Palladium(II)‐Mediated C−H Tritiation of Complex Pharmaceuticals

Abstract

Tritium-labeled molecules are critical tools for elucidating the binding and metabolic properties of bioactive compounds, particularly during pharmaceutical discovery. Direct tritiation of inert C-H bonds with T gas is an ideal approach for tritium labeling, but significant gaps remain for direct tritiation of structurally complex molecules with diverse functional groups. Here we report the first application of palladium(II) C-H activation chemistry for tritiation with T gas. This practical transformation exhibits novel substrate scope and greater functional group tolerance compared to previous state of the art tritiation methods, and has been applied to directly tritiate 9 complex pharmaceuticals and an unprotected dipeptide. The isolated tritium-labeled products exhibit >15 Ci mmol specific activity, exceeding the typical requirements for application in studies of molecular interaction and metabolism.

Directed Iridium‐Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides

“…The first selective method was reported by Yu in 2014, who discovered a palladium‐catalyzed HIE reaction of phenylacetic acids with deuterated acetic acid as a deuterium source (Scheme ) . Recently, this approach was further improved by Hoover, who generated substrate‐palladium complexes, which were reduced subsequently by deuterium or tritium. However, while Yu's acetic acid method requires harsh reaction conditions (high temperature, low pH) and employs a hydrogen isotope source that is not compatible with the requirements of tritium chemistry .…”

Highly Selective Directed Iridium‐Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic Amides

“…[22] However, ap referred tritium source is tritium gas since it is both less toxic than T 2 Oa nd is routinely handled with modern manifold systems. [23] To ensure full translatabil-Scheme 1. Known aromatic HIE reactions in comparison to our work for selectiveC(sp 3 )ÀHactivation/deuteration in aliphatic amides.…”

Highlights of aliphatic C(sp3)‐H hydrogen isotope exchange reactions

“…While the underlying mechanism is complex due to the photochemical activation and the following redox process, the observed exchange regioselectivities and deuterium/tritium values were remarkably high. However, a more preferred tritium source is tritium gas as it is both less toxic than T 2 O, routinely handled with modern manifold systems, and higher specific activities can be more easily achieved …”