Copper-Mediated Nucleophilic Fluorination for Preparing Alkyl Fluorides
The introduction of fluorine into an organic molecule is a reaction of great interest in both industrial and academic researches [1, 2, 3, 4, 5]. Despite the significant achievements made in the synthesis of aryl fluorides, there are only a limited number of examples of alkyl fluoride synthesis. These include nucleophilic  or electrophilic  substitution reactions or radical fluorination [8, 9]. Among them, the nucleophilic substitution of alkyl sulfonates and halides with fluoride ions appeared as a powerful strategy to generate alkyl fluorides [10, 11], but remains challenging. The difficulty arises from the weak nucleophilicity in protic solvent or the low solubility in aprotic solvents of fluoride ions (such as KF or CsF). To overcome these difficulties, a variety of metal fluorides such as KF/18-crown-6 , “spray-dried” KF , polymer-supported fluoride  and calcium fluoride supported on alkali metal fluoride , and tetraalkylammonium fluorides  were employed as reagents which are not solvated tightly by bulky cations or solvent molecules that facilitate efficient conversion. Despite these advances for the synthesis of simple alkyl fluorides, significant limitations remain with respect to elimination of alkyl halides, the formation of alkyl sulfonates to alkenes, and the hydroxylation to alcohols, which result from the use of basic and nucleophilic “naked” fluoride .
Therefore, there is a continued strong demand for efficient and selective syntheses of alkyl fluorides. In recent years, transition-metal-mediated nucleophilic fluorination has been recognized as an increasingly viable tool for the preparation of functionalized alkyl fluorides under mild reaction conditions [17, 18, 19]. Among them, methods that use copper-mediated nucleophilic fluorination have drawn much attention. The low cost, low toxicity, and easy availability of copper salts have made them an attractive target as catalysts for performing fluorination reactions.
Copper(I) Fluoride Complex-Mediated Nucleophilic Fluorination
Comparison of fluorinating reagent in fluorination of 3-phenylpropyl bromide
19F Yield (%)
Fluorination of alkyl bromides by complex 1
Fluorination of secondary alkyl bromides by complex 1
Copper-Catalyzed Fluorination of Alkyl Triflates
Copper-catalyzed fluorination of alkyl triflates
Copper-Catalyzed Fluorination of α-Bromoamides
Copper-catalyzed site-selective fluorination of α-bromoamides
Conclusion and Future Directions
In summary, the section described above illustrated the copper-mediated nucleophilic fluorination for synthesizing alkyl fluorides. Different types of alkyl bromides, α-bromoamides, and alkyl triflates have been successfully applied to such transformations, providing a facile and economic access to a variety of alkyl fluoride compounds. Although impressive results have been achieved in this field, more research advances regarding new catalyst development, the use of inexpensive metal fluoride as fluorine source, and detailed mechanistic investigations are still very important in order to address the remaining challenges. The expected progress will enable copper-mediated nucleophilic fluorination to be a more general and viable methodology for preparing alkyl fluorides in the near future.
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