Desmethyl SuFEx-IT: SO₂F₂-Free Synthesis and Evaluation as a Fluorosulfurylating Agent

Abstract

Access to SuFExable compounds was remarkably simplified by introduction of the solid FO₂S-donor SuFEx-IT. However, the published process for preparation of this reagent relies on the use of sulfuryl fluoride (SO₂F₂), which is difficult to obtain and highly toxic. Herein, we disclose a simple protocol for SO₂F₂-free, hectogram-scale preparation of the analogous desmethyl SuFEx-IT from inexpensive starting materials. The reagent was prepared in a high (85%) total yield and without chromatographic purification steps. In addition, we demonstrate the utility of desmethyl SuFEx-IT by successful preparation of a series of fluorosulfates and sulfamoyl fluorides in high to excellent yields. As such, our work recognizes desmethyl SuFEx-IT as a valuable alternative to common FO₂S-donors and enables cost-efficient access to substrates for SuFEx click chemistry.

Introduction

The unique chemistry of the fluorosulfuryl (FO₂S-) group has intrigued researchers since the early 20th century.^1,2 Introduction of sulfur(VI)-fluoride exchange (SuFEx) as a new class of click reactions in 2014³ fostered scientific efforts by chemists from all over the world to exploit the exceptional properties of this functional group. The S^VI–F bond in the FO₂S-group is generally highly stable and can tolerate unusually harsh conditions. However, it demonstrates a latent reactivity with various nucleophiles that can be triggered under specific conditions. In addition, the facile introduction of the FO₂S-group into target molecules using SuFEx hub-reagents has rendered FO₂S-substituted compounds valuable building blocks across diverse applications in organic synthesis, material sciences, drug discovery, and even radiochemistry.⁴

The prototypical SuFEx hub for introduction of FO₂S-groups into phenols or secondary amines is gaseous sulfuryl fluoride (SO₂F₂), which is typically obtained from pressurized lecture bottles. However, while SO₂F₂ shows ideal reactivity for fluorosulfurylation of phenols, it exhibits sluggish reactivity with secondary amines and has proven to be unsuitable for conversion of primary amines to the corresponding sulfamoyl fluorides. Moreover, despite the apparent simplicity of SO₂F₂-based fluorosulfurylation methods, their routine application is hampered by the neurotoxic nature of SO₂F₂, which has led to several fatalities beyond laboratory environments.^5,6 As a consequence, the availability of SO₂F₂ is often restricted by regulations, and the need for specialized equipment to handle toxic gases has further impeded broad adoption of this reagent as a SuFEx hub.

To overcome these limitations, de Borggraeve and co-workers introduced a fluorosulfurylation method based on ex situ generation of SO₂F₂ from 1,1′-sulfonyldiimidazole (SDI) in a two-chamber reactor.⁷ Although this method simplifies conversion of phenols into the corresponding aryl fluorosulfates, the requirement for specialized glassware, limited scalability, and the formation of HF gas as a side product represent obvious disadvantages.

Accordingly, development of a fluorosulfuryl imidazolium triflate salt (termed SuFEx-IT) as a solid equivalent for SO₂F₂ by Guo and co-workers greatly improved access to SuFExable compounds.⁸ Thus, using SuFEx-IT as a FO₂S-donor, the group was able to prepare a wide range of fluorosulfates and sulfamoyl fluorides from the corresponding alcohols and amines. Remarkably, SuFEx-IT showed better reactivity/chemoselectivity than SO₂F₂ and enabled fluorosulfurylation of primary amines, providing access to the corresponding sulfamoyl fluorides and bis(fluorosulfuryl)imides (Scheme 1). In addition, SuFEx-IT proved to be sufficiently stable for several months when stored at 4 °C or in a desiccator and could be synthesized on a multigram scale in two steps from 2-methylimidazole via fluorosulfurylation with SO₂F₂ followed by quaternization of the resulting intermediate with methyl triflate (MeOTf) (Scheme 2).

Scheme 1. Preparation of Fluorosulfates and Sulfamoyl Fluorides with SuFEx-IT⁸ and AISF⁹.

Scheme 2. Literature Procedures for the Preparation of SuFEx-IT⁸ and AISF⁹.

Another solid and bench-stable SuFEx hub developed by Zhou et al. is [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF).⁹ This FO₂S-donor could be prepared in a single step by oxidative C–H functionalization of acetanilide with bis(fluorosulfonyl)imide (Scheme 2). In addition, the authors demonstrated the utility of AISF for the synthesis of various aryl fluorosulfates and sulfamoyl fluorides. However, mono- or bifunctionalization of primary amines with the FO₂S-moiety using this reagent has proven to be challenging, indicating an inferior reactivity compared to SuFEx-IT.¹⁰

As such, SuFEx-IT remains the most widely used reagent for facile production of sulfamoyl fluorides or fluorosulfates for SuFEx click chemistry. Nevertheless, the reagent is rather expensive and its preparation still relies on the use of toxic and hardly available SO₂F₂, which is associated with the aforementioned handling and regulatory issues.

For our ongoing studies on the use of SuFEx ¹⁸F-fluorination¹¹ for the preparation of PET-tracers,¹² a series of aryl fluorosulfates and sulfamoyl fluorides had to be prepared. Therefore, the aim of the present work was to simplify access to SuFEx-IT or alternative solid fluorosulfurylating agents by development of a simple and efficient production route that utilizes inexpensive starting materials and obviates the need for SO₂F₂.

Results and Discussion

Initially, we hypothesized that application of sulfuryl chloride (SO₂Cl₂) as an inexpensive and liquid substitute for SO₂F₂ could be used to improve the synthesis of SuFEx-IT (4). In particular, it was envisioned that reaction of 2-methylimidazole (1) with SO₂Cl₂ should afford the corresponding sulfamoyl chloride 2, which could in turn be converted to sulfamoyl fluoride 3 using an adequate fluoride source (Scheme 3A). However, no formation of the desired sulfamoyl chloride was observed under various reaction conditions (see a–d in Scheme 3A). Therefore, this approach was abandoned.

Scheme 3. Attempted Preparation of SuFEx-IT via Sulfamoyl Chloride 2 (A) and SO₂F₂-Free Synthesis of SuFEx-IT (B).

Next, we turned our attention to the imidazolium salt 6 as an alternative precursor for sulfamoyl fluoride 3 (Scheme 3B). This compound bears the quaternized imidazolium moiety that serves as the leaving group in SuFEx-IT and could be prepared from 1 via 1,1′-sulfonylbis(2-methylimidazole) (5) using procedures described in the literature. To our delight, fluorination of 6 in aqueous solution proceeded efficiently and afforded sulfamoyl fluoride 3 in 83% yield. Subsequent methylation of 3 with MeOTf yielded the desired SuFEx-IT on a 3 g scale. However, a moderate overall yield of 26% (which was mainly attributable to the rather inefficient preparation of 5) limited the practical utility of this production route.

Therefore, our interest shifted to desmethyl SuFEx-IT (11), which should represent a more accessible alternative to SuFExIT. Although the preparation of 11 has been described in the patent literature,¹³ neither its suitability as a FO₂S-transfer agent nor its storage stability have been evaluated so far. In addition, the reported procedure for preparation of desmethyl SuFEx-IT is essentially the same as for the production SuFEx-IT and thus suffers from the same drawbacks.

When the above synthetic strategy was applied to this target compound (Scheme 4), the first step could be omitted by directly starting from inexpensive SDI (8; available from numerous providers for 0.5–1 €/g in 25–500 g packages). Alternatively, decagram quantities of 8(7) could be easily prepared from imidazole (7) and SO₂Cl₂ in >80% yield. Subsequent quaternization of 8 with MeOTf provided the corresponding monomethylated sulfonyldiimidazolium salt (MSDI, 9),¹⁴ which precipitated from the solution and could be readily isolated in 97% yield after a total reaction time of 3 h. Thereafter, 9 was dissolved in ice-cooled water and treated with KHF₂ to produce sulfamoyl fluoride 10(15) within 10 min. Purification of the crude product by distillation afforded 10 in 88% yield when the reaction was performed on a decagram scale (we efficiently prepared up to ∼60 g product). On a smaller scale, the yield was ∼10% lower, presumably due to increased loss of the volatile product (see the Supporting Information). Finally, methylation of 10 with MeOTf provided, after simple crystallization, desmethyl SuFEx-IT (11) as a colorless solid in almost quantitative yields. This route enabled preparation of 11 on a hectogram scale in 85% total yield and without any chromatographic purifications within 2 days. Attempts to further shorten the procedure by direct fluorination of SDI were unsuccessful due to low conversion of 8 to 10.

Scheme 4. SO₂F₂-Free Synthesis of Desmethyl SuFEx-IT (11).

Next, we investigated the reactivity and chemoselectivity of desmethyl SuFEx-IT as a FO₂S-donor by preparation of several fluorosulfates and sulfamoyl fluorides. The results confirmed that 11 reacts readily with various simple phenols to form the corresponding fluorosulfates 12a–e in yields of 78–91% within 30–90 min (Scheme 5). The reaction was unaffected by the presence of electron-withdrawing or electron-donating groups. Substrates containing a Bpin or unprotected thiol group could also be fluorosulfurylated in 73 and 45% yields, respectively (Scheme 5, 12f and 12g, respectively). In addition, reaction of desmethyl SuFEx-IT with more complex and/or sensitive substrates like ± -α-tocopherol (vitamin D), the skin-lightning glycoside arbutin, the Ni-complex Ni-Cl₃BPB-m-Tyr, the cholesterol lowering drug ezetimibe, the topoisomerase inhibitor camptothecin or the precursor for the ¹¹C-labeled TSPO-specific ligand [¹¹C]DPA-713¹⁶ afforded the desired fluorosulfurylated products in 30–98% yields (Scheme 5, 12h–m). Scalability of the procedure was confirmed by the preparation of base sensitive active ester 12n on a gram scale in 55% yield.

Scheme 5. Synthesis of Fluorosulfates from the Corresponding Phenols Using Desmethyl SuFEx-IT (11) as a FO₂S-Donor.

Indicated yields refer to isolated products.

Et₃N (2.6 equiv).

Additional Et₃N (1.0 equiv) and 11 (1.0 equiv) after 1 h.

In DMF.

Et₃N (6.4 equiv) and 11 (5.2 equiv).

In DMF/MeCN (1:1).

Gram scale, 11 (1.4 equiv) and Et₃N (1.7 equiv), 16 h.

Fluorosulfurylation of both aliphatic and aromatic secondary amines with 11 afforded the corresponding sulfamoyl fluorides 13a–g in good to excellent yields (Scheme 6). Noteworthy, 4-hydroxypiperidine and 6-hydroxy-1,2,3,4-tetrahydroisoquinoline were mono-fluorosulfurylated at the nitrogen with excellent selectivity to furnish the corresponding sulfamoyl fluorides as single products in 88–89% yields (Scheme 6, 13f and 13g). The observed chemoselectivity for fluorosulfurylation of the secondary amino over the hydroxy groups in these substrates can most likely be attributed to its higher nucleophilicity. 11 was also successfully applied for the mono- and bi-fluorosulfurylation of aniline and mono-fluorosulfurylation of 4-fluorobenzylamine (Scheme 6, 13h–j). A fluorosulfurylated derivative of the antidepressant amoxapine was prepared in 93% yield (Scheme 6, 13k). Fluorosulfurylation of an indole nitrogen, e.g., in N_α-Boc-protected tryptamine, was also possible. In this case, application of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base was necessary to prepare the desired product in a fair yield (Scheme 6, 13l). Notably, the preparation of N-fluorosulfurylated indoles using SuFEx-IT or AISF has not been described so far. Finally, desmethyl SuFEx-IT enabled installation of a FO₂S group in the presence of an unprotected carboxylic acid function, as exemplified by transformation of the GABA_A receptor partial agonist isonipecotic acid into the corresponding sulfamoyl fluoride in 39% yield (Scheme 6, 13m). Generally, desmethyl SuFEx-IT demonstrated a reactivity comparable to that of SuFEx-IT.⁸ Thus, fluorosulfurylation of sterically hindered 2,2,6,6-tetramethylpiperidine, which could not be fluorosulfurylated using SuFEx-It, AISF, or SO₂F₂, was also impossible using desmethyl SuFEx-IT (Scheme 6, 13n).

Scheme 6. Synthesis of Sulfamoyl Fluorides from the Corresponding Amines Using Desmethyl SuFEx-IT (11) as a FO₂S-Donor.

Indicated yields refer to isolated products.

11 (1.6 equiv) and Et₃N (1.0 equiv).

In CH₂Cl₂.

11 (2.5 equiv) and Et₃N (0.5 equiv; added after 10 min), 10 min at 0 °C, then 30 min at rt.

11 (1.05 equiv).

DBU (2.2 equiv).

Finally, the long-term stability of 11 during storage under different conditions was investigated by nuclear magnetic resonance (NMR) analysis (Figure 1). Bench storage under air for 288 days at ambient temperature (20–23 °C) resulted in decomposition by 34%, which could be reduced to 18% by storing the compound under argon. In contrast, minimal (<3%) or no signs of decomposition were observed after 288 days at 4 °C or −18 °C under argon, respectively, demonstrating an excellent shelf life of 11 under these conditions.

Figure 1.

¹H NMR of desmethyl SuFEx-IT (11) after storage for 288 days at the indicated temperatures under air or argon.

Conclusions

We have developed a convenient three-step procedure for the SO₂F₂-free, hectogram-scale preparation of desmethyl SuFEx-IT. This process affords the compound in 85% total yield from inexpensive starting materials without chromatographic purification steps within only 2 days. The utility of the reagent was demonstrated by the preparation of a series of fluorosulfates and sulfamoyl fluorides in good to excellent yields. Furthermore, desmethyl SuFEx-IT could be applied for N-selective mono-fluorosulfurylation of secondary amines containing aliphatic or aromatic hydroxyl groups. As such, our results identify desmethyl SuFEx-IT as a valuable alternative to common FO₂S-donors, which offers safe and cost-efficient access to substrates for SuFEx click chemistry.

Experimental Section

Unless noted otherwise, all chemicals and solvents were purchased from VWR International GmbH (Darmstadt, Germany), Sigma-Aldrich Chemie GmbH (Steinheim, Germany), ABCR GmbH (Karlsruhe, Germany), Apollo Scientific Ltd. (Bredbury, United Kingdom) or BLD Pharmatech GmbH (Kaiserslautern, Germany) and used without further purification.

If not stated otherwise, all reactions were carried out with magnetic stirring. Organic extracts were dried over anhydrous MgSO₄. Air- or moisture-sensitive reagents were handled under argon (>99.999%, Air Liquide GmbH, Düsseldorf, Germany). CH₂Cl₂ [HPLC grade (GC: 99.8%), <0.01% H₂O] was stored under argon and was used with moisture sensitive reagents (like MeOTf or SO₂Cl₂). Solutions were concentrated under reduced pressure (1–900 mbar) at 40–50 °C using a rotary evaporator (Heidolph GmbH & Co. KG, Schwabach, Germany).

Nuclear Magnetic Resonance Spectroscopy

NMR spectra were measured at ambient temperature in deuterochloroform (CDCl₃), trideuteroacetonitrile (CD₃CN), hexadeuterodimethyl sulfoxide [(CD₃)₂SO] or octadeuterotetrahydrofuran (THF-d₈) as indicated using a Bruker Ascend 400 (¹H: 400 MHz; ¹³C{¹H}: 101 MHz; ¹⁹F: 376 MHz; Bruker Biospin GmbH, Rheinstetten, Germany). The measured chemical shifts are reported in δ [ppm] relative to residual peaks of nondeuterated solvents. Higher order NMR spectra were approximately interpreted as first-order spectra if possible. The observed signal multiplicities are characterized as follows: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, sep = septet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplets, ddt = doublet of doublets of triplets, td = triplet of doublets, tt = triplet of triplets, qd = quartet of doublets, and pt = pentet of triplets. Coupling constants J are reported in hertz (Hz).

Mass Spectrometry

Low-resolution electrospray ionization mass spectrometry (LR-ESI-MS) was performed with an MSQ PlusTM mass spectrometer (Thermo Electron Corporation, San Jose, USA). High-resolution electrospray ionization mass spectrometry (HR-ESI-MS) was performed with an LTQ XL Orbitrap mass spectrometer (Thermo Fisher Scientific Inc., Bremen, Germany). Low-resolution electron ionization mass spectrometry (LR-EI-MS) was performed with an ISQ EC Single Quadrupole mass spectrometer (Thermo Fisher Scientific Inc., Bremen, Germany). High-resolution electron ionization mass spectrometry (HR-EI-MS) was performed with an Exactive GC Orbitrap mass spectrometer (Thermo Fisher Scientific Inc., Bremen, Germany).

Column Chromatography

Manual column chromatography was performed with silica gel, 60 Å, 230–400 mesh particle size from VWR International GmbH (Darmstadt, Germany) or silica gel (w/0.1% Ca), 60 Å, 230–400 mesh particle size from Sigma-Aldrich GmbH (Steinheim, Germany). Automated column chromatography was performed on a Büchi Pure C-815 flash system (Büchi Labortechnik GmbH, Essen, Germany) using Reveleris C₁₈ reversed phase cartridges (Büchi Labortechnik GmbH, Essen, Germany).

Thin-Layer Chromatography

Thin-layer chromatography (TLC) was performed using aluminum sheets coated with silica gel 0.25 mm SIL G/UV 254 (Merck KGaA, Darmstadt, Germany). Chromatograms were inspected under UV light (λ = 254 nm) and/or stained with phosphomolybdic acid (4% in EtOH), ninhydrin (0.5% in 1-butanol), or potassium permanganate solution (0.75% KMnO₄, 5% K₂CO₃, and 0.07% NaOH in H₂O).

Elemental Analysis

Elemental analyses were conducted by HEKAtech GmbH (Wegberg, Germany).

Chemistry

1,1′-Sulfonylbis(2-methyl-1H-imidazole) (5)¹⁴

A solution of SO₂Cl₂ (29.99 g, 222 mmol, 1.0 equiv) in CH₂Cl₂ (20 mL) was added over 30 min to an ice-cooled suspension of 2-methylimidazole (82.1 g, 1.00 mol, 4.5 equiv) in CH₂Cl₂. The reaction mixture was stirred overnight under argon, after which H₂O (350 mL) was added and the aqueous phase was extracted with CH₂Cl₂ (2 × 100 mL). The combined organic phases were washed with brine, dried, and the solvent was removed under reduced pressure. The residue was recrystallized from iPrOH to afford the title compound 5 (21.0 g, 93.0 mmol, 42%) as an off-white solid. Molecular formula (molecular mass): C₈H₁₀N₄O₂S (226.25 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.37 (s, 2H), 6.94 (s, 2H), 2.51 (s, 6H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 146.1, 128.6, 120.1, 15.1. HR-ESI-MS m/z: [M + H]⁺ calcd for C₈H₁₁N₄O₂S 227.0597; found, 227.0598.

2,3-Dimethyl-1-[(2-methyl-1H-imidazole-1-yl)sulfonyl]-1H-imidazole-3-ium Trifluoromethanesulfonate (6)^14,17

A solution of MeOTf (2.00 mL, 17.7 mmol, 0.7 equiv) in CH₂Cl₂ (20 mL) was added over 3.5 h to a cooled solution (−78 °C) of 5 (5.72 g, 25.3 mmol, 1.0 equiv) in CH₂Cl₂ (200 mL) and the reaction mixture was allowed to warm to ambient temperature within 16 h. The resulting precipitate was filtered under argon and washed with ice-cold CH₂Cl₂ to afford the title compound 6 (6.21 g, 15.9 mmol, 90%) as a colorless solid. Molecular formula (molecular mass): C₁₀H₁₃F₃N₄O₅S₂ (390.35 g/mol). ¹H NMR (400 MHz, CD₃CN): δ 7.89 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 3.75 (s, 3H), 2.76 (s, 3H), 2.56 (s, 3H). ¹³C{¹H} NMR (101 MHz, CD₃CN): δ 148.0, 130.0, 124.7, 121.9, 121.6, 37.0, 15.7, 12.6. ¹⁹F NMR (376 MHz, CD₃CN): δ −79.29.

2-Methyl-1H-imidazole-1-sulfonyl Fluoride (3)⁸

4.5 m KHF₂* (5.56 mL, 25.0 mmol, 0.75 equiv) was added to a solution of 6 (13.0 g, 33.3 mmol, 1.0 equiv) in H₂O (20 mL, HPLC grade) and the mixture was stirred for 5 min. The aqueous solution was extracted with Et₂O (3 × 10 mL) and the combined organic phases were dried, filtered, and concentrated under reduced pressure at room temperature (due to the volatility of the product, the pressure was kept above 300 mbar). The raw product was purified by Kugelrohr distillation with acetone/dry ice-cooling of the receiver bulb to afford the title compound 3 (4.53 g, 27.6 mmol, 83%) as a colorless liquid. Molecular formula (molecular mass): C₄H₅FN₂O₂S (164.15 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.33 (d, J = 1.9 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 2.66 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 146.9, 129.1, 120.1, 15.1. ¹⁹F NMR (376 MHz, CDCl₃): δ 58.16. LR-EI-MS m/z: [M]^•+ calcd for C₄H₅FN₂O₂S 164.01; found, 164.00.

* Safety Precaution: it is strongly recommended to ensure the availability of 2.5% calcium gluconate gel as a safety measure when handling KHF₂.

1-(Fluorosulfonyl)-2,3-dimethyl-1H-imidazole-3-ium Trifluoromethanesulfonate (SuFEx-IT, 4)⁸

MeOTf (1.31 mL, 11.6 mmol, 0.95 equiv) was added dropwise under argon to an ice-cooled solution of 3 (2.00 g, 12.2 mmol, 1.00 equiv) in CH₂Cl₂. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The solution was then concentrated under reduced pressure, tBuOMe (30 mL) was added and solidification of the residual oil was induced by addition of a seed crystal and ultrasonication. The resulting solid was crushed with a spatula, filtered off, and washed with tBuOMe (30 mL) to afford SuFEx-IT (3.29 g, 10.0 mmol, 82%) as a colorless solid. Molecular formula (molecular mass): C₆H₈F₄N₂O₅S₂ (328.25 g/mol). ¹H NMR (400 MHz, CD₃CN): δ 7.88 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 3.86 (s, 3H), 2.86 (s, 3H). ¹³C{¹H} NMR (101 MHz, CD₃CN): δ 151.3, 125.5, 122.2, 122.0 (q, J = 320.1 Hz), 37.6, 12.9. ¹⁹F NMR (376 MHz, CD₃CN): δ 60.13, −79.34.

1,1′-Sulfonyldiimidazole (SDI, 8)⁷

SO₂Cl₂ (19.4 mL, 240 mmol, 1.0 equiv) in CH₂Cl₂ (20 mL) was added dropwise to an ice-cooled solution of imidazole (75.0 g, 1.10 mol, 4.6 equiv) in CH₂Cl₂ (450 mL). The yellow suspension was stirred overnight and filtered on the next day. The solvent was removed and the crude product was recrystallized from iPrOH to afford the title compound 8 (38.97 g, 197 mmol, 82%) as a colorless solid. Molecular formula (molecular mass): C₆H₆N₄O₂S (198.20 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 8.09–7.96 (m, 1H), 7.32–7.27 (m, 1H), 7.19–7.09 (m, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 136.6,* 132.5, 117.5. LR-ESI-MS m/z: [M + H]⁺ calcd for C₆H₇N₄O₂S 199.03; found, 199.20.

* Note that phase inversion of the C-2 signal in the APT spectrum of imidazole derivatives has been described in the literature as a “regular feature” of these compounds (for details see¹⁸). HSQC data further confirmed the corresponding ¹J_CH-coupling at C-2 (see the Supporting Information).

3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazole-1-ium Trifluoromethanesulfonate (MSDI, 9)¹⁴

A solution of MeOTf (54.3 mL, 480 mmol, 0.95 equiv) in CH₂Cl₂ (80 mL) was added dropwise over the course of 30 min to an ice-cooled solution of SDI (100.0 g, 505 mmol, 1.0 equiv) in CH₂Cl₂ (1.5 L). The reaction mixture was stirred for 2.5 h in an ice bath, during which a colorless precipitate formed. The precipitate was allowed to settle, the supernatant solvent was decanted, and the precipitate was washed with CH₂Cl₂ (3 × 300 mL). The residual solvent was removed under reduced pressure to afford the title compound 9 (169.5 g, 467 mmol, 97%) as a colorless solid. Molecular formula (molecular mass): C₈H₉F₃N₄O₅S₂ (362.30 g/mol). ¹H NMR (400 MHz, CD₃CN): δ 9.37 (s, 1H), 8.27 (s, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.23 (s, 1H), 3.90 (s, 3H). ¹³C{¹H} NMR (101 MHz, CD₃CN): δ 139.7, 138.9,* 133.6, 127.3, 121.5, 119.7, 38.2. ¹⁹F NMR (376 MHz, CD₃CN): δ −79.33.

* Note that phase inversion of the C-2 signal in the APT spectrum of imidazole derivatives has been described in the literature as a “regular feature” of these compounds (for details see¹⁸).

1H-Imidazole-1-sulfonyl Fluoride (10)¹³

4.5 m KHF₂* (100 mL, 341 mmol, 0.75 equiv) was added slowly to an ice-cooled solution of MSDI (164.6 g, 454 mmol, 1.0 equiv) in H₂O (1 L, HPLC grade), and the reaction mixture was stirred for 10 min. The resulting emulsion was extracted with Et₂O (5 × 200 mL), the combined organic phases were dried, and the solvent was removed under reduced pressure (due to the volatility of the title compound, the pressure was held above 400 mbar at 40 °C). The colorless liquid raw material thus obtained was purified by distillation (80 °C, 20 mbar, collecting flask cooled in an ice bath) to afford title compound 10 (60.1 g, 400 mmol, 88%) as a colorless liquid which crystallized on storage in the fridge. The compound should be stored at ≤ −18 °C to avoid formation of SDI over time. Molecular formula (molecular mass): C₃H₃FN₂O₂S (150.13 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1H), 7.42 (pt, J = 1.7 1H), 7.24 (dd, J = 1.7, 0.6 Hz, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 137.2,** 132.4, 118.4. ¹⁹F NMR (376 MHz, CDCl₃): δ 59.59. HR-EI-MS m/z: [M]^•+ calcd for C₃H₃FN₂O₂S 149.9894; found, 149.9893.

* Safety Precaution: it is strongly recommended to ensure the availability of 2.5% calcium gluconate gel as a safety measure when handling KHF₂.

** Note that phase inversion of the C-2 signal in the APT spectrum of imidazole derivatives has been described in the literature as a “regular feature” of these compounds (for details see¹⁸).

1-(Fluorosulfonyl)-3-methyl-1H-imidazole Trifluoromethanesulfonate (Desmethyl SuFEx-IT, 11)¹³

MeOTf (46.5 mL, 411 mmol, 1.1 equiv) was added dropwise over the course of 15 min to an ice-cooled solution of 10 (56.1 g, 374 mmol, 1.0 equiv) in anhydrous Et₂O (750 mL), and the reaction mixture was stirred for 90 min. The resulting precipitate was allowed to settle, the supernatant solvent was decanted, and the precipitate was washed with Et₂O (3 × 300 mL). The residual solvent was removed under reduced pressure and the residue dried under high vacuum overnight to afford title compound 11 (116.2 g, 370 mmol, 99%) as a colorless solid. Molecular formula (molecular mass): C₅H₆F₄N₂O₅S₂ (314.23 g/mol). ¹H NMR (400 MHz, CD₃CN): δ 9.50 (s, 1H), 8.02 (pt, J = 2.0 Hz, 1H), 7.72 (pt, J = 2.0 Hz, 1H), 4.01 (s, 3H). ¹³C{¹H} NMR (101 MHz, CD₃CN): δ 141.2,* 127.7, 122.8, 122.0 (q, J = 320.1 Hz), 38.6. ¹⁹F NMR (376 MHz, CD₃CN): δ 59.89, −79.38. LR-ESI-MS m/z: [M + H]⁺ calcd for C₅H₇F₄N₂O₅S₂ 314.97; found, 315.06. Elemental analysis: Calcd for C₅H₆F₄N₂O₅S₂: C, 19.11%; H, 1.92%; N, 8.92%; S, 20.41%. Found: C, 19.06 ± 0.02%; H, 1.95 ± 0.03%; N, 8.47 ± 0.06%; S, 20.52 ± 0.08% (n = 2).

* Note that phase inversion of the C-2 signal in the APT spectrum of imidazole derivatives has been described in the literature as a “regular feature” of these compounds (for details see¹⁸).

General Procedure for Preparation of Fluorosulfates (GP1)

11 (1.3 equiv) was added to a solution of the phenol substrate (1.0 equiv) and Et₃N (1.6 equiv) in MeCN (2–5 mL), and the mixture was stirred until TLC showed full conversion (30–90 min). The products were purified by dry load column chromatography or filtration over a silica plug with an appropriate solvent unless stated otherwise.

General Procedure for Preparation of Sulfamoyl Fluorides (GP2)

11 (1.1 equiv) was added to a solution of the amine substrate (1.0 equiv) in MeCN (2–5 mL), and the mixture was stirred until TLC or HPLC showed full conversion (15–90 min). The products were purified by dry load column chromatography or filtration over a silica plug with an appropriate solvent unless stated otherwise.

4-Bromophenyl Sulfurofluoridate (12a)¹⁹

12a (119 mg, 467 μmol, 81%, colorless liquid) was prepared according to GP1 from 4-bromophenol (100 mg, 578 μmol) and purified by column chromatography (R_f = 0.38, n-hexane). Molecular formula (molecular mass): C₆H₄BrFO₃S (255.06 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.64–7.58 (m, 2H), 7.28–7.20 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 149.1, 133.7, 122.8, 122.5. ¹⁹F NMR (376 MHz, CDCl₃): δ 37.80. HR-EI-MS m/z: [M]^•+ calcd for C₆H₄⁷⁹BrFO₃S 253.9043; found, 253.9039. HR-EI-MS m/z: [M]^•+ calcd for C₆H₄⁸¹BrFO₃S 255.9023; found, 255.9018.

3-Methoxyphenyl Sulfurofluoridate (12b)¹²

12b (170 mg, 824 μmol, 90%, colorless liquid) was prepared according to GP1 from 3-methoxyphenol (113 mg, 910 μmol) and purified by filtration over a silica plug (R_f = 0.47, EtOAc:n-hexane = 1:8). Molecular formula (molecular mass): C₇H₇FO₄S (206.19 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.37 (t, J = 8.3 Hz, 1H), 6.94 (td, J = 7.3, 6.3, 1.7 Hz, 2H), 6.87 (d, J = 2.2 Hz, 1H), 3.84 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 161.1, 150.9, 130.8, 114.5, 112.8, 107.1, 55.8. ¹⁹F NMR (376 MHz, CDCl₃): δ 37.70. HR-EI-MS m/z: [M]^•+ calcd for C₇H₇FO₄S 206.0044; found, 206.0038.

4-Formylphenyl Sulfurofluoridate (12c)²⁰

12c (149 mg, 730 μmol, 89%, colorless liquid) was prepared according to GP1 from 4-hydroxybenzaldehyde (100 mg, 819 μmol) and purified by column chromatography (R_f = 0.21, EtOAc:n-hexane = 1:6). Molecular formula (molecular mass): C₇H₅FO₄S (204.17 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 10.06 (s, 1H), 8.06–8.00 (m, 2H), 7.57–7.48 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 190.2, 153.7, 136.3, 132.0, 121.9. ¹⁹F NMR (376 MHz, CDCl₃): δ 39.11. HR-EI-MS m/z: [M]^•+ calcd for C₇H₅FO₄S 203.9887; found, 203.9885.

Quinolin-8-yl Sulfurofluoridate (12d)¹²

12d (142 mg, 627 μmol, 91%, pale yellow solid) was prepared according to GP1 from 8-hydroxyquinoline (100 mg, 689 μmol) and purified by column chromatography (R_f = 0.33, EtOAc:n-hexane = 1:6). Molecular formula (molecular mass): C₉H₆FNO₃S (227.21 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 9.06 (dd, J = 4.2, 1.6 Hz, 1H), 8.24 (dd, J = 8.4, 1.6 Hz, 1H), 7.90 (dd, J = 8.4, 1.1 Hz, 1H), 7.75 (dt, J = 7.7, 1.1 Hz, 1H), 7.66–7.47 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 152.0, 146.0, 140.5, 136.1, 130.1, 128.8, 126.0, 122.8, 121.5. ¹⁹F NMR (376 MHz, CDCl₃): δ 40.66. HR-EI-MS m/z: [M]^•+ calcd for C₉H₆FNO₃S 227.0047; found, 227.0041.

4-[(4-Acetamidophenyl)ethynyl]phenyl Sulfurofluoridate (12e)

12e (65.0 mg, 195 μmol, 78%, yellow solid) was prepared according to GP1 from N-{4-[(4-hydroxyphenyl)ethynyl]phenyl}acetamide (62.8 mg, 250 μmol) and purified by column chromatography (R_f = 0.19, EtOAc:n-hexane = 1:1). Molecular formula (molecular mass): C₁₆H₁₂FNO₄S (333.33 g/mol). ¹H NMR (400 MHz, THF-d₈): δ 9.22 (s, 1H), 7.72–7.57 (m, 4H), 7.52–7.45 (m, 2H), 7.45–7.38 (m, 2H), 2.04 (s, 3H). ¹³C{¹H} NMR (101 MHz, THF-d₈): δ 168.6, 150.5, 141.6, 134.3, 133.0, 125.7, 122.2, 119.5, 117.6, 92.3, 87.2, 24.2. ¹⁹F NMR (376 MHz, THF-d₈): δ 36.77. HR-EI-MS m/z: [M]^•+ calcd for C₁₆H₁₂FNO₄S 333.0466; found, 333.0467.

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl Sulfurofluoridate (12f)

12f (100 mg, 330 μmol, 73%, pale yellow solid) was prepared according to GP1 from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100 mg, 454 μmol). The reaction mixture was extracted with n-pentane (4 × 10 mL) and the collected phases were filtered over a silica plug (R_f = 0.43, n-pentane). Molecular formula (molecular mass): C₁₂H₁₆BFO₅S (302.12 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.96–7.88 (m, 2H), 7.37–7.30 (m, 2H), 1.35 (s, 12H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 152.3, 137.2, 120.2, 84.5, 25.0. C-B was not observed. ¹⁹F NMR (376 MHz, CDCl₃): δ 38.11. HR-EI-MS m/z: [M]^•+ calcd for C₁₂H₁₆BFO₅S 302.0790; found, 302.0794; [M-CH₃]^•+ calcd for C₁₁H₁₃BFO₅S 287.0555; found, 287.0556.

2-Mercaptobenzo[d]thiazol-6-yl Sulfurofluoridate (12g)

12g (64.9 mg, 245 μmol, 45%, colorless solid) was prepared according to a modification of GP1 as follows. 2-Mercaptobenzo[d]thiazol-6-ol (100 mg, 546 μmol) was dissolved (under argon) in a solution of Et₃N (197 μL, 1.42 mmol, 2.6 equiv) in MeCN (3 mL) before 11 was added. After 1 h, a second portion of 11 and Et₃N (1 equiv of each) was added and the reaction mixture was left to stand for another 30 min before it was diluted with CH₂Cl₂ (20 mL) and washed with 0.1 M HCl (2 × 10 mL). The organic phase was dried and 12g was isolated by dry load filtration over a silica plug (R_f = 0.34, EtOAc:n-hexane = 1:3). Molecular formula (molecular mass): C₇H₄FNO₃S₃ (265.29 g/mol). ¹H NMR [400 MHz, (CD₃)₂SO]: δ 14.01 (s, 1H), 8.07 (s, 1H), 7.62 (dd, J = 8.9, 2.1 Hz, 1H), 7.41 (d, J = 8.9 Hz, 1H). ¹³C{¹H} NMR [101 MHz, (CD₃)₂SO]: δ 191.2, 145.9, 141.5, 131.0, 120.4, 115.1, 113.5. ¹⁹F NMR [376 MHz, (CD₃)₂SO]: δ 38.34. HR-EI-MS m/z: [M]^•+ calcd for C₇H₄FNO₃S₃ 264.9332; found, 264.9332.

±-α-Tocopherol-Derived Sulfurofluoridate (12h)¹²

12h (256 mg, 499 μmol, 98%, colorless oil) was prepared according to GP1 from ±-α-tocopherol (220 mg, 511 μmol) and purified by filtration over a silica plug (R_f = 0.79, EtOAc:n-hexane = 1:9). Molecular formula (molecular mass): C₂₉H₄₉FO₄S (512.77 g/mol). Mixture of diastereomers. Inequivalent signals of diastereomers in the ¹³C{¹H} NMR spectrum are separated by forward slash symbols. ¹H NMR (400 MHz, CDCl₃): δ 2.60 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.89–1.72 (m, 2H), 1.61–1.06 (m, 25H), 0.94–0.77 (m, 12H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 151.2, 142.0, 127.6, 126.2, 124.5, 118.6, 75.9, 40.1/40.0, 39.5, 37.7/37.62, 37.60/37.54, 37.49/37.4, 33.0/32.9, 32.83/32.81, 31.0, 30.9, 28.1, 25.0, 24.6, 24.0, 22.9/22.8, 21.1, 20.8, 19.9/19.83, 19.82/19.7, 13.7, 12.9, 12.1. ¹⁹F NMR (376 MHz, CDCl₃): δ 41.37. HR-EI-MS m/z: [M]^•+ calcd for C₂₉H₄₉FO₄S 512.3330; found, 512.3330.

4-{[(2S,3R,4S,5S,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}phenyl Sulfurofluoridate (12i)

12i (39.5 mg, 111 μmol, 30%, colorless solid) was prepared according to a modification of GP1 from arbutin (100 mg, 367 μmol) as follows. 11 was added to a solution of the starting material and Et₃N in DMF (3 mL) and the reaction mixture was left to stand for 1 h before another portion of Et₃N and 11 (1 equiv of each) was added. The crude material obtained was purified by RP chromatography. Conditions: column: FlashPure Select C₁₈ 12 g (Büchi Labortechnik GmbH, Essen, Germany); eluent: 0–5 min: 10% MeCN, 5–20 min: 10 → 20% MeCN, 20–25 min: 20 → 100% MeCN; flow rate: 20 mL/min; detection: UV, λ = 210 and 220 nm. Molecular formula (molecular mass): C₁₂H₁₅FO₉S (354.30 g/mol). ¹H NMR (400 MHz, CD₃OD): δ 7.37 (d, J = 9.1 Hz, 2H), 7.28–7.18 (m, 2H), 5.04–4.92 (m, 1H), 3.90 (dd, J = 12.1, 2.0 Hz, 1H), 3.70 (dd, J = 12.1, 5.7 Hz, 1H), 3.55–3.33 (m, 4H). ¹³C{¹H} NMR (101 MHz, CD₃OD): δ 158.8, 146.2, 123.1, 119.3, 102.3, 78.3, 77.9, 74.8, 71.3, 62.4. ¹⁹F NMR (376 MHz, CD₃OD): δ 34.55. HR-ESI-MS m/z: [M + Na]⁺ calcd for C₁₂H₁₅FO₉SNa 377.03130; found, 377.03180.

(S,S)-Ni-Cl₃BPB-m-Tyr Sulfurofluoridate (12j)

(S,S)-Ni-Cl₃BPB-m-Tyr

A solution of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)pyrrolidine-2-carboxamide²¹ (8.1 g, 16.6 mmol), racemic m-Tyr (5.89 g, 32.5 mmol), Ni(OAc)₂·4H₂O (8.09 g, 32.5 mmol), and K₂CO₃ (20.4 g, 147.75 mmol) in anhydrous MeOH (400 mL) was stirred at 60 °C for 24 h and at ambient temperature for 72 h. The reaction mixture was poured into an ice-cold solution of AcOH (50 mL) in H₂O (3 L) and the resulting suspension was allowed to stand at ambient temperature for 24 h, after which a fine red precipitate had formed. The precipitate was collected by filtration, washed with H₂O (3 × 100 mL), air-dried, and dissolved in EtOAc (200 mL). The resulting solution was washed with H₂O (3 × 50 mL) and brine (2 × 50 mL), dried, and concentrated under reduced pressure. The residue was triturated with Et₂O to give a red precipitate, which was recrystallized from EtOAc/hexane to afford a first crop of the title compound as a red solid. The combined mother liquors (from trituration with Et₂O and recrystallization) were concentrated under reduced pressure and the residue was purified by column chromatography (R_f = 0.25; CHCl₃:acetone = 5:1; broad spot) followed by recrystallization from EtOAc/hexane to afford a second crop of the title compound (total: 10.35 g, 88%) as a red solid. Molecular formula (molecular mass): C₃₄H₂₈Cl₃N₃NiO₄ (707.66 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 8.90 (s, 1H), 8.30 (br s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.81–7.41 (m, 4H), 7.40–7.20 (m, 3H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 22.3, 6.9 Hz, 2H), 6.80–6.70 (m, 1H), 6.69–6.53 (m, 2H), 4.29 (s, 1H), 4.13 (d, J = 12.4 Hz, 1H), 3.33–3.16 (m, 1H), 3.09 (d, J = 11.6 Hz, 2H), 2.96 (d, J = 12.4 Hz, 1H), 2.67 (d, J = 8.8 Hz, 1H), 2.45–2.19 (m, 3H), 2.17–1.83 (m, 2H). ¹³C{¹H}-NMR (101 MHz, CDCl₃): δ 180.2, 179.1, 171.0, 157.7, 140.9, 136.8, 135.0, 133.8, 133.44, 133.36, 133.3, 132.6, 132.5, 131.1, 130.5, 130.2, 129.9, 129.6, 129.4, 127.8, 127.4, 127.2, 126.0, 124.0, 122.2, 117.7, 115.3, 71.7, 71.6, 63.5, 58.8, 39.2, 30.9, 23.1. ortho- and meta-Carbons of the phenyl substituent are not equivalent owing to hindered rotation. HR-ESI-MS m/z: [M + K]⁺ calcd for C₃₄H₂₈Cl₃N₃NiO₄K 744.01387; found, 744.01305; [M + Na]⁺ calcd for C₃₄H₂₈Cl₃N₃NiO₄Na 728.04024; found, 728.03911; [M + H]⁺ calcd for C₃₄H₂₉Cl₃N₃NiO₄ 706.05836; found, 706.05716. Correct isotopic pattern.

(S,S)-Ni-Cl₃BPB-m-Tyr Sulfurofluoridate (12j)

12j (90.8 mg, 115 μmol, 82%, red solid) was prepared according to a modification of GP1 from (S,S)-Ni-Cl₃BPB-m-Tyr (100 mg, 141 μmol) as follows. 11 was added to a solution of the starting material and Et₃N in MeCN (10 mL) and the reaction mixture was left to stand for 1 h before a second portion of 11 and Et₃N (1 equiv of each) was added. TLC showed incomplete conversion of the starting material after 16 h. The crude material was purified by dry load column chromatography (R_f = 0.18, CH₂Cl₂:MeOH = 40:1). Molecular formula (molecular mass): C₃₄H₂₇Cl₃FN₃NiO₆S (789.71 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 8.90 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 7.70–7.56 (m, 3H), 7.53–7.43 (m, 2H), 7.40–7.30 (m, 3H), 7.16–7.10 (m, 2H), 7.00–6.95 (m, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 4.28–4.17 (m, 2H), 3.25 (dd, J = 10.6, 6.5 Hz, 2H), 3.16–3.05 (m, 2H), 2.97 (dd, J = 13.8, 6.4 Hz, 1H), 2.70–2.55 (m, 1H), 2.53–2.31 (m, 2H), 2.03–1.88 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 180.1, 177.6, 171.4, 150.5, 141.2, 139.0, 135.0, 133.8, 133.6, 133.5, 133.1, 132.9, 132.5, 131.2, 130.7, 130.61, 130.56, 129.90, 129.86, 129.5, 127.5, 127.4, 127.1, 126.0, 124.1, 122.8, 120.1, 71.4, 71.2, 63.3, 58.6, 40.0, 31.0, 23.4. Ortho- and meta-carbons of the phenyl substituent are not equivalent owing to hindered rotation. ¹⁹F NMR (376 MHz, CDCl₃): δ 38.15. HR-ESI-MS m/z: [M + Na]⁺ calcd for C₃₄H₂₇Cl₃FN₃NiO₆SNa 809.99158; found, 809.99107. Correct isotopic pattern.

4-{(2S,3R)-1-(4-Fluorophenyl)-3-[(S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl Sulfurofluoridate (12k)¹²

12k (90 mg, 183 μmol, 75%, colorless solid) was prepared according to GP 1 from ezetimibe (100 mg, 244 μmol) and purified by column chromatography (R_f = 0.32, EtOAc:n-hexane = 1:2). Molecular formula (molecular mass): C₂₄H₂₀F₃NO₅S (491.48 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.49–7.40 (m, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.33–7.26 (m, 2H), 7.19 (ddt, J = 8.0, 5.6, 2.8 Hz, 2H), 7.08–6.90 (m, 4H), 4.72 (t, J = 5.8 Hz, 1H), 4.68 (d, J = 2.4 Hz, 1H), 3.07 (td, J = 7.5, 2.4 Hz, 1H), 2.25 (s, 1H), 2.12–1.84 (m, 4H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 167.0, 162.4 (d, J = 245.8 Hz), 159.3 (d, J = 244.2 Hz), 150.0, 140.0 (d, J = 3.0 Hz), 138.7, 133.6 (d, J = 2.7 Hz), 128.0, 127.5 (d, J = 8.2 Hz), 122.1, 118.4 (d, J = 7.9 Hz), 116.2 (d, J = 22.7 Hz), 115.6 (d, J = 21.4 Hz), 73.3, 60.8, 60.5, 36.7, 25.3. ¹⁹F NMR (376 MHz, CDCl₃): δ 38.03, −114.62, −117.30. HR-ESI-MS m/z: [M + Na]⁺ calcd for C₂₄H₂₀F₃NO₅SNa 514.09065; found, 514.09065.

(S)-4-Ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4’:6,7]indolizino[1,2-b]quinolin-9-yl Sulfurofluoridate (12l)⁸

12l (68.9 mg, 154 μmol, 37%, green-yellow solid) was prepared according to GP1 from 10-hydroxycamptothecin (150 mg, 412 μmol) using increased amounts of 11 (5.2 equiv) and Et₃N (6.4 equiv) and purified by column chromatography (R_f = 0.14, EtOAc:n-hexane = 2:1). Molecular formula (molecular mass): C₂₀H₁₅FN₂O₇S (446.41 g/mol). ¹H NMR [400 MHz, (CD₃)₂SO]: δ 8.81 (s, 1H), 8.50 (s, 1H), 8.42–8.30 (m, 1H), 8.13–7.97 (m, 1H), 7.37 (d, J = 2.9 Hz, 1H), 6.56 (s, 1H), 5.44 (s, 2H), 5.32 (s, 2H), 1.87 (sep, J = 7.1 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). ¹³C{¹H} NMR [101 MHz, (CD₃)₂SO]: δ 172.4, 156.7, 154.3, 149.9, 147.5, 146.9, 144.9, 132.2, 132.0, 131.4, 128.2, 123.7, 120.1, 119.8, 97.3, 72.3, 65.2, 50.3, 30.3, 7.8. ¹⁹F NMR [376 MHz, (CD₃)₂SO]: δ 39.33. HR-ESI-MS m/z: [M + H]⁺ calcd for C₂₀H₁₆FN₂O₇S 447.06568; found, 447.06623; [M + Na]⁺ calcd for C₂₀H₁₅FN₂O₇SNa 469.04762; found, 469.04838.

4-{3-[2-(Diethylamino)-2-oxoethyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidin-2-yl}phenyl Sulfurofluoridate (12m)¹²

12m (73.9 mg, 170 μmol, 60%, colorless solid) was prepared according to GP1 from N,N-diethyl-2-{2-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl}-acetamide (des-Me-DPA-713) (100 mg, 284 μmol; prepared as described in²²) and purified by column chromatography (R_f = 0.26, CHCl₃:acetone = 5:1). The reaction was conducted in a mixture of DMF/MeCN (1:1, 6 mL). Molecular formula (molecular mass): C₂₀H₂₃FN₄O₄S (434.49 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 6.56 (s, 1H), 3.93 (s, 2H), 3.56 (q, J = 7.1 Hz, 2H), 3.40 (q, J = 7.1 Hz, 2H), 2.74 (s, 3H), 2.55 (s, 3H), 1.25 (t, J = 7.1 Hz, 4H), 1.10 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 170.0, 158.1, 153.4, 150.1, 147.8, 145.0, 134.8, 130.9, 121.1, 109.0, 101.7, 42.6, 40.9, 27.9, 24.8, 17.0, 14.6, 13.2. ¹⁹F NMR (376 MHz, CDCl₃): δ 37.66. HR-ESI-MS m/z: [M + Na]⁺ calcd for C₂₀H₂₃FN₄O₄SNa 457.13163; found, 457.13162; [M + H]⁺ calcd for C₂₀H₂₄FN₄O₄S 435.14968; found, 435.14983.

2,3,5,6-Tetrafluorophenyl 3-{4-[(fluorosulfonyl)oxy]phenyl}propanoate (12n)

2,3,5,6-Tetrafluorophenyl 3-(4-Hydroxyphenyl)propanoate²³

N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.2 g, 6.28 mmol, 1.04 equiv) was added to an ice-cold solution of (4-hydroxyphenyl)propionic acid (1.00 g, 6.02 mmol, 1.0 equiv) and 2,3,5,6-tetrafluorophenol (1.1 g, 6.02 mmol, 1.0 equiv) in CH₂Cl₂ (20 mL) and the reaction mixture was stirred for 15 min. The cooling bath was removed and the mixture was stirred for another 16 h. The mixture was then concentrated under reduced pressure and the residue was taken up into Et₂O and H₂O (50 mL of each). The organic phase was separated, washed with H₂O (3 × 20 mL) and brine (2 × 20 mL), dried, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (R_f = 0.15, EtOAc:n-hexane = 1:2.3) to afford the title compound (1.44 g, 4.83 mmol, 76%) as a colorless liquid. Molecular formula (molecular mass): C₁₅H₁₀F₄O₃ (314.24 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.16–7.08 (m, 2H), 7.04–6.93 (m, 1H), 6.82–6.73 (m, 2H), 4.87 (d, J = 27.4 Hz, 1H), 3.09–2.86 (m, 4H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 169.0, 154.4, 146.1 (ddd, J = 240.5, 7.1, 4.0 Hz), 142.3–139.2 (m), 131.8, 129.6, 115.6, 103.3 (t, J = 22.8 Hz), 35.5, 30.0. C_Ar-O was not observed. ¹⁹F NMR (376 MHz, CDCl₃): δ −139.02 (dd, J = 21.8, 9.8 Hz), −152.84 (dd, J = 21.8, 9.8 Hz). LR-ESI-MS m/z: [M + NH₄]⁺ calcd for C₁₅H₁₄NF₄O₃ 332.09; found, 332.22.

2,3,5,6-Tetrafluorophenyl 3-{4-[(Fluorosulfonyl)oxy]phenyl}propanoate (12n)

12n was prepared according to a modification of GP1 as follows. 11 (2.02 g, 6.40 mmol, 1.4 equiv) was added to a solution of 2,3,5,6-tetrafluorophenyl (4-hydroxyphenyl)propanoate (1.44 g, 4.58 mmol) and Et₃N (1.09 mL, 0.79 g, 7.82 mmol, 1.7 equiv) in MeCN (20 mL) and the reaction mixture was vigorously stirred for 16 h. The mixture was then concentrated under reduced pressure, the residue was taken up into Et₂O and H₂O (50 mL of each), and the insoluble tar and aqueous fraction were discarded. The organic phase was washed with H₂O (3 × 20 mL) and brine (2 × 20 mL), dried, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (R_f = 0.52, EtOAc:n-hexane = 1:15) to afford, after low-temperature (−20 °C) recrystallization from pentane, 12n (0.99 g, 2.50 mmol, 55%) as a colorless solid. Molecular formula (molecular mass): C₁₅H₉F₅O₅S (396.28 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.40–7.34 (m, 2H), 7.34–7.28 (m, 2H), 7.00 (tt, J = 9.9, 7.1 Hz, 1H), 3.14 (t, J = 7.4 Hz, 2H), 3.05–2.98 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 168.4, 149.0, 146.2 (ddd, J = 250.5, 7.0, 4.0 Hz), 142.1–139.0 (m), 130.4, 121.3, 103.5 (t, J = 22.8 Hz), 34.8, 30.1. C_Ar-O was not observed. ¹⁹F NMR (376 MHz, CDCl₃): δ 37.42, −138.79 (dd, J = 21.7, 9.8 Hz), −152.93 (dd, J = 21.7, 9.8 Hz). Elemental analysis: Calcd for C₁₅H₉F₅O₅S: C, 45.46%; H, 2.29%; S, 8.09%. Found: C, 45.85 ± 0.02%; H, 2.31 ± 0.04%; S, 8.16 ± 0.00% (n = 2).

Methyl(phenyl)sulfamoyl Fluoride (13a)⁸

13a (247 mg, 1.31 mmol, 70%, yellow oil) was prepared according to GP2 from N-methylaniline (200 mg, 1.87 mmol). After HPLC indicated full conversion, the reaction solvent was removed and the residue was taken up into CH₂Cl₂. The organic phase was washed with H₂O, dried, and the solvent was removed. The crude material thus obtained was purified by RP chromatography. Conditions: column: FlashPure Select C₁₈ 12 g (Büchi Labortechnik GmbH, Essen, Germany); eluent: 0–15 min: 40% MeCN, 15–17 min: 40 → 80% MeCN, 17–22 min: 80 → 100% MeCN; flow rate: 20 mL/min; detection: UV, λ = 210, 220, 254, 280 nm. Molecular formula (molecular mass): C₇H₈FNO₂S (189.20 g/mol). ¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.33 (m, 5H), 3.44 (d, J = 2.2 Hz, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 140.0, 130.0, 129.1, 126.7, 40.8. ¹⁹F NMR (376 MHz, CDCl₃): δ 42.33. HR-EI-MS m/z: [M]^•+ calcd for C₇H₈FNO₂S 189.0254; found, 189.0254.

1,2,3,4-Tetrahydroisoquinoline-2-sulfonyl Fluoride (13b)²⁴

13b (200 mg, 929 μmol, 83%, pale rose solid) was prepared according to GP2 from 1,2,3,4-tetrahydroisoquinoline (150 mg, 1.23 mmol). After TLC indicated full conversion, the reaction solvent was removed, the residue was dissolved in Et₂O and the organic phase was washed with H₂O. After removal of the solvent, no further purification was required. Molecular formula (molecular mass): C₉H₁₀FNO₂S (215.24 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.31–7.24 (m, 2H), 7.24–7.18 (m, 1H), 7.17–7.10 (m, 1H), 4.67 (s, 2H), 3.78 (td, J = 6.0, 1.9 Hz, 2H), 3.05 (t, J = 6.0 Hz, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 132.6, 130.4, 129.2, 127.6, 127.0, 126.3, 48.3, 45.1, 28.1. ¹⁹F NMR (376 MHz, CDCl₃): δ 40.96. HR-EI-MS m/z: [M]^•+ calcd for C₉H₁₀FNO₂S 215.0411; found, 215.0407.

Indoline-1-sulfonyl Fluoride (13c)²⁴

13c (143 mg, 711 μmol, 85%, pale rose solid) was prepared according to GP2 from indoline (100 mg, 839 μmol) and purified by filtration over a silica plug (R_f = 0.45, EtOAc:n-hexane = 1:6). Molecular formula (molecular mass): C₈H₈FNO₂S (201.22 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.54–7.37 (m, 1H), 7.30–7.19 (m, 2H), 7.17–7.05 (m, 1H), 4.14 (td, J = 8.4, 2.5 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 139.9, 131.0, 128.3, 125.6, 125.3, 114.7, 51.7, 28.1. ¹⁹F NMR (376 MHz, CDCl₃): δ 39.12. HR-EI-MS m/z: [M]^•+ calcd for C₈H₈FNO₂S 201.0254; found, 201.0252.

Isoindoline-2-sulfonyl Fluoride (13d)

11 (488 mg, 1.55 mmol, 1.6 equiv) was added to a suspension of isoindoline × HCl (150 mg, 0.96 mmol) in CH₂Cl₂ (4 mL) followed by dropwise addition of Et₃N (134 μL, 0.96 mmol, 1.0 equiv). After TLC indicated full conversion, the reaction mixture was filtered over a plug of silica. The crude product was purified by column chromatography (R_f = 0.43, EtOAc:n-hexane = 1:10) to afford the title compound 13d (191 mg, 0.95 mmol, 98%) as a colorless solid. Molecular formula (molecular mass): C₈H₈FNO₂S (201.22 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.42–7.32 (m, 2H), 7.31–7.26 (m, 2H), 4.86 (d, J = 2.4 Hz, 4H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 134.8, 128.5, 122.9, 55.0. ¹⁹F NMR (376 MHz, CDCl₃): δ 37.93. HR-EI-MS m/z: [M]^•+ calcd for C₈H₈FNO₂S 201.0254; found, 201.0251.

4-Benzylpiperidine-1-sulfonyl Fluoride (13e)⁸

13e (285 mg, 1.11 mmol, 97%, colorless solid) was prepared according to GP2 from 4-benzylpiperidine (200 mg, 1.14 mmol). After TLC indicated full conversion, the reaction mixture was diluted with Et₂O (10 mL) and washed with H₂O (10 mL) and brine (10 mL). The organic phase was dried and concentrated under reduced pressure and the product was purified by filtration over a silica plug (R_f = 0.42, EtOAc:n-hexane = 1:6). Molecular formula (molecular mass): C₁₂H₁₆FNO₂S (257.32 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.37–7.27 (m, 2H), 7.25–7.19 (m, 1H), 7.17–7.09 (m, 2H), 3.91 (dt, J = 12.7, 2.3 Hz, 2H), 2.94 (tt, J = 12.7, 3.0 Hz, 2H), 2.59 (d, J = 7.0 Hz, 2H), 1.84–1.61 (m, 3H), 1.39 (qd, J = 12.8, 4.2 Hz, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 139.4, 129.2, 128.6, 126.4, 47.6, 42.7, 37.2, 30.8. ¹⁹F NMR (376 MHz, CDCl₃): δ 40.17. HR-EI-MS m/z: [M]^•+ calcd for C₁₂H₁₆FNO₂S 257.0880; found, 257.0878.

4-Hydroxypiperidyl-1-sulfonyl Fluoride (13f)

13f (160 mg, 876 μmol, 89%, colorless solid) was prepared according to GP2 from 4-hydroxypiperidine (100 mg, 989 μmol) and purified by filtration over a silica plug (R_f = 0.46, EtOAc:n-hexane = 2:1). Molecular formula (molecular mass): C₅H₁₀FNO₃S (183.20 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 4.19–3.88 (m, 1H), 3.87–3.61 (m, 2H), 3.55–3.25 (m, 2H), 2.12–1.90 (m, 2H), 1.78–1.65 (m, 2H), 1.76 (br s, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 65.0, 44.1, 32.6. ¹⁹F NMR (376 MHz, CDCl₃): δ 41.07. HR-EI-MS m/z: [M-H₂O]^•+ calcd for C₅H₈FNO₂S 165.0254; found, 165.0253.

6-Hydroxy-1,2,3,4-tetrahydroisoquinoline-2-sulfonyl Fluoride (13g)

13g (205 mg, 887 μmol, 88%, colorless oil) was prepared according to GP2 from 1,2,3,4-tetrahydroisoquinolin-6-ol (150 mg, 1.01 mmol) and purified by filtration over a silica plug (R_f = 0.37, EtOAc:n-hexane = 1:2). Molecular formula (molecular mass): C₉H₁₀FNO₃S (231.24 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 6.97 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 8.3, 2.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 4.97 (s, 1H), 4.56 (s, 2H), 3.71 (td, J = 6.1, 1.9 Hz, 2H), 2.95 (t, J = 6.1 Hz, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 154.9, 134.2, 127.6, 122.6, 115.4, 114.5, 47.9, 44.9, 28.2. ¹⁹F NMR (376 MHz, CDCl₃): δ 41.05. HR-EI-MS m/z: [M]⁺ calcd for C₉H₁₀FNO₃S 231.0360; found, 231.0361.

Phenylsulfamoyl Fluoride (13h)⁸

A solution of aniline (147 μL, 1.61 mmol) in CH₂Cl₂ (1.5 mL) was added to an ice-cooled suspension of 11 (556 mg, 1.77 mmol, 1.1 equiv) in CH₂Cl₂ (4 mL). After TLC indicated full conversion, CH₂Cl₂ (10 mL) was added and the solution was washed with 0.1 m HCl (3 × 10 mL) and brine (20 mL). The organic phase was dried and the solvent was removed under reduced pressure to afford the title compound 13h (196 mg, 1.12 mmol, 70%) as a pale red liquid. Molecular formula (molecular mass): C₆H₆FNO₂S (175.18 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.42 (ddd, J = 8.0, 6.2, 1.8 Hz, 2H), 7.36–7.24 (m, 3H), 7.16 (br s, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 134.0, 129.9, 127.6, 123.1. ¹⁹F NMR (376 MHz, CDCl₃): δ 50.90. HR-EI-MS m/z: [M]^•+ calcd for C₆H₆FNO₂S 175.0098; found, 175.0096.

Phenyliminodisulfonyl Difluoride (13i)⁸

11 (1.26 g, 4.03 mmol, 2.5 equiv) was added to an ice-cooled solution of aniline (147 μL, 1.61 mmol) in MeCN (4 mL). The mixture was stirred for 10 min before Et₃N (112 μL, 805 μmol, 0.5 equiv) was added. After TLC indicated full conversion, silica was added, the solvent was removed, and the residue was filtered over a plug of silica (R_f = 0.50, EtOAc:n-hexane = 1:10) to afford the title compound 13i (322 mg, 1.26 mmol, 78%) as a colorless solid. Molecular formula (molecular mass): C₆H₅F₂NO₄S₂ (257.23 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.69–7.54 (m, 3H), 7.54–7.47 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 133.2, 132.5, 130.9, 129.3. ¹⁹F NMR (376 MHz, CDCl₃): δ 56.32. HR-EI-MS m/z: [M]^•+ calcd for C₆H₅F₂NO₄S₂ 256.9623; found, 256.9621.

(4-Fluorobenzyl)sulfamoyl Fluoride (13j)²⁵

11 (0.68 g, 2.10 mmol, 1.05 equiv) was added to a solution of 4-fluorobenzylamine (0.228 mL, 0.25 g, 2.0 mmol) in MeCN (2 mL). An exothermic reaction was observed. The reaction mixture was stirred for 40 min and taken up into Et₂O/H₂O (30 mL of each). The organic layer was separated, washed with H₂O (3 × 20 mL) and brine (2 × 10 mL), dried, and successively concentrated under atmospheric pressure and at 750 mbar. The crude product was purified by fast column chromatography (R_f = 0.38, CH₂Cl₂:n-pentane = 1:1; 13j is not completely stable on silica). The product containing fractions were pooled and concentrated under atmospheric pressure to afford, after drying at 100 mbar and ambient temperature, 13j (0.31 g, 75%, 1.5 mmol) as a volatile colorless liquid. Molecular formula (molecular mass): C₇H₇F₂NO₂S (207.19 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.32 (ddd, J = 8.1, 5.0, 2.5 Hz, 2H), 7.11–7.04 (m, 2H), 5.37–5.11 (br s, 1H), 4.42 (d, J = 5.9 Hz, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 163.1 (d, J = 248.2 Hz), 130.8 (dd, J = 2.9, 1.1 Hz), 130.2 (d, J = 8.5 Hz), 116.3 (d, J = 21.8 Hz), 48.0. ¹⁹F NMR (376 MHz, CDCl₃): δ 51.25, −112.67. LR-ESI-MS m/z: [M–H]⁻ calcd for C₇H₆F₂NO₂S 206.01; found, 206.06. HR-EI-MS m/z: [M]^•+ calcd for C₇H₇F₂NO₂S 207.0160; found, 207.0159.

4-(2-Chlorodibenzo[b,f][1,4]oxazepin-11 yl)piperazine-1-sulfonyl Fluoride (13k)⁸

13k (235 mg, 594 μmol, 93%, colorless solid) was prepared according to GP2 from amoxapine (200 mg, 637 μmol) and purified by filtration over a silica plug (R_f = 0.38, EtOAc:n-hexane = 1:4). Molecular formula (molecular mass): C₁₇H₁₅ClFN₃O₃S (395.83 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 7.44 (dd, J = 8.7, 2.6 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.19–7.08 (m, 3H), 7.08–7.02 (m, 1H), 3.62 (d, J = 35.1 Hz, 8H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 159.6, 158.4, 151.8, 139.5, 133.3, 130.8, 128.7, 127.3, 126.1, 125.6, 124.5, 123.1, 120.4, 46.7, 46.5. ¹⁹F NMR (376 MHz, CDCl₃): δ 39.17. HR-ESI-MS m/z: [M + H]⁺ calcd for C₁₇H₁₆ClFN₃O₃S 396.0579; found, 396.0578.

tert-Butyl {2-[1-(Fluorosulfonyl)-1H-indol-3-yl]ethyl}carbamate (13l)

11 (531 mg, 1.69 mmol, 1.1 equiv) was added to a solution of tert-butyl [2-(1H-indol-3-yl)ethyl]carbamate (400 mg, 1.54 mmol) and DBU (505 μL, 3.38 mmol, 2.2 equiv) in CH₂Cl₂. Conversion of the starting material was monitored by HPLC. After 1 h, a second portion of 11 (241 mg, 768 μmol, 0.5 equiv) was added, but no further conversion was observed after another 2 h. Therefore, silica was added, the solvent was removed, and the residue was purified by column chromatography with solid loading (R_f = 0.26, EtOAc:n-hexane = 1:4) to afford the title compound 13l (72.0 mg, 210 μmol, 14%) as a colorless solid. Molecular formula (molecular mass): C₁₅H₁₉FN₂O₄S (342.39 g/mol). ¹H NMR (400 MHz, CDCl₃): δ 8.02–7.78 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.53–7.31 (m, 2H), 7.28–7.23 (m, 1H), 4.67 (s, 1H), 3.47 (q, J = 6.7 Hz, 2H), 2.93 (t, J = 6.7 Hz, 2H), 1.44 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 156.0, 135.4, 130.8, 126.2, 124.8, 123.0, 122.2, 120.2, 113.9, 79.7, 39.9, 28.5, 25.8. ¹⁹F NMR (376 MHz, CDCl₃): δ 53.90. HR-ESI-MS m/z: [M + Na]⁺ calcd for C₁₅H₁₉FN₂O₄SNa 365.0942; found, 365.0948.

1-(Fluorosulfonyl)piperidine-4-carboxylic Acid (13m)

13m (62.6 mg, 298 μmol, 39%, colorless solid) was prepared according to GP2 from isonipecotic acid (100 mg, 774 μmol) and purified by column chromatography (R_f = 0.21, CH₂Cl₂:MeOH = 30:1). Molecular formula (molecular mass): C₆H₁₀FNO₄S (211.21 g/mol). ¹H NMR (400 MHz, CD₃OD): δ 3.93–3.74 (m, 2H), 3.26–3.11 (m, 2H), 2.65–2.47 (m, 1H), 2.14–1.97 (m, 2H), 1.90–1.68 (m, 2H). ¹³C{¹H} NMR (101 MHz, CD₃OD): δ 177.2, 47.6, 40.5, 28.2. ¹⁹F NMR (376 MHz, CD₃OD): δ 38.16. HR-EI-MS m/z: [M-CO₂H]^•+ calcd for C₅H₉FNO₂S 166.0333; found, 166.0332.

Glossary

Abbreviations

AISF

[4-(acetylamino)phenyl]imidodisulfuryl difluoride

(CD₃)₂SO

hexadeuterodimethyl sulfoxide

CD₃CN

trideuteroacetonitrile

CDCl₃

deuterochloroform

DBU

1,8-diazabicyclo[5.4.0]undec-7-ene

desmethyl SuFEx-IT

1-(fluorosulfonyl)-3-methyl-1H-imidazole trifluoromethanesulfonate

FO₂S-

fluorosulfuryl

HR-EI-MS

high-resolution electron ionization mass spectrometry

HR-ESI-MS

high-resolution electrospray ionization mass spectrometry

LR-EI-MS

low-resolution electron ionization mass spectrometry

LR-ESI-MS

low-resolution electrospray ionization mass spectrometry

MeOTf

methyl triflate

MS

mass spectrometry

MSDI

3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazole-1-ium trifluoromethanesulfonate

NMR

nuclear magnetic resonance

SDI

1,1′-sulfonyldiimidazole

SO₂Cl₂

sulfuryl chloride

SO₂F₂

sulfuryl fluoride

SuFEx

sulfur(VI)-fluoride exchange

SuFEx-IT

1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazole-3-ium trifluoromethanesulfonate

THF-d₈

octadeuterotetrahydrofuran

TLC

thin-layer chromatography

LR-EI-MS

low-resolution electron ionization mass spectrometry

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c02643.

• Appearance and preparation of 1H-imidazole-1-sulfonyl fluoride (10) and desmethyl SuFEx-IT (11) and NMR-spectra for all prepared compounds (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This work was supported by Deutsche Forschungsgemeinschaft (DFG), grant number ZL 65/4–1.

The authors declare no competing financial interest.