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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).

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...

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.

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.

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.

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.

Treatment of benzyl azide with triflic acid or titanium tetrachloride effects 1,2-phenyl migration with concomitant liberation of molecular nitrogen. The resulting N-phenyl iminium ion intermediate readily combines with enolizable carbonyl substrates to form Mannich bases.

Iridium-catalyzed selective α-dimethylation and α-methylation of ketones or phenylacetonitriles, using methanol as the methylating agent, were achieved. In addition, three-component cross α-methyl-alkylation was successfully performed using methyl ketones with methanol and primary alcohols with long-chain alkyl groups. This method provides a very convenient direct route to α-methylated ketones, using methanol.

In order to investigate the presence of adaptive response in cancerous cells, two monofunctional alkylating agents, namely, ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS), were employed to treat Ehrlich ascites carcinoma (EAC) cellsin vivo. Conditioning dose of 80 mg/kg body weight of EMS or 50 mg/kg body weight of MMS and challenging dose of 240 mg/kg body weight of EMS or 150 mg/kg body weight of MMS were selected by pilot toxicity studies. Conditioned EAC cells when challenged after 8 h time lag resulted in significant reduction in chromosomal aberrations compared to challenging dose of respective agents. As has been proved in earlier studies with normal organisms, even in cancerous cells (EAC), there is presence of adaptive response to methylating and ethylating agents. Furthermore, it is also interesting to note in the present studies that the methylating agent, MMS, is a stronger inducer of the adaptive response than the ethylating agent, EMS.

The direct N-monomethylation of aromatic primary amines, including arylamines, arylsulfonamides and amino-azoles, using methanol as a methylating agent has been accomplished in the presence of a [Cp*IrCl2]2/NaOH system. From both synthetic and environmental points of view, the reaction is highly attractive because of low catalyst loading, broad substrate scope and excellent selectivities.

The methylation of a nickel(II) complex (CTPP)NiII of 2-aza-5,10,15,20-tetraphenyl-21-carbaporphyrin (CTPPH2) with the mild methylating agent methyl iodide yields novel stable organonickel(II) complexes: diamagnetic (21-CH3TPP)NiII and two scarce paramagnetic species (2-NH-21-CH3CTPP)NiIIX and (2-NCH3-21-CH3CTPP)NiIIX (X = Cl, I). The demetalation procedure resulted in isolation of two 21-carbaporphyrin derivatives, methylated at the internal C(21) carbon atom, i.e., 2-aza-5,10,15,20-tetraphenyl-21-methyl-21-carbaporphyrin (21-CH3-CTPPH2) and 2-aza-2-methyl-5,10,15,20-tetraphenyl-21-methyl-21-carbaporphyrin (2-NCH3-21-CH3CTPPH). The methylation mechanism involves the oxidative addition of the methyl cation to the carbaporphyrin C(21) activated due to Ni−C coordination. These C-methylated macrocycles preserve their coordinating properties as the remetalation processes have been carried out. The reversible concerted addition of HX converts the diamagnetic (21-CH3TPP)NiII into the paramagnetic (2-NH-21-CH3C...

Exhaustive methylation of 1-phenylurazole (1), using ethereal diazomethane as the methylating agent, results in the formation of three products: 1-phenyl-3,5-dimethoxy-1,2,4-triazole (2), 1-phenyl-3-methoxy-4-methyl-Δ2-1,2,4-triazolinev5-one (3) and 1-phenyl-2,4-dimethylurazole (4). Based on the amounts of 2–4 isolated, the overall yields in these reactions are typically >90%. When 1 and diazomethane were allowed to react in a fashion that resulted in the formation of monomethylated analogues of 1, 1-phenyl-3-methoxy-Δ2-1,2,4-triazoline-5-one (5) and 1-phenylv2-methylurazole (6) were formed. In separate experiments, the monomethylated species 5 and 6 were allowed to react with diazomethane in efforts to develop a sequence of reactions that reasonably accounts for the formation of 2–4. Whereas N- and O-methylated products were obtained when 5 was treated with ethereal diazomethane, the reaction of 6 and diazomethane produced only the N-alkylated product 1-phenyl–2,4-dimethylurazole (in quantitative yield). The outcomes of these experiments are consistent with a sequence of reactions in which the treatment of 1 with diazomethane results, initially, in the formation of the monomethylated species 5 and 6. In the presence of sufficient diazomethane, 5 and 6 then undergo further mothylation, forming the dimethylated species 2–4.

The reactivity of BTS (x = 1) and PTS (x = 0) towards charged electrophiles has been studied in the gas phase with the aim of assessing the activating and directive properties of the Me3Si(CH2)x group in a solvent-free environment. BTS is confirmed to be highly activated towards electrophilic attack, which is directed to the ortho / para positions, consistent with a PA value of 200± 1 kcal mol−1. Ipso attack followed by desilylation is a dominant pathway in the reactions of PTS, tending to obscure its intrinsic reactivity. However, the reaction of a mild methylating agent, Me2Cl+, yields a meaningful reactivity scale: BTS >p-xylene > PTS > toluene

Phenylacetonitrile was found to be selectively methylated into α-methylphenylacetonitrile (MPAN) in the vapor phase with di-methyl carbonate or methanol by using alkali ion-exchanged zeolites as catalysts. When methanol was used as a methylating agent, a 27% yield of MPAN was obtained over CsX at 623 K. Dimethyl carbonate is far more effective as a methylating agent, and the methylation proceeds at a much lower temperature. A 72% yield of MPAN was obtained over NaY at 533 K. The effects of the reaction variables are described and the raction scheme is discussed.

At 180–210 °C, α-methylene sulfones (both benzyl aryl and alkyl aryl sulfones, RCH 2 SO 2 AR: R = Ph, p-ClC 6 H 4 , Ar = Ph, p-ClC 6 H 4 , p-MeC 6 H 4 , and R = Me, Ar = Ph, p-ClC 6 H 4 , p-MeC 6 H 4 ) react with dimethyl carbonate to yield the corresponding mono-C-methyl derivatives [RCH(CH 3 )SO 2 Ar] in a selectivity >99%, at conversions of 76–99% (isolated yields: 97–92%).

Treatment of benzyl azide with triflic acid or titanium tetrachloride effects 1,2-phenyl migration with concomitant liberation of molecular nitrogen. The resulting N-phenyl iminium ion intermediate readily combines with enolizable carbonyl substrates to form Mannich bases.

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.

3,3-Dimethyl-1-phenyltriazene (DMPT) is a methylating agent which is carcinogenic, teratogenic and mutagenic which, in the rat, provides a reproducible animal model with which to study the basis of chemically-induced micrognathism. The basis of teratogenic organotropism of DMPT and other methylating teratogens is unknown. The present study was undertaken to determine if limited chemical distribution within the embryo was responsible for the organotropism of DMPT. Whole-embryo autoradiographs and liquid scintillation analysis indicated that although DMPT may have some limitations of chemical distribution within the embryo, these limitations are not sufficient to explain its teratogenic organotropism.

An environmentally benign procedure for dimethylated 1,6-dihydropyrimidines has been developed by the reaction of 1,2,3,4-tetrahydropyrimidine-2-thiones with dimethyl carbonate, a non-toxic and environmentally friendly reagent. The methylation of 1,2,3,4-tetrahydropyrimidine-2-thione was promoted by MgO and tetrabutylammonium bromide (TBAB) under microwave. This protocol avoids the use of strong bases and highly toxic methylating agents such as methyl halide or dimethyl sulfate. Additionally, the possible role of MgO/TBAB in the reaction was also presented.

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.

A modification of commercial [11C]methylation module which can be implemented for both on-column [11C]methylation and [11C]carboxylation in the same automated system is described. This module configuration was applied to the solid-phase synthesis of N-[11C]methyl-choline ([11C]choline) and L-(S-methyl-[11C])methionine ([11C]methionine), using [11C]CH(3)I as methylating agent, as well as to the synthesis of [11C]acetate by [11C]carboxylation with [11C]CO2 of methylmagnesium chloride with high and reproducible radiochemical yields in short reaction time, demonstrating to be a fast and reliable tool for the production of these [11C]radiopharmaceuticals for clinical use.

A DNA repair assay measuring hypermutability response in the absence of nucleotide excision repair (NER) was employed to study the impact of a deficiency in NER on the induction of forward mutations (X-chromosomal recessive lethals) by methyl bromide (MeBr) in Drosophila melanogaster. Postmeiotic male germ-cell stages reacted with MeBr were introduced in either NER competent oocytes (exr+) or in cells from the NER- strain mus-201. The high average M(exr-)/M(exr+) hypermutability ratio of 8.3 determined for MeBr is similar to the M(exr-)/M(exr+) indices found for other monofunctional alkylating agents with high Swain-Scott s values, such as methyl methanesulphonate and dimethyl sulphate. It is concluded that the genotoxic profile of methyl bromide is in keeping with those of high s-value alkylating agents but it seems incompatible with a methylating agent producing substantial amounts of O6 methylguanine.

(MeF) [593-53-3] CH3F (MW 34.04) InChI = 1S/CH3F/c1-2/h1H3 InChIKey = NBVXSUQYWXRMNV-UHFFFAOYSA-N (SbF5) [7783-70-2] F5Sb (MW 216.75) InChI = 1S/5FH.Sb/h5*1H;/q;;;;;+5/p-5 InChIKey = VBVBHWZYQGJZLR-UHFFFAOYSA-I (reactive methylating agent;1 Friedel–Crafts type electrophilic methylations; preparation of onium salts) Physical Data: MeF: bp −78.2 °C; SbF5: bp 149.5 °C. Form Supplied in: MeF: gas; SbF5: viscous liquid. Both are commercially available. Preparative Methods: prepared by mixing equimolar amounts of freshly distilled MeF and Antimony(V) Fluoride in SO2F2 solution at low temperature.2 The reagent can also be prepared in situ in the reaction flask. Handling, Storage, and Precautions: corrosive, moisture sensitive, and potentially carcinogenic. Thus, caution should be exercised accordingly. Use in a fume hood.

[99966-26-4] C9H17BO (MW 152.07) InChI = 1S/C9H17BO/c1-10-8-4-2-6-9(11-10)7-3-5-8/h8-9H,2-7H2,1H3/t8-,9+ InChIKey = SOEZCXLMQINEJS-DTORHVGOSA-N (air-stable methylating agent via Suzuki–Miyaura coupling1) Physical Data: bp 50 °C/3 mmHg.1, 2 Solubility: sol organic solvents; insol water.2 Analysis of Reagent Purity: can be isolated in pure form and analyzed efficiently by GC or standard spectroscopic techniques (e.g. 11B NMR (CDCl3) δ 54.7 ppm).2 Preparative Method: a one-pot sequence (57%) from B-MeO-9-BBN by reaction with MeLi in Et2O at −78 °C, followed by Trimethylamine N-Oxide (TMANO) (1 equiv) in CH2Cl2 at 0 °C.1 Alternatively, the intermediate B-Me-9-BBN can be isolated and oxidized with TMANO in CHCl3 at 0 °C to afford the reagent (81%).2 Handling, Storage, and Precautions: indefinitely stable at 25 °C when stored under a nitrogen atmosphere; it can also be handled in the open atmosphere for brief periods of time without significant decomposition. Its preparation involves the handling of dangerously pyrophoric or flammable reagents (i.e. B-Me-9-BBN, B-MeO-9-BBN, MeLi). Individuals should thoroughly familiarize themselves with the special handling techniques required for such reagents prior to their use.3

(1; R1 = Me, R2 = Me) [21124-13-0] C8H11N3 (MW 149.22) InChI = 1S/C8H11N3/c1-7-3-5-8(6-4-7)10-11-9-2/h3-6H,1-2H3,(H,9,10) InChIKey = DNGJVDGPCGXBFF-UHFFFAOYSA-N (2; R1 = NO2, R2 = Me) [40643-39-8] C7H8N4O2 (MW 180.19) InChI = 1S/C7H8N4O2/c1-8-10-9-6-2-4-7(5-3-6)11(12)13/h2-5H,1H3,(H,8,9) InChIKey = BDSNQOSDUXHMCI-UHFFFAOYSA-N (3; R1 = Me, R2 = Et) [50707-40-9] C9H13N3 (MW 163.25) InChI = 1S/C9H13N3/c1-3-10-12-11-9-6-4-8(2)5-7-9/h4-7H,3H2,1-2H3,(H,10,11) InChIKey = BPOZIJBDYFHEJR-UHFFFAOYSA-N (4; R1 = OMe, R2 = Pr) [74849-15-3] C10H15N3O (MW 193.28) InChI = 1S/C10H15N3O/c1-3-8-11-13-12-9-4-6-10(14-2)7-5-9/h4-7H,3,8H2,1-2H3,(H,11,12) InChIKey = AZPVLFOGJFWSOI-UHFFFAOYSA-N (5; R1 = Me, R2 = i-Pr) [118399-01-2] C10H15N3 (MW 177.28) InChI = 1S/C10H15N3/c1-8(2)11-13-12-10-6-4-9(3)5-7-10/h4-8H,1-3H3,(H,11,12) InChIKey = AGDYKCPGMDASQO-UHFFFAOYSA-N (6; R1 = Br, R2 = Bn) [85013-27-0] C13H12BrN3 (MW 290.18) InChI = 1S/C13H12BrN3/c14-12-6-8-13(9-7-12)16-17-15-10-11-4-2-1-3-5-11/h1-9H,10H2,(H,15,16) InChIKey = BZCUQESUPRDMNG-UHFFFAOYSA-N (methylating agent for carboxylic acids,2 other acids, alcohols, phenols, and thiols3) Physical Data: mp: (1) 79–81 °C; (2) 112–114 °C; (3) 36–38 °C; (4) 28–30 °C; (5) 29–30 °C; (6) 87–88 °C. Alternate Name: MTT. Solubility: in general, slightly sol hexane; sol Et2O, chloroform, acetone, DMSO. May undergo degradation in protic media. Form Supplied in: (1) colorless solid; commercially available in 98% purity. Preparative Methods: disubstituted triazenes can be prepared by the reaction of Grignard4 or organolithium reagents5 with azides, or by the reaction of aryl diazonium salts with primary amines.6 Chief impurities present in the latter case are the pentazadienes (2∶1 condensation products) and diaryltriazenes. Handling, Storage, and Precautions: can be safely stored for reasonable periods. Alkyltriazenes are potent biological alkylating agents and should be treated as toxic and potentially carcinogenic. Efficient fumehoods and use of reasonable precautions are recommended when handling these compounds.

(Figure Presented) The carborane acid H(CHB11Cl11) reacts with chloroalkanes RCl to give is olable dialkylchloronium ion salts, [R2Cl][CHB11Cl11], that are stable at room temperature. X-ray crystal structures have been obtained for R = CH3and CH2CH3, revealing bent cation structures with C-Cl-C angles of 101.5 and 105.8°, respectively. The dimethylchloronium ion salt loses CH3Cl upon heating and forms sublimable CH3(CHB11Cl11), providing a clean synthetic route to an extremely potent electrophilic methylating agent. IR spectra of all species have been interpreted, including the C-Cl stretch in CH3-ClCHB11Cl10. Copyright © 2010 American Chemical Society.

Methyl bromide is widely used as an insecticidal fumigant in food supplies, warehouses, barges, buildings, and furniture, and as a termiticide for dry-wood termites (Incisitermes spp.). Its popularity as a fumigant is largely attributable to its high toxicity to many pests, the variety of settings in which it can be applied, its ability to penetrate the fumigated substances, and its rapid dissipation following application (Alexeeff and Kilgore 1983). Methyl bromide is also used in fire extinguishers and refrigerant systems, and in the chemical industry as a methylating agent and an extraction solvent (Alexeeff and Kilgorc 1983; Merck Index 1983).

The direct N-monomethylation of aromatic primary amines, including arylamines, arylsulfonamides and amino-azoles, using methanol as a methylating agent has been accomplished in the presence of a [Cp*IrCl2]2/NaOH system. From both synthetic and environmental points of view, the reaction is highly attractive because of low catalyst loading, broad substrate scope and excellent selectivities.

The reactivity of BTS (x = 1) and PTS (x = 0) towards charged electrophiles has been studied in the gas phase with the aim of assessing the activating and directive properties of the Me3Si(CH2)x group in a solvent-free environment. BTS is confirmed to be highly activated towards electrophilic attack, which is directed to the ortho / para positions, consistent with a PA value of 200± 1 kcal mol−1. Ipso attack followed by desilylation is a dominant pathway in the reactions of PTS, tending to obscure its intrinsic reactivity. However, the reaction of a mild methylating agent, Me2Cl+, yields a meaningful reactivity scale: BTS >p-xylene > PTS > toluene

Background: Temozolomide is DNA methylating agent that has been approved in the United States for treatment of astrocytoma. This drug in many ways resembles more established compounds, such as dacarbazine and procarbazine, in that it gives rise to a methyl diazonium ion that attacks nucleophilic sites including the O6-guanine position in DNA. Temozolomide, however, differs from these drugs, which have to be activated by enzymatic oxidation, in that it degrades spontaneously via base-catalyzed hydrolysis to the final active methylating species. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). Temozolomide (provided by the NCI Drug Repository) was tested in vitro at concentrations from 100 nM to 1 mM. Temozolomide was administered PO using a daily × 5 schedule repeated at 21 days at a dose of 100 mg/kg, or 66 mg/kg. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Biomarkers of temozolomide sensitivity, MGMT, MLH1, MSH2 and p53 genotype were determined. Results: The median temozolomide IC50 value for the PPTP cell lines was 380 μM (range 2 to > 1000 μM), with the neuroblastoma cell line NB-1643 having the lowest IC50 value. There were no significant differences in IC50 values between the rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, and ALL cell lines. In vivo temozolomide induced significant toxicity at 100 mg/kg resulting in exclusion of 10/42 lines from analysis. For the 32 lines evaluable there were 13 maintained complete responses (MCR) and 2 CR in the solid tumor panels and 3 MCR and 2 CR in the ALL panel. Retesting the excluded lines at 66 mg/kg resulted in excessive toxicity leading to exclusion of 2/9 lines. At this dose there were 2 MCR and progressive disease in the remaining 5 lines. Overall 17/30 tumor models demonstrated objective responses (≥PR). Of these 7 are MGMT-negative, 3 are MLH1-negative, and 11 have wild type p53. All 7/7 MGMT-negative tumors responded, irrespective of p53 genotype (5/7 wild type). Conclusions: In vitro temozolomide induced cytotoxicity with no apparent cell type specificity. In vivo temozolomide demonstrated high activity, but with a steep dose response curve, consistent with other DNA damaging agents. Responses poorly correlated with MGMT, MLH1, MSH2 levels, or p53 genotype. However, all MGMT-negative tumors were responsive, irrespective of MLH1 or p53 status. The results suggest that temozolomide may have potential for treatment of a range of pediatric malignancies. (Supported by NO1-CM91003-03) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5356. doi:10.1158/1538-7445.AM2011-5356

The thiol-dependent methylation of heptamethyl cob(II)yrinate 8r with methyl iodide and methyl tosylate was explored under a variety of conditions. The interaction of the heptamethyl cob(II)yrinate with a variety of thiols was monitored prior to the addition of the methylating agent, and the formation of the Co(I) complex was only apparent in the reaction with hexane thiol. Nevertheless, thiol-mediated methylation of the Co(II) complex 8r takes place with methyl iodide under most conditions. The Co-methylation with methyl tosylate showed a different reactivity, was inhibited by pyridine or N-methylimidazole, and was strongly dependent on the the acidity of the thiol used. Mechanistic aspects are discussed.

At 180–210 °C, α-methylene sulfones (both benzyl aryl and alkyl aryl sulfones, RCH 2 SO 2 AR: R = Ph, p-ClC 6 H 4 , Ar = Ph, p-ClC 6 H 4 , p-MeC 6 H 4 , and R = Me, Ar = Ph, p-ClC 6 H 4 , p-MeC 6 H 4 ) react with dimethyl carbonate to yield the corresponding mono-C-methyl derivatives [RCH(CH 3 )SO 2 Ar] in a selectivity >99%, at conversions of 76–99% (isolated yields: 97–92%).

Clioquinol, or 5-chloro-7-iodo-8-hydroxyquinoline (Vioform®), and the internal standard, 5,7-dichloro-8-hydroxyquinoline are extracted from biological material in the form of their tetrahexylammonium salts into dichloromethane, where, in the presence of a methylating agent, both clioquinol and the standard are spontaneously transformed into their O-methyl derivatives. These derivatives can be purified by base-specific extraction and subsequently determined by gas chromatography; concentrations down to 10 ng per sample may be assayed. The method is compared with a previously reported procedure based on the O-acetyl derivatives.

Pretreatment with diethylnitrosamine or dipropylnitrosamine increased the amount of labelled O 6 -methylguanine found in liver DNA 4 and 24 h after injection of 10 μg/kg [ 3 H] dimethylnitrosamine. Dibutylnitrosamine treatment had a similar, though smaller effect at 4 h but was ineffective when measurements were made 24 h after the dimethylnitrosamine was given. These pretreatments did not affect 7-methylguanine levels in the DNA showing that the metabolic conversion of dimethylnitrosamine into a methylating agent was not altered. Previous studies have shown that O 6 -methylguanine is rapidly removed from hepatic DNA after methylation to a small extent but removal is less efficient after higher amounts of methylation. Therefore, the most probable explanation for the present findings is that these longer dialkylnitrosamines produce a similar product in DNA which interferes with the loss of O 6 -methylguanine. This hypothesis was supported by experiments showing that diethylnitrosamine did give rise to O 6 -ethylguanine which was lost from the DNA at a rate comparable to the observed loss of O 6 -methylguanine in diethylnitrosamine pretreated rats. This method may, therefore, be of value for determination of whether other nitrosamines, not available in a radioactively labelled form, react with DNA at external oxygen atoms. The present results also suggest that different dialkylnitrosamines might have additive effects in prolonging damage to DNA which could be important in carcinogenesis.