Sulfonyl Chlorides Research Articles

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.

Carbene-Catalyzed Enantioselective Addition of Sulfinate to Ketones.

A carbene-catalyzed enantioselective addition of sulfinate to ketones between 2-benzoylbenzaldehyde and sulfonyl chloride is disclosed. Up to now, the carbon and heteroatom nucleophiles have effectively undergone catalytic enantioselective addition to carbonyl molecules to introduce functionalities and chirality. Sulfone, as an important class of sulfur-containing functional groups, represents highly valuable motifs in medicines and natural products. It remains undeveloped for the catalytic asymmetric addition of sulfinate to carbonyls. Herein we disclosed the first catalytic enantioselective addition of sulfinate to ketones for the synthesis of sulfones via N-heterocyclic carbene (NHC) catalysis. The sulfonyl chloride behaves both as an oxidant and as a nucleophilic substrate in this carbene-catalyzed process. Experimental studies suggested that the Breslow intermediate can be SET oxidized by sulfonyl chloride to generate the sulfonyl radical. This novel synthetic approach for the asymmetric addition of sulfinate to carbonyls can also be used to modify the commercially available functional molecules.

Chlorinated graphene and graphene nanoribbons: A density functional theory study

Functional groups based on halides, such as fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), are crucial for understanding the chemical reactivity of graphitic nanomaterials. Except for I, halogens exhibit electronegativity greater than carbon (C); therefore, charge transfer from carbon to halogen is expected. First-principles density functional theory calculations were performed to determine the role of different Cl-functional groups (methyl-trichloride, ethyl-trichloride, chloride, acyl-chloride, vinyl-chloride, acetyl hypochlorite, chloramines, sulfonyl chloride, and more) on the electronic properties of graphene and graphene nanoribbons (GNRs). GNRs with zigzag edges (ZGNRs) and armchair edges (AGNRs) were studied. We analyzed the optimized structures, band structure, density of states, cohesive energy, and band gap. Our results revealed that the based-Cl functional groups can provide an alternative route to activate the borders and surfaces of sp2 carbon materials. Methyl-trichloride and acyl-chloride can induce magnetism and metallicity. Chloride and acyl-chloride are the most energetically stable functional groups attached to the edges. Surprisingly, methyl-trichloride or acyl-chloride functionalizing the surface of the AGNRs showed a direct (indirect) band gap for states with spin-up (spin-down). The results of aromatic (chlorobenzene- and dichlorobenzene-like structures) functionalization considering F, Cl, Br, and I are also shown. Finally, –F2 and –ClF functionalization cases are discussed.

Visible-Light-Promoted Radical Cascade Cyclization of 2-Vinyl Benzimidazoles: Access to Benzo[4,5]imidazo[1,2-b]isoquinolin- 11(6H)-ones.

A visible-light-enabled photoredox radical cascade cyclization of 2-vinyl benzimidazole derivatives is developed. This chemistry is applicable to a wide range of N-aroyl 2-vinyl benzimidazoles as acceptors, and halo compounds, including alkyl halides, acyl chlorides and sulfonyl chlorides, as radical precursors. The Langlois reagent also serves as an effective partner in this photocatalytic oxidative cascade process. This protocol provides a robust alternative for rendering highly functionalized benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-ones.

Visible-Light-Promoted C3-Sulfenylindoles with Arylsulfonyl Chlorides via Electron Donor-Acceptor Complex.

In this study, we present an efficient approach for the synthesis of 3-sulfenyl indoles through an electron donor-acceptor (EDA) complex-promoted photoreaction. This sulfenylation reaction leverages sulfonyl chlorides as the sulfur source and employs PPh3 as the reductant without the need for any transition-metal catalyst or photocatalyst. At the same time, the relaxation process of the excited EDA complex was theoretically investigated at the method and multiconfiguration second-order perturbation//complete active space self-consistent field/PCM level of theory, which involves the π bond of indoles injecting an electron to the antibonding orbital of the S-Cl bond in arylsulfonyl chlorides.

N,N-Diarylsulfonamide Reduces Proinflammatory Cytokine Interleukin-6 Levels in Cells through Nuclear Factor-κB Regulation.

The arylsulfonamides were synthesized from aryl sulfonyl chloride and aromatic amines in dichloromethane in the presence of pyridine. The aryne chemistry was used to prepare diarylsulfonamide from arylsulfonamides and O-silylaryl triflate with CsF in acetonitrile at room temperature for 30 min. The synthesized compounds were evaluated for cytotoxicity followed by the cytokine/inflammatory marker's inhibition capability and its mechanism of action in RAW-264.7 cells. Elevated interleukin-6 (IL-6) levels have been reported in inflammatory conditions and inflammation-associated disorders. Hence, reducing the IL-6 levels in inflammatory conditions can serve as an attractive therapeutic target in dealing the inflammation. Among 42 compounds, seven compounds showed significant inhibition of IL-6 levels in lipopolysaccharide (LPS) challenged RAW-264.7 cells at 12.5 μM concentration. Further, investigation revealed that the IC50 value of these compounds for reducing IL-6 levels was found to be in the range of 2.6 to 9.7 μM. The promising compounds 5y (IC50 of 2.6 μM) and 5n (IC50 of 4.1 μM) along with other derivatives fulfil drug-likeness parameters laid down by Lipinski's rule of five. Further, RT-qPCR and Western-blot analysis revealed that treatment with 5n significantly reduced the expression of pro-inflammatory, inflammatory and macrophage marker's expression (IL-1β, CCL2, COX2 and CD68) compared to LPS control. The mechanistic evaluation showed that 5n exhibited anti-inflammatory properties by modulating the nuclear factor-κB (NF-κB) activation. The identified compound can be a promising candidate for further discovery efforts to generate a preclinical candidate effective in inflammation.

“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.