Electronegativity Governs Enantioselectivity: Alkyl-Aryl Cross-Coupling with Fenchol-Based Palladium-Phosphorus Halide Catalysts

A series of bulky, modular, monodentate, fenchol-based phosphites has been employed in an intramolecular palladium-catalyzed alkyl-aryl cross-coupling reaction. This enantioselective a-arylation of N-(2-bromophenyl)-N-methyl-2-phenylpropanamide is accomplished with [Pd(C3H5)(BIFOP-X)(Cl)] as precatalysts, which are based on biphenyl-2,2'-bisfenchol phosphites (BIFOP-X, X=F, Cl, Br, etc.). The phosphorus fluoride BIFOP-F gives the highest enantioselectivity and good yields (64% ee, 88%). Lower selectivities and yields are found for BIFOP halides with heavier halogens (Cl: 74%, 47% ee, Br: 63%, 20% ee). NMR studies on catalyst complexes reveal two equilibrating diastereomeric complexes in equal proportions. In all cases, the phosphorus-halogen moiety remains intact, pointing to its remarkable stability, even in the presence of nucleophiles. The increasing enantioselectivity of the catalysts with the phosphorus halide ligands correlates with the rising electronegativity of the halide (bromine