Efficient Aliphatic Hydrogen-Isotope Exchange with Tritium Gas through the Merger of Photoredox and Hydrogenation Catalysts

Abstract

Employment of a combination of an organophotoredox catalyst with Wilkinson's catalyst (Rh(PPh 3 ) 3 Cl) has given rise to an unprecedented method for hydrogen-isotope exchange (HIE) of aliphatic C(sp 3 )−H bonds of complex pharmaceuticals using T 2 gas directly. Wilkinson's catalyst, commonly used for catalytic hydrogenations, was exploited as a precatalyst for activation of D 2 or T 2 and hydrogen atom transfer. In this combined methodology and mechanistic study, we demonstrate that by coupling photocatalysis with Rh catalysis, carbon-centered radicals generated via photoredox catalysis can be intercepted by Rh-hydride intermediates to deliver an effective hydrogen atom donor for hydrogen-isotope labeling of complex molecules in one step. By optimizing the ratio of the photocatalyst and Wilkinson's catalyst to balance the rate of the dual catalytic cycles, we can achieve efficient HIE and high recovery yield. This protocol was readily applied to direct HIE of C(sp 3 )−H bonds in 10 complex drug molecules, showing high isotope incorporation efficiency and exceptionally good functional group tolerance and demonstrating this approach as a practical and attractive labeling method for deuteration and tritiation.

Coupling photocatalytic overall water splitting with hydrogenation of organic molecules: a strategy for using water as a hydrogen source and an electron donor to enable hydrogenation

“…The deuteration occurred at the position of carbon–bromine bonds in exclusive regioselectivity, which is in sharp contrast to the current methods for synthesizing deuterated aromatic compounds via C–H/C–D exchanges that often suffer from low regioselectivities. 37–44 Additionally, similar yields were obtained for the deuteration and hydrogenation of the same substrates, which suggests that the reaction was less susceptible to the kinetic isotope effect. For instance, 3,4-dicyanobromobenzene was converted into hydrogenation and deuteration products in 81% and 83% yields, respectively ( 2g and 2m ).…”

“…On the other hand, the incorporation of deuterium atoms into aromatic rings is of great significance for the investigation of the reaction mechanism, discovery of pharmaceuticals, and identification and quantification of metabolites. [37][38][39][40][41][42][43][44] As a result, much attention has been devoted to the deuteration of aromatic rings. [37][38][39][40][41][42][43][44] One of the most effective strategies is the deuteration of aryl halides using DMSO-D 6 , 45 CD 3 OD, 46 DCOONa, 47 THF-d 8 , 48 CH 3 OD 49 and D 2 O 50-54 as deuterium sources (Scheme 1b), among which D 2 O is undoubtedly the most attractive deuteration reagent from the perspective of safety, cost and handling.…”

“…[37][38][39][40][41][42][43][44] As a result, much attention has been devoted to the deuteration of aromatic rings. [37][38][39][40][41][42][43][44] One of the most effective strategies is the deuteration of aryl halides using DMSO-D 6 , 45 CD 3 OD, 46 DCOONa, 47 THF-d 8 , 48 CH 3 OD 49 and D 2 O 50-54 as deuterium sources (Scheme 1b), among which D 2 O is undoubtedly the most attractive deuteration reagent from the perspective of safety, cost and handling. However, those methods for the deuteration of aryl halides with D 2 O suffer from an expense of polluting reductants such as sodium formate, triethanolamine, sodium sulfite and (Bu 3 Sn) 2 .…”

Homogenous Iron-Catalysed Deuteration of Electron-Rich Arenes and Heteroarenes

“…Prevalent for numerous years, iridium-catalysed HIE procedures are now supplemented by base-metal catalysis, 11 notably with the use of iron 12 and nickel 13 molecularly defined complexes. Similarly, photocatalytic 14 and electrocatalytic 15 labelling reactions are on the rise. In addition, the use of supported catalysts becomes important in the field of HIE, with reports utilising ruthenium, 16 iridium, 17 palladium, 18 rhodium, 19 iron, 20 and manganese 21 nanoparticles.…”

“…Besides deuterium incorporation, tritium enrichment is a complementary subject of interest in isotopic labelling. 5 12a 13 14 26 Inherent to the radioactive nature of tritium, high reaction rates, short reaction times, and the use of small quantities of the isotope source are highly desirable. Thus, we explored this methodology at higher temperature (130 °C) for 1 h and observed a deuterium content superior to 80% using 20 equiv of deuterium oxide (Table 2 ).…”