Efficient Route for Construction of Fluorinated Isoxazolines through Base‐Mediated Fluorinated Amino Acid Derivatives

A base-mediated, transition-metal-free reaction between ethyl 3-bromo-2-((diphenylmethylene)amino)-3,3-difluoropropanoate and nitrones facilitates a rapid, one-step synthesis of fluorinated isoxazolidines. This streamlined protocol proceeds under mild conditions to construct the valuable heterocyclic scaffold efficiently, with broad substrate scope and high practicality.

Isoxazolines have attracted widespread attention for the development of anticancer, antiviral, and anti-inflammatory drugs due to their unique electronic properties and conformational rigidity. However, the application of fluorinated isoxazolines in the development of innovative drugs has been constrained by the lack of appropriate synthetic methods for introducing fluorine atoms into the isoxazole ring skeleton. In this article, a rapid synthesis of fluoroisoxazolines is reported based on a pre-functionalization strategy: ethyl 3-bromo-2-((diphenylmethylene)amino)-3,3-difluoropropionate is reacted with imine oxides under alkaline conditions to efficiently construct the fluoroisoxazolidine skeleton in one step without the need for transition metal catalysts. This simple operation is performed under mild green reaction conditions, offering a concise and efficient pathway for the synthesis of fluoroisoxazololidine compounds.

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