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Sulfonyl Fluoride Synthesis through Electrochemical Oxidative Coupling of Thiols and Potassium Fluoride
- Gabriele LaudadioGabriele LaudadioMicro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600 MB Eindhoven, The NetherlandsMore by Gabriele Laudadio
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- Aloisio de A. BartolomeuAloisio de A. BartolomeuMicro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600 MB Eindhoven, The NetherlandsDepartamento de Química, Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilMore by Aloisio de A. Bartolomeu
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- Lucas M. H. M. VerwijlenLucas M. H. M. VerwijlenMicro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600 MB Eindhoven, The NetherlandsMore by Lucas M. H. M. Verwijlen
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- Yiran CaoYiran CaoMicro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600 MB Eindhoven, The NetherlandsMore by Yiran Cao
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- Kleber T. de OliveiraKleber T. de OliveiraDepartamento de Química, Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilMore by Kleber T. de Oliveira
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- Timothy Noël*Timothy Noël*[email protected]Micro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600 MB Eindhoven, The NetherlandsMore by Timothy Noël
Copyright © 2019 American Chemical Society
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Abstract
Sulfonyl fluorides are valuable synthetic motifs for a variety of applications, among which sulfur(VI) fluoride exchange-based “click chemistry” is currently the most prominent. Consequently, the development of novel and efficient synthetic methods to access these functional groups is of great interest. Herein, we report a mild and environmentally benign electrochemical approach to prepare sulfonyl fluorides using thiols or disulfides, as widely available starting materials, in combination with KF, as an inexpensive, abundant and safe fluoride source. No additional oxidants nor additional catalysts are required and, due to mild reaction conditions, the reaction displays a broad substrate scope, including a variety of alkyl, benzyl, aryl and heteroaryl thiols or disulfides.
Arguably, sulfonyl fluorides can be considered a “privileged moiety” in chemistry, as they can be adopted in a wide variety of applications. This can be attributed to the unique balance between reactivity and stability of these functional groups, which is in sharp contrast with analogous sulfonyl chlorides (Figure 1A). (1) Hence, sulfonyl fluorides have been used in chemical biology as covalent protein modifiers, strong protease inhibitors and activity-based probes. (2) In addition, sulfonyl fluorides have been successfully applied as fluorinating reagents, (3)18F radiolabeling agents (4) and have been engaged in other useful transformations, (5) including polymerizations. (6) However, the breakthrough application for sulfonyl fluorides is the realization of their utility as stable and robust sulfonyl precursors using sulfur(VI) fluoride exchange “click chemistry” (SuFEx). (1,7)
Figure 1
Figure 1. Development of an electrochemical synthesis of sulfonyl fluorides. (A) Advantages and applications of sulfonyl fluorides. (B) Established synthetic routes to prepare sulfonyl fluorides. (C) Reaction conditions (Entry 1): 2-mercapto-4,6-dimethylpyrimidine (2 mmol), KF (5 equiv), pyridine (1 equiv), CH3CN/1 M HCl (20 mL, 1:1 v/v), C anode/Fe cathode, 20 mA (4.1 mA/cm2), 12 h.
Due to their evident value, efficient syntheses of sulfonyl fluorides starting from abundant starting materials are highly desired. The classical strategy to access these functional groups involves a chloride/fluoride exchange of sulfonyl chlorides using fluoride salts (Figure 1B). (8) However, sulfonyl chlorides are not widely available and need to be prepared from the corresponding thiols using a combination of oxidizing and chlorinating reagents. (9) In order to avoid toxic and unstable sulfonyl chlorides, new synthetic methods have been developed using alternative starting materials, including sulfonyl hydrazides (8b) or sodium sulfonates. (10) Also palladium-based cross-coupling strategies have been developed which utilize aryl halides in combination with 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO) and electrophilic fluorinating reagents, such as Selectfluor (11) and N-fluorodibenzenesulfonimide. (12) Kirihara et al. reported a method to transform disulfides and thiols into sulfonyl fluorides using Selectfluor and refluxing conditions. (13) Despite the synthetic value of these approaches, the use of costly and atom-inefficient fluoride sources limits their practicality to small scale applications.
It is, however, evident that the development of a synthetic method which directly uses commodity chemicals, such as thiols and metal alkali fluorides, would be particularly useful given the broad availability and the low cost of these starting materials.
Even so, it is immediately clear that a number of challenges need to be overcome to develop such a hitherto elusive transformation. First, fluoride is poorly soluble in organic solvents and is hardly reactive in its solvated form in aqueous media. Second, combining nucleophilic fluorine reagents with thiols to establish a single S–F bond appears unlikely. (14) Nevertheless, based on our recent success in the electrochemical synthesis of sulfonamides, (15) we speculated that the union of these stubborn starting materials would not only be plausible using electrochemical activation (16) but would also facilitate the subsequent oxidation to sulfonyl fluoride via anodic oxidation. Herein, we report the discovery and optimization of an electrochemical method which meets these design criteria. The method utilizes KF as a readily available, safe and cost-efficient fluoride source. Moreover, anodic oxidation allows to avoid stoichiometric amounts of oxidants and enables the direct use of thiols or disulfides as convenient and widely available starting materials.
Initial experiments on a representative thiol, 2-mercapto-4,6-dimethylpyrimidine, revealed that the combination of 5 equiv of KF, 1 equiv of pyridine in a CH3CN/1 M HCl biphasic reaction mixture using inexpensive graphite/stainless steel electrodes is highly effective, providing the targeted sulfonyl fluoride in 74% isolated yield (Figure 1C, Entry 1). Tetra-n-butylammonium fluoride and other alkali fluorides, such as NaF and CsF, are less effective (see Supporting Information). Selectfluor, an electrophilic fluorine source, is equally potent as KF, but was not further considered due to the unfavorable price difference (KF 8 $/mol vs Selectfluor 407 $/mol). (17) We surmise that KF functions partially as an electrolyte, as the total amount can be lowered when supporting electrolytes are added (see Supporting Information). However, given the low cost of KF in comparison to these supporting electrolytes, we opted to keep a higher concentration of KF. In the absence of acid or at lower concentrations, decreased yields are observed (Figure 1C, Entries 2–4). The addition of one equivalent of pyridine is beneficial (Figure 1C, Entry 5), and is speculated to function as an electron mediator (18) or as a phase transfer catalyst. The reaction was confirmed to be electrochemically driven (Figure 1C, Entry 6).
With the optimal conditions in hand, we next turned our attention to examine the generality of this electrochemical transformation. As shown in Figure 2, a wide variety of structurally and electronically distinct thiols can be transformed into the corresponding sulfonyl fluorides. First, with a diverse set of thiophenols, it was determined that substrates bearing electron-neutral (1–5), -donating (6, 7) and -withdrawing substituents (8–10) were all compatible with the reaction conditions; the yields were ranging from 37 to 99%. Due to the volatility of some products, isolated yields were in some cases lower than observed with 19F nuclear magnetic resonance (NMR). This could be partially avoided by converting the obtained volatile sulfonyl fluoride in situ to the corresponding sulfonate through reaction with phenol (e.g., 1). The electrochemical reaction is not particularly sensitive to sterical hindrance as ortho-substituted thiophenols displayed similar yields to unsubstituted variants (1 versus 4). Also, halogenated thiophenols (11–13) were suitable reaction partners, providing opportunities to further functionalize the formed sulfonyl fluorides using cross-coupling chemistry. Protected amines (14), previously unreactive in our electrochemical sulfonamide chemistry, were tolerated under the current reaction conditions. Heterocyclic thiols (15–17), which are among the most widely used moieties in pharmaceutical and agrochemical syntheses, were also effective. Notably, compound 15 is also known as PyFluor, an effective deoxyfluorination reagent reported by Doyle and co-workers. (3) We next examined a variety of different primary and secondary aliphatic thiol substrates, including methanethiol (18), ethanethiol (19), propanethiol (20), n-octanethiol (21), cyclohexylthiol (22), pyrazineethanethiol (23), benzylthiol (24), p-chlorobenzylthiol (25), 2-phenylethanethiol (26) and cysteine (27). All proved to be competent reaction partners yielding the corresponding sulfonyl fluorides in synthetically useful yields (19–96%). The use of the most volatile and odorous thiols could be avoided by using the corresponding disulfide instead (18,20). Interestingly, we were able to engage cysteine (27) in our electrochemical sulfonyl fluoride protocol, providing opportunities for the preparation of new nonproteinogenic amino acid building blocks.
Figure 2
Figure 2. Synthesis of sulfonyl fluorides. Substrate scope for the electrochemical sulfonyl fluoride synthesis. Reported yields are isolated and reproduced at least two times. Yields between [brackets] are those referring to 19F NMR yields calculated with PhCF3 as internal standard. Reaction conditions (Entry 1): thiol (2 mmol) or disulfide (1 mmol), KF (5 equiv), pyridine (1 equiv), CH3CN/1 M HCl (20 mL, 1:1 v/v), C anode/Fe cathode, 20 mA (4.1 mA/cm2). *3.2 V applied potential. **4.0 V applied potential. #Isolated as a phenyl sulfonate derivative through reaction with phenol. ¶Scale-up reaction conditions: thiophenol (10 mmol), KF (5 equiv), pyridine (1 equiv), CH3CN/1 M HCl (40 mL, 1:1 v/v), C anode/Fe cathode, 3.2 V applied potential.
To obtain insights into the underlying mechanism, a number of additional experiments were carried out (Figure 3). Kinetic experiments revealed a rapid conversion of 4-(trifluoromethyl)thiophenol via anodic oxidation to the corresponding disulfide within 45 min (Figure 3A). (19) Next, the disulfide intermediate is consumed and the corresponding sulfonyl fluoride is formed. The pseudo-zero-order behavior suggests that mass transfer limitations from the bulk to the electrode surface occur during the batch electrochemical transformation.
Figure 3
Figure 3. Mechanistic investigation of the electrochemical sulfonyl fluoride synthesis. (A) 19F NMR Kinetic batch experiment (see Supporting Information). (B) Kinetic experiment carried out in an electrochemical microreactor (gas chromatography flame ionization detector, see Supporting Information). (C) Toroidal vortices in segmented flow result in enhanced mass transport to and from the electrodes. (D) Fluorination step experiments and radical trapping experiments. Gas chromatography yield (biphenyl as internal standard). (E) Proposed mechanism.
Indeed, when the reaction is carried out in an electrochemical microflow reactor with a small interelectrode gap (250 μm), (20) full conversion is observed in only 5 min 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 and (iii) an intensified mass transport to and from the electrodes due to multiphase fluid patterns (Figure 3C). (21)
Oxidation of the disulfide results in the formation of a radical cation (22) 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 us to isolate the corresponding sulfonyl fluoride in good yields, indicating the presence of a nucleophilic fluorination. Adding (2,2,6,6-tetramethylpiperidin-1-yl)oxyl or butylated hydroxytoluene 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.
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.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b06126.
Data and materials availability: additional optimization, mechanistic data, experimental procedures and analytical data (1H, 19F and 13C NMR, high resolution mass spectrometry) for all new compounds (PDF)
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Author Information
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- Timothy Noël - Micro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600 MB Eindhoven, The Netherlands;
http://orcid.org/0000-0002-3107-6927;
- Gabriele Laudadio - Micro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600 MB Eindhoven, The Netherlands;http://orcid.org/0000-0002-2749-8393
Acknowledgments
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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).
References
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This article references 24 other publications.
- 1Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry. Angew. Chem., Int. Ed. 2014, 53, 9430– 9448, DOI: 10.1002/anie.201309399[Crossref], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtleisbzJ&md5=78e251c607d42f2506a9420f2f2f9835Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click ChemistryDong, Jiajia; Krasnova, Larissa; Finn, M. G.; Sharpless, K. BarryAngewandte Chemie, International Edition (2014), 53 (36), 9430-9448CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of org. chemists as the most commonly used SVI electrophiles, and the parent sulfuryl chloride, O2SVICl2, also was relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the SVI-Cl bond is exceedingly sensitive to reductive collapse yielding SIV species and Cl-. Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2-F and SO2F2) leaves only the substitution pathway open. As with most of click chem., many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany. Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here the authors seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2=CH-SO2-F, the most perfect Michael acceptor ever found. To this history the authors add several new observations, including that the otherwise very stable gas SO2F2 has excellent reactivity under the right circumstances. Also proton or silicon centers can activate the exchange of S-F bonds for S-O bonds to make functional products, and the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chem. to small mols., polymers, and biomols. are discussed.
- 2(a) Narayanan, A.; Jones, L. H. Sulfonyl fluorides as privileged warheads in chemical biology. Chem. Sci. 2015, 6, 2650– 2659, DOI: 10.1039/C5SC00408J[Crossref], [PubMed], [CAS], Google Scholar.2ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVamurc%253D&md5=0009feb4068e912b4784fb8411cdb702Sulfonyl fluorides as privileged warheads in chemical biologyNarayanan, Arjun; Jones, Lyn H.Chemical Science (2015), 6 (5), 2650-2659CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Sulfonyl fluoride electrophiles have found significant utility as reactive probes in chem. biol. and mol. pharmacol. As warheads they possess the right balance of biocompatibility (including aq. stability) and protein reactivity. Their functionality is privileged in this regard as they are known to modify not only reactive serines (resulting in their common use as protease inhibitors), but also context-specific threonine, lysine, tyrosine, cysteine and histidine residues. This review describes the application of sulfonyl fluoride probes across various areas of research and explores new approaches that could further enhance the chem. biol. toolkit. We believe that sulfonyl fluoride probes will find greater utility in areas such as covalent enzyme inhibition, target identification and validation, and the mapping of enzyme binding sites, substrates and protein-protein interactions.(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, DOI: 10.1002/cbic.201200531[Crossref], [PubMed], [CAS], Google Scholar2bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlyqsLnP&md5=920f5f4b4b90924725c225d5166677a5Sulfonyl Fluoride Analogues as Activity-Based Probes for Serine ProteasesShannon, D. Alexander; Gu, Christian; McLaughlin, Christopher J.; Kaiser, Markus; van der Hoorn, Renier A. L.; Weerapana, EranthieChemBioChem (2012), 13 (16), 2327-2330, S2327/1-S2327/16CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)The tools of activity-based protein profiling (ABPP) have played a pervasive role in the functional characterization of enzymes within complex biol. systems. As the application of ABPP technologies becomes more widespread, there is a const. need for an ever-expanding library of activity-based probes (ABPs) of varying reactivity and specificity. ABPP methods are particularly important for the study of proteases, which are often subject to stringent post-translational regulation. Compared to the armory of ABPs available for cysteine proteases, ABPs for the serine protease family are poorly represented, mostly due to the lower reactivity of the serine nucleophile relative to its cysteine counterpart. Fluorophosphonate (FP) based ABPs are known to target serine proteases, together with the entire family of serine hydrolases that encompass approx. 1 % of the human genome. Although sulfonate esters have previously been used as carbon electrophiles in ABPs for targeting diverse enzyme classes, there are no previous reports on adapting sulfonyl fluorides into chem. probes for activity-based profiling. Converting AEBSF into an ABP requires the incorporation of a reporter group in the form of a fluorophore, biotin or a click-chem. handle to enable visualization and enrichment of active enzymes. Three modified versions of AEBSF were synthesized, including the rhodamine-tagged DS6R and the alkyne-functionalized DAS1 and DAS2. DS6R and DAS1 were synthesized using an amide coupling reaction to the primary amine of AEBSF, whereas DAS2 was obtained using a reductive amination reaction to incorporate the alkyne functionality. DAS1 was identified as a potent and activity-based covalent modifier of serine proteases and was used to continue characterization of protease labeling. Here, the application of sulfonyl fluorides as an activity-based probe that covalently modifies endogenous serine proteases and allows for gel-based anal. of protein activity, as well as enrichment and identification using mass spectrometry was demonstrated.
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], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOlsL3N&md5=cf34a683cbf98730ac4a3e6b4e2cb211PyFluor: A Low-Cost, Stable, and Selective Deoxyfluorination ReagentNielsen, Matthew K.; Ugaz, Christian R.; Li, Wenping; Doyle, Abigail G.Journal of the American Chemical Society (2015), 137 (30), 9571-9574CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We report an inexpensive, thermally stable deoxyfluorination reagent that fluorinates a broad range of alcs. without substantial formation of elimination side products. This combination of selectivity, safety, and economic viability enables deoxyfluorination on preparatory scale. We employ the [18F]-labeled reagent in the first example of a no-carrier-added deoxy-radiofluorination. - 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, DOI: 10.1021/jo401759z[ACS Full Text.], [CAS], Google Scholar4ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1Ckt7%252FM&md5=9e697cf7ff5fb6dc0b44e0d405a0bff7Ascertaining the Suitability of Aryl Sulfonyl Fluorides for [18F]Radiochemistry Applications: A Systematic Investigation using MicrofluidicsMatesic, Lidia; Wyatt, Naomi A.; Fraser, Benjamin H.; Roberts, Maxine P.; Pham, Tien Q.; Greguric, IvanJournal of Organic Chemistry (2013), 78 (22), 11262-11270CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Optimization of [18F]-radiolabeling conditions and subsequent stability anal. in mobile phase, PBS buffer, and rat serum of 12 arylsulfonyl chloride precursors with various substituents (electron-withdrawing groups, electron-donating groups, increased steric bulk, heterocyclic) were performed using an Advion NanoTek Microfluidic Synthesis System. A comparison of radiochem. yields and reaction times for a microfluidics device vs. a conventional reaction vessel is reported. [18F]-Radiolabeling of sulfonyl chlorides in the presence of competing nucleophiles, H-bond donors, and water was also assessed and demonstrated the versatility and potential utility of [18F]-sulfonyl fluorides as synthons for indirect radiolabeling.(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 18F Labelling Agents. Chem. - Eur. J. 2012, 18, 11079– 11087, DOI: 10.1002/chem.201103450[Crossref], [PubMed], [CAS], Google Scholar4bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVGgtrnP&md5=0eb8983d755b8dc99de9c1d2899aea0bSulfonyl fluoride-based prosthetic compounds as potential 18F labeling agentsInkster, James A. H.; Liu, Kate; Ait-Mohand, Samia; Schaffer, Paul; Guerin, Brigitte; Ruth, Thomas J.; Storr, TimChemistry - A European Journal (2012), 18 (35), 11079-11087, S11079/1-S11079/9CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Nucleophilic incorporation of [18F]F- under aq. conditions holds several advantages in radiopharmaceutical development, esp. with the advent of complex biol. pharmacophores. Sulfonyl fluorides can be prepd. in water at room temp., yet they have not been assayed as a potential means to 18F-labeled biomarkers for PET chem. We developed a general route to prep. bifunctional 4-formyl-, 3-formyl-, 4-maleimido- and 4-oxylalkynl-arylsulfonyl [18F]fluorides from their sulfonyl chloride analogs in 1:1 mixts. of acetonitrile, THF, or tBuOH and Cs[18F]F/Cs2CO3(aq.) in a reaction time of 15 min at room temp. With the exception of 4-N-maleimide-benzenesulfonyl fluoride, pyridine could be used to simplify radiotracer purifn. by selectively degrading the precursor without significantly affecting obsd. yields. The addn. of pyridine at the start of [18F]fluorination (1:1:0.8 tBuOH/Cs2CO3(aq.)/pyridine) did not neg. affect yields of 3-formyl-2,4,6-trimethylbenzenesulfonyl [18F]fluoride and dramatically improved the yields of 4-(prop-2-ynyloxy)benzenesulfonyl [18F]fluoride. The N-arylsulfonyl-4-dimethylaminopyridinium deriv. of the latter (I) can be prepd. and incorporates 18F efficiently in solns. of 100 % aq. Cs2CO3 (10 mg mL-1). As proof-of-principle, [18F]3-formyl-2,4,6-trimethylbenzenesulfonyl [18F]fluoride was synthesized in a preparative fashion [88(±8) % decay cor. (n = 6) from start-of-synthesis] and used to radioactively label an oxyamino-modified bombesin(6-14) analog [35(±6) % decay cor. (n = 4) from start-of-synthesis]. Total prepn. time was 105-109 min from start-of-synthesis. Although the 18F-peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aq., room temp. 18F labeling strategy.
- 5Chinthakindi, P. K.; Arvidsson, P. I. Sulfonyl Fluorides (SFs): More Than Click Reagents?. Eur. J. Org. Chem. 2018, 3648– 3666, DOI: 10.1002/ejoc.201800464[Crossref], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1yktL%252FE&md5=819292301bdb81cab0f12f4c535d8078Sulfonyl Fluorides (SFs): More Than Click Reagents?Chinthakindi, Praveen K.; Arvidsson, Per I.European Journal of Organic Chemistry (2018), 2018 (27-28), 3648-3666CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Sulfonyl fluoride (SF)-contg. substances are currently attracting enormous attention among practitioners of both chem. biol. and synthetic org. chem. The groups of Jones and Liskamp have demonstrated the potential of sulfonyl fluorides as selective covalent inhibitors in studies related to drug discovery and chem. biol., resp., in the last few years. The Sharpless group has extended the repertoire of "click-reactions" to those involving sulfonyl fluorides, i.e., sulfur-fluoride exchange (SuFEx), a development that quickly triggered the interest in this functional group in the community of synthetic org. chemists. In this microreview, we aim to give an account of the synthetic chem. surrounding sulfonyl fluoride contg. substances from a historical perspective to present day developments.
- 6(a) Xiao, X.; Zhou, F.; Jiang, J.; Chen, H.; Wang, L.; Chen, D.; 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, DOI: 10.1039/C7PY02042B[Crossref], [CAS], Google Scholar.6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVWgsL0%253D&md5=d2a3650940e65cd6a3d0b6083f8e1a93Highly efficient polymerization via sulfur(VI)-fluoride exchange (SuFEx): novel polysulfates bearing a pyrazoline-naphthylamide conjugated moiety and their electrical memory performanceXiao, Xiong; Zhou, Feng; Jiang, Jun; Chen, Haifeng; Wang, Lihua; Chen, Dongyun; Xu, Qingfeng; Lu, JianmeiPolymer Chemistry (2018), 9 (8), 1040-1044CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Two functional polysulfates (PolyTPP-NI and CPTPP-NI) bearing large conjugated chains were obtained via a sulfur(VI) fluoride click reaction in high yields under mild reaction conditions. The corresponding soln.-processed sandwiched memory devices exhibited stable 'flash' electron storage behavior.(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, DOI: 10.1002/anie.201811051[Crossref], [CAS], Google Scholar.6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFeisbvP&md5=11f6f9ff812ef469dd3965475c6c75cfFacile Synthesis of Sequence-Regulated Synthetic Polymers Using Orthogonal SuFEx and CuAAC Click ReactionsYang, Cangjie; Flynn, James P.; Niu, JiaAngewandte Chemie, International Edition (2018), 57 (49), 16194-16199CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The orthogonal sulfur-fluoride exchange reaction (SuFEx) and copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) are employed to synthesize sequence-regulated synthetic polymers. The high efficiency and broad tolerance of SuFEx and CuAAC to diverse chem. functionalities enable the one-pot synthesis of polydispersed sequence-controlled polymers by step-growth copolymn. in high yield and sequence complexity. Furthermore, iterative SuFEx and CuAAC coupling reactions on a solid support, without the need of protecting groups, afford monodispersed sequence-defined oligomers. The use of this orthogonal pair of click reactions provides new opportunities to facilely access sequence-regulated synthetic polymers with a high degree of structural diversity.(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, DOI: 10.1002/anie.201701160[Crossref], [CAS], Google Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFGqtr8%253D&md5=6c4ebff60dd24d634a4784a4cd76a88aSuFEx-Based Polysulfonate Formation from Ethenesulfonyl Fluoride-Amine AdductsWang, Hua; Zhou, Feng; Ren, Gerui; Zheng, Qinheng; Chen, Hongli; Gao, Bing; Klivansky, Liana; Liu, Yi; Wu, Bin; Xu, Qingfeng; Lu, Jianmei; Sharpless, K. Barry; Wu, PengAngewandte Chemie, International Edition (2017), 56 (37), 11203-11208CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The SuFEx-based polycondensation between bisalkylsulfonyl fluorides (AA monomers) and bisphenol bis(t-butyldimethylsilyl) ethers (BB monomers) using [Ph3P=N-PPh3]+[HF2]- as the catalyst is described. The AA monomers were prepd. via the highly reliable Michael addn. of ethenesulfonyl fluoride and amines/anilines while the BB monomers were obtained from silylation of bisphenols by t-butyldimethylsilyl chloride. With these reactions, a remarkable diversity of monomeric building blocks was achieved by exploiting readily available amines, anilines, and bisphenols as starting materials. The SuFEx-based polysulfonate formation reaction exhibited excellent efficiency and functional group tolerance, producing polysulfonates with a variety of side chain functionalities in >99 % conversion within 10 min to 1 h. When bearing an orthogonal group on the side chain, the polysulfonates can be further functionalized via click-chem.-based post-polymn. modification.
- 7Abdul Fattah, T.; Saeed, A.; Albericio, F. Recent advances towards sulfur (VI) fluoride exchange (SuFEx) click chemistry. J. Fluorine Chem. 2018, 213, 87– 112, DOI: 10.1016/j.jfluchem.2018.07.008[Crossref], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVSrtb7J&md5=9b151ab663fcdf5227068debf1c2d8e0Recent advances towards sulfur (VI) fluoride exchange (SuFEx) click chemistryAbdul Fattah, Tanzeela; Saeed, Aamer; Albericio, FernandoJournal of Fluorine Chemistry (2018), 213 (), 87-112CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)A review. This review comprehensively focused on the sole reactivity of SuFEx click reaction and its role in the building of novel sterically hindered amides, fluorosulfates, diverse compds. from SOF4 hub, high-mol. wt. polymer materials (polysulfates and polysulfonates) and surface coatings. The SuFEx part in post-polymn. reactions, late-stage drug functionalization (LSF) and oil/water sepns. was also highlighted. Finally, the potential application of the SuFEx for bioconjugation is also analyzed.
- 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, DOI: 10.1021/acssuschemeng.8b00489[ACS Full Text.], [CAS], Google Scholar8ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntVKnsrk%253D&md5=8b02c73fe69c51eb5a239682ff2f23b0Nucleophilic Fluorination with Aqueous Bifluoride Solution: Effect of the Phase-Transfer CatalystTalko, Alicja; Barbasiewicz, MichalACS Sustainable Chemistry & Engineering (2018), 6 (5), 6693-6701CODEN: ASCECG; ISSN:2168-0485. (American Chemical Society)Nucleophilic fluorination of sulfonyl chlorides, acyl chlorides, and alkyl sulfonates with satd. aq. soln. of potassium bifluoride (KHF2) was studied under liq.-liq. two-phase conditions. Original "on-water" procedure, reported by Sharpless et al., was tested on model 1-octanesulfonyl chloride in the presence of phase transfer catalysts, some of which appeared to be beneficial for the reaction rate. Despite the high hydration energy of the fluoride ions, the catalytic system displayed numerous features typical for interfacial transportation of the nucleophilic species, being controlled by amt. and structure of the catalyst, lipophilicity of the catalyst's counterion, and rate of stirring. Besides for synthesis of acyl fluorides presence of 1 mol % of tetrabutylammonium chloride affected the selectivity of the reaction by minimizing formation of carboxylic acids and anhydrides. The presented results suggest that aq. solns. of bifluorides (or synthetically equiv. systems accessible by acidification of alkali metal fluoride solns.) can be efficient sources of the fluoride ions under two-phase conditions, provided that rate of the intrinsic reaction is sufficiently high. The methodol. supplements family of nucleophilic fluorinations, delivering a more reactive form of the solvated anions.(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, DOI: 10.1039/C5GC02755A[Crossref], [CAS], Google Scholar.8bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFKitbjL&md5=e0f69dbf83f4d896cfd7f3e63bc628fbCatalyst-free radical fluorination of sulfonyl hydrazides in waterTang, Lin; Yang, Yu; Wen, Lixian; Yang, Xingkun; Wang, ZhiyongGreen Chemistry (2016), 18 (5), 1224-1228CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The first catalyst-free fluorination of sulfonyl hydrazides for the synthesis of sulfonyl fluorides has been developed via a free-radical pathway. This protocol presents a broad substrate scope and does not require any metal catalyst and additive. All these transformations proceed smoothly in water under mild conditions, which enables a straightforward, practical, and environmentally benign fluorination for S-F bond formation.(c) Bianchi, T. A.; Cate, L. A. Phase Transfer Catalysis. Preparation of Aliphatic and Aromatic Sulfonyl Fluorides. J. Org. Chem. 1977, 42, 2031– 2032, DOI: 10.1021/jo00431a054[ACS Full Text.], [CAS], Google Scholar8chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXkt1Wlt7c%253D&md5=52fe4e02ff9bfa7a0f9996de0e2726fcPhase transfer catalysis. Preparation of aliphatic and aromatic sulfonyl fluoridesBianchi, Thomas A.; Cate, Laurence A.Journal of Organic Chemistry (1977), 42 (11), 2031-2CODEN: JOCEAH; ISSN:0022-3263.Stirring sulfonyl chloride with KF neat or in MeCN in the presence of a catalytic amt. of 18-crown-6 led to an exothermic reaction, which was complete within 4 h. The following RSO2F were prepd. (R, % yield given): Me, 84; PhCH2, 89; Ph, 92.5; p-MeC6H4, 100; p-BrC6H4 100; p-AcNHC6H4, 96; 5-(dimethylamino)-1-naphthyl, 100.(d) Davies, W.; Dick, J. H. CCLXXXVI.—Aromatic sulphonyl fluorides. A convenient method of preparation. J. Chem. Soc. 1931, 0, 2104– 2109, DOI: 10.1039/JR9310002104[Crossref], [CAS], Google Scholar8dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaA38XjslGj&md5=2d699b43e27c323832b4eca84475956dAromatic sulfonyl fluorides. A convenient method of preparationDavies, Wm.; Dick, John H.Journal of the Chemical Society (1931), (), 2104-9CODEN: JCSOA9; ISSN:0368-1769.Aromatic sulfonyl fluorides are obtained in 80-90% yield from the corresponding chloride by refluxing with an aq. soln. of a metal fluoride. KF is preferred. Snlfonyl fluorides are stable and very resistant toward hydrolysis by water or weak acids. They are sapond. easily by a caustic soln. The following derivs. are described-PhSO2F, b. 207°, nD20 1.4922; o-MeC6H4SO2F, b. 223-5°, n D20 1.5007; p-MeC6H4SO2F,m.41-2°; 1,3-dimethylbenzene-4-sulfonyl fluoride, b. 246°, nD20 1.5086; p-ClC6H4SO2F, m. 47-8°; 6-chloro-o-toluene-sulfonyl fluoride, m. 44-5°; 2-chloro-5-nitro-p-toluenesulfonyl fluoride, m. 84-5°; 1,3-dimethylbensene-4,6-disulfonyl fluoride, m. 116-8°; chlorbenzene-2,4-disulfonyl fluoride, m. 88-9°; 1,3-dichlorobenzene-4,6-disulfonylfluoride, m. 141-3 0; 1,3,5-trichloro-benzene-disulfonylfluoride, m. 109-10°; 1,3-dimethoxy-4,6-disulfonyl fluoride, m. 209-11°; benzene-1,3,5-trisulfonyl fluoride, m. 166-7°; clzlorobenzene-2,3,6-trisulfonyl fluoride, m. 179-81°; naphthalene-β-sulfonyl fluoride, m. 86-8°.
- 9Schmitt, A.-M. D.; Schmitt, D. C., Chapter 13. Synthesis of Sulfonamides. In RSC Drug Discovery Series , 2016; Vol. 2016, pp 123– 138.
- 10Brouwer, 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, DOI: 10.1016/j.tetlet.2009.02.130[Crossref], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtVemsL4%253D&md5=befb59564fccd946935a623643502a2bSynthesis of β-aminoethanesulfonyl fluorides or 2-substituted taurine sulfonyl fluorides as potential protease inhibitorsBrouwer, Arwin J.; Ceylan, Tarik; van der Linden, Tima; Liskamp, Rob M. J.Tetrahedron Letters (2009), 50 (26), 3391-3393CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)Substituted taurine sulfonyl fluorides derived from taurine or protected amino acids are conveniently synthesized from β-aminoethanesulfonyl chlorides using KF/18-crown-6 or from β-aminoethanesulfonates using DAST.
- 11Tribby, A. L.; Rodríguez, I.; Shariffudin, S.; Ball, N. D. Pd-Catalyzed Conversion of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and Selectfluor. J. Org. Chem. 2017, 82, 2294– 2299, DOI: 10.1021/acs.joc.7b00051[ACS Full Text], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsl2qtLw%253D&md5=e1169e2f4937ce3496fc24dc7d9de859Pd-Catalyzed Conversion of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and SelectfluorTribby, Ariana L.; Rodriguez, Ismerai; Shariffudin, Shamira; Ball, Nicholas D.Journal of Organic Chemistry (2017), 82 (4), 2294-2299CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A one-pot Pd-catalyzed conversion of aryl iodides to aryl sulfonyl fluorides using DABSO and Selectfluor has been developed generating aryl sulfonyl fluorides in good to excellent yields. The reaction results in the generation of electronically and sterically diverse sulfonyl fluorides. Addnl., sulfonyl fluorides can be converted to aryl sulfonamides and sulfonic esters using Cs2CO3 under mild conditions.
- 12Davies, 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, DOI: 10.1039/C6SC03924C[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1Cns7jL&md5=52ea294e24fed8236b40405aa0efe773One-pot palladium-catalyzed synthesis of sulfonyl fluorides from aryl bromidesDavies, Alyn T.; Curto, John M.; Bagley, Scott W.; Willis, Michael C.Chemical Science (2017), 8 (2), 1233-1237CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)A mild, efficient synthesis of sulfonyl fluorides from aryl and heteroaryl bromides utilizing palladium catalysis is described. The process involves the initial palladium-catalyzed sulfonylation of aryl bromides using DABSO as an SO2 source, followed by in situ treatment of the resultant sulfinate with the electrophilic fluorine source NFSI. This sequence represents the first general method for the sulfonylation of aryl bromides, and offers a practical, one-pot alternative to previously described synthesis of sulfonyl fluorides, allowing rapid access to these biol. important mols. Excellent functional group tolerance is demonstrated, with the transformation successfully achieved on a no. of active pharmaceutical ingredients, and their precursors. The prepn. of peptide-derived sulfonyl fluorides is also demonstrated.
- 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, DOI: 10.1016/j.tet.2014.02.013[Crossref], [CAS], Google Scholar.13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtl2mu7w%253D&md5=092527765be8ef5ec3a0833f4222b525Oxidation of disulfides with electrophilic halogenating reagents: concise methods for preparation of thiosulfonates and sulfonyl halidesKirihara, Masayuki; Naito, Sayuri; Nishimura, Yuki; Ishizuka, Yuki; Iwai, Toshiaki; Takeuchi, Haruka; Ogata, Tomomi; Hanai, Honoka; Kinoshita, Yukari; Kishida, Mari; Yamazaki, Kento; Noguchi, Takuya; Yamashoji, ShiroTetrahedron (2014), 70 (14), 2464-2471CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)The reaction of arom. or benzylic disulfides with 2.5 equiv of Selectfluor in acetonitrile/water (10:1) at room temp. efficiently produced the corresponding thiosulfonates. Conversely, the reaction of disulfides with 6.5 equiv of Selectfluor or thiosulfonates with 4.5 equiv of Selectfluor in refluxing acetonitrile/water (10:1) provided sulfonyl fluorides in high yields. Accufluor and FP-T300 are also effective in prepg. sulfonyl fluorides from disulfides under the similar reaction conditions. Sulfonyl chlorides or sulfonyl bromides were effectively obtained from the reaction of disulfides with 6 equiv of either N-chlorosuccinimide or N-bromosuccinimide in acetonitrile/water (10:1) at room temp. Some other electrophilic chlorinating or brominating reagents are also able to be used instead of N-chlorosuccinimide or N-bromosuccinimide for the syntheses of sulfonyl halides from disulfides. These reactions of disulfides with electrophilic halogenating reagents are convenient methods to prep. thiosulfonates and sulfonyl halides.(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, DOI: 10.1016/j.tetlet.2011.03.132[Crossref], [CAS], Google Scholar13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmtFartbc%253D&md5=bf547926fa17330252be7a4debf71030Oxidation of disulfides with Selectfluor: concise syntheses of thiosulfonates and sulfonyl fluoridesKirihara, Masayuki; Naito, Sayuri; Ishizuka, Yuki; Hanai, Honoka; Noguchi, TakuyaTetrahedron Letters (2011), 52 (24), 3086-3089CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)The reaction of arom. or benzylic disulfides with 2.5 equiv Selectfluor in MeCN/H2O (10:1) at room temp. efficiently produced the corresponding thiosulfonates. On the other hand, the reaction of disulfides with 6.5 equiv Selectfluor in refluxing MeCN/H2O (10:1) provided sulfonyl fluorides in high yields.
- 14
For other S-F bond forming transformations leading to SFx species, see:
(a) Pitts, C. R.; Bornemann, D.; Liebing, P.; Santschi, N.; Togni, A. Making the SF5 Group More Accessible: A Gas-Reagent-Free Approach to Aryl Tetrafluoro-λ 6-sulfanyl Chlorides. Angew. Chem., Int. Ed. 2019, 58, 1950– 1954, DOI: 10.1002/anie.201812356[Crossref], [CAS], Google Scholar.14ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVOmtr4%253D&md5=6289c01f81c3c86fbfe70d9bb02a31f0Making the SF5 Group More Accessible: A Gas-Reagent-Free Approach to Aryl Tetrafluoro-λ6-sulfanyl ChloridesPitts, Cody Ross; Bornemann, Dustin; Liebing, Phil; Santschi, Nico; Togni, AntonioAngewandte Chemie, International Edition (2019), 58 (7), 1950-1954CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of aryl tetrafluoro-λ6-sulfanyl chlorides R-X [R = Ph, 4-BzOC6H4, 5-Br-2-pyridyl, 5-Br-2-pyrimidinyl, etc.; X = SF4Cl] was synthesized via trifluoroacetic acid catalyzed gas-reagent-free oxidative polyfluorination of aryl disulfides. This approach overcame the reliance on hazardous fluorinating reagents and/or gas reagents (e.g. Cl2) by employing easy-to-handle trichloroisocyanuric acid, potassium fluoride and catalytic amts. of acid. Furthermore, the same approach provided an access to compds. R-X [X = SF3, SF5, SeF3] which extended the applications of this chem. beyond arene SF5-functionalization and demonstrated its ability to address a more general oxidative fluorination problem.(b) Umemoto, T.; Garrick, L. M.; Saito, N. Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry. Beilstein J. Org. Chem. 2012, 8, 461– 471, DOI: 10.3762/bjoc.8.53[Crossref], [PubMed], [CAS], Google Scholar.14bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtVOksL4%253D&md5=2ffe7ebd3c0ad76b5ffa307ce35c2f6dDiscovery of practical production processes for arylsulfur pentafluorides and their higher homologs, bis- and tris-(sulfur pentafluorides): beginning of a new era of super-trifluoromethyl arene chemistry and its industryUmemoto, Teruo; Garrick, Lloyd M.; Saito, NorimichiBeilstein Journal of Organic Chemistry (2012), 8 (), 461-471, No. 53CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)Various arylsulfur pentafluorides, ArSF5, have long been desired in both academic and industrial areas and ArSF5 compds. have attracted considerable interest in many areas such as medicine, agrochems., and other new materials, since the highly stable SF5 group is considered a super-trifluoromethyl group due to its significantly higher electronegativity and lipophilicity. This article describes the first practical method for the prodn. of various arylsulfur pentafluorides and their higher homologs, bis- and tris-(sulfur pentafluorides), from the corresponding diaryl disulfides or aryl thiols. The method consists of two steps: (step 1) treatment of a diaryl disulfide or an aryl thiol with chlorine in the presence of an alkali metal fluoride and (step 2) treatment of the resulting arylsulfur chlorotetrafluoride with a fluoride source, such as zinc fluoride (ZnF2), hydrofluoric acid (HF) and antimony fluorides, Sb(III/V) fluorides. The intermediate arylsulfur chlorotetrafluoride derivs. were isolated by distn. or recrystn. and characterized. The aspects of these new reactions are revealed and reaction mechanisms are discussed. As the method offers considerable improvement over previous methods in cost, yield, practicality, applicability and large-scale prodn., the new processes described here can be employed as the first practical method for the economical prodn. of various arylsulfur pentafluorides and their higher homologs, which could then open up a new era of super-trifluoromethyl arene chem. and its applications in many areas. A reaction (chlorine/potassium fluoride) of bis(2,3,6-trifluorophenyl)disulfide (I) gave trans-chlorotetrafluoro(2,3,6-trifluorophenyl)sulfur (II) and cis-chlorotetrafluoro(2,3,6-trifluorophenyl)sulfur (III). The synthesis of the target compd. was achieve by the treatment of II, III with fluorination agents, to provide, e.g., pentafluoro(2,3,6-trifluorophenyl)sulfur (IV).(c) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. Discovery of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride as a deoxofluorinating agent with high thermal stability as well as unusual resistance to aqueous hydrolysis, and its diverse fluorination capabilities including deoxofluoro-arylsulfinylation with high stereoselectivity. J. Am. Chem. Soc. 2010, 132, 18199– 18205, DOI: 10.1021/ja106343h[ACS Full Text], [CAS], Google Scholar14chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFShtb%252FL&md5=4f22dec27588a85d444e16494040d091Discovery of 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride as a Deoxofluorinating Agent with High Thermal Stability as Well as Unusual Resistance to Aqueous Hydrolysis, and Its Diverse Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation with High StereoselectivityUmemoto, Teruo; Singh, Rajendra P.; Xu, Yong; Saito, NorimichiJournal of the American Chemical Society (2010), 132 (51), 18199-18205CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compds. have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into mols. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, I), as a cryst. solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogs. The roles of substituents on I in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addn. to fluorinations of alcs., aldehydes, and enolizable ketones, I smoothly converts non-enolizable carbonyls to CF2 groups, and carboxylic groups to CF3 groups, in high yields. I also converts C(=S) and CH3SC(=S)O groups to CF2 and CF3O groups, resp., in high yields. In addn., I effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcs. to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of I in addn. to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas. - 15Laudadio, G.; Barmpoutsis, E.; Schotten, C.; Struik, L.; Govaerts, S.; Browne, D. L.; Noël, T. Sulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and Thiols. J. Am. Chem. Soc. 2019, 141, 5664– 5668, DOI: 10.1021/jacs.9b02266[ACS Full Text], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXlvVSlurk%253D&md5=cd1ac810b9106f662c0c13bc780034fcSulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and ThiolsLaudadio, Gabriele; Barmpoutsis, Efstathios; Schotten, Christiane; Struik, Lisa; Govaerts, Sebastian; Browne, Duncan L.; Noel, TimothyJournal of the American Chemical Society (2019), 141 (14), 5664-5668CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Sulfonamides are key motifs in pharmaceuticals and agrochems., spurring the continuous development of novel and efficient synthetic methods to access these functional groups. Herein, the authors report an environmentally benign electrochem. method which enables the oxidative coupling between thiols and amines, two readily available and inexpensive commodity chems. The transformation is completely driven by electricity, does not require any sacrificial reagent or addnl. catalysts and can be carried out in only 5 min. Hydrogen is formed as a benign byproduct at the counter electrode. Owing to the mild reaction conditions, the reaction displays a broad substrate scope and functional group compatibility.
- 16(a) Tang, S.; Liu, Y.; Lei, A. Electrochemical Oxidative Cross-coupling with Hydrogen Evolution: A Green and Sustainable Way for Bond Formation. Chem. 2018, 4, 27– 45, DOI: 10.1016/j.chempr.2017.10.001[Crossref], [CAS], Google Scholar.16ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFyitQ%253D%253D&md5=b49dcf3ad4701e118761fd12dcba7dbcElectrochemical Oxidative Cross-coupling with Hydrogen Evolution: A Green and Sustainable Way for Bond FormationTang, Shan; Liu, Yichang; Lei, AiwenChem (2018), 4 (1), 27-45CODEN: CHEMVE; ISSN:2451-9294. (Cell Press)A review. Oxidative R1-H/R2-H cross-coupling represents an ideal way for the construction of new chem. bonds. However, the bond formation with loss of H2 is typically thermodynamically unfavorable and thus usually requires an external driving force, namely, an appropriate sacrificial oxidant. Recent advances have revealed that oxidative R1-H/R2-H cross-coupling with hydrogen gas evolution can be achieved through electrochem. anodic oxidn. and concomitant cathodic proton redn. Electrochem. provides new opportunities for the construction of carbon-carbon and carbon-heteroatom bonds in an environmentally friendly manner. This review article gives an overview of the recent developments in this emerging field.(b) Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Electrifying Organic Synthesis. Angew. Chem., Int. Ed. 2018, 57, 5594– 5619, DOI: 10.1002/anie.201711060[Crossref], [CAS], Google Scholar.16bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvVygsbk%253D&md5=281b9f17c8fa7e0759fa9edf6497cbf7Electrifying Organic SynthesisWiebe, Anton; Gieshoff, Tile; Moehle, Sabine; Rodrigo, Eduardo; Zirbes, Michael; Waldvogel, Siegfried R.Angewandte Chemie, International Edition (2018), 57 (20), 5594-5619CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The direct synthetic org. use of electricity is currently experiencing a renaissance. More synthetically oriented labs. working in this area are exploiting both novel and more traditional concepts, paving the way to broader applications of this niche technol. As only electrons serve as reagents, the generation of reagent waste is efficiently avoided. Moreover, stoichiometric reagents can be regenerated and allow a transformation to be conducted in an electrocatalytic fashion. However, the application of electroorg. transformations is more than minimizing the waste footprint, it rather gives rise to inherently safe processes, reduces the no. of steps of many syntheses, allows for milder reaction conditions, provides alternative means to access desired structural entities, and creates intellectual property (IP) space. When the electricity originates from renewable resources, this surplus might be directly employed as a terminal oxidizing or reducing agent, providing an ultra-sustainable and therefore highly attractive technique. This Review surveys recent developments in electrochem. synthesis that will influence the future of this area.(c) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230– 13319, DOI: 10.1021/acs.chemrev.7b00397[ACS Full Text], [CAS], Google Scholar16chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1WntbzJ&md5=21205e55da92db4e7d27aa393fed486dSynthetic Organic Electrochemical Methods Since 2000: On the Verge of a RenaissanceYan, Ming; Kawamata, Yu; Baran, Phil S.Chemical Reviews (Washington, DC, United States) (2017), 117 (21), 13230-13319CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review discusses advances in synthetic org. electrochem. since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorg. chem.
- 17Pupo, G.; Vicini, A. C.; Ascough, D. M. H.; Ibba, F.; Christensen, K. E.; Thompson, A. L.; Brown, J. M.; Paton, R. S.; Gouverneur, V. Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of β-Fluoroamines. J. Am. Chem. Soc. 2019, 141, 2878– 2883, DOI: 10.1021/jacs.8b12568[ACS Full Text], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFKjsrk%253D&md5=21f8a83ea06b38c0147f32504b42993aHydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of β-FluoroaminesPupo, Gabriele; Vicini, Anna Chiara; Ascough, David M. H.; Ibba, Francesco; Christensen, Kirsten E.; Thompson, Amber L.; Brown, John M.; Paton, Robert S.; Gouverneur, VeroniqueJournal of the American Chemical Society (2019), 141 (7), 2878-2883CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor soly. in org. solvents coupled with limited strategies to control its reactivity has discouraged its use for asym. C-F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable β-fluoroamines in high yields and enantioselectivities. This methodol. employs a chiral N-Et bis-urea catalyst that brings solid KF into soln. as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.
- 18Francke, R.; Little, R. D. Redox catalysis in organic electrosynthesis: basic principles and recent developments. Chem. Soc. Rev. 2014, 43, 2492, DOI: 10.1039/c3cs60464k[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXks12hs70%253D&md5=4ea6098c0c8f7893463ad3a2d6400146Redox catalysis in organic electrosynthesis: basic principles and recent developmentsFrancke, Robert; Little, R. DanielChemical Society Reviews (2014), 43 (8), 2492-2521CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Electroorg. synthesis has become an established, useful, and environmentally benign alternative to classic org. synthesis for the oxidn. or the redn. of org. compds. In this context, the use of redox mediators to achieve indirect processes is attaining increased significance, since it offers many advantages compared to a direct electrolysis. Kinetic inhibitions that are assocd. with the electron transfer at the electrode/electrolyte interface, for example, can be eliminated and higher or totally different selectivity can be achieved. In many cases, a mediated electron transfer can occur against a potential gradient, meaning that lower potentials are needed, reducing the probability of undesired side-reactions. The use of electron transfer mediators can help to avoid electrode passivation resulting from polymer film formation on the electrode surface. Although the principle of indirect electrolysis was established many years ago, new, exciting and useful developments continue to be made. In recent years, several new types of redox mediators were designed and examd., a process that can be accomplished more efficiently and purposefully using modern computational tools. New protocols including, the development of double mediatory systems in biphasic media, enantioselective mediation and heterogeneous electrocatalysis using immobilized mediators were established. Also, the understanding of mediated electron transfer reaction mechanisms has advanced. This review describes progress in the field of electroorg. synthesis and summarizes recent advances.
- 19Laudadio, G.; Straathof, N. J. W.; Lanting, M. D.; Knoops, B.; Hessel, V.; Noël, T. An environmentally benign and selective electrochemical oxidation of sulfides and thiols in a continuous-flow microreactor. Green Chem. 2017, 19, 4061– 4066, DOI: 10.1039/C7GC01973D[Crossref], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1yhsLzN&md5=57ef1fce4fb40199d4d4855d09b18b18An environmentally benign and selective electrochemical oxidation of sulfides and thiols in a continuous-flow microreactorLaudadio, Gabriele; Straathof, Natan J. W.; Lanting, Menno D.; Knoops, Benny; Hessel, Volker; Noel, TimothyGreen Chemistry (2017), 19 (17), 4061-4066CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A practical and environmentally benign electrochem. oxidn. of thioethers and thiols in a com.-available continuous-flow microreactor is presented. Water is used as the source of oxygen to enable the oxidn. process. The oxidn. reaction utilizes the same reagents in all scenarios and the selectivity is solely governed by the applied potential. The procedure exhibits a broad scope and good functional group compatibility providing access to various sulfoxides (15 examples), sulfones (15 examples) and disulfides (6 examples). The use of continuous flow allows the optimal reaction parameters (e.g. residence time, applied voltage) to be rapidly assessed, to avoid mass- and heat-transfer limitations and to scale the electrochem.
- 20Laudadio, G.; De Smet, Wouter; Struik, L.; Cao, Y.; Noël, T. Design and application of a modular and scalable electrochemical flow microreactor. J. Flow Chem. 2018, 8, 157– 165, DOI: 10.1007/s41981-018-0024-3[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FgtVyruw%253D%253D&md5=7dcf96d2947ce35267aff4856194dd8eDesign and application of a modular and scalable electrochemical flow microreactorLaudadio Gabriele; de Smet Wouter; Struik Lisa; Cao Yiran; Noel TimothyJournal of flow chemistry (2018), 8 (3), 157-165 ISSN:2062-249X.Electrochemistry constitutes a mild, green and versatile activation method of organic molecules. Despite these innate advantages, its widespread use in organic chemistry has been hampered due to technical limitations, such as mass and heat transfer limitations which restraints the scalability of electrochemical methods. Herein, we describe an undivided-cell electrochemical flow reactor with a flexible reactor volume. This enables its use in two different modes, which are highly relevant for flow chemistry applications, including a serial (volume ranging from 88 μL/channel up to 704 μL) or a parallel mode (numbering-up). The electrochemical flow reactor was subsequently assessed in two synthetic transformations, which confirms its versatility and scale-up potential.
- 21(a) Pletcher, D.; Green, R. A.; Brown, R. C. D. Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory. Chem. Rev. 2018, 118, 4573– 4591, DOI: 10.1021/acs.chemrev.7b00360[ACS Full Text.], [CAS], Google Scholar21ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2qtrnN&md5=28e56b67959db2e57b7a597a56046014Flow Electrolysis Cells for the Synthetic Organic Chemistry LaboratoryPletcher, Derek; Green, Robert A.; Brown, Richard C. D.Chemical Reviews (Washington, DC, United States) (2018), 118 (9), 4573-4591CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review focuses on the use of flow electrolysis cells in synthetic org. chem. lab. Electrolysis is participating in the trend toward continuous flow synthesis, and this has led to a no. of innovations in flow cell design that make possible selective syntheses with high conversion of reactant to product with a single passage of the reactant soln. through the cell. In addn., the needs of the synthetic org. chemist can often be met by flow cells operating with recycle of the reactant soln. These cells give a high rate of product formation while the reactant concn. is high, but they perform best at low conversion. Both approaches are considered in this review and the important features of each cell design are discussed. Throughout, the application of the cell designs is illustrated with syntheses that have been reported.(b) Atobe, M.; Tateno, H.; Matsumura, Y. Applications of Flow Microreactors in Electrosynthetic Processes. Chem. Rev. 2018, 118, 4541– 4572, DOI: 10.1021/acs.chemrev.7b00353[ACS Full Text.], [CAS], Google Scholar21bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVGhsr3L&md5=1d6ad45773080253daf39d3cc852d899Applications of Flow Microreactors in Electrosynthetic ProcessesAtobe, Mahito; Tateno, Hiroyuki; Matsumura, YoshimasaChemical Reviews (Washington, DC, United States) (2018), 118 (9), 4541-4572CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The fundamental advantages and potential benefits of flow microreactor technol. include extremely large surface-to-vol. ratios, precise control over temp. and residence time, extremely fast mol. diffusion, and increased safety during reactive processes. These advantages and benefits can be applied to a wide range of electrosynthetic techniques, and so the integration of flow microreactors with electrosynthesis has received significant research interest from both academia and industry. This review presents an up-to-date overview of electrosynthetic processes in continuous-flow microreactors. The advantages of continuous-flow electrochem. are discussed, along with a thorough comparison of microreactor-based processes and conventional batch reaction systems.(c) Mitsudo, K.; Kurimoto, Y.; Yoshioka, K.; Suga, S. Miniaturization and Combinatorial Approach in Organic Electrochemistry. Chem. Rev. 2018, 118, 5985– 5999, DOI: 10.1021/acs.chemrev.7b00532[ACS Full Text.], [CAS], Google Scholar21chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVSltbfE&md5=0b69cc90f54fc6a22b44af864c693410Miniaturization and Combinatorial Approach in Organic ElectrochemistryMitsudo, Koichi; Kurimoto, Yuji; Yoshioka, Kazuki; Suga, SeijiChemical Reviews (Washington, DC, United States) (2018), 118 (12), 5985-5999CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Recent advances in electro-org. chem. involving miniaturization, integration, and combinatorial chem. were reviewed. Microelectrode array technol. for site-selective electro-org. reactions and addressable libraries provides a direct and unlabeled method for measuring small-mol.-protein interactions. Electrochem. systems using solid-supported bases and acids ("site sepn.") can realize electrolysis without the addn. of supporting electrolytes. Well-designed "bipolar electrodes" have enabled the prodn. of patterned gradient polymer brushes and microfibers. For the display of combinatorial org. electrochem., batch and flow electrolysis systems for the optimization and screening of electro-org. reactions as well as the building of chem. libraries for org. compds. are described.(d) Folgueiras-Amador, A. A.; Wirth, T. Perspectives in flow electrochemistry. J. Flow Chem. 2017, 7, 94– 95, DOI: 10.1556/1846.2017.00020[Crossref], [CAS], Google Scholar21dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygur4%253D&md5=66dde9936f79a9f20e0c8f40c311f659Perspectives in flow electrochemistryFolgueiras-Amador, Ana A.; Wirth, ThomasJournal of Flow Chemistry (2017), 7 (3-4), 94-95CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Electrosynthesis is an old method currently moving again in the focus of org. synthesis. Some limitations of conventional electrosynthesis can be overcome by the use of electrochem. flow devices. This perspective indicates where the pitfalls, where the advantages and where the challenges are in implementing flow electrosynthesis as an alternative tool for the synthetic chemist.
- 22Lam, K.; Geiger, W. E. Anodic oxidation of disulfides: Detection and reactions of disulfide radical cations. J. Org. Chem. 2013, 78, 8020– 8027, DOI: 10.1021/jo401263z[ACS Full Text], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFSisLzK&md5=b48c807b1ef18cae57a9c18c6fd4354eAnodic Oxidation of Disulfides: Detection and Reactions of Disulfide Radical CationsLam, Kevin; Geiger, William E.Journal of Organic Chemistry (2013), 78 (16), 8020-8027CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The anodic oxidn. of five diaryldisulfides were studied in a dichloromethane/[NBu4][B(C6F5)4] electrolyte. Cyclic voltammetry scans of (p-RC6H4)2S2 (R = Me, 1a; R = F, 1b; R = OMe, 1c) show modest chem. reversibility for the 10/+ couple (E1/2 values vs. ferrocene: 1.04 V for 1a, 1.21 V for 1b, 0.92 V for 1c), providing the 1st voltammetric evidence for the radical cation [Ar2S2]+. A dimer dication, [Ar4S4]2+, is proposed as an intermediate in the formation of the electrolysis product, the trisulfide [Ar3S3]+. The chem. reversibility of the 1-electron oxidns. of Ar2S2 vanishes in [PF6]--contg. electrolytes. The radical cations of the more sterically constrained ortho-substituted analogs dimesityldisulfide (2a, E1/2 = 1.01 V) and bis(2,4,6-triisopropylphenyl)disulfide (2b, E1/2 = 0.98 V) show less tendency to dimerize. In all cases except 2b, the bulk electrolysis product is [R3S3]+, consistent with earlier literature reports. A mechanism is proposed in which the trisulfide is formed by reaction of the dimer dication [Ar4S4]2+ with neutral Ar2S2 to afford the trisulfide in a net 2/3 e- process. Oxidn. of Ar2S2, either anodically or by a strong 1-electron oxidant, in the presence of cyclohexene gives an efficient synthetic route to 1,2-substituted cyclohexyldisulfides.
- 23Huba, F.; Yeager, E. B.; Olah, G. A. The formation and role of carbocations in electrolytic fluorination using hydrogen fluoride electrolytes in a nafion membrane-divided Teflon cell. Electrochim. Acta 1979, 24, 489– 494, DOI: 10.1016/0013-4686(79)85021-5[Crossref], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXitFOrtA%253D%253D&md5=7441cd885d2a6813750f0efc06e17d48The formation and role of carbocations in electrolytic fluorination using hydrogen fluoride electrolytes in a Nafion membrane-divided teflon cellHuba, Francis; Yeager, Ernest B.; Olah, George A.Electrochimica Acta (1979), 24 (5), 489-94CODEN: ELCAAV; ISSN:0013-4686.The electrofluorination of mixts of EtCO2H, EtCO2COEt, or Me2CHCH2Cl with PhMe in HF(l) contg. 2% KF was examd. in a cell fitted with a Nafion cation-exchange membrane anode compartment-cathode compartment divider. The carbocations generated in the anode cell crossed the membrane and were quenched in the cathode cell by the org. mols. Products due to Freidel-Crafts substitution, isomerization, and polymn. were identified. The electrolysis of HF-pyridine complex was also examd. and little fluorination of the pyridine was obsd. Neither direct nor ionic fluorination occurred although the conditions are suitable for both mechanisms.
- 24Seel, F.; Budenz, R.; Flaccus, R. D.; Staab, R. Zur frage der existenz des phenylschwefelmonofluorids und seines chemischen verhaltens. J. Fluorine Chem. 1978, 12, 437– 438, DOI: 10.1016/S0022-1139(00)82986-3[Crossref], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXlsVKjuw%253D%253D&md5=09f8a72c47696491c88ca4afb5aa1c81Existence of phenylsulfur monofluoride and its chemical behaviorSeel, F.; Budenz, R.; Flaccus, R. D.; Staab, R.Journal of Fluorine Chemistry (1978), 12 (5), 437-8CODEN: JFLCAR; ISSN:0022-1139.Treatment of PhSSPh with SF4 (l) in a Ni or teflon reactor gave intermediate PhSF which cyclized to give thianthrene. The existence of PhSF was confirmed by 19F NMR.
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Abstract
Figure 1
Figure 1. Development of an electrochemical synthesis of sulfonyl fluorides. (A) Advantages and applications of sulfonyl fluorides. (B) Established synthetic routes to prepare sulfonyl fluorides. (C) Reaction conditions (Entry 1): 2-mercapto-4,6-dimethylpyrimidine (2 mmol), KF (5 equiv), pyridine (1 equiv), CH3CN/1 M HCl (20 mL, 1:1 v/v), C anode/Fe cathode, 20 mA (4.1 mA/cm2), 12 h.
Figure 2
Figure 2. Synthesis of sulfonyl fluorides. Substrate scope for the electrochemical sulfonyl fluoride synthesis. Reported yields are isolated and reproduced at least two times. Yields between [brackets] are those referring to 19F NMR yields calculated with PhCF3 as internal standard. Reaction conditions (Entry 1): thiol (2 mmol) or disulfide (1 mmol), KF (5 equiv), pyridine (1 equiv), CH3CN/1 M HCl (20 mL, 1:1 v/v), C anode/Fe cathode, 20 mA (4.1 mA/cm2). *3.2 V applied potential. **4.0 V applied potential. #Isolated as a phenyl sulfonate derivative through reaction with phenol. ¶Scale-up reaction conditions: thiophenol (10 mmol), KF (5 equiv), pyridine (1 equiv), CH3CN/1 M HCl (40 mL, 1:1 v/v), C anode/Fe cathode, 3.2 V applied potential.
Figure 3
Figure 3. Mechanistic investigation of the electrochemical sulfonyl fluoride synthesis. (A) 19F NMR Kinetic batch experiment (see Supporting Information). (B) Kinetic experiment carried out in an electrochemical microreactor (gas chromatography flame ionization detector, see Supporting Information). (C) Toroidal vortices in segmented flow result in enhanced mass transport to and from the electrodes. (D) Fluorination step experiments and radical trapping experiments. Gas chromatography yield (biphenyl as internal standard). (E) Proposed mechanism.
References
ARTICLE SECTIONSThis article references 24 other publications.
- 1Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry. Angew. Chem., Int. Ed. 2014, 53, 9430– 9448, DOI: 10.1002/anie.201309399[Crossref], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtleisbzJ&md5=78e251c607d42f2506a9420f2f2f9835Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click ChemistryDong, Jiajia; Krasnova, Larissa; Finn, M. G.; Sharpless, K. BarryAngewandte Chemie, International Edition (2014), 53 (36), 9430-9448CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of org. chemists as the most commonly used SVI electrophiles, and the parent sulfuryl chloride, O2SVICl2, also was relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the SVI-Cl bond is exceedingly sensitive to reductive collapse yielding SIV species and Cl-. Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2-F and SO2F2) leaves only the substitution pathway open. As with most of click chem., many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany. Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here the authors seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2=CH-SO2-F, the most perfect Michael acceptor ever found. To this history the authors add several new observations, including that the otherwise very stable gas SO2F2 has excellent reactivity under the right circumstances. Also proton or silicon centers can activate the exchange of S-F bonds for S-O bonds to make functional products, and the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chem. to small mols., polymers, and biomols. are discussed.
- 2(a) Narayanan, A.; Jones, L. H. Sulfonyl fluorides as privileged warheads in chemical biology. Chem. Sci. 2015, 6, 2650– 2659, DOI: 10.1039/C5SC00408J[Crossref], [PubMed], [CAS], Google Scholar.2ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVamurc%253D&md5=0009feb4068e912b4784fb8411cdb702Sulfonyl fluorides as privileged warheads in chemical biologyNarayanan, Arjun; Jones, Lyn H.Chemical Science (2015), 6 (5), 2650-2659CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Sulfonyl fluoride electrophiles have found significant utility as reactive probes in chem. biol. and mol. pharmacol. As warheads they possess the right balance of biocompatibility (including aq. stability) and protein reactivity. Their functionality is privileged in this regard as they are known to modify not only reactive serines (resulting in their common use as protease inhibitors), but also context-specific threonine, lysine, tyrosine, cysteine and histidine residues. This review describes the application of sulfonyl fluoride probes across various areas of research and explores new approaches that could further enhance the chem. biol. toolkit. We believe that sulfonyl fluoride probes will find greater utility in areas such as covalent enzyme inhibition, target identification and validation, and the mapping of enzyme binding sites, substrates and protein-protein interactions.(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, DOI: 10.1002/cbic.201200531[Crossref], [PubMed], [CAS], Google Scholar2bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlyqsLnP&md5=920f5f4b4b90924725c225d5166677a5Sulfonyl Fluoride Analogues as Activity-Based Probes for Serine ProteasesShannon, D. Alexander; Gu, Christian; McLaughlin, Christopher J.; Kaiser, Markus; van der Hoorn, Renier A. L.; Weerapana, EranthieChemBioChem (2012), 13 (16), 2327-2330, S2327/1-S2327/16CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)The tools of activity-based protein profiling (ABPP) have played a pervasive role in the functional characterization of enzymes within complex biol. systems. As the application of ABPP technologies becomes more widespread, there is a const. need for an ever-expanding library of activity-based probes (ABPs) of varying reactivity and specificity. ABPP methods are particularly important for the study of proteases, which are often subject to stringent post-translational regulation. Compared to the armory of ABPs available for cysteine proteases, ABPs for the serine protease family are poorly represented, mostly due to the lower reactivity of the serine nucleophile relative to its cysteine counterpart. Fluorophosphonate (FP) based ABPs are known to target serine proteases, together with the entire family of serine hydrolases that encompass approx. 1 % of the human genome. Although sulfonate esters have previously been used as carbon electrophiles in ABPs for targeting diverse enzyme classes, there are no previous reports on adapting sulfonyl fluorides into chem. probes for activity-based profiling. Converting AEBSF into an ABP requires the incorporation of a reporter group in the form of a fluorophore, biotin or a click-chem. handle to enable visualization and enrichment of active enzymes. Three modified versions of AEBSF were synthesized, including the rhodamine-tagged DS6R and the alkyne-functionalized DAS1 and DAS2. DS6R and DAS1 were synthesized using an amide coupling reaction to the primary amine of AEBSF, whereas DAS2 was obtained using a reductive amination reaction to incorporate the alkyne functionality. DAS1 was identified as a potent and activity-based covalent modifier of serine proteases and was used to continue characterization of protease labeling. Here, the application of sulfonyl fluorides as an activity-based probe that covalently modifies endogenous serine proteases and allows for gel-based anal. of protein activity, as well as enrichment and identification using mass spectrometry was demonstrated.
- 3Nielsen, 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, DOI: 10.1021/jacs.5b06307[ACS Full Text], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOlsL3N&md5=cf34a683cbf98730ac4a3e6b4e2cb211PyFluor: A Low-Cost, Stable, and Selective Deoxyfluorination ReagentNielsen, Matthew K.; Ugaz, Christian R.; Li, Wenping; Doyle, Abigail G.Journal of the American Chemical Society (2015), 137 (30), 9571-9574CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We report an inexpensive, thermally stable deoxyfluorination reagent that fluorinates a broad range of alcs. without substantial formation of elimination side products. This combination of selectivity, safety, and economic viability enables deoxyfluorination on preparatory scale. We employ the [18F]-labeled reagent in the first example of a no-carrier-added deoxy-radiofluorination.
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- 6(a) Xiao, X.; Zhou, F.; Jiang, J.; Chen, H.; Wang, L.; Chen, D.; 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, DOI: 10.1039/C7PY02042B[Crossref], [CAS], Google Scholar.6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVWgsL0%253D&md5=d2a3650940e65cd6a3d0b6083f8e1a93Highly efficient polymerization via sulfur(VI)-fluoride exchange (SuFEx): novel polysulfates bearing a pyrazoline-naphthylamide conjugated moiety and their electrical memory performanceXiao, Xiong; Zhou, Feng; Jiang, Jun; Chen, Haifeng; Wang, Lihua; Chen, Dongyun; Xu, Qingfeng; Lu, JianmeiPolymer Chemistry (2018), 9 (8), 1040-1044CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Two functional polysulfates (PolyTPP-NI and CPTPP-NI) bearing large conjugated chains were obtained via a sulfur(VI) fluoride click reaction in high yields under mild reaction conditions. The corresponding soln.-processed sandwiched memory devices exhibited stable 'flash' electron storage behavior.(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, DOI: 10.1002/anie.201811051[Crossref], [CAS], Google Scholar.6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFeisbvP&md5=11f6f9ff812ef469dd3965475c6c75cfFacile Synthesis of Sequence-Regulated Synthetic Polymers Using Orthogonal SuFEx and CuAAC Click ReactionsYang, Cangjie; Flynn, James P.; Niu, JiaAngewandte Chemie, International Edition (2018), 57 (49), 16194-16199CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The orthogonal sulfur-fluoride exchange reaction (SuFEx) and copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) are employed to synthesize sequence-regulated synthetic polymers. The high efficiency and broad tolerance of SuFEx and CuAAC to diverse chem. functionalities enable the one-pot synthesis of polydispersed sequence-controlled polymers by step-growth copolymn. in high yield and sequence complexity. Furthermore, iterative SuFEx and CuAAC coupling reactions on a solid support, without the need of protecting groups, afford monodispersed sequence-defined oligomers. The use of this orthogonal pair of click reactions provides new opportunities to facilely access sequence-regulated synthetic polymers with a high degree of structural diversity.(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, DOI: 10.1002/anie.201701160[Crossref], [CAS], Google Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFGqtr8%253D&md5=6c4ebff60dd24d634a4784a4cd76a88aSuFEx-Based Polysulfonate Formation from Ethenesulfonyl Fluoride-Amine AdductsWang, Hua; Zhou, Feng; Ren, Gerui; Zheng, Qinheng; Chen, Hongli; Gao, Bing; Klivansky, Liana; Liu, Yi; Wu, Bin; Xu, Qingfeng; Lu, Jianmei; Sharpless, K. Barry; Wu, PengAngewandte Chemie, International Edition (2017), 56 (37), 11203-11208CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The SuFEx-based polycondensation between bisalkylsulfonyl fluorides (AA monomers) and bisphenol bis(t-butyldimethylsilyl) ethers (BB monomers) using [Ph3P=N-PPh3]+[HF2]- as the catalyst is described. The AA monomers were prepd. via the highly reliable Michael addn. of ethenesulfonyl fluoride and amines/anilines while the BB monomers were obtained from silylation of bisphenols by t-butyldimethylsilyl chloride. With these reactions, a remarkable diversity of monomeric building blocks was achieved by exploiting readily available amines, anilines, and bisphenols as starting materials. The SuFEx-based polysulfonate formation reaction exhibited excellent efficiency and functional group tolerance, producing polysulfonates with a variety of side chain functionalities in >99 % conversion within 10 min to 1 h. When bearing an orthogonal group on the side chain, the polysulfonates can be further functionalized via click-chem.-based post-polymn. modification.
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Original "on-water" procedure, reported by Sharpless et al., was tested on model 1-octanesulfonyl chloride in the presence of phase transfer catalysts, some of which appeared to be beneficial for the reaction rate. Despite the high hydration energy of the fluoride ions, the catalytic system displayed numerous features typical for interfacial transportation of the nucleophilic species, being controlled by amt. and structure of the catalyst, lipophilicity of the catalyst's counterion, and rate of stirring. Besides for synthesis of acyl fluorides presence of 1 mol % of tetrabutylammonium chloride affected the selectivity of the reaction by minimizing formation of carboxylic acids and anhydrides. The presented results suggest that aq. solns. of bifluorides (or synthetically equiv. systems accessible by acidification of alkali metal fluoride solns.) can be efficient sources of the fluoride ions under two-phase conditions, provided that rate of the intrinsic reaction is sufficiently high. The methodol. supplements family of nucleophilic fluorinations, delivering a more reactive form of the solvated anions.(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, DOI: 10.1039/C5GC02755A[Crossref], [CAS], Google Scholar.8bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFKitbjL&md5=e0f69dbf83f4d896cfd7f3e63bc628fbCatalyst-free radical fluorination of sulfonyl hydrazides in waterTang, Lin; Yang, Yu; Wen, Lixian; Yang, Xingkun; Wang, ZhiyongGreen Chemistry (2016), 18 (5), 1224-1228CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The first catalyst-free fluorination of sulfonyl hydrazides for the synthesis of sulfonyl fluorides has been developed via a free-radical pathway. This protocol presents a broad substrate scope and does not require any metal catalyst and additive. All these transformations proceed smoothly in water under mild conditions, which enables a straightforward, practical, and environmentally benign fluorination for S-F bond formation.(c) Bianchi, T. A.; Cate, L. A. Phase Transfer Catalysis. Preparation of Aliphatic and Aromatic Sulfonyl Fluorides. J. Org. Chem. 1977, 42, 2031– 2032, DOI: 10.1021/jo00431a054[ACS Full Text.], [CAS], Google Scholar8chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXkt1Wlt7c%253D&md5=52fe4e02ff9bfa7a0f9996de0e2726fcPhase transfer catalysis. Preparation of aliphatic and aromatic sulfonyl fluoridesBianchi, Thomas A.; Cate, Laurence A.Journal of Organic Chemistry (1977), 42 (11), 2031-2CODEN: JOCEAH; ISSN:0022-3263.Stirring sulfonyl chloride with KF neat or in MeCN in the presence of a catalytic amt. of 18-crown-6 led to an exothermic reaction, which was complete within 4 h. The following RSO2F were prepd. (R, % yield given): Me, 84; PhCH2, 89; Ph, 92.5; p-MeC6H4, 100; p-BrC6H4 100; p-AcNHC6H4, 96; 5-(dimethylamino)-1-naphthyl, 100.(d) Davies, W.; Dick, J. H. CCLXXXVI.—Aromatic sulphonyl fluorides. A convenient method of preparation. J. Chem. Soc. 1931, 0, 2104– 2109, DOI: 10.1039/JR9310002104[Crossref], [CAS], Google Scholar8dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaA38XjslGj&md5=2d699b43e27c323832b4eca84475956dAromatic sulfonyl fluorides. A convenient method of preparationDavies, Wm.; Dick, John H.Journal of the Chemical Society (1931), (), 2104-9CODEN: JCSOA9; ISSN:0368-1769.Aromatic sulfonyl fluorides are obtained in 80-90% yield from the corresponding chloride by refluxing with an aq. soln. of a metal fluoride. KF is preferred. Snlfonyl fluorides are stable and very resistant toward hydrolysis by water or weak acids. They are sapond. easily by a caustic soln. The following derivs. are described-PhSO2F, b. 207°, nD20 1.4922; o-MeC6H4SO2F, b. 223-5°, n D20 1.5007; p-MeC6H4SO2F,m.41-2°; 1,3-dimethylbenzene-4-sulfonyl fluoride, b. 246°, nD20 1.5086; p-ClC6H4SO2F, m. 47-8°; 6-chloro-o-toluene-sulfonyl fluoride, m. 44-5°; 2-chloro-5-nitro-p-toluenesulfonyl fluoride, m. 84-5°; 1,3-dimethylbensene-4,6-disulfonyl fluoride, m. 116-8°; chlorbenzene-2,4-disulfonyl fluoride, m. 88-9°; 1,3-dichlorobenzene-4,6-disulfonylfluoride, m. 141-3 0; 1,3,5-trichloro-benzene-disulfonylfluoride, m. 109-10°; 1,3-dimethoxy-4,6-disulfonyl fluoride, m. 209-11°; benzene-1,3,5-trisulfonyl fluoride, m. 166-7°; clzlorobenzene-2,3,6-trisulfonyl fluoride, m. 179-81°; naphthalene-β-sulfonyl fluoride, m. 86-8°.
- 9Schmitt, A.-M. D.; Schmitt, D. C., Chapter 13. Synthesis of Sulfonamides. In RSC Drug Discovery Series , 2016; Vol. 2016, pp 123– 138.
- 10Brouwer, 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, DOI: 10.1016/j.tetlet.2009.02.130[Crossref], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtVemsL4%253D&md5=befb59564fccd946935a623643502a2bSynthesis of β-aminoethanesulfonyl fluorides or 2-substituted taurine sulfonyl fluorides as potential protease inhibitorsBrouwer, Arwin J.; Ceylan, Tarik; van der Linden, Tima; Liskamp, Rob M. J.Tetrahedron Letters (2009), 50 (26), 3391-3393CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)Substituted taurine sulfonyl fluorides derived from taurine or protected amino acids are conveniently synthesized from β-aminoethanesulfonyl chlorides using KF/18-crown-6 or from β-aminoethanesulfonates using DAST.
- 11Tribby, A. L.; Rodríguez, I.; Shariffudin, S.; Ball, N. D. Pd-Catalyzed Conversion of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and Selectfluor. J. Org. Chem. 2017, 82, 2294– 2299, DOI: 10.1021/acs.joc.7b00051[ACS Full Text], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsl2qtLw%253D&md5=e1169e2f4937ce3496fc24dc7d9de859Pd-Catalyzed Conversion of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and SelectfluorTribby, Ariana L.; Rodriguez, Ismerai; Shariffudin, Shamira; Ball, Nicholas D.Journal of Organic Chemistry (2017), 82 (4), 2294-2299CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A one-pot Pd-catalyzed conversion of aryl iodides to aryl sulfonyl fluorides using DABSO and Selectfluor has been developed generating aryl sulfonyl fluorides in good to excellent yields. The reaction results in the generation of electronically and sterically diverse sulfonyl fluorides. Addnl., sulfonyl fluorides can be converted to aryl sulfonamides and sulfonic esters using Cs2CO3 under mild conditions.
- 12Davies, 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, DOI: 10.1039/C6SC03924C[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1Cns7jL&md5=52ea294e24fed8236b40405aa0efe773One-pot palladium-catalyzed synthesis of sulfonyl fluorides from aryl bromidesDavies, Alyn T.; Curto, John M.; Bagley, Scott W.; Willis, Michael C.Chemical Science (2017), 8 (2), 1233-1237CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)A mild, efficient synthesis of sulfonyl fluorides from aryl and heteroaryl bromides utilizing palladium catalysis is described. The process involves the initial palladium-catalyzed sulfonylation of aryl bromides using DABSO as an SO2 source, followed by in situ treatment of the resultant sulfinate with the electrophilic fluorine source NFSI. This sequence represents the first general method for the sulfonylation of aryl bromides, and offers a practical, one-pot alternative to previously described synthesis of sulfonyl fluorides, allowing rapid access to these biol. important mols. Excellent functional group tolerance is demonstrated, with the transformation successfully achieved on a no. of active pharmaceutical ingredients, and their precursors. The prepn. of peptide-derived sulfonyl fluorides is also demonstrated.
- 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, DOI: 10.1016/j.tet.2014.02.013[Crossref], [CAS], Google Scholar.13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtl2mu7w%253D&md5=092527765be8ef5ec3a0833f4222b525Oxidation of disulfides with electrophilic halogenating reagents: concise methods for preparation of thiosulfonates and sulfonyl halidesKirihara, Masayuki; Naito, Sayuri; Nishimura, Yuki; Ishizuka, Yuki; Iwai, Toshiaki; Takeuchi, Haruka; Ogata, Tomomi; Hanai, Honoka; Kinoshita, Yukari; Kishida, Mari; Yamazaki, Kento; Noguchi, Takuya; Yamashoji, ShiroTetrahedron (2014), 70 (14), 2464-2471CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)The reaction of arom. or benzylic disulfides with 2.5 equiv of Selectfluor in acetonitrile/water (10:1) at room temp. efficiently produced the corresponding thiosulfonates. Conversely, the reaction of disulfides with 6.5 equiv of Selectfluor or thiosulfonates with 4.5 equiv of Selectfluor in refluxing acetonitrile/water (10:1) provided sulfonyl fluorides in high yields. Accufluor and FP-T300 are also effective in prepg. sulfonyl fluorides from disulfides under the similar reaction conditions. Sulfonyl chlorides or sulfonyl bromides were effectively obtained from the reaction of disulfides with 6 equiv of either N-chlorosuccinimide or N-bromosuccinimide in acetonitrile/water (10:1) at room temp. Some other electrophilic chlorinating or brominating reagents are also able to be used instead of N-chlorosuccinimide or N-bromosuccinimide for the syntheses of sulfonyl halides from disulfides. These reactions of disulfides with electrophilic halogenating reagents are convenient methods to prep. thiosulfonates and sulfonyl halides.(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, DOI: 10.1016/j.tetlet.2011.03.132[Crossref], [CAS], Google Scholar13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmtFartbc%253D&md5=bf547926fa17330252be7a4debf71030Oxidation of disulfides with Selectfluor: concise syntheses of thiosulfonates and sulfonyl fluoridesKirihara, Masayuki; Naito, Sayuri; Ishizuka, Yuki; Hanai, Honoka; Noguchi, TakuyaTetrahedron Letters (2011), 52 (24), 3086-3089CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)The reaction of arom. or benzylic disulfides with 2.5 equiv Selectfluor in MeCN/H2O (10:1) at room temp. efficiently produced the corresponding thiosulfonates. On the other hand, the reaction of disulfides with 6.5 equiv Selectfluor in refluxing MeCN/H2O (10:1) provided sulfonyl fluorides in high yields.
- 14
For other S-F bond forming transformations leading to SFx species, see:
(a) Pitts, C. R.; Bornemann, D.; Liebing, P.; Santschi, N.; Togni, A. Making the SF5 Group More Accessible: A Gas-Reagent-Free Approach to Aryl Tetrafluoro-λ 6-sulfanyl Chlorides. Angew. Chem., Int. Ed. 2019, 58, 1950– 1954, DOI: 10.1002/anie.201812356[Crossref], [CAS], Google Scholar.14ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVOmtr4%253D&md5=6289c01f81c3c86fbfe70d9bb02a31f0Making the SF5 Group More Accessible: A Gas-Reagent-Free Approach to Aryl Tetrafluoro-λ6-sulfanyl ChloridesPitts, Cody Ross; Bornemann, Dustin; Liebing, Phil; Santschi, Nico; Togni, AntonioAngewandte Chemie, International Edition (2019), 58 (7), 1950-1954CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of aryl tetrafluoro-λ6-sulfanyl chlorides R-X [R = Ph, 4-BzOC6H4, 5-Br-2-pyridyl, 5-Br-2-pyrimidinyl, etc.; X = SF4Cl] was synthesized via trifluoroacetic acid catalyzed gas-reagent-free oxidative polyfluorination of aryl disulfides. This approach overcame the reliance on hazardous fluorinating reagents and/or gas reagents (e.g. Cl2) by employing easy-to-handle trichloroisocyanuric acid, potassium fluoride and catalytic amts. of acid. Furthermore, the same approach provided an access to compds. R-X [X = SF3, SF5, SeF3] which extended the applications of this chem. beyond arene SF5-functionalization and demonstrated its ability to address a more general oxidative fluorination problem.(b) Umemoto, T.; Garrick, L. M.; Saito, N. Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry. Beilstein J. Org. Chem. 2012, 8, 461– 471, DOI: 10.3762/bjoc.8.53[Crossref], [PubMed], [CAS], Google Scholar.14bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtVOksL4%253D&md5=2ffe7ebd3c0ad76b5ffa307ce35c2f6dDiscovery of practical production processes for arylsulfur pentafluorides and their higher homologs, bis- and tris-(sulfur pentafluorides): beginning of a new era of super-trifluoromethyl arene chemistry and its industryUmemoto, Teruo; Garrick, Lloyd M.; Saito, NorimichiBeilstein Journal of Organic Chemistry (2012), 8 (), 461-471, No. 53CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)Various arylsulfur pentafluorides, ArSF5, have long been desired in both academic and industrial areas and ArSF5 compds. have attracted considerable interest in many areas such as medicine, agrochems., and other new materials, since the highly stable SF5 group is considered a super-trifluoromethyl group due to its significantly higher electronegativity and lipophilicity. This article describes the first practical method for the prodn. of various arylsulfur pentafluorides and their higher homologs, bis- and tris-(sulfur pentafluorides), from the corresponding diaryl disulfides or aryl thiols. The method consists of two steps: (step 1) treatment of a diaryl disulfide or an aryl thiol with chlorine in the presence of an alkali metal fluoride and (step 2) treatment of the resulting arylsulfur chlorotetrafluoride with a fluoride source, such as zinc fluoride (ZnF2), hydrofluoric acid (HF) and antimony fluorides, Sb(III/V) fluorides. The intermediate arylsulfur chlorotetrafluoride derivs. were isolated by distn. or recrystn. and characterized. The aspects of these new reactions are revealed and reaction mechanisms are discussed. As the method offers considerable improvement over previous methods in cost, yield, practicality, applicability and large-scale prodn., the new processes described here can be employed as the first practical method for the economical prodn. of various arylsulfur pentafluorides and their higher homologs, which could then open up a new era of super-trifluoromethyl arene chem. and its applications in many areas. A reaction (chlorine/potassium fluoride) of bis(2,3,6-trifluorophenyl)disulfide (I) gave trans-chlorotetrafluoro(2,3,6-trifluorophenyl)sulfur (II) and cis-chlorotetrafluoro(2,3,6-trifluorophenyl)sulfur (III). The synthesis of the target compd. was achieve by the treatment of II, III with fluorination agents, to provide, e.g., pentafluoro(2,3,6-trifluorophenyl)sulfur (IV).(c) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. Discovery of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride as a deoxofluorinating agent with high thermal stability as well as unusual resistance to aqueous hydrolysis, and its diverse fluorination capabilities including deoxofluoro-arylsulfinylation with high stereoselectivity. J. Am. Chem. Soc. 2010, 132, 18199– 18205, DOI: 10.1021/ja106343h[ACS Full Text], [CAS], Google Scholar14chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFShtb%252FL&md5=4f22dec27588a85d444e16494040d091Discovery of 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride as a Deoxofluorinating Agent with High Thermal Stability as Well as Unusual Resistance to Aqueous Hydrolysis, and Its Diverse Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation with High StereoselectivityUmemoto, Teruo; Singh, Rajendra P.; Xu, Yong; Saito, NorimichiJournal of the American Chemical Society (2010), 132 (51), 18199-18205CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compds. have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into mols. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, I), as a cryst. solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogs. The roles of substituents on I in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addn. to fluorinations of alcs., aldehydes, and enolizable ketones, I smoothly converts non-enolizable carbonyls to CF2 groups, and carboxylic groups to CF3 groups, in high yields. I also converts C(=S) and CH3SC(=S)O groups to CF2 and CF3O groups, resp., in high yields. In addn., I effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcs. to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of I in addn. to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas. - 15Laudadio, G.; Barmpoutsis, E.; Schotten, C.; Struik, L.; Govaerts, S.; Browne, D. L.; Noël, T. Sulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and Thiols. J. Am. Chem. Soc. 2019, 141, 5664– 5668, DOI: 10.1021/jacs.9b02266[ACS Full Text], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXlvVSlurk%253D&md5=cd1ac810b9106f662c0c13bc780034fcSulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and ThiolsLaudadio, Gabriele; Barmpoutsis, Efstathios; Schotten, Christiane; Struik, Lisa; Govaerts, Sebastian; Browne, Duncan L.; Noel, TimothyJournal of the American Chemical Society (2019), 141 (14), 5664-5668CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Sulfonamides are key motifs in pharmaceuticals and agrochems., spurring the continuous development of novel and efficient synthetic methods to access these functional groups. Herein, the authors report an environmentally benign electrochem. method which enables the oxidative coupling between thiols and amines, two readily available and inexpensive commodity chems. The transformation is completely driven by electricity, does not require any sacrificial reagent or addnl. catalysts and can be carried out in only 5 min. Hydrogen is formed as a benign byproduct at the counter electrode. Owing to the mild reaction conditions, the reaction displays a broad substrate scope and functional group compatibility.
- 16(a) Tang, S.; Liu, Y.; Lei, A. Electrochemical Oxidative Cross-coupling with Hydrogen Evolution: A Green and Sustainable Way for Bond Formation. Chem. 2018, 4, 27– 45, DOI: 10.1016/j.chempr.2017.10.001[Crossref], [CAS], Google Scholar.16ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFyitQ%253D%253D&md5=b49dcf3ad4701e118761fd12dcba7dbcElectrochemical Oxidative Cross-coupling with Hydrogen Evolution: A Green and Sustainable Way for Bond FormationTang, Shan; Liu, Yichang; Lei, AiwenChem (2018), 4 (1), 27-45CODEN: CHEMVE; ISSN:2451-9294. (Cell Press)A review. Oxidative R1-H/R2-H cross-coupling represents an ideal way for the construction of new chem. bonds. However, the bond formation with loss of H2 is typically thermodynamically unfavorable and thus usually requires an external driving force, namely, an appropriate sacrificial oxidant. Recent advances have revealed that oxidative R1-H/R2-H cross-coupling with hydrogen gas evolution can be achieved through electrochem. anodic oxidn. and concomitant cathodic proton redn. Electrochem. provides new opportunities for the construction of carbon-carbon and carbon-heteroatom bonds in an environmentally friendly manner. This review article gives an overview of the recent developments in this emerging field.(b) Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Electrifying Organic Synthesis. Angew. Chem., Int. Ed. 2018, 57, 5594– 5619, DOI: 10.1002/anie.201711060[Crossref], [CAS], Google Scholar.16bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvVygsbk%253D&md5=281b9f17c8fa7e0759fa9edf6497cbf7Electrifying Organic SynthesisWiebe, Anton; Gieshoff, Tile; Moehle, Sabine; Rodrigo, Eduardo; Zirbes, Michael; Waldvogel, Siegfried R.Angewandte Chemie, International Edition (2018), 57 (20), 5594-5619CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The direct synthetic org. use of electricity is currently experiencing a renaissance. More synthetically oriented labs. working in this area are exploiting both novel and more traditional concepts, paving the way to broader applications of this niche technol. As only electrons serve as reagents, the generation of reagent waste is efficiently avoided. Moreover, stoichiometric reagents can be regenerated and allow a transformation to be conducted in an electrocatalytic fashion. However, the application of electroorg. transformations is more than minimizing the waste footprint, it rather gives rise to inherently safe processes, reduces the no. of steps of many syntheses, allows for milder reaction conditions, provides alternative means to access desired structural entities, and creates intellectual property (IP) space. When the electricity originates from renewable resources, this surplus might be directly employed as a terminal oxidizing or reducing agent, providing an ultra-sustainable and therefore highly attractive technique. This Review surveys recent developments in electrochem. synthesis that will influence the future of this area.(c) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230– 13319, DOI: 10.1021/acs.chemrev.7b00397[ACS Full Text], [CAS], Google Scholar16chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1WntbzJ&md5=21205e55da92db4e7d27aa393fed486dSynthetic Organic Electrochemical Methods Since 2000: On the Verge of a RenaissanceYan, Ming; Kawamata, Yu; Baran, Phil S.Chemical Reviews (Washington, DC, United States) (2017), 117 (21), 13230-13319CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review discusses advances in synthetic org. electrochem. since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorg. chem.
- 17Pupo, G.; Vicini, A. C.; Ascough, D. M. H.; Ibba, F.; Christensen, K. E.; Thompson, A. L.; Brown, J. M.; Paton, R. S.; Gouverneur, V. Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of β-Fluoroamines. J. Am. Chem. Soc. 2019, 141, 2878– 2883, DOI: 10.1021/jacs.8b12568[ACS Full Text], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFKjsrk%253D&md5=21f8a83ea06b38c0147f32504b42993aHydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of β-FluoroaminesPupo, Gabriele; Vicini, Anna Chiara; Ascough, David M. H.; Ibba, Francesco; Christensen, Kirsten E.; Thompson, Amber L.; Brown, John M.; Paton, Robert S.; Gouverneur, VeroniqueJournal of the American Chemical Society (2019), 141 (7), 2878-2883CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor soly. in org. solvents coupled with limited strategies to control its reactivity has discouraged its use for asym. C-F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable β-fluoroamines in high yields and enantioselectivities. This methodol. employs a chiral N-Et bis-urea catalyst that brings solid KF into soln. as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.
- 18Francke, R.; Little, R. D. Redox catalysis in organic electrosynthesis: basic principles and recent developments. Chem. Soc. Rev. 2014, 43, 2492, DOI: 10.1039/c3cs60464k[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXks12hs70%253D&md5=4ea6098c0c8f7893463ad3a2d6400146Redox catalysis in organic electrosynthesis: basic principles and recent developmentsFrancke, Robert; Little, R. DanielChemical Society Reviews (2014), 43 (8), 2492-2521CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Electroorg. synthesis has become an established, useful, and environmentally benign alternative to classic org. synthesis for the oxidn. or the redn. of org. compds. In this context, the use of redox mediators to achieve indirect processes is attaining increased significance, since it offers many advantages compared to a direct electrolysis. Kinetic inhibitions that are assocd. with the electron transfer at the electrode/electrolyte interface, for example, can be eliminated and higher or totally different selectivity can be achieved. In many cases, a mediated electron transfer can occur against a potential gradient, meaning that lower potentials are needed, reducing the probability of undesired side-reactions. The use of electron transfer mediators can help to avoid electrode passivation resulting from polymer film formation on the electrode surface. Although the principle of indirect electrolysis was established many years ago, new, exciting and useful developments continue to be made. In recent years, several new types of redox mediators were designed and examd., a process that can be accomplished more efficiently and purposefully using modern computational tools. New protocols including, the development of double mediatory systems in biphasic media, enantioselective mediation and heterogeneous electrocatalysis using immobilized mediators were established. Also, the understanding of mediated electron transfer reaction mechanisms has advanced. This review describes progress in the field of electroorg. synthesis and summarizes recent advances.
- 19Laudadio, G.; Straathof, N. J. W.; Lanting, M. D.; Knoops, B.; Hessel, V.; Noël, T. An environmentally benign and selective electrochemical oxidation of sulfides and thiols in a continuous-flow microreactor. Green Chem. 2017, 19, 4061– 4066, DOI: 10.1039/C7GC01973D[Crossref], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1yhsLzN&md5=57ef1fce4fb40199d4d4855d09b18b18An environmentally benign and selective electrochemical oxidation of sulfides and thiols in a continuous-flow microreactorLaudadio, Gabriele; Straathof, Natan J. W.; Lanting, Menno D.; Knoops, Benny; Hessel, Volker; Noel, TimothyGreen Chemistry (2017), 19 (17), 4061-4066CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A practical and environmentally benign electrochem. oxidn. of thioethers and thiols in a com.-available continuous-flow microreactor is presented. Water is used as the source of oxygen to enable the oxidn. process. The oxidn. reaction utilizes the same reagents in all scenarios and the selectivity is solely governed by the applied potential. The procedure exhibits a broad scope and good functional group compatibility providing access to various sulfoxides (15 examples), sulfones (15 examples) and disulfides (6 examples). The use of continuous flow allows the optimal reaction parameters (e.g. residence time, applied voltage) to be rapidly assessed, to avoid mass- and heat-transfer limitations and to scale the electrochem.
- 20Laudadio, G.; De Smet, Wouter; Struik, L.; Cao, Y.; Noël, T. Design and application of a modular and scalable electrochemical flow microreactor. J. Flow Chem. 2018, 8, 157– 165, DOI: 10.1007/s41981-018-0024-3[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FgtVyruw%253D%253D&md5=7dcf96d2947ce35267aff4856194dd8eDesign and application of a modular and scalable electrochemical flow microreactorLaudadio Gabriele; de Smet Wouter; Struik Lisa; Cao Yiran; Noel TimothyJournal of flow chemistry (2018), 8 (3), 157-165 ISSN:2062-249X.Electrochemistry constitutes a mild, green and versatile activation method of organic molecules. Despite these innate advantages, its widespread use in organic chemistry has been hampered due to technical limitations, such as mass and heat transfer limitations which restraints the scalability of electrochemical methods. Herein, we describe an undivided-cell electrochemical flow reactor with a flexible reactor volume. This enables its use in two different modes, which are highly relevant for flow chemistry applications, including a serial (volume ranging from 88 μL/channel up to 704 μL) or a parallel mode (numbering-up). The electrochemical flow reactor was subsequently assessed in two synthetic transformations, which confirms its versatility and scale-up potential.
- 21(a) Pletcher, D.; Green, R. A.; Brown, R. C. D. Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory. Chem. Rev. 2018, 118, 4573– 4591, DOI: 10.1021/acs.chemrev.7b00360[ACS Full Text.], [CAS], Google Scholar21ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2qtrnN&md5=28e56b67959db2e57b7a597a56046014Flow Electrolysis Cells for the Synthetic Organic Chemistry LaboratoryPletcher, Derek; Green, Robert A.; Brown, Richard C. D.Chemical Reviews (Washington, DC, United States) (2018), 118 (9), 4573-4591CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review focuses on the use of flow electrolysis cells in synthetic org. chem. lab. Electrolysis is participating in the trend toward continuous flow synthesis, and this has led to a no. of innovations in flow cell design that make possible selective syntheses with high conversion of reactant to product with a single passage of the reactant soln. through the cell. In addn., the needs of the synthetic org. chemist can often be met by flow cells operating with recycle of the reactant soln. These cells give a high rate of product formation while the reactant concn. is high, but they perform best at low conversion. Both approaches are considered in this review and the important features of each cell design are discussed. Throughout, the application of the cell designs is illustrated with syntheses that have been reported.(b) Atobe, M.; Tateno, H.; Matsumura, Y. Applications of Flow Microreactors in Electrosynthetic Processes. Chem. Rev. 2018, 118, 4541– 4572, DOI: 10.1021/acs.chemrev.7b00353[ACS Full Text.], [CAS], Google Scholar21bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVGhsr3L&md5=1d6ad45773080253daf39d3cc852d899Applications of Flow Microreactors in Electrosynthetic ProcessesAtobe, Mahito; Tateno, Hiroyuki; Matsumura, YoshimasaChemical Reviews (Washington, DC, United States) (2018), 118 (9), 4541-4572CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The fundamental advantages and potential benefits of flow microreactor technol. include extremely large surface-to-vol. ratios, precise control over temp. and residence time, extremely fast mol. diffusion, and increased safety during reactive processes. These advantages and benefits can be applied to a wide range of electrosynthetic techniques, and so the integration of flow microreactors with electrosynthesis has received significant research interest from both academia and industry. This review presents an up-to-date overview of electrosynthetic processes in continuous-flow microreactors. The advantages of continuous-flow electrochem. are discussed, along with a thorough comparison of microreactor-based processes and conventional batch reaction systems.(c) Mitsudo, K.; Kurimoto, Y.; Yoshioka, K.; Suga, S. Miniaturization and Combinatorial Approach in Organic Electrochemistry. Chem. Rev. 2018, 118, 5985– 5999, DOI: 10.1021/acs.chemrev.7b00532[ACS Full Text.], [CAS], Google Scholar21chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVSltbfE&md5=0b69cc90f54fc6a22b44af864c693410Miniaturization and Combinatorial Approach in Organic ElectrochemistryMitsudo, Koichi; Kurimoto, Yuji; Yoshioka, Kazuki; Suga, SeijiChemical Reviews (Washington, DC, United States) (2018), 118 (12), 5985-5999CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Recent advances in electro-org. chem. involving miniaturization, integration, and combinatorial chem. were reviewed. Microelectrode array technol. for site-selective electro-org. reactions and addressable libraries provides a direct and unlabeled method for measuring small-mol.-protein interactions. Electrochem. systems using solid-supported bases and acids ("site sepn.") can realize electrolysis without the addn. of supporting electrolytes. Well-designed "bipolar electrodes" have enabled the prodn. of patterned gradient polymer brushes and microfibers. For the display of combinatorial org. electrochem., batch and flow electrolysis systems for the optimization and screening of electro-org. reactions as well as the building of chem. libraries for org. compds. are described.(d) Folgueiras-Amador, A. A.; Wirth, T. Perspectives in flow electrochemistry. J. Flow Chem. 2017, 7, 94– 95, DOI: 10.1556/1846.2017.00020[Crossref], [CAS], Google Scholar21dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygur4%253D&md5=66dde9936f79a9f20e0c8f40c311f659Perspectives in flow electrochemistryFolgueiras-Amador, Ana A.; Wirth, ThomasJournal of Flow Chemistry (2017), 7 (3-4), 94-95CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Electrosynthesis is an old method currently moving again in the focus of org. synthesis. Some limitations of conventional electrosynthesis can be overcome by the use of electrochem. flow devices. This perspective indicates where the pitfalls, where the advantages and where the challenges are in implementing flow electrosynthesis as an alternative tool for the synthetic chemist.
- 22Lam, K.; Geiger, W. E. Anodic oxidation of disulfides: Detection and reactions of disulfide radical cations. J. Org. Chem. 2013, 78, 8020– 8027, DOI: 10.1021/jo401263z[ACS Full Text], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFSisLzK&md5=b48c807b1ef18cae57a9c18c6fd4354eAnodic Oxidation of Disulfides: Detection and Reactions of Disulfide Radical CationsLam, Kevin; Geiger, William E.Journal of Organic Chemistry (2013), 78 (16), 8020-8027CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The anodic oxidn. of five diaryldisulfides were studied in a dichloromethane/[NBu4][B(C6F5)4] electrolyte. Cyclic voltammetry scans of (p-RC6H4)2S2 (R = Me, 1a; R = F, 1b; R = OMe, 1c) show modest chem. reversibility for the 10/+ couple (E1/2 values vs. ferrocene: 1.04 V for 1a, 1.21 V for 1b, 0.92 V for 1c), providing the 1st voltammetric evidence for the radical cation [Ar2S2]+. A dimer dication, [Ar4S4]2+, is proposed as an intermediate in the formation of the electrolysis product, the trisulfide [Ar3S3]+. The chem. reversibility of the 1-electron oxidns. of Ar2S2 vanishes in [PF6]--contg. electrolytes. The radical cations of the more sterically constrained ortho-substituted analogs dimesityldisulfide (2a, E1/2 = 1.01 V) and bis(2,4,6-triisopropylphenyl)disulfide (2b, E1/2 = 0.98 V) show less tendency to dimerize. In all cases except 2b, the bulk electrolysis product is [R3S3]+, consistent with earlier literature reports. A mechanism is proposed in which the trisulfide is formed by reaction of the dimer dication [Ar4S4]2+ with neutral Ar2S2 to afford the trisulfide in a net 2/3 e- process. Oxidn. of Ar2S2, either anodically or by a strong 1-electron oxidant, in the presence of cyclohexene gives an efficient synthetic route to 1,2-substituted cyclohexyldisulfides.
- 23Huba, F.; Yeager, E. B.; Olah, G. A. The formation and role of carbocations in electrolytic fluorination using hydrogen fluoride electrolytes in a nafion membrane-divided Teflon cell. Electrochim. Acta 1979, 24, 489– 494, DOI: 10.1016/0013-4686(79)85021-5[Crossref], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXitFOrtA%253D%253D&md5=7441cd885d2a6813750f0efc06e17d48The formation and role of carbocations in electrolytic fluorination using hydrogen fluoride electrolytes in a Nafion membrane-divided teflon cellHuba, Francis; Yeager, Ernest B.; Olah, George A.Electrochimica Acta (1979), 24 (5), 489-94CODEN: ELCAAV; ISSN:0013-4686.The electrofluorination of mixts of EtCO2H, EtCO2COEt, or Me2CHCH2Cl with PhMe in HF(l) contg. 2% KF was examd. in a cell fitted with a Nafion cation-exchange membrane anode compartment-cathode compartment divider. The carbocations generated in the anode cell crossed the membrane and were quenched in the cathode cell by the org. mols. Products due to Freidel-Crafts substitution, isomerization, and polymn. were identified. The electrolysis of HF-pyridine complex was also examd. and little fluorination of the pyridine was obsd. Neither direct nor ionic fluorination occurred although the conditions are suitable for both mechanisms.
- 24Seel, F.; Budenz, R.; Flaccus, R. D.; Staab, R. Zur frage der existenz des phenylschwefelmonofluorids und seines chemischen verhaltens. J. Fluorine Chem. 1978, 12, 437– 438, DOI: 10.1016/S0022-1139(00)82986-3[Crossref], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXlsVKjuw%253D%253D&md5=09f8a72c47696491c88ca4afb5aa1c81Existence of phenylsulfur monofluoride and its chemical behaviorSeel, F.; Budenz, R.; Flaccus, R. D.; Staab, R.Journal of Fluorine Chemistry (1978), 12 (5), 437-8CODEN: JFLCAR; ISSN:0022-1139.Treatment of PhSSPh with SF4 (l) in a Ni or teflon reactor gave intermediate PhSF which cyclized to give thianthrene. The existence of PhSF was confirmed by 19F NMR.
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