Cesium Amide-Catalyzed Selective Deuteration of Benzylic C-H Bonds with D2 and Application for Tritiation of Pharmaceuticals |
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Authors: | Hui-Zhen Du Jun-Zhen Fan Zhong-Zhen Wang Dr. Neil A. Strotman Dr. Haifeng Yang Prof. Bing-Tao Guan |
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Affiliation: | 1. State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071 China;2. Department of Chemistry, Fudan University, Shanghai, 200438 China;3. Process Research & Development, Merck & Co., Inc., Rahway, New Jersey 07065 USA |
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Abstract: | Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium- and tritium-labeled compounds. Catalytic HIE methods that enable site-selective C−H bond activation and exchange labeling with gaseous isotopes D2 and T2 are of vital importance, in particular for high-specific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe3)2 to be an efficient catalyst for selective HIE of benzylic C−H bonds with D2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C−H bonds and D2 gas. By virtue of multiple C−H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high-specific-activity tritiation of pharmaceuticals. |
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Keywords: | Benzylic C−H Bonds Cesium Amide Catalyst Deuteration Pharmaceuticals Tritiation |
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