Insight into Radical Initiation, Solvent Effects, and Biphenyl Production in Iron-Bisphosphine Cross-Couplings

Abstract

Iron-bisphosphines have attracted broad interest as highly effective and versatile catalytic systems for two- and three-component cross-coupling strategies. While recent mechanistic studies have defined the role of organoiron(II)-bisphosphine species as key intermediates for selective cross-coupled product formation in these systems, mechanistic features that are essential for catalytic performance remain undefined. Specifically, key questions include the following: what is the generality of iron(II) intermediates for radical initiation in cross-couplings? What factors control reactivity toward homocoupled biaryl side-products in these systems? Finally, what are the solvent effects in these reactions that enable high catalytic performance? Herein, we address these key questions by examining the mechanism of enantioselective coupling between α-chloro- and α-bromoalkanoates and aryl Grignard reagents catalyzed by chiral bisphosphine-iron complexes. By employing freeze-trapped ⁵⁷Fe Mössbauer and EPR studies combined with inorganic synthesis, X-ray crystallography, reactivity studies, and quantum mechanical calculations, we define the key in situ iron speciation as well as their catalytic roles. In contrast to iron-SciOPP aryl-alkyl couplings, where monophenylated species were found to be the predominant reactive intermediate or prior proposals of reduced iron species to initiate catalysis, the enantioselective system utilizes an iron(II)-(R,R)-BenzP* bisphenylated intermediate to initiate the catalytic cycle. A profound consequence of this radical initiation process is that halogen abstraction and subsequent reductive elimination result in considerable amounts of biphenyl side products, limiting the efficiency of this method. Overall, this study offers key insights into the broader role of iron(II)-bisphosphine species for radical initiation, factors contributing to biphenyl side product generation, and protocol effects (solvent, Grignard reagent addition rate) that are critical to minimizing biphenyl generation to obtain more selective cross-coupling methods.

Scheme 1. Iron-Catalyzed Cross-Coupling Reactions Supported by Bisphosphine Ligands

Scheme 2. Previously Proposed Mechanism for the Iron-Catalyzed Enantioselective Coupling of α-Chloro- and α-Bromoalkanoates with Aryl Grignard Reagents

Figure 1

Freeze-trapped 80 K ⁵⁷Fe Mössbauer spectra of stoichiometric reactions. Combining SC-XRD and Mössbauer studies of the crystalline material, the individual components were assigned as the (1) Fe(BenzP*)Br₂ orange component, (2) Fe(BenzP*)PhBr purple component, and (3) Fe(BenzP*)Ph₂ and (4) Fe(BenzP*)Ph₂(THF) blue and pink components, respectively. Raw data are shown as black dots, total fit as a black line, and individual components as colored lines. Thermal ellipsoids are shown at 50% probability.

Figure 2

Freeze-trapped 80 K Mössbauer spectra of the in situ formed iron species upon reaction of ⁵⁷FeBr₂ and 2 equiv of (R,R)-BenzP*, with 2 equiv of PhMgBr for 8 min (A) and following subsequent reaction with tert-butyl 2-bromopropionate for 25 s (B). Raw data are shown as black dots, total fit as a black line, and individual components as colored lines.

Figure 3

Freeze-trapped 80 K ⁵⁷Fe Mössbauer spectra of the catalytic reaction. Note that the same iron distribution is also observed at 40 min into catalysis. Raw data are shown as black dots, total fit as a black line, and individual components as colored lines.

Figure 4

Gibbs free energy (UB3LYP-D3/6-31G(d,p)-THF(SMD); kcal/mol) profile for halogen abstraction by biphenylated iron(II)-bisphosphine complexes and radical recombination by monophenylated iron(II), leading to the formation of the Fe(I)–Br complex along with the desired organic product by reductive elimination. Multiplicities in superscripts.

Scheme 3. Reaction Pathways and Mechanism for the Enantioselective Iron-Catalyzed Coupling of α-Chloro- and α-Bromoalkanoates with Aryl Grignard Reagents

Kinetic rates measured under catalytically relevant conditions: 3 mol % of iron, in THF at 0 °C (as reported in Nakamura’s original synthetic method)