Site-Selective Deuteration of N-Heterocycles via Iridium-Catalyzed Hydrogen Isotope Exchange

Abstract

The application of iridium(I) NHC/phosphine catalysts has delivered highly selective deuteration of indole, azaindole, and pyrrole N-heterocycles, which represent an important and relatively underexplored class of labeling substrates. Common N-protecting groups have been used to selectively direct C−H activation and can be removed under mild conditions with retention of the deuterium label. The method is exemplified by the labeling of the drug molecule sumatriptan. Complementary DFT studies have been conducted to facilitate the rationalization of the very good selectivity offered by the mild and convenient labeling process.

Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals

“…[10] Over the past 30 years,m any efforts have been made to improve Ir I catalysts,and the work from the group of Kerr among others have allowed to increase substrates compatibility. [11][12][13][14][15][16][17][18] Hoover and co-workers,h ave also demonstrated recently that Pd II species can mediate the C À Ht ritiation of pharmaceuticals with selectivities and functional groups tolerance similar to those observed with homogeneous Iridium catalysis. [19] Nevertheless,s uch type of catalysis still requires the presence of as uitable directing group and particular substitution patterns to permit the formation of [5] or [6]-irida-or pallada-cycle key intermediates.R ecently,t oovercome these limitations,C hiriksgroup has developed aHIE reaction catalyzed by an iron complex allowing efficient incorporation of tritium atoms mainly at the less sterically hindered position (Figure 1b).…”

The Natural Product Lepidiline A as an N-Heterocyclic Carbene Ligand Precursor in Complexes of the Type [Ir(cod)(NHC)PPh3)]X: Synthesis, Characterisation, and Application in Hydrogen Isotope Exchange Catalysis

“…Iridium(I) complexes are amongst the most effective metal catalysts for directed HIE [10] and, in recent years, we have introduced a suite of highly active Ir(I) catalysts bearing a combination of bulky phosphine and N-heterocyclic carbene ligands ( Figure 1). These catalysts are compatible with a broad variety of directing groups, enabling HIE on a wide range of substrates [11][12][13][14][15][16][17][18]. These benchmark complexes 1-2 feature three distinct phosphine ligands.…”

Iron(III)-Mediated Rapid Radical-Type Three-Component Deuteration of Quinoxalinones With Olefins and NaBD4

“…The incorporation of deuterium is a very efficient strategy not only to measure the kinetic isotope effect and track the reaction path in synthetic chemistry but also to change the absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates in pharmaceutical chemistry (Atzrodt et al, 2007 ; Meanwell, 2011 ; Guengerich, 2012 ; Katsnelson, 2013 ; Gant, 2014 ). Since the first deuterated drug, deutetrabenazine, for the treatment of chorea associated with Huntington's disease was approved by the Food and Drug Administration in 2017 (Schmidt, 2017 ), which clearly proved a route for the development of deuterated drugs in clinical medicine ( Scheme 1A ) (Junk and Catallo, 1997 ; Gowrisankar et al, 2012 ; Tolnai et al, 2014 ; Ray et al, 2018 ), considerable interests have been devoted to developing novel and efficient methods for the synthesis of such compounds (Yu et al, 2016 ; Kerr et al, 2017 ; Liang et al, 2017 ; Li et al, 2017 ; Liu et al, 2018 ; Yang et al, 2018 ; Han et al, 2019 ; Shen et al, 2019 ; Xu et al, 2019 ; Zhao et al, 2019 ; Chang et al, 2020 ; Dong et al, 2020 ). For instances, in 2016, Chirik and coworkers reported an iron-catalyzed transformation for the deuteration and tritiation of pharmaceuticals (Yu et al, 2016 ).…”

“…For instances, in 2016, Chirik and coworkers reported an iron-catalyzed transformation for the deuteration and tritiation of pharmaceuticals (Yu et al, 2016 ). Kerr's group developed an iridium-catalyzed hydrogen isotope exchange method for the site-selective deuteration of N -heterocycles (Kerr et al, 2017 ). In 2012, Fe(III)/NaBH 4 -mediated free radical hydrofluorination of unactivated alkenes was reported by Boger's group (Barker and Boger, 2012 ) ( Scheme 1B ).…”