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

Abstract

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 β-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.

Keywords: Cross-Coupling; Homogeneous Catalysis; Iron; Ligand Effects; Mechanism.

Scheme 1

Representative examples of iron‐catalyzed alkyl‐alkyl cross‐coupling reactions using Xantphos as supporting ligand.

Figure 1

Freeze‐trapped 80 K ⁵⁷Fe Mössbauer spectra of iron speciation during catalysis in THF. Mössbauer parameters for purple component (1) δ=0.78 mm/s |ΔE_Q|=2.76 mm/s, blue component (2) δ=0.55 mm/s |ΔE_Q|=2.05 mm/s and orange component δ=0.41 mm/s |ΔE_Q|=0.64 mm/s.

Figure 2

Freeze‐trapped 80 K ⁵⁷Fe Mössbauer spectra of reaction of Fe(Xantphos)Br₂ with ⁿ butylborane. Mössbauer parameters for purple component δ=0.78 mm/s |ΔE_Q|=2.76 mm/s (1‐Br), blue component δ=0.55 mm/s |ΔE_Q|=2.05 mm/s (2), orange component δ=0.41 mm/s |ΔE_Q|=0.64 mm/s.

Figure 3

SC‐XRD of isolated crystalline material of iron(II)−Xantphos intermediates. A) Fe(II)−Xantphos dibromide (1‐Br). B) Monoalkylated Fe(II)−Xantphos (2‐CH₂SiMe₃ ). C) Monoalkylated Fe(II)−Xantphos (2‐Me). D) Bisalkylated Fe(II)−Xantphos (3‐CH₂SiMe₃ ). Thermal ellipsoids are shown at 50 % probability.

Figure 4

Freeze‐trapped 80 K ⁵⁷Fe Mössbauer spectra of reaction of 1 with 5 equiv. of ⁿ BuMgBr. The reaction time and temperature are indicated within each spectrum. Parameters for blue component δ=0.55 mm/s |ΔE_Q|=2.05 mm/s (2), red component δ=0.25 mm/s |ΔE_Q|=1.33 mm/s (3), grey component δ=0.34 mm/s |ΔE_Q|=3.47 mm/s.

Figure 5

EPR characterization of 4, Fe(I) S=1/2. Simulated g values of g₁=2.25, g₂=2.02and g₃=1.99, and hyperfine coupling to the ³¹P from the Xantphos ligand with constant A₁=111.4, A₂=91.9 and A₃=102.5 MHz. Thermal ellipsoids of 4 are shown at 50 % of probability. Fe−C (phenyl ring) bond length range 2.0853(19) – 2.136(2) Å.

Figure 6

Freeze‐trapped 80 K ⁵⁷Fe Mössbauer spectra of the in situ formed iron species upon reaction of ⁵⁷FeBr₂ and 2 equiv. of Xantphos, with 5 equiv. of [ ⁿ Bu₄B][MgCl] for 10 min (A) and following subsequent reaction with 7‐bromoheptanenitrile at different timepoints (B, C & D).

Scheme 2

Proposed mechanistic cycle for Fe‐Xantphos catalyzed C(sp³)−C(sp³) cross‐couplings.

Figure 7

Freeze‐trapped 80 K ⁵⁷Fe Mössbauer spectra of A) Reaction of FeBr₂ with 60 equivalents n‐butylborane in the presence of 2 equivalents of DPEphos, Mössbauer parameters for green component (5) δ=0.46 mm/s |ΔE_Q|=1.36 mm/s, Mössbauer parameters for pink component δ=0.28 mm/s |ΔE_Q|=0.76 mm/s. B) Catalytic reaction solution performed using 2 equivalents of DPEphos at 2.5 h. Crystal structure of 5‐Et, thermal ellipsoids are shown at 50 % probability.

Figure 8

Freeze‐trapped 80 K ⁵⁷Fe Mössbauer spectrum of the iron speciation during catalysis with dppe after 3 hours. Mössbauer parameters δ=0.25 mm/s |ΔE_Q|=0.99 mm/s.