Lanting Xu, Jiazhou Zhu, Xiaodong Shen, Jiashuang Chai, Lei Shi, Bin Wu, Wei Li, Dawei Ma
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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.</p>","PeriodicalId":125,"journal":{"name":"Angewandte Chemie International Edition","volume":" ","pages":"e202412552"},"PeriodicalIF":16.1000,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization.\",\"authors\":\"Lanting Xu, Jiazhou Zhu, Xiaodong Shen, Jiashuang Chai, Lei Shi, Bin Wu, Wei Li, Dawei Ma\",\"doi\":\"10.1002/anie.202412552\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization.
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.
期刊介绍:
Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.