Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines

Yi Gong, Zheng Zhang, Huijuan Liu, Tao Wang, Mengmeng Jiang, Nan Feng, Peiying Peng, Huimin Wang, Feng Zhou (), Xin Wang () and Jian Zhou ()
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Yi Gong: East China Normal University
Zheng Zhang: East China Normal University
Huijuan Liu: East China Normal University
Tao Wang: East China Normal University
Mengmeng Jiang: East China Normal University
Nan Feng: East China Normal University
Peiying Peng: East China Normal University
Huimin Wang: East China Normal University
Feng Zhou: East China Normal University
Xin Wang: Sichuan University
Jian Zhou: East China Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59845-5

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