Fluorination

Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

Ar-SF 4 Cl Deoxofluorination

  • Benqiang Cui
  • Norio ShibataEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-981-10-1855-8_18-1

Introduction

Eccentric properties of fluorine such as highest electronegativity and smallest atomic radius after the hydrogen atom make the fluorine atom a pivotal element in biological and material applications. A variety of methods now exist for introducing fluorine into organic molecules [1, 2, 6, 7, 8, 11, 28, 29, 30, 36, 43, 44]. Among them, deoxo- and dethioxo fluorination methods involving the direct replacement of oxygen and/or sulfur moieties in substrates with fluorine are one of the most effective approaches for the selective synthesis of organofluorine compounds. Various reagents such as SF4 [14], DAST (diethylaminosulfur trifluoride) [26], Deoxo-Fluor [bis(2-methoxyethyl)aminosulfur trifluoride] [3], DFI (2,2-difluoro-1,3-dimethylimidazolidine) [15], DFMBA (N,N-diethyl-α,α-difluoro-m-methylbenzylamine) [22], TFFH (fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate) [9], PhenoFluor [1,3-bis(2,6-diisopropylphenyl)-2,2-difluoro-2,3-dihydro-1H-imidazole] [38], CpFluors (3,3-difluoro-1,2-diarylcyclopropene) [27], XtalFluor-E [(diethylamino)difluorosulfonium tetrafluoroborate] and XtalFluor-M (difluoro-4-morpholinylsulfonium tetrafluoroborate) [3, 25], Fluolead (4-tert-butyl-2,6-dimethylphenylsulfur trifluoride) [42], and PyFluor (2-pyridinesulfonyl fluoride) [31] have been developed for this purpose. The title compounds, arylsulfur chlorotetrafluorides (ArSF4Cl), fluorinate many kinds of oxy- and sulfur-containing substrates such as alcohols, aldehydes, ketones, diketones, carboxylic acids, and sulfur compounds to corresponding fluoro-compounds in the presence of reducing reagents. Arylsulfur trifluorides (ArSF3) generated in situ from ArSF4Cl are reactive species in this transformation. Sulfur substrates are directly fluorinated with ArSF4Cl without the addition of reducing agents transferring to the corresponding fluorinated compounds (Fig. 1) [41].
Fig. 1

Deoxo- and dethioxo-fluorination using ArSF4Cl

Synthesis and Properties of ArSF4Cl

Janzen reported the preparation of ArSF4Cl (Ar = Ph, p-MePh, p-NO2Ph) by the reaction of diaryl disulfides (ArSSAr) with XeF2 in the presence of tetra-ethylammonium chloride [32]. Fifteen years later, Umemoto reported a practical method for the preparation of ArSF4Cl by the reaction of ArSSAr or aryl thiols (ArSH) with an excess amount of chlorine in the presence of potassium fluoride or cesium fluoride in dry acetonitrile between 0 °C and room temperature [40, 41] (Fig. 2). The Dolbier group developed methods for the synthesis of o-pyridylsulfur chlorotetrafluorides (o-PySF4Cl) by applying conditions analogous to those used for the reaction of ArSSAr by Umemoto. While Dolbier’s method is strictly limited to the substrates of ortho-substituted pyridines, i.e., o-PySSPy, Shibata and coworkers overcame this issue by using m- and p-pyridine disulfides (m-PySSPy, p-PySSPy) having at least one fluorine atom on the pyridine ring; thus, the synthesis of m- and p-PySF4Cl was accomplished in 2016. Both conditions are fundamentally the same in that 16 equivalents of KF (or CsF) and 8 or more equivalents of Cl2 are required per 1 equivalent of disulfide in dry acetonitrile [18, 24] (Fig. 3).
Fig. 2

Synthesis of ArSF4Cl

Fig. 3

Synthesis of PySF4Cl

Interestingly, ArSF4Cl is relatively insensitive to moisture compared with ArSF3 and has a rather high thermal stability [37, 40, 42]. On the other hand, PySF4Cl is extremely sensitive to moisture and fumes when exposed to air. They react vigorously with water [18, 24]. Thus, ArSF4Cl is considered to be a fluorinating reagent, while PySF4Cl is not useful for this purpose. ArSF4Cl can be stored for a long period in a fluoropolymer vessel at room temperature.

ArSF4Cl structurally exists as cis- and trans-isomers, the former having three types of fluorine and the latter only one. Chemical shifts of 19F NMR of phenylsulfur chlorotetrafluoride (PhSF4Cl) are shown in Fig. 4 [32]. The cis-isomer of PhSF4Cl is less stable and is generally isomerized into the corresponding trans-isomer with some exceptions [24, 32, 40].
Fig. 4

Structures of cis- and trans-PhSF4Cl and their 19F NMR chemical shifts

Fluorination Reactions Mediated by ArSF4Cl

Fluorinations with ArSF3 in Situ Prepared from ArSF4Cl

ArSF4Cl, as it is, does not directly react with alcohol, benzaldehyde, or benzoic acid during the deoxofluorination reaction in dichloromethane (DCM) at room temperature for 24 h [41]. However, after the reactive ArSF3 is generated in situ by the treatment of ArSF4Cl with reducing agents, the deoxofluorination reaction of the substrates mentioned above proceeds very well (Fig. 5) [41]. That is, ArSF4Cl 1, 2, and 5 are first treated with an equivalent amount of pyridine in DCM at room temperature for 1.5 h to support the formation of ArSF3, and then substrates such as carboxylic acids, alcohols, aldehydes, ketones, and diketones 45, 47, 49, 51, 53, 55, and 57 are added into the DCM solution, with an additive if necessary, to provide the corresponding deoxo-fluorides 46, 48, 50, 52, 54, 56, and 58 in high yields (Fig. 6) [41].
Fig. 5

In situ formation of ArSF3 from ArSF4Cl with pyridine

Fig. 6

Examples of fluorination with ArSF3 generated in situ from ArSF4Cl with pyridine

Selective monofluorination of diols using DFMBA [10, 39, 45] and Fluolead [42] have been reported, and the reactions of the former DFMBA require harsh reaction conditions 1,2-Bis(trimethylsiloxy)ethane 59 reacts efficiently with ArSF3 41, 42, and 43, generated in situ from ArSF4Cl in the presence of two equimolar amounts of pyridine, without any additives, to furnish the corresponding 2-fluoroethyl arylsulfinates 60, 61, and 62 in good yields. In addition to the fluorination, arylsulfinylation of one of the silyl ethers occurs simultaneously (Fig. 7) [41].
Fig. 7

Fluorination and functionalization of siloxylalkane 59 with ArSF3 generated in situ from ArSF4Cl with pyridine.

It is interesting to note that reactive ArSF3 is also generated in situ by the disproportionation reaction of ArSF4Cl in the presence of ArSSAr, instead of pyridine. A concentrated solution of one sixth equimolar amount of ArSSAr in a small amount of dry DCM was added to neat ArSF4Cl in a fluoropolymer reactor. The mixture was then heated at 85 °C to produce ArSF3 and chlorine gas (Fig. 8). PhSF3 41 generated in situ from PhSF4Cl 1 fluorinated alcohols 47 and 63 in DCM at room temperature without any additives to produce 48 and 64 in good yields, respectively (Fig. 9). The deoxofluorination reaction of carbonyl compounds 49 and 55 with 41 produced difluoride 50 and 56 in the presence of a small amount of ethanol (Fig. 10). In this event, ethanol generates HF with the reaction of 41. Aromatic and aliphatic carboxyl groups and carbonyl chloride were converted to the corresponding CF3 compounds in excellent yields by heating a mixture of neat 41, 42, or 43 with HF-py at 50 °C (Fig. 11). Various sulfur compounds were also efficiently converted into corresponding fluorinated compounds in DCM at room temperature via desulfurization by 41 in excellent yields (Fig. 12) [41].
Fig. 8

Preparation of ArSF3 41, 42, and 43 in situ from ArSF4Cl 1, 2, and 5 with 1/6 equiv ArSSAr

Fig. 9

Fluorination of alcohols 47 and 63 by in situ-generated PhSF3 41 from PhSF4Cl 1 with 1/6ArSSAr

Fig. 10

Fluorination of aldehyde 49 and ketone 55 by in situ-generated PhSF3 41 from PhSF4Cl 1 with 1/6ArSSAr

Fig. 11

Fluorination of carboxylic acids 45, 67, and carbonyl chloride 65 by in situ-generated ArSF3 4143 from ArSF4Cl with 1/6 equiv ArSSAr

Fig. 12

Dethiofluorination of sulfur derivatives 69, 70, and 72 by in situ-generated PhSF3 41 from PhSF4Cl 1 with 1/6 equiv ArSSAr

Fluorination of Thioacetals, Thioketones, Thioesters, and Thiocarbonates

DAST [5], Deoxo-Fluor, Fluolead [42], BrF3 [4, 12, 13, 33, 34 ], difluoroiodotoluene [23], N-halo imide/HF-pyridine [19, 20, 21, 35], and IF5-pyridine-HF [16, 17] are known dethioxo-fluorinating reagents for thioketones, thioesters, or dithiocarbonates. Umemoto reported the direct dethioxofluorination of sulfur-containing compounds with ArSF4Cl without any additive or catalyst such as pyridine, ArSSAr, and SbCl3 (Fig. 13) [41]. In contrast, DAST and Deoxo-Fluor require a catalyst in this reaction. A dithiocarbonate 72 was treated with ArSF4Cl reagents such as 1, 2, 4, 5, 6, 7, and 8 to give a OCF3 compound 73 in high yields. Various thiocarbonyl compounds 74, 76, 78, and 79 were converted to dethiofluorinated CF2 and CF3 compounds 75, 77, 66, and 80 in excellent yields with PhSF4Cl 1 (Fig. 13).
Fig. 13

Direct dethiofluorination of thiocarbonyl compounds with ArSF4Cl

Conclusion

We have described the applications of ArSF4Cl for deoxo- and dethioxofluorination reactions of various organic compounds. Alcohols, aldehydes, ketones, diketones, carboxylic acids, thioacetals, thioketones, thioesters, and thiocarbonates are converted into corresponding deoxo- and dethioxo-fluorinated compounds in good to high yields. In the presence of pyridine or ArSSAr, ArSF4Cl displays a versatile capacity for fluorinations, in which the in situ generation of ArSF3 contributes to the transformation. For dethioxofluorination reactions of several thiocarbonyl compounds, fluorination by ArSF4Cl occurs directly without any additives. Since ArSF4Cl possesses moderately high thermal stability and is relatively easily available as an intermediate for the production of ArSF5; thus, it makes further applications of ArSF4Cl attractive for various types of fluorination reactions.

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Nanopharmaceutical Sciences, Department of Life Science and Applied ChemistryNagoya Institute of TechnologyGokiso, Showa-kuJapan