Compounds labelled with heavy isotopes of hydrogen have applications in many fields, including in the elucidation of organic reaction mechanisms through the study of kinetic isotope effects, in ADMET studies as related to the pharmaceutical industry, and, more recently, in deuterated marketed drugs. Of the many methods for installation of these labels, metal-catalysed hydrogen isotope exchange (HIE) has risen to prominence in recent years. Research at our laboratories at the University of Strathclyde has investigated HIE through the development of novel iridium complexes of type 1 bearing sterically demanding phosphine and N-heterocyclic carbene (NHC) ligands. These catalysts are highly effective at facilitating a C–H activation and functionalisation process to install deuterium or tritium atoms selectively at a position ortho to a Lewis basic directing group (DG) under mild conditions. A number of directing groups are tolerated within this process, including, for example, ketones, amides, sulfonamides, and an array of heterocycles. Boron-containing compounds are prevalent moieties within organic synthesis and can be employed in a variety of different reactions, such as in the Suzuki-Miyaura and Chan-Lam cross-coupling reactions. Despite this, there have been very few C–H activation processes disclosed using such boron species as the directing functionality. To the best of our knowledge, there have been no examples of simple boronate esters, such as pinacol esters (Bpins), or free boronic acids reported to direct a C–H activation and functionalisation process to date. Herein, we report the first examples of HIE at aromatic C(sp2) centres of boronate esters, 2, using an iridium NHC/phosphine chelated catalyst, 3. This process is robust with a wide substrate scope of over 30 substrates and is tolerant to both electron-donating and electron-withdrawing substituents with excellent levels of deuterium incorporation achieved ortho to the directing group. Furthermore, structural changes to the backbone of this new DG are also accommodated. This process may allow boron containing compounds to become more widely used in C–H functionalisation processes.

Iridium(I) catalysed hydrogen isotope exchange of boronate esters

ACS Spring 2022

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