Nickel‐Catalyzed P‐Arylation of HP(= O)(R/OR)₂ Nucleophiles with (Hetero)Aryl Chlorides Enabled by DalPhos Ligation

Herein we disclose our development of broadly useful C-P cross-couplings of (hetero)aryl chlorides and HP(O)(R)2 or HP(O)(OR)2 nucleophiles, enabled by use of nickel/DalPhos-based catalysts. These typically use 5 mol% nickel at 110 °C for 18 hours, but the feasibility of shorter or milder reactions was demonstrated with one specific example. The ability to apply such transformations on gram scale, and in the P-arylation of active pharmaceutical ingredients (APIs) (i.e., chloroquine and clozapine) was also shown. Also described are our findings arising from the computational modelling of such cross-coupling reactions by use of density functional theory (DFT) calculations, which confirmed the clear preference for C-P bond formation involving three-centered reductive elimination through substrate PV pathways.