Ortho-deuterated Arenes Based on DCL™

Deuterated compounds are entering and impacting our daily lives in entirely new ways. For drug discovery, deuteration can alter the biological properties of a particular compound, while the incorporation of deuterium atoms into a drug or drug candidate provides a diagnostic tool that resolves the parent molecule without altering metabolic conditions in vivo and in vitro. To date, in the literature, deuteration has been carried out either by natural enzymatic processes, starting from commercially available stable deuterium-labeled synthons, or by direct exchange of hydrogen atoms for deuterium atoms under catalytic conditions.

Given the importance of deuterated compounds, the development of efficient methods for incorporating deuterium atoms into specific molecules is highly desirable. That's why we built the DCL™ technology platform in the first place.

Existing Strategy for the Synthesis of Ortho-deuterated Arenes

For directional C–H activation of arenes, H/D exchange catalyzed by transition metals has long been recognized as a robust method. Electrophiles are directed to the ortho and para positions by electron-donating substituents on arenes due to positive intermediate effects. The incorporation of ortho-deuterium into arenes has been accomplished by various metals. The incorporation of deuterium into aromatic hydrocarbons can be catalyzed by Ir, Pd, Rh and Ru.

Ir-catalysed ortho-deuterated arenes

Iridium is the most versatile metal catalyst for hydrogen-deuterium exchange reactions. Dichloromethane (DCM) is the most suitable solvent for this catalyst. And the crowding of space near the target C-H bond prevents the exchange. Inert iridium dimers and trimers tend to form in solution when the complexation of the directing unit is hindered. Some functional groups do not provide a good degree of exchange.

Fig.1 Different Ir complexes developed over time for ortho-selective C–H deuterium labelling of arenes and heteroarenes.^[2]

Pd-catalysed ortho-deuterated arenes

Ortho-selective deuterated aromatic acids can be synthesized via Pd catalysis using 8-aminoquinoline (8-AMQ) as a directing group and D₂O as a deuterium source. 8-AMQ binds to the Pd center in a bidentate manner via two nitrogen atoms, forming a five-membered metal ring. Then, Pd(II) activates the C-H bond, followed by H/D exchange.

Fig.2 8-Aminoquinoline directed ortho-C–H deuteration.^[2]

Rh-catalysed ortho-deuterated arenes

Rh complexes are known for regiospecific isotopic labeling of aromatic acids, amides, amines and heterocycles. A moderately regioselective ortho-tritiation of aromatic carboxylic acids, amides and aralkylamines can be achieved using Rh(III) chloride as a catalyst.

Ru-catalysed ortho-deuterated arenes

Using Ru(II) biscarboxylate complexes as catalysts and D₂O as a source of deuterium atoms, H/D exchange schemes can be developed in the ortho position of benzoic acid, sulfonamides, and some drugs. Ortho- and meta-C-H deuterium labeling of arenes was also achieved using Ru with PPh₃ and AgOAc as additives and d₄-acetic acid as deuterium source and solvent.

DCL™ in Ortho-deuterated Arenes

After comprehensively summarizing the technologies related to ortho-deuterated arenes, we have constructed a brand-new deuterated technology platform. Our DCL™ technology platform is designed to extend the ortho-deuteration reaction to a wider range of arenes with high selectivity and high deuteration levels. Our technique uses D₂O as a source of deuterium atoms and a green medium, overcoming factors such as non-selective or trace deuteration or the use of expensive metal catalysts. More importantly, we can achieve gram-level synthesis and above, helping you better commercialize.

Intellectual Property Protection

BOC Sciences has always regarded intellectual property as the most valuable asset of the company and its customers. We have signed non-disclosure agreements with customers and employees before the project starts, and provide synthetic route design and synthesis services in strict accordance with the terms of the non-disclosure agreement, striving to provide customers with target compounds in the shortest time possible.

References

1. Zhao L L, et al. Ortho-Selective Hydrogen Isotope Exchange of Phenols and Benzyl Alcohols by Mesoionic Carbene-Iridium Catalyst. Organic Letters. 2021, 23(23): 9297-9302.
2. Prakash G, et al. C–H deuteration of organic compounds and potential drug candidates. Chemical Society Reviews. 2022.
3. Manna P, et al. Palladium-catalyzed directed synthesis of ortho-deuterated phenylacetic acid and analogues. Organic & Biomolecular Chemistry. 2021, 19(28): 6244-6249.