Fluorination

Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

Copper-Mediated Nucleophilic Fluorination for Preparing Alkyl Fluorides

  • Xiaoxi LinEmail author
  • Zhiqiang Weng
Living reference work entry
DOI: https://doi.org/10.1007/978-981-10-1855-8_27-1

Introduction

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 [6] or electrophilic [7] 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 [12], “spray-dried” KF [13], polymer-supported fluoride [14] and calcium fluoride supported on alkali metal fluoride [15], and tetraalkylammonium fluorides [16] 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 [16].

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

In 2013, Weng and co-workers reported the diimine-ligated copper(I) fluoride complex-mediated nucleophilic fluorination [20]. Complexes (Me2phen)2Cu(FHF) (1) and (t-Bu2Phen)Cu(F) (2) (Me2phen, neocuproine; t-Bu2Phen, 2,9-Di-tert-butyl-l,l0-phenanthroline) were prepared from the reaction of CuOt-Bu with the phenanthroline ligand and (HF)3⋅NEt3 in THF at rt (Scheme 1).
Scheme 1

Synthesis of copper(I) fluoride complexes 1 and 2

The ionic complex 1 contained one cationic tetrahedral copper center and one anionic [HF2], in which the fluorine atoms were not directly bonded with the Cu(I) center (Fig. 1). Complex 2 possessed a trigonal planar geometry and one fluoride coordinated to the copper atom.
Fig. 1

Crystal structures of 1 (top) and 2 (bottom)

A comparison of fluorinating reagent in fluorination of 3-phenylpropyl bromide was summarized in Table 1. When complex 1 was used as reagent for fluorination in CH3CN at 110 °C for 15 h, the yield of (3-fluoropropyl)benzene was excellent (entry 1), while complex 2, KF, and Bu4NF gave the desired products in low yields (entries 2–4). The (HF)3·NEt3 alone was found to be completely ineffective under this reaction condition (entry 5).
Table 1

Comparison of fluorinating reagent in fluorination of 3-phenylpropyl bromide

Open image in new window

Entry

[F] Source

19F Yield (%)

1

Complex 1

92

2

Complex 2

21

3

KF

6

4

Bu4NF

27

5

(HF)3·NEt3

0

By using (Me2phen)2Cu(FHF) (1) as reagent, a variety of alkyl fluorides were obtained through fluorination of alkyl bromides and benzyl bromides (Table 2). The reaction tolerated a number of functional groups, such as phenoxide, benzyl ether, thioether, amide, nitrile, hydroxyl, and ester groups. Complex substrate, such as vitamin E derivative, was also fluorinated by 1 in up to excellent yield.
Table 2

Fluorination of alkyl bromides by complex 1

Unactivated secondary alkyl bromides could also be employed in this reaction, and a wide range of substitution patterns were tolerated with good yields (Table 3).
Table 3

Fluorination of secondary alkyl bromides by complex 1

It was demonstrated that reaction of 6-bromohexan-1-ol with 1 in the presence of a radical scavenger, cyclohexa-1,4-diene (CHD), afforded 6-fluorohexan-1-ol in 65% yield (Scheme 2). Moreover, fluorination of 6-bromo-1-hexene with 1 furnished 6-fluoro-1-hexene as the only product in 99% yield. The lack of any influence on the reactivity with the addition of radical scavenger and the absence of cyclization product provided evidence against a radical intermediate.
Scheme 2

Radical trapping experiments

Further experiments on the stereochemistry of the reaction with an enantiopure secondary tosylate were also investigated. Reaction of (2S,4R)-1-tert-butyl 2-methyl 4-(tosyloxy)pyrrolidine-1,2-dicarboxylate, prepared from the corresponding chiral secondary alcohol, with 1 gave the desired product (2S,4S)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate in 85% yield with complete inversion of configuration (Scheme 3). Based on these observations, the authors suggested that the fluorination occurs through an SN2-type displacement of the bromide leaving group with the copper fluoride reagent.
Scheme 3

Inversion of configuration experiments

Copper-Catalyzed Fluorination of Alkyl Triflates

In 2014, Lalic and co-workers reported the synthesis of alkyl fluorides from alkyl triflates by a copper-catalyzed fluorination with KF as a fluoride source [21]. The authors performed the fluorination by using a copper catalyst [IPrCuOTf] at 45 °C in dioxane. A number of alkyl triflate derivatives were used as substrates, and the corresponding monofluorinated products were obtained with yields ranging from 81% to 98% (Table 4).
Table 4

Copper-catalyzed fluorination of alkyl triflates

Based on the experimental results, a copper-catalyzed fluorination of alkyl triflates was proposed (Scheme 4). Initially, reaction of [IPrCuOTf] with KF would form [IPrCuF]. Subsequently, fluorination of alkyl triflate by the resulting [IPrCuF] furnished the desired alkyl fluoride and regenerated [IPrCuOTf]. In the presence of KF, the copper species acted as phase-transfer catalyst which provided a soluble and nucleophilic source of fluoride for fluorination.
Scheme 4

Proposed mechanism for copper-catalyzed fluorination of alkyl triflates

Copper-Catalyzed Fluorination of α-Bromoamides

In 2016, Nishikata and co-workers developed a copper-catalyzed site-selective fluorination of α-bromoamides using CsF as an active fluorinating reagent [22]. The reaction was optimized with CuBr2 as the catalyst and N,N,N′,N′,N″-pentamethyldiethylenetriamine (PMDETA) as nitrogen ligand. It was demonstrated that the fluorination of tertiary alkyl substrates containing more than one reactive site produced the corresponding tertiary alkyl fluorides in good yields (Table 5). However, the use of substrates having iodide and tosyl group moieties forms the fluorobrominated products.
Table 5

Copper-catalyzed site-selective fluorination of α-bromoamides

The authors presented a plausible mechanism for the copper-catalyzed site-selective fluorination of α-bromoamides involving a radical reaction (Scheme 5). Initially, the copper salt abstracted a bromide atom from α-bromoamide, and the alkyl radical species A was therefore generated. The reaction of A with CuF2, which was generated from the reaction of CuXBr and CsF, led to the intermediate B. Finally, B underwent reductive elimination to give the desired alkyl fluorides.
Scheme 5

Proposed mechanism for 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.

Cross-References

References

  1. 1.
    Kirsch P. 2014. Modern fluoroorganic chemistry: synthesis, reactivity, applications. Weinheim: Wiley-VCHGoogle Scholar
  2. 2.
    Ojima I, Editor. 2009. Fluorine In Medicinal Chemistry And Chemical Biology. John Wiley & Sons Ltd. 624 pp.Google Scholar
  3. 3.
    O’Hagan D. 2008. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37:308CrossRefGoogle Scholar
  4. 4.
    Müller K, Faeh C, Diederich F. 2007. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 317:1881-6CrossRefGoogle Scholar
  5. 5.
    Purser S, Moore PR, Swallow S, Gouverneur V. 2008. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37:320–30CrossRefGoogle Scholar
  6. 6.
    Kim K-Y, Kim BC, Lee HB, Shin H. 2008. Nucleophilic Fluorination of Triflates by Tetrabutylammonium Bifluoride. J. Org. Chem. 73:8106–8CrossRefGoogle Scholar
  7. 7.
    Nyffeler PT, Durón SG, Burkart MD, Vincent SP, Wong C-H. 2005. Selectfluor: Mechanistic Insight and Applications. Angew. Chem. Int. Ed. 44:192–212CrossRefGoogle Scholar
  8. 8.
    Sibi MP, Landais Y. 2013. C(sp)3-F Bond Formation: A Free-Radical Approach. Angew. Chem. Int. Ed. 52:3570–2CrossRefGoogle Scholar
  9. 9.
    Bloom S, Pitts CR, Miller DC, Haselton N, Holl MG, et al. 2012. A Polycomponent Metal-Catalyzed Aliphatic, Allylic, and Benzylic Fluorination. Angew. Chem. Int. Ed. 51:10580–3CrossRefGoogle Scholar
  10. 10.
    Gerstenberger MRC, Haas A. 1981. Methods of Fluorination in Organic Chemistry. Angew. Chem. Int. Ed. 20:647–67CrossRefGoogle Scholar
  11. 11.
    Mascaretti OA. 1993. Aldrichim. Acta 26:47–58Google Scholar
  12. 12.
    Liotta CL, Harris HP. 1974. Chemistry of naked anions. I. Reactions of the 18-crown-6 complex of potassium fluoride with organic substrates in aprotic organic solvents. J. Am. Chem. Soc. 96:2250–2CrossRefGoogle Scholar
  13. 13.
    Ishikawa N, Kitazume T, Yamazaki T, Mochida Y, Tatsuno T. 1981. Enhanced Effect of Spray-Dried Potassium Fluoride on Fluorination. Chem. Lett. 10:761–4CrossRefGoogle Scholar
  14. 14.
    Colonna S, Re A, Gelbard G, Cesarotti E. 1979. Anionic activation in polymer-supported reactions. Part 2. Stereochemical studies on the introduction of fluorine at chiral centres and in biologically significant molecules. J. Chem. Soc. Perkin Trans. 1:2248–52CrossRefGoogle Scholar
  15. 15.
    Clark JH, Hyde AJ, Smith DK. 1986. Calcium fluoride-supported alkali metal fluorides. New reagents for nucleophilic fluorine transfer reactions. J. Chem. Soc. Chem. Commun. :791–3Google Scholar
  16. 16.
    Cox DP, Terpinski J, Lawrynowicz W. 1984. “Anhydrous” tetrabutylammonium fluoride: a mild but highly efficient source of nucleophilic fluoride ion. J. Org. Chem. 49:3216–9CrossRefGoogle Scholar
  17. 17.
    Hollingworth C, Gouverneur V. 2012. Transition metal catalysis and nucleophilic fluorination. Chem. Commun. 48:2929–42CrossRefGoogle Scholar
  18. 18.
    Wu J. 2014. Review of recent advances in nucleophilic C–F bond-forming reactions at sp3 centers. Tetrahedron Lett. 55:4289–94CrossRefGoogle Scholar
  19. 19.
    Lin X, Weng Z. 2015. Transition metal complex assisted Csp3-F bond formation. Dalton Trans. 44:2021–37CrossRefGoogle Scholar
  20. 20.
    Liu Y, Chen C, Li H, Huang K-W, Tan J, Weng Z. 2013. Efficient SN2 Fluorination of Primary and Secondary Alkyl Bromides by Copper(I) Fluoride Complexes. Organometallics 32:6587–92CrossRefGoogle Scholar
  21. 21.
    Dang H, Mailig M, Lalic G. 2014. Mild copper-catalyzed fluorination of alkyl triflates with potassium fluoride. Angew. Chem. Int. Ed. 53:6473–6CrossRefGoogle Scholar
  22. 22.
    Nishikata T, Ishida S, Fujimoto R. 2016. Site-Selective Tertiary Alkyl–Fluorine Bond Formation from α-Bromoamides Using a Copper/CsF Catalyst System. Angew. Chem. Int. Ed. 55:10008–12CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.State Key Laboratory of Photocatalysis on Energy and Environment, College of ChemistryFuzhou UniversityFuzhouChina