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

Abstract

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.

A DFT Study on FeI/FeII/FeIII Mechanism of the Cross-Coupling between Haloalkane and Aryl Grignard Reagent Catalyzed by Iron-SciOPP Complexes

“…The DFT method (B3LYP-D3 Functional) used in this work predicted quintet as the ground state for iron(II) complexes, Fe II BrPh(SciOPP) and Fe II Br 2 (SciOPP), which is in agreement with the experimentally known spin state [33,34]. Additionally, the spin state for related iron(I) complex (Fe(η 2 -[TIPS-CC-H])Br(SciOPP)) was also predicted correctly [52]. Further, the OBPE-D3 functional (which is known to provide reliable spin state gap) [53] gave consistent results with B3LYP-D3 for the ground spin state (quartet) of iron(I) and iron(III) complexes (Table S1).…”

Intermediates and Mechanism in Iron-Catalyzed Cross-Coupling

“…Time-resolved, freeze-quenched 80 K 57 Fe Mössbauer spectra of the reaction of FeBr 2 (SciOPP) (Ar = 3,5- tert -butylphenyl) with 1 equiv of (TIPS)ethynylmagnesium bromide at room temperature. Adapted from ref 43. Copyright 2017 American Chemical Society.…”

NHC and nucleophile chelation effects on reactive iron(ii) species in alkyl–alkyl cross-coupling

“…Recently, our group has applied a series of inorganic spectroscopic techniques to study the mechanism of iron–bisphosphine catalysed cross-coupling reactions involving the coupling of alkyl electrophiles with aryl and alkynyl Grignard reagents using FeCl 2 (SciOPP) as a pre-catalyst. 36 – 38 Magnetic circular dichroism (MCD), EPR, and Mössbauer spectroscopic studies of freeze-trapped solutions of in situ generated iron species were able to identify the catalytically active iron complexes in these reactions. Importantly, EPR and Mössbauer spectroscopies allow for the quantification of iron species during catalysis.…”