Reduction of SF₅CF₃via iridium catalysis: radical trifluoromethylation of aromatics

Abstract

The greenhouse gas SF₅CF₃ acts as CF₃ source for the photocatalytic trifluoromethylation of arenes on using [Ir(dtbbpy)(ppy)₂]PF₆ (4,4′-di-tert-butyl-2,2′-dipyridyl, ppy = 2-phenylpyridine) as catalyst. The trifluoromethylation of C₆D₆ in the presence of 1-octanol results in the concomitant generation of 1-fluorooctane, presumably by intermediate SF₄.

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The CF₃ group plays an important role in medicinal chemistry in part due to their ability to increase the lipophilicity of compounds, and thereby enhance the rate of absorption and transport of drugs across the blood–brain barrier.¹ In 1963 Bedard et al. reported on the thermal homolysis of the trifluoromethyl derivatives CF₃I, CF₃Br, CF₃Cl to achieve a radical trifluoromethylation of halobenzenes.^2,3 Silver trifluoroacetate and TiO₂ as a photocatalyst were also used to form CF₃ radicals in order to synthesize trifluoromethylated aromatics.⁴ Kamigata et al. demonstrated the trifluoromethylation of aromatics on using a ruthenium(II)phosphine complex as a catalyst and trifluormethanesulfonylchloride as CF₃ source in a thermal reaction.⁵ In 2011 MacMillan et al. published a photocatalytic trifluoromethylation of aromatics with [Ru(phen)₃]Cl₂ (phen = phenanthroline) as catalyst again using F₃CSO₂Cl as a source for the trifluoromethyl group.⁶ The research group of Hu et al. described a photochemical trifluoromethylation reaction in which an electron donor–acceptor complex between an aromatic thiophenolate anion and trifluoromethylphenylsulfone initiates a single electron transfer, and therefore the generation of CF₃ radicals.⁷ In other photocatalytic trifluoromethylations of aromatics CF₃SO₂Na⁸ or trifluoromethanesulfonic anhydride⁹ were used as trifluoromethyl radical source. Note also that in 2009 MacMillan et al. reported on an enantioselective trifluoromethylation of aldehydes via a photoredox process coupled with organocatalysis on using the Ir redox catalyst [Ir(dtbbpy)(ppy)₂]PF₆ (4,4′-di-tert-butyl-2,2′-dipyridyl, ppy = 2-phenylpyridine). In an reductive quenching cycle CF₃I is being reduced to give a CF₃ radical.¹⁰ Furthermore, [Ir(dtbbpy)(ppy)₂]PF₆ was used in a photocatalytic approach for the trifluoromethylation of alkynes.¹¹ Note that apart from CF₃ transfer other fluoroalkyl groups can be transferred as well via photocatalysis.¹²

In the last few years the activation of the greenhouse gas SF₆ and its use as fluorinating agent has been studied extensively.^13–18 Conversions are often initiated by an electron transfer to SF₆ to yield SF₆⁻. The latter can either transform into a SF₅ radical and a fluoride or SF₅⁻ and a fluoro radical.^16,17,19 Examples for the photochemical activation of SF₆ include the application of the photocatalysts [Ru(phen)₃]Cl₂,⁶ 4,4-dimethoxybenzophenone¹⁵ or [Ir(dtbbpy)(ppy)₂]PF₆¹⁸ The SF₆ derivative SF₅CF₃ has also a high global warming potential and a long atmospheric life-time.²⁰ It is assumed that SF₅CF₃ is a breakdown product of SF₆ in high-voltage equipment. The latter contains fluoropolymers which are sources for CF₃ moieties that can react with SF₅ radicals formed by high voltage discharges.²⁰ However, electron transfer to SF₅CF₃ can result in the generation of SF₅⁻ and a CF₃ radical. Thus, the formation of SF₅⁻ has been observed in low-energy attachment experiments by mass spectrometry.^21,22 SF₅CF₃ activation processes are rare and in solution only one example is known in the literature, to the best of our knowledge.¹⁴

In this contribution we report on an unprecedented trifluoromethylation of aromatic compounds by photocatalytic generation of CF₃ radicals from the greenhouse gas SF₅CF₃.

Irradiation of SF₅CF₃ at a wavelength of 353 nm in C₆D₆ in the presence of 4,4′-dimethoxybenzophenone as an organic photocatalyst (Scheme 1) led to the generation of small amounts of α,α,α-trifluorotoluene-d₅. Similar, only traces of α,α,α-trifluorotoluene-d₅ were observed when 10-phenylphenothiazine (Scheme 1) was used to activate SF₅CF₃. However, irradiation of SF₅CF₃ in the presence of the photoredox catalyst [Ir(dtbbpy)(ppy)₂]PF₆ (Scheme 1), triethylamine and cesium carbonate with a 456 nm LED lamp for 16 h in C₆D₆ yielded α,α,α-trifluorotoluene-d₅ with a turnover number (TON) of 410 (TON are based on the concentration of the catalyst on using 1,4-difluorobenzene as internal standard) (Scheme 2). Note that without the presence of Et₃N the conversion does not proceed. Attempts to use K₂HPO₄ as an alternative base failed. Triethylamine and cesium carbonate in a ratio of 1 : 1 led to the highest turnover numbers. ¹⁹F NMR experiments revealed the presence of DF when no Cs₂CO₃ was present. Using 4-methoxydiphenylamine and Cs₂CO₃ as bases in a ratio of 1 : 1 led to a decrease of the TON to 26. Note that with the photoredox catalyst [Ru(bpy)₃](PF₆)₂ or [Ir(dFppy)₃] lower TONs of 28 and 46, respectively, were observed in the presence of NEt₃ and Cs₂CO₃ in a ratio of 1 : 1. Reactions with [Ir(dtbbpy)(ppy)₂]PF₆ as catalyst with only stoichiometric amounts of benzene in acetonitrile or dichloroethane as solvents gave α,α,α-trifluorotoluene-d₅ only in very low yield. Mainly the generation of trifluoromethane and other minor unidentified products was observed (ratio CF₃H to PhCF₃: 71 : 1 in acetonitrile, 52 : 1 in dichloroethane). With dichloromethane and tetrahydrofurane as solvents in the presence of stoichiometric amounts of benzene did not lead to any product formation.

Scheme 1 Catalysts studied for the reduction of SF₅CF₃.

Scheme 2 Trifluoromethylation of arenes on using [Ir(dtbbpy)(ppy)₂]PF₆ as photoredox catalyst.

To expand the scope of the conversions, pyridine, anisole, 1,2,3,4-tetrafluorobenzene and deuterated toluene (Scheme 2) were studied towards a photochemical trifluoromethylation on using a stock solution of [Ir(dtbbpy)(ppy)₂]PF as photocatalyst. All the conversions were run with the substrate as solvent. Selectivities can be explained when considering that the CF₃ radical shows an electrophilic character.^2,6 Transformations of toluene-d₈ and anisole resulted mainly in the formation of isomers with the CF₃ group in the ortho or para position. Pyridine gives mainly the ortho-product, but also considerable amounts of meta-trifluoromethylpyridine. Minor amounts of trifluoromethane were also detected. 1,2,3,4-Tetrafluorobenzene however did not show any reactivity under the standard conditions. The trifluoromethylated aromatics were characterized by their signals in the ¹⁹F NMR spectra for the CF₃ groups in the para, meta or ortho positions as well as by GC-MS.

Mechanistically, it can be presumed that after irradiation at 456 nm a single electron transfer SET from the photocatalytic system to SF₅CF₃ leads to the SF₅CF₃⁻ radical anion (Scheme 3). As mentioned above, the subsequent trifluoromethylation does not proceed without the presence of NEt₃ as reductant. Thus, NEt₃ can reduce the photoexcited species [Ir(dtbbpy)(ppy)₂]⁺* generated after excitation of [Ir(dtbbpy)(ppy)₂]⁺ in a reductive quenching cycle (Scheme 3). This step is followed by the SET from the reduced [Ir(dtbbpy)(ppy)₂] (E_pc = −1.51 V vs. SCE)^23,24 to SF₅CF₃. Alternatively, [Ir(dtbbpy)(ppy)₂]⁺* (E_pc = −0.96 V vs. SCE)^23,24 reduces SF₅CF₃ and the generated [Ir(dtbbpy)(ppy)₂]²⁺ is then reduced by NEt₃ in an oxidative quenching cycle. Note that photocatalytic conversions of [Ir(dtbbpy)(ppy)₂]⁺ have a tendency to proceed via a reductive quenching cycle.^10,25 However, the SF₅CF₃⁻ radical anion then decomposes to give a CF₃ radical and SF₅⁻.^22,26 The SF₅⁻ anion is not very stable and furnishes SF₄ and fluoride.^16,27 The CF₃ radical reacts then with benzene forming a cyclohexadienyl radical. The generation of the latter in trifluoromethylation reactions has been proposed by Kamigata et al.⁵ and others.^6,9,28 Oxidation of the cyclohexadienyl radical by the NEt₃˙⁺ radical cation and subsequent deprotonation of the cyclohexadienyl cation by fluoride yields the trifluoromethylated aromatic product and NEt₃·HF.^2,6,9,29 Alternatively, hydrogen atom abstraction HAT from the cyclohexadienyl radical would give the intermediate Et₃NH⁺, and in the presence of fluoride the same products.²³ Cesium carbonate acts as an HF scavenger. There is no indication for the formation of HD or H₂ along with an iminium ion from the NEt₃ radical. However, the observed generation of trifluoromethane in acetonitrile or dichloromethane can involve HAT from the solvent or the NEt₃˙⁺ radical. The latter is consistent with the fact that higher NEt₃ concentrations deliver more CF₃H.

Scheme 3 Proposed mechanism for the trifluoromethylation of arenes by SF₅CF₃.

Furthermore, to confirm the intermediate formation of a CF₃ radical, TEMPO (2,2,6,6-tetramethylpiperidinyloxyl) was added to the photocatalytic trifluoromethylation reaction of C₆D₆, and indeed TEMPO inhibited the conversion (Scheme 3). However, after 96 h TEMPO-CF₃ as well as the α,α,α-trifluorotoluene-d₅ were observed in a ratio of 1 : 2. The formation of SF₄ was not observed by low temperature NMR experiments, presumably because of the presence of Cs₂CO₃. Nevertheless, when the trifluoromethylation of C₆D₆ was run in the presence of 1-octanol in the generation of 1-fluorooctane was observed, which was identified by GC-MS and ¹⁹F NMR spectroscopy (Scheme 4). The experiment suggests the deoxyfluorination of the alcohol by intermediate SF₄.³⁰ Hence, trifluoromethylation steps can be coupled with the fluorination of an alcohol. However, under the UV irradiation SF₄ might also be further reduced yielding elemental sulfur, as it was also proposed by Nagorny et al. for the activation of SF₆ in the presence of the organophotocatalyst 4,4-dimethoxybenzophenone.¹⁵ Indeed, when PPh₃ was added to the reaction mixture after the photolytic formation of C₆D₅CF₃, the generation of small amounts of SPPh₃ (7) was observed after heating the reaction mixture for two hours at 60 °C, which might be due to the presence of sulfur (Scheme 4).

Scheme 4 Quenching of the photocatalytic trifluoromethylation with TEMPO or 1-octanol (a and b); generation of Ph₃P = S after addition of PPh₃ to the reaction mixture (c).

In conclusion, a catalytic photoredox process for the activation of the greenhouse gas SF₅CF₃ and a concomitant trifluoromethylation of aromatics were reported. SF₅CF₃ acts as source for CF₃ radicals and at the same time SF₄ and sulfur can be furnished. The former can be used for fluorination to couple the trifluoromehylation of aromatics with a fluorination of an alcohol. Note also that iridium photocatalyzed processes were applied for the defluorination of fluorinated organic substrates,³¹ which was not observed for the described transformations.

Experiments, data collection (NMR and GC-MS) and analysing the data was performed by D. Herbstritt. The manuscript was drafted by D. Herbstritt. T. Braun supervised the work, designed the project and contributed to manuscript writing.

We acknowledge financial support from the CRC 1349 funded by the Deutsche Forschungsgemeinschaft (German Research Foundation; Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) – Projektnummer 387284271 – SFB 1349) The work was also supported by the DFG under Germany's Excellence Strategy – EXC 2008 – 390540038 – UniSysCat.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3cc00495c

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