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

Fluorosulfurylating Agent
Jan Bertram, Felix Neumaier, Boris D. Zlatopolskiy, and Bernd Neumaier*
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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
Downloaded via 77.65.81.89 on April 13, 2025 at 21:49:33 (UTC).

analogous desmethyl SuFEx-IT from inexpensive starting materials. The

reagent was prepared in a high (85%) total yield and without chromato-
graphic 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
To overcome these limitations, de Borggraeve and co-workers
introduced a fluorosulfurylation method based on ex situ
intrigued researchers since the early 20th century.1,2 Introduc- generation of SO2F2 from 1,1′-sulfonyldiimidazole (SDI) in a
tion of sulfur(VI)-fluoride exchange (SuFEx) as a new class of two-chamber reactor.7 Although this method simplifies
click reactions in 20143 fostered scientific efforts by chemists conversion of phenols into the corresponding aryl fluorosulfates,
from all over the world to exploit the exceptional properties of the requirement for specialized glassware, limited scalability, and
this functional group. The SVI−F bond in the FO2S-group is the formation of HF gas as a side product represent obvious
generally highly stable and can tolerate unusually harsh disadvantages.
conditions. However, it demonstrates a latent reactivity with Accordingly, development of a fluorosulfuryl imidazolium
various nucleophiles that can be triggered under specific triflate salt (termed SuFEx-IT) as a solid equivalent for SO2F2 by
conditions. In addition, the facile introduction of the FO2S- Guo and co-workers greatly improved access to SuFExable
group into target molecules using SuFEx hub-reagents has compounds.8 Thus, using SuFEx-IT as a FO2S-donor, the group
rendered FO2S-substituted compounds valuable building blocks was able to prepare a wide range of fluorosulfates and sulfamoyl
across diverse applications in organic synthesis, material fluorides from the corresponding alcohols and amines.
sciences, drug discovery, and even radiochemistry.4 Remarkably, SuFEx-IT showed better reactivity/chemoselectiv-
The prototypical SuFEx hub for introduction of FO2S-groups ity than SO2F2 and enabled fluorosulfurylation of primary
into phenols or secondary amines is gaseous sulfuryl fluoride amines, providing access to the corresponding sulfamoyl
(SO2F2), which is typically obtained from pressurized lecture fluorides and bis(fluorosulfuryl)imides (Scheme 1). In addition,
bottles. However, while SO2F2 shows ideal reactivity for SuFEx-IT proved to be sufficiently stable for several months
fluorosulfurylation of phenols, it exhibits sluggish reactivity
when stored at 4 °C or in a desiccator and could be synthesized
with secondary amines and has proven to be unsuitable for
on a multigram scale in two steps from 2-methylimidazole via
conversion of primary amines to the corresponding sulfamoyl
fluorides. Moreover, despite the apparent simplicity of SO2F2- fluorosulfurylation with SO2F2 followed by quaternization of the
based fluorosulfurylation methods, their routine application is
hampered by the neurotoxic nature of SO2F2, which has led to Received: November 16, 2023
several fatalities beyond laboratory environments.5,6 As a Revised: February 5, 2024
consequence, the availability of SO2F2 is often restricted by Accepted: February 9, 2024
regulations, and the need for specialized equipment to handle Published: February 22, 2024
toxic gases has further impeded broad adoption of this reagent as
a SuFEx hub.
© 2024 The Authors. Published by
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3821 J. Org. Chem. 2024, 89, 3821−3833
The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 1. Preparation of Fluorosulfates and Sulfamoyl As such, SuFEx-IT remains the most widely used reagent for
Fluorides with SuFEx-IT8 and AISF9 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 afore-
mentioned 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.
resulting intermediate with methyl triflate (MeOTf) (Scheme
2).
Another solid and bench-stable SuFEx hub developed by
Zhou et al. is [4-(acetylamino)phenyl]imidodisulfuryl difluoride
■ RESULTS AND DISCUSSION
Initially, we hypothesized that application of sulfuryl chloride
(AISF).9 This FO2S-donor could be prepared in a single step by (SO2Cl2) as an inexpensive and liquid substitute for SO2F2 could
oxidative C−H functionalization of acetanilide with bis- be used to improve the synthesis of SuFEx-IT (4). In particular,
(fluorosulfonyl)imide (Scheme 2). In addition, the authors it was envisioned that reaction of 2-methylimidazole (1) with
demonstrated the utility of AISF for the synthesis of various aryl SO2Cl2 should afford the corresponding sulfamoyl chloride 2,
fluorosulfates and sulfamoyl fluorides. However, mono- or which could in turn be converted to sulfamoyl fluoride 3 using
bifunctionalization of primary amines with the FO2S-moiety an adequate fluoride source (Scheme 3A). However, no
using this reagent has proven to be challenging, indicating an formation of the desired sulfamoyl chloride was observed
inferior reactivity compared to SuFEx-IT.10 under various reaction conditions (see a−d in Scheme 3A).
Therefore, this approach was abandoned.
Scheme 2. Literature Procedures for the Preparation of Next, we turned our attention to the imidazolium salt 6 as an
SuFEx-IT8 and AISF9 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

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

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

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

a
Indicated yields refer to isolated products. bEt3N (2.6 equiv). cAdditional Et3N (1.0 equiv) and 11 (1.0 equiv) after 1 h. dIn DMF. eEt3N (6.4
equiv) and 11 (5.2 equiv). fIn DMF/MeCN (1:1). gGram scale, 11 (1.4 equiv) and Et3N (1.7 equiv), 16 h.

SuFExIT. Although the preparation of 11 has been described in SuFEx-IT is essentially the same as for the production SuFEx-IT
the patent literature, 13
neither its suitability as a FO2S-transfer and thus suffers from the same drawbacks.
When the above synthetic strategy was applied to this target
agent nor its storage stability have been evaluated so far. In compound (Scheme 4), the first step could be omitted by
addition, the reported procedure for preparation of desmethyl directly starting from inexpensive SDI (8; available from
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Scheme 6. Synthesis of Sulfamoyl Fluorides from the Corresponding Amines Using Desmethyl SuFEx-IT (11) as a FO2S-Donora

a
Indicated yields refer to isolated products. b11 (1.6 equiv) and Et3N (1.0 equiv). cIn CH2Cl2. d11 (2.5 equiv) and Et3N (0.5 equiv; added after 10
min), 10 min at 0 °C, then 30 min at rt. e11 (1.05 equiv). fDBU (2.2 equiv).

numerous providers for 0.5−1 €/g in 25−500 g packages). cholesterol lowering drug ezetimibe, the topoisomerase
Alternatively, decagram quantities of 87 could be easily prepared inhibitor camptothecin or the precursor for the 11C-labeled
from imidazole (7) and SO2Cl2 in >80% yield. Subsequent TSPO-specific ligand [11C]DPA-71316 afforded the desired
quaternization of 8 with MeOTf provided the corresponding fluorosulfurylated products in 30−98% yields (Scheme 5, 12h−
monomethylated sulfonyldiimidazolium salt (MSDI, 9),14 m). Scalability of the procedure was confirmed by the
which precipitated from the solution and could be readily preparation of base sensitive active ester 12n on a gram scale
isolated in 97% yield after a total reaction time of 3 h. Thereafter, in 55% yield.
9 was dissolved in ice-cooled water and treated with KHF2 to Fluorosulfurylation of both aliphatic and aromatic secondary
produce sulfamoyl fluoride 1015 within 10 min. Purification of amines with 11 afforded the corresponding sulfamoyl fluorides
the crude product by distillation afforded 10 in 88% yield when 13a−g in good to excellent yields (Scheme 6). Noteworthy, 4-
the reaction was performed on a decagram scale (we efficiently hydroxypiperidine and 6-hydroxy-1,2,3,4-tetrahydroisoquino-
prepared up to ∼60 g product). On a smaller scale, the yield was line were mono-fluorosulfurylated at the nitrogen with excellent
∼10% lower, presumably due to increased loss of the volatile selectivity to furnish the corresponding sulfamoyl fluorides as
product (see the Supporting Information). Finally, methylation single products in 88−89% yields (Scheme 6, 13f and 13g). The
of 10 with MeOTf provided, after simple crystallization, observed chemoselectivity for fluorosulfurylation of the
desmethyl SuFEx-IT (11) as a colorless solid in almost secondary amino over the hydroxy groups in these substrates
quantitative yields. This route enabled preparation of 11 on a can most likely be attributed to its higher nucleophilicity. 11 was
hectogram scale in 85% total yield and without any chromato- also successfully applied for the mono- and bi-fluorosulfur-
graphic purifications within 2 days. Attempts to further shorten ylation of aniline and mono-fluorosulfurylation of 4-fluoroben-
the procedure by direct fluorination of SDI were unsuccessful zylamine (Scheme 6, 13h−j). A fluorosulfurylated derivative of
due to low conversion of 8 to 10. the antidepressant amoxapine was prepared in 93% yield
Next, we investigated the reactivity and chemoselectivity of (Scheme 6, 13k). Fluorosulfurylation of an indole nitrogen,
desmethyl SuFEx-IT as a FO2S-donor by preparation of several e.g., in Nα-Boc-protected tryptamine, was also possible. In this
fluorosulfates and sulfamoyl fluorides. The results confirmed case, application of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
that 11 reacts readily with various simple phenols to form the as a base was necessary to prepare the desired product in a fair
corresponding fluorosulfates 12a−e in yields of 78−91% within yield (Scheme 6, 13l). Notably, the preparation of N-
30−90 min (Scheme 5). The reaction was unaffected by the fluorosulfurylated indoles using SuFEx-IT or AISF has not
presence of electron-withdrawing or electron-donating groups. been described so far. Finally, desmethyl SuFEx-IT enabled
Substrates containing a Bpin or unprotected thiol group could installation of a FO2S group in the presence of an unprotected
also be fluorosulfurylated in 73 and 45% yields, respectively carboxylic acid function, as exemplified by transformation of the
(Scheme 5, 12f and 12g, respectively). In addition, reaction of GABAA receptor partial agonist isonipecotic acid into the
desmethyl SuFEx-IT with more complex and/or sensitive corresponding sulfamoyl fluoride in 39% yield (Scheme 6,
substrates like ± -α-tocopherol (vitamin D), the skin-lightning 13m). Generally, desmethyl SuFEx-IT demonstrated a reactivity
glycoside arbutin, the Ni-complex Ni-Cl3BPB-m-Tyr, the comparable to that of SuFEx-IT.8 Thus, fluorosulfurylation of
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Figure 1. 1H NMR of desmethyl SuFEx-IT (11) after storage for 288 days at the indicated temperatures under air or argon.

sterically hindered 2,2,6,6-tetramethylpiperidine, which could

not be fluorosulfurylated using SuFEx-It, AISF, or SO2F2, was
■ EXPERIMENTAL SECTION
Unless noted otherwise, all chemicals and solvents were purchased from
also impossible using desmethyl SuFEx-IT (Scheme 6, 13n). VWR International GmbH (Darmstadt, Germany), Sigma-Aldrich
Finally, the long-term stability of 11 during storage under Chemie GmbH (Steinheim, Germany), ABCR GmbH (Karlsruhe,
different conditions was investigated by nuclear magnetic Germany), Apollo Scientific Ltd. (Bredbury, United Kingdom) or BLD
resonance (NMR) analysis (Figure 1). Bench storage under Pharmatech GmbH (Kaiserslautern, Germany) and used without
air for 288 days at ambient temperature (20−23 °C) resulted in further purification.
If not stated otherwise, all reactions were carried out with magnetic
decomposition by 34%, which could be reduced to 18% by stirring. Organic extracts were dried over anhydrous MgSO4. Air- or
storing the compound under argon. In contrast, minimal (<3%) moisture-sensitive reagents were handled under argon (>99.999%, Air
or no signs of decomposition were observed after 288 days at 4 Liquide GmbH, Düsseldorf, Germany). CH2Cl2 [HPLC grade (GC:
°C or −18 °C under argon, respectively, demonstrating an 99.8%), <0.01% H2O] was stored under argon and was used with
excellent shelf life of 11 under these conditions. moisture sensitive reagents (like MeOTf or SO2Cl2). Solutions were
concentrated under reduced pressure (1−900 mbar) at 40−50 °C using

■ CONCLUSIONS
We have developed a convenient three-step procedure for the
a rotary evaporator (Heidolph GmbH & Co. KG, Schwabach,
Germany).
Nuclear Magnetic Resonance Spectroscopy. NMR spectra
SO2F2-free, hectogram-scale preparation of desmethyl SuFEx- were measured at ambient temperature in deuterochloroform (CDCl3),
trideuteroacetonitrile (CD3CN), hexadeuterodimethyl sulfoxide
IT. This process affords the compound in 85% total yield from [(CD3)2SO] or octadeuterotetrahydrofuran (THF-d8) as indicated
inexpensive starting materials without chromatographic purifi- using a Bruker Ascend 400 (1H: 400 MHz; 13C{1H}: 101 MHz; 19F:
cation steps within only 2 days. The utility of the reagent was 376 MHz; Bruker Biospin GmbH, Rheinstetten, Germany). The
demonstrated by the preparation of a series of fluorosulfates and measured chemical shifts are reported in δ [ppm] relative to residual
sulfamoyl fluorides in good to excellent yields. Furthermore, peaks of nondeuterated solvents. Higher order NMR spectra were
desmethyl SuFEx-IT could be applied for N-selective mono- approximately interpreted as first-order spectra if possible. The
fluorosulfurylation of secondary amines containing aliphatic or observed signal multiplicities are characterized as follows: s = singlet,
bs = broad singlet, d = doublet, t = triplet, q = quartet, sep = septet, m =
aromatic hydroxyl groups. As such, our results identify multiplet, dd = doublet of doublets, ddd = doublet of doublets of
desmethyl SuFEx-IT as a valuable alternative to common doublets, dt = doublet of triplets, ddt = doublet of doublets of triplets, td
FO2S-donors, which offers safe and cost-efficient access to = triplet of doublets, tt = triplet of triplets, qd = quartet of doublets, and
substrates for SuFEx click chemistry. pt = pentet of triplets. Coupling constants J are reported in hertz (Hz).

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Mass Spectrometry. Low-resolution electrospray ionization mass 4.5 M KHF2* (5.56 mL, 25.0 mmol, 0.75 equiv) was added to a solution
spectrometry (LR-ESI-MS) was performed with an MSQ PlusTM mass of 6 (13.0 g, 33.3 mmol, 1.0 equiv) in H2O (20 mL, HPLC grade) and
spectrometer (Thermo Electron Corporation, San Jose, USA). High- the mixture was stirred for 5 min. The aqueous solution was extracted
resolution electrospray ionization mass spectrometry (HR-ESI-MS) with Et2O (3 × 10 mL) and the combined organic phases were dried,
was performed with an LTQ XL Orbitrap mass spectrometer (Thermo filtered, and concentrated under reduced pressure at room temperature
Fisher Scientific Inc., Bremen, Germany). Low-resolution electron (due to the volatility of the product, the pressure was kept above 300
ionization mass spectrometry (LR-EI-MS) was performed with an ISQ mbar). The raw product was purified by Kugelrohr distillation with
EC Single Quadrupole mass spectrometer (Thermo Fisher Scientific acetone/dry ice-cooling of the receiver bulb to afford the title
Inc., Bremen, Germany). High-resolution electron ionization mass compound 3 (4.53 g, 27.6 mmol, 83%) as a colorless liquid. Molecular
spectrometry (HR-EI-MS) was performed with an Exactive GC formula (molecular mass): C4H5FN2O2S (164.15 g/mol). 1H NMR
Orbitrap mass spectrometer (Thermo Fisher Scientific Inc., Bremen, (400 MHz, CDCl3): δ 7.33 (d, J = 1.9 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H),
Germany). 2.66 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 146.9, 129.1, 120.1,
Column Chromatography. Manual column chromatography was 15.1. 19F NMR (376 MHz, CDCl3): δ 58.16. LR-EI-MS m/z: [M]•+
performed with silica gel, 60 Å, 230−400 mesh particle size from VWR calcd for C4H5FN2O2S 164.01; found, 164.00.
International GmbH (Darmstadt, Germany) or silica gel (w/0.1% Ca), * Safety Precaution: it is strongly recommended to ensure the
60 Å, 230−400 mesh particle size from Sigma-Aldrich GmbH availability of 2.5% calcium gluconate gel as a safety measure when
(Steinheim, Germany). Automated column chromatography was handling KHF2.
performed on a Büchi Pure C-815 flash system (Büchi Labortechnik 1-(Fluorosulfonyl)-2,3-dimethyl-1H-imidazole-3-ium Trifluoro-
GmbH, Essen, Germany) using Reveleris C18 reversed phase cartridges methanesulfonate (SuFEx-IT, 4).8
(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 MeOTf (1.31 mL, 11.6 mmol, 0.95 equiv) was added dropwise under
stained with phosphomolybdic acid (4% in EtOH), ninhydrin (0.5% in argon to an ice-cooled solution of 3 (2.00 g, 12.2 mmol, 1.00 equiv) in
1-butanol), or potassium permanganate solution (0.75% KMnO4, 5% CH2Cl2. The reaction mixture was allowed to warm to ambient
K2CO3, and 0.07% NaOH in H2O). temperature and stirred for 1 h. The solution was then concentrated
Elemental Analysis. Elemental analyses were conducted by under reduced pressure, tBuOMe (30 mL) was added and solidification
HEKAtech GmbH (Wegberg, Germany). of the residual oil was induced by addition of a seed crystal and
Chemistry. 1,1′-Sulfonylbis(2-methyl-1H-imidazole) (5).14 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).
A solution of SO2Cl2 (29.99 g, 222 mmol, 1.0 equiv) in CH2Cl2 (20 13
C{1H} NMR (101 MHz, CD3CN): δ 151.3, 125.5, 122.2, 122.0 (q, J
mL) was added over 30 min to an ice-cooled suspension of 2- = 320.1 Hz), 37.6, 12.9. 19F NMR (376 MHz, CD3CN): δ 60.13,
methylimidazole (82.1 g, 1.00 mol, 4.5 equiv) in CH2Cl2. The reaction −79.34.
mixture was stirred overnight under argon, after which H2O (350 mL) 1,1′-Sulfonyldiimidazole (SDI, 8).7
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): SO2Cl2 (19.4 mL, 240 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added
C8H10N4O2S (226.25 g/mol). 1H NMR (400 MHz, CDCl3): δ 7.37 (s, dropwise to an ice-cooled solution of imidazole (75.0 g, 1.10 mol, 4.6
2H), 6.94 (s, 2H), 2.51 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ equiv) in CH2Cl2 (450 mL). The yellow suspension was stirred
146.1, 128.6, 120.1, 15.1. HR-ESI-MS m/z: [M + H]+ calcd for overnight and filtered on the next day. The solvent was removed and the
C8H11N4O2S 227.0597; found, 227.0598. crude product was recrystallized from iPrOH to afford the title
2,3-Dimethyl-1-[(2-methyl-1H-imidazole-1-yl)sulfonyl]-1H-imi- compound 8 (38.97 g, 197 mmol, 82%) as a colorless solid. Molecular
dazole-3-ium Trifluoromethanesulfonate (6).14,17 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.
A solution of MeOTf (2.00 mL, 17.7 mmol, 0.7 equiv) in CH2Cl2 (20 * Note that phase inversion of the C-2 signal in the APT spectrum of
mL) was added over 3.5 h to a cooled solution (−78 °C) of 5 (5.72 g, imidazole derivatives has been described in the literature as a “regular
25.3 mmol, 1.0 equiv) in CH2Cl2 (200 mL) and the reaction mixture feature” of these compounds (for details see18). HSQC data further
was allowed to warm to ambient temperature within 16 h. The resulting confirmed the corresponding 1JCH-coupling at C-2 (see the Supporting
precipitate was filtered under argon and washed with ice-cold CH2Cl2 Information).
to afford the title compound 6 (6.21 g, 15.9 mmol, 90%) as a colorless 3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazole-1-ium Trifluoro-
solid. Molecular formula (molecular mass): C10H13F3N4O5S2 (390.35 methanesulfonate (MSDI, 9).14
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 A solution of MeOTf (54.3 mL, 480 mmol, 0.95 equiv) in CH2Cl2 (80
(376 MHz, CD3CN): δ −79.29. mL) was added dropwise over the course of 30 min to an ice-cooled
2-Methyl-1H-imidazole-1-sulfonyl Fluoride (3).8 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

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CH2Cl2 (3 × 300 mL). The residual solvent was removed under purified by dry load column chromatography or filtration over a silica
reduced pressure to afford the title compound 9 (169.5 g, 467 mmol, plug with an appropriate solvent unless stated otherwise.
97%) as a colorless solid. Molecular formula (molecular mass): General Procedure for Preparation of Sulfamoyl Fluorides (GP2).
C8H9F3N4O5S2 (362.30 g/mol). 1H NMR (400 MHz, CD3CN): δ 9.37 11 (1.1 equiv) was added to a solution of the amine substrate (1.0
(s, 1H), 8.27 (s, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.23 (s, equiv) in MeCN (2−5 mL), and the mixture was stirred until TLC or
1H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, CD3CN): δ 139.7, HPLC showed full conversion (15−90 min). The products were
138.9,* 133.6, 127.3, 121.5, 119.7, 38.2. 19F NMR (376 MHz, purified by dry load column chromatography or filtration over a silica
CD3CN): δ −79.33. plug with an appropriate solvent unless stated otherwise.
* Note that phase inversion of the C-2 signal in the APT spectrum of 4-Bromophenyl Sulfurofluoridate (12a).19
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
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 (Rf = 0.38, n-hexane). Molecular formula
4.5 M KHF2* (100 mL, 341 mmol, 0.75 equiv) was added slowly to an (molecular mass): C6H4BrFO3S (255.06 g/mol). 1H NMR (400 MHz,
ice-cooled solution of MSDI (164.6 g, 454 mmol, 1.0 equiv) in H2O (1 CDCl3): δ 7.64−7.58 (m, 2H), 7.28−7.20 (m, 2H). 13C{1H} NMR
L, HPLC grade), and the reaction mixture was stirred for 10 min. The (101 MHz, CDCl3): δ 149.1, 133.7, 122.8, 122.5. 19F NMR (376 MHz,
resulting emulsion was extracted with Et2O (5 × 200 mL), the CDCl3): δ 37.80. HR-EI-MS m/z: [M]•+ calcd for C6H479BrFO3S
combined organic phases were dried, and the solvent was removed 253.9043; found, 253.9039. HR-EI-MS m/z: [M]•+ calcd for
under reduced pressure (due to the volatility of the title compound, the C6H481BrFO3S 255.9023; found, 255.9018.
pressure was held above 400 mbar at 40 °C). The colorless liquid raw 3-Methoxyphenyl Sulfurofluoridate (12b).12
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 12b (170 mg, 824 μmol, 90%, colorless liquid) was prepared according
formation of SDI over time. Molecular formula (molecular mass): to GP1 from 3-methoxyphenol (113 mg, 910 μmol) and purified by
C3H3FN2O2S (150.13 g/mol). 1H NMR (400 MHz, CDCl3): δ 8.05 (s, filtration over a silica plug (Rf = 0.47, EtOAc:n-hexane = 1:8).
1H), 7.42 (pt, J = 1.7 1H), 7.24 (dd, J = 1.7, 0.6 Hz, 1H). 13C{1H} NMR Molecular formula (molecular mass): C7H7FO4S (206.19 g/mol). 1H
(101 MHz, CDCl3): δ 137.2,** 132.4, 118.4. 19F NMR (376 MHz, NMR (400 MHz, CDCl3): δ 7.37 (t, J = 8.3 Hz, 1H), 6.94 (td, J = 7.3,
CDCl3): δ 59.59. HR-EI-MS m/z: [M]•+ calcd for C3H3FN2O2S 6.3, 1.7 Hz, 2H), 6.87 (d, J = 2.2 Hz, 1H), 3.84 (s, 3H). 13C{1H} NMR
149.9894; found, 149.9893. (101 MHz, CDCl3): δ 161.1, 150.9, 130.8, 114.5, 112.8, 107.1, 55.8. 19F
* Safety Precaution: it is strongly recommended to ensure the NMR (376 MHz, CDCl3): δ 37.70. HR-EI-MS m/z: [M]•+ calcd for
availability of 2.5% calcium gluconate gel as a safety measure when C7H7FO4S 206.0044; found, 206.0038.
handling KHF2. 4-Formylphenyl Sulfurofluoridate (12c).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).
12c (149 mg, 730 μmol, 89%, colorless liquid) was prepared according
1-(Fluorosulfonyl)-3-methyl-1H-imidazole Trifluoromethanesul-
fonate (Desmethyl SuFEx-IT, 11).13 to GP1 from 4-hydroxybenzaldehyde (100 mg, 819 μmol) and purified
by column chromatography (Rf = 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,
MeOTf (46.5 mL, 411 mmol, 1.1 equiv) was added dropwise over the 136.3, 132.0, 121.9. 19F NMR (376 MHz, CDCl3): δ 39.11. HR-EI-MS
course of 15 min to an ice-cooled solution of 10 (56.1 g, 374 mmol, 1.0 m/z: [M]•+ calcd for C7H5FO4S 203.9887; found, 203.9885.
equiv) in anhydrous Et2O (750 mL), and the reaction mixture was Quinolin-8-yl Sulfurofluoridate (12d).12
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. 12d (142 mg, 627 μmol, 91%, pale yellow solid) was prepared
Molecular formula (molecular mass): C5H6F4N2O5S2 (314.23 g/mol). according to GP1 from 8-hydroxyquinoline (100 mg, 689 μmol) and
1
H NMR (400 MHz, CD3CN): δ 9.50 (s, 1H), 8.02 (pt, J = 2.0 Hz, 1H), purified by column chromatography (Rf = 0.33, EtOAc:n-hexane = 1:6).
7.72 (pt, J = 2.0 Hz, 1H), 4.01 (s, 3H). 13C{1H} NMR (101 MHz, Molecular formula (molecular mass): C9H6FNO3S (227.21 g/mol). 1H
CD3CN): δ 141.2,* 127.7, 122.8, 122.0 (q, J = 320.1 Hz), 38.6. 19F NMR (400 MHz, CDCl3): δ 9.06 (dd, J = 4.2, 1.6 Hz, 1H), 8.24 (dd, J =
NMR (376 MHz, CD3CN): δ 59.89, −79.38. LR-ESI-MS m/z: [M + 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,
H]+ calcd for C5H7F4N2O5S2 314.97; found, 315.06. Elemental 1H), 7.66−7.47 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.0,
analysis: Calcd for C5H6F4N2O5S2: C, 19.11%; H, 1.92%; N, 8.92%; 146.0, 140.5, 136.1, 130.1, 128.8, 126.0, 122.8, 121.5. 19F NMR (376
S, 20.41%. Found: C, 19.06 ± 0.02%; H, 1.95 ± 0.03%; N, 8.47 ± MHz, CDCl3): δ 40.66. HR-EI-MS m/z: [M]•+ calcd for C9H6FNO3S
0.06%; S, 20.52 ± 0.08% (n = 2). 227.0047; found, 227.0041.
* Note that phase inversion of the C-2 signal in the APT spectrum of 4-[(4-Acetamidophenyl)ethynyl]phenyl Sulfurofluoridate (12e).
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 12e (65.0 mg, 195 μmol, 78%, yellow solid) was prepared according to
(1.3 equiv) was added to a solution of the phenol substrate (1.0 equiv) GP1 from N-{4-[(4-hydroxyphenyl)ethynyl]phenyl}acetamide (62.8
and Et3N (1.6 equiv) in MeCN (2−5 mL), and the mixture was stirred mg, 250 μmol) and purified by column chromatography (Rf = 0.19,
until TLC showed full conversion (30−90 min). The products were EtOAc:n-hexane = 1:1). Molecular formula (molecular mass):

3827 https://doi.org/10.1021/acs.joc.3c02643
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The Journal of Organic Chemistry pubs.acs.org/joc Article

C16H12FNO4S (333.33 g/mol). 1H NMR (400 MHz, THF-d8): δ 9.22 12i (39.5 mg, 111 μmol, 30%, colorless solid) was prepared according
(s, 1H), 7.72−7.57 (m, 4H), 7.52−7.45 (m, 2H), 7.45−7.38 (m, 2H), to a modification of GP1 from arbutin (100 mg, 367 μmol) as follows.
2.04 (s, 3H). 13C{1H} NMR (101 MHz, THF-d8): δ 168.6, 150.5, 11 was added to a solution of the starting material and Et3N in DMF (3
141.6, 134.3, 133.0, 125.7, 122.2, 119.5, 117.6, 92.3, 87.2, 24.2. 19F mL) and the reaction mixture was left to stand for 1 h before another
NMR (376 MHz, THF-d8): δ 36.77. HR-EI-MS m/z: [M]•+ calcd for portion of Et3N and 11 (1 equiv of each) was added. The crude material
C16H12FNO4S 333.0466; found, 333.0467.
obtained was purified by RP chromatography. Conditions: column:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl Sulfuro-
fluoridate (12f). 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
12f (100 mg, 330 μmol, 73%, pale yellow solid) was prepared according
7.37 (d, J = 9.1 Hz, 2H), 7.28−7.18 (m, 2H), 5.04−4.92 (m, 1H), 3.90
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- (dd, J = 12.1, 2.0 Hz, 1H), 3.70 (dd, J = 12.1, 5.7 Hz, 1H), 3.55−3.33
pentane (4 × 10 mL) and the collected phases were filtered over a silica (m, 4H). 13C{1H} NMR (101 MHz, CD3OD): δ 158.8, 146.2, 123.1,
plug (Rf = 0.43, n-pentane). Molecular formula (molecular mass): 119.3, 102.3, 78.3, 77.9, 74.8, 71.3, 62.4. 19F NMR (376 MHz,
C12H16BFO5S (302.12 g/mol). 1H NMR (400 MHz, CDCl3): δ 7.96− CD 3 OD): δ 34.55. HR-ESI-MS m/z: [M + Na]+ calcd for
7.88 (m, 2H), 7.37−7.30 (m, 2H), 1.35 (s, 12H). 13C{1H} NMR (101 C12H15FO9SNa 377.03130; found, 377.03180.
MHz, CDCl3): δ 152.3, 137.2, 120.2, 84.5, 25.0. C-B was not observed. (S,S)-Ni-Cl3BPB-m-Tyr Sulfurofluoridate (12j). (S,S)-Ni-Cl3BPB-m-
19
F NMR (376 MHz, CDCl3): δ 38.11. HR-EI-MS m/z: [M]•+ calcd for Tyr.
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. A solution of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-
After 1 h, a second portion of 11 and Et3N (1 equiv of each) was added
dichlorobenzyl)pyrrolidine-2-carboxamide21 (8.1 g, 16.6 mmol),
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 racemic m-Tyr (5.89 g, 32.5 mmol), Ni(OAc)2·4H2O (8.09 g, 32.5
mL). The organic phase was dried and 12g was isolated by dry load mmol), and K2CO3 (20.4 g, 147.75 mmol) in anhydrous MeOH (400
filtration over a silica plug (Rf = 0.34, EtOAc:n-hexane = 1:3). mL) was stirred at 60 °C for 24 h and at ambient temperature for 72 h.
Molecular formula (molecular mass): C7H4FNO3S3 (265.29 g/mol). The reaction mixture was poured into an ice-cold solution of AcOH (50
1
H NMR [400 MHz, (CD3)2SO]: δ 14.01 (s, 1H), 8.07 (s, 1H), 7.62 mL) in H2O (3 L) and the resulting suspension was allowed to stand at
(dd, J = 8.9, 2.1 Hz, 1H), 7.41 (d, J = 8.9 Hz, 1H). 13C{1H} NMR [101 ambient temperature for 24 h, after which a fine red precipitate had
MHz, (CD3)2SO]: δ 191.2, 145.9, 141.5, 131.0, 120.4, 115.1, 113.5. 19F formed. The precipitate was collected by filtration, washed with H2O (3
NMR [376 MHz, (CD3)2SO]: δ 38.34. HR-EI-MS m/z: [M]•+ calcd × 100 mL), air-dried, and dissolved in EtOAc (200 mL). The resulting
for C7H4FNO3S3 264.9332; found, 264.9332. solution was washed with H2O (3 × 50 mL) and brine (2 × 50 mL),
±-α-Tocopherol-Derived Sulfurofluoridate (12h).12
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
12h (256 mg, 499 μmol, 98%, colorless oil) was prepared according to residue was purified by column chromatography (Rf = 0.25;
GP1 from ±-α-tocopherol (220 mg, 511 μmol) and purified by CHCl3:acetone = 5:1; broad spot) followed by recrystallization from
filtration over a silica plug (Rf = 0.79, EtOAc:n-hexane = 1:9). EtOAc/hexane to afford a second crop of the title compound (total:
Molecular formula (molecular mass): C29H49FO4S (512.77 g/mol). 10.35 g, 88%) as a red solid. Molecular formula (molecular mass):
Mixture of diastereomers. Inequivalent signals of diastereomers in the
13 C34H28Cl3N3NiO4 (707.66 g/mol). 1H NMR (400 MHz, CDCl3): δ
C{1H} NMR spectrum are separated by forward slash symbols. 1H
8.90 (s, 1H), 8.30 (br s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.81−7.41 (m,
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− 4H), 7.40−7.20 (m, 3H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 22.3, 6.9
0.77 (m, 12H). 13C{1H} NMR (101 MHz, CDCl3): δ 151.2, 142.0, Hz, 2H), 6.80−6.70 (m, 1H), 6.69−6.53 (m, 2H), 4.29 (s, 1H), 4.13 (d,
127.6, 126.2, 124.5, 118.6, 75.9, 40.1/40.0, 39.5, 37.7/37.62, 37.60/ J = 12.4 Hz, 1H), 3.33−3.16 (m, 1H), 3.09 (d, J = 11.6 Hz, 2H), 2.96 (d,
37.54, 37.49/37.4, 33.0/32.9, 32.83/32.81, 31.0, 30.9, 28.1, 25.0, 24.6, J = 12.4 Hz, 1H), 2.67 (d, J = 8.8 Hz, 1H), 2.45−2.19 (m, 3H), 2.17−
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 1.83 (m, 2H). 13C{1H}-NMR (101 MHz, CDCl3): δ 180.2, 179.1,
NMR (376 MHz, CDCl3): δ 41.37. HR-EI-MS m/z: [M]•+ calcd for 171.0, 157.7, 140.9, 136.8, 135.0, 133.8, 133.44, 133.36, 133.3, 132.6,
C29H49FO4S 512.3330; found, 512.3330. 132.5, 131.1, 130.5, 130.2, 129.9, 129.6, 129.4, 127.8, 127.4, 127.2,
4-{[(2S,3R,4S,5S,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)- 126.0, 124.0, 122.2, 117.7, 115.3, 71.7, 71.6, 63.5, 58.8, 39.2, 30.9, 23.1.
tetrahydro-2H-pyran-2-yl]oxy}phenyl Sulfurofluoridate (12i).
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.

3828 https://doi.org/10.1021/acs.joc.3c02643
J. Org. Chem. 2024, 89, 3821−3833
The Journal of Organic Chemistry pubs.acs.org/joc Article

(S,S)-Ni-Cl3BPB-m-Tyr Sulfurofluoridate (12j). Molecular formula (molecular mass): C20H15FN2O7S (446.41 g/mol).
1
H 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.
12j (90.8 mg, 115 μmol, 82%, red solid) was prepared according to a 4-{3-[2-(Diethylamino)-2-oxoethyl]-5,7-dimethylpyrazolo[1,5-a]-
modification of GP1 from (S,S)-Ni-Cl3BPB-m-Tyr (100 mg, 141 μmol) pyrimidin-2-yl}phenyl Sulfurofluoridate (12m).12
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
(Rf = 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), 12m (73.9 mg, 170 μmol, 60%, colorless solid) was prepared according
4.28−4.17 (m, 2H), 3.25 (dd, J = 10.6, 6.5 Hz, 2H), 3.16−3.05 (m, to GP1 from N,N-diethyl-2-{2-(4-hydroxyphenyl)-5,7-
2H), 2.97 (dd, J = 13.8, 6.4 Hz, 1H), 2.70−2.55 (m, 1H), 2.53−2.31 dimethylpyrazolo[1,5-a]pyrimidin-3-yl}-acetamide (des-Me-DPA-
(m, 2H), 2.03−1.88 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 713) (100 mg, 284 μmol; prepared as described in22) and purified by
180.1, 177.6, 171.4, 150.5, 141.2, 139.0, 135.0, 133.8, 133.6, 133.5, column chromatography (Rf = 0.26, CHCl3:acetone = 5:1). The
133.1, 132.9, 132.5, 131.2, 130.7, 130.61, 130.56, 129.90, 129.86, 129.5, reaction was conducted in a mixture of DMF/MeCN (1:1, 6 mL).
127.5, 127.4, 127.1, 126.0, 124.1, 122.8, 120.1, 71.4, 71.2, 63.3, 58.6, Molecular formula (molecular mass): C20H23FN4O4S (434.49 g/mol).
40.0, 31.0, 23.4. Ortho- and meta-carbons of the phenyl substituent are 1
H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.1
not equivalent owing to hindered rotation. 19F NMR (376 MHz,
CDCl 3 ): δ 38.15. HR-ESI-MS m/z: [M + Na] + calcd for Hz, 2H), 6.56 (s, 1H), 3.93 (s, 2H), 3.56 (q, J = 7.1 Hz, 2H), 3.40 (q, J =
C34H27Cl3FN3NiO6SNa 809.99158; found, 809.99107. Correct iso- 7.1 Hz, 2H), 2.74 (s, 3H), 2.55 (s, 3H), 1.25 (t, J = 7.1 Hz, 4H), 1.10 (t,
topic pattern. J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 170.0, 158.1,
4-{(2S,3R)-1-(4-Fluorophenyl)-3-[(S)-3-(4-fluorophenyl)-3-hy- 153.4, 150.1, 147.8, 145.0, 134.8, 130.9, 121.1, 109.0, 101.7, 42.6, 40.9,
droxypropyl]-4-oxoazetidin-2-yl}phenyl Sulfurofluoridate (12k).12 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)-
propanoate.23

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 (Rf = 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− N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride
7.26 (m, 2H), 7.19 (ddt, J = 8.0, 5.6, 2.8 Hz, 2H), 7.08−6.90 (m, 4H), (1.2 g, 6.28 mmol, 1.04 equiv) was added to an ice-cold solution of
4.72 (t, J = 5.8 Hz, 1H), 4.68 (d, J = 2.4 Hz, 1H), 3.07 (td, J = 7.5, 2.4 (4-hydroxyphenyl)propionic acid (1.00 g, 6.02 mmol, 1.0 equiv) and
Hz, 1H), 2.25 (s, 1H), 2.12−1.84 (m, 4H). 13C{1H} NMR (101 MHz, 2,3,5,6-tetrafluorophenol (1.1 g, 6.02 mmol, 1.0 equiv) in CH2Cl2 (20
CDCl3): δ 167.0, 162.4 (d, J = 245.8 Hz), 159.3 (d, J = 244.2 Hz), mL) and the reaction mixture was stirred for 15 min. The cooling bath
150.0, 140.0 (d, J = 3.0 Hz), 138.7, 133.6 (d, J = 2.7 Hz), 128.0, 127.5 was removed and the mixture was stirred for another 16 h. The mixture
(d, J = 8.2 Hz), 122.1, 118.4 (d, J = 7.9 Hz), 116.2 (d, J = 22.7 Hz),
was then concentrated under reduced pressure and the residue was
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]+ taken up into Et2O and H2O (50 mL of each). The organic phase was
calcd for C24H20F3NO5SNa 514.09065; found, 514.09065. separated, washed with H2O (3 × 20 mL) and brine (2 × 20 mL), dried,
(S)-4-Ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H- and concentrated under reduced pressure. The resulting crude product
pyrano[3′,4’:6,7]indolizino[1,2-b]quinolin-9-yl Sulfurofluoridate was purified by column chromatography (Rf = 0.15, EtOAc:n-hexane =
(12l).8 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,
12l (68.9 mg, 154 μmol, 37%, green-yellow solid) was prepared 115.6, 103.3 (t, J = 22.8 Hz), 35.5, 30.0. CAr-O was not observed. 19F
according to GP1 from 10-hydroxycamptothecin (150 mg, 412 μmol) NMR (376 MHz, CDCl3): δ −139.02 (dd, J = 21.8, 9.8 Hz), −152.84
using increased amounts of 11 (5.2 equiv) and Et3N (6.4 equiv) and (dd, J = 21.8, 9.8 Hz). LR-ESI-MS m/z: [M + NH4]+ calcd for
purified by column chromatography (Rf = 0.14, EtOAc:n-hexane = 2:1). C15H14NF4O3 332.09; found, 332.22.

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2,3,5,6-Tetrafluorophenyl 3-{4-[(Fluorosulfonyl)oxy]phenyl}- Indoline-1-sulfonyl Fluoride (13c).24

propanoate (12n).

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 (Rf = 0.45, EtOAc:n-hexane = 1:6). Molecular formula
12n was prepared according to a modification of GP1 as follows. 11 (molecular mass): C8H8FNO2S (201.22 g/mol). 1H NMR (400 MHz,
(2.02 g, 6.40 mmol, 1.4 equiv) was added to a solution of 2,3,5,6- CDCl3): δ 7.54−7.37 (m, 1H), 7.30−7.19 (m, 2H), 7.17−7.05 (m,
tetrafluorophenyl (4-hydroxyphenyl)propanoate (1.44 g, 4.58 mmol) 1H), 4.14 (td, J = 8.4, 2.5 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H). 13C{1H}
and Et3N (1.09 mL, 0.79 g, 7.82 mmol, 1.7 equiv) in MeCN (20 mL) NMR (101 MHz, CDCl3): δ 139.9, 131.0, 128.3, 125.6, 125.3, 114.7,
and the reaction mixture was vigorously stirred for 16 h. The mixture 51.7, 28.1. 19F NMR (376 MHz, CDCl3): δ 39.12. HR-EI-MS m/z:
was then concentrated under reduced pressure, the residue was taken [M]•+ calcd for C8H8FNO2S 201.0254; found, 201.0252.
up into Et2O and H2O (50 mL of each), and the insoluble tar and Isoindoline-2-sulfonyl Fluoride (13d).
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 11 (488 mg, 1.55 mmol, 1.6 equiv) was added to a suspension of
column chromatography (Rf = 0.52, EtOAc:n-hexane = 1:15) to afford, isoindoline × HCl (150 mg, 0.96 mmol) in CH2Cl2 (4 mL) followed by
after low-temperature (−20 °C) recrystallization from pentane, 12n dropwise addition of Et3N (134 μL, 0.96 mmol, 1.0 equiv). After TLC
(0.99 g, 2.50 mmol, 55%) as a colorless solid. Molecular formula indicated full conversion, the reaction mixture was filtered over a plug of
(molecular mass): C15H9F5O5S (396.28 g/mol). 1H NMR (400 MHz, silica. The crude product was purified by column chromatography (Rf =
CDCl3): δ 7.40−7.34 (m, 2H), 7.34−7.28 (m, 2H), 7.00 (tt, J = 9.9, 7.1 0.43, EtOAc:n-hexane = 1:10) to afford the title compound 13d (191
Hz, 1H), 3.14 (t, J = 7.4 Hz, 2H), 3.05−2.98 (m, 2H). 13C{1H} NMR mg, 0.95 mmol, 98%) as a colorless solid. Molecular formula (molecular
(101 MHz, CDCl3): δ 168.4, 149.0, 146.2 (ddd, J = 250.5, 7.0, 4.0 Hz), mass): C8H8FNO2S (201.22 g/mol). 1H NMR (400 MHz, CDCl3): δ
142.1−139.0 (m), 130.4, 121.3, 103.5 (t, J = 22.8 Hz), 34.8, 30.1. CAr-O 7.42−7.32 (m, 2H), 7.31−7.26 (m, 2H), 4.86 (d, J = 2.4 Hz, 4H).
13
was not observed. 19F NMR (376 MHz, CDCl3): δ 37.42, −138.79 (dd, C{1H} NMR (101 MHz, CDCl3): δ 134.8, 128.5, 122.9, 55.0. 19F
J = 21.7, 9.8 Hz), −152.93 (dd, J = 21.7, 9.8 Hz). Elemental analysis: NMR (376 MHz, CDCl3): δ 37.93. HR-EI-MS m/z: [M]•+ calcd for
Calcd for C15H9F5O5S: C, 45.46%; H, 2.29%; S, 8.09%. Found: C, 45.85 C8H8FNO2S 201.0254; found, 201.0251.
± 0.02%; H, 2.31 ± 0.04%; S, 8.16 ± 0.00% (n = 2). 4-Benzylpiperidine-1-sulfonyl Fluoride (13e).8
Methyl(phenyl)sulfamoyl Fluoride (13a).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
13a (247 mg, 1.31 mmol, 70%, yellow oil) was prepared according to indicated full conversion, the reaction mixture was diluted with Et2O
GP2 from N-methylaniline (200 mg, 1.87 mmol). After HPLC (10 mL) and washed with H2O (10 mL) and brine (10 mL). The
indicated full conversion, the reaction solvent was removed and the organic phase was dried and concentrated under reduced pressure and
the product was purified by filtration over a silica plug (Rf = 0.42,
residue was taken up into CH2Cl2. The organic phase was washed with
EtOAc:n-hexane = 1:6). Molecular formula (molecular mass):
H2O, dried, and the solvent was removed. The crude material thus
C12H16FNO2S (257.32 g/mol). 1H NMR (400 MHz, CDCl3): δ
obtained was purified by RP chromatography. Conditions: column: 7.37−7.27 (m, 2H), 7.25−7.19 (m, 1H), 7.17−7.09 (m, 2H), 3.91 (dt, J
FlashPure Select C18 12 g (Büchi Labortechnik GmbH, Essen, = 12.7, 2.3 Hz, 2H), 2.94 (tt, J = 12.7, 3.0 Hz, 2H), 2.59 (d, J = 7.0 Hz,
Germany); eluent: 0−15 min: 40% MeCN, 15−17 min: 40 → 80% 2H), 1.84−1.61 (m, 3H), 1.39 (qd, J = 12.8, 4.2 Hz, 2H). 13C{1H}
MeCN, 17−22 min: 80 → 100% MeCN; flow rate: 20 mL/min; NMR (101 MHz, CDCl3): δ 139.4, 129.2, 128.6, 126.4, 47.6, 42.7, 37.2,
detection: UV, λ = 210, 220, 254, 280 nm. Molecular formula 30.8. 19F NMR (376 MHz, CDCl3): δ 40.17. HR-EI-MS m/z: [M]•+
(molecular mass): C7H8FNO2S (189.20 g/mol). 1H NMR (400 MHz, calcd for C12H16FNO2S 257.0880; found, 257.0878.
CDCl3): δ = 7.50−7.33 (m, 5H), 3.44 (d, J = 2.2 Hz, 3H). 13C{1H} 4-Hydroxypiperidyl-1-sulfonyl Fluoride (13f).
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 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 (Rf = 0.46, EtOAc:n-hexane = 2:1).
Molecular formula (molecular mass): C5H10FNO3S (183.20 g/mol).
13b (200 mg, 929 μmol, 83%, pale rose solid) was prepared according 1
H NMR (400 MHz, CDCl3): δ 4.19−3.88 (m, 1H), 3.87−3.61 (m,
to GP2 from 1,2,3,4-tetrahydroisoquinoline (150 mg, 1.23 mmol). 2H), 3.55−3.25 (m, 2H), 2.12−1.90 (m, 2H), 1.78−1.65 (m, 2H), 1.76
After TLC indicated full conversion, the reaction solvent was removed, (br s, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 65.0, 44.1, 32.6. 19F
the residue was dissolved in Et2O and the organic phase was washed NMR (376 MHz, CDCl3): δ 41.07. HR-EI-MS m/z: [M-H2O]•+ calcd
with H2O. After removal of the solvent, no further purification was for C5H8FNO2S 165.0254; found, 165.0253.
required. Molecular formula (molecular mass): C9H10FNO2S (215.24 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline-2-sulfonyl Fluoride
g/mol). 1H NMR (400 MHz, CDCl3): δ 7.31−7.24 (m, 2H), 7.24− (13g).
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 13g (205 mg, 887 μmol, 88%, colorless oil) was prepared according to
215.0411; found, 215.0407. GP2 from 1,2,3,4-tetrahydroisoquinolin-6-ol (150 mg, 1.01 mmol) and

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The Journal of Organic Chemistry pubs.acs.org/joc Article

purified by filtration over a silica plug (Rf = 0.37, EtOAc:n-hexane = 4-(2-Chlorodibenzo[b,f ][1,4]oxazepin-11 yl)piperazine-1-sulfon-
1:2). Molecular formula (molecular mass): C9H10FNO3S (231.24 g/ yl Fluoride (13k).8
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
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 (Rf = 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),
A solution of aniline (147 μL, 1.61 mmol) in CH2Cl2 (1.5 mL) was
7.22 (d, J = 8.7 Hz, 1H), 7.19−7.08 (m, 3H), 7.08−7.02 (m, 1H), 3.62
added to an ice-cooled suspension of 11 (556 mg, 1.77 mmol, 1.1
(d, J = 35.1 Hz, 8H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.6,
equiv) in CH2Cl2 (4 mL). After TLC indicated full conversion, CH2Cl2 158.4, 151.8, 139.5, 133.3, 130.8, 128.7, 127.3, 126.1, 125.6, 124.5,
(10 mL) was added and the solution was washed with 0.1 M HCl (3 × 123.1, 120.4, 46.7, 46.5. 19F NMR (376 MHz, CDCl3): δ 39.17. HR-
10 mL) and brine (20 mL). The organic phase was dried and the solvent ESI-MS m/z: [M + H]+ calcd for C17H16ClFN3O3S 396.0579; found,
was removed under reduced pressure to afford the title compound 13h 396.0578.
(196 mg, 1.12 mmol, 70%) as a pale red liquid. Molecular formula tert-Butyl {2-[1-(Fluorosulfonyl)-1H-indol-3-yl]ethyl}carbamate
(molecular mass): C6H6FNO2S (175.18 g/mol). 1H NMR (400 MHz, (13l).
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 (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
11 (1.26 g, 4.03 mmol, 2.5 equiv) was added to an ice-cooled solution of (241 mg, 768 μmol, 0.5 equiv) was added, but no further conversion
aniline (147 μL, 1.61 mmol) in MeCN (4 mL). The mixture was stirred was observed after another 2 h. Therefore, silica was added, the solvent
for 10 min before Et3N (112 μL, 805 μmol, 0.5 equiv) was added. After was removed, and the residue was purified by column chromatography
TLC indicated full conversion, silica was added, the solvent was with solid loading (Rf = 0.26, EtOAc:n-hexane = 1:4) to afford the title
removed, and the residue was filtered over a plug of silica (Rf = 0.50, compound 13l (72.0 mg, 210 μmol, 14%) as a colorless solid. Molecular
EtOAc:n-hexane = 1:10) to afford the title compound 13i (322 mg, formula (molecular mass): C15H19FN2O4S (342.39 g/mol). 1H NMR
1.26 mmol, 78%) as a colorless solid. Molecular formula (molecular (400 MHz, CDCl3): δ 8.02−7.78 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H),
mass): C6H5F2NO4S2 (257.23 g/mol). 1H NMR (400 MHz, CDCl3): δ 7.53−7.31 (m, 2H), 7.28−7.23 (m, 1H), 4.67 (s, 1H), 3.47 (q, J = 6.7
7.69−7.54 (m, 3H), 7.54−7.47 (m, 2H). 13C{1H} NMR (101 MHz, Hz, 2H), 2.93 (t, J = 6.7 Hz, 2H), 1.44 (s, 9H). 13C{1H} NMR (101
CDCl3): δ 133.2, 132.5, 130.9, 129.3. 19F NMR (376 MHz, CDCl3): δ MHz, CDCl3): δ 156.0, 135.4, 130.8, 126.2, 124.8, 123.0, 122.2, 120.2,
56.32. HR-EI-MS m/z: [M]•+ calcd for C6H5F2NO4S2 256.9623; 113.9, 79.7, 39.9, 28.5, 25.8. 19F NMR (376 MHz, CDCl3): δ 53.90.
found, 256.9621. HR-ESI-MS m/z: [M + Na]+ calcd for C15H19FN2O4SNa 365.0942;
(4-Fluorobenzyl)sulfamoyl Fluoride (13j).25 found, 365.0948.
1-(Fluorosulfonyl)piperidine-4-carboxylic Acid (13m).

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 13m (62.6 mg, 298 μmol, 39%, colorless solid) was prepared according
exothermic reaction was observed. The reaction mixture was stirred for to GP2 from isonipecotic acid (100 mg, 774 μmol) and purified by
40 min and taken up into Et2O/H2O (30 mL of each). The organic column chromatography (Rf = 0.21, CH2Cl2:MeOH = 30:1).
layer was separated, washed with H2O (3 × 20 mL) and brine (2 × 10 Molecular formula (molecular mass): C6H10FNO4S (211.21 g/mol).
1
mL), dried, and successively concentrated under atmospheric pressure H NMR (400 MHz, CD3OD): δ 3.93−3.74 (m, 2H), 3.26−3.11 (m,
and at 750 mbar. The crude product was purified by fast column 2H), 2.65−2.47 (m, 1H), 2.14−1.97 (m, 2H), 1.90−1.68 (m, 2H).
13
chromatography (Rf = 0.38, CH2Cl2:n-pentane = 1:1; 13j is not C{1H} NMR (101 MHz, CD3OD): δ 177.2, 47.6, 40.5, 28.2. 19F
completely stable on silica). The product containing fractions were NMR (376 MHz, CD3OD): δ 38.16. HR-EI-MS m/z: [M-CO2H]•+
pooled and concentrated under atmospheric pressure to afford, after calcd for C5H9FNO2S 166.0333; found, 166.0332.
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
■ ASSOCIATED CONTENT
Data Availability Statement
s, 1H), 4.42 (d, J = 5.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ The data underlying this study are available in the published
163.1 (d, J = 248.2 Hz), 130.8 (dd, J = 2.9, 1.1 Hz), 130.2 (d, J = 8.5 article and its Supporting Information.
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 *
sı Supporting Information

206.01; found, 206.06. HR-EI-MS m/z: [M]•+ calcd for C7H7F2NO2S The Supporting Information is available free of charge at
207.0160; found, 207.0159. https://pubs.acs.org/doi/10.1021/acs.joc.3c02643.
3831 https://doi.org/10.1021/acs.joc.3c02643
J. Org. Chem. 2024, 89, 3821−3833
The Journal of Organic Chemistry pubs.acs.org/joc Article

Appearance and preparation of 1H-imidazole-1-sulfonyl fluoromethanesulfonate; THF-d8, octadeuterotetrahydrofuran;

fluoride (10) and desmethyl SuFEx-IT (11) and NMR- TLC, thin-layer chromatography; LR-EI-MS, low-resolution
spectra for all prepared compounds (PDF) electron ionization mass spectrometry

■ AUTHOR INFORMATION
Corresponding Author
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Author Contributions Gu, Y.; Noodleman, L.; Sharpless, K. B.; Yang, G.; Wu, P. Sulfur
The manuscript was written through contributions of all [18F]Fluoride Exchange Click Chemistry Enabled Ultrafast Late-Stage
authors. All authors have given approval to the final version of Radiosynthesis. J. Am. Chem. Soc. 2021, 143 (10), 3753−3763.
the manuscript. (12) Walter, N.; Bertram, J.; Drewes, B.; Bahutski, V.; Timmer, M.;
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Zlatopolskiy, B. D. Convenient PET-Tracer Production via SuFEx 18F-
This work was supported by Deutsche Forschungsgemeinschaft Fluorination of Nanomolar Precursor Amounts. Eur. J. Med. Chem.
(DFG), grant number ZL 65/4−1. 2022, 237, 114383.
Notes (13) Dong, J.; Yang, Q.; Guo, T.; Zhan, Y.; Meng, G. Fluorosulfonyl-
The authors declare no competing financial interest. Containing Compound, Intermediate Thereof, Preparation Method
Therefor and Use Thereof. EP 3715342 A1, 2020. https://lens.org/
■ ABBREVIATIONS
AISF, [4-(acetylamino)phenyl]imidodisulfuryl difluoride;
051-128-258-520-381.
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(CD3)2SO, hexadeuterodimethyl sulfoxide; CD3CN, trideuter- Chem. 2003, 68 (1), 115−119.
oacetonitrile; CDCl 3 , deuterochloroform; DBU, 1,8- (15) Johnson, M. R. Sulfonyldiazoles and N-(Fluorosulfonyl)Azoles,
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