Iron Catalysis Research Articles

Manganese- and Iron-Catalyzed Carbonylation Reactions: A Personal Account

AbstractTransition-metal-catalyzed carbonylative transformations have been widely employed to convert CO gas into valuable carbonyl-containing molecules, mainly using noble metals (Pd, Rh, Ir, Ru) and more recently nickel and other catalysts. Although noble-metal catalysts have the advantage of reaction efficiency, their high-cost has led scientists to explore alternative procedures. Also under these backgrounds, we carried out some studies on nonexpensive metal-catalyzed carbonylative transformations. In this Account, we summarize the carbonylation reactions developed in our research group by using manganese and iron catalysis. These carbonylation reactions proceeded either via SET (single-electron transfer) or TET (two-electron transfer) mechanism.1 Introduction2 Manganese-Catalyzed Carbonylation of Alkyl Chlorides3 Manganese-Catalyzed Carbonylation of Alkyl Iodides4 Iron/Copper-Catalyzed Carbonylation of Alkyl Bromides5 Iron-Catalyzed Carbonylation of Alkyl Bromides6 Iron-Catalyzed Carbonylation of Alkyl-Boronic Pinacol7 Iron-Catalyzed Aminoalkylative Carbonylative Cyclization of Alkenes8 Conclusion and Outlook

Emerging insights into ferroptosis in cholangiocarcinoma (Review).

Cholangiocarcinoma (CCA) is a malignant tumor that arises within the biliary system, which exhibits a progressively increasing incidence and a poor patient prognosis. A thorough understanding of the molecular pathogenesis that drives the progression of CCA is essential for the development of effective molecular target therapeutic approaches. Ferroptosis is driven by excessive iron accumulation and catalysis, lipid peroxidation and the failure of antioxidant defense systems. Key molecular targets of iron metabolism, lipid metabolism and antioxidant defense systems involve molecules such as transferrin receptor, ACSL4 and GPX4, respectively. Inhibitors of ferroptosis include ferrostatin-1, liproxstatin-1, vitamin E and coenzyme Q10. By contrast, compounds such as erastin, RSL3 and FIN56 have been identified as inducers of ferroptosis. Ferroptosis serves a notable role in the onset and progression of CCA. CCA cells exhibit high sensitivity to ferroptosis and aberrant iron metabolism in these cells increases oxidative stress and iron accumulation. The induction of ferroptosis markedly reduces the ability of CCA cells to proliferate and migrate. Certain ferroptosis agonists, such as RSL3 and erastin, cause lipid peroxide build up and GPX4 inhibition to induce ferroptosis in CCA cells. Current serological markers, such as CA-199, have low specificity and cause difficulties in the diagnosis of CCA. However, novel techniques, such as non-invasive liquid biopsy and assays for oxidative stress markers and double-cortin-like kinase 1, could improve diagnostic accuracy. CCA is primarily treated with surgery and chemotherapy. A close association between the progression of CCA with ferroptosis mechanisms and related regulatory pathways has been demonstrated. Therefore, it could be suggested that multi-targeted therapeutic approaches, such as ferroptosis inducers, iron chelating agents and novel modulators such as YL-939, may improve treatment efficacy. Iron death-related genes, such as GPX4, that are highly expressed in CCA and are associated with a poor prognosis for patients may represent potential prognostic markers for CCA. The present review focused on molecular targets such as p53 and ACSL4, the process of targeted medications in combination with PDT in CCA and the pathways of lipid peroxidation, the Xc-system and GSH-GPX4 in ferroptosis. The present review thus offered novel perspectives to improve the current understanding of CCA.

Iron‐Catalyzed Cross‐Coupling Reactions of Alkyl Grignard Reagents with Alkenyl Carbonate

Herein, we report the alkylation of alkenyl carbonates using alkyl Grignard reagents and iron catalysis to generate C(sp2)–C(sp3) bonds and provide synthetically useful yields over a range of substrates. The transformation allows the alkylation of a wide range of substrates, including aromatic rings, alkanes, cycloalkanes, heterocycles. This reaction has introduced a new family of electrophiles to the iron‐catalyzed cross‐coupling reactions.

The Progress of Reductive Coupling Reaction by Iron Catalysis.

The transition metal catalyzed coupling reaction has revolutionized the strategies for forging the carbon-carbon bonds. In contrast to traditional cross-coupling methods using pre-prepared nucleophilic organometallic reagents, reductive coupling reactions for the C-C bonds formation provide some advantages. Because both coupling partners are reduced in the final products using a stoichiometric amount of a reductant, this approach not only avoids the need to use sensitive organometallic species, but also provides an orthogonal and complementary access to classical coupling reaction. Notably, the reductive coupling reactions feature readily available fragments, promote good step economy, exhibit high functional group tolerance and unique chemoselectivity, which have propelled their increasingly popular in the organic synthesis. In recent years, due to the low price, minimal toxicity, and environmentally benign character, iron-catalyzed carbon-carbon coupling reactions have garnered significant attention from the organic synthetic chemists and pharmacologists, especially the iron-catalyzed reductive coupling. This review aims to provide an insightful overview of recent advances in iron-catalyzed reductive coupling reactions, and to illustrate their possible reaction mechanisms.

Effective Alkyl-Alkyl Cross-Coupling with an Iron-Xantphos Catalyst: Mechanistic and Structural Insights.

While iron-catalyzed C(sp2)-C(sp3) cross-couplings have been widely studied and developed in the last decade, alkyl-alkyl cross-coupling systems with iron remain underdeveloped despite the importance of C(sp3)-C(sp3) bonds in organic synthesis. A major challenge to the development of these reactions is the current lack of fundamental insight into ligand effects and organoiron intermediates that enable effective alkyl-alkyl couplings. The current study addresses this longstanding limitation using a combination of 57Fe Mössbauer spectroscopy, SC-XRD (single-crystal X-ray diffraction) and reactivity studies of alkyl-alkyl coupling with iron-Xantphos to define the in situ formed iron-Xantphos intermediates in catalysis. Combined with detailed reactivity studies, the nature of the key mechanistic pathways in catalysis and ligands effects to achieve effective alkyl-alkyl cross-coupling over competing b-H elimination pathways are probed. Overall, these foundational studies provide a platform for future bespoke ligand and pre-catalyst design for alkyl-alkyl cross-coupling methods development with sustainable iron catalysis.

Effective Alkyl‐Alkyl Cross‐Coupling with an Iron‐Xantphos Catalyst: Mechanistic and Structural Insights

While iron‐catalyzed C(sp2)‐C(sp3) cross‐couplings have been widely studied and developed in the last decade, alkyl‐alkyl cross‐coupling systems with iron remain underdeveloped despite the importance of C(sp3)‐C(sp3) bonds in organic synthesis. A major challenge to the development of these reactions is the current lack of fundamental insight into ligand effects and organoiron intermediates that enable effective alkyl‐alkyl couplings. The current study addresses this longstanding limitation using a combination of 57Fe Mössbauer spectroscopy, SC‐XRD (single‐crystal X‐ray diffraction) and reactivity studies of alkyl‐alkyl coupling with iron‐Xantphos to define the in situ formed iron‐Xantphos intermediates in catalysis. Combined with detailed reactivity studies, the nature of the key mechanistic pathways in catalysis and ligands effects to achieve effective alkyl‐alkyl cross‐coupling over competing b‐H elimination pathways are probed. Overall, these foundational studies provide a platform for future bespoke ligand and pre‐catalyst design for alkyl‐alkyl cross‐coupling methods development with sustainable iron catalysis.

Iron-catalyzed radical Markovnikov hydrohalogenation and hydroazidation of alkenes

We herein report radical hydroazidation and hydrohalogenation of mono-, di- and trisubstituted alkenes through iron catalysis. The alkene moiety that often occurs as a functionality in natural products is readily transformed into useful building blocks through this approach. Commercially available tosylates and α-halogenated esters are used as radical trapping reagents in combination with silanes as reductants. The reported radical Markovnikov hydroazidation, hydrobromination, hydrochlorination, and hydroiodination occur under mild conditions. These hydrofunctionalizations are valuable and practical alternatives to ionic hydrohalogenations with the corresponding mineral acids that have to be run under harsher acidic conditions, which diminishes the functional group tolerance. Good to excellent diastereoselectivities can be obtained for the hydrofunctionalization of cyclic alkenes.

Fe-Catalyzed Fluoroalkyl(hetero)arylation of Vinyl Azaarenes: Rapid and Modular Synthesis of Unsymmetrical 1,1-Bis(hetero)arylalkanes.

In contrast to transition-metal-catalyzed difunctionalization of activated alkenes, selective alkylarylation of vinyl azaarenes is underdeveloped. Consequently, the lack of modular and rapid syntheses of 1,1-bis(hetero)arylalkanes limits their exploration in medicinal chemistry. Herein we report a protocol using commercially available iron salts, bisphosphine ligands, fluoroalkyl halides, and Grignard reagents that enables the selective 1,2-fluoroalkyl(hetero)arylation of vinyl azaarenes. We demonstrate the versatility and robustness of the method through the selective synthesis of a range of unsymmetrical 1,1-bis(hetero)arylalkenes, including pyridine N-oxides, triazoles, pyrazines, carbazoles, indazoles, and 1,2-azaborines. Mechanistic insights from experimental and computational investigations support a radical pathway and provide insights into the role of non-covalent interactions in iron catalysis.

Iron in Organometallic Transformations: A Sustainable Substitute for Noble Metals

AbstractTransition metal catalysis plays a pivotal role in chemical synthesis. Noble metals often grab significant attention in organometallic catalysis due to their high reactivity. However, the serious issues associated with these metals such as low abundance, toxicity, geopolitical limitations, and volatile prices are driving the scientific community to discover sustainable alternatives. In this context, iron appears to be the first choice as an alternative metal due to its unique properties, including a range of stable oxidation states, Lewis acidity, high abundance in the earth‘s crust, and low toxicity. Over the past two decades, substantial progress has been made in iron catalysis. This overview examines the recent developments in iron‐catalyzed industrially relevant transformations such as hydroformylation, olefin isomerization, hydrosilylation, hydrophosphination, carbonylation, Wacker‐type oxidation, and plastic depolymerization. As witnessed throughout this review, the performance of iron can be significantly altered by suitable ligand selection and by tailoring the electronic and steric properties of the iron center. While noble metals remain the industry work‐horse, iron is inching closer and with extensive scientific understanding, it may replace noble metals in the near future.

Visible-Light-Promoted Enantioselective α-Amidation of Aldehydes by Harnessing Organo-Iron Dual Catalysis.

The strategic integration of organocatalysis with transition-metal catalysis to achieve otherwise unattainable stereoselective transformations may serve as a powerful synthetic tool. Herein, we present a synthetically versatile α-amidation of aldehydes by leveraging dual iron and chiral enamine catalysis in an enantioselective manner (up to >99:1 er). Experimental and computational studies have led us to propose a new mechanistic platform, wherein visible-light-promoted LMCT generates [Fe(II)Cl3-], which effectively activates dioxazolones to form an iron-acylnitrenoid radical that inserts into chiral enamine intermediates.

Unusual S=1 Four‐Coordinate Fe(IV) Complexes Supported by Bisamide Ligands: Syntheses, Characterization, and Electronic Structures

AbstractThe catalytic relevance of Fe(IV) species in non‐heme iron catalysis has motivated synthetic advances in well‐defined five‐ and six‐coordinate Fe(IV) complexes for a better understanding of their fundamental electronic structures and reactivities. Herein, we report the syntheses of FeDipp2 and FeMes2, a pair of unusual four‐coordinate non‐heme formally Fe(IV) complexes with S=1 ground states supported by strongly donating bisamide ligands. By combining spectroscopic characterization and computational modeling, we found that small variations in ligand aryl substituents resulted in substantial changes in both structures and bonding. This work highlights the strong donor capabilities and modularity of the bisamide ligand set. More broadly, it is a critical contribution to the utilization of ligand design to modulate molecular geometries and electronic structures of low‐coordinate, high‐valent iron complexes.

Unusual S=1 Four-Coordinate Fe(IV) Complexes Supported by Bisamide Ligands: Syntheses, Characterization, and Electronic Structures.

The catalytic relevance of Fe(IV) species in non-heme iron catalysis has motivated synthetic advances in well-defined five- and six-coordinate Fe(IV) complexes for a better understanding of their fundamental electronic structures and reactivities. Herein, we report the syntheses of FeDipp2 and FeMes2, a pair of unusual four-coordinate non-heme formally Fe(IV) complexes with S=1 ground states supported by strongly donating bisamide ligands. By combining spectroscopic characterization and computational modeling, we found that small variations in ligand aryl substituents resulted in substantial changes in both structures and bonding. This work highlights the strong donor capabilities and modularity of the bisamide ligand set. More broadly, it is a critical contribution to the utilization of ligand design to modulate molecular geometries and electronic structures of low-coordinate, high-valent iron complexes.

Iron(III)-Catalysed Povarov Cyclisation for the Synthesis of Fused Dibenzo[b,f][1,7]naphthyridine Embedded Arylpyrrolo Scaffolds

AbstractAn FeCl3-catalyzed Povarov reaction for the efficient synthesis of dibenzo[b,f][1,7]naphthyridines utilizing 1-(2-alkynylaryl)-2-pyrrolecarbaldehydes and arylamines in excellent yields is demonstrated. The essential features of the present strategy are easy preparation of substrates, broad substrate scope, mild reaction conditions, and high atom economy and yields, in the presence of environmentally friendly iron catalysis.

Iron‐Catalyzed C−H Alkylation/Ring Opening with Vinylbenzofurans Enabled by Triazoles

AbstractWe report an unprecedented iron‐catalyzed C−H annulation using readily available 2‐vinylbenzofurans as the reaction pattern. The redox‐neutral strategy, based on cheap, non‐toxic, and earth‐abundant iron catalysts, exploits triazole assistance to promote a cascade C−H alkylation, benzofuran ring‐opening and insertion into a Fe−N bond, to form highly functionalized isoquinolones. Detailed mechanistic studies supported by DFT calculations fully disclosed the manifold of the iron catalysis.

Iron-Catalyzed C-H Alkylation/Ring Opening with Vinylbenzofurans Enabled by Triazoles.

We report an unprecedented iron-catalyzed C-H annulation using readily available 2-vinylbenzofurans as the reaction pattern. The redox-neutral strategy, based on cheap, non-toxic, and earth-abundant iron catalysts, exploits triazole assistance to promote a cascade C-H alkylation, benzofuran ring-opening and insertion into a Fe-N bond, to form highly functionalized isoquinolones. Detailed mechanistic studies supported by DFT calculations fully disclosed the manifold of the iron catalysis.

Investigation on formation and combustion process of carbon deposits from coke oven riser during waste heat recovery

In the context of carbon neutrality, the widespread application of waste heat recovery systems in steel production is crucial for energy conservation and emission reduction. This study investigates the formation and combustion removal mechanisms of carbon deposits in coke oven risers during waste heat recovery by analyzing the physicochemical structure, combustion behavior, and kinetics of different layers. The results revealed that lower temperatures near the tube wall produced higher volatile content in the lower layer. Over time, the carbon deposits gradually graphitized from bottom to top. Under long-term heating and iron catalysis, the lower carbon deposits showed a higher order degree and poorer combustion performance. The middle layer, characterized by more pores formed during polycondensation, exhibited a larger specific surface area than other samples and burned slightly faster than the upper layer. Increasing heating and airflow rates could linearly enhance the combustion efficiency of carbon deposits. The random pore model accurately described the combustion process of the upper and middle layers, whereas the multi-stage weight loss in lower deposits aligned better with a multi-stage reaction random pore model. This research could further strengthen the understanding of carbon deposits in the riser and improve the removal effect, thereby promoting waste heat recovery from coke oven gas.

Iron‐Catalyzed Site‐Selective α‐C−H Functionalization in N‐Benzyl Tetrahydroisoquinolines: Enabling Tertiary Amine Transformations

AbstractThis article presents a catalytic approach for site‐selective α‐C−H functionalization of N‐benzyl tetrahydroisoquinolines, which are important tertiary amine derivatives. Using iron salt as a catalyst, we have selectively functionalized carbon‐hydrogen bonds of tertiary amine molecules with diverse moieties, such as imidazopyridine, indoles, and phenylacetylenes. The method offers a broad substrate scope and excellent functional group tolerance, making it a valuable tool for the synthesis of complex molecules. A mechanism is also proposed based on control experiments, which explains the probable reason for selectivity. This iron‐catalyzed C−H functionalization represents a significant advancement in the field of organic synthesis, showcasing the potential of iron catalysis for the construction of valuable chemical motifs.

Iron-Catalyzed Photoredox Alcohol α-C-H Alkylation and Tandem Intramolecular Cyclization: Facile Access to Multisubstituted 2,3-Dihydrofurans and γ-Butyrolactones.

Multisubstituted furans occupy a pivotal position within the realms of synthetic chemistry and pharmacological science due to their distinctive chemical configurations and inherent properties. We herein introduce a tandem difunctionalization protocol of alcohols for the efficient synthesis of multisubstituted 2,3-dihydrofurans and γ-butyrolactones through the combination of photocatalysis and iron catalysis under mild conditions. Photoredox alcohol α-C(sp3)-H activation and Pinner-type intramolecular cyclization are two key processes. This method features significant convenience, economic benefits, and environmental friendliness.

Iron-catalysed nitrene transfer reaction to form C[sbnd]N bonds

Direct CN bond forming reaction by utilizing the non-precious transition metals is an attractive field of research in organic synthesis. Unlike the conventional use of precious metals like rhodium, palladium, ruthenium, and iridium that are commonly used in these reactions, the use of non-precious metals, particularly those are non-toxic and high abundant, holds distinct attention owing to the increasing demand of sustainable chemical processes. Among them, iron catalysis offers notable advantages for sustainable chemical synthesis. Iron-catalysed nitrene transfer reactions have emerged as robust and eco-friendly methods for constructing various valuable CN bonds. In this review, we provide a comprehensive overview of the advancements in iron catalysis for the nitrene transfer reactions aimed at synthesizing diverse CN bonds.

Visible-Light-Mediated Amination Using Iron Catalysis

Visible-Light-Mediated Amination Using Iron Catalysis