Preparation of diazomethane

Diazomethane is an extremely valuable reagent which is very easy to prepare and use. However, there are certain hazards associated with the compound and its preparation that should be taken into account. The observance of a few simple safety measures allow the reagent to be prepared and used with confidence. 

The single most valuable application of diazomethane is its reaction with carboxylic acids to provide the equivalent methyl ester, under very mild conditions. This and other reactions of the reagent have been well reviewed.  

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The yield of diazomethane from nitrosomethylurethan is usually given as 0.005 mole per ml. Another method for the preparation of diazomethane has recently been described. ... 

The more important methods of preparation of diazomethane include those from nitrosomethylurea, nitrosomcthylurethane, N-nitroso-/3-methylaminoisobutyl methyl ketone, and 1-methyl-l-nitroso-3-nitroguanidine. ... 

Diazomethane is a yellow gas that is toxic and explosive but that may be handled safely in solution in ether. It reacts immediately with an acid to liberate nitrogen and form the methyl ester. Its reaction with alcohols to form methyl esters requires catalysis by a Lewis acid. The procedures illustrate the use of this reagent as a methylating agent (see Chapter 17, Section III, for preparation of diazomethane). 

Methyl hydrogen sebecate, 41, 34 Kolbe electrolysis of, 41, 33 1-Methylindole,40, 68 Methyl iodide, methylation of dihydroresorcinol with, 41, 57 Methyl isocyanide, 41, 15 Methyl 4-mcthyl-4-nitrovalerate, hydrolysis to acid, 41, 24 N-Methyl-N-nitrosoterephthalamide, preparation of diazomethane from, 41, 16... 

Various N-nitroso-AT-alkyl compounds undergo elimination to give diazoalkanes. One of the most convenient methods for the preparation of diazomethane involves base treatment of V-nitroso-V-methyl-p-toluenesulfonamide (illustrated above, with... 

Carbenes from Diazo Compounds. Decomposition of diazo compounds to form carbenes is a quite general reaction that is applicable to diazomethane and other diazoalkanes, diazoalkenes, and diazo compounds with aryl and acyl substituents. The main restrictions on this method are the limitations on synthesis and limited stability of the diazo compounds. The smaller diazoalkanes are toxic and potentially explosive, and they are usually prepared immediately before use. The most general synthetic routes involve base-catalyzed decomposition of V-nitroso derivatives of amides, ureas, or sulfonamides, as illustrated by several reactions used for the preparation of diazomethane. 

The material is unstable and explodes if distilled at ambient pressure [1], or may become explosive if stored above 15°C [2], Its use for preparation of diazomethane has been superseded by more stable intermediates. 

Ethoxyethoxy)ethanol in preparation of diazomethane, 41,16 l-Ethoxy-3-ethyl-3-methyl-l,2-cyclo-propanedioic acid, 44, 61 Ethyl acetate, conversion to ethyl /8-hydioxy-/3,/3-diphenylpio-pionate, 44, 57... 

Staudinger and Kupfer2 discovered a very interesting method for the preparation of diazomethane. They observed that when the isonitrile reaction of primary amines was applied to hydrazine, diazomethane,3 and not the expected di-isocyanogen, C=N—N=C, was produced in the manner indicated in the following equations ... 

M Hudlicky. An improved apparatus for the laboratory preparation of diazomethane. J Org Chem 45, 5377, 1980. 

Trimethylailyldiazomethane is both non-exploeive and non-mutagenio. Therefore, the very oareful operations used for the preparation of diazomethane are not neaeaaary. 

A melting point in the lower part of this range generally indicates contamination with / -tolylsulfonylmethylamide, which may be removed as described in Note 6 however, this purification is not necessary since the presence of this amide does not interfere in the preparation of diazomethane. 

In the preparation of diazomethane, p-tolylsulfonylmethylnitrosoamide has been suggested as an intermediate. The preparation of this compound has been well described [58, 59]. The general method of preparation resembles that of other amides. 

Ethoxycthoxy)ethanol in preparation of diazomethane, 41, 16 Ethyl a-acetyl-j3-(2,3-dimethoxy-... 

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). 

Precursor of diazomethane, a highly toxic and unpredictably explosive gas. Possibly a carcinogen. Read details carefully before preparation. Reactions with and preparation of diazomethane should be carried out in a fume hood and behind a sturdy safety shield. Rough glass surfaces and strong sunlight are known to initiate detonation. 

The oily layer is separated from the aqueous layer, the aqueous layer is extracted with two 200-ml. portions of ether, and the combined extracts and oil are dried over calcium chloride. The drying agent is removed by filtration, and the ether is distilled on a water bath finally, all low-boiling material is removed from the mixture on a boiling water bath under the lowest pressure obtainable with a water pump (Note 6). The nitrosoaminoketone which remains in the flask is sufficiently pure for the preparation of diazomethane (Note 7). The yield is 221-257 g. (70-80% based on mesityl oxide). 

Another approach to methylation is to use diazomethane (24). This material is somewhat less reactive, so minimal side reactions are observed although spurious peaks have been reported in methylating long-chain fatty acids when freshly distilled reagent was not used (25). One preparation of diazomethane is to add 3 cm3 of 40% KOH to 10 cm3 of ether precooled to 5°C. With the temperature maintained at 5°C, 1 g of finely powdered nitro-somethvlurea is added in increments over a period of 1-2 min. 

Support Protocol 2 Preparation of Diazomethane in Diethyl Ether C4.2.11... 

Tolylsulfonylmethylnitrosamide is a useful substance for the preparation of diazomethane.2 It is apparently of low toxicity. An explosive decomposition has never been encountered by the submitters during its preparation, recrystallization, storage, or the reaction with alkali to form diazomethane. These properties afford advantages over other nitroso compounds which have been used for preparation of diazomethanc. 

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