Xu, Lanting, Zhu, Dennis, Shen, Xiaodong, Chai, Jiashuang, Shi, Lei-1, Wu, Bin, Li, Wei and Ma, Dawei (2024) 6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization. Angewandte Chemie (International ed. in English), 63 (52). e202412552. ISSN 1521-3773

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. The N-(1,3-dimethyl-9H- carbazol-9-yl)-6-hydroxypicolinamide (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; for substrates containing sensitive functional groups, the catalyst loading needs to be increased to 3.0 mol % under near-room temperature conditions. N-(2,7-Di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide (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.

Item Type:	Article
Date Deposited:	28 Jan 2025 00:45
Last Modified:	28 Jan 2025 00:45
URI:	https://oak.novartis.com/id/eprint/54407