Electrophilic fluorination using PhIO/HF·THF reagent

The unnatural isotope fluorine-18 ((18)F) is used as a positron emitter in molecular imaging. Currently, many potentially useful (18)F-labeled probe molecules are inaccessible for imaging because no fluorination chemistry is available to make them. The 110-minute half-life of (18)F requires rapid syntheses for which [(18)F]fluoride is the preferred source of fluorine because of its practical access and suitable isotope enrichment. However, conventional [(18)F]fluoride chemistry has been limited to nucleophilic fluorination reactions. We report the development of a palladium-based electrophilic fluorination reagent derived from fluoride and its application to the synthesis of aromatic (18)F-labeled molecules via late-stage fluorination. Late-stage fluorination enables the synthesis of conventionally unavailable positron emission tomography (PET) tracers for anticipated applications in pharmaceutical development as well as preclinical and clinical PET imaging.

Preparation of soluble functional polymers by modification of nanosized polyacetylene

It provides a mild, convenient and regioselective approach to 3,3‐difluoroindolin‐2‐ols.

Electrophilic fluorination of bis(phenylacetylene)-platinum(II) complexes containing bipy or dppe as ancillary ligands at room temperature leads to Csp-Csp reductive elimination. In this regard, Selectfluor (N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate)) was used in the reactions at room temperature, under air and without using dry solvents. Through experimental and computational studies, the influence of ancillary ligands on the Csp-Csp reductive elimination reaction was investigated. Based on density functional theory (DFT) calculations, the dissociation of acetonitrile (ACN) as a coordinated solvent is the rate-determining step. Therefore, in addition to the influence of the electronic properties of the ancillary ligands on the Csp-Csp coupling reaction, the energy required for the dissociation of acetonitrile from the Pt(IV) complexes significantly impacts the rate of the appearance of the experimentally observed products. The effect of various functional groups on the energy needed for the dissociation of acetonitrile and Csp-Csp reductive elimination was theoretically estimated. Our calculations show that the NMe2 group has a greater impact on the reduction of the energy requirement for the two steps necessary for observation of the Csp-Csp coupling reaction product, particularly in the dppe Pt(IV) complex.

Easy Csp2–Csp2 reductive elimination from organoplatinum complexes by electrophilic fluorinating reagents

We report the first successful example of a highly enantioselective fluorolactonization with an electrophilic fluorinating reagent, Selectfluor(®), in the presence of a novel bifunctional organocatalyst. The catalyst design includes a carboxylate anion functioning as a phase-transfer agent and a benzyl alcohol unit to capture the substrate through hydrogen bonding. Fluorinated isobenzofuranones were obtained in good yields with up to 94% ee (97:3 er). On the basis of mechanistic studies, we propose a unique reaction mechanism with potential for further applications.

7 - Syntheses of Thiophenes with Group VII Substituents

Direct electrophilic fluorination of naproxen with NF-reagents

Sulfur appears in group VI of the periodic table, just below oxygen. Similar to other second row elements, sulfur is more versatile as a reaction center than first‐row counterparts. Both oxygen and sulfur tend to alter the reactivity of an adjacent carbon atom, but sulfur itself is more reactive than oxygen toward nucleophilic, electrophilic, and radical reagents. Therefore, chemical reactions that involve organic sulfur compounds tend to occur directly at sulfur. Organic sulfur compounds are economically important in every type of industry, including manufacturing, agriculture, the environment, and pharmaceuticals. The chemicals included in this chapter were selected on the basis of their common industrial uses and commercial importance, although some compounds have multiple types of use. The chemicals have been grouped according to chemical classes. The major focus is on mercaptans (also called thiols or sulfhydryls), and sulfides, chemicals with both sulfur and oxygen atoms (sulfoxides, sulfones, sulfonates, and sulfonyl chlorides), and a miscellaneous group (thiophenes and benzothiazoles). There is a paucity of toxicological data in the open literature for many of these compounds, and a wealth of scientific information that is contained in unpublished industrial documents. Many of these unpublished reports have been referred to in previous editions of Patty's. So that the important information contained in these reports is not lost to the scientific and industrial communities, they have been maintained in the current chapter and referred to in the text, rather than in the list of references.The basic chemical and physical properties of industrially important organic sulfur compounds are summarized. The distinctive odor associated with sulfur is particularly important for many of these compounds. Often thought of as pleasant at low concentrations, higher subtoxic concentrations are often extremely offensive. The thiol containing amino acid cysteine is important in maintaining proper protein structure via disulfide bonds between two cysteine residues. In addition, cysteine forms the reactive moiety of the intracellular antioxidant glutathione that helps maintain the highly reduced state of cells and protects cells from potentially toxic electrophiles and radicals that may originate from metabolism or from foreign sources (xenobiotics).Mercaptans, it has long been known, react with several heavy metals, including mercury. The formation of insoluble mercury complexes is characteristic of this class of compounds and is the source of the namemercaptan(mercurium captans, capturing mercury). Although not in current use, the dithiol 2,3‐dimercapto‐1‐propanol (BAL, dimercaprol, British anti‐Lewisite CAS Number [59-52-9]) was developed to protect against arsenical war gases (including Lewisite) and has been used as an antidote for exposure to arsenic, mercury, and other heavy metals. Interestingly, mercaptans such as the intracellular antioxidant glutathione activate the environmentally and occupationally important heavy metal Cr6+and also the economically important solvent methylene chloride to genotoxic products.

Electrophilic N-F fluorination agents underpin the introduction of fluorine in aliphatic systems across drug and academic research. The choice of N-F reagent is currently determined through empirical experimentation in the absence of quantitative values for electrophilicities. Here we report an experimentally-determined kinetic reactivity scale for ten N-F fluorinating reagents, including Selectfluor™, NFSI, Synfluor™ and several N-fluoropyridinium salts, in CH3CN. The reactivity scale, which covers eight orders of magnitude, employs para-substituted 1,3-diaryl-1,3-dicarbonyl derivatives to measure relative and absolute rate constants. The para-substituted 1,3-diaryl-1,3-dicarbonyl scaffold delivers a convenient, sensitive spectrophotometric reporter of reactivity that also led to the discovery of a unique form of tautomeric polymorphism.

From 2000, our two research groups independently and simultaneously designed and developed a novel family of electrophilic fluorinating reagents based on the use of Cinchona alkaloids. The chiral N-fluoro ammonium salts demonstrated the highest efficiency compared to prior art in enantioselective electrophilic fluorination for a wide range of substrates. In this account, we tell our respective stories, how the same idea germinated in our laboratories, the characterization of the chiral reagents, the use in stoichiometric quantity then the development of a catalytic version, the application to the synthesis of chiral fluorinated molecules of pharmaceutical interest, and finally the exploitation of our reagents by other teams and for other applications.

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Hydrogenation and dehydrogenation reactions play a key role in synthetic organic chemistry. The discoveries that selenium and sulfur substituents could be easily introduced α to a variety of acidifying functional groups, and that these derivatives could be smoothly converted to olefins by selenoxide or sulfoxidesynelimination under mild conditions greatly broadened the range of α,β‐unsaturated carbonyl compounds that could be prepared from their saturated analogs. This chapter covers the preparation from enols or enolates of α‐RSe substituted carbonyl compounds and nitriles and their conversion to olefins by thermolysis of the derived selenoxides. Other procedures for preparing these compounds are discussed in a limited way, and they are included in the tables, but the two‐step dehydrogenation is by far the most frequently used.The rapid acceptance of the selenoxide elimination as a synthetic procedure was the result of two factors: the ease with which many organoselenium compounds could be prepared using readily available, powerful electrophilic and nucleophilic selenium reagents, and the mild conditions (−50° to 40°) under which selenoxides fragment to olefins. Recognized selenoxide eliminations to form olefins were reported in 1967 and 1970, well after the related sulfoxide eliminations had been studied extensively. The application of the sulfoxide and selenoxide eliminations were reported almost simultaneously by several groups in 1973. These reactions have been the subject of several reviews. The principal procedures and reagents for the preparation of the requisite selenium compounds were also identified at that point.Preparations discussed in this chapter areMethod A: Reaction of enolates, enols, enol ethers, and enamines with benzeneselenenyl chloride or bromide, or diphenyl diselenide.Method B: Reaction of enols with seleninylating agents [C6H5Se(O)Cl, (C6H5SeO)2O].Method C: Nucleophilic substitution of α‐halo carbonyl compounds with metal selenolates.Method D: Alkylation of α‐phenylseleno carbonyl compounds and acylation of α‐lithio selenides or selenoxides.

Regioselectivity in organic chemistry is a crucial concept for the synthesis of organic heterocyclic compounds. This concept determines the direction of a reaction towards the formation of a specific product from a possible set of structures. In this context, the regioselectivity of electrophilic heterocyclization depends on the nature of the electrophilic reagent, the structure of the substrate, and the polarity of the solvent. Special attention is given to substrates with two unsaturated fragments. Literature data have shown that the reaction depends on the type of electrophilic reagent; for example, iodination leads to the annulation of a six-membered dihydrothiazine, while bromination results in the annulation of a thiazolinone ring. In this study, the interaction of tellurium tetrahalides with 3-allyl-2-(2-methylthio)quinazolin-4(3H)-one, which has various alkene substituents, was investigated. Prior to the study, the initial metallothioether was synthesized for the first time. In the reaction of tellurium tetrahalides with 3-allyl-2-(2-methylthio)quinazolin-4(3H)-one, molecular adducts of thioether-tellurium tetrahalide with a 1:1 ratio were obtained. The experimental results demonstrate that an excess of the halogenating reagent and changes in reaction conditions do not affect the reaction product. Thus, this work highlights the importance of studying the regioselectivity of electrophilic intramolecular heterocyclization reactions and the potential use of tellurium tetrahalides for obtaining molecular complexes.

Reactions of steroid 3,5-dienol acetates with electrophilic fluorinating reagents of the N-fluoro quaternary salt class were examined for the purpose of selecting a reagent for use in commercial scale synthesis. The neutral N-fluorosulfonimides gave high β-fluoro selectivity and moderate yields. In the N-fluoropyridinium class, high temperatures or long reaction times required for complete reaction led to low yields. The change in selectivity of fluorination reported at different temperatuers with N-fluoropyridinium pyridine heptafluorodiborate (NFPy) was explained by selective dehydrohalogenation of the β-fluoro isomer to the 3-keto 4,6-diene product. With 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) the elimination was slowed. Additionally, Selectfluor was observed to react with the unactivated double bond in Δ9(11) steroids to give 11α-fluoro-9β-methyl phenols. Selectfluor was chosen as the optimum reagent, and a process was developed using that reagent. Epimerizations of 6α/β-fluoro steroid mixtures to pure 6α-fluoro steroids were also examined, and conditions for preparation of pure 6α-fluoro steroids were developed.