sulfur(VI) Fluoride Exchange Research Articles

Novel Approaches to Access Arylfluorosulfates and Sulfamoyl Fluorides Based on Sulfur (VI) Fluoride Exchange.

Sulfur (VI) fluoride exchange (SuFEx) is a new family of click chemistry reactions that relies on readily available sulfuryl fluoride (SO2 F2 ) and ethenesulfonyl fluoride to build diverse chemical structures bearing the SVI -F motif, such as fluorosulfate (-OSO2 F) and sulfonyl fluoride (-SO2 F). These motifs could be useful functional groups and connective linkers in organic synthesis. This unit describes two protocols for performing SuFEx. The first protocol describes an in situ method for rapid generation of arylfluorosulfates in 96-well plates for high-throughput screening. The second protocol outlines use of a shelf-stable fluorosulfuryl imidazolium salt for generating arylfluorosulfates and sulfamoyl fluorides. © 2019 by John Wiley & Sons, Inc.

SuFEx in Metal-Organic Frameworks: Versatile Postsynthetic Modification Tool.

A new type of click reaction, sulfur(VI) fluoride exchange (SuFEx), has been utilized to prepare five postsynthetically modified UiO-67 series metal-organic frameworks (MOFs). The postsynthetic modification (PSM) via SuFEx can be achieved selectively for the sulfonyl fluoride (R-SO2F) without degrading the MOF structure as confirmed by X-ray crystallographic analysis. The present SuFEx method provides a straightforward tool for introducing new functionality inside MOFs. Introduction of an imidazolium group into the MOF afforded a heterogeneous catalyst for the benzoin condensation reaction.

Autocatalytic Synthesis of Bifluoride Ionic Liquids by SuFEx Click Chemistry

AbstractIonic liquids with bifluoride anions possess properties such as high conductivity, wide electrochemical windows, and low viscosity that make them attractive materials for various electrochemical devices. However, owing to the lack of reliable synthetic routes, bifluoride‐based ionic liquids have seldom been explored. Herein, an autocatalytic strategy for the HF‐free synthesis of bifluoride‐based sulfonamide ionic liquids based on the sulfur(VI) fluoride exchange (SuFEx) reaction is reported. This reaction requires no chromatographic purification, and yields are quantitative. The thermophysical properties (phase transition behavior and decomposition temperature) and electrochemical stabilities of the resulting products were studied. The products with alkyl, aryl, and perfluoroalkyl side chains exhibited extraordinarily wide electrochemical windows (up to 6.0 V) with reproducible results among multiple replicate measurements.

Autocatalytic Synthesis of Bifluoride Ionic Liquids by SuFEx Click Chemistry.

Ionic liquids with bifluoride anions possess properties such as high conductivity, wide electrochemical windows, and low viscosity that make them attractive materials for various electrochemical devices. However, owing to the lack of reliable synthetic routes, bifluoride-based ionic liquids have seldom been explored. Herein, an autocatalytic strategy for the HF-free synthesis of bifluoride-based sulfonamide ionic liquids based on the sulfur(VI) fluoride exchange (SuFEx) reaction is reported. This reaction requires no chromatographic purification, and yields are quantitative. The thermophysical properties (phase transition behavior and decomposition temperature) and electrochemical stabilities of the resulting products were studied. The products with alkyl, aryl, and perfluoroalkyl side chains exhibited extraordinarily wide electrochemical windows (up to 6.0 V) with reproducible results among multiple replicate measurements.

3+2] Cycloaddition of an Azomethyne Ylide and Vinyl Sulfonyl Fluorides ― an Approach to Pyrrolidine‐3‐sulfonyl Fluorides

[3+2] Cycloaddition reactions of vinyl sulfonyl fluorides with an in‐situ generated nonstabilized azomethine ylide is described for the first time. The resulting pyrrolidine‐3‐sulfonyl fluorides were obtained in 50–83 % yield on a scale of up to 25 g. Their utility as reagents for sulfur(VI)–fluoride exchange (SuFEx) and some other transformations was also demonstrated.

Sulfur (VI) Fluoride Exchange Polymerization for Large Conjugate Chromophores and Functional Main-Chain Polysulfates with Nonvolatile Memory Performance.

Sulfur (VI) fluoride exchange (SuFEx) reactions can be applied not only in organic click synthesis, but also in the preparation of functional main-chain polymers. In this work, four functional main-chain polysulfates (PNT-PS, NPNT-PS, PHF-PS, and TPE-PS) are synthesized in high yield using the SuFEx reaction at room temperature. The polysulfates exhibit satisfactory thermal stability and solution processability. They are used as the active layer for memory devices (ITO/PNT-PS/Al, ITO/NPNT-PS/Al, ITO/PHF-PS/Al, and ITO/TPE-PS/Al). I-V measurements show that ITO/PNT-PS/Al and ITO/NPNT-PS/Al exhibit stable flash-memory (write-read-erase) behavior, while ITO/PHF-PS/Al and ITO/TPE-PS/Al exhibit WORM (write once read many) behavior. Our studies provide a feasible and efficient synthetic methodology for the preparation of new memory materials.

SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization.

Sulfur(VI) Fluoride Exchange (SuFEx) is a new family of click chemistry transformations which relies on readily available materials to produce compounds bearing the SVI-F motif. The potential of SuFEx in drug discovery has just started to be explored. We report the first method of SuFEx chemistry for the conversion of phenolic compounds to their respective arylfluorosulfate derivatives in situ in 96-well plates. This method is compatible with automated synthesis and screening to quickly assess the biological activities of the in situ generated, crude products. Using this method, we perform late-stage functionalization of a panel of known anticancer drugs to generate the corresponding arylfluorosulfates. These in situ generated arylfluorosulfates are directly tested in a cancer-cell growth inhibition assay in parallel with their phenolic precursors. We discover three arylfluorosulfates that exhibit improved anticancer cell proliferation activities compared to their phenol precursors. Among these three compounds, the fluorosulfate derivative of Fulvestrant possesses significantly enhanced activity to down-regulate estrogen receptor (ER) expression in ER+ breast cancer cell line MCF-7 and the fluorosulfate derivative of Combretastatin A4-a general anticancer drug currently being evaluated under clinical trials-exhibits a 70-fold increase in potency in the drug resistant colon cancer cell line HT-29.

SuFEx Postpolymerization Modification Kinetics and Reactivity in Polymer Brushes

Since its introduction in 2014, the sulfur(VI) fluoride exchange (SuFEx) reaction has emerged as a promising new reaction in the field of polymer chemistry, in both polymerization of diverse polymer backbones and postpolymerization modification (PPM). Previously, we successfully reported the use of SuFEx chemistry as a method for surface derivatization through the PPM of sulfonyl fluoride containing polymer brushes. However, with the diversity of conditions, substrate scope, and catalyst selection afforded by this reaction, it is advantageous to expand the use of SuFEx for PPM on polymer brushes to discern the advantages and limitations of this reaction in surface conjugation. In this work, we used three different polymer brush systems—alkyl sulfonyl fluorides, aromatic sulfonyl fluorides, and aromatic fluorosulfonates—and each was reacted with three different silyl ether derivatives (aryl, alkyl, and benzyl). Each of these reactions was subjected to different catalysts, and herein, we present rates, cond...

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies.

Extremely potent, new hepatitis C virus (HCV) nonstructural 5A (NS5A) featuring substituted biaryl sulfate core structures was designed and synthesized. Based on the previously reported novel HCV NS5A inhibitors featuring biaryl sulfate core structures which exhibit two-digit picomolar half-maximal effective concentration (EC50) values against HCV genotype 1b and 2a, the new inhibitors equipped with the sulfate core structures containing diversely substituted aryl groups were explored. In this study, highly efficient, chemoselective coupling reactions between an arylsulfonyl fluoride and an aryl silyl ether, known as the sulfur(vi) fluoride exchange (SuFEx) reaction, were utilized. Among the inhibitors prepared based on the SuFEx chemistry, compounds 14, 15 and 29 exhibited two-digit picomolar EC50 values against GT-1b and single digit or sub nanomolar activities against the HCV GT-2a strain. Nonsymmetrical inhibitors containing an imidazole and amide moieties on each side of the sulfate core structures were also synthesized. In addition, a biotinylated probe targeting NS5A protein was prepared for labeling using the same synthetic methodology.

Synthesis of novel 1,2,4-thiadiazinane 1,1-dioxides via three component SuFEx type reaction.

Herein, we report the preparation of 1,2,4-thiadiazinane 1,1-dioxides from reaction of β-aminoethane sulfonamides with dichloromethane, dibromomethane and formaldehyde as methylene donors. The β-aminoethane sulfonamides were obtained through sequential Michael addition of amines to α,β-unsaturated ethenesulfonyl fluorides followed by further DBU mediated sulfur(vi) fluoride exchange (SuFEx) reaction with amines at the S–F bond.

Combining Click Sulfur(VI)-Fluoride Exchange with Photoiniferters: A Facile, Fast, and Efficient Strategy for Postpolymerization Modification.

"Click" type reactions represent the currently most prevalent postpolymerization strategy for the preparation of functional polymeric materials. Herein, a novel photoiniferter agent 4-(fluorosulfonyl)benzyl diethylcarbamodithioate (FSB-DECT) containing both dithiocarbamates and sulfonyl fluoride moieties is developed to act as both photoinitiator and click sulfur(VI)-fluoride exchange (SuFEx) agent. The photopolymerization behavior of FSB-DECT is demonstrated via standard photoiniferter-mediated polymerization for various types of monomer including N-isopropylacrylamide (NIPAAm), glycidyl methacrylate, and vinyl acetate (VAc). Gel permeation chromatography data show that the polymerization is relatively well controlled, with polydispersity indices of the product homopolymers in the range of 1.3-1.6. 1 H and 19 F NMR spectra and "reinitiated" photopolymerization indicate that the sulfonyl fluoride and diethyldithiocarbamyl groups remain at the respective ends of the homopolymer chains. Furthermore, using the sulfonyl fluoride end-functionalized poly(N-isopropylacrylamide) as a model polymer, the utility of the SuFEx reaction for efficient postpolymerization functionalization is demonstrated.

New route to polysulfates, polysulfonates

Polysulfates and polysulfonates are exceptionally tough and impact resistant, making them useful engineering polymers. But they’ve rarely been used industrially because the chloride substitution chemistry often used to make carbon sulfate and carbon sulfonate links suffers from side reactions and is commercially impractical. Researchers now report that bifluoride salts are efficient and cost-effective catalysts for the synthesis of these tough materials (Nat. Chem. 2017, DOI: 10.1038/nchem.2796). The new chemistry, developed by K. Barry Sharpless and Peng Wu of Scripps Research Institute California, Jiajia Dong of the Shanghai Institute of Organic Chemistry, and coworkers, could potentially be scaled up to industrial levels. The new reaction is an extension of sulfur(VI) fluoride exchange (SuFEx), a click chemistry technique Sharpless and coworkers developed previously (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201309399). The group initially used SuFEx, catalyzed by strongly basic “organosuperbases,”...

Bifluoride-catalysed sulfur(VI) fluoride exchange reaction for the synthesis of polysulfates and polysulfonates.

Polysulfates and polysulfonates possess exceptional mechanical properties making them potentially valuable engineering polymers. However, they have been little explored due to a lack of reliable synthetic access. Here we report bifluoride salts (Q+[FHF]-, where Q+ represents a wide range of cations) as powerful catalysts for the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl silyl ethers and aryl fluorosulfates (or alkyl sulfonyl fluorides). The bifluoride salts are significantly more active in catalysing the SuFEx reaction compared to organosuperbases, therefore enabling much lower catalyst-loading (down to 0.05 mol%). Using this chemistry, we are able to prepare polysulfates and polysulfonates with high molecular weight, narrow polydispersity and excellent functional group tolerance. The process is practical with regard to the reduced cost of catalyst, polymer purification and by-product recycling. We have also observed that the process is not sensitive to scale-up, which is essential for its future translation from laboratory research to industrial applications.

Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI) Fluoride Exchange Connections of Diverse Modules Launched From An SOF4 Hub.

Sulfur(VI) fluoride exchange (SuFEx) is a new family of click chemistry based transformations that enable the synthesis of covalently linked modules via SVI hubs. Here we report thionyl tetrafluoride (SOF4 ) as the first multidimensional SuFEx connector. SOF4 sits between the commercially mass-produced gases SF6 and SO2 F2 , and like them, is readily synthesized on scale. Under SuFEx catalysis conditions, SOF4 reliably seeks out primary amino groups [R-NH2 ] and becomes permanently anchored via a tetrahedral iminosulfur(VI) link: R-N=(O=)S(F)2 . The pendant, prochiral difluoride groups R-N=(O=)SF2 , in turn, offer two further SuFExable handles, which can be sequentially exchanged to create 3-dimensional covalent departure vectors from the tetrahedral sulfur(VI) hub.

ChemInform Abstract: SuFEx Click: New Materials from SOxF and Silyl Ethers

AbstractReview: [24 refs.

A Heck–Matsuda Process for the Synthesis of β‐Arylethenesulfonyl Fluorides: Selectively Addressable Bis‐electrophiles for SuFEx Click Chemistry

AbstractA Heck–Matsuda process for the synthesis of the otherwise difficult to access compounds, β‐arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β‐arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E‐isomer sulfonyl analogues of cinnamoyl fluoride in 43–97 % yield. The β‐arylethenesulfonyl fluorides are found to be selectively addressable bis‐electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

A Heck-Matsuda Process for the Synthesis of β-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry.

A Heck-Matsuda process for the synthesis of the otherwise difficult to access compounds, β-arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β-arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride in 43-97 % yield. The β-arylethenesulfonyl fluorides are found to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

SuFEx Click: New Materials from SOx F and Silyl Ethers.

New forms of click chemistry present new opportunities in materials science. Sulfur(VI) fluoride exchange (SuFEx) is a recently discovered click reaction between molecules containing SOx F groups and silyl ethers, two functionalities that are orthogonal to all other known click chemistries, that generates sulfate or sulfonate connections upon the addition of certain organobases or fluoride sources. SuFEx also has several important advantages over other click reactions in that it is insensitive to ambient oxygen and water, and its precursor materials, especially SOx F, are chemically, UV, and thermally inert. This Concept article focuses on the unique reactivity of SuFEx and its relation to building high molecular weight polymers and surface coatings, both of which make it a powerful new tool for materials science.

Direct introduction of R-SO2F moieties into proteins and protein-polymer conjugation using SuFEx chemistry

The modification of proteins with reactive handles has facilitated the use of these biomolecules in diverse fields including drug delivery, diagnostics, environmental remediation, and cell culture matrices. Recently, a new “click” type reaction, sulfur(VI) fluoride exchange (SuFEx), was reported between sulfuryl fluoride and various organic moieties (e.g. hydroxyl, amine) to yield a sulfamoyl fluoride (NSO2F) or fluorosulfate (OSO2F) moiety under biphasic conditions. The model protein bovine serum albumin (BSA) was reacted with SO2F2 gas under biphasic conditions to yield SO2F functionalized protein. The resultant BSA-SO2F was characterized using gel electrophoresis, mass spectroscopy and Fourier transmission infrared spectroscopy to confirm the addition of SO2F functional group. SuFEx modification of BSA caused a marked change in the pH dependent size and zeta potential of the protein as well as increased the protein’s denaturation temperature. Crucially, BSA-SO2F was demonstrated to be biocompatible after 72 h incubation with A549 lung endothelial cells. Due to the unique and elective reactivity of the SO2F group with amines, BSA-SO2F could be self-condensed to form a biocompatible hydrogel that was used in co-culture with HEK 293 cells. In addition, polyethylene glycol (PEG) with reactive OSO2F groups at chain end was conjugated with BSA under various pH conditions through SuFEx chemistry. This communication, to our knowledge, is the first report of the application of the SuFEx in the field of bioconjugates.

Selective and Orthogonal Post-Polymerization Modification using Sulfur(VI) Fluoride Exchange (SuFEx) and Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) Reactions

Functional polystyrenes and polyacrylamides, containing combinations of fluorosulfate, aromatic silyl ether, and azide side chains, were used as scaffolds to demonstrate the postpolymerization modification capabilities of sulfur(VI) fluoride exchange (SuFEx) and CuAAC chemistries. Fluorescent dyes bearing appropriate functional groups were sequentially attached to the backbone of the copolymers, quantitatively and selectively addressing their reactive partners. This combined SuFEx and CuAAC approach proved to be robust and versatile, allowing for a rare accomplishment: triple orthogonal functionalization of a copolymer under essentially ambient conditions without protecting groups.