Journal of the American Chemical Society
Page 4 of 6
Indeed, when the reaction is carried out in an electrochemical
We acknowledge financial support from the Dutch Science
Foundation (NWO) for a VIDI grant for T.N. (SensPhotoFlow, No.
14150). A.A.B. and K.T.O. thank the São Paulo Research
Foundation for a FAPESP Fellowship Grant (2018/08772-6).
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microflow reactor with a small interelectrode gap (250μm),20 full
conversion is observed in only 5 minutes reaction time (Figure 3B).
The reduced reaction times observed in flow can be attributed to (i)
the increased electrode surface-to-volume ratio; (ii) a high
interfacial area between the organic and the aqueous phase; (iii) an
intensified mass transport to and from the electrodes due to
multiphase fluid patterns (Figure 3C).21
REFERENCES
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Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B., Sulfur(VI)
Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry.
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Angew. Chem., Int. Ed. 2014, 53, 9430-9448.
Oxidation of the disulfide results in the formation of a radical
cation22 which can react further with nucleophilic fluoride to yield
the corresponding sulfenyl fluoride (Figure 3E). At this point, we
still wondered whether a nucleophilic or electrophilic fluorination,
with an in-situ generated 1-fluoro-pyridinium reagent,23 was
operative under these reaction conditions. Hence, we carried out
the reaction in the presence of 1-fluoro-pyridinium
tetrafluoroborate and observed only traces of product formation
(Figure 3D). In contrast, using either HCl-pyridine or HCl-Et3N in
combination with KF allowed to obtain isolate the corresponding
sulfonyl fluoride in good yields, indicating the presence of a
nucleophilic fluorination. Adding TEMPO or BHT as radical
scavengers reduces the efficacy of the electrochemical process,
substantiating the presence of radical intermediates. Next, two
consecutive oxidations steps resulted in the formation of the
targeted sulfonyl fluoride. While we cannot formally rule out a
nucleophilic attack of fluoride to S-phenyl benzenethiosulfonate,
we found for most substrates no formation of the latter compound.
In contrast, during our kinetic experiments, traces of other
fluorinated intermediates were observed which are tentatively
attributed to sulfenyl fluoride and sulfinyl fluoride intermediates
(See Supporting Information). These intermediates could
unfortunately not be isolated as they are generally perceived as
unstable.24 The main byproduct formed in the electrochemical
sulfonyl fluoride synthesis is sulfonic acid, which originates from
anodic oxidation of disulfides or through hydrolysis of sulfonyl
fluoride.
2.
(a) Narayanan, A.; Jones, L. H., Sulfonyl fluorides as privileged
warheads in chemical biology. Chem. Sci. 2015, 6, 2650-2659; (b) Shannon,
D. A.; Gu, C.; McLaughlin, C. J.; Kaiser, M.; van der Hoorn, R. A. L.;
Weerapana, E., Sulfonyl Fluoride Analogues as Activity-Based Probes for
Serine Proteases. ChemBioChem 2012, 13, 2327-2330.
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Nielsen, M. K.; Ugaz, C. R.; Li, W.; Doyle, A. G., PyFluor: A
Low-Cost, Stable, and Selective Deoxyfluorination Reagent. J. Am. Chem.
Soc. 2015, 137, 9571-9574.
4.
(a) Matesic, L.; Wyatt, N. A.; Fraser, B. H.; Roberts, M. P.;
Pham, T. Q.; Greguric, I., Ascertaining the suitability of aryl sulfonyl
fluorides for [18F]radiochemistry applications: A systematic investigation
using microfluidics. J. Org. Chem. 2013, 78, 11262-11270; (b) Inkster, J.
A. H.; Liu, K.; Ait-Mohand, S.; Schaffer, P.; Guérin, B.; Ruth, T. J.; Storr,
T., Sulfonyl Fluoride-Based Prosthetic Compounds as Potential 18 F
Labelling Agents. Chem. - Eur. J. 2012, 18, 11079-11087.
5.
More Than Click Reagents? Eur. J. Org. Chem. 2018, 2018, 3648-3666.
6. (a) Xiao, X.; Zhou, F.; Jiang, J.; Chen, H.; Wang, L.; Chen, D.;
Chinthakindi, P. K.; Arvidsson, P. I., Sulfonyl Fluorides (SFs):
Xu, Q.; Lu, J., Highly efficient polymerization via sulfur( vi )-fluoride
exchange (SuFEx): novel polysulfates bearing a pyrazoline–naphthylamide
conjugated moiety and their electrical memory performance. Polym. Chem.
2018, 9, 1040-1044; (b) Yang, C.; Flynn, J. P.; Niu, J., Facile Synthesis of
Sequence-Regulated Synthetic Polymers Using Orthogonal SuFEx and
CuAAC Click Reactions. Angew. Chem., Int. Ed. 2018, 57, 16194-16199;
(c) Wang, H.; Zhou, F.; Ren, G.; Zheng, Q.; Chen, H.; Gao, B.; Klivansky,
L.; Liu, Y.; Wu, B.; Xu, Q.; Lu, J.; Sharpless, K. B.; Wu, P., SuFEx-Based
Polysulfonate Formation from Ethenesulfonyl Fluoride–Amine Adducts.
Angew. Chem., Int. Ed. 2017, 56, 11203-11208.
7.
Abdul Fattah, T.; Saeed, A.; Albericio, F., Recent advances
towards sulfur (VI) fluoride exchange (SuFEx) click chemistry. J. Fluorine
Chem. 2018, 213, 87-112.
The electrochemical approach described herein demonstrates the
ability to directly convert thiols into sulfonyl fluorides using KF as
an ideal fluoride source in terms of cost, safety and availability. In
this context, we believe that this green and mild protocol will be of
added value to prepare sulfonyl fluorides in both academic and
industrial settings.
8.
(a) Talko, A.; Barbasiewicz, M., Nucleophilic Fluorination with
Aqueous Bifluoride Solution: Effect of the Phase-Transfer Catalyst. ACS
Sustainable Chem. Eng. 2018, 6, 6693-6701; (b) Tang, L.; Yang, Y.; Wen,
L.; Yang, X.; Wang, Z., Catalyst-free radical fluorination of sulfonyl
hydrazides in water. Green Chem. 2016, 18, 1224-1228; (c) Bianchi, T. A.;
Cate, L. A., Phase Transfer Catalysis. Preparation of Aliphatic and
Aromatic Sulfonyl Fluorides. J. Org. Chem. 1977, 42, 2031-2032; (d)
Davies, W.; Dick, J. H., CCLXXXVI.—Aromatic sulphonyl fluorides. A
convenient method of preparation. J. Chem. Soc. 1931, 2104-2109.
ASSOCIATED CONTENT
Supporting Information
9.
Schmitt, A.-M. D.; Schmitt, D. C., Chapter 13. Synthesis of
Sulfonamides. In RSC Drug Discovery Series, 2016; Vol. 2016, pp 123-
138.
Data and materials availability: additional optimization,
mechanistic data, experimental procedures and analytical data (1H,
19F and 13C NMR, HRMS) for all new compounds.
10.
Brouwer, A. J.; Ceylan, T.; Linden, T. v. d.; Liskamp, R. M. J.,
Synthesis of β-aminoethanesulfonyl fluorides or 2-substituted taurine
sulfonyl fluorides as potential protease inhibitors. Tetrahedron Lett. 2009,
50, 3391-3393.
The Supporting Information is available free of charge on the ACS
Publications website.
11.
Tribby, A. L.; Rodríguez, I.; Shariffudin, S.; Ball, N. D., Pd-
Catalyzed Conversion of Aryl Iodides to Sulfonyl Fluorides Using SO 2
Surrogate DABSO and Selectfluor. J. Org. Chem. 2017, 82, 2294-2299.
AUTHOR INFORMATION
12.
Davies, A. T.; Curto, J. M.; Bagley, S. W.; Willis, M. C., One-
pot palladium-catalyzed synthesis of sulfonyl fluorides from aryl bromides.
Chem. Sci. 2017, 8, 1233-1237.
Corresponding Author
* T.Noel@tue.nl
13.
(a) Kirihara, M.; Naito, S.; Nishimura, Y.; Ishizuka, Y.; Iwai, T.;
Takeuchi, H.; Ogata, T.; Hanai, H.; Kinoshita, Y.; Kishida, M.; Yamazaki,
K.; Noguchi, T.; Yamashoji, S., Oxidation of disulfides with electrophilic
halogenating reagents: concise methods for preparation of thiosulfonates
and sulfonyl halides. Tetrahedron 2014, 70, 2464-2471; (b) Kirihara, M.;
Naito, S.; Ishizuka, Y.; Hanai, H.; Noguchi, T., Oxidation of disulfides with
Selectfluor™: concise syntheses of thiosulfonates and sulfonyl fluorides.
Tetrahedron Lett. 2011, 52, 3086-3089.
Author Contributions
§ These authors contributed equally to this work.
Notes
The authors declare no competing financial interests.
14.
For other S-F bond forming transformations leading to SFx
ACKNOWLEDGMENT
species, see: (a) Pitts, C. R.; Bornemann, D.; Liebing, P.; Santschi, N.;
Togni, A., Making the SF 5 Group More Accessible: A Gas-Reagent-Free
Approach to Aryl Tetrafluoro-λ 6 -sulfanyl Chlorides. Angew. Chem., Int.
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