Using Data Science To Guide Aryl Bromide Substrate Scope Analysis in a Ni/Photoredox-Catalyzed Cross-Coupling with Acetals as Alcohol-Derived Radical Sources.
Using Data Science To Guide Aryl Bromide Substrate Scope Analysis in a Ni/Photoredox-Catalyzed Cross-Coupling with Acetals as Alcohol-Derived Radical Sources.
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DOI：
10.1021/jacs.1c12203
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发表时间：
2022-01-19
影响因子：
15
通讯作者：
Doyle AG
中科院分区：
文献类型：
--
作者：
Kariofillis SK;Jiang S;Żurański AM;Gandhi SS;Martinez Alvarado JI;Doyle AG
镍/光氧化还原催化已成为形成C(sp2) - C(sp3)键的强大平台。虽然这些方法中的许多通常使用芳基溴作为C(sp2)偶联伙伴，但多种脂肪族自由基源已被研究。原则上，这些反应能够获得相同的产物支架，但由于在范围评估中使用了非标准化的芳基溴组，可能很难辨别应采用哪种方法。在此我们报道了一种镍/光氧化还原催化的芳基卤化物的（氘代）甲基化和烷基化反应，其中苯甲醛二（烷基）缩醛作为源自醇的自由基源。介绍了反应开发、机理研究以及一种具有生物相关性的芳基氯化物（非诺贝特）的后期衍生化。然后，我们描述了数据科学技术的整合，包括密度泛函理论（DFT）特征化、降维和层次聚类，以描绘出一组多样且简洁的芳基溴，其代表了底物类别的化学空间。通过将已发表的镍/光氧化还原方法的范围实例叠加在同一化学空间上，我们确定了覆盖稀疏的区域以及平均产率的高低，从而能够对现有技术和这种新方法进行比较。此外，我们证明了系统选择的芳基溴范围可用于量化总体反应性趋势，并通过监督式机器学习揭示可能的官能团不相容性的来源。
Ni/photoredox catalysis has emerged as a powerful platform for C(sp2)–C(sp3) bond formation. While many of these methods typically employ aryl bromides as the C(sp2) coupling partner, a variety of aliphatic radical sources have been investigated. In principle, these reactions enable access to the same product scaffolds, but it can be hard to discern which method to employ because non-standardized sets of aryl bromides are used in scope evaluation. Herein we report a Ni/photoredox-catalyzed (deutero)methylation and alkylation of aryl halides where benzaldehyde di(alkyl) acetals serve as alcohol-derived radical sources. Reaction development, mechanistic studies, and late-stage derivatization of a biologically-relevant aryl chloride, fenofibrate, are presented. Then, we describe the integration of data science techniques, including DFT featurization, dimensionality reduction, and hierarchical clustering, to delineate a diverse and succinct collection of aryl bromides that is representative of the chemical space of the substrate class. By superimposing scope examples from published Ni/photoredox methods on this same chemical space, we identify areas of sparse coverage and high versus low average yields, enabling comparisons between prior art and this new method. Additionally, we demonstrate that the systematically-selected scope of aryl bromides can be used to quantify population-wide reactivity trends and reveal sources of possible functional group incompatibility with supervised machine learning.
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影响因子：
5.6
作者：
Mok NY;Brenk R;Brown N
通讯作者：
Brown N
在化学空间中丢失？支持有机金属催化的地图。
影响因子：
--
作者：
Fey N
通讯作者：
Fey N
影响因子：
16.6
作者：
Corce, Vincent;Chamoreau, Lise-Marie;Fensterbank, Louis
通讯作者：
Fensterbank, Louis
影响因子：
15
作者：
Cong, Fei;Lv, Xin-Yang;Martin, Ruben
通讯作者：
Martin, Ruben
影响因子：
15
作者：
Heitz DR;Tellis JC;Molander GA
通讯作者：
Molander GA