Diazomethane, methylation using

As follows from Table I (see Section VII Index of Tables), the yields in 4-acetylenyl compounds depend both on the reaction time and on the structure of the aromatic and acyclic components (molecular polarity). If more than one equivalent of diazomethane is used, N-methylation of pyrazole occurs. 

The hydrogen chloride thus produced can in turn react with the diazoketone to yield a a-chloro ketone. In order to avoid this side reaction, two equivalents of diazomethane are used. The second equivalent reacts with HCl to give methyl chloride. ... 

Dream reactions can be performed using chemical micro process engineering, e.g., via direct routes from hazardous elements [18]. The direct fluorination starting from elemental fluorine was performed both on aromatics and aliphatics, avoiding the circuitous Anthraquinone process. While the direct fluorination needs hours in a laboratory bubble column, it is completed within seconds or even milliseconds when using a miniature bubble column. Conversions with the volatile and explosive diazomethane, commonly used for methylation, have been conducted safely as well with micro-reactors in a continuous mode. 

Dialkylation occurs if a stronger base (NaOH) and dimethyl sulfate is used. Entry 18 is a typical diazomethane methylation of a carboxylic acid. The toxicity of diazomethane... 

Pyrazolopyrazolopyrazines can be prepared from a stereoselective dipolar cycloaddition between the alkene group of 284 and diazomethane (Equation 45). Ten equivalents of diazomethane are used in this reaction when only 1 equiv is used, the corresponding methyl ester of the starting material was formed <20020L773>. 

Figure 7.1 Total ion current (TIC) chromatogram obtained by GC-MS analysis of a resin (Pinus sylvestris). The diterpenoid resin acids were methylated (using diazomethane) to improve chromatographic performance. Peak identities 1, Methyl pimarate 2, Methyl sandaracopimarate 3, Methyl isopimarate 4, Methyl palustrate 5, Methyl dehydroabietate 6, Methyl abietate 7, Methyl neoabietate. For GC-MS operating conditions, see Heron and Pollard (1988).

Acidic pesticides and metabolites were concentrated from aqueous solution by the anion procedure of Richard and Fritz (10). The anionic materials in these concentrates were methylated using diazomethane and the derivatized products were separated and detected by gas chromatography. Test results of the recovery efficiencies by this method for several pesticides and suspected metabolites have been reported elsewhere (11). An overall recovery of 93% was achieved for sixteen acidic pesticides and metabolites spiked into water at 200 ppb. 

Confirmation was provided by the observation that the species produced by the photolysis of two different carbene sources (88 and 89) in acetonitrile and by photolysis of the azirine 92 all had the same strong absorption band at 390 nm and all reacted with acrylonitrile at the same rate (fc=4.6 x 10 Af s" ). Rate constants were also measured for its reaction with a range of substituted alkenes, methanol and ferf-butanol. Laser flash photolysis work on the photolysis of 9-diazothioxan-threne in acetonitrile also produced a new band attributed the nitrile ylide 87 (47). The first alkyl-substituted example, acetonitrilio methylide (95), was produced in a similar way by the photolysis of diazomethane or diazirine in acetonitrile (20,21). This species showed a strong absorption at 280 nm and was trapped with a variety of electron-deficient olefinic and acetylenic dipolarophiles to give the expected cycloadducts (e.g., 96 and 97) in high yields. When diazomethane was used as the precursor, the reaction was carried out at —40 °C to minimize the rate of its cycloaddition to the dipolarophile. In the reactions with unsymmetrical dipolarophiles such as acrylonitrile, methyl acrylate, or methyl propiolate, the ratio of regioisomers was found to be 1 1. 

If the C=N function is attached to an electron-withdrawing group, 1,3-dipolar cycloaddition with diazoalkanes occurs leading to 1,2,3-triazoles (5, 276). When diazomethane is used, the initially formed NH-triazole is not isolated due to a rapid subsequent NH deprotonation followed by N-methylation. Consequently, a mixture of the three Wmethyltriazoles is formed when methyl cyanoformate (71) (216) or trichloroacetonitrile (276) (217) is treated with excess diazomethane (Scheme 8.51). Huisgen and co-workers found that methyl diazoacetate reacts with TCNE by a 1,3-dipolar cycloaddition at the C=C bond and not, as published earlier by other authors, at one of the nitrile functions (72). 

Method 2. For smaller quantities of diazomethane, the use of a dropping funnel is unnecessary. Dissolve 2.14g of ZV-methyl-ZV-nitrosotoluene-p-sulphonamide in 30 ml of ether, cool in ice and add a solution of 0.4 g of potassium hydroxide in 10 ml of 96 per cent ethanol. If a precipitate forms, add more ethanol until it just dissolves. After 5 minutes, distil the ethereal diazomethane solution from a water bath. The ethereal solution contains 0.32-0.35 g of diazomethane (1). 

Attempts to alkylate the 4-hydroxy-l,2,4-triazoles 535 with Mel, Me2S04, or PhCH2Br using different bases and solvents invariantly gave difficult to separate mixtures. However, diazomethane methylated 535 to 534 together with the O-methylated isomer in a 1 2.2 ratio from which the pure N-oxide 534 could be isolated. Acylation of 535 with PhNCO gave the N-oxide 536 (1972JPR101) (Scheme 159). 

GLC-FID/FPD and GC-MS Analysis of Oxidation Products. To obtain information regarding the molecular structure of the organic sulfur compounds present in samples, each of the soluble oxidation products were methylated using the diazomethane method and then analysed, initially by both dual FID/FPD gas chromatography, and by GC-MS. Representative FID and FPD traces obtained from the Herrin No. 6 samples are shown in Figures 2 and 3 respectively, while those for the Indiana No.5 samples are shown in Figures 4 and 5 respectively. 

Only two normal Erythrina alkaloids have been isolated from Cocculus species, dihydroerysodine (47) (75) and dihydroerysovine (44), the latter recently from C. trilobus (57). Neither alkaloid has been found in Erythrina species. The structure 44 for dihydroerysovine was deduced from the spectroscopic evidence and by methylation using diazomethane to give the known dihydroerysotrine (38). The positions of the aromatic substituents were determined by detailed NMR experiments using NOE and INDOR techniques (see Section II,C,2d). 

However, carbacepham derivatives 179 and 180 could be generated from 178 by Jones oxidation to furnish a mixture (10 90) of keto-enol isomers 179 and 180, which can be methylated using diazomethane to give 181 in 63% yield (Scheme 24). Evaluation of various carbacepham analogues as well as carbapenam analogues indicated that some are promising potent antibiotics. 

Diazomethane methylation is a good way of making methyl esters from carboxylic acids on a small scale because yields are excellent and the only by-product is nitrogen. However, there is a drawback diazomethane has a boiling point of-24°C, and it is a toxic and highly explosive gas. It therefore has to be used in solution, usually in ether the solution must be dilute, because concentrated solutions of diazomethane are also explosive. It is usually produced by reaction of N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulfonamide with base, and distilled out of that reaction mixture as an azeotrope with ether, straight into a solution of the carboxylic acid. 

Pyromellitic acid tetramethyl ester, mp 142-143 °C, prepared by diazomethane methylation of pyromellitic acid, is used as the internal standard and is stored as a dichloromethane solution (—1 mg/ml) in a freezer. (Any loss of solvent from the solution is conveniently verified by weighing.) From this solution, the exact volume corresponding to from 200 to 1000 pg of the internal standard is withdrawn and added to the ester mixture to be analyzed. The amount of internal standard chosen is dependent on the amount and type of sample. For samples where a high yield of esters is expected, the upper level of internal standard is used. 

In another case, instead of methyl tosylate, for the methylation of a hydroxyl group diazomethane was used <2003S2518>. 

Double bonds adjacent to complexed dienes can be cyclopropanated using diazomethane, methyl diazoacetate, or sulfur-based ylids. Cycloheptatriene iron tricarbonyl undergo a [2 -F 2] cycloaddition with chloroketene derived from trichloroacetyl chloride (Scheme 161). 

The orientation of methylation using diazomethane is not easy to explain since the mechanism is in doubt. One interpretation of the preferential formation of 5-substituted 1-methylimidazoles (with a highly electron-dense potential 5-substituent) is via the initial formation of an ion pair [Im MeN2 ] in which the cationic portion is situated near to the nitrogen adjacent to the substituent. This may be true, but the results obtained with unsymmetrical pyrazoles (79AJC2203) cannot be explained entirely in this way. 

Alcohols react with diazo compounds to form ethers, but diazomethane and diazo ketones are most readily available, giving methyl ethers or a-keto ethers, respectively. With diazomethane " the method is expensive and requires great caution, but the conditions are mild and high yields are obtained. Diazomethane is used chiefly to methylate alcohols and phenols that are expensive or available in small amounts. Hydroxy compounds react better as their acidity increases ordinary alcohols do not react at all unless a catalyst, such as HBp4 or silica gel, is present. The more acidic phenols react very well in the absence of a catalyst. The reaction of oximes, and ketones that have substantial enolic contributions. 

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