Fluorinated Ethers

Fluorinated Ethers

Introduction

Fluorinated ethers have good solubility and chemical stability, and can efficiently synthesize organic fluorides, which has aroused widespread interest among researchers. Currently, more and more synthetic methods have been developed for the synthesis of fluorinated. Research on the application of fluorinated ethers is also becoming increasingly mature. As fluorinated building blocks, fluorinated ethers can synthesize acyl fluoride compounds through oxidative cleavage reactions. They can also generate corresponding fluorinated ester compounds through oxidation reactions initiated by hydroxyl groups.

Synthesis

The following are some synthesis methods of monofluorinated ethers, difluorinated ethers and trifluorinated ethers.

• Synthesis of monofluorinated ethers. Hu's group used NaH as a base, N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP) as a solvent, and achieved the synthesis of monofluorinated ethers with high yield through the reaction of aryl alcohols and chlorofluoromethane at 80 °C^[1].

Fig.1 Synthesis of monofluorinated ethers using chlorofluoromethane

• Synthesis of difluorinated ethers. In 2006, the Hu's group developed a synthesis method for difluorinated ethers. They found that 2-chloro-2,2-difluoroacetophenone is a good difluorocarbene reagent that can easily react with a variety of structurally diverse phenol derivatives in the presence of potassium hydroxide or potassium carbonate to prepare aryl difluoromethyl ethers in good yields^[2]. In 2007, the research group switched to chlorodifluoromethyl phenyl sulfone as the difluorocarbene reagent, reacted with aryl alcohols under the condition of KOH as a base, and successfully achieved the synthesis of difluoroethers^[3].

Fig.2 Synthesis of difluorinated ethers using 2-chloro-2,2-difluoroacetophenone

Fig.3 Synthesis of difluorinated ethers using chlorodifluoromethyl phenyl sulfone

• Synthesis of trifluorinated ethers. Togni's group developed a straightforward method for the preparation of trifluorinated ethers. Under the activation of zinc bis(triflimide), they efficiently synthesized trifluorinated ethers through the reactions of hypervalent iodine trifluoromethylation reagents and aliphatic alcohols. Especially in the reactions with primary alcohols, trifluorinated ethers can be obtained in yields up to 99% under very mild and easy-to-operate reaction conditions^[4].

Fig.4 Synthesis of trifluorinated ethers using hypervalent iodine trifluoromethylation reagents

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References

1. Hu, J. B.; et al. Electrophilic monofluoromethylation of O-, S-, and N-nucleophiles with chlorofluoromethane. Tetrahedron. 2007, 63(43): 10569-10575.
2. Hu, J. B.; et al. 2-Chloro-2,2-difluoroacetophenone: A non-ODS-based difluorocarbene precursor and its use in the difluoromethylation of phenol derivatives. J. Org. Chem. 2006, 71(26): 9845-9848.
3. Hu, J. B.; et al. Chlorodifluoromethyl phenyl sulfone: a novel non-ozone-depleting substance-based difluorocarbene reagent for O- and N-difluoromethylations. Chem. Commun. 2007, 48: 5149-5151.
4. Togni, A.; et al. Zinc-mediated formation of trifluoromethyl ethers from alcohols and hypervalent iodine trifluoromethylation reagents. Angew. Chem. Int. Ed. 2009, 48: 4332-4336.