Pd-Catalyzed Cross-Coupling of Hindered, Electron-Deficient Anilines with Bulky (Hetero)aryl Halides Using Biaryl Phosphorinane Ligands

Biaryl phosphorinane ligands derived from addition of biaryl primary phosphines to trans,trans-dibenzylideneacetone (Alison-Phos and AliPhos) form highly active ligands for Pd-catalyzed coupling of hindered, electron-deficient anilines with hindered (hetero)aryl halides, a challenging class of C-N cross-coupling reaction with few precedents. Broad substrate scope and functional group tolerance were observed under the reaction conditions. Computational studies suggest that ligands containing phenyl substituents provide greater activity through more favorable aniline binding in the catalytic cycle in comparison to alkyl-substituted phosphorinanes. A general and high-yielding procedure for the synthesis of biaryl phosphorinanes by phospha-Michael addition of primary biarylphosphines to 1,4-dien-3-ones in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), under relatively mild conditions (23-110 degrees C), is also described. HFIP as the solvent significantly accelerates the phospha-Michael addition, allowing the preparation of previously inaccessible ligands and higher yields overall.