The SF5 group has great potential in influencing the drug-like features of organic molecules due to its chemical stability, hydrophobic surface, electron-withdrawing capability and unique octahedral geometry. However, the difficulty in synthesising SF5-containing compounds, particularly in aromatic systems, has impeded the widespread incorporation of this group into desired scaffolds in medicinal chemistry. The most troublesome step operationally involves the synthesis of the intermediate species ArSF4Cl from aryl-disulfides. Here, we report an analytical-scale synthesis of ArSF4Cl using flow microfluidic technology, allowing for safer handling of reagents and avoiding the need for gloveboxes or Cl2 cylinders. The system is fairly straightforward to prepare, clean to assemble and can be adapted easily to further developments. As well as making progress towards continuous de novo syntheses of ArSF5 compounds, this result broadly highlights the potential of flow chemistry in providing new avenues to perform challenging batch reactions.
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Altomonte S, Zanda M (2012) Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules. J Fluor Chem 143:57–93. https://doi.org/10.1016/j.jfluchem.2012.06.030
Savoie PR, Welch JT (2015) Preparation and utility of organic pentafluorosulfanyl-containing compounds. Chem Rev 115:1130–1190. https://doi.org/10.1021/cr500336u
Duveau DY, Hu X, Walsh MJ, Shukla S, Skoumbourdis AP, Boxer MB, Ambudkar SV, Shen M, Thomas CJ (2013) Synthesis and biological evaluation of analogues of the kinase inhibitor nilotinib as Abl and kit inhibitors. Bioorganic Med Chem Lett 23:682–686. https://doi.org/10.1016/j.bmcl.2012.11.111
Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Acenã JL, Soloshonok VA, Izawa K, Liu H (2016) Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II-III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem Rev 116:422–518. https://doi.org/10.1021/acs.chemrev.5b00392
Stump B, Eberle C, Schweizer WB, Kaiser M, Brun R, Krauth-Siegel RL, Lentz D, Diederich F (2009) Pentafluorosulfanyl as a novel building block for enzyme inhibitors: Trypanothione reductase inhibition and antiprotozoal activities of diarylamines. ChemBioChem 10:79–83. https://doi.org/10.1002/cbic.200800565
Wipf P, Mo T, Geib SJ, Caridha D, Dow GS, Gerena L, Roncal N, Milner EE (2009) Synthesis and biological evaluation of the first pentafluorosulfanyl analogs of mefloquine. Org Biomol Chem 7:4163–4165. https://doi.org/10.1039/b911483a
Welch JT, Lim DS (2007) The synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine, and norfenfluramine. Bioorganic Med Chem 15:6659–6666. https://doi.org/10.1016/j.bmc.2007.08.012
Umemoto T, Garrick LM, Saito N (2012) Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry. Beilstein J Org Chem 8:461–471. https://doi.org/10.3762/bjoc.8.53
Pitts CR, Bornemann D, Liebing P, Santschi N, Togni A (2019) Making the SF5 group more accessible: a gas-reagent-free approach to aryl Tetrafluoro-λ 6 -sulfanyl chlorides. Angew Chemie - Int Ed 58:1950–1954. https://doi.org/10.1002/anie.201812356
Wang L, Cornella J (2020) A unified strategy for Arylsulfur(VI) fluorides from aryl halides: access to Ar-SOF3 compounds. Angew Chemie - Int Ed 1–7. https://doi.org/10.1002/anie.202009699
Kanishchev OS, Dolbier WR (2015) Synthesis and characterization of 2-pyridylsulfur pentafluorides. Angew Chemie - Int Ed 54:280–284. https://doi.org/10.1002/anie.201409990
Lummer K, Ponomarenko MV, Röschenthaler GV, Bremer M, Beier P (2014) An improved method for the fluorination of arylsulfur chlorotetrafluorides to arylsulfur pentafluorides. J Fluor Chem 157:79–83. https://doi.org/10.1016/j.jfluchem.2013.10.009
Cui B, Jia S, Tokunaga E, Saito N, Shibata N (2017) Silver-induced self-immolative cl-F exchange fluorination of arylsulfur chlorotetrafluorides: synthesis of arylsulfur pentafluorides. Chem Commun 53:12738–12741. https://doi.org/10.1039/c7cc07222h
Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017) The Hitchhiker’s guide to flow chemistry. Chem Rev 117:11796–11893. https://doi.org/10.1021/acs.chemrev.7b00183
Chambers RD, Spink RCH (1999) Microreactors for elemental fluorine. Chem Commun 2:883–884. https://doi.org/10.1039/a901473j
Singh SJ, Devi NS (2016) Diacetoxyiodobenzene mediated oxidative transformation of thione to disulfides. Tetrahedron Lett 57:5941–5943. https://doi.org/10.1016/j.tetlet.2016.11.091
Strauss FJ, Cantillo D, Guerra J, Kappe CO (2016) A laboratory-scale continuous flow chlorine generator for organic synthesis. React Chem Eng 1:472–476. https://doi.org/10.1039/c6re00135a
Jadhav VH, Jeong HJ, Choi W, Kim DW (2015) Crown ether metal complex fluoride salt as a facile and low hygroscopic fluoride source for nucleophilic fluorination. Chem Eng J 270:36–40. https://doi.org/10.1016/j.cej.2015.01.087
Sheppard WA (1962) Alkyl- and Arylsulfur Trifluorides. J Am Chem Soc 84:3058–3063. https://doi.org/10.1021/ja00875a005
Berton M, Sheehan K, Adamo A, McQuade DT (2020) Disposable cartridge concept for on-demand synthesis of Turbo Grignards, Knochel-Hauser Amides and Magnesium Alkoxides. Beilstein J Org. Chem 16:1343–1356. https://doi.org/10.3762/bjoc.16.115
Talla A, Driessen B, Straathof NJW, Milroy LG, Brunsveld L, Hessel V, Noël T (2015) Metal-free Photocatalytic aerobic oxidation of Thiols to disulfides in batch and continuous-flow. Adv Synth Catal 357:2180–2186. https://doi.org/10.1002/adsc.201401010
This work was supported financially by an Australian Government Research Training Program (RTP) Scholarship; and AINSE Limited through the Residential Student Scholarship (RSS). The National Imaging Facility is gratefully acknowledged. The authors also thank C.R. Pitts and A. Togni for helpful discussions.
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Surjadinata, G., Hunter, L., Matesic, L. et al. Analytical-scale synthesis of aryl-SF4Cl via flow microfluidic technology. J Flow Chem 11, 107–115 (2021). https://doi.org/10.1007/s41981-020-00130-5
- Flow chemistry
- Arylsulfur chlorotetrafluoride