Outer-Sphere Electrophilic Fluorination of Organometallic ComplexesJ. Am. Chem. Soc.


Lucy M. Milner, Natalie E. Pridmore, Adrian C. Whitwood, Jason M. Lynam, John M. Slattery
Colloid and Surface Chemistry / Biochemistry / Chemistry (all) / Catalysis


Outer-Sphere Electrophilic Fluorination of Organometallic


Lucy M. Milner, Natalie E. Pridmore, Adrian C. Whitwood, Jason M. Lynam,* and John M. Slattery*

Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom *S Supporting Information

ABSTRACT: Organofluorine chemistry plays a key role in materials science, pharmaceuticals, agrochemicals, and medical imaging. However, the formation of new carbon−fluorine bonds with controlled regiochemistry and functional group tolerance is synthetically challenging. The use of metal complexes to promote fluorination reactions is of great current interest, but even state-of-the-art approaches are limited in their substrate scope, often require activated substrates, or do not allow access to desirable functionality, such as alkenyl

C(sp2)−F or chiral C(sp3)−F centers. Here, we report the formation of new alkenyl and alkyl C−F bonds in the coordination sphere of ruthenium via an unprecedented outersphere electrophilic fluorination mechanism. The organometallic species involved are derived from nonactivated substrates (pyridine and terminal alkynes), and C−F bond formation occurs with full regio- and diastereoselectivity. The fluorinated ligands that are formed are retained at the metal, which allows subsequent metal-mediated reactivity. ■ INTRODUCTION

Fluorine-containing organic molecules are found in a wide range of applications from liquid crystals to blockbuster drugs such as fluoxetine and atorvastatin but are of particular interest in pharmaceuticals,1 agrochemicals, and medical imaging.2,3

The unique properties of C−F bonds, which can improve metabolic stability, bioavailability, and lipophilicity, mean that around 30% of all agrochemicals and 20% of all pharmaceuticals now contain fluorine.4 In addition, the use of 18F-labeled compounds in positron emission tomography (PET) is a highly active and important area of medical imaging research.3 As such, there is a synthetic requirement to develop simple and efficient (and in the case of 18F labeling, where the 18F half-life is short, rapid) methods for the introduction of fluorine into organic molecules.

Selective formation of new carbon−fluorine bonds, particularly in the presence of sensitive functional groups, is synthetically challenging.5 In addition to organocatalytic and photocatalytic C−F bond formation,5−11 enzymatic C−F bond formation,12 and the use of metal complexes to produce new fluorinated building blocks by selective C−F activation,13,14 there has been a major focus in recent years on the development of new transition-metal-mediated C−F bondforming reactions, which offer significant potential for regioselectivity and atom- and step-economy under mild conditions. There have recently been some significant advances in metal-catalyzed fluorination using fluoride salts as the fluorine source.5,15−24 However, fluoride salts are not always ideal for the introduction of fluorine into organic molecules, particularly those with sensitive functional groups, as the nucleophilicity and basicity of F− can result in unwanted side reactions.

To circumvent these problems, a number of metal-catalyzed electrophilic fluorination reactions have been developed, where

C−F bonds are formed from latent sources of “F+”.5,25−30

These reactions can typically be divided into two key mechanistic classes (e.g., Scheme 1). In the first, reaction of a redox-active metal complex with F+ leads to initial metal−

Received: June 24, 2015

Scheme 1. Examples of Some Transition-Metal-Mediated

Electrophilic Fluorination Mechanismsa aConditions: (a) Aryl C−H fluorination via reductive elimination from a Pd(IV) intermediate. D = donor group, e.g., pyridyl; L = ligand. (b)

Lewis-acid-mediated C−F bond formation via stabilized carbanion. M = e.g. Ti, Ru; L = ligand.5

Article pubs.acs.org/JACS © XXXX American Chemical Society A DOI: 10.1021/jacs.5b06547

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX fluoride bond formation, with concomitant oxidation of the metal. The high oxidation state of the metal (potentially assisted by ligand dissociation or by formation of multimetallic species)31−34 then facilitates C−F reductive elimination.

Alternatively, the redox-active metal may initiate one-electron transfer processes that promote subsequent radical reactions.35

In the second class, Lewis acidic metals are used to stabilize carbanionic nucleophiles, which react with F+ without any redox chemistry occurring at the metal. CuII, NiII, ZnII, TiIV, and even PdII and RuII have been used in this way to stabilize anions derived from β-ketocarbonyl compounds during C(sp3)−F bond-forming reactions.5

These are powerful strategies that are broadly applicable, but there are some limitations. For example, in Pd-catalyzed C−H fluorination reactions, directing groups (e.g., pyridyl, amino, Nperfluorotolylamide groups) are required to provide regioselectivity.36−39 In other cases, preactivation of the substrate (for example, by formation of an aryl stannane, silane, or boronic acid) is required to promote the reaction.28,34,38,40−42 In addition, recent developments have often focused on aryl C−F bond formation.43 Those metal-mediated electrophilic C(sp3)−

F forming reactions that have been developed typically require highly activated substrates (e.g., β-ketocarbonyl compounds such as β-diketones, β-keto esters, or N-Boc-protected amides),5 which reduces potential substrate scope. As such, the development of new organometallic reactivity that may lead to new regio- and stereoselective metal-mediated electrophilic fluorination reactions, without the need for directing and/or activating groups, is of great interest. Reactions that allow the construction of less common structural frameworks, for example, those containing alkenyl or alkyl C−F bonds (especially chiral C(sp3)−F centers) are particularly interesting.

This paper describes the formation of new alkenyl and alkyl