Diazomethane methyl ethers

Nitraminothiazoles are sufficiently acidic to be alkylated by diazomethane the methyl substituent is introduced on the exocyclic nitrogen (194). When sulfathiazole is methylated with diazomethane in ether, a mixture of ring-methylated and amino-methylated products is obtained, the ratio being 30 70 (85). With anion 31 (R = p-NO CsH4SO -) the ratio becomes 15 85 (195). 

Forms yellow plates from AcOH, and needles from EtOH [Slotta and Szyszke Chem Ber 68 184 7955]. With diazomethane,. 5-nitro-3,4-dimethoxyacetophenone is formed [Brady and Manjunath J Chem Soc 125 1067 1924]. The methyl ether crystallises from EtOAc or AcOH, m 88", 90-91", and the phenylhydrazone has m 108-110° (from aqueous EtOH). [Finger and Schott 7 C/icm [2] 115 288 7927.] Vor oxime m 216° (from EtOH or AcOH) and the oxime acetate has m 147° (from aq EtOH) [Vogel Monatsh Chem 20 384 1899 Brady and Dunn J Chem Soc 107 1861 7975]. 

Bisd Idori methyl) Ether 542-88-1 100 Diazomethane 334-x.h- 1 ilHi... 

Thus, the acidity oi a lactam is evidently not a reliable quantity for predicting the course of the methylation. The acidity gives information only as to the reaction velocity. In this connection the reaction course of isomethylreductone (6) is illuminating, " With diazomethane in ether containing 1 mole of water, the enolraethyl ether (7) is formed. However, if water is present only in traces, then the alcoholic hydroxyl group is selectively attacked to give 8. 

The indole derivative corynantheine is iV-methylated by diazomethane in ether. ... 

As expected, heterocyclic enols and potential enols (i.e, compounds existing mainly in the CH form) behave toward diazomethane similarly to the open chain and isocyclic enols, i.e. they form enol methyl ethers by reactions of the SnI type (cf. footnote 29). Examples of this behavior are barbituric acid, picrolonic acid, dchydroacetic acid (64), 3-methyl-l-phenylpyrazolin-5-one, 1-phenylpyrazoli-dine-3,5-dione, 1,2-diphenylpyrazolidine-3,5-dionc, 3-hydroxy-... 

MethylATiON of Thiacetic Acid L.actone with Diazomethane in Ether ... 

To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H) one 4-oxide in approximately 150 ml of methanol was added in portions an excess of a solution of diazomethane in ether. After about one hour, almost complete solution had occurred and the reaction mixture was filtered. The filtrate was concentrated in vacuo to a small volume and diluted with ether and petroleum ether. The reaction product, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1 H)-one 4-oxide, crystallized in colorless prisms. The product was filtered off and recrystallized from acetone, MP 188°-189°C. 

The above keto-nitrile (15 grams) was methylated with a solution of diazomethane in ether. (The diazomethane solution was prepared using 20 grams of N-nitrosomethylurea.) The ether and excess diazomethane were evaporated on the steam bath and the oil dissolved in ethanol (50 ml). To this was added a solution of guanidine in ethanol (100 ml) (prepared from 8.1 grams of the hydrochloride). The solution was refluxed for 5 hours, the alcohol removed and the residue treated with 5N sodium hydroxide. The insoluble material was then filtered. After purification by precipitation from dilute acetic acid with sodium hydroxide and by recrystallization from ethanol the product formed clear colorless needles (8.0 grams), MP 218°-220°C as described in U.S. Patent 2,602,794. 

Reaction with alcohols is general for diazo compounds, but it is most often performed with diazomethane to produce methyl ethers or with diazo ketones to produce ot-keto ethers, since these kinds of diazo compounds are most readily available. With diazomethane the method is expensive and requires great caution. It is used chiefly to methylate alcohols and phenols that are expensive or available in small amounts, since the conditions are mild and high yields are obtained. Hydroxy compounds react better as their acidity increases ordinary alcohols do not react at... 

The action of diazomethane in aqueous 1,2-dimethoxyethane on 4-methoxy-l-/3-D-ribofuranosyl-2(lf/)-pyrimidinone gave, after purification, the corresponding 2 -methyl ether in 37% yield.333 N.m.r. spectroscopy showed that the crude mono-O-methyl fraction contained the 2 - and 3 - isomers in the ratio of 7 2. The 2 -methyl ether proved to be a versatile intermediate, as acid hydrolysis yielded 2 -0-methyluridine, whereas reaction with ammonia or methylamine... 

Dissolve 100 g malonic acid in 360 g dry pyridine and heat 48-52° C for forty hours with 100 g n-hexaldehyde (n-capronaldehyde) or homolog. Cool in ice bath and with good stirring add dropwise 150 ml ice cold concentrated sulfuric acid (keep temperature below 5° C). After addition add water to dissolve the precipitate and extract with ether two times. Dry, evaporate in vacuum the ether and distill (70/0.7 or 102/5) to get about 98 g 2-octenoic acid (I). 95 g (1) in 300 ml ether cool to -5° C and slowly add a solution of an excess of diazomethane in ether dried over KOH and let react for about one hour. Let stand twelve hours, evaporate in vacuum and distill (91/17) to get about 94 g clear methyl-2-octenoate (II). 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

Incomplete methylation of silica gel with diazomethane in etheric solution was also observed by Shcherbakova (234) and Shcherbakova and Slovetskaya (235). The reaction product showed decreased adsorption capacity for methanol vapor. The influence of esterification of silica surfaces on the adsorption of vapors was also studied by Slinyakova and Neimark (236), Ganichenko et al. (237), and Aristov et al. (238). 

General ProcedureforMethylation with Diazomethane. The ethereal solution as prepared above is added to a suspension or solution of the compound to be methylated. Reaction is indicated by the disappearance of the yellow color, and is completed when the color persists on warming. Nitrogen will be evolved and the product is recovered from the ethereal solution. 

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