Xue Jing, Zhang Yu-Shan, Huan Zhen, Yang Jin-Dong, Cheng Jin-Pei
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, China.
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
J Org Chem. 2022 Nov 18;87(22):15539-15546. doi: 10.1021/acs.joc.2c02085. Epub 2022 Nov 8.
The Vilsmeier-Haack reaction is a powerful tool to introduce formyl groups into electron-rich arenes, but its wide application is significantly restricted by stoichiometric employment of caustic POCl. Herein, we reported a catalytic version of the Vilsmeier-Haack reaction enabled by a P(III)/P(V)═O cycle. This catalytic reaction provides a facile and efficient route for the direct construction of C1-deuterated indol-3-carboxaldehyde under mild conditions with stoichiometric DMF-d7 as the deuterium source. The products feature a remarkably higher deuteration level (>99%) than previously reported ones and are not contaminated by the likely unselective deuteration at other sites. The present transformation can also be used to transfer other carbonyl groups. Further downstream derivatizations of these deuterated products manifested their potential applications in the synthesis of deuterated bioactive molecules. Mechanistic insight was disclosed from studies of kinetics and intermediates.
维尔斯迈尔-哈克反应是将甲酰基引入富电子芳烃的有力工具，但其广泛应用受到腐蚀性POCl化学计量使用的显著限制。在此，我们报道了一种由P(III)/P(V)═O循环实现的维尔斯迈尔-哈克反应的催化版本。该催化反应提供了一条简便有效的途径，可在温和条件下以化学计量的DMF-d7作为氘源直接构建C1-氘代吲哚-3-甲醛。产物的氘化水平（>99%）明显高于先前报道的产物，且未被其他位点可能的非选择性氘化所污染。目前的转化反应也可用于转移其他羰基。这些氘代产物的进一步下游衍生化表明了它们在合成氘代生物活性分子中的潜在应用。通过动力学和中间体研究揭示了反应机理。
