Search

Abstract: The present account surveys the results of a myriad of works on the C-methylation of organic substrates with methanol as an eco-friendly methylating agent. The innumerable reports on this issue reveal the widespread use of a set of solid catalysts such as molecular sieves, zeolites, metal phosphates, metal oxides and transition metal complexes to accomplish such methylation. One related facet was the impact of the numbers of Brønstëd acid sites, Lewis acid sites, and Lewis base sites present in solid catalysts, such as zeolites, their ratios, and strengths that affect the distribution of the methylation products and their selectivities. Moreover, specific surface area and porosity of some solid catalysts, such as zeolites, play additional roles in the overall reaction. Not only do these catalyst properties influence the methylation outcome, the temperature, space velocity (WHSV, LHSV, GSHV), weight of catalyst per reactant flow rate (W/F), time of stream (TOS), and methanol/ substrate molar ratio also do. The treated substrates herein discussed were aromatic hydrocarbons (benzene, biphenyls, naphthalenes, toluene, xylenes), alkenes, phenolics (phenol, cresols, anisole), Nheteroarenes, carbonyls, alcohols, and nitriles. Methylation of benzene affords not only toluene as the main product but also polymethylated benzenes (xylenes, pseudocumene, hexamethylenebenzene, and also ethylbenzene as a side-chain product). Furthermore, toluene is sensitive to the reaction conditions, giving rise to ring methylation and to side-chain one (ethylbenzene and styrene), besides the formation of benzene as a disproportionation product. A number of results from the methylation of phenolic compounds bear witness to the interest of different investigators in this special research. With respect to these phenolics, concurrent O-methylation inevitably parallels the C-methylation, and the selectivity of the latter one remains dependent on the above-cited factors; ortho-cresol and 2,6-xylenol have been the main C-ring methylated phenols. Methylation of olefins with methanol over solid catalysts, leading to higher olefins, is of great interest. The chemistry involved in the methylation of N-heteroarenes, such as pyridines, indoles, and pyrroles, is significant. Application of the methylation protocols, using methanol as a reagent and transition of metal complexes as catalysts to ketones, esters, aldehydes, nitriles, and alcohols, ends up with some important molecules, such as acrylonitrile (a monomer) and isobutanol (a biofuel).

Nitroacetonitrile (NAN) serves as a cyano(nitro)methylating agent facilitating the construction of polyfunctionalized compounds; however, its explosive property is a significant drawback in terms of practical handling. Alkali metal salts of NAN are thermally stable, but their insolubility in organic solvents restricts their use as a synthetic reagents. On the contrary, dipyrrolidinium cyano-aci-nitroacetate is soluble in common organic solvents and thermally stable, allowing for its use as an alternative synthetic equivalent of nitroacetonitrile for the construction of polyfunctionalized frameworks via cyano(nitro)methylation.

This review is a survey of S-methylation of sulfur-containing organic substrates. S-methylation, being a part of S-C making bond reactions such as alkylation, arylation, alkenylation, and alkynylat...

Catalytic methylation of aromatic hydrocarbons using CO2 and H2 as a methylating agent was conducted over a combination of TiO2-supported Re (Re(1)/TiO2; Re = 1 wt %) and H-β (SiO2/Al2O3 = 40) in a...

The formation of covalently bound DNA-protein crosslinks (DPCs) is linked to the pathophysiology of cancers and many other degenerative diseases. Knowledge of the proteins that were frequently involved in forming DPCs will improve our understanding of the etiological mechanism of diseases and facilitate the establishment of preventive measures and treatment methods. By using SDS-PAGE and nano-LC coupled Orbitrap LC-MS/MS analyses, we identified, for the first time, that the major DNA-cross-linked proteins in HeLa cells exposed to a methylating agent (methylmethanesulfonate) or hydroxyl free radicals are transcription-associated proteins. In particular, histone H2B3B and poly(rC) binding protein 2 were identified as the most frequent DPC-forming proteins.

A literature survey on C-methylation of organic substrates with methane as a methylating agent is analyzed. Of the substrates that undergo C-methylation are benzene, naphthalenes, toluene, alkanes, alkenes, acetonitrile, and other functionalized organic compounds. None of these methylation reactions occur in the absence of a catalyst. A direct introduction of a methyl group on the carbon sites of a molecule is concomitant with the formation of other products, as a result of either a possible rearrangement or a further reaction with methane. Mechanistically, the C-methylation with methane proceeds oxidatively. The products selectivities depend on several factors, mainly on the acid/ base character of the solid catalyst.

Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine(1,2). Folate deficiency is associated with a number of developmental, immune and neurological disorders(3–5). Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body(3,6). The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus(4,7), and is an important route for the delivery of antifolate drugs in cancer chemotherapy(8–10). How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT.

We herein disclose the use of tetramethylammonium fluoride (TMAF) as a direct and selective methylating agent of a variety of amides, indoles, pyrroles, imidazoles, alcohols, and thiols. The method is characterized by operational simplicity, wide scope, and ease of purification. Our computational studies suggest a concerted methylation–deprotonation as the preferred reaction pathway.

Bench- and air-stable 1-methoxy-2,2,6,6-tetramethylpiperidine (TEMPO-Me) is relatively unreactive at ambient temperature in the absence of an electrochemical stimulus. In this report, we demonstrate that the one-electron electrochemical oxidation of TEMPO-Me produces a powerful electrophilic methylating agent in situ. Our computational and experimental studies are consistent with methylation proceeding via a SN2 mechanism, with a strength comparable to the trimethyloxonium cation. A protocol is developed for the electrochemical methylation of aromatic acids using TEMPO-Me.

A Ru(II) complex mediated synthesis of various N,N-dimethyl and N-monomethyl amines from organic azides using methanol as a methylating agent is reported. This methodology was successfully applied for a one-pot reaction of bromide derivatives and sodium azide in methanol. Notably, by controlling the reaction time several N-monomethylated and N,N-dimethylated amines were synthesized selectively. The practical applicability of this tandem process was revealed by preparative scale reactions with different organic azides and synthesis of an anti-vertigo drug betahistine. Several kinetic experiments and DFT studies were carried out to understand the mechanism of this transformation.

A series of novel substituted 3,3,3-trifluoro-2-methoxy-N-methyl-N,2-diphenylpropanamides were synthesized from α-hydroxyacetamide using CH3I as the methylating agent. Their chemical structures were characterized by 1H NMR, 13C NMR, 19F NMR, and HRMS X-ray analysis. The dimethylated trifluoroatrolactamide exhibited moderate antifungal activity.

Synthesis of pyridinium based ionic liquids were reported and applied as catalyst for the selective O-methylation of phenols and benzyl alcohols. The reactions were carried out by using dimethylcarbonate (DMC) as the methylating agent. High selectivity, high yield and recyclability of the ionic liquids are important features of the reactions.

A cobalt-catalyzed directed ortho C-H methylation reaction of arenes has been achieved using readily available methyl tosylate as a methylating agent. An in situ-generated cobalt-N-heterocyclic carbene catalyst in combination with neopentylmagnesium bromide promotes the methylation at room temperature. The reaction is applicable to various substrates bearing nitrogen directing groups such as N-aryl imine, N-H imine, and 2-pyridyl groups. The present protocol also allows for facile introduction of a trideuteriomethyl group into arenes. MOE (Min. of Education, S’pore) Accepted version

Iridium-catalyzed methylation of indoles and pyrroles using methanol as the methylating agent was achieved. This transformation takes place via a borrowing hydrogen methodology under an air atmosphere, which constitutes a direct route to 3-methyl-indoles and methyl-pyrroles.

C-, N-, and/or O-methylation products were generated from 11H-isoindolo[2,1-a]quinazoline-5-one upon treatment with NaH followed by iodomethane under air, and possible recrystallization from methanol. Two products were fully characterized by NMR and X-ray diffraction analysis. In accordance with the HSAB principle, this soft methylating agent (MeI) leads mainly to the C,C-dimethylated product 11,11-dimethyl-11H-isoindolo[2,1-a]quinazoline-5-one, which was previously not observed, beside the N-methylated product, in a procedure using methyl tosylate as a hard methylating agent of the same substrate in the initial absence of a base. A mechanism is finally proposed for the formation of methyl 2-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate as an oxidation side product.

The use of N,N-dimethylformamide dimethylacetal (DMF-DMA) as a suitable methylating agent for the methylation of NH-containing groups and heterocycles has been investigated. Use of ReactArray and calculated pK a measurements have allowed additional helpful information to be collated to determine optimum reaction conditions for a variety of substrates.

Background The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models.

10-[(11)C]methoxy-20(S)-camptothecin was synthesized automatically. The radiochemical yield was 30%-50% (all calculated at EOB, n=20) with [(11)C]methyl triflate as a methylating agent. The radiochemical purity was greater than 96%, and the specific activity was 8.72±2.18 GBq/μmoL at EOS. Biodistribution showed that 10-[(11)C]methoxy-20(S)-camptothecin is characterized by quick clearance from the blood and by significant uptake in the liver (5.72±1.92% ID/g at 15 min), intestines (2.43±0.38% ID/g at 15 min), and kidney (1.57±0.85% ID/g at 15 min). Micro-PET imaging clearly showed high radioactivity accumulation in liver, intestines and bladder, indicating that the primary modes of excretion of the radiotracer are through the hepatobiliary system and, to a lesser extent, through the renal system.

Factorial design analysis was applied to optimize the synthesis, via a new route, of N,N,N-trimethylchitosan, based on dimethylsulfate as a methylating agent. The responses analyzed were weight yield, solubility and average degree of quaternization. Temperature was verified as the most important variable, as it caused the most variation in the response. X(T) = ―54.52, ―9.50 and ―7.25, respectively, for weight yield, solubility and degree of quaternization. A sharp decrease in the viscosimetric and gel permeation chromatography parameters proved that severe depolymerization took place at high reaction temperatures. Contact angle measurements showed a decrease in the hydrophilic character of over-methylated samples.

Dichlorvos (DDVP) is a methylating agent. In DNA from mice given 1.9 x 10(-6) mol/kg of DDVP, a degree of alkylation of guanine-N-7 amounting to 8 x 10(-13) mol methyl per g DNA, was found. From this, a rate of clearance of 29 hr-1 was estimated. This value is in reasonable agreement with the value (55 hr-1), calculated from published data on the concentration over time of DDVP in the brain after injection of the compound in mice. Applying a risk estimation on humans exposed to DDVP, the genetic risk connected with the methylating activity of DDVP is low or very low. Comparing the mutagenic effectiveness of DDVP with that of methyl methanesulfonate, indicates that DDVP is more effective than expected from reaction kinetic data. The possible contribution of the dichloroacetaldehyde formed in vivo from DDVP has to be evaluated before a complete risk estimate can be made for DDVP.

We have evaluated the potential of using tetramethylammonium chloride (Me4NCl) as an alternative methylating agent for phenols under microwave-assisted conditions. Its chemical behavior was tested in a reaction with 2-naphthol in the presence of various bases and solvents. The method was then applied in 1,2-dimethoxyethane or toluene under heterogeneous conditions for the O-methylation of a series of phenolic compounds. We found that many simple phenols can be methylated in the presence of K2CO3, whereas some other less-reactive phenols require the presence of the more reactive Cs2CO3.

Iridium-catalyzed methylation of indoles and pyrroles using methanol as the methylating agent was achieved. This transformation takes place via a borrowing hydrogen methodology under an air atmosphere, which constitutes a direct route to 3-methyl-indoles and methyl-pyrroles.

N-methyl-2-phenylbenzotellurazolinium iodide, like other N-methylbenzochalcogenazolium salts, readily undergoes reduction, hydrolysis, and recyclization with hydrazine hydrate and o-phenylene diamine. 1-Methyl-2-phenylbenzotelluronioazole perchlorate is an effective methylating agent in reactions with nucleophiles.

The rapid, simple and high-yield synthesis of the extraordinarily reactive 11C-methylating agent, [11C]methyl nona-fluorobutyl-1-sulfonate ([11C]MeONf), and its use in the synthesis of the promising β-amyloid imaging agent, [11C]-6-OH-BTA-1, is reported. In terms of radioactive methylation yields, [11C]MeONf seems to surpass [11C]methyl trifluoromethansulfonate ([11C]MeOTf) as a methylating agent in this particular case giving the 11C-labelled compound in high-preparative radiochemical yields between 27 and 29% EOS with a minimum formation of radioactive by-products. Copyright © 2007 John Wiley & Sons, Ltd.

N-Alkylation of anilines by dimethyl carbonate (DMC) catalyzed by onium salts has been demonstrated. The work presented here shows that a simple catalytic system consisting of onium salts in the presence of a small amount of water is extremely effective in enhancing the DMC mediated N-alkylation of anilines to dialkylated products. The effect of reaction conditions, on the synthesis of N,N-dimethyl aniline (NNDMA) from aniline and DMC has been investigated. Under the optimized conditions highest yield of NNDMA obtained was 99.8%, which is the best reported for liquid phase N-alkylation of aniline using DMC. The role of water in enhancing the yield of NNDMA is explained and a reaction-networking scheme is constructed, which summarizes the chemistry behind liquid phase N-alkylation of anilines by DMC. The catalyst has been shown to recycle up to five times and at the end of fifth recycle almost 98% of NNDMA yields were obtained.

Background Methyl iodide is a monohalomethane used as an analytic and organic chemistry reagent, as a methylating agent in organic chemical synthesis, and as a fumigant. In an acute exposure, methyl iodide is a pulmonary and dermal irritant. Chronic neurotoxicity has been reported in survivors of acute exposure. Methods A review of the 11 case reports of methyl iodide poisoning in the medical literature of the 20th century found that six of the patients experienced a chronic neurological syndrome characterized primarily by delayed psychiatric, behavioral, and cognitive sequelae. Results The case patient experienced a massive exposure to methyl iodide with resulting life-threatening burns. During convalescence, various cognitive and behavioral deficits became apparent. The results of a comprehensive evaluation at our occupational toxicology clinic, which included sequential neuropsychometric testing, are described. Conclusion The findings in the case patient may advance our understanding of the mechanisms and clinical manifestations of chronic neurotoxicity after exposure to methyl iodide. Am. J. Ind. Med. 47:550–556, 2005. © 2005 Wiley-Liss, Inc.

Methylation of phloroglucinol was performed using dimethyl sulfate as the methylating agent in the presence and absence of a glycoluril clip. The results showed that the yield of the di-methylated product decreased significantly in the presence of a glycoluril clip (host), due to the formation of a host–guest complex between the clip and phloroglucinol. Also, the reaction was conducted with different quantities (mol %) of the host.

Monohalomethanes are alkylating agents that have been used as methylating agents, laboratory reagents, refrigerants, aerosol propellants, pesticides, fumigants, fire-extinguishing agents, anesthetics, degreasers, blowing agents for plastic foams, and chemical intermediates. Compounds in this group are methyl chloride, methyl bromide, methyl iodide (MI), and methyl fluoride. MI is a colorless volatile liquid used as a methylating agent to manufacture a few pharmaceuticals and is also used as a fumigative insecticide. It is a rare intoxicant. Neurotoxicity is known with both acute and chronic exposure to MI. We present the characteristic magnetic resonance imaging (MRI) brain findings in a patient who developed neuropsychiatric symptoms weeks after occupational exposure to excessive doses of MI.

Umicore has opened a facility in Hanau, Germany, that produces trimethylgallium and triethylgallium, organometallic precursors used to make semiconductors and light-emitting diodes. Umicore says the plant debuts a solvent-free manufacturing process in which gallium chloride reacts with an efficient methylating agent in molten salt. Waste per kilogram of trimethylgallium is reduced by more than 50%, the firm claims.

A practical C–H functionalization method for the methylation of heteroarenes is presented. Inspiration from Nature’s methylating agent, S-adenosylmethionine (SAM), allowed for the design and development of zinc bis(phenylsulfonylmethanesulfinate), or PSMS. The action of PSMS on a heteroarene generates a (phenylsulfonyl)methylated intermediate that can be easily separated from unreacted starting material. This intermediate can then be desulfonylated to the methylated product or elaborated to a deuteriomethylated product, and can divergently access medicinally important motifs. This mild, operationally simple protocol that can be conducted in open air at room temperature is compatible with sensitive functional groups for the late-stage functionalization of pharmacologically relevant substrates.