Alkylation Of Sulfonamides Research Articles

Palladium-Catalyzed Selective Benzylic C-H Alkylation of Aromatic Sulfonamides with Maleimides.

An efficient method for the selective benzylic C-H alkylation of sulfonamides using maleimides has been developed. The reaction proceeds via the benzylic C(sp3)-H bond activation of sulfonamide in the presence of a Pd(II) catalyst without requiring any oxidant, additive, or external ligand. This methodology is highly compatible with a wide variety of substituted maleimides. A plausible reaction mechanism is also proposed to account for this alkylation reaction.

Antibacterial Activities and Underlying Mechanisms of the Compound SYAUP-491 against Xanthomonas oryzae pv. oryzae.

SYAUP-491 is a novel alkyl sulfonamide. In this study, in vivo and in vitro tests were performed along with a proteomic analysis to determine the effects and underlying mechanisms of the antibacterial activity of SYAUP-491 against the causative agent of bacterial leaf blight in rice. The antibacterial test results suggested that SYAUP-491 exhibited significant activities against Xanthomonas oryzae pv. oryzae (Xoo) in vitro and in vivo. The minimal EC50 values reached 6.96 μg/mL and the curative activity reached 74.1%. Detailed studies demonstrated that SYAUP-491 altered membrane permeability and caused morphological changes. Based on proteomics results, SYAUP-491 might inhibit bacterial protein synthesis. SYAUP-491 may disrupt and alter cell membrane permeability and could further act on ribosomes in the bacterial body. Given the above results, SYAUP-491 could serve as a new lead compound in the research of antibacterial control of plant pathogenic bacterial disease.

Photocatalyst-Free Activation of Sulfamoyl Chlorides for Regioselective Sulfamoyl-Oximation of Alkenes via Hydrogen Atom Transfer (HAT) and Halogen-Atom Transfer (XAT) Relay Strategy.

The use of readily available and diverse sulfamoyl chlorides for synthesizing sulfonamide compounds presents an intriguing, yet significantly underexplored strategy. Activating sulfamoyl chlorides via single-electron reduction poses challenges due to their high reduction potential. Alternatively, the SO2-Cl bond in sulfamoyl chlorides could be readily cleaved by XAT. However, the existing methodologies have been limited to either the use of photocatalyst or the monofunctionalization of activated alkenes. Here, we report a regioselective sulfamoyl-oximation of alkenes by involving the activation of sulfamoyl chlorides through a HAT and XAT relay strategy in a photocatalyst-free way. The key to this success lies in the dual roles of tert-butyl nitrite (TBN), which not only serves as the source of oximes but also acts as the HAT reagent to generate the crucial XAT reactive species. The exclusion of metal catalysts or photosensitizers for utilizing light energy renders this protocol versatile and universally applicable for synthesizing a broad range of structurally diverse oxime-containing alkyl sulfonamides.

Photoinduced Vicinal 1,2-Difunctionalization of Olefins for the Synthesis of Alkyl Sulfonamides.

Alkyl sulfonamides are an important class of bioactive molecules. Historical syntheses have relied on multistep sequences incorporating harsh reaction conditions. Photochemical methods have been limited to hydrosulfamoylation, installing only one substituent across an olefin. Herein, radical/polar crossover (RPC) is used to establish the first multicomponent 1,2-difunctionalization reaction incorporating a sulfonamide moiety and a second reaction partner. This protocol, exemplified on a range of olefins, utilizes various commercial sulfamoyl chlorides and organotrifluoroborates as coupling partners.

Sulfonamide Moiety as "Molecular Chimera" in the Design of New Drugs.

The -SO2NH- group is of great significance in modern pharmaceutical use since, in sulfa-drugs, it is possible to introduce easily chemical modifications, and even small changes may lead to an improved version of an already existing drug. This paper aims to describe updated information in the sulfonamide field with a particular focus on new mechanisms of action, especially if discovered by employing computational approaches. Research articles that focused on the use of the sulfonamide moiety for the design, synthesis, and in vitro/in vivo tests of various diseases were collected from various search engines like PubMed, Science Direct, Google Scholar, and Scopus, using keywords like sulfonamide moiety, aryl/heteroary lsulfonamides, alkyl sulfonamides, in silico drug design, etc. Conclusion: The more relevant reports highlighting the prominent role of sulfonamide moiety in drug discovery have been critically analyzed. Sulfonamides can be considered as "molecular chimera", which are found to form hydrogen bonds as well as interact with unipolar environments within proteins. Therefore, based on the analysis reported herein, it is strongly foresight that new entities can be developed easily to improve the available machinery helpful in the fight against new and emerging diseases.

Mono‐N‐Alkylation of Sulfonamides with Alcohols Catalyzed by Iridium N‐Heterocyclic Carbene‐Phosphine Complexes

AbstractA N‐heterocyclic carbene‐phosphine iridium complex is presented for the efficient and selective mono‐N‐alkylation of sulfonamides with alcohols based on a borrowing hydrogenation strategy. Herein, water is the only by‐product and this methodology thus offers a more environmentally benign and interesting alternative to the use of traditional alkylating reagents. This facile protocol tolerates a large number of (hetero) aromatic and aliphatic sulfonamides as well as (hetero) aromatic and aliphatic alcohols to obtain the desired product is high isolated yield (up to 98%). The alkylation completely retards after the formation of the secondary sulfonamide and no over‐alkylation was observed in all cases. The option to run the reaction under solvent‐free conditions as well as the scalability of this borrowing hydrogenation are key features of this protocol.

Late-stage sulfonic acid/sulfonate formation from sulfonamides via sulfonyl pyrroles

Sulfonamides are present in a range of useful molecules, such as drugs and agrochemicals. In recent years, the functionalization of sulfonamides via S–N bond cleavage has received increased attention. In this report, we detail an accessible and low-cost route for transforming primary sulfonamides into the corresponding sulfonic acids/sulfonates via sulfonyl pyrroles. The reaction is demonstrated with a range of substrates including aryl and alkyl sulfonamides, and in the late-stage functionalization of several sulfonamide-containing drug molecules.

Synthesis and biological evaluation of N-alkyl sulfonamides derived from polycyclic hydrocarbon scaffolds using a nitrogen-centered radical approach.

Polycyclic hydrocarbons (PH) provide intriguing potential as lipophilic scaffolds within medicinal chemistry, but are currently limited by the availability of synthetic tools for predictable modification of the PH unit. Herein we report the development of new methods for installation of a sulfonamide unit to PH cores. In the first method, a xanthate ester serves as reagent for aminosulfonation using pre-formed imidoiodinane as N-source. An investigation of the reaction mechanism was performed to implicate a process involving a N-centered radical. An additional method for sulfonamide installation is described that involves the use of commercially available reagents and operationally convenient conditions. Using the new synthetic methods, 22 compounds were prepared and screened for biological activity against 6 mammalian cell lines along with Gram-positive and Gram-negative bacterial strains. Results of the viability assays have identified compounds that exhibit higher potency than other known anticancer agents such as indisulam and ABT-751. Additionally, the physicochemical and drug-likeness properties of the synthesized compounds have been determined experimentally and using in silico predictive tools. The initial exploration into sulfonamide insertion into PH cores has resulted in a number of compounds that warrant further development to produce molecules with therapeutic value.

Photoredox-Mediated Mono- and Difluorination of Remote Unactivated Methylene C(sp3)-H Bonds of N-Alkyl Sulfonamides.

A photoredox-mediated δ-C(sp3)-H fluorination of sulfonyl-protected primary alkylamines with Selectfluor is developed. The reaction can proceed in excellent monofluorination selectivity for amine substrates without α substituent. For α-substituted substrates, a slightly modified reaction conditions with two rounds of operation gives the δ,δ-difluorination products in good yield. Mechanistic studies suggest SET oxidation of sulfonamide group directly generates the key sulfonamide N radical intermediate, which triggers a 1,5-HAT process to form the δ alkyl radical.

Enhanced Suppression of a Protein–Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an N-Acyl-N-alkyl Sulfonamide Warhead

Protein-protein interactions (PPIs) intimately govern various biological processes and disease states and therefore have been identified as attractive therapeutic targets for small-molecule drug discovery. However, the development of highly potent inhibitors for PPIs has proven to be extremely challenging with limited clinical success stories. Herein, we report irreversible inhibitors of the human double minute 2 (HDM2)/p53 PPI, which employ a reactive N-acyl-N-alkyl sulfonamide (NASA) group as a warhead. Mass-based analysis successfully revealed the kinetics of covalent inhibition and the modification sites on HDM2 to be the N-terminal α-amine and Tyr67, both rarely seen in traditional covalent inhibitors. Finally, we demonstrated prolonged p53-pathway activation and more effective induction of the p53-mediated cell death in comparison to a noncovalent inhibitor. This study highlights the potential of the NASA warhead as a versatile electrophile for the covalent inhibition of PPIs and opens new avenues for the rational design of potent covalent PPI inhibitors.

PhI(OAc)2 and iodine-mediated synthesis of N-alkyl sulfonamides derived from polycyclic aromatic hydrocarbon scaffolds and determination of their antibacterial and cytotoxic activities.

The development of new approaches toward chemo- and regioselective functionalization of polycyclic aromatic hydrocarbon (PAH) scaffolds will provide opportunities for the synthesis of novel biologically active small molecules that exploit the high degree of lipophilicity imparted by the PAH unit. Herein, we report a new synthetic method for C-X bond substitution that is speculated to operate via a N-centered radical (NCR) mechanism according to experimental observations. A series of PAH sulfonamides have been synthesized and their biological activity has been evaluated against Gram-negative and Gram-positive bacterial strains (using a BacTiter-Glo assay) along with a series of mammalian cell lines (using CellTiter-Blue and CellTiter-Glo assays). The viability assays have resulted in the discovery of a number of bactericidal compounds that exhibit potency similar to other well-known antibacterials such as kanamycin and tetracycline, along with the discovery of a luciferase inhibitor. Additionally, the physicochemical and drug-likeness properties of the compounds were determined experimentally and using in silico approaches and the results are presented and discussed within.

H‐*BEA Zeolite‐Catalyzed Nucleophilic Substitution in Allyl Alcohols Using Sulfonamides, Amides, and Anilines

Herein, we report a novel zeolite‐catalyzed nucleophilic substitution in allyl alcohols. The product yield was improved upon the addition of NaOTf (0.05 mol‐%) using the studied zeolites. The highest yields were observed using H‐*BEA(Si/Al2 = 40)/NaOTf. The scope of the reaction with respect to the nucleophile was examined using 1,3‐diphenylprop‐2‐ene‐1‐ol as a model substrate under optimized reaction conditions. p‐Substituted aryl sulfonamides bearing electron‐rich or electron‐deficient substituents, alkyl sulfonamides, and heteroaryl sulfonamides undergo the amidation reaction to produce their corresponding allyl sulfonamides in good yield. Amides and anilines exhibited low activity under the optimized conditions, however, performing the reaction at 90 °C produced the target product. The scope of the allyl alcohol was investigated using p‐toluenesulfonamide as the nucleophile and the reaction proceeded with a variety of allylic alcohols. To probe the practical utility of the H‐*BEA‐catalyzed amidation reaction, a gram‐scale reaction was performed using 1.01 g (4.8 mmol) of allyl alcohol, which afforded the target product in 88 % yield.

Copper‐Catalyzed N‐Arylation of Polysubstituted Pyridines Synthesized by the Novel Reaction of N‐Sulfonyl Ketenimine and Malononitrile‐Trichloroacetonitrile Adduct

In this study, we synthesized some new derivatives of N‐(4‐amino‐5‐cyano‐6‐(trichloromethyl)pyridin‐2‐yl)alkyl sulfonamides in the presence of a copper catalyst. A one‐pot reaction system was used, and four components participated in the process. These four components were sulfonyl azides, terminal alkynes, malononitrile, and trichloroacetonitrile. The reaction rate was increased by the use of copper (I) iodide as the catalyst and tetrahydrofuran was used as the solvent. We achieved the final compounds in moderate to good yields. Moreover, we converted “NH2” side group to N‐aryl by the use of various aryl halide analogs in acetonitrile as the solvent, under mild reaction and at the room temperature.

Manganese-Catalyzed N-Alkylation of Sulfonamides Using Alcohols.

An efficient manganese-catalyzed N-alkylation of sulfonamides has been developed. This borrowing hydrogen approach employs a well-defined and bench-stable Mn(I) PNP pincer precatalyst, allowing benzylic and simple primary aliphatic alcohols to be employed as alkylating agents. A diverse range of aryl and alkyl sulfonamides undergoes mono- N-alkylation in excellent isolated yields (32 examples, 85% average yield).

ChemInform Abstract: One‐Step Synthesis of Sulfonamides from N‐Tosylhydrazones.

The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides.

One-Step Synthesis of Sulfonamides from N-Tosylhydrazones.

The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides.

Novel binary deep eutectic electrolytes for rechargeable Li-ion batteries based on mixtures of alkyl sulfonamides and lithium perfluoroalkylsulfonimide salts

Ionic liquids (IL's) were proposed for use in Li-ion batteries (LIBs), in order to mitigate some of the well-known drawbacks of LiPF6/mixed organic carbonates solutions. However, their large cations seriously decrease lithium transference numbers and block lithium insertion sites at electrode-electrolyte interfaces, leading to poor LIB rate performance. Deep eutectic electrolytes (DEEs) (which share some of the advantages of ILs but possess only one cation, Li+), were then proposed, in order to overcome the difficulties associated with ILs. We report herein on the preparation, thermal properties (melting, crystallization, and glass transition temperatures), transport properties (specific conductivity and viscosity) and thermal stability of binary DEEs based on mixtures of lithium bis(trifluoromethane)sulfonimide or lithium bis(fluoro)sulfonimide salts with an alkyl sulfonamide solvent. Promise for LIB applications is demonstrated by chronoamperometry on Al current collectors, and cycling behavior of negative and positive electrodes. Residual current densities of 12 and 45 nA cm−2 were observed at 5 V vs. Li/Li+ on aluminum, 1.5 and 16 nA cm−2 at 4.5 V vs. Li/Li+, respectively for LiFSI and LiTFSI based DEEs. Capacities of 220, 130, and 175 mAh· g−1 were observed at low (C/13 or C/10) rates, respectively for petroleum coke, LiMn1/3Ni1/3Co1/3O2 (a.k.a. NMC 111) and LiAl0.05Co0.15Ni0.8O2 (a.k.a. NCA).

RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model.

Capsaicin, the primary pungent component of the chili pepper, has antitumor activity. Herein, we describe the activity of RPF151, an alkyl sulfonamide analogue of capsaicin, against MDA-MB-231 breast cancer cells. RPF151 was synthetized, and molecular modeling was used to compare capsaicin and RPF151. Cytotoxicity of RPF151 on MDA-MB-231 was also evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis, by flow cytometry, and Western blot analysis of cycle-related proteins were used to evaluate the antiproliferative mechanisms. Apoptosis was evaluated by phosphatidyl-serine externalization, cleavage of Ac-YVAD-AMC, and Bcl-2 expression. The production of reactive oxygen species was evaluated by flow cytometry. RPF151 in vivo antitumor effects were investigated in murine MDA-MB-231 model. This study shows that RPF151 downregulated p21 and cyclins A, D1, and D3, leading to S-phase arrest and apoptosis. Although RPF151 has induced the activation of TRPV-1 and TRAIL-R1/DR4 and TRAIL-2/DR5 on the surface of MDA-MB-231 cells, its in vivo antitumor activity was TRPV-1-independent, thus suggesting that RPF151 should not have the same pungency-based limitation of capsaicin. In silico analysis corroborated the biological findings, showing that RPF151 has physicochemical improvements over capsaicin. Overall, the activity of RPF151 against MDA-MB-231 and its lower pungency suggest that it may have a relevant role in cancer therapy.

N-Alkylation of Sulfonamides with Alcohols by Tf2O

Abstract N-sulfonylpyrrolidines and N-alkyl sulfonamides were efficiently prepared via alkylation of sulfonamides with 1,4-diols or alcohols by Tf2O. The reaction occurred under mild reaction conditions in moderate to high yields and tolerated aryl and aliphatic sulfonamides.

$$\hbox {Ph}_{3}\hbox {P/CCl}_{4}$$ Ph 3 P/CCl 4 as a highly efficient reagent for one-pot $$N$$ N -alkylation of sulfonamides from alcohols: a rapid route to $$N$$ N -alkyl sulfonamides synthesis

A mild, efficient, and selective protocol for the one-pot $$N$$ -alkylation of sulfonamides with alcohols using triphenylphosphine and carbon tetrachloride is described. In this method, treatment of alcohols with a mixture of triphenylphosphine, carbon tetrachloride, and potassium sulfonylamide salts in refluxing anhydrous DMF furnishes the corresponding $$N$$ -alkyl sulfonamides in good to excellent yields. This protocol is highly efficient for various structurally diverse alcohols and potassium sulfonylamide salts. In this paper the influence of solvents and various reagents as sources for electrophilic-halogen instead of carbon tetrachloride in combination with triphenylphosphine have been examined. This protocol demonstrates the selectivity between primary and secondary alcohols. A plausible mechanism for this protocol has been described.