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

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.