Base-Promoted Iridium-Catalyzed Deuteration and C-H Bond Activation of N-Heterocycles

Hydrogen isotope exchange (HIE) of N-heterocycles is highly important in synthesis, where it is often used to prepare probes suitable for pharmaceutical studies. In this work, we show that pharmaceuticals such as anastrozole, trimethoprim, and bisacodyl can be easily deuterated in up to 84-95%, with high site selectivity using an [IrCl(COD)(IMes)]/H₂/NaOMe/methanol-d₄ derived catalytic system. We studied in detail the deuteration of quinoxaline using NMR spectroscopy, mass spectrometry, and X-ray crystallography and characterized a range of C-H bond activated products that include [Ir(H)₂(quinoxaline)(IMes)(κ²-μ₂-C,N-quinoaxline)₂Ir(H)₂(quinoxaline)(IMes)]; [Ir(H)₂(quinoxaline)(IMes)(κ²-μ₂-C,N-quinoxaline)₂Ir(Cl)(H)(quinoxaline)(IMes)]; [Ir(H)₂(IMes)(κ²-μ₂-C,N-quinoxaline)₂Ir(H)₂(IMes)]; and [Ir(H)₂(IMes)(κ²-μ₂-C,N-quinoxaline)₂(μ₂-H)Ir(H)(quinoxaline)(IMes)]. Reaction scope is demonstrated by the examination of 17 structurally diverse substrates, with functional groups spanning pyridines, quinoxalines, quinolines, purine/xanthines, triazoles, and pyrimidines. Four analogous C-H-bond-activated X-ray structures were obtained for the additional substrates. Catalytic turnover was found to dramatically increase upon the addition of NaOMe and is linked to a demonstrated role for trihydride species [Ir(H)₃(COD)(IMes)] in the HIE process, with the reactive fragment {IrH(IMes)} implicated in the formation of catalytically competent dinuclear C-H bond activation products.