Fluorinated Cyclic Ethers

Fluorinated Cyclic Ethers

Introduction

Fluorinated cyclic ethers are liquids with low viscosity, non-flammability and high safety. They have good solubility and extremely high chemical stability and thermal stability. Various advantages make fluorinated cyclic ethers as fluorinated building blocks widely involved in organic synthesis reactions to obtain organic fluorides. For example, fluorinated cyclic ethers can undergo reduction reactions through reducing agents to generate corresponding fluorinated alcohols. Fluorinated cyclic ethers can also undergo ring opening reactions to generate bifunctionalized products. At the same time, the preparation of fluorinated cyclic ethers has also attracted widespread attention from researchers, and many simple and efficient methods have been developed.

Synthesis

There are many methods for synthesizing fluorinated cyclic ethers. The following mainly introduces the synthesis of fluorinated cyclic ethers through Mitsunobu cyclodehydration, Dyotropic rearrangement, and electrochemical fluorination.

• Mitsunobu cyclodehydration. Olah's group has achieved the synthesis of trifluoromethylated cyclic ethers through the Mitsunobu cyclodehydration of fluorinated diols with high efficacy. The methodology is found to be widely applicable to the synthesis of trifluoromethylated cyclic ethers with varying ring size (n = 3-7) from fluorinated diols of differing acidities and steric demands. A range of primary and secondary alcohols as well as benzylic and aliphatic alcohols can serve as electrophiles to afford the corresponding trifluoromethylated cyclic ethers in moderate to good yields^[1].

Fig.1 Synthesis of trifluoromethylated cyclic ethers through the Mitsunobu cyclodehydration

• Dyotropic rearrangement. Dyotropic rearrangement refers to the rearrangement process in which two σ-bonds migrate simultaneously. The use of dyotropic rearrangement combined with a set transformation process can effectively change the structure of the product and achieve the construction of complex polycyclic systems. Zhu's group developed a Pd(II)-catalyzed, Selectfluor-mediated Dyotropic rearrangement reaction of γ-hydroxyalkenes, and achieved the synthesis of a series of fluorinated cyclic ethers with high efficacy^[2].

Fig.2 Synthesis of fluorinated cyclic ethers through the Dyotropic rearrangement

• Electrochemical fluorination. Fuchigami's group first developed the direct electrochemical fluorination method of cyclic ethers using anodic fluorination, and synthesized fluorinated cyclic ethers. They successfully carried out regioselective anodic fluorination of tetrahydrofuran, 1,4-dioxane and 1,3-dioxolane using a small amount of Et₄NF·4HF at high current density, and obtained the corresponding fluorinated cyclic ethers in moderate yields^[3].

Fig.3 Synthesis of fluorinated cyclic ethers through electrochemical fluorination

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References

1. Olah, G. A.; et al. Cyclodehydration of fluorinated diols using the Mitsunobu reaction: highly efficient synthesis of trifluoromethylated cyclic ethers. Synthesis. 2010, 11: 1891-1898.
2. Zhu, J. P.; et al. Diverting the 5-exo-trig oxypalladation to formally 6-endo-trig fluorocycloetherification product through 1,2-O/Pd(IV) Dyotropic rearrangement. J. Am. Chem. Soc. 2023, 145(29): 15735-15741.
3. Fuchigami, T.; et al. Electroorganic synthesis under solvent-free conditions. Highly regioselective anodic monofluorination of cyclic ethers, lactones, and a cyclic carbonate. Tetrahedron lett. 2002, 43(8): 1503-1505.