Catalyst Metamorphosis: In Situ Oxidation of Diphosphines in Palladium-Catalyzed Regioselective and Enantioselective Heck Reactions

In palladium-catalyzed Heck reactions, partial oxidation of diphosphines often occurs to form diphosphine mono-oxides, which form active Pd species for olefin insertion. It is an overlooked yet kinetically dominant phenomenon under many Heck conditions. Pd(OAc)₂ or in situ-generated palladium(II) salts rapidly convert diphosphines (dippf and QuinoxP* here) to mono-oxides. The weakened P=O donation may remain bound to cationic complex LPd(Ar)⁺ or transiently vacate a coordination site to allow olefins to insert on neutral complex LPd(Ar)X. These mechanistic scenarios are observed in the enantioselective Heck reactions of 1,4-dihydronaphthalene and β-selective arylations of benzofused olefins. These benzofused olefins showed low activity and poor regioselectivity in Heck reactions in previous reports. The partial oxidation of diphosphines is supported by ³¹P NMR detection of resting states in catalytic reactions, kinetic profiling using different Pd precatalysts, stoichiometric insertion of isolated complexes, and DFT calculations of olefin insertion. Conversely, cationic complex (dippf)Pd(Ar)⁺ is an active species for olefin insertion in the α-selective Heck reaction of 1,2-dihydronaphthalene. To ensure good α-selectivity, in situ oxidation of dippf should be suppressed instead. DABCO base is proposed to reversibly bind and stabilize the cationic species. Three Heck protocols deliver arylated tetralin scaffolds in high regioselectivity or excellent enantioselectivity, enabling concise syntheses of several natural products and drug motifs.