Iron-Catalyzed Cross-Coupling Reactions of Alkyl Grignards with Aryl Sulfamates and Tosylates

Iron-catalyzed cross-coupling reactions using alkynyl nucleophiles represent an attractive approach for the incorporation of alkynyl moieties into organic molecules. In the present study, a multitechnique approach combining inorganic spectroscopic methods, inorganic synthesis, and reaction studies is applied to iron-SciOPP catalyzed alkynyl-alkyl cross-couplings, providing the first detailed insight into the effects of variation from sp2- to sp-hybridized nucleophiles on iron speciation and reactivity. Reaction studies demonstrate that reaction of FeBr2(SciOPP) with 1 equiv (triisopropylsilyl)ethynylmagnesium bromide (TIPS-CC-MgBr) leads to a distribution of mono-, bis-, and tris-alkynylated iron(II)-SciOPP species due to rapid alkynyl ligand redistribution. While solvents such as THF promote these complex redistribution pathways, nonpolar solvents such as toluene enable increased stabilization of these iron species and further enabled assessment of their reactivity with electrophile. While the tris-alkynylated iron(II)-SciOPP species was found to be unreactive with the cycloheptyl bromide electrophile over the average turnover time of catalysis, the in situ formed neutral mono- and bis-alkynylated iron(II)-SciOPP complexes are consumed upon reaction with the electrophile with concomitant generation of cross-coupled product at catalytically relevant rates, indicating the ability of one or both of these species to react selectively with the electrophile. The nature of the reaction solvent and Grignard reagent addition rate were found to have broader implications in overall reaction selectivity, reaction rate, and accessibility of off-cycle iron(I)-SciOPP species. Additionally, the effects of steric substitution of the alkynyl Grignard reagent on catalytic performance were investigated. Fundamental insight into iron speciation and reactivity with alkynyl nucleophiles reported herein provides an essential foundation for the continued development of this important class of reactions.

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“…1 H NMR (400 MHz, C 6 D 6 ): δ 7.6, 7.5, 7.3, 7.2, 7.0, 3.4, 1.2–1.0 ppm. 31 P NMR (162 MHz, C 6 D 6 ) δ 72.4 ppm (br s). Anal.…”

Section: Methodsmentioning

confidence: 99%

Intermediates and Reactivity in Iron-Catalyzed Cross-Couplings of Alkynyl Grignards with Alkyl Halides

2017

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“…[29] Good to high yields in the cross-couplingo f electron-rich, electron-deficient, sterically hindered,a nd heterocyclic substrates were obtained. [29] Good to high yields in the cross-couplingo f electron-rich, electron-deficient, sterically hindered,a nd heterocyclic substrates were obtained.…”

Section: Introduction and Early Studiesmentioning

confidence: 97%

Iron‐Catalyzed C−O Bond Activation: Opportunity for Sustainable Catalysis

Bisz

Szostak

2017

ChemSusChem

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Oxygen-based electrophiles have emerged as some of the most valuable cross-coupling partners in organic synthesis due to several major strategic and environmental benefits, such as abundance and potential to avoid toxic halide waste. In this context, iron-catalyzed C-O activation/cross-coupling holds particular promise to achieve sustainable catalytic protocols due to its natural abundance, inherent low toxicity, and excellent economic and ecological profile. Recently, tremendous progress has been achieved in the development of new methods for functional-group-tolerant iron-catalyzed cross-coupling reactions by selective C-O cleavage. These methods establish highly attractive alternatives to traditional cross-coupling reactions by using halides as electrophilic partners. In particular, new easily accessible oxygen-based electrophiles have emerged as substrates in iron-catalyzed cross-coupling reactions, which significantly broaden the scope of this catalysis platform. New mechanistic manifolds involving iron catalysis have been established; thus opening up vistas for the development of a wide range of unprecedented reactions. The synthetic potential of this sustainable mode of reactivity has been highlighted by the development of new strategies in the construction of complex motifs, including in target synthesis. The most recent advances in sustainable iron-catalyzed cross-coupling of C-O-based electrophiles are reviewed, with a focus on both mechanistic aspects and synthetic utility. It should be noted that this catalytic manifold provides access to motifs that are often not easily available by other methods, such as the assembly of stereodefined dienes or C(sp )-C(sp ) cross-couplings, thus emphasizing the synthetic importance of this mode of reactivity.

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“…[22] This includes the challenging C(sp 2 )ÀC(sp 3 )c ross-coupling of biphenyl tosylate 2t and C(sp 2 )ÀC(sp 2 )a rylation of deactivated tosylate 2u,a sw ell as C(sp 2 )ÀC(sp 3 )c ross-coupling of deactivated carbamate 2v. [22] This includes the challenging C(sp 2 )ÀC(sp 3 )c ross-coupling of biphenyl tosylate 2t and C(sp 2 )ÀC(sp 2 )a rylation of deactivated tosylate 2u,a sw ell as C(sp 2 )ÀC(sp 3 )c ross-coupling of deactivated carbamate 2v.…”

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confidence: 99%

2‐Methyltetrahydrofuran: A Green Solvent for Iron‐Catalyzed Cross‐Coupling Reactions

Bisz

Szostak

2018

ChemSusChem

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Iron-catalyzed cross-coupling reactions allow sustainable formation of C-C bonds using cost-effective, earth-abundant base-metal catalysis for complex syntheses of pharmaceuticals, natural products, and fine chemicals. The major challenge to maintain full sustainability of the process is the identification of green and renewable solvents that can be harnessed to replace the conventional solvents for this highly attractive reaction. Herein, iron-catalyzed cross-coupling of aryl chlorides and tosylates with challenging organometallic reagents possessing β-hydrogens is found to proceed in good to excellent yields with the green, sustainable, and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as solvent. The reaction operates with excellent functional group tolerance under very mild conditions. Furthermore, large-scale cross-coupling, cross-coupling of heteroaromatic substrates, and cross-coupling of challenging aryl tosylates and carbamates mediated by Fe-N-heterocyclic carbene catalytic systems in eco-friendly 2-MeTHF were also carried out. The developed method was applied to the key cross-coupling in the synthesis of a fibrinolysis inhibitor, further highlighting the potential of 2-MeTHF as a general solvent for sustainable iron-catalyzed cross-coupling reactions.

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Iron-Catalyzed Cross-Coupling Reactions of Alkyl Grignards with Aryl Sulfamates and Tosylates

Cited by 90 publications

References 48 publications

Intermediates and Reactivity in Iron-Catalyzed Cross-Couplings of Alkynyl Grignards with Alkyl Halides

Intermediates and Reactivity in Iron-Catalyzed Cross-Couplings of Alkynyl Grignards with Alkyl Halides

Iron‐Catalyzed C−O Bond Activation: Opportunity for Sustainable Catalysis

2‐Methyltetrahydrofuran: A Green Solvent for Iron‐Catalyzed Cross‐Coupling Reactions

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