Fluorination

Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

Copper-Mediated Fluorination for Preparing Aryl Fluorides

  • Wenjun Miao
  • Jinbo HuEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-981-10-1855-8_63-1

Introduction

Functionalized aryl fluorides are important motifs because of their widespread application in pharmaceuticals, agrochemicals, materials, and medical diagnosis (positron emission tomography, PET) [1]. As a result, the development of efficient and practical procedures for the construction of aryl C–F bonds has received much attention. Recently, a series of transition metals have been explored for preparing aryl fluorides [2, 3]. Inexpensive metals such as copper have emerged as alternative mediators of C−F bond formation [4]. This section mainly focused on recent advances in copper-mediated/-catalyzed fluorination reactions to construct aryl fluorides. Among these reactions, the fluoride sources could be divided into nucleophilic fluorinating reagents and electrophilic fluorinating reagents (Scheme 1).
Scheme 1

Copper-mediated arene fluorination

Nucleophilic Fluorinations

In 2012, Hartwig and co-workers reported a copper-mediated fluorination of aryl iodides using AgF as a fluorine source (Scheme 2) [5]. The author emphasized that an excess amount of copper reagents relative to AgF, was essential for this process due to the side effect of AgF which acted as an oxidant to consume the reactive Cu(I) reagent. Mechanistic studies excluded an aryl radical intermediate pathway including a single-electron-transfer (SET) reaction and proposed an Ar-Cu(III)–F intermediate pathway for this transformation (Scheme 3).
Scheme 2

Copper-mediated fluorination of aryl iodides

Scheme 3

Proposed mechanism for the fluorination of aryl iodides with AgF

In 2014, Liu and co-workers developed a copper-catalyzed fluorination of aryl bromides using AgF as the fluorine source (Scheme 4) [6]. In this transformation, a pyridyl directing group was essential for the successful catalytic fluorination. Further mechanistic studies implicated a Cu(I/III) catalytic cycle in this Cu(I)-catalyzed fluorination and the final aryl C–F bond formation possibly proceeded through an irreversible reductive elimination of the ArCu(III)–F species.
Scheme 4

Copper-catalyzed fluorination of (2-pyridyl) aryl bromides

Diaryliodonium salts [7] have been widely used as electrophilic arylating reagents in both metal-free [8] and transition-metal-catalyzed reactions [9]. Sanford and co-workers disclosed a copper-catalyzed fluorination of unsymmetrical diaryliodonium salts with potassium fluoride (Scheme 5) [10]. The desired (mesityl)(aryl)iodonium salts were readily synthetically accessible from commercially available MesI(OAc)2 and aryl boronic acids, and the less-sterically hindered aryl moiety on iodine was fluorinated with high selectivity. Preliminary DFT calculations supported the involvement of a CuI/CuIII catalytic cycle in this reaction.
Scheme 5

Copper-catalyzed fluorination of diaryliodonium salts with KF

Electrophilic Fluorinations

As alternative aryl sources, readily available arylboron reagents have been successfully applied for copper-mediated fluorination reactions. Hartwig and co-workers reported a straightforward copper-mediated fluorination of arylboronate esters using electrophilic fluorinating reagents as the fluorine source (Scheme 6) [11]. AgF was beneficial to promote the transmetallation step without affecting the decomposition of the F+ source. Arylboronate esters provided better yields than other boronic acid derivatives. Tandem reactions were also developed for the fluorination of arenes and aryl bromides through arylboronate ester intermediates. Mechanistic studies suggested that this fluorination reaction occurred through facile oxidation of Cu(I) to Cu(III), followed by rate-limiting transmetalation of a bound arylboronate to Cu(III). Fast C−F reductive elimination was proposed to occur from an aryl−copper(III)−fluoride complex. Cu(III) intermediates were generated independently and identified by NMR spectroscopy and ESI-MS.
Scheme 6

Copper-mediated fluorination of arylboronate esters

Furthermore, aryl stannanes and aryl borates could also been converted to the corresponding aryl fluorides by employing Cu(I) in combination with an electrophilic fluoride source (Scheme 7) [12]. The electrophilic fluorinating reagent performed both as an oxidant for Cu(I) and a fluorine source. The reaction was proposed to proceed via an arylcopper(III) fluoride intermediate.
Scheme 7

Copper-mediated fluorination of aryl metal reagents with electrophilic fluorinating reagents

Oxidative Fluorinations

Employing nucleophilic fluorinating reagents instead of electrophilic fluorinating reagents in combination with an external oxidant is an attractive approach to obtain aryl fluorides. Several groups have reported copper-mediated oxidative fluorination transformations. Sanford and co-workers reported a copper-mediated fluorination of aryltrifluoroborates with KF (Scheme 8a) [13]. The copper(II) salt played a dual role in this transformation; it served as a mediator for the aryl−F coupling and an oxidant to generate the key reactive Cu(III) intermediate. In 2016, Murphy and co-workers developed an oxidative fluorination of aryl stannanes with copper(II) triflate and a nucleophilic fluoride (Scheme 8b) [14].
Scheme 8

Copper-mediated oxidative fluorination of aryl metal reagents with nucleophilic fluorinating reagents

Daugulis and co-workers described a copper-catalyzed aryl C–H bond fluorination reaction with AgF using N-(8-quinolinyl)amido group as the directing group (Scheme 9) [15]. Selective mono- or difluorination could be achieved by simply changing reaction conditions.
Scheme 9

Copper-catalyzed directing fluorination of aryl C–H bonds

18F-Fluorinations

Positron emission tomography (PET) is a quantitative molecular imaging technology used routinely in the clinic to diagnose cancers, neurological disorders, and cardiovascular diseases and has become a useful tool to facilitate drug discovery and development [1e, 16]. The most common PET radionuclide is 18F, due to its convenient half-life (110 min), excellent imaging properties, and minimal perturbation of radioligand binding [17]. Based on the previously reported copper-mediated fluorination of aromatics, the Sanford group, the Scott group, and the Gouverneur group disclosed the copper-mediated radiofluorination of (mesityl)(aryl)iodonium salts, arylboronic acids, and arylboronate esters with K18F (Schemes 10, 11, and 12) [18].
Scheme 10

Copper-catalyzed [18F]fluorination of (mesityl)(aryl)iodonium salts

Scheme 11

Synthesis of [18F]arenes via the copper-mediated [ 18F]fluorination of boronic acids

Scheme 12

Cu(II)-mediated 18F-fluorination of (hetero)aryl pinacol-derived boronic esters with [18F]fluoride

Conclusion and Future Directions

The copper-mediated fluorination of aryl reagents has recently received much attention. Although some progress has been achieved, preliminary mechanistic interpretations have been provided to address the formation of aryl C–F bonds. However, for some reactions, the detailed mechanism remains unclear. In the future, a catalytic version of copper-catalyzed fluorination for preparing aryl fluorides would be anticipated based on further detailed analysis of reaction mechanisms, elaborate design of new ligands and copper catalysts in order to make this toolbox more applicable. Furthermore, the development of a novel catalytic system is also highly desirable, which would substantially improve the reaction efficiency and expand the substrate scope to construct aryl fluorides.

Cross-References

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular SynthesisShanghai Institute of Organic Chemistry, Chinese Academy of SciencesShanghaiChina