中国科学院上海有机化学研究所马大为团队报道了机器学习加速配体设计和反应优化——6-羟基吡啶酰肼促进Cu（I）催化的水中羟基化反应。相关研究成果发表在2024年8月27日出版的《德国应用化学》。

羟基化（杂）芳烃是天然产物、材料、小分子药物中的优良基序，也是合成有机化学中的多用途中间体。

该文报道了一种高效的Cu（I）/6-羟基吡啶酰肼催化（杂）芳基卤化物（Br，Cl）在水中的羟基化反应。通过建立机器学习（ML）模型，有效地加速了配体的设计和反应条件的优化。L32（6-HPA-DMCA）对（杂）芳基溴化物表现出高效率，在80°C下以0.01 mol%（100 ppm）的最小催化剂负载促进羟基化反应，达到10000吨，或在含有敏感官能团的底物（3.0 mol%）的近室温条件下促进羟基化反应；L42（6-HPA-DTBCA）对氯化物底物显示出优异的反应活性，能够在100°C下以2-3mol%的催化剂负载进行羟基化反应。

这些代表了铜催化羟基化反应中最低催化剂负载和温度的最新技术。此外，该方法具有可持续和环保的溶剂系统，可容纳各种底物，并显示出为关键药物中间体开发稳健和可扩展的合成工艺的潜力。

附：英文原文

Title: 6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization

Author: Lanting Xu, Jiazhou Zhu, Xiaodong Shen, Jiashuang Chai, Lei Shi, Bin Wu, Wei Li, Dawei Ma

Issue&Volume: 2024-08-27

Abstract: Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. L32 (6-HPA-DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol% (100 ppm) at 80 °C to reach 10000 TON or under near-room temperature conditions for substrates containing sensitive functional groups (3.0 mol%); L42 (6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2-3 mol% catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

DOI: 10.1002/anie.202412552

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202412552