0-Alkylation alkyl iodide-alkoxide method

As esters the alkyl halides are hydrolysed by alkalis to alcohols and salts of halogen acids. They are converted by nascent hydrogen into hydrocarbons, by ammonia into amines, by alkoxides into ethers, by alkali hydrogen sulphides into mercaptans, by potassium cyanide into nitriles, and by sodium acetate into acetic esters. (Formulate these reactions.) The alkyl halides are practically insoluble in water but are, on the other hand, miscible with organic solvents. As a consequence of the great affinity of iodine for silver, the alkyl iodides are almost instantaneously decomposed by aqueous-alcoholic silver nitrate solution, and so yield silver iodide and alcohol. The important method of Ziesel for the quantitative determination of alkyl groups combined in the form of ethers, depends on this property (cf. p. 80). 

Allyl bromide, methyl iodide and benzyl bromide are the triumvirate of common alkyl halides that alkylate metal alkoxides readily. In the case of phenols, potassium carbonate [Scheme 4.230]438 or cesium carbonate are competent bases whereas primary and secondary alcohols require potassium hydroxide [Scheme 4.231J,402 but the strongly basic conditions limit the scope of the method. For example, attempts to alkylate the secondary and phenolic hydroxyl groups of the intermediate 232.1 in a synthesis of the antibiotic Nogalamycin using the traditional metal alkoxide alkylation failed owing to competing sec-... 

Previously published methods for the synthesis of dimethylzinc, a useful alkylating agent, include the reaction of dimethylmercury with metallic zinc,1 the reaction of a zinc-copper couple with methyl iodide,2 and the Grignard method.3 The reaction of trimethylaluminum with zinc(II) halides or alkoxides can be used,4 but it is more convenient to use zinc(ll) acetate, which is very readily obtained by dehydrating the commercial dihydrate with boiling acetic anhydride or by the reaction5 ... 

Although the procedure for the O-methylation of the carbinol from acetylene and acetone (exp. 2.4) gives a fair yield, it is less suitable for the O-methyladon 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 methyladon with methyl iodide can then be accomplished under relatively mild conditions and there is no indication for decomposition of the lithium carbinolate into LiCsCH and cyclohexanone. 

The method is an extension of the well-known Grignard synthesis in ethers to the use of nonsolvating media, and is a development of procedures previously reported.2-6 A version of it has been employed with straight-chain primary alkyl chlorides, bromides, and iodides from C2 to Cu,5-7 and in solvents (or an excess of the halide) which permit reaction temperatures above 120°, with simple aryl halides such as chlorobenzene and 1-chloro-naphthalene. Branched-chain primary, secondary, and tertiary alkyl halides, allyl, vinyl, and benzyl halides either fail to react or give extensive side reactions. Better results are reported to be obtained in such cases with the use of catalytic quantities of a mixture of an alkoxide and an ether such as diethyl ether or tetrahydrofuran in a hydrocarbon medium, but the products are not, of course, completely unsolvated.4... 

The best available method for converting nonactivated aryl halides into aryl alkyl ethers employs copper(I). Aryl bromides and iodides react with copper(I) alkoxides in pyridine to give the ethers in high yield, Eq. (30). Although substitution... 

These two reactants illustrate a most versatile method in the preparation of ethers, the Williamson synthesis. In this synthesis, an alkyl halide (or substituted alkyl halide), such as ethyl iodide, is allowed to react with a sodium alkoxide (RO Na+) or a sodiiam phenoxide (ArO Na+) to produce the ether as shown ... 

Now let s use alkoxides to make ethers—the Williamson ether synthesis. Several modifications of the original procedure have made this venerable method quite useful, although there are some restrictions. The reaction works only for alkyl halides that are active in the Sn2 reaction. Therefore, tertiary halides cannot be used. They are too hindered to undergo the crucial Sn2 reaction. Sometimes there is an easy way around this problem, but sometimes there isn t. For example, tert-huXy methyl ether cannot be made from tert-hnty iodide and sodium methoxide, but it can be made from / r/-butoxide and methyl iodide (Fig. 7.106). However, there is no way to use the Williamson ether synthesis to make di-Z rZ-butyl ether. 

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