Ethenesulfonyl Fluoride Research Articles

Synthesis of γ‐Alkenylated δ‐Sultones Via Brønsted Base‐Catalyzed Annulative SuFEx Reaction of Allyl Ketones and Ethenesulfonyl Fluorides

AbstractA tandem annulation reaction of allyl ketones and β‐aryl ethenesulfonyl fluorides has been described. Under the catalysis of Brønsted base, allyl ketones reacted with β‐aryl ethenesulfonyl fluorides through a tandem intermolecular Michael addition‐intramolecular SuFEx process to afford γ‐alkenylated δ‐sultones in good to excellent yields. In this reaction, no additional base was needed, and 4 Å molecular sieves were used as efficient HF scavenger to restrict the neutralization and deactivation of the Brønsted base catalyst.

A Portal to Highly Valuable Pyridonyl Vinyl Sulfonyl Fluorides and Aliphatic Sulfonyl Fluorides

AbstractA novel and efficient method for selective Michael addition of 2-pyridones to ethenesulfonyl fluoride (ESF) and 1-bromoethene-1-sulfonyl fluoride (BESF) has been developed for constructing a class of pyridonyl aliphatic sulfonyl fluorides and pyridonyl vinyl sulfonyl fluorides in good to excellent yields. This practical method features easy operation, wide substrate scope, and mild reaction conditions.

High‐Pressure‐Mediated Fragment Library Synthesis of 1,2‐Disubsituted Cyclobutane Derivatives

AbstractCyclobutanes have attracted significant interest in medicinal chemistry because of their unique structure and potential advantages in pharmacological properties. Nevertheless, 1,2‐disubstituted cyclobutanes remain underrepresented, both in the general chemical space and in fragment‐based drug discovery libraries. In this study, a two‐diversification‐point library of cyclobutanesulfonamides was synthesized through a hyperbaric [2+2] cycloaddition reaction between ethenesulfonyl fluoride and tert‐butyl vinyl ether as the key step. The sulfonyl fluoride was subsequently transformed into various sulfonamides, whereas the tert‐butyl ether was converted into carbamates and triazoles to synthesize a fragment library. Overall, this synthesis contributes to addressing the underrepresentation of 1,2‐disubstituted cyclobutane fragments, making a valuable addition to the field of fragment‐based drug discovery.

Synthesis of Dithiocarbamate‐Functionalized Aliphatic Sulfonyl Fluoride via a One‐Pot Three‐Component Reaction

AbstractAn eco‐friendly and efficient method was developed for synthesizing a novel class of aliphatic sulfonyl fluorides in a catalyst‐free one‐pot reaction. The new approach offers a streamlined synthesis for N‐(Substituted)‐2‐(fluorosulfonyl) ethyl carbamodithioates by combining amines, carbon disulfide, with ethenesulfonyl fluoride. The synthesized compounds were obtained in good yields under mild conditions, making this reaction a valuable tool for exploring new chemical transformations.

Highly Functionalized SuFEx-able Hub Bearing All-Carbon Quaternary Center via Rapid Brønsted Superbase Catalysis.

A rapid Brønsted superbase catalysis for highly functionalized sulfur(VI)-fluoride exchange (SuFEx) hubs bearing all-carbon quaternary centers was developed. Remarkable functional group tolerance toward esters and nitriles was achieved by Michael addition of cyanoacetate derivatives to ethenesulfonyl fluoride with low catalyst loadings (∼0.5 mol %) within a short reaction time (0.5-30 min). Gram-scalability, water tolerance, and compatibility in polymeric catalysis showcase its unique practicability. SuFEx click conjugations were demonstrated using various amines, including DNA-tethered biomolecules.

Synthesis of α-Bromo Arylethyl Sulfonyl Fluorides and β-Arylethenesulfonyl Fluorides via Copper-Catalyzed Meerwein Arylation.

A practical copper-catalyzed process for the synthesis of the β-arylethenesulfonyl fluorides is described. A series of α-bromo arylethyl sulfonyl fluorides was prepared via Meerwein reaction from arenediazonium tetrafluoroborates and ethenesulfonyl fluoride (ESF) under mild conditions. The following β-arylethenesulfonyl fluorides were further obtained through a β-elimination reaction. This protocol features excellent regio- and stereoselectivity and broad substrate scope.

Accessing SuFExable Cyclobutane‐Fused Indolines via Photocatalytic Intermolecular [2+2] Cycloaddition of Indoles

AbstractIndoline‐fused polycycles are commonly found as a key structural component in numerous natural products and biologically active compounds. In recent times, the incorporation of sulfonyl fluoride groups has drawn significant attention in research due to their potential to enhance or confer new biological activities to molecules. In this study, we report the development of a modular approach for synthesizing FSO2‐functionalized cyclobutane‐fused indolines by employing an intermolecular [2+2] cycloaddition reaction between indoles and SuFExable ethenesulfonyl fluoride under triplet energy‐transfer catalysis. This method features mild reaction conditions, metal‐free photocatalysts, and excellent tolerance to various functional groups. Moreover, we demonstrate the feasibility of further modifying the FSO2‐functionalized indoline products via SuFEx click reactions, enabling their conjugation with other molecules.

“On-Water” accelerated dearomative cycloaddition via aquaphotocatalysis

Sulfur(VI) fluoride exchange (SuFEx) has emerged as an innovative click chemistry to harness the pivotal connectivity of sulfonyl fluorides. Synthesizing such alkylated S(VI) molecules through a straightforward process is of paramount importance, and their water-compatibility opens the door to a plethora of applications in biorelevant and materials chemistry. Prior aquatic endeavors have primarily focused on delivering catalysts involving ionic mechanisms, studies regarding visible-light photocatalytic transformation are unprecedented. Herein we report an on-water accelerated dearomative aquaphotocatalysis for heterocyclic alkyl SuFEx hubs. Notably, water exerts a pronounced accelerating effect on the [2 + 2] cycloaddition between (hetero)arylated ethenesulfonyl fluorides and inert heteroaromatics. This phenomenon is likely due to the high-pressure-like reactivity amplification at the water-oil interface. Conventional solvents proved totally ineffective, leading to the isomerization of the starting material.

Reactivities of tertiary phosphines towards allenic, acetylenic, and vinylic Michael acceptors.

The addition of phosphines (PR3) to Michael acceptors is a key step in many Lewis-base catalysed reactions. The kinetics of the reactions of ten phosphines with ethyl acrylate, ethyl allenoate, ethyl propiolate, ethenesulfonyl fluoride, and ethyl 2-butynoate in dichloromethane at 20 °C was followed by photometric and NMR spectroscopic methods. The experimentally determined second-order rate constants k 2 show that electronic effects in sterically unencumbered phosphines affect their nucleophilicity towards different classes of Michael acceptors in the same ordering. Michael acceptors with sp-hybridised electrophilic centres, however, are less susceptible to changes in the PR3 nucleophilicity than those with sp2-hybridised reactive sites. Linear correlations of lg k 2 from this work with published rate constants for SN2 and SN1 reactions as well as with Brønsted basicities and fugalities for PR3 demonstrate the generality of the detected reactivity trends. Computed reaction barriers (ΔG ‡ calc) as well as reaction energies (ΔG add) for Michael adduct formations show excellent correlations with experimentally obtained reaction barriers (ΔG ‡ exp) corroborating the interpretation of the kinetic data and revealing the philicity/fugality features of the reactants in phospha-Michael additions.

Brønsted base-catalyzed assembly of sulfochromeno[4,3-b]pyrrolidines via tandem [3 + 2] cycloaddition–SuFEx click reaction of ethenesulfonyl fluorides and o-hydroxyaryl azomethines

o-Hydroxyaryl azomethine ylides react with ethenesulfonyl fluorides via a tandem [3 + 2] cycloaddition–SuFEx click process to produce sulfochromeno[4,3-b]pyrrolidines in high yields.

Phosphorus fluoride exchange: Multidimensional catalytic click chemistry from phosphorus connective hubs

Phosphorus Fluoride Exchange (PFEx) represents a cutting-edge advancement in catalytic click-reaction technology. Drawing inspiration from Nature's phosphate connectors, PFEx facilitates the reliable coupling of P(V)-F loaded hubs with aryl alcohols, alkyl alcohols, and amines to produce stable, multidimensional P(V)-O and P(V)-N linked products. The rate of P-F exchange is significantly enhanced by Lewis amine base catalysis, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). PFEx substrates containing multiple P-F bonds are capable of selective, serial exchange reactions via judicious catalyst selection. In fewer than four synthetic steps, controlled projections can be deliberately incorporated along three of the four tetrahedral axes departing from the P(V) central hub, thus taking full advantage of the potential for generating three-dimensional diversity. Furthermore, late-stage functionalization of drugs and drug fragments can be achieved with the polyvalent PFEx hub, hexafluorocyclotriphosphazene (HFP), as has been demonstrated in prior research.

First GC/MS identification of aqueous ammonia: utilization of ethenesulfonyl fluoride as a selective and rapid derivatization reagent of ammonia in aqueous media.

Identification as well as quantification of ammonia are required in some analytical fields including forensic science. For this purpose, gas chromatography/mass spectrometry (GC/MS) analysis is one of the most suitable techniques. Although ammonia needs to be derivatized for GC/MS analysis, conventional derivatization reagents require anhydrous conditions because they are highly reactive with water. Here, we investigated ethenesulfonyl fluoride (ESF) as a selective reagent for ammonia derivatization in aqueous media to develop a rapid identification method for ammonia in aqueous media. The Michael addition reaction of ammonia with ESF rapidly produced a tri-ESF derivative suitable for GC/MS analysis. We optimized the derivatization reaction conditions and extraction solvent. With the optimized protocol, the detection limit for aqueous ammonia was 0.05 μg mL-1. The calibration curve showed good linearity (R2 = 0.9998) in the range of 0.10-100.0 μg mL-1, and the accuracy (% bias) and the precision (% relative standard deviation) for concentrations of 0.10, 0.25, 10.0, and 75.0 μg mL-1 were within ± 10% (intra- and inter-day). The proposed ESF-based method could quantify ammonia in samples containing interfering nucleophilic substances. This method was successfully applied to ammonia-containing commercial products.

Rhodium‐Catalyzed Vinyl Sulfonylation of 3‐Carbonyl‐Substituted Indoles with Ethenesulfonyl Fluoride by Cross‐Dehydrogenative Coupling: An Application in (3+2) Cycloaddition

AbstractA Rh(III)‐catalyzed site‐selective vinyl sulfonylation of indoles with ethenesulfonyl fluoride (ESF) by a carbonyl oxygen‐directed method is reported. This chemoselective strategy delivers the corresponding cross‐dehydrogenative coupled products exclusively as E‐isomers in high yields under mild conditions and has shown high efficiency and good functional group tolerance. The synthetic potential of the developed route is demonstrated by utilizing the cross‐coupled adducts in click chemistry to access triazoles through thermal (3+2) cycloaddition with excellent regioselectivity in the absence of a metal catalyst.

Cyclobutane Formation by the Reaction of Ethenesulfonyl Fluoride with Dimethyl Diazomalonate

AbstractAttempts to synthesize fluorosulfonyl‐substituted pyrazolines by Huisgen reactions (1,3‐dipolar cycloadditions) of dimethyl diazomalonate with ethenesulfonyl fluoride led to the formation of dimethyl (2R*,3S*,4R*)‐2‐(1,3‐dimethoxy‐1,3‐dioxopropan‐2‐yl)‐3‐(fluorosulfonyl)‐4‐((fluorosulfonyl)methyl)cyclobutane‐1,1‐dicarboxylate, a highly substituted cyclobutane derivative, which was characterized by NMR spectroscopy and single crystal X‐ray crystallography. The mechanism of its formation was elucidated by carrying out the reaction at different temperatures and workup conditions. It is shown that an initial 1,3‐dipolar cycloaddition yields a pyrazoline which extrudes nitrogen with formation of 1‐fluorosulfonyl‐2,2‐bis(methoxycarbonyl)cyclopropane and dimethyl 2‐(2‐(fluorosulfonyl)ethylidene)malonate, the latter of which dimerized during chromatography on silica gel with formation of the isolated cyclobutane.

Synthesis of 2-arylethenesulfonyl fluorides and isoindolinones: Ru-catalyzed C–H activation of nitrones with ethenesulfonyl fluoride

A novel strategy for the synthesis of 2-arylethenesulfonyl fluorides from nitrones and ethenesulfonyl fluoride (ESF) by the activation of the C-H bond using an inexpensive and readily available Ru-catalyst has been developed. In this process, the directing group can be concomitantly converted to an amide group. Interestingly, changing the substituent of the nitrogen of nitrones from a tert-butyl to a methyl group resulted in the formation of cyclic isoindolinones. Detailed mechanistic studies are also presented.

A cascade reaction for regioselective construction of pyrazole-containing aliphatic sulfonyl fluorides.

A copper-catalyzed cascade reaction of α-diazocarbonyl compounds with ethenesulfonyl fluoride (ESF) is developed, affording a variety of highly functionalized pyrazolyl aliphatic sulfonyl fluorides in good to excellent yields (66-98%). This transformation features broad substrates, exclusive regioselectivity, high atom economy and operational simplicity, thus providing a straightforward method for the direct construction of pyrazole-containing aliphatic sulfonyl fluorides, which will provide great applicable value in medicinal chemistry and other related disciplines.

Copper-Promoted Conjugate Addition of Carboxylic Acids to Ethenesulfonyl Fluoride (ESF) for Constructing Aliphatic Sulfonyl Fluorides.

A CuO-promoted direct hydrocarboxylation of ethenesulfonyl fluoride (ESF) was developed using carboxylic acid as a nucleophile under mild conditions. A variety of molecules containing both ester group and aliphatic sulfonyl fluoride moiety exhibit great potential in medicinal chemistry and chemical biology. Furthermore, the modification of the known drugs Ibuprofen and Aspirin was also demonstrated.

Cu-catalyzed endo-selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ethenesulfonyl fluorides: Efficient access to chiral pyrrolidine-3-sulfonyl fluorides

Cu-catalyzed endo-selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ethenesulfonyl fluorides (ESFs) was successfully developed, this protocol provided an efficient and facile method to a wide range of chiral pyrrolidine-3-sulfonyl fluorides with good to excellent results (up to 87% yield, >20:1 dr, 94% ee). Some other chiral sulfonyl derivatives, such as sulfonamide and sulfonate, were easily accessible through simple transformations with high yields, which demonstrated that the cycloaddition products could be synthetically useful in the sulfur(VI) fluoride exchange (SuFEx) chemistry.

An Easy, General and Practical Method for the Construction of Alkyl Sulfonyl Fluorides

AbstractA visible light‐induced reductive addition of 1°, 2° and 3° alkyl iodides to ethenesulfonyl fluoride, employing Hantzsch ester as a hydrogen source at room temperature was developed. This method featured a wide substrate scope and great functional group compatibility, providing facile and robust process to alkyl sulfonyl fluorides including enzyme inhibitors, natural products and drugs derivatives in up to 99% yield. Further derivatization of resultant aliphatic sulfonyl fluorides was also achieved through sulfur fluoride exchange (SuFEx) reactions to deliver sulfonates and sulfonamides as privileged motifs for medicinal chemistry.magnified image

Light-induced [2 + 2] cycloadditions for the construction of cyclobutane-fused pyridinyl sulfonyl fluorides.

Cyclobutanes are an important class of motifs present in a wide range of natural products and other biologically significant molecules. A photocatalytic [2 + 2] cycloaddition between pyridones or isoquinolones and ethenesulfonyl fluoride was achieved, providing a portal to a class of unique cyclobutane-fused pyridinyl sulfonyl fluorides with quaternary rigid rings (30 examples). Further applications of these novel sulfonyl fluoride molecules in SuFEx click chemistry were also accomplished, providing the corresponding sulfonates and sulphonamides with reasonable yields.