Aromatic SF5 Derivatives

Prepared in High Yield via Highly Versatile & Cost Competitive Methods

UBE Aromatic SF5 compounds are expected to be useful as BUILDING BLOCKS for pharmaceutical agents, pesticides, liquid crystals, conductive polymer, and higher performance organic materials.

PRODUCT LINE-UP

UBE Aromatic SF5 derivatives, prepared in high yield via highly versatile & cost competitive methods

Introduction:

Concurrent with significant developments in the synthetic methodology for the preparation of SF5 containing compounds, many potential applications, derived from the interesting and unique properties of the SF5 function, have been proposed, particularly in certain advanced specialty chemical fields such as pharmaceuticals, agrochemicals and electronics.

The SF5 function, one of the most electron-withdrawing groups known, imparts outstanding lipophilic properties to compounds which incorporate it, as well as added chemical and thermal stability. It is expected that the higher lipophilicity and other properties of SF5 compounds will show interesting and unique influences on biological activities other than those observed with fluorine or trifluoromethyl-groups 1).

Regarding electronics chemicals, it is reported that there has been a rapid increase in the number of patents which list the SF5 group and other groups in liquid crystals due to the strong dipole moment which can be achieved by the SF5 group 1), 2).

Properties of Aromatic SF5 compounds:

Electron-withdrawing Effect 3)
SF5 group is recognized as a strong electron-withdrawing group. Fig.1 below shows the comparative values of pKa in the substituted benzoic acid derivatives which have SF5, CF3, SCF3, OCF3 and F, respectively. In Fig.1, SF5 derivative is ranked as the second strongest group after the nitro-substituted one.

B) Lipophilicity 2)
It is well known that compounds which incorporate fluorine(s) show greater lipophilicity. Table 1 shows the comparative values of lipophilicity with varying substituents in the molecule. SF5 substituted compounds are expected to show excellent lipophilicity compared with other fluorine-containing compounds.

C) Thermal and Chemical Stability
Aromatic SF5 compounds possess excellent thermal and chemical stability. For example, it was demonstrated that the thermal decomposition rate of PhSF5 (PSF) was less than 20% after it was heated in a sealed tube at 400oC for 7 hours 3a). It was also demonstrated that　aromatic SF5 compounds are more tolerant than aromatic CF3 compounds under strong conditions of Brønsted acids and bases 3a, 4a) and can be widely applied for common synthetic transformations in high yield. Examples of reactions for Aromatic SF5 compounds are shown below 4).

D) Toxicity
Regarding the assessment of toxicity of Aromatic SF5 compounds, the aromatic SF5 compounds shown in Table 2 below were assayed for both Ames and Acute Oral Toxicity. Table 2 below shows both results including the empirical data obtained from the Acute Oral Toxicity test. 4MPSF showed the weak toxicity, whose range is 50-300mg/Kg and ranked as Category 3 in UN GHS (Table 2).

E) Biological Activities

Currently, the introduction of fluorine into organic molecules has become very common methodology in biomedical fields, and numerous fluorine containing molecules have been developed and many have shown significant promise and advantages in this field. In particular, the pentafluorosulfanyl (SF5) group, which is a highly fluorinated functional group, has shown remarkable activity in biochemical molecules. The introduction of the SF5 group brings not only the novel properties which originate from Fluorine element (Strong electronegativity, high lipophilicity and high chemical stability) to the molecule, but also a larger steric effect than the CF3 group, which is also recognized as a highly fluorinated functional group. The relative steric demand of the SF5 group is slightly less than that of a tert-butyl group and considerably larger than that of a CF3 group 5). Examples of biological activities comparing the CF3 substituted agent vs. the SF5 analog are shown below;
Mefloquine is used for both treatment and prophylaxis of malaria (Fig. 2). 8-SF5-Mefloquine showed a longer half-life(68h) than Mefloquine(23h) after administration to mice 4e), 6). Fipronil is a broad spectrum insecticide (Table 3).SF5 analogue of Fipronil was not only more active than Fipronil but showed no loss of potency towards the resistant strain of housefly, in contrast to the Fipronil 7).

UBE Preparation Methods:

In order to contribute to and improve SF5 chemistry above, UBE has started to deliver a series of aromatic pentafluorosulfanyl compounds prepared by new innovative processes including our KF/Cl2 method, which was developed by IM&T Research Inc. (Scheme 1) 8).

Our KF/Cl2 method is widely applicable to various aromatic disulfide compounds, which are direct starting materials for the corresponding aromatic SF5 compounds. This has enabled us to introduce the SF5 group into various aromatic rings via a 2 step process from the corresponding aryl-disulfide, as compared to the direct fluorination process utilizing elemental fluorine, which is limited by the use of only nitro-aryl compounds as starting materials 9).

With the KF/Cl2 process, aryl-disulfide is converted to the corresponding aryl tetrafluorosulfanyl- chloride. This process is equally applicable to aromatic thiophenol compounds. The obtained Aryl-SF4Cl from the KF/Cl2 process can then be converted to the corresponding aryl-pentafluoro- sulfanyl compound with zinc difluoride or anhydrous HF. Aryl-SF4Cl preparation proceeds with high yield around 80-90% at room temperature, and the starting materials provided for this reaction, aryl-disulfide, KF and Cl2, are commodity materials, which can be obtained conveniently and at relatively low prices for industrial scale production.

The conversion to Aryl-SF5 from the corresponding Aryl-SF4Cl, proceeds with high yield (around 70-80%) with zinc difluoride at 100℃, and it also has been demonstrated that this reaction proceeds with aHF in high yield (70-75%) below 20℃.

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Contact:

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UBE America Inc. ,

http://www.ube.com/index_US.php
6860 N. Broadway Suite B, Denver, CO 80221, USA
Phone: +1-(303)412-5650
E-mail: fluorine@ube.com

References:

1. R. W. Winter, R. A. Dodean, and G. L.Gard, Fluorine-Containing Synthons, V. A. Soloshonok edited; American Chemical Society, Washington,2005, 911, 87.

2. P. Kirsch, Modern Fluoroorganic Chemistry; WILEY-VCH, Weinheim, 2004,146.

3. a) W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, 3072-76. b) C. J. Byrne, et al., J. Chem. Soc. Perkin Trans. 2 1987, 1649-53. c) J. Shorter, Pure Appl. Chem. 1997, 69, 2497-2510.

4. a) R. D. Bowden et al., Tetrahedron 2000, 56, 3399-3408. b) P. Kirsch et al., Angew. Chem. Int. Ed. 1999, 38, 1989-1992. c) S. Nishino et al., JP Patent 2009-96740, 2009. d) A. M. Sipyagin et al., J. Fluorine Chem. 2004, 125, 1305-1316. e) T. Mo et al., Tetrahedron Lett., 2010, 51, 5137-5140.

5. D. Lentz et al., In Chemistry of Hypervalent Compounds, K. Akiba, (Eds), Wiley-VCH, New York, 1998, 295.

6. G. S. Dow et al., WO 2010/144434, 2010.

7. P. J. Crowley et al., CHIMIA 2004, 58, 138-142.

8. T. Umemoto et al., Beilstein J. Org. Chem. 2012, 8, 461–471.

9. R. D. Bowden et al., WO 97/05106, 1997.

10. T. Umemoto et al., US 7592491, 2009.