Etheral diazomethane

Upon shaking nitrosomethylurea in the cold with a mixture of aqueous potassium hydroxide solution and pure ether, diazomethane is formed the latter may be distilled off at 50° and collected in ether ... 

The following procedures may be used for the preparation of ethereal solutions of diazomethane containing ethyl alcohol they differ slightly according to as to whether large or small quantities are required. The presence of alcohol is not harmful for many appUcatioiis of diazomethane. (It may be pointed out that ethereal diazomethane solution prepared from nitrosomethylurea is free from alcohol.)... 

To determine the exact diazomethane content, allow an aliquot portion of the ethereal diazomethane solution to react with an accurately weighed amount (say, about 1 g.) of A. R. benzoic acid in 60 ml. of anhydrous ether. The solution should be completely decolourised, thus showing that the benzoic acid is present in excess. Dilute the solution with water and titrate the excess of benzoic acid with standard 0 IN alkali using phenolphthalein as indicator. 

Experimental procedures A The substance is dissolved or suspended in ether and treated with ethereal diazomethane. B The substance is dissolved in methanol (or ethanol, acetone, chloroform) and reacted with ethereal diazomethane. C A solution or suspension of the substance in ether is mixed with ethereal diazomethane,... 

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

Finally the so-called kinetic dependence of methylation by diazomethane must be mentioned. (This phenomenon was first observed by Arndt in 6-methylthiacoumarindioh see later.) Kinetic dependence is found in various amides (or enols) which are methylated principally on nitrogen if they are introduced into excess ethereal diazomethane, but principally on oxygen if the diazomethane is gradually dropped into the ethereal amide solution (or suspension). 

The acid (0.1 to 0.5 g) is dissolved or suspended in ether, and the ethereal diazomethane solution is added in small portions with swirling until the yellow color of diazomethane persists and nitrogen gas is no longer evolved. The solution is then warmed on a steam bath briefly to expel the excess reagent and the ether is evaporated to give the desired methyl ester. Examples are given in Table 7.2. 

For smaller quantities of diazomethane, the use of a dropping funnel is unnecessary. Dissolve 2 14 g. of p-tolylsulphonylmethylnitrosamide 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, ffistil the ethereal diazomethane solution from a water bath (7). The ethereal solution contains 0 32-0-35 g. of diazomethane (8). 

The (5 5 5) fused heterocycles have also been synthesized from enedione 88 by utilizing its susceptibility to the nucleophilic attack. The enedione 88 was accordingly treated with excess of ethereal diazomethane in methanol at 4°C to afford the 7 -methyl derivative 31 presumably via 374 which was not isolated. 2-Pyrazoline derivative 31 was isolated in 46% yield under the same reaction conditions at room temperature (Scheme 80) <2002OL4387>. 

L-dihydroxy-succinic acid (L(dexiro)-tartaric acid, CXIII). This result establishes the position of the double bond between C4 and C5 and demonstrates that C4 carries only one hydrogen atom while C5 has attached to it the enolic hydroxyl group. Treatment of the enol CXI with ethereal diazomethane gives 5-methyl-A4-D-glucosaccharo-3,6-lactone methyl ester (CXIY) which upon further methylation with silver oxide and methyl iodide yields 2,5-dimethyl-A4-D-glucosaccharo-3,6-lactone methyl ester (CXV). When the latter is subjected to ozonolysis there is formed oxalic acid and 3-methyl-L-threuronic acid (CXVI). Oxidation of this aldehydic acid (CXYI) with bromine gives rise to a monomethyl derivative (CXVII) of L-ilireo-dihydroxy-succinic acid. 

The ethereal diazomethane was prepared from N-nitro-somethylurea and aqueous potassium hydroxide and dried over potassium hydroxide pellets for 2-3 hours. The solid potassium hydroxide was replaced once or twice to ensure complete dryness. The checkers used the procedure of Arndt2 3 4 for this preparation and for the estimation of the diazomethane. 

Fales, H. M., Jaouni, T. M., and Babashak, J. F. (1973). Simple device for preparing ethereal diazomethane without resorting to codistillation. Analytical Chemistry 45 2302-2303. 

Methoxy groups are also formed on the surface of silica by the action of diazomethane. This reaction was first described by Berger (232) and Ebert (233). Boehm and Schneider (1S8) found that methylation was somewhat incomplete when etheric diazomethane solutions were used. More methoxy groups were formed with gaseous diazomethane. However, polymethylene was formed as a by-product and explosions occurred occasionally. 

The ethereal diazomethane is prepared by the method of Arndt. The checkers employed undistilled material as described in Note 3 of the preparation cited. 

A closely related example involving a seven-membered transition state (6) hydrogen atom abstraction in the crystalline state is shown in Scheme 9. Based on earlier work by Wagner and coworkers [38], Cheung, Rademacher, Scheffer, and Trotter prepared carboxylic acid 41a and treated it with a variety of optically pure amines to form chiral salts 41b [39]. Irradiation of crystalline samples of the salts followed by workup with ethereal diazomethane afforded the chiral in-... 

Fractionation of Porphyrin Methyl Ester. The product mixture (50 mg) was dissolved in methylene chloride (2.0 ml) and treated with excess ethereal diazomethane freshly prepared from p toluenesulfonylmethylnitrosamide (Diazald). The mixture was stirred in subdued light at room temperature. The solvents were evaporated gradually in a fume cupboard. The residue was dried in vacuo and separated on preparative TLC plates to give the methoxyethyl diporphyrin methyl ester whose NMR is shown in Fig. 7 and 8. 

Gas chromatographic analysis (10% Carbowax 20 M on 80-100 mesh Chromosorb W, 2.5 m x 2 mm, column temperature 180°C, injection temperature 230°C, flow rate 10 mL/min, retention time 10 min) of the corresponding dimethyl ester, formed with ethereal diazomethane, indicated a purity of greater than 99%. 

A hitherto unpublished preparation of diazomethane is given on p. 16. The starting material is the commercially available bis-(N-methyl-N-nitroso)-terephthalamide, and the procedure conveniently affords 0.76 to 0.86 mole of ethereal diazomethane. Ozonization in polar solvents is illustrated by two preparations (pp. 41 and 46). Many other unusual and interesting preparations are included, such as ruthenocene (p. 96), N,N-di thyltri-chlorovinylamine (p. 21), phenyl tert-butyl ether (p. 91), and tetramethylammonium 1,1,2,3,3-pentacyanopropenide (p. 99). 

Hydroxycinnoline (252) slowly dissolves in ethereal diazomethane producing a brilliant emerald green colour which changes to deep blue. Comparison with the analogous reaction of 8-hydroxyquinoline (Section III,B,5) has led to the suggestion that this blue product, mp 120°C, is l-methylcinnolinium-8-olate (251 R = Me). 

Crvsts mp 2 71.5—272°. Can be prepd by treating 2-nitraminothiazole either with dimethyl sulfate or ethereal diazomethane as described in Ref 2... 

Methylation of 7-hydroxy-8-cyano-5,9-dihydro-ll//-pyrido[2,l-b]-quinazoline-9,ll-dione (45) with etheral diazomethane yielded ring-opened product 46 [84AP(317)824]. 

Oxidation of dimethyl l-phenyl-2-oxo-l,2-dihydro-llb//-pyrimido[2,l-a]-isoquinoline-3,4-dicarboxylate (64) by potassium permanganate either in acetone or in aqueous potassium hydroxide, followed by treatment with ethereal diazomethane, gave isocarbostyril and methyl oxanilate, respectively (67CB1094). Oxidation of 4-phenyl-2//-pyrimido[2,l-a]isoquinolin-2-one with potassium permanganate in a 1 5 mixture of pyridine and 2 N potassium hydroxide yielded 2-(2-carboxyphenyl)-6-phenylpyrimidin-4(3//)-one (72CB108). 2-Methyl-4//-pyrimido[2,l-a]isoquinolin-4-one and 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione with potassium permanganate afforded phthalimide in low yield. 

Oxopyrrolidine-3-carboxylic esters (132) are readily available but tend to give the enol anion when attacked by nucleophiles. Conversion to the enol ether (diazomethane) allows reactions similar to those of Scheme 42 (74S837). 

PREPARATION OF THE METHYL ESTER—TRIMETHYLSILYL ETHER. The standard acid (0.5 mg) or the residue obtained from the urine extraction was dissolved in 0.5 cm3 of methanol. Ethereal diazomethane (1 cm3) was then added and allowed to stand for 1 min. Ethereal diazomethane was prepared by the reaction of p-tolylsulphonyl-methyl nitrosamide with an alcoholic solution of KOH. 

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