Ni(I)-X Complexes Bearing a Bulky α-Diimine Ligand: Synthesis, Structure, and Superior Catalytic Performance in the Hydrogen Isotope Exchange in Pharmaceuticals

The synthesis and spectroscopic characterization of a family of Ni-X (X = Cl, Br, I, H) complexes supported by the bulky α-diimine chelate N,N′-bis(1R,2R,3R,5S)-(-)-isopinocampheyl-2,3-butanediimine ( ^ipc ADI) are described. Diimine-supported, three-coordinate nickel(I)-X complexes have been proposed as key intermediates in a host of catalytic transformations such as C-C and C-heteroatom cross-coupling and C-H functionalization but have until now remained synthetically elusive. A combination of structural, spectroscopic, electrochemical, and computational studies were used to establish the electronic structure of each monomeric [( ^ipc ADI)NiX] (X = Cl, Br, I) complex as a nickel(I) derivative supported by a redox-neutral α-diimine chelate. The dimeric nickel hydride, [( ^ipc ADI)Ni(μ ₂ -H)] ₂ , was prepared and characterized by X-ray diffraction; however, magnetic measurements and ¹ H NMR spectroscopy support monomer formation at ambient temperature in THF solution. This nickel hydride was used as a precatalyst for the hydrogen isotope exchange (HIE) of C-H bonds in arenes and pharmaceuticals. By virtue of the multisite reactivity and high efficiency, the new nickel precatalyst provided unprecedented high specific activities (50-99 Ci/mmol) in radiolabeling, meeting the threshold required for radioligand binding assays. Use of air-stable and readily synthesized nickel precursor, [( ^ipc ADI)NiBr ₂ ], broad functional group tolerance, and compatibility with polar protic solvents are additional assets of the nickel-catalyzed HIE method.