Synthesis of Dibenzothiophenium Salts and Observations in Radiofluorination

Abstract

We demonstrate an alternative synthesis of dibenzothiophenium (DBT) salts through a three-step Pd-catalyzed arylation, oxidation, and cyclization sequence. This approach is operationally straightforward and compatible with a variety of common functional groups. We observed that radiofluorination of a set of related DBT salt precursors gave higher radiochemical incorporation (RCI) with substrates bearing ortho-substituents to the DBT leaving group, suggestive of an ortho-effect.

Key words

dibenzothiophenium salts - ortho-effect - radiofluorination

• References and Notes


For reviews and recent advances of radiofluorination of arenes, see
• 1a Tredwell M, Gouverneur V. Angew. Chem. Int. Ed. 2012; 51: 11426
• 1b Kilbourn MR, Scott PJ. H. Handbook of Radiopharmaceuticals: Methodology and Applications, 2nd ed. John Wiley & Sons; Hoboken: 2021: 251-290
• 1c Deng X, Rong J, Wang L, Vasdev N, Zhang L, Josephson L, Liang SH. Angew. Chem. Int. Ed. 2019; 58: 2580
• 1d Fan R, Tan C, Liu Y, Wei Y, Zhao X, Liu X, Tan J, Yoshida H. Chin. Chem. Lett. 2021; 32: 299
• 1e Halder R, Ritter T. J. Org. Chem. 2021; 86: 13873
• 1f Liu Z, Sun Y, Liu T. Front. Chem. 2022; 10: 883866
• 2 Sander K, Gendron T, Yiannaki E, Kalber TL, Lythgoe MF, Årstad E. Sci. Rep. 2015; 5: 9941
• 3 Gendron T, Sander K, Cybulska K, Benhamou L, Sin PK. B, Khan A, Wood M, Porter MJ, Årstad E. J. Am. Chem. Soc. 2018; 140: 11125
• 4 Sirindil F, Maher S, Schöll M, Sander K, Årstad E. Int. J. Mol. Sci. 2022; 23: 15481
• 5 Schüll A, Grothe L, Rodrigo E, Erhard T, Waldvogel SR. Org. Lett. 2024; 26: 2790
• 6 Xu P, Zhao D, Berger F, Hamad A, Rickmeier J, Petzold R, Kondratiuk M, Bohdan K, Ritter T. Angew. Chem. Int. Ed. 2020; 59: 1956
• 7 Sirindil F, Årstad E, Sander K, Awais R, Twyman F, Marcolan C, Glaser M. Nucl. Med. Biol. 2022; 108: S137
• 8 Varlow C, Murerell E, Holland JP, Kassenbrock A, Shannon W, Liang SH, Vasdev N, Stephenson NA. Molecules 2020; 25: 982

For selected applications of dibenzothiophenium salts, see:
• 9a Berger F, Alvarez EM, Frank N, Bohdan K, Kondratiuk M, Torkowski L, Engl PS, Barletta J, Ritter T. Org. Lett. 2020; 22: 5671
• 9b Kafuta K, Korzun A, Böhm M, Golz C, Alcarazo M. Angew. Chem. Int. Ed. 2020; 59: 1950
• 9c Tian Z, Lin Z, Zhang C. Org. Lett. 2021; 23: 4400
• 9d Selmani A, Schoenebeck F. Org. Lett. 2021; 23: 4779
• 9e Tian Z, Zhang C. Org. Chem. Front. 2022; 9: 2220
• 9f Zhang Q, Xue X, Hong B, Gu Z. Chem. Sci. 2022; 13: 3761
• 9g Hamad A, Mrozowicz M, Xie Y, Ritter T. Synlett 2024; 35: 1028
• 10 Maitro G, Vogel S, Prestat G, Madec D, Poli G. Org. Lett. 2006; 8: 5951
• 11 Xiong H, Hoye AT, Fan K.-H, Li X, Clemens J, Horchler CL, Lim NC, Attardo G. Org. Lett. 2015; 17: 3726
• 12 We have also examined hyperiodinanes (PIFA/PIDA) as the activator, but they tend to have low functional group tolerance.
• 13 We also performed radiolabeling of 6i under various temperatures and summarized the results in the Supporting Information.

Early reports of ortho-effects in S_NAr reactions:
• 14a Branchand GE. K, Calvin M. The Theory of Organic Chemistry, 2nd ed. Prentice Hall, Inc; New York: 1947: 257
• 14b Taft RW. Steric Effects in Organic Chemistry . Newman MS. John Wiley and Sons; New York: 1956. Chap. XIII

Earlier examples of ortho-effects in halogenation of iodonium salts:
• 15a Le Count DJ, Reid JA. J. Chem. Soc. C 1967; 1298
• 15b Yamada Y, Okawara M. Bull. Chem. Soc. Jpn. 1972; 45: 1860
• 15c Shah A, Pike VW, Widdowson DA. J. Chem. Soc., Perkin Trans. 1 1998; 2043
• 16a Hostetler ED, Jonson SD, Welch MJ, Katzenellenbogen JA. J. Org. Chem. 1999; 64: 178
• 16b Martin-Santamaria S, Caroll MA, Caroll CM, Carter CD, Pike VW, Rzepa HS, Widdowson DA. Chem. Commun. 2000; 8: 649
• 17 Ross TL, Ermert J, Hocke C, Coenen HH. J. Am. Chem. Soc. 2007; 129: 8018
• 18 Wang L, Jacobson O, Avdic D, Rotstein BH, Weiss ID, Collier L, Chen X, Vasdev N, Liang SH. Angew. Chem. Int. Ed. 2015; 54: 12777
• 19 Sharninghausen LS, Brooks A, Winton W, Makaravage K, Scott P, Sanford MS. J. Am. Chem. Soc. 2020; 142: 7362

For mechanisms of the ortho-effect, see:
• 20a Wang X, Salaski EJ, Berger DM, Powell D. Org. Lett. 2009; 11: 5662
• 20b Wendt MD, Kunzer AR. Tetrahedron Lett. 2010; 51: 641
• 20c Cheron N, El Kaim L, Grimaud L, Fleurat-Lessard P. Chem. Eur. J. 2011; 17: 14929
• 20d Qian W, Wang H, Bartberger MD. J. Am. Chem. Soc. 2015; 137: 12261
• 20e Um I.-H, Kim M.-Y, Dust JM. Can. J. Chem. 2017; 95: 1273
• 20f Yap JL, Hom K, Fletcher S. Tetrahedron Lett. 2011; 52: 4172
• 21 Sulfoxide Intermediates; General Procedure A The starting aryl iodide or bromide (1 equiv), 2-ethylhexyl 3-((3′,5′-dimethoxy-5-methyl-[1,1′-biphenyl]-2-yl)thio)propanoate (1.5 equiv), Pd₂(dba)₃ (0.05 equiv), and XantPhos (0.1 equiv) were dissolved in 1,4-dioxane (0.2 M) in a vial, followed by the addition of KOtBu solution (1.0 M in THF, 1.5 equiv) at ambient temperature. The resulting slurry was heated to 85 °C and was monitored by TLC or LCMS. The dark-red reaction mixture was either concentrated directly or quenched with water and was extracted three times with ethyl acetate. The organic layers were combined and concentrated, and the residue was purified by silica gel column (hexanes and ethyl acetate) to yield the aryl sulfide. To a stirred solution of aryl sulfide (1 equiv) in DCM (0.2 M) was added m-CPBA (1.01 equiv) in DCM dropwise at 0 °C. The mixture was allowed to warm to ambient temperature and stirred until the reaction was complete (monitored by LCMS). The mixture was then concentrated and purified by silica gel column (hexanes and ethyl acetate) to yield the aryl sulfoxide as a solid. Dibenzothiophenium Salts; General Procedure B To the solution of aryl sulfoxide (1 equiv) in DCM (0.1 M) was added polystyrene-supported diethylamine (1.5–3 equiv). The slurry was cooled to 0 °C and Tf₂O solution (1.0 M in DCM, 3 equiv) or neat TFAA (3 equiv) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and was further stirred for 30 min. The reaction was quenched with several drops of water and was filtered to give a clear solution. The solid was further washed with DCM and the combined solution was directly purified by silica gel column (0–20% MeOH in DCM) to yield the dibenzothiophenium salt as a solid. Radiofluorination; General Procedure Radiofluorinations were carried out in DMSO and tetraethylammonium bicarbonate (TEAHCO₃). For consistency, the precursor concentration was maintained at 1.5 ± 0.2 mM and the molar ratio of TEAHCO₃ to precursor was set to 6 ± 1 to 1. In a typical study, [¹⁸F]fluoride was isolated from ¹⁸O-water using a Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge (Waters, 40 mg Sorbent per Cartridge, 40 μm Particle Size). The QMA cartridge was then rinsed with water for injection (WFI). Activity was then eluted using 0.8 mL of tetraethyl ammonium bicarbonate (TEAHCO₃) in MeCN/WFI (4:1) solution into a vial, where the solvent was removed by heating at 100 °C with N₂ flow purging for 5 minutes and dried further by the addition of 300 μL of MeCN for azeotropic drying for approximately 5 minutes. The dried [¹⁸F]TEAF/TEAHCO₃ was then redissolved in anhydrous DMSO. An aliquot of the [¹⁸F]TEAF/TEAHCO₃ in DMSO solution was then added to a vial containing the sulfonium salt precursor being evaluated. The reaction mixture was then heated at different temperatures (80–160 °C) for 15 minutes and then cooled to room temperature. A sample of the reaction mixture was taken immediately and analyzed via HPLC for radiochemical incorporation (RCI) and product identity confirmation against a reference standard of the expected product.