Methylation procedures

FIGURE2.10 Chemical structure of Me-TAG (R = H or CH3) the methylation procedures yielded an average of four to five methyl groups. 

The Hofmann exhaustive N-methylation procedure, often used in classical structure determinations of alkaloids containing the piperidine nucleus, depends upon the formation of quaternary methyl salts. 

A compound could be either 4-methoxycarbonyl-2,5-diphenylpiperi-dine or 4-methoxycarbonyl-3,5-diphenylpiperidine. How could you determine which formulation is correct, using the Hofmann exhaustive methylation procedure followed by reductive ozonolysis ... 

An interesting N-methylation procedure for pyridazin-3(2//)-ones is based on a simple heating of the substrates with dimethylformamide dimethylacetal (DMFDMA) in DMF <2002SC1675>. 

This methylation procedure is quite generally satisfactory for simple primary and secondary amines. For methylation of a secondary amine only half as much formaldehyde is required, although a larger amount does no harm. The submitters also have prepared, in uniformly good yields, benzyldodecylmethylamine (b.p. 180-182°/4 mm.) from benzyldodecylamine, and a-amyl-hexyldimethylamine (b.p. It5°/16mm.) from a-amylhexylamine. It is reported 2 that the reaction can be successfully applied to the methylation of butylamine, benzylamine, tetramethylenediamine, piperidine, and phenyl-a-aminobutyric acid. 

Plant oils and animal fat samples (vegetable oils, tallow, lard, fish oils) do not need to be extracted before methylation. A small amount of these samples (10 to 20 mg) can be subjected to the methylation procedures directly. 

Other than the time specified in the individual steps of each protocol, the total time spent on each methylation procedure depends largely on the sample size, the time required for evaporation of organic solvents, and the availability of space for sample tubes in the heating block and the manifold of the nitrogen-stream evaporator. 

Among the features of Volume 41 is the smallest-scale synthesis yet published in Organic Syntheses, namely, the preparation of 0.0005 mole of cholestanyl methyl ether by a generally useful methylation procedure that employs diazomethane and fluoboric acid (p. 9). Two preparations of isocyanides by dehydration of formamides are included. One of these, illustrated by cyclohexyl isocyanide (p. 13), is most suitable for aliphatic isocyanides while the other, illustrated by o-tolyl isocyanide (p. 101), is most suitable for aromatic isocyanides. 

This sugar was first prepared by Irvine and Moodie48 by the methyla-tion of methyl a-D-mannopyranoside with methyl iodide and silver oxide in the presence of methanol as solvent. The crystalline methyl tetra-methyl-a-D-mannoside yielded, on acid hydrolysis, sirupy 2,3,4,6-tetra-methyl-D-mannose. Methylation has been carried out subsequently using dimethyl sulfate and sodium hydroxide49 60 and by the reaction of the potassium salt of methyl a-D-mannopyranoside with methyl iodide in liquid ammonia.61 The Haworth methylation procedure has also been... 

General methylation procedure with diazomethane. The reaction must be carried out in the fume cupboard. Dissolve 2-3 g of the compound (say, a phenol or a carboxylic acid) in a little anhydrous ether or absolute methanol, cool in ice and add the ethereal solution of diazomethane in small portions until gas evolution ceases and the solution acquires a pale yellow colour. Test the coloured solution for the presence of excess of diazomethane by removing a few drops into a test tube and introducing a glass rod moistened with glacial acetic acid immediate evolution of gas should occur. Evaporate the solvent, and purify the product by distillation or crystallisation. 

An alternative bimolecular elimination process involves the thermal decomposition in an atmosphere of nitrogen of a quaternary ammonium hydroxide (Hofmann exhaustive methylation procedure). 

Samples were methylated by one of two procedures. Ten milliliters methanol and 1 mL of 14% BF3 in methanol were added to the residue in the flask and the contents boiled on a hot plate for 1.5 min. Excess methanol was evaporated with dry air. About 0.5 mL of a brown oily substance remained. Two mL of 95% hexane plus 5% toluene were added to the oil residue, mixed and placed into the refrigerator until gas-liquid chromatographic (GLC) analysis. An alternate methylation procedure involved transferring the residue to a 15 mL pointed tube with four 0.5 mL increments of BF3 CH3OH in methanol (1 2 v/v). The pointed tube was stoppered and placed in an 80°C tube heater. After 1 h the tube was removed and allowed to cool. Five milliliters hexane and 2 mL saturated NaCl were added to the tube and the contents mixed thoroughly on a vortex mixer. Four mL of the hexane layer were pipeted from the tube and placed into a vial. The contents of the vial were evaporated just to dryness with dry N2 at room temperature. Four milliliters of hexane were added to the vial and the contents shaken. Aliquots from the vial were taken for GLC assay. 

Analysis of the CLA content and profile of animal tissues or biological fluids containing a mixture of lipid classes is more difficult. In order for all of the fatty acids to be methylated, a two-stage methylation procedure is recommended. Kramer et al. (1997) evaluated many different combinations of acid/base catalysts and concluded that the best compromise was the use of sodium methoxide followed by a mild acidic methylation, which resulted in the methylation of the majority of the fatty acids with minimal isomerization of the CLA isomers. However, mild boron triflouride or 1% methanolic sulphuric acid with a minimal temperature and reaction time are often used with good success. 

O-Methylglycosides obtained in this way are further treated, prior to GC analysis, either by the methylation procedures described above or, more often, by acylation and silylation. 

The disadvantage of the methylation procedures is that some metabolites give, after methylation, the same derivative as the initial substituted urea and they therefore cannot be determined simultaneously. 

The p-anisyloxymethyl group520 (abbreviated AOM) played an important role in the synthesis of Calicheamicinone reported by Clive and co-workers.521 Its removal from the sensitive multifunctional substrate 285 1 [Scheme 4.285] was accomplished with CAN in a mixture of pyridine, methanol and water. The excellent yield (89%) attests to the mildness of the conditions. Attempts to apply the same conditions to the deprotection of an AOM group from 286 1 [Scheme 4.286]522 failed but the deprotection was successful if it was conducted in the presence of 2,6-pyridinedicarboxylic acid N-oxide — conditions previously used to convert a phenol methyl ether to a quinone.523 AOM ethers undergo easy reductive cleavage to the corresponding methyl ethers with borane in toluene — a reaction that could have synthetic value when simple O-methylation procedures fail. 

TMS production involves one specific functional group (-OH, -COOH, =NH, -NH2, or -SH), which loses an activated hydrogen and is replaced by a trimethylsilyl group (Proestos et ah, 2006). To achieve silylation, some authors have used BSTFA (N,0-hA(trimethyl-silyl)trifluoroacetamide) and TMCS (trimethylchlorosilane) successfully in several matrices (e.g. aromatic plants, cranberry fixiit) (Zuo et ah, 2002 Proestos et ah, 2006). Using silylated derivatives is advantageous for several reasons phenols and carboxylic acids are prone to silylation, these compounds can be derivatized in the same part of the process, and the minor products do not impede analysis and are well documented (Little, 1999 Stalikas, 2008). A two-step methylation procedure was used to analyze catechins and tannins in plant extracts. The first step used trimethylsilyl diazomethane (TMS-diazomethane) to pre-methylate the sample, and the second step used thermally assisted hydrolysis and methylation (THM). The pre-methylation step with TMS-diazomethane stabilized the dimer molecule m/z 540) by minimizing isomerization and reducing reactivity. (Shadkami et ah, 2009). 

The usefulness of reductive amination is augmented by the facile methylation of amines with formaldehyde (usually in MeCN), which provides a convenient, mild alternative to Clark-Eschweiler and other methylation procedures. Table 8 presents a selection of successful methylation applications with various amines, and further illustrates the chemoselectivity and versatility of the process. 

A commonly used synthetic method for these substituted phosphines involves the deprotonation of phosphine (or methylphosphine ) by a sodium-ammonia solution, followed by treatment with a methyl halide. More recently, methylphosphine has been produced by the reduction of methyldichloro-phosphine (unfortunately, not a readily available compound) by lithium hydroaluminate. The present method is essentially the deprotonation-methylation procedure, but instead of sodium-ammonia solutions, relatively easily handled KOH-dimethyl sulfoxide suspensions are used. 

Haworth, Raistrick and Stacey discovered that the action of Peni-cillium varians on glucose produces a polysaccharide which they named varianose. By the usual methylation procedures, varianose was found to be composed of about 70% D-galactose, 14% D-glucose, and 14% of a third hexose which they believed to be either D-idose or L-altrose however, from the evidence presented by those authors, it is not clear to the reviewer how D-idose would be possible. The third component was isolated as a liquid methyl trimethylhexoside of —15.6° in 2%... 

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