Iron-Catalyzed Cross-Coupling Research Articles

Mechanistic investigation of iron-catalyzed cross-coupling using sterically encumbered β-diketonate ligands

Iron β-diketonate compounds are reported using the hindered 2,6-dimesitylbenzoyl pinacolone (Aracac), which sterically precludes formation of tris-Aracac complexes. Fe(Aracac)2 (1), Fe(Aracac)2Cl (2) were synthesized and characterized using crystallographic, spectroscopic, elemental analysis, and electrochemical techniques. Iron complexes with only one Aracac ligand form dimers [Fe(Aracac)(THF)2]2(μ-OTf)2 (3) and [(Aracac)Fe(μ-mesityl)]2 (4). Complexes 1–4 were evaluated in a Kumada cross-coupling reaction and compared with the parent FeIII(acac)3 complex. Whereas the bis-acac complexes 1 and 2 show only modest activity (∼50 % yield after 60 min), the mono-acac complexes 3 and 4 are nearly as effective as the parent compound (∼90 % yield). DFT computations, in conjunction with catalytic results and electrochemical observations, suggest a catalytic cycle involving an oxidative addition of an aryl-chloride to Fe(II) to produce a high-spin Fe(IV) complex that could alternately be described as a high-spin Fe(II) stabilizing two coordinated organoradicals. These results suggest that a unique aspect of acac as a ligand for this reaction is its ability to support high-spin organoiron complexes, which can provide low-barrier pathways for C–Cl bond cleavage and CC bond formation reactions.

Regioselective Propargylic Suzuki-Miyaura Coupling by SciPROP-Iron Catalyst.

The iron-catalyzed Suzuki-Miyaura cross-coupling of secondary propargyl electrophiles with lithium organoborates has been established. A propyl-bridged bulky bisphosphine ligand, SciPROP-TB, cooperated with the bulky TIPS substituent at the alkyne terminal position to achieve the cross-coupling reaction with exclusive propargylic selectivity. The reaction features high functional group compatibility, regioselectivity, and yield with a broad substrate scope. The reaction of an optically active chiral propargyl bromide proceeds with complete racemization, supporting a mechanism involving propargyl radical formation.

Iron-Catalyzed Direct Cross-Coupling of Arenes and Aliphatic Hydrocarbons under Visible-Light Irradiation

Iron-Catalyzed Direct Cross-Coupling of Arenes and Aliphatic Hydrocarbons under Visible-Light Irradiation

Iron-Catalyzed Enantioselective Multicomponent Cross-Couplings of α-Boryl Radicals.

Despite recent interest in the development of iron-catalyzed transformations, methods that use iron-based catalysts capable of controlling the enantioselectivity in carbon-carbon cross-couplings are underdeveloped. Herein, we report a practical and simple protocol that uses commercially available and expensive iron salts in combination with chiral bisphosphine ligands to enable the regio- and enantioselective (up to 91:9) multicomponent cross-coupling of vinyl boronates, (fluoro)alkyl halides, and Grignard reagents. Preliminary mechanistic studies are consistent with rapid formation of an α-boryl radical followed by reversible radical addition to monoaryl bisphosphine-Fe(II) and subsequent enantioselective inner-sphere reductive elimination. From a broader perspective, this work provides a blueprint to develop asymmetric Fe-catalyzed multicomponent cross-couplings via the use of alkenes as linchpins to translocate alkyl radicals, modify their steric and electronic properties, and induce stereocontrol.

Regioselective Fluoroalkylarylation of Enamides Enabled by an Iron-Catalyzed Multicomponent Radical Cross-Coupling Strategy.

Fluoroalkylated compounds are important entities in agrochemicals, pharmaceuticals, and materials. The catalytic dicarbofunctionalization of alkenes represents a powerful strategy for the rapid construction and diversification of compounds. In this vein, multicomponent cross-coupling reactions (MC-CCR) can provide an efficient synthetic route to build molecular complexity. In this work, we report the first iron-catalyzed three-component fluoroalkylarylation of enamides via selective formation and trapping of α-amide radicals under mild conditions and fast reaction times. The reaction tolerates a variety of commercially available aryl Grignard reagents and fluoroalkyl halides. Finally, the use of a removable phthalimido group provides an efficient strategy to prepare highly valuable γ-difluoroalkylated amines.

Iron-Catalyzed Reductive Cross-Coupling of Alkyl Electrophiles with Olefins.

In terms of its abundance and its minimal toxicity, iron has advantages relative to other transition metals. Although alkyl-alkyl bond construction is central to organic synthesis, examples of iron-catalyzed alkyl-alkyl couplings of alkyl electrophiles are relatively sparse. Herein we report an iron catalyst that achieves cross-coupling reactions of alkyl electrophiles wherein olefins, in the presence of a hydrosilane, are used in place of alkylmetal reagents. Carbon-carbon bond formation proceeds at room temperature, and the method employs commercially available components (Fe(OAc)2 , Xantphos, and Mg(OEt)2 ); interestingly, this set of reagents can be applied directly to a distinct hydrofunctionalization of olefins, hydroboration. Mechanistic studies are consistent with the generation of an alkyl radical from the alkyl electrophile, as well as with reversibility for elementary steps that precede carbon-carbon bond formation (olefin binding to iron and β-migratory insertion).

Total synthesis of insect sex pheromones: recent improvements based on iron-mediated cross-coupling chemistry.

In the current ecological context, use of insect sex pheromones as an alternative to conventional pesticides is in constant growth. In this report, we discuss the recent contributions brought by our groups in the field of iron-catalyzed cross-couplings applied to the synthesis of insect pheromones. The pivotal question of the development of sustainable synthetic procedures involving cheap, non-toxic and efficient additives is also discussed, as well as the mechanistic features guiding the reactivity of such catalytic systems.

Iron-Catalyzed Cross-Coupling of α-Allenyl Esters with Grignard Reagents for the Synthesis of 1,3-Dienes.

Structurally diverse 1,3-dienes are valuable building blocks in organic synthesis. Herein we report the iron-catalyzed coupling between α-allenyl esters and Grignard reagents, which provides a fast and practical approach to a variety of complex substituted 1,3-dienes. The reaction involves an inexpensive iron catalyst, mild reaction conditions, and provides easy scale up.

Enantioselective synthesis of atropisomeric indoles via iron-catalysed oxidative cross-coupling.

Heterobiaryl compounds that exhibit axial chirality are of increasing value and interest across several fields, but direct oxidative methods for their enantioselective synthesis remain elusive. Here we disclose that an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables direct coupling between naphthols and indoles to yield atropisomeric heterobiaryl compounds with high levels of enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively yields cross-coupled products without competing homocoupling. Mechanistic investigations enable us to postulate that an indole radical is generated in the reaction but that this is probably an off-cycle event, and that the reaction proceeds through formation of a chiral Fe-bound naphthoxy radical that is trapped by a nucleophilic indole. We envision that this simple, cheap and sustainable catalytic manifold will facilitate access to a range of heterobiaryl compounds and enable their application across the fields of materials science, medicinal chemistry and catalysis.

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

Iron-catalyzed cross-couplings of propargylic substrates with Grignard reagents

One of the main challenges of modern chemical industry is the inevitable transition to greener, more sustainable manufacturing processes that utilize raw materials more effectively, minimize waste streams, and avoid the use of toxic and hazardous materials. The development of new iron-based catalytic systems can eliminate the need for the currently widely used, costly and potentially toxic heavy metal catalysts in industrially relevant chemical reactions. Prominent examples of such processes include transition metal-catalyzed cross-coupling reactions for formation of carbon-carbon (CC) bonds. This minireview outlines recent developments in the area of iron-catalyzed cross-coupling chemistry during the last couple of decades, with special emphasis on the use of propargylic substrates and Grignard reagents as coupling partners.

Iron-catalysed reductive cross-coupling of glycosyl radicals for the stereoselective synthesis of C-glycosides

Iron-catalysed reductive cross-coupling of glycosyl radicals for the stereoselective synthesis of C-glycosides

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.

Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

Iron-catalyzed cross-coupling of N‑methoxy amides and arylboronic acids for the synthesis of N-aryl amides

An efficient iron-catalyzed synthesis of N-aryl amides from N‑methoxy amides and arylboronic acids is developed. FeCl3 is used as the sole catalyst for the cross-coupling reaction between N‑methoxy amides and arylboronic acids without any other additives, and the corresponding N-aryl amides are obtained in moderate to excellent yields.

Iron-Catalyzed Cross-Coupling of Propargyl Ethers with Grignard Reagents

Key words iron catalysis - allenes - Grignard reagents - alcohols

Iron-Catalyzed Cross-Coupling of Propargyl Ethers with Grignard Reagents for the Synthesis of Functionalized Allenes and Allenols.

Herein we disclose an iron‐catalyzed cross‐coupling reaction of propargyl ethers with Grignard reagents. The reaction was demonstrated to be stereospecific and allows for a facile preparation of optically active allenes via efficient chirality transfer. Various tri‐ and tetrasubstituted fluoroalkyl allenes can be obtained in good to excellent yields. In addition, an iron‐catalyzed cross‐coupling of Grignard reagents with α‐alkynyl oxetanes and tetrahydrofurans is disclosed herein, which constitutes a straightforward approach towards fully substituted β‐ or γ‐allenols, respectively.

Dilithium Amides as a Modular Bis-Anionic Ligand Platform for Iron-Catalyzed Cross-Coupling.

Dilithium amides have been developed as a bespoke and general ligand for iron-catalyzed Kumada-Tamao-Corriu cross-coupling reactions, their design taking inspiration from previous mechanistic and structural studies. They allow for the cross-coupling of alkyl Grignard reagents with sp2-hybridized electrophiles as well as aryl Grignard reagents with sp3-hybridized electrophiles. This represents a rare example of a single iron-catalyzed system effective across diverse coupling reactions without significant modification of the catalytic protocol, as well as remaining operationally simple.

Stereospecific Iron-Catalyzed Carbon (sp2)-Carbon (sp2) Cross-Coupling of Aryllithium with Vinyl Halides.

We present herein an efficient synthetic protocol involving iron-catalyzed cross-coupling of organolithium compounds with vinyl halides as key coupling partners. More than 30 examples were obtained with moderate to good yields and high stereoselectivities. The practicality of this method is evidenced by a gram-scale synthesis. In addition, a preliminary mechanistic investigation was also performed.

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.