C−H Functionalisation for Hydrogen Isotope Exchange

Abstract

The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demand a range of methods for their installation in an array of molecular architectures. In this Review, we describe recent advances in synthetic C-H functionalisation for hydrogen isotope exchange.

Efficient Access to Deuterated and Tritiated Nucleobase Pharmaceuticals and Oligonucleotides using Hydrogen‐Isotope Exchange

“…These nitrogencontaining heterocycles are involved in many biological processes such as transmission of genetic information, energetic processes,orcell communication. [5] Indeed, tritiated analogues of drug candidates,are essential tools for investigating the in vivo fate of substances within absorption, distribution, metabolism and excretion (ADME) studies. [1] More recently,R NA interference has emerged as an experimental tool to inhibit the expression of genes and gave birth to,r espectively,a ntisense oligonucleotides [2] and small interfering RNA( siRNA), [3] which are under intensive studies as high potential therapeutic agents.…”

B(C6F5)3‐Catalyzed α‐Deuteration of Bioactive Carbonyl Compounds with D2O

“…[1][2][3][4] A deuterated drug could have significantly lower rates of metabolism relative to the original molecule because of the kinetic isotope effect, and hence a longer half-life. [1][2][3][4] A deuterated drug could have significantly lower rates of metabolism relative to the original molecule because of the kinetic isotope effect, and hence a longer half-life.…”

“…[a,b,c] Yield and deuterium incorporation level was determined by1 H NMR analysis of unpurified reaction mixtures with mesitylene as the internal standard. [a,b,c] Yield and deuterium incorporation level was determined by1 H NMR analysis of unpurified reaction mixtures with mesitylene as the internal standard.…”

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

“…Circumventing the need for additional synthetic steps, hydrogen isotope exchange (HIE), the most fundamental of all C À Hf unctionalization processes, [1] has become ab roadly utilized strategy for the incorporation of deuterium or tritium into organic molecules. [2,3] In drug discovery,r adioactive tritium tracers are increasingly utilized as discovery tools, [4] in covalent binding assays, [5] for tissue distribution studies [6] and for absorption distribution metabolism excretion (ADME) profiling of new drug candidates.…”

“…[7,8] Numerous HIE methods based on homogeneous or heterogeneous catalysis have already been described. [1,2,9] Recent research has strongly focused on selective ortho-directed HIE reactions of aromatic substrates based on homogeneous iridium(I) complexes,with the commercial Crabtreescatalyst [10] and Kerrscatalyst [11,12] (1)b eing the most prominent catalysts applied today.E ven though anew generation of bidentate catalyst systems such as those from the groups of Pfaltz, [13] Burgess, [14] and Tamm [15] have extended the scope of aromatic ortho-directing HIE (Scheme 1), this is still restricted to C(sp 2 )carbons.…”