Facile Synthesis of Fluorinated Isoxazoles via Consecutive Double C—F Bond Cleavage

doi:10.6023/A18070279

Acta Chim. Sinica ›› 2018, Vol. 76 ›› Issue (12): 940-944.DOI: 10.6023/A18070279 Previous Articles Next Articles

Special Issue: 有机氟化学

Communication

碳-氟键断裂用于构建氟代异噁唑化合物

任智雯, 任楠, 张发光, 马军安

天津大学理学院化学系天津市分子光电科学重点实验室天津化学化工协同创新中心天津 300072

投稿日期:2018-07-17 发布日期:2018-09-14
通讯作者: 张发光,E-mail:zhangfg1987@tju.edu.cn;马军安,E-mail:majun_an68@tju.edu.cn E-mail:zhangfg1987@tju.edu.cn;majun_an68@tju.edu.cn
基金资助:
项目受国家自然科学基金（Nos.21472137，21532008，21772142）和国家重点基础研究发展计划（973计划，No.2014CB745100）资助.

Facile Synthesis of Fluorinated Isoxazoles via Consecutive Double C—F Bond Cleavage

Ren Zhiwen, Ren Nan, Zhang Faguang, Ma Junan

Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin Collaborative Innovation Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072

Received:2018-07-17 Published:2018-09-14
Contact: 10.6023/A18070279 E-mail:zhangfg1987@tju.edu.cn;majun_an68@tju.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China (Nos. 21472137, 21532008, 21772142) and the National Basic Research Program of China (973 Program, No. 2014CB745100).

1. Facile Synthesis of Fluorinated Isoxazoles via Consecutive Double C—F Bond Cleavage.PDF(2012KB)

Abstract

Fluorinated heterocycles represent a ubiquitous structural motif found in numerous pharmaceuticals, agrochemicals, and functional materials. This is especially true for fluorine-containing five-membered heteroaromatic compounds that have been widely investigated in various fields for a long time. In this context, fluorinated isoxazoles have emerged as valuable scaffolds owing to their diverse biological properties. Among various approaches that have been developed for the synthesis and functionalization of isoxazoles, efficient and modular route to fluorine-substituted isoxazoles are still limited. Traditional methods include the condensation of 2-fluoro-1,3-dicarbonyl derivatives with hydroxylamine, Au-catalyzed fluorocyclization of 2-alkyne O-methyloximes, and direct fluorination of isoxazoles. However, the wide applicability of these approaches often suffers from low chemical yields, harsh reaction conditions, and limited substrate scope. Herein, we describe a one-pot protocol for the construction of fluorinated isoxazoles from CF₃-containing precursors with hydroxylammonium chloride. Typical features of this reaction include mild conditions, simple operations, and good functional group compatibility. This method provides facile access to a series of 3-F-5-aryl-isoxazoles in moderate to good yields from easily available α-CF₃-β-keto esters. Moreover, further synthetic transformations of obtained isoxazoles to important bio-active molecular derivatives have also been demonstrated. A representative procedure for this reaction is as following: α-CF₃-β-keto ester 1 (0.2 mmol, 1.0 equiv.), HONH₂·HCl (46 mg, 0.66 mmol), pyridine (71 μL, 0.88 mmol), and CH₃CN (3.0 mL) were added into an oven-dried vial equipped with a magnetic stir bar. The mixture was stirred at 75 ℃ for 12 h and monitored by thin-layer chromatography (TLC). After completion, 10 mL of water was added and the mixture was extracted with EtOAc for three times. The combined organic layers were washed with saturated NaCl and dried over Na₂SO₄. The mixture was evaporated under reduced pressure and residue was purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (V:V＝30:1) to afford the 3-F-5-aryl-isoxazole 2.

Key words: C—F bond cleavage, isoxazole, one-pot reaction, F-containing heterocycle, hydroxylammonium chloride

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Ren Zhiwen, Ren Nan, Zhang Faguang, Ma Junan. Facile Synthesis of Fluorinated Isoxazoles via Consecutive Double C—F Bond Cleavage[J]. Acta Chim. Sinica, 2018, 76(12): 940-944.

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碳-氟键断裂用于构建氟代异噁唑化合物

Facile Synthesis of Fluorinated Isoxazoles via Consecutive Double C—F Bond Cleavage

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