Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines
Abstract We report the highly enantioselective Cu-catalyzed asymmetric propargylic substitution (APS) of α-tertiary propargylic electrophiles using hydrazines and hydroxylamines as a fruitful strategy to access multifunctional α-tertiary hydrazines or hydroxylamines. Using trifluoroethanol (TFE) as...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59845-5 |
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| author | Yi Gong Zheng Zhang Huijuan Liu Tao Wang Mengmeng Jiang Nan Feng Peiying Peng Huimin Wang Feng Zhou Xin Wang Jian Zhou |
| author_facet | Yi Gong Zheng Zhang Huijuan Liu Tao Wang Mengmeng Jiang Nan Feng Peiying Peng Huimin Wang Feng Zhou Xin Wang Jian Zhou |
| author_sort | Yi Gong |
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| description | Abstract We report the highly enantioselective Cu-catalyzed asymmetric propargylic substitution (APS) of α-tertiary propargylic electrophiles using hydrazines and hydroxylamines as a fruitful strategy to access multifunctional α-tertiary hydrazines or hydroxylamines. Using trifluoroethanol (TFE) as the solvent play a key role to decrease the nucleophilicity of hydrazines to suppress side reactions such as elimination, thus improve the yield and the enantioselectivity. NMR analysis and theoretical calculations suggest the formation of an H-bond adduct of TFE with hydrazide, stabilized by multiple H-bonding interactions, including C–F···H–N interaction. The sterically confined pyridinebisoxzolines (PYBOX), featuring a bulky benzylthio shielding group also contribute to the excellent enantioselectivity. Aryl- and aliphatic-ketone-derived α-ethynylalcohol carbonates, α-tertiary α-ethynyl epoxides, cyclic carbonates and and α-hydroxycarboxylates all are competent substrates to afford α-tertiary α-ethynylhydrazines with high structural diversity. The obtained products can be readily converted into various α-tertiary hydrazines and azacycles featuring an aza-quaternary stereocenter. |
| format | Article |
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| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-37abcd7484ec4e47b02dcbdfe24bf82a2025-08-20T01:51:38ZengNature PortfolioNature Communications2041-17232025-05-0116111210.1038/s41467-025-59845-5Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolinesYi Gong0Zheng Zhang1Huijuan Liu2Tao Wang3Mengmeng Jiang4Nan Feng5Peiying Peng6Huimin Wang7Feng Zhou8Xin Wang9Jian Zhou10State Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityCollege of Chemistry, Sichuan UniversityState Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal UniversityAbstract We report the highly enantioselective Cu-catalyzed asymmetric propargylic substitution (APS) of α-tertiary propargylic electrophiles using hydrazines and hydroxylamines as a fruitful strategy to access multifunctional α-tertiary hydrazines or hydroxylamines. Using trifluoroethanol (TFE) as the solvent play a key role to decrease the nucleophilicity of hydrazines to suppress side reactions such as elimination, thus improve the yield and the enantioselectivity. NMR analysis and theoretical calculations suggest the formation of an H-bond adduct of TFE with hydrazide, stabilized by multiple H-bonding interactions, including C–F···H–N interaction. The sterically confined pyridinebisoxzolines (PYBOX), featuring a bulky benzylthio shielding group also contribute to the excellent enantioselectivity. Aryl- and aliphatic-ketone-derived α-ethynylalcohol carbonates, α-tertiary α-ethynyl epoxides, cyclic carbonates and and α-hydroxycarboxylates all are competent substrates to afford α-tertiary α-ethynylhydrazines with high structural diversity. The obtained products can be readily converted into various α-tertiary hydrazines and azacycles featuring an aza-quaternary stereocenter.https://doi.org/10.1038/s41467-025-59845-5 |
| spellingShingle | Yi Gong Zheng Zhang Huijuan Liu Tao Wang Mengmeng Jiang Nan Feng Peiying Peng Huimin Wang Feng Zhou Xin Wang Jian Zhou Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines Nature Communications |
| title | Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines |
| title_full | Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines |
| title_fullStr | Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines |
| title_full_unstemmed | Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines |
| title_short | Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines |
| title_sort | trifluoroethanol assisted asymmetric propargylic hydrazination to α tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines |
| url | https://doi.org/10.1038/s41467-025-59845-5 |
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