Site-Selective Nickel-Catalyzed Hydrogen Isotope Exchange in N-Heterocycles and Its Application to the Tritiation of Pharmaceuticals

A nickel-catalyzed method for the site-selective hydrogen isotope exchange (HIE) of C(sp2)–H bonds in nitrogen heteroarenes is described and applied to the tritiation of pharmaceuticals. The α-diimine nickel hydride complex [(iPrDI)Ni(μ2–H)]2 (iPrDI = N,N′-bis(2,6-diisopropylphenyl)-2,3-butanediimine) mediates efficient HIE when employed as a single component precatalyst or generated in situ from readily available and air-stable metal and ligand precursors (iPrDI, [(NEt3)Ni(OPiv)2]2 (Piv = pivaloyl) and (EtO)3SiH). The nickel catalyst offers distinct advantages over existing methods, including: (i) high HIE activity at low D2 or T2 pressure; (ii) tolerance of functional groups, including aryl chlorides, alcohols, secondary amides, and sulfones; (iii) activity with nitrogen-rich molecules such as the chemotherapeutic imatinib; and (iv) the ability to promote HIE in sterically hindered positions generally inaccessible with other transition metal catalysts. Representative active pharmaceutical ingredients we...