Sulfonate Research Articles

Transition-metal-catalyzed remote meta-C[sbnd]H alkylation and alkynylation of aryl sulfonic acids enabled by an indolyl template

Transition-metal-catalyzed remote sp2CH functionalization of aryl sulfonic acids was hardly ever realized owing to competitive ortho-CH functionalization of aryl sulfonates and electron-deficient nature of phenyl ring. Herein, with the assistance of a practical biaryl indolyl directing template, palladium-catalyzed remote sp2CH alkylation of aryl sulfonic acids have been achieved in moderate to good yields with exclusive meta selectivity. Moreover, remote meta-selective CH alkynylation of aryl sulfonic acids was also accomplished with a rhodium catalyst. These meta-CH functionalized products proved to be the superior synthetic precursors, which are difficult to access using the conventional strategy.

Metal-organic framework boosts heterogeneous electron donor–acceptor catalysis

Metal-organic framework (MOF) is a class of porous materials providing an excellent platform for engineering heterogeneous catalysis. We herein report the design of MOF Zr-PZDB consisting of Zr6-clusters and PZDB (PZDB = 4,4’-(phenazine-5,10-diyl)dibenzoate) linkers, which served as the heterogeneous donor catalyst for enhanced electron donor–acceptor (EDA) photoactivation. The high local concentration of dihydrophenazine active centers in Zr-PZDB can promote the EDA interaction, therefore resulting in superior catalytic performance over homogeneous counterparts. The crowded environment of Zr-PZDB can protect the dihydrophenazine active center from being attacked by radical species. Zr-PZDB efficiently catalyzes the Minisci-type reaction of N-heterocycles with a series of C-H coupling partners, including ethers, alcohols, non-activated alkanes, amides, and aldehydes. Zr-PZDB also enables the coupling reaction of aryl sulfonium salts with heterocycles. The catalytic activity of Zr-PZDB extends to late-stage functionalization of bioactive and drug molecules, including Nikethamide, Admiral, and Myristyl Nicotinate. Systematical spectroscopy study and analysis support the EDA interaction between Zr-PZDB and pyridinium salt or aryl sulfonium salt, respectively. Photoactivation of the MOF-based EDA adduct triggers an intra-complex single electron transfer from donor to acceptor, giving open-shell radical species for cross-coupling reactions. This research represents the first example of MOF-enabled heterogeneous EDA photoactivation.

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery

In Vitro and In Silico Evaluation of Amylase, Tyrosinase, and Pancreatic Lipase Inhibitions of Novel Benzothiazole‐Sulfonate Derivatives

AbstractThis paper provides a comprehensive account of the synthesis and assessment of newly developed aryl sulfonate derivatives based on benzothiazole as enzyme inhibitors, specifically focusing on their ability to target tyrosinase, amylase, and pancreatic lipase. The assessments were performed utilizing experimental (in vitro) and computational (in silico) methodologies. For this aim, nine different aryl sulfonate derivatives were synthesized. The synthesized compounds were subjected to structural characterizations by utilizing Nuclear Magnetic Resonance (1H NMR, 13C NMR) and High‐Resolution Mass Spectrometry (HRMS) studies, which provided confirmation of their structural properties. The inhibitory efficiency of the compounds was determined by measuring their 50 % inhibitory concentration (IC50) values and comparing them with the standard inhibitory compounds. According to the in vitro amylase activity, benzo[d]thiazol‐2‐yl 4‐methylbenzenesulfonate showed the best inhibition with the lowest IC50 value (43.31±4.3 μM) which was calculated to be at a close level to the IC50 value of standard acarbose (38.50±3.8 μM). Also, benzo[d]thiazol‐2‐yl 4‐bromobenzenesulfonate (22.73±4.15 μM) and benzo[d]thiazol‐2‐yl 4‐chlorobenzenesulfonate (25.28±1.95 μM) were calculated to have the lowest IC50 values and the most effective inhibition capacities against pancreatic lipase. Benzo[d]thiazol‐2‐yl 4‐fluorobenzenesulfonate and benzo[d]thiazol‐2‐yl 4‐methylbenzenesulfonate significantly exhibited superior tyrosinase inhibition compared to other derivatives and conventional kojic acid. In silico molecular docking affirmed that benzo[d]thiazol‐2‐yl naphthalene‐2‐sulfonate presented the highest binding affinities to the studied enzymes, with values of −7.8 kcal/mol for tyrosinase, −10.7 kcal/mol for pancreatic lipase, and −9.4 kcal/mol for α‐amylase. The pharmacokinetic characteristics and drug‐likeness of the synthesized sulfonate derivatives were also evaluated using absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. Density Functional Theory (DFT) calculations were employed at the DFT/B3LYP/6‐311 g(d,p) level of theory to investigate the electronic characteristics of the compounds, therefore facilitating the comprehension of the reported enzyme inhibitory actions. In summary, our research highlights the potential of benzothiazole aryl sulfonate derivatives as effective enzyme inhibitors that hold promise for therapeutic applications.

Interactions and mechanisms of sulfonium salts with metal interfaces: An in-depth computational exploration of COSMO-RS profiles, quantum chemistry and molecular dynamics on iron, copper, and aluminum

Sulfonium salts (SSs) exhibit diverse structural and electronic attributes, offering rich prospects in corrosion inhibition strategies. This research employed a combination of methodologies, such as COSMO-RS and Density Functional Theory (DFT), to investigate six specific SSs, including Phenacyl dimethyl sulfonium bromide (SH) and its p-derivatives 4-Methyl-SH (SM), 4-Chloro-SH (SC), 4-Bromo-SH (SB), 4-Methoxy-SH (SMe), and 4-Nitro-SH (SN). Additionally, Molecular Dynamics (MD) simulations were utilized to examine their adsorption configurations and affinities to Fe, Cu, and Al surfaces. The initial investigation through COSMO-RS sigma-profiles confirmed the SSs' propensity for hydrogen bonding in water. Quantum chemical calculations (QCCs) further elucidated the distinctive reactivity effects of various functional groups. For instance, methyl-substituted SS displayed remarkable reactivity with metals, whereas nitro groups led to strong electron acceptance in the SN molecule. Fukui functions identified pronounced electrophilic and nucleophilic characteristics within atoms, with carbonyl atoms emerging as key reactive sites. MD simulations provided insights into the adsorption of SSs on metal surfaces, revealing parallel disposition as the most stable mode and a strong affinity towards copper, iron, and aluminum, in the order of SM > SMe > SH > SB > SC > SN. This correlation aligned with the ΔN data. The study revealed the substantial effects of both methyl and methoxy groups on SSs' reactivity with metals, with electron-withdrawing groups exerting a negative influence. Overall, the findings enrich our comprehension of SSs and offer a solid foundation for their further exploration and utilization, especially in customized design and applications such as corrosion protection.

Dithiolation of Alkenyl Sulfonium Salts with Arylthiols to Access 1,2-Dithioalkanes.

A dithiolation of alkenyl sulfonium salts with arylthiols is described, affording a series of 1,2-dithioalkanes in high yields. This protocol features mild and catalyst-free conditions and involves the formation of two C-S bonds sequentially via the regioselective addition of an arylthiol to the unsaturated C═C bonds, followed by the attack of another arylthiol to form 1,2-dithioalkanes exclusively.

Stereoselective Synthesis of Fluoroalkanes via FLP Mediated Monoselective C─F Activation of Geminal Difluoroalkanes.

A method of desymmetrization of geminal difluoroalkanes using frustrated Lewis pair (FLP) mediated monoselective C-F activation where a chiral sulfide is the Lewis base component is reported. The stereoselective reaction provides generally high yields of diastereomeric sulfonium salts with dr of up to 95:5. The distribution of diastereomers is found to be thermodynamically controlled via facile sulfide exchange. The use of enantiopure chiral sulfides allows for high stereospecificity in nucleophilic substitution reactions and the formation of stereoenriched products.

Convenient high resolution mass spectrometry characterization of aromatic sulfur-containing petroleum components following by preliminary S-alkylation with aliphatic alcohols

This paper describes rather suitable and variable preliminary derivatization strategy that may precede the molecular level characterization of sulfur-containing compounds of a particularly aromatic nature by high-resolution MALDI and ESI mass spectrometry. We demonstrated for the first time that free aliphatic alcohols (primary 1-alkanols C3–C20) in the presence of triflic acid provide easy S-alkylation of not only saturated sulfides but also most typical aromatic sulfur-containing compounds (benzothiophene, dibenzothiophene and their homologues) widely distributed and frequently analyzed in oil. The reaction proceeds quantitatively at rather mild conditions and gives rise to corresponding S-alkyl sulfonium salts the cation moieties of which can be detected using MALDI and ESI mass spectrometry with excellent signal/noise (S/N) ratios; the response ratios for target ions being quite close for both methods. Collision-induced dissociation (CID) of S-alkylsulfonium cations proceeds only by the elimination of entire S-alkyl group yielding protonated molecule of the analyte. This process can be useful for a reliable determination of target aromatic heterocyclic compounds in complex mixtures. The applicability of the method is illustrated by the analysis of deasphalted medium petroleum sample. The proposed derivatization principle is considered to be highly applicable as an alternative approach to routine characterization and sensitive determination of most typical sulfur-containing compounds and particularly of aromatic S-heterocycles in crude oils by soft-ionization mass spectrometry methods.

Recent Advances in Monocomponent Visible Light Photoinitiating Systems Based on Sulfonium Salts

During the last decades, multicomponent photoinitiating systems have been the focus of intense research efforts, especially for the design of visible light photoinitiating systems. Although highly reactive three-component and even four-component photoinitiating systems have been designed, the complexity to elaborate such mixtures has incited researchers to design monocomponent Type II photoinitiators. Using this approach, the photosensitizer and the radical/cation generator can be combined within a unique molecule, greatly simplifying the elaboration of the photocurable resins. In this field, sulfonium salts are remarkable photoinitiators but these structures lack absorption in the visible range. Over the years, various structural modifications have been carried out in order to redshift their absorptions in the visible region. In this work, an overview of the different sulfonium salts activable under visible light and reported to date is proposed.

Cobalt-Catalyzed Reductive Cross-Coupling To Construct Csp3-Csp3 Bonds via Csp3-S and Csp3-X Bonds Activation.

A cross-electrophilic coupling of benzyl sulfonium salts with alkyl halides forming Csp3-Csp3 bonds is described by using a Co-based catalytic system. The activation of the stable Csp3-S bond of benzyl sulfonium salts under mild reaction conditions leads to various functionalized alkyl derivatives. Preliminary mechanistic studies suggest the involvement of alkyl radicals formed from both alkyl halides and benzyl sulfoniums through a single electron transfer.

Intra- and Intermolecular Cation-π Interactions between Onium Salts and Alkynes/Acetylene: Experimental and Theoretical Insights.

Cation-π interactions between various onium salts, alkynes, and acetylene were studied, taking into account the substituents of the triple bond, the nature of the anions, and the polarity of the solvent, through a combination of MP2 calculations and experiments. In an intramolecular setting, these data (including single-crystal X-ray crystallography) concurred with the stability of folded conformers of alkynyl onium salts, even substituted with electron-withdrawing groups. To examine the contribution of these interactions on the alkyne electronic population, a thorough in silico study was carried out using natural bonding orbital analysis of the conformers. Intramolecular interactions from sulfonium salt tethered to phenylalkyne were highlighted, as illustrated above by the computed folded conformation (MP2) along with noncovalent interaction (NCI) analysis. Furthermore, investigations of intermolecular interactions, involving acetylene or phenylacetylene with various onium ions, revealed the high energy interactions of their complexes with phenyldimethylsulfonium chloride, as illustrated above with the complex PhC≡CH/PhMe2SCl (MP2 calculations and NCI analysis).

Electrochemical Synthesis of S-Aryl Dibenzothiophenium Triflates as Precursors for Selective Nucleophilic Aromatic (Radio)fluorination.

A novel electrosynthetic approach to aryl dibenzothiophenium salts, including the direct intramolecular formation of a C-S bond in a metal-free, electrochemical key step under ambient conditions, is reported. The broad applicability of this method is demonstrated with 14 examples, including nitrogen-containing heterocycles in isolated yields up to 72%. The resulting sulfonium salts can be used as precursors for fluorine labeling to give [18F]fluoroarenes as found in PET tracer ligands.

Visible Light-Accelerated Palladium-Catalyzed Thiocarbonylation Using Oxalic Acid Monothioester with Aryl/Alkenyl Sulfonium Salts.

Herein, we present a decarboxylative thiocarbonylation of aryl and alkenyl sulfonium salts with oxalic acid monothioethers (OAMs), which can be achieved by visible light-accelerated palladium catalysis. Sulfonium salts are widely available, and OAM is an easily accessible and stored reagent; this mild reaction method can also be used for the synthesis of different types of thioester compounds. The reaction represents a new application of visible light-accelerated palladium catalysis in catalytic decarboxylative cross-couplings.

Synthetic Applications of Sulfonium Salts as Aryl Radical Precursors

AbstractThe utilization of aryl radicals as open‐shelled intermediates has become an essential tool for both conventional and state‐of‐the‐art synthetic chemistry. However, the current methods for generating aryl radicals are still inefficient, greatly impeding their practical applications. Encouragingly, sulfonium salts have emerged as appealing sources of aryl radicals for a wide range of transformations aimed at creating novel chemical bonds driven by their distinctive structural attributes and chemical tendencies. This review primarily focuses on the specific reaction mechanisms underlying the cleavage of C−S bonds in sulfonium salts, leading to the generation of corresponding aryl radicals within diverse reaction conditions.

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery

AbstractThe pharmacokinetics of pharmaceutical drugs can be improved by replacing C−H bonds with the more stable C−D bonds at the α‐position to heteroatoms, which is a typical metabolic site for cytochrome P450 enzymes. However, the application of deuterated synthons is limited. Herein, we established a novel concept for preparing deuterated reagents for the successful synthesis of complex drug skeletons with deuterium atoms at the α‐position to heteroatoms. (dn‐Alkyl)diphenylsulfonium salts prepared from the corresponding nondeuterated forms using inexpensive and abundant D2O as the deuterium source with a base, were used as electrophilic alkylating reagents. Additionally, these deuterated sulfonium salts were efficiently transformed into dn‐alkyl halides and a dn‐alkyl azide as coupling reagents and a dn‐alkyl amine as a nucleophile. Furthermore, liver microsomal metabolism studies revealed deuterium kinetic isotope effects (KIE) in 7‐(d2‐ethoxy)flavone. The present concept for the synthesis of deuterated reagents and the first demonstration of a KIE in a d2‐ethoxy group will contribute to drug discovery research based on deuterium chemistry.

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery.

The pharmacokinetics of pharmaceutical drugs can be improved by replacing C-H bonds with the more stable C-D bonds at the α-position to heteroatoms, which is a typical metabolic site for cytochrome P450 enzymes. However, the application of deuterated synthons is limited. Herein, we established a novel concept for preparing deuterated reagents for the successful synthesis of complex drug skeletons with deuterium atoms at the α-position to heteroatoms. (dn -Alkyl)diphenylsulfonium salts prepared from the corresponding nondeuterated forms using inexpensive and abundant D2 O as the deuterium source with a base, were used as electrophilic alkylating reagents. Additionally, these deuterated sulfonium salts were efficiently transformed into dn -alkyl halides and a dn -alkyl azide as coupling reagents and a dn -alkyl amine as a nucleophile. Furthermore, liver microsomal metabolism studies revealed deuterium kinetic isotope effects (KIE) in 7-(d2 -ethoxy)flavone. The present concept for the synthesis of deuterated reagents and the first demonstration of a KIE in a d2 -ethoxy group will contribute to drug discovery research based on deuterium chemistry.

Co‐Catalyzed Reductive Cross‐Couplings of Csp3−S with Callyl−O Electrophiles to form Csp3−Csp3 Bonds

AbstractCross‐electrophilic coupling of various benzyl sulfonium salts with Callyl−O electrophiles is described using a simple Co−Mn catalytic system. This catalytic system is able to activate both the stable Csp3−S bond of sulfonium salts and the Csp3−O bond of allylic acetate or ether under mild reaction conditions to form various functionalized alkyl olefinic compounds. Allyl methyl ethers were employed for the first time in transition metal‐catalyzed cross‐electrophilic coupling to build Csp3−Csp3 bonds. Preliminary mechanistic studies suggested the involvement of benzyl radicals generated from C−S bond cleavage through a single electron transfer.

Copper‐Catalyzed Highly Stereoselective Hydrodifluoroallylation of Cyclopropenes and Alkenyl Boronates with 3,3‐Difluoroallyl Sulfonium Salts†

Comprehensive SummaryDespite the paramount applications of organofluorine compounds in life and materials sciences, efficient strategies for stereoselectively constructing the C(sp3)‐CF2R bond at the stereogenic center remain limited. Here, we report a copper‐catalyzed hydrodifluoroallylation of cyclopropenes and alkenyl boronates with 3,3‐difluoroallyl sulfonium salts (DFASs). The use of DFASs overcomes the previous challenge of suppressing the reduction of fluoroalkylating reagents with M‐H species. The reaction provides an array of gem‐difluoroallyl cyclopropanes and borylalkanes with high efficiency and stereoselectivity under mild reaction conditions. Using chiral phosphine ligand could provide gem‐difluoroallyl borylalkanes with high enantioselectivities, paving a new way for the catalytic asymmetric fluoroalkylation with ubiquitous alkenes. The advantages of this protocol are synthetic convenience, high functional group tolerance, and the synthetic versatility of the resulting gem‐difluoroallyl cyclopropanes and borylalkanes. The synthetic utility of this approach has also been demonstrated by the diversified transformations of the gem‐difluoroallylated products and the rapid synthesis of bioactive molecule analogs.

Sulfonium-based precise alkyl transposition reactions.

S-adenosyl-L-methionine (SAM), a sulfonium-based cofactor, plays an important role in numerous biological processes as methyl donor. Inspired by the function of sulfonium motif in this nature's synthetic toolkit, we here present an aryne-activation strategy that the sulfonium intermediates in situ generated from thioethers display unique reactivity toward alkyl group transposition. Experimental and theoretical studies indicate that the reaction occurs in an intermolecular fashion where the TfO--incorporated [K(18-crown-6)] complex acts as a key promoter for this thermodynamically favored process. Next, a series of robust, easy-to-prepare sulfonium salts are designed and developed as electrophilic alkylation reagents accordingly. Both systems feature for broad scope, excellent selectivity, and simple operation. Moreover, we highlight the synthetic value through molecular editing and late-stage modification of complex scaffolds or even active pharmaceutical ingredients.

Photo‐induced Desulfurative Processes for Carbon Radical Generation

AbstractThiols constitute an important family among sulfur‐containing compounds, with well‐established applications in various fields ranging from medicine to material science. For instance, thiol residues are good hydrogen donors which reduce radical species in biological or chemical processes. However, even though the S−H bond activation of thiols for providing access to thiyl radicals has been largely studied, desulfurative processes affording carbon‐based radicals by C−S bond activation have been less explored. In recent years, photoredox catalysis has become the prevalent method for the generation of radicals under soft reaction conditions from readily available starting materials under visible light. In this context, recent studies have been devoted to the development of photocatalytic procedures aiming at the desulfurization of thiol derivatives leading to new C−H, C−C or C‐Het bond formation reactions. This review will cover the synthetic methodologies and strategies for photo‐mediated desulfurization of native thiols, thioethers, sulfonium salts and xanthates to access new organic compounds. This emerging field is especially interesting for new transformations of cysteine and peptide derivatives.