Tlahuext-Aca Adrian, Hartwig John F
Department of Chemistry, University of California, Berkeley, California 94720, United States.
ACS Catal. 2021 Feb 5;11(3):1119-1127. doi: 10.1021/acscatal.0c04917. Epub 2021 Jan 10.
Catalytic methods for the direct introduction of hydrogen isotopes into organic molecules are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metabolism, and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Here, we show that a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C-H bonds in five-membered aromatic heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CHOD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic experiments, including deuterium kinetic isotope effects, determination of kinetic orders, and identification of the catalyst resting state, support C-H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-determining step of the catalytic cycle.
将氢同位素直接引入有机分子的催化方法对于开发改良药物以及改变其吸收、分布、代谢和排泄（ADME）特性至关重要。然而，在实际条件下，在没有导向基团的情况下开发用于选择性掺入同位素的均相催化剂仍然是一个长期存在的挑战。在此，我们表明，一种膦配位的碳酸银络合物催化五元芳香杂环和对催化氢/氘交换具有抗性的活性药物成分中C-H键的位点选择性氘化反应。这些反应以CHOD作为低成本的同位素源发生。银催化剂与缺乏导向基团的五元杂芳烃反应，能耐受多种官能团，并能在极性和非极性溶剂中反应。机理实验，包括氘动力学同位素效应、动力学级数的测定以及催化剂静止状态的鉴定，支持膦配位的碳酸银中间体的C-H键断裂作为催化循环的速率决定步骤。
