High-Throughput Screening of Ullmann Reaction Conditions and Study of Their Regularity

doi:10.6023/cjoc202507012

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (3): 993-999.DOI: 10.6023/cjoc202507012 Previous Articles Next Articles

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Ullmann反应条件的高通量筛选及其规律性研究

郭在翔^†, 邹昀^†, 程沛浩, 李富军, 陶胜洋^*()

大连理工大学化学学院辽宁大连 116024

收稿日期:2025-07-09 修回日期:2025-10-16 发布日期:2025-12-09
通讯作者: 陶胜洋
作者简介:
†共同第一作者
基金资助:
国家自然科学基金(22372025); 中央高校基本科研业务费(DUT22LAB607); 中央高校基本科研业务费(DUT22QN226)

High-Throughput Screening of Ullmann Reaction Conditions and Study of Their Regularity

Zaixiang Guo, Yun Zou, Peihao Cheng, Fujun Li, Shengyang Tao^*()

School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116024

Received:2025-07-09 Revised:2025-10-16 Published:2025-12-09
Contact: Shengyang Tao
About author:
†The authors contributed equally to this work.
Supported by:
National Natural Science Foundation of China(22372025); Fundamental Research Funds for the Central Universities(DUT22LAB607); Fundamental Research Funds for the Central Universities(DUT22QN226)

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Abstract

Although classical physical organic chemistry theories have undergone significant development, it remains challenging to rapidly determine the optimal reaction conditions and elucidate possible mechanisms for specific reactions. In recent years, high-throughput experimentation and data-driven analysis have emerged as powerful tools to address these challenges. In this study, an automated high-throughput experimental platform combined with big data and machine learning techniques was employed to optimize the reaction conditions and investigate the mechanism of the Ullmann coupling for the synthesis of pirfenidone (5-methyl-1-phenylpyridin-2(1H)-one). A total of 984 different reaction conditions were screened using the automated platform. This approach not only identified the optimal copper/ligand combination but also revealed, through a combination of machine learning and statistical analysis, that oxalamide ligands and short Cu-L interaction distances are key factors contributing to higher yields in the Ullmann coupling for pirfenidone synthesis.

Key words: high-throughput experiments, C—N coupling, machine learning, big data

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Zaixiang Guo, Yun Zou, Peihao Cheng, Fujun Li, Shengyang Tao. High-Throughput Screening of Ullmann Reaction Conditions and Study of Their Regularity[J]. Chinese Journal of Organic Chemistry, 2026, 46(3): 993-999.

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Fig. & Tab. 5

Scheme 1. Copper-catalyzed Ullmann coupling reaction as a template reaction

Figure 1. (a) Heat map of reaction yields of the primary screening; (b) Heat map of reaction yields of the secondary screening Reaction conditions: 2-hydroxy-5-methylpyridine (1.0 equiv.), bromobenzene (1.5 equiv.), catalyst (10 mol%), ligand (10 mol%), base (2.0 equiv.) and solvent (0.6 mL), at 140 ℃ for 10 h. The yield of the product was determined by HPLC using 1,3,5-trimethoxybenzene as an internal standard

Figure 2. (a) Average yields of different ligands in preliminary screening; (b) average yields of different catalysts in preliminary screening; (c) average yields of different bases in preliminary screening; (d) average yields of different solvents in preliminary screening

Figure 3. (a) Decision tree classification model and its accuracy in classifying catalyst-ligand combinations as “on” or “off” reactive states in the Ullmann C-N coupling reaction; (b) correlation between reaction yield and the Cu-L interaction distance (d) Red dots represent oxamide ligands, black dots represent non-oxamide ligands. The vertical dashed lines indicate the 60% yield threshold distinguishing “on/off” reactivity and the calculated d threshold of 1.919 Å, highlighting the significance of d in determining reaction yield

Figure 4. (a) Distribution histogram of yield; (b) normal Q-Q plot of yields, the red diagonal line is the normal reference line; (c) the effect of ligand type on yield, the yield distribution of oxamide and non-oxamide ligands; (d) the effect of Cu-L interaction distance (d value) on yield, the yield distribution of the two combinations of d<1.919 Å and d≥1.919 Å

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Ullmann反应条件的高通量筛选及其规律性研究

High-Throughput Screening of Ullmann Reaction Conditions and Study of Their Regularity

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