Abstract
Isotope labelling, particularly deuteration, is an important tool for the development of new drugs, specifically for identification and quantification of metabolites. For this purpose, many efficient methodologies have been developed that allow for the small-scale synthesis of selectively deuterated compounds. Due to the development of deuterated compounds as active drug ingredients, there is a growing interest in scalable methods for deuteration. The development of methodologies for large-scale deuterium labelling in industrial settings requires technologies that are reliable, robust and scalable. Here we show that a nanostructured iron catalyst, prepared by combining cellulose with abundant iron salts, permits the selective deuteration of (hetero)arenes including anilines, phenols, indoles and other heterocycles, using inexpensive D2O under hydrogen pressure. This methodology represents an easily scalable deuteration (demonstrated by the synthesis of deuterium-containing products on the kilogram scale) and the air- and water-stable catalyst enables efficient labelling in a straightforward manner with high quality control.
Highlights
Acid-mediated hydrogen–deuterium exchange reactions (H/D exchange) are among the oldest methods known for labelling of arenes
Homogeneous iridium-based Crabtree and Kerr catalysts have been used for C(sp2)–H hydrogen isotope exchange reactions using D2 gas[16,17]
Using D2O in the presence of a biomass-derived iron catalyst under hydrogen pressure allows for the preparation of >90 selectively deuterated building blocks, representative drugs and natural products with high and reliable deuterium incorporation (Fig. 1g)
Summary
We tested standard, commercially available heterogeneous catalysts and tailor-made supported nanoparticles (NPs) for selective deuteration of 4-phenylmorpholine in D2O (Supplementary Table 1) This benchmark substrate was chosen because it permits labelling both at the nitrogen-containing heterocycle and the phenyl ring. To understand the structure of the most active material (Fe-Cellulose-1000), powder X-ray diffraction, XPS, scanning transmission electron microscopy (STEM) and X-ray absorption spectroscopy (XAS) investigations were performed. These results show that the freshly pyrolysed catalyst consists of Fe/Fe3C particles 20–50 nm in size, covered by a shell of up to 30 graphene layers with a overall thickness of 6–10 nm. By comparing the deuteration of aniline and 3,5-dideuterioaniline, a Articles
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