A General Strategy to Deuterium Labeling

Deuterium labeling is of vital importance in organic synthesis, given that deuterated compounds are widely used in the investigation of reaction mechanism, the modification of reaction selectivity in total synthesis, and the preparation of advanced materials with enhanced performance. In the pharmaceutical industry, deuterium labeling has received particular attention because the properties of the drugs can be changed, while their original potency and selectivity are retained, upon incorporation of heavy hydrogen.

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Mar 20, 2018
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Traditional methods for deuterium incorporation are metal catalyzed or acid/base promoted C–H/C–D exchange. These methods are suffering from a couple of drawbacks, i.e. complexity of catalyst synthesis and high cost, poor control in selectivity, harsh reaction conditions leading to safety concerns and poor functional group tolerances. Therefore, the development of a general strategy to deuterium labeling with wide functional group tolerance is highly desirable in synthetic chemistry and pharmaceutical industry. 

Excitingly, this challenge has been addressed recently by a group led by Prof. Loh in Shenzhen University and National University of Singapore. In their recent paper published in Nature Communications, Prof. Loh and coworkers repot a universal C–X (where X is a halogen) to C–D transformation strategy using D2O as deuterium source and porous two-dimensional CdSe (2D-CdSe) as photocatalyst.

Inspired by previous studies that photoinduced electron transfer from excited photocatalysts to halides (C–I, C–Br, C–Cl, and C–F) can generate highly reactive carbon radicals, Prof. Loh and coworkers envisioned that illuminating the reaction mixture of halides and D2O with UV or visible light in the presence of a photocatalyst can break both C-X and O-D bonds simultaneously, yielding reactive carbon and deuterium radicals which subsequently couple to form deuterated products. In this context, looking for an appropriate photocatalyst that effectively split both C-X and O-D bonds is the key to the success of this strategy. CdSe eventually became the choice owing to its appropriate bandgap for solar energy absorption and a conduction band edge that is more favorable to water reduction. To further increase the density of catalytic sites, the authors synthesized ultrathin CdSe nanosheets (~ 1.7 nm) by a colloidal method and subsequently introduced porosity to the 2D-CdSe via acidic corrosion. 

The feasibility of this strategy, as well as its generality, has been tested by a broad substrate scope. First, C-I to C-D was examined using different aryl, heteroaryl, alkyl, and alkynyl iodides. The scope was then successfully extended to other C-X (X = Br, Cl, F) bonds, yielding corresponding hydrogenated products in good to excellent yields with good functional groups tolerance. In addition to broad substrate scope, the strategy is very chemoselective and flexible. For example, the C-I bonds can be selectively hydrogenated in the presence of other halogen substituents (F, Cl, and Br) on aryl rings. 1,3,5-triiodobenzene  can be deuterated stepwise leading to benzene, iodobenzene, and 1,3-diiodobenezene via the slight modification of reaction conditions. Similarly, the number of deuterium on aryl ring can be controlled by halogen chemistry to produce mono-, bi-, or multi-deuterated products, which is extremely challenging by traditional C–H/C–D exchange method.

In addition to direct deuteration on target molecules, the strategy can be further developed into a series of useful D-containing tool kits including both deuterium atom and linkage moieties. For example, deuterated boronic acids, halides, alkynes, and aldehydes can be used as synthons in Suzuki coupling, Click reaction, Heck reaction, or C–H bond insertion reaction etc. for the synthesis of more complex deuterated molecules. 

The robustness and scalability of the strategy has been attempted by a gram-scale hydrodehalogenation of iodobenzene. With 1.53 g of iodobenzene, the authors obtained a hydrogenation yield of 71% after irradiation for 16 h at room temperature. 

To confirm the radical pathway for this strategy, the authors have performed electron paramagnetic resonance measurements and successfully trapped some important radicals. A reasonable reaction mechanism is thus proposed based on these investigations. 

It is no doubt that this work will inspire new ideas for the production of deuterated compounds in organic synthesis and the pharmaceutical industry, which will thus impact both academic research and industrial manufacturing.


https://www.nature.com/articles/s41467-017-02551-8

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Long Chen

Associate Editor, Springer Nature

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