Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification
Abstract Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C−H activations, these arene functionalizations generally require directing groups to enable the C−H activati...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39747-0 |
| _version_ | 1797778857366913024 |
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| author | Zhipeng Lin Uttam Dhawa Xiaoyan Hou Max Surke Binbin Yuan Shu-Wen Li Yan-Cheng Liou Magnus J. Johansson Li-Cheng Xu Chen-Hang Chao Xin Hong Lutz Ackermann |
| author_facet | Zhipeng Lin Uttam Dhawa Xiaoyan Hou Max Surke Binbin Yuan Shu-Wen Li Yan-Cheng Liou Magnus J. Johansson Li-Cheng Xu Chen-Hang Chao Xin Hong Lutz Ackermann |
| author_sort | Zhipeng Lin |
| collection | DOAJ |
| description | Abstract Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C−H activations, these arene functionalizations generally require directing groups to enable the C−H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C−H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C−H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C−H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C−H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations. |
| first_indexed | 2024-03-12T23:22:36Z |
| format | Article |
| id | doaj.art-bdac31ddba7c44d8801256119bb301a1 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T23:22:36Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-bdac31ddba7c44d8801256119bb301a12023-07-16T11:21:24ZengNature PortfolioNature Communications2041-17232023-07-011411810.1038/s41467-023-39747-0Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversificationZhipeng Lin0Uttam Dhawa1Xiaoyan Hou2Max Surke3Binbin Yuan4Shu-Wen Li5Yan-Cheng Liou6Magnus J. Johansson7Li-Cheng Xu8Chen-Hang Chao9Xin Hong10Lutz Ackermann11Wöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität GöttingenWöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität GöttingenWöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität GöttingenWöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität GöttingenWöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität GöttingenCenter of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang UniversityWöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität GöttingenMedicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaCenter of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang UniversityCenter of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang UniversityCenter of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang UniversityWöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität GöttingenAbstract Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C−H activations, these arene functionalizations generally require directing groups to enable the C−H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C−H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C−H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C−H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C−H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.https://doi.org/10.1038/s41467-023-39747-0 |
| spellingShingle | Zhipeng Lin Uttam Dhawa Xiaoyan Hou Max Surke Binbin Yuan Shu-Wen Li Yan-Cheng Liou Magnus J. Johansson Li-Cheng Xu Chen-Hang Chao Xin Hong Lutz Ackermann Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification Nature Communications |
| title | Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification |
| title_full | Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification |
| title_fullStr | Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification |
| title_full_unstemmed | Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification |
| title_short | Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification |
| title_sort | electrocatalyzed direct arene alkenylations without directing groups for selective late stage drug diversification |
| url | https://doi.org/10.1038/s41467-023-39747-0 |
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