Direct Catalytic Trifluoromethylthiolation of Boronic Acids and Alkynes Employing Electrophilic Shelf‐Stable N‐(trifluoromethylthio)phthalimide

A new and safe method for the synthesis of N‐(trifluoromethylthio)phthalimide, a convenient and shelf‐stable reagent for the direct trifluoromethylthiolation, has been developed. N‐(Trifluoromethylthio)phthalimide can be used as an electrophilic source of F₃CS⁺ and reacts readily with boronic acids and alkynes under copper catalysis. The utility of CF₃S‐containing molecules as biologically active agents, the mild reaction conditions employed, and the high tolerance of functional groups demonstrate the potential of this new methodology to be widely applied in organic synthesis as well as industrial pharmaceutical and agrochemical research and development.     

Dehydroxylative Trifluoromethylthiolation,Trifluoromethylation, and Difluoromethylation of Alcohols

Summary of main observation and conclusion CF3S,CF3 and HCF2 groups have been identified as valuable functionalities for drug development.Despite significant accomplishments in the trifluoromethylthiolation,trifluoromethylation and d讦luoromethylation reactions,directly converting common functional groups into CF3S,CF3 or HCF2 groups is still highly desirable.     

Direct Trifluoromethylthiolation and Perfluoroalkylthiolation of C(sp2)H Bonds with CF3SO2Na and RfSO2Na

A new method for CF₃SO₂Na‐based direct trifluoromethylthiolation of C(sp²)? H bonds has been developed. CF₃SSCF₃ is generated in situ from cheap and easy‐to‐handle CF₃SO₂Na, and in the presence of CuCl can be used for electrophilic trifluoromethylthiolation of indoles, pyrroles, and enamines. The method has been extended to perfluoroalkylthiolation reactions using R_fSO₂Na.     

Triphenylphosphine‐Mediated Deoxygenative Reduction of CF3SO2Na and Its Application for Trifluoromethylthiolation of Aryl Iodides

We report herein a practical method for taming Langlois’ reagent CF₃SO₂Na to generate CuSCF₃ by a triphenylphospine‐mediated deoxygenative reduction process. This chemistry highlights a novel utilization of the inherent CF₃S skeleton of Langlois’ reagent as a CF₃S feedstock under mild conditions. The CuSCF₃ intermediate generated by this protocol can react with a wide array of supporting ligands to furnish several air‐stable [LCu(SCF₃)] complexes as valuable trifluoromethylthiolating agents. In addition, the CuSCF₃ intermediate can be directly employed for the trifluoromethylthiolation of (hetero)aryl iodides with operational simplicity and atomic efficiency.     

An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18F‐Labeled α‐SCF3 Carbonyl Compounds

Trifluoromethylthiolation by sulfuration of difluorocarbene with elemental sulfur is described for the first time, which overrides long‐standing trifluoromethyl anion‐based theory. Mechanistic elucidation reveals an unprecedented chemical process for the formation of thiocarbonyl fluoride and also enables transition‐metal‐mediated trifluoromethylthiolation and [¹⁸F]trifluoromethylthiolation of α‐bromo carbonyl compounds with broad substrate scope and compatibility.     

Bis(dimethylamino)trifluoromethylsulfonium Salze: [CF3S(NMe2)2]+[Me3SiF2]‐, [CF3S(NMe2)2]+[HF2]‐ und [CF3S(NMe2)2]+[CF3S]‐

Bis(dimethylamino)trifluoro sulfonium Salts: [CF₃S(NMe₂)₂]⁺[Me₃SiF₂]^‐, [CF₃S(NMe₂)₂]⁺ [HF₂]^‐ and [CF₃S(NMe₂)₂]⁺[CF₃S]^‐ From the reaction of CF₃SF₃ with an excess of Me₂NSiMe₃ [CF₃(NMe₂)₂]⁺[Me₃SiF₂]^‐ (CF₃‐BAS‐fluoride) ( 5 ), from CF₃SF₃/CF₃SSCF₃ and Me₂NSiMe₃ [CF₃S(NMe₂)₂]⁺‐ [CF₃S]^‐ ( 7 ) are isolated. Thermal decomposition of 5 gives [CF₃S(NMe₂)₂]⁺ [HF₂]^‐ ( 6 ). Reaction pathways are discussed, the structures of 5 ‐ 7 are reported.     

Sulfonyl Fluoride‐Based Prosthetic Compounds as Potential 18F Labelling Agents

Nucleophilic incorporation of [¹⁸F]F^? under aqueous conditions holds several advantages in radiopharmaceutical development, especially with the advent of complex biological pharmacophores. Sulfonyl fluorides can be prepared in water at room temperature, yet they have not been assayed as a potential means to ¹⁸F‐labelled biomarkers for PET chemistry. We developed a general route to prepare bifunctional 4‐formyl‐, 3‐formyl‐, 4‐maleimido‐ and 4‐oxylalkynl‐arylsulfonyl [¹⁸F]fluorides from their sulfonyl chloride analogues in 1:1 mixtures of acetonitrile, THF, or tBuOH and Cs[¹⁸F]F/Cs₂CO_3(aq.) in a reaction time of 15 min at room temperature. With the exception of 4‐N‐maleimide‐benzenesulfonyl fluoride ( 3 ), pyridine could be used to simplify radiotracer purification by selectively degrading the precursor without significantly affecting observed yields. The addition of pyridine at the start of [¹⁸F]fluorination (1:1:0.8 tBuOH/Cs₂CO_3(aq.)/pyridine) did not negatively affect yields of 3‐formyl‐2,4,6‐trimethylbenzenesulfonyl [¹⁸F]fluoride ( 2 ) and dramatically improved the yields of 4‐(prop‐2‐ynyloxy)benzenesulfonyl [¹⁸F]fluoride ( 4 ). The N‐arylsulfonyl‐4‐dimethylaminopyridinium derivative of 4 ( 14 ) can be prepared and incorporates ¹⁸F efficiently in solutions of 100 % aqueous Cs₂CO₃ (10 mg mL^?1). As proof‐of‐principle, [¹⁸F] 2 was synthesised in a preparative fashion [88(±8) % decay corrected (n=6) from start‐of‐synthesis] and used to radioactively label an oxyamino‐modified bombesin(6–14) analogue [35(±6) % decay corrected (n=4) from start‐of‐synthesis]. Total preparation time was 105–109 min from start‐of‐synthesis. Although the ¹⁸F‐peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aqueous, room temperature ¹⁸F labelling strategy.     

Novel use of an isotope separator to determine the position of fluorine-18 in labelled 1,1,1,2-tetrafluoroethanes

A novel technique is described for measuring the site selectivity of methods for labelling the major CFC-alternative, 1,1,1,2-tetrafluoroethane (HFA 134a), with fluorine-18 (t_1/2 = 109.7 min). The carbon–carbon bond in radiofluorinated HFA 134a is broken in the ion source of an isotope separator. Radioactivity associated with the ion beam of the [CF₂ ¹⁸F]^+. fragment (m/z = 68) is collected, measured and divided by the integrated mass of the simultaneously collected ion beam for the [CF₃]^+. fragment (m/z = 69) to give the ‘specific radioactivity’ (in nCi nmol^–1) of the radiolabel in the 1-position. Similarly, the ‘specific radioactivity’ of the radiolabel in the 2-position is calculated from the measured radioactivity of the ion beam from the [CH₂ ¹⁸F]^+. fragment (m/z = 32) and the integrated mass of the simultaneously collected ion beam from the [CH₂F]^+. fragment (m/z = 33). The selectivity of the labelling procedure for a particular position is then given by the decay-corrected ratio of specific radioactivity at that position to the sum of specific radioactivities. The labelling of HFA 134a by the reaction of [¹⁸F] fluoride with trifluoroethylene was found to have 97% selectivity for the CF₃ group, whereas labelling by the reaction of [¹⁸F] fluoride with 2,2,2-trifluoroethyl p-toluenesulphonate was found to have 91% selectivity for the CH₂F group. This information is of value for tracer studies of the fate of HFA 134a in man following its inhalation as a drug propellant. The described technique is of potentially wider value for determining the position of fluorine-18 in labelled polyfluorinated molecules.     

A Universal Procedure for the [18F]Trifluoromethylation of Aryl Iodides and Aryl Boronic Acids with Highly Improved Specific Activity

Herein, we describe a valuable method for the introduction of the [¹⁸F]CF₃ group into arenes with highly improved specific activity by the reaction of [¹⁸F]trifluoromethane with aryl iodides or aryl boronic acids. This [¹⁸F]trifluoromethylation reaction is the first to be described in which the [¹⁸F]CF₃ products are generated in actual trace amounts and can therefore effectively be used as PET tracers. The method shows broad scope with respect to possible aryl iodide and aryl boronic acid substrates, as well as good to excellent conversion. In particular, the [¹⁸F]trifluoromethylation of boronic acids was found to outperform [¹⁸F]trifluoromethylation reactions of halogenated aryl precursors with regard to conversion, reaction conditions, and kinetics.     

Polymerization of Fluorothiocarbonyl Compounds

Recently it was shown that the C[dbnd]S group in fluorothiocarbonyl compounds readily undergoes addition polymerization. This review describes polymers obtainable from such compounds as CF₂[dbnd]S, CF₃CF[dbnd]S, ClCF₂CF[dbnd]S, HCFClCF[dbnd]S, and hexafluorothioacetone. The polymerization of CF₂[dbnd]S is readily brought about in anionic systems at low temperatures, giving a high-molecular-weight poly(thiocarbonyl fluoride) with a number-average molecular weight in the range of 300,000 to 400,000. It is believed that the major portion of this polymer is composed of chains of CF₃–-S—(—CF₂S—)_n–CF[dbnd]S. Poly(thiocarbonyl fluoride) is a highly resilient elastomer in the amorphous form but suffers the disadvantage of slow crystallization at temperatures below 35°C and concomitant loss of rubbery properties. Above 175°C it depolymerizes. Fluorothioacyl fluorides also undergo anionic polymerization, but the products are logy elastomers. Copolymers of fluorothioacyl fluorides with CF₂[dbnd]S have better thermal stability but poorer resilience than poly(thiocarbonyl fluoride). Hexafluorothioacetone has been polymerized at—110°C to give a white elastomer that slowly depolymerizes at room temperature to regenerate monomer. Thiocarbonyl fluoride is also susceptible to free-radical polymerization, and in free-radical systems it copolymerizes with conventional vinyl monomers, giving a wide variety of new elastomeric products.     

Synthesis and Derivatization of 1,1‐[18F]Difluorinated Alkenes

A general method for the synthesis of 1,1‐[¹⁸F]difluorinated alkenes from [¹⁸F]fluoride is reported. This transformation is highly regioselective giving the desired ¹⁸F‐fluoroalkenes with radiochemical purities of up to 77 % within 20 minutes and a molar activity (A_m) of 1 GBq μmol^?1. The transformations are operationally simple to perform and were readily translated onto a commercial automated synthesis unit. The resultant 1,1‐[¹⁸F]difluorinated alkene motif is prevalent in numerous drug molecules, and this is the first general method to synthesize this motif with fluorine‐18. ¹⁸F‐fluorinated alkenes are excellent building blocks and participate in a number of post‐labeling transformations to access a range of ¹⁸F‐perfluorinated functional groups that have never before been radiolabeled with non‐carrier‐added [¹⁸F]fluoride. This method considerably expands the range of ¹⁸F‐motifs accessible to radiochemists.     

Direct Trifluoromethylthiolation and Perfluoroalkylthiolation of C(sp2)?H Bonds with CF3SO2Na and RfSO2Na

A new method for CF₃SO₂Na‐based direct trifluoromethylthiolation of C(sp²) H bonds has been developed. CF₃SSCF₃ is generated in situ from cheap and easy‐to‐handle CF₃SO₂Na, and in the presence of CuCl can be used for electrophilic trifluoromethylthiolation of indoles, pyrroles, and enamines. The method has been extended to perfluoroalkylthiolation reactions using R_fSO₂Na.     

Synthesis of 18F‐Difluoromethylarenes from Aryl (Pseudo) Halides

A general method for the synthesis of [¹⁸F]difluoromethylarenes from [¹⁸F]fluoride for radiopharmaceutical discovery is reported. The method is practical, operationally simple, tolerates a wide scope of functional groups, and enables the labeling of a variety of arenes and heteroarenes with radiochemical yields (RCYs, not decay‐corrected) from 10 to 60 %. The ¹⁸F‐fluorination precursors are readily prepared from aryl chlorides, bromides, iodides, and triflates. Seven ¹⁸F‐difluoromethylarene drug analogues and radiopharmaceuticals including Claritin, fluoxetine (Prozac), and [¹⁸F]DAA1106 were synthesized to show the potential of the method for applications in PET radiopharmaceutical design.     

Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers

The first transition‐metal‐free, site‐specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp³)–SCF₃ coupling under redox‐neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL‐based phosphorothiols can site‐selectively cleave tertiary sp³ C(sp³)–O ether bonds in complex molecules initiated by a polarity‐matching hydrogen‐atom‐transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp³)?H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C?O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site‐selective C?O bond functionalization of unsymmetrical tertiary alkyl ethers.     

Novel Source of Trifluoromethyl Radical As Efficient Initiator for the Polymerization of Vinylidene Fluoride

A persistent perfluoroalkyl radical (PPFR), perfluoro‐3‐ethyl‐2,4‐dimethyl‐3‐pentyl, is shown to be a good source of •CF₃ radicals and a useful radical capable of initiating the polymerization of vinylidene fluoride (VDF). NMR characterizations of the resulting PVDF homopolymers showed that polymerization of VDF was exclusively initiated by •CF₃ radicals. The addition of •CF₃ radical onto VDF was regioselective leading to CF₃‐CH₂‐CF₂‐PVDF and the CF₃ end‐group acted as an efficient label to assess the molecular weights by ¹⁹F NMR spectroscopy. Various [PPFR]₀/[VDF]₀ initial molar ratios lead to CF₃–PVDF–CF₃ of different molecular weights. When that ratio decreased, both the molecular weights and the thermostability of these PVDFs increased, showing less defects of chaining and higher crystallinity.     

Targeted Fluorination with the Fluoride Ion by Manganese‐Catalyzed Decarboxylation

We describe the first catalytic decarboxylative fluorination reaction based on the nucleophilic fluoride ion. The reported method allows the facile replacement of various aliphatic carboxylic acid groups with fluorine. Moreover, the potential of this method for PET imaging has been demonstrated by the successful ¹⁸F labeling of a variety of carboxylic acids with radiochemical conversions up to 50 %, representing a targeted decarboxylative ¹⁸F labeling method with no‐carrier‐added [¹⁸F]fluoride. Mechanistic probes suggest that the reaction proceeds through the interaction of the manganese catalyst with iodine(III) carboxylates formed in situ from iodosylbenzene and the carboxylic acid substrates.     

Synthesis of [F]xenon difluoride as a radiolabeling reagent from [F]fluoride ion in a micro-reactor and at production scale

[¹⁸F]Xenon difluoride ([¹⁸F]XeF₂), was produced by treating xenon difluoride with cyclotron-produced [¹⁸F]fluoride ion to provide a potentially useful agent for labeling novel radiotracers with fluorine-18 (t_1/2 = 109.7 min) for imaging applications with positron emission tomography. Firstly, the effects of various reaction parameters, for example, vessel material, solvent, cation and base on this process were studied at room temperature. Glass vials facilitated the reaction more readily than polypropylene vials. The reaction was less efficient in acetonitrile than in dichloromethane. Cs⁺ or K⁺ with or without the cryptand, K 2.2.2, was acceptable as counter cation. The production of [¹⁸F]XeF₂ was retarded by K₂CO₃, suggesting that generation of hydrogen fluoride in the reaction milieu promoted the incorporation of fluorine-18 into xenon difluoride. Secondly, the effect of temperature was studied using a microfluidic platform in which [¹⁸F]XeF₂ was produced in acetonitrile at elevated temperature (≥85 °C) over 94 s. These results enabled us to develop a method for obtaining [¹⁸F]XeF₂ on a production scale (up to 25 mCi) through reaction of [¹⁸F]fluoride ion with xenon difluoride in acetonitrile at 90 °C for 10 min. [¹⁸F]XeF₂ was separated from the reaction mixture by distillation at 110 °C. Furthermore, [¹⁸F]XeF₂ was shown to be reactive towards substrates, such as 1-((trimethylsilyl)oxy)cyclohexene and fluorene.     

A General Copper‐Mediated Nucleophilic 18F Fluorination of Arenes

Molecules labeled with fluorine‐18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (S_NAr) with [¹⁸F]F^?. In the ideal case, the ¹⁸F fluorination of these substrates would be performed through reaction of [¹⁸F]KF with shelf‐stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of ¹⁸F arenes from pinacol‐derived aryl boronic esters (arylBPin) upon treatment with [¹⁸F]KF/K₂₂₂ and [Cu(OTf)₂(py)₄] (OTf=trifluoromethanesulfonate, py=pyridine). This method tolerates electron‐poor and electron‐rich arenes and various functional groups, and allows access to 6‐[¹⁸F]fluoro‐L ‐DOPA, 6‐[¹⁸F]fluoro‐m‐tyrosine, and the translocator protein (TSPO) PET ligand [¹⁸F]DAA1106.     

Novel fluorinated polymers by radical polyaddition: Inspiration and progress

The story of the outset and the growth of radical polyaddition of bisperfluoroisopropenyl derivatives [CF₂?C(CF₃)? R? C(CF₃)? CF₂] with several organic compounds possessing carbon–hydrogen bonds is described. The reaction afforded novel fluorinated polymers bearing such organic segments in polymer main chains as 1,4‐dioxane, diethyl ether, dimethoxyethane, 18‐crown‐6, triethylamine, glutaraldehyde, and alkanes which have never been supposed as direct starting compounds for preparation of polymers. The facile method for preparation of fluorinated hybrid polymers bearing alkylsilyl groups was developed with diethoxydimethylsilane and silsesquioxanes. Taking advantage of the high reactivity of the perfluoroisopropenyl group as a radical acceptor, self‐polyaddition and cyclopolymerization were investigated. Triethysilyl perfluoroisopropenyl ether [CF₂? C(CF₃)? O? Si(C₂H₅)₃] was proved to be the most probable candidate for self‐polyaddition. Cyclopolymerization of perfluoroisopropenyl vinylacetate [CF₂?C(CF₃) OCO? CH₂CH? CH₂] was investigated to afford polymers possessing five‐membered‐ring units in main chains. The interconversion of the unstable fluorinated carbon radical and the stable hydrocarbon radical had an important role in the reaction. The radical addition reaction presented herein may be developed for preparation of a wide variety of novel fluorinated polymers and organic compounds possessing functional groups. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4101–4125, 2004     

Direct Trifluoromethylthiolation of Unactivated C(sp3)H Using Silver(I) Trifluoromethanethiolate and Potassium Persulfate

A practical and efficient method for the direct trifluoromethylthiolation of unactivated C(sp³)? H bonds by AgSCF₃/K₂S₂O₈ under mild conditions is described. The reaction has a good functional‐group tolerance and good selectivity. Initial mechanistic investigations indicate that the reaction may involve a radical process in which K₂S₂O₈ plays key roles in both the activation of the C(sp³)? H bond and the oxidation of AgSCF₃.