by using this strategy.

Iron Catalysis in Target Synthesis

The use of iron-catalysed organic transformations in the total syntheses of natural products has increased significantly. Iron-catalysed cross-coupling reactions are now widely applied in total syntheses and many other transformations, such as alkene functionalisation, oxidation, and cyclisation. The development of these processes, as well as many examples of their use in target synthesis, is presented here.1 Introduction2 Cross-Coupling Reactions3 Functionalisation of Unactivated Alkenes4 Carbocyclisation Reactions5 Oxidations6 Further Examples7 Conclusions

Iron-Catalyzed Cross-Coupling Reaction in Flow

Iron-Catalyzed Cross-Coupling Reaction in Flow

Recent advances on iron-catalyzed coupling reactions involving organolithium reagents

Owing to their inexpensive and environmentally friendly properties, iron-based catalysts have been actively investigated for new organic reactions. In this account, we summarized our recent results on iron-catalyzed cross-coupling reactions and homo-coupling reactions. With iron-based catalysts, we constructed diverse carbon-carbon bonds, i.e., C(sp2)−C(sp3), C(sp3)−C(sp3), C(sp3)−C(sp2) and C(sp2)−C(sp2) bonds. In order to demonstrate the usefulness of our iron protocol, we also carried out these reactions on gram-scale reactions, leading to good yields

Stereospecific Iron-Catalyzed Carbon(sp2)-Carbon(sp3) Cross-Coupling with Alkyllithium and Alkenyl Iodides.

An efficient synthetic protocol involving iron-catalyzed cross-coupling reactions between organolithium compounds and alkenyl iodides as key coupling partners was achieved. More than 30 examples were obtained with moderate to good yields and high stereospecificity. Gram-scale and synthetic applications of this procedure are recorded herein to demonstrate its feasibility and potential utilization.

Iron-catalyzed Alkyl–Alkyl Negishi Coupling of Organoaluminum Reagents

The first iron-catalyzed cross-coupling reaction of alkyl halides with alkylaluminum reagents (alkyl–alkyl Negishi coupling) is developed using an iron/bisphosphine catalyst system. The reaction sh...

Radical-clock α-halo-esters as mechanistic probes for bisphosphine iron-catalyzed cross-coupling reactions

The mechanism of chiral bisphosphine iron-catalyzed C(sp2)-C(sp3) cross-coupling reactions has been studied via the synthesis of novel radical-clock α-halo-esters and quantum mechanical calculations. These results provide insights into the role of the substrate (halogen and substituents) in competing in-cage and out-of-cage arylation pathways and provide a basis for the future rational design of novel tandem cyclization-arylation reactions using bisphosphine-iron as catalysts.

An efficient protocol for the synthesis of thioethers via iron-catalyzed cross-coupling reaction and its mechanistic investigation

One of the most straightforward methods for the synthesis of diaryl sulfides is the transition metal catalyzed CS coupling reaction. Herein we report a study on the iron-catalyzed protocol for cross-coupling reaction of aryl halides with thiols. Structurally diverse diaryl sulfides were prepared efficiently by using a catalyst system involving cheap and environment-friendly FeCl3 and non-toxic universal ligand l-proline. The reaction mechanism for the iron-catalyzed CS coupling reaction was investigated by means of density functional theory (DFT) methods on a model system. The calculations were performed using hybrid PBE1PBE functional in conjugation with the LANL-2DZ basis set. The key step involved in the mechanism is the formation of a reactant complex in which both reactants are electrostatically bound to Fe(III) proline complex catalyst. The elimination of HI occurs with a much lower TS energy (20.0 kcal/mol) than the uncatalyzed reaction (44.7 kcal/mol).

Intermediates and Mechanism in Iron-Catalyzed Cross-Coupling.

Iron-catalyzed cross-coupling reactions have attracted significant research interest, as they offer numerous favorable features compared with cross-coupling reactions with precious metal catalysis. While this research has contributed to an empirical understanding of iron-catalyzed cross-coupling, the underlying fundamental mechanisms of reaction and structures of catalytically active species have remained poorly defined. The lack of such detail can be attributed to the difficulties associated with studying such iron-catalyzed reactions, where unstable paramagnetic intermediates abound. Recently, the combined application of physical-inorganic spectroscopic methods, concomitant organic product analysis, and air- and temperature-sensitive inorganic synthesis has yielded the most detailed insight currently available on reactivity and mechanism in iron-catalyzed cross-coupling. This Perspective highlights this approach and the limitations of the contributing techniques as well as some of the key features of the catalytic reactions studied and lessons learned.

LiHMDS-Promoted Palladium or Iron-Catalyzed ipso-Defluoroborylation of Aryl Fluorides.

A novel and efficient method for the synthesis of arylboronic acid pinacol esters via a palladium- or iron-catalyzed cross-coupling reaction of aryl fluorides with bis(pinacolato)diboron (B2pin2) in the presence of LiHMDS was developed. The Pd-catalyzed defluoroborylation of fluoroarenes is compatible with a variety of functional groups such as primary and secondary amine, ketone, trifluoromethyl, alkoxy, and boryl. Remarkably, no external ligand is required for enhanced conversion efficiency.

Iron-Catalyzed Suzuki–Miyaura Cross-Coupling Reactions between Alkyl Halides and Unactivated Arylboronic Esters

An iron-catalyzed cross-coupling reaction between alkyl halides and arylboronic esters was developed that does not involve activation of the boronic ester with alkyllithium reagents nor requires magnesium additives. A combination of experimental and theoretical investigations revealed that lithium amide bases coupled with iron complexes containing deprotonated cyanobis(oxazoline) ligands were best to obtain high yields (up to 89%) in catalytic cross-coupling reactions. Mechanistic investigations implicate carbon-centered radical intermediates and highlight the critical importance of avoiding conditions that lead to iron aggregates. The new iron-catalyzed Suzuki-Miyaura reaction was applied toward the shortest reported synthesis of the pharmaceutical Cinacalcet.

The role of tetramethylethylenediamine (TMEDA) in iron-catalyzed cross-coupling reactions

The role of tetramethylethylenediamine (TMEDA) in iron-catalyzed cross-coupling reactions

Oxidation States, Stability, and Reactivity of Organoferrate Complexes

We have applied a combination of electrospray-ionization mass spectrometry, electrical conductivity measurements, and Mössbauer spectroscopy to identify and characterize the organoferrate species R nFe m- formed upon the transmetalation of iron precursors (Fe(acac)3, FeCl3, FeCl2, Fe(OAc)2) with Grignard reagents RMgX (R = Me, Et, Bu, Hex, Oct, Dec, Me3SiCH2, Bn, Ph, Mes, 3,5-(CF3)2-C6H3; X = Cl, Br) in tetrahydrofuran. The observed organoferrates show a large variety in their aggregation (1 ≤ m ≤ 8) and oxidation states (I to IV), which are chiefly determined by the nature of their organyl groups R. In numerous cases, the addition of a bidentate amine or phosphine changes the distributions of organoferrates and affects their stability. Besides undergoing efficient intermolecular exchange processes, several of the probed organoferrates react with organyl (pseudo)halides R'X (R' = Et, iPr, Bu, Ph, p-Tol; X = Cl, Br, I, OTf) to afford heteroleptic complexes of the type R3FeR'-. Gas-phase fragmentation of most of these complexes results in reductive eliminations of the coupling products RR' (or, alternatively, of R2). This finding indicates that iron-catalyzed cross-coupling reactions may proceed via such heteroleptic organoferrates R3FeR'- as intermediates. Gas-phase fragmentation of other organoferrate complexes leads to β-hydrogen eliminations, the loss of arenes, and the expulsion of organyl radicals. The operation of both one- and two-electron processes is consistent with previous observations and contributes to the formidable complexity of organoiron chemistry.