Inspired by the success of fluorinated corticosteroids in the 1950s and fluoroquinolones in the 1980s, fluorine-containing pharmaceuticals, which are also known as fluoro-pharmaceuticals, have been attracting attention for more than half of a century. Presently, about 20% of the commercial pharmaceuticals are fluoro-pharmaceuticals. In this mini-review, we analyze the prevalence of fluoro-pharmaceuticals in the market and categorize them into several groups based on the chemotype of the fluoro-functional groups, their therapeutic purpose, and the presence of heterocycles and/or chirality to highlight the structural motifs, patterns, and promising trends in fluorine-based drug design. Our database contains 340 fluoro-pharmaceuticals, from the first fluoro-pharmaceutical, Florinef, to the latest fluoro-pharmaceuticals registered in 2019 and drugs that have been withdrawn. The names and chemical structures of all the 340 fluorinated drugs discussed are provided in the Supporting Information.

Contribution of Organofluorine Compounds to Pharmaceuticals.

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)−F bonds with CO2

Si-B reagents, namely silylboronic esters and silylboranes, have become increasingly attractive as versatile reagents to introduce silicon and boron atoms into organic frameworks. Diverse transformations through transition-metal-catalysed or transition-metal-free Si-B bond activation have become available. This Review summarises the recent developments in the now broad field of Si-B chemistry and covers the literature from the last seven years as an update of our review on the same topic published in early 2013 (M. Oestreich, E. Hartmann and M. Mewald, Chem. Rev., 2013, 113, 402-441). It mainly focuses on new applications of Si-B reagents but new methods of their preparation and, where relevant, reaction mechanisms are also discussed.

/pdf/activation-of-the-si-b-interelement-bond-related-to-o8py3vdb7p.pdf

Activation of the Si–B interelement bond related to catalysis

Groundwater contamination by halogenated organic compounds, especially fluorinated ones, threatens freshwater sources globally. Sulfidized nanoscale zero-valent iron (SNZVI), which is demonstrably effective for dechlorination of groundwater contaminants, has not been well explored for defluorination. Here, we show that SNZVI nanoparticles synthesized via a modified post-sulfidation method provide rapid dechlorination (∼1100 μmol m-2 day-1) and relatively fast defluorination (∼6 μmol m-2 day-1) of a halogenated emerging contaminant (florfenicol) under ambient conditions, the fastest rates that have ever been reported for Fe0-based technologies. Batch reactivity experiments, material characterizations, and theoretical calculations indicate that coating S onto the metallic Fe surface provides a highly chemically reactive surface and changes the primary dechlorination pathway from atomic H for nanoscale zero-valent iron (NZVI) to electron transfer for SNZVI. S and Fe sites are responsible for the direct electron transfer and atomic H-mediated reaction, respectively, and β-elimination is the primary defluorination pathway. Notably, the Cl atoms in florfenicol make the surface more chemically reactive for defluorination, either by increasing florfenicol adsorption or by electronic effects. The defluorination rate by SNZVI is ∼132-222 times higher with chlorine attached compared to the absence of chlorine in the molecule. These mechanistic insights could lead to new SNZVI materials for in situ groundwater remediation of fluorinated contaminants.

Unveiling the Role of Sulfur in Rapid Defluorination of Florfenicol by Sulfidized Nanoscale Zero-Valent Iron in Water under Ambient Conditions.

Mild methods to cleave the carbon-oxygen (C−O) bond in alkyl ethers could simplify chemical syntheses through the elaboration of these robust, readily available precursors. Here we report that dibromoboranes react with alkyl ethers in the presence of a nickel catalyst and zinc reductant to insert boron into the C−O bond. Subsequent reactivity can effect oxygen-to-nitrogen substitution or one-carbon homologation of cyclic ethers and more broadly streamline preparation of bioactive compounds. Mechanistic studies reveal a cleavage-then-rebound pathway via zinc/nickel tandem catalysis.

Boron insertion into alkyl ether bonds via zinc/nickel tandem catalysis.

Direct activation of carbon-fluorine bonds (C-F) to introduce the silyl or boryl groups and generate valuable carbon-silicon (C-Si) or carbon-boron (C-B) bonds is important in the development of synthetically useful reactions, owing to the unique opportunities for further derivatization to achieve more complex molecules. Despite considerable progress of C-F bond activation to construct carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation, the defluorosilylation via C-F cleavage has been rarely demonstrated. Here, we report an ipso-silylation of aryl fluorides via cleavage of unactivated C-F bonds by a Ni catalyst under mild conditions and without the addition of any external ligand. Alkyl fluorides are also directly converted into the corresponding alkyl silanes under similar conditions, even in the absence of the Ni catalyst. Applications of this protocol in late-stage defluorosilylation of potentially bioactive pharmaceuticals and in further derivatizations are also carried out.

/pdf/defluorosilylation-of-fluoroarenes-and-fluoroalkanes-2syunvbdv8.pdf

Defluorosilylation of fluoroarenes and fluoroalkanes.

Although there are ways to synthesize ortho-pentafluoro-λ6-sulfanyl (SF5) pyridines, meta- and para-SF5-substituted pyridines are rare. We disclose herein a general route for their synthesis. The fundamental synthetic approach is the same as reported methods for ortho-SF5-substituted pyridines and SF5-substituted arenes, that is, oxidative chlorotetrafluorination of the corresponding disulfides to give pyridylsulfur chlorotetrafluorides (SF4Cl-pyridines), followed by chloride/fluoride exchange with fluorides. However, the trick in this case is the presence on the pyridine ring of at least one fluorine atom, which is essential for the successful transformation of the disulfides into m-and p-SF5-pyridines. After enabling the synthesis of an SF5-substituted pyridine, ortho-F groups can be efficiently substituted by C, N, S, and O nucleophiles through an SNAr pathway. This methodology provides access to a variety of previously unavailable SF5-substituted pyridine building blocks.

Importance of a Fluorine Substituent for the Preparation of meta- and para-Pentafluoro-λ6-sulfanyl-Substituted Pyridines

Silver-induced self-immolative Cl-F exchange fluorination of arylsulfur chlorotetrafluorides: synthesis of arylsulfur pentafluorides

Pd-NHC catalyzed Suzuki cross-coupling of benzyl ammonium salts

A nickel-catalyzed cross-coupling reaction of aryl methyl sulfides with aryl bromides has been developed to access biaryls in yields of up to 86%. The reactions proceeded well using Ni(COD)2 as catalyst with the ligand BINAP (2,2'-bis(diphenylphosphanyl)-1,1'-binaphthalene) in the presence of magnesium. The method has a broad scope of substrates and is scalable. The wide availability of commercially available aryl bromides and the absence of preparation and preparation of organometallic reagents make the reaction of high application value. 

Nickel-Catalyzed Cross-Coupling Reaction of Aryl Methyl Sulfides with Aryl Bromides.

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