Diazomethane continuous preparation

Determination of the Diazomethane Content of Solutions (according to Marshall and Acree, Ber., 1910,43, 2324).—An aliquot portion of the solution (about one-twentieth) diluted with absolute ether is run with shaking into an ice-cooled 0-2 N ethereal solution of benzoic acid. This latter solution, which must contain an excess of acid with respect to the diazomethane, is prepared by dissolving 1-22 g. of purest benzoic acid in absolute ether in a 50 c.c. measuring flask. The presence of an excess of acid is proved by the continued evolution of nitrogen, until the last portions of diazomethane have been added, when the solution should remain colourless. The excess of benzoic acid is titrated with 0-1 A-sodium hydroxide solution. 

The original reaction discovered by Pechmann involved the cycloaddition of diazomethane and acetylene. Although a better understanding of the reaction has led to the common use of more electron-deficient alkynes, diazomethane continues to be synthetically useful. A recent elegant example of the use of diazomethane as the 1,3-dipole was demonstrated in the preparation of 2,3-benzodiazepine derivatives as potential non-competitive AMPA antagonists. " Beginning with the alkyne, the pyrazole moiety could be incorporated into the benzodiazepine structure, using the Pechmann pyrazole synthesis, to produce the 2,3-benzodiazepines. 

Diazomethane. This formula is designed for immediate use. 10 g of nitrosomethylurea is added (with continued shaking) in small portions to 100 cc of ether and 30 cc of 40% caustic potash, in a wide mouthed flask and cooled to 0°. This must be done very carefully in a fume cupboard. After 10 min, the yellow ethereal extract is separated, and dried for 3 hours with a little solid caustic potash. This ethereal solution of diazomethane should not be kept for more than several days, and for preparative work, it is used in solutions only. 

Another method used to prepare dialkyl-substituted diazomethanes involves the photolysis of 2-alkoxy-2,5-dihydro-1,3,4-oxadiazoles (209), which can be prepared by the oxidative cyclization of A(-acetyUiydrazones. The diazoalkanes are trapped in situ by cycloaddition with dimethyl acetylenedicarboxylate (54) (Scheme 8.49). The resulting pyrazoles 210 are converted into cyclopropenes 211 by continued irradiation. 

The combined ethereal solutions are then placed in a small flask not too tightly stoppered, as diazomethane undergoes continuous decomposition, even in an atmosphere of nitrogen. It should, therefore, be prepared immediately before use, and is usually employed in the form of a solution in ether, alcohol, benzene, or petroleum ether. 

If one does not require a pure, water-free solution, as is frequently the case when carrying out tests with small amounts of material, a simplified procedure may be used. To 100 cc. of ether is added 30 cc. of 40 per cent potassium hydroxide, and the mixture is cooled to 5°. To this with continued cooling and shaking is added 10 g. of finely powdered nitrosomethylurea in small portions over a period of one to two minutes. The deep yellow ether layer can be decanted readily it contains about 2.8 g. of diazomethane, together with some dissolved impurities and water. The latter may be removed by drying for three hours over pellets of pure potassium hydroxide. Solutions of diazomethane in benzene and other water-immiscible organic solvents may be prepared in the same way,... 

The following procedure has been used by Hartmann (1963) to prepare alcohol-free C-diazomethane in about 60-65% yield. N-Methyl-C -N-nitroso-p-toluenesulfonamide (22 mg, 0.103 mmole, 0.1 mC of C " ) was dissolved in 1 ml of anhydrous, peroxide-free diethyl ether in a 5-ml distilling flask fitted with a gas inlet tube. The side arm was bent vertically downward near the top and connected through a two-holed rubber stopper to a 10-ml Erlenmeyer flask. A tube from the second hole led to the back of the hood. The latter flask was cooled in a Dry-Ice-Cellosolve bath. With the reaction flask at room temperature, 1 ml of a solution of 10 mg of sodium metal in dry n-octyl alcohol was added all at once. The gas inlet tube was immediately connected and a slow stream of dry nitrogen was passed through the system. The temperature of the mixture was then raised to 70°C in an oil bath and the C-diazomethane was flushed into the cooled collection flask for about 15 min. A further 1 ml of ether was then added through the gas inlet tube and collection was continued until the distillation of the ether was complete. Use of C-dia-zomethane represents the most general method for the introduction of radioactivity into a haloketone. 

Aromatic a-diazoketones can be prepared from 1 equivalent of CH N2, instead of the 2 equivalents usually used, by addition of triethyl-amine. The results with aliphatic compounds were less encouraging. —E A soln. of p-methoxybenzoyl chloride in ether added to a well stirred, ice-salt cooled soln. of diazomethane and triethylamine in ether during 20 min., and stirring continued in the cold for 12 hrs. —y p-methoxy-a-diazoacetophenone. Y 73%. (M. S. Newman and P. Beal, 3rd., Am. Soc. 71, 1506 (1949) s. a. M. Berenbom and W. S. Fones, Am. Soc. 71, 1629 (1949).)... 

Diazomethane from iV-methyl-JV-nitrosourea 385 The methylnitrosourea (10 g) is added in small portions to ether (100 ml) which is placed over strongly cooled 40% potassium hydroxide solution (30 ml). The temperature is kept at +5° while the mixture is continuously shaken. After 10 min the deep yellow ethereal layer is decanted and dried for 3 h over solid potassium hydroxide. The diazomethane solution can be kept for some time if cold and in the dark with the flask closed by a capillary tube it decomposes slowly with evolution of nitrogen [cf. the preparation as described in Organic Syntheses, Coll. Vol. IH, 244 (1955)]. 

The continuing development of solid-phase synthesis and combinatorial chemistry has led to solid-phase oxazole syntheses with a minimum of purification. Iso and co-workers generated ot-(trimethylsilyl)diazoketones on a Wang resin and employed rhodium-catalyzed diazo transfer methodology to prepare oxazoles (Scheme 1.47). Reaction of the resin-bound benzoyl chloride 169 with (trimethyl-silyl)diazomethane gave the corresponding a-(trimethylsilyl)diazoketone 170 in excellent yield. Treatment of 170 with an aryl nitrile in the presence of catalytic Rh2(OAc)4 then furnished a resin-bound 2,5-diaryl-4-(trimethylsilyl)oxazole 171. 

DSM Fine Chemicals, Austria [93]. Continuous supply, mixing the precursor of a diazo compound, the water-miscible solvent, the base, and water to generate a diazo compound, and continuous removing from micro- or millireactors are involved in the preparation of diazomethane and diazoethane. 

Component Identification. In preparation for gas chromatography the acidic urine fraction was reacted with diazomethane produced from DIAZALD, N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich Chemical Company ( ). As the diazomethane was generated by the addition of potassium hydroxide, the ethereal diazomethane solution was distilled into an ice bath-cooled reaction flask which contained the urine acids fraction. The production of diazomethane was continued until a bright yellow color persisted In the reaction flask. The reaction mixture was allowed to sit in a hood overnight during which time the ice melted allowing the reaction mixture to come to room temperature (23°C). 

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