Synthesis Of Sulfonamides Research Articles

Overview on Design and Synthesis of Sulfonamide Derivative through Condensation of Amino Group Containing Drug

In medicinal and non-pharmacological chemistry, sulfonamides (SN) are an advisory functional group that forms the basis of many drugs. As such, they are very important. Recently, very significant techniques for the synthesis of sulfonamides have been developed. Numerous pharmacologic activities, including anti-dydropteroate synthetase and anti-carbonic anhydrase, are displayed by sulfonamides. Derivatives of sulfonamides can be used to treat a range of medical conditions, including glaucoma, hypoglycemia, stasis, diarrhea, and inflammation. Our current work has concentrated on creating and synthesizing sulfonamide derivatives via condensation reaction between amino group-containingdrugs.The functionality of sulfonamideinthe clinical trial for the treatment of various medical conditions. For these reasons, development of an efficient process for the synthesis of sulfonamides has always been in the focus for research in organic field synthesis. The most typical method for the synthesis involves reaction between primary or secondary amines and sulfonyl chloride in presence of organic or inorganic bases. Although this method is effective, but the nucleophilicity of amines may vary depending on the groups attached to it. In general, primary amines are highly reactive, whereas secondary amines show very low to almost nil reactivity. In this study, we have reviewed past and recent biological effects of some sulfonamide derivatives and some advances efficient synthetic procedures for some types of sulfonamides. A sulfonamide is a functional group that is the basis of several sulfa drugs and thereby are very much important scaffolds in medicinal as well as in synthetic organic chemistry. Recently very important methodologies have been developed for the synthesis of sulfonamide. This complex review article covers the recent developments (mainly in period 2013- 2019) of powerful methodologies for the synthesis of sulfonamide compounds, particularly where SO2N(R) moiety is not present in a cyclic structure and their applications in various fields during this period. A critical view of the mechanisms of the developed methodologies together with the scope and limitation of these methods adds an extra dimension to the text

Optimization of Reaction Conditions for On‐DNA Synthesis of Ureas, Thioureas, and Sulfonamides

Isocyanates, isothiocyanates, and sulfonyl chlorides can be found in valuable building blocks for the construction of DNA‐Encoded Chemical Libraries (DELs), leading to the generation of ureas, thioureas, and sulfonamides. We present the development of reaction conditions for the addition of isocyanates, isothiocyanates, and sulfonyl chlorides to single‐stranded oligonucleotides, with a focus on maximizing on‐DNA conversion while preserving DNA integrity. We explored and optimized reaction parameters to achieve efficient coupling and minimize DNA degradation and by‐product formation. The protocols reported in this paper broaden the scope of DNA‐compatible reactions and may be applicable to the construction of novel DELs.

Based on magnetically recoverable catalysts: a green strategy to sulfonamides.

The synthesis of sulfonamides, a class of compounds with significant pharmaceutical and medicinal applications, has seen remarkable advancements with the advent of magnetic nanocatalysts. Magnetic nanocomposites are one of the most efficient and widely used catalysts, and they are in complete harmony with the principles of modern green chemistry from the point of view of catalysis. These catalysts, typically composed of metal complexes supported on magnetic nanoparticles, offer unique advantages such as ease of recovery and reusability, which are crucial for sustainable and eco-friendly chemical processes. This review comprehensively examines recent developments in applying magnetic nanocatalysts to prepare sulfonamides. Key focus areas include the design and synthesis of various magnetic nanocatalysts (MNC), their catalytic performance in different reaction conditions, and mechanistic insights into their catalytic activity. By summarizing the latest research and technological advancements, this article aims to provide a valuable resource for researchers and practitioners in catalysis and pharmaceutical chemistry.

Therapeutic Potential of Aryl Sulfonamides: Synthesis, Antiproliferative, Antioxidant, Antiparasitic and Molecular Docking Studies

AbstractThis study outlines the synthesis of pyrazine sulfonamides (3 a–3 i) along with halo‐phenyl derivatives (4 a–4 j and 5 a–5 e). The antiproliferative effects were tested against MCF‐7 breast cancer, and colon carcinoma HT‐29, HCT‐116 WT, and HCT‐116 p53 knock‐out mutant cell lines. Compounds 3 b and 3 c were notably active against HCT‐116 WT cells, while 3 e and 3 h were moderately effective against MCF‐7 cells. Among the halo‐phenyl sulfonamides, 4e and 4j were active against MCF‐7 cells, and 5 b was active against HCT‐116 WT cells. The most promising compounds were evaluated against non‐tumorigenic cells, demonstrating cancer selectivity. Compounds 3 b, 3 c, 3 e, 3 h, and 5 b showed dose‐dependent inhibition of colony formation. Compound 3 f exhibited free radical scavenging activity comparable to ascorbic acid. Molecular docking revealed strong binding to thymidylate synthase (3 b, 5 b), Akt‐3 protein kinase (3 e, 3 h, 4 e, 4 j), and tyrosinase (3 f, 3 h). The compounds also exhibited antiparasitic activity against Toxoplasma gondii and Leishmania major, with modifications enhancing selectivity for T. gondii. Substitutions in compounds 4 b and 4 d increased activity against T. gondii while reducing toxicity. Notably, compound 4 f emerged as a T. gondii‐selective lead drug. These findings suggest sulfonamides may help treat complex diseases like cancer and infections.

Effect of Nucleophile Deprotonation on SuFEx: Synthesis of Sulfonamides

In a quest for efficient SuFEx-type transformations we studied reactions of amines with 4-fluorobenzenesulfonyl fluoride. The substrate may react by fluoride substitution at the aromatic ring (SNAr) and at the sulfonyl group (SuFEx). Analysis of the reaction course revealed that deprotonation of N-nucleophile controls the reaction course: neutral amines in DMF attack at the aromatic ring, whereas amine anions, generated in equilibrium with LiHMDS in toluene, favor sulfonyl substitution. Using the base-promoted conditions we synthesized a set of substituted sulfonamides in high yields.

Electro-promoted radical-radical cross-coupling reaction to synthesize sulfonamides

An electrochemical decarbonylation of DMF to achieve N,N-dimethyl amino radical and denitrification of sulfonyl hydrazide to achieve sulfonyl radical in the absence of transition metal and additional oxidant was reported here. Signifyingly, cross-coupling reaction rather than homocoupling reactions completely prevail in competition to obtain sulfonamides, which usually exist as skeletons of pharmaceuticals. This work provides a new method for cracking DMF into N,N-dimethylamino radical, and found a value-added application of this industrialized bulk chemical to the synthesis of sulfonamides.

Generation of Sulfamoyl Radicals via Visible‐Light Mediated Fixation of Sulfur Dioxide for the Synthesis of Sulfonamides

Abstract. Herein, we report a new approach for the light‐mediated generation of sulfamoyl radicals using sulfur dioxide as key building block and the direct application of these radicals in the synthesis of sulfonamides. In the presence of different photoredox catalysts, sulfamoyl radicals can be generated directly from SO2 or the SO2 surrogate DABSO (1,4‐diazabicyclo[2.2.2]octane·bis (sulfur dioxide) adduct) and N‐aminopyridinium salts as nitrogen radical precursors. Trapping of the in situ generated sulfamoyl radicals with selected electron‐rich olefins affords different sulfonamides in up to 86% yield in a three‐component procedure. This transformation provides an attractive and complementary approach for the in situ generation of sulfamoyl radicals as synthetic intermediates for the assembly of the sulfonamide functionality, a motif in active pharmaceutical ingredients.

Ligand‐Enabled Pd‐Catalyzed sp3 C−H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease

AbstractThe development of simplified synthetic strategy to create structurally and functionally diverse pseudo‐natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand‐enabled Pd(II)‐catalyzed sp3 C−H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo‐natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C−H activation is also demonstrated by an unprecedented enantioselective sp3 C−H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro‐grafted macrocyclic sulfonamide 2 a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3).

Ligand-Enabled Pd-Catalyzed sp3 C-H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease.

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalyzed sp3 C-H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C-H activation is also demonstrated by an unprecedented enantioselective sp3 C-H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2 a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3).

Photocatalytic Synthesis and Functionalization of Sulfones, Sulfonamides and Sulfoximines.

Sulfur(VI)-based functional groups are popular scaffolds in a wide variety of research fields including synthetic and medicinal chemistry, as well as chemical biology. The growing interest in sulfur(VI)-containing molecules has motivated the scientific community to explore new methods to synthesize and modify them. Here, photocatalysis plays a key role granting access to new types of reactivity under mild reaction conditions. In this Perspective, we present a selection of works reported in the last six years focused on the photocatalytic assembly and reactivity of sulfones, sulfonamides, and sulfoximines. We addressed the key synthetic intermediates for each transformation, while discussing limitations and strength points of the protocols. Future directions of the field are finally presented.

Synthesis of 2-aminothiazole sulfonamides as potent biological agents: Synthesis, structural investigations and docking studies

A simplified synthetic approach involving sulfonylation followed by amino group alkylation produced new 2-aminothiazole derivatives. UV/Vis, infrared, and NMR spectroscopies confirmed their structures. Compounds 36, 22, 34, and 35 showed strong inhibition against Jack bean and Bacillus Pasteurii urease, with IC50 values from 14.06 to 20.21 μM/mL. Compounds 20, 26, 21, 29, 30, 31, and 32 exhibited potent inhibitory effects against α-glucosidase and α-amylase, with IC50 values between 20.34 and 37.20 μM/mL. Compounds 33, 26, and 27 demonstrated potent DPPH scavenging, with IC50 values around 34.4–39.2 μM/mL. FMO analysis showed compounds 21, 22, 24, and 25 having parallel aromatic ring systems due to π cloud interactions, while compounds 32 and 38 had distinct electronic density distributions. Compound 22 had HOMO and LUMO energy gaps of 5.805 eV, with bromo and fluoro substitutions in compounds 21 and 24 slightly increasing the gaps to 6.089 eV and 6.078 eV, respectively. Nitro groups in compounds 25 and 32 reduced the gaps to 0.384 eV and 1.187 eV. All compounds demonstrated high gastrointestinal absorption, non-permeability to the blood-brain barrier, and optimal skin permeation (Log Kp between −5.83 and −6.54 cm/s). Compounds 22, 24, and 38 had promising QED scores of 0.719, 0.707, and 0.860, respectively, with synthetic accessibility scores from 2.057 to 2.517. ADMET predictions indicated minimal toxicity, cardiovascular safety, and significant inhibitory potential for CYP enzymes. Strong in silico binding affinities (binding energies −5.75 to −7.63 kcal/mol) and metabolic stability suggest these derivatives are promising candidates for further drug development.

Sandmeyer Chlorosulfonylation of (Hetero)Aromatic Amines Using DABSO as an SO2 Surrogate.

Sulfonyl chlorides not only play a crucial role in protecting group chemistry but also are important starting materials in the synthesis of sulfonamides, which are in-demand motifs in drug discovery chemistry. Despite their importance, the number of different synthetic approaches to sulfonyl chlorides is limited, and most of them rely on traditional oxidative chlorination chemistry from thiol precursors. In this report, we disclose a novel Sandmeyer-type sulfonyl chloride synthesis from feedstock anilines and DABSO, used as a stable SO2 surrogate, in the presence of HCl and a Cu catalyst. The method works on a wide range of anilines and allows for the isolation of the sulfonyl chloride after aqueous workup or its direct conversion into the sulfonamide by simple addition of an amine after the completion of the Sandmeyer reaction. The scalability of this method was demonstrated on a 20 g scale, and the corresponding heterocyclic sulfonyl chloride was isolated in 80% yield and excellent purity.

Library‐Friendly Synthesis of Bicyclo[1.1.1]pentane‐Containing Sulfonamides via a Transition Metal‐Free Three‐Component Reaction

AbstractHerein we report the synthesis of bicyclo[1.1.1]pentane (BCP)‐containing sulfonamides via a transition metal‐free process of a three‐component reaction among BCP‐containing N‐tosyl hydrazones, 1,4‐diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), and amines. Different from existing methods to synthesize BCP‐containing sulfonamides, our method avoids the usage of sulfonyl halides, which could be challenging due to chemical instabilities. We have also demonstrated that this methodology is suitable for library synthesis of such sulfonamides. As a result, we can expect future application in drug discovery.

Magnetic Nanoparticles Immobilized Palladium Complex: A Novel and Highly Active Catalyst for Synthesis of Sulfonamides

Magnetic Nanoparticles Immobilized Palladium Complex: A Novel and Highly Active Catalyst for Synthesis of Sulfonamides

C(sp3)–H sulfinylation of light hydrocarbons with sulfur dioxide via hydrogen atom transfer photocatalysis in flow

Sulfur-containing scaffolds originating from small alkyl fragments play a crucial role in various pharmaceuticals, agrochemicals, and materials. Nonetheless, their synthesis using conventional methods presents significant challenges. In this study, we introduce a practical and efficient approach that harnesses hydrogen atom transfer photocatalysis to activate volatile alkanes, such as isobutane, butane, propane, ethane, and methane. Subsequently, these nucleophilic radicals react with SO2 to yield the corresponding sulfinates. These sulfinates then serve as versatile building blocks for the synthesis of diverse sulfur-containing organic compounds, including sulfones, sulfonamides, and sulfonate esters. Our use of flow technology offers a robust, safe and scalable platform for effectively activating these challenging gaseous alkanes, facilitating their transformation into valuable sulfinates.

Palladium-Catalyzed Amino-Sulfonylation of Aryl Iodide Derivatives via the Insertion of Sulfur Dioxide: One-Pot Synthesis of Aryl Primary Sulfonamides with Thiourea Dioxides

AbstractA palladium-catalyzed one-pot amino-sulfonylation of aryl iodide derivatives with thiourea dioxide, PdCl2dppf, and one-pot added hydroxylamine-O-sulfonic acid is presented. This amino-sulfonylation gave structure diversity to aryl primary sulfonamides and features good functional group compatibility, mild reaction conditions, excellent regioselectivity, and moderate to good yields. The robustness and potential of this method have also been successfully demonstrated by late-stage elaboration and gram-scale reaction. This approach achieves the divergent construction of the complex core structures that are prevalent in highly valuable natural products such as Sulpiride, Venetoclax, and Furosemide­.

Synthesis and characterization of sulfonamide appended rigid phenyl-based and non-rigid 1,4-benzodioxan-based ring systems and their Pt(II) complexes towards potential therapeutic targets

Two novel non-rigid; 1,4-benzodioxan (bzd) based and rigid; 4-methylbiphenyl (4-Mebip) based di-(2-picolyl)amine derived sulfonamide ligands, and their cis-dichloroplatinum(II) complexes have been synthesized. The ligands; L1: N(SO2)(bzd)dpa and L2: N(SO2)(4-Mebip)dpa were synthesized via N-sulfonylation of di-(2-picolyl)amine in good yield. Their platinum(II) complexes; C1: [PtCl2(N(SO2)(bzd)dpa)], C2: [PtCl2(N(SO2)(4-Mebip)dpa)]·CH3CN were synthesized and characterized by 1H NMR, FTIR, UV–Vis and fluorescence spectroscopies. Structural studies revealed that the L1 and L2 ligands coordinate Pt(II) in a bidentate mode in C1 and C2 complexes, forming an eight-membered chelate ring. Interestingly, L1 possesses two conformations because the dioxan ring exists with a 95:5 occupancy ratio. The L2 ligand crystal undergoes a phase transition to triclinic form with twinning at 90 K whereas, at 150 K, the ligand exists in a monoclinic system; the populations of the two orientations for one pyridine substituent are approximately 78:22. The 1H NMR spectra of both Pt complexes obtained in DMSO‑d6 revealed two doublets (exo-CH2 and endo-CH2) for the magnetically inequivalent methylene protons, in contrast to their uncoordinated ligands, which show a singlet peak for the methylene protons. The NCI-H292 (non-small cell lung cancer cells) and MRC-5 (human normal lung fibroblast cells) were used to examine the in vitro cytotoxic activity of all synthesized compounds. All tested compounds demonstrated notable cytotoxicity against NCI-H292 cells, with the most pronounced cytotoxic effect being displayed by [PtCl2(N(SO2)(4-Mebip)dpa)]·CH3CN (C2). Docking studies strengthen in vivo antiproliferation activity where specific interactions with AKT1, BAX, STK-11, and BCL-2 were explored. Further predictions revealed that the compounds have inhibitory effects on COX-2 and PDE10A proteins.

Iron‐Based Deep Eutectic Solvents: Key Players for Amide and Sulfonamide Synthesis and Alcohol Oxidation

AbstractA sustainable protocol has been devised for the oxidation of activated secondary alcohols to their corresponding carbonyl compounds, as well as their utilization as selective mono‐alkylating reagents for both amide and arylsulfonamide derivatives. These reactions proceed smoothly and in good yields (up to 98 %) when conducted in Fe‐based deep eutectic solvents (DESs), which serve dual roles as solvents and catalysts. Operating under mild (40 °C) and aerobic conditions, these transformations are completed within a 4 h time frame. A pharmacologically relevant amide derivative, specifically a PMRT1 inhibitor, has also been successfully synthesized on a 3 g‐scale utilizing a reusable FeCl3 ⋅ 6H2O/glycerol Lewis acidic DES.

Synthesis, Characterization, Antibacterial Evaluation, and Enzyme Inhibition Activity of a Novel Nitrogen-containing Heterocyclic Sulfonamide

Synthesis, Characterization, Antibacterial Evaluation, and Enzyme Inhibition Activity of a Novel Nitrogen-containing Heterocyclic Sulfonamide

Asymmetric synthesis of allylic sulfonamides with axially and central chirality via palladium-catalyzed of atroposelective N-allylic alkylation

Axially chiral anilide compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as chiral catalysts, biologically active scaffolds and functional materials. Compared to the C–C axially chiral molecules, the synthesis of axially chiral anilide compounds is a challenge owing to the lower rotation barriers. Herein, the construction of chiral allylic amine bearing axial chirality and central chirality via Pd-catalyzed atroposelective N-allylic alkylation reaction of cyclic vinyl carbonates and sulfonamides is reported. A diverse range of chiral sulfonamides bearing axial chirality and central chirality were synthesized in high yields and excellent enantioselectivities (up to 92 ​% yield and 99 ​% ee). In addition, the practical application of this protocol was also demonstrated by gram-scale synthesis and derivatives of the compound.