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Sodium Acetate-promoted Oxa-Michael-Aldol [3+2] Annulation Reactions: Facile Access to the Fused Heterocycle

[ Vol. 7 , Issue. 1 ]

Author(s):

Jia-Ning Xie, Liang-Nian He*, Hong-Chen Fu, Ning Wang and Mei-Yan Wang   Pages 60 - 64 ( 5 )

Abstract:


Background: The development of simple yet efficient functionalization protocols has gained considerable importance for the discovery of useful heterocycle compounds, such as isoxazolo, isoindol and their derivatives. 3a-hydroxyisoxazolo[3,2-a]isoindol-8(3aH)-ones are a type of novel heterocycles first reported by Lu group involving Ph3P-catalyzed annulation process. In this work, we aim to explore the synthesis of this novel complex heterocycles using simple base catalyst from internal alkynoates with N-hydroxyphthalimide.

Methods: The reactions were conducted in the Schlenk flasks, protected by N2. The products were identified by TLC, and isolated by column chromatography on silica gel (200-300 mesh) using petroleum ether (60-90 oC) and ethyl acetate. All products were characterized by 1H NMR, 13C NMR and mass spectroscopy.

Results: A highly active base-promoted system based on NaOAc•3H2O has been designed for the oxa- Michael-aldol [3+2] annulation reactions of internal alkynoates with N-hydroxyphthalimide, giving a series of pharmaceutically attractive 3a-hydroxyisoxazolo[3,2-a]isoindol-8(3aH)-ones in synthetically useful yields of up to 98%. Only 10 mol% NaOAc•3H2O is needed for the reaction at room temperature within 6 h. Besides, a plausible base-promoted intermolecular [3+2] oxa-Michael-aldol type mechanism is proposed.

Conclusions: We have demonstrated the simple cascade reaction between alkynoates and NHPI as a facile access to pharmaceutically attractive 3a-hydroxyisoxazolo[3,2-a]isoindol-8(3aH)-ones, with a base-promoted intermolecular [3+2] oxa-Michael-aldol type mechanism. Target heterocycles with various functional groups were achieved in good to excellent yields at room temperature for 6 h. Such a synthetic methodology provides an effective approach of the synthesis of the fused heterocyclics in combination with CO2 utilization.

Keywords:

Heterocycles, Oxa-Michael-aldol, sodium acetate, synthetic method, annulation, N-hydroxyphthalimide.

Affiliation:

State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071

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