As the H/D has the greatest isotopic difference, introducing deuterium into pharmaceutical compounds could improve the stability during metabolism with the minimum impact on the medicinal property of original compounds. In 2017, FDA of United States approved the first deuterated medicine AUSTEDOTM (deutetrabenazine, Drug Des. Devel. Ther. 2018, 12, 313–319) to treat the Huntington's disease chorea. The labeling a molecule with D at specific position could lead to the distinct kinetic profile, a procedure adopted in reaction elucidation. In addition, the incorporation of deuterium into molecule gives rise to probe in NMR, X-Ray, and mass spectroscopy.
Since the extensive application of deuterated compounds, tremendous efforts had been applied to discover deuteration methods. A number of protocols were established with d4-MeOD, d6-EtOD, d6-DMSO, d3-acetonitirle, d6-benzene, and D2. As D2O was the most direct and available deuterium source, it is advantageous to develop a deuteration protocol using D2O directly. As the water is the most stable storage of element hydrogen, conventional deuteration reactions with D2O frequently used highly reactive reductants, for example, Mg, Zn, or Mn. These reductants will increase the pH of reaction mixture during the conversion and pose challenges to various base-labile groups. So, it is important to develop procedures to run the deuteration with D2O in the absence of any external reductant under neutral condition.
Electrochemical synthesis is undergoing a new round of peak of research as the need for clean, safe and energy-saving chemistry to meet the ever-growing demands of materials. Recently, the electromchemical dehydrogenative cross coupling emerged as a powerful strategy to synthesize compound without external oxidant by evolution of hydrogen at cathode. (Ref. Acc. Chem. Res. 2019, 52, 3309-3324.; 3339-3350; 2020, 53, 300-310; Chin. J. Chem. 2019, 37, 92-301; 513-528; Chemsuschem2019, 12, 115-132; 2020, 13, 1661-1687; ChemElectroChem, 10.1002/celc.202000252). Inspired by these progresses, Xu Cheng group of School of Chemistry and Chemical Engineering developed an electrochemical deuteration reaction under reductant-free-conditions. (Angew. Chem. Int. Ed. DOI:10.1002/anie.202005765)
The features of this transformation include:
1) The reaction proceeds in common DMF, with nBu4NBF4 as supporting electrolyte, and D2O as deuterium source. No additional reagent is required.
2) The reaction remains around neutral conditions from the beginning to the completion.
3) External reductant is not required.
4) The substrate scope includes; a,b-unsaturated ester, amide and acid containing alkene or alkyne.
5) The yields are from moderate to excellent and the deuterium ratios are typically above 90% and up to 99%.
6) The reaction use graphite felt as electrodes under controlled cell potential. The overall cost is inexpensive.
7) It is readily to scale up to 15 g scale almost without any loss of yield and d-incorporation.
8) The reaction tolerates a variety of functional groups, for example, isolated alkene, 5,6-membered heteroarenes, N-Boc, N-Cbz, N-alloc, silyl ether, sulfur ether, epoxide, cyclopropanyl, ketones, halogen atoms, cyano.
With this protocol, a series of d2, d4- pharmaceutical compounds were prepared, including, a-amino acid, b-amino acid, DOPA precursor, building block of CCR3 antagonist, isobuprofen, pain relief compound. In addition, the d2-acid can serve as a versatile synthon to link the deuterated moiety to borate, azide, alkyne and heterocycles. (Figure 1b).
Figure 1 Electrochemical deuteration with D2O as deuterium source.
It was found that graphite felt is essential to achieve the desired transformation. Even by changing the graphite felt anode to graphite anode, only trace of desired conversion could be detected. This strong anodic effect in an cathodic reduction reaction was unusual. In the proposed reaction pathway, OD- anion generated at cathode during the dueteration migrates to anode quickly and is oxidized instantly to give D2O and oxygen. The overall pH is regulated around neutral that facilitate the compatibility to a series of functional groups. (Figure 2)
Figure 2 Stepwise electron transfer pathway involving oxygen evolution
Mr. Xu Liu, a graduate student of School of Chemistry and Chemical Engineering was the first author. The work dedicated to the 100 anniversary of School of Chemistry and Chemical Engineering. This work was supported National Science Foundation of China, the State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology (Zhejiang University of Technology, Hangzhou 310032), and QingLan Project of Jiangsu Education Department.