Efficient Aliphatic Hydrogen-Isotope Exchange with Tritium Gasthrough the Merger of Photoredox and Hydrogenation Catalysts br

Employment of a combination of an organophotoredoxcatalyst with Wilkinson's catalyst (Rh(PPh3)3Cl) has given rise to anunprecedented method for hydrogen-isotope exchange (HIE) ofaliphatic C(sp3)-H bonds of complex pharmaceuticals using T2gasdirectly. Wilkinson's catalyst, commonly used for catalytic hydro-genations, was exploited as a precatalyst for activation of D2or T2andhydrogen atom transfer. In this combined methodology andmechanistic study, we demonstrate that by coupling photocatalysiswith Rh catalysis, carbon-centered radicals generated via photoredoxcatalysis can be intercepted by Rh-hydride intermediates to deliver aneffective hydrogen atom donor for hydrogen-isotope labeling ofcomplex molecules in one step. By optimizing the ratio of the photocatalyst and Wilkinson's catalyst to balance the rate of the dualcatalytic cycles, we can achieve efficient HIE and high recovery yield. This protocol was readily applied to direct HIE of C(sp3)-Hbonds in 10 complex drug molecules, showing high isotope incorporation efficiency and exceptionally good functional grouptolerance and demonstrating this approach as a practical and attractive labeling method for deuteration and tritiation.