Methylation of alcohols

Although the procedure for the O-methylation of the carhinol from acetylene and acetone (exp. 2.4) gives a fair yield, it is less suitable for the O-methylation of alcohols that are not available in large amounts. In such cases there is need for a very clean high-yield method. The procedure for the O-methylation of ethynylcyclohexanol meets this condition. Ethynylcyclohexanol can be O-lithiated quantitatively by BuLi in a mixture of THF and hexane. Since O-alkylations of lithium alkoxides in solvents of moderate polarity proceed very sluggishly (even in the case of methyl iodide), a sufficient amount of the polar DMSO has to be added as a co-solvent. The methylation with methyl iodide can then be accomplished under relatively mild conditions and there is no indication for decomposition of the lithium carbinolate into LiCfeCH and cyclohexanone. 

Reference should also be made to the use of diazomethane in the presence of a strong acid, such as hydrogen fluoborate or boron trifluoride etherate, for the methylation of alcoholic hydroxyl groups. It has not, however, as yet been used for polysaccharides. 

Methylation of alcohols. Alcohols can be methylated by diazomethane in the presence of silica gel (30-100 wt. equiv.), silicic acid, neutral alumina, or zeolite. The methylation is faster as the polarity of the alcohol increases. The method is useful for sensitive substrates such as prostaglandins and carbohydrates. 

Neeman made use of both uncatalyzed methylation of the phenolic group and BF3-catalyzed methylation of alcoholic groups. 

Also, operating at 200°C tlie reaction occurs at the carbonyl atom only. In fact, when 1-octanol was used in reactions with DMC in the presence of K2CO3, no methyl ether was observed, but methyl octyl carbonate and dioctyl carbonate were the only products formed. Methylation of alcohols was reported to occur also operating in the presence of tertiary amines (N,N -dimethylamino-pyridine, l,4-diazobicyclo[2,2,2]octane). In this case, however, the catalyst modifies the hard-soft character of the two centers, thus allowing the nucleophilic displacement by the alkoxide to occur. 

Methylation of alcohols [I, 193, after citation of ref. 18]. Diazomcthane-boron trifluoride ethcrate is useful for the methylation of carbohydrates containing base-... 

There are very few exceptions. The most important are the methylation of alcoholic and carboxylic OH groups with diazomethane. This reaction is used for cases where high yields and mild conditions are required, e. g., for expensive hydroxy compounds like certain natural products. The methyl ester formation as well as the methylation of phenols does not need an acid catalyst as these substrates catalyze themselves the dediazoniation. For ether formation an acid catalyst, e. g., HBF4, is added (except from phenols). Typical is the methylation of 3)ff-hydroxycholestane, which proceeds in dichloromethane in 95 0 yield, as shown in the Organic Syntheses method of Neeman and Johnson (1973). Analogously, ethers can be transferred in dialkylmethyloxonium salts, as described in another Organic Syntheses procedure (Helmkamp and Pettitt, 1973) for the formation of a trimethyloxonium salt obtained... 

Because of the toxicity and the relative instability of diazomethane, this methylation reagent has been replaced in recent years in many cases by (trimethylsilyl)diazo-methane. The latter is now commercially available as a 2 m solution in hexane (Aldrich). Aoyama and Shioiri (1990) described a general method for the methylation of alcohols in the presence of esters, ketones and CC double bonds. Methyl car-boxylates are quickly obtained from carboxylic acids with this reagent in the presence of methanol (Hashimoto et al., 1981 information from Aldrich, 1994). 

The drastic effect of molecular sieves of 4 A (4 A MS) was reported by Ireland etal. [11], Although, methylation of alcohol with Meerwein s salt and Proton Sponge (1) in combination took place much faster than in the alternative protocol, the reaction stopped at about 50% conversion in the case of alcohol, and decomposition of the spiroketal moiety was observed... 

Methylation of Alcohols and Other Less Acidic Functional Groups. As previously mentioned, alcohols require the addition of a catalyst in order to react with diazomethane. The most commonly used is boron trifluoride etherate (eq 11), but Tetrafluo-roboric Acid has been used as well (eq 12). Mineral acids are not effective since they rapidly react with diazomethane to provide the corresponding methyl halides. Acids as mild as silica gel have also been found to be effective (eq 13). Monomethylation of 1,2-diols with diazomethane has been reported using various Lewis acids as promoters, the most effective of which is Tin(II) Chloride (eq 14). ... 

Methylation of Alcohols Using Methanol as an Alkylating Agent... 

Scheme 20 Beller s Ir-catalyzed methylation of alcohols using methanol...

Sodium hydroxide/benzyltrimethylammonium chloride NaOH/PhCH N Me Cl O-Methylation of alcohols OH OMe... 

Diazomethane is a valuable and useful agent in organic synthesis that can be employed as a Ci building block in many single-step chemical reactions, for example, the methylation of alcohols or phenols, esteriflcations of carbonic adds, cyclopropanation reactions with alkenes, the synthesis of heterocycles, and the synthesis of a-diazoketones from acid chlorides or anhydrides. In general, the reactions proceed with release of nitrogen. Usually, diazomethane is freshly prepared from N-methyl-nitroso compounds and aqueous KOH solution and can be stored as a cooled solution for a couple of days. However, its low boiling point... 

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