Cu-Catalyzed Regioselective Synthesis of Sterically Congested N-Aryl Pyrazoles Using a Traceless Protecting Group
Soumalya Panja1, Pratap Kumar Mandal1, Subhra Kanti Mahato1
1Department of Chemical Sciences, Indian Institute of Science Education and Research Berhampur, Berhampur760003, India.
Abstract:
Herein, the allenal reactivity rather than the classical copper-allenylidene reactivity of cyclic ethynylethylene carbonate (EEC) has been developed by employing a "traceless protecting group" (TPG) strategy on hydrazine. Fundamentally, in hydrazine, the terminal-free N-center is more nucleophilic due to the α effect, and this phenomenon is responsible for exhibiting the traditional copper-allenylidene reactivity of EEC. In this work, we have described that, by switching the reactive nucleophilic N center via employing a protecting group strategy and diminishing the nucleophilicity via hydrogen bonding, allenal reactivity of EEC can be achieved. This copper-catalyzed protocol furnished medicinally important sterically congested unsymmetrical N-aryl pyrazoles in a highly regioselective manner (>20:1 rr) under mild conditions. In addition, valuable synthetic transformations and late-stage functionalization on the "methyl" group have been performed to show the practical advantage of "Me" substitution on pyrazole. Further preliminary mechanistic investigation shed light on the course of the reaction sequence, e.g., in situ cyclization and methanol-assisted hydrolysis.
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