Methylene Reagents Research Articles

Fluoromethyl Triflate and Fluoromethyl Fluorosulfonate: Easily Accessible and Powerful Fluoromethylation Reagents.

Fluoromethyl triflate (superfluoromethyl, SFM, FCH2OSO2CF3) and fluoromethyl fluorosulfonate (magic fluoromethyl, MFM, FCH2OSO2F) are two easily synthesized, highly effective and non-ozone depleting fluoromethylation reagents. They are analogous to the well-known and widely used methylation re-agents CH3OSO2CF3 and CH3OSO2F. Both SFM and MFM have been fully characterized by multinuclear NMR spectroscopy (1H, 13C, 17O, 19F, 33S). Their structures have been determined in the solid state on in situ grown crystals by X-ray diff-raction and in the gas phase by electron diffraction. The fluoromethylation efficiency of SFM and MFM was shown by reaction with chalcogen nucleophiles of differing nucleophilicity. All fluoromethylated products were isolated as pure com-pounds and charac-terized by NMR and vibrational spec-troscopy, as well as in some cases by single crystal X-ray diffraction.

Highly selective production of 2-methylnaphthalene by CO2 hydrogenation and naphthalene alkylation

Many researchers have extensively studied the alkylation of naphthalene with methanol for the preparation of high-value-added chemicals, especially methylnaphthalenes (MNs). Studies indicated that methanol generates a large number of methanol-to-olefin by-products on zeolites, resulting in low selectivity of the target product and poor stability of the catalyst, limiting its application in the industrial field. In this study, CO2 hydrogenation was coupled with naphthalene alkylation, and the H3CO* active intermediate generated in situ was alkylated with naphthalene by using metal oxide-zeolite (OX-ZEO) bifunctional catalysts, which exhibited the ‘slow release’ phenomenon of the methylation reagent. It improved naphthalene conversion, suppressed deep alkylation and coke deposition side reactions and kept the catalyst stable for up to 500 h. A high-density and medium-strength Brønsted acid center facilitated the efficient migration of H3CO* active intermediates with the desorption of 2-methylnaphthalene (2-MN), which was particularly important for improving naphthalene conversion and 2-MN selectivity. The in situ IR showed that more Brønsted acid sites of Ga-S-1 effectively pulled the migration process of H3CO* species to the zeolitic acid center and increased the efficiency of C-C coupling compared to ZSM-5, which promoted the alkylation of H3CO* species with naphthalene. The results of chemisorption experiments showed that the medium-strength Brønsted acid site, which promoted the desorption of 2-MN, inhibited the deep alkylation reaction. The 2,6-dTBPy-IR results showed that the presence of fewer Brønsted centers on the outer surface of Ga-S-1 further optimized the product distribution and enhanced the selectivity of 2-MN in MNs to more than 90 %. Under optimal conditions, 80.1 % selectivity for MNs was obtained via ZnZrOx&Ga-S-1 bifunctional catalysts, with 97.4 % selectivity for 2-MN in MNs.

A Rare Example of a Gallium-Based Lewis Superacid: Synthesis and Reactivity of Ga(OTeF5)3.

The Lewis superacid Ga(OTeF5)3 has been synthesized and characterized, revealing a monomeric structure in solution and a dimeric structure in the solid state. Isolated adducts of Ga(OTeF5)3 with strong and weak Lewis bases have been characterized spectroscopically as well as by single-crystal X-ray diffractometry. The Lewis acidity of this new species has been evaluated by means of different experimental and theoretical methods, which has allowed to classify it as one of only a few examples of a gallium-based Lewis superacid. The high Lewis acidity of Ga(OTeF5)3 was used to amplify the strength of the Brønsted acid HOTeF5, leading to the protonation of diethyl ether. Furthermore, Ga(OTeF5)3 was utilized to access the strong oxidizing system Ga(OTeF5)3/Xe(OTeF5)2 in SO2ClF, which was successfully employed in the synthesis of the dimethyl chloronium salt [Cl(CH3)2][Ga(OTeF5)4], a strong electrophilic methylation reagent.

Palladium-Catalyzed Cascade Distal C-H Methylation and Cyclization for the Construction of Spirooxindole Skeletons.

Transition metal-catalyzed C-H methylation represents a straightforward approach for introducing methyl groups into organic molecules. Herein, we report a palladium-catalyzed alkene-relayed remote C-H methylation reaction that utilizes dimethyl carbonate as the methylation reagent. The aryl groups distal to a bromo group were dimethylated via C-H activation, leading to the formation of spirooxindoles as the final products through C(sp3)-H activation and C(sp3)-C(sp3) coupling. This cascade process involves the formation of four C-C bonds and the activation of three C-H bonds. The reaction not only provides a new approach to C-H methylation but also offers a novel method for constructing spirooxindole skeletons by merging skeleton construction and methylation into a single step.

Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis.

Benzo[1,3,2]dithiazole-1,1,3-trioxides are bench-stable and easy-to-use reagents. In photoredox catalysis, they generate methyl and perdeuteromethyl radicals which can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N-Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale-up further underscoring the synthetic usefulness of these methylation reagents. Mechanistic investigations suggest a single-electron transfer (SET) pathway induced by photoredox catalysis.

Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis

AbstractBenzo[1,3,2]dithiazole‐1,1,3‐trioxides are bench‐stable and easy‐to‐use reagents. In photoredox catalysis, they generate methyl and perdeuteromethyl radicals which can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N‐Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale‐up further underscoring the synthetic usefulness of these methylation reagents. Mechanistic investigations suggest a single‐electron transfer (SET) pathway induced by photoredox catalysis.

Homogeneous Catalysis in N-Formylation/N-Methylation Utilizing Carbon Dioxide as the C1 Source.

The growing emphasis on sustainable chemistry has driven research into utilizing carbon dioxide (CO2) as a nontoxic, abundant, and cost-effective C1 building block. CO2 offers a promising avenue for direct conversion into valuable chemicals ranging from fuels to pharmaceuticals. This review focuses on the utilization of CO2 for reductive N-formylation/N-methylation reactions of various amines, providing advantages over conventional methods involving toxic CO and other methylating reagents. The approach employs readily available reductants such as silane, borane reagents, and hydrogen (H2). The discussion encompasses recent developments in transition metal and organocatalyst systems for these reactions, highlighting mechanistic interpretations and factors influencing product selectivity.

Synthesis of Some Novel Thiophene Analogues as Potential Anticancer Agents.

The aim of this study involves the synthesis novel thiophene analogues that can be used as anticancer medications through a strategic multicomponent reaction connecting ethyl 4-chloroacetoacetate (1), phenyl isothiocyanate, and a series of active methylene reagents, including ethyl acetoacetate (2), malononitrile, ethyl cyanoacetate, cyanoacetamide 6a-c, N-phenyl cyanoacetamide derivatives 13a-c, and acetoacetanilide derivatives 18. This reaction was facilitated by dry dimethylformamide with a catalytic quantity of K2CO3. The resultant thiophene derivatives were identified as 4, 8a-b, 9, 12a-d, 15a-c, and 20a-b. Further reaction of compound 4 with hydrazine hydrate yielded derivative 5, respectively. When compound 1 was refluxed with ethyl 3-mercapto-3-(phenylamino)-2-(p-substituted phenyldiazenyl)acrylate 10a-e in the presence of sodium ethoxide, it produced thiophene derivatives 12a-d. Comprehensive structural elucidation of these newly synthesized thiophene-analogues was accomplished via elemental and spectral analysis data. Furthermore, the study delves into the cytotoxicity of the newly synthesized thiophenes was evaluated using the HepG2, A2780, and A2780CP cell lines. The amino-thiophene derivative 15b exhibited an increased growth inhibition of A2780, and A2780CP with IC50 values 12±0.17, and 10±0.15 μM, respectively compared to Sorafenib with IC50 values 7.5±0.54 and 9.4±0.14. This research opens new avenues for developing thiophene-based anticancer agents.

Electrochemical-induced direct approach to methylthiolated pyrazoles via a four-component one-pot strategy

Herein, a multicomponent electrochemical protocol for direct access to methylthiolated pyrazoles using potassium thiocyanate (KSCN) as sulfur source has been developed, where the methanol acts as both the solvent and the methylation reagent. This electrosynthesis strategy provides an eco-friendly and sustainable way to access methylthiolated pyrazoles by avoiding expensive metal catalysts and highly toxic sulfur reagent. Mechanism studies revealed that the key CH methylthiolation reaction proceeded via a radical pathway.

Synthesis of 5-Amino-3(2H)-furanones via S-Methylation/Intramolecular Cyclization of γ-Sulfanylamides.

The S-methylation/intramolecular cyclization of γ-sulfanylamide is depicted. Different methylating reagents were successfully employed for S-methylation, depending on the substituent pattern of the amide in the starting γ-sulfanylamides; trimethyloxonium tetrafluoroborate was used for N-aryl substituted γ-sulfanylamides, and the combination of methyl iodide and silver(I) tetrafluoroborate was used for N-alkyl substituted γ-sulfanylamides. When the resulting sulfonium salt was treated with DBU, it smoothly underwent intramolecular cyclization to produce a series of N-aryl, N-alkyl, N,N-dialkyl or N-alkyl-N-aryl substituted 5-amino-3(2H)-furanones in 55%-quantitative yields.

Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

Methylation of phase II metabolites of endogenous anabolic androgenic steroids to improve analytical performance.

The study of intact phase II metabolites of endogenous anabolic androgenic steroids (EAAS) gives important information about metabolism and has the potential to improve the detection of doping with testosterone. For analysis with liquid chromatography-mass spectrometry (LC-MS), chemical derivatization at the steroid moiety is a technique to improve the positive ionization efficiency of glucuronidated/sulfated EAAS under collision-induced dissociation (CID) conditions. However, regarding the chromatographic performance, there are still challenges to address, for example, poor peak shape, which is mainly caused by nondefined adsorption in the chromatographic system. Here, we show a novel derivatization technique for the analysis of selected phase II metabolites of EAAS, where the acidic moiety of the glucuronide/sulfate is methylated with different methylation reagents to reduce nondefined adsorption. The methylation reagent trimethylsilyl-diazomethane (TMSD) was preferred over the other tested reagents methyl iodide (MeI) and dimethyl sulfate (DMS). Glucuronidated and sulfated testosterone and epitestosterone were methylated, and their chromatographic performance and CID ion mass spectra obtained in positive ionization mode were investigated. The peak width and peak height were significantly improved for all substances. Methylated testosterone sulfate showed the best results with a 3.5 times narrower peak and 14 times increased intensity compared with underivatized testosterone sulfate. Furthermore, CID ion mass spectra obtained in positive ionization mode showed product ions characteristically for the steroidal backbone for all substances. This preliminary study shows the potential of methylation as a supplementary derivatization technique, which can assist in the development of more sensitive methods due to the improvements in method performance.

First Synthesis of Ergotamine-13CD3 and Ergotaminine-13CD3 from Unlabeled Ergotamine.

Ergot alkaloids (EAs) formed by Claviceps fungi are one of the most common food contaminants worldwide, affecting cereals such as rye, wheat, and barley. To accurately determine the level of contamination and to monitor EAs maximum levels set by the European Union, the six most common EAs (so-called priority EAs) and their corresponding epimers are quantified using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The quantification of EAs in complex food matrices without appropriate internal standards is challenging but currently carried out in the standard method EN 17425:2021 due to their commercial unavailability. To address the need for isotopically labeled EAs, we focus on two semi-synthetic approaches for the synthesis of these reference standards. Therefore, we investigate the feasibility of the N6-demethylation of native ergotamine to yield norergotamine, which can subsequently be remethylated with an isotopically labeled methylating reagent, such as iodomethane (13CD3-I), to yield isotopically labeled ergotamine and its C8-epimer ergotaminine. Testing the isotopically labeled ergotamine/-inine against native ergotamine/-inine with HPLC coupled to high-resolution HR-MS/MS proved the structure of ergotamine-13CD3 and ergotaminine-13CD3. Thus, for the first time, we can describe their synthesis from unlabeled, native ergotamine. Furthermore, this approach is promising as a universal way to synthesize other isotopically labeled EAs.

Electro-oxidative Methylation of 2-Isocyanobiaryls Using N,N-dimethylformamide (DMF) as Carbon Source: Synthesis of 6-Methylphenanthridines.

A benign electrochemical method to access 6-methylphenanthridines from 2-isocyanobiaryls using N,N-dimethylformamide (DMF) as a methyl source is reported. The protocol operates at ambient temperature without the need for harmful methylating reagents. Mechanistic studies suggested that DMF delivered a methylene synthon, followed by reduction at the cathode and tautomerization. The method offers environmental benefits by avoiding metal-based reagents and harsh conditions.

Iron-catalyzed methylation of quinoxalin-2(1H)-ones with dimethyl sulfoxide under visible light irradiation

The synthesis of iron-catalyzed N-methylation of quinoxalin-2(1H)-ones using dimethyl sulfoxide as the methylating reagent is described herein. The cross-coupling reactions proceeded smoothly under visible-light irradiation, which generated the corresponding products in moderate to good yields. Further investigation on the application of the methylation reaction using readily available DMSO as the methylation reagent is currently underway.

N1-Selective Methylation of Pyrazoles via α-Halomethylsilanes as Masked Methylating Reagents.

The development of a highly selective N-methylation of pyrazole heterocycles using commercially available, bench-stable α-halomethylsilanes as masked methylating reagents is described. Sterically bulky α-halomethylsilanes significantly improve the selectivity of N-alkylation over traditional methylating reagents and readily undergo protodesilylation in the presence of a fluoride source and water to give N-methyl pyrazoles. Selectivities of 92:8 to >99:1 N1/N2 regioisomeric ratios were achieved with a range of pyrazole substrates in good yields.

The development and application of a novel trideuterium methylation reagent

The development and application of a novel trideuterium methylation reagent

Photoredox Catalyzed Radical Fluoroalkylation with Non-Classical Fluorinated Reagents.

The emergence of photocatalysis has greatly advanced radical fluoroalkylation reactions. Central to this advancement is the introduction and refinement of radical reagents, which play a pivotal role in driving these reactions forward. Intriguingly, some of these reagents, previously not recognized for their radical properties, have emerged as key players in this area. In this Perspective, we provide an overview of four representative reagents pioneered by our laboratory, which have subsequently garnered extensive application in broader research contexts, including difluorocarbene precursors bromodifluoromethylphosphonium bromide, electrophilic sulfonylation reagent triflic anhydride, and nucleophilic trifluoromethylation reagent methyl fluorosulfonyldifluoroacetate (Chen's reagent). The integration of phosphonium reagents, triflic anhydride, and methyl fluorosulfonyldifluoroacetate into photocatalysis has enabled some unexpected reactivities and now notably expanded the capabilities in radical difluoromethylation, trifluoromethylation, and difluoroalkylation. Our discussion highlights how these atypical reagents have enriched the toolkit available for radical fluoroalkylations, offering insights that could inspire future research and application in this area.

One-Step Green Synthesis of Isoeugenol Methyl Ether from Eugenol by Dimethyl Carbonate and Phase-Transfer Catalysts.

In this paper, the green synthesis of isoeugenol methyl ether (IEME) from eugenol by O-methylation and isomerization is completed using a one-step green process. In the methylation reaction, dimethyl carbonate (DMC) was used as a green chemistry reagent instead of the traditional harmful methylation reagents, in accordance with the current concept of green chemistry. The phase transfer catalyst (PTC) polyethylene glycol 800 (PEG-800) was introduced into the isomerization reaction to break the barrier of difficult contact between solid and liquid phases and drastically reduce the reaction conditions by shortening the reaction time and reducing the alkalinity of the reaction system. The catalytic systems for the one-step green synthesis of IEME were screened, and it was shown that the catalytic system "K2CO3 + PEG-800" was the most effective. The effects of reaction temperature, n(DMC):n(eugenol) ratio, n(PEG-800):n(eugenol) ratio, and n(K2CO3):n(eugenol) ratio on eugenol conversion, IEME yield, and IEME selectivity were investigated. The results showed that the best reaction was achieved at a reaction temperature of 140 °C, a reaction time of 3 h, a DMC drip rate of 0.09 mL/min, and n(eugenol):n(DMC):n(K2CO3):n(PEG-800) = 1:3:0.09:0.08. As a result of the conversion of 93.1% of eugenol to IEME, a yield of 86.1% IEME as well as 91.6% IEME selectivity were obtained.

Synthesis of a novel twisted π-conjugated macrocycle via double Friedel-Crafts reaction and its physical properties.

We synthesized a cyclic molecule from diarylalkynes and Meldrum's acid derivatives as the methylenation reagent via double Friedel-Crafts reaction. Single-crystal X-ray structure analysis confirmed the twisted structure of the molecule. We also investigated their physical properties and homoconjugation by UV-Vis, photoluminescence, DFT and TD-DFT calculations.