Sulfonyl Chlorides Research Articles

Green and Efficient Protocols for the Synthesis of Sulfonyl Fluorides Using Potassium Fluoride as the Sole Fluorine Source

Green and Efficient Protocols for the Synthesis of Sulfonyl Fluorides Using Potassium Fluoride as the Sole Fluorine Source

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.

Amidation of β‐Keto Sulfonyl Fluorides via C−C Bond Cleavage

AbstractA simple protocol for amide bond construction using β‐keto sulfonyl fluorides (BKSFs) as the acyl surrogates has been achieved. The reaction of BKSFs with a range of amines could be performed in presence of N‐bromosuccinimide (NBS), affording various amides with diverse functionalities. Preliminary mechanistic studies revealed that the dibromo‐substituted sulfonyl fluorides could be the key intermediate in this amidation process.

De novo design of covalent bonding peptides for target protein

To rapidly develop hyper-stable inhibitors that bind specifically and covalently to functional proteins is critical for diagnostics and therapeutics. Taking targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants as an example, we report a fast and low-cost de novo design strategy on covalent bonding peptides toward the SARS-CoV-2 spike protein receptor-binding domain (RBD), hence blocking its interaction with the human angiotensin-converting enzyme 2 (hACE2). As a proof-of-concept, peptide scaffolds built by ligating the hotspot residues at the hACE2-Omicron RBD interface were docked against RBD, and then the chemically modified peptides were designed by predicting their reactivity against RBD using a modified Amber ff14SB force field. Two peptides (15- and 16-mer peptides) were equipped with sulfonyl fluoride warheads bound with the conserved Y449 residue of RBD via the sulfur (VI) fluoride exchange (SuFEx) click chemistry. With permanent bonding and without dissociation, the two peptides blocked Omicron BA.2 pseudovirus infection with IC50 values of 1.07 μM and 1.56 μM, respectively. Our design approach greatly promotes the discovery of hyper-stable inhibitors against SARS-CoV-2 variants and other rapidly evolving viruses, potentially applicable to combat future viral outbreaks efficiently.

Nickel-Catalyzed Direct Sulfonylation of Styrenes and Unactivated Aliphatic Alkenes with Sulfonyl Chlorides.

A nickel-catalyzed direct sulfonylation of alkenes with sulfonyl chlorides has been developed using 1,10-phenanthroline-5,6-dione as the ligand. Unactivated alkenes and styrenes including 1,1-, 1,2-disubstituted alkenes can be subjected to the protocol, and a wide range of vinyl sulfones was obtained in high to excellent yields with good functional group compatibility. Notably, the process did not allow the desulfonylation of sulfonyl chloride or chlorosulfonylation of alkenes. Radical-trapping experiment supported that a sulfonyl free-radical was likely produced and triggered subsequent transformation in the process.

Radical Ring-Opening Fluorosulfonylation of Methylenecyclobutanols via Electron Donor-Acceptor Photoactivation.

A visible-light-mediated catalyst- and additive-free method for radical ring-opening fluorosulfonylation of methylenecyclobutanols is reported. Sulfuryl chlorofluoride acts as a FSO2 radical precursor as well as an electron acceptor to form electron donor-acceptor complexes with various methylenecyclobutanol substrates. This method shows fully regioselective and (E)-stereoselective ring-opening processes, providing a variety of FSO2-functionalized γ,δ-unsaturated carbonyls in 38-77% yields. A selection of product diversifications has been studied to demonstrate the versatility of these sulfonyl fluoride products.

Synthesis of sulfonylamides containing an isoxazole moiety

The authors obtained a number of new sulfonylamides with isoxazole moiety by sulfonyl chlorination of bicyclic systems containing isoxazole heterocycle and interaction of the obtained sulfonyl chlorides with amino compounds. The authors also obtained isoxazole derivatives containing a sulfogroup in the isoxazole ring by sulfonyl chlorination of 3-aryl-5-N-acylaminoisoxazoles.

Sensory detection of selective substituted acyl chloride and nitrobenzene sulfonyl chloride by interaction with 1-amino-4-hydroxy-9,10-anthraquinone using spectrophotometry and cyclic voltammetry

Sensory detection of selective substituted acyl chloride and nitrobenzene sulfonyl chloride by interaction with 1-amino-4-hydroxy-9,10-anthraquinone using spectrophotometry and cyclic voltammetry

Photocatalytic Chemoselective Cyclic Oxysulfonylation of 2,3-Allenoic Acids.

Photoinduced cyclization of 2,3-allenoic acids with sulfonyl chloride providing an efficient synthesis of 4-sulfonylated furan-2(5H)-ones under mild reaction conditions has been achieved. The reaction enjoys a high chemoselectivity and tolerates a wide range of functional groups. The catalytic cycle has been validated through control experiments, cyclic voltammetry studies, and Stern-Volmer quenching studies.

An Unexpected Synthesis of 2-Sulfonylquinolines via Deoxygenative C2-Sulfonylation of Quinoline N-Oxides with Sulfonyl Chlorides.

A mild, efficient and practical protocol for the preparation of 2-sulfonylquinolines through CS2/Et2NH-induced deoxygenative C2-H sulfonylation of quinoline N-oxides with readily available RSO2Cl was developed. The reaction proceeded well under transition-metal-free conditions and exhibited a wide substrate scope and functional group tolerance. The preliminary studies suggested that the nucleophilic sulfonyl sources were generated in situ via the reaction of CS2, Et2NH and sulfonyl chlorides.

Catalyst-Free Visible Light-Driven Hydrosulfonylation of Alkenes and Alkynes with Sulfonyl Chlorides in Water.

A convenient and sustainable method for synthesizing sulfonyl-containing compounds through a catalyst-free aqueous-phase hydrosulfonylation of alkenes and alkynes with sulfonyl chlorides under visible light irradiation is presented. Unactivated alkenes, electron-deficient alkenes, alkyl and aryl alkynes can be hydrosulfonylated with various sulfonyl chlorides at room temperature with excellent yields and geometric selectivities by using tris(trimethylsilyl)silane as a hydrogen atom donor and silyl radical precursor to activate sulfonyl chlorides. Mechanistic studies revealed that the photolysis of tris(trimethylsilyl)silane in aqueous solution to produce silyl radical is crucial for the success of this reaction.

Evaluation of antibacterial, cytotoxicity, and apoptosis activity of novel chromene-sulfonamide hybrids synthesized under solvent-free conditions and 3D-QSAR modeling studies

In this study, eleven novel chromene sulfonamide hybrids were synthesized by a convenient method in accordance with green chemistry. At first, chromene derivatives (1–9a) were prepared through the multi-component reaction between aryl aldehydes, malononitrile, and 3-aminophenol. Then, synthesized chromenes were reacted with appropriate sulfonyl chlorides by grinding method to give the corresponding chromene sulfonamide hybrids (1–11b). Synthesized hybrids were obtained in good to high yield and characterized by IR, 1HNMR, 13CNMR, CHN and melting point techniques. In addition, the broth microdilution assay was used to determine the minimal inhibitory concentration of newly synthesized chromene-sulfonamide hybrids. The MTT test was used to determine the cytotoxicity and apoptotic activity of the newly synthesized compounds against fibroblast L929 cells. The 3D‑QSAR analysis confirmed the experimental assays, demonstrating that our predictive model is useful for developing new antibacterial inhibitors. Consequently, molecular docking studies were performed to validate the findings of the 3D-QSAR analysis, confirming the potential binding interactions of the synthesized chromene-sulfonamide hybrids with the target enzymes. Molecular docking studies were employed to support the 3D-QSAR predictions, providing insights into the binding interactions between the newly synthesized chromene-sulfonamide hybrids and their target bacterial enzymes, thereby reinforcing the potential efficacy of these compounds as antibacterial agents. Also, some of the experimental outcomes supported or conflicted with the pharmacokinetic prediction (especially about compound carcinogenicity). The performance of ADMET predictor results was assessed. The work presented here proposes a computationally driven strategy for designing and discovering a new sulfonamide scaffold for bacterial inhibition.

Recent Advances in Developing Radical Methods for the Synthesis of Aliphatic Sulfonyl Fluorides

AbstractSulfonyl fluorides have widespread applications in many fields, including organic synthesis, chemical biology, drug discovery and materials science. In particular, in the past decade, a number of aliphatic sulfonyl fluorides have been identified showing various biological activities. These applications and appealing features of sulfonyl fluorides have brought about a significant advancement in developing synthetic methods to access sulfonyl fluorides. In this review, we will discuss the recent developments of radical approaches for the synthesis of aliphatic sulfonyl fluorides.

Synthesis of 18F‐labeled Aryl Trifluoromethyl Sulfones, ‐Sulfoxides, and ‐Sulfides for Positron Emission Tomography

AbstractPositron emission tomography (PET) is becoming increasingly important in nuclear medicine and drug discovery. To date, the development of many potential PET tracers is hampered by the lack of suitable synthetic pathways for their preparation. This is particularly true for the highly desired radiolabeling of compounds bearing [18F]CF3‐groups. For instance, S(O)nCF3‐groups (n=0, 1, 2) serve as structural motif in a range of biologically active compounds, but their radiosynthesis remains largely unprecedented (for n=1, 2). Herein, we describe general methods for the radiosynthesis of 18F‐labeled aryl trifluoromethyl sulfones, ‐sulfoxides, and ‐sulfides. All three methods are operationally straightforward, start from widely available precursors, i.e., sulfonyl fluorides and thiophenols, and make use of the recently established [18F]Ruppert‐Prakash reagent. Further, the syntheses display good functional group tolerance as demonstrated by the 18F‐labeling of more than 40 compounds. The applicability of the new method is demonstrated by the radiolabeling of three bioactive molecules, optionally to be used as PET tracers. In a broader context, this work presents a substantial expansion of the chemical space of radiofluorinated structural motifs to be used for the development of new PET tracers.

Synthesis of 18F-labeled Aryl Trifluoromethyl Sulfones, -Sulfoxides, and -Sulfides for Positron Emission Tomography.

Positron emission tomography (PET) is becoming increasingly important in nuclear medicine and drug discovery. To date, the development of many potential PET tracers is hampered by the lack of suitable synthetic pathways for their preparation. This is particularly true for the highly desired radiolabeling of compounds bearing [18F]CF3-groups. For instance, S(O)nCF3-groups (n=0, 1, 2) serve as structural motif in a range of biologically active compounds, but their radiosynthesis remains largely unprecedented (for n=1, 2). Herein, we describe general methods for the radiosynthesis of 18F-labeled aryl trifluoromethyl sulfones, -sulfoxides, and -sulfides. All three methods are operationally straightforward, start from widely available precursors, i.e., sulfonyl fluorides and thiophenols, and make use of the recently established [18F]Ruppert-Prakash reagent. Further, the syntheses display good functional group tolerance as demonstrated by the 18F-labeling of more than 40 compounds. The applicability of the new method is demonstrated by the radiolabeling of three bioactive molecules, optionally to be used as PET tracers. In a broader context, this work presents a substantial expansion of the chemical space of radiofluorinated structural motifs to be used for the development of new PET tracers.

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation.

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

Nontarget Discovery of Per- and Polyfluoroalkyl Sulfonyl Halides in Soils by Integration of Derivatization and Specific Fragment-Based Liquid Chromatography-High Resolution Mass Spectrometry Screening.

Though long recognized as synthetic precursors to other poly- and perfluoroalkyl substances (PFASs), most poly- and perfluoroalkyl sulfonyl halides (PASXs) cannot be directly measured and have generally received minimal attention. Inspired by the redox reaction between sulfonyl halide groups and p-toluenethiol in organic chemistry, we developed a novel nontarget analysis strategy for PASXs by intergrating derivatization and specific fragment-based liquid chromatography-high resolution mass spectrometry screening for m/z 82.961 [SO2F-] and m/z 95.934 [S2O2-]. By using this strategy, we discovered 11 PASXs, namely, perfluoroalkyl sulfonyl fluorides (5), polyfluoroalkyl sulfonyl fluorides (2), unsaturated perfluoroalkyl sulfonyl fluoride (1), and perfluoroalkyl sulfonyl chlorides (3) in soil samples collected from an abandoned fluorochemical manufacturing park. These average ∑PASXs concentrations were 1120 μg kg-1 (range: 9.7-9860 μg kg-1), which were very likely to be the key intermediates and undesired byproducts of electrochemical fluorination processes. Spatial variation in the mass ratio of ∑PASXs to ∑PFSAs (range: 0.7-795%) also indicates their different transportation pathways. More importantly, the decline of PASXs and increase of perfluoroalkyl sulfonates (when compared to a prior study at this site) suggest the continued hydrolysis of PASXs and the relatively fast environmental transformation rates in the abandoned fluorochemical park soils. Overall, these findings demonstrated the utility of a novel nontarget analysis strategy, which may change most PASXs from inferred precursors to measured intermediates and further could be adapted for structures, distribution, and transformation studies of PFASXs in other matrices.

Ultrafast Flow Synthesis of o-Functionalized Benzenesulfonyl Fluorides and Subsequent SuFEx Connections via Lithiated Chemistry.

Herein we present a flow-based, rapid, and straightforward approach to synthesize diverse functionalized sulfonyl fluorides by harnessing an aryllithium intermediate. The aryllithium intermediate was fully utilized under optimized conditions (0.016 s, -18 °C) to afford various functionalized sulfonyl fluorides and also intramolecular SuFEx cyclization products in high yields (27-94%). Furthermore, the integrated synthesis incorporating subsequent SuFEx connections with even unstable organolithium nucleophiles facilitated one-flow molecular assembly in high yields (42-72%).

Development of Putative Bivalent Dicovalent Ligands for the Adenosine A1 Receptor.

Accumulating evidence suggests that G protein-coupled receptors (GPCRs) can exist and function in homodimer and heterodimer forms. The adenosine A1 receptor (A1R) has been shown to form both homodimers and heterodimers, but there is a lack of chemical tools to study these dimeric receptor populations. This work describes the synthesis and pharmacological evaluation of a novel class of bivalent GPCR chemical tools, where each ligand moiety of the bivalent compound contains a sulfonyl fluoride covalent warhead designed to be capable of simultaneously reacting with each A1R of an A1R homodimer. The novel compounds were characterised using radioligand binding assays, including washout assays, and functionally in cAMP assays. The bivalent dicovalent compounds were competitive A1R antagonists and showed evidence of covalent binding and simultaneous binding across an A1R homodimer. Greater selectivity for A1R over the adenosine A3 receptor was observed for bivalent dicovalent over the equivalent monovalent compounds, indicating subtype selectivity can be achieved with dual occupation by a bivalent dicovalent ligand.

2‐ and 3‐Fluorocyclobutane Building Blocks for Organic and Medicinal Chemistry

Multigram synthesis of 3‐fluorinated cyclobutane building blocks has been disclosed. The proposed synthetic schemes were based on the nucleophilic fluorination and eventually led to 3‐fluorocyclocutanecarboxylic acid as a key target compound and intermediate. Further functional group transformations provided monofluorinated cyclobutane‐derived alcohols, amines, bromides, thiols, sulfonyl chlorides, etc. Furthermore, the synthesis of diastereopure cis‐ and trans‐isomeric 2‐ and 3‐fluorocyclobutane­carboxylic acids and amines was also performed. In both cases, diastereomer separation was used to obtain pure stereoisomers. The effect of the fluorine position and relative spatial orientation on the physicochemical properties of the corresponding monoflurinated derivatives was studied by measurements of pKa and logP values.