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.

Fluorine-18 substituted arenes have become a common moiety in positron emission tomography (PET) radiotracers due to their common occurrence in CNS-penetrant small molecules and enhanced metabolic stability compared to aliphatic fluorides. Synthesis strategies to install fluoroarenes generally involve (1) nucleophilic aromatic substitution (S_NAr) reactions in which precursor molecules often bear a leaving group on the aromatic ring such as a nitro, halide, -onium salt, or ylide, or (2) metal-catalyzed coupling reactions with borates or stannanes.[1]

Among substrates used in S_NAr-type radiofluorination reactions, aryl dibenzothiophenium (DBT) salt precursors enable facile radiosyntheses and have shown good radiochemical yields (RCYs) and reasonable storage stabilities.[2] [3] Initially reported by the Årstad group in 2018, the synthesis of DBT salts was achieved using an oxidation–cyclization strategy featuring N-chlorosuccinimide (NCS) and Lewis acid (Scheme [1a]).[3] Although this method enabled DBT formation from aryl sulfides in a single step, it could not be applied to neutral and electron-deficient substrates due to a lack of oxidation regioselectivity. Later, an optimized synthesis of DBT salts was reported involving periodic acid oxidation of the sulfide to the sulfoxide followed by cyclization under elevated (70 °C) or low (–40 °C) temperatures.[4] A similar approach was accomplished by the Waldvogel group in 2024 using electrosynthesis.[5] Following a different approach, the Ritter group synthesized DBT salts via a late-stage intermolecular C–H functionalization (Scheme [1b]).[6] The synthesis was accomplished by an aromatic C–H insertion using a Pummerer-type intermediate derived from dibenzothiophene S-oxides. While this novel method utilizes matching electron density to enable labeling of electron-rich arenes, the regioselectivities of DBT introduction were governed by the substrates and, in some cases, provided mixtures of DBT products.

Recent publications of process improvements and synthetic applications reflect an increasing interest in DBT salts within the field of radiochemistry[7] [8] and beyond.[9] Here, we report an alternative synthesis of DBT salt precursors bearing diverse functional groups using mild conditions with readily available reagents (Scheme [1c]).

Our first objective was to identify a robust pathway to access sulfoxide 4. As shown in Scheme [2], the synthesis of biaryl sulfide 3 was achieved by a Pd-catalyzed coupling between Halide 1 and commercially available sulfide 2, the latter having undergone retro-Michael elimination in situ to reveal the active coupling partner. Next, meta-chloroperoxybenzoic acid (m-CPBA) oxidation at ambient temperature afforded the aryl sulfoxide intermediate 4 in moderate yields and high purities following column chromatography.

Aryl sulfoxides 4a–w, bearing ortho- or para-substituents relative to the sulfoxide, were prepared by following the two-step approach. Nitrogen-containing heterocycles were tolerated, including pyridine (4a,b, and 4g–h), pyrazole (4c,d, and 4p), triazole (4i), quinoline and isoquinoline (4j–m), imidazopyridine (4n), and benzothiazole (4o) highlighting the excellent chemoselectivity of sulfide oxidation. Carboxylic acid (4r) and tert-butoxycarbonyl (Boc)-group (4u) substituents were also compatible; however, aniline derivatives (4s–t) were formed in slightly lower yields. Finally, morpholine (4v) and sulfide (4w) substrates were prepared by palladium-catalyzed arylation of the corresponding sulfenate anion using the Madec/Poli method to avoid anticipated chemoselectivity challenges (see the Supporting Information).[10]

Having secured access to a variety of biaryl sulfoxides, we began screening reaction conditions for DBT formation by dehydrative intramolecular cyclization (Table [1], also see the Supporting Information).[11] Initially, several known sulfoxide activating agents were investigated while controlling time and temperature. In all cases, polystyrene-supported diethylamine was used as a Brønsted base. Both para-toluenesulfonyl chloride (TsCl) and methanesulfonyl chloride (MsCl) gave low conversion (entries 1and 2), while para-toluenesulfonic anhydride (Ts₂O) yielded 88% of the desired product after overnight reaction (entry 3). Trifluoromethanesulfonic anhydride (Tf₂O, entry 4) and trifluoroacetic anhydride (TFAA, entry 5), both resulted in faster conversion and higher yields of 5a (84% and 90%, respectively), whereas acetic anhydride (Ac₂O) resulted in no conversion (entry 6). Next, a series of peptide coupling and dehydrating reagents were investigated: N,N′-dicyclohexylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), oxalyl chloride, and cyanuric chloride (entries 7–10). Only oxalyl chloride converted the sulfoxide into the desired product, albeit with a 19% yield.

Table 1 Optimization of DBT Salt Formation

^a Styrene-supported diethylamine (5 equiv.) was used as a mild base.

^b Overnight reaction.

^c Reaction without the base.

We discovered that 3 equivalents of TFAA provided the best results (entries 5, 11, and 12), and the reaction was found to be compatible with acetonitrile, THF, CHCl₃, and DMF as the solvent (entries 13–16), all of which generated 5a in high yields. Brønsted acids such as trifluoroacetic acid (TFA), trifluoromethanesulfonic acid (TfOH), and camphorsulfonic acid (CSA) (entries 17–19) and Lewis acid Zn(OTf)₂ (entry 20) were investigated, and product formation was observed only with TfOH (61% yield).[12] In summary, TFAA or a commercially prepared solution of Tf₂O were selected as the preferred sulfoxide activating reagents for the formation of DBT salts due to their overall performance in the reaction, low cost, and operational simplicity.

Having optimized the conditions for DBT formation, we turned our attention to the cyclization of sulfoxides 4a–w (Scheme [3]). In all cases, 5 was formed as the exclusive product from the reaction to afford DBT salts possessing pyridine (5a,b, and 5g,h), pyrazole (5c,d, and 5p), phenyl (5e,f, and 5q), triazole (5i), quinoline and isoquinoline (5j–m), imidazopyridine (5n), benzothiazole (5o), carboxylic acid (5r), aniline (5s,t, and 5v), carbamate (5u), morpholine (5v), and sulfide (5w) functionalities. We found that DBT salts 5a–w could be purified by normal- or reverse-phase column chromatography and were stable upon storage at ambient temperature for months without decomposition as observed by LCMS or NMR spectroscopy.

With the DBT salts in hand, we investigated the radiofluorination reaction using several DBT precursors under general ¹⁸F radiolabeling conditions (fluoride source, triethylammonium bicarbonate [TEAHCO₃] and DMSO, 100–160 °C, 15 min). As shown in Table [2], we observed a general trend that ortho-substituted precursors provided higher radiochemical incorporations (RCIs) than their para-substituted counterparts, as shown in DBTs 5a vs. 5b, 5c vs. 5d, and 5e vs. 5f. Increasing the temperature of the reaction improved the RCI of each pair of precursor substrates. However, an opposite trend was observed in the formation of [¹⁸F]6g and [¹⁸F]6h, where the para-substituted precursor 5h outperformed its ortho-counterpart 5g.[13]

Table 2 Radiochemical Incorporation under Different Labeling Temperatures

Taken together, our results demonstrate an influence of substituent orientation and composition on the efficiency of the radiolabeling reaction, suggestive of an ortho-effect.[14] [15] It has been demonstrated that substituents on the arene ring ortho to the leaving group can improve regioselectivities and radiofluorination yields even at lower reaction temperatures.[16] This phenomenon has been observed in the context of heteroaromatic iodonium salt precursors,[17] oxygen-stabilized iodonium ylide precursors,[18] and specific aryl halides under copper-mediated conditions.[19] Additional experiments to further elucidate the mechanism are ongoing.[20]

In summary, we have demonstrated an alternative and operationally straightforward method for synthesizing DBT salts. Our approach utilizes mild reaction conditions and inexpensive reagents that are compatible with functionalities commonly found in drug candidates and radiotracer molecules.[21] Finally, we observed an ortho-effect trend upon radiolabeling matched ortho- and para-substituted pairs of DBT salts. Additional studies are ongoing to further understand the scope and the underlying mechanism of this phenomenon. We hope that this synthesis can increase the application of DBT salts in drug discovery and development.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors thank Justin Wright for LCMS support.

• 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
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• 1b Kilbourn MR, Scott PJ. H. Handbook of Radiopharmaceuticals: Methodology and Applications, 2nd ed. John Wiley & Sons; Hoboken: 2021: 251-290
  Search in Google Scholar
• 1c Deng X, Rong J, Wang L, Vasdev N, Zhang L, Josephson L, Liang SH. Angew. Chem. Int. Ed. 2019; 58: 2580
  CrossrefPubMedSearch in Google Scholar
• 1d Fan R, Tan C, Liu Y, Wei Y, Zhao X, Liu X, Tan J, Yoshida H. Chin. Chem. Lett. 2021; 32: 299
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• 1e Halder R, Ritter T. J. Org. Chem. 2021; 86: 13873
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• 1f Liu Z, Sun Y, Liu T. Front. Chem. 2022; 10: 883866
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• 2 Sander K, Gendron T, Yiannaki E, Kalber TL, Lythgoe MF, Årstad E. Sci. Rep. 2015; 5: 9941
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• 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
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• 4 Sirindil F, Maher S, Schöll M, Sander K, Årstad E. Int. J. Mol. Sci. 2022; 23: 15481
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• 5 Schüll A, Grothe L, Rodrigo E, Erhard T, Waldvogel SR. Org. Lett. 2024; 26: 2790
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• 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
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• 7 Sirindil F, Årstad E, Sander K, Awais R, Twyman F, Marcolan C, Glaser M. Nucl. Med. Biol. 2022; 108: S137
  Search in Google Scholar
• 8 Varlow C, Murerell E, Holland JP, Kassenbrock A, Shannon W, Liang SH, Vasdev N, Stephenson NA. Molecules 2020; 25: 982
  PubMedSearch in Google Scholar

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
  CrossrefPubMedSearch in Google Scholar
• 9b Kafuta K, Korzun A, Böhm M, Golz C, Alcarazo M. Angew. Chem. Int. Ed. 2020; 59: 1950
  CrossrefPubMedSearch in Google Scholar
• 9c Tian Z, Lin Z, Zhang C. Org. Lett. 2021; 23: 4400
  CrossrefPubMedSearch in Google Scholar
• 9d Selmani A, Schoenebeck F. Org. Lett. 2021; 23: 4779
  CrossrefPubMedSearch in Google Scholar
• 9e Tian Z, Zhang C. Org. Chem. Front. 2022; 9: 2220
  CrossrefSearch in Google Scholar
• 9f Zhang Q, Xue X, Hong B, Gu Z. Chem. Sci. 2022; 13: 3761
  PubMedSearch in Google Scholar
• 9g Hamad A, Mrozowicz M, Xie Y, Ritter T. Synlett 2024; 35: 1028
  Search in Google Scholar
• 10 Maitro G, Vogel S, Prestat G, Madec D, Poli G. Org. Lett. 2006; 8: 5951
  CrossrefPubMedSearch in Google Scholar
• 11 Xiong H, Hoye AT, Fan K.-H, Li X, Clemens J, Horchler CL, Lim NC, Attardo G. Org. Lett. 2015; 17: 3726
  CrossrefPubMedSearch in Google Scholar
• 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
  Search in Google Scholar
• 14b Taft RW. Steric Effects in Organic Chemistry . Newman MS. John Wiley and Sons; New York: 1956. Chap. XIII
  Search in Google Scholar

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
  Search in Google Scholar
• 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
  PubMedSearch in Google Scholar
• 16b Martin-Santamaria S, Caroll MA, Caroll CM, Carter CD, Pike VW, Rzepa HS, Widdowson DA. Chem. Commun. 2000; 8: 649
  Search in Google Scholar
• 17 Ross TL, Ermert J, Hocke C, Coenen HH. J. Am. Chem. Soc. 2007; 129: 8018
  PubMedSearch in Google Scholar
• 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
  Search in Google Scholar
• 19 Sharninghausen LS, Brooks A, Winton W, Makaravage K, Scott P, Sanford MS. J. Am. Chem. Soc. 2020; 142: 7362
  CrossrefPubMedSearch in Google Scholar

For mechanisms of the ortho-effect, see:
• 20a Wang X, Salaski EJ, Berger DM, Powell D. Org. Lett. 2009; 11: 5662
  PubMedSearch in Google Scholar
• 20b Wendt MD, Kunzer AR. Tetrahedron Lett. 2010; 51: 641
  Search in Google Scholar
• 20c Cheron N, El Kaim L, Grimaud L, Fleurat-Lessard P. Chem. Eur. J. 2011; 17: 14929
  PubMedSearch in Google Scholar
• 20d Qian W, Wang H, Bartberger MD. J. Am. Chem. Soc. 2015; 137: 12261
  PubMedSearch in Google Scholar
• 20e Um I.-H, Kim M.-Y, Dust JM. Can. J. Chem. 2017; 95: 1273
  Search in Google Scholar
• 20f Yap JL, Hom K, Fletcher S. Tetrahedron Lett. 2011; 52: 4172
  Search in Google Scholar
• 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.

Corresponding Authors

Publication History

Received: 04 April 2025

Accepted after revision: 05 May 2025

Accepted Manuscript online:
05 May 2025

Article published online:
18 June 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• 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
  CrossrefPubMedSearch in Google Scholar
• 1b Kilbourn MR, Scott PJ. H. Handbook of Radiopharmaceuticals: Methodology and Applications, 2nd ed. John Wiley & Sons; Hoboken: 2021: 251-290
  Search in Google Scholar
• 1c Deng X, Rong J, Wang L, Vasdev N, Zhang L, Josephson L, Liang SH. Angew. Chem. Int. Ed. 2019; 58: 2580
  CrossrefPubMedSearch in Google Scholar
• 1d Fan R, Tan C, Liu Y, Wei Y, Zhao X, Liu X, Tan J, Yoshida H. Chin. Chem. Lett. 2021; 32: 299
  CrossrefSearch in Google Scholar
• 1e Halder R, Ritter T. J. Org. Chem. 2021; 86: 13873
  CrossrefPubMedSearch in Google Scholar
• 1f Liu Z, Sun Y, Liu T. Front. Chem. 2022; 10: 883866
  CrossrefPubMedSearch in Google Scholar
• 2 Sander K, Gendron T, Yiannaki E, Kalber TL, Lythgoe MF, Årstad E. Sci. Rep. 2015; 5: 9941
  PubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 4 Sirindil F, Maher S, Schöll M, Sander K, Årstad E. Int. J. Mol. Sci. 2022; 23: 15481
  PubMedSearch in Google Scholar
• 5 Schüll A, Grothe L, Rodrigo E, Erhard T, Waldvogel SR. Org. Lett. 2024; 26: 2790
  PubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 7 Sirindil F, Årstad E, Sander K, Awais R, Twyman F, Marcolan C, Glaser M. Nucl. Med. Biol. 2022; 108: S137
  Search in Google Scholar
• 8 Varlow C, Murerell E, Holland JP, Kassenbrock A, Shannon W, Liang SH, Vasdev N, Stephenson NA. Molecules 2020; 25: 982
  PubMedSearch in Google Scholar

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
  CrossrefPubMedSearch in Google Scholar
• 9b Kafuta K, Korzun A, Böhm M, Golz C, Alcarazo M. Angew. Chem. Int. Ed. 2020; 59: 1950
  CrossrefPubMedSearch in Google Scholar
• 9c Tian Z, Lin Z, Zhang C. Org. Lett. 2021; 23: 4400
  CrossrefPubMedSearch in Google Scholar
• 9d Selmani A, Schoenebeck F. Org. Lett. 2021; 23: 4779
  CrossrefPubMedSearch in Google Scholar
• 9e Tian Z, Zhang C. Org. Chem. Front. 2022; 9: 2220
  CrossrefSearch in Google Scholar
• 9f Zhang Q, Xue X, Hong B, Gu Z. Chem. Sci. 2022; 13: 3761
  PubMedSearch in Google Scholar
• 9g Hamad A, Mrozowicz M, Xie Y, Ritter T. Synlett 2024; 35: 1028
  Search in Google Scholar
• 10 Maitro G, Vogel S, Prestat G, Madec D, Poli G. Org. Lett. 2006; 8: 5951
  CrossrefPubMedSearch in Google Scholar
• 11 Xiong H, Hoye AT, Fan K.-H, Li X, Clemens J, Horchler CL, Lim NC, Attardo G. Org. Lett. 2015; 17: 3726
  CrossrefPubMedSearch in Google Scholar
• 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
  Search in Google Scholar
• 14b Taft RW. Steric Effects in Organic Chemistry . Newman MS. John Wiley and Sons; New York: 1956. Chap. XIII
  Search in Google Scholar

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
  Search in Google Scholar
• 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
  PubMedSearch in Google Scholar
• 16b Martin-Santamaria S, Caroll MA, Caroll CM, Carter CD, Pike VW, Rzepa HS, Widdowson DA. Chem. Commun. 2000; 8: 649
  Search in Google Scholar
• 17 Ross TL, Ermert J, Hocke C, Coenen HH. J. Am. Chem. Soc. 2007; 129: 8018
  PubMedSearch in Google Scholar
• 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
  Search in Google Scholar
• 19 Sharninghausen LS, Brooks A, Winton W, Makaravage K, Scott P, Sanford MS. J. Am. Chem. Soc. 2020; 142: 7362
  CrossrefPubMedSearch in Google Scholar

For mechanisms of the ortho-effect, see:
• 20a Wang X, Salaski EJ, Berger DM, Powell D. Org. Lett. 2009; 11: 5662
  PubMedSearch in Google Scholar
• 20b Wendt MD, Kunzer AR. Tetrahedron Lett. 2010; 51: 641
  Search in Google Scholar
• 20c Cheron N, El Kaim L, Grimaud L, Fleurat-Lessard P. Chem. Eur. J. 2011; 17: 14929
  PubMedSearch in Google Scholar
• 20d Qian W, Wang H, Bartberger MD. J. Am. Chem. Soc. 2015; 137: 12261
  PubMedSearch in Google Scholar
• 20e Um I.-H, Kim M.-Y, Dust JM. Can. J. Chem. 2017; 95: 1273
  Search in Google Scholar
• 20f Yap JL, Hom K, Fletcher S. Tetrahedron Lett. 2011; 52: 4172
  Search in Google Scholar
• 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.

• Supplementary Material