Highlights of C (sp²)–H hydrogen isotope exchange reactions

Abstract

The highlights of C (sp 2 )-H hydrogen isotope exchange (HIE) methods developed over the past 10 years are summarized in this review. Major developments include improved Ir(I) catalysts with greater functional group and solvent compatibility and the development of novel base metal catalysts for HIE. In addition, a number of novel Ru-based catalysts have been developed with promising activity. In the area of Pt-and Pd-catalysed exchange, in addition to new advances on heterogeneous Pt-and Pd-catalysed HIE by Sajiki and Shevchenko, a number of groups have reported on homogenous catalysts of Pt and Pd that show an interesting activity and selectivity.

Tritium hydrogen‐isotope exchange with electron‐poor tertiary benzenesulfonamide moiety; application in late‐stage labeling of T0901317

“…Due to the lack of a powerful ortho-directing group in the core structure of 1, unspecific heterogeneous catalysis of HIE reactions on 1 proceeding through palladium-or iridium-mediated hydrogen-deuterium exchange was initially studied. 1,2,[19][20][21][22] However, these deuteration reactions carried out in various solvents (CH 2 Cl 2 , CCl 4 , DMF, EtOAc, or PhCl) at room temperature and atmospheric pressure of deuterium gas (<1.5 bar) over a long period of time (overnight or over weekend) in the presence of one equivalent of PdO or iridium black catalyst failed in the incorporation of deuterium into 1 (Table 1, entries 1-2, 4-6, and 8). Although the reaction temperature was significantly increased to 120 C, such similar condition did not provide a desired improvement in deuterium enrichment of 1 (Table 1, entry 9).…”

“…The failure in tritium incorporation using heterogeneous catalysts shifted our research focus to the study of specific homogenous HIE reactions on substrate 1 mediated by universal Crabtree (6), and Kerr (3b and 7) iridium catalysts. 2,23 Catalyst 8 applicable for polar compounds was also included in this study because of its ability to facilitate HIE reactions mediated by weak orthodirecting groups in a wide range of solvents. 24,25 Unfortunately, homogenous catalysts 6, 7, and 8 examined in the labeling of 1 under various reaction conditions did not provide substantial incorporation of deuterium (Table 1, entries [12][13][14][15][16][17][18][19].…”

“…have therefore been extensively studied lately. [1][2][3] HIE allows for the direct late-stage incorporation of deuterium or tritium into the target compound without the necessity to synthesize precursors or to prepare isotope-enriched materials from the beginning of the synthesis. Facilitated by a broad scope of functionalized substrates, such as carboxylic acids, 4 amides, 4,5 carbonyl groups, 5,6 sulfones, 4 sulfonamides, [7][8][9] and N-heterocycles, 4,10 the ortho-directed HIE reactions in the presence of homogeneous iridium(I) complexes represent feasible and powerful methods in isotopic labeling of drug molecules with heavy hydrogen atoms.…”

Palladium Nanoparticles for the Deuteration and Tritiation of Benzylic Positions on Complex Molecules

“…Several reports have demonstrated, how transition metal catalyzed HIE might be employed to label complex molecules directly in one catalytic step by the incorporation of either deuterium or tritium. [1] Hence,H IE reactions remain highly attractive techniques for the delivery of deuterium labeled compounds as stable isotopically labeled internal standards (SILSs) [2] and tritium labeled compounds as radioligands for in vitro assays. [3] In order to obtain robust SILSs for metabolism studies,i ti so ften necessary to incorporate several deuterium atoms per molecule and to eliminate the signal of the non-labeled isotopologue.O wing to the large number of HIE methods being controlled by the presence of specific directing groups,s uch as amines, [4] anilines, [5] Nheterocycles [6] and carbonyls, [7] it becomes increasingly appealing to develop efficient HIE methods as complementary tools for deuterium and tritium labeling (Figure 1, top).…”

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

“…Amongst the synthetic methods available for incorporation of deuterium or tritium into a molecule, hydrogen isotope exchange (HIE) stands out due to its simplicity and generality [7][8][9]. A particularly powerful variant of this process is directed HIE, whereby a Lewis basic group within the molecule directs a metal catalyst to an adjacent site, and a subsequent C-H activation results in a metallocyclic intermediate which facilitates HIE at this adjacent position (Scheme 1).…”