Fluoroalkylated hypervalent sulfur fluorides: radical addition of arylchlorotetrafluoro-λ⁶-sulfanes to tetrafluoroethylene

Abstract

Fluorinated groups are essential hydrophobic groups in drug design. Combining a carbon-free tetrafluoro-λ⁶-sulfanyl (SF₄) group with a polyfluoroalkyl group (R_F) provides SF₄R_F groups, exhibiting high hydrophobicity with a short carbon chain. In this study, various aryltetrafluoro(polyfluoroalkyl)-λ⁶-sulfanes (ArSF₄R_F) were synthesized through the radical addition of arylchlorotetrafluoro-λ⁶-sulfanes (ArSF₄Cl) to tetrafluoroethylene. In addition, quantification of hydrophobic constants (π_Ph) indicated that the SF₄ group is considerably more hydrophobic than a difluoromethylene (CF₂) group. Further transformation reactions revealed the stabilities and reactivities of these novel fluorinated groups. The high hydrophobicity and synthetic utility of the SF₄R_F group lead to the potential applications of the SF₄R_F group in the pharmaceutical field.

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Introduction

Substituents based on hexacoordinated sulfur fluorides have gained significant attention in medicinal and material chemistry.¹ The pentafluoro-λ⁶-sulfanyl (SF₅) group has been regarded as a “super-trifluoromethyl” group owing to its enhanced size, electronegativity, hydrolytic stability, and hydrophobicity (π_Ph(SF₅): 1.23, π_Ph(CF₃): 0.88).² Therefore, researchers have explored various applications of this moiety and dedicated substantial efforts to developing effective synthetic methods for compounds containing the SF₅ group.^2–7 Initial direct fluorination methods require strong oxidants, leading to low yields and poor functional group tolerance because of side reactions, such as overfluorination or C–C/C–S fragmentation.³ However, recent advancements in the synthesis of aliphatic compounds with the SF₅ group have been achieved through the rapid development of synthetic methods using SF₅X reagents, expanding the accessible range.^2,4 Arylpentafluoro-λ⁶-sulfanes (ArSF₅) have also gained significant importance in medicinal chemistry attributed to the significant effect of the SF₅ group bound to an aromatic ring on hydrophobicity and metabolic stability.⁸ A notable breakthrough in the synthesis of ArSF₅ has been the development of two-step routes via arylchlorotetrafluoro-λ⁶-sulfanes (ArSF₄Cl) (Scheme 1A, left).^5,6 These methods have enabled the scalable and inexpensive synthesis of ArSF₅ compounds by using less expensive and milder oxidants, such as Cl₂ and trichloroisocyanuric acid (TCICA).

Scheme 1 Synthetic methods for the aromatic compounds with sulfur–fluorine functional groups. (A) Chlorine–fluorine exchange reactions and radical addition reactions of ArSF₄Cl compounds. (B) Conventional synthesis of ArSF₄CF₃ compounds through direct fluorination. (C) This work: radical addition reactions of ArSF₄Cl compounds to tetrafluoroethylene.

The more hydrophobic SF₄R_F (R_F = polyfluoroalkyl) group is a promising option for the enhancement of biological activity.⁹ For instance, the synthesis of aryltetrafluoro(trifluoromethyl)-λ⁶-sulfanes (ArSF₄CF₃) and the π_Ph constant of the SF₄CF₃ group (2.13) were first reported in 2006, demonstrating the high hydrophobicity of the SF₄R_F group (Scheme 1B).^9c However, direct fluorination is not feasible without deactivating the aromatic ring with a nitro group because of the high reactivity of fluorine gas. Consequently, the synthesis of a wide range of ArSF₄CF₃ compounds remains challenging thus far.

Based on this background, we envisioned using ArSF₄Cl compounds in synthesizing ArSF₄R_F compounds. Several radical addition reactions of ArSF₄Cl compounds have been reported thus far (Scheme 1A, right).^5c,10 These synthetic methods are considerably milder than conventional direct fluorination of sulfides and have enabled the preparation of a variety of aromatic compounds with the tetrafluoro-λ⁶-sulfanyl (SF₄) moiety. However, radical addition reactions of ArSF₄Cl compounds to fluoroolefins have not been reported. In this study, we discuss radical addition reactions of ArSF₄Cl compounds to tetrafluoroethylene (TFE) as a simple synthetic approach for aryltetrafluoro(polyfluoroethyl)-λ⁶-sulfanes (Scheme 1C).¹¹ The enhanced hydrophobicity of the novel SF₄R_F groups and their reactivities will also be discussed.

Results and discussion

Radical addition of arylchlorotetrafluoro-λ⁶-sulfanes to tetrafluoroethylene

We synthesized chlorotetrafluoro(phenyl)-λ⁶-sulfane 1a using the optimized conditions involving TCICA/KF,^5c,d and then the radical addition reaction of 1a to TFE was examined by exploring various radical initiators (Table 1). Although triethylborane effectively catalyzed the addition reaction of ArSF₄Cl compounds to terminal alkynes and alkenes,^10a–c a low yield was obtained in the reaction with TFE (entry 1). Irradiation with a blue LED, known as the activation method for ArSF₄Cl compounds,^10b,d afforded the adduct 2a in 49% yield (entry 2). A higher yield was obtained when BDK (2,2-dimethoxy-2-phenylacetophenone) was used as the photoinitiator (entry 3). Subsequently, we examined several thermal initiators, such as AIBN, ADVN, and AMDVN, each requiring different initiation temperatures (entries 4–6). Azo-type initiators exhibited good yields, with ADVN demonstrating the best performance and affording 2a in 88% yield (entry 5). Reducing the reaction time to 20 h resulted in incomplete substrate conversion (entry 7). Although increasing the amount of ADVN or elevating the reaction temperature accelerated the reaction, the yield did not reach the optimal condition attributed to the decomposition of 1a (entries 8–9). Alternation of solvents to acetonitrile, hexane, THF, or 1,2-dichloroethane did not afford satisfactory results (Table S1†), and the formation of a hydrogenated adduct, PhSF₄CF₂CF₂H, was predominant in the case of THF (entry 10). Inspired by the result, we examined the selective formation of 3avia a three-component addition reaction with hydrogenating agents.^4f However, several investigations revealed that the hydrogen sources such as (Me₃Si)₃SiH caused decomposition of 1a rather than the desired reaction (see the ESI†).

Table 1 Effect of radical initiators on the radical addition reaction of 1a to tetrafluoroethylene

Entry	Initiator	Temp.	Yield^a (%)
a Determined by ^19F NMR analysis of the crude mixture relative to an internal standard (1,4-bis(trifluoromethyl)benzene). b Irradiated with blue LED. c 20 h. d 30 mol% initiator added. e THF (0.10 M) instead of EtOAc. f Isolated yield. g Yield of 3a. AIBN = 2,2′-azobis(isobutyronitrile), ADVN = 2,2′-azobis(2,4-dimethylvaleronitrile), AMDVN = 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile), BDK = 2,2-dimethoxy-2-phenylacetophenone.
1	BEt3	rt	5
2^b	—	rt	49
3^b	BDK	rt	68
4	AIBN	60 °C	80
5	ADVN	40 °C	88 (77^f)
6	AMDVN	25 °C	72
7^c	ADVN	40 °C	23
8^c^,^d	ADVN	40 °C	75
9^c	ADVN	60 °C	65
10^e	ADVN	40 °C	38^g

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With the optimal reaction conditions in hand, we explored the substrate scope of this radical addition reaction using various ArSF₄Cl compounds. Substrates 1 were synthesized according to the literature method (Scheme 2A).^5c,d Notably, the electron-rich diaryl disulfide underwent arene chlorination during the oxidative fluorination step, affording 1j as the major product (Scheme 2B). Bis(pentafluorophenyl) disulfide gave 1n as a mixture of cis- and trans-isomers as previously reported, although the oxidative fluorination generally afforded 1 in trans conformation (Scheme 2C).^5a,c,d Initially, the screening of substrates focused on the para-substituents on the benzene ring (Scheme 3). Both electron-withdrawing (2b–e) and electron-donating groups (2f–g) were tolerated, as were protected carboxylic acid and phenol (2h–i). Meta-substituted (2j–l) and ortho-fluorinated substrates (2m–n) afforded the desired products in moderate to high yields. Using a mixture of cis- and trans-ArSF₄Cl, only the trans product was obtained (2n). Additionally, this reaction could be applied to pyridines and pyrimidines (2o–q). The structure of 2e was unambiguously determined through X-ray diffraction analysis. Expectedly, the sulfur atom of 2e shows an octahedral geometry characteristic of the hexavalent sulfur species as well as the ArSF₄CF₃ compound^9c (see the ESI†).

Scheme 2 Synthesis of (A) 1 (except 1j and 1n), (B) 1j and (C) 1n. Yields were determined by ¹⁹F NMR analysis relative to an internal standard (trifluorotoluene). TCICA = trichloroisocyanuric acid, TFA = trifluoroacetic acid.

Scheme 3 Substrate scope. 1 (1.0 equiv.) and ADVN (10 mol%) were stirred in anhydrous EtOAc at 40 °C under TFE (1 atm). Yields were determined by ¹⁹F NMR analysis relative to an internal standard (1,4-bis(trifluoromethyl)benzene); isolated yields are shown in parentheses. ^a AIBN (10 mol%), 60 °C. ^b ADVN (30 mol%). ^c Substrate was a mixture of cis- and trans-isomers (39 : 61). ^d EtOAc (0.50 M).

In several cases where ArSF₄Cl compounds were added to TFE, the dimerized products (ArSF₄(CF₂CF₂)₂Cl) were also obtained (less than 5%).¹² To shed light on the mechanism of the present reactions, a radical addition reaction was performed at higher TFE pressures. Consequently, 2a and the telomer were obtained in 49% and 32% yields, respectively (Scheme 4A). Compared to the standard conditions under atmospheric pressure of TFE, the telomer ratio showed significant improvement. The telomers (2 ≤ n ≤ 7) were detected using GC-MS after treating with silica-gel column chromatography (Fig. S1†).

Scheme 4 (A) Telomerization reaction. Yields were determined by ¹⁹F NMR analysis relative to an internal standard (1,4-bis(trifluoromethyl)benzene). (B) Free energy change and free energy of activation at 25 °C (in kcal mol⁻¹).

DFT calculations

Based on the single addition and telomerization reaction results, our next objective was to elucidate the energy profiles associated with these reactions. In the context of the radical reactions involving hexavalent sulfur fluorides, DFT calculations were performed to study the addition of SF₅Cl to alkynes, demonstrating the high stability of the SF₅ radical resulting from hyperconjugation.^4f According to the literature, DFT calculations were performed at the M06-2X/Def2TZVPP/SMD(EtOAc) level of theory at 25 °C (Scheme 4B, see the ESI† for more details). Firstly, we computed the energy diagram for the formation of 2a (Scheme 4B, path (a)). After abstracting chlorine from 1a, IM1 adds to TFE with a free energy barrier of 15.1 kcal mol⁻¹ to form IM2. Notably, the formation of IM2 from IM1 and TFE was endergonic owing to the high stability of IM1. When the SF₅ radical was added, the formation of the SF₅CF₂CF₂ radical was slightly exergonic, indicating apparent resonance stabilization by the benzene ring of IM1 (Scheme S4†). After IM2 is formed, chlorine abstraction from 1a proceeds with a 13.9 kcal mol⁻¹ free energy barrier, regenerating IM1 and yielding 2a. The chlorine transfer is significantly exergonic and is the driving force of a series of reactions. Next, we investigated the propagation reaction (Scheme 4B, path (b)). A dimerized product was obtained from IM2 through a second addition to TFE, followed by chlorine abstraction from 1a. Notably, the formation of 2a through chlorine abstraction was irreversible, and further elongation from 2a could no longer occur. The stability of 2a was also supported by the unsuccessful telomerization from 2a (Scheme S2†). Therefore, the telomer/2a ratio is influenced by the selectivity of chlorine abstraction and propagation from IM2. The calculations showed that these two reactions proceed with comparable activation energies. Considering that the reaction rate depends on the activation energy and the concentrations of reactants, the concentration ratio of TFE and 1a should affect the selectivity. This is consistent with the experimental results (Scheme 4A).

Synthetic applications

Compound 2 exhibited stability against silica gel column chromatography and could be stored in air at room temperature for several months. Next, we carried out the transformation of 2 to investigate its stability and reactivity. Several transformations retaining the SF₄CF₂CF₂Cl group were tested initially (Scheme 5A). Bromoarene 2d was converted to 2rvia a Suzuki–Miyaura cross-coupling reaction, facilitating the synthesis of various ArSF₄CF₂CF₂Cl compounds. SF₄CF₂CF₂Cl-substituted aniline 2s and benzoic acid 2t were successfully synthesized from 2e and 2h, respectively. These methods overcome the difficulty in synthesizing 2s and 2t through radical addition because of the low stability of ArSF₄Cl with amino and carboxyl groups. In contrast, the SF₄CF₂CF₂Cl group can be reduced to the SF₄CF₂CF₂H group using tris(trimethylsilyl)silane (Scheme 5B). The set of transformation reactions mentioned in Schemes 5A–B enables the synthesis of functional molecules; for instance, an analog of the bioactive molecule Tetrafluron¹³ was synthesized from 2l in 70% yield over three steps (Scheme 5C). Furthermore, the iodosulfanylation of tetrafluoroethylene followed by fluorination was investigated to prepare a perfluorinated SF₄CF₂CF₃ group (Scheme 5D). After evaluating several external iodine sources, carbon tetraiodide was identified as the most effective iodinating agent in yield and selectivity (Table S4†). Under the optimized reaction conditions, tetrafluoro(tetrafluoroiodoethyl)(phenyl)-λ⁶-sulfane 4 was synthesized from 1a and TFE in 63% yield. Subsequently, 4 underwent fluorination using AgF₂ to form 5. When AgF as a fluorinating agent or 2a (PhSF₄CF₂CF₂Cl) as a substrate was employed, the fluorination did not proceed (Table S5†). We then compared the stability of 5 and PhCF₂CF₂CF₃ to clarify the difference between the SF₄ and CF₂ linkers (Table 2). Under high temperature conditions, 5 was decomposed by nearly 30%, but PhCF₂CF₂CF₃ was not decomposed at all (entries 1–2). In addition, heating under the basic conditions¹⁴ or exposure to large excess of TfOH/C₆H₆ (ref. 15) resulted in complete degradation of 5, whereas PhCF₂CF₂CF₃ was partially degraded (entries 3–6). These results indicate the higher degradability of the SF₄ linker than that of the CF₂ linker.

Scheme 5 Derivatizations of aryltetrafluoro(polyfluoroethyl)-λ⁶-sulfanes. Isolated yields are provided. (A) Transformation reactions retaining the SF₄CF₂CF₂Cl group. (B) Reduction of the SF₄CF₂CF₂Cl group. (C) Synthesis of an analog of Tetrafluron. (D) Synthesis of tetrafluoro(perfluoroethyl)(phenyl)-λ⁶-sulfane 5.

Table 2 Comparison of degradability of 5 and PhCF₂CF₂CF₃

Entry	Substrate	Cond.	Result^a
a Conversion of 5 or PhCF2CF2CF3 was determined by ^19F NMR analysis of the crude mixture relative to an internal standard (trifluorotoluene or 4,4′-difluorobiphenyl). b 100% recovery of substrate.
1	5	8 : 1 DMSO : H2O, 120 °C, 24 h	Decomposition 32%
2	PhCF2CF2CF3	8 : 1 DMSO : H2O, 120 °C, 24 h	Decomposition 0%^b
3	5	NaOH, 8 : 1 DMSO : H2O, 120 °C, 24 h	Decomposition 100%
4	PhCF2CF2CF3	NaOH, 8 : 1 DMSO : H2O, 120 °C, 24 h	Decomposition 49%
5	5	1 : 1 TfOH : C6H6, rt, 4 h	Decomposition 100%
6	PhCF2CF2CF3	1 : 1 TfOH : C6H6, rt, 4 h	Decomposition 77%

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Substituent effects

Since aromatic compounds with the SF₄CF₂CF₂Cl and SF₄CF₂CF₃ groups were synthesized for the first time, we investigated their substituent effects such as hydrophobic parameters (π_Ph)¹⁶ and Hammett substituent parameters (σ_m and σ_p).¹⁷

The log P (P being the partition coefficient in an n-octanol/water system) values for 2a and 5 were measured using HPLC.¹⁸ The log P(2a) and log P(5) were measured to be 4.62 and 4.44, respectively. Based on these values, π_Ph(SF₄CF₂CF₂Cl) and π_Ph(SF₄CF₂CF₃) were estimated to be 2.49 and 2.31, respectively, indicating a slight hydrophobic effect of the terminal chlorine. Subsequently, the hydrophobicity of other fluorinated groups was compared with that of the SF₄CF₂CF₂Cl and SF₄CF₂CF₃ groups (Fig. 1). π_Ph(SF₄CF₂CF₂Cl) and π_Ph(SF₄CF₂CF₃) exhibited higher values than π_Ph(SF₅) (1.23) and π_Ph(SF₄CF₃) (2.13) owing to their longer carbon chains.^2,9c Comparing the SF₄CF₂CF₃ group with the perfluoroalkyl groups, π_Ph(SF₄CF₂CF₃) was higher than π_Ph(C₃F₇) and lower than π_Ph(C₄F₉), suggesting that the hydrophobic effect of the SF₄ group falls between those of one and two difluoromethylene (CF₂) groups.

Fig. 1 Hydrophobicity of fluorinated substituents. ^a From ref. 16c. ^b From ref. 2. ^c From ref. 9c.

The Hammett parameters of the SF₄CF₂CF₂Cl group were estimated through the ¹⁹F NMR approach developed by Taft (Table 3).¹⁹ As a result, the meta- and para-σ values (σ_m and σ_p) of the SF₄CF₂CF₂Cl group were estimated to be 0.61 and 0.66, respectively. Among electron-withdrawing functional groups, the values were higher than those of the CF₃ group (σ_m: 0.43, σ_p: 0.54), comparable to those of the CN (σ_m: 0.56, σ_p: 0.66), SF₅ (σ_m: 0.61, σ_p: 0.68), and SF₄CF₃ (σ_p: 0.68) groups, and lower than those of the NO₂ group (σ_m: 0.71, σ_p: 0.78).^9c,17b Although the SF₄CF₂CF₂Cl group has a longer carbon chain than the SF₄CF₃ group, the electron-withdrawing ability decreases; a similar trend has been reported for linear perfluoroalkyl groups (σ_p(CF₃): 0.54, σ_p(CF₂CF₃): 0.52, σ_p(CF₂CF₂CF₃): 0.48).^17b

Table 3 Hammett substituent parameters for the SF₄CF₂CF₂Cl group

δ H ^m-X	δ H ^p-X	σ I	σ ^0R	σ ^0m	σ ^0p
a Negative values of δH^m-X and δH^p-X represent downfield ^19F NMR shifts of the fluorobenzene derivatives relative to fluorobenzene.
−3.41^a	−6.29^a	0.56	0.10	0.61	0.66

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Conclusions

In summary, we unveiled an unexplored synthetic route for ArSF₄R_F compounds based on the addition reaction of ArSF₄Cl compounds to TFE. It was demonstrated that the inexpensive and scalable radical addition reactions can be applied to the synthesis of an analog of the bioactive molecule and perfluoroalkyl compounds. Additionally, we have estimated the π_Ph constant for the SF₄CF₂CF₂Cl and SF₄CF₂CF₃ groups, providing preliminary evidence of the significantly higher hydrophobicity of the SF₄ group compared to the CF₂ group. We believe that the development of the SF₄R_F groups and the elucidation of their fundamental properties achieved in this study provide promising options for the application of fluorinated functional groups.

The ArSF₄R_F compounds are related to per- and polyfluoroalkyl substances (PFAS), and therefore potential accumulation cannot be ruled out at present.²⁰ Close attention should be paid to this issue for further application.

Data availability

All experimental data and detailed procedures are available in the ESI.†

Author contributions

E. Y. conducted the experiments, analysed the data, and wrote the original draft. K. A. and T. O. directed the project. K. N. provided advice and discussed the data. All the authors discussed the results and contributed to the review and editing of the manuscript.

Conflicts of interest

An application for a patent (application number: WO2022JP035414) related to this work has been submitted by K. A., E. Y., K. N., and T. O. as co-inventors.

Acknowledgements

The computation was performed using Research Center for Computational Science, Okazaki, Japan (Project: 22-IMS-C017). E. Y. would like to thank the Program for Leading Graduate Schools (MERIT-WINGS) for financial support. This work was supported by JSPS KAKENHI, Grant No. 20K05460 (K. A.). AGC Inc. is acknowledged for supporting this study.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2282789. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc04837c

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