德国马克斯·普朗克煤炭研究所Ritter, Tobias团队报道了钯分子催化剂实现芳基噻吩盐的氚化反应。相关研究成果于2021年12月15日发表于国际一流学术期刊《自然》。

氚标记是研究药物的药代动力学和药效学特性、放射自显影、受体结合和受体占用研究的关键工具。氚气是制备标记分子的首选氚源，因为它具有高同位素纯度。从氚气体中引入氚标记通常通过芳基（伪）卤化物的非均相过渡金属催化氚化来实现。然而，碳负载钯等多相催化剂通过一种反应机制进行操作，该反应机制还导致其他官能团的还原，这些官能团在药剂学中具有显著的特征。均相钯催化剂可与芳基（伪）卤化物发生化学选择性反应，但尚未用于氢解反应，因为在要求的氧化加成后，它们不能分解二氢化合物。

该文中，研究人员报告了一个具有明确定义的分子钯催化剂的均相氢解反应。研究人员展示了可通过后期C–H功能化选择性引入药物的噻吩离开基团与相关钯（II）催化剂的配位能力如何不同于传统离开基团，从而实现之前未实现的二氢催化。该独特的反应性与明确定义的分子钯催化剂的化学选择性相结合，能够对小分子药物进行氚化，而这些小分子药物所含的功能可能是异构催化剂所不能容忍的。氚化反应不需要惰性气氛或干燥条件，因此具有实用性和鲁棒性，可对药物的发现和开发产生直接影响。

附：英文原文

Title: Tritiation of aryl thianthrenium salts with a molecular palladium catalyst

Author: Zhao, Da, Petzold, Roland, Yan, Jiyao, Muri, Dieter, Ritter, Tobias

Issue&Volume: 2021-12-15

Abstract: Tritium labelling is a critical tool for investigating the pharmacokinetic and pharmacodynamic properties of drugs, autoradiography, receptor binding and receptor occupancy studies1. Tritium gas is the preferred source of tritium for the preparation of labelled molecules because it is available in high isotopic purity2. The introduction of tritium labels from tritium gas is commonly achieved by heterogeneous transition-metal-catalysed tritiation of aryl (pseudo)halides. However, heterogeneous catalysts such as palladium supported on carbon operate through a reaction mechanism that also results in the reduction of other functional groups that are prominently featured in pharmaceuticals3. Homogeneous palladium catalysts can react chemoselectively with aryl (pseudo)halides but have not been used for hydrogenolysis reactions because, after required oxidative addition, they cannot split dihydrogen4. Here we report a homogenous hydrogenolysis reaction with a well defined, molecular palladium catalyst. We show how the thianthrene leaving group—which can be introduced selectively into pharmaceuticals by late-stage C–H functionalization5—differs in its coordinating ability to relevant palladium(II) catalysts from conventional leaving groups to enable the previously unrealized catalysis with dihydrogen. This distinct reactivity combined with the chemoselectivity of a well defined molecular palladium catalyst enables the tritiation of small-molecule pharmaceuticals that contain functionality that may otherwise not be tolerated by heterogeneous catalysts. The tritiation reaction does not require an inert atmosphere or dry conditions and is therefore practical and robust to execute, and could have an immediate impact in the discovery and development of pharmaceuticals.

DOI: 10.1038/s41586-021-04007-y

Source: https://www.nature.com/articles/s41586-021-04007-y