Methyl Sulfonium Research Articles

Sodium Metabisulfite Mediated Synthesis of Bis(pyrazolo[1,5-a] pyrimidin-3-yl)methanes from Pyrazolo[1,5-a]pyrimidines with Dimethyl Sulfoxide as a C1 Synthon

AbstractWe report an unprecedented synthesis of bis(pyrazolo[1,5-a]pyrimidin-3-yl)methanes, a new class of di(hetaryl)methanes, from pyrazolo[1,5-a]pyrimidines by using DMSO as a C1 synthon (methylene source). The transformation is mediated by sodium metabisulfite (Na2S2O5), which plays a crucial role in the presence of acetic acid as a promoter. A wide variety of bis(pyrazolo[1,5-a]pyrimidin-3-yl)methanes were synthesized in moderate to good yields of up to 90%. Mechanistic studies suggested that the reaction follows an ionic pathway, probably involving a methyl(methylene)sulfonium ion as an active electrophilic species formed in situ by the reaction of DMSO with Na2S2O5.

"Cation Pool" generated from DMSO and 1,2-dihaloethanes and their application in organic synthesis.

Conventionally, carbenium and onium ions are prepared in the presence of nucleophiles due to their instability and transient nature. The nucleophiles that are unstable or inert to the reaction media cannot be used for reaction with the cationic species to access the desired compounds. To overcome these limitations, developing methods for generating organic cations irreversibly in the absence of nucleophiles is essential. The "cation pool" method developed by Yoshida and co-workers stands out as a reliable strategy to generate and accumulate the reactive cations in solution in the absence of nucleophiles. The cation pool method involves the electrolysis of the substrate in the absence of nucleophiles, usually at low temperature. Moreover, the generation of halogen and chalcogen cations through electrolysis needs extra care because of their low stability. This review covers our effort in generating and accumulating halogen cations as "cation pools", most importantly by simply heating a mixture of dimethyl sulfoxide (DMSO) and 1,2-dihaloethane (DXE, X = Cl, Br, I), and their use in the halogenation reactions. Furthermore, condition-dependent Pummerer-type fragmentations of DMSO-stabilized halogen cations to methyl(methylene)sulfonium ions and chlorodimethylsulfonium ions for synthetic applications are described.

DMSO-DCE Triggered Chemodivergent C-Methylenation of Electron-Rich Arenes: An Easy Access to Diarylmethanes.

The chemodivergent property of dimethyl sulfoxide (DMSO) along with 1,2-dichloroethane (DCE) was exploited for the incorporation of a methylene group to form diarylmethanes through a dearomatization/rearomatization process. Methyl(methylene)sulfonium ions (CH2=S+-Me) were generated by simple heating of commonly used solvents such as DMSO and DCE. These ions were subsequently trapped by electron-rich arenes and heteroarenes, resulting in the synthesis of both symmetrical and unsymmetrical diarylmethanes. This protocol was further extended to access N-methylenamides by reacting 2-naphthol with amides or nitriles in the presence of DMSO and DCE.

Arylative Methylation of 2,3-Dihydropyrazines and Pyrazinones Using Dimethyl Sulfoxide as a C1 Source.

Divergent synthesis of α-C-H methylated pyrazines and pyrazinones using dimethyl sulfoxide as a nonconventional methylating agent under metal-free conditions was reported. Dimethyl sulfoxide-coordinated bromine cation pools generated from the treatment of dimethyl sulfoxide and 1,2-dibromoethane undergo Pummerer-type fragmentation to afford an electrophilic methyl(methylene)sulfonium ion for reaction with a carbon nucleophile followed by aromatization to afford α-methylated pyrazines and pyrazinones.

Benzannulation and N‐Annulation of β‐Ketoenamines for Synthesizing Aniline and Pyridine Derivatives Using DMSO as a Methine Source

AbstractBenzannulation and N‐annulation of β‐ketoenamines by the in‐situ generated methyl(methylene)sulfonium ion from the reaction of dimethyl sulfoxide (DMSO) and 1,2‐dibromoethane (DBE) was achieved. The β‐ketoenamines underwent N‐annulation to pyridine derivatives, while the N‐alkylated enamines were benzannulated to afford substituted anilines. The utility of the intermediate methyl(methylene)sulfonium ion was further extended for synthesizing methylene‐bridged bis‐1,3‐dicarbonyl compounds.magnified image

Isolation and characterization of sulfur-containing compounds by positive-ion electrospray ionization and online HPLC/Atmospheric pressure chemical ionization coupled to Orbitrap mass spectrometry

Extraction and fractionation of sulfur-containing compounds from vacuum gas oil were carried out by using non-reactive methods such as ligand exchange chromatography (LEC) on solid-phase extraction cartridges and a molecularly imprinted polymer (MIP). All fractions obtained by these methods were methylated, and sulfur compounds (S1) were analyzed as methyl sulfonium ions [M + CH3]+ by positive-ion ESI Orbitrap mass spectrometry. LEC on strong cation exchange sorbents modified with Ag+ (SCX-Ag+) and Cu2+ (SCX-Cu2+) cations isolate sulfides and thiophenes through complexation of the sulfur atoms with the metal cations. In contrast, LEC on the stationary silica phase modified with Ag+ cations (Si-Ag+) was selective of sulfur species (S1) with higher DBE values near the planar limit. Interestingly, LEC/SCX-Cu2+ allowed the extraction of disulfides and other sulfur compound classes such as OS and OS2 detected as [M + H]+. Among LEC separations, the Si-Ag+ provides the largest number of molecular assignments (565) of sulfur species (S1) followed by SCX-Ag+ and SCX-Cu2+ with 463 and 408 formulae, respectively. On the other hand, a polymer with dibenzothiophene molecules imprinted afforded the highest number (820) of molecular formulae (CcHhS1) with a wider DBE ~1–20 and carbon number ~30–70 in comparison with the species (S1) eluted by LEC methods. A further separation by online HPCL/APCI (+) Orbitrap MS of the fractions obtained by SCX-Ag+ allows detecting sulfur compounds with DBE values up to 23. This contribution provides alternatives for the isolation and fractionation of sulfur-containing compounds that may be extended to heavy crude oil and asphaltenes.

RAFT polymerization of tertiary sulfonium zwitterionic monomer in aqueous media for synthesis of protein stabilizing double hydrophilic block copolymers

AbstractThe reversible addition‐fragmentation chain‐transfer (RAFT) polymerization of a tertiary sulfonium‐containing zwitterionic monomer (N‐acryloyl‐L‐methionine methyl sulfonium salt: A‐Met[S+]‐OH) was performed in aqueous media in the presence of a water‐soluble chain‐transfer agent (CTA). Several parameters, such as the radical initiator, nature of the salt used as an additive, polymerization temperature, and solvent (water, buffer solution, and mixed solvents), were studied. The polymerization of A‐Met(S+)‐OH in acetate buffer using a trithiocarbonate‐type CTA having two carboxylic acid moieties proceeded in a controlled fashion at 45°C, as confirmed by the low polydispersity of the products (M w/M n < 1.1) and pre‐determined molecular weights. Poly(ethylene glycol)‐based macro‐CTA was also employed for the polymerization of A‐Met(S+)‐OH in mixed solvents (H2O/EtOH and H2O/DMF = 70/30 vol%) to afford novel nonionic‐zwitterionic double hydrophilic block copolymers. The chain extension of the hydrophilic poly(N,N‐dimethylacrylamide) macro‐CTA with A‐Met(S+)‐OH was well controlled in pure water under the appropriate conditions, resulting in the formation of block copolymers with “as‐designed” chain structures and relatively low dispersities (M w/M n < 1.3). The resulting sulfonium‐containing double hydrophilic block copolymers having optimal nonionic/zwitterionic balance were efficient protein‐stabilizing agents.

Protein-Stabilizing Effect of Amphiphilic Block Copolymers with a Tertiary Sulfonium-Containing Zwitterionic Segment.

Tertiary sulfonium-containing zwitterionic block copolymers consisting of N-acryloyl-l-methionine methyl sulfonium salt (A-Met(S+)-OH) and n-butyl acrylate (BA) were newly synthesized to develop a novel protein stabilizer. The zwitterionic block copolymers were prepared by reversible addition–fragmentation chain-transfer (RAFT) polymerization of BA using a hydrophilic macro-chain-transfer agent (CTA) obtained from N-acryloyl-l-methionine (A-Met-OH) and subsequent postmodification. RAFT polymerization of A-Met-OH using poly(BA) macro-CTA, followed by postmodification, also afforded the target poly(A-Met(S+)-OH)-b-poly(BA). The block copolymers stabilized horseradish peroxidase (HRP) during storage at 37 °C for 5 days, and the protein-stabilizing effect was enhanced with increase in the A-Met(S+)-OH content. In particular, the block copolymer with ∼85% A-Met(S+)-OH content showed a significant protein-stabilizing effect at a temperature (37 °C) higher than the room temperature, which is highly desirable for practical and industrial applications. The addition of sucrose into the block copolymer–protein solution led to a considerable increase in the HRP activity under the same conditions. Excellent alkaline phosphatase stabilization at 37 °C for 12 days was also achieved using the block copolymers. The zwitterionic block copolymers with the optimal hydrophilic/hydrophobic balance were found to serve as efficient protein-stabilizing agents, in comparison with the corresponding homopolymer and random copolymers. Dynamic light scattering, zeta potential, transmission electron microscopy, and circular dichroism measurements revealed that the zwitterionic block copolymer stabilizes an enzyme by wrapping with a slight change in the size, whereas the secondary and ordered structures of the enzyme are maintained.

Selective Methylation of Sulfides in Petroleum for Electrospray Ionization Mass Spectrometry Analysis

A method for selective methylation of sulfides (particularly aliphatic sulfides) but not thiophenes in petroleum has been developed for positive-ion electrospray ionization (ESI) mass spectrometry. The new method uses only CH3I without AgBF4 to produce methyl sulfonium ions of sulfides for molecular composition analysis. It provides simplicity and saves time compared to a previously developed methylation method using CH3I/AgBF4 to methylate all sulfur compounds into ionic species analyzable by positive-ion ESI. The composition of sulfides by this method agrees with that of the sulfide fraction obtained from CH3I/AgBF4 methylation/demethylation. Hence, the separation of sulfides from thiophenes through elaborate procedures is eliminated. The new method was validated by model compounds and has been successfully applied to the analysis of sulfides in diesel, vacuum gas oil, crude oil, and atmospheric pressure distillation residue. When combined with the previously developed CH3I/AgBF4 method, the new method may have the potential to differentiate reactive sulfur, such as sulfides, from nonreactive sulfur, such as thiophenes. This could provide a means to develop correlations between sulfur types and corrosion, and possibly for other studies.

Synthesis of Zwitterionic Polymers Containing a Tertiary Sulfonium Group for Protein Stabilization.

The present study demonstrates the controlled synthesis and biological potential of poly( N-acryloyl-l-methionine methyl sulfonium salt)s (poly(A-Met(S+)-OH)s), which mimic dimethylsulfoniopropionate (DMSP), a compound produced by marine algae to protect their proteins. The novel sulfonium-containing zwitterionic polymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of the amino acid-based monomer N-acryloyl-l-methionine (A-Met-OH) followed by a postmodification process in which the sulfide groups were reacted with iodomethane. The DMSP-mimic zwitterionic macromolecules were shown for the first time to exhibit low cytotoxicity and the ability to stabilize proteins. By adding the resulting poly(A-Met(S+)-OH)s to horse radish peroxidase (HRP) solution, the activity of HRP was maintained even after storage at 4 °C for several days. In addition, the protein activities were tested using peroxidase-labeled antibody to mouse immunoglobulin G (IgG-HRP) and alkaline phosphatase (ALP) after storage and for HRP after freeze-thaw cycles. Amphiphilic random copolymers, poly(A-Met(S+)-OH- co-BA)s, also exhibited excellent properties for protein stabilization.

Identification of Artifacts in the Methylation Process of Sulfur Compounds in Petroleum

Methylation of sulfides and thiophenes into methyl sulfonium salts for electrospray ionization (ESI) mass spectrometry analysis has been a widely used approach for molecular characterization of sul...

Capturing Unknown Substrates via in Situ Formation of Tightly Bound Bisubstrate Adducts: S-Adenosyl-vinthionine as a Functional Probe for AdoMet-Dependent Methyltransferases.

Identifying an enzyme's substrates is essential to understand its function, yet it remains challenging. A fundamental impediment is the transient interactions between an enzyme and its substrates. In contrast, tight binding is often observed for multisubstrate-adduct inhibitors due to synergistic interactions. Extending this venerable concept to enzyme-catalyzed in situ adduct formation, unknown substrates were affinity-captured by an S-adenosyl-methionine (AdoMet, SAM)-dependent methyltransferase (MTase). Specifically, the electrophilic methyl sulfonium (alkyl donor) in AdoMet is replaced with a vinyl sulfonium (Michael acceptor) in S-adenosyl-vinthionine (AdoVin). Via an addition reaction, AdoVin and the nucleophilic substrate form a covalent bisubstrate-adduct tightly complexed with thiopurine MTase (2.1.1.67). As such, an unknown substrate was readily identified from crude cell lysates. Moreover, this approach is applicable to other systems, even if the enzyme is unknown.

A Divalent Metal Ion-Dependent N1-Methyl Transfer to G37-tRNA

The catalytic mechanism of the majority of S-adenosyl methionine (AdoMet)-dependent methyl transferases requires no divalent metal ions. Here we report that methyl transfer from AdoMet to N(1) of G37-tRNA, catalyzed by the bacterial TrmD enzyme, is strongly dependent on divalent metal ions and that Mg(2+) is the most physiologically relevant. Kinetic isotope analysis, metal rescue, and spectroscopic measurements indicate that Mg(2+) is not involved in substrate binding, but in promoting methyl transfer. On the basis of the pH-activity profile indicating one proton transfer during the TrmD reaction, we propose a catalytic mechanism in which the role of Mg(2+) is to help to increase the nucleophilicity of N(1) of G37 and stabilize the negative developing charge on O(6) during attack on the methyl sulfonium of AdoMet. This work demonstrates how Mg(2+) contributes to the catalysis of AdoMet-dependent methyl transfer in one of the most crucial posttranscriptional modifications to tRNA.

Enhancement of Acid Photogeneration Through a Para-to-Meta Substitution Strategy in a Sulfonium-Based Alkoxystilbene Designed for Two-Photon Polymerization

This contribution reports on the synthesis and the photochemical behavior of two new sulfonium-based photoacid generators (PAGs). We demonstrate that a para-to-meta substitution of a methyl (p-cyanobenzyl) sulfonium group in a 4-alkoxystilbene core strongly influences the photodissociation efficiency of the PAGs and leads to an increase of the quantum yield for acid generation by a factor 2.4. This substantial effect, which was also corroborated by a reactivity enhancement in cationic photopolymerization, is assigned to the modulation of the electronic interaction between two low lying excited states whose energy gap is strongly influenced by this substitution effect. Moreover, it was found that the position of the sulfonium moiety hardly affects the two-photon absorption properties of these push–pull chromophores. By the two-photon fabrication of microstructures, we finally show the potential use of the meta derivative as cationic two-photon initiator.

Do Glycosyl Sulfonium Ions Engage in Neighbouring‐Group Participation? A Study of Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity

Neighbouring-group participation has long been used to control the synthesis of 1,2-trans-glycosides. More recently there has been a growing interest in the development of similar strategies for the synthesis of 1,2-cis-glycosides, in particular the use of auxiliary groups that generate sulfonium ion intermediates. However, there has been some debate over the role of sulfonium ion intermediates in these reactions: do sulfonium ions actually engage in neighbouring-group participation, or are they a resting state of the system prior to reaction through an oxacarbenium ion intermediate? Herein, we describe the reactivities and stereoselectivities of a family of bicyclic thioglycosides in which an oxathiane ring is fused to the sugar to form a trans-decalin-like structure. A methyl sulfonium ion derived from one such glycosyl donor is so stable that it can be crystallised from ethanol, yet it reacts with complete stereoselectivity at high temperature. The importance of a ketal group in the oxathiane ring for maintaining this high stereoselectivity is investigated using a combination of experiment and ab initio calculations. The data are discussed in terms of S(N)1 and S(N)2 type mechanisms. Trends in stereoselectivity across a series of compounds are more consistent with selective addition to oxacarbenium ions rather than a shift between S(N)1 and S(N)2 mechanisms.

Direct Evidence for Methyl Group Coordination by Carbon-Oxygen Hydrogen Bonds in the Lysine Methyltransferase SET7/9

SET domain lysine methyltransferases (KMTs) are S-adenosylmethionine (AdoMet)-dependent enzymes that catalyze the site-specific methylation of lysyl residues in histone and non-histone proteins. Based on crystallographic and cofactor binding studies, carbon-oxygen (CH · · · O) hydrogen bonds have been proposed to coordinate the methyl groups of AdoMet and methyllysine within the SET domain active site. However, the presence of these hydrogen bonds has only been inferred due to the uncertainty of hydrogen atom positions in x-ray crystal structures. To experimentally resolve the positions of the methyl hydrogen atoms, we used NMR (1)H chemical shift coupled with quantum mechanics calculations to examine the interactions of the AdoMet methyl group in the active site of the human KMT SET7/9. Our results indicated that at least two of the three hydrogens in the AdoMet methyl group engage in CH · · · O hydrogen bonding. These findings represent direct, quantitative evidence of CH · · · O hydrogen bond formation in the SET domain active site and suggest a role for these interactions in catalysis. Furthermore, thermodynamic analysis of AdoMet binding indicated that these interactions are important for cofactor binding across SET domain enzymes.

Dimerization of ionized 4‐(methyl mercapto)‐phenol during ESI, APCI and APPI mass spectrometry

A novel ion/molecule reaction was observed to occur under electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photo ionization (APPI) conditions, leading to dimerization of ionized 4-(methyl mercapto)-phenol followed by fast H(*) loss. The reaction is particularly favored during ESI, which suggests that this ion/molecule reaction can occur both in the solution inside the ESI-charged droplets and in the gas-phase environment of most other atmospheric pressure ionization techniques. The dimerization reaction is inherent to the electrolytic process during ESI, whereas it is more by ion/molecule chemistry in nature during APCI and APPI. From the tandem mass spectrometry (MS/MS) data, accurate mass measurements, hydrogen/deuterium (H/D) exchange experiments and density functional theory (DFT) calculations, two methyl sulfonium ions appear to be the most likely products of this electrophilic aromatic substitution reaction. The possible occurrence of this unexpected reaction complicates mass spectral data interpretation and can be misleading in terms of structural assignment as reported herein for 4-(methyl mercapto)-phenol.

Novel analytical method for the crosslinking process: Infrared thermographic analysis of the thermally latent cationic polymerization of a spiroorthoester and a bifunctional oxetane for the construction of a low‐shrinkage curing system

AbstractThermal behaviors were monitored by infrared thermographic analysis in the copolymerization of a spiroorthoester and a bifunctional oxetane with thermally latent initiators [benzyl tetrahydrothiophenium hexafluoroantimonate (BTHT) and benzyl 4‐hydroxyphenyl methyl sulfonium hexafluoroantimonate (BPMS)]. The copolymerization with BPMS increased the temperature during the copolymerization more than that with BTHT, whereas the exothermicities were lowered with the increase in the initial feed ratio of the spiroorthocarbonate monomer. The high exothermicity in the copolymerization with BPMS is ascribable to the faster propagation of the oxetane monomer with a high heat of polymerization, and this is supported by model reactions and computational calculation. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2820–2826, 2007

Palladium-catalyzed synthesis of oligo(methylthio)aniline and conversion to polyacene-type electrolytes bearing phenothiazinium repeating units

The synthetic routes to ladder polymers which consist of benzenetetrayl subunits with imino and methylsulfonio linkages are described. As the key intermediate, oligo- and polyaniline derivatives having pendant methylthio groups are prepared by the Pd-catalyzed aryl amination from various monomers. The oxidation of the polymers with H2O2 in the presence of CH3COOH effects the high yielding conversion of methylthio to methylsulfinyl groups without the formation of the undesired methylsulfonyl groups. The superacid-induced condensation of the resulting polymers under dilution conditions induced the polymer-analogous intramolecular electrophilic ring closure reaction of the hydroxy(methyl)(phenyl)sulfonium cation onto the adjacent benzene ring to yield the required ladder polymers which have proved to be semiconductors with intrinsic electric conductivities of ca. 10−5 S · cm−1. 1H NMR spectra of (a) 8a in CD2Cl2, (b) 9 in CD2Cl2 and (c) 2 in DMSO-d6. TMS was used as the internal standard. Residual proton signals in the deuterated solvents are marked with an asterisk.

Synthesis of glycosylated human interleukin-1alpha, neoglyco IL-1alpha, coupled with N-acetylneuraminic acid.

In order to develop glycosylated cytokine, recombinant human IL-1alpha was chemically modified with N-acetylneuraminic acid (NANA). NANA with C9 spacer, 8-(hydrazinocarbonyl)octyl 5-acetamido-3, 5-dideoxy-D-glycero-alpha-D-galacto-2-nonulo-pyranosidonic acid potassium salt (6), was synthesized by glycosylation of C9 spacer, 8-[2-N-(benzyloxycarbonyl)hydrazinocarbonyl]octanol, with methylthio glycoside derivatives of NANA in the presence of molecular sieves 3A and methyl (methylthio)sulfonium trifrate in propionitrile, followed by separation of a and beta anomers with a column chromatography and deprotection. Compound 6 was coupled to IL-1alpha by the acyl azide method. The glycosylated IL-1 was purified by anion-exchange chromatography, and NANA coupled to IL-1 was confirmed by oxidation with NaIO4. Based on the molecular weight average number of carbohydrate molecules introduced per molecule of IL-1alpha was estimated to be 2.9.