Sulfonyl Esters Research Articles

8-Iodo-4-methyl-2-oxo-2H-chromen-7-yl Benzenesulfonate

We report a straightforward and efficient synthesis of 4-methyl-2-oxo-2H-chromen-7-yl benzenesulfonate (3a) and 8-iodo-4-methyl-2-oxo-2H-chromen-7-yl benzenesulfonate (3b) in good yields through an O-sulfonylation reaction of 7-hydroxy-2H-chromen-2-ones 1a and 1b with benzenesulfonyl chloride 2 mediated by triethylamine in dichloromethane at ambient temperature. The aryl sulfonyl esters were characterized using spectroscopic, spectrometric, and thermal analyses.

Fe-Catalyzed Fluorosulfonylation of Alkenes via Sulfur Dioxide Insertion: Synthesis of Lactam-Functionalized Alkyl Sulfonyl Fluorides.

A novel Fe-catalyzed fluorosulfonylation of alkenes with Na2S2O4 and N-fluorobenzenesulfonimide (NFSI) for assembling various lactam-functionalized alkyl sulfonyl fluorides is disclosed. In this reaction, Na2S2O4 acts as both an SO2 source and a reductant. Furthermore, the resulting products can be efficiently transformed into valuable chemicals, including sulfonyl esters and sulfonamides, via the sulfur(VI) fluoride exchange (SuFEx) click reaction. Preliminary mechanistic studies suggest that the transformation proceeds through intramolecular radical cyclization, SO2 insertion, sulfite anion formation, and fluorination.

The isocyanide SN2 reaction

The SN2 nucleophilic substitution reaction is a vital organic transformation used for drug and natural product synthesis. Nucleophiles like cyanide, oxygen, nitrogen, sulfur, or phosphorous replace halogens or sulfonyl esters, forming new bonds. Isocyanides exhibit unique C-centered lone pair σ and π* orbitals, enabling diverse radical and multicomponent reactions. Despite this, their nucleophilic potential in SN2 reactions remains unexplored. We have uncovered that isocyanides act as versatile nucleophiles in SN2 reactions with alkyl halides. This yields highly substituted secondary amides through in situ nitrilium ion hydrolysis introducing an alternative bond break compared to classical amide synthesis. This novel 3-component process accommodates various isocyanide and electrophile structures, functional groups, scalability, late-stage drug modifications, and complex compound synthesis. This reaction greatly expands chemical diversity, nearly doubling the classical amid coupling’s chemical space. Notably, the isocyanide nucleophile presents an unconventional Umpolung amide carbanion synthon (R-NHC(-) = O), an alternative to classical amide couplings.

Visible-light-driven reactions for the synthesis of sulfur dioxide-inserted compounds: generation of S-F, S-O, and S-N bonds.

Sulfur dioxide-containing compounds such as sulfonyl fluorides, sulfonyl esters, and sulfonyl amides are important structural frameworks in many natural products, pharmaceuticals, and organic compounds. Thus, synthesis of these molecules is a very valuable research topic in organic chemistry. Various synthetic methods to introduce SO2 groups into the structure of organic compounds have been developed for the synthesis of biologically and pharmaceutically useful compounds. Recently, visible-light-driven reactions were carried out to create SO2-X (X = F, O, N) bonds, and their effective synthetic approaches were demonstrated. In this review, we summarized recent advances in visible-light-mediated synthetic strategies for generation of SO2-X (X = F, O, N) bonds for various synthetic applications along with proposed reaction mechanisms.

Natural products-based: Synthesis and antifungal activity evaluation of novel L-pyroglutamic acid analogues.

Botanical pesticides are one of the sources of third-generation pesticides, which have received much attention at home and abroad in recent years due to their degradable and pollution-free advantages in nature. This article explored a concise approach toward synthesizing a series of novel L-pyroglutamic acid analogues from L-hydroxyproline. Furthermore, bioassay studies of these sulfonyl ester derivatives against Pyricularia oryzae, Fusarium graminearum, Alternaria brassicae, Valsa mali, and Alternaria alternariae showed moderate antifungal activity. For instance, C08a and C08l provide potential lead agents for controlling Fusarium graminearum because of their inhibitory activity.

Differential Dihydrofunctionalization: A Dual Catalytic Three-Component Coupling of Alkynes, Alkenyl Bromides, and Pinacolborane.

A new method for differential dihydrofunctionalization of terminal alkynes enables the synthesis of allylic boronate esters through reductive three-component coupling of terminal alkynes, alkenyl bromides, and pinacolborane. The transformation is promoted by cooperative action of a copper/palladium catalyst system and results in hydrofunctionalization of both π-bonds of an alkyne. The synthesis of allylic boronate esters can be accomplished in the presence of a wide range of functional groups, including, esters, nitriles, alkyl halides, sulfonyl esters, acetals, protected terminal alkynes, aryl halides, and silyl ethers. Mechanistic experiments reveal the importance of subtle ligand effects on the performance of the palladium co-catalyst.

Differential Dihydrofunctionalization: A Dual Catalytic Three‐Component Coupling of Alkynes, Alkenyl Bromides, and Pinacolborane

AbstractA new method for differential dihydrofunctionalization of terminal alkynes enables the synthesis of allylic boronate esters through reductive three‐component coupling of terminal alkynes, alkenyl bromides, and pinacolborane. The transformation is promoted by cooperative action of a copper/palladium catalyst system and results in hydrofunctionalization of both π‐bonds of an alkyne. The synthesis of allylic boronate esters can be accomplished in the presence of a wide range of functional groups, including, esters, nitriles, alkyl halides, sulfonyl esters, acetals, protected terminal alkynes, aryl halides, and silyl ethers. Mechanistic experiments reveal the importance of subtle ligand effects on the performance of the palladium co‐catalyst.

Ultrasensitive Detection of COVID-19 Virus N Protein Based on p-Toluenesulfonyl Modified Fluorescent Microspheres Immunoassay

The pandemic of new coronary pneumonia caused by the COVID-19 virus continues to ravage the world. Large-scale population testing is the key to controlling infection and related mortality worldwide. Lateral flow immunochromatographic assay (LFIA) is fast, inexpensive, simple to operate, and easy to carry, very suitable for detection sites. This study developed a COVID-19 N protein detect strip based on p-toluenesulfonyl modified rare earth fluorescent microspheres. The p-toluenesulfonyl-activated nanomaterials provide reactive sulfonyl esters to covalently attach antibodies or other ligands containing primary amino or sulfhydryl groups to the nanomaterial surface. Antibodies are immobilized on these nanomaterials through the Fc region, which ensures optimal orientation of the antibody, thereby increasing the capture rate of the target analyte. The use of buffers with high ionic strength can promote hydrophobic binding; in addition, higher pH could promote the reactivity of the tosyl group. The detection limit of the prepared COVID-19 N protein strips can reach 0.01 ng/mL, so it has great application potential in large-scale population screening.

SO2F2‐Promoted Dehydroxylative Fluorination of Alcohols

AbstractReported here is the development of a novel, mild and practical protocol for the SO2F2‐promoted dehydroxylative fluorination of readily available alcohols. The advantages of this protocol include an inexpensive and available reagent, and operational simplicity. This method enables the transformation of many kinds of primary, secondary and tertiary (hetero) arene alcohols into the corresponding fluorides and tolerates a range of functional groups. And the reactions occur smoothly to give the desired products in moderate to high yields. And a tentative mechanism was proposed involving formation and elimination of key intermediate, sulfonyl ester.

Reaction-based fluorescence probes for "turn on" sensing fluoride ions.

Introducing a weak covalent bond into an originally highly fluorescent molecule to create a non-fluorescent probe is able to provide a new way to detect some nucleophilic targets with enhanced sensitivity. Herein, this is the first time that a tetraphenylethene (TPE)-based probe (TPEONO2) bearing a p-nitrobenzenesulfonyl moiety for the sensing of F- ions in aqueous solution via a cleavage reaction of the sulfonyl ester bond to induce aggregation-induced emission (AIE) has been reported.

Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL

While the biochemistry of rhomboid proteases has been extensively studied since their discovery two decades ago, efforts to define the physiological roles of these enzymes are ongoing and would benefit from chemical probes that can be used to manipulate the functions of these proteins in their native settings. Here, we describe the use of activity-based protein profiling (ABPP) technology to conduct a targeted screen for small-molecule inhibitors of the mitochondrial rhomboid protease PARL, which plays a critical role in regulating mitophagy and cell death. We synthesized a series of succinimide-containing sulfonyl esters and sulfonamides and discovered that these compounds serve as inhibitors of PARL with the most potent sulfonamides having submicromolar affinity for the enzyme. A counterscreen against the bacterial rhomboid protease GlpG demonstrates that several of these compounds display selectivity for PARL over GlpG by as much as two orders of magnitude. Both the sulfonyl ester and sulfonamide scaffolds exhibit reversible binding and are able to engage PARL in mammalian cells. Collectively, our findings provide encouraging precedent for the development of PARL-selective inhibitors and establish N-[(arylsulfonyl)oxy]succinimides and N-arylsulfonylsuccinimides as new molecular scaffolds for inhibiting members of the rhomboid protease family.

Identification, synthesis, and characterization of potential genotoxic impurities of sildenafil citrate drug substance

BackgroundSildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specifil phophodiesterase type 5 (PDE5). Sildenafil enhances the effect of nitric oxide by inhibiting phosphodiesterase type 5, which is responsible for the degradation of cGMP in the corpus cavernosum. The possible genotoxic impurities of sildenafil were synthesized, i.e., sildenafil sulfonyl methyl ester, sildenafil sulfonyl ethyl ester, and sildenafil sulfonyl isopropyl ester. The present work describes the synthesis and characterization of these sulfonyl ester compounds related to sildenafil.ResultsAll the synthesized sildenafil sulfonyl esters have proved to be beneficial for the pharmaceutical industry in view of the regulatory importance.ConclusionA simple, efficient, and repeatable method was developed for the preparation of sildenafil sulfonyl esters in view of the regulatory importance of the potential genotoxic impurities in the active pharmaceutical ingredient. A detailed study of various impurities in sildenafil was conducted. Different process-related sulfonyl esters in sildenafil were identified, synthesized, and characterized by using various spectroscopic techniques like liquid chromatography-mass spectrometry (LCMS), mass, 1H NMR, and FT-IR. These efforts to synthesize and characterize them effectively have proved to be beneficial.

Synthesis, PASS Predication, Antimicrobial, DFT, and ADMET Studies of Some Novel Mannopyranoside Esters

Due to the biodegradability and drug-likeness properties sugar esters (SEs) are getting especial attention to the synthetic and bioorganic chemists. In this context, we have synthesized several 6-O-pentanoyl mannopyranoside esters (5-9) with alkanoyl and sylfonyl chains reasonably in good yields. Both the prediction of activity spectra for substances (PASS) and in vitro tests indicated that these mannopyranoside esters possess better potentiality against fungal pathogens than the bacterial organisms. These SEs were also optimized with quantum chemical density functional theory (DFT), and various thermodynamic properties like frontier molecular orbital, and molecular electrostatic potential (MEP) were calculated and discussed. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations indicated that these SEs can pass through blood brain barrier and less toxic. Drug-likeness results indicated good conditions for alkanoyl esters rather than sulfonyl esters despite their promising antifungal results. All the in vitro and in silico results indicated that the combination of pentanoyl (C5) and lauroyl (C12) chains in mannopyranoside framework, as in 9, might be a potential candidate for novel antifungal agent.

Synthesis, characterization, electrochemical and DNA binding studies of regio-isomeric sulfonyl esters of substituted isoxazoles

Abstract In the present study, four regio-isomeric isoxazole derivatives (5–8) were synthesized. The structures elucidation was performed using FTIR, NMR, and single crystal X-ray diffraction methods. Electrochemical response of compounds was recorded by cyclic voltammetry (CV). CV results indicated that all the compounds undergo reduction process involving one electron. Compound-DNA interactions were studied using CV titrations and it was observed that all the compounds exhibited interaction with DNA. Compound 8 exhibited strongest interaction with a binding constant (K) value of 5.09 × 104 M−1.

SO2F2‐Activated Efficient Beckmann Rearrangement of Ketoximes for Accessing Amides and Lactams

A novel, mild and practical protocol for the efficient activation of the Beckmann rearrangement utilizing the readily available and economical sulfuryl fluoride (SO2F2 gas) has been developed. The substrate scope of the operationally simple methodology has been demonstrated by 37 examples with good to nearly quantitative isolated yields (over 90 % yield in most cases) in a short time, including B(OH)2, COOH, NH2, and OH substituted substrates. A tentative mechanism was proposed involving formation and elimination of key intermediate, sulfonyl ester.

A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP1-1 ) in Human Cells.

Glutathione S-transferase π (GSTP1-1 ) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP1-1 is an important target in cancer therapy, and many GST inhibitors have been reported. We had previously developed an irreversible inhibitor, GS-ESF, as an effective GST inhibitor; however, its cellular permeability was too low for it to be used in inhibiting intracellular GST. We have now developed new irreversible inhibitors by introducing sulfonyl fluoride (SF) into chloronitrobenzene (CNB). The mechanism of action was revealed to be that CNBSF first reacts with glutathione (GSH) through an aromatic substitution in the cell, then the sulfonyl group on the GSH conjugate with CNBSF reacts with Tyr108 of GST to form a sulfonyl ester bond. Our new inhibitor irreversible inhibited GSTP1-1 both in vitro and in cellulo with a long duration of action.

Synthesis and anticancer activity of chalcone analogues with sulfonyl groups

Three series of sulfonyl esters were synthesized in reactions of sulfonyl chlorides with three different phenolic chalcone analogues (dehydrozingerone (4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one), (E)-1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one, and (E)-1-(4-hydroxy-3-methoxyphenyl)-5-methylhex-1-en-3-one). The structures of the new compounds were determined by IR, MS, and NMR methods. Screening of the new sulfonyl esters’ in vitro cytotoxic activities against human epithelial cervical carcinoma (HeLa) and normal human fibroblast (MRC-5) cell lines by the MTT method was performed. The five most active were selected and further tested on HeLa, MRC-5, and MCF-7 (breast carcinoma) cell lines. The examined compounds exhibit strong in vitro anticancer activities with moderate-to-high selectivity, inducing apoptotic cell death and cell cycle arrest in both HeLa and MCF-7 cell lines, but have little to no effect on the non-cancerous MRC-5 cell line.

A cascade process for directly converting nitriles (RCN) to cyanamides (RNHCN) via SO2F2-activated Tiemann rearrangement.

A simple, mild and practical process for the direct conversion of nitriles to cyanamides was newly discovered and exhibited a wide substrate scope as well as great functional group-tolerability (36 examples). In this efficient strategy, the in situ generated amidoximes obtained from the reaction of nitriles with hydroxylamine subsequently underwent Tiemann rearrangement, producing the corresponding cyanamides with great isolated yields under SO2F2. Additionally, the control experiments reportedly shed light on the tentative mechanism involved in the formation and elimination of the key intermediate: a sulfonyl ester.

Novel dauricine derivatives suppress cancer via autophagy-dependent cell death

Eleven dauricine derivatives were synthesized and evaluated for their anti-cancer effect in different cancer cells and their autophagic activity in HeLa model cell. Among these newly synthesized compounds, carbamates 2a, 2b, carbonyl ester 3a and sulfonyl ester 4a exhibited potent cytotoxic effects on tested cancer cells with IC50 values ranged from 2.72 to 12.53 μM, which were more potent than that of dauricine (higher than 15.53 μM). The above four derivatives are validated to induce autophagy-dependent cell death in HeLa cancer cells. These findings offer us a promising source for generating novel autophagic enhancers for anti-cancer therapy.

Coumarin sulfonates: New alkaline phosphatase inhibitors; in vitro and in silico studies

A library of coumarin derived sulfonyl esters (1–38) was synthesized by reacting various hydroxy coumarins with different alkyl and aryl sulfonyl chlorides. All compounds were evaluated for their potential to inhibit alkaline phosphatases (hTNAP and hIAP). Most of the compounds were found to be inhibitors of APs. Compound 20 was found to be the most active hIAP inhibitor (IC50 = 1.11 ± 0.15 μM), whereas, compound 13 was found to be the most active hTNAP inhibitor (IC50 = 0.58 ± 0.17 μM). Detailed structure activity relationship studies (SAR), and molecular docking studies were carried out to identify structural elements necessary for AP inhibition, in addition to rationalize most probable binding site interaction of the inhibitors with the AP enzymes.