Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects

Abstract

The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp³ Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment-cone angle and % buried volume-are not equivalent, despite their treatment in the literature.

Figure 1. Design of new ligands for Ni catalysis enables Suzuki coupling of benzylic acetals

a, Ligand development in Pd versus Ni-catalysed cross-coupling. Ligands engineered for Pd catalysis have facilitated many advances in cross-coupling, including the discovery of altogether new transformations and the refinement of existing methods such that they can be used for large-scale synthesis. By contrast, minimal effort has been directed at ligand design for Ni-catalysed cross-coupling, despite the opportunity it presents for discovering novel reactions and for improving the efficiency of existing methods. b, Ligand design for Suzuki coupling of acetals. The development of a Ni-catalysed Suzuki coupling of acetals with readily available boronic acids would facilitate the preparation of valuable ether products by C–C bond formation. Application of known ligands for Ni and re-purposing ligands designed for Pd to this transformation were both unsuccessful in this regard, prompting the development and study of a new phosphine ligand class for Ni.

Figure 2. Ligand evaluation and timepoint studies

a, Screen of existing and novel phosphines for Ni. Ligand evaluation reveals that phosphines bearing tertiary alkyl groups or ortho-substituted aryl groups are completely ineffective. However, dialkylaryl [(alkyl)₂PAr] and alkyldiaryl [(alkyl)PAr₂] phosphines with secondary alkyl substituents and 3,5-substituted aryl groups are highly effective. IMes = 1,3-bis(2,4,6-trimethylphenyl)-imidazolium. Yields determined by ¹⁹F NMR with 2-fluorobiphenyl as a quantitative internal standard. b, Timepoint studies comparing the reaction profile with L16, L17 and PCy₃ (L2). Ligands L16 and L17 afford highly active Ni catalysts in the Suzuki coupling; ligand L17 delivers the highest overall yields, despite a slower initial rate of reaction. Reactions were conducted at 60 °C in toluene (0.06 M), 15 mol% Ni(cod)₂ and 30 mol% of ligand. cod = 1,5-cyclooctadiene.

Figure 3. Steric parameterization and analysis

a, Plot of yield versus cone angle (θ) and buried volume (%V_bur). A comparison of the ligand steric parameters against reaction yield reveals that larger cone angle correlates with higher yield (circles), with the exception of ligands featuring high buried volume (triangles). The regression equation only includes the circle data points. b, Plot of cone angle versus buried volume. Cone angle and buried volume have previously been treated as equivalent measures of ligand steric environment, as illustrated by a 1:1 mapping of the two parameters (circle data points). The regression equation only includes circle data points. The new phosphines prepared in this study (triangles) fall outside this 1:1 mapping, highlighting that these two terms are not equivalent, by definition. c, Definition of cone angle and buried volume. Both measure steric encumbrance but with different distance dependencies. Buried volume only accounts for steric hindrance proximal to the metal whereas cone angle is sensitive to ligand size at a distance. A ligand with a large cone angle and low %V_bur, such as those most successful in this new method, therefore possesses remote steric hindrance. d, Plot of predicted yield versus actual yield. A quantitative model to relate cone angle, buried volume and V_min to yield was obtained by regression analysis. This model accounts for the entire scope of ligands tested in the study and features a mathematical representation of the remote steric effect concept. We show that the model can predict the performance of ligands (green squares) that feature unique structural motifs to those included in the ligand training set.