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

Haifeng Yang, Cayetana Zarate, W. Neil Palmer, Nelo Rivera, David Hesk, Paul J. Chirik

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56 Scopus citations


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 were tritiated with specific activities in excess of the thresholds required for drug absorption, distribution, metabolism, and excretion studies (1 Ci/mmol) and for protein receptor-ligand binding assays (15 Ci/mmol). The activity and selectivity of the nickel-catalyzed method are demonstrated by comparison with the current state-of-the-art single-site (iridium and iron) and heterogeneous (Raney nickel and rhodium black) catalysts. A pathway involving C(sp2)-H activation by a α-diimine nickel hydride monomer is consistent with the experimentally measured relative rate constants for HIE with electronically disparate pyridines, the pressure-dependence of activity, positional selectivity preferences, and kinetic isotope effects.

Original languageEnglish (US)
Pages (from-to)10210-10218
Number of pages9
JournalACS Catalysis
Issue number11
StatePublished - Nov 2 2018

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry


  • C-H activation
  • isotope
  • nickel
  • pyridine
  • tritium


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