Recent Advances in the Synthesis of Difluoromethylated Arenes (original) (raw)
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This report is concerned with an efficient, Cu I -mediated method for the radiosynthesis of [ 18 F]trifluoromethyl arenes, abundant motifs in small molecule drug candidates and potential radiotracers for positron emission tomography. Three 18 F-labelled radiotracer candidates were synthesised from [ 18 F]fluoride ions as proof of principle. The new protocol is widely applicable for the synthesis of novel radiotracers in high radiochemical yields.
Direct C-H trifluoromethylthiolation of (hetero)arenes: A review
Journal of Fluorine Chemistry, 2019
This review highlights up-to-date developments and achievements in direct trifluoromethylthiolation of (hetero)aryl C-H bonds with particular emphasis on the mechanistic aspects of the reactions. The review is divided into two major sections. The first will discuss direct C-H trifluoromethylthiolation of simple arenes while the second focuses exclusively on trifluoromethylthiolation of heteroarene C-H bonds. This review will highlight the developments in direct trifluoromethylthiolation of (hetero)aryl C-H bonds during the past three years but mention to earlier work when it is necessary.
Iron-Catalyzed Halogen Exchange of Trifluoromethyl Arenes
2021
We report the facile production of ArCF2X and ArCX3 from ArCF3 using catalytic iron(III)halides, which constitutes the first iron-catalyzed halogen exchange for non-aromatic CF bonds. Theoretical calculations suggest direct activation of C–F bonds by iron coordination. ArCX3 and ArCF2X products of the reaction are synthetically valuable due to their diversification potential. In particular, bromo-, chloro-, and iododifluoromethyl arenes (ArCF2Br, ArCF2Cl, ArCF2I, respectively) provide access to a myriad of difluoromethyl arene derivatives (ArCF2R). To optimize for mono-halogen exchange, a statistical method called Design of Experiments was used. Optimized parameters were successfully applied to electron rich and electron deficient aromatic substrates, and to the late stage diversification of flufenoxuron, a commercial insecticide.
Improved Arene Fluorination Methodology for I(III) Salts
Organic Letters, 2010
The use of low polarity aromatic solvents (benzene or toluene) and/or the removal of inorganic salts results in dramatically improved yields of fluorinated arenes from diaryliodonium salts. This methodology is shown to "scale down" to the conditions used typically for radiotracer synthesis. The inability to functionalize electron-rich arenes with fluoride ion sources narrows the scope and increases the expense of practical 18 F-labeled imaging agents for positron emission tomography.1 Two fluoride-based approaches to fluoroarenes have been heavily investigated of late: 1) transition-metal-catalyzed fluorination,2-6 and 2) elimination of aryl fluorides from diaryliodonium salts.7 , 8 Stang and coworkers have stressed the similarities of iodonium ion and late transition metal ion chemistries,9 thus we thought that the use of low polarity, non-coordinating media, which often suppresses ionic (disproportionation, ligand exchange, electron transfer) side reactions of transition metal complexes,10 might be a strategy to improve diaryliodonium fluoride chemistry. Here we show that the use of benzene solvent and/or removal of "inert" electrolyte is associated with substantially improved yields of fluorinated aromatic compounds from the decomposition of diaryliodonium fluorides. These results have significant ramifications for the preparation of fluorinated radiotracers. Previously we reported the preparation of phenyliodonium difluoride from anhydrous tetrabutylammonium fluoride11 (TBAF) and phenyliodonium diacetate.12 In the course of this work we noted that excess fluoride ion led to the eventual reduction of PhIF 2 to PhI and bifluoride ion by an unknown mechanism. This reaction was largely suppressed in nonpolar solvents such as benzene. Similarly, if bis(4-methoxyphenyl)iodonium hexafluorophosphate 1 is treated with excess anhydrous TBAF or anhydrous tetramethylammonion fluoride13 (TMAF) in acetonitrile at ambient temperature, 4-iodoanisole is formed without the generation of any fluorinated arenes. If substoichiometric amounts of fluoride are present the decomposition reaction is largely suppressed at room temperature, but upon heating of the
Journal of the American Chemical Society, 2017
Monodefluoroborylation of polyfluoroalkenes has been achieved in a regioselective manner under mild conditions via copper catalysis. The method has showed an extremely broad scope of substrates, including (difluorovinyl)arenes, tetrafluoroethylene (TFE), (trifluorovinyl)arenes, and trifluoromethylated monofluoroalkenes. The choice of boron source was important for the efficient transformation of (difluorovinyl)arenes; (Bpin) 2 was suitable for substrates with an electron-deficient aryl group and (Bnep) 2 for those with an electron-rich aryl group. Derivatization of the (fluoroalkenyl)boronic acid esters to the corresponding potassium trifluoroborate salts has rendered the products easily isolable, which greatly improved the synthetic practicality of the monodefluoroborylation reaction. Stoichiometric experiments indicate that the fate of the regioselectivity depends on the mode of β-fluorine elimination, which depends on the substrate. Further transformation of the boryl group has allowed facile preparation of fluoroalkene derivatives as exemplified by the synthesis of a fluoroalkene mimic of atorvastatin, which potently inhibited the enzyme activity of HMG-CoA reductase.
Perfluoroalkylation reactions of (hetero)arenes
RSC Advances, 2015
Methods for the perfluoroalkylation of (hetero)arenes can be classified as thermal and photochemical, which in turn can be conducted in the presence or absence of metals.
Copper-Mediated Halotrifluoromethylation of Unactivated Alkenes
Advanced Synthesis & Catalysis, 2015
Ac opper-mediated halotrifluoromethylation of unactivated alkenesusing Umemotos reagent and copper(I) halide (CuX, X = Cl, Br, and I) was developed. TheC uX species (CuI, CuBr, and CuCl) were chosen as the source for bothc opper andh alides because of theirb enchtop stability,c ommercial availability,a nd relatively low cost. Simple exchange of the copper salt provided the desired simultaneous and regioselective incorporation of the halogen atom and of the CF 3 group to various alkenes. This protocol offers an efficienta nd practical route to various b-halotrifluoromethylateda lkanes.F urther modifications of the C À Br bond to C À B, C À Na nd C À Sb onds were performed. These derivatizations show the feasibility of late-stage modifications.
Copper-based fluorinated reagents for the synthesis of CF2R-containing molecules (R ≠ F)
Beilstein Journal of Organic Chemistry, 2020
Over the years, the development of new methodologies for the introduction of various fluorinated motifs has gained a significant interest due to the importance of fluorine-containing molecules in the pharmaceutical and agrochemical industries. In a world eager to eco-friendlier tools, the need for innovative methods has been growing. To address these two challenges, copper-based reagents were developed to introduce CF2H, CF2RF, CF2CH3, CF2PO(OEt)2 and CF2SO2Ph motifs on a broad range of substrates. Copper-based fluorinated reagents have the advantage of being inexpensive and generally in situ generated or prepared in a few steps, which make them convenient to use. In this review, an overview of the recent advances made for the synthesis of fluorinated molecules using copper-based fluorinated reagents will be given.