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(sp(2))-F or chiral C(sp(3))-F centers. Here, we report the formation of new alkenyl and alkyl C-F bonds in the coordination sphere of ruthenium via an unprecedented outer-sphere 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.
Highlights
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 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 methods for the introduction of fluorine into organic molecules
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
This paper describes the formation of new alkenyl and alkyl C−F bonds in the coordination sphere of ruthenium via an unprecedented outer-sphere electrophilic fluorination (OSEF)
Summary
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, agrochemicals, and medical imaging. 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 contain fluorine. In addition, the use of 18F-labeled compounds in positron emission tomography (PET) is a highly active and important area of medical imaging research. 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, in the presence of sensitive functional groups, is synthetically challenging.. In addition to organocatalytic and photocatalytic C−F bond formation,− enzymatic C−F bond formation, and the use of metal complexes to produce new fluorinated building blocks by selective C−F activation, 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.− fluoride salts are not always ideal for the introduction of fluorine into organic molecules, those with sensitive functional groups, as the nucleophilicity and basicity of F− can result in unwanted side reactions
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